ANATOMY-Musculoskeletal The radial nerve is responsible for extension of the hand Damage to the radial nerve results in wrist drop The musculocutaneous nerve innervates the flexor muscles of the upper arm and provides sensory innervation to the lateral forearrn The musculocutaneous nerve is derived from the upper trunk of the brachial The musculocutaneous nerve innervates the flexor muscles of the upper arm and provides sensory innervation to the lateral forearm The musculocutaneous nerve is derived from the upper trunk of the brachial plexus and can be injured by forceful injuries that cause separation of the neck and shoulder Muscles used when sitting up from the supine position include the external abdomirSc frd abdominis, and the hip flexors The ihopsoas muscle is the most important of the hip fiexors and inctudes the psoas major, psoas minor, and iliacus The rectus femoris. sartorius, tensor fascia lata, and the medial compartment of the thigh also conthbute to hip flexion Flattening of the deftoid muscle after a shoulder injury suggests anterior shoulder dislocation This injury most commonly results from forceful external rotation and abduction at the shoulder joint. Axillary nerve injury, resulting in deltoid paralysis and loss of sensation over the lateral arm, is often associated. The most commonly injured structure in rotator cuff syndrome is the tendon of the supraspinatus muscle. Because thearm supraspinatus is an abductor of the humerus, injury to its tendon causes pain on abduction of the Injections given in the superomedial part of the buttock risk injury to the gluteal nerves: Injections given in the inferomedial part of the buttock risk injury to the sciatic nerve The superolateral quadrant of the buttock is a safe site for intramuscular injections. Lesions of the femoral nerve can occur due to trauma. nerve compression. stretch Injury, or ischemia Patients develop weakness of the quadriceps muscle, loss of the patellar reflex, and loss of sensation over the anterior and medial thigh and medial leg. The median nerve courses between the humeral and ulnar heads of the pronator teres muscle and then runs between the flexor digitorum superficialis and the flexor digitorum profundus muscles before entering the wrist and hand within the carnal tunneL The supraspinatus muscle assists in abduction of the arm and stabilization of the glenohumeral joint The mostmuscle commonly injured isstructure in rotator cuffdue syndrome is the tendon of the the supraspinatus This tendon vulnerable to injury to impingement between acromion and the hemurus
Trauma or sustained pressure to the neck of the fibula can cause injury to the common peroneal nerve as it courses superficially and laterally to this structure The tibial nerve innervates the flexors of the lower leg. the extrinsic digital flexors of the toes, and the skin of the sole of the foot. 1) Injury to the superior gluteal nerve causes weakness of the gluteus medius and gF’.iI$ceen Wridow Sq Shape producing a positive Trendelenburg tea 2) The inferior gluteal nerve innervates the gluteus maximus muscle Injury of the inferior gluteal nerve causes difficuLty rising from the seated position and climbing stairs The deep brachial artery and radial nerve course along the posterior aspect of the humerus Mdshaft fractures of the humerus risk injury to these structures. Supracondylar fractures are associated with injury to the brachial artery The posterior cruciate ligament prevents posterior displacement of the tibia relative to the femur It srcinates from the anterolateral surface of the medial femoral condyle and inserts into the posterior intercondylar area of the tibia Its integrity can be tested in the clinical setting by using the posterior drawer test The psoas muscle srcinates from the anterior surface of the transverse processes and lateral surface of the corresponding vertebral bodies T12-L5 The psoas muscle acts primarily to flex the thigh at the hip It contributes somewhat to lateral rotation and abduction of the thigh as well The anterior cruciate ligament (ACL) can be damaged by forceful anterior motion of the tibia with respect to the femur. Ulnar nerve injury classically causes a “claw hand” deformity. The ulnar nerve can be IrIjUreCt either near the medial epicondyle of the humerus or in Guyon’s canal near the hook of the hamate and pisiform bone in the wrist. Sudden upward stretc[ng on the arm at the shoulder can damage the lower trunk of the brachial plexus. This trunk carries nerves from the C8 and Ti spinal levels that ultimately form the median and ulnar nerves These nerves innervate all of the inthnsic muscles of the hand. Mastectomy is a commonly tested cause of long thoracic nerve injury, but any trauma or surgery in the axitfary region is at risk of damaging this nerve. Injury to this nerve causes winging of the scapula and inability to abduct the shoulder past 90 degrees. The common peroneal nerve is vulnerable to injury where it courses around the nec F. creWi - Sc neck fractures can lesion this nerve, causing weakness of dorsiflexion (deep peroneat nerve) and eversion (superficial peroneal nerve) of the foot as well as loss of sensation over the dorsum of the foot. Inversion and plantarfiexion would remain intact due to the action of the tibial nerve.
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 srcinates on the medial clavicle and manubrium and inserts on the mastoid process of the skull. It is innervated by CN Xl and functions to turn the head in the opposite direction. The serratus anterior muscle serves to fix the scapula against the posterior chest watt and rotate the scaputa to allow abduction of the arm over the head Paralysis of this muscle occurs with injury to the long thoracic nerve and results in winging of the scapula. The Valsalva maneuver increases vagal tone and can be used to abolish paroxysmal supraventncular tachycardia. The rectus abdominis is the most important muscle in achieving the increased intraabdominal and intrathoracic pressure of the Valsalva maneuver. The obturator nerve is the only major nerve that exits the peMs through the obturatorforamen This nerve supplies the muscles of the medial (adductor) compartment of the thigh and can be damaged dunng pelvic surgery, especially in procedures such as lymph node dissection The posterior cruciate ligament prevents anterior displacement of the femur relative to the tibia when the knee is flexed. It attaches to the posterior part of the intercondylar area of the tibia and the anterior part of the lateral surface of the medial epicondyle of the femur. Fall on an outstretched hand may cause fracture of the scaphoid bone Examination anatomical snuff box The scaphoid bone is vulnerable to avascular necrosis and nonuñian due to as tenuàii blood supply Repeated and prolonged kneeling can cause prepatellar bursitis Dubbed housemacfs kne&’ today it is most commonly seen in roofers, carpenters and plumbers Signs and symptoms of prepatellar bursitis include knee pain, erythema. swelling and inability to kneel on the affected side Improperly fitted crutches can cause radial nerve injury, resulting in weakness of all forearm, wrist and finger extensors (“wristdrop”).
ANATOMY-Neurology The ventromedial hypothalamic nuclei contain the satiety center and regulate food intake Lesions of the ventromedial nuclei result in obesity secondary to hyperphagia as well as aggressive, savage behavior The third branch of the trigerninal nerve (CN V3) exits the skull through the foramen ovale and innervates the muscles of mastication. including the masseter. the medial and lateral pterygoids, and the temporalis muscles. Trochlear nerve palsy is charactenzed by vertical diplopia Common peroneal nerve injury is common and typically results from trauma to the leg near the head of the fibula Signs include foot drop and a characteristic high-stepping gait The posterior cerebral artery branches off the basilar artery and supplies cranial nerves Ill and IV and other structures in the midbrain It also supplies the thalamus, mesial temporal lobe, splenium of the corpus callosum, parahippocampal gyrus, fusiform gyms, and occipital Iobe The combination of fixed segmental loss of upper extremity pain and temperature sensation, upper extremity lower motor neuron signs, and/or lower extremity upper motor neuron signs in the setting of scoliosis suggests a diagnosis of syringomyelia. Lesions of the glossopharyngea nerve result in loss of the gag reflex (afferent limb), loss of sensation in the upper pharynx, posterior tongue. tonsils. and middle ear cavity, and loss of taste sensation on the posterior one-third of the tongue The third cranial nerve (oculomotor) carrying general somatic efferent fiber and general visceral efferent parasympathetic fiber exits the midbrain and courses between the posterior cerebral and superior cerebellar arteries. An aneurysm arising from either artery can lead to a non—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. The tight junctions between endothelial cells in the capillary beds of the CNS form the bloodbrain barrier Solutes and fluids cannot move freely across the capillary membrane in the CNS material can only move transcellularly by diffusing across the epithehal plasma membranes or by carrier-mediated transport The thalamic syndrome is characterized by total sensory loss on the contralateral skie of the body Although there are no motor deficits, proprioception is often profoundly affected and may lead to difficulty ambulating and falls. Lacunar infarctions are the result of small vessel lipohyalinosis and atherosclerosis invoMng the penetrating vessels supplying the deep brain structures Uncontrolled hypertension and diabetes mellitus are risk factors for this condition
Neurofibromatosis Type I (NFl. or von Recklinghausens disease) is a common autosomaldominant disorder resulting from a defect in the NF-l gene on chromosome 17. Cutaneous and subcutaneous neurofibromas are common in this condition and are tumors of Schwann celIs which are embryologicalty derived from the neural crest. Upper motor neuron lesions cause spastic rigidity, hyperreflexia. and paresis Corticospinal tract, internal capsule (posterior limb), and primary motor cortex lesions can cause these symptoms Injury to Meyer’s loop in the temporal lobe results in contralateral superior quadrantanopia A lesion in Wemicke’s area can cause receptive aphasia. which is characterized by 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 the oculomotor nerve. When an optic nerve is damaged. light in that eye will cause neither pupil to constrict (the nerve can’t sense the light). However, light in the contralateral eye will cause both pupils to constrict (because the motor pathways are intact). Lesions involving CN Ill cause ptosis. a downward and laterally deviated eye, impaired pupillary constriction and accommodation, and diagonal diplopia The most dreaded cause of CN Ill palsy is an enlarging intracranial aneurysm. A lesion in the optic tract can produce contralateral homonymous hemianopia and a relative afferent pupillary defect (Marcus Gunn pupil) in the contralateral eye.
The stapedius muscle is innerv ted by the stapedius nerve, a branch of facia nerve (CN Vll) Paralysis of the st apedius muscl e allows wider oscillation of the stapes. and l ads to increased sensitivity to sound (hyperacusis ) Hydrocephalus in infants prese ts with irritability, poor feeding. increased he d circumference and enlarged ventricles on CT Long-term sequelae of hydrocephalus include lower extremity spasticity due to stretching of the periventncular pyramidal tracts, visual isturbances, and learning disabilities. General features levels that aidhave in loca a More proximal inc a Lower cervical and lumbosacr a Thoracic and early lumbar sect
zing a transverse section: easing amounts ofspinal whitecord matter and more ovoi sections l regions have large ventral horns ions (Ti -L2) contain lateral grey matter horns
General features that aid in local izing a transverse spinal cord section: a More proximal levels have inc easing amounts of white matter and more ovoi sections a Lower cervical and lumbosacr l regions have large ventral horns a Thoracic and early lumbar sect ions (T1-L2) contain lateral grey matter homs The head of the caudate lies in t e inferolateral wall of the anterior horn of the l ateral ventricle It is separated from the globus allidus and putamen by the internal capsule. The caudate is atrophied in Huntington’s diseas . Neonatal intraventncular hemorr hage usually occurs in the fragile germinal mat rix and increases in frequency with decreasing ag e and birth weight It is a common complicati n of prematurity that can lead to long-term neuro
evelopmental impairment.
CSF flows from the third ventric le to the fourth ventricle via the cerebral aqued ct of Sylvius. Sciatica is a painful condition c that typically results from impi column. Compression of the Si leg as well as diminution of the
haracterized by shooting pain down the poster ior thigh and leg ngement of one of the spinal nerves as it lea ves the vertebral oot results specifically in pain purely in the p sterior thigh and nkle jerk reflex.
Thiamine (ie., vitamin B1)defici ency acutely leads to Wemicke encephalopath and chronically leads to Korsakoff psychosis. he neural structure most frequently affected in patients with Wernicke encephalopathy is the mammillary body, which is part of the Papez circuit Alcoholic or malnourished patients sh uld receive intravenous thiamine supple entation before intravenous dextrose administ ation because giving dextrose without pri r thiamine can precipitate a Wemicke encephaI pathy
General sensation from the anter ior 2/3 of the tongue is carñed by the mandibul ar division of the trigeminal nerve Gustatory inn rvation of anterior 2/3 of the tongue is pro vided by chorda tympani branch of the facial The first arch can be poorly ormed during embryonic development result ing in first arch syndrome. Abnormalities inclu de malformation of the mandible. maxilla. malleus, incus, zygoma, vorner, palate, and tem oral bone. The first arch is associated with the rigeminal nerve. Wilson’s disease can cause cysti c degeneration of the putamen as well as dam ge to other basal ganglia structures. The putamen is located medial to the insula and lateral to th e globus pallidus on coronal sections. Meningiomas are located adja ent to the cerebral surface, Parasagittal me ningiomas cause contralateral spastic paresis of th e leg due to compression of the leg-foot motor rea Motor (Broca) aphasia is a non fluent aphasia that results from damage to Br oca’s area in the inferior frontal gyrus of the d minant hemisphere. Patients understand lang uage but cannot properly formulate the motor co mands to form words or write. Speech is slow and fragmented, with short agrammatic phrases. ord-finding difficulty is often prominent Pati ents have insight into their aphasia and are often f ustrated by it. Saddle anesthesia and loss of th anocutaneous reflex are symptoms of cauda quina syndrome, which is associated with damage to the S2 through S4 nerve roots Ulnar nerve injury causes sensati on loss to the medial 11/2 digits of the hand. Sensorineural heanng tinnit us. Viii. paralysis of facial muscles, and loss of com signify the involvement of CNloss. V, Vii, a nd Simultaneous compression of these ne eal vesreflex is caused by tumor of the cerebeliopontine an gle. which are most commonly acoustic neurom as
Acute nausea following adminis ration of systemic chemotherapy results from s timulation of the chemoreceptor trigger zone (CT ), which lies in the area postrema of the dorsal medulla near the fourth ventricle.
ANATOMY-Rest-1 The right testicular vein drains directly into the IVC while the left testicular vein drains into the left renal vein. The proximal 1/3 of the ureter receives its blood supply from branches of the renal artery For this reason, this portion of the donor ureter is typically viable after renal transplantation Conductive hearing loss (bone conduction > air conduction): abnormal Rinne test (in affected ear) and Weber test localizes to affected ear Sensorineural hearing loss (air conduction> bone conduction): normal Rinne test and Weber test localizes to unaffected ear. The oculomotor nerve (ON Ill), ophthalmic nerve (CN V1) branches, trochlear nerve (ON IV), abducens nerve (ON VI), and superior ophthalmic vein enter the orbit via the superior orbital fissure
The gastroduodenal artery lies along the posterior wall of the duodenal bulb and is likely to be eroded by posterior duodenal ulcers Ulceration into the gastroduodenal artery can be a source of life-threatening hemorrhage. Aneurysm or atherosclerotic calcification of the internal carotid artery can laterally impinge on the optic chiasm. This can cause nasal hemianopia by damaging uncrossed optic nerve fibers from the temporal portion of the ipsilateral retina. Indirect inguinal hernias are located lateral to the inferior epigastric vessels They can continue into the scrotum and are felt by deep palpation of the external inguinal ring with the tip of the finger In contrast, direct inguinal hernias are located medially to the inferior epigastric vessels. They do not protrude into the scrotum and are best felt with the pulp of the flnger All skin from the umbilicus down. including the anus (up to the dentatelpectinate line) but excluding the posterior calf, drains to the superficial inguinal lymph nodes The spleen is not a gut denvative: it forms from the mesodermal dorsal mesentery The splenic artery, however, is a branch of the celiac trunk (the primary blood supply of the foregut) Cncothyrotomy is indicated when an emergency airway is required and orotracheal or nasotracheal intubation is either unsuccessful or contraindicated The cricothyrotomy incision passes through the superficial cervical fascia. pretracheal fascia, and the cncothyroid membrane In addition to unilateral facial patientsover withtheBells palsy may experience decreased tearing, hyperacusis, and/or loss paralysis, of taste sensation anterior two-thirds of the tongue
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 partvessels; of the and duodenum the left ligament. kidney, aorta. IVC and superior mesenteric also by by the its tailbody lying overlying in the splenorenal The recurrent laryngeal nerve travels in close approximation to the inferior thyroid artery and can be injured in surgical procedures of the anterior neck (e.g thyroidectomy), resulting in laryngeal muscle paralysis, hoarseness and dyspnea. The left gonadal (testicular or ovarian) vein drains into the left renal vein. commonly leading to left-sided vancoceles in males with obstructions of the left renal vein The right gonadal vein drains directly into the inferior vena cava The nerves and vessels supplying the ovary are delivered through the suspensory ligament of the ovary. Gallstone ileus results from the passage of a large gallstone (typically greater than 25 cm) through a cholecystenteric fistula into the small bowel where it ultimately causes obstruction at the ileocecal is seenand within the gallbladder and signs biliaryand treesymptoms on abdominal X-ray bowel due to the presence valve. of theGas fistula, patients present with of small obstruction. The brachiocephalic vein drains the ipsilateral jugular and subclavian veins. The bilateral brachiocephalic veins combine to form the SVC. Brachiocephalic vein obstruction causes symptoms similar to those seen in SVC syndrome, but on just one side of the body. The lesser omentum is a double layer of peritoneum that extends from the liver to the lesser curvature of the stomach and the beginning of the duodenum it is divided into the hepatogastnc and hepatoduodenal ligaments Femoral hernias are inferior to the inguinal ligament lateral to pubic tubercie, and medial to the femoral vein. They can present with groin discomfort or manifest with a bulge on the upper thigh Incarceration and strangulation are common complications of fernoral hernias The esophagus is located between the trachea and the vertebral bodies in the superior thorax It is typically collapsed with no visible lumen on CT images of the chest
Injury to the posterior urethra is associated with pelvic fracture whereas anterior urethral injury most commonly occurs in straddle injuries Inability to void with a sensation of a full bladder, a high riding boggy prostate, and blood at the urethral meatus are all suggestive of urethral injury particularly in the presence of a pelvic fracture. A retrograde urethrogram should be performed before Foley catheter placement if there is concern for a urethral injury The hindgut encompasses the distal 113 of the transverse colon, the descending colon, the sigmoid colon, and the rectum These structures receive their main arterial blood supply from the inferior rnesentenc artery Direct hernias occur most commonly in older menmedial and are caused by epigastric weakness vessels, of the transversalis fascia in Hesselbach’s triangle They are to the inferior protrude only through the external inguinal ring, and are covered by the external spermatic fascia In cirrhosis, portal hypertension arises from increased resistance to portal flow at the hepatic sinusoids This causes increased pressure in the portosystemic collateral veins within the lower end of esophagus, anterior abdomen, and lower rectum Dilation of these collaterals is responsible for the esophageal varices, caput medusae, and hemorrhoids commonly seen in cirrhotic patients The middle meningeal artery is a branch of the maxillary artery that enters the skull at the foramen spinosum and courses intracranially deep to the pterion. Skull fractures at this site may cause laceration of this vessel, leading to an epidural hematoma A branch of the mandibular division of the tngerninal nerve (CN V3) provides somatic sensory innervation to the anterior 2/3 of the tongue. The chorda tympani branch of the facial nerve provides taste sensation from the anterior 2/3 of the tongue. The glossopharyngeal nerve (CN IX) provides somatic sensory and taste innervation to the posterior portion of the tongue. Cardiovascular dysphagia can result from pressure on the esophagus by a dilated left atrium The left atrium is commonly enlarged in patients with mitral stenosis and left ventricular failure The great majority of gastric ulcers occur over the lesser curvature of the stomach, at the border between acid-secreting and gastnn-secreting mucosa The left and right gastric arteries run along the lesser curvature and are likely to be penetrated by ulcers. causing gastric bleeding. Testicular hydrocele results when serous fluid accumulates within the tunica vaginalis. The tunica vaginalis is embryologically derived from the peritoneum, when it remains in communication with the peritoneum, a communicating hydrocele results. Retroperitoneal hematoma in a stable patient is likely to occur due to pancreatic injury It may present with mild symptoms, be asymptomatic or be masked by symptoms from other injuries related to trauma Abdominal CT is the diagnostic modality of choice. Frequently nonexpanding hematomas in this location will be treated conservatively (ie. non-operatively)
Due to its intra-abdominal origi n. lymphatic drainage of the testis is to the p ara-aortic lymph nodes. In contrast, lymph drain age from the scrotum goes into the superficia l inguinal lymph nodes The pupillary light reflex is asse sed by shining light in an eye and observing th response in that eye (direct) and the opposite e e (consensual). The optic nerve (CN U) is re ponsible for the afferent limb of the pupillary r flex, and the oculomotor nerve (CN Ill) is re ponsible for the efferent limb Low-frequency sound is best d tected at the apex of the cochlea near the h
licotrema High-
frequency sound is best detected at the base ofdthe windOws. cochlea near the oval and rou The external branch of the super ior laryngeal nerve is at risk of injury during th yroidectomy due to its proximity to the superior thyroid artery and vein This nerve innervates the cricothyroid muscle The splenic artery originates fro the celiac artery and gives off several branch s to the stomach and pancreas (pancreatic, short gastric, and left gastroepiploic arteries) before finally reaching the spleen Due to poor anasto oses. the gastric tissue supplied by the short astric arteries is vulnerable to ischemic injury fol lowing splenic artery blockage BPH is a common, age-related condition that causes urinary symptoms and an be medically treated with aa drenergic block rs or 5-ci reductase inhibitors. The prostate is located between the pubic symphysis and the ana canal in inferior sections of the pelvis on CT s an.
The third part of the duodenum ourses horizontally across the abdominal aorta and inferior vena cava at the level of the third lu bar vertebra. Here it is in close association ith the uncinate process of the pancreas and the s uperior mesentenc vesse1s Prolonged exposure to loud noi es causes hearing loss due to damage of the s cells of the organ of Corti
tereociliated hair
ANATOMY-Rest-2 In horseshoe kidney, both kidn ys are fused together at the poles in early em bryonic Iife The isthmus of horseshoe kidney usu ally lies anterior to the aorta and inferior vena c ava and posterior to the inferior mesentenc arter This centrally located isthmus becomes tra pped behind the inferior mesentenc artery during the relative ascent of the kidney The inferior vena cava is forme d by the union of the right and left common iliac veins at the level of L4-L5. The renal arterie s and veins lie at the level of Li. The IVC retu rns venous blood from the lower extremities, port l system and abdominal and pelvic viscera to t e right atrium of the heart
The inferior vena cava is formed by the union of the right and left common iliac veins at the level of L4-L5. The renal arteries and veins lie at the level of Li The IVC returns venous blood from the lower extremities, portal system and abdominal and pelvic viscera to the right atrium of the heart A penetrating injury at the left sternal border in the fourth intercostal space would puncture the anterior surface of the heart The right ventricle composes most of the hearts anterior surface The left ventncle forms the apex of the heart and reaches as far as the fifth intercostal space at the midclavicular lineofAll chambers lie medial to the left midclavicular Iine Theleft lungs overlap much theother anterior surfaceofofthe theheart heart. The coronary sinus communicates freely with the right atrium and therefore may become dilated secondary to any factor that causes right atrial ddatation The most common such factor is pulmonary artery hypertension, which leads to elevated right heart pressures. The left atrium forms the majority of the postenor surface of the heart and resides adjacent to the esophagus. Enlargement of the left atnum can compress the esophagus and cause dysphagia. The descending thoracic aorta lies posterior to the esophagus and the left atrium. This position permits clear visualization of the descending aorta by transesophageal echocardiography, allowing for the detection of abnormalities such as dissection or aneurysm. Aspirated or inhaled particles are most likely to become lodged in the right main bronchus or its branches because this bronchus is shorter, wider and more vertically oriented than the left main bronchus. Aortic rupture is most commonly due to motor vehicle accidents, and the most common site of injury is the aortic isthmus, which is the connection between the ascending and descending aorta distal to where the left subclavian artery branches off the aorta Lesions of the jugular foramen can result in jugular foramen (Vernet) syndrome, which is characterized by the dysfunction of CN IX, X, and XL The lung apices extend above the level of the clavicle and first rib through the superior thoracic aperture. Penetrating injury in this area may lead to pneumothorax Lymph from the testes drains through lymph channels directly back to the para-aortic lymph nodes. In contrast, lymph from the scrotum drains to the superficial inguinal lymph nodes. The internal laryngeal nerve mediates the afferent limb of the cough reflex above the vocal cords Foreign bodies (eg, chicken or fish bones) can become lodged in the piriform recess and may cause damage to the nerve, impairing the cough reflex
Thoracocentesis should be performed above the 7 rib in midclavicular line, the 9 rib along midaxillary line and the 1 1’ rib along posterior scapular hne Insertion of a needle lower than these points increases the risk of penetrating abdominal structures, and insertion of the needle on the inferior margin of the rib risks striking the subcostal neurovascular bundle The chest x-ray in acute left ventricular failure with pulmonary edema shows cardiomegaly (heart> I hemithorax in size), pleural effusions, Kerley B lines, and increased vascular shadowing (alveolar edema) bilaterally. Left ventricular leads in biventricular pacemakers course through the coronary sinus, which resides in the atrioventncular groove on the posterior aspect of the heart The inferior wall of the left ventricle forms most of the diaphragmatic surface of the heart The posterior descending artery supplies this area In 85-90% of individuals, the posterior descending artery derives from the right coronary artery Irntaton of the mediastinal or diaphragmatic panetal pleura wiN cause sharp pain, worse on inspiration, in the C3-C5 distribution. Pain sensation from these areas is carned by the phrenic nerVe. The left kidney lies immediately deep to the tip of the 1 2th rib on the Ieft The arrow on the chest X-ray above points to the right atiium On postero-antenor (PA) chest Xray projections, the right atrium composes most of the right side of the cardiac silhouette The right atrium superior and receives inferior venous blood from the superior and inferior vena cavae, which compose the 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 srcinates on the medial side of the foot, courses anterior to the medial mafleolus and then traveis up the medial aspect of the leg and thigh It drains into the femoral vein within the region of the femoral triangle, a few centimeters inferolateral to the pubic tubercle. The portal vein can be identified on cross-sectional scans lying medial to (or just within) the right lobe of the liver and anterior to the inferior vena cava. The pressure in the portal system is elevated in liver cirrhosis. A pudendal nerve block can be performed by injecting anesthetic intravaginally in the region of the ischial spine Blocking the pudendal nerve provides anesthesia to the majority of the perineum
additional blockade of the genitofemoral and ilioinguinal nerves would provide complete penneal and genital anesthesia Apical lung tumors are called Pancoast tumors Pancoast tumors can cause Homer syndrome, SVC syndrome, arm weakness, arm paresthesias, and hoarseness The inferior vena cava courses through the abdomen and interior thorax in a location anterior to the right half of the vertebral bodies. The renal veins join the PlC at the level of L1112, and the common iliac veins merge to become the IVC at the level of L4 An early systolic best heard over the left lower sternal border that is accentuated by inspiration is most murmur likely due to tncuspid regurgitation
BEHAVIORAL-1 Schizoaffective disorder is cha racterized by symptoms of schizophrenia in the presence of prominent mood symptoms A pe riod of at least 2 weeks of psychotic symptoms in the absence of mood symptoms is required for t he diagnosis. A temporary course of benzodi zepines is sometimes used during the SSRI i itiation period if there is a significant increase in anxiety related symptoms. Triazolam is a be zodiazepine that can be useful for treating insom ia in patients employed in mission-critical posi tions, as its short half-life minimizes undesirable aytime side effects. Obstructive sleep apnea is the ost common medical cause of excessive dayti me sleepiness in the US It occurs due to poor ropharyngeal tone and results in daytime sle piness, morning headaches, and depression Obstructive sleep apnea is the ost common medical cause of excessive dayti me sleepiness in the US It occurs due to poor ropharyngeal tone and results in daytime sle piness, morning headaches, and depression The hallmark of generalized an xiety disorder is excessive worry over severa l different issues lasting at least 6 months. It is tre ated with antidepressants and benzodiazepines. Among drugs of abuse. intoxicat ion with hallucinogens (psychotomimetic drugs ), amphetamines, and cocaine is most commonly a ssociated with violent behavior. Hallucinogens include LSD and phencyclidine (PCP, angel dus t) Belligerence and psychomotor agitation t end to be more common with PCP than with LS intoxication. According to gui delines release by the American Psychiatric Association (20 02) the mainstay of therapy for acute mania is a ood stabilizing agent (eg lithium, vaiproate, o carbamazepine) plus an atypical antipsychotic (e. g olanzapine). In non-emergent settings. one s ould always use a trained obj ective interprete when there is a language barrier involving a atient. This also applies to hearing-impaire patients using American Sign Language. Suppression is a conscious, m ature defense mechanism invoMng withhold ing troublesome thoughts or impulses Avoidant personality disorder is a maladaptive pattern of behavior characteriz d by feelings of inadequacy, timidity, and fear of rejection. There are five subtypes of schi
ophrenia. each characterized by a set of pro
inent symptoms.
