Uworld Objectives

1


ANATOMY-Musculoskeletal

The radial nerve is responsible for extension of the hand Damage to the radial nerve results in
wrist drop

The musculocutaneous nerve innervates the flexor muscles of the upper arm and provides
sensory innervation to the lateral forearrn The musculocutaneous nerve is derived from the upper
trunk of the brachial

The musculocutaneous nerve innervates the flexor muscles of the upper arm and provides
sensory innervation to the lateral forearm The musculocutaneous nerve is derived from the upper
trunk of the brachial plexus and can be injured by forceful injuries that cause separation of the
neck and shoulder

Muscles used when sitting up from the supine position include the external abdomirSc frd
abdominis, and the hip flexors The ihopsoas muscle is the most important of the hip fiexors and
inctudes the psoas major, psoas minor, and iliacus The rectus femoris. sartorius, tensor fascia
lata, and the medial compartment of the thigh also conthbute to hip flexion

Flattening of the deftoid muscle after a shoulder injury suggests anterior shoulder dislocation
This injury most commonly results from forceful external rotation and abduction at the shoulder
joint. Axillary nerve injury, resulting in deltoid paralysis and loss of sensation over the lateral
arm, is often associated.

The most commonly injured structure in rotator cuff syndrome is the tendon of the supraspinatus
muscle. Because the supraspinatus is an abductor of the humerus, injury to its tendon causes pain
on abduction of the arm

Injections given in the superomedial part of the buttock risk injury to the gluteal nerves:
Injections given in the inferomedial part of the buttock risk injury to the sciatic nerve The
superolateral quadrant of the buttock is a safe site for intramuscular injections.

Lesions of the femoral nerve can occur due to trauma. nerve compression. stretch Injury, or
ischemia Patients develop weakness of the quadriceps muscle, loss of the patellar reflex, and loss
of sensation over the anterior and medial thigh and medial leg.

The median nerve courses between the humeral and ulnar heads of the pronator teres muscle and
then runs between the flexor digitorum superficialis and the flexor digitorum profundus muscles
before entering the wrist and hand within the carnal tunneL

The supraspinatus muscle assists in abduction of the arm and stabilization of the glenohumeral
joint The most commonly injured structure in rotator cuff syndrome is the tendon of the
supraspinatus muscle This tendon is vulnerable to injury due to impingement between the
acromion and the hemurus
2


Trauma or sustained pressure to the neck of the fibula can cause injury to the common peroneal
nerve as it courses superficially and laterally to this structure

The tibial nerve innervates the flexors of the lower leg. the extrinsic digital flexors of the toes,
and the skin of the sole of the foot.

1) Injury to the superior gluteal nerve causes weakness of the gluteus medius and gF’.iI$ceen
Wridow Sq Shape
producing a positive Trendelenburg tea
2) The inferior gluteal nerve innervates the gluteus maximus muscle Injury of the inferior gluteal
nerve causes
difficuLty rising from the seated position and climbing stairs

The deep brachial artery and radial nerve course along the posterior aspect of the humerus
Mdshaft fractures of the humerus risk injury to these structures. Supracondylar fractures are
associated with injury to the brachial artery

The posterior cruciate ligament prevents posterior displacement of the tibia relative to the femur
It originates from the anterolateral surface of the medial femoral condyle and inserts into the
posterior intercondylar area of the tibia Its integrity can be tested in the clinical setting by using
the posterior drawer test

The psoas muscle originates from the anterior surface of the transverse processes and lateral
surface of the corresponding vertebral bodies T12-L5 The psoas muscle acts primarily to flex the
thigh at the hip It contributes somewhat to lateral rotation and abduction of the thigh as well

The anterior cruciate ligament (ACL) can be damaged by forceful anterior motion of the tibia
with respect to the femur.

Ulnar nerve injury classically causes a “claw hand” deformity. The ulnar nerve can be IrIjUreCt
either near the medial epicondyle of the humerus or in Guyon’s canal near the hook of the
hamate and pisiform bone in the wrist.

Sudden upward stretc[ng on the arm at the shoulder can damage the lower trunk of the brachial
plexus. This trunk carries nerves from the C8 and Ti spinal levels that ultimately form the
median and ulnar nerves These nerves innervate all of the inthnsic muscles of the hand.

Mastectomy is a commonly tested cause of long thoracic nerve injury, but any trauma or surgery
in the axitfary region is at risk of damaging this nerve. Injury to this nerve causes winging of the
scapula and inability to abduct the shoulder past 90 degrees.

The common peroneal nerve is vulnerable to injury where it courses around the nec F. creWi - Sc
neck fractures can lesion this nerve, causing weakness of dorsiflexion (deep peroneat nerve) and
eversion (superficial peroneal nerve) of the foot as well as loss of sensation over the dorsum of
the foot. Inversion and plantarfiexion would remain intact due to the action of the tibial nerve.
3


Radial head subluxation (nursemaid’s elbow) results from sudden traction on the outstretched
and pronated arm of a child Affected children are usually in little distress unless attempts are
made to move the elbow. The annular ligament is torn and displaced in this injury

A femoral neck fracture can damage the blood supply to the femoral head and necic This is most
common with displaced fractures. The medial femoral circumflex artery provides the majority of
the blood supply to the femoral head and neck injury to this vessel can cause avascular necrosis
of the femoral hea&

The lunate bone can be identified on a hand X-ray as the more medial of the two carpal bones
that articulate with the radius. It lies immediately medial to the scaphoid bone.

Common peroneal nerve injury as it traces the lateral aspect of the fibular neck is common Bony
fracture and compression are the most common causes. Clinically this manifests as foot drop.

The sternocleidornastoid muscle originates on the medial clavicle and manubrium and inserts on
the mastoid process of the skull. It is innervated by CN Xl and functions to turn the head in the
opposite direction.

The serratus anterior muscle serves to fix the scapula against the posterior chest watt and rotate
the scaputa to allow abduction of the arm over the head Paralysis of this muscle occurs with
injury to the long thoracic nerve and results in winging of the scapula.

The Valsalva maneuver increases vagal tone and can be used to abolish paroxysmal
supraventncular tachycardia. The rectus abdominis is the most important muscle in achieving the
increased intraabdominal and intrathoracic pressure of the Valsalva maneuver.

The obturator nerve is the only major nerve that exits the peMs through the obturatorforamen
This nerve supplies the muscles of the medial (adductor) compartment of the thigh and can be
damaged dunng pelvic surgery, especially in procedures such as lymph node dissection

The posterior cruciate ligament prevents anterior displacement of the femur relative to the tibia
when the knee is flexed. It attaches to the posterior part of the intercondylar area of the tibia and
the anterior part of the lateral surface of the medial epicondyle of the femur.

Fall on an outstretched hand may cause fracture of the scaphoid bone Examination
anatomical snuff box The scaphoid bone is vulnerable to avascular necrosis and nonuñian due to
as tenuàii blood supply

Repeated and prolonged kneeling can cause prepatellar bursitis Dubbed housemacfs kne&’ today
it is most commonly seen in roofers, carpenters and plumbers Signs and symptoms of prepatellar
bursitis include knee pain, erythema. swelling and inability to kneel on the affected side

Improperly fitted crutches can cause radial nerve injury, resulting in weakness of all forearm,
wrist and finger extensors (“wristdrop”).
4


ANATOMY-Neurology

 The ventromedial hypothalamic nuclei contain the satiety center and regulate food intake
Lesions of the ventromedial nuclei result in obesity secondary to hyperphagia as well as
aggressive, savage behavior

The third branch of the trigerninal nerve (CN V3) exits the skull through the foramen ovale and
innervates the muscles of mastication. including the masseter. the medial and lateral pterygoids,
and the temporalis muscles.

Trochlear nerve palsy is charactenzed by vertical diplopia

Common peroneal nerve injury is common and typically results from trauma to the leg near the
head of the fibula Signs include foot drop and a characteristic high-stepping gait

The posterior cerebral artery branches off the basilar artery and supplies cranial nerves Ill and IV
and other structures in the midbrain It also supplies the thalamus, mesial temporal lobe, splenium
of the corpus callosum, parahippocampal gyrus, fusiform gyms, and occipital Iobe

The combination of fixed segmental loss of upper extremity pain and temperature sensation,
upper extremity lower motor neuron signs, and/or lower extremity upper motor neuron signs in
the setting of scoliosis suggests a diagnosis of syringomyelia.

Lesions of the glossopharyngea nerve result in loss of the gag reflex (afferent limb), loss of
sensation in the upper pharynx, posterior tongue. tonsils. and middle ear cavity, and loss of taste
sensation on the posterior one-third of the tongue

The third cranial nerve (oculomotor) carrying general somatic efferent fiber and general visceral
efferent parasympathetic fiber exits the midbrain and courses between the posterior cerebral and
superior cerebellar arteries. An aneurysm arising from either artery can lead to a non—pupil-
sparing third nerve palsy, which clinically presents with unilateral headache, eye pain, diplopia.
dilated nonreactive pupil, and ptosis with the ipsilateral eye in a down and out position.

The tight junctions between endothelial cells in the capillary beds of the CNS form the blood-
brain barrier Solutes and fluids cannot move freely across the capillary membrane in the CNS
material can only move transcellularly by diffusing across the epithehal plasma membranes or by
carrier-mediated transport

The thalamic syndrome is characterized by total sensory loss on the contralateral skie of the body
Although there are no motor deficits, proprioception is often profoundly affected and may lead to
difficulty ambulating and falls.

Lacunar infarctions are the result of small vessel lipohyalinosis and atherosclerosis invoMng the
penetrating vessels supplying the deep brain structures Uncontrolled hypertension and diabetes
mellitus are risk factors for this condition
5



Neurofibromatosis Type I (NFl. or von Recklinghausens disease) is a common autosomal-
dominant disorder resulting from a defect in the NF-l gene on chromosome 17. Cutaneous and
subcutaneous neurofibromas are common in this condition and are tumors of Schwann celIs
which are embryologicalty derived from the neural crest.

Upper motor neuron lesions cause spastic rigidity, hyperreflexia. and paresis Corticospinal tract,
internal capsule (posterior limb), and primary motor cortex lesions can cause these symptoms

Injury to Meyer’s loop in the temporal lobe results in contralateral superior quadrantanopia

A lesion in Wemicke’s area can cause receptive aphasia. which is characterized by well-
articulated, nonsensical speech paired with a lack of language comprehension (Wemicke-Word
salad) Wemicke’s area is located in the auditory association cortex within the posterior portion of
the superior temporal gyrus in the dominant temporal lobe. The middle cerebral artery supplies
Broca’s area (superior division) and Wernicke’s area (inferior division).

The deep branch of the radial nerve arises near the lateral epicondyle of the humerus, where the
humerus articulates with the head of the radius Radial head subluxation can damage the deep
branch of the radial nerve, causing weakness of the forearm and hand extensors but no sensory
deficits

All sensory pathways except olfaction (smell) have relay nuclei in the thaIamus The VPL
receives impulses from spinothalamic and medial lemniscus pathways, the VPM from the
tngeminal and gustatory pathways, and the lateral and medial geniculate bodies are relay nuclei
for the visual and auditory pathways, respectively

The vagus nerve provides some cutaneous sensation to the posterior external auditory canal via
its small auricular branch Sensation to the rest of the canal is from CN V3 A vasovagal syncopal
episode results from stimulation of the vagus nerve, leading to a decrease in blood pressure and
heart rate

The afferent limb of the light reflex pathway is the optic nerve: the efferent limb is the
parasympathetic fibers of
the oculomotor nerve. When an optic nerve is damaged. light in that eye will cause neither pupil
to constrict
(the nerve can’t sense the light). However, light in the contralateral eye will cause both pupils to
constrict
(because the motor pathways are intact).

Lesions involving CN Ill cause ptosis. a downward and laterally deviated eye, impaired pupillary
constriction and accommodation, and diagonal diplopia The most dreaded cause of CN Ill palsy
is an enlarging intracranial aneurysm.

A lesion in the optic tract can produce contralateral homonymous hemianopia and a relative
afferent pupillary defect (Marcus Gunn pupil) in the contralateral eye.
6



The stapedius muscle is innervated by the stapedius nerve, a branch of facial nerve (CN Vll)
Paralysis of the stapedius muscle allows wider oscillation of the stapes. and leads to increased
sensitivity
    itivity to sound (hyperacusis)

Hydrocephalus in infants presents with irritability, poor feeding. increased head circumference
and enlarged ventricles on CT Long
                                Long-term
                                     term sequelae of hydrocephalus include lower extremity
spasticity due to stretching of the periventncular pyramidal tracts, visual disturbances, and
learning disabilities.

General features that aid in locahzing a transverse spinal cord section:
a More proximal levels have increasing amounts of white matter and more ovoid sections
a Lower cervical
           rvical and lumbosacral regions have large ventral horns
a Thoracic and early lumbar sections (Ti -L2) contain lateral grey matter horns

General features that aid in localizing a transverse spinal cord section:
a More proximal levels have increasing am amounts
                                              ounts of white matter and more ovoid sections
a Lower cervical and lumbosacral regions have large ventral horns
a Thoracic and early lumbar sections (T1
                                       (T1-L2) contain lateral grey matter homs

The head of the caudate lies in the inferolateral wall of the anterior horn of the lateral ventricle It
is separated from the globus pallidus and putamen by the internal capsule. The caudate is
atrophied in Huntington’s disease.

Neonatal intraventncular hemorrhage usually occurs in the fragile germinal matrix and increases
in frequency with decreasing age and birth weight It is a common complication of prematurity
that can lead to long-term
                      term neurodevelopmental impairment.




CSF flows from the third ventricle to the fourth ventricle via the cerebral aqueduct of Sylvius.

Sciatica is a painful condition characterized by shooting pain down the posterior thigh and leg
that typically results from impingement of one of the spinal nerves as it leaves the vertebral
column. Compression of the Si root results specifically in pain purely in the posterior thigh and
leg as well as diminution of the ankle jerk reflex.

Thiamine (ie., vitamin B1)deficiency acutely leads to Wemicke enceph
                                                               encephalopathy
                                                                     alopathy and chronically
leads to Korsakoff psychosis. The neural structure most frequently affected in patients with
Wernicke encephalopathy is the mammillary body, which is part of the Papez circuit Alcoholic
or malnourished patients should receive intra  intravenous
                                                    venous thiamine supplementation before
intravenous dextrose administration because giving dextrose without prior thiamine can
precipitate a Wemicke encephaIopathy
7


General sensation from the anterior 2/3 of the tongue is carñed by the mandibular division of the
trigeminal nerve Gustatory innervation of anterior 2/3 of the tongue is provided by chorda
tympani branch of the facial

The first arch can be poorly formed during embryonic development resulting in first arch
syndrome. Abnormalities include malf
                                   malformation
                                        ormation of the mandible. maxilla. malleus, incus,
zygoma, vorner, palate, and temporal bone. The first arch is associated with the trigeminal nerve.

Wilson’s disease can cause cystic degeneration of the putamen as well as damage to other basal
ganglia structures. The putamen is located medial to the insula and lateral to the globus pallidus
on coronal sections.

Meningiomas are located adjacent to the cerebral surface, Parasagittal meningiomas cause
contralateral spastic paresis of the leg due to comp
                                                compression of the leg-foot
                                                                       foot motor area

Motor (Broca) aphasia is a nonfluent aphasia that results from damage to Broca’s area in the
inferior frontal gyrus of the dominant hemisphere. Patients understand language but cannot
properly formulate the motor comma
                               commandsnds to form words or write. Speech is slow and fragmented,
with short agrammatic phrases. Word
                                  Word-finding
                                         finding difficulty is often prominent Patients have insight
into their aphasia and are often frustrated by it.

Saddle anesthesia and loss of the anocutaneous reflex are symptoms of cauda equina syndrome,
which is associated with damage to the S2 through S4 nerve roots

Ulnar nerve injury causes sensation loss to the medial 11/2 digits of the hand.

Sensorineural heanng loss. tinnitus. paralysis of facial mu
                                                         muscles,
                                                            scles, and loss of comeal reflex signify
the involvement of CN V, Vii, and Viii. Simultaneous compression of these nerves is caused by
tumor of the cerebeliopontine angle. which are most commonly acoustic neuromas




Acute nausea following administrati
                        administration
                                    on of systemic chemotherapy results from stimulation of the
chemoreceptor trigger zone (CTZ), which lies in the area postrema of the dorsal medulla near the
fourth ventricle.
8


ANATOMY-Rest-1
The right testicular vein drains directly into the IVC while the left testicular vein drains into the
left renal vein.

The proximal 1/3 of the ureter receives its blood supply from branches of the renal artery For this
reason, this portion of the donor ureter is typically viable after renal transplantation

Conductive hearing loss (bone conduction > air conduction): abnormal Rinne test (in affected
ear) and Weber test localizes to affected ear
Sensorineural hearing loss (air conduction> bone conduction): normal Rinne test and Weber test
localizes to unaffected ear.

The oculomotor nerve (ON Ill), ophthalmic nerve (CN V1) branches, trochlear nerve (ON IV),
abducens nerve (ON VI), and superior ophthalmic vein enter the orbit via the superior orbital
fissure



The gastroduodenal artery lies along the posterior wall of the duodenal bulb and is likely to be
eroded by posterior duodenal ulcers Ulceration into the gastroduodenal artery can be a source of
life-threatening hemorrhage.

Aneurysm or atherosclerotic calcification of the internal carotid artery can laterally impinge on
the optic chiasm. This can cause nasal hemianopia by damaging uncrossed optic nerve fibers
from the temporal portion of the ipsilateral retina.

Indirect inguinal hernias are located lateral to the inferior epigastric vessels They can continue
into the scrotum and are felt by deep palpation of the external inguinal ring with the tip of the
finger In contrast, direct inguinal hernias are located medially to the inferior epigastric vessels.
They do not protrude into the scrotum and are best felt with the pulp of the flnger

All skin from the umbilicus down. including the anus (up to the dentatelpectinate line) but
excluding the posterior calf, drains to the superficial inguinal lymph nodes

The spleen is not a gut denvative: it forms from the mesodermal dorsal mesentery The splenic
artery, however, is a branch of the celiac trunk (the primary blood supply of the foregut)

Cncothyrotomy is indicated when an emergency airway is required and orotracheal or
nasotracheal intubation is either unsuccessful or contraindicated The cricothyrotomy incision
passes through the superficial cervical fascia. pretracheal fascia, and the cncothyroid membrane

In addition to unilateral facial paralysis, patients with Bells palsy may experience decreased
tearing, hyperacusis, and/or loss of taste sensation over the anterior two-thirds of the tongue
9


Blunt trauma to the globe can cause orbital blowout fractures. These fractures most commonly
involve the medial or inferior orbital walls, because the bone bordenng the ethmoid and
maxillary sinuses is thin.

Superior mesentenc artery syndrome occurs when the transverse portion of the duodenum is
entrapped between the SMA and aorta, causing symptoms of partial intestinal obstruction This
syndrome occurs when the aortomesentenc angle critically decreases, secondary to diminished
mesenteric fat, pronounced lordosis, or surgical correction of scoliosis.

On abdominal CT scans, the pancreas can be identified by its head in close association with the
second part of the duodenum by its body overlying the left kidney, aorta. IVC and superior
mesenteric vessels; and also by the tail lying in the splenorenal ligament.

The recurrent laryngeal nerve travels in close approximation to the inferior thyroid artery and can
be injured in surgical procedures of the anterior neck (e.g thyroidectomy), resulting in laryngeal
muscle paralysis, hoarseness and dyspnea.

The left gonadal (testicular or ovarian) vein drains into the left renal vein. commonly leading to
left-sided vancoceles in males with obstructions of the left renal vein The right gonadal vein
drains directly into the inferior vena cava

The nerves and vessels supplying the ovary are delivered through the suspensory ligament of the
ovary.

Gallstone ileus results from the passage of a large gallstone (typically greater than 25 cm)
through a cholecystenteric fistula into the small bowel where it ultimately causes obstruction at
the ileocecal valve. Gas is seen within the gallbladder and biliary tree on abdominal X-ray due to
the presence of the fistula, and patients present with signs and symptoms of small bowel
obstruction.

The brachiocephalic vein drains the ipsilateral jugular and subclavian veins. The bilateral
brachiocephalic veins combine to form the SVC. Brachiocephalic vein obstruction causes
symptoms similar to those seen in SVC syndrome, but on just one side of the body.

The lesser omentum is a double layer of peritoneum that extends from the liver to the lesser
curvature of the stomach and the beginning of the duodenum it is divided into the hepatogastnc
and hepatoduodenal ligaments

Femoral hernias are inferior to the inguinal ligament lateral to pubic tubercie, and medial to the
femoral vein. They can present with groin discomfort or manifest with a bulge on the upper thigh
Incarceration and strangulation are common complications of fernoral hernias

The esophagus is located between the trachea and the vertebral bodies in the superior thorax It is
typically collapsed with no visible lumen on CT images of the chest
10


Injury to the posterior urethra is associated with pelvic fracture whereas anterior urethral injury
most commonly occurs in straddle injuries Inability to void with a sensation of a full bladder, a
high riding boggy prostate, and blood at the urethral meatus are all suggestive of urethral injury
particularly in the presence of a pelvic fracture. A retrograde urethrogram should be performed
before Foley catheter placement if there is concern for a urethral injury

The hindgut encompasses the distal 113 of the transverse colon, the descending colon, the
sigmoid colon, and the rectum These structures receive their main arterial blood supply from the
inferior rnesentenc artery

Direct hernias occur most commonly in older men and are caused by weakness of the
transversalis fascia in Hesselbach’s triangle They are medial to the inferior epigastric vessels,
protrude only through the external inguinal ring, and are covered by the external spermatic fascia

In cirrhosis, portal hypertension arises from increased resistance to portal flow at the hepatic
sinusoids This causes increased pressure in the portosystemic collateral veins within the lower
end of esophagus, anterior abdomen, and lower rectum Dilation of these collaterals is responsible
for the esophageal varices, caput medusae, and hemorrhoids commonly seen in cirrhotic patients

The middle meningeal artery is a branch of the maxillary artery that enters the skull at the
foramen spinosum and courses intracranially deep to the pterion. Skull fractures at this site may
cause laceration of this vessel, leading to an epidural hematoma

A branch of the mandibular division of the tngerninal nerve (CN V3) provides somatic sensory
innervation to the anterior 2/3 of the tongue. The chorda tympani branch of the facial nerve
provides taste sensation from the anterior 2/3 of the tongue. The glossopharyngeal nerve (CN IX)
provides somatic sensory and taste innervation to the posterior portion of the tongue.

Cardiovascular dysphagia can result from pressure on the esophagus by a dilated left atrium The
left atrium is commonly enlarged in patients with mitral stenosis and left ventricular failure

The great majority of gastric ulcers occur over the lesser curvature of the stomach, at the border
between acid-secreting and gastnn-secreting mucosa The left and right gastric arteries run along
the lesser curvature and are likely to be penetrated by ulcers. causing gastric bleeding.

Testicular hydrocele results when serous fluid accumulates within the tunica vaginalis. The
tunica vaginalis is embryologically derived from the peritoneum, when it remains in
communication with the peritoneum, a communicating hydrocele results.

Retroperitoneal hematoma in a stable patient is likely to occur due to pancreatic injury It may
present with mild symptoms, be asymptomatic or be masked by symptoms from other injuries
related to trauma Abdominal CT is the diagnostic modality of choice. Frequently nonexpanding
hematomas in this location will be treated conservatively (ie. non-operatively)
11


Due to its intra-abdominal
                 abdominal origin. lymphatic drainage of the testis is to the para-aortic
                                                                              para        lymph
nodes. In contrast, lymph drainage from the scrotum goes into the superficial inguinal lymph
nodes

The pupillary light reflex is assessed by shini
                                          shining
                                                ng light in an eye and observing the response in that
eye (direct) and the opposite eye (consensual). The optic nerve (CN U) is responsible for the
afferent limb of the pupillary reflex, and the oculomotor nerve (CN Ill) is responsible for the
efferent limb

Low-frequency
     frequency sound is best detected at the apex of the cochlea near the helicotrema High-
                                                                                          High
frequency sound is best detected at the base of the cochlea near the oval and round windOws.

The external branch of the superior laryngeal nerve is at risk of injury during thyroidectomy due
to its proximity to the superior thyroid artery and vein This nerve innervates the cricothyroid
muscle

The splenic artery originates from the celiac artery and gives off several branches to the stomach
and pancreas (pancreatic, short gastric, and left gastroepiploic arteries) before finally reaching
the spleen Due to poor anastomoses. the gastric tissue supsupplied
                                                             plied by the short gastric arteries is
vulnerable to ischemic injury following splenic artery blockage

BPH is a common, age-related
                         related condition that causes urinary symptoms and can be medically
treated with aa drenergic blockers or 55-ci
                                         ci reductase inhibitors. The prostate is located between
the pubic symphysis and the anal canal in inferior sections of the pelvis on CT scan.



The third part of the duodenum courses horizontally across the abdominal aorta and inferior vena
cava at the level of the third lumbar vertebra. Here it is in close association with the uncinate
process of the pancreas and the superior m
                                         mesentenc vesse1s

Prolonged exposure to loud noises causes hearing loss due to damage of the stereociliated hair
cells of the organ of Corti


ANATOMY-Rest-2
In horseshoe kidney, both kidneys are fused together at the poles in early embryonic Iife The
isthmus of horseshoe kidney usually lies anterior to the aorta and inferior vena cava and posterior
to the inferior mesentenc artery This centrally located isthmus becomes trapped behind the
inferior mesentenc artery during the relative ascent of the kidne
                                                            kidney

The inferior vena cava is formed by the union of the right and left common iliac veins at the
level of L4-L5.
            L5. The renal arteries and veins lie at the level of Li. The IVC returns venous blood
from the lower extremities, portal system and abdominal and pelvic viscera to the right atrium of
the heart
12



The inferior vena cava is formed by the union of the right and left common iliac veins at the
level of L4-L5. The renal arteries and veins lie at the level of Li The IVC returns venous blood
from the lower extremities, portal system and abdominal and pelvic viscera to the right atrium of
the heart

A penetrating injury at the left sternal border in the fourth intercostal space would puncture the
anterior surface of the heart The right ventricle composes most of the hearts anterior surface

The left ventncle forms the apex of the heart and reaches as far as the fifth intercostal space at
the left midclavicular line All other chambers of the heart lie medial to the left midclavicular Iine
The lungs overlap much of the anterior surface of the heart.

The coronary sinus communicates freely with the right atrium and therefore may become dilated
secondary to any factor that causes right atrial ddatation The most common such factor is
pulmonary artery hypertension, which leads to elevated right heart pressures.

The left atrium forms the majority of the postenor surface of the heart and resides adjacent to the
esophagus. Enlargement of the left atnum can compress the esophagus and cause dysphagia.

The descending thoracic aorta lies posterior to the esophagus and the left atrium. This position
permits clear visualization of the descending aorta by transesophageal echocardiography,
allowing for the detection of abnormalities such as dissection or aneurysm.

Aspirated or inhaled particles are most likely to become lodged in the right main bronchus or its
branches because this bronchus is shorter, wider and more vertically oriented than the left main
bronchus.

Aortic rupture is most commonly due to motor vehicle accidents, and the most common site of
injury is the aortic isthmus, which is the connection between the ascending and descending aorta
distal to where the left subclavian artery branches off the aorta

Lesions of the jugular foramen can result in jugular foramen (Vernet) syndrome, which is
characterized by the dysfunction of CN IX, X, and XL

The lung apices extend above the level of the clavicle and first rib through the superior thoracic
aperture. Penetrating injury in this area may lead to pneumothorax

Lymph from the testes drains through lymph channels directly back to the para-aortic lymph
nodes. In contrast, lymph from the scrotum drains to the superficial inguinal lymph nodes.

The internal laryngeal nerve mediates the afferent limb of the cough reflex above the vocal cords
Foreign bodies (eg, chicken or fish bones) can become lodged in the piriform recess and may
cause damage to the nerve, impairing the cough reflex
13


Thoracocentesis should be performed above the 7 rib in midclavicular line, the 9 rib along
midaxillary line and the 1 1’ rib along posterior scapular hne Insertion of a needle lower than
these points increases the risk of penetrating abdominal structures, and insertion of the needle on
the inferior margin of the rib risks striking the subcostal neurovascular bundle

The chest x-ray in acute left ventricular failure with pulmonary edema shows cardiomegaly
(heart> I
hemithorax in size), pleural effusions, Kerley B lines, and increased vascular shadowing
(alveolar edema)
bilaterally.

Left ventricular leads in biventricular pacemakers course through the coronary sinus, which
resides in the atrioventncular groove on the posterior aspect of the heart

The inferior wall of the left ventricle forms most of the diaphragmatic surface of the heart The
posterior descending artery supplies this area In 85-90% of individuals, the posterior descending
artery derives from the right coronary artery

Irntaton of the mediastinal or diaphragmatic panetal pleura wiN cause sharp pain, worse on
inspiration, in the C3-C5 distribution. Pain sensation from these areas is carned by the phrenic
nerVe.

The left kidney lies immediately deep to the tip of the 1 2th rib on the Ieft

The arrow on the chest X-ray above points to the right atiium On postero-antenor (PA) chest X-
ray projections, the right atrium composes most of the right side of the cardiac silhouette The
right atrium receives venous blood from the superior and inferior vena cavae, which compose the
superior and inferior

The right atrium receives venous blood from both the superior vena cava and the inferior vena
cava The right atrium makes up the majority of the right border of the heart on PA chest fIlms
The right ventricle forms the anterior waN of the heart and is best seen on lateral chest X-rays
The SVC and IVC compose the superior and inferior borders of the cardiac silhouette on the
right side.

The great saphenous vein is a superficial vein of the leg that originates on the medial side of the
foot, courses anterior to the medial mafleolus and then traveis up the medial aspect of the leg and
thigh It drains into the femoral vein within the region of the femoral triangle, a few centimeters
inferolateral to the pubic tubercle.

The portal vein can be identified on cross-sectional scans lying medial to (or just within) the
right lobe of the liver and anterior to the inferior vena cava. The pressure in the portal system is
elevated in liver cirrhosis.

A pudendal nerve block can be performed by injecting anesthetic intravaginally in the region of
the ischial spine Blocking the pudendal nerve provides anesthesia to the majority of the perineum
14


additional blockade of the genitofemoral and ilioinguinal nerves would provide complete
penneal and genital anesthesia

Apical lung tumors are called Pancoast tumors Pancoast tumors can cause Homer syndrome,
SVC syndrome, arm weakness, arm paresthesias, and hoarseness

The inferior vena cava courses through the abdomen and interior thorax in a location anterior to
the right half of the vertebral bodies. The renal veins join the PlC at the level of L1112, and the
common iliac veins merge to become the IVC at the level of L4

An early systolic murmur best heard over the left lower sternal border that is accentuated by
inspiration is most likely due to tncuspid regurgitation
15


BEHAVIORAL-1

Schizoaffective disorder is characterized by symptoms of schizophrenia in the presence of
prominent mood symptoms A period of at least 2 weeks of psychotic symptoms in the absence of
mood symptoms is required for the diagnosis.

A temporary course of benzodiazepines
                             zodiazepines is sometimes used during the SSRI initiation period if
there is a significant increase in anxiety related symptoms. Triazolam is a benzodiazepine that
can be useful for treating insomnia in patients employed in mission
                                                            mission-critical
                                                                    critical positions, as its
                                                                                           i short
half-life
     life minimizes undesirable daytime side effects.

Obstructive sleep apnea is the   most common medical cause of excessive daytime sleepiness in
the US It occurs due to poor     oropharyngeal tone and results in daytime sleepiness, morning
headaches, and depression
Obstructive sleep apnea is the   most common medical cause of excessive daytime sleepiness in
the US It occurs due to poor     oropharyngeal tone and results in daytime sleepiness, morning
headaches, and depression

The hallmark of generalized zed anxiety disorder is excessive worry over several different issues
lasting at least 6 months. It is treated with antidepressants and benzodiazepines.

Among drugs of abuse. intoxication with hallucinogens (psychotomimetic drugs), amphetamines,
and cocaine
       aine is most commonly associated with violent behavior. Hallucinogens include LSD and
phencyclidine (PCP, angel dust) Belligerence and psychomotor agitation tend to be more
common with PCP than with LSD intoxication.

According to guidelines released by the American Psychiatric Association (2002) the mainstay
of therapy for acute mania is a mood stabilizing agent (eg lithium, vaiproate, or carbamazepine)
plus an atypical antipsychotic (e.g olanzapine).

In non-emergentt settings. one should always use a trained objective interpreter when there is a
language barrier involving a patient. This also applies to hearing
                                                               hearing-impaired
                                                                       impaired patients using
American Sign Language.

Suppression is a conscious, mature defense mechanism inv
                                                     invoMng
                                                         oMng withholding troublesome
thoughts or impulses

Avoidant personality disorder is a maladaptive pattern of behavior characterized by feelings of
inadequacy, timidity, and fear of rejection.

There are five subtypes of schizophrenia. each characterize
                                               characterized
                                                           d by a set of prominent symptoms.
Disorganized schizophrenia is distinguished by disorganized speech and behavior and a flat or
inappropriate affect.
16



PCP or phencyclidine is a hallucinogen that works by inhibiting the excitatory NMDA receptor.
Moderate amounts of PCP cause feelings of detachment and distance Additionally, PCP can
produce slurred speech, loss of coordination (ataxia). involuntary movements, exaggerated gait,
and nystagmus It can induce paranoia and hallucinations and most users will become very hostile
and aggressive.

Passive-aggressive behavior is the expression of hostile feelings in a non-confrontational
manner.

Patients with delusional disorder harbor nonbizarre delusions but do not meet the criteria for
schizophrenia and can function without significant impairment in day-to-day life

Clinicians have ethical and moral obligations to report elder abuse. neglect and exploitation If
there is reason to suspect abuse or neglect, the patient should be interviewed alone to avoid
intimidation by possible abusers

The only serotonin-releasing neurons in the CNS are found in the raphe nuclei These neurons
disseminate widely to synapse on numerous structures in the CNS

Marijuana contains THC which stimulates cannabinoid receptors to produce effects on mood,
perception, and memory. Marijuana produces a mild euphoria with laughing behavior, slowed
reflexes, dizziness, impaired coordination, and short term memory loss. Rapid heart rate and
conjunctival injection are the two most immediate physical symptoms of marijuana use. It
remains in tissues for a significant amount of time and can be detected up to 30 days after use.

Obsessive-compulsive disorder is characterized by recurrent, obsessive, anxiety-inducing
thoughts, plus behavioral compulsions aimed at reducing the anxiety. In most cases of OCD, the
patient understands the unreasonable nature of their thoughts and behaviors OCD often starts in
childhood

Conversion disorder refers to the unconscious manifestation of neurologic symptoms when
pathophysiological explanations for the symptoms cannot be found It occurs more commonly in
women and often occurs after a significant life stress

Obsessive compulsive disorder is characterized by persistent intrusive thoughts that lead to
repetitive behaviors These thoughts and actions cause significant distress and functional
impairment Affected individuals recognize the absurdity of their thoughts and actions but are
unable to stop them

Transference is the unconscious shifting of emotions or desires associated with one person (eg.
sibling, parent, spouse) to another (eg physician. therapist) It can be positive or negative

Differentiation of Delirium and Dementia
1 Onset: Acute in delirium vs. gradual in dementia
2. Consciousness Impaired in delirium vs. intact in dementia
17


3. Course: Fluctuating symptoms in delinum vs. progressive decline in dementia
4 Prognosis: Reversible symptoms in delinum vs. irreversible symptoms in dementia
5. Memory impairment: Global in delirium vs. remote memory spared in dementia

Patients with prefrontal lobe injury often experience behavioral and personality changes,
secondary to impairment of the organizational, restraint, and motivational systems Frontal lobe
syndrome can manifest in variable ways, but can often be categorized into disorganized.
disinhibited. and apathetic types.

Narcolepsy is a disorder characterized by excessive daytime sleepiness and REM steep—related
phenomena such as cataplexy, sleep paralysis, and hypnagogicihypnopompic hallucinations.

There are three categories of postpartum mood disturbances The most common is the postpartum
blues, a benign, self-limited change in affect that lasts up to 10 days postpartum It is treated with
watchful waiting and the knowledge that up to 20% of these women will develop postpartum
depression

Reaction f0rmaon the replacement of an unpleasant or unacceptable thought or desire with an
emphasis on its opposfte

Bulimia nervosa is an eating disorder characterized by binge-eating and either restrictive or
purging compensatory behaviors. Anorexia nervosa is distinguished from bulimia nervosa by
abnormally low body weight (< 85% of ideal or BMI < 175 kg/m) and amenorrhea

Acute stress disorder and post-traumatic stress disorder present with identical symptoms
(recurrent nightmares and flashbacks, potential memory loss, and exaggerated startle respOnse).
Acute stress disorder can last no more than four weeks, however, while post-traumatic stress
disorder lasts longer than four weeks.

Projection refers to transplanting ones unacceptable impulses or affect onto another person or
situation. It is an immature defense mechanism.

Basic interviewing techniques include facilitation, reflection, confrontation, support, empathy.
silence, and direct and indirect questioning. Support involves expressing concern independent of
understanding. This is in contrast to empathy, where the physician expresses understanding and
vicarious experiencing of a patients situation.

There are numerous defense mechanisms (all of which the USMLE loves). Splitting refers to
seeing the world in “black and white’ and is common amongst patients with borderline
personality disorder

At three years of age a child is expected to be able to play in parallel. speak in simple sentences,
copy a simple shape, and ride a tricycle
18


Psychotic symptoms that interfere with the patients functional status are classified as brief
psychotic disorder if the symptoms last less than one month. schizophreniform disorder if the
symptoms last one to six months, and schizophrenia if the symptoms last more than six months.

Opiate withdrawal is marked by abdominal pain. nausea. vomiting. diarrhea. piloerection,
pupillary dilation, diaphoresis and fever. It can occur in patients taking narcotics legally or
Illegally.

When patients are unable to make their wishes known and there is no written documentation of
these wishes, the responsibility for medical decision making falls to their designated health care
proxy If a patient has not designated a surrogate decision-maker, medical decisions default to the
next of kin In the case of a married person, the next of kin is usually the spouse.



BEHAVIORAL-2
In situations where patients are unable to make decisions for themselves, responsibility for those
decisions falls on the next of kin if the patient has no written directives clearly stating their
intentions. The next of kin for a married person is their spouse followed by their adult children
The next of kin is to make decisions based on how they believe the patient would have wanted
things.

Bulimia nervosa is an eating disorder characterized by alternating bingirig and weight reduction
behaviors. Patients can develop bilateral parotid gland enlargement, erosion of tooth enamel, and
irregular menses.

Minors can consent to treatment for pregnancy, sexually transmitted disease, birth control, and
drug or alcohol addiction without Darental consent or notification.

Disability is a form of assistance provided to workers who can no longer work due to their
general medical condition: it requires certification of disability by a physician When interacting
with difficult patients, it is best to try to calm them, explain your position and inquire more about
what troubles them by using open-ended questions.

There are numerous somatoform disorders Body dysmorphic disorder is one in which a patient
believes his or her body is pathologically flawed when, in fact, it is not There is a high rate of
comorbid major depressive disorder and suicide attempts among patients with BDD


Adult patients who are competent or have outlined their wishes in a living will have the authority
to refuse any form of treatment, including life-saving therapies In an emergency situation, if
there is any doubt in a clinician’s mind concerning the wishes of a patient, the best course of
action is to treat according to the accepted standard of care. In an emergency, the physician
should always provide potentially life-saving therapy to a minor.
19


Adult patients who are competent or have outlined their wishes in a living will have the authority
to refuse any form of treatment, including lifelife-saving
                                                    saving therapies In an emergency situation, if
there is any doubt in a cIinicians mind concerning the wishes of a patlea the best course of action
is to treat according to the accepted standard of care In an emergency, the physician should
always provide potentially life-saving
                                 saving therapy to a minor.




Psychogenic causes of ED account for approximately 10% of cases and include performance
anxiety, sexual partner dissatisfaction, and marital problems Important clues that point toward
psychogenic impotence include sudden onset and the presence of morning eerectIons.
                                                                          rectIons.

When an ill patient requests your prayers in an acute setting. it is appropriate to offer your
personal support without interjecting your personal beliefs into the interaction The overriding
goal in these situations is to do no harm” This can be achieved by not disagreeing with the
patient, not entering into a religious debate with them, and not displacing responsibility for the
care of the patient onto others.

If as part of a medical team you have been asked to perform an action that you feelfe will cause
harm to the patient, it is your ethical obligation to discuss that order with your supervising or
colleague physician who has made the questionable suggestion in order to reach a consensus
without invoMng the patient or ancillary staff.

   en treating patients that are referred to you for specialty care or second opinions, it is
When
imperative to not undermine the patienVs relationship with his or her primary provider Avoid
making negative comments about the quality of care rendered by that prac
                                                                    practitioner
                                                                        titioner

PaIents who are temporarily incapacitated should not be allowed to make important health care
decisions.

In situations where a parent is complicating an interview or where you feel you will not be able
to get honest answers from the adolesce
                                  adolescent
                                          nt patient with the parent present, it is appropriate to
politely ask the parent to wait outside while you interview the patient This is also important
when discussing drugs, alcohol, tobacco and sexual activity with teenagers.

Displacement is one of thee less mature defense mechanisms In displacement. a patient will
redirect emotions from the person or object that is causing the negative emotions to a more
acceptable, but still inappropriate, person or object.

Patient confidentiality is strongly prote
                                    protected
                                         cted because patients must feel free to disclose details on
all aspects of their lives so that physicians can provide optimal care. Patient confidentiality can
be breached in only 4 exceptional circumstances suspected child or elder abuse, gunshot or
stabbing
      ing injuries, diagnosis of a reportable communicable disease, and when patients believably
threaten to physically harm themselves or others.
20



A patient who is competent and not incapacitated has the right to refuse treatment by a physician
at any time, even if that treatment is life-saving. A competent patient understands their situation
as well as the possible consequences of decisions made in that situation.

Health care information should be fully disclosed, unless the patient has expressly asked not to
be informe<i

Dysthymic disorder is a chronic. low-intensity mood disorder that responds well to
antidepressant medications. Its symptoms are less severe than those of major depressive disorder,
but they must be present for at least 2 years before the diagnosis can be made

As a rule, physicians should maintain a general policy of not accepting gifts from patients or
their families; especially if the gifts are of great value. preferential treatment is expected, or if the
patient is demented. Exceptions to this rule would be in the case of a one-time gift of small or
token value (eg, cookies).

No matter how serious or trivial a medical error, a physician is ethically obligated to inform a
patient that a mistake has been made. Ethics committees and risk management personnel can
assist if a patient wishes to speak with someone or threatens a lawsuit

Just as competent patients have the right to refuse medical care. they also have the right to refuse
knowledge of their own medical information and diagnoseS. In cases such as these it is essential
to ensure that the patient is well-informed before they make their decision and find out from the
patient who their surrogate decision-maker should be.

Consent of a married or unmarried significant other is not required for a patient to undergo any
type of procedure, elective or nonelective. It is necessary to counsel the patient of the risks,
benefits, alternatives and contraindications of any procedure or treatment, and the physician
should additionally counsel the patient that she may want to discuss her decision with her
significant other to avoid social difficulties later.

Ethical principles as well as the Health Insurance Portabibty and Accountability Act of 1996
(HIPAA, Title II) dictate that patient information can not be disclosed to others, including loved
ones and family members, without the explicit consent of the patient Documentation that the
patient has granted consent for disclosure of their health information should be placed in the
patienfs chart

The first step in addressing noncomphant patients is to educate them about the disease being
treated, the risks of not treating this disease, and how interventions can help them avoid or lessen
these risks

The responsibility of the physician who serves in a medical capacity at a sporting event is to
protect the health and safety of the players The desire of the spectators, coaches, or patient that
an athlete not be removed from the game should not affect the physician’s decision The
physician’s judgment should be guided only by medical considerations.
21



Using open-ended questions is the most effective way to start clinical histories Once the patient
has started his history, one can use closed-ended follow-up questions to clarify certain pointS.

In situations where you need to relay difficult information to a patient. you should take the
approach of immediately informing the patient of the news, gMng them a moment to think about
the news, and subsequently explaining what the news means and what their options are. You
should always end by answering any questions the patient may have.

White coat syndrome’ (patient anxiety evoked by healthcare workers dressed in white coats) is
an example of classical conditioning, wherein the white coat serves as a conditioned stimulus for
anxiety

Prescription of antibiotics for diseases that are not bacterial in origin is not proper procedure.
This practice contributes to the societal prob$ern of antibiotic resistance, and it places the patient
at unreasonable risks due to adverse reactions to antibiotic therapy

It is unethical to discuss any information regarding the patient’s diagnosis. treatment, prognosis,
etc. with a physician who is not involved in the patient’s care. Likewise, the physician should
neither confirm nor deny whether the person of interest is, in fact, a patient

Advance care planning for end of life issues such as desire for intubation. mechanical ventilation,
tube feedings, parenteral feedings, CPR and cardioversion are best initially discussed during
outpatient visits with primary care providers These decisions must also be readdressed during the
admission process for acute admissions so that medical staff can adhere to the specific wishes of
patients
22


BIOCHEMISTRY 1
Ubiqurtin is a protein that undergoes ATP-dependent attachment to other proteins, labeling them
for degradation. These modified prote.ns enter the proteasome and are degraded into small
peptides Impairment of the ubiquitin-proteasome system can contribute to the development of
neurodegenerative disorders. including Parldnson’s and Alzheimer’s diseases

All three prokaryotic DNA polymerases have proof reading actrvity and remove mismatched
nucleotides via 3’ to 5’ exonuclease activity. Only DNA polymerase I has 5’ to 3’ exonuclease
activity which is used to excise and replace RNA primers and damaged DNA sequences.

The 1P3 second messenger system begins with hormone binding and G-protein activation
leading to activation of phospholipase C. Phospholipase C forms diacyiglycerol and lP3 from
phospholipids, and 1P3 causes an increase in intracellular calcium, which then activates protein
kinase C.

Arginase is an enzyme of the urea cycle that produces urea and ornEthine from arginine

Helicase unwinds DNA at the replication fork and separates dsDNA into ssDNA during the
replication process. Initial separation of dsDNA at the origin of replication is facilitated by DnaA
protein and strand binding proteins (SSB) proteins

Extracellular propeptidases cleave disulfide-rich terminal extensions from the procollagen
molecule. This results in formation of water-insoluble triple helical collagen fibrils.

Tyrosine becomes essential in PKU pabents because can no longer be synthesized from
phenylalanine Phenylketonuna (P1(U) results from an rnabihty to convert phenylalanwie to
tyrosine by the phenylalanine hydroxylase system Although neonatal hyperphenylalaninemia can
be caused by deficiences in any of the phenylalanine hydroxylase system, most are attnbutable to
abnormaIies in the phenylalanine hydroxylase enzyme

snRNPs (small nuclear nbonucleoproteins) are synthesized by RNA polymerase II in the nucleus.
They help to remove introns from the RNA transcript and are thus necessary for synthesis of
messenger RNA

The zinc-containwig 6-Aminolevulinate dehydratase and ferrochelatase are enzymes in the heme
biosynthetic pathway that are inactivated by lead Thus, in lead poisoning, ö-AL4 and
protoporphyrin IX accumulate, and the production of heme is decreased, leading to microcytic
anemia secondary to a lack of hemoglObin.

DNA poiymer;selhas 5’ to 3’ exonuclease activify in addition to its 5’ to 3’ polymerase and 3’ to
5’ exonuclease activities. This 5’ to 3’ exonuclease activity is used to remove the RNA primer
(which initiates DNA polymerization) and to remove damaged DNA.

Hydrogen bonds are the principal stabdizing force for the secondary structure of proteins.
23


A patient with orotic aciduna (impaired de novo pyrimidine synthesis) will present with
hypochromic megaloblastic anemia, neurologic abnorrnahties. growth retardation and excretion
of orotic acid in the urine Uridine supplementation impioves symptoms by inhibiting carbamoyl
phosphate synthetase II.

Homocystinuna is caused by cystathionirie synthetase deficiency Affected individuals manifest
with skeletal abnormalities resembling those of Marfan syndrome In addition, they are also at
high risk of developing thromboembolism About 50% of affected patients respond to high doses
of vitamin B6 (pyridoxine)

N-acetylglutamate is an essential activator of carbamoyl phosphate synthase I and is formed by
the enzyme N-acetylglutamate synthetase from the precursors acetyl-CoA and glutamate.

In Niemann-Pick disease. deficiency of sphingomyelinase causes abnormal accumulations of the
ceramide phospholipid sphingomyehn and neurologic detenoration within the first year of life

The nitrogen atoms in the urea moIecue are derived from NH3 and aspartate in the urea cycle
Remember that carbamoyl phosphate synthetase I (CPS I) is the rate-limiting enzyme in the urea
cycle reaction and is activated by N-acetylglutamate (NAG)

Vitamin A ovewse can result in intracranial hypertension. skin changes and hepatosplenomegaly

tRNA is the smallest subtype of cellular RNA It is responsible for transporting amino acids to the
site of protein synthesis and introducing them into the growing polypeptide chain at the correct
locations The 3k-end of the tRNA molecule is the site of amino acid binding. The opposite side
of the molecule contains the antic odon loop, which recognizes a specific codon on the mRNA
molecule

Glycine is the most abundant amino acid in the collagen molecule. IL occurs in AT LEAST
every third amino acid position The amino acid formula & collagen is (-Gly-X-Y-)333

LeSCh-Nyhan syndrome is an X-Iinked recessive disorder caused by a defect in hypoxanthine-
guanine phosphoribosyltransferase (HGPRT). This results in failure of the purine salvage
pathway Because they are not recycled, increased amounts of the purine bases hypoxanthine and
guanine are degraded to uric acid. De novo purine synthesis must increase to replace the lost
bases.

Chronic thiamine (BI) deficiency leads to the diminished abihty of cerebral cells to utilize
glucose The mechanism is decreased function of the enzymes that use vitamin Bi as a cot actor
(pyruvate dehydrogenase. a-ketoglutarate dehydrogenase, and transketolase) Thiamine
deficiency can be diagnosed by measuring erythrocyte transketolase activity

Propionyl CoA is derived from amino acids (Val, lie, Met, and Thr), odd-numbered fatty acids,
and cholesterol side chains Congenital deficiency of propionyl C0A carboxylase, the enzyme
responsible for the conversion of propionyl CoA to methylmalonyl C0A, leads to the
development of propionic acidemia
24



Ornithine transcarbamoylase deficiency is the most common disorder of the urea cycle, resulting
in severe neurological abnorrnahties due to high blood and tissue ammonia levels, Increased
urine orotic acid excretion is typica[

Branched.chaina-ketoacid dehydrogenase. similar to pyruvate and a-ketoglutarate
dehydrogenase, requires
several coenzymes Thiamine pyrophosphate, Lipoate, Coenzyme A. FAD, NAD (mnemonic
Tender Loving
Care For Nancy). Some patients with maple syrup unne disease improve with high-dose thiamine
treatment
(thiamine-responsive), but most still require lifelong dietary restncbons

Deficiency of the enzyme phenylalanine hydroxylase or of its cofactor tetrahydrobiopterin
causes accumulation of phenylalanine in body fluids and the central nervous system (CNS). The
homozygous infant is normal at birth, but mental retardation develops gradually in untreated
infants and is frequently evident within six months of life

Transamination reactions typically occur between an amino acid and an a-keto acid The amino
group from the amino acid is transferred to the a-keto acid, and the a-keto acid in turn becomes
an amino acid. Pyndoxal phosphate (vitamin B6) serves as a cofactor in amino acid
transamination and in decarboxylation reactions.

Antibodies to citrulinated peptides/proteins have a high specificity for rheumatoid arthritis.

Marfans syndrome is due to a defect m fibrillin. an extracellular glycoprotein that is abundant in
the zonular fibers of the lens, the periosteum and the aortic media The different locations of
fibrillin production explains the varied clinical manifestations of Marfan’s syndrome.

Peroxisomal diseases are rare inborn errors of metabolism where peroxisomes are either absent
or nonfunctional Very long chain fatty acids or fatty acids with branch points at odd-numbered
carbons can not undergo mitochondnal beta-oxidation, these fatty acids are metabolized by a
special form of beta oxidation (very long chain fatty acids) or by alpha oxidation (branched chain
fatty acids such as phytanic acid) within peroxisomes These diseases commonly lead to
neurologic defects from improper CNS myelination.

Gout can occur with increased frequency in patients with activating mutations in
5’-phosphoribosyl-P-pyrophosphate (PRPP) synthetase due to an increased production of
purines, which results in hyperuricemia

Coichicine is useful in the acute management of gouty arthritis because it inhibits the chemotaxis
of neutrophils by preventing microtubule formation.

Niernann-Pick disease is an autosomal recessive disorder characterized by a deficiency of the
sphingomyelinase enzyme and resuttant accumaiation of sphingomyelin. Patients present ii
25


infancy with loss of motor skiBs. hepatosplenomegaly, hypotonia and a cherry-red macular spot.
Foamy histiocytes are the classic finding on tissue histology Death occurs before age 3

Tetrahydrobiopterin (BH4) is a cofactor used in the synthesis of tyrosine, DOPPL serotonin. and
nitric oxide.
Initially. tyrosine is converted to DOPA by the enzyme tyrosine hydroxylase, with BH used as a
cofactor
Next, DOPA is decarboxylated to dopamine by the enzyme DOPA decarboxyLase In atypical
phenylketonuna
(PKU) wrth tyrosine supplementation, only the catecholamine synthesis reachons downstream of
tyrosine are
compromised

Ehiers-Danlos syndrome is a heritable connective tissue disease associated with abnormal
collagen forrnation EDS usually manifests clinically as over-flexible (hypermobile) joints, over-
elastic (hyperelastic) skin, and fragile tissue susceptible to bruising, wounding, and
herna,’throsis.

Procollagen is synthesized by a series of steps within the endoplasmic reticulum of cells such as
fibroblasts. This molecule is then released into the extracellular space by transport through the
Golgi apparatus and converted into collagen by procollagen peptidases that cleave the water
soluble, non-helical N- and C-terminal portions of the procollagen molecule from procollagen to
form collagen Collagen monomers are then covalently crosslinked with each other after certain
residues are oxidized by lysyl oxidase.

Glycogen degradation is coupled with skeletal muscle contraction due to calcium-mediated
myophosphorylase activation Increased calcium in the cytosol allosterically activates
phosphorylase kinase, which then phosphorylates (activates) muscle phosphorylase

Alkaptonuria is an autosomal-recessive disorder caused by a deficiency of the enzyme
homogentisic acid oxidase, which normally breaks down the tyrosine bypoduct homogentisic
acid (also called alkapton). Accumulated homogentisic acid causes pigment deposits in
connective tissues throughout the body.

Maple syrup urine disease (MSUD) is caused by a defect in a-keto acid dehydrogenase. leading
to an inability to degrade branched chain amino acids beyond their deaminated a-keto acid state
This illness classically results in dystonia and poor feeding as well as the maple syrup scent of
the patients urine within the first few days of life Treatment rests on dietary restnchon of
branched-chain amino acids

Aikaptonuna is an autosomal-recessive disorder in which the lack of homogentisic oxidase
blocks the metabolism of phenylalanine and tyrosine at the level of homogentisic acid, leading to
an accumulation of homogentisic acid Homogenhsic acid excreted in the urine imparts a black
color to urine. if allowed to undergo oxidation Aikaptonuna also causes ocl’wonosis, a blue-
black pigmentation that is most evident in the ears, nose, and cheeks.
26


Hydroxylation of proline and lysine residues in the collagen precursor occurs m the RER and
requires vitamin C as a cofactor Terminal peptide cleavage and collagen fibnl crosshnking occur
in the extracellular space

BHsacofactorusedby hydroxytase enzymes m the synthesis of tyrosine. dopa, and serotonin, as
well as nitric oxide Serotonin is synthesized from tryptophan, and the initial step in this reaction
is catalyzed by an enzyme that uses BH4 as a cofactor Enzyme dihydrobioptenn reductase
deficiency causes defective regeneration of BH4, and is an uncommon cause of phenylketonuna
(PKU).

Methylmalonic acidemia (also known as methylmalonic aciduria) results from a defect in the
isomerization reaction that transforms methylmalonyl CoA to succinyl CoA, prior to succinyl
CoA entering the TCA CycIe

Alanine is the major amino acid responsible for transferring nitrogen to the liver for disposal
During the catabolism of proteins, amino groups are transferred to a-ketoglutarate to form
glutarnate. Glutamate is then processed in the liver to form urea, the primary disposal form of
nitrogen in humans. Free ammonia is also excreted into the urine by the kidney for regulation of
acid-base status.




BIOCHEMISTRY 2
Cobalamin (Vitamin B12) deficiency results ii homocystinemia due to impaired methionine re-
synthesis Homocystinuria occurs in cobalamin (Vitamin B12) deficiency because homocysteine
methyltransferase, the enzyme that converts homocysteine and methyttetrahydrofolate to
methionine and tetrahydrofolate, requires B12 as a cofactor.

Heme oxygenase converts heme to biliverdin. a pigment that causes the greenish color to
develop in bruises several days after an injury.

There is one codon that signals initiation of protein synthesis (AUG), while three codons stop
protein synthesis (UM, UAG, and UGA) Transfer RNA molecules (tRNA) transport amino acids
to the site of protein synthesis and ensure placement of the proper amino acid for a given mRNA
codon Each tRNA contains a specific anticodon that is complementary (oriented in an
antiparallel direction) to certain mRNA codons,

In the lungs, hemoglobin binds oxygen and releases protons while, in the tissues, it releases and
acquires protons. Deoxyhemoglobin is stabilized by ionic bonding of 2,3 DPG to the two beta
subunits and by salt bridges between N-terminal histidine residues in each globuIin

Pnmase is a DNA-dependent RNA polymerase that mcorporates short RNA primers into
replicating DNA.
27


Hemoglobin S (HbS) aggregates in the deoxygenated state HbS polymers form fibrous strands
that reduce red blood cell membfane flexibility and promote sickling Sickling occurs under all
conditions associated with anoxia including low pH and high 2,3     2,3-DPG.
                                                                        DPG. These inflexible
                                                                                    inflexibl
erythrocytes predispose to microvascular occlusion and microinfarction




The PI3KJAkt)mTOR pathway is an intracellular signaling pathway important for anti-apoptosis,
                                                                                  anti
cellular proliferation, and angiogenesis. Mutations in growth factor receptors. Akt
                                                                                  Ak mTOR. or
PTEN that enhance the activity of this pathway contribute to cancer pathogenesis.

Decreased heme concentration resu’ts in an increase in hepatic ALA synthase activity, which in
turn, leads to increased formation of öö-aminolevuhnic acid and porphobdinogen
                                                                       rphobdinogen Increased
formation of ö-arninolevulinic
                arninolevulinic acid and porphobilinogen occurs because heme normally serves to
inhibit the synthesis of ALA synthase.

The liver takes up indirect (unconjugated) bilirubin through a passive process and secretes direct
                                                                                               dire
(conjugated) bilirubin through an active process. Unconjugated bilirubin is virtually insoluble in
water at physiologic pH and is tightly complexed to serum albumin while in the circulation This
form cannot be excreted in the urine, even when blood levelevels
                                                              ls are high. Conjugated bihrubin is
water-soluble, non-toxic,
                    toxic, and only loosely bound to albumin. it is freely excreted in the urine.

Releasing factors recognize the stop codons (UAA, UAG and UGA) to terminate protein
synthesis They facditate release of the polypeptide chain from the hbosome and dissolution of
the ribosome-mRNA complex

Exertional dyspnea. pneumonia resulting in life
                                             life-threatening
                                                  threatening acute chest syndrome. and recurrent
abdominal and bone pain are clinical features of sickle cell anemia SicklSicklee cell anemia results
from a point mutation that causes valine to substitute for glutamic acid in the sixth position of the
b-globin chain of hemoglobin.

Glucose 6-phosphate
          phosphate dehydrogenase deficiency is a common X     X-Iinked
                                                                 Iinked disorder of the hexose
monophosphate
           ate pathway that results in episodes of hemolytic anemia due to oxidative stress.

The key functions of important apolipoproteins are as follows:
ApoA-l:
      l: LCAT activation (cholesterol esterification)
ApoB48: Chylomicron assembly and secretion by the intestine
ApoB-100:
      100: LDL particle uptake by extrahepatic cells
ApoC-Il:
      Il: Lipoprotein hpase activation
ApoE-33 & 4: VLDL and chytomicron remnant uptake by Irver cells

Fabry disease is an inherited deficie
                              deficiency of alpha-galactosidase
                                                  galactosidase A that causes accumulation of the
globoside ceramide tnhexoside ii tissues The earliest manifestations of Fabry disease are
angiokeratomas, hypohidrosis and acroparesthesia Without enzyme replacement, patients
typically develop progressive
                   rogressive renal failure
28



Glucose 6-phosphate dehydrogenase deficiency is a defect in the HMP shunt that impairs
glutathione reduction due to failure to produce NADPH. Glutathione reductase deficiency causes
a similar clinical picture and is pathophysiologically similar to G6PD deficiency

Western blotting is used to identify proteins. Northern blotting identifies specific RNA
sequences and Southern blotting identifies specific DNA sequences in an unknown sample

HbF dominates in newboms It consists of two alpha and two gamma protein subunits (ci2y2),
has a high affinity for oxygen and is produced during the final seven months of gestation
Switching to HbA (a232) occurs during the first six months of life

SngIe nucleotide deIeions shift the reading frame, often creating a premature stop codon or
dramatically changing the protein structure,

Methemoglobinemla causes dusky discoloration to the skin (similar to cyanosis), and because
methemoglobin is unable to carry oxygen. a state of functional anemia is induced The blood
partial pressure of 02, however, will be unchanged in this condition because oxygen’s partial
pressure is a measure of dissolved in the plasma and is not related to hemoglobin funchon

The individual subunits of the hemoglobin molecule are structurally analogous to myoglobin. If
separated, the subunits will demonstrate a hyperbolic oxygen-dissociation curve similar to that of
myoglobin.

In order for a child to have sickle cell disease, both parents must be carriers. The carrier status of
prospective parents can be established by hemoglobin electrophoresis.

Normally, 2, 3-DPG forms ionic bonds with the two beta subunits of HbA in the tissues after
hemoglobin has been deoxygenated Fetal hemoglobrn binds oxygen with a higher affinity due to
its inability to interact with 2, 3- DPG. Ultimately, the fetal hemoglobin must be able to extract
02 from maternal hemoglobrn in the placenta

Transketolase and transaldolase carry out the nonoxidative reactions of HMP shunt Some cells
do not use the oxidative phase reactions to produce cytosohc NADPH, but all cells can
synthesize nbose from fructose-6-phosphate using the nonoxidative reactions

Nitrites are oxidizing agents that are effective in the treatment of cyanide poisoning due to their
ability to cause methemoglobinemia Methemoglobin contains femc rather than ferrous iron
Cyanide binds to ferric iron more avidly than to mitochondnal cytochrome enzymes. which saves
these mitochondnal enzymes from cyanides toxic effect.

The thaassemias result from mutations that cause detective mRNA processing, which leads to
deficiency of certain protein chains required for hemoglobin synthesis Beta-thalassemia minor is
typically an asymptomatic disorder Laboratory tests will show a mild hypochromic microcytic
anemia with increased HbF, Hb% and target cefls
29


CO binds to hemoglobin with an affinity that is 220 times that of oxygen for hemoglobin The
binding of CO and 0. to hemoglobin are reversible. CO. therefore, competes with O for binding
                                                                                      bin
on the heme iron of hemoglobin

The symptoms of difficulty in swallowing (dysphagia) and disfigured fingernails (spoon nails or
koilonychia) are specific for iron deficiency anemia

Homocysteine is converted to methionine using methylcobalamin and methyl tetrahydrofolate.

Folate deficiency inhibits the formation of deoxythymidine monophosphate (dTMP), which
limits DNA synthesis and promotes megaloblastosis and erythroid precursor cell apoptosis
Because thymidine supplementation can moderately in  increase
                                                       crease dTMP levels, it can reduce
erythroid precursor cell apoptosis

Matunng erythrocytes lose their abihty to synthesize herne when they lose their mitochondria.
Mitochondria are necessary for the first and final three steps of herne synthesis.

     vate kinase deficiency causes hemolytic anemia due to failure of glycolysis and resultant
Pyruvate
failure to generate sufficient ATP to maintain erythrocyte structure. In this case, splenic
hypertrophy results from increased work of the splenic parenchyma, which m must
                                                                             ust remove these
deformed erythrocytes from the circulation.

The Kozak sequence plays a role in the initiation of translation A mutation three bases upstream
from the start codon (AUG) in this sequence is associated with thalassemia intermedia

A mutation
       tion in the Kozak sequence of the betabeta-globin
                                                  globin gene is associated with thalassemia
intermedia. which results in hypochromic, microcytic anemia.

