1

. \ANATOMY-Musculoskeletal

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

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

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.

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
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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

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.

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.

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.
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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

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”).

ANATOMY-Neurology

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

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
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superior cerebellar arteries. An aneurysm arising from either artery can lead to a non—pupilsparing
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.

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

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

A lesion in Wemicke’s area can cause receptive aphasia. which is characterized by wellarticulated,
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
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the oculomotor nerve.

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.

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 to sound (hyperacusis)

Long-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 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 amounts of white matter and more ovoid sections a Lower
cervical and lumbosacral regions have large ventral horns
a Thoracic and early lumbar sections (T1-L2) contain lateral grey matter homs

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 neurodevelopmental impairment.

The first arch can be poorly formed during embryonic development resulting in first arch
syndrome. Abnormalities include malformation 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 compression of the leg-foot motor area
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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 muscles, 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 administration 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.

ANATOMY-Rest-1
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 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.

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)
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The cricothyrotomy incision passes through the superficial cervical fascia. pretracheal fascia, and
the cncothyroid membrane

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.

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

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
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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

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

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)

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

Low-frequency sound is best detected at the apex of the cochlea near the helicotrema
Highfrequency 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 supplied by the short gastric arteries is
vulnerable to ischemic injury following splenic artery blockage
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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 mesentenc vesse1s

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

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 kidney

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

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.
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.

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 XI

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
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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

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

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
BEHAVIORAL-1

A temporary course of benzodiazepines 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-critical positions, as its short half-life
minimizes undesirable daytime side effects.

Among drugs of abuse. intoxication with hallucinogens (psychotomimetic drugs), amphetamines,

and cocaine 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).

Disorganized schizophrenia is distinguished by disorganized speech and behavior and a flat or inappropriate
affect.

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.

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
12

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

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 Memory impairment: Global in delirium vs. remote memory spared in dementia

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

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.

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

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.
13

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.

Bulimia nervosa can develop bilateral parotid gland enlargement, erosion of tooth enamel, and
irregular menses.

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.

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 erectIons.

When treating patients that are referred to you for specialty care or second opinions, it is 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 practitioner

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

Patient confidentiality is strongly protected 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
injuries, diagnosis of a reportable communicable disease, and when patients believably threaten to
physically harm themselves or others.
14

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.

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 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.

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.

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
15

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.

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.

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.

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)
16

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.

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

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

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
17

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.

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

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

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

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
18

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

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.

Cobalamin (Vitamin B12) deficiency results ii homocystinemia due to impaired methionine

resynthesis 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.

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.
19

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-DPG. These inflexible
erythrocytes predispose to microvascular occlusion and microinfarction

The PI3KJAkt)mTOR pathway is an intracellular signaling pathway important for anti-apoptosis,

cellular proliferation, and angiogenesis. Mutations in growth factor receptors. Akt 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 ö-aminolevuhnic acid and porphobdinogen Increased
formation of ö-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
(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 levels are high. Conjugated bihrubin is
water-soluble, non-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-threatening acute chest syndrome. and recurrent
abdominal and bone pain are clinical features of sickle cell anemia

The key functions of important apolipoproteins are as follows: ApoA-l:

LCAT activation (cholesterol esterification)
ApoB48: Chylomicron assembly and secretion by the intestine
ApoC-Il: Lipoprotein hpase activation
ApoE-3 & 4: VLDL and chytomicron remnant uptake by Irver cells

Fabry disease is an inherited deficiency of alpha-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 renal failure

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
20

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.

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

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

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 on
the heme iron of hemoglobin

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 increase 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.
21

Pyruvate kinase deficiency causes hemolytic anemia due to failure of glycolysis and resultant
failure to generate sufficient ATP to maintain erythrocyte structure. In this case, splenic
hypertrophy results from increased work of the splenic parenchyma, which must 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 in the Kozak sequence of the beta-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, 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) often have a mutation (V617F) in the cytoplasmic tyrosine kinase, Janus
kinase 2 (JAK2) This results in constitutive tyrosine kinase activity, and consequently,
cytokineindependent activation of STAT transcription factors.