Disorganized is d istinguished by disorganized speech and beha ior and a flat or inappropriate schizophrenia affect.
PCP or phencyclidine is a hallucinogen that works by inhibiting the excitatory NMDA receptor. Moderate amounts of PCP cause feelings of detachment and distance Additionally, PCP can produce slurred speech, loss of coordination (ataxia). involuntary movements, exaggerated gait, and nystagmus It can induce paranoia and hallucinations and most users will become very hostile and aggressive. Passive-aggressive behavior is the expression of hostile feelings in a non-confrontational manner. Patients with delusional disorder harbor nonbizarre delusionsinbut do not meet schizophrenia and can function without significant impairment day-to-day life the criteria for Clinicians have ethical and moral obligations to report elder abuse. neglect and exploitation If there is reason to suspect abuse or neglect, the patient should be interviewed alone to avoid intimidation by possible abusers The only serotonin-releasing neurons in the CNS are found in the raphe nuclei These neurons disseminate widely to synapse on numerous structures in the CNS Marijuana contains THC which stimulates cannabinoid receptors to produce effects on mood, perception, and memory. Marijuana produces a mild euphoria with laughing behavior, slowed reflexes, dizziness, impaired coordination, and short term memory loss. Rapid heart rate and conjunctival injection are the two most immediate physical symptoms of marijuana use. It remains in tissues for a significant amount of time and can be detected up to 30 days after use. Obsessive-compulsive is characterized by recurrent, obsessive, anxiety-inducing thoughts, plus behavioraldisorder compulsions aimed at reducing the anxiety. In most cases of OCD, the patient understands the unreasonable nature of their thoughts and behaviors OCD often starts in childhood Conversion disorder refers to the unconscious manifestation of neurologic symptoms when pathophysiological explanations for the symptoms cannot be found It occurs more commonly in women and often occurs after a significant life stress Obsessive compulsive disorder is characterized by persistent intrusive thoughts that lead to repetitive behaviors These thoughts and actions cause significant distress and functional impairment Affected individuals recognize the absurdity of their thoughts and actions but are unable to stop them Transference is the unconscious shifting of emotions or desires associated with one person (eg. sibling, parent, spouse) to another (eg physician. therapist) It can be positive or negative Differentiation of Delirium and Dementia 1 Onset: Acute in delirium vs. gradual in dementia 2. Consciousness Impaired in delirium vs. intact in dementia
3. Course: Fluctuating symptoms in delinum vs. progressive decline in dementia 4 Prognosis: Reversible symptoms in delinum vs. irreversible symptoms in dementia 5. Memory impairment: Global in delirium vs. remote memory spared in dementia Patients with prefrontal lobe injury often experience behavioral and personality changes, secondary to impairment of the organizational, restraint, and motivational systems Frontal lobe syndrome can manifest in variable ways, but can often be categorized into disorganized. disinhibited. and apathetic types. Narcolepsy is a disorder characterized by excessive daytime sleepiness and REM steep—related phenomena such as cataplexy, sleep paralysis, and hypnagogicihypnopompic hallucinations. There are three categories of postpartum mood disturbances The most common is the postpartum blues, a benign, self-limited change in affect that lasts up to 10 days postpartum It is treated with watchful waiting and the knowledge that up to 20% of these women will develop postpartum depression Reaction f0rmaon the replacement of an unpleasant or unacceptable thought or desire with an emphasis on its opposfte Bulimia nervosa is an eating disorder characterized by binge-eating and either restrictive or purging compensatory behaviors. Anorexia nervosa is distinguished from bulimia nervosa by abnormally low body weight (< 85% of ideal or BMI < 175 kg/m) and amenorrhea Acute stress disorder and post-traumatic stress disorder present with identical symptoms (recurrent nightmares and flashbacks, potential memory loss, and exaggerated startle respOnse). Acute stress canfour lastweeks. no more than four weeks, however, while post-traumatic stress disorder lasts disorder longer than Projection refers to transplanting ones unacceptable impulses or affect onto another person or situation. It is an immature defense mechanism. Basic interviewing techniques include facilitation, reflection, confrontation, support, empathy. silence, and direct and indirect questioning. Support involves expressing concern independent of understanding. This is in contrast to empathy, where the physician expresses understanding and vicarious experiencing of a patients situation. There are numerous defense mechanisms (all of which the USMLE loves). Splitting refers to seeing the world in “black and white’ and is common amongst patients with borderline personality disorder At three years of age a child is expected to be able to play in parallel. speak in simple sentences, copy a simple shape, and ride a tricycle
Psychotic symptoms that interfere with the patients functional status are classified as brief psychotic disorder if the symptoms last less than one month. schizophreniform disorder if the symptoms last one to six months, and schizophrenia if the symptoms last more than six months. Opiate withdrawal is marked by abdominal pain. nausea. vomiting. diarrhea. piloerection, pupillary dilation, diaphoresis and fever. It can occur in patients taking narcotics legally or Illegally. When patients are unable to make their wishes known and there is no written documentation of these wishes, the responsibility for medical decision making falls to their designated health care proxy a patient has not a surrogate decision-maker, medical decisions default to the next ofIfkin In the case of adesignated married person, the next of kin is usually the spouse.
BEHAVIORAL-2 In situations where patients are unable to make decisions for themselves, responsibility for those decisions falls on the next of kin if the patient has no written directives clearly stating their intentions. The next of kin for a married person is their spouse followed by their adult children The next of kin is to make decisions based on how they believe the patient would have wanted things. Bulimia nervosa is an eating disorder characterized by alternating bingirig and weight reduction behaviors. Patients can develop bilateral parotid gland enlargement, erosion of tooth enamel, and irregular menses. Minors can consent to treatment for pregnancy, sexually transmitted disease, birth control, and drug or alcohol addiction without Darental consent or notification. Disability is a form of assistance provided to workers who can no longer work due to their general medical condition: it requires certification of disability by a physician When interacting with difficult patients, it is best to try to calm them, explain your position and inquire more about what troubles them by using open-ended questions. There are numerous somatoform disorders Body dysmorphic disorder is one in which a patient believes his or her body is pathologically flawed when, in fact, it is not There is a high rate of comorbid major depressive disorder and suicide attempts among patients with BDD
Adult patients who are competent or have outlined their wishes in a living will have the authority to refuse any form of treatment, including life-saving therapies In an emergency situation, if there is any doubt in a clinician’s mind concerning the wishes of a patient, the best course of action is to treat according to the accepted standard of care. In an emergency, the physician should always provide potentially life-saving therapy to a minor.
Adult patients who are compete t or have outlined their wishes in a living will ave the authority to refuse any form of treatmen , including life-saving therapies In an emerg ncy situation, if there is any doubt in a cIinicians mind concerning the wishes of a patlea the bes course of action is to treat according to the acc pted standard of care In an emergency, the physician should always provide potentially life-s ving therapy to a minor.
Psychogenic causes of ED acc unt for approximately 10% of cases and incl de performance anxiety, sexual partner dissatisf ction, and marital problems Important clues t hat point toward psychogenic impotence include udden onset and the presence of morning erect ons. When an ill patient requests y ur prayers in an acute setting. it is appropri te to offer your personal support without interje cting your personal beliefs into the interactio The overriding goal in these situations is to d no harm” This can be achieved by not disa greeing with the patient, not entering into a relig ious debate with them, and not displacing resp onsibility for the care of the patient onto others. If as part of a medical team yo have been asked to perform an action that yo u feel will cause harm to the patient, it is your e thical obligation to discuss that order with yo r supervising or colleague physician who has m ade the questionable suggestion in order to r ach a consensus without invoMng the patient or a ncillary staff. When treating patients that ar referred to you for specialty care or secon d opinions, it is imperative to not undermine th patienVs relationship with his or her primar provider Avoid making negative comments abou t the quality of care rendered by that practitione r PaIents who are temporarily inc apacitated should not be allowed to make imp decisions.
rtant health care
In situations where a parent is c mplicating an interview or where you feel yo will not be able to get honest answers from the adolescent patient with the parent present, it is appropriate to politely ask the parent to wait outside while you interview the patient This s also important when discussing drugs, alcohol, obacco and sexual activity with teenagers. Displacement is one of the les s mature defense mechanisms In displaceme t. a patient will redirect emotions from the per on or object that is causing the negative em tions to a more acceptable, but still inappropriat , person or object. Patient confidentiality is strongl protected because patients must feel free to d isclose details on all aspects of their lives so that physicians can provide optimal care. Patient c nfidentiality can be breached in only 4 excepti nal circumstances suspected child or elder a use, gunshot or stabbing injuries, diagnosis of a reportable communicable disease, and when p tients believably threaten to physically harm them selves or others.
A patient who is competent and not incapacitated has the right to refuse treatment by a physician at any time, even if that treatment is life-saving. A competent patient understands their situation as well as the possible consequences of decisions made in that situation. Health care information should be fully disclosed, unless the patient has expressly asked not to be informe
Using open-ended questions is the most effective way to start clinical histories Once the patient has started his history, one can use closed-ended follow-up questions to clarify certain pointS. In situations where you need to relay difficult information to a patient. you should take the approach of immediately informing the patient of the news, gMng them a moment to think about the news, and subsequently explaining what the news means and what their options are. You should always end by answering any questions the patient may have. White coat syndrome’ (patient anxiety evoked by healthcare workers dressed in white coats) is an example of classical conditioning, wherein the white coat serves as a conditioned stimulus for anxiety Prescription of antibiotics for diseases that are not bacterial in srcin is not proper procedure. This practice contributes to the societal prob$ern of antibiotic resistance, and it places the patient at unreasonable risks due to adverse reactions to antibiotic therapy It is unethical to discuss any information regarding the patient’s diagnosis. treatment, prognosis, etc. with a physician who is not involved in the patient’s care. Likewise, the physician should neither confirm nor deny whether the person of interest is, in fact, a patient Advance care planning for end of life issues such as desire for intubation. mechanical ventilation, tube feedings, parenteral feedings, CPR and cardioversion are best initially discussed during outpatient visits with primary care providers These decisions must also be readdressed during the admission process for acute admissions so that medical staff can adhere to the specific wishes of patients
BIOCHEMISTRY 1 Ubiqurtin is a protein that undergoes ATP-dependent attachment to other proteins, labeling them for degradation. These modified prote.ns enter the proteasome and are degraded into small peptides Impairment of the ubiquitin-proteasome system can contribute to the development of neurodegenerative disorders. including Parldnson’s and Alzheimer’s diseases All three prokaryotic DNA polymerases have proof reading actrvity and remove mismatched nucleotides via 3’ to 5’ exonuclease activity. Only DNA polymerase I has 5’ to 3’ exonuclease activity which is used to excise and replace RNA primers and damaged DNA sequences. The 1P3 second messenger system begins with hormone binding and G-protein activation leading to activation of phospholipase C. Phospholipase C forms diacyiglycerol and lP3 from phospholipids, and 1P3 causes an increase in intracellular calcium, which then activates protein kinase C. Arginase is an enzyme of the urea cycle that produces urea and ornEthine from arginine Helicase unwinds DNA at the replication fork and separates dsDNA into ssDNA during the replication process. Initial separation of dsDNA at the srcin of replication is facilitated by DnaA protein and strand binding proteins (SSB) proteins Extracellular propeptidases cleave disulfide-rich terminal extensions from the procollagen molecule. This results in formation of water-insoluble triple helical collagen fibrils. Tyrosine becomes essential in PKU pabents because can no longer be synthesized from phenylalanine (P1(U) results from an rnabihty to hyperphenylalaninemia convert phenylalanwiecan to tyrosine by the Phenylketonuna phenylalanine hydroxylase system Although neonatal be caused by deficiences in any of the phenylalanine hydroxylase system, most are attnbutable to abnormaIies in the phenylalanine hydroxylase enzyme snRNPs (small nuclear nbonucleoproteins) are synthesized by RNA polymerase II in the nucleus. They help to remove introns from the RNA transcript and are thus necessary for synthesis of messenger RNA The zinc-containwig 6-Aminolevulinate dehydratase and ferrochelatase are enzymes in the heme biosynthetic pathway that are inactivated by lead Thus, in lead poisoning, ö-AL4 and protoporphyrin IX accumulate, and the production of heme is decreased, leading to microcytic anemia secondary to a lack of hemoglObin. DNA poiymer;selhas 5’ to 3’ exonuclease activify in addition to its 5’ to 3’ polymerase and 3’ to 5’ exonuclease activities. This 5’ to 3’ exonuclease activity is used to remove the RNA primer (which initiates DNA polymerization) and to remove damaged DNA. Hydrogen bonds are the principal stabdizing force for the secondary structure of proteins.
A patient with orotic aciduna (impaired de novo pyrimidine synthesis) will present with hypochromic megaloblastic anemia, neurologic abnorrnahties. growth retardation and excretion of orotic acid in the urine Uridine supplementation impioves symptoms by inhibiting carbamoyl phosphate synthetase II. Homocystinuna is caused by cystathionirie synthetase deficiency Affected individuals manifest with skeletal abnormalities resembling those of Marfan syndrome In addition, they are also at high risk of developing thromboembolism About 50% of affected patients respond to high doses of vitamin B6 (pyridoxine) N-acetylglutamate is an essential activatorfrom of carbamoyl phosphate synthase and is formed by the enzyme N-acetylglutamate synthetase the precursors acetyl-CoA and Iglutamate. In Niemann-Pick disease. deficiency of sphingomyelinase causes abnormal accumulations of the ceramide phospholipid sphingomyehn and neurologic detenoration within the first year of life The nitrogen atoms in the urea moIecue are derived from NH3 and aspartate in the urea cycle Remember that carbamoyl phosphate synthetase I (CPS I) is the rate-limiting enzyme in the urea cycle reaction and is activated by N-acetylglutamate (NAG) Vitamin A ovewse can result in intracranial hypertension. skin changes and hepatosplenomegaly tRNA is the smallest subtype of cellular RNA It is responsible for transporting amino acids to the site of protein synthesis and introducing them into the growing polypeptide chain at the correct locations The 3k-end of the tRNA molecule is the site of amino acid binding. The opposite side of the molecule contains the antic odon loop, which recognizes a specific codon on the mRNA molecule Glycine is the most abundant amino acid in the collagen molecule. IL occurs in AT LEAST every third amino acid position The amino acid formula & collagen is (-Gly-X-Y-)333 LeSCh-Nyhan syndrome is an X-Iinked recessive disorder caused by a defect in hypoxanthineguanine phosphoribosyltransferase (HGPRT). This results in failure of the purine salvage pathway Because they are not recycled, increased amounts of the purine bases hypoxanthine and guanine are degraded to uric acid. De novo purine synthesis must increase to replace the lost bases. Chronic thiamine (BI) deficiency leads to the diminished abihty of cerebral cells to utilize glucose The mechanism is decreased function of the enzymes that use vitamin Bi as a cot actor (pyruvate dehydrogenase. a-ketoglutarate dehydrogenase, and transketolase) Thiamine deficiency can be diagnosed by measuring erythrocyte transketolase activity Propionyl CoA is derived from amino acids (Val, lie, Met, and Thr), odd-numbered fatty acids, and cholesterol side chains Congenital deficiency of propionyl C0A carboxylase, the enzyme responsible for the conversion of propionyl CoA to methylmalonyl C0A, leads to the development of propionic acidemia
Ornithine transcarbamoylase deficiency is the most common disorder of the urea cycle, resulting in severe neurological abnorrnahties due to high blood and tissue ammonia levels, Increased urine orotic acid excretion is typica[ Branched.chaina-ketoacid dehydrogenase. similar to pyruvate and a-ketoglutarate dehydrogenase, requires several coenzymes Thiamine pyrophosphate, Lipoate, Coenzyme A. FAD, NAD (mnemonic Tender Loving Care For Nancy). Some patients with maple syrup unne disease improve with high-dose thiamine treatment (thiamine-responsive), but most still require lifelong dietary restncbons Deficiency of the enzyme phenylalanine hydroxylase or of its cofactor tetrahydrobiopterin causes accumulation of phenylalanine in body fluids and the central nervous system (CNS). The homozygous infant is normal at birth, but mental retardation develops gradually in untreated infants and is frequently evident within six months of life Transamination reactions typically occur between an amino acid and an a-keto acid The amino group from the amino acid is transferred to the a-keto acid, and the a-keto acid in turn becomes an amino acid. Pyndoxal phosphate (vitamin B6) serves as a cofactor in amino acid transamination and in decarboxylation reactions. Antibodies to citrulinated peptides/proteins have a high specificity for rheumatoid arthritis. Marfans syndrome is due to a defect m fibrillin. an extracellular glycoprotein that is abundant in the zonular fibers of the lens, periosteum and the aorticofmedia The syndrome. different locations of fibrillin production explains the the varied clinical manifestations Marfan’s Peroxisomal diseases are rare inborn errors of metabolism where peroxisomes are either absent or nonfunctional Very long chain fatty acids or fatty acids with branch points at odd-numbered carbons can not undergo mitochondnal beta-oxidation, these fatty acids are metabolized by a special form of beta oxidation (very long chain fatty acids) or by alpha oxidation (branched chain fatty acids such as phytanic acid) within peroxisomes These diseases commonly lead to neurologic defects from improper CNS myelination. Gout can occur with increased frequency in patients with activating mutations in 5’-phosphoribosyl-P-pyrophosphate (PRPP) synthetase due to an increased production of purines, which results in hyperuricemia Coichicine is useful in the acute management of gouty arthritis because it inhibits the chemotaxis of neutrophils by preventing microtubule formation. Niernann-Pick disease is an autosomal recessive disorder characterized by a deficiency of the sphingomyelinase enzyme and resuttant accumaiation of sphingomyelin. Patients present ii
infancy with loss of motor skiBs. hepatosplenomegaly, hypotonia and a cherry-red macular spot. Foamy histiocytes are the classic finding on tissue histology Death occurs before age 3 Tetrahydrobiopterin (BH4) is a cofactor used in the synthesis of tyrosine, DOPPL serotonin. and nitric oxide. Initially. tyrosine is converted to DOPA by the enzyme tyrosine hydroxylase, with BH used as a cofactor Next, DOPA is decarboxylated to dopamine by the enzyme DOPA decarboxyLase In atypical phenylketonuna (PKU) wrth tyrosine supplementation, only the catecholamine synthesis reachons downstream of tyrosine are compromised Ehiers-Danlos syndrome is a heritable connective tissue disease associated with abnormal collagen forrnation EDS usually manifests clinically as over-flexible (hypermobile) joints, overelastic (hyperelastic) skin, and fragile tissue susceptible to bruising, wounding, and herna,’throsis. Procollagen is synthesized by a series of steps within the endoplasmic reticulum of cells such as fibroblasts. This molecule is then released into the extracellular space by transport through the Golgi apparatus and converted into collagen by procollagen peptidases that cleave the water soluble, non-helical N- and C-terminal portions of the procollagen molecule from procollagen to form collagen Collagen monomers are then covalently crosslinked with each other after certain residues are oxidized by lysyl oxidase. Glycogen degradation is coupled with skeletal muscle contraction due to calcium-mediated myophosphorylase calcium in themuscle cytosol allosterically activates phosphorylase kinase,activation which thenIncreased phosphorylates (activates) phosphorylase Alkaptonuria is an autosomal-recessive disorder caused by a deficiency of the enzyme homogentisic acid oxidase, which normally breaks down the tyrosine bypoduct homogentisic acid (also called alkapton). Accumulated homogentisic acid causes pigment deposits in connective tissues throughout the body. Maple syrup urine disease (MSUD) is caused by a defect in a-keto acid dehydrogenase. leading to an inability to degrade branched chain amino acids beyond their deaminated a-keto acid state This illness classically results in dystonia and poor feeding as well as the maple syrup scent of the patients urine within the first few days of life Treatment rests on dietary restnchon of branched-chain amino acids Aikaptonuna is an autosomal-recessive disorder in which the lack of homogentisic oxidase blocks the metabolism of phenylalanine and tyrosine at the level of homogentisic acid, leading to an accumulation of homogentisic acid Homogenhsic acid excreted in the urine imparts a black color to urine. if allowed to undergo oxidation Aikaptonuna also causes ocl’wonosis, a blueblack pigmentation that is most evident in the ears, nose, and cheeks.
Hydroxylation of proline and lysine residues in the collagen precursor occurs m the RER and requires vitamin C as a cofactor Terminal peptide cleavage and collagen fibnl crosshnking occur in the extracellular space BHsacofactorusedby hydroxytase enzymes m the synthesis of tyrosine. dopa, and serotonin, as well as nitric oxide Serotonin is synthesized from tryptophan, and the initial step in this reaction is catalyzed by an enzyme that uses BH4 as a cofactor Enzyme dihydrobioptenn reductase deficiency causes defective regeneration of BH4, and is an uncommon cause of phenylketonuna (PKU). Methylmalonic acidemia known as methylmalonic aciduria) results fromprior a defect in the isomerization reaction that(also transforms methylmalonyl CoA to succinyl CoA, to succinyl CoA entering the TCA CycIe Alanine is the major amino acid responsible for transferring nitrogen to the liver for disposal During the catabolism of proteins, amino groups are transferred to a-ketoglutarate to form glutarnate. Glutamate is then processed in the liver to form urea, the primary disposal form of nitrogen in humans. Free ammonia is also excreted into the urine by the kidney for regulation of acid-base status.
BIOCHEMISTRY 2 Cobalamin (Vitamin B12) deficiency results ii homocystinemia due to impaired methionine 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. There is one codon that signals initiation of protein synthesis (AUG), while three codons stop protein synthesis (UM, UAG, and UGA) Transfer RNA molecules (tRNA) transport amino acids to the site of protein synthesis and ensure placement of the proper amino acid for a given mRNA codon Each tRNA contains a specific anticodon that is complementary (oriented in an antiparallel direction) to certain mRNA codons, In the lungs, hemoglobin binds oxygen and releases protons while, in the tissues, it releases and acquires protons. Deoxyhemoglobin is stabilized by ionic bonding of 2,3 DPG to the two beta subunits and by salt bridges between N-terminal histidine residues in each globuIin Pnmase is a DNA-dependent RNA polymerase that mcorporates short RNA primers into replicating DNA.
Hemoglobin S (HbS) aggregate in the deoxygenated state HbS polymers for fibrous strands that reduce red blood cell mem fane flexibility and promote sickling Sickling occurs under all conditions associated with an xia including low pH and high 2,3-DPG. These inflexible erythrocytes predispose to micro vascular occlusion and microinfarction
The PI3KJAkt)mTOR pathway i s an intracellular signaling pathway important f r anti-apoptosis, cellular proliferation, and angio genesis. Mutations in growth factor receptor s . Akt mTOR. or PTEN that enhance the activity f this pathway contribute to cancer pathogenesi s. Decreased heme concentration r turn, leads to increased forma formation of ö -arninolevulinic a inhibit the synthesis of ALA syn
su’ts in an increase in hepatic ALA synthase ctivity, which in ion of ö-aminolevuhnic acid and porphobdi nogen Increased id and porphobilinogen occurs because heme n ormally serves to hase.
The liver takes up indirect (unco njugated) bilirubin through a passive process a d secretes direct (conjugated) bilirubin through a active process. Unconjugated bilirubin is virt ally insoluble in water at physiologic pH and is ti ghtly complexed to serum albumin while in th circulation This form cannot be excreted in the rine, even when blood levels are high. Conju gated bihrubin is water-soluble, non-toxic, and on y loosely bound to albumin. it is freely excrete in the urine. Releasing factors recognize th stop codons (UAA, UAG and UGA) to t erminate protein synthesis They facditate release of the polypeptide chain from the hbosome a d dissolution of the ribosome-mRNA complex Exertional dyspnea. pneumonia resulting in life-threatening acute chest syndro e. and recurrent abdominal and bone pain are cl inical features of sickle cell anemia Sickle ce ll anemia results from a point mutation that cause valine to substitute for glutamic acid in the six th position of the b-globin chain of hemoglobin. Glucose 6-phosphate dehydroge nase deficiency is a common X-Iinked disord er of the hexose monophosphate pathway that res ults in episodes of hemolytic anemia due to oxi ative stress. The keyfunctions of important a polipoproteins are as follows: ApoA-l: LCAT activation (chole sterol esterification) ApoB48: Chylomicron assembly and secretion by the intestine ApoB-100: LDL particle uptake by extrahepatic cells ApoC-Il: Lipoprotein hpase acti ation ApoE-3 & 4: VLDL and chytom icron remnant uptake by Irver cells Fabry disease is an inherited deficiency of alpha-galactosidase A that causes ac umulation of the globoside ceramide tnhexoside ii tissues The earliest manifestations of F bry disease are angiokeratomas, hypohidrosis and acroparesthesia Without enzyme repla ement, patients typically develop progressive re al 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 Western blotting is used to identify proteins. Northern blotting identifies specific RNA sequences and Southern blotting identifies specific DNA sequences in an unknown sample HbF dominates in newboms It consists of two alpha and two gamma protein subunits (ci2y2), has a high affinity for oxygen and is produced during the final seven months of gestation Switching to HbA (a232) occurs during the first six months of life SngIe nucleotide deIeions shift the reading frame, often creating a premature stop codon or dramatically changing the protein structure, Methemoglobinemla causes dusky discoloration to the skin (similar to cyanosis), and because methemoglobin is unable to carry oxygen. a state of functional anemia is induced The blood partial pressure of 02, however, will be unchanged in this condition because oxygen’s partial pressure is a measure of dissolved in the plasma and is not related to hemoglobin funchon The individual subunits of the hemoglobin molecule are structurally analogous to myoglobin. If separated, the subunits will demonstrate a hyperbolic oxygen-dissociation curve similar to that of myoglobin. In order for a child to have sickle cell disease, both parents must be carriers. The carrier status of prospective parents can be established by hemoglobin electrophoresis. Normally, 2, 3-DPG forms ionic bonds with the two beta subunits of HbA in the tissues after hemoglobin has been deoxygenated Fetal hemoglobrn binds oxygen with a higher affinity due to its inability to interact with 2, 3- DPG. Ultimately, the fetal hemoglobin must be able to extract 02 from maternal hemoglobrn in the placenta Transketolase and transaldolase carry out the nonoxidative reactions of HMP shunt Some cells do not use the oxidative phase reactions to produce cytosohc NADPH, but all cells can synthesize nbose from fructose-6-phosphate using the nonoxidative reactions Nitrites are oxidizing agents that are effective in the treatment of cyanide poisoning due to their ability to cause methemoglobinemia Methemoglobin contains femc rather than ferrous iron Cyanide binds to ferric iron more avidly than to mitochondnal cytochrome enzymes. which saves these mitochondnal enzymes from cyanides toxic effect. The thaassemias result from mutations that cause detective mRNA processing, which leads to deficiency of certain protein chains required for hemoglobin synthesis Beta-thalassemia minor is typically an asymptomatic disorder Laboratory tests will show a mild hypochromic microcytic anemia with increased HbF, Hb% and target cefls
CO binds to hemoglobin with a n affinity that is 220 times that of oxygen for hemoglobin The binding of CO and 0. to hemogl obin are reversible. CO. therefore, competes w ith O for binding on the heme iron of hemoglobin The symptoms of difficulty in s allowing (dysphagia) and disfigured fingernai s (spoon nails or koilonychia) are specific for iron deficiency anemia Homocysteine is converted to m
thionine using methylcobalamin and methyl te
rahydrofolate.