HbC is caused by a missense mutation that causes a substitution of glutamate wIth lysine in the
beta globin chain,
              ain, resufting in increased positive charge of the molecule Thus, HbC moves more
slowly than both HbA and HbS on hemoglobin gel electrophoresis

The chronic myeloproliferative disorders (polycythemia vera. essential thrombocytosis, and
primary myelofibrosis)
                   sis) often have a mutation (V617F) in the cytoplasmic tyrosine kinase, Janus
kinase 2 (JAK2) This results in constitutive tyrosine kinase activity, and consequently, cytokine-
                                                                                         cytokine
independent activation of STAT transcription factors.

With the exception of vitamin
                         tamin B.. the body’s stores of most water
                                                                water-soluble
                                                                      soluble vitamins are rapidly
depleted without dietary intake. In contrast, hepatic stores of vitamin B2 may last up to several
years Severe vitamin K deficiency rarely results from poor dietary intake because colon*c colon
bacteria produce functional forms of vitamin
K
30


The P refers to the partial pressure of oxygen where hemoglobin is 50% saturated A decrease in
the P means that hemoglobin has an increased oxygen affinity An increased oxygen-affinity of
hemoglobin causes less oxygen to be released in the tssues. and results in hypoxia then reflex
polycythemia

Vitamin K assistance of glutamate residue carboxytation is essential for some clotting factor
production

Hypoxia-induced lactic acidosis is caused by a low activity of pyruvate dehydrogenase
(oxidative phosphorylation pathway) and a high activity of lactate dehydrogenase.

HbS contains valine in place of glutamic acid in the amino acid position of the beta subunit This
promotes hydrophobic interaction among hemoglobin molecules and results in polymerization of
HbS molecules and red blood cell distortion

A left shift of the hemoglobin oxygen dissociation curve indicates increased hemoglobin 02
affinity and can be caused by increased pH, decreased 2, 3-DPG, and decreased temperature A
left-shift of the

Increased 2,3-BPG concentrations within erythrocytes enable increased oxygen delivery in the
peripheral tissues in the presence of lower blood oxygen concentration because 2,3-BPG
decreases the affinity of hemoglobin for oxygen 2,3-BPG is produced from 1 ,3-BPG by the
enzyme bisphosphoglycerate mutase This reaction consumes the energy that would have been
otherwise used by the erythrocyte to produce energy in the form of ATP

HbF contains y-globin instead of 13-gIObEi Patients with homozygoüc -thaIassemia (-
thaIassemia major) are asymptomatic at birth due to the presence of y-globins and HbF
Switching to HbA production and the cessation of y-globEn synthesis precipitates the symptoms
of 13-thalassemia

While DNA synthesis occurs in the 5’ to 3’ direction on both strands, the leading and lagging
strands are constructedin both the 5’ to 3 and 3’ to 5 directions, respectively The lagging strand
is synthesized discontinuously and is composed of short stretches of RNA primer plus newly
synthesized DNA segments called Okazak fragments Thus, the lagging strand requires the
repetitive action of DNA pnmase and DNA ligase.




BIOCHEMISTRY 3
In contrast to the rough endoplasmc reticulum (ER). the smooth ER contains enzymes for steroid
and
phospholipid biosynthesis. All steroid-prnducing ce’ls (eg, cells m the adrenals. gonads, and
liver) contain a weII-civp1nned smonth PR
31


High-output congestive heart failure and neurological symptoms are strongly suggestive of wet
beriberi (thiamine deficiency)

Elastin’s pIasticty and abdity to recod upon release of tension is attributable to a unique form of
desmosine crosslinking between four different lysine residues on four different elastin chains
This crosslinking is accomplished by the action of extraceliular lysyl hydroxylase

Exposure to radiation including therapeutic and palliative radiation therapy, induces DNA
damage through DNA double-strand fractures and the formation of oxygen free radicals

Resembling prokaryotic DNA and being derived completely from the mother. mitochondrial
DNA (mtDNA) is the most common non.-nuclear DNA found in eukaryotic Cells.

After 12 to 18 hours of fasting, gluconeogenesis is the principal source of blood glucose
Gluconeogenesis uses many of the bidirectional enzymes involved in the process of glycolysis,
but a few unidirectional enzymes need to be bypassed The initial committed step of
gluconeogenesis involves the conversion of pyruvate to oxaloacetate, and oxaloacetate to
phosphoenolpyruvate

Protein kinase Ais primarily responsible for the intracellular effects of the G-protein I adenylate
cyclase second messenger system. Some hormone receptors that use this mechanism include the
TSH, glucagon, PTH, and beta-adrenergic receptors.

If AG° is a negative number. K will be greater than 1, and the concentration of products at
equilibrium wil exceed that of the substrates If AG° is positive, K will be less than 1, and the
formation of substrates will be favored.

Pyruvate dehydrogenase deficiency is a disease with multiple possible presentations ranging
from neonatal death to mild episodic symptoms in aduRbood By preventing the conversion of
pyruvate to acetyl C0A. pyruvate is shunted to lactic acid resulting in lactic acidosis in these
patients Lysine and leucine are exclusively ketogenic and would not increase the blood lactate
level in patients suffering from pyruvate dehydrogenase deflciency

Integral membrane proteins contain transmembrane domains composed of alpha helices with
hydrophobic amino acid residues such as valine, alanine, isoleucme. methionine. and
phenylalan*ne

Cysteine becomes an essential amino acid m patients with homocystinuria, as the defective
enzyme cystathionine synthetase produces the substrate used by cystathionase for the
endogenous production of cysteine

In patients with essential fructosura. metabolism of fructose by hexokinase to fructose-6-
phosphate is the primary method of metabolizing dietary fructose: this pathway Es not
significant in normal individuals.
32


Aldose reductase converts glucose into sorbitol. which is further metabolized into fructose by
sorbitol dehydrogenase This pathway is most active in the seminal vesicles The lens also
contains significant levels of sorbitol dehydrogenase, which become overwhelmed in the setting
of hyperglycemia Other tissues, such as the retina, renal papilla, and Schwann cells, have much
less sorbetol dehydrogenase activity

Okazaki fragments are short stretches of newly synthesized DNA that are separated by RNA
primers They are formed by the discontinuous synthesis of DNA on the lagging strand dunng
replication

Deletions or the addthons of a number of base pairs which are not a multiple of three indicate
that a frameshift mutation has occurred Frameshift mutations alter the reading frame of the
genetic code, resulting in the formation of non-functional proteins

Glucokinase is a glucose sensor within pancreatic beta ceIIs Inactivating mutations of the
enzyme result in mild hyperglycemia that can be exacerbated by pregnancy

Phenylethanolarnine-N-methyltransterase (PNMT), wtich is responsible for the synthesis of
epinephnne, is under the control of cortisol

Lactic acidosis occurs in patients with septic shock because of tissue hypoxia, which results in
impaired oxidative phosphorylation and the shunting of pyruvate to lactate following glycolysis.
Hepatic hypoperfusion also contributes to the buildup of lactic acid, as the liver is the primary
site of lactate clearance.

Elderly patients with dementia or hemiparesis may also have dysphagia, which is a risk factor for
aspiration pneumonia. Dependent lung consolidation is commonly seen in aspiration pneumonia.

Fructose 2,6-bisphosphate activates glycolysis by inducing phosphofructokinase-1 and inhibits
gluconeogenesis by inhibiting fructose 1 ,6-bisphosphatase High concentrations of fructose 2,6-
bisphosphate also decreases the gluconeogenic conversion of alanine to glucose Fructose 2,6-
bisphosphate concentration is regulated by a bifunctional enzyme composed of
phosphofructokinase-2 and fructose 2,6-bisphosphatase.

Dietary fructose is phosphorylated in the liver to F-i-P and is rapidly metabohzed because it
bypasses PFK-1, the rate-limiting enzyme of glycolysis. Other sugars enter glycolysis before this
rate-limiting step and are therefore metabolized more slowty due to regulahon of PFK-1.

Biotin acts as a CO carrier on the surface of the carboxylase enzyme and is necessary for
numerous conversions, including pyruvate to oxaloacetate, Excessive ingestion of avdin (which
is found in egg whites) has been associated with biotin deficiency.

Receptors for cortisol are located within the cytoplasm and are translocated to the nucleus after
binding to cortisol In the nucleus, the cortisol-receptor complex binds to the hormone responsive
elements, causing an alternation in the transcription of target genes
xKnow the second messengers very well
33



The genetic code is “degenerate, meaning that there are more codons (61) than amino
                                                                               am   acids (20)
Each tRNA molecule is specific for a given amino acid Many tRNA anticodons can bind to a
few different codons coding for the same amino acid This is called the wobble phenomenon

ATP is the regulatory substance that stimulates KATP channel closure in insulin-producing
                                                                        insulin
pancreatic beta cells

PCR requires primers that are complementary to the regions of DNA flanking the segment to be
amplified. Thermostable DNA polymerase, deoxynucleotide triphosphates, and the target DNA
template strand aree also necessary.

Glycogenolysis provides immediate energy for strenuous muscle contraction Myophosphorylase
deficiency (McArdle’s syndrome or type 5 glycogen storage disease) leads to a failure of
glycogenolysis with clinical manifestations of decrease
                                               decreased
                                                       d exercise tolerance, myoglobinuna, and
muscle pain with physical activity.

After IJV damage. pyrimidine dimers are formed in cellular DNA. which are recognized by a
specdic endonuclease which irütiates the process of repair by nicking the strand at the thymine
dimer, This action signals the removal and replacement of this damaged DNA.

After a hormone binds a G-protein
                           protein coupled receptor that activates phospholipase C, the initial
step of the lP second messenger system involves degradation of membrane lipids    l       into
diacyiglycerol (DAG) and inositol triphosphate (1P3) by that enzyme. Protein kinase C is
activated by DAG as well as calcium released from sarcoplasmic reticulum under the influence
of lP




Southern blotting is a technique used to identity UNA mutations. It involves resinction
endonuclease digestion of sample DNA, gel electrophoresis, and gene identification with a
radoactivety-Iabeled
             Iabeled DNA probe vv

Amino acids with three titratable protons include histidine, arginine. lysine, aspartic acid,
glutamic acid, cysteine and tyrosine

UV-specific
    specific endonuclease deficiency is the most common cause of the autosomal recessive
disorder xeroderma pigmentosum

Heavily methylated DNA is typically found in heterochromatin, which is condensed and
transcriptionally inactive Tight association with non
                                                  non-acetylated
                                                      acetylated histones and methylation both
contribute to the compact nature of heterochromatin and its transcnptionally inactive state
34


Colony-stimulating factors, prolactin, growth hormones and cytokines utilize tyrosine kinase-
associated rtrtAr rvl th I /cTtT iw,nIenn nthiwu

The nucleolus, the dark intranuclear body visible both by light microscopy and electron
microscopy, is the site of ribosomal RNA synthesis

Insulin is an anabolic hormone that acts via a tyrosine kinase second messenger system to
stimulate the synthesis of glycogen. proteins, fatty acids and nucleic acids. Tyrosine kinase leads
to the activation of protein phosphatase within cells, and protein phosphatase directly modulates
the activity of enzymes in the metabolic pathways regulated by insuhn

The breast milk content of vitamins [) and K is typically insufficient to meet the nutritional needs
of the newbom Vitamin K is given parenterally to infants at birth to prevent hemorrtiagic disease
of the newbom Exclusively breastfed infants may develop vitamin D deficiency they are not
exposed to adequate sunlight Dark-skinned infants are at especially high risk because they must
be exposed to sunlight for longer periods of time to generate adequate vitamin D

Protons dissociate from amino acids when the pH exceeds the pK) associated with each given
proton.

fl the free energy of the products is lower than that of the substrates, the sign of will be negative.
indicating that the reaction favors product formation I the free energy of the products is higher
than that of the substrates, G° will be positive and the reaction favors substrate formation

Thyroid hormones alter gene transcription by binding to receptors situated inside of the nucleus
Receptors for several steroid hormones such as glucocorticoids, mineralocorticoids, androgens,
and estrogens are usually initially present in cytoplasm, although they do migrate to the nucleus
once activated

GTP is synthesized by the citric acid cycle enzyme succinyl-CoA synthetase during the
conversion of succinyl CoA to succinate. In gluconeogenesis. the hydrolysis of GTP is required
for the phosphorylation and decarboxylation of oxaloacetate to phosphoenolpyruvate by
phosphoenolpyruvate carboxykinase

Nitric oxide is synthesized from arginine by nitric oxide synthase As a precursor of nitric oxide,
arginine supplementation may play an adjunct role in the treatment of conditions that improve
with vasodilation. such as stable angina

Aidolase B deficiency causes hereditary fructose intolerance This disease manifests after
introduction of fructose into the diet with vomiting and hypoglycemia about 20-30 minutes after
fructose ingestion. These infants can present with failure to thrive, jaundice, and hepatomegaly.
35


BIOCHEMISTRY 4
Hartnup disease can result in niacin deficiency due to an excess loss of dietary tryptophan,
resulting from
defective intestinal and renal tubular absorpbon of that amino acid Remember that niacin
(nicotinamide I
Vitamin B3) is synthesized from tryptophan and that tryptophan is an essential amino acid

The MAP-kinase signal transduction pathway inch.ides Ras protein, a (3-protein that exists in
inactive (GDP-containing) and active (GTP-containing) forms Mutated (permanently activated)
Ras is associated with the development of malignant tumors

Small nuclear nbonucieoprotein particles (snRNPs) are important components of the
spliceosome, a molecule which functions to remove introns from pre-mRNA during processing
within the nucleus.

Telomerase is an enzyme that possesses reverse transcriptase (RNA-dependent DNA
polymerase) activity and is normally expressed in stem cells as well as cancer cells. However,
cancer cells are immortal because these cells continue to divide without aging and shortening of
their telomeres

Splice site mutations frequently result in the production of larger proteins with altered function
but preserved immune reactivity.

Lynch syndrome is an autosomal dominant disease caused by abnormal nucleotide mismatch
repair. The mismatch repair system involves several genes, including MSH2 and MLH1, which
code for components of the human MutS and MutL homologs. Mutations in these 2 genes
account for around 90% of cases of Lynch syndrome.

The nucleolus is the site of rRNA synthesis from rONA. the site of nbosomal protein synthesis,
and the site of ribosome formation. RNA polymerase I synthesizes rRNA with its greatest
activity being in the nucleolus.

Leptin is a protein hormone produced by adipocytes in proportion to the quantity of fat stored
Leptin acts on the arc uate nucleus of the hypothalamus to inhibit production of neuropeptide Y
(decreasing appetite) and stimulate production of alpha-MSH (increasing satiety) Mutations in
the leptin gene or receptor result in hyperphagia and profound obesity

Trypsinogen is activated to trypsin by duodenal enteropeptidase Trypsin is essential for protein
digestion and absorption in two ways It degrades complex peptides to dipeptides and amino
acids, and it activates other proteases such as carboxypeptidase. elastase and chymotrypsin.

Pyndoxal phosphate is a necessary cofactor in the synthesis of delta-aminolevulinic acid (which
is elevated in cases of lead poisoning)
36


Secondary lactase deficiency can occur after viral gastroenteritis or other diseases that damage
the intestinal epithelium. This disease causes abdominal distention, flatulence, and diarrhea after
lactose ingestion.

Secondary lactase deficiency can occur after viral gastroenteritis or other diseases that damage
the intestinal epithelium. This disease causes abdominal distention, flatulence, and diarrhea after
lactose ingestion.

Amatoxins are fOund ma vanety of poisonous mushrooms (eq. Aman#aphaioides, known as
death cap) and are potent inhibitors of RNA polymerase U (halting mRNA synthesis)

When mRNA is first transcribed from DNA. it is in an unprocessed form called pre-mRNA or
heterogeneous nuclear mRNA (hnRNA). Several processing steps are required before finalized
mRNA molecules can leave the nucleus, including 5’-capping, poly A tail addition, and intron
splicing Cytoplasmic P bodies play an important role in mRNA translation regulation and
mRNA degradation

Bacterial mRNA can be polycistronic. meaning that one mRNA codes for several proteins An
example of polycistronic mRNA is the bacterial lac operon, which codes for the proteins
necessary for lactose metabolism by E co/i, the transcription and translation of these bacterial
proteins is regulated by a single promoter, operator, and set of regulatory elements.

The sequence of amino acids in a growing polypeptide chain is dictated by the interaction of the
mRNA codon with the tRNA anticodon. tRNA that is mischarged with the incorrect amino acid
(and not corrected by M-tRNA synthetase proofreading) will incorporate the wrong amino acid
into the growing polypeptide chain, as there is no amino acid proofreading during protein
translation.

Hyperammonerniain hepatic encephalopathy results in depletion of a-ketoglutarate. causing
inhibition of the Krebs cycle. Excess ammonia also depletes glutamate. an excitatory
neurotransmitter, and causes accumulation of glutamine. resulting in astrocyte swelling and
dysfunction.

Unlike hereditary fructose intolerance and classic galactosernia. essential fructosuria is a benign
disorder resulting from a defect or deficiency in the enzyme fructokinase

As a consequence of aging. fine skin wrinkles appear secondary to the decreased synthesis and
net loss of dermal collagen and elastin

Base excision repair is used to correct defects in single bases induced spontaneous’y or by
exogenous chemicals In this process. glycosylases remove the defective base, and the
corresponding sugar-phosphate is cleaved and removed by endonuclease. followed by the action
of lyase DNA polymerase then replaces the missing nucleotides and ligase reconnects the DNA
strand.
37


Enzyme deficiencies of the early steps in porphyrin synthesis cause neuropsychiatric
manifestations without photosensitivity, while late step derangements lead to photosensitivity
Photosensitivity in porphyria causes vesicle and blister formation on sun-exposed areas as well
as edema pruritus, pain and erythema

Glucose induced decreased adenylate cyclase activfly leads to low intracellular concentrations of
cAMR Low cAMP levels, in turn, cause poor binding of catabolite activator protein (CAP) to the
CAP-DNA binding domain, leading to decreased expression of the structural genes of the lac
operon

The symptoms of scurvy are primarily caused by impaired collagen formation, and include
hemorrhages, subperiosteal hematomas. bleeding into Joint spaces, gingival swelling, secondary
periodontal infection, anemia, hyperkeratotic papular rashes, impaired wound healing, and
weakened immune response to local infections.

Niacin (vitamin B3) can be synthesized endogenously from tryptophan. A deficiency of this
vitamin resufts in pellagra, which is characterized by dermatitis, diarrhea, and dementia

The lac operon is regulated by two distinct mechanisms: negatively by binding of the repressor
protein to the operator locus and positively by cAMP-CAP binding upstream from the promoter
region Constitutive expression of the structural genes of the lac operon occurs with mutations
that impair the binding of the repressor protein (Lac I) to its regulatory sequence in the operator
region

tRNA is a small. noncoding form of RNA that contains unusual nucleosides such as
pseudouridine and thymidine. Remember that tRNA has a CCA sequence at its 3’-end that is
used as a recognition sequence by proteins, and that the 3’ terminal hydroxyl group of the CCA
tail is used as the binding site for the amino acid.

Vitamin A can beof benefit in the treatment of measles infection
38


BIOSTATISTICS 1

The chi-square
          square test for independence is used to test the association between 2 categorical
variables In the case of an exposure status and a binomial outcome, patients are dMded into 2
groups based on exposure, and the number of patients that experience each outcome Es recorded
in a 2 x 2 table

Smoking cessation is by far the most effective preventive intervention in almost every patient
(very high yield!)

sensitivity is me number ot true positives aiviaea oy me totai numoer or suojects actuaiiy wan tne
aisease.
True positives = (Sensitivity) (Number of patients actually with the disease)
False negatives = (1 - Sensitivity) (Number of patients actually wit
                                                                 withh the disease)




Confounding bias occurs when the exposure
                                       exposure-disease
                                                disease relationship is muddied by the effect of an
extraneous factor that has correlations with both the exposure and the disease Confounding bias
can result in the false association of an exposure with a disease

Positive predictive value represents the probability of truly having a disease for a given positive
test result. It increases with increasing disease prevalence and decreases with decreasing disease
prevalence

The median is the value that is located in the precise center of an ordered dataset. It divides the
right half of the data from the left half.

In a normal (bell-shaped)
                  shaped) distributon
68% - within I standard deviation from the mean
95% - within 2 standard deviations from the mean
99.7% - within
             in 3 standard deviations from the mean

Matching is used in case-control
                           control studies in order to control confounding Remember matching
variables should always be the potential confounders of the study (eg, age. race) Cases and
controls are then selected basedd on the matchina variables, such that both arouos have a similar
distribution in accordance

The two-sample
         sample t test is a statistical method commonly employed to compare the means of 2
groups of Subjects.

The number needed to treat (NNT) is calculated by dMding 1 by absolute risk reduction (ARR)
The ARR is the event rate in the placebo group (25/1000=2.5%) minus the event rate in the
treatment group (10/1000=1 %), or 1.5%. Dividing I by 0.015 gives us a NNT of 66.6 but, since
treating 66.6 of a person iss seldom a good idea, we round up to 67.
39



NPV is the probability of being free of a disease f the test result is negative Remember that the
NPV will vary with the pretest probability of a disease A patient with a high probability of
having a disease will have a low NPV with a negative test but a patient with a low probability of
having a disease will have a high NPV with a negative test.

The specificity ofatest is given by d/(b+d). ft should be high in confirmatory tests in order to
decrease false positives.

In a cross-sectional study. exposure and outcome are measured simultaneously at a particular
point of time (“snapshot study”). In other study designs, a certain time period separates the
exposure from the outcome

A reliable test is reproducible in that it gives similar results on repeat measurements Reliability is
maximal when random error is minimal.

The power of a study increases proportionally with the sample size. Thus, the larger a sample the
greater the ability to detect a difference when one truly exists

In a normal (bell-shaped) distribution curve. 68% of observations lie within one standard
deviation of the mean. 95% of observations lie within two standard deviations of the mean, and
997% of observations lie within three standard deviations of the mean

In a crossover study, subjects are randomly allocated to a sequence of 2 or more treatments given
consecutively. A washout (no treatment) period is often added between treatment intervals to
limit the confounding effects of prior treatment.

Selection of control subjects in case-control studies is intended to provide an accurate estimation
of exposure frequency among the non-diseased general population. Cases and controls are often
matched in order to decrease confounding. However, matching must be carefully performed so
as to not introduce selection bias.

The positive and negative predictive values of a test depend on the disease prevalence in the
population The sensitivity and specificity of a test do not depend on the prevalence of the disease
in the popuIation

The reliability of a measurement technique refers to its reproducibility The accuracy of a
measurement technique is the degree to which the average measurement value matches that of
the gold standard technique

In a positively skewed distribution. the mean is the most shifted in the positive direction,
followed by the median and then the mode.

Effect modification is present when the effect of the main exposure on the outcome is modified
by the presence of another variable Effect modification is not a bias
40


The Hawthorne effect is the tendency of a study population to affect an outcome due to the
knowledge of being studied.

The main purpose of blinding is to prevent patient or researcher expectancy from interfering with
an outcome

Sensitivity equals aJ(a+c). Screening tests are designed to have high sensitivities

Understand the measures of center (mean/averages. median and mode) They are common topics
on the USMLE exams

Power(1-3) is the probabihty of rejecting a null hypothesis when it is truly false It is typically set
at 80% and depends upon sample size and difference between outcomes.

Specificity is the number of true negatives divided by the total number of subjects actually
without the disease
True negatives = (Specificity) * (Number of patients actually without the disease)
False positives = (1 - Specificity) (Number of patients actually without the disease)

Lowering the cut-off point will increase the sensitivity of a test The true positives will also
increase but the false positives will have a relatively larger increase This results in a decrease in
the PPV and the FN.

Power of a study indicates the probability of seeing a difference when there is one; Power = 1 —

An increasing prevalence and stable incidence can be attributed to factors which prolong the
duration of a disease (e.g, improved quality of care this scenario is typical for the USMLE)

Incidence is the measure of new cases diagnosed in a given period of time. Prevalence is the
measure of the total cases at a particular point in time Any treatment that prolongs survwal but
does not cure the disease will increase prevalence due to an increase in the number of afflicted
(but still alive) individuals over time


BIOSTATISTICS-2
Prospective cohort studies are organized by selecting a group of individuals (ie., cohort),
determining their exposure status, and then following them over time for development of the
disease of interest

Loss to follow-up in prospective studies creates a potential for selection bias

Recall bias results from inaccurate recall of past exposure by people in the study and applies
mostly to retrospective studies such as case—control studies People who have suffered an
adverse event are more likely to recall risk factors than those without adverse experiences Like
all sources of bias, recall bias is a threat to the validity of a study.
41



 A t-test is used to compare the difference between the means of 2 groups Analysis of variance
(ANOVA) compares the difference between the means of 2 or more groups

Observer bias occurs when the investigator’s decision is affected by prior knowledge of the
exposure status.

Risk is the probability of getting a disease over a certain period of time. To calculate the risk,
divide the number of diseased subjects by the total number of subjects in the corresponding
group (ie., all the people at risk).

The correlation coefficient ranges from -Ito +1 and describes two important characteristics of an
association:
the strength and the polarity.

There are essentially 4 basic methods that health insurance plans use to reimburse physicians:
capitation, fee-for-service (FFS), discounted FFS, and salary Physicians paid under FFS face
little financial risk and have incentives to increase services, tests, and patient visits Physicians
paid under capitation face the greatest financial risk and have incentives to provide more
preventive care and better health counseling.

Confidence interval for the mean is calculated using the mean. SD, z-score and sample size.

Know ho; to witerpret the confidence intervaL Know the relationship between the confidence
interval and ‘p’ value.

The incidence of a disease is the number of new cases of a disease per year divided by the total
population at risk

It is important to have high sensitivity in screening tests

Positive predictive and negative predictive values are influence by disease prevalence whereas
specificity and sensitivity are not

RRR = [Absolute Risk., - Absolute Risk] / Absolute Risk1

Negative predictive value (NPV) represents the probability of not having a disease given a
negative test result Unlike sensitivity and specificity, NPV varies based upon disease prevalence
and is inversely proportional to the prevalence of a disease.

ARP represents the excess nsk in the exposed population that can be attributed to the risk factor
It can be easily derived from the relative risk using the following formula: ARP = (RR - 1 )/RR

An increase in lung cancer incidence and mortality has been observed in women over the last
four decades
42


The concept of a latent period can be applied to both disease pathogenesis and exposure to risk
modifiers. The initial steps in pathogenesis and/or exposure to a risk factor sometimes occur
years before clinical manifestations of a disease are evident. Mditionally, exposure to risk
modifiers may need to be continuous over a certain period of time before influencing the
outcome.

The degree of overlap between the healthy and diseased population curves limits the maximum
combined sensitivity and specificity of a test (the area under its ROC curve) The degree to which
sensitivity or specificity is affected depends upon the chosen cutoff value

An outlier is defined as an extreme and unusual observed in a dataset The mean, standard
deviation, variance, and range are sensitive to outliers The mode is more resistant to outhers

Number needed to harm = 1! Attributable risk

Positive predictive value is defined as the proportion of subjects with a positive test that actually
have the disease.

The typical example of lead-time bias is an apparent increase in survival in patients diagnosed
with a new test who actually have an unchanged prognosis. Think of lead4ime bias when you see
“a new screening test” for poor prognosis diseases like lung or pancreatic

A case-control study is used to compare the exposure of people with the disease (cases) to the
exposure of people without the disease (controls) The main measure of association is the
exposure odds ratio.

ARR = Event Rate(CQI) - Event Ratetreatment

According to 2011 statistics, the most common cancers (aside from skin cancer) in women in
order of incidence were breast, lung, and colon cancer. In terms of mortality, lung cancer
claimed the most lives, followed by breast and then colon cancer.

Case-fatality rate is calculated by dividing the number of fatal cases by the total number of
people with the disease.

Questions about relative risk are commonly asked Make sure you can construct 2*2 table
(Exposure in rows and Outcome in columns) and calculate relative risk

 If events are independent, the probability that all events will turn out the same is the product of
the separate probabilities for each event The probability of at least 1 event turning out differently
is given as 1 - (probability of all events being the same)
43


GENETICS 1
Lymphedema is a characteristic finding in a fetus afflicted with Turner syndrome (45XO) The
lymphedema can vary in severity, ranging from edema of the hands and feet to hydrops fetalis
Other common fetal Turner syndrome abnormalities include coarctation of aorta and horseshoe
kidney

Pleiotropy descnbes instances where multiple phenotypic manifestations result from a single
genetic mutation. Most syndromic genetic illnesses exhibit pleiotropy

FoIhcur Iymphoma is a non-HodgIn lymphoma of follicular B-lymphocytes Patients with
follicular lymphoma characteristically have a translocation between chromosomes 14 and 18
which causes Bc/-2 overexpression. Bc/.2 is considered a protooncogene because it has anti-
apoptotic effects.

Androgenetic alopecia is the most common cause of hair loss in both males and females, and
demonstrates polygenic inheritance with variable penetrance The pattern and severity of the
baldness varies between males and females, and circulating androgen levels along with the
degree of genetic predisposition are thought to play a prominent role in determining clinical
manifestations.

Neonates with Edwards syndrome (47,)O( +18) have small jaws (micrognathia), small eyes
(microphthalmia), and malformed and low-set ears. Note that rocker-bottom feet are seen, as
with Patau syndrome (trisomy 13). The presence of clenched hands with oveilapping fingers is
considered one of the distinguishing features of this syndrome.

Primary amenorrhea in a patient with fully developed secondary sexual characteristics suggests
the presence of an anatomic defect in the genital tract, such as imperforate hymen or MUllerian
duct abnormalities

Aspirin irreversibly inhibits COX-1 and COX-Z COX-2 is an inducible enzyme that is normally
undetectable in most tissues except in the case of inflammatiOn.

Renal angiomyolipoma is a benign tumor composed of blood vessels, smooth muscle, and fat
Bilateral renal angiomyolipomas are associated with tuberous sclerosis, an autosomal dominant
condItIon.

After participating in this learning exercise, you should be able to calculate the probability that a
child of parents from two populations with different mutant allele carner frequencies will inherit
an autosomal recessive disease.

A complete mole results from fertilization of an ovum that is devoid of genetic material and
subsequent reduplication of the paternal genetic complement giving a characteristic 46 XX
genotype
44


Achondroplasia is an autosomal-dominant disorder The transmission of autosomal dominant
disorders statistically occurs in 50% of the offspring of an affected parent

Turners syndrome (45 XO) manifests in the neonate with lyrnphedema and cystic hygromas
Short stature, primary amenorrhea and coarctation of the aorta are the other important chnical
features of Turner’s syndrome in adults.

Diminished fernoral pulses compared to brachial pulses, symptoms of inadequate perfusion of
the lower extremities during ambulation, and enlarged intercostal arteries in a child/young adult
are typical of adult-type congenital coarctation of the aorta Turner’s syndrome is associated with
coarctation of the aorta in girls.
A variety of other autosomal and sex chromosomal inherited disorders are associated with
cardiovascular developmental defects and/or pathology The major associations are as follows
• Down syndrome: endocardial cushion detects (ostium pnmum ASD, regurgitant atrioventricular
valves)
• DiGeorge syndrome: tetralogy of Fallot and interrupted aortic arch
• Friedreich’s ataxia: hypertrophic cardiomyopathy
• Marfan syndrome: cystic medial necrosis of the aorta
• Tuberous sclerosis: valvular obstruction due to cardiac rhabdomyomas

GenOmiC impnnng refers to the phenomenon in which an offspring’s genes are expressed in a
parent-specific manner Genomic imprinting is produced by DNA methylation, which is an
epigenetic process

Genome recombination between two defective viruses co—infecting the same host cell can yield
a cytopathic wild-type genome. Recombination is gene exchange that occurs through the
crossing over of two double-stranded DNA molecules. Reassortment describes the mixing of
genome segments in two or more segmented viruses that infect the same host cell.

The presence of rod-shaped intracytoplasmic inclusions known as Auer rods is characteristic of
many forms of acute myeloblastic leukemia (AML) The M3 variant of AML. acute
promyelocytic leukemia, is associated with the cytogenetic abnormality t( 15; 17).

The probability that an autosomal recessive disease will be transmitted to a child can be
calculated based on the maternal and paternal pedigrees. An unaffected individual (with
unaffected parents) who has a sibling affected by an autosomal recessive condition has a 2/3
chance of being a carrier for that condition.

Common findings in Down syndrome include mental retardation. facial dysmorphism and
cardiac defects 95% of cases are caused by the presence of an extra chromosome 21 (trisomy).
Less commonly, unbalanced Robertsonian translocations or mosaicism may be responsible

Xeroderma pigmentosum develops due to a defect in DNA excisional repair This disease is
characterized by increased sensitivity to UV radiation and a high incidence of all forms of
cutaneous malignancy
45


Nondisjunction is the failure of chromosome pairs to separate properly during cell division This
could be due to a failure of homologous chromosomes to separate in melosis I or a failure of
sister chromatids to separate during meiosis II or mitosis.

In most cases of CF, the mutation in the CFTR gene product causes defective post-translational
folding and glycosylation The resuft is degradation of the CFTR integral membrane protein
before it reaches the cell surface.

A variety of genetic disorders can result in facial and/or palatal malformations, including
deletions of the long arm of chromosome 22. However, deletions invoMng the long arm of
chromosome 22 are also associated with DiGeorge syndrome (congenital thymic and parathyroid
aplasia, congenital cardiovascular anomalies).

Patients with both sporadic and hereditary (associated with Von Hippel-Lindau disease) renal
cell carcinomas are found to have deletions of the VHL gene on chromosome 3p.

47 X)(Y is the most common karyotype producing Kilnefelter Syndrome. Patients present with
tall stature, small firm testes, azoospermia and gynecomastia Mild mental retardation may be
present.

Phenotypic mixing refers to co-infection of a host cell by two viral strains. resulting in progeny
vinons that contain nucleocapsid proteins from one strain and the genome of the other strain.
Since there is no change in the underlying viral genomes (no genetic exchange), the next
generation of virions revert to their original, unmixed phenotypes.

Down syndrome (tnsomy 21) occurs in approximately 1 in 730 bye births The majority of fetuses
with this chromosomal defect die in utero. The thple marker test, quadruple marker test, and
integrated test allow for Down syndrome sCreening. Amniocentesis and chromosomal analysis
of fetal cells can be used to verify the diagnosis.

The cytogenetic defect t(1517) is associated with acute promyelocytic leukemia (AML type
M3). Translocation of the gene for the retinoic acid receptor alpha from chromosome 17 to
chromosome 15 leads to formation of the fusion gene PMLIRARa. This abnormal fusion gene
product inhibits differentiation of myeloblasts and triggers the development of acute
promyelocytic leukemia

Patients with Turner syndrome may have karyotype 45,XO (complete monosomy), 45X0146XX
(mosaicism), or 46XX (with partial deletion of one X chromosome) Monosomy appears to
account for the majority of cases of Turner syndrome

Mental retardation, eczema, and a “mousy or musty body odor in a toddler are signs of
phenylketonuria (PKU). Most infants with PKU are born to two heterozygous carrier parents The
probability that heterozygous carrier parents will transmit an autosomal recessive disease like
PKU to a child is 1/4.
46


Primary amenorrhea, high arched palate. and widely spaced nipples are characteristic
manifestations of Turner syndrome. An additional characteristic finding is ovarian dysgenesis,
with the pathologic finding of streak gonads.

Elevated alpha-fetoprotein levels are seen in multiple gestation, neural tube defects (including
spina bifida. anencephaly), and abdominal wall defects.
2 In contrast, Down syndrome is associated with low alpha-f etoprotein levels in maternal serum
and amniotic fluid The definitive prenatal diagnosis is made by karyotyping of fetal cells

Trisorny 21 (Down syndrome) is characterized by mental retardation, facial dysmorphism, single
palmar crease, endocardial cushion detects. and duodenal atresia Affected individuals have an
increased risk of AML-M7 and ALL in childhood and early Alzheimer disease in adufthood.

On average, autosomal recessive conditions affect 25% of offspring of asymptomatic
heterozygous carrier parents Classical galactosemia is an autosomal recessive disease

In X-linked recessive inheritance 1) affected males will always produce unaffectedsons and
camerdaughters, and 2) carrier females have a 50% chance of producing affectedsons and
camèrdaughters G6PD deficiency follows this inheritance pattern and causes acute hemolytic
anemia in response to oxidant drugs.

Alternative splicing is a process where the exons of a gene are reconnected in multiple ways
during post- transcriptional processing This creates different mRNA sequences and
subsequently, different protein isoforms It is a normal phenomenon in eukaryotes that greatly
increases the biodiversity of proteins encoded by the genome

The presence of lactic acidosis and ragged red skeletal muscle fibers histologically suggest a
mitochondrial myopathy. There may be vanable clinical expression of mitochondrial DNA
defects in different affected family members due to heteroplasmy, which is the coexistence of
both mutated and wild type versions of mitochondrial genomes in an individual celL

In Kallmann syndrome. there is an absence of GnRH secretory neurons in the hypothalamus due
to defective migration from the olfactory placode. These patients have central hypogonadism and
anosmia, and often present with delayed puberty

Trisornyi3(Patau syndrome) most often occurs secondary to nondisjunction during maternal
meiosis I A severe condition, tnsomy 13 is strongly associated with cleft lip and palate.
polydactyly, rocker-bottom feet and holoprosencephaly.

TWO allele IOCi are said to be in linkage disequilibrium when a pair of alleles are inherited
together in the same gamete (haplotype) more or less often than would be expected given
random chance It is important to understand that this can occur even if the genes are on different
chromosomes.
47


Thsorny21isdetectab by cytogenetic karyotype analysis and is the most common genetic cause of
congenital mental retardation. Patients with Down syndrome are at increased risk of developing
acute lymphoblastic leukemia and acute myelogenous leukemia

Klinefelter syndrome is characterized by hypogonadism. eunuchoid habitus. small firm testes,
and genotype
47 XXY.

“Streak ovanes.” amenorrhea and infertility are the gonadal manifestations of Turner’s syndrome
This condition is associated with short stature, webbed neck, low posterior hairline and
coarctation of the aOrta.

Sweat chloride concentrations >60 mEqII. are found in patients with cystic fibrosis (CF). The
most common CF transmembrane conductance regulator (CFTR) mutation is a 3-base pair
deletion that removes a phenylalanine at amino acid position 508 This mutation impairs
posttranslational processing of the CFTR gene transcript and results in degradation of the gene
product before it can be transported to the cell surface, causing a complete absence of the CFTR
protein from the apical membrane of exocrine duct epithelial cells

Down syndrome is associated with characteristic physical exam findings such as a flattened
facies, epicanthal folds, oblique palpebral fissures, single palmar crease, shortened fifth digit,
large tongue and others. Congenital heart defects. especially endocardial cushion defects, are
common in children with Down’s syndrome The majority of cases occur due to maternal meiotic
nondisjunction



GENETICS 2

Friedreich ataxia is an autosomal recessive condition. The mutated gene on chromosome 9 has
an increased number of trinucleotide repeats Friedreich ataxia is often associated with
hypertrophic cardiomyopathy. diabetes mellitus. kyphoscoliosis. and foot deformities

Tay-Sachs disease is an autosomal recessive disorder caused by a deficiency in -hexosaminidase
A, which results in accumulation of GM2 ganglioside. It is characterized by progressive
neurodegeneration and a cherry- red macular spot. In contrast to Niemann-Pick disease, there is
no hepatosplenomegaly.

A 13- amyloid plays an important role in the development of Alzheimer disease Its precursor
protein (APP) is coded by a gene located on chromosome 21 Patients with tnsomy 21 (Down
syndrome) are likely to develop Azheimer disease after age 40.

Mitochondnal diseases are characterized by exclusively—maternal inheritance The variable
severity of these diseases is explained by the random distribution of normal and mutated
mitochondria between daughter cells during mitosis; as a result, some cells may have completely
48


healthy mitochondria, while other cells contain mitochondria affected by genetic mutation
(heteroplasmy) MELAS is a mitochondnal syndrome

Fragile X syndrome arises secondary to an increase in the number of trinucleotide repeats within
the FMR1 gene on the X chromosome Typical clinical features of this condition include mental
retardation, facial deformities, and macroorchidism.

Aft;ration of gene expression in Huntington disease is believed to occur due to hypermethylation
of histones Hypermethylated histones bind DNA and prevent transcription of certain genes. This
reads to the disruption of synthesis of some neurotrophic proteins.

Fragile X syndrome is a common cause of inherited mental retardation. The disorder is X-linked
and affects males. Patients have mental retardation, dysmorphic facial features (large jaw, large
protruding ears) and macroorchidism.

Early-onset familial Alzheimer disease is associated with three gene mutations: APP
(chromosome 21), presenilin 1 and presenilin 2. Late-onset familial Alzheimer disease is
associated with apolipoprotein E4 genotype.

An increased number of thnucleotide repeats on the HD gene is associated wTth Huntington
disease The larger the number of the repeats. the earlier the onset of the disease Tnnucleotide
expansion occurs during paternal transmission, causing a genetic phenomenon called anticipation

“Red ragged” muscle fibers are seen in mitochondrial diseases. Muscle fibers have this
appearance because abnormal mitochondna accumulate under the sarcolemma Mitochondrial
diseases show maternal inheritance.

The fragile X mental retardation 1 gene is located on the long arm of the X chromosorne An
increased number of CGG tnnucleotide repeats leads to hypermethylation of cytosine bases and
subsequent gene inactivation This defect is the cause of fragile X syndrome, which manifests as
mental retardation, facial dysmorphism, and macroorchidism.

Neurofibromatosis type 1 is a single-gene autosomal-dominant disorder. It occurs due to
mutation of the NFl gene located on chromosome 17. Café-au-Iait spots, multiple neurofibromas,
and Lisch nodules are the most common symptoms.
49


HISTOLOGY
RER functions include protein modification, folding and transfer The RER is well-developed in
protein-secreting cells. The SER lacks surface ribosomes, and functions in lipid synthesis,
carbohydrate metabolism, and detoxification of harmful substances

The respiratory tract lining changes in structure and function as it progresses distally. Bronchi
have a pseudostratified columnar ciliated epithelium with goblet cells and submucosal
mucoserous glands and cartilage Bronchioles, terminal bronchioles, and respiratory bronchioles
generally lack goblet cells, glands, and cartilage. By the level of the terminal bronchioles, the
airway epithelium is ciliated simple cuboida[ Epithelial cilia persist up to the end of the
respiratory bronchioles

The lamellar bodies of type II pneumocytes store and release pulmonary surlactant into the fluid
layer lining the inner surfaces of alveoli. Since the major function of suifactant is to reduce
surface tension in this fluid layer, a surfactant deficiency can cause patchy alveolar atelectasis, as
is seen in neonatal respiratory distress syndrome.

HPV infection causes cutaneous and genital warts as well as benign and malignant epithelial
neoplasia Koilocytosis is a hallmark of HPV infection. Koilocytes are pyknotic superficial or
immature squamous cells with a dense, irregularly staining cytoplasm and perinuclear clearing

[i-i stimulates the theca intema cells of the ovarian follicle to produce androgens Aromatase
within the follicle’s granulosa cells subsequently converts these androgens to estradiol under
FSH stimulation The theca extema cells serve as a connective tissue support structure for the
follicle.

All sympathetic preganglionic neurons release acetyicholine. which activates nicotinic
acetylcholine receptors on postganglionic neurons. Medullary chromaffin cells are modified
postganglionic sympathetic neurons that release catecholamines into the bloodstream The
neurons that innervate sweat glands are also different from most postganglionic sympathetic
neurons in that they release acetylcholine.

Neutral proteases such as elastase in intra-alveolar fluid are derived from infiltrating neutrophils
and alveolar macrophages When secreted in excess or if unchecked by serum antiprotease
activity, they can cause destruction of terminal lung parenchyma, yielding centriacinar or
panacinar emphysema.

Kinesin and dynein are microtubuIe-assocated motor proteins that function in the rapid transport
of materials and organelles within cells. Dynein also functions in ciliary and flagellar movement

Type II pneumocytes have two important functions 1) regeneration of the alveolar lining
following injury, and 2) surfactant production.

The pnmary abnormality in Pagets disease is the increase in osteoclastic bone resorption.
50


Unique to the duodenum. the compound tubular Brunner’s glands of the submucosa secrete
alkaline mucus into ducts that empty into the crypts of Lieberkühn. Peyer’s patches, in contrast,
are lymphoid aggregates specific to the ileum.

In the respiratory tract, the nose. paranasal sinuses. nasopharynx. most of the larynx, and the
tracheobronchial tree are lined with pseudostratifled. columnar, mucus-secreting epithelium
Stratified squamous epithelium is found only in the oropharynx. laryngopharynx, anterior
epiglottis, upper half of the posterior epiglottis, and vocal folds (true vocal cords).

C peptide is formed from proinsulin in the pancreatic 13-cell Golgi apparatus. packaged along
with insulin in islet cell secretory granules, and secreted in equimolar concentrations with insulin

The ovary is covered by a simple cuboidal germinar epthelium This epithelium is the site of
origin for many benign and malignant ovarian neoplasms

Osteocytes have long intracanahcular processes that extend through the ossified bone matrix.
These cytoplasmic processes send signals to and exchange nutrients and waste products with the
osteocytes within neighboring lamellae via gap junctions Osteocytes can sense mechanical
stresses and send signals to modulate the activity of surface osteoblasts, thereby helping to
regulate bony remodeling

Kinesin is a microtubule-associated. ATP-powered motor protein that facilitates the anterograde
transport of neurotransmitter-containing secretory vesicles down axons to synaptic terminals.

Actin filaments are anchored into the Z-Iine of the sarcomere The Z-hne lies in the center of the
lucent region referred to as the I-band. Mnemonic: An Interesting Zoo Must Have Mammals
(Actin in the I-band attaches at the Z-line, Myosin in the H-band attaches at the M-hne)

Type I collagen is the most prevalent collagen in the human body and is the primary collagen in
mature scars
51


IMMUNOLOGY 1
Educational Objective:

C tetan/produces the protein exotoxin tetanospasmin that blocks release of inhibitory
neurotransmitters from inhibitory motor interneurons in the CNS Tetanus is prevented by
immunization with toxoid that triggers the production of antitoxin antibodies (active immunIty).

Hyperacute rejection is a process that is mediated by preformed recipient antibodies against
antigens on the host organ (Type II hypersensitivity). Examples of such mismatches include
ABO blood group antibodies and anti-H LA antibodies. This form of rejection occurs
immediately upon perfusion of the transplanted organ by recipient blood and is often diagnosed
intraoperatively due to immediate mottling of the organ.

lnterleukin-2 (IL-2) is produced by helper T cells and stimulates the growth of CD4+ and CD8+
T cells and B cells. IL-2 also activates natural killer cells and monocytes. The increased activity
of T cells and natural killer cells is thought to be responsible for lL-2s anti-cancer effect on
metastatic melanoma and renal cell carcinoma.

Secretory form of IgA consists of two immunoglobuhn monomers, J chain and secretory
component. This immunoglobulin is abundant in tears. saliva, mucus and colostrum It is
particularly important as a component of the colostrum, or the first breast milk fed to an infant
after birth, where is functions to provide the infant with passive mucosal immunity.

Of the cytokines released in the setting of tissue injury, TGF- and IL-lO are thought to down-
regulate local cytokine production and inflammatory reactions contributing to the systemic acute
phase response IL-i, IL-4, IL-5, and IL-12 stimulate local immune reactions, and may therefore
be considered proinflammatory IL-i also acts systemically to promote fever and other aspects of
the acute phase response

Interleukin-8 is a chemokine produced by macrophages that induces chemotaxis and
phagocytosis in neutrophils. Other significant chemotactic agents include n-formylated peptides,
leukotriene B, 5-HETE (the leukotriene precursor), and complement component C5a

The carboxy terminal of the Fc portion of the heavy immunoglobulin chains represents the site
that binds to the Fc receptors on neutrophils and macrophages Antibody bound to antigen is able
to signal for the phagocytosis of that antigen by a conformational change of the Fc region
allowing binding to the Fc receptor on phagocytes This leads to subsequent phagocytosts of the
organism I antibody complex and subsequent destruction of the organism

Antibodies against double-stranded DNA (anti-dsDNA) are specific for systemic lupus
erythematosus.
However, they are only present in 60% of cases, so absence of anti-dsDNA does not rule out the
diagnosis
Anti-Smith antibodies are also specific for SLE
52


Mutation of the FAS protein is thought to prevent apoptosis of auto-reactive lymphocytes,
thereby disposing the individual to develop autoimmune disorders such as systemic lupus
erythematosus

Cerebellarataxia.tetangiectasias, and increased risk of sinoputmonary infections constitute a
characteristic triad of ataxia telangiectasia. This illness exhibits autosomal recessive inheritance,
and the defect is in a gene that codes for the “ATM” gene which plays a role in DNA break
repair. The immune deficiency primarily manifests as an gA deficiency and predisposes to
infections of the upper and lower airways.

The classic mad of reactive arthritis is as follows: non-gonococcal urethritis, conjunctivrtis
(possibly with anterior uveitis). and arthritis It is the most common cause of asymmetric
inflammatory arthritis of the lower extremities in young men Reactive arthritis is a HLA-B27
associated arthropathy that occurs within several weeks of a GU (especially non-gonococcal
urethritis) or 61 (especially bacterial enteritis) infection It belongs to the group of seronegative
spondyloarthropathies (including ankylosing spondyhtis) and can cause sacroiliitis in about 20%
of cases.

Inherited defects invoMng the interferon-gamma signaling pathway result in disseminated
mycobacterial disease in infancy or early childhood. Patients require lifelong treatment with
antimycobacterial agents

Polymyositis presents with symmetnc proximal muscle weakness. Muscle biopsy reveals
inflammation. necrosis and regeneration of muscle fibers Preceding damage to myocytes with
subsequent over- expression of MHC class I proteins on the sarcolemma leads to infiltration with
CD8 T lymphocytes and myocyte damage

Deficiency of the complement factors that form the membrane attack complex (ie., C5b-C9)
results in recurrent infections by Ne,sser,à species.

MHC Class II is expressed on the surface of antigen presenting cells (APC) and functions by
presenting antigen that is foreign to the body. This antigen is taken into the APC by phagocytosis
or endocytosis and is loaded onto MHC Class II within acidified endosomes. and the MHC Class
Il protein-antigen complex is then expressed on the cell surface for subsequent interaction with
T-lymphocytes Failure to acidify lysosomes would lead to deficient expression of MHC Class II
bound to foreign antigen and subsequent lack of interaction between APCs and T-cells.

Loc&defseagaist Cand,dais performed by T-cells, whereas systemic infection is prevented by
neutrophils. For this reason, localized candidiasis is common in HIV-positive patients, while
neutropenic individuals are more likely to have systemic disease.

The caseating granulornas of tuberculosis almost always contain large epithehoid macrophages
with pale pink granular cytoplasm and surface CD14 at the penphery. CD14 is a surface marker
of the
monocyte-macrophage cell lineage. CD4 and CD8 are surface markers of T-helper and T-killer
cells, respectively.
53



Cytochrome c is a mitochondnal enzyme that activates caspases and indirectly brings about cell
death through intrinsic pathway apoptosis.

Myasthenia gravis is caused by circulating antibodies against the acetylcholine receptors of the
neuromuscular junction. Autoantibody binding causes complement-mediated destruction of these
receptors, producing weakness that most commonly affects the extraocular muscIes Myasthenia
gravis is associated with thymoma or thymic hyperplasia.

Patients with post-Streptococcal glomerulonephrihs will present with edema and hematuna with
a history of Streptococcal infection such as impetigo. cellulitis or pharyngitis The Streptococcal
infection must be caused by a “nephritogenic” strain of Group A b-hemolytic Streptococcus This
is one example of a type Ill, or immune complex mediated. hypersensitivity syndrome.

Leukocyte adhesion deficiency results from the autosomal recessive genetic absence of CD18
This leads to the inability to synthesize integrins. lritegrins are necessary for leukocytes to exit
the bloodstream, and sequelae of this illness include recurrent skin infections WITHOUT pus
formation, delayed detachment of the umbilical cord and poor wound healing.

An infection with Ne,ssenà gonorrhoeae does not result in lasting immunity because of the
ability of these bacteria to modify their outer membrane proteins by the process of antigenic
variation. Antibodies generated during one infection will only be specific for that single
antigenic epitope Also recall that repeated Neisseria infections can be caused by terminal
complement deficiencies leading to an inability to form the membrane attack complex.

Serum sickness is a Type Ill hypersensitivity reaction characterized by deposition of circulating,
complement-fixing immune complexes and resulting vasculihs Associated findings include
fever, urticaria, arthralgias, glomerulonephritis. lymphadenopathy. and a low serum C3 level 5-
10 days after intravascular exposure to antigen.

G,àrd,à Iamb/ia causes injury to the duodenal and jejunal mucosa by adhering to the intestinal
brush border and releasing molecules that induce a mucosal inflammatory response Secretory
IgA. which impairs adherence, is the major component of adaptive immunity against G Iambi/a
infection Severe IgA deficiency predisposes patients to chronic giardiasis.

Eosinophils play a role in host defense during parasitic infection. When stimulated by IgE bound
to a parasitic cell, they destroy the parasite via antibody-dependent cellular cytotoxicity (ADCC)
with enzymes from their cytoplasmic granules. Another function of eosinophils is regulation of
type I hypersensthvity reactions.

Major adaptive immune mechanisms that prevent reinfection with the influenza virus include
anti-hemagglutinin lgG antibodies in circulation and mucosal anti-hemagglutinin IgA antibodies
in the nasopharynx.
54


NK cells recognize and kill cells with decreased MHC class I antigen cell surface expression,
such as virusi nfected cells and tumor cells. They are large lymphocytes that contain performs
and granzymes in cytoplasmic granules. NK cells kill target cells by inducing apoptosis

Acute carcac transplant rejection occurs weeks following transplantation and is primarily a cell-
mediated process. On histopathologic analysis of an endomyocardial biopsy, a dense
mononuclear Lymphocytic infiltrate with cardiac myocyte damage will be visualized. Treatment
with immunosuppressive drugs is aimed primarily at preventing this form of rejection.

bII Ia. JabI V
Angioedema can be hereditary (autosomal dominant) or acquired (associated with ACE inhibitor
treatment) In hereditary angioedema. low Cl esterase inhibitor activity leads to increases in
bradykinin actMty ACE inhibitors should not be used in these patients.

Aprotease 5 produced by N meningitidi and Ft gonorrhoeae This enzyme cleaves secretory gA at
its hinge region rendering it ineffective. Secretory IgA exists on mucosal surfaces and in
secretions and acts to bind and inhibit the action of pdi and flmbnae as well as other cell surface
antigens that normally mediate mucosal adherence and penetration.

Rheumatoid hritis is an autoimmune disease triggered by an unknown antigen Cartilage
components serve as autoantigens that activate CD4 T-cells. which in turn stimulate B-cells to
secrete rheumatoid factor, an 1gM antibody specific for the Fc component of self lgG.

lL-4producedbytheTH2 subset of T-helper cells It facilitates growth of B-cells and TH2
lymphocytes, and stimulates antibody isotype switching. particularty to IgE.

Chronic renal allograft rejection can manifest months to years after transplantation It is mediated
by recipient antibodies to graft endothelium formed after engraftment and causes an obliterative
intimal smooth muscle hypertrophy and fibrosis of cortical arteries.
Hyperacute rejection involves pre-formed recipient anti-donor endothelial antibodies which
immediately cause vascular fibrinoid necrosis. neutrophil infdtration, and infarction of the graft
Acute rejection may be cellular and/or humoral, causing, respectively, an interstitial
mononuclear infiltrate andlor a graft vasculitis intermediate in severity between hyperacute
thrombosis and chronic intimal thickening

Anti-Rh (D) immunoglobuhri (Rh0GAM) consists of lgG anti-Rh (D) antibodies It is routinely
administered to Rh-negative females at 28 weeks gestation and immediately postpartum lgG
antibody isotypes are effective in blocking the maternal immune response to ‘foreign fetal Rh (0)
antigens after fetomaternal transfusion

DiGeorge syndrome is a T-Iymphocyte immunodeficiency that results from maldevelopment of
the third and fourth branchial (pharyngeal) pouches due to a deletion on chromosome 22.
Clinical associations with this syndrome include absence of a thymic shadow on neonatal X-ray,
hypocalcemic tetany from absence of the parathyroids, cleft palate. mandibular deformity, low-
set ears, and aortic arch abnormalities.
55


Glomerulonephritis, a photosensitive skin rash, and arthralgias in a young female are suggestive
of systemic lupus erythematosus (SLE) 10-30% of patients with SLE have luDus anticoagulant.
the most frequent cause of a prolonged PU and a false positive VDRL without any other
hematological abnormality Lupus anticoagulant can cause an antiphospholipid antibody
syndrome defined by elevated blood levels of antiphospholipid antibody(ies) with
hypercoagulability (venous and arterial thromboembolism) andlor repeated second or third
trimester miscarriages.

Myasthenia gravis (MG) results from an autoimmune type II, antibody mediated,
hypersensitivity reaction against skeletal myocyte surface acetyicholine receptors. Goodpasture
syndrome similarly involves autoantibodies against basement membrane collagen of glomerular
and alveolar epithelia (Type II hypersensitivy). A Type Ill hypersensitivity mechanism apphes to
poststreptococcal glomerulonephritis, hypersensitivity pneumonitis, and possibly Churg-Strauss
syndrome Contact dermatitis and sarcoidosis result from Type IV, cell mediated,
hypersensitivity.

Immotile cilia syndrome (Kartagener syndrome) is characterized by the triad of situs inversus,
chronic respiratory infections and infertility. It occurs due to a defect in the gene coding for the
dynein arms of cilia Cystic fibrosis also causes recurrent infections and infertility, but not situs
inversus,

The seronegative spondyloarthropathies include ankylosing spondylitis, reactive arthritis,
psoriatic arthritis and arthritis associated with inflammatory bowel disease. Individuals
expressing HLA B27 are at increased risk for the seronegative spondyloarthropathies

When a live attenuated vaccine (eg the Sabin oral polio vaccine) is applied to mucosal surfaces,
it appears to promote more prolonged synthesis and secretion of local mucosal IgA than does a
killed vaccine (eg, the Salk inactivated polio vaccine) This increase in mucosal IgA offers
immune protection at the normal site of viral entry.

The wheal observed after an insect sting results from an allergic, or Type I hypersensitivity
reaction. The allergens present in the insect venom result in antibody class switching to IgE on
initial exposure. and subsequent exposure results in degranulation of mast cells and basophils
with release of histamine and heparin among other vasoactive mediators. This degranulation can
cause a response as mild as an urticarial wheal, or as severe as anaphylaxis.

The best way to prevent neonatal tetanus is to ensure that all pregnant women have been
vaccinated with the tetanus toxoid, to allow transfer of protective lgG antitoxin antibodies across
the placenta to the fetus

The acute hemolytic transfusion reaction is an antibody-mediated (Type II) hypersensitivity
reaction wherein host antibody binds antigen on transfused donor red blood cells, activating
complement The complement membrane attack complex causes erythrocyte lysis, and
anaphylatoxins mediate vasodilatation and symptoms of shock
56


Ataxia-telangiectasia is an autosomal-recessive disorder resulting from a defect in DNA-repair
genes. The DNA of these patients is hypersensitive to ionizing radiation Manifestations include
cerebeNar ataxia, oculocutaneous telangiectasias, repeated sinopulmonary infections, and an
increased incidence of maIignancy

Organ rejection is divided into three forms: hyperacute, acute and chronic. Acute rejection
occurs within weeks of transplantation and is primarily mediated by host T-lymphocytes that act
against donor MHC (HLA) antigens. This causes a mononuclear infiltrate on histopathology and
clinical reduction in function of the transplanted organ. Prevention is attempted with calcineurin
inhibitors and systemic corticosteroids.

The second most common cause of severe combined immunodeficiency (SCID) is autosomal
recessive deficiency of adenosine deaminase. an enzyme necessary for the elimination of excess
adenosine within cells Toxic levels of adenosine accumulate within lymphocytes in this
condibon, leading to lymphocyte cell death and resultant cellular and humoral immune
deficiency. Treatment is presently being researched using retroviral vectors to “infect’ patient
stem cells with the gene coding for adenosine deaminase.


IMMUNOLOGY 2
The Haemophi/us ,nfluenzae type b (Hib) vaccine contains bacterial capsular polysaccharide
conjugated with diphtheria toxoid.

Patients with SCID present with recurrent infections caused by bacteria, viruses, fungi, and
opportunistic pathogens as well as failure to thrive and chronic diarrhea within the first year of
life.

The candida skin test gauges the activity of the cell-mediated immune response The active cells
in the cell-mediated response are macrophages CD4 and CD8 T-Iymphocytes and NK cells

Poison ivy dermatitis is one form of allergic contact dermatitis, which is a type IV
hypersensthvity reaction Type IV hypersensitivity reactions are mediated primarily by T
lymphocytes. The cutaneous lesions in poison ivy dermatitis are typically linear erythernatous
papules. vesicles, or bullae that are pruritic.

hTWnUflObC abnormahties in sarcoidosis include intraalveolar and interstitial accumulation of
CD4+ T cells, resulting in high CD4:CD8 T-cell ratios in bronchoalveolar lavage (BAL) fluid.

Contact dermatitis, granulomatous inflammation, the tuberculin skin test and the Candida extract
skin reaction are all examples of delayed-type hypersensitMty reactions (DTH) The cells that
mediate DTH reactions are TH1 -lymphocytes that release interferon-g to cause recruitment and
stimulation of macrophages 0TH reactions take days to reach their peak activity; this is in
contrast to the other hypersensitivity reactions which cause clinical effects within minutes of
antigen exposure.
57


Langerhans cells are dendntic cells found in the skin that act as professional antigen presenting
celIs These cells are derived from the myeloid cell line and they possess characteristic racquet-
shaped intracytoplasmic granules known as Birbeck granules

Sensitized T,2 cells secrete IL-4 and 11-13, which together promote B-lymphocyte class
switching for IgE synthesis. They also secrete IL-5, which activates eosinophils and promotes
IgA synthesis An excess of these T2-produced lymphokines may contribute to the pathogenesis
of extrinsic allergic asthma IL-i is secreted by macrophages to stimulate helper T-ceIIs IL-3 from
helper T-cells recruits bone marrow stem cells. V-Interferon from helper T-cefls functions
mainly to activate macrophages. TGF-13 is growth factor involved in tissue regeneration and
repair.

Erythroblastosis fetalis and hemolytic disease of the newborn are diseases resulting from
maternal anti-fetal erythrocyte antigen lgG antibodies. The mother is sensitized to antigens
present on fetal blood and mounts a humoral immune response to these antigens causing
hemolysis in the fetus in utero due to the capability of lgG to cross the placenta and enter the
fetal circulation. This is one form of Type II (antibody mediated) hypersensitivity

Henoch-Schonlein purpura is a leukocytoclastic vascuhtis that occurs due to deposition of IgA-
containing immune complexes and manifests with palpable lower extremity purpura. abdominal
pain, arthralgias and renal involvement. It is the most common cause of systemic vasculitis in
children and classically occurs in young males 3-10 years old.

Chronic granulomatous disease is an X-hnked disorder resulting in deficiency of NADPH
oxidase. the enzyme responsible for formation of reactive oxygen species in neutrophil
phagolysosomes Neutrophils affected by this disorder are unable to kill catalase-producing
organisms (Staphylococcus, Serratia, E. coli etc.), but they remain effective in killing non-
catalase-producing organIsms.

Hyper-lgM syndrome results from an inability of B-lymphocytes to undergo isotype switching
from 1gM to other immunoglobulin isotypes such as lgD, lgG, IgE and IgA Clinically, hyper-
lgM syndrome most commonly results in lymphoid hyperplasia and recurrent sinopulmonary
infections The syndrome results most commonly from a genetic absence of the CD-40 ligand on
T-lymphocytes or from a genetic deficiency in the enzymes responsible for the DNA
modification that takes place dunng isotype switching

[anans giant cells are characteristic of granulomatous conditions, including the caseating
granulomas associated with MycobacteriUm tuberculosis infection They have multiple nuclei
peripherally organized in the shape of a horseshoe. The macrophages that form these giant cells
are activated by CD4+ Li lymphocytes.

The prOCeSS of negativeselection in T cell maturation is essential for eliminating T cells that
bind to self MHC or self antigens with overly high affinity. This process occurs in the thymic
medulla If these cells were permitted to survive, they would likely induce immune and
inflammatory reactions against self antigens leading to autoimmune disease.
58


Killed or viral component vaccines predominantly generate a humoral immune response instead
of a strong cell-mediated immune response

Selective gA deficiency predisposes to recurrent sinopulmonary and GI tract infections due to
the absence of secretory IgA It is also associated with an anaphylactic response to transfused
blood products due to an immune response against transfused IgA which the patierits body
recognizes as foreign

Graft-versus-host disease is mediated by T-tymphocytes of the donor tissue that are sensthzed
against MHC antigens of recipient. Skin, liver and intestine are commonly involved.