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

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

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
22

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.

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

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

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
23

In patients with essential fructosura. metabolism of fructose by hexokinase to fructose-6phosphate is the

primary method of metabolizing dietary fructose: this pathway Es not significant in normal individuals.

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.

Fructose 2,6-bisphosphate activates glycolysis by inducing phosphofructokinase-1 and inhibits

gluconeogenesis by inhibiting fructose 1 ,6-bisphosphatase High concentrations of fructose
2,6bisphosphate also decreases the gluconeogenic conversion of alanine to glucose Fructose
2,6bisphosphate 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
24

elements, causing an alternation in the transcription of target genes xKnow the second messengers
very well

ATP is the regulatory substance that stimulates KATP channel closure in insulin-producing
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 are 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 decreased 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 coupled receptor that activates phospholipase C, the initial step
of the lP second messenger system involves degradation of membrane lipids 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 DNA probe vv

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

UV-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-acetylated histones and methylation both
contribute to the compact nature of heterochromatin and its transcnptionally inactive state

Colony-stimulating factors, prolactin, growth hormones and cytokines utilize tyrosine

kinaseassociated rtrtAr rvl th I /cTtT iw,nIenn nthiwu
25

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

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.

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

Splice site mutations frequently result in the production of larger proteins with altered function but
preserved immune reactivity.
26

Lynch syndrome is an autosomal dominant disease 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

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)

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.

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
27

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

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.

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 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.

BIOSTATISTICS 1

The chi-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

Confounding bias occurs when the exposure-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 increases with increasing disease prevalence and decreases with decreasing
disease prevalence
28

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.

Matching is used in case-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 based on the matchina variables, such that both arouos have a similar distribution
in accordance

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 is seldom a good idea, we round up to 67.

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.

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 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
29

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

Power(1-B) 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.

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

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)

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

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.

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
30

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.

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

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

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

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

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

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
31

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)

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

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 antiapoptotic 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.

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

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.

Turners syndrome manifests in the neonate with lyrnphedema

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
32

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 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.

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.

A variety of genetic disorders can result in facial and/or palatal malformations, including deletions
of the long arm of chromosome 22.

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.

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

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.

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.
33

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

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

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.

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

Friedreich ataxia is often associated with hypertrophic cardiomyopathy. diabetes mellitus.

kyphoscoliosis. and foot deformities

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

Alteration 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.

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
34

Koilocytosis is a hallmark of HPV infection. Koilocytes are pyknotic superficial or immature

squamous cells with a dense, irregularly staining cytoplasm and perinuclear clearing

LH 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

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

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).

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.
35

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)

IMMUNOLOGY 1

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
downregulate local cytokine production and inflammatory reactions contributing to the systemic
acute phase response IL-1, 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

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
36

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.

reactive arthritis is the most common cause of asymmetric inflammatory arthritis of the lower
extremities in young men 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

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.

Local defense 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.

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

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.
37

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,

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

Serum sickness result in vasculihs Associated findings include fever, urticaria, arthralgias,
glomerulonephritis. lymphadenopathy. and a low serum C3 level 510 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.

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
cellmediated 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.

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.
38

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

lgG antibody isotypes are effective in blocking the maternal immune response to ‘foreign fetal Rh
(0) antigens after fetomaternal transfusion

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.

The seronegative spondyloarthropathies include ankylosing spondylitis, reactive arthritis, psoriatic

arthritis and arthritis associated with inflammatory bowel disease.

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 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

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
39

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 Treatment is presently being researched using retroviral vectors to “infect’
patient stem cells with the gene coding for adenosine deaminase.

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

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.

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.