Folate deficiency inhibits the ormation of deoxythymidine monophosphate (dTMP), which limits DNA synthesis and pro ation otes can megaloblastosis erythroid cellcan apoptosis Because thymidine supplemen moderately and increase dTMPprecurs level ,r it reduce erythroid precursor cell apoptosi s Matunng erythrocytes lose their abihty to synthesize herne when they lose th ir mitochondria. Mitochondria are necessary for t he first and final three steps of herne synthesis. Pyruvate kinase deficiency caus es hemolytic anemia due to failure of glycol sis and resultant failure to generate sufficient TP to maintain erythrocyte structure. In t is case, splenic hypertrophy results from increa ed work of the splenic parenchyma, which m st remove these deformed erythrocytes from the irculation. The Kozak sequence plays a rol in the initiation of translation A mutation thre e bases upstream from the start codon (AUG) in t is sequence is associated with thalassemia inter media A mutation in the Kozak seq
ence of the beta-globin gene is associated
ith thalassemia
intermedia. which results in hyp HbC is caused by a missense m beta globin chain, resufting in in slowly than both HbA and HbS
chromic, microcytic anemia. tation that causes a substitution of glutamate creased positive charge of the molecule Thus, n hemoglobin gel electrophoresis
Ith lysine in the bC moves more
The chronic myeloproliferative disorders (polycythemia vera. essential thro mbocytosis, and primary myelofibrosis) often ha e a mutation (V617F) in the cytoplasmic tyros ine kinase, Janus kinase 2 (JAK2) This results in onstitutive tyrosine kinase activity, and conseq uently, cytokineindependent activation of STAT transcription factors. With the exception of vitamin .. the body’s stores of most water-soluble vit mins are rapidly depleted without dietary intake. In contrast, hepatic stores of vitamin B2 may ast up to several years Severe vitamin K defici ncy rarely results from poor dietary intake because colon*c bacteria produce functional form s of vitamin K
The P refers to the partial pressure of oxygen where hemoglobin is 50% saturated A decrease in the P means that hemoglobin has an increased oxygen affinity An increased oxygen-affinity of hemoglobin causes less oxygen to be released in the tssues. and results in hypoxia then reflex polycythemia Vitamin K assistance of glutamate residue carboxytation is essential for some clotting factor production Hypoxia-induced lactic acidosis is caused by a low activity of pyruvate dehydrogenase (oxidative phosphorylation pathway) and a high activity of lactate dehydrogenase. HbS contains valine in place of glutamic acid in the amino acid position of the beta subunit This promotes hydrophobic interaction among hemoglobin molecules and results in polymerization of HbS molecules and red blood cell distortion A left shift of the hemoglobin oxygen dissociation curve indicates increased hemoglobin 02 affinity and can be caused by increased pH, decreased 2, 3-DPG, and decreased temperature A left-shift of the Increased 2,3-BPG concentrations within erythrocytes enable increased oxygen delivery in the peripheral tissues in the presence of lower blood oxygen concentration because 2,3-BPG decreases the affinity of hemoglobin for oxygen 2,3-BPG is produced from 1 ,3-BPG by the enzyme bisphosphoglycerate mutase This reaction consumes the energy that would have been otherwise used by the erythrocyte to produce energy in the form of ATP HbF contains y-globin instead of 13-gIObEi Patients with homozygoüc -thaIassemia (thaIassemiato major) are asymptomatic at birthofdue to thesynthesis presenceprecipitates of y-globins and HbF Switching HbA production and the cessation y-globEn the symptoms of 13-thalassemia While DNA synthesis occurs in the 5’ to 3’ direction on both strands, the leading and lagging strands are constructedin both the 5’ to 3 and 3’ to 5 directions, respectively The lagging strand is synthesized discontinuously and is composed of short stretches of RNA primer plus newly synthesized DNA segments called Okazak fragments Thus, the lagging strand requires the repetitive action of DNA pnmase and DNA ligase.
BIOCHEMISTRY 3 In contrast to the rough endoplasmc reticulum (ER). the smooth ER contains enzymes for steroid and phospholipid biosynthesis. All steroid-prnducing ce’ls (eg, cells m the adrenals. gonads, and liver) contain a weII-civp1nned smonth PR
High-output congestive heart failure and neurological symptoms are strongly suggestive of wet beriberi (thiamine deficiency) Elastin’s pIasticty and abdity to recod upon release of tension is attributable to a unique form of desmosine crosslinking between four different lysine residues on four different elastin chains This crosslinking is accomplished by the action of extraceliular lysyl hydroxylase Exposure to radiation including therapeutic and palliative radiation therapy, induces DNA damage through DNA double-strand fractures and the formation of oxygen free radicals Resembling prokaryotic DNA and being derivedDNA completely the mother. DNA (mtDNA) is the most common non.-nuclear found infrom eukaryotic Cells. mitochondrial After 12 to 18 hours of fasting, gluconeogenesis is the principal source of blood glucose Gluconeogenesis uses many of the bidirectional enzymes involved in the process of glycolysis, but a few unidirectional enzymes need to be bypassed The initial committed step of gluconeogenesis involves the conversion of pyruvate to oxaloacetate, and oxaloacetate to phosphoenolpyruvate Protein kinase Ais primarily responsible for the intracellular effects of the G-protein I adenylate cyclase second messenger system. Some hormone receptors that use this mechanism include the TSH, glucagon, PTH, and beta-adrenergic receptors. If AG° is a negative number. K will be greater than 1, and the concentration of products at equilibrium wil exceed that of the substrates If AG° is positive, K will be less than 1, and the formation of substrates will be favored. Pyruvate dehydrogenase deficiency is a disease with multiple possible presentations ranging from neonatal death to mild episodic symptoms in aduRbood By preventing the conversion of pyruvate to acetyl C0A. pyruvate is shunted to lactic acid resulting in lactic acidosis in these patients Lysine and leucine are exclusively ketogenic and would not increase the blood lactate level in patients suffering from pyruvate dehydrogenase deflciency Integral membrane proteins contain transmembrane domains composed of alpha helices with hydrophobic amino acid residues such as valine, alanine, isoleucme. methionine. and phenylalan*ne Cysteine becomes an essential amino acid m patients with homocystinuria, as the defective enzyme cystathionine synthetase produces the substrate used by cystathionase for the endogenous production of cysteine In patients with essential fructosura. metabolism of fructose by hexokinase to fructose-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 a number base pairs which are not of three that a frameshift mutationofhas occurredof Frameshift mutations altera multiple the reading frameindicate of the genetic code, resulting in the formation of non-functional proteins Glucokinase is a glucose sensor within pancreatic beta ceIIs Inactivating mutations of the enzyme result in mild hyperglycemia that can be exacerbated by pregnancy Phenylethanolarnine-N-methyltransterase (PNMT), wtich is responsible for the synthesis of epinephnne, is under the control of cortisol Lactic acidosis occurs in patients with septic shock because of tissue hypoxia, which results in impaired oxidative phosphorylation and the shunting of pyruvate to lactate following glycolysis. Hepatic hypoperfusion also contributes to the buildup of lactic acid, as the liver is the primary site of lactate clearance. Elderly patients with dementia or hemiparesis may also have dysphagia, which is a risk factor for aspiration pneumonia. Dependent lung consolidation is commonly seen in aspiration pneumonia. Fructose 2,6-bisphosphate activates glycolysis by inducing phosphofructokinase-1 and inhibits gluconeogenesis by inhibiting fructose 1 ,6-bisphosphatase High concentrations of fructose 2,6bisphosphate 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 elements, causing an alternation in the transcription of target genes xKnow the second messengers very well
The genetic code is “degenerate, meaning that there are more codons (61) than amino acids (20) Each tRNA molecule is specifi for a given amino acid Many tRNA anticod ns can bind to a few different codons coding for he same amino acid This is called the wobble p henomenon ATP is the regulatory substanc e that stimulates KATP channel closure in i nsulin-producing pancreatic beta cells PCR requires primers that are c mplementary to the regions of DNA flanking t he segment to be amplified. Thermostable DNA olymerase, deoxynucleotide triphosphates, an the target DNA template strand are also necessar y. Glycogenolysis provides immed iate energy for strenuous muscle contraction M yophosphorylase deficiency (McArdle’s syndro e or type 5 glycogen storage disease) lead to a failure of glycogenolysis with clinical ma ifestations of decreased exercise tolerance, m oglobinuna, and muscle pain with physical activi y. After IJV damage. pyrimidine imers are formed in cellular DNA. which are recognized by a specdic endonuclease which irü iates the process of repair by nicking the stra d at the thymine dimer, This action signals the re oval and replacement of this damaged DNA. After a hormone binds a G-pro step of the lP second messe diacyiglycerol (DAG) and ino activated by DAG as well as ca of lP
ein coupled receptor that activates phospholip ase C, the initial ger system involves degradation of memb rane lipids into itol triphosphate (1P3) by that enzyme. Pro ein kinase C is cium released from sarcoplasmic reticulum un der the influence
Southern blotting is a techniq ue used to identity UNA mutations. It in olves resinction endonuclease digestion of sam ple DNA, gel electrophoresis, and gene iden tification with a radoactivety-Iabeled DNA probe vv Amino acids with three titrata ble protons include histidine, arginine. lysin e, aspartic acid, glutamic acid, cysteine and tyros ine UV-specific endonuclease defic iency is the most common cause of the aut disorder xeroderma pigmentosu
somal recessive
Heavily methylated DNA is t ypically found in heterochromatin, which is condensed and transcriptionally inactive Tight association with non-acetylated histones and ethylation both contribute to the compact nature of heterochromatin and its transcnptionally ina tive state
Colony-stimulating factors, prolactin, growth hormones and cytokines utilize tyrosine kinaseassociated rtrtAr rvl th I /cTtT iw,nIenn nthiwu The nucleolus, the dark intranuclear body visible both by light microscopy and electron microscopy, is the site of ribosomal RNA synthesis Insulin is an anabolic hormone that acts via a tyrosine kinase second messenger system to stimulate the synthesis of glycogen. proteins, fatty acids and nucleic acids. Tyrosine kinase leads to the activation of protein phosphatase within cells, and protein phosphatase directly modulates the activity of enzymes in the metabolic pathways regulated by insuhn The breast milk content of vitamins [) and K is typically insufficient to meet the nutritional needs of the newbom Vitamin K is given parenterally to infants at birth to prevent hemorrtiagic disease of the newbom Exclusively breastfed infants may develop vitamin D deficiency they are not exposed to adequate sunlight Dark-skinned infants are at especially high risk because they must be exposed to sunlight for longer periods of time to generate adequate vitamin D Protons dissociate from amino acids when the pH exceeds the pK) associated with each given proton. fl the free energy of the products is lower than that of the substrates, the sign of will be negative. indicating that the reaction favors product formation I the free energy of the products is higher than that of the substrates, G° will be positive and the reaction favors substrate formation Thyroid hormones alter gene transcription by binding to receptors situated inside of the nucleus Receptors for several steroid hormones such as glucocorticoids, mineralocorticoids, androgens, and estrogens once activated are usually initially present in cytoplasm, although they do migrate to the nucleus 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.
BIOCHEMISTRY 4 Hartnup disease can result in niacin deficiency due to an excess loss of dietary tryptophan, resulting from defective intestinal and renal tubular absorpbon of that amino acid Remember that niacin (nicotinamide I Vitamin B3) is synthesized from tryptophan and that tryptophan is an essential amino acid The MAP-kinase signal transduction pathway inch.ides Ras protein, a (3-protein that exists in inactive (GDP-containing) and active (GTP-containing) forms Mutated (permanently activated) Ras is associated with the development of malignant tumors
Small nuclear nbonucieoprotein particles (snRNPs) are important components of the spliceosome, a molecule which functions to remove introns from pre-mRNA during processing within the nucleus. Telomerase is an enzyme that possesses reverse transcriptase (RNA-dependent DNA polymerase) activity and is normally expressed in stem cells as well as cancer cells. However, cancer cells are immortal because these cells continue to divide without aging and shortening of their telomeres Splice site mutations frequently result in the production of larger proteins with altered function but preserved immune reactivity. Lynch syndrome is an autosomal dominant disease caused by abnormal nucleotide mismatch repair. The mismatch repair system involves several genes, including MSH2 and MLH1, which code forfor components human MutSsyndrome. and MutL homologs. Mutations in these 2 genes account around 90%ofofthe cases of Lynch The nucleolus is the site of rRNA synthesis from rONA. the site of nbosomal protein synthesis, and the site of ribosome formation. RNA polymerase I synthesizes rRNA with its greatest activity being in the nucleolus. Leptin is a protein hormone produced by adipocytes in proportion to the quantity of fat stored Leptin acts on the arc uate nucleus of the hypothalamus to inhibit production of neuropeptide Y (decreasing appetite) and stimulate production of alpha-MSH (increasing satiety) Mutations in the leptin gene or receptor result in hyperphagia and profound obesity Trypsinogen is activated to trypsin by duodenal enteropeptidase Trypsin is essential for protein digestion and absorption in two ways It degrades complex peptides to dipeptides and amino acids, and it activates other proteases such as carboxypeptidase. elastase and chymotrypsin. Pyndoxal a necessary cofactor in the synthesis of delta-aminolevulinic acid (which is elevatedphosphate in cases ofislead 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. Secondary lactase deficiency can occur after viral gastroenteritis or other diseases that damage the intestinal epithelium. This disease causes abdominal distention, flatulence, and diarrhea after lactose ingestion. Amatoxins are fOund ma vanety of poisonous mushrooms (eq. Aman#aphaioides, known as death cap) and are potent inhibitors of RNA polymerase U (halting mRNA synthesis) When mRNA is first transcribed from DNA. it is in an unprocessed form called pre-mRNA or heterogeneous nuclear mRNA (hnRNA). Several processing steps are required before finalized mRNA molecules can leave the nucleus, including 5’-capping, poly A tail addition, and intron splicing Cytoplasmic P bodies play an important role in mRNA translation regulation and mRNA degradation Bacterial mRNA can be polycistronic. meaning that one mRNA codes for several proteins An example of polycistronic mRNA is the bacterial lac operon, which codes for the proteins necessary for lactose metabolism by E co/i, the transcription and translation of these bacterial proteins is regulated by a single promoter, operator, and set of regulatory elements. The sequence of amino acids in a growing polypeptide chain is dictated by the interaction of the mRNA codon with the tRNA anticodon. tRNA that is mischarged with the incorrect amino acid (and not corrected by M-tRNA synthetase proofreading) will incorporate the wrong amino acid into the growing polypeptide chain, as there is no amino acid proofreading during protein translation. Hyperammonerniain hepatic encephalopathy results in depletion of a-ketoglutarate. causing inhibition of the Krebs cycle. Excess ammonia also depletes glutamate. an excitatory neurotransmitter, and causes accumulation of glutamine. resulting in astrocyte swelling and dysfunction. Unlike hereditary fructose intolerance and classic galactosernia. essential fructosuria is a benign disorder resulting from a defect or deficiency in the enzyme fructokinase As a consequence of aging. fine skin wrinkles appear secondary to the decreased synthesis and net loss of dermal collagen and elastin Base excision repair is used to correct defects in single bases induced spontaneous’y or by exogenous chemicals In this process. glycosylases remove the defective base, and the corresponding sugar-phosphate is cleaved and removed by endonuclease. followed by the action of lyase DNA polymerase then replaces the missing nucleotides and ligase reconnects the DNA strand.
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 symptomssubperiosteal of scurvy are primarilybleeding caused by collagen formation, and include hemorrhages, hematomas. intoimpaired Joint spaces, gingival swelling, secondary periodontal infection, anemia, hyperkeratotic papular rashes, impaired wound healing, and weakened immune response to local infections. Niacin (vitamin B3) can be synthesized endogenously from tryptophan. A deficiency of this vitamin resufts in pellagra, which is characterized by dermatitis, diarrhea, and dementia The lac operon is regulated by two distinct mechanisms: negatively by binding of the repressor protein to the operator locus and positively by cAMP-CAP binding upstream from the promoter region Constitutive expression of the structural genes of the lac operon occurs with mutations that impair the binding of the repressor protein (Lac I) to its regulatory sequence in the operator region tRNA is a small. noncoding form of RNA that contains unusual nucleosides such as pseudouridine and thymidine. Remember that tRNA has a CCA sequence at its 3’-end that is usedisas a recognition sequence proteins, and that the 3’ terminal hydroxyl group of the CCA tail used as the binding site forbythe amino acid. Vitamin A can beof benefit in the treatment of measles infection
BIOSTATISTICS 1 The chi-square test for indepe ndence is used to test the association betwe en 2 categorical variables In the case of an expo sure status and a binomial outcome, patients re dMded into 2 groups based on exposure, and t e number of patients that experience each outc ome Es recorded in a 2 x 2 table Smoking cessation is by far the most effective preventive intervention in al m ost every patient (very high yield!) sensitivity is me number ot true ositives aiviaea oy me totai numoer or suojects actuaiiy wan tne aisease. True positives = (Sensitivity) (N mber of patients actually with the disease) False negatives = (1 - Sensitivity ) (Number of patients actually with the disease)
Confounding bias occurs when he exposure-disease relationship is muddied b the effect of an extraneous factor that has correl ations with both the exposure and the disease onfounding bias can result in the false association of an exposure with a disease Positive predictive value represe nts the probability of truly having a disease fo a given positive test result. It increases with incr asing disease prevalence and decreases with d creasing disease prevalence The median is the value that is l ocated in the precise center of an ordered data et. It divides the right half of the data from the le t half. In a normal (bell-shaped) distrib ton 68% - within I standard deviatio from the mean 95% - within 2 standard deviatio ns from the mean 99.7% - within 3 standard deviat ions from the mean Matching is used in case-contr l studies in order to control confounding Re ember 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 arou os have a similar distribution in accordance The two-sample t test is a stati tical method commonly employed to compar the means of 2 groups of Subjects. The number needed to treat (N T) is calculated by dMding 1 by absolute risk reduction (ARR) The ARR is the event rate in t he 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 f 66.6 but, since treating 66.6 of a person is seldo m a good idea, we round up to 67.
NPV is the probability of being free of a disease f the test result is negative Remember that the NPV will vary with the pretest probability of a disease A patient with a high probability of having a disease will have a low NPV with a negative test but a patient with a low probability of having a disease will have a high NPV with a negative test. The specificity ofatest is given by d/(b+d). ft should be high in confirmatory tests in order to decrease false positives. In a cross-sectional study. exposure and outcome are measured simultaneously at a particular point of time exposure from (“snapshot the outcomestudy”). In other study designs, a certain time period separates the A reliable test is reproducible in that it gives similar results on repeat measurements Reliability is maximal when random error is minimal. The power of a study increases proportionally with the sample size. Thus, the larger a sample the greater the ability to detect a difference when one truly exists In a normal (bell-shaped) distribution curve. 68% of observations lie within one standard deviation of the mean. 95% of observations lie within two standard deviations of the mean, and 997% of observations lie within three standard deviations of the mean In a crossover study, subjects are randomly allocated to a sequence of 2 or more treatments given consecutively. A washout (no treatment) period is often added between treatment intervals to limit the confounding effects of prior treatment. Selection of control subjects in case-control studies is intended to provide an accurate estimation of exposure frequency among the non-diseased general population. Cases and controls are often matched in order to decrease confounding. However, matching must be carefully performed so as to not introduce selection bias. The positive and negative predictive values of a test depend on the disease prevalence in the population The sensitivity and specificity of a test do not depend on the prevalence of the disease in the popuIation The reliability of a measurement technique refers to its reproducibility The accuracy of a measurement technique is the degree to which the average measurement value matches that of the gold standard technique In a positively skewed distribution. the mean is the most shifted in the positive direction, followed by the median and then the mode. Effect modification is present when the effect of the main exposure on the outcome is modified by the presence of another variable Effect modification is not a bias
The Hawthorne effect is the tendency of a study population to affect an outcome due to the knowledge of being studied. The main purpose of blinding is to prevent patient or researcher expectancy from interfering with an outcome Sensitivity equals aJ(a+c). Screening tests are designed to have high sensitivities Understand the measures of center (mean/averages. median and mode) They are common topics on the USMLE exams Power(1-3) is the probabihty of rejecting a null hypothesis when it is truly false It is typically set at 80% and depends upon sample size and difference between outcomes. Specificity is the number of true negatives divided by the total number of subjects actually without the disease True negatives = (Specificity) * (Number of patients actually without the disease) False positives = (1 - Specificity) (Number of patients actually without the disease) Lowering the cut-off point will increase the sensitivity of a test The true positives will also increase but the false positives will have a relatively larger increase This results in a decrease in the PPV and the FN. Power of a study indicates the probability of seeing a difference when there is one; Power = 1 — An increasing prevalence and stable incidence can be attributed to factors which prolong the duration of a disease (e.g, improved quality of care this scenario is typical for the USMLE) Incidence is the measure of new cases diagnosed in a given period of time. Prevalence is the measure of the total cases at a particular point in time Any treatment that prolongs survwal but does not cure the disease will increase prevalence due to an increase in the number of afflicted (but still alive) individuals over time
BIOSTATISTICS-2 Prospective cohort studies are organized by selecting a group of individuals (ie., cohort), determining their exposure status, and then following them over time for development of the disease of interest Loss to follow-up in prospective studies creates a potential for selection bias Recall bias results from inaccurate recall of past exposure by people in the study and applies mostly to retrospective studies such as case—control studies People who have suffered an adverse event are more likely to recall risk factors than those without adverse experiences Like all sources of bias, recall bias is a threat to the validity of a study.
A t-test is used to compare the difference between the means of 2 groups Analysis of variance (ANOVA) compares the difference between the means of 2 or more groups Observer bias occurs when the investigator’s decision is affected by prior knowledge of the exposure status. Risk is the probability of getting a disease over a certain period of time. To calculate the risk, divide the number of diseased subjects by the total number of subjects in the corresponding group (ie., all the people at risk). The correlation coefficient ranges from -Ito +1 and describes two important characteristics of an association: the strength and the polarity. There are essentially 4 basic methods that health insurance plans use to reimburse physicians: capitation, fee-for-service (FFS), discounted FFS, and salary Physicians paid under FFS face little financial risk and have incentives to increase services, tests, and patient visits Physicians paid under capitation face the greatest financial risk and have incentives to provide more preventive care and better health counseling. Confidence interval for the mean is calculated using the mean. SD, z-score and sample size. Know ho; to witerpret the confidence intervaL Know the relationship between the confidence interval and ‘p’ value. The incidence of a disease is the number of new cases of a disease per year divided by the total population at risk It is important to have high sensitivity in screening tests Positive predictive and negative predictive values are influence by disease prevalence whereas specificity and sensitivity are not RRR = [Absolute Risk., - Absolute Risk] / Absolute Risk1 Negative predictive value (NPV) represents the probability of not having a disease given a negative test result Unlike sensitivity and specificity, NPV varies based upon disease prevalence and is inversely proportional to the prevalence of a disease. ARP represents the excess nsk in the exposed population that can be attributed to the risk factor It can be easily derived from the relative risk using the following formula: ARP = (RR - 1 )/RR An increase in lung cancer incidence and mortality has been observed in women over the last four decades
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 outliervariance, is defined an extreme and to unusual inisamore dataset The mean, standard deviation, andasrange are sensitive outliersobserved The mode resistant to outhers Number needed to harm = 1! Attributable risk Positive predictive value is defined as the proportion of subjects with a positive test that actually have the disease. The typical example of lead-time bias is an apparent increase in survival in patients diagnosed with a new test who actually have an unchanged prognosis. Think of lead4ime bias when you see “a new screening test” for poor prognosis diseases like lung or pancreatic A case-control study is used to compare the exposure of people with the disease (cases) to the exposure of people without the disease (controls) The main measure of association is the exposure odds ratio. ARR = Event Rate(CQI) - Event Ratetreatment According to 2011 statistics, the most common cancers (aside from skin cancer) in women in order of incidence were breast, lung, and colon cancer. In terms of mortality, lung cancer claimed the most lives, followed by breast and then colon cancer. Case-fatality rate is calculated by dividing the number of fatal cases by the total number of people with the disease. Questions about relative risk are commonly asked Make sure you can construct 2*2 table (Exposure in rows and Outcome in columns) and calculate relative risk If events are independent, the probability that all events will turn out the same is the product of the separate probabilities for each event The probability of at least 1 event turning out differently is given as 1 - (probability of all events being the same)
GENETICS 1 Lymphedema is a characteristic finding in a fetus afflicted with Turner syndrome (45XO) The lymphedema can vary in severity, ranging from edema of the hands and feet to hydrops fetalis Other common fetal Turner syndrome abnormalities include coarctation of aorta and horseshoe kidney Pleiotropy descnbes instances where multiple phenotypic manifestations result from a single genetic mutation. Most syndromic genetic illnesses exhibit pleiotropy FoIhcur Iymphoma is a non-HodgIn lymphoma of follicular B-lymphocytes Patients with follicular lymphoma characteristically have a translocation between chromosomes 14 and 18 which causes Bc/-2 overexpression. Bc/.2 is considered a protooncogene because it has 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. Neonates with Edwards syndrome (47,)O( +18) have small jaws (micrognathia), small eyes (microphthalmia), and malformed and low-set ears. Note that rocker-bottom feet are seen, as with Patau syndrome (trisomy 13). The presence of clenched hands with oveilapping fingers is considered one of the distinguishing features of this syndrome. Primary amenorrhea in a patient with fully developed sexual characteristics suggests the presence of an anatomic defect in the genital tract, secondary such as imperforate hymen or MUllerian duct abnormalities Aspirin irreversibly inhibits COX-1 and COX-Z COX-2 is an inducible enzyme that is normally undetectable in most tissues except in the case of inflammatiOn. Renal angiomyolipoma is a benign tumor composed of blood vessels, smooth muscle, and fat Bilateral renal angiomyolipomas are associated with tuberous sclerosis, an autosomal dominant condItIon. After participating in this learning exercise, you should be able to calculate the probability that a child of parents from two populations with different mutant allele carner frequencies will inherit an autosomal recessive disease. A complete mole results from fertilization of an ovum that is devoid of genetic material and subsequent genotype reduplication of the paternal genetic complement giving a characteristic 46 XX
Achondroplasia is an autosomal-dominant disorder The transmission of autosomal dominant disorders statistically occurs in 50% of the offspring of an affected parent Turners syndrome (45 XO) manifests in the neonate with lyrnphedema and cystic hygromas Short stature, primary amenorrhea and coarctation of the aorta are the other important chnical features of Turner’s syndrome in adults. Diminished fernoral pulses compared to brachial pulses, symptoms of inadequate perfusion of the lower extremities during ambulation, and enlarged intercostal arteries in a child/young adult are typical of adult-type congenital coarctation of the aorta Turner’s syndrome is associated with coarctation of the aorta in girls. and sex chromosomal inherited disorders are associated with A variety of other autosomal cardiovascular developmental defects and/or pathology The major associations are as follows • Down syndrome: endocardial cushion detects (ostium pnmum ASD, regurgitant atrioventricular valves) • DiGeorge syndrome: tetralogy of Fallot and interrupted aortic arch • Friedreich’s ataxia: hypertrophic cardiomyopathy • Marfan syndrome: cystic medial necrosis of the aorta • Tuberous sclerosis: valvular obstruction due to cardiac rhabdomyomas GenOmiC impnnng refers to the phenomenon in which an offspring’s genes are expressed in a parent-specific manner Genomic imprinting is produced by DNA methylation, which is an epigenetic process Genome recombination between two defective viruses co—infecting the same host cell can yield a cytopathic wild-type genome. Recombination is gene exchange that occurs through the crossing segments over of two double-stranded DNAviruses molecules. Reassortment genome in two or more segmented that infect the same describes host cell. the mixing of The presence of rod-shaped intracytoplasmic inclusions known as Auer rods is characteristic of many forms of acute myeloblastic leukemia (AML) The M3 variant of AML. acute promyelocytic leukemia, is associated with the cytogenetic abnormality t( 15; 17). The probability that an autosomal recessive disease will be transmitted to a child can be calculated based on the maternal and paternal pedigrees. An unaffected individual (with unaffected parents) who has a sibling affected by an autosomal recessive condition has a 2/3 chance of being a carrier for that condition. Common findings in Down syndrome include mental retardation. facial dysmorphism and cardiac defects 95% of cases are caused by the presence of an extra chromosome 21 (trisomy). Less commonly, unbalanced Robertsonian translocations or mosaicism may be responsible Xeroderma pigmentosum develops due to a defect in DNA excisional repair This disease is characterized by increased sensitivity to UV radiation and a high incidence of all forms of cutaneous malignancy
Nondisjunction is the failure of chromosome pairs to separate properly during cell division This could be due to a failure of homologous chromosomes to separate in melosis I or a failure of sister chromatids to separate during meiosis II or mitosis. In most cases of CF, the mutation in the CFTR gene product causes defective post-translational folding and glycosylation The resuft is degradation of the CFTR integral membrane protein before it reaches the cell surface. A variety of genetic disorders can result in facial and/or palatal malformations, including deletions of the long arm of chromosome 22. However, deletions invoMng the long arm of chromosome 22 arecardiovascular also associatedanomalies). with DiGeorge syndrome (congenital thymic and parathyroid aplasia, congenital Patients with both sporadic and hereditary (associated with Von Hippel-Lindau disease) renal cell carcinomas are found to have deletions of the VHL gene on chromosome 3p. 47 X)(Y is the most common karyotype producing Kilnefelter Syndrome. Patients present with tall stature, small firm testes, azoospermia and gynecomastia Mild mental retardation may be present. Phenotypic mixing refers to co-infection of a host cell by two viral strains. resulting in progeny vinons that contain nucleocapsid proteins from one strain and the genome of the other strain. Since there is no change in the underlying viral genomes (no genetic exchange), the next generation of virions revert to their srcinal, unmixed phenotypes. Down syndrome (tnsomy 21) occurs in approximately 1 in 730 bye births The majority of fetuses with this chromosomal in utero. The thpleAmniocentesis marker test, quadruple marker test, and integrated test allow fordefect Down die syndrome sCreening. and chromosomal analysis of fetal cells can be used to verify the diagnosis. The cytogenetic defect t(1517) is associated with acute promyelocytic leukemia (AML type M3). Translocation of the gene for the retinoic acid receptor alpha from chromosome 17 to chromosome 15 leads to formation of the fusion gene PMLIRARa. This abnormal fusion gene product inhibits differentiation of myeloblasts and triggers the development of acute promyelocytic leukemia Patients with Turner syndrome may have karyotype 45,XO (complete monosomy), 45X0146XX (mosaicism), or 46XX (with partial deletion of one X chromosome) Monosomy appears to account for the majority of cases of Turner syndrome Mental retardation, eczema, and a “mousy or musty body odor in a toddler are signs of phenylketonuria (PKU). Most infants with PKU are born to two heterozygous carrier parents The probability that heterozygous carrier parents will transmit an autosomal recessive disease like PKU to a child is 1/4.