• The findings of hilar adenopathy. pulmonary infiltrates, and non-caseating lung granulomas in
an African American female point to a diagnosis of sarcoidosis. Granuloma formation is a
manifestation of cell-mediated immunity driven by products of TH1 type CD4+ helper T cells,
particularly IL-2 and interferon-y (IFN-y), which stimulate TH1 type cell proliferation and
macrophage activation, respectively.
• TH2 type CD4+ helper T cells predominantly drive humoral immune responses. Their products
include IL-4, which promotes IgE antibody production by B-cells, and IL-5, which promotes the
production and activation of eosinophils and B-cell synthesis of Ig&

X-linked agammaglobulinemia is characterized by low levels of circulating B-cells and low
levels of all immunoglobulins. including IgA. Patients with IgA deficiency are predisposed to
recurrent respiratory infections and persistent giardiasis. CD1 9. CD2O and CD21 are B-cell
surface markers

IFN- y secreted by T-Iymphocytes contributes to granuloma formation

Pulmonary tuberculosis infection is controlled through the action of CD4+ TH1 lymphocytes and
macrophages These cells work together to contain Al. tuberculosis within a caseous granuloma,
which offers the macrophages inside an opportunity to kill the remaining organisms if the
necrotic area is small enough

Immature T-Iymphocytes express both the CD4 and CD8 cell surface antigens in addition to a
complete TCR or a pro-TCR These lymphocytes exist in the thymic cortex where they undergo
positive selection and in the thymic medulla where they undergo negative selection.

Atypical lymphocytes observed in the peripheral blood smears of patients with infectious
mononucleosis represent activated CD8+ cytotoxic T-lymphocytes. These activated T-
lymphocytes function to destroy virally-infected B-lymphocytes

Chediak-Higashi syndrome is an autosomal recessive disorder of neutrophil phagosome
lysosome fusion that resufts in neurologic abnormalities, partial albinism and an
immunodetlciency caused by defective neutrophil function
59


fr silicosis, there may be disrupbon of macrophage phagolysosomes by internalized silica
particles Macrophage killing of intracellular mycobactena may be impaired as a result, causing
increased susceptibility of patients with silicosis to pulmonary tuberculosis

h,flarnrnation ischaractenzed by the passage of circulating inflammatory leukocytes into the
inflamed tissue The steps involved include margination. rolling. activation, tight adhesion and
crawling, and transmigration.

Omalizumab is aneffective and acceptable add-on therapy for patents with severe allergic asthma
It has been shown to be effective in reducing dependency on both oral and inhaled steroids

Bruton’s agammaglobulinemia is an X-hnked immunodeficiency resulting in an absence of B
cells and all forms of immunoglobuhn due to a defect in B cell maturatiOn. T cell numbers and
function are intact. Due to the absence of B cells. germinal centers and primary lymphoid
follicles will not form within lymph nodes.

Anaphylaxis is the systemic version of a local allergic response Systemic vasodilatation and
increased vascular permeability as well as airway constriction are mediated by agents such as
histamine, heparin and other vasoactive peptides released from mast cells and basophils after
cross-linking of at least two molecules of surface lgE delivers the signal for degranulation.

The chemokine receptor CCR5 acts as a coreceptor that enables the HIV virus to enter cells
Deletion of both of the genes that code for this receptor results in resistance to HIV infection
Deletion of one allele leads to delayed manifestations of the disease in infected individuals

Wth maternal blood types A and B, erythroblastosis fetalis and hemolytic disease of the newborn
do not occur, as the naturally occurring antibodies (anti-A and -B) are of the 1gM type and
cannot cross the placenta. In contrast, in type 0 mothers. the antibodies are predominantly lgG
and can cross the placenta to cause fetal hemolysis.

IL-12 stimulates the differentiation of ‘naive T-helper cells into the T_1 subpopulation. Patients
with IL-12 receptor deficiency suffer from severe mycobacterial infections due to the inability to
mount a strong cell- mediated granulomatous immune response. They are treated with IFN-y

DiGeorge syndrome causes an extreme deficiency in the number of mature T ‘ymphocytes,
leading to poor development of the lymph node paracortex. In contrast. agammaglobulinemia
causes an absence of B cells, preventing primary lymphoid follicles and germinal centers from
forming in the lymph node cortex.

Chronic granulomatous disease (CGD) is most frequently an X-linked disorder resulting from a
deficiency of NADPH oxidase Deficiency of this enzyme leads to an inability of neutrophils to
form the oxidative burst to kill organisms in their phagolysosomes Organisms that produce
catalase are ineffectively killed by these defective neutrophils while organisms that do not
produce catalase can still be killed due to accumulation of bacterial hydrogen peroxide within the
phagosome.
60


Severe combined immunodeficiency (SCID) is a disorder marked by combined T- and B-cell
dysfunction Some important features include: frequent fungal. viral, and bacterial infections
early in life; marked hypogammaglobulinemia; thymic hypoplasia; persistent diarrhea; failure to
thrive; severe lymphopenia; and lack of clinically apparent involvement of any other organ
systems

The Wiskott-Aidnch syndrome consists of the triad of eczema. thrombocytopenia and combined
B-lymphocyte and T-lymphocyte deflciency Onset of disease is early in life with
thrombocytopenia present at birth and eczema and repeated infections, particularly by
encapsulated organisms, following at 6 to 12 months of age

The classical complement cascade begins with binding of the Cl complement component to
either two molecules of lgG or to two molecules of 1gM. Because 1gM circulates in pentameric
form, it is a much better activator of the complement system The Cl molecule binds to the Fc
region of the heavy immunoglobulin chain in the region near the hinge point.

CD8 cells recognize foreign antigens presented with MHC class I proteins. Each MHC class I
molecule consists of a heavy chain and a -rnicroglobuIin.

The staphylococcal scalded skin syndrome occurs in infants and children due to the production
of the exotoxin extoliatin by Staphylococcus species It causes widespread epidermal sloughing,
especially with gentle pressure (Nikoisky’s sign)
61



MICROBIOLOGY- Cardiology
Diphtheria toxin is an AR exotoxin that nbosylates and inactivates elongation factor-2 (EF-2)
This inhibits protein synthesis and ultimately leads to cell death

Rheumatic fever is an autoimmune reaction that occurs following untreated Streptococcus
pyogenes(GAS) pharyngths Antigenc similarity between bacterial antigens and normal self
antigens in the heart and CNS are believed to cause formation of anti-self antibodies resulting in
RE

Enterococcus is a component of the normal colonic flora capable of growing in hypertonic (65%)
NaCI and bile Urine in the bladder is usually sterile but can be contaminated by instruments or
catheters passed through the outer part of urethra Contaminating organisms include colonec flora
(which are also frequently found on the perineum and skin surrounding the genitals), such as
enterococcus Thus, genitourinary manipulation has been known to cause enterococcal
endocarditis.

Viridans streptococci produce dextrans from glucose that aid these organisms in colonizing host
surfaces such as dental enamel and heart valves These organisms cause subacute bacterial
endocarditis most classically in patients with preexisting cardiac valvular defects after dental
manipulation This is why antibiotic prophylaxis is used prior to dental work in patients with
valvular abnormalities

S. aureus is the most common cause of tricuspid endocarditis in intravenous drug users. P
aeruginosa is the second most common cause in this patient population. These patients can
develop muttiple septic emboli in lungs. Pulmonary infarcts are almost always hemorrhagic due
to the dual blood supply to the lungs (pulmonary and bronchial arteries).

Viridans streptococc are normal inhabitants of the oral cavity and are a cause of transient
bacteremia after dental procedures in healthy and diseased individuals. In order to cause subacute
bacterial endocarditis they require preexisting valve damage leading to the local deposition of
flbnn required for them to adhere

Rheumatic fever (RE) can be reduced, as it has been in industrialized nations, by prompt
treatment of streptococcal pharyngitis and eradication of infective streptococci with prolonged
penicillin treatment. RF follows untreated Group A Streptococcal (GAS) pharyngitis while acute
post-streptococcal glomerulonephritis can follow either pharyngitis or skin infection by GAS
regardless of treatment

The treatment of a coagulase-negative staphylococcal infecbon involves initial empiric treatment
with vancomycin with or without rifampin or gentamicin due to the widespread antibiotic
resistance of S epiderinidís, especially in nosocomial infections

Staphylococcus epidermidis and S saprophyticus are both coagulase-negative staphylococci
species. Staphylococcus epidermidis is the most common cause of infective endocarditis in
62


patients with prosthetic valves and septic arthritis with prosthetic joints It is susceptible to
novobiocin

C d,phtheriàe causes diphthena. an acute bacterial disease that initially affects the oropharynx
The organism is spread by respiratory droplet transmission and causes disease via its AB
exotoxin The B (think:
binding) subunit allows penetration of the A (think: active) subunit into the cell, to inhibit
ribosome function Neural and cardiac toxicity are serious potential sequelae. Immunization with
the diphtheria toxoid induces production of circulating lgG against the exotoxin B subunit,
effectively preventing disease




MICROBIOLOGY-Genitourinary
Antiviral drugs currently recommended for the treatment of primary genital herpes include the
nucleoside analogs (eg, acyclovir). These nucleoside analogs are incorporated into newly
replicated viral DNA and ultimately terminate viral DNA chain synthesis.

Streptococci are catalase-negative, staphylococci are catalase-positive S pyogenes (Group A
Streptococcus) is beta-hemolytic and bacitracin susceptible S agalactiàe (Group B
Streptococcus) is beta-hemolytic and bacitracin resistant Streptococcus pneurnoniàe is bile
soluble (unable to be cultured in bile) and optochin susceptible

PeMc inflammatory disease is most commonly caused by Neisseriagonorrhoeaeor Chlamydià
trachomatjs and is strongly associated with an increased incidence of ectopic pregnanCy.

The gonococci use their pill to mediate adherence to the mucosal epithelium. An antibody
against the specific pilus protein expressed by a gonococcus would prevent mucosal adherence
and initiation of infection, but each gonococcus possesses the ability to modify the pilus protein
that it expresses by the process of antigenic variation and thus avoid host defense to some degree
as well as make vaccination directed against the pilus protein difficult.

Neissena organisms can be isolated by culture on selective media such as the Thayer-Martin
VCN medium, which inhibits the growth of contaminants such as Gram positive organisms,
Gram negative organisms other than Ne,sser,à. and fungi.

11 V
Rheumatic fever and acute post-streptococcal glomerulonephritis are the late sequelae of Group
A Streptococcal (Streptococcus pyogenes) infections Post-streptococcal glomerulonephritis can
follow either a skin infection (impetigo) or an episode of streptococcal pharyngitis, whereas
rheumatic fever is associated only with streptococcal throat infection.

Human papilloma virus (HPV) types 16. 18. and 31 are strongly associated with anal and
cervical squamous cell carCinoma. HIV infection increases the prevalence of HPV infection and
the risk of anal carcinoma this risk is further augmented in men who have sex with men.
63


 Use of broad-spectrum antibiotics suppresses the normal bacterial flora of the vagina and
facilitates Candkla overgrowth. Antibiotic use is the most common cause of Candklavaginitis
Other potential causes include contraceptive use, systemic corticosteroid use, diabetes mellitus,
and immunosuppression

E co//is one of the dominant components of the normal flora in the intestinal tract of humans and
animals It causes approximately 80% of all urinary tract infections P fimbnae are the most
important viwlence factor that uropathogenic Eco/,express Without P flmbnae, Ecokwould not
be able to bind to uroepithelial cells and infect the bladder, ureters, and kidneys, Instead, the
bacteria would simply be washed away during urination.

Enterobiàs,s Verm/CU/aFiS infection (enterobiasis) occurs most frequently in school-age
children and presents with penanal pruritus Diagnosis is made by the Scotch tap& test
Albendazole or mebendazole is the first- line treatment, with pyrantel pamoate as an alternate
agent preferred in pregnant patients.

Enterotoxins, Exfoliative Toxins and Toxic Shock Syndrome Toxin (TSST-1) are the toxins with
superantigen activity Superantigens interact with major histocompatibdity complex molecules on
antigen presenting cells and the variable region of the T lymphocyte receptor to cause
nonspecthc widespread” activation of T-cells resulting in the release of iriterteukin-2 (IL-2) from
the T cells and IL-i and TNF from macrophages. The immune cascade, in turn, is responsible for
the effects of TSS.

E co//is the most common cause of urinary tract infection in both healthy adults and elderly
patients. E coil is a part of the normal bowel flora, and special adhesive proteins allow some
strains to colonize and ascend the urinary tract This can result in pyelonephritis or bacteremia
and sepsis from access to the bloodstream The most common cause of E co/,bacteremia is a
urinary tract infection.

Gram-negative sepsis is caused by the release of LPS from bacterial cells during division or by
bacteriolysis; LPS is not actively secreted by bacteria. Lipid A is the toxic component of LPS: it
causes activation of macrophages leading to the widespread release of IL-i and TNF-alpha.
which cause the signs and symptoms of septic shock: fever, hypotension, diarrhea. oliguria.
vascular compromise. and DIC

P. aeruginosa is a non-lactose fermenting gram-negative organism. It is a common cause of
urinary tract infections in patients with indwelling bladder catheters.

Mucopurulent cervicitis with cervical motion tenderness is a frequent indicator of PlO caused by
N. gonorrhoeae or ChlamydIà trachomatis PlO can potentially lead to ectopic pregnancy and
infertility due to salpingitis leading to scarring of the fallopian tubes if not treated appropriately.

S saprophyticus is responsible for almost half of all UT1s in sexually active young women
Staphylococcus saprophyticus belongs to coagulase negative staphylococci and is unique among
these because ft is resistant to novobiocin.
64


Protein M is the major virulence factor for Streptococcus pyogenes It inhibits phagocytosis and
complement activation, mediates bacterial adherence, and is the target of type-specific humoral
immunity to S pyogenes

Ch/amydiä trachomat,s serotypes Li through L3 cause lymphogranuloma venereum (LGV), a
sexually transmitted disease characterized initially by painless ulcers with later progression to
painful inguinal lymphadenopathy and ulceration Histologically, LGV is characterized by
chlamydial inclusion bodies in the cellular cytoplasm.

Humans acquire schistosomiasis via contact with freshwater that contain snails infected with
Schistosoma Iarvae Sjàponicum and S mansonicause intestinal and hepatic schistosomiasis, and S
haematob,um causes urinary schistosomiasis

Acute bacterial arthritis in sexually active young adults is most commonly caused by N
gonorrhoeae. S aureus septic arthritis is most common in children and non-sexually active adults

The combination of new onset genital vesicular rash with a positive Tzanck smear in a
previously asymptomatic patient is suggestive of primary genital herpes due to HSV-2
Recurrences of genital herpes can be reduced through daily treatment with oral valacyclovir.
acyclovir, or famciclovir, these drugs suppress reactivation of latent HSV infection. Condom use
can help prevent a pnmary genital HSV infection, but does not prevent reactivation of latent
infection.

E co//is the most common pathogen causing cystitis and acute pyelonephritis The second most
common cause of UTI in sexually active women is Staphylococcus saprophyticus tJTls most
commonly affect women because of their very short urethra: recurrent UT1s in boys or men
require investigation for urinary tract obstruction or reflux.

The visualiza1on of spirochetes (such as T pallidum. the causative organism in syphilis) can be
accomplished with darkfield microscopy, which reveals helical motile Organisms.




MICROBIOLOGY-GIT
Travelers diarrhea is most frequently related to ETEC that produces heat labile (LT, choleragen-
like) and heat stable (ST) enterotoxins LT activates adenytate cyclase leading to increased
intracellular cAMP, and ST activates guanylate cyclase leading to increased intracellular cGMP,
Both cause water and electrolyte loss and watery diarrhea

Cases of typhoid fever in the United States usually occur after a patient has traveled to a location
where the disease is endemic. Typhoid fever is caused by Salmonella typh/and paratyphi and
causes a clinical presentation of escalating fever with initial diarrhea or constipation followed by
hepatosplenomegaly, the formation of “rose spots” on the abdomen, and possible hemorrhagic
enteritis with bowel perforation.
65


In absence of the normal intestinal microbial flora (as may be the case after a course of
antibiotics), ClostridAim dñWdlle can overgrow and produce enterotoxin (toxin A) and cytotoxin
(toxin B) Clinical disease resulting from C dif/icile overgrowth can range from transient diarrhea
to severe pseudomembranous colitis.

In absence of the normal intestinal microbial flora (as may be the case after a course of
antibiotics), ClostridAim dñWdlle can overgrow and produce enterotoxin (toxin A) and cytotoxin
(toxin B) Clinical disease resulting from C dif/icile overgrowth can range from transient diarrhea
to severe pseudomembranous colitis.

Trypanosoma cruis endemic in rural areas of Central and South America It causes Chagas
disease (American trypanosomiasis). This parasite can destroy the myenteric plexi in the
esophagus, intestines, and ureters, causing secondary achalasia. megacolon, and megaureter,
respectively

Intraabdominal infections are polymicrobia[ with B. fragthsandE co//being the most prominent
organisms isolated.

The minimal infectious dose for cholera infection is usually quEte high with 1O organisms
required to cause infection after ingestion of contaminated water. V. cholerae is very sensitive to
gastric acidity and any condition that increases gastric pH will lower the minimum infective dose
of V cholerae by many orders of magnitude. Gastric pH can be increased by achlorhydria. food
ingestion. and antacid ingestion

The UreaSe breath test is used to noninvasively detect H pyIoiiinfection The patient consumes
13C-Iabeled urea and his breath is then monitored for the presence of ‘3C-Iabeled carbon
dioxide, which would indicate the presence of the H pylon product urease in the stomach.

Mucosal invasn is an essential pathogenic mechanism for Shigeffa infection and is the most
significant factor in causing disease. Shigella gains access to the gut mucosal epithehum,
specifically by entering M cells in Peyer’s patches. It then escapes the phagosome, spreads
laterally to other eprthehal cells, and releases shiga toxin. The process of cellular invasion
induces a robust inflammatory response in the host it is this response that is primarily responsible
for the diarrhea seen in shigellosis

Campy/obacterinfection is a common cause of inflammatory gastroententis and can be acquired
from domestic animals (cattle, chickens. dogs) or from contaminated food. The diarrhea is
inflammatory and is accompanied by fever, abdominal pain and tenesmus Canoyhbacterinfection
is associated with Guillain-Barré syndrome.

Infant botulism is frequently due to honey consumption More than 12% of honey samples
contain low numbers of C botu/,num spores. Whereas infant botulism results from consuming C
botu/,hum spores, adult botulism results from consuming preformed toxin, typically in canned
food Symptoms of infant botulism include constipation, mild weakness. lethargy. and poor
feeding.
66


The strain of Enterohemorrhagic E coh’(EHEC) 0157:H7 is thought to cause at least 80% of
cases of hemolytic-uremic syndrome (HUS) in North Amenca, and is recognized as a common
cause of bloody diarrhea in developed countries It is associated with consumption of
undercooked ground beef and elaborates a Shiga-like toxin capable of inhibiting protein
synthesis in colonic mucosal cells and renal endothelial cells This particular strain of E cob is
unable to ferment sorbitol and does not produce a glucuronidase.

Shiga-like toxins (ak.a. Vera cytotoxins) are produced by Enterohemorrhagic E coIi(EHEC). As
their name implies, these toxins are nearly identical to the Shiga toxin produced by Shigella
dysenteriäe These toxins function to inhibit the 60s ribosomal subunit in human cells thereby
blocking protein synthesis by preventing binding of tRNA. This mechanism differs from that of
diphthena toxin and exotoxin A of Pseudomonas in that the latter toxins act on EF-2, not the 60S
ribosomal subunit.

Antibiotics disturb the normal intestinal flora and can lead to C diffkiie overgroWth. C difhdlle
causes colitis with severity ranging from transient watery diarrhea to pseudomembranous colitis.
Diarrhea may begin up to four weeks after antibiotic therapy. Metronidazole is the treatment of
choice

Depending on the age and condition of host as few as 10 cells of any Shigella species can cause
infection, although the infectious dose is usually much higher Other organisms that can cause
diarrhea with only a small inoculum include Campylobacterjejuni(500), Entamoeba histolytica
(as few as one organism), and Giärd,à Iamb/ia (as few as one organism)

The P/comaviidae family includes the rhinovirus and enterovirus genera Rhinoviruses are acid-
labile and therefore cannot colonize the Gl tract or cause gastroenteritis Enteroviruses are
relatively acid stable and can therefore pass through the stomach to colonize or infect the GI tract

V,brio cholerae along with Enterotoxigenic E coil (ETEC) cause a purely toxin-mediated watery
diarrhea The toxins secreted by these organisms do not cause cell death they modify electrolyte
handling by enterocytes, so no blood or pus (leukocytes) is noted on stool microscopy during
infection by these organisms.


This iodinestained stool smear shows Giàrdia Iamb/ia cySts. Giardia is the most common enteric
parasite in the U.S and Canada, and is a common cause of diarrhea in camperslhikers
Metronidazole is the treatment of choice.
67


MICROBIOLOGY-Head & Neck
Fever, vesiculoulcerative gingivostomatitis. and cervical lymphadenopathy are the most common
clinical manifestations of primary infection with herpes simplex virus (HSV-1). Reactn,ation of a
latent HSV infection in the trigeminal ganglia generally results in more limited perioral blisters
or “cold sores An abortive viral infection does not cause significant cytopathic effects

Scarlet fever is characterized by fever. pharyngitis. sandpaper—like rash. circumoral pallor, and
a strawberry tongue. It is caused by strains of Group A streptococcus that produce pyrogenic
exotoxins. Scarlet fever can predispose to acute rheumatic fever and glomerulonephritis.

Non-pathogerucCorynebacterium can cause severe pseudomembranous pharyngitis after
acquiring the Tox gene via lysogenization by a temperate bacteriophage.

Neutropenic patients are at risk for infection with Aspergillus fumigatus This fungus produces
septate hyphae with acute V-shaped branching It causes invasive aspergillosis, aspergillomas,
and allergic pulmonary aspergillosis.

Diphtheria exotoxin inhibits host cell protein synthesis by catalyzing the ADP-nbosylation of
host cell elongation factor-2 (EF-2)

Dhtheria infection is associated with a 5-10% mortality rate, especially in younger patients or
those with myocarditis. Cardiomyopathy is the most common cause of death. Treatment includes
diphtheria antitoxin (passive immunization), antibiotics, and active immunization. Of these,
passive immunization with antitoxin is the most important and has the greatest effect on
prognosis.

Interferons a and 13 are produced by a wide variety of eukaryotic cells in response to viral
infection. These interferons act as cytokines on neighboring cells, stimulating them to synthesize
antiviral proteins that impair viral protein synthesis

Diphtheria toxin and pseudomonal exotoxin A act by nbosylating and inactivating elongation
factor-2, inhibiting host cell protein synthesis and causing cell death.

Pseudomonas aeruginosa is a nonlactose-fermenting, oxidase-positive, motile. Gram-negative
rod. It is the most common cause of malignant otitis extema (MOE), a serious infection of the ear
seen in elderly diabetic patients. MOE presents with exquisite ear pain and drainage, and
granulation tissue is often seen within the ear canal.

C. diphtheriäe is cultured on cysteine-tellurite agar. The resultant colonies are black in color.
The bacterium produces intracellular polyphosphate granules, called metachromatic granules,
that can be detected on microscopy after methylene blue staining.

Actinomyces israeli/is a Gram positive organism that is best known for causing cervicofacial
actinomycosis in patients following dental manipulation or other oral trauma The disease is
characterized by a slowly growing and firm-feeling abscess in the face or neck region that
68


eventually forms cutaneous sinus tracts. Long-term penicillin treatment and surgical debndement
are required.

Typical clinical and laboratory features of Epstein-Barr mononucleosis include fever,
pharyngitis, lymphadenopathy, hepatosplenomegaly, atypical lymphocytosis, and a positive
Monospot test (ie, positive heterophil antibodies) EBV is generally transmitted from an
asymptomatic virus shedder to a susceptible individual through saliva transfer (eg, kisSing).

The DNA form of the HIV genome includes structural and regulatory genes. Structural gene
(gag, pol and env) products include nucleocapsid proteins p24 and p? (from the gag gene) and
envelope glycoproteins gpl2O and gp4l (from the envgene) Important enzymes are produced
from transcription and translation of the po/gene The regulatory tat and rev genes are required
for viral rephcation

Oral thrush is caused by Cand/da alb,cans infection It is associated with wearing dentures,
diabetes mellitus, and immunosuppression. Unexplained oral thrush in an otherwise healthy
person suggests the possibility of HIV infection

CMV is typically associated with subclinical infection in the immunocompetent. with the
occasional individual developing a mononucleosis-like syndrome that is Monospot negative In
the immunocompromised, primary or reactivated CMV infection can result in severe retinitis,
pneumonia, esophagitis, colitis, andlor hepatitis.

Viruses with segmented genomes (eg. orthomyxoviruses and rotaviruses) are capable of genetic
shifts through reassortment. Reassortment involves exchange of entire genome segments, a far
more dramatic process than the point mutations responsible for genetic drift

The findings of facial pain. headache. and black necrotic eschar in the nasal cavity in a patient
with diabetic ketoacidosis are highly suggestive of mucormycosis Histologic examination of the
affected tissue is necessary to confirm the diagnosiS. These fungi show broad nonseptate hyphae
with nght angle branching. Treatment consists of surgical debñdernent and amphotericin B.

The Thayer-Martin selective medium is used to isolate Neiseria species from clinical cultures. It
is a chocolate (i.e., heated blood) agar that contains vancomycin to inhibit the growth of gram-
positive organisms, colistin (i.e., polymyxin) to inhibit gram-negative bacteria. nystatin to inhibit
the growth of fungi, and trimethoprim to inhibit the growth of gram-negative organisms other
than Ne,sser,a such as the Proteus species.

Children aged one to three years who develop gingivostomatitis characterized by ulcerative
lesions with intranuclear inclusions are likely experiencing primary infection with herpes
simplex virus type 1 (HSV-1). HSV-1 and other herpesviruses are enveloped and possess double-
stranded DNA genomes

The congenital rubella syndrome is predominantly characterized by neonatal defects of the head
(microcephaly, mental retardation), eyes (cataracts), ears (deafness), and heart/cardiovascular
system
69


(patent ductus arteriosus, peripheral pulmoruc stenosis). To decrease the incidence of this
syndrome, the
CDC currently recommends the vaccination of children and non-pregnant females of
childbearing age with
live, attenuated rubella virus vaccine.

Mucormycosis is an opportunistic infection caused by Rhizopus, Mucor and Abs,d,à species. The
classic clinical picture is paranasal sinus involvement in a diabetic or immunosuppressed patient
The fungi form broad nonseptate hyphae that branch at right angles

The Haemophiius ,hfiuenzae type b vaccine is composed of cell wall polysaccharide conjugated
with protein toxoid from either diphtheria or tetanus This vaccination can be given as earty as 2
months of age and has drastically reduced the incidence of clinical disease caused by I-I
influenzae such as meningitis, pneumonia, sepsis and epiglottitis.

Changes in host range are most commonly caused by a mutation in the viral encoded surface
glycoprotein that mediates vinon attachment to target host cell plasmalemma receptors.
Mutations in viral encoded capsid proteins, RNA polymerases, endonucleases, or proteases could
nonspecifically affect viral replication in the standard host cell but would be less likely to
significantly alter the range of host cell types that an enveloped RNA virus could successfully
infect.

CMV is the most common cause of heterophil antibody-negative (ie, Monospot-negative)
mononucleosis. The Monospot test is positive in up to 90% of cases with EBV-associated
mononucleosis

Adenoviruses are the cause of a pharyngoconjunctival fever that classically occurs in small
outbreaks among individuals living together in close quarters (such as military barracks or camp
dormitories)




MICROBIOLOGY-Hepatic
Hepatitis A virus can be inactivated with water chlorination, bleach (1:100 dilution), formalin,
ultraviolet irradiation, or boiling to 85° C for one minute

Transmission of the hepatitis A virus occurs through the fecal-oral route and is common in areas
with overcrowding and poor sanitation Outbreaks frequently result from contaminated water or
food, with raw or steamed shellfish a common culprit in the United States

Chioroquine is the treatment of choice for uncomplicated malaria contracted in a chioroquine-
sensitive geographic region. It eliminates susceptible erythrocytic forms of all Plasmodia species
Pnmaquine is added in the treatment of infections with P v/vax and P ovale in order to eradicate
the intrahepatic stages of these two malarial species.
70


Because of the remarkable variety in the antigenic structure of hepatitis C virus envelope
proteins, the production of host antibodies lags behind the production of new mutant strains of
HCV and effective immunity against infection is not conferred

The hepatitis B virus genome consists of partially double-stranded circular DNA Replication is
accomplished through a reverse transcriptase DNA polymerase that creates an intermediate +
single-stranded RNA template and double-stranded DNA progeny

Often referred toas the delta agent or the hepatitis delta virus, hepatitis D virus is a replication-
defective RNA virus that is only capable of causing infection when encapsulated with HBSAg

Most enveloped nucleocapsid viruses acquire their lipid bilayer envelope by budding through the
plasma membrane of the host cell. Exceptions include the herpesviruses, which bud through and
acquire their envelope from the host cell nuclear mernbrane

The HBsAg of hepatitis B virus must coat the HDAg of hepatitis D virus before it can infect
hepatocytes and muitiply

Seronegative individuals who receive the hepatitis B vaccination will develop immunity and be
positive for anti-HBsAg but negative for HBSAg

If HBeAg persists for several months and host anti-HBeAg remain at low or undetectable levels,
suspect chronic hepatitis B infection with high infectivity

The hepatitis B virus replicates via the following sequence: double-stranded DNA —k template
+RNA progeny double-stranded DNPL

Blood is the primary means of HBV transmission. but the virus can also be spread by exposure to
semen, saliva, sweat, tears, breast milk, and pathologic effusions

Hepatitis E virus is an unenveloped. single-stranded RNA virus spread through the fecal-oral
route. The most concerning feature of hepatitis E infection is the high mortality rate observed in
infected pregnant women.

A resolved hepatitis B infection is suggested by moderate to high levels of anti-HBc and anti-
HBs without detectable viral antigens.

The hepatitis C virus is genetically unstable because it lacks proofreading 3’ —k 5 exonuclease
activity in its RNA polymerase and its envelope glycoprotein contains a hypervariable region
prone to frequent genetic mutation.

Vertical transmission of hepatitis B from pregnant females to the unbom child can occur in
women with active hepatitis B infection. The presence of HBeAg (a marker of viral replication
and increased infectivity) in the mother greatly increases the risk of vertical transmission of the
virus Because of this concern, the newborns of all mothers with active hepatitis B are passively
71


immunized at birth with hepatitis B immune globulin (HBIG), followed by active immunization
with recombinant HBV vaccine

Hepatitis A virus infection is most commonly silent or subclinical (“anicteric) in children but can
also present as an acute, self-limited illness characterized by jaundice, malaise, fatigue, anorexia,
nausea, vomiting, right upper quadrant pain, or an aversion to smoking

A component of the hepatitis B virus envelope. HBSAg is a noninfective glycoprotein that forms
spheres and tubules 22 nm in diameter Infected hepatocytes may secrete enormous quantities of
HBsAg, often considerably exceeding the amount of HBcAg produced.

Neonates born to HBsAg- and HBeAg-positive mothers are at high risk of chronic infection,
experience fast HBV replication, and demonstrate mild hepatic injury histologically



MICROBIOLOGY-Neurology
E. coli is a frequent cause of neonatal meningitis, second only to Group B Streptococci (GBS)
The capsule synthesized by some E cok(K-1 antigen) is a virulence factor that allows the bacteria
to survive hematogenous spread and to establish meningeal infection. Most strains of E
co//causing neonatal meningitis do possess this K-i antigen.

The finding of multiple ring-enhancing lesions in an HIV patient is most likely due to
toxoplasmosis

C/OSt,ithum tetanñs responsible for tetanus, a toxin-mediated disease that causes uncontrolled
muscle spasms and respiratory failure. Toxin travels within the motor neuron by retrograde
transport into the spinal cord where it causes inhibition of inhibitory intemeurons and
unregulated firing of primary motor neurons.

Ne,sseriä meningit/dis can cause upper respiratory infection, meningitis and meningococcemia
Immunity against these bacteria is provided by antibodies against their polysaccharide capsules.
The meningococcal vaccine contains immunogenic capsular polysaccharides from four major
serotypes of N. meningitidis and induces production of protective anticapsular antibodies

Subacute headache. fever, and neck stiffness in the presence of a lymphocytic CSF pleocytosis,
modestly elevated CSF protein level, and otherwise normal CSF parameters points to a diagnosis
of aseptic meningitis. Enteroviruses, including coxsackievirus and echovirus, are the most
common causes of aseptic meningitis

Varicella lgG antibodies suggest an antecedent primary varicella-zoster virus (VZV) infection.
These antibodies generally confer immunity against chickenpox reinfection but not against
herpes zoster, which is reactivation of VZV
72


Rhabdoviridae (rabies) are single-stranded RNA viruses enveloped by a bullet-shaped capsule,
which is studded by glycoprotein spikes that bind to nicotinic acetyicholine receptors Once
deposited in a wound, the virus stays local for a period of days or weeks before binding to
acetylchohne receptors on peripheral nerve axons and traveling retrograde to the central nervous
system

Ne,sseriä meningit/dis gains access to the CNS by first colonizing the nasopharynx and
subsequently invading the mucosal epithelium and gaining access to the bloodstream. Through
the blood. it spreads to the choroid plexus, gains access to the CNS through the blood—brain
barrier, and initiates an inflammatory process.

Congenital toxoplasmosis is a transpiacental infection (acquired in utero). Its classic triad
includes hydrocephalus, intracranial calcifications and chorioretinitis Expecting mothers should
avoid cat feces to help prevent exposure to Toxoplasma.

Meningococcaliipooiigosaccharide (LOS) is responsible for many of the toxic effects observed
in meningitis and meningococcemia Blood levels of LOS correlate closely with morbidity and
mortality

Clostridia are Gram positive spore-forming anaerobic rods. C botulinum is the bacteria
responsible for botulism, a toxin-mediated disease Local injections of botulinum toxin into
muscle are used to treat focal dystonias, achalasia and spasms.

Enteroviruses are the most common cause of viral aseptic menirigitis The enterovirus group
includes the coxsackieviruses, echoviruses and pohoviruses Pohovirus can cause lower motor
neuron injury in addition to meningitis, especially in non-immunized individuals from endemic
regiOns.

In AIDS patients, the radiographic finding of ring-enhancing lesions in both cerebral
hemispheres is most often indicative of toxoplasmosis

Primary CNS lymphorna is typically composed of B-lymphocytes and most commonly occurs in
immunocompromised patients (such as those with AIDS).

Bacterial meningitis causes an increase in cerebrospinal fluid (CSF) neutrophil count and protein
concentration as well as a decrease in CSF glucose. Streptococcus pneumoniàe is a leading cause
of community-acquired pneumonia. otitis media, and meningitis in adults. Spneumoniàe appears
on Gram stain as lancet-shaped, Gram-positive cocci in pairs.

Cryptococcus neoformans causes meningoencephalitis in HIV (+) patients The latex
agglutination test detects the polysaccharide capsule antigen of Cryptococcus and is used for
diagnosis India ink staining of the CSF shows round or oval budding yeast.

Cryptococcus neoformans is present in soil and pigeon droppings. The yeast is transmitted via
the respiratory route, with the lungs as the primary site of entry In immunocompromised patients,
lung infection may be followed by dissemination of C neoforinans. often into the CNS
73



There are three main kinds of botulism: food-borne botulism, wound botulism and infant
botulism In food-borne botulism, botulinum neurotoxin in food (produced by the organism
Clostridium botulinum) prevents release of acetyicholine from nerve terminals at the
neuromuscular junction, thereby preventing muscular contraction

Campylobacferjejunhinfection can lead to Guillain-Barre syndrome (GBS) in rare instances.
GBS is a demyelinating syndrome of the peripheral nerves characterized by ascending musc’e
weakness and paralysiS.

Illness caused by Clostridium tetani (tetanus) can be prevented by proper immunization with a
childhood series and a booster immunization every ten years thereafter in adulthood An
immunized mother will be able to pass lgG through the placenta to the fetus and provide passive
immunity against neonatal tetanus until the child receives its first tetanus vaccination at two
months of age. Neonatal tetanus usually results from C. tetani colonization of the umbilical
stump

Meningococcal sepsis may be associated with disseminated intravascular coagulation and
hemorrhagic destruction of the bilateral adrenal glands. This constellation of findings is known
as the
Waterhouse-Friderichsen syndrome. N. nieniigiidis sepsis does not necessarily include
meningitis.

Meningococcal pi are responsible for epithelial attachment to nasopharynx Antibody coating
these pili would prevent pilus-mediated attachment of the meningococcus to the mucosal
epithelium of the nasopharynx, thereby preventing invasion and disease.

Staphylococcus epidermidis is a common cause of foreign body infections due to its ability to
produce adherent biofilms

Cryptococcal meningitis is diagnosed by India ink staining of cerebrospinal fluid The main
treatment for this infection is amphotericin B and flucytosine

The clinical presentation of restlessness, agitation, and dysphagia progressing to coma 30 to 50
days following an exposure to cave bats is strongly suggestive of rabies encephahtis Prophylactic
vaccination is recommended by the CDC for indMduals at high risk of exposure to rabid animals
or their tissues The FDA approved rabies vaccine consists of various rhabdovirus strains grown
in tissue cell culture and then inactivated to produce killed virus vaccine

Infection of the sac ral sensory ganglia with a double-stranded DNA virus is likely to eventually
result in a recurrent, painful genital rash (genital herpes) secondary to reactivation of the latent
herpes simplex virus
(HSV-2)
74


1. Listeriosis is most commonly transmitted through food ingestions and causes sepsis and
meningitis in immunocompromised adults, Listeria can also cause neonatal meningitis, being
transmitted transplacentaUy or via vaginal contact during delivery,
2. Listeria grows well in cold temperatures (cold enrichment) and thus can contaminate
refrigerated food,
3. Listeria is a gram positive rod with V or L formations resembling corynebacterium, but its
tumbling motility is a unique feature.

Tetanospasmin is the neurotoxin released by C tetani It causes an inhibition of the inhibitory
intemeurons in the spinal cord that regulate firing of pnmary motor neurons These inhibitory
intemeurons use GABA and glycine as their neurotransmitters, but tetanospasmin prevents the
release of these neurotransmitters

1. Intact cell-mediated immunity is essential for the elimination of Listeria monocytogenes from
the body. Neonates up to 3 months of age are especially vulnerable because they have yet to fully
develop their cell-mediated immunity Listeria rarely causes disease in normal healthy adults
2. This bacterium produces a very narrow zone of beta-hemolysis on sheep blood agar
(resembling the pattern produced by 3-hemolytic Streptococci), shows tumbling motility at 22°C,
and can be cultured at temperatures as low as 4°C.



MICROBIOLOGY-Pulumunology

The Hib vaccine consists of PRP capsular polysacchahde conjugated with either tetanus or
diphtheria toxoid. Protein conjugation causes a T-ceIl mediated immune response leading to
immunoglobulin class switching and generation of memory B-lymphocytes This response would
not occur with pure polysaccharide immunization

Leg/onellapneurnophiia is a facultative intracellular gram-negative bacilli that can cause a
systemic infection Symptoms frequently include high fever, cough, confusion, and diarrhea. The
most common laboratory abnormality seen with Legionella pneumonia is hyponatremia, and
sputum Gram stain often shows many neutrophils, but few or no organIsms.

Studies have shown that maternal prophylaxis during pregnancy with the nucleoside analog
zidovudine (ZDV, AZT), a retroviral reverse transcriptase inhibitor, reduces the risk of pennatal
transmission by about two-thirds in HIV-positive women who have not pre’iousIy received
antiretroviral therapy.

Patients older than 65 are particularly prone to developing secondary bacterial pneumonia after
influenza infection. In order, the pathogens most often responsible for secondary bacterial
pneumonia are Streptococcus pneumoniàe, Staphylococcus aureus and Haemophiius ,hfluenzae.
75


The finding of interstitial pneumonia in a transplant patient with intranuclear and cytoplasmic
inclusion bodies histologically points to opportunistic infection with CMV. CMV is an
enveloped viws that contains a double-stranded DNA genome.

Histop/asma capsu/atum can survive intracellularty within macrophages It causes a disseminated
mycosis in immunocompromised patients. The clinical features include systemic symptoms
(fever and weight loss), painful oral ulcers, lymphadenopathy, and hepatosplenomegaly

Dimorphic fungi grow as molds at 25-30°C and as yeast at body temperature (35-37°C)
Medically important dimorphic fungi include Sporothri Coccidioldes Histoplasma Blastomyces
and Paracocc,diO,desspecies

Penichnscephalosporins and vancomycin are able to disrupt the peptidoglycan cell wall of Gram-
posrtive and Gram-negative organisms. The peptidoglycan cell wall of these organisms gives
them the ability to survive osmotic stress; this ability is lost after treatment with these antibiotic
agents.

Meningitis is the most common presentation of Cryptococcus neoformans infection. It occurs in
immunosuppressed patients and can be diagnosed by India ink staining of the CSF Cryptococcal
pneumonia is diagnosed by mucicarmine staining of lung tissue and bronchoalveolar washings

Ether and other organic solvents dissolve the lipid bdayer that makes up the outer viral envelope.
Loss of infectivity after ether exposure is a charactenstic feature of enveloped viruses

Blastomyces deimatitides can cause pulmonary disease in the immunocompetent host In
immunocompromised individuals, it may lead to disseminated mycosis (fever, pulmonary
symptoms, skin and bone involvement).

AspeigiiIusfiimigatuscauses opportunistic infections in immunosuppressed and neutropenic
patients (invasive aspergillosis). Aspergillosis can also be colonizing (aspergilloma) and allergic
(ABPA).

HIV-positive patients often experience reactivation of latent EBV infections with a resulting
increased incidence of EBV-induced lymphoprohferative disorders, including the aggressive
non-Hodgkin’s diffuse B-cell lymphomas.

• S pneumoniàe is able to undergo transformation, which is the uptake and expression of
chromosomal fragments from the environment made available when another bactenal cell dies
and undergoes lysis.
• Conjugation is pilus-mediated transfer of DNA Conjugation occurs in most bacteria but was
first described in the gram negative rod E co/i
• In transduction, DNA from one bacterial cell is transferred to another bacterial cell by a
bacteriophage (virus).
76


AUercbronchopulmonary aspergiflosis (ABPA) due to Aspergillus fumigatus may complicate
asthma, ABPA can result in transient recurrent pulmonary infiltrates and eventual proximal
bronchiectasis,

Candida a/b/cans is a normal inhabitant of the GI tract (including the oral cavity) in up to 40%
of the population Thus, it is a common contaminant of sputum cuttures The presence of Candida
in sputum does not indicate disease.

Cryptococcusneoformans is the only pathogenic fungus that has a polysaccharide capsule The
capsule appears red on mucicarmine stain, and as a clear unstained zone with India ink

H. influenza is a “blood loving” organism. Part of the laboratory identification process of H.
,nfluenzae is demonstration of the requirement of X (hematin) and V (NAD+) factors for growth
This can be accomplished by growing H. influenzae in the presence of S aureus and
demonstrating the “satellite phenomenon” where H. /h/luenzae grow only near the beta-
hemolytic S aireus colonies because they produce the needed X and V factors.

Mycoplasma pneumoniae is the causative agent in walking pneumonia and many cases of
tracheobronchitis. It is an organism with no peptidoglycan cell wall, it only has a phospholipid
bilayer cell membrane. It shares antigens with human erythrocytes, and when the body mounts a
response against these antigens it also lyses red blood cells leading to anemia. The antibodies
causing this RBC destruction are referred to as cold agglutinins.

S. pneumoniàe are Gram-positive, aipha-hernolytic, optochin-sensitive, bile-sensitive diplococci
S wridans is also aipha-hemolytic. but it is optochin-resistant S pyogenes (Group A Strep)
appears as Gram-positive cocci in chains and can be identified by its susceptibdityto bacitracin

Brassy, barking cough; dyspnea: and recent history of upper respiratory infection in a child are
suggestive of viral laryngotracheitis (croup). The most common cause of croup is parainfiuenza
virus.

The acid-fast staw identifies organisms that have mycolic acid present in their cell walls.
including Mycobacterium and some Nocard,à species Acid-fast staining is carried out by
applying an aniline dye (eg, carbolfuchsin) to a smear and then decolorizing with acid alcohol to
reveal whether the organisms present are “acid fast”

Chronic gran1omatous disease (CGD) results from a genetic defect in NADPH oxidase
Normally, NADPH oxidase participates in the killing of microbes within neutrophil
phagolysosomes Patients with CGD develop recurrent pulmonary, cutaneous, lymphatic. and
hepatic infections, with a tendency toward granuloma formation, usually beginning in childhood
These infections are predominantly caused by:
• Staphylococcus aureus
a Pseudomonas cepacia (Burkhokiena cepacia)
a Serrat,à marcesc ens
a Nocard,ä species
a A spergillus species
77


In the general population at any given time. 25-30% of individuals have nasal colonization with
Staphylococcus aureus The anterior nares are the most common site of colonization for both
methicillin-sensitive and methicillin-resistant Staphylococcus aureus

S pneumoniàe expresses a polysaccharide capsule that inhibits phagocytosis by macrophages and
polymorphonuclear leukocytes. It is the primary virulence factor, without which S pneumoniàe
cannot cause disease.

Virulent mycobactena will grow as “serpentine cords on enriched media secondary to the
presence of cord factor, a mycoside. Cord factor establishes virulence through neutrophil
inhibition, mitochondnal destruction, and the induced release of tumor necrosis factor.

All organisms in the Mycoplasma genus, including Ureaplasma. lack peptidoglycan cell walls
and are therefore resistant to agents that attack the peptidoglycan cell wall such as penicillins,
cephalosporins, carbapenems and vancomycin. Mycoplasma infections can be treated with anti-
ribosomal agents like tetracycline and erythromycin.

Coccidloides immitis infection can be asymptomatic or it can cause pulmonary disease ranging
from a flu-like illness to chronic pneumonia. It causes disseminated disease in
immunocompromised patients. Spherules containing endospores are found in tissue samples.

Cocc,d,O ides ,mm/t,s is a dimorphic fungus endemic to the southwestern United States. It exists
in the environment as a mold (with hyphae) that forms Spores. These spores are inhaled and turn
into spherules in the lungs.

Universal prenatal screening for group B strep Colonization by vaginal-rectal culture at 35-37
weeks gestation is recommended to identify colonized women who require INTRAPARTIJM
antibiotics, most frequently with penicillin or ampicillin. to prevent neonatal GBS sepsis.
pneumonia and meningitis

The pathogenicftyofHIhftLen2ae is dependent on the presence of the antiphagocytic
polysaccharide capsule. The type b strain is the most invasive and virulent it has a capsule with a
ribose as the sugar rather than a hexose as is used in the other strains of encapsulated H.
influenzae and this may be a reason for the increased virulence of Hib compared to the others.
Unencapsulated (nontypable) H. ,hfluenzae are part of the normal flora and cause only local
infections.

Nontypable strains of Haemophiius ,nfluer,zae are strains of H. !hfluenzae that do not form an
antiphagocytic capsule They are part of the normal flora of the upper respiratory tract, but can
cause otitis media, sinusitis and bronchitis. Immunity to nontypable strains, as well as capsular
strains other than type b, is not conferred by vaccination with the Hib Vaccine.

Rapidly progressing fever, severe sore throat, drooling and progressive airway obstruction
potentially accompanied by stridor are the presenting symptoms of acute epiglottitis. This illness
is most commonly caused by H. ,nfluenzae type b, but the Hib vaccine has dropped the incidence
78


of this disease considerably H. influenzae type b can still cause disease in unimmunized or
improperly immunized patients as well as fully immunized patients in some cases.

Lpneumophilacornmonly contaminates natural bodies of water, municipal water, humidification
systems and air conditioning and water-based cooling systems as are used in many commercial
applications The organism is inhaled in aerosohzed water and establishes infection by the
pulmonary route It requires special enriched media for growth specificaHy it requires media
supplemented with L-cysteine and culture on charcoal-yeast extract agar

The most common cause of community-acquired pneumonia in immunocompetent hosts (which
would include an HIV+ patient with normal CD4+ counts) is Streptococcus pneumonlàe

Infection with Mycoplasma pneumoniae can result in the formation of cold agglutinins Other
illnesses resulting in cold agglutinin formation include EBV infection and hematologic
malignancy Cold agglutinins are antibodies specific for red blood cells that only cause
agglutination, or clumping, of red blood cells at low temperatures

Mycop/asmaprieumoniáeis the causative agent of “walking pneumonia’ a condition
characterized by a nagging nonproductive cough, low-grade fever and malaise Often, the chest
X-ray suggests a severe pneumonia even though the patient appears relatively welL Mycoplasma
species require cholesterol supplementation in order to grow on artificial media.

Blastomyces dermat,tid,s is a dimorphic fungus that is seen in tissue as round yeasts with doubly
refractive walls and “broad based budding” it is endemic to the Great Lakes, and the Ohio and
Mississippi River regions The lungs are the primary site of involvement

The Haemophi/usuifluerizaetype b (Hib) vaccine is composed of polynbosy[-nbito-phosphate
(PRP), a component of the Hib capsule, conjugated with diphtheria or tetanus toxoid. Immune
activation with antibody production and memory B-lymphocyte induction against PRP provides
lasting immunity against Hib in children as young as 2 months old. Epiglottitis is almost
exclusively caused by Haemophdusinfluenzaetype b

For a naked RNA molecule to induce viral protein synthesis in a host cell, it must be able to act
directly as mRNA using the host’s intracellular machinery for translation Thus naked viruses
containing single-stranded positive-sense RNA can be infectious, whereas naked viruses
containing single- or double-stranded negative sense RNA are not infectious.

The pneumococcal polysaccharide vaccine is recommended for all adults over 65 years of age
and for patients with CQPD, asplenia. or immunosuppression. Vaccination does not completely
prevent pneumonia, as this vaccine only contains antigen from 23 of the more than 80 different
capsular serotypes known The adult pneumococcal vaccine is an unconjugated polysacchande
vaccine that, unlike the infant vaccine, does not stimulate a T-helper response.

Histoplasma capsu/atum is a dimorphic fungus located intraceIluIary within macrophages ft
affects the lungs and reticuloendothelial systern It is present in bird and bat droppings, and is
endemic to the Mississippi and Ohio River basins.
79



The spleen serves both as a site of antibody synthesis and as a reservoir of phagocytic cells
capable removing circulating pathogens. Asplenic patients are prone to infections caused by
encapsulated organisms such as S. pneumoniàe, H ,nfluenzae. and Ii meningitiths

BeCaUSe VIrUSeS must use eukaryotic nbosomes for protein synthesis, they must convert their
polycistronic genome into monocistronic mRNA Some viruses accomplish this through the
production of a polyprotein product from a single mRNA transcript. This product is later cleaved
by a viral protease to generate a complete set of functional, individual viral proteins

Spore-forming bacteria can survive boiling. Bacillus anthrac,s and members of the genus
Clostridium are potentially pathogenic bacteria found in the soil and capable of forming spores.

LegiOnel/apneurnophllacauses Legionnaires disease. Legionnaires disease has a propensity to
affect smokers and is characterized by very high fever, diarrhea, headache, and confusion.
Laboratory studies frequently show hyponatremia. L pneumophlla is a gram-negative rod that is
often not detected on Gram stain.
Microbiology

Reproductive+Vascular+Haematology

Educational objective:
The most important steps for the prevention of central venous catheter infections are as follows:
• Proper hand washing
• Full barrier precautions dunng insertion of a central hne
• Chlorhexidine for skin disinfection
• Avoidance of the femoral insertion site
a Removal of catheter(s) when no longer needed

Epstein-Barr virus (EBV) commonly infects B cells, stimulating them to enter the cell cycle and
proliferate continuously (a process termed “transformation or ‘immortahzation). EBV is an
oncogenic virus that promotes polyclonal B cell proliferation and heterophil antibody production
The Monospot test is a highly specific test used to diagnose EBV infection; the test is positive
when horse red blood cells are agglutinated in vitro by heterophil antibodies

A total of 50,000 to 120,000 central venous catheters-associated bloodstream infections have
been estimated to occur annually in the US. Indwelling central catheters predispose to bacteremia
and sepsis and should be monitored regularly for signs and symptoms of infection and suspected
in hospitalized patients with new-onset fever or bacteremia.

The high mutability of HIV-1 allows for the evasion of host humoral and cellular immune
responses and the development of resistance to anti-retroviral drugs Pol gene mutations are
responsible for acquired resistance to HIV reverse transcriptase inhibitors and HIV protease
Inhibitors. Env gene mutations enable escape from host neutralizing antibodies.
80


There is only one clinically significant nral family in which the members are both non-enveloped
and contain single-stranded DNA: Parvovihdae Parvovirus Bi 9 causes erythema infectiosum
(fifth disease), aplastic crises in sickle cell anemia, and hydrops fetalis

Red blood cel[s filled with multiple. smaller round nucleated cells suggests Plasmodia (malana)
infection Erythrocytic forms of this parasite may be treated with chloroquine or mefloquine
Primaquine is required to kill P v/vaKand P ova/eliverschizonts.

Essential to viral invasion of cells and the viral tropism for specific tissues is the initial
attachment of the virion
envelope or capsid surface proteins to the complementary host cell surface receptors Many
viruses bind to
normal host cell plasma membrane receptors in order to enter host cells Known host cell receptor
— virion/virion protein binding specificities include: CD4 and HIV gpl2O; CD21 and EBV
gp350; and erythrocyte P
antigen and parvovirus 819

Pelvic inflammatory disease is most frequently caused by N. gononhoeae and C trachomatis If
Neisserial or Chiamydial urethritis, cervicitis or PID is not treated, they can lead to scarring of
the fallopian tubes and infertility or ectopic pregnancy Treatment of gonococcal genital tract
infections must always include treatment for Chlamydia as well: the usual treatment is a third-
generation cephalosporin as well as azithromycin or doxycycline.

Candida a/b/cans is the most common cause of opportunistic mycosis It can affect any organ and
cause generalized candidemia. Yeasts and pseudohyphae on light microscopy and a positive
germ tube test are diagnostic of Cand/daa/b/cansinfection.

A febrile upper respiratory illness in a child followed by the sudden appearance of red, flushed
cheeks approximately 2-5 days later is characteristic of erythema infectiosum (parvovirus B 19
infection) This virus is highly tropic for erythroid precursor cells and replicates predominantly in
the bone marrOw.

Escherich,à co/,strain 0157:H7 can cause hemolytic-uremic syndrome (HUS) HUS is a rare
condition affecting mostly children under the age of 10 This strain of E coli is most commonly
contracted after eating undercooked ground beef.

Maternal rubella infection produces a low-grade fever, a maculopapular rash with cephalocaudal
progression, and posterior auricular and suboccipital lyrnphadenopathy. Most adult women
patients develop polyarthritis and polyarthralgia as sequelae. Congenital rubella syndrome is
associated with serisonneural deafness, cataracts, and cardiac malformations (PDA).

In patients with sickle cell anemia and other chronic hemolytic disorders, the most common viral
cause of an aplastic crisis is infection of erythroid progenitor cells with parvovirus B19, a non-
enveloped, single-stranded DNA virus
81


Microbiology-Skeletal
C. perfringens causes late-onset food poisoning and closthdial myonecrosis (gas gangrene) The
food poisoning is toxin-mediated. late-onset. and chnically causes a transient watery diarrhea

Methicillin-resistant S aureus (MRSA) is resistant to all —Iactam antibiotics. including beta-
lactamase resistant antibiotics, because it has an altered penicillin binding protein in its
peptidoglycan cell wall that does not bind beta-lactams as effectively

Erythema infectiosum (fifth disease) is caused by parvovirus B19 and is transmitted most
commonly via the respiratory route Symptoms of this infection include a bright-red rash on the
cheeks slapped cheeks”) and lacelike rash on the trunk and extremities.

Lecithinase, also known as alpha toxin. is the main toxin produced by C perfrlhgens Its function
is to degrade lecithin, a component of cellular phospholipid membranes, leading to membrane
destruction, cell death and widespread necrosis and hernotysis.

Hypo- or hyperpigmented skin patches that become more visible after tanning are characteristic
of pitynasis versicolor, a condition caused by Malassezià fwñir KOH preparation of skin
scrapings reveals a “spaghetti and meatballs” appearance on light microscopy

Salmonella, followed by E co/, is the most common cause of osteomyelitis in patients with sickle
cell anemia Patients with sickle cell disease have functional asplenia secondary to multiple
infarctions of the spleen. which makes these patients more prone to infection by encapsulated
Organisms.

1. Pulmonary anthrax, also known as woolsorters disease, is caused by inhalation of spores most
commonly while working with goat hair or hides Hemorrhagic mediastinitis evident as widened
mediastinum on chest- x ray is an important clue
2. On microscopy it forms long chains that are descnbed as being serpentine” or “medusa head’
on appearance
3. Bacillus anthracis produces an antiphagocytic capsule that is required for pathogenicity The
capsule is unique in that it contains 0-glutamate instead of polysaccharide.

Protein A, characteristic for S aureus binds to the Fc portion of IgG at the complement-binding
site, thus preventing the activation of complement This results in decreased production of C3b
leading to impaired opsonization.

Cutaneous anthrax leads to the formation of a necrotic skin wound with an erythematous and
edematous border and a necrotic center after inoculation of spores of Bacillus anthracis into the
skin. Anthrax is most commonly acquired occupationally by those who handle livestock that
have not been immunized for the disease as well as those who handle the hides of such animals.
Anthrax is also used as a biological weapon due to the near 100% mortality of the pulmonary
form.
82


Sporothrix schenck,lis a dimorphic fungus that causes a subcutaneous mycosis. It is often
transmitted by a thorn pnck. The disease manifests with nodules that spread along Iymphatics

Ecthyma gangrenosum is a cutaneous necrotic disease with a strong association with
Pseudomonas aeruginosa bacteremia and septicemia. It occurs after P aeruginosa invades
penvascularly and releases tissue destructive exotoxins causing vascular destruction and resultant
insufficiency of blood flow to patches of skin which become edematous and subsequently
necrose. Pseudomonas infections are common in neutropenic patients. hospitalized patients,
patients with bums and chronic indwelling catheters.

Hematogenousosteomyelitis most commonly occurs in male children and is most frequently
caused by Staphylococcus aureus after some bacteremic event Symptoms are vague and include
fever, malaise and pain in the long bones most frequently.

“Hot tub folliculitis” is a superficial and self-limited R aeruginosa infection of the hair follicles
that tends to occur in minor outbreaks following exposure to a pool or spa where the chemicals
have not been maintained at appropriate levels The culture of a pustule Will reveal Gram-
negative. oxidase positive, non-lactose fermenting, motile rods that produce pigment

Bacillus anthrac;ederna factor is an adenylate cyclase that causes massive increases in
intracellular cAMP leading to neutrophil dysfunction and collection of fluid within and between
cells with resultant edema This mechanism of action is similar to that of a toxin produced by
Bo,detella pertussis simply called “extracellular adenylate cyclase”
83


PATHOLOGY

Cardiology 1
Educational Objective:
Mitochondrial vacuohzation is typcaIly a sign of irreversible cell injury, signifying that the
involved mitochondria are permanently unable to generate ATP

In contrast to angina, the chest pain of pericarditis is sharp and pleuritic, and may be exacerbated
by swallowing or relieved by leaning forward, Early-onset pencarditis develops m about 10-20%
of patients between days 2 and 4 following a transmural myocardial infarction It represents an
inflammatory reaction to cardiac muscle necrosis that occurs in the adjacent visceral and parietal
pericardium Late-onset post-myocardial infarction (MI) pencarditis (Dressier’s syndrome) begins
one week to a few months following the MI, and affects less than 4% of cases. Dressier’s
syndrome is thought to be an autoimmune polyserositis.

Constitutional symptoms, a mid-diastobc rumbling murmur heard best at the apex. positional
cardiovascular symptoms (eg, dyspnea and syncope), embolic symptoms, and a large
pedunculated mass in the left atrium are the typical findings of athal myxoma Histologically,
these tumors are composed of scattered cells within a mucopolysaccharide stroma, abnormal
blood vessels, and hemorrhaging

Left atnal enlargement can sometimes cause left recurrent laryngeal nerve impingement
Neurapraxia resuLting in left vocal cord paresis and hoarseness may resuL

The combination of jugular venous distension, hypotension, and muffled heart sounds is highly
suggestive of cardiac tamponade Tachycardia and pulsus paradoxus are also frequently seen with
tamponade Lung examination is normal, which can help distinguish cardiac tamponade from
tension pneumothorax

In 90% of individuals, occlusion of the right coronary artery can result in transmural ischernia of
the inferior wall of the left ventricle, producing ST elevation in leads U, Ill, and aVF as well as
possible sinus node dysfunction Occlusion of the proximal LAD would be expected to result in
anteroseptal transmural ischernia, with ST elevations in leads V1—V4. Occlusion of the LCX
would produce transmural ischemia of the lateral wall of the left ventricle, with ST elevations
mainly in V5 and V6, and possibly also in I and aVL.

Severe aortic stenosis (AS) presents clinically with exertional syncope, angina and dyspnea
(SAD). In AS, a systolic ejection murmur is heard at the right second intercostal space (aortic
area) and may radiate to the carotids Senile calcific aortic valve degeneration is the most
common cause of AS. Senile calcthc aortic valve degeneration usually becomes clinically
apparent in the decade of life, whereas the AS associated with congenitally bicuspid aortic valves
tends to present by the 6th decade Rheumatic aortic heart disease usually produces combined AS
and aortic regurgftatlon. Aortic valve infective endocarditis tends to cause aortic regurgitation.
84


Patent ductus artenosus (PDA) is associated with prematurity and congenital rubella infection.
Therapy with indomethacin successfully closes this defect in the majority of pahents.

Aithough lightning injuries are rare. they are associated with a 25% fatahty rate Two-thirds of
lightning-related deaths occur within the first hour after injury, with fatal arrhythmias and
respiratory failure as the most common causes Patients with minor cutaneous involvement may
still have major internal injury after lightning strikes and high-voltage electncal contact.

Dystrophic calcification is a hallmark of preceding cell injury and necrosis

The foramen ovale is patent in 20-30% of normal adults Aithough it usually remains functionally
closed, any abnormality increasing nght atnal pressure above left atnal pressure can produce a
nght-to-left shunt across a patent foramen ovale

1 Hypertrophic cardiomyopathy often presents as sudden cardiac death in a young athlete Jmost
all cases are due to autosomal dominant mutations in cardiac sarcomere proteins The most
common protein involved is beta-myosin heavy chain
2. Approximately 1/3 of cases of dilated cardiomyopathy are genetic The malonty of these cases
are due to autosomal dominant mutations of cardiac myocyte cytoskeletal proteins (dystrophin)
or mitochondrial enzymes.

Chronic constrictive pencarditis results in replacement of the normal pericardial space by a thick
fibrous shell which can cause heart failure by restncting ventflcular filling Restncted nght
ventricular filling produces a positive Kussmauls sign in most cases Restncted left venthcular
filling may underlie the pulsus paradoxus that is seen in 1/3 of cases There may be a pencardial
knock as well. The pericardial knock occurs earlier in diastole than an S3 qallop

In patients with hypertrophic cardiomyopathy. dynamic left ventricular outflow tract obstruction
is due to abnormal systolic anterior motion of the antenor leaflet of the mitral valve toward a
hypertrophied interventric ular septum.

Differential cyanosis restricted to the lower body m a child is most suggestive of patent ductus
arteriosus with late-onset reversal of shunt flow (from left-to-right to right-to-left). Whole-body
cyanosis results when there is shunt reversal in patients with septal defects or tetralogy of Fallot
Coarctation of the aorta can limit lower- extremity exercise tolerance but does not cause cyanosis
in children or adults.

Prinzmetals (variant) angina is charactenzed by episodic. transient attacks of coronary
vasospasm, typically occurring at rest and during the midnight-to-eaiiy morning hours These
episodes generally produce temporary transmural myocardial schemia with ST-segment
elevation Ergonovine can provoke this coronary vasospasm, and can aid in the diagnosis This
condition can be effectively treated with vasodilating nitrates and calcium channel blockers.

Jervell and Lange-Nielsen syndrome is one of the most common congenital long-QT syndromes
This is an autosomal recessive condition which is accompanied by congenital neurosensory
85


deafness. QT-interval
              interval prolongation predisposes to synco
                                                   syncopal
                                                         pal episodes and possible sudden cardiac
death due to torsades depointes

Microemboh from the valvular vegetations of bacteral endocarditis are the most common cause
of subungual splinter hemorrhages The presence of these lesions necessitates careful cardiac
                                                                                     car
auscultation to detect a possible new
                                  new-onset regurgitant murmur.