Langerhans cells are derived from the myeloid cell line and they possess characteristic
racquetshaped 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
40

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

Chronic granulomatous disease is an X-hnked disorder , enzyme responsible for formation of

reactive oxygen species in neutrophil phagolysosomes

Clinically, hyperlgM 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

Langhans 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.

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

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.

• 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.

CD1 9. CD2O and CD21 are B-cell surface markers

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
41

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 Tlymphocytes
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

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.
42

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.

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.

MICROBIOLOGY- Cardiology

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.

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
43

infarcts are almost always hemorrhagic due to the dual blood supply to the lungs (pulmonary and
bronchial arteries).

Viridans streptococc 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 is the most common cause of infective endocarditis in patients with
prosthetic valves and septic arthritis with prosthetic joints It is susceptible to novobiocin

C d,phtheriàe 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

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.

Streptococcus pneurnoniàe is bile soluble (unable to be cultured in bile) and optochin susceptible

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.

Rheumatic fever and acute post-streptococcal glomerulonephritis are the late sequelae of Group A
Streptococcal (Streptococcus pyogenes) infections Post-streptococcal glomerulonephritis can
44

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.

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 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.

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
45

painful inguinal lymphadenopathy and ulceration Histologically, LGV is characterized by

chlamydial inclusion bodies in the cellular cytoplasm.

Sjàponicum and S mansonicause intestinal and hepatic schistosomiasis, and S haematob,um causes
urinary schistosomiasis

S aureus septic arthritis is most common in children and non-sexually active adults

Recurrences of genital herpes can be reduced through daily treatment with oral valacyclovir.
acyclovir, or famciclovir, these drugs suppress reactivation of latent HSV infection.

ETEC that produces heat labile (LT, choleragenlike) 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.

Clostridium difficile 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 cru can destroy the myenteric plexi in the esophagus, intestines, and ureters, causing
secondary achalasia. megacolon, and megaureter, respectively

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

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 The diarrhea is inflammatory and is accompanied by fever, abdominal

pain and tenesmus Canoyhbacterinfection is associated with Guillain-Barré syndrome.
46

adult botulism results from consuming preformed toxin, typically in canned food Symptoms of
infant botulism include constipation, mild weakness. lethargy. and poor feeding.

The strain of Enterohemorrhagic E coh’(EHEC) 0157:H7 unable to ferment sorbitol and does not
produce a glucuronidase, 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.

C difhdlle 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
acidlabile 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.

Fever, vesiculoulcerative gingivostomatitis. and cervical lymphadenopathy are the most common
clinical manifestations of primary infection with herpes simplex virus (HSV-1). Reactivation 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.
47

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 beta 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

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
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

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.

Reassortment involves exchange of entire genome segments, a far more dramatic process than the
point mutations responsible for genetic drift
48

mucormycosis show broad nonseptate hyphae with nght angle branching. Treatment consists of
surgical debñdernent and amphotericin B.

The Thayer-Martin is a chocolate (i.e., heated blood) agar that contains vancomycin to inhibit the
growth of grampositive 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.

HSV-1 and other herpesviruses are enveloped and possess doublestranded DNA genomes

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

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.

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
49

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
replicationdefective 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 antiHBs
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
immunized at birth with hepatitis B immune globulin (HBIG), followed by active immunization
with recombinant HBV vaccine
50

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

Tetanus, 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

Enteroviruses, including coxsackievirus and echovirus, are the most common causes of aseptic
meningitis

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

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

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.

Spneumoniàe appears on Gram stain as lancet-shaped, Gram-positive cocci in pairs.

51

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.
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

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.

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)
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
52

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
1. 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.

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.

In order, the pathogens most often responsible for secondary bacterial pneumonia are
Streptococcus pneumoniàe, Staphylococcus aureus and Haemophiius ,hfluenzae.
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
Gramposrtive 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
53

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).
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 betahemolytic 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.
54

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.

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”

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:
a Nocard,ä species a
A spergillus species
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
antiribosomal 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.
55

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 pathogenicity of Hib 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
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

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

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
56

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 COPD, 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.