Primary amenorrhea, high arched palate. and widely spaced nipples are characteristic manifestations of Turner syndrome. An additional characteristic finding is ovarian dysgenesis, with the pathologic finding of streak gonads. Elevated alpha-fetoprotein levels are seen in multiple gestation, neural tube defects (including spina bifida. anencephaly), and abdominal wall defects. 2 In contrast, Down syndrome is associated with low alpha-f etoprotein levels in maternal serum and amniotic fluid The definitive prenatal diagnosis is made by karyotyping of fetal cells Trisorny 21 (Down syndrome) is characterized by mental retardation, facial dysmorphism, single palmar crease, cushion and duodenal Affected individuals have an increased risk ofendocardial AML-M7 and ALL detects. in childhood and early atresia Alzheimer disease in adufthood. On average, autosomal recessive conditions affect 25% of offspring of asymptomatic heterozygous carrier parents Classical galactosemia is an autosomal recessive disease In X-linked recessive inheritance 1) affected males will always produce unaffectedsons and camerdaughters, and 2) carrier females have a 50% chance of producing affectedsons and camèrdaughters G6PD deficiency follows this inheritance pattern and causes acute hemolytic anemia in response to oxidant drugs. Alternative splicing is a process where the exons of a gene are reconnected in multiple ways during post- transcriptional processing This creates different mRNA sequences and subsequently, different protein isoforms It is a normal phenomenon in eukaryotes that greatly increases the biodiversity of proteins encoded by the genome The presence of lactic acidosis red skeletal muscle fibers histologically suggest a mitochondrial myopathy. Thereand mayragged be vanable clinical expression of mitochondrial DNA defects in different affected family members due to heteroplasmy, which is the coexistence of both mutated and wild type versions of mitochondrial genomes in an individual celL In Kallmann syndrome. there is an absence of GnRH secretory neurons in the hypothalamus due to defective migration from the olfactory placode. These patients have central hypogonadism and anosmia, and often present with delayed puberty Trisornyi3(Patau syndrome) most often occurs secondary to nondisjunction during maternal meiosis I A severe condition, tnsomy 13 is strongly associated with cleft lip and palate. polydactyly, rocker-bottom feet and holoprosencephaly. TWO allele IOCi are said to be in linkage disequilibrium when a pair of alleles are inherited together in the same gamete (haplotype) more or less often than would be expected given random chance It is important to understand that this can occur even if the genes are on different chromosomes.
Thsorny21isdetectab by cytogenetic karyotype analysis and is the most common genetic cause of congenital mental retardation. Patients with Down syndrome are at increased risk of developing acute lymphoblastic leukemia and acute myelogenous leukemia Klinefelter syndrome is characterized by hypogonadism. eunuchoid habitus. small firm testes, and genotype 47 XXY. “Streak ovanes.” amenorrhea and infertility are the gonadal manifestations of Turner’s syndrome This condition is associated with short stature, webbed neck, low posterior hairline and coarctation of the aOrta. Sweat chloride concentrations >60 mEqII. are found in patients with cystic fibrosis (CF). The most common CF transmembrane conductance regulator (CFTR) mutation is a 3-base pair deletion that removes a phenylalanine at amino acid position 508 This mutation impairs posttranslational processing of the CFTR gene transcript and results in degradation of the gene product before it can be transported to the cell surface, causing a complete absence of the CFTR protein from the apical membrane of exocrine duct epithelial cells Down syndrome is associated with characteristic physical exam findings such as a flattened facies, epicanthal folds, oblique palpebral fissures, single palmar crease, shortened fifth digit, large tongue and others. Congenital heart defects. especially endocardial cushion defects, are common in children with Down’s syndrome The majority of cases occur due to maternal meiotic nondisjunction
GENETICS 2 Friedreich ataxia is an autosomal recessive condition. The mutated gene on chromosome 9 has an increased number of trinucleotide repeats Friedreich ataxia is often associated with hypertrophic cardiomyopathy. diabetes mellitus. kyphoscoliosis. and foot deformities Tay-Sachs disease is an autosomal recessive disorder caused by a deficiency in -hexosaminidase A, which results in accumulation of GM2 ganglioside. It is characterized by progressive neurodegeneration and a cherry- red macular spot. In contrast to Niemann-Pick disease, there is no hepatosplenomegaly. A 13- amyloid plays an important role in the development of Alzheimer disease Its precursor protein (APP) is coded by a gene located on chromosome 21 Patients with tnsomy 21 (Down syndrome) are likely to develop Azheimer disease after age 40. Mitochondnal diseases are characterized by exclusively—maternal inheritance The variable severity of these diseases is explained by the random distribution of normal and mutated mitochondria between daughter cells during mitosis; as a result, some cells may have completely
healthy mitochondria, while other cells contain mitochondria affected by genetic mutation (heteroplasmy) MELAS is a mitochondnal syndrome Fragile X syndrome arises secondary to an increase in the number of trinucleotide repeats within the FMR1 gene on the X chromosome Typical clinical features of this condition include mental retardation, facial deformities, and macroorchidism. Aft;ration of gene expression in Huntington disease is believed to occur due to hypermethylation of histones Hypermethylated histones bind DNA and prevent transcription of certain genes. This reads to the disruption of synthesis of some neurotrophic proteins. Fragile X syndrome is a common cause of inherited mental retardation. The disorder is X-linked and affects males. Patients have mental retardation, dysmorphic facial features (large jaw, large protruding ears) and macroorchidism. Early-onset familial Alzheimer disease is associated with three gene mutations: APP (chromosome 21), presenilin 1 and presenilin 2. Late-onset familial Alzheimer disease is associated with apolipoprotein E4 genotype. An increased number of thnucleotide repeats on the HD gene is associated wTth Huntington disease The larger the number of the repeats. the earlier the onset of the disease Tnnucleotide expansion occurs during paternal transmission, causing a genetic phenomenon called anticipation “Red ragged” muscle fibers are seen in mitochondrial diseases. Muscle fibers have this appearance because abnormal mitochondna accumulate under the sarcolemma Mitochondrial diseases show maternal inheritance. The fragile X mental retardation 1 gene is located on the long arm of the X chromosorne An increased number of CGG tnnucleotide repeats leads to hypermethylation of cytosine bases and subsequent gene inactivation This defect is the cause of fragile X syndrome, which manifests as mental retardation, facial dysmorphism, and macroorchidism. Neurofibromatosis type 1 is a single-gene autosomal-dominant disorder. It occurs due to mutation of the NFl gene located on chromosome 17. Café-au-Iait spots, multiple neurofibromas, and Lisch nodules are the most common symptoms.
HISTOLOGY RER functions include protein modification, folding and transfer The RER is well-developed in protein-secreting cells. The SER lacks surface ribosomes, and functions in lipid synthesis, carbohydrate metabolism, and detoxification of harmful substances The respiratory tract lining changes in structure and function as it progresses distally. Bronchi have a pseudostratified columnar ciliated epithelium with goblet cells and submucosal mucoserous glands and cartilage Bronchioles, terminal bronchioles, and respiratory bronchioles generally lack goblet cells, glands, and cartilage. By the level of the terminal bronchioles, the airway epithelium is ciliated simple cuboida[ Epithelial cilia persist up to the end of the respiratory bronchioles The lamellar bodies of type II pneumocytes store and release pulmonary surlactant into the fluid layer lining the inner surfaces of alveoli. Since the major function of suifactant is to reduce surface tension in this fluid layer, a surfactant deficiency can cause patchy alveolar atelectasis, as is seen in neonatal respiratory distress syndrome. HPV infection causes cutaneous and genital warts as well as benign and malignant epithelial neoplasia Koilocytosis is a hallmark of HPV infection. Koilocytes are pyknotic superficial or immature squamous cells with a dense, irregularly staining cytoplasm and perinuclear clearing [i-i stimulates the theca intema cells of the ovarian follicle to produce androgens Aromatase within the follicle’s granulosa cells subsequently converts these androgens to estradiol under FSH stimulation The theca extema cells serve as a connective tissue support structure for the follicle. All sympathetic preganglionic neurons release acetyicholine. which activates nicotinic acetylcholine receptors on postganglionic neurons. Medullary chromaffin cells are modified postganglionic sympathetic neurons that release catecholamines into the bloodstream The neurons that innervate sweat glands are also different from most postganglionic sympathetic neurons in that they release acetylcholine. Neutral proteases such as elastase in intra-alveolar fluid are derived from infiltrating neutrophils and alveolar macrophages When secreted in excess or if unchecked by serum antiprotease activity, they can cause destruction of terminal lung parenchyma, yielding centriacinar or panacinar emphysema. Kinesin and dynein are microtubuIe-assocated motor proteins that function in the rapid transport of materials and organelles within cells. Dynein also functions in ciliary and flagellar movement Type II pneumocytes have two important functions 1) regeneration of the alveolar lining following injury, and 2) surfactant production. The pnmary abnormality in Pagets disease is the increase in osteoclastic bone resorption.
Unique to the duodenum. the compound tubular Brunner’s glands of the submucosa secrete alkaline mucus into ducts that empty into the crypts of Lieberkühn. Peyer’s patches, in contrast, are lymphoid aggregates specific to the ileum. In the respiratory tract, the nose. paranasal sinuses. nasopharynx. most of the larynx, and the tracheobronchial tree are lined with pseudostratifled. columnar, mucus-secreting epithelium Stratified squamous epithelium is found only in the oropharynx. laryngopharynx, anterior epiglottis, upper half of the posterior epiglottis, and vocal folds (true vocal cords). C peptide is formed from proinsulin in the pancreatic 13-cell Golgi apparatus. packaged along with insulin in islet cell secretory granules, and secreted in equimolar concentrations with insulin The ovary is covered by a simple cuboidal germinar epthelium This epithelium is the site of srcin for many benign and malignant ovarian neoplasms Osteocytes have long intracanahcular processes that extend through the ossified bone matrix. These cytoplasmic processes send signals to and exchange nutrients and waste products with the osteocytes within neighboring lamellae via gap junctions Osteocytes can sense mechanical stresses and send signals to modulate the activity of surface osteoblasts, thereby helping to regulate bony remodeling Kinesin is a microtubule-associated. ATP-powered motor protein that facilitates the anterograde transport of neurotransmitter-containing secretory vesicles down axons to synaptic terminals. Actin filaments are anchored into the Z-Iine of the sarcomere The Z-hne lies in the center of the lucent region referred to as the I-band. Mnemonic: An Interesting Zoo Must Have Mammals (Actin in the I-band attaches at the Z-line, Myosin in the H-band attaches at the M-hne) Type I collagen is the most prevalent collagen in the human body and is the primary collagen in mature scars
IMMUNOLOGY 1 Educational Objective: C tetan/produces the protein exotoxin tetanospasmin that blocks release of inhibitory neurotransmitters from inhibitory motor interneurons in the CNS Tetanus is prevented by immunization with toxoid that triggers the production of antitoxin antibodies (active immunIty).
Hyperacute rejection is a process that is mediated by preformed recipient antibodies against antigens on the host organ (Type II hypersensitivity). Examples of such mismatches include ABO blood group antibodies and anti-H LA antibodies. This form of rejection occurs immediately upon perfusion of the transplanted organ by recipient blood and is often diagnosed intraoperatively due to immediate mottling of the organ. lnterleukin-2 (IL-2) is produced by helper T cells and stimulates the growth of CD4+ and CD8+ T cells and B cells. IL-2 also activates natural killer cells and monocytes. The increased activity of T cells and natural killer cells is thought to be responsible for lL-2s anti-cancer effect on metastatic melanoma and renal cell carcinoma. Secretory form of IgA consists of two immunoglobuhn monomers, J chain and secretory component. This immunoglobulin is abundant in tears. saliva, mucus and colostrum It is particularly important as a component of the colostrum, or the first breast milk fed to an infant after birth, where is functions to provide the infant with passive mucosal immunity. Of the cytokines released in the setting of tissue injury, TGF- and IL-lO are thought to downregulate local cytokine production and inflammatory reactions contributing to the systemic acute phase responseproinflammatory IL-i, IL-4, IL-5, IL-i and also IL-12 stimulate local immune reactions, andother mayaspects therefore be considered acts systemically to promote fever and of the acute phase response Interleukin-8 is a chemokine produced by macrophages that induces chemotaxis and phagocytosis in neutrophils. Other significant chemotactic agents include n-formylated peptides, leukotriene B, 5-HETE (the leukotriene precursor), and complement component C5a The carboxy terminal of the Fc portion of the heavy immunoglobulin chains represents the site that binds to the Fc receptors on neutrophils and macrophages Antibody bound to antigen is able to signal for the phagocytosis of that antigen by a conformational change of the Fc region allowing binding to the Fc receptor on phagocytes This leads to subsequent phagocytosts of the organism I antibody complex and subsequent destruction of the organism Antibodies against double-stranded DNA (anti-dsDNA) are specific for systemic lupus erythematosus. However, diagnosis they are only present in 60% of cases, so absence of anti-dsDNA does not rule out the Anti-Smith antibodies are also specific for SLE
Mutation of the FAS protein is thought to prevent apoptosis of auto-reactive lymphocytes, thereby disposing the individual to develop autoimmune disorders such as systemic lupus erythematosus Cerebellarataxia.tetangiectasias, and increased risk of sinoputmonary infections constitute a characteristic triad of ataxia telangiectasia. This illness exhibits autosomal recessive inheritance, and the defect is in a gene that codes for the “ATM” gene which plays a role in DNA break repair. The immune deficiency primarily manifests as an gA deficiency and predisposes to infections of the upper and lower airways. The classic madanterior of reactive arthritis is as follows: non-gonococcal urethritis, (possibly with uveitis). and arthritis It is the most common cause ofconjunctivrtis asymmetric inflammatory arthritis of the lower extremities in young men Reactive arthritis is a HLA-B27 associated arthropathy that occurs within several weeks of a GU (especially non-gonococcal urethritis) or 61 (especially bacterial enteritis) infection It belongs to the group of seronegative spondyloarthropathies (including ankylosing spondyhtis) and can cause sacroiliitis in about 20% of cases. Inherited defects invoMng the interferon-gamma signaling pathway result in disseminated mycobacterial disease in infancy or early childhood. Patients require lifelong treatment with antimycobacterial agents Polymyositis presents with symmetnc proximal muscle weakness. Muscle biopsy reveals inflammation. necrosis and regeneration of muscle fibers Preceding damage to myocytes with subsequent over- expression of MHC class I proteins on the sarcolemma leads to infiltration with CD8 T lymphocytes and myocyte damage Deficiency of the complement factors that form the membrane attack complex (ie., C5b-C9) results in recurrent infections by Ne,sser,à species. MHC Class II is expressed on the surface of antigen presenting cells (APC) and functions by presenting antigen that is foreign to the body. This antigen is taken into the APC by phagocytosis or endocytosis and is loaded onto MHC Class II within acidified endosomes. and the MHC Class Il protein-antigen complex is then expressed on the cell surface for subsequent interaction with T-lymphocytes Failure to acidify lysosomes would lead to deficient expression of MHC Class II bound to foreign antigen and subsequent lack of interaction between APCs and T-cells. Loc&defseagaist Cand,dais performed by T-cells, whereas systemic infection is prevented by neutrophils. For this reason, localized candidiasis is common in HIV-positive patients, while neutropenic individuals are more likely to have systemic disease. The caseating granulornas of tuberculosis almost always contain large epithehoid macrophages with pale pink granular cytoplasm and surface CD14 at the penphery. CD14 is a surface marker of the monocyte-macrophage cell lineage. CD4 and CD8 are surface markers of T-helper and T-killer cells, respectively.
Cytochrome c is a mitochondnal enzyme that activates caspases and indirectly brings about cell death through intrinsic pathway apoptosis. Myasthenia gravis is caused by circulating antibodies against the acetylcholine receptors of the neuromuscular junction. Autoantibody binding causes complement-mediated destruction of these receptors, producing weakness that most commonly affects the extraocular muscIes Myasthenia gravis is associated with thymoma or thymic hyperplasia. Patients with post-Streptococcal glomerulonephrihs will present with edema and hematuna with ainfection history must of Streptococcal such as impetigo. pharyngitisStreptococcus The Streptococcal be caused byinfection a “nephritogenic” strain ofcellulitis Group Aorb-hemolytic This is one example of a type Ill, or immune complex mediated. hypersensitivity syndrome. Leukocyte adhesion deficiency results from the autosomal recessive genetic absence of CD18 This leads to the inability to synthesize integrins. lritegrins are necessary for leukocytes to exit the bloodstream, and sequelae of this illness include recurrent skin infections WITHOUT pus formation, delayed detachment of the umbilical cord and poor wound healing. An infection with Ne,ssenà gonorrhoeae does not result in lasting immunity because of the ability of these bacteria to modify their outer membrane proteins by the process of antigenic variation. Antibodies generated during one infection will only be specific for that single antigenic epitope Also recall that repeated Neisseria infections can be caused by terminal complement deficiencies leading to an inability to form the membrane attack complex. Serum sickness is a Type Ill hypersensitivity reaction characterized by deposition of circulating, complement-fixing immuneglomerulonephritis. complexes and resulting vasculihs Associated findings include fever, urticaria, arthralgias, 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. bII Ia. JabI V Angioedema be hereditary (autosomal or acquired withtoACE inhibitor treatment) Incan hereditary angioedema. lowdominant) Cl esterase inhibitor (associated activity leads increases in bradykinin actMty ACE inhibitors should not be used in these patients. Aprotease 5 produced by N meningitidi and Ft gonorrhoeae This enzyme cleaves secretory gA at its hinge region rendering it ineffective. Secretory IgA exists on mucosal surfaces and in secretions and acts to bind and inhibit the action of pdi and flmbnae as well as other cell surface antigens that normally mediate mucosal adherence and penetration. Rheumatoid hritis is an autoimmune disease triggered by an unknown antigen Cartilage components serve as autoantigens that activate CD4 T-cells. which in turn stimulate B-cells to secrete rheumatoid factor, an 1gM antibody specific for the Fc component of self lgG. lL-4producedbytheTH2 subset of T-helper cells It facilitates growth of B-cells and TH2 lymphocytes, and stimulates antibody isotype switching. particularty to IgE. Chronic renalantibodies allograft rejection can manifestformed monthsafter to years after transplantation It is mediated by recipient to graft endothelium engraftment and causes an obliterative intimal smooth muscle hypertrophy and fibrosis of cortical arteries. Hyperacute rejection involves pre-formed recipient anti-donor endothelial antibodies which immediately cause vascular fibrinoid necrosis. neutrophil infdtration, and infarction of the graft Acute rejection may be cellular and/or humoral, causing, respectively, an interstitial mononuclear infiltrate andlor a graft vasculitis intermediate in severity between hyperacute thrombosis and chronic intimal thickening Anti-Rh (D) immunoglobuhri (Rh0GAM) consists of lgG anti-Rh (D) antibodies It is routinely administered to Rh-negative females at 28 weeks gestation and immediately postpartum lgG antibody isotypes are effective in blocking the maternal immune response to ‘foreign fetal Rh (0) antigens after fetomaternal transfusion DiGeorge syndrome is a T-Iymphocyte immunodeficiency that results from maldevelopment of the third and fourth branchial (pharyngeal) pouches due to a deletion on chromosome 22. Clinical associations with this syndrome include absence of a thymic shadow on neonatal X-ray, hypocalcemic tetany from absence of the parathyroids, cleft palate. mandibular deformity, lowset ears, and aortic arch abnormalities.
Glomerulonephritis, a photosensitive skin rash, and arthralgias in a young female are suggestive of systemic lupus erythematosus (SLE) 10-30% of patients with SLE have luDus anticoagulant. the most frequent cause of a prolonged PU and a false positive VDRL without any other hematological abnormality Lupus anticoagulant can cause an antiphospholipid antibody syndrome defined by elevated blood levels of antiphospholipid antibody(ies) with hypercoagulability (venous and arterial thromboembolism) andlor repeated second or third trimester miscarriages. Myasthenia gravis (MG) results from an autoimmune type II, antibody mediated, hypersensitivity reaction against skeletal myocyte surface acetyicholine receptors. Goodpasture syndrome similarly involves against basement membrane collagen of glomerular and alveolar epithelia (Type IIautoantibodies hypersensitivy). A Type Ill hypersensitivity mechanism apphes to poststreptococcal glomerulonephritis, hypersensitivity pneumonitis, and possibly Churg-Strauss syndrome Contact dermatitis and sarcoidosis result from Type IV, cell mediated, hypersensitivity. Immotile cilia syndrome (Kartagener syndrome) is characterized by the triad of situs inversus, chronic respiratory infections and infertility. It occurs due to a defect in the gene coding for the dynein arms of cilia Cystic fibrosis also causes recurrent infections and infertility, but not situs inversus, The seronegative spondyloarthropathies include ankylosing spondylitis, reactive arthritis, psoriatic arthritis and arthritis associated with inflammatory bowel disease. Individuals expressing HLA B27 are at increased risk for the seronegative spondyloarthropathies When a live attenuated vaccine (eg the Sabin oral polio vaccine) is applied to mucosal surfaces, it appears to promote more synthesis and secretion local mucosal IgA than killed vaccine (eg, the Salkprolonged inactivated polio vaccine) This of increase in mucosal IgA does offersa immune protection at the normal site of viral entry. The wheal observed after an insect sting results from an allergic, or Type I hypersensitivity reaction. The allergens present in the insect venom result in antibody class switching to IgE on initial exposure. and subsequent exposure results in degranulation of mast cells and basophils with release of histamine and heparin among other vasoactive mediators. This degranulation can cause a response as mild as an urticarial wheal, or as severe as anaphylaxis. The best way to prevent neonatal tetanus is to ensure that all pregnant women have been vaccinated with the tetanus toxoid, to allow transfer of protective lgG antitoxin antibodies across the placenta to the fetus The acute hemolytic transfusion reaction is an antibody-mediated (Type II) hypersensitivity reaction wherein host antibody binds antigen on transfused donor red blood cells, activating complement The complement membrane attack complex causes erythrocyte lysis, and anaphylatoxins mediate vasodilatation and symptoms of shock
Ataxia-telangiectasia is an autosomal-recessive disorder resulting from a defect in DNA-repair genes. The DNA of these patients is hypersensitive to ionizing radiation Manifestations include cerebeNar ataxia, oculocutaneous telangiectasias, repeated sinopulmonary infections, and an increased incidence of maIignancy Organ rejection is divided into three forms: hyperacute, acute and chronic. Acute rejection occurs within weeks of transplantation and is primarily mediated by host T-lymphocytes that act against donor MHC (HLA) antigens. This causes a mononuclear infiltrate on histopathology and clinical reduction in function of the transplanted organ. Prevention is attempted with calcineurin inhibitors and systemic corticosteroids. The second most common cause of severe combined immunodeficiency (SCID) is autosomal recessive deficiency of adenosine deaminase. an enzyme necessary for the elimination of excess adenosine within cells Toxic levels of adenosine accumulate within lymphocytes in this condibon, leading to lymphocyte cell death and resultant cellular and humoral immune deficiency. Treatment is presently being researched using retroviral vectors to “infect’ patient stem cells with the gene coding for adenosine deaminase.