Extreme myofiber disarray with interstitial fibrosis on cardiac histology strongly suggests
hypertrophic cardiomyopathy (HCM) Aimost 100% cases of HCM result from mutations in
genes encoding
        coding cardiac sarcomere proteins (most commonly beta
                                                         beta-rnyosin
                                                              rnyosin heavy chain).

A vanety of autosomal and sex chromosomal
                                        chromosomal-inherited
                                                       inherited disorders are associated with
developmental cardiac and/or aortic defects or cardiac pathology. The major associations are as
follows
1 Down syndrome endocardial cushion defects (ostium pnmum ASD. regurg regurgitant
                                                                            itant AV valves)
2. DiGeorge syndrome: tetralogy of Fallot and aortic arch anomahes
3. Friedreichs ataxia hypertrophic cardiomyopathy
4. Marfan syndrome: cystic medial necrosis of the aorta
5. Tuberous sclerosis: valvular obstruction due to cardiac rha
                                                           rhabdomyomas
6. Tume?s syndrome: coarctation of the aorta

Organ susceptibdity to infarction after occlusion of a feeding artery is ranked from greatest to
least as follows:
central nervous system. myocardium. kidney, spleen. and liver The presence of a dual  d   andlor
collateral blood supply (as seen in the liver, which is supplied by the hepatic artery and portal
vein) enables an organ to tolerate arterial occlusion better than those with end-arterial
                                                                                      end
circulations.




Unprovoked syncope in a previously aasymptomatic
                                       symptomatic young person may result from a congenital
QT pcolongation syndrome The two most important congenital syndromes with QT prolongation
— RomanoW ard syndrome and Jervell and Lange  Lange-Nielsen syndrome — are thought to result
from mutations in a K channel
                          nel protein that contnbutes to the delayed rectifier current (1K) of the
cardiac action potential.

The adult (postductal) type of congentaI aortic coarctation can pcesent with symptoms/signs of
hypertension in the arterial tree proximal to the coarctati
                                                  coarctation,
                                                            on, and of hypoperfusion of the lower
86


extremities, especially duflng ambulation Collateral circulation to the distal aorta results in
ditated intercostal arteries The triad of upper body hypertension, diminished lower extremity
ptises, and enlarged intercostal artery colaterals is typical of adult-type coarctation and is not
seen in other congenital cardiovascular maIformations

After the onset of severe ischemia $eading to myocardial infarction (Ml), early signs of
coagulative necrosis do not become apparent on light microscopy until 4 hours after the onset of
ML

Ion pump failure due to ATP deficiency during cardiac ischemia causes intracellular
accumulation of Na and Ca2 The increased intracellular solute concentration draws free water
into the cell, causing the cellular and mitochondrial swelling that is observed histologically

Sydenham chorea is the most common acquired chorea of childhood and is the sole neurologic
manifestation of acute rheumatic fever. A patient with this disorder would be at increased risk for
Chronic rheumatic heart disease, including mitral and aortic valve involvement.

Mitral valve prolapse is the most common cardiac abnormality predisposing to native vatve
bacterial endocarditis (NVBE) in the 15-to 60-year-old age group in the United States Mitral
valve prolapse predisposes to infected vegetations on mitral leaflets Rheumatic valvular disease
is also a potential, although less common, precipitant of NVBE

The major determinant of whether or not a coronary artery plaque will cause ischemic
myocardial injury is the rate at which it occludes the involved artery A slowly developing
occlusion would allow for formation of collaterals that could prevent myocardial necrosis A thin
fibrous cap, a nch lipid core, and actrve inflammation in the atheroma would all decrease plaque
stability and thus potentially promote rapid coronary occlusion via superimposed thrombosis it
the plaque were to rupture

An auscultatory finding of a mid systolic click followed by a murmur during the remainder of
systole is quite specific for mitral valve prolapse (MVP). MVP is thought to be predominantly
caused by defects in mitral valve connective tissue proteins which predispose to myxomatous
degeneration and stretching of the valve leaflets by chronic hemodynamic stress.

The pathogenesis of nonbactenal thrombotic endocarditis (NBTE) often involves a
hypercoagulable state When the hypercoagulabhty is the result of the procoagulant effects of
circulating products of cancers, the resulting cardiac valve vegetations may also be cal’ed
marantic endocarditis The pathophysiology of NBTE is similar to that of Trousseaus syndrome
(migratory thrombophiebitis) which may also be induced by disseminated cancers

An acute transmural myocardial infarction marked by ST-elevation and subsequent Q-wave
formation is most likely the result of a fuRy obstructive thrombus superimposed on a ruptured
atherosclerotic coronary artery plaque A lesser degree of occlusion by a thrombus supenmposed
on an acute plaque change would more likely cause unstable angina A stable atheromatous lesion
without an overlying thrombus, but obstructing greater than 75% of the coronary artery lumen,
would likely cause only stable angina.
87



The most likely cause of fatigue and new-onset cardiac murmur in a young adult is bacterial
endocarditis (BE). Acute, diffuse. proliferative glomerulonephntis secondary to circulating
immune complexes may complicate BE and can result in acute renal insufficiency

In the rare cases of lethal acute rheumatic fever (ARF), the cause of death is heart failure due to
severe myocarditis. Mitral stenosis after ARF requires years or decades to develop.

Lipofuscin is the product of lipid peroxidation. accumulating in aging cells (especially in patients
with malnutrition and cachexia).

In patients with Mart an syndrome. there are stnking skeletal abnormalities, including long
extremities and long tapering fingers, as well as spinal scoliosis and/or kyphosis However,
cardiovascular lesions are the most life-threatening features, Cystic medial degenerabon of the
aorta predisposes these patients to aortic dissection Aortic dissection is the most common cause
of death after infancy in patients with Marfan syndrome.

Cyanotic spells are common with TOF Remember the five Ts of cyanotic congenital heart
disease: tetralogy of Fallot, tricuspid atresia, transposition of the great vessels, truncus arteriosus,
and total anomalous pulmonary venous return. Atrial septal defect ventricular septal defect
patent ductus arteriosus, and aortic coarctation are generally considered noncyanotic congenital
heart diseases

Coronary artery disease is the underlying etiology in most cases of sudden cardiac death
Typically, an acute plaque change will result in acute myocardial ischernia, which may
precipitate ventricular fibrillation Cardiac arrhythmia is the most common cause of death in Ml
patients dunng the prehospital phase Ventricular failure is the most common cause of death
during the in-hospital phase Other later-onset, potentially lethal complications include ventncular
rupture and mural thrombosis with thromboembohsm.

Kawasaki disease is a vascuhtis of medium-sized arteries that presents with persistent fever,
bilateral conjunctivitis, cervical lymphadenopathy. and mucocutaneous involvement Formation
of coronary artery aneurysms is the most serious complication of Kawasaki disease

Pulsusparadoxus is an important clue to cardiac tamponade It is defined as a decrease in the
systolic pressure of 10 mmHg or more during inspiration as compared with the pressure during
exhalation

Orthopnea is a quite specific sign of left-sided heart failure. Bilateral lower extremity edema and
congestive hepatomegaly are more specific for right-sided heart failure Left-sided heart failure
may also produce a productive cough and exertional wheezing or chest tightness, but these are
nonspecific signs seen in a variety of disorders.

Atherosclerotic plaques develop predominantty in large elastic arteries (e.g., aorta, carotid, and
iliac arteries), and in large or mediumsized muscular arteries (e.g.. coronary and pophteal
88


arteries). In humans, the most heavily involved vessel is the abdominal aorta, followed by the
coronary artenes, the pophteal arteries, the internal carotid arteries, and the circle of Willis.

1 Concentric ventricular hypertrophy uniformly thickens the ventricular wall while the outer
dimensions of the ventricle remain virtually unchanged. thus causing a narrowed ventricular
cavity Concentric ventricular hypertrophy is often seen in patients with longstanding
hypertension because of the increased left ventricular afterload (pressure overload).
2 Volume overload of a ventricle, as seen in mitral regurgitation, results in dilatation of the
ventricle, with an associated increase in chamber size. An increase in LV cavity size may also be
seen in dilated cardiomyopathy and after myocardial infarction

Acute-onset, mid-chest pleuritic pain that decreases on sitting up and leaning forward is
characteristic of acute pencarditis. Fibcinous or serofibrinous pencarditis is the most common
form Peñcardial friction rub is the most striking physical finding.

SLE affects women 20-40 years of age and presents with a malar facial rash, photosensitivity,
arthraigias and proteinuna Pericarditis is the most common cardiovascular syndrome associated
with SLE It presents with chest pain that radiates to the neck and shoulders and is relieved by
sitting up

A diamond-shaped (crescendo-decrescendo) systolic murmur is characteristic for aortic stenosis.
The most common cause of this valvular heart disease is degenerative (senile) calcinosis of the
aortic leaflets.



PATHOLOGY-Cardiology 2

Cyanotic spells are common with TOF. Remember the five 7s of cyanotic congenital heart
disease: tetralogy of Fallot, tricuspid atresia, transposition of the great vessels, truncus arteriosus,
and total anomalous pulmonary venous return. Atrial septal defect, ventricular septal defect,
patent ductus arteriosus, and aortic coarctation are generally considered noncyanotic congenital
heart diseases

A variety of autosomal and sex chromosomal-inhented disorders are associated with
developmental cardiac and/or aortic defects or cardiac pathology. The major associations are as
follows:
1. Down syndrome endocardial cushion defects (ostium pnmum ASD, regurgitant AV valves)
2 DiGeorge syndrome tetralogy of Fallot and aortic arch anomalies
3. Friedreich’s ataxia hypertrophic cardiomyopathy
4. Marfan syndrome: cystic medial necrosis of the aorta
5. Tuberous sclerosis: valvular obstruction due to cardiac rhabdomyomas
6. Turner’s syndrome: coarctation of the aorta
89


Extended consurnpbon (for longer than three months) of appetite suppressants such as
fenfluramine or phentermine is associated with an increased incidence of pulmonary
hypertension Pulmonary hypertension classically manifests with dyspnea on exertion, and can
progress to cor pulmonale with right ventricular hypertrophy, potentially leading to sudden
cardiac death

Approximately 7 days following severe ischernia and myocardial infarction, granulation tissue
begins to grow into and replace the zone of dead myocardaum This process is most prominent
under bght microscopy during days 10-14 post-intarchon

Decreased outward K current duhng the repolarization phase of the cardiac action potential
results in QT prolongation. The major cardiac pathophysological consequence of QT
prolongation is an increased risk of episodic polymorphic verithcular tachycardia. including
torsades depointes

Myocardial infarction results in coagulative necrosis of cardiac myocytes Irreversible ischemic
injury to the brain tissue results in hquefactive necrosis. Fibrinoid necrosis is seen Ki some
vascuhtides Gaseous necrosis results from tuberculosis, Enzymatic fat necrosis results from the
action of abnormally released pancreatic lipases on adipose tissue.

Orthopnea is a quite specific sign of left-sided heart failure Bilateral lower extremity edema and
congestive hepatornegaly are more specific for nght-sided heart failure Left-sided heart failure
may also produce a productrve cough and exertional wheezing or chest tightness, but these are
nonspecific signs seen in a variety of disorders.

Atherosclerotic plaques develop predominantly in large elastic arteries (eg. aorta. carotid, and
iliac arteries), and in large or medium-sized muscular arteries (e.g.. coronary and popliteal
arteries). In humans, the most heavily involved vessel is the abdominal aorta. followed by the
coronary arteries, the pophteal arteries, the internal carotid arteries, and the circle of Willis.

1. Hypertrophic cardiomyopathy often presents as sudden cardiac death in a young athIete
Almost all cases are due to autosomal dominant mutations in cardiac sarcomere proteins The
most common protein involved is beta-myosin heavy chain
2. Approximately 1/3 of cases of ddated cardiomyopathy are genetic The majority of these cases
are due to autosomal dominant mutatons of cardiac myocyte cyloskeletal proteins (dystrophin) or
mitochondrial enzymes

Chronic constrictive pencarditis results in replacement of the normal pericardial space by a thick
fibrous shell which can cause heart failure by restricting ventncular filling Restncted right
ventricular filling produces a positrve Kussmauls sign in most cases Restncted left ventricular
filling may underlie the pulsus paradoxus that is seen in 1/3 of cases There may be a pencardial
knock as well The pencardial knock occurs earlier in diastole than an S3 gallop.

Dilated cardiomyopathy is a diagnosis of excluson once other etiologies of heart failure are ruled
out, namely pericardial disease, valvular defects, coronary artery disease, and cardiac rhythm
disturbances. It is characterized by dilation of all 4 chambers of the heart, systolic dysfunction,
90


and myocardial failure A systolic pressure gradient between the left ventricle and aorta would
not be expected m dilated cardiomyopathy and is more suggestive of left ventricular outflow
tract obstruction (eg, aortic stenosis)

The pathogenesis of nonbactenal thrombotic endocarditis (NBTE) often involves a
hypercoagulable state When the hypercoagulabahty is the result of the procoagulant effects of
circulating products of cancers, the resulting cardiac valve vegetations may also be called
marantic endocarditis The pathophysiology of NBTE is similar to that of Trousseaus syndrome
(migratory thrombophiebdis) which may also be induced by disseminated cancers

Hypertrophic cardiomyopathy (HCM) is the most common cause of ventricular fibrillation in
individuals younger than 30 and the most common cause of sudden cardiac death ii a young
athlete. Myocardial infarction, multifocal myocardial fibrosis, and dilated or restnctive
cardiomyopathies can end in sudden cardiac death. but woukl be unlikely in a teenager with no
past medical history

The foramen ovale is patent in 20-30% of normal adults. Although it usually remains
functionally closed, any abnormality increasing right atrial pressure above left atnal pressure can
produce a right-to-left shunt across a patent foramen ovale.

Extreme myofiber disarray with interstitial fibrosis on cardiac histology strongly suggests
hypertrophic cardiomyopathy (HCM) Almost 100% cases of HCM result from mutations in
genes encoding cardiac sarcomere proteins (most commonly beta-myosin heavy chain)

SLE affects women 20-40 years of age and presents with a malar facial rash, photosensitivity,
arthralgias and proteinuria Peñcarditis is the most common cardiovascular syndrome associated
with SLE. It presents with chest pain that radiates to the neck and shoulders and is relieved by
sitting up.

Differential CyanOsis restricted to the lower body .i a child is most suggestive of patent ductus
arteriosus with late-onset reversal of shunt flow (from left-to-nght to right-to-left). Whole-body
cyanosis results when there is shunt reversal in patients with septal defects or tetralogy of Fallot.
Coarctation of the aorta can limit lower- extremity exercise tolerance but does not cause cyanosis
in children or aduRs

The most likely cause of fatigue and new-onset cardiac murmur in a young adult is bacterial
endocarditis (BE). Acute, diffuse, proliferative glomerulonephritis secondary to ciculating
immune complexes may complicate BE and can result in acute renal insufficiency.

Left atrial enlargement can sometimes cause left recurrent laryngeal nerve impingement
Neurapraxia resulting in left vocal cord paresis and hoarseness may result.

An acute transmural myocardial infarction marked by ST-elevation and subsequent 0-wave
formation is most likely the result of a fully obstructive thrombus superimposed on a ruptured
atherosclerotic coronary artery plaque A lesser degree of occlusion by a thrombus supenmposed
on an acute plaque change would more likely cause unstable angina A stable atheromatous lesion
91


without an overlying thrombus, but obstructing greater than 75% of the coronary artery lumen,
would likely cause only stable angina.

Valvular inflammation, damage. and scarring predispose to infective endocarditis, which is
characterized grossly and on an echocardiogram by the presence of valvular vegetations
The vegetations associated with bacterial endocarditis represent fibrin and platelet deposition at a
site of bacterial colonization.

Mitral valve prolapse is the most common cardiac abnormality predisposing to native valve
bacterial endocarditis (NVBE) in the 15- to 60-year-old age group in the United States Mitral
valve prolapse pi-edisposes to infected vegetations on mitral leaflets. Rheumatic valvular disease
is also a potential, although less common, precipitant of NVBE

Bicuspid aortic valve is the most common congen4al malformation affecting the heart in Turner
syndrome. It is usually an isolated abnormality however, it may occur in combination with other
anomalies, particularly aortic coarctation. A nonstenotic bicuspid aortic vatve can mandest as an
earty systolic, high-frequency click over the cardiac apex and/or the right second interspace

Jervell and Lange-Nielsen syndrome is one of the most common congenital long-QT syndromes
This is an autosomal recessive condition which is accompanied by congenital neurosensory
deafness QT-interval prolongation predisposes to syncopal episodes and possible sudden cardiac
death due to torsades depointes

1. Concentric ventricular hypertrophy uniformly thickens the ventricular wall while the outer
dimensions of the ventricle remain virtually unchanged. thus causing a narrowed ventricular
cavity Concentric ventricular hypertrophy is often seen in patients with longstanding
hypertension because of the increased left ventricular afterload (pressure overload)
2. Volume overload of a ventricle, as seen in mitral regurgitation, results in dilatation of the
ventricle, with an associated increase in chamber size An increase in LV cavity size may also be
seen in dilated cardiomyopathy and after myocardial infarction.

The combination of jugular venous distension. hypotension, and muffled heart sounds is highly
suggestive of cardiac tamponade Tachycardia and pulsus paradoxus are also frequently seen with
tamponade Lung examination is normal, which can help distinguish cardiac tamponade from
tension pneumothorax

Acute-onset, mid-chest pleuritic pain that decreases on sitting up and leaning forward is
characteristic of acute pericarditis. Fibnnous or seroflbnnous pencarditis is the most common
form, Pericardial friction rub is the most striking physical finding.

Prinzrnetars (variant) angina is characterized by episodic, transient attacks 01 coronary
vasospasm, typically occurring at rest and during the midnight-to-earty morning hos These
episodes generally produce temporary transmural myocardial ,schemia with ST-segment
elevation Ergonovine can provoke this coronary vasospasm, and can aid in the diagnosis, This
condition can be effectively treated with vasodilating nrtrates
in€1 riIri,ui cmmI bInckrc
92



Congenital bicuspid aortic valves are strongly associated with accelerated onset of calcific aortic
stenosis Clinically significant aortic stenosis may develop ri patients with bicuspid aortic valves
beginning in the sixth decade, whereas senile calcific stenosis of normal aortic valves generally
becomes symptomatic in the eighth decade.

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric ventricular septal
hypertrophy and variable dynamic left ventricular outflow tract obstruction which may produce a
systolic election murmur Decreases in the LV end diastolic volume increase the obstruction,
causing the murmur of HCM to be enhanced Actions like standing suddenly from the supine
position and the Valsalva maneuver decrease venous return and thus accentuate the murmur

The normal morphological changes ui the aging heart include a decrease in left ventricular
chamber apex-to-base dimensions, development of a sigmoed-shaped ventncular septum,
myocyte atrophy with interstitial fibrosis, and accumulation of cytoplasmic lipofuscin p*gment
Hypertensive heart disease is associated with concentric hypeftrophy of the left ventncle

S atreus causes acute bactenal endocarditis with rapid onset of symptoms including shaking
chills (rigors), high fever, dyspnea on exertion and malaise. In IV drug abusers it causes right-
sided eridocarditis with septic ernbolization into the lungs leading to pulmonary abscesses. In
non-!VDU, it causes rapid decompensation, heart failure, sepsis, septic embolization to the brain
and other end organs

Kawasaki disease is a vascuhtis of medium-sized arteries that presents with persistent fever,
bilateral conjunctivitis, cervical lymphadenopathy, and mucocutaneous involvement Formation
of coronary artery aneurysms is the most senous complication of Kawasaki disease.

The aduft (postductal) type of congenital aortic coarctation can present with symptoms/signs of
hypertension in the arterial tree proximal to the coarctation, and of hypoperfusion of the lower
extremities, especially dunng ambulation, Collateral circulation to the distal aorta results in
diLated intercostal arteries The triad of upper body hypertension, diminished lower extremity
pulses, and enlarged intercostal artery coaterals is typical of adult-type coarctation and is not
seen in other congenital cardiovascular maltorrnations

Mitochondrial vacuolization is typically a sign of irreversible cell injury, signifying that the
involved mitochondria are permanently unable to generate ATP.

In patients with Marlan syndrome, there are striking skeletal abnormalities, including long
extremities and long tapering fingers, as well as spinal scoliosis and/or kyphosts. However,
cardiovascular lesions are the most life-threatening features. Cystic medial degenerabon of the
aorta predisposes these pabents to aortic dissection. Aortic dissection is the most common cause
of death after infancy in patients with Marfan syndrome.

The carcinoid syndrome can cause predominantly right-sided endocardial fibrosis which may
progress to pulmonic stenosis and/or restrictive cardiomyopathy The severity of carcinoid heart
93


disease correlates with plasma levels of serotonin and urinary excretion of the serotonin
metabolite. 5-hydroxyindoleacetic acid.

Aft;r the onset of severe ischema leading to myocardial infarction (Ml), early signs of
coagulative necrosis do not become apparent on light microscopy until 4 hours after the onset of
M[

Although lightning injuries are rare, they are associated with a 25% fatality rate. Two-thirds of
lightning-related deaths occur within the first hour after injury, with fatal arrhythmias and
respiratory failure as the most common causes. Patients with minor cutaneous involvement may
still have major internal injury after lightning strikes and high-voftage electrical contact.

In the rare cases of lethal acute rheumatic fever (ARF), the cause of death is heart fadure due to
severe myocardths Mitral stenosis after ARF requires years or decades to develop

Patent ductus arteriosus (PDA) is associated with prematurity and congenital rubella infection.
Therapy with indomethacin successfully closes this defect in the majority of patients

Organ susceptibility to infarction after occlusion of a feeding artery is ranked from greatest to
least as follows:
central nervous system, myocardium, kidney, spleen, and hver The presence of a dual and/or
collateral blood supply (as seen in the liver, which is supplied by the hepatic artery and portal
vein) enables an organ to tolerate arterial occlusion better than those with end-arterial
circulations

Almost all cases of mitral stenosis are caused by chronic rheumatic heart disease Infective
endocarditis of the mitral valve tends to cause destruction and regurgitation Congenital heart
defects may produce mitral regurgitation, but are generally not associated with stenosis Mitral
valvular calcinosis generally does not impair valve function. Rheumatoid arthritis and tertiary
syphilis only rarely affect cardiac valves.

Severe aortic stenosis (AS) presents chnically with exertional syncope. angina and dyspnea
(SAD). In AS, a systolic ejection murmur is heard at the hght second intercostal space (aortic
area) and may radiate to the carotids Senile calcafic aortic valve degeneration is the most
common cause of AS Senile calcific aortic valve degeneration usually becomes clinically
apparent in the 7111 decade of life, whereas the AS associated with congenitally bicuspid aortic
valves tends to present by the decade Rheumatic aortic heart disease usually produces combined
AS and aortic regurgItation Aortic valve infective endocarditis tends to cause
air+i, r#
94


PATHOLOGY-Dermatology
          Dermatology
BRAF is a protein kinase involved in activation of ságnaling pathways for melanocyte
proliferation, and the
BRAF V600E mutation is seen in 40
                               40-60% of patients with melanoma.

Herpes zoster (shingles) develops due to reactivation of varicella
                                                          varicella-zoster
                                                                    zoster vüus in the dorsal root
ganglia It presents with a painful vesicular rash in a dermatomal distribution. On light
microscopy
  icroscopy intranuclear inclusions in keratinocytes and multinucleated giant cells are seen

Bullous pemphigoid is characterized by autoantibodies to the hemidesmosomes along the
basement membrane of the dermal
                         dermal-epidermal junction.

Measurement of the depth  pth of invasion (Breslow thickness) is the most important prognostic
indicator for patients with malignant melanoma.

Pemphigus vulgans is an autoimmune bullous disease characterized by autoantibodies directed
against desmosomal proteins 3 and 1 Bullous pemphigoid is characterized by autoantibodies
against hemidesmosomal proteins.

Actinic keratosis develop in predisposed individuals on chronically sun
                                                                    sun-exposed
                                                                        exposed areas of the skin
The lesions consist of erythematous papules with a central scale and a “sand
                                                                         “sandpaper
                                                                              paper-like texture.
Actinic keratosis can convert to squamous cell carcinoma in approximately 1% of cases.




Seborrheic keratosis is a benign epidermal tumor that presents as a tan to brown, round, flat,
greasy, coinlike lesion with a “stuck on” appearance

Keloids result from excessive collagen formation during tissue repair in susceptible individuals
They present as soft or firm nodules that grow beyond the borders of the wounds with claw-like
                                                                                       claw
extensions into normal tissue. Keloids are composed of large. di
                                                              disorganized
                                                                 sorganized collagen bundles and
excess cellular connective tissue.

Acanthosis nigncans presents with thickening and hyperpigmentation of skin in the fiexural areas
The ‘esions have a classic “velvety’ texture. Acanthosis ngncans is commonly associated withw
insulin-resistant
        resistant states (eg, diabetes mellitus. acromegaly. obesity) and gastrointestinal
malignancies

Xanthomas are suggestive of hyperhpidemia. especially when present in conjunction with a
family history of early cardiac death.

Urticaria is characterized
              haracterized by superficial dermal edema and lymphatic channel dilation. No
epidermal changes are present.
95


Granulomatous inflammation is a form of chronic inflammation characterized by aggregates of
activated macrophages that assume an epithelloid appea  appearance
                                                             rance Persistent granulomatous
inflammation with subsequent fibrosis can cause organ dysfunction, which is seen in a number of
granuomatous diseases

Cooper’s ligament infiltration by invasive breast cancer causes retraction of the overlying skin




Dermatitis herpetiformis is a rare condition that presents with erythematous, pruhtic papules,
vesicles, and bullae that appear bilaterally and symmetñcally on the extensor surfaces Dermatitis
herpetiformis is stron9ly associated with celiac disease

Psoriasis
    riasis is characterized by hyperparakeratosis. acanthosis. rete ridge elongation, mitotic
activity above the epidermal basal cell layer, and a reduced or absent stratum granulosum.
Neutrophils may fomi spongiotic clusters in the superficial dermis and the parakeratotic stratum
comeum (Munro microabscesses).

Red blood cell extravasation into the skin or subcutaneous tissue results in the formation of
petechiae (<5 mm in diameter), purpura (5 mm to 1 cm in diameter), or ecchymoses (>1 cm in
diameter) These lesions do not completely blanch under pressure. unlike telangectasias

A yellowish eyelid papule or plaque containing lipid
                                                 lipid-laden
                                                       laden macrophages is most hkety
xanthelasma Xanthelasma may occur in association with pnmary or secondary hyperlipidemia
Cholestatic
       atic conditions such as primary bihary cirrhosis are a potential cause of
hypercholesterolemia leading to xanthelasma.

The lepromin skin test will be positive in patients with tuberculoid leprosy because they exhibit a
strong CD4+ Thi cellmediated immun
                               immune response to M Ieprae.

Atopic dermatitis (eczema) is a common inflammatory disorder of childhood It presents with
pruritus and erythematous weeping papules and plaques that occur in response to certain
environmental antigens Atopic dermatitis is associ
                                            associated
                                                   ated with other atopic diseases, such as
allergic rhinitis and asthma

Actinic keratoses are small (usually < 1 cm), erythematous epidermal lesions with adherent scale
Histologically, there is basal cell layer atypia. hyperkeratosis, and parakeratosis These
                                                                                    Th    lesions are
the result of chronic sun exposure and thus affect sun   sun-exposed
                                                             exposed areas A small percentage of
actinic keratoses progress to invasive squamous cell carcinoma, thus monitonng is necessary.

Axillary lymph node dissection is a risk factor for the development of chronic lymphedema
invoMng the ipsilateral arm. Chronic lymphedema predisposes to the development of
angiosarcoma (Stewart-Treves
                      Treves syndrome)
96


PATHOLOGY-Endocrinology
Hemorrhage into a preexisting pituitary adenoma is called pituitary apoplexy It presents with a
sudden severe headache and cranial nerve paralysis. with other more chronic symptoms of a
pituitary tumor Since signs of meningeal irritation can be seen, it is very important to evaluate
the visual fields for bitemporal hemianopsia. Cardiovascular collapse can occur due to
adrenocortical deficiency.

Cushrng syndrome caused by a pituitary adenoma or ectopic ACT1-l secretion will present with
elevated ACTH levels High-dose dexamethasone suppression testing will suppress ACTH and
cortisol levels when Cushing syndrome is caused by a pituitary adenoma (Cushing disease) but
not when is caused by ectopic ACTH secretion (eg, small-cell Carcinoma).

The most common pituitary adenoma is a prolactinoma. sometimes called a lactotroph adenoma:
however, somatotrophs are the most common cell type in the normal pituitary

Myocardial infarction is the most common cause of death in patients with diabetes

The stimulatory effect of high estrogen levels during pregnancy causes the pituitary gland to
enlarge and become more vascular If significant hypotension occurs while the pituitary is still
enlarged ([e postpartum hemorrhage), the pituitary gland can undergo ischemic necrosis This
results in deficiencies of multiple pituitary hormones (panhypopituitansm), including prolactin—
and is called Sheehan syndrome

Features of thyrotoxicosis. tenderness over the thyroid gland, increased ESR, and a markedly-
reduced radioactive iodine uptake are diagnostic of granulomatous thyroiditis Mixed, cellular
infiltration with occasional multinucleate giant cells are characteristic histologic findings.

Pancreatic islet amoid deposition is characteristic of type 2 diabetes meibtus A strong linkage
with HLA class II gene makeup, pancreatic islet infiltration with leukocytes (insuhtis), and
antibodies against islet antigens are frequently seen in type I diabetes

Autoimmune insubtis is the most common cause of type 1 diabetes Insulin resistance is the main
mechanism responsible for type 2 diabetes

Pheochromocytoma is usually a benign (90%) tumor arising from the adrenal medulla
Pheochromocytomas typically produce episodic symptoms Diagnosis is confirmed by the
measurements of urine and plasma catecholamines and catecholamine metabohtes such as
metanephnnes

Infiltrative dermopathy (1e, pretibial myxedema) and exophthalmos are symptoms more specific
for Graves disease

Patients with anorexia nervosa often experience amenorrhea due to loss of pulsatile secretion of
gonadotropin-releasing hormone (GnRH) from the hypothalamus. It is important to remember
that the defect
97



Patients with anorexia nervosa often experience amenorrhea due to loss of pulsatile secretion of
gonadotropin-releasing hormone (GnRH) from the hypothaIamus It is important to remember
that the defect in anorexia-related amenorrhea begins in the hypothalamus. not the pituitary or
ovahes Low estrogen levels over the long-term can result in osteoporosis if left untreated

Sulfonylurea or megidinide abuse and insulinoma cause increased insulin, c-peptide, and pro-
insulin leveIs The only way to distinguish between insulinoma and sulfonylurea or meglitinide
abuse is by screening the urine or blood for hypoglycemic agents.

Long-term use of supraphysiological doses of glucocorticoids causes suppression of the
hypothalamic-pituitary-adrenal axis, which in turn leads to bilateral adrenocortical atrophy. if the
patient then suddenly stops taking the doses of exogenous corticosteroids for whatever reason,
adrenal crisis can result.

Neonates of diabetic mothers may be exposed to high maternal glucose levels in utero and thus
may develop compensatory insulin hypersecretion Th.s results in fetal macrosomia and can cause
neonatal hypoglycemia Note that maternal insulin does not cross the placenta

Multiple endocrine neoplasia type 2B consists of medullary thyroid cancer, pheochromocytomas,
mucosal neuromas, and marfanoid habtus Pheochromocytomas should be excluded in all patients
with medullary thyroid cancer

Hydrochlorothiazide causes hypercalcerrna by increasing the distal tubular reabsorption of
filtered calcium, The increased serum calcium levels usually suppress PTH

Episodic hypertension, tachycardia. headaches. diaphoresis. and tremors are important clinical
clues for the presence of catec holamine-secreting tumors

Multiple endocrine neoplasia type 2B (MEN2B) is characterized by medullary carcinoma of the
thyroid. pheochromocytoma, and oral and intestinal mucosal neuromas MEN2A is also
associated with parathyroid hyperplasia, whereas MEN2B is not

1 The anterior pituitary is formed from an out-pouching of the pharyngeal roof and is called
Rathke’s pouch The postenor pituitary gland arises from an extension of the hypothalamic
neurons
2 Craniopharyngiomas are tumors ansing from Rathkes pouch remnants in the anterior pituitary
They characteristically have three components. solid, cystic, and cakIaed. They present during
childhood, usually, with mass effect and visual deficits.

Type 1 diabetes mellitus typically presents subacutely with polyuria, polydipsia, and polyphagia
accompanied by fatigue arid weight loss In the United States, fasting blood sugar is the most
preferred way to screen patients for diabetes mellitus. The USMLE will sometimes give you a
history of recent viral infection and the patient wift often be a young Caucasian adult
98


Hypercalcemia treated with neck surgery is hkely secondary to a parathyroid adenoma. A
pituitary tumor that compresses the optic chiasm can produce temporal visual field defects. The
MEN type 1 syndrome is characterized by tumors of the pituitary, parathyroid gland, and
pancreas (the 3 Ps’) individuals who have ttwo
                                            wo out of the three tumors should be evaluated for the
presence of the third tumor type.

Mononuclear, parenchymal infiltration with well
                                              well-developed
                                                   developed germinal centers is a characteristic
histological finding of Hashimotos thyroidths

High blood glucose lev&s in maternal circulation crosses the placenta causing fetal
hyperglycemia and islet cell hyperplasia. Hypennsulinernia caused by islet cell hyperplasia is
thought to cause fetal macrosomia.

Males with classic, non-salt-wasting
                                wasting 21
                                        21-hydroxylase
                                           hydroxylase deficiency present at age 2-4 2 years with
early virilization, increased linear growth, and elevated levels of 1717-hydroxyprogesterone
                                                                         hydroxyprogesterone and
androgens Females with classic 21  21-hydroxylase deficiency (with or without salt--wasting) present
with ambiguousous genitalia at birth.

Treatment of congenital adrenal hyperplasia involves low doses of exogenous corticosteroids to
suppress excessive ACTH secretion and reduce stimulation of the adrenal cortex.

Distorted body image. inadequate diet, regular exer
                                               exercise
                                                    cise while underweight, dry skin, and lanugo
hair in a female teenager suggest anorexia nervosa, Anorexic females commonly have low levels
of LH, FSH, estradiol. and estrone (hypogonadotropic amenorrhea).

Hypertension with low plasma rerUn activity is ssuggestive
                                                  uggestive of primary hyperaldosteronism, a
condition biochemically characterized by hypokalernia and metabolic alkalosis

Gastrinoma is characterized by upper GI ulcerations (jeunaI ulcers are quite specific), abdominal
pain and diarrhea

Activating mutations
              tations of the RET proto
                                  proto-oncogene
                                         oncogene are strongly associated with medullary thyroid
cancer RAS mutations are common in follicular thyroid cancer and some follicular adenomas.
Inactivating mutations of p53 are fairly common in anaplastic thyroid cancer

Multiple
     iple endocnne neoplasia type 1 consists of hyperparathyroidism. pancreatic tumors
(gastrinoma), and pftultary tumors (remember 3 ‘PsTM). The genetic defect in multiple
endocnne type I neoplasia involves the MENIN gene on the chromosome 11. Gastrinomas are
not present m the other MEN syndromes.

Meningococcal sept cerna can cause adrenal hemorrhage leading to acute adrenal crisis.




Psammoma bodies and ground glass. grooved nuclei are characteristic microscopic features of
papillary cancer of the thyroid
                            oid gland.
99



Medullary carcinoma of the thyroid gland is characterized by extracellular deposits of amyloid
formed by calcitonin secreted from neoplastic parafollicular C-cells.



PATHOLOGY-Genitourinary
A patient with a ruptured ectopic pregnancy would present with abdominal pain, vaginal
bleeding, hemorrhagic

A patient with a ruptured ectopic pregnancy would present with abdominal pain, vaginal
bleeding, hemorrhagic shock, and a history of amenorrhea Endometnal biopsy would reveal
decidual (gestateonal) changes in the endometrium but no chorionic villi

TNF-o is one of the cytokines that induces the systemic inflammatory response In high
concentrations. TNFc i causes symptoms of septic shock and cachexa Other cytoidnes
responsible for inducing the systemic inflammatory response include IL-i and IL-6.

A partial mole will have a tnploid karyotype Patients present with vaginal bleeding and lower
abdominal pain Unlike complete moles, partial moles are associated with low risk of invasive
trophoblastic disease

Clear cell carcinoma is the most common subtype of renal ce carcinoma and is composed of
large, rounded or polygonal cells with clear cytoplasrn The classic triad of hernaturia, flank pain,
and palpable mass occurs in a minority of patients Non-specific symptoms and paraneoplastic
syndromes are more common. These tumors are often detected incidentally at an advanced stage,
and the lung is the most common site for metastasiS.

Fever. maculopapular rash and symptoms of acute renal failure one to three weeks after
beginning treatment with a f3.Iactam antibiotic or a number of other drugs are highly suggestive
of acute interstitial nephntis Peripheral eosinophiha and eosinophiluna are important clinical
clues Symptoms resolve completely after cessation of the medication.

Massive interstitial infiltration with polymorphonuclear leukocytes is seen in acute
pyelonephritis Neutrophils also fill the tubular lurnina. Tubulonhexis and microabscesses may
also be present

The suppression of endogenous flora, the colonization of the distal urethra by pathogenic gram-
negative rods, and the attachment of these pathogens to the bladder mucosa are the stages of
pathogenesis in lower UT1s. Anatomic or functional vesicouretera reflux is virtually necessary
for the development of acute pyelonephntis.

Histologically, chonocarcinoma is composed of an abnormal proliferation of both
cytotrophoblasts and syncytiotrophob1asts No VdIi are present.
100


Urine supersaturation
                   tion is the mechanism underlying all types of kidney stones. Low fluid intake
increases the concentration of stone
                                  stone-forming
                                        forming agents, thus encouragwg stone formation All
patients with a history of nephrohthiasis should be advised to consume ample fluids

Endometriosis
   dometriosis is the presence of endometrial glands and stroma outside the uterus It may be
asymptomatic or present with severe dysmenorthea, dyspareunia and infertility.

Serial measurements of 13—hCG hCG should be performed following evacuation of a hydatidiform
                                                                                    hydatidi
mole. Persistently elevated or rising levels may signify the development of an invasive mole or c
horiocarcinoma

The clinical presentation of tertiary syphilis includes neurosyphilis. cardiovascular involvement,
and gummas. Gummas are necrotizing granulomas occumng on the skin, mucosa, subcutaneous
tissue, bones, and within other organs.

Polycystic ovarian syndromee (PCOS) is associated with oligomenorrhea, obesity, hirsutism and
polycystic ovanes These pabents are at increased risk for developing endometrial
adenocarcinoma and type 2 diabetes melhtus

The simultaneous development of stroke. intestinal or foot isc ischemia,
                                                                  hemia, and renal infarction should
make you think of embolic phenomena These emboli may anse from left atrial clots, left
ventricular clots, vavular vegetations, or aortic atherosclerotic plaques

WBC casts are formed in tubules. and are pathognomonic fo             forr acute pyeionephritis when
accompanied by systemic manifestations of febrile illness WBC casts are also seen with acute
interstitial nephritis. but clinical presentation is different in that patients have only a low-grade
                                                                                            low
fever and do not experience painf painful urination Pyuna and bactenuria are non--specific and are
found in both upper and lower UTIs.



A patient with signs of renal failure and toe gangrene or livedo reticularis following an invasive
vascular procedure likely has atheroembolic renal disea
                                                    disease
                                                         se Light microscopy shows cholesterol
emboli obstructing renal arterioles

A history of multiple sexual partners is a significant risk factor for development of squamous cell
carcinoma of
the cervix due to the increased nsk of transmission of carcinogen
                                                                carcinogenic
                                                                           ic strains of the Human
papdloma virus (16,
18, 31 & 33). Other nsk factors include cigarette smoking, lower socioeconomic status, and early
coitarche

Fibroadenomas are characterized by a cellular. often myxoid stroma that encircles and
sometimes compresses
               esses epithehum.
                     epithehum.-Iined glandular and cystic spaces
101


Primary ciliary dyskinesia. caused by an autosomal recessive mutation in the microtubule-
associated protein dynein, can cause Kartagener’s syndrome in about 50% of patients (vanable
penetrance). Kartagener4s syndrome is characterized by male infertibty. situs inversus, recurrent
sinusitis, and bronchiectasis.

Fever, pharyngibs, Iymphadenopathy hepatosplenomegaly. atypical lymphocytosis, and a
positive heterophile antibody reaction characterize infectious mononucleosis, which is caused by
the Epstein-Barr virus (EBV). EBV infection is also associated with an increased incidence of
Burkitt lymphoma and nasopharyngeal carcinoma.

Cystinuna results from a defect in the renal proximal tubules, which results in decreased
resorption of the amino acid cystine. The clinical manifestation is recurrent stone formation from
a young age Urinalysis shows pathognomonic hexagonal cystine crystals. The sodium cyanide-
nitroprusside test, which detects
rvctinp’c ci ilfhurfrvl nrni nc ic dinnnctir

Cystinuna results from a defect in the renal proximal tubules, which results in decreased
resorption of the amino acid cystine. The clinical manifestation is recurrent stone formation from
a young age. Urinalysis shows pathognomonic hexagonal cystine crystals. The sodium cyanide-
nitroprusside test, which detects cyshne’s sulfhydryl groups, is diagnostic

Benign prostatic hyperplasia leads to intermittent bladder outlet obstruction and overflow
incontinence. Urinary retention results in increased pressure in the urinary tract and resultant
reflux nephropathy. Ultimately, hydronephrosis and renal interstitial atrophy and scarring ensue
The condition should be promptly treated, as prolonged obstruction can cause permanent damage
and chronic renal failure

Famdial retinoblastoma occurs as a result of mutations of each of the two Rb genes (‘two hits”)
These patients have an increased risk of secondary tumors, especially osteosarcomas, later in Iife

Endornetnal cells undergo apoptosis upon withdrawal of endocrine stimulation by progesterone.

Central retinal artery occlusion (CRAO) presents with sudden, painless, and permanent
monocular blindness Funduscopic examination reveals a pale retina and a “cherry-red macula

Central retinal artery occlusion (CRAO) presents with sudden, painless, and permanent
monocular blindness. Funduscopic examination reveals a pale retina and a cherry-red” macula

Idiopathic hypercalciuria is the most common cause of calcium lódney stone disease This
condition is characterized by normal serum calcium levels with high levels of calcium excreted
in the urine. Other causes of calcium nephrolithiasis include hyperoxaluna. hyperuricosuria, low
urinary volume, and hypocitraturia.

Idiopathic hypercalciuha is the most common cause of calcium kidney stone disease This
condibon is characterized by normal serum calcium levels with high levels of calcium excreted
102


in the unne Other causes of calcium nephrohtheasis include hyperoxaluna, hyperuricosuna, low
urinary volume, and hypocitratuha

Hydronephrosis a dilation of the renal pelvis and calyces due to obstruction of urine flow.
Kidney enlargement and distortion, compression of the papdlae. thinning of the parenchyma
around the calyces, and cortical atrophy are seen on gross examination Microscopic changes
consist of dilation of the tubular lumen, flattening of the tubular epithelium, and interstitial
fibrosis The most common cause of urinary tract obstruction in elderly male patients is benign
prostatic hyperplasia (BPH)

Unc acid stones are the only type of renal calculi that are radiolucent They can be detected on
abdominal ultrasound or CT Afl other types of stones are radiopaque and can be seen on plain
abdominal X-ray.

PapiIary necrosis occurs in patients with sickle cell disease or trait, diabetes mellitus, analgesic
nephropathy. or severe obstructive pyelonephritis. Acute colicky flank pain, gross hematuria and
the passage of tissue fragments in urine are characteristic.

In pahents with cryptorchidism. the seminiferous tubules become atrophic and hyalinized as a
result of temperature-induced damage, resulting in a signihcantly depressed sperm count as well
as decreased inhibin levels Hormonal function of Leydig cells is usually not impaired Thus,
secondary sexual characteristics and sexual performance are normal Cryptorchidism should be
surgically corrected early in life to prevent damage to the seminiferous tubules and decrease the
pahent’s risk of testicular cancer

Cystinuna is an InbOrn defect of the transporter of cystine, omithine, arginine and lysine It is
inherited in an autosomal recessive fashion The only clinical manifestation of this disorder is
nephrohthiasis that classically presents as renal colic dunng the 2nd or 3rd decades of life
Unnalysis shows pathognomonic hexagonal cystine crystals.



PATHOLOGY-Git1
Shigeliosis is an infectious disease caused by vanous species of Sh.ieI!a S sonneiis the most
common (-80%) etiological agent in the United States Shigella invades the gastrointestinal
mucosa by first gaining access to M cells in Peye?s patches in the ileum through endocytosis
Shigella subsequently lyses the endosome, multiplies, and spreads laterally into other epithelial
cells, causing cell death and ulceration with hemorrhage and diarrhea

Carcinoid syndrome may accompany extraintestinal metastases of GI carcinoids Octreotide is a
synthetic somatostatin analog used to control the symptoms of carcinoid syndrome

Pancrealk pseudocyst is a common complication of acute pancreatitis It is a col’ection of fluid
rich in enzymes and inflammatory debns Its walls consist of granulation tissue and fibrosis
Unlike true cysts, pseudocysts are not lined by epithelium
103



80% of the cases of acute pancreatitis are caused by gallstones and chronic alcohohsm A number
of less common causes account for the other 20% of cases Inherited or acquired
hypertriglyceridemia can cause an acute pancreatitis if the level of triglycerides in serum exceeds
1000 mg/dL

IgA anti-tissue transglutaminase and IgA endomysial antibody are very sensitive and specific for
the diagnosis of celiac disease Small intestinal biopsy is confirmatory, severe atrophy and
blunting of the villi along with a chronic inflammatory infiltrate of the lamina propna is seen
Symptoms of celiac disease (diarrhea, steatorrhea, and nutritional deficiencies) subside with
exclusion of gluten-containing products from the diet.

Intussusception most often occurs in ciNidren younger than 2 years ol age and in the region of
the ileocecal valve. It manifests with intermittent, severe, colicky abdominal pain, “currant jelly”
stools, and sometimes a palpable mass in the light lower abdominal quadrant

Squamous cell carcinoma of the esophagus presents with progressive dysphagia as the tumor
gradually obstructs the esophageal lumen Chronic alcohol consumption and cigarette smoking
are 2 major risk factors On light microscopy, the tumor is composed of squamous cells with
vanous degrees of atypia Foci of keratinization are present in well-differenbated tumors.

Diarrhea, weight loss, and epigastnc region calcifications in a patient with chronic alcoholism
suggest chronic pancreatitis with resutting pancreatic exocnne insufficiency and malabsorption

Crohn’s disease is associated with increased activity of the NF-KB protein, which is responsible
for cytokine production. When the appropriate immune response to intracellular microbes is
blunted, the microbes persist and induce chronic inflammation within the gastrointestinal tract

Carcinoid tumors are composed of nests or sheets of uniform cells. They have eosinophihc
cytoplasm and oval-to-round stippled nuclei. These tumors are derived from enterochromaffin
cells of intestinal mucosa.

Colonic diverticula usually develop due to increased intraluminal pressure and are composed of
mucosa and submucosa. The most common site is the sigmoid colon Diverticula may be
asymptomatic or may manifest with painless rectal bleeding or acute diverticuhtis. Chronic
constipation is a risk factor for this condition.

Aicohol abuse is 1 of the 2 most common causes of acute pancreatitis (gallstones are the other)
Macrocytosis, an ASTALT ratio > 2, and elevated gamma-glutamyltransferase (GGT) are
indirect indicators of chronic alcohol consumption. Macrocytosis can occur independently of
folate or cobalamin deficiency

Crohn’s disease causes transmural inflammation of any area of the gastrointestinal tract The
involvement of all layers of the intestinal wall explains the most common complications of
Crohn’s disease strictures and fistula formation.
104


Vitamin A deficiency can cause night blindness Vitamin A deficiency may result from any cause
of fat soluble vitamin malabsorption, including ciwonic cholestasis from bihary obstruction

Dermatitis herpetiformis is associated with celiac disease. Dermatitis herpetiformis describes
groups of small vesicles that occur symmetrically on the extensor surfaces and are extremely
pruritic. Immunofluorescence reveals IgA deposits in the tips of dermal papillae.

Congenital pylohc stenosis ahses secondary to hypertrophy of the pyloric muscularis mucosae.

In acute interstitial pancreatitis the pancreas is grossly edematous Focal areas of fat necrosis,
calcium deposition and interstitial edema are seen on light microscopy. In necrotizing
(hemorrhagic) pancreatitis, chalky-white areas of fat necrosis interspersed with hemorrhage are
seen on macroscopic examination

Adenomatous polyps contain dysplastic mucosa and are premalignant Regular screening with
timely excision of polyps is effective for the prevention of colon adenocarcinoma. Studies have
linked increased activity of COX-2 to some forms of colon adenocarcinoma and suggest that
aspirin use decreases adenomatous polyp formation.

In ulcerative colitis:
1. The rectum is always involved.
2. Inflammation is limited to mucosa and submucosa only
3. Mucosal damage is continuous

Metastasis of gastric cancer can present as Virchows node, a Sister Mary Joseph nodule, or as
Krukenberg tumor of the ovary

Several factors are considered to be involved in the pathogenesis of Crohn’s disease Increased
activity of T1 helper cells increases production of IL.2, interferon-y, and TNF, causing
subsequent intestinal injury Nonc aseating granulomas, like the one seen on the slide above, are
charactenstic of Crohn’s disease

GERD is the most common cause of esophagitis. Gastroesophageal junction incompetence is the
pnmary pathophysiologic mechanism responsible for GERD Repeated exposure of esophageal
mucosa to acidic gastric contents causes chemical injury and inflammatory reachon Basal zone
hyperplasia, elongation of lamina propria papillae. and inflammatory cells (eosinophils,
neutrophils and lymphocytes) are characteristic histologic findings.

The 2 most significant risk factors for the development of esophageal squamous cell carcinoma
in the United
States are smoking tobacco and drinking alcohol. Betel nut chewing and the consumption of
foods containing
N-nitroso compounds are important risk factors in Asian countries.

Toxic megacolon is a well-recognized comphcabon of ulcerative colitis Abdominal pain and
distention, along with fever, diarrhea, and signs of shock are typical Plain abdominal X-ray
105


should be used for diagnosis Banum contrast studies and colonoscopy are con(raindicated due to
risk of perforation

Hereditary non-polyposis colon cancer (HNPCC) is also referred to as Lynch syndrome It leads
to occurrence of colonic adenocarcinomas at a young age (<50 years old), along with
predisposition for extraintestinal malignancies. Mutations of DNA mismatch repair genes are
responsible for this syndrome

Zolhnger-Elhson syndrome occurs due to hypersecretion of gastrin by a pancreatic tumor Gastnn
increases gastnc acid production, which causes peptic ulcers in the maionty of patients Mother
common symptom of Zollinger-Ellison syndrome, diarrhea, occurs due to the inactivation of
intestinal and pancreatic enzymes by excess gastric acid.

Cystic fibrosis is a genetic abnormality of exocrine secretion that leads to formation of thick,
viscous mucus The respiratory tract and pancreas are the organs most commonly affected The
pancreas characteristically shows duct obstruction by mucous plugs

Caused by the gram-positive actinomycete Tropheryma iihiopefr/ Whipple disease is a rare
systemic illness that involves the small intestine. joints, and central nervous system. Classic
histologic findings include small intestine mucosa containing enlarged. foamy macrophages
packed with both rod-shaped bacilli and PAS-positive, diastase-resistant granules.

Because the splenic flexure and distal sigmoid colon he between areas of perfusion of major
artenes. they are called “watershed” areas These two areas of the intestine are the most
susceptible to ischemic damage during hypotension I low perfusion states.

Obstruction of the lumen of the appendix is the first event in pathogenesis of acute appendicitis
Fec aliths, hyperplastic lymphoid follicles, foreign bodies, or tumors may cause the obstruction
Right lower quadrant abdominal pain, nausea, vomiting, diarrhea, and fever are the typical
manifestations of acute appendicitis

Crohn’s disease is associated with oxalate kidney stones Impaired bile acid absorption in the
terminal ileum leads to loss of bde acids in the feces with subsequent fat malabsorption Lipids
then bind calcium ions, and the resulting soap complex is excreted. Free oxalate (which is
normally bound by calcium ions to form an unabsorbable complex) is absorbed and forms
urinary calculi.

Adenomatous polyps are divided into tubular. villous. and tubulovillous according to their
histologic appearance Villous adenomas tend to be larger. sessile, and more severely dysplastic
than tubular adenomas. Villous adenomas can cause bleeding. secretory diarrhea, and partial
intestinal obstruction.

Intestinal metaplasia in the esophagus is a complication of long-standing GERD and is called
Barrett esophagus. Originally a protective response to injury by acidic stomach contents. Barrett
esophagus signitlcantty increases the nsk of esophageal adenocarcinoma
106


Mallory-Weiss tears account for about 10% of cases of upper GI hemOrrhage. They occur due to
increased intraluminal gastric pressure due to retching. vomiting, or other abdominal strainIng.

The main manifestation of Crohns disease is abdominal pain. Diarrhea, low-grade fever, and
symptoms of malabsorption are also common. Intestinal complications of Crohn’s disease
include fistulas and intestinal stnctures

The insèdious onset of nonbloody diarrhea. fever, maIase, and perianal fistulae should prompt an
evaluation for Crohn’s Disease, a form of inflammatory bowel disease that may wwolve any
portion of the GI tract from the mouth to the anus

Long-standing ulcerative colitis is associated with an increased risk of colorectal cancer The
duration and extent of colitis are the most significant risk factors Unlike sporadic colorectal
carcinomas, colitis-associated carcinomas are more likely to arise from non-polypoid dysplastk
lesions, be multifocal in nature, develop early p53 mutations and late APC gene mutations, and
be of a higher histological grade.

An anal fissure is a tear m the lining of the anal canal distal to the dentate line that occurs most
often on the posterior midline Patients complain of severe tearing pain associated with the
passage of bowel movements. There may be a skin tag on physical examination. Anal fissures
are associated with low-fiber diets and constipation.

Barrett esophagus is an intestinal metaplasia of esophageal epithelium It occurs in GERD and is
the most important risk factor for development of esophageal adenoc arc inoma As the sequence
of GERD —.Barrett esophagus —esophageal adenocarcinoma is well-recognized, early
diagnosis and regular monitonng of patients with gastroesophageal reflux is wnportant

Colon adenocarcinoma is the most common GI malignancy. It is most frequently located in the
rectosigmoid colon Patients with cancer at this location tend to present with obstructing
symptoms (altered bowel habits, constipation, abdominal distension, nausea and vomiting).

H. pyh,ninfection is associated with the formation of duodenal ulcers due to increased gastric
acidity The increased gastric acidity is caused by a decrease in somatostatin-secreting cells in the
gastric mucosa leading to unchecked gastrin production H pylonis also strongly associated with
the formation of gastric ulcers, gastritis. gastric adenocarcinoma, and gastric lymphoma.

Smoking is the most important environmental risk factor for pancreatic cancer Age> 50 years,
chronic pancreatftis, diabetes meibtus, and genetic predisposition also increase the risk of this
malignancy.

Type B chronic gastntis typically affects the gastric antrum and is usually the result of H. pylon
infection of the gastric mucosa, This type of gastritis is associated with an increased risk of
gastric adenocarcinoma and MALT lymphoma.

The rapid urease test is used in the diagnosis of HekcobacferpyIoriinfection Here, a samp’e from
the gastric mucosa is added to a solution containing a pH indicator and urea Urease will convert
107


urea to carbon dioxide and ammonia and cause a pH increase and resultant color change of the
pH indicator, indicating alkahnization of the solution.

Submucosal (Meissner) and myentenc (Auerbach) autonom,c plexi are absent in the affected
se9ment of the bowel in Hirschsprung disease The submucosa of the narrowed area is the most
superficial layer where the absence of ganglion cells can be seen




PATHOLOGY-Git 2
Carcinoid syndrome may accompany extraintestinal metastases of GI carcinoids Octreotide is a
synthetic somatostatin analog used to control the symptoms of carcinoid syndrome

Ulcers arising in the proximal duodenum in association with severe trauma or bums are called
Curling ukers
Ulcers arising in the esophagus, stomach, or duodenum in patients with high intracranial pressure
are
particularly prone to perforation and are called Cushing ulcers

Educational Objective:
Several factors are considered to be involved in the pathogenesis of Crohn’s disease Increased
activity of T_I helper cells increases production of IL-2, interferon-y, and TNF, causing
subsequent intestinal injury Nonc aseabng granulomas, like the one seen on the slide above, are
characteristc of Crohn’s disease

Shigellosis is an infectious disease caused by vahous species of Shigella S sonrielis the most
common (—80%) etiological agent in the United States, Shigella invades the gastrointestinal
mucosa by first gaining access to M cells in Peyer’s patches in the ileum through endocytosis
Shigella subsequently lyses the endosome, multiplies, and spreads laterally into other epithelial
cells, causing cell death and ulceration with hemorrhage and diarrhea

Adenomatous polyps are divided into tubular. vitlous. and tubulovillous according to their
histologic appearance. Villous adenomas tend to be larger, sessile, and more severely dysplastic
than tubular adenomas. Villous adenomas can cause bieeding, secretory diarrhea, and partial
intestinal obstruction.

Toxic megacolon is a well-recognized complication of ulcerative colitis Abdominal pain and
distention, along with fever, diarrhea, and signs of shock are typical Plain abdominal X-ray
should be used for diagnosis Barium contrast studies and colonoscopy are contraindicated due to
risk of perforation

Colon adenocarcinoma is the most common GI malignancy. It is most frequently located in the
rectosigmoid colon. Patients with cancer at this location tend to present with obstructing
symptoms (altered bowel habits, constipation, abdominal distension, nausea and vomiting).
108


He/icobacterpyloncan cause duodenal ulcers and is typically found in greatest concentration in
the prepylonc area of the gastric antrum As a result, biopsy of the prepytonc area would have the
greatest yield of the organism.

Type B chronic gastntis typically affects the gastnc antrum and is usually the result of H.
pyhxiinfection of the gastric mucosa This type of gastntis is associated with an increased risk of
gastric adenocarcinoma and MALT lymphoma

The 2 most significant nsk factors for the development of esophageal squamous cell carcinoma
in the United
States are smoking tobacco and drinking alcohol Betel nut chewing and the consumption of
foods containing
N-nitroso compounds are important risk factors m Asian countries.

The insidious onset of nonbloody diarrhea, fever, malaise, and perianal fistulae should prompt an
evaluation for Crohn’s Disease, a form of inflammatory bowel disease that may involve any
portion of the GI tract from the mouth to the anus.

An anal fissure is a tear in the lining of the anal canal distal to the dentate line that occurs most
often on the posterior midline. Patients complain of severe tearing pain associated with the
passage of bowel movements. There may be a skin tag on physical eXamination. Anal fissures
are associated with low-fiber diets and constipation

Non-neoplastic polyps (hyperplastic. hamartomatous. inflammatory) usually do not progress into
adenoc arc inoma of the colon Adenomatous polyps, however, can undergo mahgnant
transformation Villous adenomas are more likely than tubular adenomas to progress to adenoc
arc inoma

The rapid urease test is used in the diagnosis of H obacterpyIoiiinfection Here, a sample from the
gastric mucosa is added to a solution containing a pH indicator and urea Urease will convert urea
to carbon dioxide and ammonia and cause a pH increase and resultant color change of the pH
indicator, indicating alkalinization of the solution

The main manifestation of Crohn’s disease is abdominal pain Diarrhea. low-grade fever, and
symptoms of malabsorption are also common. Intestinal complications of Crohn’s disease
include fistulas and intestinal strictures.

Colonic diverticula usually develop due to increased intraluminal pressure and are composed of
mucosa and submucosa The most common site is the sigmod colon Diverticula may be
asymptomatic or may manifest with painless rectal bleeding or acute diverticulitis Chronic
constipation is a nsk factor for this condition.

Smoking is the most important environmental risk factor for pancreatic cancer. Age> 50 years,
chronic pancreatitis, diabetes mellitus, and genetic predisposition also increase the risk of this
malignancy
109


Carcinoid tumors are composed of nests or sheets of undorm cells They have eosinophilic
cytoplasm and oval-to-round stippled nuclei These tumors are derived from enterochromaffin
cells of intestinal mucosa

AJcohol abuse is 1 of the 2 most common causes of acute pancreatitis (gallstones are the other).
Macrocytosis, an ASTALT ratio >2, and elevated gamma-glutamyltransferase (GGT) are indirect
indicators of chronic alcohol consumption. Macrocytosis can occur independently of folate or
cobalamin deficiency.

Atherosclerotic artehal changes diminEsh blood flow to the intestine causing chronic mesenteric
ischemEa Its pathogenesis is similar to angina pectons. Postprandial abdominal pain, wesght
loss, and pain out of proporbon to physical findings are common.

GERD is the most common cause of esophagitis. Gastroesophageal junction incompetence is the
primary pathophysiologic mechanism responsible for GERD. Repeated exposure of esophageal
mucosa to acidic

GERD is the most common cause of esophagitis Gastroesophageal junction incompetence is the
primary pathophysiologic mechanism responsible for GERD Repeated exposure of esophageal
mucosa to acidic gastric contents causes chemical injury and inflammatory reaction Basal zone
hyperplasia, elongation of lamina propria papillae, and inflammatory cells (eosinophils,
neutrophils and lymphocytes) are characteristic histologic findings

Carcinoembryonic antigen (CEA) level is increased in colon cancer, as well as in other
malignancies and certain benign diseases CEA cannot be used to diagnose colon cancer, but is
helpful for detecting disease recurrence

Kaposi’s sarcoma usually involves the skin and (31 tract and is common in HIV patients not on
antiretroviral therapy Endoscopy reveals characteristic lesions, which range from reddishMolet
flat maculopapular lesions to raised hemorrhagic nodules or polypoid masses Biopsy can show
spindle cells, neovascularization. and extravasated red blood cells.

Hereditary non-polyposis colon cancer (HNPCC) is also referred to as Lynch syndrome It leads
to occurrence of colonic adenocarcinomas at a young age (<50 years old), along with
predisposition for extraintestinal malignancies Mutations of DNA mismatch repair genes are
responsible for this syndrome

Obstruction of the lumen of the appendix is the first event in pathogenesis of acute appendicths
Fecaliths, hyperplastic lyrnphoid follicles, foreign bodies, or tumors may cause the obstruction
Right lower quadrant abdominal pain, nausea. vomiting, diarrhea, and fever are the typical
manifestations of acute appendicitis.

Uohns disease causes transmural inflammation ot any area 01 the gastrointestinal tract I he
involvement of all layers of the intestinal wall explains the most common complications of
Crohn’s disease stnctures and fistula formation
110


There are two morphologcal variants of gastric adenocarcinoma Intestinal type forms a solid
mass that projects into the stomach lumen and is composed of glandular-forming cuboidal or
columnar cells Diffuse carcinoma (linitis plastica) infiltrates the stomach wall and displays a
signet-ring pattern on light microscopy

Subinucosal (Meissner) and myenteric (Auerbach) autonomic plexi are absent in the affected
segment of the bowel in Hirschsprung disease The subrnucosa of the narrowed area is the most
superficial layer where the absence of ganghon cells can be seen

The glycoprotein in the cell walls of the actinomycete Tropheryma ih4eWcolors magenta with
PAS and is diastase-resistant, making this stain an excellent choice in evaluating tissue for
Whipple disease.

Malabsorption isa syndrome of impaired intestinal digestion and absorption Diarrhea,
steatorrhea, weight loss, and vitamin and mineral deficiencies are common Sudan Ill stain of
stool identifies fecal fat and is used to screen for malabsorption

H pyloninfection is associated with the formation of duodenal ulcers due to increased gastric
acidity The increased gastric acidity is caused by a decrease in sornatostatin-secreting cells in the
gastric mucosa leading to unchecked gastnn production. H. pyhnis aiso strongly associated with
the formation of gastric ulcers, gastritis, gastric adenocarcinoma, and gastric lymphoma

The size of adenomatous polyps determines their malignant potential. Adenomas <1 cm are
unlikely to undergo malignant transformation, while those >4 cm are very likely (40%) to
progress to adenocarcinoma K! asprotooncogene mutation facilitates the growth of adenomas by
causing uncontrolled cell prohferation

Cystic fibrosis is a genetic abnormality of exocrine secretion that leads to formation of thick,
viscous mucus The respiratory tract and pancreas are the organs most commonly affected The
pancreas characteristically shows duct obstruction by mucous plugs

One of the earliest visceral manifestations of systemic sclerosis is esophageal hypomotihty and
incompetence of the lower esophageal sphincter due to atrophy and fibrous replacement of the
esophageal muscles Esophageal dilatation causes reflux, which increases the nsk of Barrett
esophagus and esophageal adenoc arc inoma,

In ulcerative colitis:
1 The rectum is always involved
2. Inflammation is limited to mucosa and submucosa only.
3. Mucosal damage is continuous.