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

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.

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
57

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.

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

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.

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
nonenveloped, single-stranded DNA virus
58

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

betalactamase resistant antibiotics, because it has an altered penicillin binding protein in its
peptidoglycan cell wall that does not bind beta-lactams as effectively

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.

Salmonella, followed by E co/, is the most common cause of osteomyelitis in patients with sickle
cell anemia

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.

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.
59

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 P. 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 Gramnegative.
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”

PATHOLOGY

Cardiology 1
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

Neurapraxia resuLting in left vocal cord paresis and hoarseness may resuL

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
60

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.

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

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.
61

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

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
auscultation to detect a possible new-onset regurgitant murmur.

Extreme myofiber disarray with interstitial fibrosis on cardiac histology strongly suggests
hypertrophic cardiomyopathy (HCM)

A vanety of autosomal and sex chromosomal-inherited disorders are associated with

developmental cardiac and/or aortic defects or cardiac pathology. The major associations are as
follows
2. DiGeorge syndrome: tetralogy of Fallot and aortic arch anomahes
3. Marfan syndrome: cystic medial necrosis of the aorta
4. Tuberous sclerosis: valvular obstruction due to cardiac rhabdomyomas

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 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 circulations.

Unprovoked syncope in a previously asymptomatic 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-Nielsen syndrome — are thought to result from
mutations in a K channel protein that contnbutes to the delayed rectifier current (1K) of the cardiac
action potential.
62

The adult (postductal) type of congentaI aortic coarctation can pcesent with symptoms/signs of
hypertension in the arterial tree proximal to the coarctation, and of hypoperfusion of the lower
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
63

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.

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.

In Marfan 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.

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 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
64

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

Fibrinous or serofibrinous pencarditis is the most common form Peñcardial friction rub is the most
striking physical finding.

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

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.

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
65

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, 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)

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). 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.

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
without an overlying thrombus, but obstructing greater than 75% of the coronary artery lumen,
would likely cause only stable angina.
66

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.

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

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,
67

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 rightsided
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

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.

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
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[

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

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
68

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

BRAF is a protein kinase involved in activation of ságnaling pathways for melanocyte

proliferation, and the
BRAF V600E mutation is seen in 40-60% of patients with melanoma.

Herpes zoster (shingles) On light microscopy intranuclear inclusions in keratinocytes and

multinucleated giant cells are seen

Pemphigus vulgans is an autoimmune bullous disease characterized by autoantibodies directed

against desmosomal proteins 3 and 1

Acanthosis nigncans presents with thickening and hyperpigmentation of skin in the fiexural areas
The ‘esions have a classic “velvety’ texture.

Urticaria is characterized by superficial dermal edema and lymphatic channel dilation. No

epidermal changes are present.

Granulomatous inflammation is a form of chronic inflammation characterized by aggregates of

activated macrophages that assume an epithelloid appearance Persistent granulomatous
inflammation with subsequent fibrosis can cause organ dysfunction, which is seen in a number of
granuomatous diseases

Psoriasis 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-laden macrophages is most hkety

xanthelasma Cholestatic 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 immune response to M Ieprae.
69

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 associated 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 lesions are
the result of chronic sun exposure and thus affect sun-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 syndrome)

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 ACTH 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 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
markedlyreduced radioactive iodine uptake are diagnostic of granulomatous thyroiditis Mixed,
cellular infiltration with occasional multinucleate giant cells are characteristic histologic findings.

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

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
70

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

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.

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

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 two out of the three tumors should be evaluated for the presence of the third
tumor type.

Mononuclear, parenchymal infiltration with well-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 21-hydroxylase deficiency present at age 2-4 years with early
virilization, increased linear growth, and elevated levels of 17-hydroxyprogesterone and androgens
Females with classic 21-hydroxylase deficiency (with or without salt-wasting) present with
ambiguous 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.
71

Anorexic females commonly have low levels of LH, FSH, estradiol. and estrone
(hypogonadotropic amenorrhea).