IMMUNOLOGY 2 The Haemophi/us ,nfluenzae type b (Hib) vaccine contains bacterial capsular polysaccharide conjugated with diphtheria toxoid. Patients with SCID present with recurrent infections caused by bacteria, viruses, fungi, and opportunistic pathogens as well as failure to thrive and chronic diarrhea within the first year of life. The candida skin test gauges the activity of the cell-mediated immune response The active cells in the cell-mediated response are macrophages CD4 and CD8 T-Iymphocytes and NK cells Poison ivy dermatitis is one form of allergic contact dermatitis, which is a type IV hypersensthvity reaction Type IV hypersensitivity reactions are mediated primarily by T lymphocytes. The cutaneous lesions in poison ivy dermatitis are typically linear erythernatous papules. vesicles, or bullae that are pruritic. hTWnUflObC abnormahties in sarcoidosis include intraalveolar and interstitial accumulation of CD4+ T cells, resulting in high CD4:CD8 T-cell ratios in bronchoalveolar lavage (BAL) fluid. Contact dermatitis, granulomatous inflammation, the tuberculin skin test and the Candida extract skin reaction are all examples of delayed-type hypersensitMty reactions (DTH) The cells that mediate DTH reactions are TH1 -lymphocytes that release interferon-g to cause recruitment and stimulation of macrophages 0TH reactions takewhich days cause to reach theireffects peak activity; this is in contrast to the other hypersensitivity reactions clinical within minutes of antigen exposure.
Langerhans cells are dendntic cells found in the skin that act as professional antigen presenting celIs These cells are derived from the myeloid cell line and they possess characteristic 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 blood and mounts a humoral immune response to these antigens causing hemolysis in the fetus in utero due to the capability of lgG to cross the placenta and enter the fetal circulation. This is one form of Type II (antibody mediated) hypersensitivity Henoch-Schonlein purpura is a leukocytoclastic vascuhtis that occurs due to deposition of IgAcontaining immune complexes and manifests with palpable lower extremity purpura. abdominal pain, arthralgias and renal involvement. It is the most common cause of systemic vasculitis in children and classically occurs in young males 3-10 years old. Chronic granulomatous disease is an X-hnked disorder resulting in deficiency of NADPH oxidase. the enzyme responsible for formation of reactive oxygen species in neutrophil phagolysosomes Neutrophils affected by this disorder are unable to kill catalase-producing organisms (Staphylococcus, catalase-producing organIsms.Serratia, E. coli etc.), but they remain effective in killing nonHyper-lgM syndrome results from an inability of B-lymphocytes to undergo isotype switching from 1gM to other immunoglobulin isotypes such as lgD, lgG, IgE and IgA Clinically, 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 [anans giant cells are characteristic of granulomatous conditions, including the caseating granulomas associated with MycobacteriUm tuberculosis infection They have multiple nuclei peripherally organized in the shape of a horseshoe. The macrophages that form these giant cells are activated by CD4+ Li lymphocytes. The prOCeSS of negativeselection in T cell maturation is essential for eliminating T cells that bind to self MHC or self antigens with overly high affinity. This process occurs in the thymic medulla If these cells were permitted to survive, they would likely induce immune and inflammatory reactions against self antigens leading to autoimmune disease.
Killed or viral component vaccines predominantly generate a humoral immune response instead of a strong cell-mediated immune response Selective gA deficiency predisposes to recurrent sinopulmonary and GI tract infections due to the absence of secretory IgA It is also associated with an anaphylactic response to transfused blood products due to an immune response against transfused IgA which the patierits body recognizes as foreign Graft-versus-host disease is mediated by T-tymphocytes of the donor tissue that are sensthzed against MHC antigens of recipient. Skin, liver and intestine are commonly involved. • The findings of hilar adenopathy. pulmonary infiltrates, and non-caseating lung granulomas in an African American female point to a diagnosis of sarcoidosis. Granuloma formation is a manifestation of cell-mediated immunity driven by products of TH1 type CD4+ helper T cells, particularly IL-2 and interferon-y (IFN-y), which stimulate TH1 type cell proliferation and macrophage activation, respectively. • TH2 type CD4+ helper T cells predominantly drive humoral immune responses. Their products include IL-4, which promotes IgE antibody production by B-cells, and IL-5, which promotes the production and activation of eosinophils and B-cell synthesis of Ig& X-linked agammaglobulinemia is characterized by low levels of circulating B-cells and low levels of all immunoglobulins. including IgA. Patients with IgA deficiency are predisposed to recurrent respiratory infections and persistent giardiasis. CD1 9. CD2O and CD21 are B-cell surface markers IFN- y secreted by T-Iymphocytes contributes to granuloma formation Pulmonary tuberculosis infection is controlled through the action of CD4+ TH1 lymphocytes and macrophages These cells work together to contain Al. tuberculosis within a caseous granuloma, which offers the macrophages inside an opportunity to kill the remaining organisms if the necrotic area is small enough Immature T-Iymphocytes express both the CD4 and CD8 cell surface antigens in addition to a complete TCR or a pro-TCR These lymphocytes exist in the thymic cortex where they undergo positive selection and in the thymic medulla where they undergo negative selection. Atypical lymphocytes observed in the peripheral blood smears of patients with infectious mononucleosis represent activated CD8+ cytotoxic T-lymphocytes. These activated 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 cross occur,the as placenta. the naturally occurring antibodies (anti-A -B) areare of predominantly the 1gM type lgG and cannot In contrast, in type 0 mothers. the and antibodies and can cross the placenta to cause fetal hemolysis. IL-12 stimulates the differentiation of ‘naive T-helper cells into the T_1 subpopulation. Patients with IL-12 receptor deficiency suffer from severe mycobacterial infections due to the inability to mount a strong cell- mediated granulomatous immune response. They are treated with IFN-y DiGeorge syndrome causes an extreme deficiency in the number of mature T ‘ymphocytes, leading to poor development of the lymph node paracortex. In contrast. agammaglobulinemia causes an absence of B cells, preventing primary lymphoid follicles and germinal centers from forming in the lymph node cortex. Chronic granulomatous disease (CGD) is most frequently an X-linked disorder resulting from a deficiency of NADPH oxidase Deficiency of this enzyme leads to an inability of neutrophils to form the oxidative burst to kill organisms in their phagolysosomes Organisms that produce catalase are ineffectively killed by these defective neutrophils while organisms that do not produce catalase can still be killed due to accumulation of bacterial hydrogen peroxide within the phagosome.
Severe combined immunodeficiency (SCID) is a disorder marked by combined T- and B-cell dysfunction Some important features include: frequent fungal. viral, and bacterial infections early in life; marked hypogammaglobulinemia; thymic hypoplasia; persistent diarrhea; failure to thrive; severe lymphopenia; and lack of clinically apparent involvement of any other organ systems The Wiskott-Aidnch syndrome consists of the triad of eczema. thrombocytopenia and combined B-lymphocyte and T-lymphocyte deflciency Onset of disease is early in life with thrombocytopenia present at birth and eczema and repeated infections, particularly by encapsulated organisms, following at 6 to 12 months of age The classical complement cascade begins with binding of the Cl complement component to either two molecules of lgG or to two molecules of 1gM. Because 1gM circulates in pentameric form, it is a much better activator of the complement system The Cl molecule binds to the Fc region of the heavy immunoglobulin chain in the region near the hinge point. CD8 cells recognize foreign antigens presented with MHC class I proteins. Each MHC class I molecule consists of a heavy chain and a -rnicroglobuIin. The staphylococcal scalded skin syndrome occurs in infants and children due to the production of the exotoxin extoliatin by Staphylococcus species It causes widespread epidermal sloughing, especially with gentle pressure (Nikoisky’s sign)
MICROBIOLOGY- Cardiology Diphtheria toxin is an AR exotoxin that nbosylates and inactivates elongation factor-2 (EF-2) This inhibits protein synthesis and ultimately leads to cell death Rheumatic fever is an autoimmune reaction that occurs following untreated Streptococcus pyogenes(GAS) pharyngths Antigenc similarity between bacterial antigens and normal self antigens in the heart and CNS are believed to cause formation of anti-self antibodies resulting in RE Enterococcus is a component of the normal colonic flora capable of growing in hypertonic (65%) NaCI and bile Urine in the bladder is usually sterile but can be contaminated by instruments or catheters passed through the outer part of urethra Contaminating organisms include colonec flora (which are also frequently found on the perineum and skin surrounding the genitals), such as enterococcus Thus, genitourinary manipulation has been known to cause enterococcal endocarditis. Viridans streptococci produce dextrans from glucose that aid these organisms in colonizing host surfaces such as dental enamel and heart valves These organisms cause subacute bacterial endocarditis most classically in patients with preexisting cardiac valvular defects after dental manipulation This is why antibiotic prophylaxis is used prior to dental work in patients with valvular abnormalities S. aureus is the most common cause of tricuspid endocarditis in intravenous drug users. P aeruginosa is the second most common cause in this patient population. These patients can develop muttiple septic emboli in lungs. Pulmonary arearteries). almost always hemorrhagic due to the dual blood supply to the lungs (pulmonary and infarcts bronchial Viridans streptococc are normal inhabitants of the oral cavity and are a cause of transient bacteremia after dental procedures in healthy and diseased individuals. In order to cause subacute bacterial endocarditis they require preexisting valve damage leading to the local deposition of flbnn required for them to adhere Rheumatic fever (RE) can be reduced, as it has been in industrialized nations, by prompt treatment of streptococcal pharyngitis and eradication of infective streptococci with prolonged penicillin treatment. RF follows untreated Group A Streptococcal (GAS) pharyngitis while acute post-streptococcal glomerulonephritis can follow either pharyngitis or skin infection by GAS regardless of treatment The treatment of a coagulase-negative staphylococcal infecbon involves initial empiric treatment with vancomycin with or without rifampin or gentamicin due to the widespread antibiotic resistance of S epiderinidís, especially in nosocomial infections Staphylococcus epidermidis and S saprophyticus are both coagulase-negative staphylococci species. Staphylococcus epidermidis is the most common cause of infective endocarditis in
patients with prosthetic valves and septic arthritis with prosthetic joints It is susceptible to novobiocin C d,phtheriàe causes diphthena. an acute bacterial disease that initially affects the oropharynx The organism is spread by respiratory droplet transmission and causes disease via its AB exotoxin The B (think: binding) subunit allows penetration of the A (think: active) subunit into the cell, to inhibit ribosome function Neural and cardiac toxicity are serious potential sequelae. Immunization with the diphtheria toxoid induces production of circulating lgG against the exotoxin B subunit, effectively preventing disease
MICROBIOLOGY-Genitourinary Antiviral drugs currently recommended for the treatment of primary genital herpes include the nucleoside analogs (eg, acyclovir). These nucleoside analogs are incorporated into newly replicated viral DNA and ultimately terminate viral DNA chain synthesis. Streptococci are catalase-negative, staphylococci are catalase-positive S pyogenes (Group A Streptococcus) is beta-hemolytic and bacitracin susceptible S agalactiàe (Group B Streptococcus) is beta-hemolytic and bacitracin resistant Streptococcus pneurnoniàe is bile soluble (unable to be cultured in bile) and optochin susceptible PeMc inflammatory disease is most commonly caused by Neisseriagonorrhoeaeor Chlamydià trachomatjs and is strongly associated with an increased incidence of ectopic pregnanCy. The gonococci use their pill to mediate adherence to the mucosal epithelium. An antibody against the specific pilus protein expressed by a gonococcus would prevent mucosal adherence and initiation of infection, but each gonococcus possesses the ability to modify the pilus protein that it expresses by the process of antigenic variation and thus avoid host defense to some degree as well as make vaccination directed against the pilus protein difficult. Neissena organisms can be isolated by culture on selective media such as the Thayer-Martin VCN medium, which inhibits the growth of contaminants such as Gram positive organisms, Gram negative organisms other than Ne,sser,à. and fungi. 11 V Rheumatic fever and acute post-streptococcal glomerulonephritis are the late sequelae of Group A Streptococcal (Streptococcus pyogenes) infections Post-streptococcal glomerulonephritis can follow either a skin infection (impetigo) or an episode of streptococcal pharyngitis, whereas rheumatic fever is associated only with streptococcal throat infection. Human papilloma virus (HPV) types 16. 18. and 31 are strongly associated with anal and cervical squamous cell carCinoma. HIV infection increases the prevalence of HPV infection and the risk of anal carcinoma this risk is further augmented in men who have sex with men.
Use of broad-spectrum antibiotics suppresses the normal bacterial flora of the vagina and facilitates Candkla overgrowth. Antibiotic use is the most common cause of Candklavaginitis Other potential causes include contraceptive use, systemic corticosteroid use, diabetes mellitus, and immunosuppression E co//is one of the dominant components of the normal flora in the intestinal tract of humans and animals It causes approximately 80% of all urinary tract infections P fimbnae are the most important viwlence factor that uropathogenic Eco/,express Without P flmbnae, Ecokwould not be able to bind to uroepithelial cells and infect the bladder, ureters, and kidneys, Instead, the bacteria would simply be washed away during urination. Enterobiàs,s Verm/CU/aFiS infection (enterobiasis) occurs most frequently in school-age children and presents with penanal pruritus Diagnosis is made by the Scotch tap& test Albendazole or mebendazole is the first- line treatment, with pyrantel pamoate as an alternate agent preferred in pregnant patients.
Enterotoxins, Exfoliative Toxins and Toxic Shock Syndrome Toxin (TSST-1) are the toxins with superantigen activity Superantigens interact with major histocompatibdity complex molecules on antigen presenting cells and the variable region of the T lymphocyte receptor to cause nonspecthc widespread” activation of T-cells resulting in the release of iriterteukin-2 (IL-2) from the T cells and IL-i and TNF from macrophages. The immune cascade, in turn, is responsible for the effects of TSS. E co//is the most common cause of urinary tract infection in both healthy adults and elderly patients. E coil is a part of the normal bowel flora, and special adhesive proteins allow some strains to colonize and ascend the urinary tract This can result in pyelonephritis or bacteremia
and sepsis access to the bloodstream The most common cause of E co/,bacteremia is a urinary tractfrom infection. Gram-negative sepsis is caused by the release of LPS from bacterial cells during division or by bacteriolysis; LPS is not actively secreted by bacteria. Lipid A is the toxic component of LPS: it causes activation of macrophages leading to the widespread release of IL-i and TNF-alpha. which cause the signs and symptoms of septic shock: fever, hypotension, diarrhea. oliguria. vascular compromise. and DIC P. aeruginosa is a non-lactose fermenting gram-negative organism. It is a common cause of urinary tract infections in patients with indwelling bladder catheters. Mucopurulent cervicitis with cervical motion tenderness is a frequent indicator of PlO caused by N. gonorrhoeae or ChlamydIà trachomatis PlO can potentially lead to ectopic pregnancy and infertility due to salpingitis leading to scarring of the fallopian tubes if not treated appropriately. S saprophyticus is responsible for almost half of all UT1s in sexually active young women Staphylococcus saprophyticusbelongs to coagulase negative staphylococci and is unique among these because ft is resistant to novobiocin.
Protein M is the major virulence factor for Streptococcus pyogenes It inhibits phagocytosis and complement activation, mediates bacterial adherence, and is the target of type-specific humoral immunity to S pyogenes Ch/amydiä trachomat,s serotypes Li through L3 cause lymphogranuloma venereum (LGV), a sexually transmitted disease characterized initially by painless ulcers with later progression to painful inguinal lymphadenopathy and ulceration Histologically, LGV is characterized by chlamydial inclusion bodies in the cellular cytoplasm.
Humans acquire schistosomiasis via contact with freshwater that contain snails infected with Schistosoma and S mansonicause intestinal and hepatic schistosomiasis, and S causesSjàponicum urinary schistosomiasis haematob,umIarvae
Acute bacterial arthritis in sexually active young adults is most commonly caused by N gonorrhoeae. S aureus septic arthritis is most common in children and non-sexually active adults The combination of new onset genital vesicular rash with a positive Tzanck smear in a previously asymptomatic patient is suggestive of primary genital herpes due to HSV-2 Recurrences of genital herpes can be reduced through daily treatment with oral valacyclovir. acyclovir, or famciclovir, these drugs suppress reactivation of latent HSV infection. Condom use can help prevent a pnmary genital HSV infection, but does not prevent reactivation of latent infection. E co//is the most common pathogen causing cystitis and acute pyelonephritis The second most common cause of UTI in sexually active women is Staphylococcus saprophyticus tJTls most commonly affect women because of their very short urethra: recurrent UT1s in boys or men
require investigation for urinary tract obstruction or reflux. The visualiza1on of spirochetes (such as T pallidum. the causative organism in syphilis) can be accomplished with darkfield microscopy, which reveals helical motile Organisms.
MICROBIOLOGY-GIT Travelers diarrhea is most frequently related to ETEC that produces heat labile (LT, 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.
In absence of the normal intestinal microbial flora (as may be the case after a course of antibiotics), ClostridAim dñWdlle can overgrow and produce enterotoxin (toxin A) and cytotoxin (toxin B) Clinical disease resulting from C dif/icile overgrowth can range from transient diarrhea to severe pseudomembranous colitis. In absence of the normal intestinal microbial flora (as may be the case after a course of antibiotics), ClostridAim dñWdlle can overgrow and produce enterotoxin (toxin A) and cytotoxin (toxin B) Clinical disease resulting from C dif/icile overgrowth can range from transient diarrhea to severe pseudomembranous colitis. Trypanosoma cruis trypanosomiasis). endemic in rural areas of Central Souththe America It causes disease (American This parasite canand destroy myenteric plexi Chagas in the esophagus, intestines, and ureters, causing secondary achalasia. megacolon, and megaureter, respectively
Intraabdominal infections are polymicrobia[ with B. fragthsandE co//being the most prominent organisms isolated. The minimal infectious dose for cholera infection is usually quEte high with 1O organisms required to cause infection after ingestion of contaminated water. V. cholerae is very sensitive to gastric acidity and any condition that increases gastric pH will lower the minimum infective dose of V cholerae by many orders of magnitude. Gastric pH can be increased by achlorhydria. food ingestion. and antacid ingestion The UreaSe breath test is used to noninvasively detect H pyIoiiinfection The patient consumes 13C-Iabeled urea and his breath is then monitored for the presence of ‘3C-Iabeled carbon dioxide, which would indicate the presence of the H pylon product urease in the stomach. Mucosal invasn is an essential pathogenic mechanism for Shigeffa infection and is the most significant factor in causing disease. Shigella gains access to the gut mucosal epithehum, specifically by entering M cells in Peyer’s patches. It then escapes the phagosome, spreads laterally to other eprthehal cells, and releases shiga toxin. The process of cellular invasion induces a robust inflammatory response in the host it is this response that is primarily responsible for the diarrhea seen in shigellosis Campy/obacterinfection is a common cause of inflammatory gastroententis and can be acquired from domestic animals (cattle, chickens. dogs) or from contaminated food. The diarrhea is inflammatory and is accompanied by fever, abdominal pain and tenesmus Canoyhbacterinfection is associated with Guillain-Barré syndrome.
Infant botulism is frequently due to honey consumption More than 12% of honey samples contain low numbers of C botu/,num spores. Whereas infant botulism results from consuming C botu/,hum spores, adult botulism results from consuming preformed toxin, typically in canned food Symptoms of infant botulism include constipation, mild weakness. lethargy. and poor feeding.
The strain of Enterohemorrhagic E coh’(EHEC) 0157:H7 is thought to cause at least 80% of cases of hemolytic-uremic syndrome (HUS) in North Amenca, and is recognized as a common cause of bloody diarrhea in developed countries It is associated with consumption of undercooked ground beef and elaborates a Shiga-like toxin capable of inhibiting protein synthesis in colonic mucosal cells and renal endothelial cells This particular strain of E cob is unable to ferment sorbitol and does not produce a glucuronidase. Shiga-like toxins (ak.a. Vera cytotoxins) are produced by Enterohemorrhagic E coIi(EHEC). As their name implies, these toxins are nearly identical to the Shiga toxin produced by Shigella dysenteriäe These toxins function to inhibit the 60s ribosomal subunit in human cells thereby blocking synthesis by A preventing bindinginofthat tRNA. This mechanism that of diphthenaprotein toxin and exotoxin of Pseudomonas the latter toxins act ondiffers EF-2, from not the 60S ribosomal subunit. Antibiotics disturb the normal intestinal flora and can lead to C diffkiie overgroWth. C difhdlle causes colitis with severity ranging from transient watery diarrhea to pseudomembranous colitis. Diarrhea may begin up to four weeks after antibiotic therapy. Metronidazole is the treatment of choice Depending on the age and condition of host as few as 10 cells of any Shigella species can cause infection, although the infectious dose is usually much higher Other organisms that can cause diarrhea with only a small inoculum include Campylobacterjejuni(500), Entamoeba histolytica (as few as one organism), and Giärd,à Iamb/ia (as few as one organism) The P/comaviidae family includes the rhinovirus and enterovirus genera Rhinoviruses are 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.
MICROBIOLOGY-Head & Neck Fever, vesiculoulcerative gingivostomatitis. and cervical lymphadenopathy are the most common clinical manifestations of primary infection with herpes simplex virus (HSV-1). Reactn,ation of a latent HSV infection in the trigeminal ganglia generally results in more limited perioral blisters or “cold sores An abortive viral infection does not cause significant cytopathic effects Scarlet fever is characterized by fever. pharyngitis. sandpaper—like rash. circumoral pallor, and a strawberry tongue. It is caused by strains of Group A streptococcus that produce pyrogenic exotoxins. Scarlet fever can predispose to acute rheumatic fever and glomerulonephritis. Non-pathogerucCorynebacterium can cause severe pseudomembranous pharyngitis after acquiring the Tox gene via lysogenization by a temperate bacteriophage. Neutropenic patients are at risk for infection with Aspergillus fumigatus This fungus produces septate hyphae with acute V-shaped branching It causes invasive aspergillosis, aspergillomas, and allergic pulmonary aspergillosis. Diphtheria exotoxin inhibits host cell protein synthesis by catalyzing the ADP-nbosylation of host cell elongation factor-2 (EF-2) Dhtheria infection is associated with a 5-10% mortality rate, especially in younger patients or those with myocarditis. Cardiomyopathy is the most common cause of death. Treatment includes diphtheria antitoxin (passive immunization), antibiotics, and active immunization. Of these, passive immunization with antitoxin is the most important and has the greatest effect on prognosis. Interferons a and 13 are produced by a wide variety of eukaryotic cells in response to viral infection. These interferons act as cytokines on neighboring cells, stimulating them to synthesize antiviral proteins that impair viral protein synthesis Diphtheria toxin and pseudomonal exotoxin A act by nbosylating and inactivating elongation factor-2, inhibiting host cell protein synthesis and causing cell death. Pseudomonas aeruginosa is a nonlactose-fermenting, oxidase-positive, motile. Gram-negative rod. It is the most common cause of malignant otitis extema (MOE), a serious infection of the ear seen in elderly diabetic patients. MOE presents with exquisite ear pain and drainage, and granulation tissue is often seen within the ear canal. C. diphtheriäe is cultured on cysteine-tellurite agar. The resultant colonies are black in color. The bacterium produces intracellular polyphosphate granules, called metachromatic granules, that can be detected on microscopy after methylene blue staining. Actinomyces israeli/is a Gram positive organism that is best known for causing cervicofacial actinomycosis in patients following dental manipulation or other oral trauma The disease is characterized by a slowly growing and firm-feeling abscess in the face or neck region that
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 envgene) envelope glycoproteins gpl2O andofgp4l (from the Important from transcription and translation the po/gene The regulatory tat and enzymes areproduced required rev genesare for viral rephcation
Oral thrush is caused by Cand/da alb,cans infection It is associated with wearing dentures, diabetes mellitus, and immunosuppression. Unexplained oral thrush in an otherwise healthy person suggests the possibility of HIV infection CMV is typically associated with subclinical infection in the immunocompetent. with the occasional individual developing a mononucleosis-like syndrome that is Monospot negative In the immunocompromised, primary or reactivated CMV infection can result in severe retinitis, pneumonia, esophagitis, colitis, andlor hepatitis. Viruses with segmented genomes (eg. orthomyxoviruses and rotaviruses) are capable of genetic shifts through reassortment. Reassortment involves exchange of entire genome segments, a far more dramatic process than the point mutations responsible for genetic drift The findings of facial pain. headache. and black necrotic eschar in the nasal cavity in a patient with diabetic ketoacidosis are highly suggestive of mucormycosis Histologic examination of the affected tissue is necessary to confirm the diagnosiS. These fungi show broad nonseptate hyphae with nght angle branching. Treatment consists of surgical debñdernent and amphotericin B. The Thayer-Martin selective medium is used to isolate Neiseria species from clinical cultures. It is a chocolate (i.e., heated blood) agar that contains vancomycin to inhibit the growth of 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. Children aged one to three years who develop gingivostomatitis characterized by ulcerative lesions with intranuclear inclusions are likely experiencing primary infection with herpes simplex virus type 1 (HSV-1). HSV-1 and other herpesviruses are enveloped and possess doublestranded DNA genomes The congenital rubella syndrome is predominantly characterized by neonatal defects of the head (microcephaly, mental retardation), eyes (cataracts), ears (deafness), and heart/cardiovascular system
(patent ductus arteriosus, peripheral pulmoruc stenosis). To decrease the incidence of this syndrome, the CDC currently recommends the vaccination of children and non-pregnant females of childbearing age with live, attenuated rubella virus vaccine. Mucormycosis is an opportunistic infection caused by Rhizopus, Mucor and Abs,d,à species. The classic clinical picture is paranasal sinus involvement in a diabetic or immunosuppressed patient The fungi form broad nonseptate hyphae that branch at right angles The type b vaccine composed cell wall polysaccharide with Haemophiius protein toxoid,hfiuenzae from either diphtheria oristetanus This of vaccination can be given asconjugated 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 areindividuals the cause living of a pharyngoconjunctival fever(such that asclassically occurs in small outbreaks among together in close quarters military barracks or camp dormitories)
MICROBIOLOGY-Hepatic Hepatitis A virus can be inactivated with water chlorination, bleach (1:100 dilution), formalin, ultraviolet irradiation, or boiling to 85° C for one minute Transmission of the hepatitis A virus occurs through the fecal-oral route and is common in areas with overcrowding and poor sanitation Outbreaks frequently result from contaminated water or food, with raw or steamed shellfish a common culprit in the United States Chioroquine is the treatment of choice for uncomplicated malaria contracted in a chioroquinesensitive geographic region. It eliminates susceptible erythrocytic forms of all Plasmodia species Pnmaquine is added in the treatment of infections with P v/vax and P ovale in order to eradicate the intrahepatic stages of these two malarial species.