APC mutation is required for the emergence of small adenomatous polyps from normal colonic
mucosa. This mutation constitutes the first step of the adenoma-to-carcinoma sequence APC
gene mutation is found in most cases of sporadic colon cancer and in all familial polyposis
syndromes
111


Zollinger-Ellison syndrome occurs due to hypersecretion of gastrin by a pancreatic tumor Gastrin
increases gastric acid production, which causes peptic ulcers in the majonty of patients Mother
common symptom of Zollinger-Ellison syndrome, diarrhea, occurs due to the inactivation of
intestinal and pancreatic enzymes by excess gastric acid.

Acute erosive gastropathy can be caused by a number of factors, including nonsteroidal anti-
inflammatory drug use, head trauma, severe bums, acute stress, and alcohol or tobacco use,
Erosions are defined as mucosal defects that do not fully extend through the musculans mucosa.
Acute erosive gastropathy can cause upper gastrointestinal hemorrhage that leads to meleria

In acute interstitial pancreatitis the pancreas is grossly edematous Focal areas of fat necrosis,
calcium deposition and interstitial edema are seen on light micrOscopy. In necrotizing
(hemorrhagic) pancreatitis, chalky-white areas of fat necrosis interspersed with hemorrhage are
seen on macroscopic examination.

Congenital pyloric stenosis anses secondary to hypertrophy of the pyloric muscularis mucosae,

Diarrhea, weight loss, and epigastric region calcitlcations in a patient with chronic alcoholism
suggest chronic pancreatitis with resulting pancreatic exocrine insufficiency and malabsorption

Abetalipoproteinemia is an inherited inability to synthesize apolipoprotein B, an important
component of chylomicrons Lipids absorbed in the small intestine cannot be transported and
therefore accumulate in the intestinal epithelium. Lack of lipids in the cell membranes causes
abnormal red blood cells (acanthocytes) and neurologic deficits.

Parietal cells secrete hydrochloric acid and intrinsic factor and are primarily found in the
superficial region of gastric glands. Chief cells synthesize and secrete pepsinogen and are
primarily found in the deeper region of gastric glands

Pancreatic pseudocyst is a common complication of acute pancreatitis It is a collection of fluid
hch in enzymes and inflammatory debns Its walls consist of granulation tissue and fibrosis
Unlike true cysts, pseudocysts are not lined by epithehum

Patients with Crohn’s disease affecting the terminal ileum are prone to the development of
gallstones. Decreased bile acid reabsorption and its loss via feces increases the lithogenicity of
bile Cholesterol precipitates and forms gallstones.

Because the splenic flexure and distal sigmoid colon lie between areas of perfusion of malor
arteries, they are called “watershed” areas. These two areas of the intestine are the most
susceptible to ischemic damage during hypotension I low perfusion states.
112


PATHOLOGY-Hepatic
Absorbed copper is used to form ceruloplasmin, which accounts for 90-95% of circulating
copper Senescent ceruloplasmin and the unabsorbed copper are secreted into bile and excreted in
stool, which is the primary route for copper elimination.

Hepatitis B virus infection is associated with a serum-sickness like syndrome in the prodromal
period.

Hepatocyte injury in vial hepatitis is characterized by a diffuse swelling termed Thallooning
degeneration’ Hepatocyte death in wal hepatitis is charactenzed by lobular architectural
disruption and confluent hepatocyte necrosis, a process called “bndging necrosis In response to
the hepatocellular injury and death. mononuclear inflammation develops m the sinusoids and
portal tracts.

Gallbladder hypomotibty often results in bile precipitation and the formation of biliary sludge.

Acute acalculous cholecysttis is an acute inflammahon of the gallbladder in the absence of
gallstones It is most commonly seen in the hospitalized and severely ill

The Kayser-Fleischer ring is an ophthalmologic finding most strongly associated with Wilsons
disease It is seen most frequently in patients with neuropsychiatric complications. Basal gangha
atrophy is typically present in these patients.

The diagnosis of alpha-i antitrypsin deficiency should be suspected in all patients with premature
onset (< 50 years) of chronic bronchitis. emphysema. or dyspnea, as well as in nonsmokers
suffering from chronic obstructive pulmonary disease (COPD) A history of neonatal hepatitis
with cholestasis should heighten suspicion for A1AT deficiency.

Brown pigment stones typically arise secondary to infection of the biliary tract, which results in
the release of 3-glucuronEdase by injured hepatocytes and bactena The presence of this enzyme
contnbutes to the hydrolysis of bibrubin glucuronides and increases the amount of unconjugated
bilirubin in bile

To reduce the likelihood of cholesterol precipitahon (and gallstone formation), cholesterol
quantities should be kept low and bile acid quantities kept high. High levels of
phosphatidyicholine. a phospholipid that renders cholesterol soluble, are also associated with
decreased risk of gallstones

The most common hepatic lesion is a metastasis from another pnmary site (eg, breast, lung,
colon), not hepatocellular carcinoma

The cIassc picture of primary biliary cirhosis is a middle-aged Caucasian female with a long
history of pruntus and fatigue who now develops pale stool and xanthelasma (suggestive of
cholestasis)
113


High levels of dietary aflatoxin exposure is associated with a G:C —a T:A transversion in codon
249 of the p53 gene, a mutation thought to greatly increase the risk of developing hepatocellular
carcinoma

Acute cakulous choecystitis is an acute inflammation of the gallbladder that is initiated 90% of
the time by obstruction of the gallbladder neck or cystic duct.

Total parenteral nutrition can induce gallstone formation secondary to biliary stasis from absent
enteral stimulation or disturbance of the enterohepatic bile acid circulation in those with deal
resections

Late-stage hemochromatosis can be characterized by bronze diabetes, the tnad of skin
hyperpigmentation, diabetes meUitus, and pigment cirrhosis with hepatomegaly

Inhaled anesthetics, such as halothane. can be associated with a highly lethal fulminant hepatitis
that cannot be histologically distinguished from acute viral hepatitis. Patients present with
significantly elevated aminotransferase levels, a prolonged prothrombin time, and eosinophilia.

Black pigment stones are associated with chronic extravascular hemolysis.

Hepatocellular carcinoma is strongly associated with HBV infection. Integration of viral DNA
into the genome of host hepatocytes triggers neoplastic changes Other risk factors for
hepatocellular carcinoma include HCV, akoholic cirrhosis, aflatoxins and hemochromatosis.

The most common outcome in HBV-infected adults (> 95%) is acute hepatitis with mild or
subclinical symptoms that eventually completely resolve.

Anorexia. nausea, and low-grade fever followed by bElirubnuria and right upper quadrant
tenderness suggest acute hepatitis, which is most commonly caused by the Hepatitis A virus in
young adults Acute hepatitis due to most hepatotropic viruses causes hepatocyte ballooning
degeneration and apoptosis on histologic exam

Cholecystectomy is recommended for those with porcelain galibladders because 11-33% of this
patient population will eventually develop gallbladder carcinoma

Dubin-Johnson syndrome is characterized by a defect in the hepatic excretion of bilirubin
glucuronides across the canalicular membrane Grossly. the liver is stnkingly black Histological
features are normal, though a dense pigment composed of epinephnne metabohtes within the
lysosomes can be seen

Individuals with stable. compensated cirrhosis who suddenly decompensate without apparent
reason should be carefully evaluated for hepatocellular carcinoma, especially when serum AFP
levels are also elevated.

Primary biliary cirrhosis and graft versus host disease have similar histologic findings, including
granulomatous bile duct destruction and a heavy lymphocyte-predominant poital tract infiftrate
114


The genetic mutation of hemochromatosis prevents expression of the HFE protein on the
basolateral surface of the intestinal cells where it normally binds to the transfemn receptor and
regulates transferrin/iron complex endocytosis into the cells As a result. there is unregulated
expression of the iron uptake proteins and an excessive amount of iron is absorbed
gastrointestinally Liver cirrhosis and hepatocellular carcinoma are two of the more ominous
potential complications of this disease.

Cirrhosis is microscopically charactenzed by diffuse hepatic fibrosis with replacement of the
normal lobular architecture by fibrous-lined parenchymal nodules.

Hepatitis B infection causes the hepatocellular cytoplasm to fill with the spheres and tubules of
HBsAg (the hepatitis B surface antigen) and take on a finely granular. eosinophihc appearance
commonly described as “ground glass.”

Estrogen-induced cholesterol hypersecretion and progesterone-induced gallbladder hypomotility
are responsible for the increased incidence of cholelithiasis in women who are pregnant or using
oral contraceptives.

The pathogenesis of alcohol-induced hepatic steatosis appears related primarily to a decrease in
free fatty acid oxidation secondary to excess NADH production by the 2 major alcohol
metabolism enzymes, alcohol dehydrogenase and aldehyde dehydrogenase

Stable chronic hepatitis is the most likely outcome for a patient acutely infected with hepatitis C
virus, followed closely by chronic hepatitis progressing to cirrhosis.

Physiologic iron loss through menstruation and pregnancy slows the progression of
hemochromatosis in women.

Alpha-i antitrypsin (AIAT) is a serum protein that reduces tissue damage caused by
inflammation through the inhibition of neutrophil elastase, Histologically. A1AT deficiency is
associated with reddish-pink, periodic acid-Schiff-positive granules of unsecreted, polyrnerized
AIAT in the periportal hepatocytes

Alcoholic liver injury develops through the stages of alcoholic steatosis. alcoholic hepatitis anJ
cirrhosis. Increased AST and ALT are indicators of hepatocellular damage The serum albumin
level and prothrombin time reflect liver function and are of greatest prognostic Significance.

A positive HIDA scan confirms cystic duct obstruction, which is necessary for a definitive
diagnosis of acute calculous cholecystitis Nonobstructing biliary stones seen by ultrasound are
suggestive but not diagnostic of the condition

Reye syndrome occurs in children with febrile illness treated with saIicyIates It consists of
hepatic failure and encephalopathy The characteristic histological finding is microvesicular
steatosis of hepatocytes without inflammation and cerebral edema.
115


Staphylococcus aureus can cause hepatic abscess through hernatogenous seeding of the liver
Enteric bacteria can cause hepatic abscess by ascending the biliary tract or directly invading from
an adjacent area

Extrahepatic bitiary atresia occurs due to complete obstruction of extrahepatic bile ducts Patients
develop persistent jaundice beginning around the 3 or week of life, accompanied by dark urine,
acholic stools and a conjugated hyperbihwbinemia Liver biopsy shows marked intrahepatic bile
ductular proliferation, portal tract edema and fibrosis, and parenchymal cholestasis.

The findings of fever. jaundice. and anorexia in an IV drug user suggest the diagnosis of viral
hepatitis, most likely due to hepatitis C mfection. Acute viral hepatitis causes hepatocyte
apoptosis and necrosis. Apoptotic hepatocytes shrink, undergo nuclear fragmentation and
become intensely eosinophilic. They may also be referred to as acidophibc bodies, Councilman
bodies, and apoptotic bodies.

Primary biliary cirrhosis is a chronic hver disease characterized by autoimmune destruction of
the intrahepatic bile ducts and cholestasis (elevated alkaline phosphatase). The condition is most
common in middle-aged women, with severe pruntus (especially at night) one of the first
symptoms reported.

Aipha-fetoproteinis a useful marker in the evaluation of cirrhotic patients who are at increased
risk for developing hepatocellular carcinoma Regular monitoring of AFP in this patient
population is recommended

Cavernous hemangiorna is the most common benign liver tumor Microscopically, these tumors
consist of cavernous, blood-filled vascular spaces of variable size lined by a single epithehal
layer The biopsy of a suspected hemangioma is not advisable, as the procedure has been known
to cause fatal hemorrhage and is of low diagnostic yield.

The hemochromatosis gene (HLA-H) is on the short arm of chromosome 6 and encodes for a
molecule that appears to affect iron absorption from the gastrointestinal tract

Estrogenc influence facilitates the biosynthesis of cholesterol by increasing hepatic HMG-CoA
reductase actMty Suppression of cholesterol 7cz-hydroxylase actMty (by medications such as
fibrates) reduces the conversion of cholesterol to bile acids, resulting in excess cholesterol
secretion in bile

Advanced Wilson disease is often characterized by neuropsychiatnc symptoms, including
Parkinsonian-hke tremor, rigidity, ataxia. slurred speech, drooling, personality changes.
depression, paranoia, and catatonia OJmost all patients with neuropsychiatric involvement will
also have Kayser-Fleisc her rings, which can be identified on slit lamp examination.

Aspiration of hydatid cysts is generally inadvisable, as the spilling of cyst contents within the
peritoneum can cause anaphylactic shock.
116


Gallstone ileus is a rare type of mechanical bowel obstruction caused when a large gallstone
erodes into the intestinal lumen. Pneumobiha (air in the bihary tract) is suggestive of the
diagnosis.




PATHOLOGY-Neuro 1
Cerebral amyloid angiopathy is a common cause of recurrent lobar hemorrhage This type of
intracranial hemorrhage has a lower mortality rate and more benégn clinical course than
hemorrhagic strokes associated with hypertension

Synaptophysin is a protein found in the presynaptic vesicles of neurons. neuroendocrine and
neuroectodermal cells, CNS tumors of neuronal origin frequently stain positively for
synaptophysin on immunohistology Neoplasms of glial origin (astrocytomas, ependymomas. and
oligodendrogliomas) stain for GFAP

Liquefactive necrosis is characterized by complete digestion and removal of necrotic tissue with
formation of cystic cavity. Hypoxic CNS injury is often followed by hquefactive necrosis.
Abscess formation due to bacterial or fungal infection is another example of this type of necrosis.

The subthalamic nucleus is one of the components of the basal ganglia Damage to this nucleus
(most often due to lacunar stroke) leads to hemibalhsm, The wwoluntary flinging movements of
one side of the body (arm and/or leg) that constitutes hemiballism are always contralateral to the
lesion

Subarachnoid hemorrhage presents with a generakzed. excruciating headache It is classically
described by patients as ‘The worst headache of my life.” Subarachnoid hemorrhage usually
occurs due to rupture of saccular (berry) aneurysms or artenovenous maWormatons. Berry
aneurysms of the circle of Willis are associated with autosomal dominant polycystic kidney
disease

The hippocampus is the area of the brain demonstrating the greatest degree of atrophy in
AIzheimers disease Hippocampal atrophy on MRI is highly suggestive of the diagnosis

Duchenne muscle dystrophy manifests with proximal muscle weakness and atrophy. True
hypertrophy of the distal muscle is noted early in the disease as distal muscles compensate for
weak proximal ones. Later, muscle fibers of the distal extremities are replaced by fat and
connective tissue (pseudohypertrophy).

Both myasthenia gravis and Lambert-Eaton syndrome are caused by poor sgnaI transmission at
the neuromuscular junction Lambert-Eaton syndrome is associated with underlying malignancy
Antibodies to voftage-gated presynaptic calcium channels are found in these patients
117


Bilateral acoustic neuromas are associated with r,eurofibromatosis type 2, an autosomal
dominant condition caused by mutation of the NF-2 gene on chromosome 2Z

Severe vitamin E deficiency closely resembles the clinical presentation of Friedreich ataxia
Vitamin E is a lipd-solubIe vitamin that has antiox,dative properties

Pituitary adenornas cause symptoms from mass effect and often produce endocrine disorders
from the vanous hormones that they can produce. Prolactinomas are the most common
adenoma—excess prolactin causes amenorrhea and galactorrhea. Bitemporal hemianopsia from
compression of the optic chiasm is common.

A cystic tumor in the cerebellum of a child is most likely a pdocytic astrocytoma Biopsy will
show a welld ifferentiated neoplasm comprised of spindle cells with hair-like ghal processes that
are associated with microcysts These cells are mixed with Rosenthal fibers and granular
eosinophilic bodies

Subacute scierosing encephahtis is a rare complication of measles infection. It occurs several
years after apparent recovery from initial infecbon Oligoclonal bands of antibodies to the
measles virus are found in the CSF of these patients. Antibodies to the M component of the
measles virus are absent

CNS involvement in syphihs (neurosyphiks) may manifest as a number of syndromes Tabes
dorsalis occurs due to demyelination of dorsal columns and dorsal roots of the spinal cord Loss
of proprioception and vibration senses, ataxia. and Argyll Robeftson pupil may be seen.

A cerebellar hernangioblastoma in association with congenital cysts of the kidneys, liver, and/or
pancreas is highly suggestive of von Hippel—Lindau disease. a rare autosomal dominant
condition
Note: The syndromes descnbed above are common’y tested on USMLE exams It is important to
be familiar with them.

Counting down from 100 by 7 or3, reciting the months of the year in reverse order, and spelling
“world” backwards are quick clinical tests to assess attention and concentration Attention and
concentration are tested as part of the Mini-Mental State Examination (MMSE), a wdely used
screening tool for cognitive impairment The MMSE also measures onentaton to time and place,
short-term memory, calculation, language, and constructional praxis.

1. Holoprosencephaly results from failure of forebrain cleavage into cerebral hemispheres. It is
an example of a congenital malformation, a primary abnormality in a development process
2 Amniotic band syndrome is an example of a disruption (secondary destruction of a previously
well-formed tissue or organ).
3. Congenital hip dislocabon, clubbed feet and flat facies (Potter syndrome) are examples of
deformations (secondary to extnnssc compression).
4. Potter syndrome is also an example of a sequence.
118


Subdural hematoma occurs due to the rupture of cortical bridging veins In young patients, it
results from a fall or motor vehicle accident, and manifests with gradual onset of headache and
confusion In elderly patients it may occur after a minor trauma and present with a variety of
neurologic symptoms. You should know how to recognize this on CT scan

Meniére’sdEsease is characterized by the triad of tinnetus, vertigo and sensorineural hearing loss
Its pathogenesis is related to an increased volume and pessure of endolymph in the vestibular
apparatus

Cluster headaches cause severe. episodic. unilateral periorbital and temporal pain associated with
lacrimation, nasal congestion and ptosis Cluster headaches classically occur at the same time
each day and are more common in males.

A neuron that is responding to irreversible injury is called a red neurons Characteristic changes
become evident 12-24 hours after the injurious event and include shrinkage of the cell body,
eosinophilia of the cytoplasm. pyknosis of the nucleus and loss of Nissl substance

The infusion of glucose without thiamine in a patient with chronic thiamine deficiency
precipitates encephalopathy Confusion, ataxia. and ophthalmoplegia form the thad of Wemicke
encephalopathy. Hemorrhage into the mamillary bodies is characteristic

Picks disease causes pronounced atrophy of the frontal lobe. Clinically, it manifests with
progressive dementia, behavioral disinhibition. and speech difficulties, such as dysarthna.
aphasia, and echolalia

Guillain-.Barre syndrome is an acute demyelinating peripheral neuropathy. It affects young
adults and is usually preceded by a febrile illness. Segmental demyehnation of peripheral nerves
and an endoneural inflammatory infiltrate are seen on light microscopy.

Meningiomas are slowly growing. weli-circumscribed and benign tumors. Psammoma bodies are
characteristic of meningiomas Psammoma bodies are composed of a core of dense calcification
with surrounding collagen-fiber bundles

Arnold-Chiari malformations are congenital abnormalities They are caused by impaired
development of the posterior fossa Arnold-Chiari type I is relatively benign and may manifest in
adulthood Arnold-Chiari type II is severe and is evident in the newbom

Myelopathy associated wfth vitamin B2 deficiency is called subacute combined degeneration.
“Combined refers to degeneration of both the ascending (dorsal columns) and descending
(corticospinal tract) pathways Loss of position and vibration sensation. ataxia, and spastic paresis
are common manifestations.

Duchenne muscular dystrophy is an X-liriked condition. It occirs due to deletion of the
dystrophin gene Dystrophin is a protein that allows interaction between extracellular connective
tissue and the intracellular contraction apparatus The disease manifests in boys aged 3-6 with
proximal muscle weakness and enlargement of the distal muscles.
119



Subarachnoid hemorrhage occurs due to rupture of saccular (berry) aneurysm or arteriovenous
malformation. Severe vasospasm 4— 12 days after the initial insult is the major cause of
morbidity and mortality in patients recovering from SAH Nimodipine. a selective calcium
channel blocker, is often prescribed to prevent this vasospasm.

Demyelination (denudation means removal of covering) of axons in the white matter is a
hallmark of multiple sclerosis. The areas of demyehnation form charactenstic plaques. The
symptoms of the disease depend on the plaque location. Involvement of the MLF leads to
internuclear ophthalmoplegia

Tremulousness is commonly the first symptom of alcohol withdrawa[ Other common symptoms
are GI distress, agitation, anxiety, and autonomic disturbance Delirium tremens is the most
severe manifestation of alcohol withdrawal and typically begin between 48 and 72 hours after the
last drink

Irreversible ischernic injury to the brain tissue results in liquefactive necrosis The infarcted CNS
tissue is eventually replaced with a cystic astroglial scar In other organs, lethal Eschemic injury
generally produces coagulative necrosis Fibnnoid necrosis is seen in some vasculitides Caseous
necrosis results from tuberculosis Nonenzymatic f at necrosis follows local trauma to adipose
tissue.

Primary CNS lymphomas occur in immunosuppressed patients. such as those suffering from
AiDS These tumors arise from B cells and are universally associated with EBV They are high-
grade tumors with a poor prognosis.

The changes in the body of a neuron after the axon has been severed are called axonal reaction.
This process reflects an increased protein synthesis that facilitates axon repair Enlarged, rounded
cells with peripherally located nuclei and dispersed finely granular Nissi substance are seen.

Hemiparesis with the arm affected more than the leg occurs due to occlusion of the middle
cerebral artery (MCA). If the occluded NCA is in the dominant hemisphere (usually the left),
aphasia may also occur.

Neurofibrillary tangles and amyloid plaques are classic findings in Alzheimerrs dementia.

Medulloblastoma is the second most common brain neoplasm of childhood It is located in the
cerebellum. often at the vermis, and consists of sheets of small, blue cells, Like other PNE
tumors, medulloblastomas are poorly differentiated and have a bad prognosis.

Vitamin E deficiency can occur in indivdua1s suffering from fat malabsorption or
abetalipoproteinemia. Deficiency of this fat-soluble vitamin is associated with increased
susceptibility of the neuronal and erythrocyte membranes to oxidative stress.
120


Rapid correction of chronic hyponatrerrna may lead to osmotic demyelination of the axons in the
central part of the pons. This condition is called central pontine myehnolysis It manifests with
spastic quadriplegia and pseudobulbar palsy.

Friedre,ch ataxia is characterized by cerebellar ataxia. loss of position and vibration sensation,
kyphoscohosis. and hypertrophic cardiomyopathy. Foot abnormalities and diabetes mellitus are
also common.

Neuropathy is a frequent complication of diabetes melhtus It is caused by diabetic
microangiopathy which leads to nerve schemia Mother pathogenetic factor is the accumulation
of sorbitol, which leads to osmotic nerve injury. The symmetric peripheral neuropathy descnbed
in this vignette is common

True hydrocephalus is an increase in CSF volume and pressure that occurs due to the abnormal
production, flow, or absorption of CSF. The pressure increase then causes ventricular
enlargement hi hydrocephalus e.r vacuc, ventricular enlargement occxs due to brain atrophy and
is not accompanied by increase in CSF presSure.

Proliferation of aStrOCyteS in an area of neuron degeneration is called gIiosis It leads to the
formation of a glial scar which compensates for the volume loss that occurs after neuronal death

Hypertension is the most common overall cause of intraparenchymal hemorrhage, usually
through the formation of small Charcot-Bouchard pseudoaneurysms in the small arterio’es that
penetrate the basal ganglia and thalami, This should be contrasted with rupture of a saccular
aneurysm which typically presents with subarachnoid hemorrhage.

Mu(tiple sclerosis is viewed as an autoimmune condition. Viral and environmental factors are
also considered to play a role in its development Increased levels of lgG in the CSF. detected as
an oligoclonal band on electrophoresis, supports the immunologic theory

Multiple sclerosis is an autoimmune dernyelinating disease Within the p’aques, loss of myelin
sheaths and depletion of ohgodendrocytes is seen Ohgoclonal bands of lgG may be detected in
cerebrospinal fluid Oligodendrocyte depletion is also seen in progressive multifocal
leukoencephalopathy
121


PATHOLOGY-Neuro 2
CNS involvement in syphilis (neurosyphilis) may manifest as a number of syndromes Tabes
dorsahs occurs due to demyehnation of dorsal columns and dorsal roots of the spinal cord Loss
of propnoceptlon and vibration senses, ataxta. and Argyll Robertson pupd may be seen

Syringomyelia is characterized by the formation of a cavity (syrinx) in the cervical region of the
spinal cord. The syrinx damages the ventral white commissure, leading to bilateral loss of pain
and temperature sensation that is limited to the affected levels (typically the arms and hands);
distal sensation is preserved Destruction of the motor neurons in the ventral horns (due to
extension of the syrinx) causes flaccid paralysis and atrophy of the intrinsic muscles of the hand

Amold-Chiari malformations are congenital abnormalities. They are caused by impaired
development of the posterior fossa Arnold-C hian type I is relatively benign and may manifest in
adulthood Arnold-Chiari type II is severe and is evident in the newbom

Multiple sclerosis is viewed as an autoimmune condition Viral and environmental factors are
also considered to play a role in its development. Increased levels of lgG in the CSF, detected as
an oligoclonal band on electrophoresis, supports the immunologic theory.

Multiple sclerosis is an autoimmune demyehnating disease. Within the plaques, loss of myelin
sheaths and depletion of oligodendrocytes is seen Ohgoclonal bands of lgG may be detected in
cerebrospinal fluid Oligodendrocyte depletion is also seen ii progressive multifocal
leukoencephalopathy.

Subacute sclerosing encephalitis is a rare complication of measles infection It occurs several
years after apparent recovery from iwtial infection Ohgoclonal bands of antibodies to the
measles virus are found in the CSF of these patients Antibodies to the M component of the
measles virus are absent,

A cerebellar hemangiobLastoma in association with congenital cysts of the kidneys, bver. and/or
pancreas is highly suggestive of von Hippel—Lindau disease, a rare autosomal dominant
condibon

Vitamin E deficiency can occur in individuals suffering from fat malabsorption or
abetahpoproteinemia Deficiency of this fat-soluble vitamin is associated with increased
susceptibility of the neuronal and eMhrocyte membranes to oxidative stress

Subarachnoid hemorrhage occurs due to rupture of saccular (berry) aneurysm or artenovenous
malformation, Severe vasospasm 4— 12 days after the initial insult is the major cause of
morbidity and mortality in patients recovering from SAl-I. Nimodipine. a selective calcium
channel blocker, is often prescribed to prevent this vasospasm

Primary CNS lymphomas occur in immunosuppressed patients, such as those suffering from
AIDS These tumors arise from B cells and are universally associated with EBV. They are high-
grade tumors with a poor prognosis
122



Anemia associated with neurologic abnormalities is fairty specific to vitamin B12 deflciency
Neurological damage associated with B12 deficiency includes subacute, combined degeneration
of the posterior and lateral spinal columns Increased serum level of methylmalonic acid is
diagnostic of vtamin B12 deficiency.

A biphasic pattern (Antoni A and B areas) and S-100 positivdy indicate schwannoma Cranial
nerves are covered by Schwann cells: therefore. schwannomas can arise from any cranial nerve,
except CN II The acoustic neuroma, which is located at the cerebellopontine angle at CN Vill, is
the most common schwannoma Melanomas are also S-tOO positive because both melanocytes
and Schwann cells are derived from the neural crest.

The hippocampus is the area of the brain demonstrating the greatest degree of atrophy in
Alzheimer’s disease Hippocampal atrophy on MRI is highly suggestive of the diagnosis

Amyotrophic lateral sclerosis (ALS) causes both upper and lower motor neuron lesions Loss of
neurons of the anterior horns of the spinal cord (LMN lesion) causes muscle weakness and
atrophy Demyelination of the lateral corticospinal tract (UMN lesion) leads to spasticity and
hyperreflexia

Elevated protein, normal glucose. and lymphocytic predominance are characteristic of viral
meningitis

Transtentorial (i.e., uncal) hemiation is a complication of an ipsilateral mass lesion, such as a
hemorrhage or brain tumor. The first sign of uncal herniation is a fixed and dilated pupil on the
side of the lesion IpsiLateral paralysis of oculomotor muscles. contralateral or ipsilateral
hemiparesis, and contralateral homonymous hernianopsia with macular sparing may also occur

Lacunar infarcts are small ischernic infarcis (< 15 mm in diameter). usually rivoMng the basal
ganglia, pons. internal capsule, or deep white matter of the brain Lacunar infarcts occur most
often due to hypertensive artenolosclerosis of small, penetrating artenoles

Liquefactive necrosis is characterized by complete digestion and removal of necrotic tissue with
formation of cystic cavity. Hypoxic CNS injury is often followed by liquefactive necrosis.
Abscess formation due to bacterial or fungal infection is another example of this type of necrosis.

Normal pressure hydrocephalus (NPH) causes the triad of urinary incontinence and ataxic gait,
then dementia (wacky, wobbly & wet). NPH is a communicating hydrocephalus that occurs due
to a diminished reabsorptive capacity of the arachnoid villi. CT scan of the bran shows
symmetric dilation of ventricuk.

Diabetic mononeuropathy often involves CN III. Nerve damage is ischemic. and only somatic
nerve fibers are affected. Parasympathetic fibers of CN Ill retain function. Ptosis and a down and
out” gaze in conjunction with normal light and accommodation reflexes indicate diabetic CN Ill
neuropathy.
123


1 Holoprosencephaly results from failure of forebrain cleavage rito cerebral hemispheres lt is an
example of a congenital malformation, a primary abnormality i a development process
2. Amniotic band syndrome is an example of a disruption (secondary destruction of a prevousIy
well-formed tissue or organ)
3. Congenital hip dislocation, clubbed feet and flat facies (Potter syndrome) are examples of
deformations (secondary to extnnsic compression).
4 Potter syndrome is also an example of a sequence.

Both myastheniagravis and Lambert-Eaton syndrome are caused by poor signal transmission at
the neuromuscular junction. Lambert-Eaton syndrome is associated with undertying malignancy.
Antibodies to voltage-gated presynaptic calcium channels are found in these patients

Severe vitamin E deficiency close’y resembles the clinical presentation of Friedreich ataxia
Vitamin E is a lipid-soluble vitamin that has antioxidative properties.

Epidural hematoma occurs due to tear of the middle meningeal artery It is often associated with
temporal bone fracture, and is located between the bone and dura mater Clinical presentation is
characterized by a “lucid interval”, followed by loss of consciousness

Polymyalgia rheumatica occurs in more than half of patients with temporal arteritis It is
characterized by neck, torso, shoulder, and pelvic girdle pain and morning stiffness Fatigue,
fever and weight loss may also occur Monocular vision loss is a common complication of
temporal arteritis

In patients with Alzheimer disease. there are decreased levels of acetyicholine in the nucleus
basalis of Meynert and hippocampus. Diminished activity of choline acetyftransferase in these
cerebral structures is the cause.

Subarachnoid hemorrhage presents with a generalized. excruciating headache It is classically
described by patients as ‘The worst headache of my life.” Subarachnoid hemorrhage usuafly
occurs due to rupture of saccular (berry) aneurysms or artenovenous malformations Berry
aneurysms of the circle of Willis are associated with autosomal dominant polycystic kidney
disease

Demyelination (denudation means removal of covering) of axons in the white matter is a
hallmark of multiple sclerosis The areas of demyehnatiori form characteristic plaques The
symptoms of the disease depend on the plaque location. Involvement of the MLF leads to
internuclear ophthalmoplegia

Rapid correction of chronic hyponatremia may lead to osmo& demyelination of the axons in the
central part of the pons This condition is called central pontine myeIinolysis k manifests with
spastic quadriplegia and pseudobulbar palsy.

Microglia move to the area of ischerriic infarct approximately 3-5 days after the onset of isc
hernia and phagocytize the fragments of neurons, myelin, and necrotic debris A cystic space
replaces the necrosis. and astrocytes form a glial scar along the periphery
124



Tremulousness is commonly the first symptom of alcohol withdrawal Other common symptoms
are GI distress, agitation, anxiety, and autonomic disturbance Delinum tremens is the most
severe manifestation of alcohol withdrawal and typically begin between 48 and 72 hours after the
last dnnk

Carpal tunnel syndrome is caused by median nerve compression. Pt is the most common
example of compression (entrapment) neuropathy and is associated with repetitive wrist
movements Carpat tunnel syndrome is also associated with hypothyroidism, diabetes meibtus,
rheumatoid arthritis and diatysisa ssociated amyloidosis

Pituitary adenornas cause symptoms from mass effect and often produce endocrine disorders
from the various hormones that they can produce. Prolactinomas are the most common
adenorna—excess prolactin causes amenorrhea and galactorrhea. Bitemporal hemianopsia from
compression of the optic chiasm is common.

Neurofibrillary tangles and amyloid plaques are classk findings in Alzheimer’s dementia

Hypeftension is the most common overall cause of intraparenchymal hemorrhage, usually
through the formaton of small Charcot-Bouchard pseudoaneurysms in the small arterioles that
penetrate the basal ganglia and thalami This should be contrasted with rupture of a saccular
aneurysm which typically presents with subarachnoid hemorrhage.

Proliferation of astrocytes in an area of neuron degeneration is called gliosis It leads to the
formation of a glial scar which compensates for the volume loss that occurs after neuronal death

Huntington disease is inherited as an autosomal dominant trait It manifests with progressive
dementia and choreilorm movements. Loss of neurons in the caudate nucleus and putamen is
characteristic.

Counting down from I 00 by 7 or 3, reciting the months of the year in reverse order, and spelling
world” backwards are quick clinical tests to assess attention and concentration Attention and
concentration are tested as part of the Mine-Mental State Examination (MMSE), a widely used
screening tool for cognitive impairment The MMSE also measures onentation to time and place,
short-term memory, calculation, language, and constructional praxis.

Paraneoplastic syndromes occur due to the tumor cells producing substances that frequently
induce an autoimmune reaction and cause damage and degeneration of healthy organs and
tissues Neurologic paraneoplastic syndromes such as paraneoplastic cerebellar degeneration are
considered to be autoimmune.

The pineal region is the most common location of brain gerrninomas Histologically, germinomas
are similar to testicular seminomas. Classic symptoms of pineal germinomas are precocious
puberty, Pannaud syndrome, and obstwctive hydrocephalus.
125


Accumulation of an abnormal prion protein is considered a cause of phon diseases. Characteristic
microscopic findings are vacuoles in the gray matter (spongiform encephalopathy) with no
inflammatory changes Creutzfeldt-Jakob disease is an example of pñon disease

Friedreich ataxia is characterized by cerebellar ataxia. loss of position and vibration sensation,
kyphoscoliosis, and hypertrophic cardiomyopathy. Foot abnormalities and diabetes meflitus are
also common.

Normal pressure hydrocephalus occurs in elderly patients It causes the triad of ataxic gait and
urinary incontinence, then dementia These symptoms are explained by distortion of
periventricular white matter Bladder control is influenced by descending cortical fibers that run
in the distended paraventricular area. Later, loss of cortical inhibition on the sacral mictuntion
center causes the development of urge incontinence.

Ophthalmoplegia, ataxia. and confusion form the triad of Wemicke syndrome Most of these
symptoms resolve after thiamine admInistration. Korsakoff syndrome is a complication of
Wemicke encephalopathy. The hallmarks of Korsakoff syndrome are permanent memory loss
and confabulation

Neuropathy is a frequent complication of diabetes mellitus. It is caused by diabetic
microangiopathy which leads to nerve ischernia Another pathogenetic factor is the accumulation
of sorbitol, which leads to osmotic nerve injury. The symmetric peripheral neuropathy described
in thés vignette is common.

The subthalamic nucleus is one of the components of the basal gangIia Damage to this nucleus
(most often due to lacunar stroke) leads to hen-übaflsm. The involuntary flinging movements of
one side of the body (arm and/or leg) that constitutes hemibalksm are always contralateral to the
lesion




PATHOLOGY-Oncology
Symptoms of urinary urgency, noctuna. frequency, and hesitancy associated with constant back
pain in an elderly man are suggestive of metastatic prostate cancer. Asymmetric nodular
enlargement of the prostate on digital rectal examination is also suggestive. Metastatic prostate
cancer has a strong predilection for bones (especially the axial skeleton). The bony metastases of
prostate cancer are blastic (sclerotic), and can be detected by radionuclide bone scanning.

Most chemical carcinogens enter the body in an inactive state (ie, as pro-carcinogens) These pro-
carcinogens are converted into active metabolites by the cytochrome P450 oxidase system
Individual susceptibility to chemical carcinogens depends on the activity of these P450 enzymes.
which is genetically determined.
126


Dysplasia is a reversible change in epithelial cells Epithelial malignancies progress through the
sequence of low-grade dysplasia —. high-grade dysplasia/carcinoma in situ invasive carcinoma
Once the dysplastic cells have breached the basement membrane (as seen in invasive carcinoma),
the process is no longer considered reversible

Follicular lymphoma is the most common indolent non-Hodgkin Iyrnphoma in adults It is of B-
cell origin and presents with painless “waxing and waning” Iymphadenopathy The cytogenetic
change t(14;18) is charactenstic and resuIts in overexpression of the bcl-2 oncogene

Hereditary breast cancer is associated with mutation of BRCA-1 and BRCA-2 These are tumor
suppressor genes that function in gene repair and regulation of the cell cycle. Mutation of these
genes increases the risk of breast and ovarian cancer.

Metalloproteinases are Zn-containing enzymes that degrade extracellular matrix They participate
in the normal tissue remodeling and in tumor invasion through the basement membrane and
connective tissue.

A cerebellar tumor in a child is most likely a pilocytic astrocytoma or a medulloblastoma These
two tumors can be differentiated on brain imaging Pilocytic astrocytomas have both cystic and
solid components, while medulloblastomas are always solid.

The Rb tumor suppressor gene encodes the Rb protein, which regulates the cell cycle Active
(hypophosphorylated) Rb protein prevents damaged cells from proceeding past the Gi to S
checkpoint, while the inactive (hyperphosphorylated) Rb protein allows the damaged cell to
enter mitosis Abnormal phosphorylation of Rb protein results in its inactivation.

Burkitt lymphoma is characterized by aggressive. rapid growth and a starry-sky” microscopic
appearance Translocation of the c-myc oncogene on the long arm of chromosome 8 with the Ig
heavy chain region on chromosome 14 produces a nuclear phosphoprotein (c-Myc) that functions
as a transcription activator

Cushing syndrome in a patient with small cell (oat cell) lung cancer is most likely the result of a
paraneoplastic syndrome involving ectopc produchon of ACTH by the tumor cells

Li-Fraumeni syndrome is an autosomal dominant predisposition to a variety of Cancers.
Sarcomas and tumors of the breast. brain, and adrenal cortex are most common. This syndrome
is associated with mutation of the p53 gene.

The majority of bladder carcinomas are urothelial (formerly known as transitional cell)
carcinomas Painless gross hematuria is the main presenting symptom Tumor penetration of the
bladder wall is the maior determinant of prognosis.

Proliferation signals activate CDK4 (cyclin-dependent kinase-4), resulting in
hyperphosphorylation of the Rb protein, Because hyperphosphorylated Rb is inactive, cells are
allowed to transition unchecked from the Gi phase to the S phase in the cell cycle
127


The P450 mcrosomaI oxidase system plays an important role in detoxification In carbon
tetrachloride poisoning, however, it produces free radicals that start a vicious cycle of hepatic
injury

p53 is a tumor suppressor gene that controls cell division and apoptosis. It is inactivated in many
tumors.

The finding of a high peak in the gamma-globulin region on serum protein electrophoresis
(SPEP) usually represents an M protein consisting of an overproduced monoclonal
immunoglobulin Multiple myeloma causes an M protein peak on SPEP as well as anemia
(weakness). lytic bone lesions (back pain, pathologic fractures), and renal insufficiency (related
to amyloid deposition and hypercalcemia)

Glioblastoma multiforme is the most common primary brain tumor in adults Areas of necrosis
and hemorrhage are seen on gross examination Light microscopy showing pseudopalisading
tumor cells around areas of necrosis is diagnostic.

ERJPR positivity in breast cancer indicates expected sensitivity to tamoxifen treatment ERB-
B2positMty in breast cancer is consistent with a more aggressive tumor that should respond to
therapy with the monoclonal antibody trastuzumab.

Gliobtastoma multiforme, meningioma. and acoustic neuroma are the most common primary
brain tumors in aduits Glioblastoma multiforme arises within the cerebral hemispheres and
frequently crosses the midline. Foci of necrosis and hemorrhage are seen on macroscopic
examination.

Peau dOrange descnbes the presence of pitting edema in subcutaneous breast tissue
accompanied by skin thickening around exaggerated hair folhcles. The pitting edema occurs
when neoplastic cells plug the dermal lymphatic channels.

EBV virus causes infectious mononucleosis an teenagers and young adults It is also associated
with a number of malignant conditions, including Burtatt lymphoma and nasopharyngeal
carcinoma

TNF-a was shown to induce a wasting syndrome (cachexia) in experimental animals It is thought
to mediate paraneoplastic cachexia in humans by suppressing appetite. inhibiting lipoprotein
lipase and increasing insulin resistance of peripheral tissues

Oral contraceptives reduce the risk of non-hereditary ovarian and endometnal cancer. Muttiparity
and breast-feeding also decrease the risk ot ovarian cancer.

Prognosis of colorectaladenocarcinoma is directly related to the stage of the tumor (not to the
grade!)
128


Most tumors possess multiple cytogenetic abnormalities Activation of proto-oncogenes results in
stimulation of cellular proliferation Inactivation of anti-oncogenes eliminates oversight of the
cell cycle

Cytokeratin is a commonly-used immunohistochemical marker of epithehai-dehved tissues.

The HER2Ineu oncogene encodes for a 1 85-kD transmembrane glycoprotein that has
intracellular tyrosine kinase activity and is a member of the family of epidermal growth factor
receptors Overexpression of this protein is associated with increased rates of breast and ovanan
cancer

Integnn-mediated adhesion of cells to basement membrane and the extracellular matrix involves
the binding of integrins to fibronectin, collagen, and Iaminin

Kaposs sarcoma typically presents as blue-violet skin p’aques on the extremities and mucous
membranes of HIV-positive patients This tumor arises from primitive mesenchymal cells and is
strongly associated with human herpes virus type 8 (HHV-8)

Reed-Stemberg cells are large binuceated cells with an owI’s eyes appearance that appear on a
background of lymphocytic infiltrates. Reed-Stemberg cells must be present histopathologically
in order to make the diagnosis of Hodgkin lymphoma.

Benign lymph node enlargement in response to antigenic stimulation is associated with a
polyclonal proliferation of lymphocytes. A monoclonal lymphocytic proliferation is strong
evidence of nialignancy

Keratin is a marler of epfthelial cell origin

The key growth factors that promote angiogenesis ii neoplastic and granulation tissue are
vascular endotheleal growth factor (VEGF) and fibroblast growth factor (FGF). Proinflammatory
cytolanes (like IL-I and INF.y) can indirectly promote angiogenesis throu9h increased VEGF
expression The larnanin in basement membranes may pose a physical barner to the sprouting of
new blood vessels

Apoptosss can occur through either the intrinsic (mitochondria-mediated) pathway or the
extrinsic (receptor-initiated) pathway. Both pathways converge in the activation of caspases
Caspases are proteolttic enzymes that cleave cellular proteins.

The avid uptake of bromodeoxyuridine by the tumor reflects the high number of tumor cells in S
phase (preparing to divide) that are present in this mans brain tumor A high proliferation rate
suggests a high tumor grade and, therefore, a poor prognosis.

Small cell carcinoma of the lung is the most aggressive lung neoplasm. This tumor is thought to
have a neuroendocrine ongin. Tumor cells express neuroendocnne markers and contain
neurosecretory granules in the cytoplasm.
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Overexpression of bc/-2leads to increased secretion of BcI-2 protein. which inhibits apoptosis
and promotes survival of tumor cells, This overexpression occurs in follicular lymphoma
secondary to translocation of the bcl-2oncogene from chromosome 18 to the Ig heavy chain
locus on chromosome 14 [t(14j8)]

Undifferentiated (anaplastic) tumors bear no resemblance to the tissue of origin They are
composed of pleomorphic cells with hyperchromatic nuclei that grow in a disorganized fashion.
Many abnormal mitoses and giant tumor cells may be seen.




PATHOLOGY-Pulmonology

Small cel carcinoma is the most aggressive type ol lung cancer Most patients have distant
metastases at the time of diagnosis Surgery is usually not a treatment option, even when the
disease is localized This tumor is sensitive to chemotherapy and radiation

Secondary (reactivation) tuberculosis occurs in patients who have been previously infected with
tuberculosis Primary tuberculosis causes the formation of Ghon foci in the lower lung fields
Reactivation tuberculosis occurs in immunosuppressed patients, and is characterized by apical
cavitary lesions and hemoptysis.

Prolonged, burning substernal pain and ST segment elevation in leads I and V3-V6 is strongly
suggestive of anterolateral left ventricle infarction. Common consequences of left ventricle
infarction include left ventricular failure, cardiogenic acute pulmonary edema, pulmonary venous
hypertension (congestion), and transudate of plasma into the lung interstitium and alveoli.

Sarcoidos,s is a disease that is characterized by hilar adenopathy, pulmonary disease, and
constitutional symptoms Histologically, non-caseating granulomas are seen, helping to
distinguish sarcoidosis from tuberculosis infection

Patients with a long history of asbestos exposure are at risk for developing asbestosis,
bronchogenic carcinoma and mesothelioma Bronchogenic carcinoma is the most common
malignancy in this population, while mesothelioma is the second

Bronchioloaiveolar carcinoma is a subtype of lung adenocarcinoma This uncommon tumor
occurs in non-smokers and arises from alveolar epithelium It is located in the penpheral parts of
the lun9 and is often multifocal On microscopc examination, it is composed of tall, columnar
cells that line the alveolar septa without evidence of vascular or stromal invasion.

The incidental chest x-ray finding of fibrocalcific panetal pleural plaques in the posterolateral
mid-lung zones and over the diaphragm are highly suggestive of asbestosis.
130



The interstitial and alveolar edema and exudate in ARDS result in large part from increased
pulmonary capillary permeability. The result is a decrease in lung compliance, an increase in the
work of breathing, and worsened V/Q mismatching. The pulmonary capillary wedge pressure
(PCWP) is typically normal. An elevated PCWP would be more suggestive of a cardiogenic
cause in a patient with pulmonary edema.

Thickened bronchial walls, neutrophil infittration, mucous gland enlargement, and patchy
squamous metaplasia of the bronchial mucosa are features of chronic bronchitis Cigarette
smoldng is the leading cause of chronic bronchitis.

The green discoloraton of pus or sputum noted during bacteria’ infections is associated with the
release of myeloperoxidase (MPO) from neutrophil azurophdic granules. MPO is a herne-
containing pigmented molecule.

Pulmonary hypertension develops in patients with scieroderma as a result of damage to the
pulmonary arterioles It manifests with an accentuated pulmonary component of the second heart
sound and signs of right-sided heart failure

Metaplasia is an adaptive change that occurs in response to chronic epithelial irritation. Smoking
induces squamous bronchial metaplasia, while long-standing reflux results in columnar
metaplasia of the distal esophagus (BarretVs esophagus). Both these conditions increase the risk
of malignancy and are therefore referred to as premalignant.

Insidious-onset progressive exertional dyspnea. pulmonary function tests showing a restrictive
profile, and surgical biopsy showing extensive interstitial fibrosis together with paraseptal and
subpleural cystic airspace enlargement (honeycomb lung) are charactenstic of idiopathic
pulmonary fibrosis.

Use of concentrated oxygen therapy for neonatal respiratory distress syndrome may be
complicated by retinopathy of prematurity This abnormal retinal neovascularization is a major
cause of blindness in developed nations.

Sarcoidosis most commonly affects young black women and presents with malaise, cough and
varied cutaneous findings including erythema nodosum. Chest X-ray reveals bilateral hilar
lymphadenopathy. Transbrorichial biopsy showing non-caseating granulomas is necessary for
diagnosis.

Leukotriene B stimulates neutrophil migration to the site of inflammation. Other significant
chemotactic agents include 5-HETE (the leukotriene precursor) and complement component
C5a.

Tissue damage and resuftant abscess formation is pnmanly caused by lysosomal enzyme release
from neutrophds and macrophages.
131


Malignant mesothelioma is a rare neoplasm that arises from the pleura or pehtoneum It is
strongly associated with asbestos exposure. Hemorrhagic pleural effusions and pleural
thickening are characteristic. Electron microscopy is the gold standard for diagnosis, revealing
tumor cells with numerous, long, slender microvilli and abundant tonofilaments.

Erytherna nodosum, arthralgias. hilar Iyrnphadenopathy, and elevated serum ACE levels are
common findings in sarcoidosis There may be evidence of liver involvement on histologic
examination in up to 75% of cases Needle biopsy of the liver frequently demonstrates scattered
noncaseating granulomas

Sepsis and shock are two major risk factors for developing adult respiratory distress syndrome
(ARDS, also known as ‘shock lung’). ARDS produces non-cardiogenic pulmonary interstitial
and intra-atveolar edema, inflammation, and alveolar hyatine membranes

Tumors located in the lung apex (superior sulcus) are called Pancoast tumors. Pancoast
syndrome is characterized by ipsitateral Homer’s syndrome, rib destruction, atrophy of hand
muscles, and pain in the distribution of C8. Ti. and T2 nerve roots

An obstructive lesion in a mainstern bronchus can prevent ventilation of an entire lung, leading
to lung collapse Characteristic findings on chest x-ray include unilateral pulmonary opacification
and deviation of the mediastinum toward the opacified lung.

Intrathoracic spread of bfonchogenic carcinoma may lead to compression of the superior vena
cava causing impaired venous return from the upper part of the body Signs and symptoms
include facial swelling and headache.

Cystic fibrosis (CF) is a common cause of congenital bilateral absence of the vas deferens,
resuLting in azoospermia. A diagnosis of CF can be made based on this urogenital anomaly with
an abnormal sweat chloride test or an abnormal nasal transepithehal potential difference.

Adenocarcinoma Es the most common lung cancer in the general population ft is also the most
common subtype in women and nonsmokers It is located peripherally and consists of tumor cells
that form glandular or papillary structures

In lobar pneumonia. the inflammation involves an entire lobe of the lung. The course of the
disease includes four morphologic stages: congestion, red hepatization1 gray hepatization and
resolution

Peptostreptococciand Fusobacterià are anaerobèc bacteria normally found in the oral cavity
They cause lung abscesses associated with aspiration R’sk factors for such abscesses include
alcoholism, seizure disorder, CVA and dementia.

Patients with sarcoidosis or other granulomatous diseases are prone to developing hypercalcemia
secondary to high levels of active vitamin 0 (calcitriol).
132


Intermittent respwatory symptoms in a patient with a normal CXR, occasional sputum
eosinophils, and reduced FEV1 suggest a diagnosis of asthma Extnnsic allergic asthma provoked
by inhaled allergens such as animal dander is the most common type

Acute necrotizing pancreatitis is a major risk factor for progression to adult respiratory distress
syndrome (ARDS). Diffuse injury to the alveolocapillary membrane resu*s in interstitial and
intraalveolar edema, acute inflammation, and alveolar hyahne membranes Hyahne membranes
result from alveoocapitlary membrane leakage and consist of fibnn exudate and plasma protein-
nch edema fluid mixed with the cytoplasmic and lipid remnants of necrotic epithehal cells
(Hyahne membranes are produced by a different mechanism of alveolocapillary injury in
neonatal respiratory distress syndrome).

The development of respiratory distress. diffuse neurological impairment (e.g. confusion), and an
upper body petechial rash (due to thrombocytopenia) within days of severe long bone fractures is
characteristic of the fat embolism syndrome. The multiple fat emboli occluding the pulmonary
microvasculature stain black with osmium tetroxide.

Asthma develops due to the interaction of genetic and environmental factor& Patients are born
with a genetic predisposition to have an imbalance between Thi and Th2 lymphocytes.
Environmental irritants, such as smoking, trigger bronchospasm in predisposed IndMduals

Fat embolism syndrome should be strongly suspected in a patient with severe long bone and/or
peMc fractures who then develops acute-onset neurologic abnormalities, hypoxemia, and a
petechial rash. Occlusion of the pulmonary microvessels by fat globules is an early histologic
finding of this syndrome.

Chronic rejection can occur months to years following transplantation. In lung transplantation,
the immune reaction affects the small airways, causing bronchiohtis obliterans syndrome
Symptoms include dyspnea and wheezing.

Rupture of apical subpleural blebs is the most common cause of primary spontaneous
pneumothorax. These blebs may arise due to distal acinar (paraseptal) emphysema Tall, thin,
young adult males are most commonly affected Other types of emphysema may predispose to a
secondary spontaneous pneumothorax. Compensatory and obstructive hypennflation cause
distention of normal lung parenchyma and would be unlikely to cause pneumothorax.

al-antitrypsin deficiency is associated with chronic panacinar emphysema. which is preferentially
localized to the lower pulmonary lobes. Centnacinar emphysema has a predominantly upper lung
lobe distnbution and is strongly associated with chronic smoking.

Small cell carcinoma is strongly associated with smoking and usually is centrally located. This
tumor arises from the primitive cells of the basal layer of the bronchial epithelium
Immunohistochemical stains are frequently positive for neuroendocrine markers, such as neuron
specific enolase, chromogranin and synaptophysin
133


Dry cough, pulmonary infiltrates, and hilar adenopathy in an African American female strongly
suggest sarcoidosis. This diagnosis may be confirmed by the finding of non-caseating
granulomas on lung biopsy.

The tissue destruction caused by Al &,bercc.*sis infection is the direct resuk of host immune
activation and inflammation through a type IV delayed-type hypersensitivity reaction The
characteristic pathologic lesion consists of granulomatous inflammation and caseous necroSis.

Lung abscess is a common comphcation of aspiration pneumonia, Aspiration pneumonia occurs
in individuals with impaired consciousness or decreased ability to swallow (alcoholics,
demented, chronically ill patients). The anaerobic bactena of the gingivodental sulcus are the
most common cause of lung abscesses.

Pulmonary tuberculosis is a disease passed from person to person through the transmission of
aerosolized respiratory secretions that contain Mycobact er/urn tubercuksis Organisms. The
smaller droplets deposit organisms in the alveoli of lower lung fIelds These organisms are
engulfed by alveolar macrophages that allow for intracellular bacterial proliferatIon.

Primary infection by M tuberculosis occurs after inhaling the organism in the aerosolized
respiratory secretions of an infected person Initial M tuberculosis infection is characterized by a
Ghon complex, which consists of a lower lobe lung lesion (Ghon focus) and ipsilateral hilar
adenopathy

Recurrent sinopulmonary infections and exocnne gland fibrotic atrophy in a young Caucasian are
suggestive of cystic fibrosis (CF), CF can lead to pancreatic insufficiency, fat malabsorption. and
a deficiency of vitamins A, 0, E and K. Vitamin A maintains ordedy differentiation of
specialized epitheha, including the mucus-secreting columnar epitheha of the ocular conjunctiva,
respiratory and urinary tracts, and pancreatic and other exocnne ducts Avitaminosis A can cause
squamous metaplasia of such epethelia to a keratinizing epithelium.

PathOphySIOIOgiCaHy, deep venous thrombosis arises due to Virchows triad of endothelial
injury, venous stasis, and a hypercoagulable state.

Of the pneumoconioses that can cause exertional dyspnea and interstitial densities on chest x-ray,
silicosis is the only one that produces eggshell calcifications of hilar nodes and birefringent
particles surrounded by fibrous tissue on histologic exam Asbestosis is associated with calcified
pleural plaques and ferruginous bodies Berylliosis and hypersensitivity pneumonitis may
produce noncaseating granulomas Coal mine?s lung is associated with penlymphatic
accumulations of coal dust-laden macrophages
134


PATHOLOGY-Renal
Membranous glomerulopathy is one of the most common causes of nephrotic syndrome in
adufts, It can occur secondary to underlying malignant tumors, infections, and certain
medications Diffuse increased thickness of the glomerular basement membrane on light
microscopy (without increased cellularity), “spike and dome” appearance on methenamine silver
stain, and granular deposits on immunofluorescence are diagnostic

lschemic ATN is one of the most common causes of intrinsic renal failure (acute renal failure) in
hospitalized patients. Renal ischernia triggers hypoxic changes in tubular epithelial cells
(especially in proximal tubules and the thick ascending limb of Henles loop), decreasing their
functional capacity Muddy brown casts are pathognomonic for ATN.

The most common renal malignancy is clear cell carcinoma, which arises from renal tubular
cells. Routine histological staining of this tumor shows rounded or polygonal cells with abundant
clear cytoplasm. These cells have this appearance because they are packed with glycogen and
lipids On any histologic preparation. clear cells” are generaity those with a high glycogen or lipid
content

Henoch-Schônlein purpura (HSP) generally affects young children and is classically preceded by
an upper respiratory infection This IgA-mediated hypersensitivity (leukocytoclastic) vasculitis
commonly causes abdominal pain, joint pain, lower extremity palpable purpura and hematuria

Poststreptococcal glomerulonephntis occurs most frequently in cMdren, but adults can be
affected, too. Immunofluorescence microscopy shows granular deposits of lgG. 1gM, and C3 in
the mesangium and basement membranes, producing a ‘starry sky’ appearance.

Idiopathic membranous nephropathy is associated with circulating IgG4 antibodies to the
phospholipase A2 receptor, which might play a role in the development of the disease

Age is an important prognostic factor in poststreptococcal glomenilonephritis 95% of affected
children, but only 60% of affected adults. recover completely

During the recovery phase (polyuric phase) of acute tubular necrosis, patents can become
dehydrated and can develop severe hypokalemia due to high volume. hypotonic urine

ANCA-associated RPGN is also ca$ed pauci immune GN due to the absence or scarcity of Ig
and C3 deposits Pahents present with renal failure, pulmonary symptoms (cough, dyspnea,
hemoptysis), and upper respiratory tract symptoms (epistaxis. mucosal ulceration, chroruc
sinusitis). Crescents are found on light microscopy.

The histological picture of poststreptococcal glomerulonephritis includes
I Enlarged. hypercellular glomeruh on light microscopy
2 “Lumpy-bumpy” granular deposits of lgG and C3 on immunofluorescence
3. Electron-dense deposits on the epithehal side of the basal membrane on electron microscopy
135


Nephrotic syndrome isa hypercoagulable state. Sudden onset abdominal or flank pain, hematuria
and lefts ided varicocele together suggest renal vein thrombosis, a well-known complication of
nephrotic syndrome. Loss of anticoagulant factors, especially antithrombin Ill, is responsible for
the thrombotic and thromboembolic complications of nephrotic syndrome

Nephrotic syndrome is characterized by massive proteinuria (>35 gm/day), hypoalbuminemia,
generalized edema. hyperlipidemia, and hpiduria. Depending on the ratio of low- to high-
molecular weight proteins in the urine with nephrotic syndrome, proteinuna can be either hgh’or
p004’ selective, Minimal change disease is an example of a highly selective proteinuna mostly
low-molecular weight proteins, such as albumin and transferrin, are excreted.

Goodpasture syndrome is caused by anti-GBM antibodies that react with a component of the
alpha3-chain of collagen type IV. Patients typically present with rapidly progressive
glomerulonephritis resulting in acute renal failure and hemoptysis due to pulmonary hemorrhage

Mti-GBM antibodies react with the a3 chain of collagen type IV, found in the glomerular
basement membrane Anti-GBM antibodies are found in Goodpasture syndrome, a condition
characterized by pulmonary hemorrhages (hemoptyss) and rapidly progressive
glomerulonephr*is (RPGN) On light microscopic examination, there is glomerular crescent
formation On immunofluorescence, linear deposits of lgG and C3 along the glomerular basement
membrane are characteristic

Autosomal dominant polycystic kidney disease manifests in patients 40-50 years old with
enlarged kidneys, hypertension, and renal failure. In newborns, the kidneys are of normal size,
and the cysts are too small to be detected on abdominal ultrasonography. As the cysts enlarge.
they compress the renal parenchyma and cause symptoms

The ureters are at hsk of injury during pelvic surgeries Hysterectomies are especially risky
because the ureters course just posterior to the utenne arteries, which are ligated in this procedure

Most patents with ATN experience tubular re-epithelization and regain renal function When
ATN is associated with multi-organ failure, renal function may be permanently impaired (foci of
interstitial scarring can be seen on light microscopy).

Crescent formation on light microscopy is diagnostic for rapidly progressive glomerulonepliritis.
Crescents consist of glomerular parietal cells monocytes, macrophages as well as abundant fibrin
Crescents eventually become sclerotic, disrupting glomerutar function and causing irreversible
renal injury

Granulomatosis with poiyangiitis (Wegeners) is a cause of rapidly progressive (crescentic)
glomerulonephritis (RPGN) type 3 (pauci-immune). The symptoms of nephntis are accompanied
by signs of upper and lower respiratory tract involvement. Crescents on bght microscopy, the
absence of deposits on immunofluorescence, and elevated serum c-ANCA are diagnostic

Minimal change disease (MCD) presents as a nephrotic syndrome in children between 2-8 years
ol& The pathognomonic finding is a diffuse effacement of the foot processes of podocytes found
136


on electron microscopy Light microscopy shows normal glomeruh and immunofluorescence fails
to reveal any immunoglobulin or complement deposits. Renal function is also norma[ An
important feature of this condition is its rapid response to corticosteroid therapy.

Acute renal allograft rejection can be an anhbodymediated or cell-mediated pcocess The latter of
the two is associated with lymphocytic infiltration of the renal parenchyrna

Anti-CD3 antibodies such as muromonab-CD3 (OKT3) inhibit T-lyrnphocytes. which is useful
in the treatment of acute rejection in patients with kidney, heart, and liver transplants.

Transitional cell carcinoma of the bladder typically presents as gross hematuna m an elderly
man, A history of smoking or occupational exposure to rubber, plastics, aromatic amine-
containing dyes, textiles, or leather increases the nsk of developing transitional cell carcinoma.

NephntiC syndrome is manifested by hypertenson. mild proteinuna (<1 g/day), RBC casts or
dysmorphic red cells in the urine, and azotemia. In contrast, the nephrotic syndrome is
manifested by heavy proteinuria (>3.5 glday), lipiduria, absence of RBC casts in the urine, and
usua*y normal renal function.

Painless hematuna 2-3 days following an upper respiratory tract infection is suggestive of IgA
nephropathy (Berger disease). Diagnosis is made via the detection of IgA deposits in the
mesangium of glomerub on immunofluorescence microscopy. When IgA nephropathy is
accompanied by extrarenal symptoms (e.g., abdominal pain, purpuric skin lesions), the diagnosis
is Henoc h-Sc honlein purpura.

ADPKD is one of the most common inherited disorders in humans It is the most frequent genetic
cause of renal failure in adults, accounting for 10% of patients on dialysis in the United States Its
mode of inheritance is autosomal dominant (ADult PKDAD).

Hemolybc-uremic syndrome (HUS) is a common cause of acute renal failure ii children k is
associated with shiga toxin-producing organisms like E cok0157:H7 and Shigeffa dysentenàe
HUS is characterized by the triad of acute renal failure, microangiopathic hemolytic anemia, and
thrombocytopenia

Medullary sponge kidney (MSK) is a relatively common and benign congenital disorder
characterized by cystic dilatations of the medullary collecting ducts Cysts usually do not involve
the renal cortex Kidney stones are the most common complication of the disease Patients with
MSK do not typically develop chronic renal failure

Microalbuminuna detection is the preferred method for diagnosing incipient diabetic
nephropathy, the leading cause of end stage renal disease in the United States

Easy fatigabihty. constipation, back pain, and azotemia in an elderly patient are the classic
constellation of findings for multiple myeloma. On kidney biopsy, large eosinophilic casts
composed of Bence-Jones proteins are seen in the tubular lumens.
137


Ethylene glycol ingestion leads to acute renal fadure due to the precipitation of calcium oxalate
crystals in renal tubules and subsequent damage to tubular epthehum Typical clinical findings
include anion gap metabolic acidosis, increased osmolar gap. and presence of calcium oxalate
crystals in urine

Although nephrotic syndrome can result from a number of different disease processes, the
pathogenesis underlying its symptoms is consistent in the vast majority of patients This process
involves increased permeability of the glomerular capillary wall to plasma proteins, decreased
plasma oncotic pressure of the blood, fluid shift into the interstitium, increased aldosterone
synthesis, and increased antidiuretic hormone release, with resultant sodium and water retention,
hypertipidemia. and subsequent lipiduria

Most renal cell carcinomas (also known as clear ccl carcinomas) originate from the epithelial
cells of the proximal renal tubules Clear cell carcinoma is the most common type of kidney
tumor. it is easily recognizable on both macroscopic and microscopic examination due to its high
lipid content On gross examination, this tumor appears as a golden yellow mass. On light
microscopic examination, these tumors are composed of cells with abundant clear cytoplasm and
eccentnc nuclei.