Hypertension with low plasma rerUn activity is suggestive of primary hyperaldosteronism, a

condition biochemically characterized by hypokalernia and metabolic alkalosis

Activating mutations of the RET proto-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

Psammoma bodies and ground glass. grooved nuclei are characteristic microscopic features of
papillary cancer of the thyroid gland.

Medullary carcinoma of the thyroid gland is characterized by extracellular deposits of amyloid

formed by calcitonin secreted from neoplastic parafollicular C-cells.

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

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.

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
gramnegative 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.
72

Histologically, chonocarcinoma is composed of an abnormal proliferation of both cytotrophoblasts

and syncytiotrophob1asts No villi are present.

Gummas are necrotizing granulomas occumng on the skin, mucosa, subcutaneous tissue, bones,
and within other organs.

The simultaneous development of stroke. intestinal or foot ischemia, 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 for 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
fever and do not experience 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 disease Light microscopy shows cholesterol
emboli obstructing renal arterioles

Fibroadenomas are characterized by a cellular. often myxoid stroma that encircles and sometimes
compresses epithehum.-Iined glandular and cystic spaces

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 cyanidenitroprusside
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
cyanidenitroprusside test, which detects cyshne’s sulfhydryl groups, is diagnostic

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”)
73

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

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.

Hydronephrosis: 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

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.

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

74

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

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

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 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. Diverticula may be asymptomatic or may manifest with painless rectal
bleeding or acute diverticuhtis. Chronic constipation is a risk factor for this condition.

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
75

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

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

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 should
be used for diagnosis Banum contrast studies and colonoscopy are con(raindicated due to risk of
perforation

Most common symptom of Zollinger-Ellison syndrome, diarrhea, occurs due to the inactivation of
intestinal and pancreatic enzymes by excess gastric acid.

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.

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.
76

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.

The main manifestation of Crohns disease is abdominal pain. Diarrhea, low-grade fever, and
symptoms of malabsorption are also common.
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.

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.pylori infection: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
urea to carbon dioxide and ammonia and cause a pH increase and resultant color change of the pH
indicator, indicating alkahnization of the solution.
77

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

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

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

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

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 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

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
78

asymptomatic or may manifest with painless rectal bleeding or acute diverticulitis Chronic
constipation is a nsk factor for this condition.

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

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 Basal zone hyperplasia, elongation of lamina
propria papillae, and inflammatory cells (eosinophils, neutrophils and lymphocytes) are
characteristic histologic findings

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.

the involvement of all layers of the intestinal wall explains the most common complications of
Crohn’s disease stnctures and fistula formation

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

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

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

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
79

esophageal muscles Esophageal dilatation causes reflux, which increases the nsk of Barrett
esophagus and esophageal adenoc arc inoma,

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

Acute erosive gastropathy can be caused by a number of factors, including nonsteroidal

antiinflammatory 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.

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.

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.

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.

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
80

Wilsons disease 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 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)

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

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
81

young adults Acute hepatitis due to most hepatotropic viruses causes hepatocyte ballooning
degeneration and apoptosis on histologic exam

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

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.

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.

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
82

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

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.

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

Aspiration of hydatid cysts is generally inadvisable, as the spilling of cyst contents within the
peritoneum can cause anaphylactic shock.
83

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.

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.

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 sclerosing encephalitis 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

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.

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.
84

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

Guillain-.Barre syndrome 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

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.

Subarachnoid hemorrhage : 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.

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 highgrade
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.

Medulloblastoma 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.
85

Central pontine myehnolysis It manifests with spastic quadriplegia and pseudobulbar palsy.

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.

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: 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 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.

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.
86

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.

Severe vitamin E deficiency close’y resembles the clinical presentation of Friedreich ataxia

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.

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

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

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.

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.
87

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
procarcinogens 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.

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 Bcell
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

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

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.
88

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

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

ERBB2positMty 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.