Because of the remarkable variety in the antigenic structure of hepatitis C virus envelope proteins, the production of host antibodies lags behind the production of new mutant strains of HCV and effective immunity against infection is not conferred The hepatitis B virus genome consists of partially double-stranded circular DNA Replication is accomplished through a reverse transcriptase DNA polymerase that creates an intermediate + single-stranded RNA template and double-stranded DNA progeny Often referred toas the delta agent or the hepatitis delta virus, hepatitis D virus is a 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 Hepatitis A virus infection is most commonly silent or subclinical (“anicteric) in children but can also present as an acute, self-limited illness characterized by jaundice, malaise, fatigue, anorexia, nausea, vomiting, right upper quadrant pain, or an aversion to smoking A component of the hepatitis B virus envelope. HBSAg is a noninfective glycoprotein that forms spheres and tubules 22 nm in diameter Infected hepatocytes may secrete enormous quantities of HBsAg, often considerably exceeding the amount of HBcAg produced. Neonates born to HBsAg- and HBeAg-positive mothers are at high risk of chronic infection, experience fast HBV replication, and demonstrate mild hepatic injury histologically
MICROBIOLOGY-Neurology E. coli is a frequent cause of neonatal meningitis, second only to Group B Streptococci (GBS) The capsule synthesized by some E cok(K-1 antigen) is a virulence factor that allows the bacteria to survive hematogenous spread and to establish meningeal infection. Most strains of E co//causing neonatal meningitis do possess this K-i antigen. The finding of multiple ring-enhancing lesions in an HIV patient is most likely due to toxoplasmosis C/OSt,ithum tetanñs responsible for tetanus, a toxin-mediated disease that causes uncontrolled muscle spasms and respiratory failure. Toxin travels within the motor neuron by retrograde transport into the spinal cord where it causes inhibition of inhibitory intemeurons and unregulated firing of primary motor neurons. Ne,sseriä meningit/dis can cause upper respiratory infection, meningitis and meningococcemia Immunity against these bacteria is provided by antibodies against their polysaccharide capsules. The meningococcal vaccine contains immunogenic capsular polysaccharides from four major serotypes of N. meningitidis and induces production of protective anticapsular antibodies
Subacute headache. fever, and neck stiffness in the presence of a lymphocytic CSF pleocytosis, modestly elevated CSF protein level, and otherwise normal CSF parameters points to a diagnosis of aseptic meningitis. Enteroviruses, including coxsackievirus and echovirus, are the most common causes of aseptic meningitis Varicella lgG antibodies suggest an antecedent primary varicella-zoster virus (VZV) infection. These antibodies generally conferofimmunity against chickenpox reinfection but not against herpes zoster, which is reactivation VZV
Rhabdoviridae (rabies) are single-stranded RNA viruses enveloped by a bullet-shaped capsule, which is studded by glycoprotein spikes that bind to nicotinic acetyicholine receptors Once deposited in a wound, the virus stays local for a period of days or weeks before binding to acetylchohne receptors on peripheral nerve axons and traveling retrograde to the central nervous system Ne,sseriä meningit/dis gains access to the CNS by first colonizing the nasopharynx and subsequently invading the mucosal epithelium and gaining access to the bloodstream. Through the blood. it spreads to the choroid plexus, gains access to the CNS through the blood—brain barrier, and initiates an inflammatory process.
Congenital toxoplasmosis is a transpiacental infection (acquired in utero). Its classic triad includes hydrocephalus, intracranial calcifications and chorioretinitis Expecting mothers should avoid cat feces to help prevent exposure to Toxoplasma. Meningococcaliipooiigosaccharide (LOS) is responsible for many of the toxic effects observed in meningitis and meningococcemia Blood levels of LOS correlate closely with morbidity and mortality Clostridia are Gram positive spore-forming anaerobic rods. C botulinum is the bacteria responsible for botulism, a toxin-mediated disease Local injections of botulinum toxin into muscle are used to treat focal dystonias, achalasia and spasms. Enteroviruses are the most common cause of viral aseptic menirigitis The enterovirus group includes the coxsackieviruses, echoviruses and pohoviruses Pohovirus can cause lower motor neuron injury in addition to meningitis, especially in non-immunized individuals from endemic regiOns. In AIDS patients, the radiographic finding of ring-enhancing lesions in both cerebral hemispheres is most often indicative of toxoplasmosis Primary CNS lymphorna is typically composed of B-lymphocytes and most commonly occurs in immunocompromised patients (such as those with AIDS). Bacterial meningitis causes an increase in cerebrospinal fluid (CSF) neutrophil count and protein concentration as well as a decrease in CSF glucose. Streptococcus pneumoniàeis a leading cause of community-acquired pneumonia. otitis media, and meningitis in adults. Spneumoniàe appears on Gram stain as lancet-shaped, Gram-positive cocci in pairs. Cryptococcus neoformans causes meningoencephalitis in HIV (+) patients The latex agglutination test detects the polysaccharide capsule antigen of Cryptococcus and is used for diagnosis India ink staining of the CSF shows round or oval budding yeast. Cryptococcus neoformans is present in soil and pigeon droppings. The yeast is transmitted via the respiratory route, with the lungs as the primary site of entry In immunocompromised patients, lung infection may be followed by dissemination of C neoforinans. often into the CNS
There are three main kinds of botulism: food-borne botulism, wound botulism and infant botulism In food-borne botulism, botulinum neurotoxin in food (produced by the organism Clostridium botulinum) prevents release of acetyicholine from nerve terminals at the neuromuscular junction, thereby preventing muscular contraction Campylobacferjejunhinfection can lead to Guillain-Barre syndrome (GBS) in rare instances. GBS is a demyelinating syndrome of the peripheral nerves characterized by ascending musc’e weakness and paralysiS.
Illness caused by Clostridium tetani (tetanus) canevery be prevented by thereafter proper immunization withAn a childhood series and a booster immunization ten years in adulthood immunized mother will be able to pass lgG through the placenta to the fetus and provide passive immunity against neonatal tetanus until the child receives its first tetanus vaccination at two months of age. Neonatal tetanus usually results from C. tetani colonization of the umbilical stump Meningococcal sepsis may be associated with disseminated intravascular coagulation and hemorrhagic destruction of the bilateral adrenal glands. This constellation of findings is known as the Waterhouse-Friderichsen syndrome. N. nieniigiidis sepsis does not necessarily include meningitis. Meningococcal pi are responsible for epithelial attachment to nasopharynx Antibody coating these pili would prevent pilus-mediated attachment of the meningococcus to the mucosal epithelium of the nasopharynx, thereby preventing invasion and disease. Staphylococcus epidermidis is a common cause of foreign body infections due to its ability to produce adherent biofilms
Cryptococcal meningitis is diagnosed by India ink staining of cerebrospinal fluid The main treatment for this infection is amphotericin B and flucytosine The clinical presentation of restlessness, agitation, and dysphagia progressing to coma 30 to 50 days following an exposure to cave bats is strongly suggestive of rabies encephahtis Prophylactic vaccination is recommended by the CDC for indMduals at high risk of exposure to rabid animals or their tissues The FDA approved rabies vaccine consists of various rhabdovirus strains grown in tissue cell culture and then inactivated to produce killed virus vaccine Infection of the sac ral sensory ganglia with a double-stranded DNA virus is likely to eventually result in a recurrent, painful genital rash (genital herpes) secondary to reactivation of the latent herpes simplex virus (HSV-2)
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 useneurotransmitters GABA and glycine as their neurotransmitters, but tetanospasmin prevents the release of these 1. Intact cell-mediated immunity is essential for the elimination of Listeria monocytogenes from the body. Neonates up to 3 months of age are especially vulnerable because they have yet to fully develop their cell-mediated immunity Listeria rarely causes disease in normal healthy adults 2. This bacterium produces a very narrow zone of beta-hemolysis on sheep blood agar (resembling the pattern produced by 3-hemolytic Streptococci), shows tumbling motility at 22°C, and can be cultured at temperatures as low as 4°C.
MICROBIOLOGY-Pulumunology The Hib vaccine consists of PRP capsular polysacchahde conjugated with either tetanus or diphtheria toxoid.class Protein conjugation causes aofT-ceIl mediated immune This response leading to immunoglobulin switching and generation memory B-lymphocytes response would not occur with pure polysaccharide immunization Leg/onellapneurnophiia is a facultative intracellular gram-negative bacilli that can cause a systemic infection Symptoms frequently include high fever, cough, confusion, and diarrhea. The most common laboratory abnormality seen with Legionella pneumonia is hyponatremia, and sputum Gram stain often shows many neutrophils, but few or no organIsms.
Studies have shown that maternal prophylaxis during pregnancy with the nucleoside analog zidovudine (ZDV, AZT), a retroviral reverse transcriptase inhibitor, reduces the risk of pennatal transmission by about two-thirds in HIV-positive women who have not pre’iousIy received antiretroviral therapy. Patients older than 65 are particularly prone to developing secondary bacterial pneumonia after influenza infection. In order, the pathogens most often responsible for secondary bacterial pneumonia are Streptococcus pneumoniàe, Staphylococcus aureusand 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 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. S. pneumoniàe are Gram-positive, aipha-hernolytic, optochin-sensitive, bile-sensitive diplococci S wridans is also aipha-hemolytic. but it is optochin-resistant S pyogenes (Group A Strep) appears as Gram-positive cocci in chains and can be identified by its susceptibdityto bacitracin
Brassy, barking cough; dyspnea: and recent history of upper respiratory infection in a child are suggestive of viral laryngotracheitis (croup). The most common cause of croup is parainfiuenza virus. The acid-fast staw identifies organisms that have mycolic acid present in their cell walls. including Mycobacterium and some Nocard,à species Acid-fast staining is carried out by applying an aniline dye (eg, carbolfuchsin) to a smear and then decolorizing with acid alcohol to reveal whether the organisms present are “acid fast” Chronic gran1omatous disease (CGD) results from a genetic defect in NADPH oxidase Normally, NADPH oxidase participates in the killing of microbes within neutrophil phagolysosomes Patients with CGD develop recurrent pulmonary, cutaneous, lymphatic. and hepatic infections, with a tendency toward granuloma formation, usually beginning in childhood These infections are predominantly caused by: • Staphylococcus aureus a Pseudomonas cepacia (Burkhokiena cepacia) a Serrat,à marcesc ens a Nocard,ä species a A spergillus species
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. 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 recommended identify colonized women who require INTRAPARTIJM antibiotics, mostisfrequently with topenicillin or ampicillin. to prevent neonatal GBS sepsis. pneumonia and meningitis The pathogenicftyofHIhftLen2ae is dependent on the presence of the antiphagocytic polysaccharide capsule. The type b strain is the most invasive and virulent it has a capsule with a ribose as the sugar rather than a hexose as is used in the other strains of encapsulated H. influenzae and this may be a reason for the increased virulence of Hib compared to the others. Unencapsulated (nontypable) H. ,hfluenzae are part of the normal flora and cause only local infections. Nontypable strains of Haemophiius ,nfluer,zae are strains of H. !hfluenzae that do not form an antiphagocytic capsule They are part of the normal flora of the upper respiratory tract, but can cause otitis media, sinusitis and bronchitis. Immunity to nontypable strains, as well as capsular strains other than type b, is not conferred by vaccination with the Hib Vaccine. Rapidly progressing fever, severe sore throat, drooling and progressive airway obstruction potentially accompanied by stridor are the presenting symptoms of acute epiglottitis. This illness is most commonly caused by H. ,nfluenzae type b, but the Hib vaccine has dropped the incidence
of this disease considerably H. influenzae type b can still cause disease in unimmunized or improperly immunized patients as well as fully immunized patients in some cases. Lpneumophilacornmonly contaminates natural bodies of water, municipal water, humidification systems and air conditioning and water-based cooling systems as are used in many commercial applications The organism is inhaled in aerosohzed water and establishes infection by the pulmonary route It requires special enriched media for growth specificaHy it requires media supplemented with L-cysteine and culture on charcoal-yeast extract agar The most common cause of community-acquired pneumonia in immunocompetent hosts (which would include an HIV+ patient with normal CD4+ counts) is Streptococcus pneumonlàe Infection with Mycoplasma pneumoniae can result in the formation of cold agglutinins Other illnesses resulting in cold agglutinin formation include EBV infection and hematologic malignancy Cold agglutinins are antibodies specific for red blood cells that only cause agglutination, or clumping, of red blood cells at low temperatures Mycop/asmaprieumoniáeis the causative agent of “walking pneumonia’ a condition characterized by a nagging nonproductive cough, low-grade fever and malaise Often, the chest X-ray suggests a severe pneumonia even though the patient appears relatively welL Mycoplasma species require cholesterol supplementation in order to grow on artificial media. Blastomyces dermat,tid,s is a dimorphic fungus that is seen in tissue as round yeasts with doubly refractive walls and “broad based budding” it is endemic to the Great Lakes, and the Ohio and Mississippi River regions The lungs are the primary site of involvement
The Haemophi/usuifluerizaetype b (Hib)conjugated vaccine is with composed of polynbosy[-nbito-phosphate (PRP), a component of the Hib capsule, diphtheria or tetanus toxoid. Immune activation with antibody production and memory B-lymphocyte induction against PRP provides lasting immunity against Hib in children as young as 2 months old. Epiglottitis is almost exclusively caused by Haemophdusinfluenzaetype b For a naked RNA molecule to induce viral protein synthesis in a host cell, it must be able to act directly as mRNA using the host’s intracellular machinery for translation Thus naked viruses containing single-stranded positive-sense RNA can be infectious, whereas naked viruses containing single- or double-stranded negative sense RNA are not infectious. The pneumococcal polysaccharide vaccine is recommended for all adults over 65 years of age and for patients with CQPD, asplenia. or immunosuppression. Vaccination does not completely prevent pneumonia, as this vaccine only contains antigen from 23 of the more than 80 different capsular serotypes known The adult pneumococcal vaccine is an unconjugated polysacchande vaccine that, unlike the infant vaccine, does not stimulate a T-helper response. Histoplasma capsu/atum is a dimorphic fungus located intraceIluIary within macrophages ft affects the lungs and reticuloendothelial systern It is present in bird and bat droppings, and is endemic to the Mississippi and Ohio River basins.
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 Bacillus anthrac,s Spore-forming canpathogenic survive boiling. members of the genus Clostridium are bacteria potentially bacteria found in the soil andand capable of forming spores. LegiOnel/apneurnophllacauses Legionnaires disease. Legionnaires disease has a propensity to affect smokers and is characterized by very high fever, diarrhea, headache, and confusion. Laboratory studies frequently show hyponatremia. L pneumophlla is a gram-negative rod that is often not detected on Gram stain. Microbiology
Reproductive+Vascular+Haematology Educational objective: The most important steps for the prevention of central venous catheter infections are as follows: • Proper hand washing • Full barrier precautions dunng insertion of a central hne • Chlorhexidine for skin disinfection the femoral insertion site needed a• Avoidance Removal ofofcatheter(s) when no longer Epstein-Barr virus (EBV) commonly infects B cells, stimulating them to enter the cell cycle and proliferate continuously (a process termed “transformation or ‘immortahzation). EBV is an oncogenic virus that promotes polyclonal B cell proliferation and heterophil antibody production The Monospot test is a highly specific test used to diagnose EBV infection; the test is positive when horse red blood cells are agglutinated in vitro by heterophil antibodies A total of 50,000 to 120,000 central venous catheters-associated bloodstream infections have been estimated to occur annually in the US. Indwelling central catheters predispose to bacteremia and sepsis and should be monitored regularly for signs and symptoms of infection and suspected in hospitalized patients with new-onset fever or bacteremia. The high mutability of HIV-1 allows for the evasion of host humoral and cellular immune responses and the development of resistance to anti-retroviral drugs Pol gene mutations are responsible for acquired resistance to HIV reverse transcriptase inhibitors and HIV protease Inhibitors. Env gene mutations enable escape from host neutralizing antibodies.
There is only one clinically significant nral family in which the members are both non-enveloped and contain single-stranded DNA: Parvovihdae Parvovirus Bi 9 causes erythema infectiosum (fifth disease), aplastic crises in sickle cell anemia, and hydrops fetalis Red blood cel[s filled with multiple. smaller round nucleated cells suggests Plasmodia (malana) infection Erythrocytic forms of this parasite may be treated with chloroquine or mefloquine Primaquine is required to kill P v/vaKand P ova/eliverschizonts. Essential to viral invasion of cells and the viral tropism for specific tissues is the initial attachment of the virion envelope or to capsid surface proteins to the complementary host cell surface receptors Many viruses bind normal host cell plasma membrane receptors in order to enter host cells Known host cell receptor — virion/virion protein binding specificities include: CD4 and HIV gpl2O; CD21 and EBV gp350; and erythrocyte P antigen and parvovirus 819 Pelvic inflammatory disease is most frequently caused by N. gononhoeae and C trachomatis If Neisserial or Chiamydial urethritis, cervicitis or PID is not treated, they can lead to scarring of the fallopian tubes and infertility or ectopic pregnancy Treatment of gonococcal genital tract infections must always include treatment for Chlamydia as well: the usual treatment is a thirdgeneration cephalosporin as well as azithromycin or doxycycline. Candida a/b/cans is the most common cause of opportunistic mycosis It can affect any organ and cause generalized candidemia. Yeasts and pseudohyphae on light microscopy and a positive germ tube test are diagnostic of Cand/daa/b/cansinfection.
A febrile upper respiratory illness in a child followed by the sudden appearance of red, flushed cheeks approximately 2-5 days later is characteristic of erythema infectiosum (parvovirus B 19 infection) This virus is highly tropic for erythroid precursor cells and replicates predominantly in the bone marrOw. Escherich,à co/,strain 0157:H7 can cause hemolytic-uremic syndrome (HUS) HUS is a rare condition affecting mostly children under the age of 10 This strain of E coli is most commonly contracted after eating undercooked ground beef.
Maternal rubella infection produces a low-grade fever, a maculopapular rash with cephalocaudal progression, and posterior auricular and suboccipital lyrnphadenopathy. Most adult women patients develop polyarthritis and polyarthralgia as sequelae. Congenital rubella syndrome is associated with serisonneural deafness, cataracts, and cardiac malformations (PDA). In patients with sickle cell anemia and other chronic hemolytic disorders, the most common viral cause of an aplastic crisis is infection of erythroid progenitor cells with parvovirus B19, a nonenveloped, single-stranded DNA virus
Microbiology-Skeletal C. perfringens causes late-onset food poisoning and closthdial myonecrosis (gas gangrene) The food poisoning is toxin-mediated. late-onset. and chnically causes a transient watery diarrhea
Methicillin-resistant S aureus (MRSA) is resistant to all —Iactam antibiotics. including betalactamase resistant antibiotics, because it has an altered penicillin binding protein in its peptidoglycan cell wall that does not bind beta-lactams as effectively Erythema infectiosum (fifth disease) is caused by parvovirus B19 and is transmitted most commonly via the respiratory route Symptoms of this infection include a bright-red rash on the cheeks slapped cheeks”) and lacelike rash on the trunk and extremities. Lecithinase, also known as alpha toxin. is the main toxin produced by C perfrlhgens Its function is to degrade lecithin, a component of cellular phospholipid membranes, leading to membrane destruction, cell death and widespread necrosis and hernotysis. Hypo- or hyperpigmented skin patches that become more visible after tanning are characteristic of pitynasis versicolor, a condition caused by Malassezià fwñir KOH preparation of skin scrapings reveals a “spaghetti and meatballs” appearance on light microscopy Salmonella, followed by E co/, is the most common cause of osteomyelitis in patients with sickle cell anemia Patients with sickle cell disease have functional asplenia secondary to multiple infarctions of the spleen. which makes these patients more prone to infection by encapsulated Organisms. 1. Pulmonary anthrax, alsowith known woolsorters is caused by inhalation of spores most commonly while working goatashair or hides disease, 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 form. is also used as a biological weapon due to the near 100% mortality of the pulmonary
Sporothrix schenck,lis a dimorphic fungus that causes a subcutaneous mycosis. It is often transmitted by a thorn pnck. The disease manifests with nodules that spread along Iymphatics
Ecthyma gangrenosum is a cutaneous necrotic disease with a strong association with Pseudomonas aeruginosa bacteremia and septicemia. It occurs after P aeruginosa invades penvascularly and releases tissue destructive exotoxins causing vascular destruction and resultant insufficiency of blood flow to patches of skin which become edematous and subsequently necrose. Pseudomonas infections are common in neutropenic patients. hospitalized patients, patients with bums and chronic indwelling catheters. Hematogenousosteomyelitis most after commonly occurs in event male Symptoms children and mostand frequently caused by Staphylococcus aureus some bacteremic areisvague include fever, malaise and pain in the long bones most frequently. “Hot tub folliculitis” is a superficial and self-limited R aeruginosa infection of the hair follicles that tends to occur in minor outbreaks following exposure to a pool or spa where the chemicals have not been maintained at appropriate levels The culture of a pustule Will reveal 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 Educational Objective: Mitochondrial vacuohzation is typcaIly a sign of irreversible cell injury, signifying that the involved mitochondria are permanently unable to generate ATP In contrast to angina, the chest pain of pericarditis is sharp and pleuritic, and may be exacerbated by swallowing or relieved by leaning forward, Early-onset pencarditis develops m about 10-20% of patients between days 2 and 4 following a transmural myocardial infarction It represents an inflammatory reaction to cardiac muscle necrosis that occurs in the adjacent visceral and parietal pericardium Late-onset post-myocardial infarction (MI) pencarditis (Dressier’s syndrome) begins one week to a few months following the MI, and affects less than 4% of cases. Dressier’s syndrome is thought to be an autoimmune polyserositis. Constitutional symptoms, a mid-diastobc rumbling murmur heard best at the apex. positional cardiovascular symptoms (eg, dyspnea and syncope), embolic symptoms, and a large pedunculated mass in the left atrium are the typical findings of athal myxoma Histologically, these tumors are composed of scattered cells within a mucopolysaccharide stroma, abnormal blood vessels, and hemorrhaging Left atnal enlargement can sometimes cause left recurrent laryngeal nerve impingement Neurapraxia resuLting in left vocal cord paresis and hoarseness may resuL The combination of jugular venous distension, hypotension, and muffled heart sounds is highly suggestive of cardiac tamponade Tachycardia and pulsus paradoxus are also frequently seen with tamponade Lung examination is normal, which can help distinguish cardiac tamponade from tension pneumothorax In 90% of individuals, occlusion of the right coronary artery can result in transmural ischernia of the inferior wall of the left ventricle, producing ST elevation in leads U, Ill, and aVF as well as possible sinus node dysfunction Occlusion of the proximal LAD would be expected to result in anteroseptal transmural ischernia, with ST elevations in leads V1—V4. Occlusion of the LCX would produce transmural ischemia of the lateral wall of the left ventricle, with ST elevations mainly in V5 and V6, and possibly also in I and aVL. Severe aortic stenosis (AS) presents clinically with exertional syncope, angina and dyspnea (SAD). In AS, a systolic ejection murmur is heard at the right second intercostal space (aortic area) and may radiate to the carotids Senile calcific aortic valve degeneration is the most common cause of AS. Senile calcthc aortic valve degeneration usually becomes clinically apparent in the decade of life, whereas the AS associated with congenitally bicuspid aortic valves tends to present by the 6th decade Rheumatic aortic heart disease usually produces combined AS and aortic regurgftatlon. Aortic valve infective endocarditis tends to cause aortic regurgitation.
Patent ductus artenosus (PDA) is associated with prematurity and congenital rubella infection. Therapy with indomethacin successfully closes this defect in the majority of pahents. Aithough lightning injuries are rare. they are associated with a 25% fatahty rate Two-thirds of lightning-related deaths occur within the first hour after injury, with fatal arrhythmias and respiratory failure as the most common causes Patients with minor cutaneous involvement may still have major internal injury after lightning strikes and high-voltage electncal contact. Dystrophic calcification is a hallmark of preceding cell injury and necrosis The foramen ovale is patent in 20-30% of atnal normal adults Aithough usually remains functionally closed, any abnormality increasing nght pressure above leftitatnal pressure can produce a nght-to-left shunt across a patent foramen ovale 1 Hypertrophic cardiomyopathy often presents as sudden cardiac death in a young athlete Jmost all cases are due to autosomal dominant mutations in cardiac sarcomere proteins The most common protein involved is beta-myosin heavy chain 2. Approximately 1/3 of cases of dilated cardiomyopathy are genetic The malonty of these cases are due to autosomal dominant mutations of cardiac myocyte cytoskeletal proteins (dystrophin) or mitochondrial enzymes. Chronic constrictive pencarditis results in replacement of the normal pericardial space by a thick fibrous shell which can cause heart failure by restncting ventflcular filling Restncted nght ventricular filling produces a positive Kussmauls sign in most cases Restncted left venthcular filling may underlie the pulsus paradoxus that is seen in 1/3 of cases There may be a pencardial knock as well. The pericardial knock occurs earlier in diastole than an S3 qallop In patients with hypertrophic cardiomyopathy. dynamic left ventricular outflow tract obstruction is due to abnormal systolic anterior motion of the antenor leaflet of the mitral valve toward a hypertrophied interventric ular septum. Differential cyanosis restricted to the lower body m a child is most suggestive of patent ductus arteriosus with late-onset reversal of shunt flow (from left-to-right to right-to-left). Whole-body cyanosis results when there is shunt reversal in patients with septal defects or tetralogy of Fallot Coarctation of the aorta can limit lower- extremity exercise tolerance but does not cause cyanosis in children or adults. Prinzmetals (variant) angina is charactenzed by episodic. transient attacks of coronary vasospasm, typically occurring at rest and during the midnight-to-eaiiy morning hours These episodes generally produce temporary transmural myocardial schemia with ST-segment elevation Ergonovine can provoke this coronary vasospasm, and can aid in the diagnosis This condition can be effectively treated with vasodilating nitrates and calcium channel blockers. Jervell and Lange-Nielsen syndrome is one of the most common congenital long-QT syndromes This is an autosomal recessive condition which is accompanied by congenital neurosensory
deafness. QT-interval prolongati on predisposes to syncopal episodes and possib e sudden cardiac death due to torsades depointes Microemboh from the valvular egetations of bacteral endocarditis are the m o t common cause of subungual splinter hemorrha ges The presence of these lesions necessitate s careful cardiac auscultation to detect a possible ew-onset regurgitant murmur. Extreme myofiber disarray wi h interstitial fibrosis on cardiac histology s trongly suggests hypertrophic cardiomyopathy ( CM) Aimost 100% cases of HCM result fr om mutations in genes encoding cardiac sarcome e proteins (most commonly beta-rnyosin heavy chain). A vanety of autosomal and sex chromosomal-inherited disorders are associated with developmental cardiac and/or a rtic defects or cardiac pathology. The major a sociations are as follows 1 Down syndrome endocardial c shion defects (ostium pnmum ASD. regurgitan t AV valves) 2. DiGeorge syndrome: tetralog of Fallot and aortic arch anomahes 3. Friedreichs ataxia hypertrophi c cardiomyopathy 4. Marfan syndrome: cystic med al necrosis of the aorta 5. Tuberous sclerosis: valvular o bstruction due to cardiac rhabdomyomas 6. Tume?s syndrome: coarctatio of the aorta Organ susceptibdity to infarctio n after occlusion of a feeding artery is ranked from greatest to least as follows: central nervous system. myocar dium. 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 to lerate arterial occlusion better than those ith end-arterial circulations.