Laboratory findings in poststreptococcal glomerulonephritis include: elevated anti-streptolysin 0
(ASO) titers, elevated anti-DNase B titers, decreased C3 and total complement levels, and the
presence of cryoglobulins C4 level is usually normal.

The selective protenuna (loss of albumin only) of minimal change disease is currently explained
by a loss of negatively charged components in the glomerular basement membrane The loss of
negative particles destroys the negative-negative repulsion between the GBM and albumin.

Diabetic nephropathy starts with glomerular hyperfiltration and leads to an increase m mesangial
matrix and thickening of GBM, Diabetes affects glomeruh and the arterioles, The classic
morphologic features of diabetic nephropathy inchide nodular glomerulosclerosis (i.e. K-W
nodules), diffuse glomeruloscierosis, and hyaline artenolosclerosis. ACE inhibitors and ARBs
can prevent the progression of diabetic nephropathy.

The electron-dense deposits on the epithehal side of the glomerular basement membrane
(subepithehal humps) seen in patients with poststreptococcal glomerulonephnt3s represent
immune complexes composed of lgG, 1gM and C3.
138



PATHOLOGY-Reproductive
Anovulation is common during the first five to seven years after menarche and the last ten years
before menopause, and manifests with marked menstrual cycle vanabihty

Granulosa cell tumors are sex-cord strornal tumors that secrete estrogen.

Prolactinomas are the most common pfluitary adenomas The excess prolactin produced by these
tumors can cause galactorrhea and amenorrhea Visual changes may also occur due to
compression of the optic chiasm

CenAcal epitheliahnfection with human papilloma virus (HPV), especially HPV 16 and HPV 18.
is the strongest known risk factor for development of CIN and invasive cervical carcinoma Early
age at first intercourse and multipe sexual partners increase the incidence of HPV infection.

A uniformly enlarged uterus with normal appearing endometrial tissue within the myometrium
indicates a diagnosis of adenomyosis Menorrhagia and dysmenorrhea are common presenting
syrnptoms

PCOS is clinicaHy charactenzed by obesity, hyperandrogenism, ohgomenorrhea, nfertility, and
enlarged ovanes with multiple cysts

Patients with PCOS who desire fertility are treated with clomiphene. which is an estrogen
receptor modulator that decreases negative feedback inhibition on the hypothalamus by
circulating estrogen and thereby increases gonadotropin production.

Granulosa cell tumors are estrogen-secreting primary ovarian tumors. The hyperestrogenemic
state that results can cause endometnal hyperplasia and abnormal uterine bIeeding it also
predisposes to endometrial adenoc arc inoma

Pre-eclampsia is the triad of hypertension. proteinuria and edema. Eclampsia is pre-eclampsia
with seizures Pre-eclampsia may also progress to HELIP syndrome (Hemolytic anemia, Elevated
Liver enzymes, and Low PlateletS).

Ovarian malignancy is the most likely explanation for an adnexal mass in an elderly female
Approximately 90% of ovarian malignancies originate from the ovars surface epithehum CA-125
is produced by malignant ovarian epithelial tumors and can be used as a serum marker of this
condition.

Comedocarcinoma (DCIS) is characterized by solid sheets of pleomorphic, high-grade cells with
central necrosis

A positive ‘whifr test — production of a fishy odor on addition of potassium hydroxide (KOH)
to vaginal discharge — is a sign of bacterial vaginosis. Clue cells on saline wet mount
microscopy also suggest this diagnosis.
139


PATHOLOGY-Skeletal
Pathologic atrophy generally occurs secondary to one of the following mechanisms: decreased
physical workload, loss of innervation, decreased blood supply, inadequate nutrition, absent
endocrine stimulation aging, or pressure

Enthesopathies (inflammation at sites of tendon insertion) are common in ankyosing spondyhtis
Involvement of the costovertebral and costosternal junctions may cause Iimation of chest
movements, resulting in hypoventilation.

Osteogenesis imperfecta results from defective synthesis of type 1 collagen. Clinical findings
include a history of fractures after only minimal trauma abnormal (blue) sclerae, and small,
malformed teeth. In most patients, osteogenesis imperfecta is transmitted by autosomal dominant
inheritance

• The most common defect in achondroplasia is an activating mutation of the fibroblast growth
factor receptor-3 at the epiphyseal growth plate which inhibits growth at the epiphyseal growth
plate. The result is short, thick tubular long bones in the appendicular (limb) skeleton and normal
axial (spine) length
• Short stature in growth hormone I IGF-1 deficiency is proportional; that is, the axial and
appendicular skeleton are proportionate

Parvoviws B 19 causes erythema infectiosum (fifth disease) in children and arthritis in adults
Parvovirus arthritis can mimic rheumatoid arthritis, but is unique in that it is usually self
resoMng

In the United States. vitamin C deficiency (scurvy) is most often seen in severely malnourished
individuals (the homeless, alcoholics, drug users). Vitamin C is necessary for the hydroxylation
of proline and lysine residues in pro-collagen. Patients with vitamin C deficiency demonstrate
perifollicular hemorrhages. easy bruising and gum disease. Additionally, in children, bony
deformities and subperiosteal hemorrhages are characteristic.

Severe injury to living tissue can cause necrosis. There are several morphologic types of
necrosis. Coagulative necrosis is the most common

Osteoarthrrtis usually involves the distal interphalangeal joints whereas rheumatoid arthntis
typically affects the metacarpophalangeal and proximal interphalangeal joints

Fibromyalgia is a chronic disorder with unclear etiology that presents most commonly in women
20 to 50 years of age with diffuse musculoskeletal pain, insomnia and emotional disturbances

During wound heahng, excessive matrix metalloproteinase activity and myotibroblast
accumulation in the wound margins can result in contracture Contractures produce deformities of
the wound and surrounding tissues, most often on the palms. soles. anterior thorax, or at serious
bum sites.
140


Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disorder presenting wfth
proximal muscle weakness, cranial nerve involvement, and autonomic symptoms Approximately
half of all patients with LEMS also have a malignancy (classically, small-cell lung cancer)

• Metaphysis of long bones are typic ally affected by hernatogenous osteomyehtis due to rich
vascularization and capdlary fenestrae
• Staphylococcus aureus and Strtococcuspyogenes(Group A Strep) are the first and second most
common causes of this disease, respectively, and hematogenous osteomyelitis most frequently
affects children and young adults
• Pseudomonas aeiz.çzinosa frequently plays a role in osteomyelitts resulting from chronic
wounds such as in diabetics

Digital clubbing is often associated w4h prolonged hypoxia It can be found m patients with
large-cell lung cancer, tuberculosis, cystic fibrosis, and suppurative lung diseases such as
empyema, bioncheectasis. and chronic lung abscesses.

Osteoporosis (porous bones) represents loss of “total bone mass” that results in trabecular
thinning. Subperiosteal resorption with cystic degeneration is characteristic of
hyperparathyroidism Vitamin D deficiency result in “excessive unmineralized osteoid. resulting
in low mineral densy. Osteopetrosis is characterized by “the persistence of pnmary,
unminerahzed spongiosa in the medullary canals.”

Dactyhtis (painful swelling of hands and feet) is a common presentation of sickle cel disease in
young children. It is one of many vasoocclusive symptoms that occur in this condition In the
case of hemolysis, haptoglobin levels decrease by binding to free hemoglobin, and the complex
is hepatically cleared

Gottron papules are flat-topped violaceous papules over the joints of the fingers This cutaneous
symptom, along with a heliotrope rash. is characteristic for dermatomyositis

Avascular necrosis of the femoral head is associated with sickle cell disease, steroid therapy,
SLE and alcoholism. It presents with acute onset of hip pain that is exacerbated by weight
bearing. No swelling, erythema or temperature change is seen. MRI is the diagnostic modality of
choice.

Presbyopia and skin wrinkles are age-related changes. Presbyopia occurs due to sclerosis of the
lens Decreased synthesis and increased breakdown of collagen and elastin contnbute into
development of skin wrinkles

CREST syndrome (limited scleroderma) manifests with calcinosis. Raynaud’s phenomenon,
esophageal dysmotility, scierodactyly and telangiectasias. Anti-centromere antibodies are found
in about 40% of patients with CREST syndrome. Anti-DNA topoisomerase I (Scl-70) antibodies
are highly specific for systemic sclerosis.
141


The presence of rhomboid-shaped calcium pyrophosphate crystals is diagnostic of pseudogout
These crystals are positively birefringent under polarized light The knee joint is involved in more
than 50% of cases.

The histological hallmark of rickets is an increase in unminerahzed osteoid matrix and widened
osteoid seams. Clinically, there are many notable features. including bowed legs, a rachitic
rosary, Harrison’s sulci, craniotabes, and growth retardation.

A psoas abscess can occur as the result of hernatogenous or lymphatic seeding from a distant site
or by spread from an adjacent site. Patients can present with fever, back or flank pain, inguinal
mass, and difficulty walking Inflammation of the psoas muscle causes pain when the hip is
extended (psoas sign)

Dystonia is a syndrome of prolonged. repetitive muscle contractions This condition may be the
result of impaired function of the basal gangha Cervical dystonia (spasmodic torticollis),
blepharospasm, and writer’s cramp are the most common types of focal dystonia

Hypercalcernia in sarcoidosis is caused by increased extrarenal formation of 1 25-dihydroxy
vitamw D by activated macrophages The hypercakemia of sarcosdosas suppresses PTH secretion

Reactive arthritis is an HLA-B27 spondyloarthropathy that can occur following infection by
Chiamydia. Campylobacter, Salmonella. Shigella or Yersinia. It is an asymmetric large joint
arthritis with sterile synovial fluid on joint aspiration.

Gout results from the deposition of monosodium urate, not uric acid, in the joints and soft
tissues. Under polarized light, monosodium urate crystals appear needle-shaped and negatively
birefringent The subcutaneous deposition of monosodium urate leads to the formation of tophi

Shaken baby syndrome is the combination of subdural hematoma with bilateral retinal
hemorrhages in an infant Any suspicion of child abuse should be reported to state protective
agencies
142


PATHOLOGY-Vascular
 Marked, one-sided kidney atrophy is suggestive of renal artery stenosas (RAS) It occurs in
elderty individuals due to atherosclerotic changes in the artenal intima or in women of
chddbeanng age due to fibromuscular dysplasia Hypertension and an abdominal bruit are present

Familial hypercholesterolemia. one of the most common autosomal dominant disorders, is the
result of heterozygous or homozygous LDL receptor gene mutations, which cause hepatocyte
under-expression of functional LDL receptors. This condition can lead to accelerated
atherosclerosis and early-onset coronary artery disease.

Intermittent muscle pain reproducibly caused by exercise and relieved by a brief period of rest
defines claudication, Claudication is almost always the result of atherosclerosis of larger, named
arteries The obstruction of blood flow in these arteries is the result of fixed stenohc lesions
produced by atheromas, which are lipid-filled intimal plaques that bulge into the artenal lumen
The stenoses prevent sufficient increases in blood flow to exercising muscles, resulting in
ischemic muscle pain.

Hyperplastic arteholosclerosis in renal arterioles can result from and perpetuate malignant
hypertension The pathological lesion is an onion-like concentnc thickening of artenolar walls in
the renal vasculature and elsewhere.

Severe retrosternal pain that radiates to the back is the classic presentation of an aortic dissection
An intimal tear is thought to be the initiating process in a dissecting aortic aneurysm. The
dissection can extend through the media along the aorta, both proximally and distally The
intramural hematoma dissects through the media and can compress major arterial branches.

Unilateral renal artery stenosis is a cause of secondary hypertension in two to five percent of
hypertensive patients The kidney affected by the stenosis may become atrophied due to oxygen
and nutrient deprivation.

Small vessel leukocytoclastic angiltis associated with IgA and C3 deposition is typical of HSR
HSP is most common in children 3 to 11 years old and is most often related to a recent infection
Most children present with palpable skin lesions, with or without abdominal pain and arthralgias
Although usually self-limiting, patients afflicted with HSP should be observed carefully because
glomerulonephritis and even end-stage renal disease are possible complications.

Takayasu arteritis and temporal arterdis involve artenal vessels of different sizes and locations
(aorta and proximal aortic arterial branch involvement versus more distal carotid artery branch
involvement, respectively), and have different clinical presentations Even so. they may share a
common pathologic morphology, consisting of granulomatous inflammation of the media.

Xanthelasmas. a type of xarithoma. are yellowish maculeslpapules found on the medial eyelids.
They are dermal accumulations of macrophages containing cholesterol and triglycerides, and are
generally associated with a primary or secondary hypeilipidemia or dyslipidemia An LDL
receptor abnormality is the most common cause.
143



Thromboangiitis obliterans (Buerger’s disease) is usually seen among heavy cigarette smokers
with onset before age 35, and is associated with hypersensitivity to intradermal injections of
tobacco extracts This segmental thrombosing vasculitis often extends into contiguous veins and
nerves, encasing them in fibrous tissue.

GCAis characterized by granulomatous inflammation of the media, with fragmentation of the
internal elastic lamina of medium and small branches of the carotid artery. GCA is most common
in patients older than 50. and jaw claudication is the most specific symptom. Irreversible
blindness due to ophthalmic artery occlusion is a severe complication of GCA, and can be
prevented by immediate prednisone therapy.

Patients with adult-type coarctation of the aorta commonly die of hypertension-associated
complications, including left ventricular failure, ruptured dissecting aortic aneurysm, and
intracranial hemorrhage. These patients are at increased risk for ruptured intracranial aneurysms
because of the increased incidence of congenital berry aneurysms of the Circle of Willis as well
as aortic arch hypertension

Hepatic angiosarcoma is associated with exposure to carcinogens such as arsenic, thorotrast, and
polyvinyl chloride Tumor cells express CD 31, an endothelial cell marker

Abdominal pain due to acute pancreatitis is the most likely presentation for
hyperchylomicronemia (hypertriglyceridemia). Patients with this disorder are not usually at
increased risk for premature coronary artery disease. Skin xanthomas may be present in
hypertriglyceridemia. but tubular/tendon xanthomas and xanthelasmas are present with
hypercholesterolemia (high LDL).

Cutaneous, strawberry4ype capillary hemangiomas are common. benign, congenital tumors,
which are composed of unencapsulated aggregates of closely packed, thin-walled capillanes
Initially, strawberry hemangiomas grow in proportion to the growth of the child, before
eventually regressing In 75-95% of cases, the vascular tumor will regress completely by age 7

Cherry hemangiomas are small. red. cutaneous papules common in aging adults They do not
regress spontaneously and typically increase in number with age Light microscopy of these
lesions shows piohferabon of capillanes and post-capdlary venules in the papillary dermis

The malor cause of AAA is atherosclerosis Atherosclerotic atheromas can sufficiently progress
to weaken the underlying media of the aortic wall.

Asnificantrnrnatched defect on ventilation-perfusion scan is a specific finding for a pulmonary
embolism, which is usually the result of a deep vein thrombosis and part of a continuum of the
same disease known as pulmonary thromboembolism.

A benign glomus tumor (glomangioma) can produce a very tender, small (a few millimeters in
diameter); red-blue lesion under the nail bed. This type of tumor onginates from the modified
smooth muscle cells that control the thermoregulatory functions of dermal glomus bodies.
144



ChurgStrauss syndrome is an idiopathic systemic vasculitis associated with adult-onset asthma,
eosinophilia, and p-ANCA. Additional clinical criteria for this diagnosis include a history of
allergy, mono- or polyneuropathy, migratory/transient pulmonary infiltrates, and paranasal sinus
abnormalities.

Persistent lymphederna (with chronic dilatation of lymphatic channels) predisposes to the
development of lymphangiosarcoma. a rare malignant neoplasrn of the endothekal lining of
lymphatic channels This cancer may arise approximately 10 years after radical mastectomy with
axiflary lymph node dissection for breast cancer

Myxomatous changes in the media ol large arteries are found m cystic medial degeneration.
which predisposes to the development of aortic dissechons and aortk aneurysms Medial
degeneration is frequently seen in younger individuals with Marfan syndrome.

Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia) is an autosomal dominant
condition marked by the presence of telangiectasias in the skin as well as the mucous membranes
of the lips, oronasopharynx, respiratory tract, gastrointestinal tract, and urinary tract Rupture of
these telangiectasias may cause epistaxis, gastrointestinal bleeding, or hematuria

Incompetent venous valves in the lower extremities allow retrograde blood flow from deep to
superficial veins. This increases the pressure in the superficial veins, leading to their dilation
(vancose veins). The resulting chronic venous insufficiency causes stasis dermatitis, which
manifests as erythema and scaling with progressive dermal fibrosis and hyperpgmentation.

PAN is segmental. transmural. necrotizing inflammation of medium- to small-sized arteries
Renal artery involvement is often prominent Vessels of the kidneys, heart liver, and
gastrointestinal tract are most commonly involved in resulting ischemia, infarction, or
hemorrhage Cutaneous manifestations occur in up to one-third of patients, and include palpable
purpura The lung is very rarely involved

Strawberry hemangiomas (capillary hernangiomas) are benign vascular tumors of childhood
They appear during the first weeks of life, initially grow rapidly, and typically regress by 5-8
years old These tumors are composed of capillaries separated by connective tissue

Homogeneous deposition of eosinophilic hyahne material in the intima and media of small
arteries and arterioles characterizes hyaline artenoloscierosis, which is typically produced by
long-standing nonmalignant hypertension and/or diabetes

Fatty streaks are the earliest lesion of atherosclerosis and are present in all individuals after age
10. They are composed of intimal, lipid-filled foam cells, derived from macrophages and SMC
that have engulfed lipoproteins Although some fatty streaks may progress to full-fledged
atherosclerotic plaques later in life, in general their occurrence and location in a child do not
predict the occurrence or location of atheromatous plaques later in life.
145


Pulmonary embolism is common in hospitalized patients. Large emboli lodge in the pulmonary
artery bifurcation. Smaller emboh occlude the peripheral branches of the pulmonary artery,
producing wedge-shaped, red Themorrhagic” infarcts This condition is precipitated by
hypercoagulability and can be prevented by the anticoagulant heparin

A paraneoplastic syndrome of hypercoagulability may be seen in some patients with cancer,
especially adenocarcinomas of the pancreas, colon, or lung Superficial venous thromboses may
thus appear in one site and then resolve, only to recur in another site, producing “Trousseau’s
syndrome.” or migratory superficial thrombophlebitis—an indication of visceral cancer.

Temporal (giant cell) arteritis is characterized by granulomatous inflammation of the media, and
is the most common form of systemic vascuhtis in adults It predominantly involves medium to
smaller branches of the carotid artery, especially the temporal artenes, The resulting headache,
facial pain, jaw claudication, and visual deterioration generally respond well to glucocorticoid
therapy.

Hypertension is the single most important nsk factor for the development of intimal tears leading
to aortic dissections. In addition to hypertension, smoking, diabetes, and hypercholesterole.ma
are all major nsk factors for atheroscleios,s, which predisposes to aortsc aneurysm formahon
more than to aortic dissection.

Necrotizing vasculitis of the upper and lower respiratory tract (causing nasal ulcerations,
sinusitis, hemoptysis) and rapidly progressive glomerulonephritis—producing a variable degree
of renal failure—is characteristic of granulomatosis with polyangutis (Wegeners) This disease is
associated with C-ANCAs,

Necrotizing vasculitis of the upper and lower respiratory tract (causing nasal ulcerations,
sinusitis, hemoptysis) and rapidly progressive glomerulonephritis—producing a variable degree
of renal failure—is characteristic of granulomatosis with polyangiltis (Weqener’s). This disease
is associated with C-ANCAs, which may target neutrophil proteinase 3.

Among the arterthdes. transmural inflammation with fibhnOid necrosis is most characteristic of
PAN Fever. malaise, weight loss, abdominal pain, and melena are frequent symptoms of PAN.
PAN is associated with hepatitis B infection in 10 to 30% of cases

Varicose veins are dilated. tortuous veins resulting from prolonged increases in intraluminal
pressure and loss of vessel wall tensile strength Incompetent venous valves, venous
stasis/congestion, edema, and an increased incidence of superficiaI venous thrombosis may result
However, thromboembolism is a very infrequent complication of vancose veins Venous stasis
ulcers are very common and often occur over the medial malleolus

Tertiary syphilis can result in thoracic aortic aneurysm. It the aneurysm compress adjacent
structures and dilates the aortic valve ring, a murmur and mediastinal widening might be present,
as in this pabent. The pathogenesis of such an aneurysm begins with vasa vasorum endarteritis
and obhteration, resufting in inflammation, ischemia, and weakening of the aortic adventitia.
FTA.-ABS is a test specific for syphilis.
146


PATHOPHYSIOLOGY-Cardiology+Renal

The major determinant of the ratio of forward4o-regurgitant left ventricular (LV) output in
patients with mitral regurgitation (MR) is LV afterload. An increase in steady state LV afterload
tends to decrease this ratio. An increase in steady state LV end diastolic volume may contribute
to or worsen MR.

Decreased cardiac output triggers a number of compensatory mechanisms. Renin-angiotensin-
aldosterone activation and increased sympathetic output raise arterial resistance (aftertoad) and
exacerbate heart failure by making it more difficult for the failing heart to pump blood to the
tissues.

Pulsus paradoxus is defined by a decrease in systolic blood pressure of greater than 10 mmHg
with inspiration, and occurs in the setting of acute cardiac tamponade, constrictive pericarditis,
severe obstructive lung disease, and restrictive cardiomyopathy.

Pulsus paradoxus can occur in the setting of severe obstructive pulmonary disease such as
asthma Beta-adrenergc agonists control acute asthma exacerbations by causing bronchial smooth
muscle relaxation via increased intracellular cAMP

In patients with chronic aortic stenosis (AS) and concentric left ventricular hypertrophy:
1 The loss of the contribution of atnal contraction to ventricular tilling that occurs with acute
atrial fibrillation (AF) can reduce left ventricular peload and cardiac output sufficiently to result
in dangerous systemic hypotension, and
2. Acute AF might also increase steady state pulmonary Venous pressures sufficiently to cause
acute pulmonary edema.

Collateral microvessels form adjacent pathways for blood flow to areas distal to an occluded
vessel Adenosine and dipyridamole are selective vasoddators of coronary vessels that can cause
coronary steal, a phenomenon in whsch blood flow m ischemic areas is reduced due to artenolar
vasodilabon in nonischemic areas Coronary steal can lead to hypoperfusion and worsening of
existing ischemia

Loss of cardiomyocyte contractility occurs within 60 seconds after the onset of total ischemia.
When
ischernia lasts less than 30 minutes, restoration of blood flow leads to reversible contractile
dysfunction
(myocardial stunning), with contractility gradually returning to normal over the next several
hours to days
However, after about 30 minutes of total ischemia, ischemic injury becomes irreversible.

Under normal circumstances, the right ventñcular (RV) thickness is between 3-4mm during
diastole, significantly thinner than the left ventricular wall thickness (1 cm). RVH is a feature of
cor pumonale. a condition caused by pulmonary hypertension resulling from disease of the lung
parenchyma or the pulmonary vasculature. In young females between the ages of 20 and 40.
primary pulmonary hypertension may be responsible for cor pulmonale.
147



The abnormally large (wide) pulse pressure caused by aortic regurgitation (AR) is responsible
for many of the symptoms and signs of AR

An abnormally prominent (regurgitant) left atrial v wave during cardiac catheterization is a
major hemodynamic finding indicative of mitral regurgitation.

Diastolic heart failure is characterized by a decrease in ventricular diastolic compliance but
normal ventricular contractile performance As a result, LVEDP must be increased En order to
achieve a normal LVEDV and stroke volume Systolic heart failure results from a decrease ii
ventricular contractile performance (decreased ejection fraction) and requires an increase in both
LVEDP and LVEDV to imp1ove stroke volume

Heart failure due to left ventricular (LV) diastolic dysfunction is the result of a decrease in
diastolic LV compliance. Restrictive cardiomyopathy, as can be caused by amyloidosis, may
cause diastolic dysfunction. Infectious myocarditis and cardiotoxic agents inckiding alcohol and
doxorubicin tend to produce a dilated

The renal hypoperfusion characteristic of renal artery stenosis activates the renin-angiotensin-
aldosterone system. The hypertrophied smooth muscle cells of the afferent and efferent
glornerular arterioles synthesize renin, which increases angiotensin Il-mediated vasoconstnction
and aldosterone- mediated sodium and water retention

A presystohc sound on cardiac auscultation that immediately precedes Si is most often an S4
gallop An S4 requires normal atrial contraction and results from rapid emptying of atnal blood
Into a ventricle with reduced compliance (stiff ventncle).

On jugular venous pressure tracings. the first peak is the a wave. which is generated by atrial
contraction This is notably absent in patients with atnal fibrillatIon.

Calcthcation and thickening of the pencardium > 4 mm are common features of constrictive
pencarditis on CT Clinical findings include slowty pogressrve dyspnea, peripheral edema, and
ascites

In the kidney, angiotensin II preferentially constricts the efferent arteriole, thereby maintaining
the GFR ACE-inhibitors promote efferent arteriolar dilation, causing GFR reductions.

Paradoxical thromboembolism occurs when a blood clot from the venous system crosses directly
into the arterial circulation via an abnormal connection between right arid left cardiac chambers,
such as an ASD or ventricular septal defect, Auscultatory findings in an ASD include a wide and
fixed sphtting of S2. Additional associations between auscultatory findings and cardiac lesions
are as follows
1 Systolic ejection murmur accentuated by standing hypertrophic obstructive cardiomyopathy
2. Early diastolic decrescendo murmur decreased by amyl nitrite: aortic regurgitation
3. Late diastolic murmur eliminated by atnal fibrillation: mitral (and/or tricuspid) stenosis
148


Brain Natnuretic Peptide (BNP) is elevated in patients with heart failure and is often used as a
laboratory test in the clinical setting to determine a patient is siifering from a CHF exacerbation
It is released by the ventncles when they are stretched as they often are in CHF from systolic
dysfunction ft acts along with ANP to cause vasodilatation (decreased preload) and diuresis Both
ANP and BNP activate guanytate cyclase. which induces an increase of intracellular cycbc GMP

The murmur of AR is a diastolic decrescendo murmur, heard loudest in early diastole when the
pressure gradient between the aorta and the left ventncle is maximal The murmur of AR is
typically best heard at the left sternal border, with the patient leaning forward and at end
expirahon

In patients with TOF, the degree of RV outflow tract obstruction is the major determinant of the
degree of nght4o-Ieft intracardiac shunting, and thus of hypoxemEc symptom severity.

Left ventricular dysfunction can lead to increased pulmonary arterial pressure due to reactive
vasoconstriction secondary to pulmonary venous congestion. Reactive changes in the pulmonary
vasculature (e.g., endothelial dysfunction resulting in further vasoconstriction) also contribute to
pulmonary hypertension

Cardiac (or pencardial) tamporiade presents clinically with hypotension, tachycardia, and an
elevated central venous pressure that produces jugular venous distension (JVD). Heart sounds
may be muffled on cardiac auscultation and systolic blood pressure may drop more than 1
OmmHg on wispiration (pulsus paradoxus).

In a patient with mitral regurgitation (MR). the most reliable auscultatory finding indicating a
high regurgitant volume (severe MR) and left ventricular volume overload is a left sided S3
gallop Intensity of a holosystolic murmur due to MR may not correlate well with regurgitant
volume A left sided S4 would suggest end stage decompensation of severe MR to left ventncular
failure, however, many patients with severe MR may not have developed left heart failure

Isolated mitral stenosis (MS) elevates the left atrial end diastolic pressure and can therefore cause
an elevated pulmonary capillary wedge pressure (PCWP), pulmonary hypertension, pulmonary
vascular sclerosis and decreased compliance, nght venincular dilatation, and functional tncuspid
regurgitation Note that in patients with isolated MS, PCWP does not reflect the left ventricular
end diastolic pressure, which may be normal.

Acute hemodynamic changes can produce functional heart murmurs, in the absence of any fixed
valve lesion Dilatation of the left venincle in response to increased preload can result in
functional mitral regurgitation, which can be eliminated by preload reduchon and reduced by
afterload reduction

Aortic stenosis (AS) may cause exertional syncope The murmur of AS is a systolic ejection-type,
crescendo-decrescendo murmur that starts after the first heart sound and typically ends before the
A2 component of the second heart sound. The intensity of the AS murmur is proportional to the
magnitude of the left ventricle-to-aorta pressure gradient during systole.
149


An accessory AV conduction pathway (Wolff-Parkinson-White syndrome) can manifest
clinically as recurrent paroxysmal supraventricular tachycardia in an otherwise healthy
individua[ The baseline ECG generally shows a triad of abnormalities corresponding to
ventricular pre-excitation: a shortened PR-interval, a delta wave at the start of the QRS complex.
and a widened QRS intervaL

Wide, fixed splitting of the second heart sound is a characteristic auscultatory finding in patients
with ASD A hemodynamically significant ASD can produce chronic pulmonary hypertension as
a result of left-to-right intracardiac shunting Eisenmenger syndrome is the late-onset reversal of a
left-to-right shunt due to pulmonary vascular sclerosis resulting from chronic pulmonary
hypertension. Closure of the ASD may be required to prevent irreversible pulmonary vascular
sclerosis and a permanent Eisenmenger syndrome

The major long-term hemodynamic compensatory response to the volume overload of aortic
regurgitation includes an increase in left ventncular preload (LV end-diastohc volume) in
association with eccentric left ventricular hypeitrophy

A significant increase in blood oxygen saturation between 2 nght-sided vessels or chambers
indicates the presence of a left-to-right shunt. If such an oxygen step-up occurs between the right
atrium and right ventricle, a ventricular septal defect (VSD) is most likely responsible VSD is the
most common congenital heart disease, and a small VSD produces a holosystohc murmur that is
loudest over the left mid-sternal border.

The triad of muffled heart sounds. elevated jugular venous pressure. and profound hypotension
indicates pericardial tamponade Rupture of the ventricular free wall as a consequence of an acute
transmural Ml can cause tamponade Rupture usually occurs 3 to 7 days after the onset of total
ischemia, when coagulative necrosis, neutrophil infiftration, and enzymatic lysas of connective
tissue have sufficiently weakened the infarcted myocardium.

In patients with TOF. squatting increases SVR and decreases right-to-’eft shunting, thereby
increasing pulmonary blood flow Squatting thus counteracts arterial desaturation during
hypoxemic speIIs

Patients with mitral stenosis due to abnormal mitral valves may have an opening snap in early
diastole shortty after the aortic component of the second heart sound (A2) The opening snap
occurs shortly after the mitral valve opens.

Patients with acute mitral regurgitation have near-normal left atrial (LA) compliance. Therefore,
they tend to develop marked pulmonary hypertension and pulmonary edema Patients with
chronic mitral regurgitation acquire an adaptive increase in LA volume and compliance Thus,
they are less prone to pulmonary hypertension/edema but are more prone to atrial fibrillation and
mural thromboembolism

1. Both ventricular hypertrophy and volume overload cause release of both ANP and BNP from
the ventricular myocytes to facilitate natriuresis and diuresis
2. Reperfusion injury is thought to result from generation of oxygen-free radicals.
150



• A persistent or repetitive low flow state causes myocardial hibernation that can be reversed by
reperfusion. Myocardial stunning is a less severe form of ischemia-induced reversible loss of
contractile function
• Repetitive stunning can result in hibernation lschemic preconditioning is the development of
resistance to infarction by cardiac myocytes previously exposed to repetitive non-lethal ischemia.
• Ventricular remodeling involves chronic changes in mass, volume, shape, and myocyte
composition of the heart, to compensate for an increased hemodynamic load.

The best, most reliable, and most continuous auscultatory indicator of the severity of mitral
stenosis is the A2-OS interval The shorter this interval, the more severe the stenosis Other
auscultatory findings that may accompany MS include a diastolic rumble (intensity vanes
depending on patient anatomy) and pre-systohc accentuation due to left atnal contraction. A
nght-sided S3 andlor S4 might anse with end-stage MS critical enough to produce severe
pulmonary hypertension.
151


Pathophysiology-Endcrine+Vascular+Neuro
Glucagon increases serum glucose by increased production of glucose from the liver Glucagon
stimulates insulin secretion from the pancreas However, patients with type 1 diabetes rarely have
significant residual beta cells. Unlike epinephnne. glucagon has an insignificant effect on skeetal
muscle cells and adipocytes

Reduced gallbladder contractility. due to decreased cholecystokinin secretion, is responsible for
biliary stones in patients with somatostatinoma.

Most patients with diabetic ketoacidosis have normal to increased serum potassium levels despite
low intracellular potassium. Replacement of potassium is a crucial step in management of
patients with diabetic ketoacidosis.

Atherosclerosis is inthated by repetitive endothelial cell injury, which leads to a chronic
inflammatory state in the underlying intima of large elastic artenes as well as large and medium-
size muscular arteries

Hypothyroidism is a common cause of an elevated creahne kinase level due to hypothyroid
myopathy
Sometimes. it can be the first manifestation of hypothyroidism. Other common causes of
elevated creatine
kinase include medicahons such as HMG Co-A reductase inhibitors (stahns), autoimmune
disease
(polymyositis/dermatomyositis), and muscular dystrophies (Duchenne muscular dystrophy).

One-aipha-hydroxylation transforms calcidiol to calcithol in the renal tubules In chronic kidney
disease, the conversion of 25-hydroxy vitamin D to I ,25-dihydroxy vitamin D is impaired,
leading to decreased circulating levels of I ,25-dihydroxy vitamin D. Low levels of the active
form of vitamin D cause an increase in circulating PTH, called “secondary hyperparathyroidism
Note that 24,25-dihydrocholecalcderol is an inactive substance

DUnrig a water deprivation test. most patients with primary polydipsia will demonstrate a
significant increase in urine osmolality. Additionally, patients with primary polydipsia will have
low serum sodium levels and osmolality. Restriction of water intake normahzes unne output in
patients with primary polydipsia

Increase in levels of thyroid binding globulin lead to increase wi circulating total T4 and total T3
However, the level of free thyroid hormone is normal. Increase in TBG is typically seen m
pregnancy, with use of oral contraceptives, or with hormone replacement therapy

Sertoli cells maintain spermatogenesis. release inhibin, and secrete Mullerian inhibiting factor
during male embryogenesis. Inhibin provides negative feedback on FSH secretion by the anterior
pituitary
152


I 7ahydroxyiase deficiency impairs the synthesis of androgens. estrogens. arid cortisol but does
not inhibit mineralocorticoid production Boys appear phenotypically female at birth, but gills
develop normal genitalia Patients typically present with hypogonadism, hypertension, and
hypokalemia

Frothy or foamy urine may be caused by proteinuna Heavy proteinuria, as in nephrotic
syndrome, can cause regional or generalized interstitial edema because the decrease in serum
albumin and total protein concentrations lowers the plasma oncotic pressure and increases net
plasma filtration in capillary beds

Acetyicholine release from presynaptic terminal vesicles at the neuromuscular junction depends
upon the influx of extracellular calcium into the presynaptic terminal. Calcium influx into the
nerve terminal occurs following neuronal depolarization and opening of voftage-gated calcium
channels

The syndrome of inappropnate antidiuretic hormone secretion (SLADH) is characterized by low
plasma sodium and osmolality. inappropriately concentrated unne, increased unnary sodium, and
clinically normal body fluid volume An important cause of SIADH is a paraneoplastic effect
secondary to small cell carcinoma of the lung.

Adrenal adenoma and carcinoma will have low levels of ACTh in combination with the clinical
features of Cushing syndrome ACTH levels are elevated in pituitary adenomas, and are
suppressed by high-dose, but not low-dose, dexamethasone Serum ACTI-I levels are generally
markedly elevated in ectopic ACTH production by malignant tumors; even high-dose
dexamethasone does not suppress these levels

Depression of the entire hypothalamus-pituitary-adrenal axis by glucocorticoid therapy is the
most common cause of adrenal insufficiency Adrenal crisis can be precipitated in these patients
under stressful situations (i. e., infections or surgery) if their glucocorticoid dose is not
appropnately increased

Serum TSH level is the single most important screening test m diagnosing pnmary
hypothyroidism Although TSH is not elevated in patients with hypothyroidism in central
hypothyroidism, central hypothyroidism is uncommon.

Secondary hyperparathyroidism is seen in patients with chronic renal failure These patients have
an elevated serum PTH, accompanied by normal to low serum calcium levels, and high serum
phosphorus levels. Circulating 1 ,25-dihydroxy vitamin D levels are low due to the deficiency of
1-alpha hydroxylase, an enzyme that resides in the kidneys.

Pufferfish poisoning is caused by tetrodotoxin, a neurotoxin produced by microorganisms
associated with the fish Tetrodotoxin binds to vottage-gated sodium channels in nerve and
cardiac tissue, preventing sodium influx and depolarization.

The likelihood of acute plaque change (especially rupture) producing an acute coronary
syndrome via supenmposed thrombosis and/or thromboembohsm is most related to plaque
153


stabibty Plaque stability depends significantly on mechanical strength of the fibrous cap
Inflammatory macrophages in the intima may reduce plaque stability by secreting
metalloproteinases, which degrade collagen

An age-related decrease in compliance (increased stiffness) of the aorta and its proximal major
branches often causes isolated systolic hypertension (ISH)

Patients with clasc, salt-wasting 21-hydroxylase deficiency have deficient cortisol and
aldosterone synthesis combined with adrenal androgen overproduction. Male infants have
normal genitalia and present 1-2 weeks after birth with vomiting, hypotension. hyponatremia.
and hyperkalemia Females present at birth with ambiguous genitalia

The diarrhea caused by cehac disease can lead to vTtamin D deficiency through malabsorption
Patients with vitamin D deficiency have decreased serum phosphorus. increased serum
parathyroid hormone (secondary hyperparathyroidism), and low serum calcium. They may also
have symptoms such as bone pain and muscle weakness.

Anytime a patient has bitemporal hemianopsia, a pituitary tumor should be suspected. The most
common
functional pituitary tumor is a prolactinoma Secreting prolactinomas thhibit the entire axis of
GnRH-LHIFSH-sex hormones, causing impotence in men and amenorrhea in women of
reproductive age
(hypogonadotropic amenorrhea).

Reperfuson injury is thought to occur secondary to oxygen free radical generation, mitochondrial
damage, and inflammation.

Sex hormones promote both growth and epiphyseal plate closure: hence, precocious puberty may
resuLt in a shorter stature, despite an initial growth spurt Gigantism is caused by excessive
pituitary production of growth hormone, these patients achieve enormous heights because, unlike
excessive sex steroids, excessive IGF-1 does not lead to premature closure of the epiphysis

Hyperproactinernia causes hypogonadism, which leads to reduced estrogen in women Low
estrogen due to any cause is risk factor for accelerated bone loss.

When the central venous piessure (CVP) is increased, as in right heart failure, the interstitial
fluid pressure rises due to an increase in net plasma filtration, As the interstitial fluid pressure
increases, so does lymphatic drainage Increased lymphatic drainage can compensate for
moderate CVP elevations to prevent the development of clinically apparent interstitial edema
With large CVP elevations, the net capillary filtration increases in excess of the lymphatic
reabsorptive capacity and overt edema develops

More than a 10% increase in urine osmolality following administration of vasopressin dunng a
water deprivation test suggests central D[ A urine osmolality increase above 50% is strongly
suggestive of complete central Dl.
154


The dominant effect of the hypothalamus on prolactiri secretion is inhibitory via dopamine
production Prolactin regulation by dopamine is a commonly tested concept on USMLE Step 1

In response to calcium loading. PTh decreases. cakitonin increases, and the renal synthesis of the
active form of vitamin D decreases

The adrenal cortex consists of three distinct zones: the outer zona glomerulosa. the middle zona
fasciculata, and the inner zona reticularis (remember GFR) The zona glomerulosa synthesizes
mineralocorticoids (e.g. aldosterone), the zona fasciculata predominantly produces cortisol, and
the zona reticulans predominantly produces androgens

21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia. Affected
female infants present at birth with ambiguous (virilized) genitaha Male infants have normal
genitalia and present later with salt-wasting or precocious puberty. A high serum level of 17-
hydroxyprogesterone is diagnostic.

An ACTH surge with a resultant increase in steroid half-product’ excretion is a normal reaction
to metyrapone administration, because metyrapone blocks the last step of cortisol synthesis

Patients with type I diabetes mellitus are prone to develop other autoimmune endocrinopathies,
including Hashimoto thyroiditis, Graves’ disease. and Mdison’s disease (hypoadrenocorticism).
These patients are at increased risk for other non-endocnne autoimmune disorders as well,
including vitiligo and pernicious anemia.

Low bone density is a well-known complication of hyperprolactinemia that is associated with
prolactin-induced hypogonadism (i.e.. low estrogen), Vaginal dryness is another very common
manifestation of estrogen deficiency.

ACTH is the major trophic hormone of the zona fasciculata and reticularis, whereas the zona
glomerulosa is primarily regulated by angiotensin I. Prolonged ACTH stimulation causes
hyperplasia of the zona fasciculata and reticulans, resulting in excessive cortisol production
(Cushing syndrome).

FFA and serum tnglycendes are bebeved to increase insulin resistance in overweight individuals.

1 1-hydroxylase deficiency typically results in excessive adrenal androgen and
riNneralocorticoid (11- deoxycorticosterone) production. Females are born wdh ambiguous
genitalia, and affected individuals develop hypertension and hypokalemia early in life

Visceral obesity as measured by waist-to-hip ratio is an important determinant of insulin
resistance.

If a hypersecrehng-adrenal tumor has the functionality of the outer. intermediate, or inner layers
of the adrenal cortex, the hormone(s) released and clinical syndrome produced will be
aldosteronelConns syndrome, cortisoLlCushings syndrome, and androgens/hirsutism and
vinkzation, respectiveIy
155



Morphine tolerance is a common problem in the treatment of pain. The exact mechanism of
tolerance is unknown but may involve increased phosphorylation of opioid receptors, increased
adenylyl cylcase activity, or increased nitric oxide levels Activation of NMDA receptors by
glutamate is believed to enhance morphine tolerance by increasing phosphorylation of optoid
receptors and increasing nitric oxide evels NMDA receptor blockers, like ketamine. block the
actions of glutamate and effectively decrease morphine tolerance

Subpenosteal thinning is a characteristic feature of hyperparathyroidism Radiologically, this
thinning appears as subperiosteal erosions in the medial sides of the second and third phalanges
of the hand, and as a granular, salt-and-peppe?’ appearance of the calvarium.

In the pathogenesis of atherosclerotic plaques. release of platelet-derived growth factor (PDGF)
by locally adherent platelets, endothelial cells, and macrophages promotes the migration of
smooth muscle cells from the media into the intima and their subsequent prohferation

1. Growth hormone increases linear growth by stimulating the production of IGF-1 from the liver
2. Defective growth hormone receptors will lead to decrease in linear growth and is called Laron
dwarfism. It is characterized by hágh serum levels of growth hormone in the piesence of low
IGF-1 leve1s

The vascular reaction to endothelial and intimal injury is intimal hyperplasia and fibrosis,
predominantly mediated by reactive smooth muscle cells that migrate from the media to the
intima

During hyperglycemia. excess plasma glucose is converted to sorbitol by aldose reductase
Sorbitol accumulates within some cells and attracts water into these tissues leading to osmotic
cellular injury This mechanism is implicated in the pathophysiology of cataracts and penpheral
neuropathy in diabetes




Pathophysiology-GIT+Pulm+Haem+Hepa+Skeletal
After vasectomy, viable sperm remain in the portion of the vas deferens proximal to the ligation
Twenty percent of patients still have viable sperm in their ejaculate after 3 months and at least 20
ejaculations

Aromatase converts androgens into estrogens in the ovaries, testes, placenta and other peripheral
tissues Genetic deficiency of this enzyme leads to an inability to synthesize estrogens It presents
with maternal vinlization during pregnancy and masculinization of the female fetus

Trypsin activates all proteolytic pancreatic enzymes including itself I activated prematurely (i.e.
before reaching the duodenal lumen), it can cause autodigestion of the pancreatic tissue A
number of inhibitory mechanisms exist to prevent premature activation of trypsin A gene
mutation that renders trypsinogen insensitive to inhibhon causes hereditary pancreat.tis
156



Diffuse esophageal spasm (DES) occurs due to uncoordinated contractions of the esophagus
These contractions are both inefficient in propelling food mto the stomach and may cause
symptoms of dysphagia and chest pain This chest pain may mimic unstabie angina, thus,
complete cardiac work-up should be considered in every patient suspected of having DES, so
that a cardiac cause may be ruled oul

The pathogenesis of centnacinar emphysema associated with chronic, heavy smoking
predominantly involves intraalveolar release of proteases, especially elastase, from infdtrahng
neutrophils and from alveolar macrophages.

A moderately elevated alkaline phosphatase of unclear etiology should be followed up with y-
gtutamyl transpeptidase.

ViPomas are non-beta cell pancreatic islet cell tumors that hypersecrete VIP ViP increases
intestinal chloride loss into the stool, which causes excess losses ol the accompanying water,
sodium and potassium as well. ViP also inhibits gastric acid secretion. Somatostatin inhibits the
secretion of VIP and is used to treat the symptoms of ViPoma

In cystic fibrOSis, abnormalities of the CFTR transmembrane protein reduce luminal chloride
secretion and increase sodium and net water absorption, resulting in dehydrated mucus and a
widened, negative transepithelial potential difference These electrolyte changes occur in most
exocrine glands (other than sweat glands).

Duodenal ulcers are not associated with an increased risk of carcinoma in the same location. In
contrast, esophageal, gastric, and colorectal cancers are frequently identified as ulcerative lesions
on endoscopy

Cheyne-Stokes respiration describes cyclic breathing in which apnea is followed by gradually
increasing tidal volumes, and then gradually decreasing tidal volumes until the next apneic
period It is commonly seen in advanced congestive heart faifure

Lactase-deticient individuals have increased stool osmotic gap, increased breath hydrogen
content, and decreased stool pH upon lactose challenge.

Airway challenge testing with methachohne is a highly sensitive but nonspecific measure that
can detect the degree of bronchial hyperreactivity in patients suspected of having asthma A
negative methacholine challenge test can help to exclude (rule out) the diagnosis Chest x-ray,
blood eosinophil count, serum IgE level, and skin reactivity to vanous allergens are less
sensitive, normal findings on these tests cannot exclude the diagnosis

Hepatic encephalopathy appears to be secondary to increased levels of ammonia in circulation
Frequently, hepatic encephalopathy is precipitated by a stressor that alters the ammonia balance
(eg, gastrointestinal bleeding)
157


Gilbert syndrome is the likely diagnosis in patients with no apparent liver disease who have mild
unconjugated hyperbilirubinemia that appears provoked by one of the classic triggers.

Arterial PaCO. is a direct indicator of the status of alveolar ventilation Hypocapnia implies
ongoing alveolar hyperventilation Upper airway obstruction, reduced ventilatory drive,
respiratory muscle fatigue, and decreased chest wall compliance are possible causes of alveolar
hypoventilation and cause hypercapnia

Renal calculi occur when there is an imbalance of the factors that facilitate and prevent stone
formation. Increased concentrations of calcium, phosphate. oxalate. and uric acid promote salt
crystallization, whereas increased citrate and high fluid intake help prevent calculi formation.

The RANK receptor/RANK-Ugand interaction is essential for the formation and differentiation
of osteoclasts. The over-expression of RANK receptors in hypoestrogenic states causes increased
bone resorpUon due to increased osteoclastic activity. In short, low estrogen means a lower bone
mass.

Patients with osteoporosis have low bone mass. resulting in increased susceptibihty for fragihty
fractures In primary osteoporosis (osteoporosis not caused by a medical disorder), serum
calcium, phosphorus, and PTH levels are typically normal.

Patients with CF produce eccrine sweat that contains high concentrations of sodium and chloride
compared to normal individuals

Although numerous substances are thought to play a role in the pathogenesis of allergic asthma,
only leukotrienes (LTC4, LTD4, and LTE4) and acetyicholine have pharmacologc receptor
antagonists that offer clear therapeutic benefit.

Metabolic alkalosis is characterized by a high arterial blood pH. HCO3 and pCO2. It is most
commonly caused by vomiting, NG suction, diuretic use or hyperaldosteronism Measuring the
urinary chloride concentration and determining the patienUs volume status helps to identify the
cause of metabolic alkalosis

Hyperestrinism in alcohohc cirrhosis arises due to decreased catabolism of estrogens as well as
increased sex hormone-binding globulin (which decreases the free testosterone-to-estrogen
ratio). This imbalance leads to gynecomastia, testicular atrophy, decreased body hair, and spider
angiomata

Emphysema most commonly results from chronic smoking. but can also occur in genetically
predisposed individuals with alpha-i antitrypsin deficiency Patients with emphysema have a
decreased FEV1/FVC ratio, increased total lung volume, and decreased diffusing capacity

Sunlight exposure catalyses the first reaction in the chain of active vitamin D synthesist 7-
dehydrocholesterol transforms to cholecalciferol (Vitamin D3). Then, 26-hydroxylation occurs in
the liver and the kidney enzyme 1-alpha hydroxylase catalyzes the final step in the synthesis of
active vitamin D
158



Chgler-Najjar syndrome is an autosomal recessive disorder of bdirubin metabolism caused by a
genetic lack of the UGT enzyme needed to catalyze bile glucuronidation. Unconjugated
hyperbilirubinemia develops in these infants, causing kemicterus and often death.

Chronic obstwctive pulmonary disease (COPD) in a heavy smoker may consist of both
emphysema and chronic bronchitis and thus may present with both progressive exertional
dyspnea (characteristic of emphysema) and frequent respiratory infections (charactenstic of
chronic bronchitis) On pulmonary function testing, all COPD yields a decreased FEV1!FVC
ratio Emphysema also tends to increase TLC and RV In contrast, restrictive lung diseases can
cause reduced lung volumes and increased FEV1/FVC.

Decreased esophageal body peristalsis and poor relaxation of the LES on manometry are typical
for achalasia Achalasia presents with progressive dysphagia chest pain, food regurgitation and
aspiration Barium swallow shows a dilated esophagus and a “bird’s beak deformity of the LES

D-xylose is a monosaccharide: thus. its absorption does not require pancreatic enzymes and is
not affected by pancreatic insufficiency. Oral administration of a fixed dose of D-xylose can be
used to differentiate between malabsorption of pancreatic versus gastrointestinal mucosal
etiology.

Paroxysmal breathlessness and wheezing in a young patient that is unrelated to ingestion of
aspirin, pulmonary infection, inhalation of irritants, stress, and/or exercise should raise a strong
suspicion for extrinsic allergic asthma. Classic sputum findings include easinophils and Charcot-
Leyden crystals. Eosinophils are recruited and activated by IL-5 secreted by T2 type helper T-
cells

In patients with emphysema. total lung capacity. residual volume, and funcbonal residual
capacity are generally increased, due to decreased lung elastic recoil. Air trapping in
emphysematous patients tends to increase expiratory reserve volume and thereby further
contnbutes to an increased FRC

The abnormal activation of trypsin within the pancreas is a central event in the pathogenesis of
acute necrotizing pancreatitis All pcoteolytic pancreatic enzymes are converted into their active
forms by trypsin. Intracellular pancreatic activation of trypsin leads to activation of other
proteolytic enzymes and pancreatic autodigestion

Gastrin increases gastric acid secretion and stimulates parietal cell proliferation, thus increasing
parietal cell mass (trophic effect). Both these effects are seen in patients with Zollinger-Ellison
syndrome

The work of breathing is minimized in patients with increased elastic resistance (eg, pulmonary
fibrosis) when their respiratory rate is high and tidal volume is low (fast, shallow breaths) In
contrast, patients with diseases that increase airflow resistance (e.g asthma, COPE)) breathe at a
lower rate/higher tidal volume (slow, deep breaths) in order to minimize the work of breathing.
159


hi patients with an al -antitrypsin deficiency, smoking dramatically increases the risk of
developing panacinar emphysema

Osteoclasts originate from hematopoietic progenitor cells. RANK-L and M-CSF play an
important role in osteoclast differentiation Paget’s disease of the bone is caused by excessive
osteoclastic resorption.

Major basic protein released by eosinophils normally functions to kill helminths. It is also
thought to contribute to the bronchial epithelial damage sustained by patients with atopic
(extrinsic allergic) asthma

A normal bleeding time indicates adequate platelet hemostatic function. A normal aPTT
indicates an intact intnnsic coagulation system. A prolonged PT indicates a defect in the extrinsic
system at a step not shared with the intrinsic system.

Remember the risk factors for osteoporosis:
1 Smoking
2. Menopause
3. Corticosteroid therapy
4 Physical inactivity
5. Caucasian race (immutable)
6. Low total body weight
7. Aicohol use

Digestive disorders such as cholestasis can cause malabsoiption and nutritional deficiencies of
the fat-soluble vitamins This may result in osteomalacia, which is frequently associated with
vitamin D deficiency

The hypercalcernia associated with squamous cell lung cancer, and several other tumors, is
usually due to over-production of parathyroid hormone-related peptide and is termed the
‘humoral hypercalcemia of malignancy”

Systemic mastocytosis is characterized by the abnormal proliferation of mast cells and increased
histamine secretion Histamine increases the production of gastric acid by parietal cells Gastric
hypersecretion, therefore, is a common occurrence r systemic mastocytosis

Intectous esaphagths is common in HIV-positive patients The most common cause s Candida
a/b/cans. although CMV and HSV-1 are also frequently implicated Diagnosis relies on
endoscopic and microscopic findings.

5a-reductase converts testosterone to dihydrotestosterone (DHT). DHT mediates development of
the external genitaha in the male fetus Male neonates with 5cs4eductase deficiency are born with
feminized external genitalia that typically masculinize at puberty. Small phallus and hypospadias
are commonly found
160


Cricopharyngeal muscle dysfunction is a condition caused by diminished relaxation of
pharyngeal muscles dunng swallowing The subsequently increased intraluminal pressure in the
oropharynx causes the mucosa to herniate through the wall at a point of muscle weakness,
forming a Zenker diverticulum Clinically, patients (elderly) present with oropharyngeal
dysphagia, coughing, choking, and recurrent aspiration

Reduced expiratory airflow velocity, decreased bdal volume, and increased residual volume
together characterize chronac obstructive pulmonary disease (COPD) Chronic bronchitis and/or
emphysematous destruction of interalveolar walls may be responsible In companson, restnctive
lung disorders tend to decrease all lung volumes without significantly affecting expiratory flow
rates

COPD can cause hypoxia sufficient to stimulate increased erythropoietin production by the
cortical cells of the kidney
161


PHARMACOLOGY-Cardiology
Bipolar disorder is commonly treated with lithium, an anti-manic medication Lhium has been
linked to cases of Ebstein’s anomaly in infants exposed in utero Ebsteins anomaly is
characterized by apical displacement of the tncuspid valve leaflets, decreased right ventricular
volume, and atrialization of the right ventricle

Clearance (CL) determines the dose rate required to maintain a steady-state plasma concentration
(CpJ:
Maint.nanc. dos. • Cp x CL I [Bloavaflability fraction]
The bioavailabihty fraction = 1 if administered intravenously

1 Warfarin inhibits the carboxylahon of vitamin K-dependent coagulation factors II, VII, IX, and
X. Prothrombin time should be monitored regularly during treatment with this medication. The
most common adverse effect is bleeding
2. Activated partial thromboplastin time (aPTT) is used for monitonng unfractionated heparin

Class Ill antiarrhythmics such as amiodarone, sotalol, ibutilide and dofetilide will slow potassium
efflux from the ventricular myocyte, prolong repolarization and prolong the refractory penod.

Nitrate drugs mimic the action of endothelial derived relaxing factor (nitric oxide, NO) They are
transformed to NO at the vascular smooth muscle cell membrane which leads to increased
cGMP, decreased intracellular calcium and myosin dephosphorylation.

The best treatment of chronic dry cough caused by an ACE inhibitor is replacement of this drug
with an angiotensin receptor blocking drug (ARB), such as losartan Remember that ARBs are
also beneficial for both hypertension and diabetic nephropathy and do not interfere with the
catabolism of bradykinin as ACE inhibitors do.

receptors are found in cardiac tissue and on renal juxtaglomerular cells, but not on vascular
smooth
muscle. Blockade of the , receptor leads to decreasing cAMP levels in cardiac and renal tissue
without
affecting cAMP levels in vascular smooth muscle.

Daptomycin is a lipopeptide antibiotic with activity limited to Gram-positive organisms,
including methicillin-resistant Staphylococcus aureus It causes depolarization of bacterial
cellular membrane and inhibition of DNA RNA. and protein synthesis. Daptomycin is associated
with increased CPK levels and an increased incidence of myopathy

Amiodarone along with the class IA and the remainder of the class Ill antiarrhythmic agents will
cause a prolongation of the QT interval on the EKG. These drugs have this effect because they
all slow phase 3 repolarization in the ventncular myocardium Amiodarone is unique in that it
does not predispose to torsade de pointes as the remainder of these agents do
162


Patients taking daály maintenance nitrates need to have a nitrate-free period every day to avoid
tolerance to the drug

Lidocaine is a class lB antiarrhythmic agent which very specifically binds rapidly depolarizing
and depolarized cells lschemic myocardium is depolarized tissue: this is why ocaine is specific
for ischernic tissue and is the agent of choice for prevention and treatment of post-myocardial
infarction arrhythmias Currently amiodarone has replaced the lidocaine in the management of
ventricular tachycardia

Nitrates can lead to a reflex tachycardia by causing a relative hypotension that the body responds
to with catecholamirie release This adverse effect can be prevented by administering beta-
adrenergic blockers with nitrates

It is important to know the difference in the cardioselectivity and vascular selectivity of the 3
classes of calcium channel blockers, Verapamil has the most effect on the heart while nifedipine
is most selective for the peripheral vasculature with diltiazem having an effect somewhere in
between The most frequent adverse reactions noted with verapamil are constipation and gingival
hyperplasia, though they also are known to cause bradycardia as well as first. second or third
degree AV nodal block in 1-2% of patients treated.




 Class I antiarrhvthmics




 1A
          nterrnediate bindrng to Na but also blocks K :hannels                   j Vfl;( pro1o
                                                                                  APD


 1B       ate of binding and release is so raped no :hange (fl is seen Since they APD j,
          also block la window current, they APD


 1C       very tight binding and slow release                                     U M’&)

In patients with hypertension and chronic ischernic myocardial failure, ACE inhibitors are
considered to be the most effective long-term treatment option, as they inhibit myocardial
remodeling and the associated deterioration of ventricular contractile function, m addition to
reducing blood pessure A beta-blocker would also be beneficial for these patients.
163


In this case, digoxin toxicity manifested as changes in color vision and anorexia Digoxin toxicity
can also cause ventricular dysrhythmias. headache, fatigue and confusion

Isoproterenol is an agonist at both 31 and 32-adrenergic receptors and has little or no a-
adrenergic agonist effects It causes a dose-dependent increase in myocardial contractility and a
dose-dependent decrease in systemic vascular resistance

The mechanism of action of digitalis is the inhibition of the Na-K-ATPase in cardiac pacemaker
cells leading to AV nodal blockade (increased diastolic filling time for greater contraction by the
Frank-Starling mechanism) and increased contractility from increased intracellular calcium

Procainamide and hydralazine have the highest risk of causing drug-induced lupus
erythematosus (DuE), which is charactenzed by the development of lupus-like symptoms in
addition to positive ANA and anti-histone antibodies Unlike with SLE, anti-dsDNA antibodies
are rarely seen

Using nitrates together with phosphodiesterase (PDE) inhibitors used for erectile dysfunction and
pulmonary hypertension causes a profound systemic hypotension because they both increase
intracellular cGMP which causes vascular smooth muscle relaxation. Their use together is
absolutely contraindicated

Sotalol has both beta-adrenergic blocking properties and class 3 antiarrhythmic (K channel
blocking) properties. It prolongs both the PR interval and the QT interval.

Adenosine is a rapidly acting antiarrhythmic used to quickly convert people out of PSVT (drug
of choice) It is also rapidly cleared and has a half-life of only less than 10 seconds It commonly
causes chest burning (bronchospasm), flushing and high grade block as adverse reactions
(remember, this is the drug used for chemical stress tests!)

Thiazide diuretics cause elevations in the serum LDL, calcium, unc acid and glucose levels They
lower serum potassium. serum sodium and blood pressure

Class 3 antiarrhythmic agents block potassium efflux from cardiac myocytes and prolong phase
3 of the myocyte action potential.

It is important that students know the correlation between the EKG waves and the cardiac cycle,
and how drugs that act on the heart affect both of these. Beta-blockers, includmg esmolol, slow
AV conduction Delayed conduction through the AV node causes PR interval prolongation.

Digoxin will increase cardiac contractility by blocking the Na-K-ATPase in cardiac myocytes
leading to an increased intracellular calcium concentration, and it will decrease AV nodal
conduction by a mechanism of increased parasympathetic tone

Phosphodiesterase inhibitors lead to increased cardiac contractility via increased intracellular
cAMP concentration. cAMP promotes increased intracellular calcium in cardiac myocytes and is
normally metabolized by phosphodiesterases k vascular smooth muscle, increases in cAMP
164


cause vasodilation, a well-known side effect of phosphodiesterase inhibitors which can
occasionally limit their use in hypotensrve patients.

The QRS complex corresponds to ventricular depolarization and phase 0 on the action potential
graph. Ventncular myocyte depolarization is mediated by inward sodium movement and can be
modulated by class I antiarrhythmics.

The anthracycline chemotherapeutic agents (doxowbicw, daunorubicm. epirubicin and
idarubicin) form free radicals in the myocardium. Their most severe side effect is a cumulative
dose-related dilated cardiomyopathy. It presents with symptoms of left and right ventricular
CHF.

Nifedipine causes peripheral vasodilatation which may result in reflex tachycardia Therefore this
antihypertensive drug is useful for patients with bradycardia.

Beta-blockers inhibit the production and release of rerun from renal juxtaglomerular cells
through antagonism of 131 receptors on these cells Inhibition of renan release causes suppression
of the renin-angiotensina ldosterone pathway, which results in decreased vasoconstnction and
decreased renal sodium and water retention

All nitrates, both long and short acting. are most commonly associated with the side effects of
headache and facial flushing. These reactions occur because of the vasodilatory properties of
nitrates in the meninges and skin.

Nitroglycerin is primarily a venoddator It decreases preload which decreases myocardial oxygen
demand and thereby treats angina pectons.

Nitroglycenn and Isosorbide dinitrate undergo considerable first-pass metabolism in the liver
when taken by the oral route. Interestingly, isosorbide mononitrate is nearly 100% bioavailable
when taken by the oral route.

Torsades de pointes is a form of ventricular tachycardia with characteristic ECG findings that is
always associated with an underlying prolongation of the QT riterval. It is most commonly
precipitated by pharmacologic agents that prolong the QT interval such as some antiarrhythmics,
TCAs and others.

Clopidogrel is an antiplatelet agent that works by inhibiting the platelet surface ADP receptor It
is as efficacious as aspirin in the pcevention of thromboernbolic disease.

Dobutamine is a relatively selective 31-adrenergic agonist that increases heart rate, contractility,
conduction velocity, and myocardial oxygen consumption

Sublingual or aerosohzed nitroglycehn is a rapidly acting agent taken by patients with stable
angina pectoris as needed to rapidly relieve their symptoms, Nitrates act primanly as venodilators
causing a decrease in cardiac work by decreasing left ventncular fiNing volume o preload.
165


Digitalis (digoxin) is a commonly used drug with a well-characterized side effect profile making
it a favorite testing item among question writers ft leads to AV block and ventricular
tachyarrhythmias Hyperkalemia is frequently found in acute digoxin toxicity However, please
note - hypokalemia increase patient susceptibility to the toxic effects of digoxin.

The class IA antiarrhythmacs (quindine. procainamide, and disopyramide) are sodium channel
blocking agents that slow phase 00! the ventncular myocyte action potential and prolong
repolarization as well as the refractory period of these cels

ôJI diuretics except for the potassium-sparing class cause potassium loss They do this by
increasing the volume delivered to the collecting duct, where aldosterone then attempts to
reclaim the additional volume at the expense of potassium. êJl of the potassium-spanng diuretics
act at the collecting duct

Direct arteriolar vasodilators like hydralazine and minoxidd are effective antihypertensives
Because they cause significant arterial vasoddation, they also cause reflex sympathetic activation
resulting in tachycardia and edema To counteract these compensatory effects, these agents are
often given in combination with sympatholytics and diuretics.