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

Prognosis of colorectaladenocarcinoma is directly related to the stage of the tumor (not to the
grade!)

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

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
89

Integnn-mediated adhesion of cells to basement membrane and the extracellular matrix involves
the binding of integrins to fibronectin, collagen, and Iaminin

Kaposs sarcoma arises from primitive mesenchymal cells

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

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.

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.

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.

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.
90

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.

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
hernecontaining 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.

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.

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.
91

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

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.

Adenocarcinoma is 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.

Intermittent respiratory 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 proteinnch
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 Th1 and Th2 lymphocytes.
Environmental irritants, such as smoking, trigger bronchospasm in predisposed IndMduals
92

Fat embolism syndrome should be strongly suspected in a patient with severe long bone and/or
pelvic 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.

chronic panacinar emphysema. is preferentially localized to the lower pulmonary lobes.

Centnacinar emphysema has a predominantly upper lung lobe distnbution

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

TB: 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.
1ry: characterized by a Ghon complex, which consists of a lower lobe lung lesion (Ghon focus) and ipsilateral
hilar adenopathy

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.

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

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
93

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

Poststreptococcal glomerulonephntis: 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

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
4. Electron-dense deposits on the epithehal side of the basal membrane on electron
microscopy

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 highmolecular
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.
94

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
On light microscopic examination, there is glomerular crescent formation On immunofluorescence, linear
deposits of lgG and C3 along the glomerular basement membrane are characteristic

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 : 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.

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.

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

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.
95

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.

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.

Clomiphene. which is an estrogen receptor modulator that decreases negative feedback inhibition
on the hypothalamus by circulating estrogen and thereby increases gonadotropin production.
96

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

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

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.

• 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

Parvovirus arthritis can mimic rheumatoid arthritis, but is unique in that it is usually self resoMng

During wound heahng, excessive matrix metalloproteinase activity and myotibroblast

accumulation in the wound margins can result in contracture

Metaphysis of long bones are typic ally affected by hernatogenous osteomyehtis due to rich
vascularization and capdlary fenestrae
• 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.

Subperiosteal resorption with cystic degeneration is characteristic of hyperparathyroidism Vitamin

D deficiency result in “excessive unmineralized osteoid. resulting in low mineral densy.
97

Osteopetrosis is characterized by “the persistence of pnmary, unminerahzed spongiosa in the

medullary canals.”

In the case of hemolysis, haptoglobin levels decrease by binding to free hemoglobin, and the
complex is hepatically cleared

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

Anti-DNA topoisomerase I (Scl-70) antibodies are highly specific for systemic sclerosis.

The presence of rhomboid-shaped calcium pyrophosphate crystals is diagnostic of pseudogout

The histological hallmark of rickets is an increase in unminerahzed osteoid matrix and widened
osteoid seams.

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.

Shaken baby syndrome is the combination of subdural hematoma with bilateral retinal
hemorrhages in an infant

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
98

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.

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 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.

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.
99

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 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, strawberry type 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 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.

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.

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
100

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

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

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.

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,

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
101

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 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

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.

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-

angiotensinaldosterone 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 ccurs 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.
102

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.

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-
angiotensinaldosterone 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: a wave absent in patients with atrial fibrillatIon.
103

Calcification 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

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

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

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.
104

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 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.

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

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.

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.

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
105

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.

• 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.

Glucagon increases serum glucose by increased production of glucose from the liver 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 mediumsize
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).

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
106

low serum sodium levels and osmolality. Restriction of water intake normahzes unne output in
patients with primary polydipsia

Increase in TBG is typically seen m pregnancy, with use of oral contraceptives, or with hormone
replacement therapy

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

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

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

Although TSH is not elevated in patients with hypothyroidism in central hypothyroidism, central
hypothyroidism is uncommon.

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 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)
107

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.