Unprovoked syncope in a previ usly asymptomatic young person may result f rom a congenital QT pcolongation syndrome The two most important congenital syndromes with QT prolongation — RomanoW ard syndrome an Jervell and Lange-Nielsen syndrome — are thought to result from mutations in a K channel p rotein that contnbutes to the delayed rectifier c rrent (1K) of the cardiac action potential. The adult (postductal) type of c ongentaI aortic coarctation can pcesent with s mptoms/signs of hypertension in the arterial tree proximal to the coarctation, and of hypoperfu ion 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 thustopotentially promote rapid coronary occlusion via superimposed thrombosis it the plaque were rupture An auscultatory finding of a mid systolic click followed by a murmur during the remainder of systole is quite specific for mitral valve prolapse (MVP). MVP is thought to be predominantly caused by defects in mitral valve connective tissue proteins which predispose to myxomatous degeneration and stretching of the valve leaflets by chronic hemodynamic stress. The pathogenesis of nonbactenal thrombotic endocarditis (NBTE) often involves a hypercoagulable state When the hypercoagulabhty is the result of the procoagulant effects of circulating products of cancers, the resulting cardiac valve vegetations may also be cal’ed marantic endocarditis The pathophysiology of NBTE is similar to that of Trousseaus syndrome (migratory thrombophiebitis) which may also be induced by disseminated cancers An acute transmural myocardial infarction marked by ST-elevation and subsequent Q-wave formation is most likely the result of a fuRy obstructive thrombus superimposed on a ruptured atherosclerotic coronary artery plaque A lesser degree of occlusion by a thrombus supenmposed on an acute plaque change would more likely cause unstable angina A stable atheromatous lesion without an overlying thrombus, but obstructing greater than 75% of the coronary artery lumen, would likely cause only stable angina.
The most likely cause of fatigue and new-onset cardiac murmur in a young adult is bacterial endocarditis (BE). Acute, diffuse. proliferative glomerulonephntis secondary to circulating immune complexes may complicate BE and can result in acute renal insufficiency In the rare cases of lethal acute rheumatic fever (ARF), the cause of death is heart failure due to severe myocarditis. Mitral stenosis after ARF requires years or decades to develop. Lipofuscin is the product of lipid peroxidation. accumulating in aging cells (especially in patients with malnutrition and cachexia). In patients with Mart an syndrome. there are stnking skeletal abnormalities, including long extremities and long tapering fingers, as well as spinal scoliosis and/or kyphosis However, cardiovascular lesions are the most life-threatening features, Cystic medial degenerabon of the aorta predisposes these patients to aortic dissection Aortic dissection is the most common cause of death after infancy in patients with Marfan syndrome. Cyanotic spells are common with TOF Remember the five Ts of cyanotic congenital heart disease: tetralogy of Fallot, tricuspid atresia, transposition of the great vessels, truncus arteriosus, and total anomalous pulmonary venous return. Atrial septal defect ventricular septal defect patent ductus arteriosus, and aortic coarctation are generally considered noncyanotic congenital heart diseases Coronary artery disease is the underlying etiology in most cases of sudden cardiac death Typically, an acute plaque change will result in acute myocardial ischernia, which may precipitate ventricular fibrillation Cardiac arrhythmia is the most common cause of death in Ml patientsthe dunng the prehospital phase Ventricular failurelethal is the most common causeventncular of death during in-hospital phase Other later-onset, potentially complications include rupture and mural thrombosis with thromboembohsm. Kawasaki disease is a vascuhtis of medium-sized arteries that presents with persistent fever, bilateral conjunctivitis, cervical lymphadenopathy. and mucocutaneous involvement Formation of coronary artery aneurysms is the most serious complication of Kawasaki disease Pulsusparadoxus is an important clue to cardiac tamponade It is defined as a decrease in the systolic pressure of 10 mmHg or more during inspiration as compared with the pressure during exhalation Orthopnea is a quite specific sign of left-sided heart failure. Bilateral lower extremity edema and congestive hepatomegaly are more specific for right-sided heart failure Left-sided heart failure may also produce a productive cough and exertional wheezing or chest tightness, but these are nonspecific signs seen in a variety of disorders. Atherosclerotic plaques develop predominantty in large elastic arteries (e.g., aorta, carotid, and iliac arteries), and in large or mediumsized muscular arteries (e.g.. coronary and pophteal
arteries). In humans, the most heavily involved vessel is the abdominal aorta, followed by the coronary artenes, the pophteal arteries, the internal carotid arteries, and the circle of Willis. 1 Concentric ventricular hypertrophy uniformly thickens the ventricular wall while the outer dimensions of the ventricle remain virtually unchanged. thus causing a narrowed ventricular cavity Concentric ventricular hypertrophy is often seen in patients with longstanding hypertension because of the increased left ventricular afterload (pressure overload). 2 Volume overload of a ventricle, as seen in mitral regurgitation, results in dilatation of the ventricle, with an associated increase in chamber size. An increase in LV cavity size may also be seen in dilated cardiomyopathy and after myocardial infarction Acute-onset, mid-chest pleuritic pain that decreases on sitting up and leaning forward is characteristic of acute pencarditis. Fibcinous or serofibrinous pencarditis is the most common form Peñcardial friction rub is the most striking physical finding. SLE affects women 20-40 years of age and presents with a malar facial rash, photosensitivity, arthraigias and proteinuna Pericarditis is the most common cardiovascular syndrome associated with SLE It presents with chest pain that radiates to the neck and shoulders and is relieved by sitting up A diamond-shaped (crescendo-decrescendo) systolic murmur is characteristic for aortic stenosis. The most common cause of this valvular heart disease is degenerative (senile) calcinosis of the aortic leaflets.
PATHOLOGY-Cardiology 2 Cyanotic spells are common with TOF. Remember the five 7s of cyanotic congenital heart disease: tetralogy of Fallot, tricuspid atresia, transposition of the great vessels, truncus arteriosus, and total anomalous pulmonary venous return. Atrial septal defect, ventricular septal defect, patent ductus arteriosus, and aortic coarctation are generally considered noncyanotic congenital heart diseases A variety of autosomal and sex chromosomal-inhented disorders are associated with developmental cardiac and/or aortic defects or cardiac pathology. The major associations are as follows: 1. Down syndrome endocardial cushion defects (ostium pnmum ASD, regurgitant AV valves) 2 DiGeorge syndrome tetralogy of Fallot and aortic arch anomalies 3. Friedreich’s ataxia hypertrophic cardiomyopathy 4. Marfan syndrome: cystic medial necrosis of the aorta 5. Tuberoussyndrome: sclerosis: valvular obstruction due to cardiac rhabdomyomas 6. Turner’s coarctation of the aorta
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 K current duhng the repolarization phase of the cardiac action potential results in outward 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 inthe large medium-sized (e.g.. coronary and popliteal arteries). In humans, mostorheavily involvedmuscular vessel is arteries the abdominal aorta. followed by the coronary arteries, the pophteal arteries, the internal carotid arteries, and the circle of Willis. 1. Hypertrophic cardiomyopathy often presents as sudden cardiac death in a young athIete Almost all cases are due to autosomal dominant mutations in cardiac sarcomere proteins The most common protein involved is beta-myosin heavy chain 2. Approximately 1/3 of cases of ddated cardiomyopathy are genetic The majority of these cases are due to autosomal dominant mutatons of cardiac myocyte cyloskeletal proteins (dystrophin) or mitochondrial enzymes Chronic constrictive pencarditis results in replacement of the normal pericardial space by a thick fibrous shell which can cause heart failure by restricting ventncular filling Restncted right ventricular filling produces a positrve Kussmauls sign in most cases Restncted left ventricular filling may underlie the pulsus paradoxus that is seen in 1/3 of cases There may be a pencardial knock as well The pencardial knock occurs earlier in diastole than an S3 gallop. Dilated cardiomyopathy is a diagnosis of excluson once other etiologies of heart failure are ruled out, namely pericardial disease, valvular defects, coronary artery disease, and cardiac rhythm disturbances. It is characterized by dilation of all 4 chambers of the heart, systolic dysfunction,
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 thecommon most common of ventricular fibrillation in individuals younger than 30 and the most cause ofcause sudden cardiac death ii a young athlete. Myocardial infarction, multifocal myocardial fibrosis, and dilated or restnctive cardiomyopathies can end in sudden cardiac death. but woukl be unlikely in a teenager with no past medical history The foramen ovale is patent in 20-30% of normal adults. Although it usually remains functionally closed, any abnormality increasing right atrial pressure above left atnal pressure can produce a right-to-left shunt across a patent foramen ovale. Extreme myofiber disarray with interstitial fibrosis on cardiac histology strongly suggests hypertrophic cardiomyopathy (HCM) Almost 100% cases of HCM result from mutations in genes encoding cardiac sarcomere proteins (most commonly beta-myosin heavy chain) SLE affects women 20-40 years of age and presents with a malar facial rash, photosensitivity, arthralgias and proteinuria Peñcarditis is the most common cardiovascular syndrome associated with SLE. sitting up. It presents with chest pain that radiates to the neck and shoulders and is relieved by Differential CyanOsis restricted to the lower body .i a child is most suggestive of patent ductus arteriosus with late-onset reversal of shunt flow (from left-to-nght to right-to-left). Whole-body cyanosis results when there is shunt reversal in patients with septal defects or tetralogy of Fallot. Coarctation of the aorta can limit lower- extremity exercise tolerance but does not cause cyanosis in children or aduRs The most likely cause of fatigue and new-onset cardiac murmur in a young adult is bacterial endocarditis (BE). Acute, diffuse, proliferative glomerulonephritis secondary to ciculating immune complexes may complicate BE and can result in acute renal insufficiency. Left atrial enlargement can sometimes cause left recurrent laryngeal nerve impingement Neurapraxia resulting in left vocal cord paresis and hoarseness may result. An acute transmural myocardial infarction marked by ST-elevation and subsequent 0-wave formation is most likely the result of a fully obstructive thrombus superimposed on a ruptured atherosclerotic coronary artery plaque A lesser degree of occlusion by a thrombus supenmposed on an acute plaque change would more likely cause unstable angina A stable atheromatous lesion
without an overlying thrombus, but obstructing greater than 75% of the coronary artery lumen, would likely cause only stable angina. Valvular inflammation, damage. and scarring predispose to infective endocarditis, which is characterized grossly and on an echocardiogram by the presence of valvular vegetations The vegetations associated with bacterial endocarditis represent fibrin and platelet deposition at a site of bacterial colonization. Mitral valve prolapse is the most common cardiac abnormality predisposing to native valve bacterial endocarditis (NVBE) in the 15- to 60-year-old age group in the United States Mitral valve pi-edisposes to infected vegetations onofmitral leaflets. Rheumatic valvular disease is alsoprolapse a potential, although less common, precipitant 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 of atheventricle, increasedasleft ventricular (pressure overload) 2. Volume overload seen in mitralafterload regurgitation, results in dilatation of the ventricle, with an associated increase in chamber size An increase in LV cavity size may also be seen in dilated cardiomyopathy and after myocardial infarction. The combination of jugular venous distension. hypotension, and muffled heart sounds is highly suggestive of cardiac tamponade Tachycardia and pulsus paradoxus are also frequently seen with tamponade Lung examination is normal, which can help distinguish cardiac tamponade from tension pneumothorax Acute-onset, mid-chest pleuritic pain that decreases on sitting up and leaning forward is characteristic of acute pericarditis. Fibnnous or seroflbnnous pencarditis is the most common form, Pericardial friction rub is the most striking physical finding. Prinzrnetars (variant) angina is characterized by episodic, transient attacks 01 coronary vasospasm, typically occurring at rest and during the midnight-to-earty morning hos These episodes generally produce temporary transmural myocardial ,schemia with ST-segment elevation Ergonovine can provoke this coronary vasospasm, and can aid in the diagnosis, This condition can be effectively treated with vasodilating nrtrates in€1 riIri,ui cmmI bInckrc
Congenital bicuspid aortic valves are strongly associated with accelerated onset of calcific aortic stenosis Clinically significant aortic stenosis may develop ri patients with bicuspid aortic valves beginning in the sixth decade, whereas senile calcific stenosis of normal aortic valves generally becomes symptomatic in the eighth decade. Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric ventricular septal hypertrophy and variable dynamic left ventricular outflow tract obstruction which may produce a systolic election murmur Decreases in the LV end diastolic volume increase the obstruction, causing the murmur of HCM to be enhanced Actions like standing suddenly from the supine position and the Valsalva maneuver decrease venous return and thus accentuate the murmur The normal morphological changes ui the aging heart include a decrease in left ventricular chamber apex-to-base dimensions, development of a sigmoed-shaped ventncular septum, myocyte atrophy with interstitial fibrosis, and accumulation of cytoplasmic lipofuscin p*gment Hypertensive heart disease is associated with concentric hypeftrophy of the left ventncle S atreus causes acute bactenal endocarditis with rapid onset of symptoms including shaking chills (rigors), high fever, dyspnea on exertion and malaise. In IV drug abusers it causes 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 Kawasaki disease is a vascuhtis of medium-sized arteries that presents with persistent fever, bilateral conjunctivitis, cervical lymphadenopathy, and mucocutaneous involvement Formation of coronary artery aneurysms is the most senous complication of Kawasaki disease. The aduft (postductal) type of congenital aortic coarctation can present with symptoms/signs of hypertension in the arterial tree proximal to the coarctation, and of hypoperfusion of the lower extremities, especially dunng ambulation, Collateral circulation to the distal aorta results in diLated intercostal arteries The triad of upper body hypertension, diminished lower extremity pulses, and enlarged intercostal artery coaterals is typical of adult-type coarctation and is not seen in other congenital cardiovascular maltorrnations Mitochondrial vacuolization is typically a sign of irreversible cell injury, signifying that the involved mitochondria are permanently unable to generate ATP. In patients with Marlan syndrome, there are striking skeletal abnormalities, including long extremities and long tapering fingers, as well as spinal scoliosis and/or kyphosts. However, cardiovascular lesions are the most life-threatening features. Cystic medial degenerabon of the aorta predisposes these pabents to aortic dissection. Aortic dissection is the most common cause of death after infancy in patients with Marfan syndrome. The carcinoid syndrome can cause predominantly right-sided endocardial fibrosis which may progress to pulmonic stenosis and/or restrictive cardiomyopathy The severity of carcinoid heart
disease correlates with plasma levels of serotonin and urinary excretion of the serotonin metabolite. 5-hydroxyindoleacetic acid. Aft;r the onset of severe ischema leading to myocardial infarction (Ml), early signs of coagulative necrosis do not become apparent on light microscopy until 4 hours after the onset of M[ Although lightning injuries are rare, they are associated with a 25% fatality rate. Two-thirds of lightning-related deaths occur within the first hour after injury, with fatal arrhythmias and respiratory failure as the most common causes. Patients with minor cutaneous involvement may still have major internal injury after lightning strikes and high-voftage electrical contact. In the rare cases of lethal acute rheumatic fever (ARF), the cause of death is heart fadure due to severe myocardths Mitral stenosis after ARF requires years or decades to develop Patent ductus arteriosus (PDA) is associated with prematurity and congenital rubella infection. Therapy with indomethacin successfully closes this defect in the majority of patients Organ susceptibility to infarction after occlusion of a feeding artery is ranked from greatest to least as follows: central nervous system, myocardium, kidney, spleen, and hver The presence of a dual and/or collateral blood supply (as seen in the liver, which is supplied by the hepatic artery and portal vein) enables an organ to tolerate arterial occlusion better than those with end-arterial circulations Almost all cases of mitral stenosis are caused by chronic rheumatic heart disease Infective endocarditis of the mitral tends to cause and associated regurgitation heart defects may produce mitralvalve regurgitation, but aredestruction generally not withCongenital stenosis Mitral valvular calcinosis generally does not impair valve function. Rheumatoid arthritis and tertiary syphilis only rarely affect cardiac valves. Severe aortic stenosis (AS) presents chnically with exertional syncope. angina and dyspnea (SAD). In AS, a systolic ejection murmur is heard at the hght second intercostal space (aortic area) and may radiate to the carotids Senile calcafic aortic valve degeneration is the most common cause of AS Senile calcific aortic valve degeneration usually becomes clinically apparent in the 7111 decade of life, whereas the AS associated with congenitally bicuspid aortic valves tends to present by the decade Rheumatic aortic heart disease usually produces combined AS and aortic regurgItation Aortic valve infective endocarditis tends to cause air+i, r#
PATHOLOGY-Dermatol gy BRAF is a protein kinase in volved in activation of ságnaling pathways for melanocyte proliferation, and the BRAF V600E mutation is seen i 40-60% of patients with melanoma. Herpes zoster (shingles) develo s due to reactivation of varicella-zoster vüus i n the dorsal root ganglia It presents with a pa inful vesicular rash in a dermatomal distri ution. On light microscopy intranuclear inclusio ns in keratinocytes and multinucleated giant cel ls are seen Bullous pemphigoid is charact erized by autoantibodies to the hemidesmo omes along the basement membrane of the dermal-epidermal junction. Measurement of the depth of i nvasion (Breslow thickness) is the most imp rtant prognostic indicator for patients with malig ant melanoma. Pemphigus vulgans is an autoi mune bullous disease characterized by autoan tibodies directed against desmosomal proteins 3 and 1 Bullous pemphigoid is characterized b y autoantibodies against hemidesmosomal protein s. Actinic keratosis develop in pre isposed individuals on chronically sun-exposed areas of the skin The lesions consist of erythema ous papules with a central scale and a “sandp aper-like texture. Actinic keratosis can convertquamous to cell carcinoma in approximately 1% f cases.
Seborrheic keratosis is a ben ig epidermal tumor that presents as a tan to br own, round, flat, greasy, coinlike lesion with a “st uck on” appearance Keloids result from excessive c llagen formation during tissue repair in susce tible individuals They present as soft or firm nod ules that grow beyond the borders of the woun s with claw-like extensions into normal tissue. K loids are composed of large. disorganized coll gen bundles and excess cellular connective tissue. Acanthosis nigncans presents wi th thickening and hyperpigmentation of skin in the fiexural areas The ‘esions have a classic “vel ety’ texture. Acanthosis ngncans is commonl associated with insulin-resistant states (eg, d iabetes mellitus. acromegaly. obesity) and gastrointestinal malignancies Xanthomas are suggestive of h yperhpidemia. especially when present in co njunction with a family history of early cardiac d ath. Urticaria is characterized by s epidermal changes are present.
perficial dermal edema and lymphatic chan nel dilation. No
Granulomatous inflammation is a form of chronic inflammation characterized by aggregates of activated macrophages that a ssume an epithelloid appearance Persisten granulomatous inflammation with subsequent fi rosis can cause organ dysfunction, which is se n in a number of granuomatous diseases Cooper’s ligament infiltration by invasive breast cancer causes retraction of the verlying skin
Dermatitis herpetiformis is a ra re condition that presents with erythematous, pruhtic papules, vesicles, and bullae that appear ilaterally and symmetñcally on the extensor su rfaces Dermatitis herpetiformis is st ron9ly associa ed with celiac disease Psoriasis is characterized by yperparakeratosis. acanthosis. rete ridge el ngation, mitotic activity above the epidermal b asal cell layer, and a reduced or absent stra um granulosum. Neutrophils may fomi spongioti clusters in the superficial dermis and the para keratotic stratum comeum (Munro microabscesses ). Red blood cell extravasation in to the skin or subcutaneous tissue results in the formation of petechiae (<5 mm in diameter), purpura (5 mm to 1 cm in diameter), or ecchy moses (>1 cm in diameter) These lesions do not c mpletely blanch under pressure. unlike telange ctasias A yellowish eyelid papule or plaque containing lipid-laden macrophages is most hkety xanthelasma Xanthelasma may occur in association with pnmary or secondar y hyperlipidemia Cholestatic conditions such as primary bihary cirrhosis are a pot ntial cause of hypercholesterolemia leading to xanthelasma. The lepromin skin test will be p sitive in patients with tuberculoid leprosy beca se they exhibit a strong CD4+ Thi cellmediated i mune response to M Ieprae. Atopic dermatitis (eczema) is a common inflammatory disorder of childhood It presents with pruritus and erythematous wee ping papules and plaques that occur in res ponse to certain environmental antigens Atopic dermatitis is associated with other atopic d iseases, such as allergic rhinitis and asthma Actinic keratoses are small (usu lly < 1 cm), erythematous epidermal lesions wi th adherent scale Histologically, there is basal cell layer atypia. hyperkeratosis, and parakeratosis hese lesions are the result of chronic sun expo ure and thus affect sun-exposed areas A sm ll percentage of actinic keratoses progress to inv sive squamous cell carcinoma, thus monitonng is necessary. Axillary lymph node dissection is a risk factor for the development of chro nic lymphedema invoMng the ipsilateral arm. Chronic lymphedema predisposes to the development of angiosarcoma (Stewart-Treves s ndrome)
PATHOLOGY-Endocrinology Hemorrhage into a preexisting pituitary adenoma is called pituitary apoplexy It presents with a sudden severe headache and cranial nerve paralysis. with other more chronic symptoms of a pituitary tumor Since signs of meningeal irritation can be seen, it is very important to evaluate the visual fields for bitemporal hemianopsia. Cardiovascular collapse can occur due to adrenocortical deficiency. Cushrng syndrome caused by a pituitary adenoma or ectopic ACT1-l secretion will present with elevated ACTH levels High-dose dexamethasone suppression testing will suppress ACTH and cortisol levels when Cushing syndrome is caused by a pituitary adenoma (Cushing disease) but not when is caused by ectopic ACTH secretion (eg, small-cell Carcinoma). The most common pituitary adenoma is a prolactinoma. sometimes called a lactotroph adenoma: however, somatotrophs are the most common cell type in the normal pituitary Myocardial infarction is the most common cause of death in patients with diabetes The stimulatory effect of high estrogen levels during pregnancy causes the pituitary gland to enlarge and become more vascular If significant hypotension occurs while the pituitary is still enlarged ([e postpartum hemorrhage), the pituitary gland can undergo ischemic necrosis This results in deficiencies of multiple pituitary hormones (panhypopituitansm), including prolactin— and is called Sheehan syndrome Features of thyrotoxicosis. tenderness over the thyroid gland, increased ESR, and a markedlyreduced radioactive iodine uptake are diagnostic of granulomatous thyroiditis Mixed, cellular infiltration with occasional multinucleate giant cells are characteristic histologic findings. Pancreatic islet amoid deposition is characteristic of type 2 diabetes meibtus A strong linkage with HLA class II gene makeup, pancreatic islet infiltration with leukocytes (insuhtis), and antibodies against islet antigens are frequently seen in type I diabetes Autoimmune insubtis is the most common cause of type 1 diabetes Insulin resistance is the main mechanism responsible for type 2 diabetes Pheochromocytoma is usually a benign (90%) tumor arising from the adrenal medulla Pheochromocytomas typically produce episodic symptoms Diagnosis is confirmed by the measurements of urine and plasma catecholamines and catecholamine metabohtes such as metanephnnes Infiltrative dermopathy (1e, pretibial myxedema) and exophthalmos are symptoms more specific for Graves disease Patients with anorexia nervosa often experience amenorrhea due to loss of pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. It is important to remember that the defect
Patients with anorexia nervosa often experience amenorrhea due to loss of pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothaIamus It is important to remember that the defect in anorexia-related amenorrhea begins in the hypothalamus. not the pituitary or ovahes Low estrogen levels over the long-term can result in osteoporosis if left untreated Sulfonylurea or megidinide abuse and insulinoma cause increased insulin, c-peptide, and proinsulin leveIs The only way to distinguish between insulinoma and sulfonylurea or meglitinide abuse is by screening the urine or blood for hypoglycemic agents. Long-term use of supraphysiological doses of causesadrenocortical suppression ofatrophy. the hypothalamic-pituitary-adrenal axis, which in glucocorticoids turn leads to bilateral if the patient then suddenly stops taking the doses of exogenous corticosteroids for whatever reason, adrenal crisis can result. Neonates of diabetic mothers may be exposed to high maternal glucose levels in utero and thus may develop compensatory insulin hypersecretion Th.s results in fetal macrosomia and can cause neonatal hypoglycemia Note that maternal insulin does not cross the placenta Multiple endocrine neoplasia type 2B consists of medullary thyroid cancer, pheochromocytomas, mucosal neuromas, and marfanoid habtus Pheochromocytomas should be excluded in all patients with medullary thyroid cancer Hydrochlorothiazide causes hypercalcerrna by increasing the distal tubular reabsorption of filtered calcium, The increased serum calcium levels usually suppress PTH Episodic hypertension, headaches. diaphoresis. and tremors are important clinical clues for the presence oftachycardia. catec holamine-secreting tumors Multiple endocrine neoplasia type 2B (MEN2B) is characterized by medullary carcinoma of the thyroid. pheochromocytoma, and oral and intestinal mucosal neuromas MEN2A is also associated with parathyroid hyperplasia, whereas MEN2B is not 1 The anterior pituitary is formed from an out-pouching of the pharyngeal roof and is called Rathke’s pouch The postenor pituitary gland arises from an extension of the hypothalamic neurons 2 Craniopharyngiomas are tumors ansing from Rathkes pouch remnants in the anterior pituitary They characteristically have three components. solid, cystic, and cakIaed. They present during childhood, usually, with mass effect and visual deficits. Type 1 diabetes mellitus typically presents subacutely with polyuria, polydipsia, and polyphagia accompanied by fatigue arid weight loss In the United States, fasting blood sugar is the most preferred way to screen patients for diabetes mellitus. The USMLE will sometimes give you a history of recent viral infection and the patient wift often be a young Caucasian adult
Hypercalcemia treated with ne ck surgery is hkely secondary to a parathyr oid adenoma. A pituitary tumor that compresses the optic chiasm can produce temporal visual ield defects. The MEN type 1 syndrome is cha racterized by tumors of the pituitary, parath roid gland, and pancreas (the 3 Ps’) individuals ho have two out of the three tumors should be evaluated for the presence of the third tumor type. Mononuclear, parenchymal infil tration with well-developed germinal centers i s a characteristic histological finding of Hashimot os thyroidths High blood glucose lev&s i n maternal circulation crosses the placent a causing fetal hyperglycemia islet cell hy ia. perplasia. Hypennsulinernia caused by islet c ll hyperplasia is thought to causeand fetal macrosom Males with classic, non-salt-wa sting 21-hydroxylase deficiency present at ag 2-4 years with early virilization, increased line ar growth, and elevated levels of 17-hydroxy rogesterone and androgens Females with classic 1-hydroxylase deficiency (with or without salt -wasting) present with ambiguous genitalia at birt . Treatment of congenital adrenal hyperplasia involves low doses of exogenous orticosteroids to suppress excessive ACTH secret ion and reduce stimu lation of the adrenal cort ex . Distorted body image. inadequa e diet, regular exercise while underweight, dry skin, and lanugo hair in a female teenager sugges anorexia nervosa, Anorexic females commonl have low levels of LH, FSH, estradiol. and estro e (hypogonadotropic amenorrhea). Hypertension with low plasma rerUn activity is suggestive of primary hype
aldosteronism, a
condition biochemically charact rized by hypokalernia and metabolic alkalosis Gastrinoma is characterized by pper GI ulcerations (jeunaI ulcers are quite spe cific), abdominal pain and diarrhea Activating mutations of the RE proto-oncogene are strongly associated with edullary thyroid cancer RAS mutations are com on in follicular thyroid cancer and some foll icular adenomas. Inactivating mutations of p53 ar fairly common in anaplastic thyroid cancer Multiple endocnne neoplasia type 1 consists of hyperparathyroidism. p ncreatic tumors (gastrinoma), and pftultary tu ors (remember 3 ‘PsTM). The genetic de fect in multiple endocnne type I neoplasia invol ves the MENIN gene on the chromosome 11. Gastrinomas are not present m the other MEN sy dromes. Meningococcal sept cerna can ca use adrenal hemorrhage leading to acute adren l crisis.
Psammoma bodies and ground glass. grooved nuclei are characteristic micros opic features of papillary cancer of the thyroid gl and.