Patients who have overdosed on beta blockers should be treated with glucagon, which increases
heart rate and contractility independent of adrenergic receptors Glucagon activates G-protein-
coupled receptors on cardiac myocytes, causing activation of adenylate cyclase and raising
intracellular cAMP The result is calcium release from intracellular stores and increased sinoatnal
node firing

Combined use of non-dihydropyridine calcium channel blockers (eq. verapamil, diltiazem) and
3-adrenergic blockers (eg, atenolol) can have additive negative chronotropic effects yielding
severe bradycardia and hypotension

Beta-blockers, and carvedilol in particular. have been shown to slow the progression of heart
failure and reduce all.-cause mortality in patients with CHF Beta-adrenergic blockers decrease
cardiac work by slowing the ventricular rate and decreasing afterload




PHARMACOLOGY-Endocrine+Dermatology
Treatment of psonasis ranges from topical therapies to systemic treatment with conventional and
biological drugs. Topical vitamin D analogs (calcipotriene. calcitriol, and tacalcitol) bind to the
vitamin D receptor and inhibit keratinocyte proliferation and stimulate keratinocyte
differentiation

Exophthalmos is due to increased soft tissue mass within the bony orbit, which results from
enlargement of the extraocular muscles and increased fibroblast proliferation and ground
substance production Exophthalmos does not typicafly improve with beta-blocker therapy.
166


Non-selective B-blockers exacerbate hypoglycernea and mask s adrenergic symptoms For this
reason, they should not be used in patients with diabetes melLitus Selective (, antagonists should
be used instead if a B-blocker is necessary

Acyclovir, the acyclovir prodrug vaiacyclovir, famciclovir, and ganciclovir are all nucleoside
analogues that require both herpes viral and cellular kinases for conversion to their active
nucleoside triphosphate form. Cidofovir is a nucleoside monophosphate (ie, a nucleotide) that
requires only cellular kinases for activation

The acute effects of corticosterods on the CBC inck,de increased neutrophil count. and decreased
lymphocyte, monocyte, basophd, and eosinophil counts The increase in neutrophd count results
from 0dargition of neutrophils previousty attached to the vessel wal

The desmopressan analog DDAVP is used in patients with von Willebrand disease because it
induces endothelial procoagulatory protein release (including vWF). Remember, that
desmopressin tablets can also be used for the treatment of enuresis.

Isotretinoin is used to treat severe acne refractory to topical therapies. Its main adverse effects
are hypertriglyceridemia and teratogenicity. Pregnancy is an absolute contraindication to its use
Sexually active females should be advised to use two forms of contraception and to have
monthly pregnancy tests.

1. TZDs decrease insulin resistance by binding to peroxisome prohierator activated receptor
gamma (PPAR-gamma), which is a transcriptional regulator of genes involved in glucose and
lipid metabolism.
2. Adiponectin levels are low in type 2 diabetes, and treatment with TZDs increases the levels of
adiponectin.

Anastrozole is a selective inhibitor of aromatase. the enzyme responsible for the conversion of
androgens to estrogens Ketoconazole is an antifungal agent that decreases androgen synthesis by
inhibiting multiple enzyme pathways involved En the synthesis of androgens. lnhibion of the
epidermal growth factor and HER2Jneu pathways by trastuzumab leads to the apoptosis of breast
cancer cells Activation of the HER2Ineu receptor leads to activation of tyrosine lanase.

Thionamides (e.g.. methimazole and propyithiouracil) act as antithyroid medications by
decreasing the formation of thyroid hormones via inhibition of the enzyme thyroid peroxidase
Propyithiouracil also decreases the peripheral conversion of T4 to T3

Thiazolidinediones bind to peroxisome prohferatoractivated receptor-gamma (PPAR-y), a
receptor that belongs to the steroid and thyroid superfamily of nuclear receptors.

Diabetic ketoacidosis (DKA) presents as volume depletion (hypotension and tachycardia) with
ketones and glucose in the unne It occurs most commonly in type 1 diabetics Regular insulin is
preferred for the acute treatment of DKA.
167


Male pattern baldness is an inherited trait that produces a distinctrve pattern of progressive hair
loss The anterior (frontal) scalp is affected first, then the vertex Pathogenesis involves scalp 5-ci-
reductase activity and the androgenic effects of the resulting dihydrotestosterone. 5-a-reductase
inhibitors like finasteride can be used to treat this condition.

Thyroid function tests should be monitored in patients receiving amiodarone therapy
Amiodarone is associated with many side effects: thyroid dysfunction, comeal micro-deposits,
blue-gray skin discoloration, drug-related hepatitis, and pulmonary flbrosis

Insulin is the medication of choice fo the treatment of gestational diabetes in patients for whom
diet and light exercise have failed to control blood glucose levels.

The secretion of prolactin is controlled by the inhibitory effect of hypothalamic dopamine
Hyperprolactinemia causes hypogonadism by inhibiting the release of gonadotroph releasing
hormone from the hypothalamus Risperidone and other antipsychotics cause hyperprolactinemia
by their antidopaminergic action.

The mechanism of action of 13 receptor blockers i thyrotoxicosis is dual: there is a decrease in
the effect of sympathetic adrenergic impulses reaching target organs and a decrease in the rate of
peripheral conversion ofT4toT3.

Fluid retention, with resultant weight gain and edema. is a common side effect of
thiazolidinedione therapy. This excess fluid can exacerbate underlying congestive heart failure.

Terbinafine is used for treatment of dermatophytosis. It inhibits synthesis of fungal membrane
ergosterol by suppressing the enzyme squalene epoxidase.

Diabetic patients often need 2 types of insuhn. a basal long-acting insulin and a postprandial
short-acting insulin. The best basal long-acting insulins are glargine and detemir insulin
(administered as once-a-day shots) NPH is good for about 18 hours (shots given twice a day) The
best short-acting insulins are lispro, aspart, and glulisine (shots given 3 times a day with meals).
They have a very rapid onset of action with peak effects coinciding with peak postprandial
hyperglycemia.

Flutamide is a non-steroid anti-androgen that competes with testosterone and DHT for
testosterone receptors It is used for treatment of prostate cancer in combination with GnRH
agonists

High-dose glucocorticoids such as prednisone are used to control severe Graves’
ophthalmopathy They are helpful in decreasing the severity of inflammation and decreasing
extraocular voIume Conventional antithyroid drugs do not improve ophthalmopathy

Glucocorticoids are predominantly catabolic, causing muscle weakness, skin thinning, impaired
woundh ealing, osteoporosis, and immunosuppression However, they ricreasekver protein
synthesis, specifically the enzymes involved in gluconeogenesis and glycogenesis This, along
168


with peripheral antagonism of the effects of insulin, contnbutes to the development of
hyperglycemia

Tamoxifen and raloxifene are called “selective estrogen receptor modulators (SERMs)” because
of their tissue-selective estrogen agonist and antagonist properties Tamoxifen is useful for the
treatment of osteoporosis and breast cancer. However, it is associated with an increased
incidence of endometrial cancer and thromboembolic disease.

Nafcilhn, methiciHin and oxacillin are penicdlinase-resistant pemcdhns active against isolates of
S aureus and S epdetmidis that are resistant to other peniciflins They are not effective against
MRSA. however

FinasterideisaS-aipha-reductase inhibitor that suppresses peripheral conversion of testosterone to
dihydrotestosterone ft is used for treatment of benign prostatic hyperplasia and androgenetic
alopecia

Local cutaneous adverse effects of chronic topical corticosteroid administration include
atrophy/thinning of the dermis that is associated with loss of dermal collagen, drying, cracking,
andlor tightening of the skin, telangiectasias. and ecchymoses

Agranulocytosis is a rare but very serious comphcation of antithyroid drugs A WBC count with a
differential is necessary in any pabent receMng eher methimazole or PTU who presents with a
fever

Administration of potassium iodide may prevent thyroid absorption of radioactive iodine
isotopes by competitive inhibition.

1 Anion inhibitors (perchiorate. pertechnetate) block iodide absorption by the thyroid gland via
competitive inhib4ion
2. Thionamides (methemazole and propylthiouracd) decrease the formation of thyroid hormones
by inhibiting thyroid peroxidase
3. Iodide salts inhabit synthesis as well as release of thyroid hormones.

1. Because troghtazone was withdrawn from the market due to hepatotoxicity, periodic liver
function tests are now recommended in all patients treated with thiazohdinediones
2. The other important side effect of TZDs includes fluid retention, which can exacerbate
congestive heart failure in patients with underlying cardiac dysfunction.

Loss of consciousness brought about by severe hypoglycemia is typically treated with
intramuscular glucagon in the non-medical setting and with intravenous dextrose in the medical
setting

Metformin is absolutely contraindicated in patients with renal failure, due to a risk of lactic acid
accumuIation In fact, metformin is contraindicated in any situation that might precipitate lactic
acidosis, such as liver dysfunction, congestive heart failure, alcoholism, and Sepsis.
169


The ideal treatment for patients in adrenal crisis is administration of stress-dose corticosteroids.
Response to vasopressors in the presence of adrenal insufficiency is generally suboptimal.

TZDs activate PPAR-gamma. whkh is the nuclear receptor that alters the transcription of genes
responsible for glucose and lipid metabolism Thiazohdined*ones (TZDs) exert their glucose-
lowering effect by decreasing insulin resistance

Hirsutism is an excessive growth of terminal hair in a male-like pattern. It occurs due to
increased testosterone secretion or increased conversion of testosterone to DHT Spironolactone
has anti-androgenic properties and is used for treatment of hirsutism The other drugs that can be
used for hirsutism include antiandrogens flutamide (inhibits binding to testosterone receptors)
and finastende (5-aipha-reductase inhibitor).

PABA esters are widely used UVB radiation absorbers However, they do not significantly
absorb or block radiation in the UVA wavelength range

Aipha-glucosidase inhibitors decrease the activity of the membrane-bound disaccharidases on the
intestinal brush border. Carbohydrates are absorbed as monosacchahdes. therefore, the action of
alpha-glucosidase inhibitors in preventing disaccharide breakdown allows the delay in
carbohydrate absorption In the United States, acarbose and miglitol are the two alpha glucosidase
inhibitors available for clinical use.

Leuprolideis a GnRH agonist that causes first a transient increase. then a decrease in both
testosterone and DHT leveIs Finasteride causes a discordant decrease in DHT level.




PHARMACOLOGY-GIT + Genitourinary
Clinical features of adult lead toxicity include abdominal colic. constipation, headache, lead line
and peripheral neuropathy Microcytic hypochromic anemia and basophihc stippling is also
present.

Polyethylene glycol is an osmotic Iaxat,ve. Diarrhea associated wflh lactase deficiency is also
osmotic and occurs due to accumulabon of nonabsorbable lactose m the intestinal lumen
Magnesium hydroxide (and other magnesium-containing compounds, such as magnesium citrate)
is another osmotic laxative that is often used, although its efficacy is questionable and there is
not enough evdence to support its widespread use

Oral metronidazole can cause disulfiram-hke effects when combined with alcohol It is used to
treat giardiasis, tnchomonas vaginitis and bacterial vaginosis

D-AIa-D-Ala is the amino acid sequence on peptidoglycan precursor molecules that is
recognized by the enzyme transpeptidase Penicilhns are structural analogs of D-Ala-D-Ala that
170


inhibit this enzyme by binding covalently to its active site. The result is failed synthesis of the
bactenal peptidoglycan cell wall.

The mec hanism of varicomycin resistance in organisms such as VRE is a substitution of 0-
lactate in the place of D-alanine during the process of peptidoglycan cell wall synthesis This
prevents the binding of vancomycin to its usuai D-alanyt-D-alanine binding site in the cell wall.

Opioid analgesics can cause contraction of smooth muscles in the sphincter of Oddi leading to
increased pressures in the bile duct and the gall bladder. Increased pressures can lead to a rare
painful crisis known as biliary colic Although meperidine has been reported to cause less
constriction of the sphincter of Oddi, there is little evidence to support this notion.

Mifepristone is an anti-progestin agent that can be used to terminate earty pregnancy The
prostaglandin-El analogue, misoprostol, is available for clinical use in combination with the
abortifacient, mifepristone
References:
1. Review of medical abortion using mifepristone in combination with a prostaglandin analogue
2. Progesterone rec.ptor blockag.: Effect on uterine contractility and early pr.gnancy

Enterococci produce aminoglycoside-modifying enzymes that transfer different chemical groups
(acetyl, adenyl or phosphate) to the aminoglycosáde molecule and therefore impair antibiotic
binding to ribosomal subunits

1. Diphenoxylate is an opiate anti-diarrheal structurally related to meperidine It binds to mu
opiate receptors in the gastrointestinal tract and slows motihty Low therapeutic doses allow for
potent anti-diarrheal effects without euphonc effects Since higher doses can lead to euphoria and
physical dependence, the drug is combined with atropine at therapeutic doses to discourage
abuse
2. Octreotide is helpful for secretory diarrhea.

Urge incontinence, or overactive bladder syndrome, is caused by uninhibited bladder
contractions (detrusor instabdity). It results in a sense of urgency accompanied by an iwoluntary
loss of urine If behavioral therapy alone is unsuccessfuL pharmacologic therapy with an
antimuscannic drug (targeting M3 receptors) can help improve symptoms. These agents should
be used with caution m the elderly, as they may cause confusion and functional decline
References:
1 Antimuscannic agents: implications and concerns in the management of overactive bladder In
the elderly.

Postoperative urinary retention. wfth incomplete bladder emptying. is a common complication
thought to involve decreased micturition reflex activity, decreased contractility of the bladder
detrusor, and/or increased vesical sphincter tone. This condition may be treated with a
muscarinic agonist (bethanechol) or an al blocking drug
171


Clavulanic acid. sulbactam and tazobactam are beta-lactamase inhibitors that extend the
spectrum of penicillin-family antibiotics to include beta-lactamase producing organisms such as
S aureus. if ,nfluenzae. Bacteroides. and other gram-negative bacteria.

The absolute contraindications to the use of OCPs are:
1. Prior history of thromboembohc event or stroke
2. History of an estrogen-dependent tumor
3. Women over age 35 years who smoke heavily
4 Hypertriglycendemia
5. Decompensated or active kver disease (would impair steroid metaboksm)
6 Pregnancy
R.f.r.nc.s:
1. Smoking increases the risk of venous thrombosis and acts synergistically with oral
contraceptive use.

Gonococcal urethritis causes dysuna and copious. purulent, yellow-green urethral discharge.
Gram stain of this discharge shows neutrophils with Gram negative intracellular diplococci.
Because co-infection with C lrachomat,s is common in patients with gonorrhea. azithromycin
(for C trachomatis) should be given in addition to ceftriaxone (for N gonorrhoeae) in patients
with acute gonococcal urethritis.

Urethritis in a young male is most likely to be due to N. gonol7hoeaeor C trachomatis both of
which cause dysuria and mucopurulent urethral discharge The standard treatment for sexually
transmitted urethritis presumes infection by both organisms ceftnaxone is given for N gonorrhea
and doxycycline or azithromycin is given for C. trachomatis

Combination oral contraceptives inhibit ovulation by decreasing synthesis of FSH and LH in the
anterior pituitary Their effects on cervical mucus and endometnum play a minor role

Dimercaprol is a chelating agent used in the treatment of arsenic poisoning It displaces arsenic
ions from sulfhydryl groups of enzymes and facilitates their excretion. Arsenic causes poisoning
by inactivating numerous enzymes involved in cellular metabolism. Symptoms of poisoning
include stomach pains, vomiting and delirium in addition to a garlic odor on the breath.

Sildenafil is a selective inhibitor of the cGMP phosphodiesterase. and use of this drug will
prevent degradation of cGMP leading to higher intracellular levels. Nitric oxide and atrial
natriuretic peptide act via a cGMP second messenger system (NO being primarily responsible for
causing erection), and binding of these hormones to their receptors will also increase intracellular
cGMP concentrations.

Bioavailability refers to the fraction of administered drug that reaches the systemic circulation in
a chemically unchanged form, Bioavailability for a drug administered by a non-intravenous route
is always less than 1 It can be determined by examining a graph of plasma concentration versus
time and then applying the formula
F • (AUC oral x dose IV) I (AUC IV x dose oral)
172


Proton pump inhibitors block the final common pathway of gastric acid secretion from panetal
cells, which is simulated by acetyicholine, histamine, and gastnn.

Treatment of chronc hepatitis C involves the use of interferon alpha and ribavinn. Ribavirin’s
mechanism of action is multifactorial and includes inducing lethal hypermutation. inhibiting
RNA polymerase and inosine monophosphate dehydrogenase (depleting GTP), causing defective
5-cap formation on viral mRNA transcnpts, and modulating a more effective immune response
R.f.r.nc.s:
1. Mechanisms of action of ribavinn against distinct viruses.

The changes in the log dose-response curve expected for the effect of a reversible competitive
antagonist added to a full agonist are: 1) a parallel shift to the nght in the log-dose response
curve, illustrating an increase in the ED, and 2) no change in the maximum effect (E,,.).
* Competitive=change EDshift nght: noncompetitivechange Ezshift down

Chlamydià trachomatis lacks peptidoglycan within the cell wall, and Ureaplasma urea/yticum
lacks a cell wall entirely Therefore, they are not effectively treated by perncillins and
cephalosponns Antiribosomal antibiotics, like macrobdes and tetracychnes, are effective against
these organisms
References:
1. Penicillin induced persistence in Chiamydia trachomatis: high quality time lapse video
analysis of the developmental cycle.

For patients with peptic ulcer disease, the most effective way to provide long-term relief is to
eradicate Helicobacter pytori infection of the gastric mucosa with antibiotic therapy.

Iron absorption occurs predominantly in the duodenum and proximal jejunum Bypass of this
segment of small bowel by gastrojejunostomy results in iron deficiency anemia Malabsorption of
vitamin Bi:, folate, fat-soluble vitamins (especially vitamin D), and calcium may also be
observed following gastric bypass procedures


PHARMACOLOGY-Head & Neck+Heamatology
Educational Objective:
Neutropenia is a significant adverse effect of ganciclovir therapy, and ts incidence is increased
with Co. administration of zidovudine Both drugs can affect DNA synthesis in hematopoietic
stem cell lines, resufting in bone marrow suppression.

Raltegravir is an integrase inhibitor that disrupts the ability of HIV to integrate its genome into
the host cells chromosomes, thus preventing host cellular machinery from being used to
synthesize HIV mRNA

Nystatin is a polyene antifungal and the drug of choice for oropharyngeal candidiasis in patients
without advanced immunodeficiency It acts by binding to ergosterol in the fungal cell
173


membrane, causing the formation of pores and leakage of fungal cell contents. Nystatin is not
absorbed from the gastrointestinal tract and is administered as an oral “swish and swallow agent

Fever. cutaneous flushing, dry oral mucosa, dilated poorly reactive pupils and confusion are all
signs of antichohnergic toxicity Tricyclic antidepressants, particularly amitriptyline, have
antimuscarinic side effects that may mimic atropine toxicity

Most available rodenticides contain broditacoum a long acting 4-hydroxycoumarin derivative If
a patient has ingested a quantity of rodenticide sufficient to cause coagulopathy and abnormal
bleeding, immediate treatment with fresh frozen plasma and vitamin K1 is required

Both unfractionated hepann and LMWH can bind to antithrombin to increase its activity against
Factor Xa Only unfractionated heparin is able to bind to both antithrombin and thrombin to allow
antithromb,n to inactivate thrombin.

Clavulanic acid, sulbactam and tazobactam are beta-lactamase inhibitors Concurrent
administration of clavulanate with amoxicilhn expands amoxciHins spectrum of activity to
include strains of 13-lactamase synthesizing bacteria that are resistant to amoxicdlin alone.

1 Rifampicin, phenobarbital and phenytoin are universal enhancers of the cytochrome P-450
pathway
and concurrent use of warfarin with these medications results in decreased efficacy of warfann.
2. Cimetidine, amiodarone and TMP-SMX, on the other hand, inhibit warfarin metabolism.

Heparin-inducedthrornbocytopenia (HIT) is treated with direct thrombin inhibitors (DTIs) such
as argatroban Both high molecular weight heparin and LMWH should be avoided in these
patients

Protamine sulfate binds with heparin causing chemical inactivation Vitamin K is used for
reversal of warfarin effect Arninocaproic acid and tranexamic acid inhibits ftbrinolysis

Antithrombin-Ill. protein C and protein S are natural anticoagulants that are present m the blood.
Warfann inhibits protein C and S synthesis and thus can pose a risk of paradoxical thrombosis in
patients with congenital deficiency of protein C and S. This is usualy seen in the fist week of
therapy

Unhke the majority of non-selective NSAJDs, aspirin has irreversib’e effects on COX.

The most common cause of retinitis in HIV-positive patients is cytomegalovirus infection
Cytomegalovirus retinitis most frequently affects S4JDS patients with a CD4+ lymphocyte count
<50 cefls/pl It is best treated with ganciclovir.

Enoxaparin is a low molecular weight hepann that functions like heparin in that it binds and
activates antithrombin Ill.
174


HIV-1 protease inhibitors and glucocorticoids are strongly associated with medication-induced
body fat redistribution syndrome, which is characterized by the redistribution of body fat from
the extremities to the abdominal viscera and the subcutaneous adipose tissues of the thorax,
posterior neck, and supraclavicular region
References:
1. Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV
protease inhibitors.

Oseltamivir is a neuraminidase inhibitor useful in the treatment and prevention of both influenza
A and B virus infections This medication impairs the release of newly formed vinons from
infected host cells and impairs viral penetration of mucous secretions that overlie the respiratory
epithehum.

1. Hydroxyurea increases fetal hemoglobin (Hb F) synthesis by an unknown mechanism
Hydroxyurea is reserved for patients with frequent pain crises
2. Gardos channel blockers hinder the efflux of potassium and water from the cell, preventing
dehydration of erythrocytes and reducing the polymerization of Hb S.

Flushed skin and mydnasis result from muscarinic receptor blockade It is important that students
be familiar with the following medications with antimuscannic effects atropine, tricychc
antidepressants (e.g. amitriptyline), Hi receptor antagonists (e.g diphenhydramine), neuroleptics,
and antiparkinsonian drugs.

ApIastc anemia (pancytopenia) is caused by many drugs and environmental toxins
Chloramphenicol can lead to both dose-dependent (reversible) and dose-independent (often
irreversible) pancytopenia.

• Hemolytic anemia is a possible side effect of dapsone and is most significant ii patients
deficient for glucose-6-phosphate dehydrogenase (G6PD).
• G6PD deficiency anemia is characterized by episodes of hemolytic anemia precipitated by
oxidative stress (drugs, infections). Penpheral smear typically shows bite cells and Heinz bodies
(requires special preparation)

The majority of patients with vitamin B3 deficiency require parenteral B,2 administrahon Poor
absorption secondary to gastric atrophy, intnnsic factor deficiency, or terminal deal disease Es
the most common cause of deficiency, with dietary vitamin 8,: deficiency far less common
References:
1. Diagnosis and treatment of vitamin 812 deficiency--an update.
2. Causes and .arty diagnosis of vitamin B12 deficiency.

Antiretroviral agents that selectively bind to the HIV envelope transmembrane glycoprotein gp4l
prevent the conformational changes necessary for the viral membrane to fuse with the target
cellular membrane These agents are therefore known as “fusion inhibitors”
175


Both vitamin K and fresh frozen plasma are used for reversing warfann-induced anticoagulation.
Fresh frozen plasma rapidly reverses warfarin’s effects whereas vitamin K requires time for
clotting factor re-synthesis

Increased gastrointestinal blood loss is the most common side effect of aspirin The relative risk
of gastrointestinal bleeding is increased when high-dose aspirin is used because there is loss of
gastric cytoprotection in addition to impaired platelet aggregation.
References:
1 Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis
2. Plat.let-activ. drugs: the relationships among dos•, effectiveness, and side .ff.cts

Abciximab is a blocker of GP lb/lila receptor GP Ilb/llla is either deficient or defective in
patients with Glanzmann thrombasthenia

Neutropenia is seen in about 1 percent of patients on ticlopidine and typically presents with fever
and mouth ulcers Though this is rare. it is a serious complication and complete blood count
should be monitored biweekly for the first three months.

Of all the antMral agents that bind and inhibit DNA potymerase in herpesvirus and reverse
transcnptase in HIV, the pyrophosphate analog foscamet is one of few that do not require
intracellular activation by viral or cellular kinases.

Hepann is the drug of choice for acute management of venous thrombosis or thromboembohsm,
Heparin activates antithrombin III Warfann is used for long-term prevention of recurrent venous
thromboembolism (VTE). Warfann inhibits vitamin K dependent -carboxylation of glutamic acid
residues of clotting factors II, VII, IX and X (vitamin K dependent clotting factors)

Wet age-related macular degeneration is due to increased vascular endothehal growth factor
(VEGF) causing angiogenesis Active disease should be treated with anti-VEGF therapy
R.f.r.nc.s:
1 Anti-VEGF compounds in the treatment of neovascular age related macular degeneration

Monophosphorylation of acyclovir by a viral thymidine kinase is the first (and rate-limrting) step
in the conversion of acyclovir to its active triphosphate form. Acyclovir and related drugs (eq.
famciclovir, valaciclovir) are more effective against herpes simplex virus and varicella zoster
virus than cytomegalovirus and Epstein-Barr virus.

Selective CCX 2 inhibitors have no effect on platelet aggregation and cause little GI irritation
The reduced risks of bleeding and GI ulceration are the only advantages over traditional NSAlDs

Selective CCX 2 inhibitors have potent anti-inflammatory effects without the side effects of
bleeding and gastrointestinal ulceration associated with non-selective CCX inhibitors. Selective
COX 2 inhibitors do not impair platelet function because platelets predominantly express COX 1
References:
1. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults:
a randomized, controlled trial
176



Heparin is the drug of choice for prevention of venous thrombosis in non-ambulatory patients or
patients undergoing elective surgery, especially hip and knee surgery. Heparin increases the
effect of the naturally occurring anticoagulant antithrombin-ll[

In pregnant women. hepann is used to treat DVT Heparin increases antithrombin Ill activity
Although wart ann is normally the drug of choice for DVT. it is contraindicated in pregnancy
because it is teratogenic Neither aspirin nor clopidogrel are independently sufficient to treat DVT

Nonnucleoside reverse transcnptase inhibitors (NNRT1s) are antiretroviral drugs that do not
require activation via intracellular phosphorylation. The more common NNRTIs include
nevirapine, efavirenz, and delavirdine



PHARMACOLOGY-Hepatic+Skeletal
Aithough very effective and capable of producing quick symptom relief. glucocorticoids are
usually used only for short4erm therapy of rheumatoid arthritis due to their unfavorable side
effect profile.
References:
1. Efficacy of prednlsone 1-4 mglday In patients with rheumatoid arthritis: a randomised,
double-blind, placebo controlled withdrawal clinical trial.

Treatment with many of the hypolipidernic drugs (especially statins) warrants monitoring of liver
function tests. Statins are known to cause myopathy and liver toxicity in some patients

Androgens stimulate follicular epiderrnal hyperprohferation and excessive sebum production,
thereby promoting acne development Anabolic steroid misuse is a known cause of acne,
especially in competitive athletes

ZidOVUdine (AZT)is a nUcleoside reverse trariscnptase inhibitor used to treat HIV infection It
competitively binds to reverse transcnptase and is incorporated into the viral genome as a
thymidine analog AZT does not have a 3’-OH group, making 3’—5’ phosphodiester bond
formation impossible

Oral administration subjects a drug to a large amount of first-pass metabolism, whereas IV,
sublingual, and rectal administration bypasses some or all of this process and allows more drug
to reach the systemic circulation.

The pathoqenesis of Wilson’s disease (hepatolenticular degeneration) involves an excess of non-
ceruloplasmin-bound serum copper, leading to injurious accumulation of this element in the
hver. CNS lenticular nucleus, and cornea. Chelation therapy with penicillamine is indicated to
remove excess loosely bound serum copper.
177


Osteoporosis is a common cause of pathological vertebral fractures. Chronic systemic use of
corticosteroids such as prednisone promotes osteoporosis. and therefore may cause such fractures

Piperacillin-tazobactam is a combination of extended-spectrum penicdlln with 13-lactamase
inhibitor. It is effective against most Gram (-) enteñc rods, including Pseudomonas aenigihosa
and Bactero/desfragiks

Succinyicholine can cause si9niflcant potassium release and hfe-threatening arrhythmias in
patients at high risk for hyperkalemia. including those with bums, myopathies, crush injunes, and
denervating snjunes or disease.

While the kidney is the primary site of elimination of most drugs. the liver is the main site of
biotransformation of these agents in preparation for ebmination, Drugs that are more lipophdic
(hgh Vd, good penetration into CNS) are preferentially processed by the liver into more polar
compounds for easier ehmmation in the bile and unne Liver disease (e g., cirrhosis) or the
concomitant use of other drugs may limit or enhance the clearance of drugs metabolized in the
liver

Bisphosphonates are structural analogues of pyrophosphate. an important component of
hydroxyapatite. These drugs are used in the treatment of osteoporosis. PageVs disease of the
bone, and malignancy-induced hypercalcemia. These agents are administered in the fasting state
with plenty of water. The patient must also stay upright for at least 30 minutes to prevent reflux
esophagitis.

NSAIDs are the first-line therapy for treatment of acute gouty arthritis. Coichicine is considered
as second-line therapy due to its side effects of nausea and diarrhea Glucocorticoids are indicated
in patients with a contraindication to both NSAIDs and coichicine, such as patients with renal
failure Uricosuric agents and allopurinol are contraindicated dunng acute attacks however, they
are used as prophylactic treatment in certain patients.

Methotrexate is the preferred disease-modifying treatment for patients with moderate to severe
rheumatoid arthritis Methotrexate treatment may cause stomatitis and liver function
abnormaIthes

1. Many drugs can accelerate (induce) the hepatic metabolism of warfarin leading to reduced
anticoagulation and enhanced thrombotic risk These include antibiotics such as rifampin and
griseofulvin as well as antiepileptic drugs such as barbiturates, carbamazepine, and phenytoin
2. Warfarin metabolism may be inhibited by antibiotics such as tnmethopnm, isoniazid, and
fluconazole, as well as other drugs such as cimetidine Inhibition of warfarin metabolism can
increase the risk of bleeding.

All patients beginning treatment with TNF-o inhibitors should be evaluated for latent
tuberculosis.
178


Isoniazid (INH) can be directly hepatotoxic, causing acute mild hepatic dysfunction in 10-20%
of patients. In a smaller percentage of cases, frank hepatitis may develop, causing fever,
anorexia, and nausea.

The suffix of a biological agent indicates whether a medication is a monoclonal antibody (mab),
a receptor molecule (cept), or a kinase inhibitor (nib) Monoclonal antibodies also include in their
names the type of target (eg, bacterial or immune system) and their origin (eg, human or mouse)

Colchicine inhibits tubulin polyrneiization and microtubule formation in leukocytes, reducing
neutrophil chemotaxis and emigrabon to sites inflamed by uric acid crystal deposition in acute
gouty arthritis Many patients treated with coichicine also develop diarrhea as the gastrointestinal
mucosa is adversely affected by colchicine

Earty Lyme disease causes flu-like symptoms and erythema chronicum migrans The second
stage of Lyme disease may involve AV block and Beirs palsy Chronic Lyme disease can cause
chronic asymmetric large joint arthntis and encephalopathy Lyme disease is easily treated with
doxycycline or penicdhn-type antibiotics

Allopunnol is the best long4erm treatment choice for chronic tophaceous gout regardless of the
urinary excretion of uric acid, In patients who excrete large amounts of uric acid, uricosuric
drugs should be avoided to prevent uric acid nephrohthiasis.

Protease inhibitors are anti-HIV medications that inhibit cleavage of the polypeptide precursor
into mature viral proteins Their side effects as a class include hyperglycemia. lipodystrophy, and
drug-drug interactions due to inhibition of cytochrome p-450

lsoniazid is metabolized by acetylation. The speed with which a patient is able to acetylate drugs
depends on whether they are genetically “fasr or slow” acetylators The presence of fast and slow
acetylators within the same population results in a bimodal distribution of the speed of isoniazid
metabolism Slow acetylators are at increased risk of adverse side effects.

Drug induced lupus has been linked to drugs that are metabohzed by N-acetylation in the hver
Two classic examples include hydralazine and procainamade Genetic predisposition determines
acetylator phenotype and it appears that patients who are slow acetylators are at greater nsk for
developing lupus-like syndrome Discontinuation of the offending agent is warranted only in
patients who develop clinical symptoms of lupus

The half-life of a drug (t 112) is a measure of how quickly a drug is eliminated from the body
and how soon
steady-state concentrations are achieved after repeated dosing. Generally, the half-Ide of a drug
in plasma is
a determinant of the duration of its pharmacologic effects in the body A drug is virtually totally
eliminated after
5 half-life intervals To calculate half -kfe, use the formula
t 112 = (V x In 2) I CL
179


Coichicine is used for both acute gouty arthritis and prophylaxis of recurrent gouty arthritis
Coichicine inhibits leukocyte migration and phagocytosis by blocking tubulin polymerization
Coichicine does not have any effect on the metabolism or urinary excretion of uric acid The most
troublesome side effects of coichicine are nausea and diarrhea.

TNF-a inhibitors (infliximab. etanercept. and adabmumab) decrease macrophage function and
may cause reactivation of latent tuberculosis

The paralytic action of nondepolanzing neuromuscular junction (NMJ)-blocking drugs can be
reversed by anticholinesterase agents such as neostigmine. Succinylchohne is a depolarizing
NMJ blocker that is augmented by neostigmine during phase I block but reversed by neostigmine
during phase II block The duration of paralysis caused by succinylchohne depends largely on its
catabolism by plasma cholinesterase.

In first-order kinetics, a constant fraction (or proportion) of drug is metabolized per unit time
based on the serum concentration In zero-order kinetics, a constant amow#of drug is metabolized
per unit tame, independent of concentration

Tetracycline use duñng pregnancy can cause fetal bone growth retardation and discoloration of
the deciduous teeth

A high synovial fluid white blood cell count (100.000/pL) and absent crystals on microscopic
examination strongly suggest bacterial joint infection. Septic arthritis requires immediate
antibiotic treatment to prevent joint destruction, osteomyelitis, and sepsis.

Acetaminophen toxicity can be effectively treated by sulIhydryl group Supplementation. N-
acetyl cysteine provides the sulfhydryl groups. NAC also acts as a glutathione substitute and
binds to the toxic metaboifte.

Cokhicine affects tubulin polymehzation into microtubules. Important side effects of colchácines
are nausea, abdominal pain, and diarrhea.

As a selective estrogen receptor modulator (SERM). raloxifene binds to estrogen receptors and
exhibits tissue-specific behavior that either imitates or antagonizes the effects of natural estrogen
In bone, the estrogen agonist effects of raloxifene predominate and osteoporosis is inhibited In
mammary tissue, the estrogen antagonist effects of raloxifene predominate and protection is
provided against estrogen receptor- positive breast cancer.

Acute extrapyrarnidal symptoms (eg, dystonic reactions. akathisia, and parkinsonism) are related
to an imbalance between dopamine (D2) and muscarinic (M1) activity in the nigrostriatal tract
Traditional-high potency antipsychotics (haloperidol. fluphenazine) strongly block D. receptors
and are the most likely to cause extrapyramidal symptoms.

A decrease in the intravascular fluid volume stimulates aldosterone secretion and leads to
increased excretion of potassium and hydrogen ions in the urine This results in hypokalemic
180


metabolic alkalosas, which is a common side effect of most diurehcs other than the potassium-
sparing class Hypokalema manifests with muscle weakness and cramping

A side effect of hydrochlorothiazide is that it increases the absorption of calcium from the distal
convoluted tubules within the nephron, making it an ideal agent for treating hypertension or CHF
in a woman who is also at nsk for osteoporosis Furosemide will increase urinary calcium loss,
making it a possible treatment for hypercalcemia. but not for women with porous bones,
References:
1 Effect of thiazide on rates of bone mineral loss: a longitudinal study.
2. Do b.ta-blockers and thiazld.s reduc. fracture risk?




PHARMACOLOGY-Neuro 1
Muscarinic antagonists inhibit the postsynaptic action of acetyicholine, and botulinum
neurotoxin blocks the presynaptic exocytosis of acetyicholine vesicles Organophosphates
prevent the degradation of acetyicholine within the synaptic cleft Anticholinergic poisoning,
botulism, and organophosphate toxicity affect nicotinic and muscarinic acetylcholine receptors
differently, and thus produce different symptomatologies

Sympathetic output to the viscera is transmitted through two-neuron units that synapse on
noradrenergic receptors of the target organs The sympathetic innervation of the adrenal and
sweat glands differs from this typical setup

The onset of action of a gas anesthetic depends on its solubility in the blood (bloodlgas partition
coefficient). Drugs with high blood/gas partition coefficients are more soluble in the blood and
demonstrate slower onset of action and slower equilibration with the brain.

Cholinomimetics are indicated in non-obstructive urinary retention, paralytic ileus, and glaucoma
Their side effects include nausea, vomiting, abdominal cramps, diarrhea. dyspnea and increased
secretions (sweating, lacrimation and salivation).

Alpha-receptors inhibit insulin secretion and beta-receptors stimulate insulin secretion
Pretreatment with an alpha-blocker would result in predominance of beta-effects

Tricyclic antidepressants (TCAs) such as imipramine doxepin. amitriptyhne. and clomipramine
have stronger anticholinergic properties than heterocyclics or SSRIs and should be used with
caution in patients with benign prostatic hyperplasia (BPH), as they may cause urinary retention.
References:
1. Antimuscarinic and other receptor-blocking properties of antidepressants.
2. Effects of treatments for symptoms of painful diabetic neuropathy: systematic review

Antimuscarinic agents and antihistamines with antimuscarinic action are most effective for
motion sickness prevention.
181


Carbamazepine is used for simple partial. complex partial. and generalized tonic-clonic seizures
It acts by blocking voftage-gated sodium channels in neuronal membranes Carbamazepine can
cause bone marrow suppression, so blood counts should be revewed often

Rifampin is most typically used as chernoprophylaxis of meningococcal meningItis. It must be
prescribed to all close contacts of any patient who has active disease within 2 weeks of diagnosis
in order to be effective. Vaccine is typically not used for post exposure prophyIaxis it is used to
develop population immunity in at-risk groups such as military recruits, college freshmen and
healthcare Workers.

Sertralineisserotonin-speciflc reuptake inhibitor (SSRIs) that has a better side effect profile
compared to tricyclic antidepressants (TCAs). Sexual dysfunction is a relatively common side
effect of the SSRIs and limits their use for many patients.
References:
1. Antidepressant-induced sexual dysfunction during treatment with moclobemide. parox.tin.,
s.rtralin.. and venlafaxin.

Berizodiazepines increase the frequency of opening of the CNS GABAA receptor-chloride
channels and have anxiolytic, anticonvulsant, and muscle relaxant effects as well as sedative-
hypnotic effects.

Adding carbidopa can reduce most of the peripheral side effects of levodopa However,
behavioral changes from levodopa can actually worsen with addhon of carbidopa because more
dopamine becomes available to the brain.

Massive hepatic necrosis is a rare but severe complication of halothane exposure It occurs due to
direct liver injury by halothane metabolites and formation of autoantibodies against liver proteins
Light microscopy shows massive centnlobular hepatic necrosis

Co-administration of an SSRI and MAO inhibitor can produce excessive serotonin levels
secondary to decreased reuptake and decreased metabolism Excessive serotonin evels can lead to
the development of a potentially fatal condition known as serotonin syndrome To avoid the risk
faq’ serotonin syndrome, it is recommended to wait at least 14 days after MAO inhibitor
discontinuation before initiating SSRI therapy This should allow sufficient time for the
regeneration of MAO

Tngeminal neuralgia presents with brief episodes of sudden and severe electric shock-like or
stabbing pain in the disthbution of CN V (particularly V2 and V3) Carbamazepine is the drug of
choice
References:
Trigemmal neuralgia and Its management
2. Drug therapy of trigeminal neuralgia

Minimal alveolar concentration is the best measure of potency of an inhaled anesthetic (actually
ED50). The less MAC is required for anesthesia, the more potent the inhalation anesthetic is.
182


Thiondazine causes retinal deposits that resemble retinitis pigmentosa Chiorpromazine is
associated with Corneal deposits

Lithium is almost exclusively excreted by the kidneys. with filtration and resorption in the
proximal tubules following sodium reabsorption Renal injury, toxins, and drugs that lead to
increased proximal tubular absorption of sodium (e.g NSJDs, thiazide diuretics, and ACE
inhibitors) also increase lithium levels and elevate the nsk of lithium toxicity Hemodialysis is the
most effective way of acutely reducing the blood lithium level
References:
1 Clinic ance of drug inerictIons ..ih I[hcurn

As opposed to the serotonin syndrome, the Neuroleptk Malignant Syndrome is distinguished
clinically by an absence of myoclonus and by the presence of ngidity Dopamine agonists
(bromocnptine) and/or direct muscle relaxants (dantrolene) have been used to decrease mortality
rates associated with the neuroleptic malignant syndrome (NMS), but there is no way to prevent
NMS.

1 Antimuscahnic agents are usually pieferred in pabents with medicabon-induced Parkinsonism
2. Levodopa is contraindicated for drug-induced Partonsonism because it can precipitate
psychosis

Buspirone is considered a first line treatment for generalized anxiety disorder. Dependence does
not occur with chronic buspirone treatment, b the clinical response is often delayed for up to 2
weeks of regular use and is not effective when used on an as-needed basis.

Commonly used drugs such as the analgesic tramadol. the antiemetic ondansetron, and the
antibiotic linezolid can induce serotonin syndrome when used concomitantty with other
serotonergic drugs
References:
1 Risk of serotonin syndrome with concomitant administration of linezolid and serotonin
agonists.

Benzodiazepines substitute for the action of alcohol on GABA receptors and are indicated for the
treatment of alcohol withdrawal Long-acting benzodiazepines (chiordiazepoxide, diazepam) are
first-line medications Short-acting benzodiazepines (lorazepam. oxazepam) are preferred in
patients with advanced liver dysfunction.

The “on-off’ phenomenon is an unpredictable and dose-independent characteristic of advanced
Parkinson disease-there is no clear etiology this phenomenon On the other hand, the “wearing
off” phenomenon of Parkinson disease is due to progressive destruction of striatonigral
dopaminergic neurons over a period of time

Zolpidem is a short-acting hypno& medication chemically unrelated to benzodiazepines It has
the same mechanism of action as benzodiazepines, but a much lower risk of tolerance and
dependence
183


Treatment for narcolepsy includes scheduled daytime naps and psychostimulants (e.g..
modafinil) for daytime sleepiness.

Phenytoin’s undesirable cosmetic effects (hirsutisni, coarsening of facial features, acneiforrn skin
rash, and gingival hypertrophy), limit its use It has also been associated with generalized
lymphadenopathy (pseudotymphoma),

Ampicillin is the treatment of choice for Listeria. It is not sensitive to cephalosporins. Listeria
causes disease in neonates and immunocompromised adults.

Sexual dysfunction is seen in up to 50% of patients treated with SSRIs. Symptoms include
decreased libido. anorgasmia, and increased latency to ejaculation Bupropion is an excellent
alternative

Body temperature greater than 40 C is called hyperpyrexia and may lead to permanent brain
damage if left untreated Emergent treatment of hyperpyrexia should consist of increasing body
heat loss (cooling) and decreaseng the hypothalamic set pomt (antipyretics). Facilitating body
heat loss takes precedence because it is effective immediately as opposed to antipyretics which
take time to act

disease due to increased intraocu’ar pressure. develops due to decreased outflow or increased
production of aqueous humor Timolol and other beta-blockers decrease aqueous humor
production by the ciliary epithelium

Cholinergic agonists bind to muscahnic receptors on endothelial cells and promote release of NO
(EDRF). NO activates guanylate cyclase and diminishes endothehum calcium concentration This
produces vasodilatation.

The use of opioids can lead to the development of tolerance or a decrease in opioid effectiveness
and physiological response with continued use Tolerance to opioid induced constipation and
miosis does not readily occur. To prevent bowel complications, it is recommended to treat
patients prophylactically with adequate fluid intake and daily laxatives.

Traditional high potency agents are more likely to cause extrapyramidal symptoms and less
likely to cause ariticholinergic and antihistamine side effects. In contrast, low potency
antipsychotics more likely to cause ant)cholinergic and anti histamine side effects,
(Mency = Extrafy’ramidal)

Exacerbation of myasthenia graves in a patient treated wdh cholinesterase inhib4ors occurs due
to myasthenic or cholinergic crisis The edrophonium (Tensdon) test helps to differentiate these
two conditions Clinical improvement after edrophonium administration indicates that the patient
is undertreated (myasthenic crisis)

Unlike other traditional antipsychotks, which act on D2 receptors. clozapine acts on D4 receptors
Due to the nsk of life-threatening agranulocytosis with clozapine, the FDA requires periodic
184


monitoring of the white blood cell count (WBC) for the duration of treatment The other
impoflant side effect of clozapine is seizures

The tertiary amine physostigmine can reverse both the CNS and peripheral symptoms of severe
atropine toxicity. The antichohnesterase agents neostigmine and edrophonium have a quatemary
ammonium structure that limits CNS penetration

Exposure to certain insecticides can cause organophosphate poisoning The resultant
cholinesterase inhibition is profound and prolonged because organophosphates bind wreversably
to cholinesterase This causes a state of chohnergic excess, marked by excessive salivation,
lacnmation, diaphoresis, urinary incontinence, diarrhea, emesis, miosis and bradycardia

Sodium bicarbonate is the single most effective agent in treating TCA-associated cardiac
abnormalities

Methadone is the drug of choice for treating heroin addiction and abuse It is a very potent. long
acting opiate with good oral bioavadablity Its long half-life allows for prolonged effects to
suppress withdrawal symptoms in heroin dependent patients

The symptoms of schizophrenia include the following:
1, Positive symptoms hallucinations (usually auditory), delusions, and disorganized speech and
behavior
2. Negative symptoms a decrease in emotional range, poverty of speech, and loss of interest in
living

The symptoms of schizophrenia include the following:
1. Positive symptoms: hallucinations (usually auditory), delusions, and disorganized speech and
behavior.
2, Negative symptoms: a decrease in emotional range, poverty of speech, and loss of interest in
living.
Unlike first-generation neuroleptics, second-generation (atypical) agents (clozapine, risperidone,
olan.zapine, quetiapine) improve both positive and negative symptoms of schizophrenia
References:
1. Pharmacological approaches to the management of schizophrenia.

1 Phenytoin, carbamazepine and vaiproic acid inhts neuronal high-frequency flung by reducing
the abdity of sodium (Na’)channels to recover from mactivation
2 Ethosuximide is believed to block T-type calcium channels in thalamic neurons causing
hyperpolanzation and is approved for the treatment of absence seizures

The autonomic nervous system utilizes three types of signal pathways: cAMP. lP3, and ion
channels. Nicotinic receptors are hgand-gated ion channels that open after binding acetyIchoIine
This results in an immediate influx of Na and C& into the cell and an outfiux of K from the cel
References:
1. Neuromuscular junction in health and disease.
185


Second-generation
        generation antihistamines htce fexofenadine have minimal sedative and antimuscannic
effects

1. Buspirone is a selective
                        tive agonist of the 5HT1A receptor and is a safe and effective treatment
for generalized anxiety disorder It has no muscle relaxant or anticonvulsant properties
2 Buspirone is an anti-anxiety
                         anxiety agent that is useful in patients wrth a history of abuse of anti-
                                                                                             ant
anxiety drugs due to its reduced potential for abuse compared to benzodiazepines

Atropine is indicated for the treatment of bradycardia as it decreases vagal influence on the SA
and AV nodes. A common side effect is increased intraocular pressure It m  mayay precipitate acute
closed-angle
       angle glaucoma in susceptible individuals.


PHARMACOLOGY-Neuro
             Neuro 2
Lithium is almost exclusively excreted by the kidneys. with filtrahon and resorption in the
proximal tubules following sodium reabsorption. Renal injury, toxins, and drugs that lead to
increased proximal tubular absorption of sodium (eg. NSAIDs, thiazide ddiuretics,
                                                                               iuretics, and ACE
inhibitors) also increase lithium levels and elevate the nsk of lithium toxicity. Hemodialysis is
the most effective way of acutely reducing the blood lithium level
F References:
1 Clinical relevance of drug interactions with lithium

As opposed to the serotonin syndrome. the Neuroleptic Malignant Syndrome is distinguished
clinically by an absence of myoclonus and by the presence of ngidity Dopamine agonists
(bromocriptine) and)or direct muscle relaxants (dantrolene) have been used to decrease mortality
rates associated with the neuroleptic malignant syndrome (NMS), but there is no way to prevent
NMS

Penicdhns and cephalosponns function by irreversdly binding to penicillin
                                                               penicillin-binding
                                                                          binding proteins such
as transpeptidases.




Lamotrigine is a newer anticonvulsant used for the treatment of refractory partial seizures It may
cause skin rash Because this rash is life threatening in children, the drug should be discontinued
immediately at the first sign of rash
F References:
1. Predictors of Lamotrigine-associated
                              associated rash.
2. The new anti.pil.ptic drugs
3. Rash In adult and pediatric patients treated with lamotngine

Sexual dysfunction is seen in up to 50% of patients treated with SSRIs Symptoms include
decreased libido, anorgasmia, and incr
                                  increased
                                      eased latency to ejaculation Bupropion is an excellent
alternative.
186



Benzodiazepines (lorazepam) are first-hne agents in the management of status epdepticus
Phenytoin (or fosphenytoin) is administered simultaneously to prevent the recurrence of seizures.
Phenytoin inhibits neuronal high-frequency firing by reducing the ability of sodium (Na)
channels to recover from inactivation.

Essential tremor is the most common movement disorder. Patients experience a slowly
progressive symmetric postural and/or kinetic tremor that most commonly affects the upper
extremities. Essential tremor is believed to be inherited in an autosomal dominant fashion, hence,
it is sometimes also referred to as familial tremor. First-line treatment is the nonspecific beta-
adrenergic antagonist propranolol.

Inhibehon of uterine contractions (tocolysis) is a result of 132 adrenergic receptor stimulation
Alpha -1 receptor stimulation causes contraction of the ocular puplary dilator muscle, resulting in
mydriasis (pupillary dilation).

First generation Hi-histamine receptor antagonists, including diphenhydramine and
chiorpheniramine, can cause significant sedation. especially when used with other medications
that cause CNS depression (such as benzodiazepines)
References:
1. Influence of lansoprazole treatment on diazepam plasma concentrations
2. Ranitidine does not impair oxidative or conjugative metabolism: noninteraction with
antipyrin., diaz.pam. and loraz.pam

Unlike other traditional antipsychotics. which act on 02 receptors. clozapine acts on D4
receptors. Due to the risk of life.threatening agranulocytosis with clozapine, the FDA requires
penodic monitorin9 of the white blood cell count (WBC) for the duration of treatment The other
important side effect of clozapine is seizures

4Jmost all volatile anesthetics increase cerebral blood flow It is an undesirable effect as it results
m increased ICP Other important effects of inhalation anesthetics are myocardial depression,
hypotension, respiratory depression and decreased renal function

Benzodiazepines increase the frequency of opening of the CNS GABAA receptor-chloride
channels and have anxiolytic, anticonvulsant, and muscle relaxant effects as well as sedative-
hypnotic effects.

Chohnergic agonists bEnd to muscarinic receptors on endothehal celts and promote release of
NO (EDRF). NO activates guariytate cyclase and diminishes endothehum calcium concentration
This produces vasodilatation

Remember — drugs that may cause seizures:
Bupropion (antidepressant)
Isoniazid (anti-tuberculosis drug, if given without pyridoxine)
Imipenem (antibiotic)
187


____s._. .I V —.
Exposure to certain insecticides can cause organophosphate poisoning. The resultant
cholinesterase inhibition is profound and prolonged because organophosphates bind irreversibly
to chohnesterase This causes a state of chohnergic excess, marked by excessive salivation,
lacrimation. diaphoresis. urinary incontinence, diarrhea emesis. miosis and bradycardia

Phenytoin’s undesirable cosmetic effects (hirsutism, coarsening of facial features, acneiform skin
rash, and gingival hypertrophy), limit its use It has also been associated with generalized
lymphadenopathy (pseudolymphoma)

Co-administration of an SSRI and MAO inhibitor can produce excessive serotonin levels
secondary to decreased reuptake and decreased metabolism Excessive serotonin levels can lead
to the development of a potentially fatal condibon known as serotonin syndrome To avoid the
risk for serotonin syndrome, it is recommended to wait at least 14 days after MAO inhibitor
discontinuation before lnItlatln9 SSRI therapy This should allow sufficient time for the
regenerabon of MAO.

Migraine headaches are unilateral. have a pulsating or throbbing quality, and are associated with
photophobia, phonophobia. and nausea Tnptans are sei-otonin 5-HTd5-HT,0 agonists used as
abortive therapy during an acute migraine Beta-blockers, antidepressants (eg, amitnptyiine and
venlafaxine), and anticonvulsants (eg, vaiproate and topiramate) are commonly used for
migraine prophylaxis.

Sodium vaiproate is the drug of choice for patients with absence and associated tonic-clonic
seizures Ethosuximide is also effective against absence seizures but does not suppress tonic-
clonic seizures.

Glaucoma, a disease due to increased intraocu’ar pressure. develops due to decreased outflow or
increased production of aqueous humor Timolol and other beta-blockers decrease aqueous
humor production by the ciliary epithehum

Calcium channel blockers, specifically Nimodipine. can be used to assist in the prevention of
cerebral vascular spasm following SAH This is an alternative use of calcium channel blockers
References:
1. Nimodipine and its use in cerebrovascular disease: evidence from recent preclinical and
controlled clinical studies.
2. Calcium antagonists for aneurysmal subarachnoid ha.morrhage.

Minimal alveolar concentration is the best measure of potency of an inhaled anesthetic (actually
ED50) The less MAC is required for anesthesia, the more potent the inhalation anesthetic is.

Antimuscarinic agents and antihistamines with antimuscarinic action are most effective for
motion sickness prevention
188


The onset of action of a gas anesthetic depends on its solubility in the blood (blood/gas partition
coefficient). Drugs with high blood/gas partition coefficients are more soluble in the blood and
demonstrate slower onset of action and slower equilibration with the brain

A majonty of opioid narcot,cs are selective mu receptor agonists that work by binding to mu
receptors and mimicking the effects of endogenous opioid peptides Pentazocine is an opioid
narcotic specificalty designed to produce analgesic effects with little to no abuse potential
Pharmacc4ogically, it worksks through partial agonist activity and weak antagonist activity at mu
receptors. Because of its weak antagonistic effects, it can cause withdrawal symptoms in patients
who are dependent or tolerant to morphine oi other opioids




1. Selegiline is an inhibitor of MAO. type B and can prevent MPTP       MPTP-induced
                                                                              induced damage of
dopaminergic neurons
2 Selegiline is used clinically to delay the progression of Parkinson disease
3, Many neurologists favor the use of combinations of selegihne, antichohnergics. and
amantadine
   antadine until they no longer provde control of symptoms Only then is levodopa/carbidopa
introduced

Buspirone is considered a first line treatment for generalized anxiety disorder. Dependence does
not occur with chronic buspirone treatment, but the clin
                                                     clinical
                                                         ical response is often de’ayed for up to 2
weeks of regular use and is not effective when used on an as
                                                           as-needed basis

Cholinomimetics are indicated in non
                                  non-obstructive
                                       obstructive urinary retention, paralytic ileus, and glaucoma
Their side effects include nausea, vom
                                   vomiting,
                                        iting, abdominal cramps, diarrhea, dyspnea and increased
secretions (sweating, lacrimation and saIivation)

.ILIl.ISI II V V.
Commonly used drugs such as the analgesic tramadol. the antiernetic ondansetron, and the
antibiotic linezolid can induce seroto
                                serotonin
                                       nin syndrome when used concomitantly with other
serotonergic drugs.
R.f.r.nc.s:
1. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin
agonists.

1 Antimuscannic agents are usually preferred in patients with medication
                                                              medication-induced
                                                                         induced Parkinsonism
2. Levodopa is contraindicated for drugdrug-induced
                                            induced Padansonism because it can precipitate
psychosis
189


Muscannic antagonists inhibit the postsynaptic action of acetyicholine. and botuhnum neurotoxin
blocks the presynaptic exocytosis of acetyicholine vesicles. Organophosphates prevent the
degradation of acetyicholine within the synaptic cleft. Anticholinergic poisoning, botulism, and
organophosphate toxicity affect nicotinic and muscarinic acetyicholine receptors differently, and
thus produce different symptomatologies.

The mnemonic for the clinical manifestations of atropine poisoning is: wblind as a bat, mad as a
hatter, red as a beet, hot as a hare. dry as a bone, the bowel and bladder lose their tone, and the
heart runs alone” Atropine is a reversible chohnergic antagonist that acts selectively on
muscarinic receptors Its effects can be reversed by cholinesterase inhibitors (physosbgmine).

Methadone is the drug of choice for treating heroin addiction and abuse. It is a very potent, long
acting opiate with good oral bioavailabihty. Its long half-life allows for prolonged effects to
suppress withdrawal symptoms in heroin dependent patients.

Lithium, vaiproic acid, and carbarnazepine are mood stabihzing agents. Vaiproic acid and
carbamazepine also work as anticonvulsants Vaiproic acid increases the inhtitory effect of
GABA in the CNS.

Arteriovenous concentration gradient reflects the solubihty of anesthetic in tissues Highty
soluble anesthetics are charactenzed by high artenovenous concentration gradients and slow
onset of action

The first-generation antihistaminics, chiorpheniramine and diphenhydramine, have antimusc
arinic, anti-alpha adrenergic, and anti-serotonergic properties that are responsible for the
majority of side effects.

Antidepressants, when used in the depressEve phase of bipolar disorder wahout an antipsychotic
or mood stabilizer, can precipitate a mania

A chronically progressive pe-senile dementia with cortical atrophy but no other radiological or
laboratory abnormalities permits a clinical diagnosis of Alzheimei’s disease (AD), which is a
diagnosis of exclusion Current AD-specific therapies include cholinesterase inhibitors
(Donepezil), antioxidants (vitamin E), and NMDA receptor antagonists (e.g. memantine)

Sertrahne is serotonin-specific reuptake inhibitor (SSRIs) that has a better side effect profile
compared to tncychc antidepressants (TCAs). Sexual dysfunction is a relatively common side
effect of the SSRIs and limits their use for many patients

The autonomic nervous system utilizes three types of signal pathways cAMP, 1P3, and ion
channels. Nicotinic receptors are ligand-gated ion channels that open after binding acety$chohne
This results in an immediate influx of Na and Ca into the cell and an outfiux of K from the cell.

Ampicillin is the treatment of choice for Listeria It is not sensitive to cephaIosporins Listena
causes disease in neonates and immunocompromised adults
190


Akathisia is a movement disorder characterized by inner restlessness and an inability to sit or
stand in one position. Onset of akathisia can be a complication of anti-psychotic therapy A
diagnosis of akathisia is often missed because the movements and restlessness are msinterpreted
as worsening psychotic behavior and agitation, and instead of decreasing the patients dose, the
pat,ents neuroleptic dosing is often ,ncreased exacerbating the akathisia

Cocaine intoxication causes agitation. dramatic symmetric pupillary dilation that remains
responsive to light, tachycardia. and blood piessure elevation. Both cocaine and tricyclic
antidepcessants inhibit neurotransmitter reuptake in adrenergic synapses


PHARMACOLOGY-Oncology
Folinic acid (leucovorin) can reverse the toxicity of methotrexate in non-cancerous cells in the
GI mucosa and bone marrow if administered at the appropriate time Leucovorin, a 5-formyl-
derivative of tetrahydrofolic acid, does not require the action of dihydrofolate reductase for its
conversion to tetrahydrofolate

Hemorrhagic cystitis during therapy with cyclophosphamide or ifosfamide is caused by the
urinary excretion of the toxic metabolite acrolein This can be prevented by aggressive hydration,
bladder irrigation, and administration of mesna. a sulfhydryl compound that binds acrolein in the
urine

Ondansetron inhibits serotonin (5-HT3) receptors and is used primarily to treat nausea and
vomiting following chemotherapy 5.HT3 receptors are located penpherally in the presynaptic
nerve terminals of the vagus nerve in the GI tract These receptors are also present centrally in the
chemoreceptor trigger zone and the solitary nucleus and tract.

Methotrexate and 5-FU both effectively inhibt thymidylate formation. but the chemotherapeutic
effect of methotrexate is overcome by N5-formyi-tetrahydrofolate (fohnic acid, leucovonn)
suppIementation

Cladnbine is a punne analog that achieves high intracellular concentrations because it is resistant
to degradation by adenosine deaminase Cladribine is the drug of choice for hairy cell leukemia

Some patients with non-small cell lung carcinoma (NSCLC) harbor a chromosomal
rearrangement that creates a fusion gene between EML4 (echinoderm microtubule-associated
potein-like 4) and ALK (anaplastic lymphoma kinase) This results in a constitutive active
tyrosane kinase that causes malignancy

Neurotoxicity is the dose-limiting side effect of vincristine therapy This toxicity results from
failure of microtubule polymerization in neuronal axons. Other notable adverse effects
classically associated with chemotherapeutic agents include pulmonary fibrosis and flagellate
skin discoloration with bleomycin use; congestive heart failure with doxorubicin; and
hemorrhagic cystitis with cyclophosphamide.
191


Etoposide is a chemotherapeutic agent that inhibits the sealing activity of topoisomerase Ii
Treatment with etoposide causes chromosomal breaks to accumulate in dividing cells, ultimately
causing cell death

6-mercaptopurine is mainly degraded in the liver by xanthine oxidase Allopurinol, which is an
inhibitor of xanthine oxidase, can increase the concentration of 6—rnercaptopurine significantly
Both 6-mercaptopurine and 6-thioguanine are prodrugs that require activation by HGPRT.

The ymca alkaloids are cell-cycle specific agents that prevent proper separation of chromosomes
into daughter cells during the M-phase of the cell cycle. The main dose-limiting side effect of
vincristine is neurotoxicity, which commonly manifests as peripheral neuropathy

The human multidrug resistance (MDRI) gene codes for P-glycoprotein, a transmembrane ATP-
dependent efflux pump protein that has a broad specificity for hydrophobic compounds This
protein can both reduce the influx of drugs into the cytosol and can increase efflux from the
cytosol, thereby preventing the action of chemotherapeutic agents.

Methotrexate is an antimetabolite drug that is structurally similar to folk acid. It competitively
inhibits the enzyme dihydrofolate reductase. which catalyzes the synthesis of tetrahydrofolate
Failure of dihydrofolate reductase causes the intermediate dihydrofolic acid polyglutamate to
accumulate within treated cells.

Aggressive hydration and amifostine should be UtiliZed to prevent nephrotoxicity in patients
receiving a platinum-based chemotherapeutic regimen.




PHARMACOLOGY-Pulmonology
In a young Caucasian, a history of recurrent respiratory infections with P aelz.çlnosa, chronic
diarrhea, weight loss, and death of a sibling due to respiratory infection suggests a diagnosis of
cystic fibrosis (CF) Chronic diarrhea and weight loss in patients with CF are typically caused by
malabsorption secondary to pancreatic insufficiency and can be corrected by pancreatic enzyme
supplementation

Acute obstruction of the small airways in infants is usually secondary to respiratory sync ytial
virus (RSV) bronchiolitis. Ribavirin is an antMral drug that may be of benef ii RSV
bronchiolitis, especially in patients with severe infection who are at risk for disease progression
References:
1. Respiratory syncytlal virus disease: update on treatment and prevention.

Rif;rnpwiisan;ntimycobactenal drug that blocks the action of the bacterial DNA-dependent RNA
polymerase, thereby inhibiting transcnption The subsequent absence of mRNA leads to a
deficiency of proteins necessary for bacterial survival Rifampin resistance is acquired by
modification of the nfampin binding site on the bacterial DNA-dependent RNA polymerase.
192


lsoniazid is stwcturally similar to pyridoxine (vitamin B) As a result, this antibiotic increases the
urinary excretion of pyridoxine — often causing a frank deficiency of vitamin B — and
competes for vitamin B6-binding sites, leading to the defective synthesis of neurotransmitters
like GABA lsoniazid-iriduced neuropathy can usually be prevented with pyndoxine
supplementation

Isoniazid is chemically related to pyridoxine, also known as Vitamin B6 It inhibits mycolic acid
synthesis in mycobacterial cells and is specific to the mycobacteria. Mycolic acid is a long
branched chain saturated fatty acid used in the mycobacterial cell wall and in the formation of
virulence factors

N-acetylcysteineis a mucolytic agent used in the treatment of CF N-acetylcysteine works by
cleaving the disulfide bonds within mucus glycoproteins. thus loosening thick sputum

Mycobacterial resistance to isoniazid can be accomplished through non-expression of the
catalase-peroxidase enzyme or through genetic modification of the isoriiazid binding site on the
mycolic acid synthesis enzyme.