Reperfuson injury is thought to occur secondary also to 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

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

In response to calcium loading. PTh decreases. cakitonin increases, and the renal synthesis of the
active form of vitamin D decreases

21-hydroxylase deficiency Male infants have normal genitalia and present later with salt-wasting
or precocious puberty.

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.

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.
108

11-hydroxylase deficiency typically results in excessive adrenal androgen and riNneralocorticoid

(11- deoxycorticosterone) production.

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

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 Sorbitol accumulates within some cells and attracts water into these
tissues leading to osmotic cellular injury

After vasectomy: Twenty percent of patients still have viable sperm in their ejaculate after 3
months and at least 20 ejaculations

Aromatase: 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
109

of inhibitory mechanisms exist to prevent premature activation of trypsin A gene mutation that
renders trypsinogen insensitive to inhibhon causes hereditary pancreat.tis

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

ygtutamyl transpeptidase.

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

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.

Frequently, hepatic encephalopathy is precipitated by a stressor that alters the ammonia balance
(eg, gastrointestinal bleeding)

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.
110

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 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

Sunlight exposure catalyses the first reaction in the chain of active vitamin D synthesist
7dehydrocholesterol 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

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.

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) 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.
111

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 CharcotLeyden
crystals. Eosinophils are recruited and activated by IL-5 secreted by T2 type helper Tcells

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. 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 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:

4 Physical inactivity
5. Caucasian race (immutable)
6. Aicohol use

Digestive disorders such as cholestasis can cause malabsoiption and nutritional deficiencies of the fat-soluble
vitamins
112

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 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

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

COPD can cause hypoxia sufficient to stimulate increased erythropoietin production by the cortical
cells of the kidney

PHARMACOLOGY

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
The bioavailabihty fraction = 1 if administered intravenously

1 Warfarin: 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.
113

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

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

Patients taking daály maintenance nitrates need to have a nitrate-free period every day to avoid
tolerance to the drug

Lidocaine 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
betaadrenergic 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.

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.

In this case, digoxin toxicity manifested as changes in color vision and anorexia Digoxin toxicity
can also cause ventricular dysrhythmias. headache, fatigue and confusion
114

Isoproterenol is an agonist at both 31 and 32-adrenergic receptors and has little or no aadrenergic
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: leading to AV nodal blockade (increased diastolic filling
time for greater contraction by the Frank-Starling mechanism) and increased contractility from
increased intracellular calcium

Using nitrates together with phosphodiesterase (PDE) inhibitors both increase intracellular cGMP
which causes vascular smooth muscle relaxation.

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 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 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.
115

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

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.

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.

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

Diuretics 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.

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-
116

proteincoupled 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.

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

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.

1. Adiponectin levels are low in type 2 diabetes, and treatment with TZDs increases the levels
of adiponectin.
117

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.

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.

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-
cireductase 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.

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.

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
118

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 with
peripheral antagonism of the effects of insulin, contnbutes to the development of hyperglycemia

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

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

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.

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.
119

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
glucoselowering 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 inhibit this
enzyme by binding covalently to its active site. The result is failed synthesis of the bactenal
peptidoglycan cell wall.
120

The mec hanism of varicomycin resistance in organisms such as VRE is a substitution of 0lactate
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

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:

121

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)

Proton pump inhibitors block the final common pathway of gastric acid secretion from panetal
cells, which is simulated by acetyicholine, histamine, and gastnn.
122

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 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
123

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.

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
124

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”

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
125

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
126

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

nonceruloplasmin-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.
127

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.
128

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
129

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. Nacetyl

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.
130

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 metabolic
alkalosas, which is a common side effect of most diurehcs other than the potassiumsparing 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
131

Antimuscarinic agents and antihistamines with antimuscarinic action are most effective for motion
sickness prevention.

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
sedativehypnotic 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
132

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.

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
133

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
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)
134

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
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
135

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.
Second-generation antihistamines htce fexofenadine have minimal sedative and antimuscannic
effects

1. Buspirone is a selective 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 agent that is useful in patients wrth a history of abuse of antianxiety
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 may precipitate acute closed-
angle glaucoma in susceptible individuals.