Echinocandins (eg caspofungin and micafungin) are a newer group of antifungal medications
that inhibit synthesis of the polysaccharide glucan, an essential component of the fungal cell wall

Alcoholics are more likely than the general population to develop pulmonary infections and
abscesses involving combinations of anaerobic oral flora (Bacteroides. Prevotella.
Fusobacterium, and Peptostreptococcus) and aerobic bacteria Clindamycin covers most of these
organisms and is thus the antibiotic of choice for treating lung abscesses.
References:
1. How important are anaerobic bacteria In aspiration pneumonia: when should they be treated
and what Is optimal therapy.
2. Etiology and outcome of community-acquired lung abscess.
3, Aspiration pneumonia and primary lung abscess: diagnosis and therapy of an aerobic or an
anaerobic infection?

Antimuscannic agents (ipratropium) only reverse vagally-mediated bronchoconstriction
Methyixanthines like theophylline and aminophylline cause bronchial dilatation by decreasing
phosphodiesterase enzyme activity, thereby increasing intracellular cAMP.

MycobacteriUm avium is a common opportunsbc pathogen that causes disseminated disease
(MAC) in HIV+ patients Weekly azithromycin is used as prophylaxis in patients at risk for MAC
(eg, HIV+ patients with CD4 counts less than 50 cells/mL).
References:
1. Infections due to non-tub.rculous mycobactena (NTM).
2. The pathophysiology of disseminated Mycobacterium avium complex disease in AIDS.

• The aminoglycoside streptomycin inhibits protein synthesis by inactivating the 30S (small)
ribosomal subunit
193


• Decreased activity of bactenal catalase-peroxidase is one mechanism of mycobactenal
resistance to isoniazid
• Structural alteration of enzymes involved in RNA synthesis (DNA-dependent RNA
polymerase) is the mechanism through which organisms become resistant to ntampin

Cromolyn and nedocromd are mast cell stabihzing agents They inhibit mast cell degranulation
independent of stimuli present These are less effective than inhaled glucocorticoids. and are
considered second-line for the treatment of allergic rtiinitis and bronchial asthma
References:
1. The effects of anti-asthma drugs on mediator release from cultured human mast cells.
2. Mast-cell stabilising agents to prevent .xercis.4nduc.d bronchoconstriction.

Bosentan is a competitive antagonist of endothelin receptors used for treatment of primary
(idiopathic) pulmonary arterial hypertension.

Isoniazid is an antimycobacterial agent that specificaWy inhibits the synthesis of mycolic acids.
Mycolic acids are essential components of the unique mycobacterial peptidoglycan cell wall.
Without mycolic acids, the mycobactena lose their acid-fastness and become unable to
synthesize new cell walls or multiply

Every patient using inhaled corticosteroids should be instructed about oral rinsing to prevent
oropharyngeal candidiasis.
References:
1. Salivary IgA and oral candidlasis In asthmatic patients treated with Inhaled corticosterold.
2. Influence of mouth washing procedures on the removal of drug residues following inhalation
of corticosteroids.
3. Oesophageal candidiasis in elderly patients: risk factors, prevention and management.

Rifampin is the preferred prophylaxis for persons who have been definthvely exposed to IV
mening#ichs Rifampin can eliminate the camer state as well as prevent active infection in those
who have been exposed to N ,nen,ngitidis Rifampan as also used as a component of multi-agent
therapy for both typical and atypical mycobactenal pulmonary infections, leprosy, and
staphylococcal endocardatis When used alone, bacteria rapidly acquire resistance to nfamp*n
through spontaneous genetic mutations of the bacterial DNA-dependent RNA potymerase

The main groups of antifungal drugs are the polyenes, azoles, echinocandins and pyrimidines
The polyene antifungals (amphotencin B and nystatin) act by binding ergosterol in the fungal cell
membrane

Azoles inhibit the synthesis of ergosterol by the fungal cytochrome P450 enzymes They also
suppress the human P450 system, resulting in many drug-drug interactions

Cortácosteroids have the strongest and most predictable effects on the inflammatory component
of asthma
References:
1. Evidence-based selection of inhaled corticosteroid for treatment of chronic asthma.
194


2. Efficacy and safety of Inhaled corticost.rolds In asthma. Report of a workshop held In Eze,
Franc., October 1992.
3. Review Pharmacological treatment of airway remodeling: inhaled corticosteroids or
antileukotrienes?

Ethambutol is noted for causing optic neuritis that results in color blindness, central scotoma, and
decreased visual acuity This adverse side effect may be reversible with discontinuation of the
drug

Non-selective 3-adrenergic blockers cause bronchoconstriction. peripheral vasospasm, and can
predispose diabetic patients to hypoglycemia Selective f3-blockers (metoprolol, atenolol.
acebutolol, and esmolol) are preferred in patients with COPD and/or asthma

Seizures are the major cause of morbidity and mortality from theophylline intoxication
Tachyarrhythmias are the other major concern.

Seizures are the major cause of morbidity and mortality from theophylline intoxication
Tachyarrhythmias are the other major concern
References:
1 Role of extracorporeal drug removal in acute iheophylline poisoning. A review.
2. First-line therapy for theophylline-associated seizures.

Ethambutol is an antimycobactenal agent that inhibits carbohydrate polymeñzation, thereby
preventing peptidoglycan cell wall synthesis One unique adverse effect of ethambutol is optic
neuritis, which typically presents in conjunction with decreased visual acuity, central scotoma
and color blindness

Active tuberculosis is never treated with drug monotherapy due to the fast emergence of
mycobacterial antibiotic resistance from rapid. selective gene mutations. Isoniazid monotherapy
may be used for patients who have a positive PPD and a negative chest x-ray (ie, no evidence of
clinical disease)
R.f.r.nc.s:
1. The catalas.-p.roxldas. gene and isoniazid r.sistanc. of Mycobact.num tub.rculosis.
2. Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis.

Arnphotencln t3 binds tfle ergosterol ot tungal cell memoranes to exert its antitungal ettects
However, it also binds cholesterol to some degree, causing toxicity to human tissues, The most
important adverse effects of amphotencin B are nephrotoxicity, hypokalemia. and
hypomagnesemia

Of the first-line agents for MycabacteriUm tuberculosis, only pyrazinamide requires an acidic
environment (as is present within macrophage phagotysosomes) to exert antimicrobial effects
Isoniazid, fliampin, and ethambutol are more active than PZA against extraceflular mycobacteria
195


PHARMACOLOGY-Renal
Spironolactone is an aldosterone antagonist commonly used in treating class Ill and IV heart
failure patients. Since it is structurally similar to steroids. spironolactone can cause endocrine
effects including gynecomastia, decreased libido, and impotence. Gynecomastia occurs in
approximately 10 % of patients. Eplerenone is a newer and more selective aldosterone antagonist
that may produce less endocrine effects.

Mannitol is an osmotk diuretic that works by increasing plasma or tubular fluid osmolality
Increased plasma and fluid osmolality causes extraction of water from the interstitial space into
the vascular space or tubular lumen, with subsequent diuresis. h, the brain, water redistribution
from the tissues into the plasma helps reduce edema and intracranial pressure in the setting of
cerebral edema. One of the more severe toxicibes of aggressive osmotic diuretics is pulmonary
edema
R.f.r.nc.s:
1 Mannitol revisited

Digoxin is a cardiac glycoside that is predominantly cleared by the kidneys. Elderly patients
typically exhibit age-related renal insufficiency, even in the presence of normal creatinine levels.
The dose of digoxin must be reduced in these patients in order to prevent toxicity.

Calcineuhn is an essential protein in the activation of IL-2, which promotes the growth and
differentiation of T ceIls Immunosuppressants such as cyclosporine and tacrohmus wOrk by
inhibiting calcineurin activation

Amphotericin B is a polyene antifungal notorious for its renal toxicity Severe hypokalemia and
hypomagnesemia are commonly seen during therapy, and often require daily supplementation.

Acyclovir can cause crystalline nephropathy if adequate hydration is not also provided.

Thiazide diuretics work by blocking Na”-Ci’ symporters in the distal convoluted tubules, causing
enhanced Na, Cl, and water excretion. Since only a small amount of filtered Na” reaches the
distal tubules, thiazides are not as efficacious as loop diuretics. Unlike loop diuretics, thiazides
can cause hypercalcemia

Common side-effects of ACE-inhibftors include decreased glomerular filtration rate (GFR),
hyperkalemia. and cough Angioedema is a rare, but hie-threatening. side-effect.

Thiazide diuretics are the only diuretics that increase calcium reabsorption from the nephron.
They are indicated in patients with nephrolithiasis secondary to hypercalciuria and
contraindicated in hypercalcemia.

Carbonic anhydrase is found in high concentrations in the proximal tubule and is responsible for
catalyzing reactions necessary for NaHCO3 reabsorption Acetazolamide is a diuretic that works
by inhibiting carbonic anhydrase, which effectively blocks NaHCO and water reabsorption in the
196


poximal tubules resulting in unnary bicarbonate wasting. Carbonic anhydrase inhibitors are also
used to relieve intraocular pressure in open-angle and angle-closure glaucoma.
References:
1 Ophthaproblem. Acute angle-closur, glaucoma.

Spironolactone is an aldosterone antagonist with mild diuretic effects. Based on results from the
RALES trial, addition of low dose spironolactone to standard therapy sgniticantly reduced
morbidity and mortality in class Ill and IV heart failure patients The benefits of spironolactone in
heart failure patients are more than likely secondary to inhibition of the neurohormonal effects of
aldosterone leading to decreased ventricular remodeling and cardiac fibrosis.

Lithium-induced diabetes insipidus is the result o( lithium’s inhibitory action on vasopressin
receptors in the collecting ducts

Foscamet is an analog of pyrophosphate that can chelate calcium and promote nephrotoxic renal
magnesium wasting These toxicities can result in symptomatic hypocalcemia and
hypomagnesemia

Hypokalemia and hypomagnesemia are common electrolyte disturbances in patients undergoing
treatment with amphotencin B. Hypokalemia and hypomagnesernia reflect an rncrease in distal
tubular membcane permeability

Loop diuretics woric by inhibiting Na’-K-2C1 symporters in the thick ascending limb of the loop
of Henle and effectively block Na’ and Cl- transport resulting in increased Na, Cl-, and H0
excretion They are the most potent class of diuretics and are used for treating edema in many
different conditions Common side effects include hypokalemia, hypomagnesemia, and
hypocalcemia

Ototoxicity secondary to loop diuretics usually occurs with higher dosages, rapid intravenous
administration, or when they are used in combination with other ototoxic agents
(aminoglycosides, salicylates, and cisplatin) Hearing impairment is usually reversible but has
been reported to be permanent in some cases
References:
1. Systematic review noninvasive testing for Chiamydia trachomatis and Neisseria gonorrhoeae.
197


PHARMACOLOGY-Vascular
Many drugs can cause nephrotoxkity and ARF via different mechanisms ki particular, ACE
inhibitors can cause an acute nse in the serum creatinine by blocking angeotensin mediated
efferent artenole vasoconstriction This leads to a reduction in renal filtration fraction. For
patients dependent on efferent artenole constriction to maintain renal perfusion (those with renal
artery stenosis), ACE inhibitors can be detnmental by precipitating acute renal failure
References:
1 The r.nin-angiotensin aldosterone system: pathophyslological role and pharmacologic
Inhibition.

Efficacy is a measure of the maximum pharmacodynamic effect achievable with a dwg Potency
refers to the dose of drug that is required to produce a given effect. Drugs that bind their
receptors with a higher affinity or are better able to gain access to th& target tissues will have
greater potency (lower ED).

The HOPE tnal demonstrates the potential benefits of ACE inhibitors in patients with signthcant
cardiovascular and peripheral vascular disease. Although ACE inhibitor therapy should be
considered in most patients. the development of ARF may preclude the use of these agents in
patients with extensive atherosclerotic disease and concomitant bilateral renal artery stenosis.

Treatment with statins causes hepatocytes to increase their LDL receptor density as a means of
increasing their uptake of circulating LDL

CoUgh is a very well recognized side effect of ACE inhibitor therapy. Cough secondary to ACE
inhibitor therapy is characterized as dry, nonproductive, and persistent The mechanism behind
ACE inhibitor induced cough is accumulation of bradykinin. substance P. or prostaglandins.
Because angiotensin receptor blockers (ARB5) do not affect ACE activity, they theoretically
should not cause cough

Niacin and fibrates are the most effective agents for the treatment of hypertnglyceridemia

This is a very common clinical issue given the prevalence of diabetes in the US population. and
the ACE-I class of drugs together with the ARB class of drugs have been shown to decrease the
progression of diabetic nephropathy.

First-dose hypotension is an adverse effect and concern when initiating ACE inhibitors
Predisposing risk factors for first-dose hypotension include hyponatremia, hypovolemia
secondary to diuretics, low baseline blood pressure, high renin or aldosterone levels, renal
impairment, and heart failure To minimize the risk for first-dose hypotension, identify patients at
nsk, initiate therapy at low dosages, and follow with cautious dosage titration and blood pressure
monitoring

Myopathy is a well-known side effect of some hypolipidemic drugs (especially statins)

Simvastatin decreases and cholestyramine increases hepabc cholesterol production
198


independently Combination therapy results in a net decrease m hepatic cholesterol synthesis and
plasma
LDL level Agents that increase hepatic cholesterol synthesis (eg., fibrates and bile acid—binding
                                                                                     acid
agents) are associated with an increased risk of galls
                                                 gallstones.
References:
1 0. ?rvIe of pharma: olocjic therap r L irnen r

Simvastatin decreases and cholestyramine increases hepabc cholesterol production
independently Combination therapy results in a net decrease m hepatic cholesterol synthesis and
plasma
LDL level Agents that increase hepatic cholesterol synthesis (eg., fibrates and bile acid—binding
                                                                                     acid
agents) are associated with an increased risk of gallstones.
References:
1 0. ?rvIe of pharma: olocjic therap r L irnen r

Fatty oxidation inhibitors are
                            re newer agents that inhibit fatty acid oxidation and shift energy
production to glucose oxidation, thus promoting oxygen efficiency. This not only decreases the
amount of oxygen needed to support cardiac function, but also decreases potentially toxic fty
acid metabobte production.

Charactehstcs of a drug such as high molecular weight. high plasma protein binding, high
charge. and hydrophihcity tend to trap the drug in the plasma compatment resulting in a low Vd
(3-5 L).

al -adrenergic agonists increase
                              se both systolic and diastolic blood pressure via stimulation of ala
drenoreceptors in the vascular walls Elevated systemic blood pressure is associated with a reflex
increase in vagal influence on the heart This results in decreased heart rate, contractility,
                                                                                 contractil   and
conductance

References:

1 Sympathetic neural mechanisms in human cardiovascular health and disease.
2. N.ural control of the circulation.




Low doses of dopamine stimulate Di receptors in the renal and mesentenc vasculature resulting
in vasodilation and increased blood flow to these sites. Higher doses of dopamine increase
cardiac contractility by stimulation of beta
                                        beta-i adrenergic receptors, and
                                                                       d still higher doses produce
generalized vasoconstriction by an alpha
                                    alpha-i adrenergc effect
199


References:
1. The pharmacological basis of the clinical use of dopamine.


 Drug class
                           Primary indication    Major toxicity


 Statins                   High LDL              Hepatitis, myopathy


 Niacin                    Low HDL               Cutaneous vasodilation
                                                 Hypergycernia (acanthosis nigricans)
                                                 Hyperuncernialgout
                                                 Hepatitis


 Fibnc acid derivatives    High TG               Gallstones
                                                 Myopathy (worse when combined with statins)


 Bile acid-binding resms   High LDL              GI upset
                                                 Hypertnglyceridemia
                                                 Malabsorption

Topical preparations of o-adrenergic agonists cause vasoconstriction of the nasal mucosa vessels
and are used as decongestants Overuse of these drugs causes negative feedback, resufting in
decreased norepinephrine synthesis and release from nerve endings, which diminishes their
effect (ie, tachyphy1axis)

Amlodipine is a calcium channel blocker used in hypertension that can lead to flushing and
peripheral edema

ARBs work by blockmg AT-f receptors and inhibiting the effects of angiotensin I[ This results in
arterial vasodilation and decreased aldosterone secretion Since ARBs work at the level of AT-i
receptors and do not affect ACE activity, they do not interfere with bradykinin degradation or
levels By blocking AT-i receptors, ARBs also interfere with negatwe feedback mechanisms
resulting in increased renin, angiotensin I, and angiotensin II levels.

1. The combination of statins plus fibrates increases the risk of myopathy in patients being
treated for hyperhpidemia Statin use is also associated with hepatotoxicity
2. The combination of fibric acid denvates and bile acid-binding resins increases the risk for
cholesterol gallstones. This reflects an increased cholesterol concentration ii bile

1. Niacin is believed to inhibit hepatic VLDL production It is mainly used to increase HDL
levels.
2. Statins inhibit cholesterol synthesis and thereby up-regulate the LOL receptors
200


Bile acid-binding resins can cause constipation and abdominal bloating (potentially worsening
diverticulosis), hypertriglyceridemia, cholesterol gallstones, and vitamin K malabsorption.

ACE inhibitors cause renal failure by altering renal hemodynamics. ACE inhibition results m
efferent arteriole dilatation, thereby decreasing glomerular pressure and renal perfusion For
patients dependent on efferent artenole constriction to maintain renal perfusion (those with renal
artery stenosis), ACE inhibitors can be detrimental causing acute renal failure or complicating
existing renal disease
References:
1. Ath.roscl.rotic r.nal artery st•nosis, ACE inhibitors, and avoiding cardiovascular d.ath.

One major pathway that regulates the RAAS involves the beta-adrenergic receptor pathway The
beta-adrenergic pathway is mediated through sympathetic stimulation of beta-i receptors located
on juxtaglomerular cells Beta adrenergic blockers like propranolol inhibit renin release by
blocking the beta-i receptor mediated pathway Thus, beta adrenergic blockers can also reduce
angiotensin I, angiotensin II, and aldosterone levels, Since beta blockers do not affect ACE
activity, they do not affect bradykinin levels.

Angioedema is a rare but potentially serious adverse effect of ACE inhibitor therapy occurring in
less than I % of patients. Although it can affect any tissue. angioedema most commonly involves
swelling of the tongue, lips, or eyelids and patients can also experience laryngeal edema and
difficulty breathing ACE inhibitor induced angioedema is more than hkely due to increased
bradykinin levels as a result of ACE inhibition
Ref erences:
1. Bradykinin and the pathophysiology of angioedema.

Bile acid-binding resins are unique among hypohpidemic agents m that they rncrease blood
triglyceride levels Fibnc acid derivatives are the first-line treatment for hypertriglycendemia
References:
1. Hypertriglyceridemia: a contraindication to the use of bile acid binding resins.
2. An overview of lipid-lowering drugs.

Most statins are metabolized by cytochrome P-450 3A4, with the exception of pravastatin
Concomitant administration of drugs that inhibit statin metabobsin (e.g. macrohdes) is associated
with increased incidence of statin-induced myopathy and rhabdomyolysis Acute renal failure is a
possible sequela of rhabdomyolysis
R•f•r• nc.s:
1. Risk management of simvastatin or atorvastatin interactions with CYP3A4 inhibitors.

ACE inhibitors block the effect of ACE. decreasing angiotensin II and aldosterone levels. By
decreasing angiotensin II levels. ACE inhibitors directly interrupt negative feedback loops, thus
increasing renin and angiotensin I levels. Without effective ACE, bradykinin metabolism
decreases and bradykinin levels will inCrease.
201


Cilostazol is a phosphodiesterase inhibitor used in pabents with intermittent claudication In
addition to inhibition of platelet aggregation. cilostazol is also a direct arterial vasodilator
Cilostazol has been shown to be superior to aspirin in the treatment of penpheral artenal disease
References:
1 Safety and efficacy of cilostazol in th. management of intermittent claudication.
2. Cilostazol has beneficial effects in treatment of intermittent claudication: results from a
multicenter. randomized, prospective, double-blind trial.
3. Management of lower .xtr.mity peripheral arterial disease.

Phenoxybenzarnine is a nonselective. irreversible a-i and a-2 adrenergic antagonist that
effectively reduces the number of receptors availab’e for norepinephrine binding Because
phenoxybenzamine is an irreversible antagonist, even very high concentrations of norepinephnne
cannot overcome its inhibitory effects.

1 Alpha 1 -blockers such as Doxazosin. Prazosin and Terazosin are useful for the treatment of
both benign prostatic hyperplasia and hypertension
2. Patients with coronary artery disease and heart failure along with hypertension will benefit
from cardioselective beta-blockers
3. Hydrochlorothiazide is presently the first-line medication for the treatment of essential
hypertension in the general population.

Niacin can potentiate the effects of some anti-hypertensive medications because of its
vasodilatory effects. Dose adjustment may be required Niacin also causes insulin resistance and
oftentimes necessitates an increase in diabetes medications
References:
1. Treatment of diabetic dyslipidemia.
2. Does nicotinic acid (niacin) lower blood pressure?

Streptokinase is a thrombolytic agent that acts by converting plasminogen into plasmin, which
subsequently degrades fibrin Its most common side effect is hernorrhage Streptokinase is a
foreign protein derived from Streptococci and can induce hypersensitivity reactions.

Fenoldopam is a newer parenteral agent that is classified as a selective dopamine-1 receptor
agonist. It causes artenolar dilation and natnuresis leading to decreased systemic vascular
resistance and blood pressure reduction. Since fenoldopam is the only intravenous agent that
improves renal perfusion, it may be exceptionally beneficial in hypertensive patients with
concomitant renal insufficiency.

Norepinephrine stimulates cardiac 31 adrenoreceptors. which utilize the cAMP signal
transduction pathway. Stimulation of these receptors by norepinephrine causes increases in
cAMP concentration within cardiac myocytes.
References:
1. Early administration of norepinephrine increases cardiac preload and cardiac output in septic
patients with life-threatening hypotension.
202


ACE inhibitors block the conversion of angiotensin Ito angiotensin II, thus reducing
vasoconstriction and aldosterone secretion Decreased aldosterone causes increased potassium
retention, which can potentially lead to hyperkalemia Hyperl’calemia secondary to ACE
inhibitor therapy is most common in patients with renal insufficiency and in patients taking K-
spanng diuretics (amilonde, tnamterene, and spironolactone) or K’ supplements

Blanching of a vein into which norepinephrine (NE) is being infused together with induration
and pallor of the tissues surrounding the IV site are signs of NE extravasation and resulting
vasoconsthction Tissue necrosis is best prevented by local injection of an aiphal blocking drug,
such as phentolamine

During continuous infusion of a drug metabolized by first-order kinetics, the steady state
concentration is reached in 4 to 5 hatt-Iives

Aldosterone excess Wril cause hypertension, hypokalemia, metabolic alkalosis and depressed
renin Alternatively, hypoaldosteronism is the cause of type IV renal tubular acidosis Aldosterone
antagonists such as spironolactone or eplerenone can be used as medical therapy for Conn’s
syndrome

Epinephrine increases systolic blood pressure (al + p1), increases heart rate (p1), and either
increases or decreases diastolic blood pressure depending on the dose (either al or 132
predominates) Pretreatment with propranolol eliminates the 3 effects of epinephnne
(vasodilatation and tachycardia), leaving onty the a effect (vasoconstriction).

Nitroprusside is the agent of choice in treating hypertensive emergency. It has a quick onset of
action and short duration of action Nitroprusside is initially metabohzed to cyanide, with
subsequent conversion to thiocyanate by liver rhodanase Thus, one major disadvantage of its use
involves the risk for developing cyanide toxicity Sodium thiosulfate is used to treat cyanide
toxicity and works by donating sulfur to hver rhodanase to enhance conversion of cyanide to
thiocyanate

1. Patients with familial hypoalphalipoproteinemia (low HDL) are at increased risk of
developing premature coronary artery disease Niacin (vitamin B3) is the best agent currently
available to increase HDL cholesterol levels
2. Statins and ezetimibe are mainly used for hypercholesterolemia (high LDL). High LDL is a
risk factor for atherogenesis
3, Fibnc acid derivatives are mainly used for hyperinglycendemia Remember that severe
hypertnglyceridernia can cause pancreatitis
Ref erences:
1, High- density lipoprotein therapy: is there hop.’

1. The cutaneous flushing associated with ruacin is mediated by prostaglandins and can be
prevented with aspirin pre-treatment
2. Capsaicin reduces pain by decreasing the level of substance P in the penpheral nervous system
References:
1. Niacin use and cutaneous flushing: mechanisms and strategies for prevention.
203


2. Aspirin reduces cutaneous flushing after administration of an optimized
•xtend.d-r.l.as. niacin formulation.

Both gemfibrozil and cholestyramine increase cholesterol excretion by the Wver Along with the
reduction in serum LDL, there is an increased risk for gallstone formation
References:
1. Role of fiurates and HMG-CoA reductase inhibitors in gallstone formation:
•pld.mlologlcal study In an uns.l.ct.d population.
2. Triglycerides and gallstone formation.
3. Biliary lipids, lithogenic index and biliary drug concentrations during etofibrate and
bezaflbrate treatment.
204


PHYSIOLOGY-Cardiology+Vascular
The total resistance for a group of vessels arranged in parallel is equal to one divided by the sum
of the inverse values for resistance of each of the contributing vessels as follows 1ITPR = 1/Ri +
1/R2 + 1/R3 + 1/Rn. Total body circulation can be best descnbed as a parallel circuit, whereas
circulation in an individual organ is often best described by a series arrangement.

Educational Objective:
Atnal natriuretic peptide (ANP) is secreted by atrial cardiomyocytes in response to atnal stretch
induced by hypertension or hypervolemia ANP actions include peripheral vasodilation and
increased urinary excretion of sodium and water.

Exercising muscles can receive up to 85% of the total cardiac output during periods of strenuous
activity thanks to local release of vasodilatory factors. Although sympathetic discharge during
exercise causes an increase in cardiac output and increased contraction of blood vessels, there is
only a modest blood pressure increase because the vasodilatation within muscle so significantly
decreases the total systemic vascular resistance

An increased ejection fraction (increased stroke volume) is represented on a ventricular pressure-
volume loop as a widening of the graph. The isovolumetnc relaxation hne is shifted to the left
indicating less volume remaining in the ventricle after contraction is complete

A holosystolic murmur that increases in intensity on inspiration most likely represents tricuspid
regurgitation. The other holosystolic murmurs (which are secondary to mitral regurgitation or a
ventricular septal defect) do not typically increase in intensity during inspiration

Paroxysmal supraventncular tachycardia is a common dysrhythmia that frequently occurs in
patients with no other heart disease The cause is typically a re-entrant circuit in the AV node
Episodes are usually treated with adenosine in the hospital setting. but vagal maneuvers such as
carotid sinus massage and Valsalva can also be used

Only 10% of total perfusion through the myocardial capillaries of the LV occurs during systole,
while the majority of left ventricular blood flow occurs during diastole. The systolic reduction in
coronary blood flow is greatest in the subendocardial myocardium of the LV.

Metabolic acidosis is characterized primarily by a decrease in serum bicarbonate and a decrease
in pH. The PaCO. will also decrease as a resuft of respiratory compensation for the primary
metabolic acidosis

The treatment of choice for diabetic ketoacidosis is intravenous hydration with normal saline and
insulin. These therapies will result in decreases in the serum glucose, osmolality, and potassium,
as well as increases in serum bicarbonate and sodium

Most of the blood supply to the heart occurs during diastole and the duration or length of diastole
is a critical factor in determining coronary blood flow.
205


Intravenous fluid infusions increase the intravascular volume by varying degrees depending on
the composition of the solute. The resultant preload increase causes increased ventricular
myocardial sarcomere length and thus increased stroke volume and cardiac output

In cardiac pacemaker cells, phase 0 depolarization is mediated by an inward flux of calcium This
differs from phase 0 of cardiomyocytes and Purkinje cells, which results from an inward sodium
current.

The carotid sinus is a dilatation of the internal carotid artery that lies at the bifurcation of the
carotid artery Blood pressure increases or external pressure on the carotid sinuses stimulate
baroreceptors in the carotid sinus walls, leading to vasodilatation. a decrease in heart rate and
contractility, and a decrease in blood pressure

Cardiac pacemaker impulse generation normally occurs in the SA node. which has the fastest
firing rate of all conductive cells. The cells in other areas of the conduction system (eg, AV node,
bundle of His, and Purkinje fibers) may serve as pacemakers if normal impulse conduction is
impaired

An S3 sound is a low frequency heart sound that can be physiologic in younger individuals It is
typically pathologic in older adults, and in these patients. it generally results from left ventricular
systolic failure or restrictive cardiomyopathy The S3 sound can be accentuated by having the
patient lie in the left lateral decubitus position and fully exhale.

Cardiac failure results in stimulation of the sympathetic nervous system and the renin-
angiotensin-aldosterone system Angiotensin converting enzyme (ACE) is expressed by the
vascular endothelium, particularly in the lungs, and functions to convert angiotensin Ito the
functional angiotensin IL

Arteriovenous (AV) shunts can be congenital or acquired acquired forms can result from medical
interventions or penetrating injuries. AV shunts increase preload and decrease afterload by
routing blood directly from the arterial system to the venous system, bypassing the arterioles.
High-volume AV shunts can eventually result in high-output cardiac failure.

Pressure-volume loops represent the relationship between pressure and volume in the left
ventricle during systole and diastole. An increase in the circulating volume would increase
preload and cause a rightward widenina of the nressiire-vnhime loon

Blood flow is directly proportional to the vessel radius raised to the fourth power Resistance to
blood flow is inversely proportional to the vessel radius raised to the fourth power

‘Water-hammer” pulses and head-bobbing with each heart beat (de Musset sign) are
characteristic findings in patients with aortic regurgitation.

Calcium efflux prior to myocyte relaxation is accomplished through the use of Ca2-ATPase and
Na/Ca2 exchange mechanisms.
206


Myocardial infarction causes a sharp decrease in cardiac ou
                                                         output
                                                            tput due to loss of function of a zone
of myocardium On a cardiac function curve. myocardial infarction would decrease both the slope
and the maximal height of the line.




Pregnant women > 20 weeks gestation can experience compression of the inferior cava by the
gravid uterus while in the supine position This reduces venous return and cardiac output. which
can result in hypotension and syncope.

Verapamil is a calcium channel blocker that slows depolarization of cardiac slow-response
                                                                            slow          tissue
(sinoatrial
         al and atrioventncular nodes) by decreasing the calcium ion influx that occurs during
phase 0 and the latter part of phase 4. Verapamil also decreases the amount of intracellular
calcium available within cardiomyocytes (fast
                                          (fast-response
                                                response tissue), which can reduce
                                                                              red    myocardial
contractihty

The pulmonary capillary wedge pressure (PCWP) measures the left atrial end diastolic pressure
(LAEDP). Under normal conditions, the LAEDP is nearly equal to the LV end
                                                                       end-diastolic
                                                                           diastolic pressure
(LVEDP). Mitral stenosis elevates the LAEDP and PCWP relative to the LVEDP

Carrier-mediated
        mediated transport includes facihtated diffusion and active transpoit Movement of
substrate across the cell membrane by these mechanisms depends on the presence of carrier
proteins in the membrane. Transport mechanisms utilizing proteins are able to be saturated

In patients with heart failure. compensatory activation of the renin renin-angiotensin
                                                                           angiotensin-akiosterone
pathway and sympathetic nervous system results in increased afterload (from excessive
vasoconstnction), excess
                   xcess fluid retention, and deleterious cardiac remodeling.

Atnal fibrillation occurs due to irregular. chaotic electrical activity within the atria While some
of the atrial impulses are transmitted to the ventricles, most are not due to the AV nodal
refractory period.

The Fick principle can be used to calculate the cardiac output It states that the cardiac output is
equal to the oxygen consumption by the tissues divided by the arteriovenous oxygen difference

Any significant acute change in heart rarate
                                          te or rhythm or the force of ventricular contraction may
cause palpitations. An irregularly irregular tachyarrhythmia in a conscious patient is most likely
atrial fibrillation, the most common chronic arrhythmia In AF. the EKG shows absent p waves
and irregularly
         gularly spaced ventricular contractions evidenced by a variable R
                                                                         R-R
                                                                           R interval

The cardiac myocyte action potential consists of rapid depolarization (phase 0), initial rapid
repolarization
(phase 1), plateau (phase 2), late rapid repolarization (phase 3), and resting potential (phase 4).
The action
potential is associated with increased membrane permeability to Na and Ca4 and decreased
permeability to K.
207


Achrornc artenovenous shunt would increase cardiac output because of increased sympathetic
stimulation to the heart, decreased total peripheral resistance, and increased venous return. It
would also cause the venous return curve to shift to the right because the circulating blood
volume is increased through renal retention of fluids and because venous pooling is reduced by
the increased sympathetic tOne.

Myocardial oxygen extraction exceeds that of any other tissue or organ in the body. Resting
myocardium extracts 75% to 80% of the oxygen present in the blood, while myocardium at work
extracts up to 90% of oxygen from the blood. Hypoxia and adenosine accumulation increase
cardiac perfusion, which is the main mechanism by which increases in myocardial oxygen
demand are satisfied.

The classic cardiac auscultation findings in mitral valve stenosis include an opening snap
followed by a diastolic rumbling murmur that is heard best over the apex of the heart On the
ventricular pressure-volume loop, mitral valve opening occurs at the point between isovolumetnc
relaxation and diastolic filling.

Nitroprusside is a short-acting balanced venous and arterial vasodilator that decreases both
preload and afterload Since these changes are balanced, stroke volume is maintained

Ventricular pressure and volume curves allow one to identdy the phases of the cardiac cyc’e and
to determine the exact time of opening and closure of the cardiac valves.

The law of conservation of mass applied to the steady state flow of an incompressible fluid
through a system of cylinders of varying cross sectional areas tells us that
Total Flow = Flow Velocity x Cross Sectional Area = Constant

Skeletal muscle is resistant to the effect of calcium channel blockers because it does NOT
require an influx of extracellular calcium for excitation-contrachon coupling, whereas cardiac
and smooth muscle depend on extracellular calcium entering the cell via voltage-gated gated L-
type calcium channels for
excitation-contraction coupling These voltage-gated calcium channels are the target of verapamil
and other calcium channel blockers.

The cardiac action potential conduction velocity is slowest in the AV node and is fastest in the
Purkinje system The conduction speed of the atnal muscle is higher than that of the ventncular
muscle

The action potential of pacemaker cells includes phases 0, 3, and 4 Phase 4 consists of
spontaneous depolarization and occurs due to the closure of K channels, the slow influx of Na,
and the opening of T- and L-type Ca channels. Acetyicholine and adenosine reduce the rate of
spontaneous depolarization in cardiac pacemaker cells

Nitric oxide is the most important mediator of coronary vascular dilation in large arteries and
pre-arteriolar vessels. ft is synthesized from arginine and oxygen by endothelial cells and causes
vascular smooth muscle relaxation by a guanylate cyclase-mediated cGMP second messenger
208


system. Adenosine, a product of ATP metabolism, acts as a vasodilatory element in the small
coronary arterioles.


PHYSIOLOGY-Endocrine+GIT+Neuro
A scotoma is a visual field defect that occurs due to a pathologic process that involves parts of
the retina or the optic nerve resulting in a discrete area of altered vision surrounded by zones of
normal vision Lesions of the macula cause central scotomas

Progressively weakening diaphragmatic contractions during maximal voluntary ventilation with
intact phrenic nerve stimulation indicate neuromuscular lunction pathology (eg, myasthenia
gravis) and/or abnormally rapid diaphragmatic muscle fatigue (eg. restrictive lung or chest wall
disease)

Cholecystokinin (CCK) is the hormone responsible for gallbladder contraction It is made in the
duodenum and jejunum in response to fatty acids and amino aCids.

Elevated serum FSH level confirms menopause and can be used if the diagnosis is uncertain.
Atthough LH level is also elevated, it is a later and less prominent phenomenon.

The suprachiasmatic nucleus regulates circadian rhythm. It processes light information received
from the retina and relays it to other hypothalamic nuclei and the pineal gland to modulate body
temperature and the production of hormones such as cortisol and melatonin Melatonin
supplementation is recommended for the treatment of insomnia associated with jet lag

Hypoglycemia can be precipitated in a diabetic patient after vigorous exercise due to increased
glucose uptake by muscles as well as rapid subcutaneous insulin absorption when the injection
occurs in a limb that is subsequently exercised

Mu receptors are G protein-hnked receptors whose actions are mediated through various
secondary messenger pathways. One identified pathways involves increased potassium efflux.
Binding of morphine to mu receptors results in G protein-coupled activation of potassium
conductance. Potassium efflux increases and causes hyperpolarization of postsynaptic neurons
effectively blocking pain transmission.

Volume contraction and volume expansion can be dMded into isoosmotic, hypoosmotic and
hyperosmotic forms. The loss of free water with retention of electrolytes is seen in diabetes
insipidus and in excessive sweating without fluid and solute replacement. These conditions cause
hyperosmotic volume contraction.

Insulin opposes glucagon action. Glucagon stimulates glycogenolysis, gluconeogenesis, lipolysis
and ketone body production while insulin increases glucose. amino acid and potassium uptake by
cells, inhibits ketoacid formation and inhibits Ilpolysis.
209


Pulsatile administration of GnRH agonists stimulates FSH and LH release and is useful for the
treatment of infertility. Nonpulsatile (constant) infusion of GnRH, or a longer-lasting analogue,
suppresses FSH and LH release and is useful for the treatment of the other diseases listed in the
scenario

Neuromuscular hyperexcitability can become clinically apparent when serum calcium levels are
TO mg/dL. A common cause of hypocalcernia is primary hypoparathyroidism, which is often
due to loss of parathvroid tissue durinci thvroidectomv.

Neurophysins are carrier proteins for oxytocin arid vasopressin (ADH) Oxytocin and vasopressin
are carried by unique neurophysins from their site of production in the cell bodies of the
paraventricular and supraoptic nuclei to their site of release in the axon terminals of the posterior
pituitary Point mutations in neurophysin II underlie most cases of hereditary hypothalamic
diabetes insipidus. a disorder resulting from insufficient ADH

C peptide can be used as a marker of the total rate of endogerious 13—cell insulin secretion
under steady-state conditions. Sulfonylureas increase the rate of insulin secretion and C peptide
levels in patients with type 2 diabetes.

The length constant is a measure of how far along an axon an electrical impulse can propagate. A
low-length constant reduces the distance an impulse can travel. Myelination increases the ‘ength
constant and decreases the time constant, both of which improve axonal conduction speed.
Demyelination thus impairs stimulus transmission.

Inhibin B is produced by the Sertoli cells and is the physiological inhibitor of FSH secretion LH
concentration is controlled primarily by testosterone feedback

Patients undergoing total gastrectomy require lifelong vaamin B, supplementation due to the
poor B12 absorption that occurs with intrinsic factor deficiency

Elevated systemic T3 and T4 (via intracellular conversion to T3) cause negative feedback on the
hypothalamus and anterior pituitary leading to decreased TSH production and release T4 can be
converted in the peripheral tissues to the more active T3 or to the inactive rT3. T3 cannot be
converted to rT3 or to T4 Exogenous T3 administration causes decreased TSH levels, which act
upon the thyroid gland to reduce endogenous T4 production (and thus reduce peripheral
conversion to rT3)

Energy is supplied by the metabolism of protein. fat and carbohydrates Metabolism of 1 g of
protein or carbohydrate produces 4 cal of energy. while metabolism of 1 g of fat produces 9 cal.

Neurophysins are proteins involved in the posttranslational processing of oxytocin and
vasopressin These hormones and their respective neurophysins are produced within the neuronal
cell bodies of the paraventricular and supraoptic nuclei and they are released into the circulation
from axon terminals in the posterior pituitary gland
210


The action potential results from changes in the membrane permeability to K and Na ions.
Depolarization results from massive influx of Na through voltage-gated Na channels
Repolarization occurs due to closure of voltage-gated Na channels and opening of voltage-gated
K channels. K ion permeance is highest during the repolarization phase of the action potential.

The main cell types that express GLUT 4 glucose transporter are adipocytes and skeletal muscle
cells; their glucose uptake is insulin-mediated.

Transport of glucose into the cells of most tissues occurs by means of facilitated diffusion
Glucose moves from areas of high concentration to areas of low concentration with the help of
transmembrane glucose transporter proteins (GLUT) These carrier proteins are stereoselective
and have preference for D-glucose

Cortisol has several permissive effects For example. cortisol increases vascular and bronchial
smooth muscle reactivity to catecholamiries.

Duodenal S-cells secrete secretin in response to increasing W conceritrations Secretin increases
pancreatic bicarbonate secretion The chloride content of pancreatic secretions decreases in
proportion to bicarbonate concentration increases

Beta-endorphin is one endogenous opioid peptide that is derived from proopiomelanocortin
(POMC). POMC is a polypeptde precursor that goes through enzymatic cleavage and mod
ification to produce not only beta-endorphins, but also ACTH and MSH The fact that beta-
endorphin and ACTH are derived from the same precursor suggests that there may be a close
physiological relationship between the stress axis and the opioid system.

Thyroid peroxidase catalyses iodide oxidation, the formation of mono- and diiodotyrosine, and
the coupling that forms T3 andT4.

Anovulation is a common cause of infertility One way to treat anovulation is the administration
of drugs that act like FSH and LH Treatment with menotropin (human menopausal
gonadotrophin) acts like FSH and leads to the formation of a dominant ovarian follicle Ovulation
is then induced by administration of a large dose of hCG, which simulates the LH surge

Pancreatic exocrine secretions are the major source of bicarbonate entering the duodenum
Secretin is the hormone that stimulates the release of bicarbonate-rich secretions from the
exocrine pancreas Secretin is produced by S enteroendocnne cells in the duodenal mucosa in
response to stimulation by intraluminal acidity Hydrochloric acid is the most potent stimulus for
secretin release

The cephalic and gastric phases stimulate gastric acid secretion. while intestinal influences tend
to reduce gastric acid secretion

Parietal cells release hydrogen ions into the gastric lumen by means of the H/K ATPase. which
requires hydrolysis of ATP and is therefore an active transport mechanism Omeprazole and other
211


proton pump inhibitors suppress the activity of the gastric parietal cell H/K ATPase leading to an
increase in the pH of the gastric lumen

The resting potential of the neuronal membrane is close to the equilibrium potential of potassium
because the resting membrane is most permeable to potassium. Changes in the membrane
potential occur in response to changes in neuronal membrane permeability to various cellular
ions The more permeable the membrane becomes to a cellular ion, the more that ion’s
equilibrium potential contributes to the total membrane potential.

Lipids (triglycerides. cholesterol and phospholipids) are digested in the duodenum and absorbed
in the jejunum Bile acids are necessary for lipid absorption Cholecystectomy typically has little
effect on lipid digestion and absorption though patients may find it difficult to eat a large fatty
meal.




PHYSIOLOGY-Musculoskeletal+Skin
Myasthenia gravis is an autoimmune disease that results in a decrease in acetyicholine receptors
on the postsynaptic terminal of the muscle end plate. This results in decreased ability of
acetytcholine to bind and open postsynaptic cation channels, thereby decreasing the end plate
potential.

The treatment of myasthenia gravis involves cholinesterase inhibitors, immunosuppressants and
possibly thymectomy Cholinesterase inhibitors may cause adverse effects related to muscarinic
overstimulation, which can be ameliorated by use of an antimuscarinic agent like scopolamine

During skeletal muscle contraction, calcium is released from the sarcoplasmic reticulum arid
binds troponin C thereby allowing the binding of actin to myosin

During the skeletal muscle contraction cycle. ATP binding to myosin causes release of the
myosin head from its binding site on the actin filament.

The H band is the region of the sarcomere containing only myosin thick filaments It is the part of
the A band on either side of the M line where myosin thick filaments do not have any
overlapping actin thin filaments.

Once specific channels are open. ions will flow across the membrane to bring the resting
membrane potential toward their equilibrium potential.

T-tubules are invaginations of the sarcolemma that extend into each muscle fiber They transmit
depolarization signals to the sarcoplasmic reticulum and trigger the release of calcium The
uniform distribution of T-tubules ensures coordinated contraction of all myofibrils
212


The resting membrane potential is the difference in the electrical charges across the cell
membrane under steady-state conditions. The ions that are most permeable to the cell membrane
make the largest contribution to the resting membrane potential In general. a high potassium
efflux and some sodium influx are responsible for the value of the resting potential. which is
typically about -70 mV

In healthy individuals, the differences in the bone density curves can be best explained by
genetic differences. Other factors, like calcium intake and daily physical activity, play a smaller
roIe These lifestyle modifications should not be ignored, however, as women at risk for
osteoporosis can modify their environmental factors to achieve their maximum potential bone
density.

The contractile mechanism in skeletal muscle depends on proteins (myosin II, actin,
tropomyosin, and troponin) as well as calcium ions.

The muscle spindle system is a feedback system that monitors and maintains muscle length,
while the Golgi tendon system is a feedback system that monitors and maintains muscle force
GTOs are exquisitely sensitive to increases in muscle tension but are relatively insensitive to
passive stretch

Bone-specific akaIine phosphatase reflects osteoblastic actMty Tartrate-resistant acid
phosphatase, urinary hydroxyproline, and urinary deoxypyridinoline reflect osteoclastic activity;
urinary deoxypyridinoline is the most reliable of the three.

Postural skeletal muscles such as the soleus and paraspinal muscles contain predominantly Type
I slow twitch, red muscle fibers that derive ATP primarily from oxidative (aerobic) metabolism

Apocrine sweat gland secretion is initially odorless but can become malodorous secondary to
bacterial decomposition on the skin surface.

• The main action of PTH on bone is increased bone resorption PTH acts on osteoclasts by an
indirect method It is osteoblasts, not osteoclasts that have PTH receptors PTH causes osteoblasts
to increase the production of RANK-hgand and monocyte colony-stimulating factor (M-CSF);
these two factors stimulate osteoclastic precursors to differentiate into bone-resorbing, mature
osteoclasts
• PTH increases serum calcium level and decreases serum phosphate level (the phosphate is lost
to urine).
213


PHYSIOLOGY -Pulmonology+Haematology

During aerobic exercise, increased skeletal muscle CO2 production increases the PCO2 of mixed
venous blood Homeostatic mechanisms maintain artenal blood gas levels and arterial pH near the
resting values.

The residual volume (RV) is the lung volume that remains after maximal expiration The RV is
increased in chronic obstructive pulmonary disease (COPD) This increase is illustrated on the
above graph by a larger-than-normal lung volume at the end of maximal exhalation

Normal tracheal p0. is 150 mm Hg and normal alveolar p0. is 104 mm Hg The equilibration of
02 in a normal individual at rest is perfusion-limited Situations where 0. equilibration can
become diffusion-limited include disease states such as emphysema and pulmonary fibrosis, and
physiologically in states of very high pulmonary blood flow, such as during exercise.

Three variables affect the total oxygen content of blood: 1 Hemoglobin concentration, 2 Oxygen
saturation of hemoglobin (SaC2) and 3 The partial pressure of oxygen dissolved in blood (Pa02)

The pulmonary vascular bed is relatively unique in that hypoxemia causes a vasoconstrictive
response. Such hypoxic vasoconstriction occurs in the small muscular pulmonary arteries in
order to divert blood flow away from underventilated regions of the lung toward more well-
ventilated areas

The minute ventilation is equal to the product of the tidal volume and the respiratory rate and
includes dead space ventilation. The alveolar ventilation does not take into account the air in the
physiologic dead space. It is the product of the respiratory rate and the difference between the
tidal volume and the dead space volume.

High &titude exposure lasting more than a few days results in hypoxemia with a chronic
respiratory alkalosis. The corresponding decrease in serum bicarbonate levels reflects renal
compensation

Panic attacks are associated with hyperventilation and decreased pCO Hypocapnia causes
cerebral vasoconstnction and decreased cerebral blood flow

The integrated cardiorespiratory response to exercise includes increased heart rate, increased
cardiac output, and increased respiratory rate in order to balance the increased total tissue 02
consumption and CO2 production. These increases are coordinated so that arterial blood gases
remain relatively constant, while venous PC2 is decreased and venous pco2 is increased.

The center of the airway pressure-volume curve is the functional residual capacity (FRC) of the
lungs; it identifies the resting state where the airway pressure equals zero At the FRC, the
intrapleural pressure is negative with a value of -5 cm H20
214


Carbon monoxide (CO) binds to hemoglobin with much higher affinity than 02, thus preventing
oxygen binding to hemoglobin. It also reduces oxygen unloading from hemoglobin in the tissues
CO poisoning does not affect the Pa02 and does not precipitate methemoglobinemia.

Factor Xa inhibitors are a new class of anticoagulants with specific activity against factor Xa
without significant antithrombin activity. These drugs increase the prothrombin and activated
partial thromboplastin times but do not affect the thrombin time. Hepann and drugs that directly
inhibit thrombin formation can prolong TT.

Nocturnal upper airway obstruction (manifested by snoring) and episodic nocturnal apnea
characterize obstructive sleep apnea, a condition associated with systemic hypertension
Prolonged, untreated obstructive sleep apnea can also cause pulmonary hypertension and right
heart failure

Anaphylaxis is the resuft of widespread mast cell degranulation Although histamine is the major
effector of anaphylaxis, tryptase is also released in excess and can be used as a marker for mast
cell activation.

Degrariulation of mast cells is accomplished by the cross-linking of multiple membrane-bound
IgE antibodies by a specific antigen, resulting in lgE-Fc receptor aggregation on the cell surface

The p02 in the left athum is lower than that in the pulmonary capillaries because deoxygenated
blood originating from the bronchial arteries mixes with oxygenated blood in the pulmonary
veins

Stimulation of the vagus nerve branches that supply the lung would cause bronchoconstriction
and increased bronchial mucus secretion. These effects increase airway resistance and the work
of
breathing. Anticholinergic agents such as tiotropium and ipratropium work to counteract these
effects.

Pulmonary vascular resistance (PVR) is lowest at the functional residual capacity Inhalation
increases PVR due to the pressure placed on pulmonary vessels by the expanding alveoli Forced
exhalation increases PVR due to the collapsing positive pressure placed on the lung parenchyma

Total body iron content is regulated through hepeidin’s effects on the absorption of dietary iron
by intestinal epithelial cells and the release of iron by macrophages

Hospitalized and postoperative patients are at risk for pulmonary embolism, which presents with
tachypnea, tachycardia, cough and pleuritic chest pain Hypoxemia in patients with pulmonary
embolism develops due to ventilation-perfusion mismatch

Erythrocytosis is defined as a hematocrit level > 52% in men and > 48% in women Measurement
of red blood cell mass is necessary to distinguish absolute from relative erythrocytosis. A normal
red blood cell mass indicates plasma volume contraction as the cause of polycythemia
215


pCO2 is the most potent cerebral vasodilator. It decreases cerebral vascular resistance leading to
increased cerebral perfusion and increased intracranial pressure. Patients with COPD usualty
have low p02 (hypoxia) and high pCO2 (hypercapnia). Thus their cerebral circulation is most
likely to be increased

Restnctive lung diseases are associated with decreased lung volumes, as well as increased
expiratory flow rates at the corresponding lung volumes. The expiratory flow rates are increased
due to decreased lung compliance (increased elastic recoil) and increased radial traction exerted
on the conducting airways by the fibrotic lung

Determining the difference between the alveolar and arterial P02 (A-a gradient) can help
determine the cause of hypoxemia The arterial PC2 is measured with an arterial blood gas
analysis, and the alveolar P02 is determined using the alveolar gas equation

Cystic fibrosis isa common autosomal recessive disease that usually results from a mutation in
the CFTR gene on chromosome 7. The CFTR protein is a transmembrane ATP-gated chloride
channel.

The methacholine challenge test can be used to induce bronchoconstnction in patients with
asthma, thereby allowing demonstration of the disease on spirometry Methacholine is a
muscarinic cholinergic agonist that acts by inducing bronchial smooth muscle contraction and
increased bronchial mucous production

Hypoventilation causes an increase in artenal pCO and a decrease in the serum pH (respiratory
acidosis). Acute respiratory acidosis presents with a low pH, a high pCO2 and a normal to mildly
increased HCO because renal compensation requires at least 24 hours of persistent respiratory
acidosis. Chronic respiratory acidosis is characterized by a low normal pH, a high pCO and a
high HCO; (> 30).

The pulmonary circulation is part of a continuous circuit with the systemic circulation The rate
of blood flow through the pulmonary circulation must equal the rate of blood flow in the
systemic circulation at all times The arterial pressures and oxygen contents of the pulmonary and
systemic arterial systems are considerably different both at rest and during exercise.

PaCO2 is the major stimulator of respiration in healthy people. Even a slight increase in PaCO2
results in increased pulmonary ventilation. In prolonged hypercapnia. however, high PaCO2
ceases to stimulate the respiratory drive, In such patients. respiration is stimulated by hypoxia
(low PaO) sensed by peripheral chemoreceptors. Rapid increases in the fraction of inspired
oxygen may lead to respiratory failure in these patients.

According to Laplace’s law, as the radius of a sphere with constant surface tension decreases, the
distending pressure increases: thus, smaller spheres collapse before larger ones Surfactant
counteracts alveolar collapse by decreasing surface tension as the alveolar radius decreases
216


In general, inhaled particles are cleared by epithelial cilia (present to the level of the terminal
bronchioles) via mucociliary clearance Mucus-secreting cells are present to the level of the
smallest bronchi

Perfusion increases significantly from the apex of the lung to the base, and ventilation increases
slightly from the apex to the base For this reason the VIQ ratio decreases from the lung apex to
the base

The combination of acute onset dyspnea. calf swelhng. obesity. and a history of prolonged
immobility is strongly suggestive of pulmonary ernbohsm A significant pulmonary embolism is
associated with hypoxemia and respiratory alkalosis.

The majority of total frictional airway resistance is localized to the medium and small-sized
bronchi greater than 2 mm in diameter in normal individuals. Regional airway resistance is
maximal in the second to fifth generation airways, including the segmental bronchi Airway
resistance is minimal in bronchioles

Reduction in the slope of the curve depicting lung volume versus distending pressure indicates
decreased lung compliance Decreased lung compliance is the hallmark of pulmonary fibrosis

There are four major causes of hypoxemia (low Pa02): alveolar hypoventilation, ventilation-
perfusion mismatch. diffusion impairment, and right-to-left shunting The A-a gradient is normal
in alveolar hypoventilation and helps to distinguish this from the other types of hypoxemia

Patients who receive the equivalent of more than one body blood volume (5-6 liters) of whole
blood transfusions or packed red blood cells over a period of 24 hours may develop elevated
plasma levels of citrate (a substance added to stored blood) Citrate chelates calcium and
magnesium and may reduce their plasma levels, causing paresthesias

Fibrinolytics may cause reperfusion arrhythmia on arterial re-opening These arrhythmias are
usually benign.

Dust particles smaller than 2 un in size reach the alveoli. They are taken up by macrophages and
stimulate connective tissue growth The pneumoconioses are diseases that result from the
inhalation of fine dust particles

In left ventricular failure. fluid accumulation in the lung interstitium results in decreased
compliance.

Carbonic anhydrase activity within erythrocytes forms bicarbonate from CO: and water Many of
the bicarbonate ions diffuse out of the RBC into the plasma To maintain the electrical neutrality
chloride ions diffuse into the RBC to take their place This process is called chloride shift, and it
is the principal cause of high RBC chloride content in venous blood.
217


PHYSIOLOGY-Renal+Reproductive+Urinary

Ureteral constriction or obstruction acutely decreases the GFR and glomerular filtration fraction

The renal blood flow (RBF) refers to the volume of blood that flows through the kidney per unit
time and can be calculated by dividing the renal plasma flow by (1 - hematocrit)

PAH (para-aminohippurate) is filtered at the glomerulus into Bowmans space and is
subsequently secreted into the nephron lumen by the proximal tubule. Thus, the lowest
concentration of PAH in luminal fluid is in Bowman’s space.

Due to ovarian failure, the majority of women with Turner syndrome can become pregnant only
by in vitro fertilization using donor oocytes Turner syndrome patients have a normal uterus and
so the endometrial response to estrogen and progesterone is norma[

Metabolic acidosis is normally partially compensated for by respiratory alkalosis When the
steady-state PaCO. persists above the range given by Winter’s formula (PaCO2 11 5 HCO] + 8 ±
2), the patient has a superimposed degree of respiratory acidosis and failure

Acid excretion in urine occurs in the form of free hydrogen ions and titratable acids (NH4 or
H2PO4 During
metabolic acidosis, excretion of free W and titratable acids increases, excretion of HCQ3
decreases, and urinary pH decreases.

Normal renal handling of plasma glucose is characterized by complete reabsorption of low
filtered loads at low plasma concentrations. Increasing fractional excretion of glucose is
observed at higher plasma concentrations.

Acute salicylate intoxication first causes an acute respiratory alkalosis If high doses are ingested,
this phase is soon followed by a superimposed metabolic acidosis due to organic acid
accumulation There may also be a slight metabolic alkalosis resulting from volume contraction
related to vomthng

The filtration fraction is the fraction of the RPF that is filtered across the glomerular capillaries
into Bowman’s space It can be calculated by dividing the GFR by the RPF The GFR can be
estimated with the creatinine clearance or inulin clearance, while the RPF is estimated with the
PAH clearanCe.

ADH acts primarily on the collecting ducts, increasing their permeability to water. In the
presence of ADH, the urine is at its most concentrated at the ends of the collecting ducts In the
absence of ADH, the tubular fluid is most concentrated at the junction between the descending
and ascending limbs of the loop of Henle

As the follicular phase advances, a progressive rise in serum estradiol is seen. High levels of
estrogen in the late follicular phase have a positive feedback effect on LH production, causing a
218


very high LH level, known as “LH surge” Progesterone secretion increases following ovulation
with the formation of corpus luteum.

As the foHicur phase advances, a progressive rise in serum estradiol is seen High levels of
estrogen in the late follicular phase have a positive feedback effect on LH production, causing a
very high LH level, known as “LH surge.” Progesterone secretion increases following ovulation
with the formation of corpus luteum.

Vasopressin produces a V2 receptor-mediated increase in permeability to water and urea at the
luminal membrane of the inner medullary collecting duct The increase in urea reabsorption
corresponds to a decrease in the fractional excretion of urea and a decrease in renal clearance of
urea from plasma

Regardless of the patient1s hydration status, the majority of free water reabsorption in the
nephron occurs in the proximal tubule passively with the reabsorption of solutes.

Antkliuretic hormone (ADH) acts on the meduftary segment of the collecting duct to increase
water reabsorption and concentrate the urine

End-stage renal disease causes hypocalcernia via renal retention of phosphate and decreased
renal synthesis of 1 ,25-dihydroxycholecalciferol vitamin D (calcitriol). Both hypocalcemia and
the resultant secondary hyperparathyroidism contribute to renal osteodystrophy

A Mallory-Weiss tear is a tear in the gastric mucosa near the gastroesophageal junction They are
typically the result of repetitive, forceful vomiting, which can lead to metabolic alkalosis

Aldosterone is a component of the renin-angiotensin-aldosterone system that acts on the
principal cells and intercalated cells of the renal collecting tubules to cause resorption of sodium
and water and loss of potassium and hydrogen ions

The net number of molecules diffusing across a semipermeable membrane per second is
proportional to the molecule’s concentration difference across the membrane, the total membrane
surface area, and the solubility of the substance Diffusion is inversely proportional to the total
membrane thickness and the molecular weight of the molecule

Inulin clearance can be used to estimate the GFR and to calculate the total filtration rate of a
freely filtered substance when the plasma concentration of the substance is known If the
substance is subsequently reabsorbed from the nephron lumen, then the net renal excretion rate
of the substance will be equal to its filtration rate minus the total tubular reabsorption rate

Brown adipose tissue is found in newborns and in hibernating mammals Brown adipose cells
contain several intracytoplasmic fat droplets and many more mitochondria than white adipose
cells They function to produce heat by uncoupling oxidative phosphorylation with the protein
thermogenin
219


Chronic renal failure is a common cause of secondary hyperparathyroidism. Typical laboratory
abnormalities include high PTH, low calcium, high phosphate. and low calcitriol.

Educational Objective: The concentrations of PAH. creatinine. inulin, and urea increase as fluid
wns along the proximal tubule, while the concentrations of bicarbonate, glucose, and amino acids
decrease

Paraaminohippuric acid (PAH) is freely tittered fr from
                                                     om the blood in the glomerular capillaries to
the tubular fluid in Bowman’s space. It is also secreted from the blood into the tubular fluid by
the cells of the proximal tubule by a carrier protein
                                              protein-mediated
                                                      mediated process. The secretion of PAl-I
                                                                                         PAl can
be saturated at high blood concentrations

Dehydration leads to a decrease in renal plasma flow (RPF) and a decrease in the glornewlar
filtration rate (GFR). Compensatory activation of the renin
                                                          renin-angiotensin
                                                                angiotensin mechanism in response
to hypotension leads to constriction ooff the efferent (outgoing) arteriole to maintain GFR as best
as possible The filtration fraction, which is equal to the GFR divided by the RPF, increases in
hypovolemia as the RPF drops proportionately more than the GFR due to the aforementioned
compensatory mechanism

Selective vasoconstnction of the efferent arteriole (up to certain extent) increases hydrostatic
pressure in the glomerular capillaries, and therefore increases the glomerular filtration rate As
efferent arteriolar constriction continues to increase, the glomerular filtration rate begins to
decrease due to a flow-mediated
                            mediated rise in oncotic pressure in the glomerular capillaries The
filtration fraction always increases with increasing efferent arteriole constriction.

Furosemide is a loop diuretic
                         etic that works by inhibiting Na
                                                       Na-K-2C1
                                                            2C1 symporters in the loop of Henle
effectively causing increased Na. Cl, and fluid excretion Additionally, loop diuretics also
stimulate prostaglandin release By stimulating renal prostaglandin release, loop diuretics also
                                                                                           al
increase renal blood flow leading to increased GFR and enhanced drug delivery Thus concurrent
use of NSAIDs with loop diuretics can result in a decreased diuretic response.



The filtration fraction (FF) can be calculated if the glomerular filtration rate (GFR), renal blood
flow (RBF), and hematocrit (Hct) are known: FF = GFR)j(1 - HctXRBF)].

Dehydration stimulates ADH secretion ADH acts on the collecting ducts, increasing their     t
permeability to water Thus, in the presence of ADH, the collecting ducts contain the most
concentrated fluid in the nephron, while the thick ascending limb of the loop of Henle and distal
convoluted tubule contain the most dilute fluid.

Increases inn the capillary hydrostatic pressure or the Bowman’s space oncotic pressure will
increase GFR, while increases in capillary oncotic pressure or Bowman’s space hydrostatic
pressure will decrease GFR The filtration fraction (FF) can be calculated by dMding the
                                                                                    t GFR by
the renal plasma flow (RPF). Increases in GFR or decreases in RPF will increase the FF.
220


The ascending limb of the loop of Henle is impermeable to water It is a site of reabsorption of
electrolytes by the Na/K/Cl cotransporter.

Human placental lactogen (hPL) increases insulin resistance. stimulates proteolysis and lipolysis,
and inhibits gluconeogenesis. Maternal insulin resistance results from increased secretion of
hPL, placental growth hormone, estrogens. progesterone, and glucocorticoids.

In secondary hyperaldosteronism. both rerun and aldosterone levels are elevated Causes of
secondary hyperaldosteronism include renovascular hypertension (typically associated with
fibromuscular dysplasia or atherosclerosis), diuretic use, malignant hypertension, and renin-
secreting tumors.

High circulating levels of estrogen and progesterone prevent lactogenesis while also promoting
breast growth and development during pregnancy.

Glucose is normally filtered at the glomerulus and completely reabsorbed by the proximal tubule
Inhibition of sodium..coupled. carriermediated transport of glucose by the proximal tubule would
cause the glucose clearance t approach the value of the GFR, which is typically estimated by
calculating the clearance of inulin.

Diabetic ketoacidosis (DKA) is characterized by the triad of polydipsia. polyuria, and a fruity
odor to the breath and/or urine DKA is associated with a high anion gap metabolic acidosis that
is typically accompanied by a compensatory respiratory alkalosis. This combination yields a low
pH, low serum bicarbonate, and low

The secretory phase of the menstrual cycle occurs from day 15 through day 28 of the normal
menstrual cycle (between ovulation and the onset of menses). Progesterone released by the
corpus luteum causes the utenne glands to coil and secrete glycogen-nch mucus. The endometrial
stroma becomes edematous and completely traversed by tortuous spiral arteries that extend from
the deeper layers to the uterine lumen