PHARMACOLOGY-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 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 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-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 rash.
2. The new anti.pil.ptic drugs
3. Rash In adult and pediatric patients treated with lamotngine
136

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.

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 betaadrenergic
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
sedativehypnotic 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
137

Remember — drugs that may cause seizures:

Bupropion (antidepressant)
Isoniazid (anti-tuberculosis drug, if given without pyridoxine)
Imipenem (antibiotic)
____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 tonicclonic
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.
138

Antimuscarinic agents and antihistamines with antimuscarinic action are most effective for motion
sickness prevention

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 works 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-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
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 clinical response is often de’ayed for up to 2
weeks of regular use and is not effective when used on an as-needed basis

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 saIivation)

.ILIl.ISI II V V.
Commonly used drugs such as the analgesic tramadol. the antiernetic ondansetron, and the
antibiotic linezolid can induce serotonin 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.
139

1 Antimuscannic agents are usually preferred in patients with medication-induced Parkinsonism

2. Levodopa is contraindicated for drug-induced Padansonism because it can precipitate psychosis
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.
140

Ampicillin is the treatment of choice for Listeria It is not sensitive to cephaIosporins Listena causes
disease in neonates and immunocompromised adults
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-formylderivative
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
141

discoloration with bleomycin use; congestive heart failure with doxorubicin; and hemorrhagic
cystitis with cyclophosphamide.
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
ATPdependent 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.
142

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.
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).
143

2. The pathophysiology of disseminated Mycobacterium avium complex disease in AIDS.

• The aminoglycoside streptomycin inhibits protein synthesis by inactivating the 30S (small)
ribosomal subunit
• 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
144

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.
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
145

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

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.
146

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
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.
147

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
148

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

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
agents) are associated with an increased risk of 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
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 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 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, and
conductance

References:

1 Sympathetic neural mechanisms in human cardiovascular health and disease.

2. N.ural control of the circulation.
149

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-i adrenergic receptors, and still higher doses produce
generalized vasoconstriction by an alpha-i adrenergc effect
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.
150

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
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.
151

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.

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.
152

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.

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 Kspanng
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:
153

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.
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.
154

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

pressurevolume 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
155

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.

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 reninangiotensin-
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
156

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.

Myocardial infarction causes a sharp decrease in cardiac output 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 tissue
(sinoatrial 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-response tissue), which can reduce 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-diastolic pressure
(LVEDP). Mitral stenosis elevates the LAEDP and PCWP relative to the LVEDP

Carrier-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-angiotensin-akiosterone

pathway and sympathetic nervous system results in increased afterload (from excessive
vasoconstnction), excess 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 rate or rhythm or the force of ventricular contraction may
cause palpitations. An irregularly irregular tachyarrhythmia in a conscious patient is most likely
157

atrial fibrillation, the most common chronic arrhythmia In AF. the EKG shows absent p waves and
irregularly spaced ventricular contractions evidenced by a variable 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.
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 Ltype 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
158

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
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.
159

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.

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
160

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

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 betaendorphin 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
161

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
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
162

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

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
163

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).

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 wellventilated
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.
164

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

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.
165

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

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).
166

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

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,
ventilationperfusion 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
167

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.

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.
168

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
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
169

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

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 from 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-mediated process. The secretion of PAl-I 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-angiotensin mechanism in response to
hypotension leads to constriction of 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
170

efferent arteriolar constriction continues to increase, the glomerular filtration rate begins to
decrease due to a flow-mediated rise in oncotic pressure in the glomerular capillaries The filtration
fraction always increases with increasing efferent arteriole constriction.

Furosemide is a loop diuretic that works by inhibiting Na-K-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 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
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 in 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 GFR by
the renal plasma flow (RPF). Increases in GFR or decreases in RPF will increase the FF.

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
reninsecreting 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.
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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