Medullary carcinoma of the thyroid gland is characterized by extracellular deposits of amyloid formed by calcitonin secreted from neoplastic parafollicular C-cells.
PATHOLOGY-Genitourinary A patient with a ruptured ectopic pregnancy would present with abdominal pain, vaginal bleeding, hemorrhagic A patient with a ruptured ectopic pregnancy would present with abdominal pain, vaginal bleeding, hemorrhagic shock, and a history of amenorrhea Endometnal biopsy would reveal decidual (gestateonal) changes in the endometrium but no chorionic villi TNF-o is one of the cytokines that induces the systemic inflammatory response In high concentrations. TNFc i causes symptoms of septic shock and cachexa Other cytoidnes responsible for inducing the systemic inflammatory response include IL-i and IL-6. A partial mole will have a tnploid karyotype Patients present with vaginal bleeding and lower abdominal pain Unlike complete moles, partial moles are associated with low risk of invasive trophoblastic disease Clear cell carcinoma is the most common subtype of renal ce carcinoma and is composed of large, rounded or polygonal cells with clear cytoplasrn The classic triad of hernaturia, flank pain, and palpable mass occurs in a minority of patients Non-specific symptoms and paraneoplastic syndromes common. These are often detected incidentally at an advanced stage, and the lungare is more the most common site tumors 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. Histologically, chonocarcinoma is composed of an abnormal cytotrophoblasts and syncytiotrophob1asts No VdIi are present.
proliferation
of
both
Urine supersaturation is the me hanism underlying all types of kidney stones. Low fluid intake increases the concentration of stone-forming agents, thus encouragwg ston e formation All patients with a history of nephro thiasis should be advised to consume ample fl ids Endometriosis is the presence f endometrial glands and stroma outside the terus It may be asymptomatic or present with se ere dysmenorthea, dyspareunia and infertility. Serial measurements of 13—hC G should be performed following evacuation f a hydatidiform mole. Persistently elevated or ris ing levels may signify the development of an i vasive mole or c horiocarcinoma The clinical presentation of terti ary syphilis includes neurosyphilis. cardiovasc lar involvement, and gummas. Gummas are necr tizing granulomas occumng on the skin, muco sa, subcutaneous tissue, bones, and within other o gans. Polycystic ovarian syndrome (P OS) is associated with oligomenorrhea, obesi ty, hirsutism and polycystic ovanes These pa ents are at increased risk for develop ng endometrial adenocarcinoma and type 2 diab tes melhtus The simultaneous development f stroke. intestinal or foot ischemia, and renal infarction should make you think of embolic p enomena These emboli may anse from left atrial clots, left ventricular clots, vavular vegetat ions, or aortic atherosclerotic plaques WBC casts are formed in tub ules. and are pathognomonic for acute pye onephritis when accompanied by systemic mani estations of febrile illness WBC casts are als seen with acute interstitial nephritis. but clinical presentation is different in that patients have nly a low-grade fever and do upper not experience paTIs. inful urination Pyuna and bactenuria are non specific and are found in both and lower U
A patient with signs of renal fail ure and toe gangrene or livedo reticularis follo wing an invasive vascular procedure likely has at heroembolic renal disease Light microscopy s hows cholesterol emboli obstructing renal arteriol s A history of multiple sexual part ners is a significant risk factor for development of squamous cell carcinoma of the cervix due to the increase nsk of transmission of carcinogenic strain s of the Human papdloma virus (16, 18, 31 & 33). Other nsk factors i nclude cigarette smoking, lower socioeconomic status, and early coitarche Fibroadenomas are characteriz ed by a cellular. often myxoid stroma th t encircles and sometimes compresses epithehu .-Iined glandular and cystic spaces
Primary ciliary dyskinesia. caused by an autosomal recessive mutation in the microtubuleassociated protein dynein, can cause Kartagener’s syndrome in about 50% of patients (vanable penetrance). Kartagener4s syndrome is characterized by male infertibty. situs inversus, recurrent sinusitis, and bronchiectasis. Fever, pharyngibs, Iymphadenopathy hepatosplenomegaly. atypical lymphocytosis, and a positive heterophile antibody reaction characterize infectious mononucleosis, which is caused by the Epstein-Barr virus (EBV). EBV infection is also associated with an increased incidence of Burkitt lymphoma and nasopharyngeal carcinoma. Cystinuna results fromacid a defect inThe the clinical renal proximal tubules, which stone resultsformation in decreased resorption of the amino cystine. manifestation is recurrent 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 Benign prostatic hyperplasia leads to intermittent bladder outlet obstruction and overflow incontinence. Urinary retention results in increased pressure in the urinary tract and resultant reflux nephropathy. Ultimately, hydronephrosis and renal interstitial atrophy and scarring ensue The condition should be promptly treated, as prolonged obstruction can cause permanent damage and chronic renal failure Famdial retinoblastoma occurs as a result of mutations of each of the two Rb genes (‘two hits”) These patients have an increased risk of secondary tumors, especially osteosarcomas, later in Iife Endornetnal cells undergo apoptosis upon withdrawal of endocrine stimulation by progesterone. Central retinal artery occlusion (CRAO) presents with sudden, painless, and permanent monocular blindness Funduscopic examination reveals a pale retina and a “cherry-red macula Central retinal artery occlusion (CRAO) presents with sudden, painless, and permanent monocular blindness. Funduscopic examination reveals a pale retina and a cherry-red” macula Idiopathic hypercalciuria is the most common cause of calcium lódney stone disease This condition is characterized by normal serum calcium levels with high levels of calcium excreted in the urine. Other causes of calcium nephrolithiasis include hyperoxaluna. hyperuricosuria, low urinary volume, and hypocitraturia. Idiopathic hypercalciuha is the most common cause of calcium kidney stone disease This condibon is characterized by normal serum calcium levels with high levels of calcium excreted
in the unne Other causes of calcium nephrohtheasis include hyperoxaluna, hyperuricosuna, low urinary volume, and hypocitratuha Hydronephrosis a dilation of the renal pelvis and calyces due to obstruction of urine flow. Kidney enlargement and distortion, compression of the papdlae. thinning of the parenchyma around the calyces, and cortical atrophy are seen on gross examination Microscopic changes consist of dilation of the tubular lumen, flattening of the tubular epithelium, and interstitial fibrosis The most common cause of urinary tract obstruction in elderly male patients is benign prostatic hyperplasia (BPH) Unc acid stones are the typeother of renal that are are radiopaque radiolucent and Theycan canbebeseen detected on abdominal ultrasound oronly CT Afl typescalculi of stones 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 that autosomal recessive fashion The only of decades this disorder is nephrohthiasis classically presents as renal colicclinical dunng manifestation the 2nd or 3rd of life Unnalysis shows pathognomonic hexagonal cystine crystals.
PATHOLOGY-Git1 Shigeliosis is an infectious disease caused by vanous species of Sh.ieI!a S sonneiis the most common (-80%) etiological agent in the United States Shigella invades the gastrointestinal mucosa by first gaining access to M cells in Peye?s patches in the ileum through endocytosis Shigella subsequently lyses the endosome, multiplies, and spreads laterally into other epithelial cells, causing cell death and ulceration with hemorrhage and diarrhea Carcinoid syndrome may accompany extraintestinal metastases of GI carcinoids Octreotide is a synthetic somatostatin analog used to control the symptoms of carcinoid syndrome Pancrealk pseudocyst is a common complication of acute pancreatitis It is a col’ection of fluid rich in enzymes and inflammatory debns Its walls consist of granulation tissue and fibrosis Unlike true cysts, pseudocysts are not lined by epithelium
80% of the cases of acute pancreatitis are caused by gallstones and chronic alcohohsm A number of less common causes account for the other 20% of cases Inherited or acquired hypertriglyceridemia can cause an acute pancreatitis if the level of triglycerides in serum exceeds 1000 mg/dL IgA anti-tissue transglutaminase and IgA endomysial antibody are very sensitive and specific for the diagnosis of celiac disease Small intestinal biopsy is confirmatory, severe atrophy and blunting of the villi along with a chronic inflammatory infiltrate of the lamina propna is seen Symptoms of celiac disease (diarrhea, steatorrhea, and nutritional deficiencies) subside with exclusion of gluten-containing products from the diet. Intussusception most often occurs in ciNidren younger than 2 years ol age and in the region of the ileocecal valve. It manifests with intermittent, severe, colicky abdominal pain, “currant jelly” stools, and sometimes a palpable mass in the light lower abdominal quadrant Squamous cell carcinoma of the esophagus presents with progressive dysphagia as the tumor gradually obstructs the esophageal lumen Chronic alcohol consumption and cigarette smoking are 2 major risk factors On light microscopy, the tumor is composed of squamous cells with vanous degrees of atypia Foci of keratinization are present in well-differenbated tumors. Diarrhea, weight loss, and epigastnc region calcifications in a patient with chronic alcoholism suggest chronic pancreatitis with resutting pancreatic exocnne insufficiency and malabsorption Crohn’s disease is associated with increased activity of the NF-KB protein, which is responsible for cytokine production. When the appropriate immune response to intracellular microbes is blunted, the microbes persist and induce chronic inflammation within the gastrointestinal tract Carcinoid tumors are composed of nests or sheets of uniform cells. They have eosinophihc cytoplasm and oval-to-round stippled nuclei. These tumors are derived from enterochromaffin cells of intestinal mucosa. Colonic diverticula usually develop due to increased intraluminal pressure and are composed of mucosa and submucosa. The most common site is the sigmoid colon Diverticula may be asymptomatic or may manifest with painless rectal bleeding or acute diverticuhtis. Chronic constipation is a risk factor for this condition. Aicohol abuse is 1 of the 2 most common causes of acute pancreatitis (gallstones are the other) Macrocytosis, an ASTALT ratio > 2, and elevated gamma-glutamyltransferase (GGT) are indirect indicators of chronic alcohol consumption. Macrocytosis can occur independently of folate or cobalamin deficiency Crohn’s disease causes transmural inflammation of any area of the gastrointestinal tract The involvement of all layers of the intestinal wall explains the most common complications of Crohn’s disease strictures and fistula formation.
Vitamin A deficiency can cause night blindness Vitamin A deficiency may result from any cause of fat soluble vitamin malabsorption, including ciwonic cholestasis from bihary obstruction Dermatitis herpetiformis is associated with celiac disease. Dermatitis herpetiformis describes groups of small vesicles that occur symmetrically on the extensor surfaces and are extremely pruritic. Immunofluorescence reveals IgA deposits in the tips of dermal papillae. Congenital pylohc stenosis ahses secondary to hypertrophy of the pyloric muscularis mucosae. In acute interstitial pancreatitis the pancreas is grossly edematous Focal areas of fat necrosis, calcium deposition and interstitial edema seen on light microscopy. In necrotizing (hemorrhagic) pancreatitis, chalky-white areasare of fat necrosis interspersed with hemorrhage are seen on macroscopic examination Adenomatous polyps contain dysplastic mucosa and are premalignant Regular screening with timely excision of polyps is effective for the prevention of colon adenocarcinoma. Studies have linked increased activity of COX-2 to some forms of colon adenocarcinoma and suggest that aspirin use decreases adenomatous polyp formation. In ulcerative colitis: 1. The rectum is always involved. 2. Inflammation is limited to mucosa and submucosa only 3. Mucosal damage is continuous Metastasis of gastric cancer can present as Virchows node, a Sister Mary Joseph nodule, or as Krukenberg tumor of the ovary Several factors are considered to be involved in the pathogenesis of Crohn’s disease Increased activity of T1 helper cells increases production of IL.2, interferon-y, and TNF, causing subsequent intestinal injury Nonc aseating granulomas, like the one seen on the slide above, are charactenstic of Crohn’s disease GERD is the most common cause of esophagitis. Gastroesophageal junction incompetence is the pnmary pathophysiologic mechanism responsible for GERD Repeated exposure of esophageal mucosa to acidic gastric contents causes chemical injury and inflammatory reachon Basal zone hyperplasia, elongation of lamina propria papillae. and inflammatory cells (eosinophils, neutrophils and lymphocytes) are characteristic histologic findings. The 2 most significant risk factors for the development of esophageal squamous cell carcinoma in the United States are smoking tobacco and drinking alcohol. Betel nut chewing and the consumption of foods containing N-nitroso compounds are important risk factors in Asian countries. Toxic megacolon is a well-recognized comphcabon of ulcerative colitis Abdominal pain and distention, along with fever, diarrhea, and signs of shock are typical Plain abdominal X-ray
should be used for diagnosis Banum contrast studies and colonoscopy are con(raindicated due to risk of perforation Hereditary non-polyposis colon cancer (HNPCC) is also referred to as Lynch syndrome It leads to occurrence of colonic adenocarcinomas at a young age (<50 years old), along with predisposition for extraintestinal malignancies. Mutations of DNA mismatch repair genes are responsible for this syndrome Zolhnger-Elhson syndrome occurs due to hypersecretion of gastrin by a pancreatic tumor Gastnn increases gastnc acid production, which causes peptic ulcers in the maionty of patients Mother common of Zollinger-Ellison syndrome, diarrhea, occurs due to the inactivation of intestinal symptom and pancreatic enzymes by excess gastric acid. Cystic fibrosis is a genetic abnormality of exocrine secretion that leads to formation of thick, viscous mucus The respiratory tract and pancreas are the organs most commonly affected The pancreas characteristically shows duct obstruction by mucous plugs Caused by the gram-positive actinomycete Tropheryma iihiopefr/ Whipple disease is a rare systemic illness that involves the small intestine. joints, and central nervous system. Classic histologic findings include small intestine mucosa containing enlarged. foamy macrophages packed with both rod-shaped bacilli and PAS-positive, diastase-resistant granules. Because the splenic flexure and distal sigmoid colon he between areas of perfusion of major artenes. they are called “watershed” areas These two areas of the intestine are the most susceptible to ischemic damage during hypotension I low perfusion states. Obstruction of the lumenlymphoid of the appendix the firstbodies, event in of acute Fec aliths, hyperplastic follicles,isforeign or pathogenesis tumors may cause theappendicitis obstruction Right lower quadrant abdominal pain, nausea, vomiting, diarrhea, and fever are the typical manifestations of acute appendicitis Crohn’s disease is associated with oxalate kidney stones Impaired bile acid absorption in the terminal ileum leads to loss of bde acids in the feces with subsequent fat malabsorption Lipids then bind calcium ions, and the resulting soap complex is excreted. Free oxalate (which is normally bound by calcium ions to form an unabsorbable complex) is absorbed and forms urinary calculi. Adenomatous polyps are divided into tubular. villous. and tubulovillous according to their histologic appearance Villous adenomas tend to be larger. sessile, and more severely dysplastic than tubular adenomas. Villous adenomas can cause bleeding. secretory diarrhea, and partial intestinal obstruction. Intestinal metaplasia in the esophagus is a complication of long-standing GERD and is called Barrett esophagus. Originally a protective response to injury by acidic stomach contents. Barrett esophagus signitlcantty increases the nsk of esophageal adenocarcinoma
Mallory-Weiss tears account for about 10% of cases of upper GI hemOrrhage. They occur due to increased intraluminal gastric pressure due to retching. vomiting, or other abdominal strainIng. The main manifestation of Crohns disease is abdominal pain. Diarrhea, low-grade fever, and symptoms of malabsorption are also common. Intestinal complications of Crohn’s disease include fistulas and intestinal stnctures The insèdious onset of nonbloody diarrhea. fever, maIase, and perianal fistulae should prompt an evaluation for Crohn’s Disease, a form of inflammatory bowel disease that may wwolve any portion of the GI tract from the mouth to the anus Long-standing ulcerative colitis is associated with an increased risk of colorectal cancer The duration and extent of colitis are the most significant risk factors Unlike sporadic colorectal carcinomas, colitis-associated carcinomas are more likely to arise from non-polypoid dysplastk lesions, be multifocal in nature, develop early p53 mutations and late APC gene mutations, and be of a higher histological grade. An anal fissure is a tear m the lining of the anal canal distal to the dentate line that occurs most often on the posterior midline Patients complain of severe tearing pain associated with the passage of bowel movements. There may be a skin tag on physical examination. Anal fissures are associated with low-fiber diets and constipation. Barrett esophagus is an intestinal metaplasia of esophageal epithelium It occurs in GERD and is the most important risk factor for development of esophageal adenoc arc inoma As the sequence of GERD —.Barrett esophagus —esophageal adenocarcinoma is well-recognized, early diagnosis and regular monitonng of patients with gastroesophageal reflux is wnportant Colon adenocarcinoma is the most common GI malignancy. It is most frequently located in the rectosigmoid colon Patients with cancer at this location tend to present with obstructing symptoms (altered bowel habits, constipation, abdominal distension, nausea and vomiting). H. pyh,ninfection is associated with the formation of duodenal ulcers due to increased gastric acidity The increased gastric acidity is caused by a decrease in somatostatin-secreting cells in the gastric mucosa leading to unchecked gastrin production H pylonis also strongly associated with the formation of gastric ulcers, gastritis. gastric adenocarcinoma, and gastric lymphoma.
Smoking is the most important environmental risk factor for pancreatic cancer Age> 50 years, chronic pancreatftis, diabetes meibtus, and genetic predisposition also increase the risk of this malignancy. Type B chronic gastntis typically affects the gastric antrum and is usually the result of H. pylon infection of the gastric mucosa, This type of gastritis is associated with an increased risk of gastric adenocarcinoma and MALT lymphoma. The rapid urease test is used in the diagnosis of HekcobacferpyIoriinfection Here, a samp’e from the gastric mucosa is added to a solution containing a pH indicator and urea Urease will convert
urea to carbon dioxide and ammonia and cause a pH increase and resultant color change of the pH indicator, indicating alkahnization of the solution. Submucosal (Meissner) and myentenc (Auerbach) autonom,c plexi are absent in the affected se9ment of the bowel in Hirschsprung disease The submucosa of the narrowed area is the most superficial layer where the absence of ganglion cells can be seen
PATHOLOGY-Git 2 Carcinoid syndrome may accompany extraintestinal metastases of GI carcinoids Octreotide is a synthetic somatostatin analog used to control the symptoms of carcinoid syndrome Ulcers arising in the proximal duodenum in association with severe trauma or bums are called Curling ukers Ulcers arising in the esophagus, stomach, or duodenum in patients with high intracranial pressure are particularly prone to perforation and are called Cushing ulcers Educational Objective: Several factors are considered to be involved in the pathogenesis of Crohn’s disease Increased activity of T_I helper cells increases production of IL-2, interferon-y, and TNF, causing subsequent intestinal injury Nonc aseabng granulomas, like the one seen on the slide above, are characteristc of Crohn’s disease Shigellosis is an infectious disease caused by vahous species of Shigella S sonrielis the most common (—80%) etiological agent in the United States, Shigella invades the gastrointestinal mucosa by first gaining access to M cells in Peyer’s patches in the ileum through endocytosis Shigella subsequently lyses the endosome, multiplies, and spreads laterally into other epithelial cells, causing cell death and ulceration with hemorrhage and diarrhea Adenomatous polyps are divided into tubular. vitlous. and tubulovillous according to their histologic appearance. Villous adenomas tend to be larger, sessile, and more severely dysplastic than tubular adenomas. Villous adenomas can cause bieeding, secretory diarrhea, and partial intestinal obstruction. Toxic megacolon is a well-recognized complication of ulcerative colitis Abdominal pain and distention, along with fever, diarrhea, and signs of shock are typical Plain abdominal X-ray should be used for diagnosis Barium contrast studies and colonoscopy are contraindicated due to risk of perforation Colon adenocarcinoma is the most common GI malignancy. It is most frequently located in the rectosigmoid colon. Patients with cancer at this location tend to present with obstructing symptoms (altered bowel habits, constipation, abdominal distension, nausea and vomiting).
He/icobacterpyloncan cause duodenal ulcers and is typically found in greatest concentration in the prepylonc area of the gastric antrum As a result, biopsy of the prepytonc area would have the greatest yield of the organism.
Type B chronic gastntis typically affects the gastnc antrum and is usually the result of H. pyhxiinfection of the gastric mucosa This type of gastntis is associated with an increased risk of gastric adenocarcinoma and MALT lymphoma The 2 most significant nsk factors for the development of esophageal squamous cell carcinoma in the United States are smoking tobacco and drinking alcohol Betel nut chewing and the consumption of foods containing N-nitroso compounds are important risk factors m Asian countries. The insidious onset of nonbloody diarrhea, fever, malaise, and perianal fistulae should prompt an evaluation for Crohn’s Disease, a form of inflammatory bowel disease that may involve any portion of the GI tract from the mouth to the anus. An anal fissure is a tear in the lining of the anal canal distal to the dentate line that occurs most often on the posterior midline. Patients complain of severe tearing pain associated with the passage of bowel movements. There may be a skin tag on physical eXamination. Anal fissures are associated with low-fiber diets and constipation Non-neoplastic polyps (hyperplastic. hamartomatous. inflammatory) usually do not progress into adenoc arc inoma of the colon Adenomatous polyps, however, can undergo mahgnant transformation Villous adenomas are more likely than tubular adenomas to progress to adenoc arc inoma The rapid urease test is used in the diagnosis of H obacterpyIoiiinfection Here, a sample from the gastric mucosa is added to a solution containing a pH indicator and urea Urease will convert urea to carbon dioxide and ammonia and cause a pH increase and resultant color change of the pH indicator, indicating alkalinization of the solution The main manifestation of Crohn’s disease is abdominal pain Diarrhea. low-grade fever, and symptoms of malabsorption are also common. Intestinal complications of Crohn’s disease include fistulas and intestinal strictures. Colonic diverticula usually develop due to increased intraluminal pressure and are composed of mucosa and submucosa The most common site is the sigmod colon Diverticula may be asymptomatic or may manifest with painless rectal bleeding or acute diverticulitis Chronic constipation is a nsk factor for this condition. Smoking is the most important environmental risk factor for pancreatic cancer. Age> 50 years, chronic pancreatitis, diabetes mellitus, and genetic predisposition also increase the risk of this malignancy
Carcinoid tumors are composed of nests or sheets of undorm cells They have eosinophilic cytoplasm and oval-to-round stippled nuclei These tumors are derived from enterochromaffin cells of intestinal mucosa AJcohol abuse is 1 of the 2 most common causes of acute pancreatitis (gallstones are the other). Macrocytosis, an ASTALT ratio >2, and elevated gamma-glutamyltransferase (GGT) are indirect indicators of chronic alcohol consumption. Macrocytosis can occur independently of folate or cobalamin deficiency. Atherosclerotic artehal changes diminEsh blood flow to the intestine causing chronic mesenteric ischemEa Its out pathogenesis is similar to angina pectons. Postprandial abdominal pain, wesght loss, and pain of proporbon to physical findings are common. GERD is the most common cause of esophagitis. Gastroesophageal junction incompetence is the primary pathophysiologic mechanism responsible for GERD. Repeated exposure of esophageal mucosa to acidic GERD is the most common cause of esophagitis Gastroesophageal junction incompetence is the primary pathophysiologic mechanism responsible for GERD Repeated exposure of esophageal mucosa to acidic gastric contents causes chemical injury and inflammatory reaction Basal zone hyperplasia, elongation of lamina propria papillae, and inflammatory cells (eosinophils, neutrophils and lymphocytes) are characteristic histologic findings Carcinoembryonic antigen (CEA) level is increased in colon cancer, as well as in other malignancies and certain benign diseases CEA cannot be used to diagnose colon cancer, but is helpful for detecting disease recurrence Kaposi’s sarcoma usually involves the skin and (31 tract and is common in HIV patients not on antiretroviral therapy Endoscopy reveals characteristic lesions, which range from reddishMolet flat maculopapular lesions to raised hemorrhagic nodules or polypoid masses Biopsy can show spindle cells, neovascularization. and extravasated red blood cells. Hereditary non-polyposis colon cancer (HNPCC) is also referred to as Lynch syndrome It leads to occurrence of colonic adenocarcinomas at a young age (<50 years old), along with predisposition for extraintestinal malignancies Mutations of DNA mismatch repair genes are responsible for this syndrome Obstruction of the lumen of the appendix is the first event in pathogenesis of acute appendicths Fecaliths, hyperplastic lyrnphoid follicles, foreign bodies, or tumors may cause the obstruction Right lower quadrant abdominal pain, nausea. vomiting, diarrhea, and fever are the typical manifestations of acute appendicitis. Uohns disease causes transmural inflammation ot any area 01 the gastrointestinal tract I he involvement of all layers of the intestinal wall explains the most common complications of Crohn’s disease stnctures and fistula formation
There are two morphologcal variants of gastric adenocarcinoma Intestinal type forms a solid mass that projects into the stomach lumen and is composed of glandular-forming cuboidal or columnar cells Diffuse carcinoma (linitis plastica) infiltrates the stomach wall and displays a signet-ring pattern on light microscopy Subinucosal (Meissner) and myenteric (Auerbach) autonomic plexi are absent in the affected segment of the bowel in Hirschsprung disease The subrnucosa of the narrowed area is the most superficial layer where the absence of ganghon cells can be seen The glycoprotein in the cell walls of the actinomycete Tropheryma ih4eWcolors magenta with PAS anddisease. is diastase-resistant, making this stain an excellent choice in evaluating tissue for Whipple Malabsorption isa syndrome of impaired intestinal digestion and absorption Diarrhea, steatorrhea, weight loss, and vitamin and mineral deficiencies are common Sudan Ill stain of stool identifies fecal fat and is used to screen for malabsorption H pyloninfection is associated with the formation of duodenal ulcers due to increased gastric acidity The increased gastric acidity is caused by a decrease in sornatostatin-secreting cells in the gastric mucosa leading to unchecked gastnn production. H. pyhnis aiso strongly associated with the formation of gastric ulcers, gastritis, gastric adenocarcinoma, and gastric lymphoma
The size of adenomatous polyps determines their malignant potential. Adenomas <1 cm are unlikely to undergo malignant transformation, while those >4 cm are very likely (40%) to progress to adenocarcinoma K! asprotooncogene mutation facilitates the growth of adenomas by causing uncontrolled cell prohferation Cystic fibrosis is a genetic abnormality of exocrine secretion that leads to formation of thick, viscous mucus The respiratory tract and pancreas are the organs most commonly affected The pancreas characteristically shows duct obstruction by mucous plugs One of the earliest visceral manifestations of systemic sclerosis is esophageal hypomotihty and incompetence of the lower esophageal sphincter due to atrophy and fibrous replacement of the esophageal muscles Esophageal dilatation causes reflux, which increases the nsk of Barrett esophagus and esophageal adenoc arc inoma, In ulcerative colitis: 1 The rectum is always involved 2. Inflammation is limited to mucosa and submucosa only. 3. Mucosal damage is continuous. APC mutation is required for the emergence of small adenomatous polyps from normal colonic mucosa. This mutation constitutes the first step of the adenoma-to-carcinoma sequence APC gene mutation is found in most cases of sporadic colon cancer and in all familial polyposis syndromes
Zollinger-Ellison syndrome occurs due to hypersecretion of gastrin by a pancreatic tumor Gastrin increases gastric acid production, which causes peptic ulcers in the majonty of patients Mother common symptom of Zollinger-Ellison syndrome, diarrhea, occurs due to the inactivation of intestinal and pancreatic enzymes by excess gastric acid. Acute erosive gastropathy can be caused by a number of factors, including nonsteroidal 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 the pancreas edematous Focal areas of necrosis, calcium deposition pancreatitis and interstitial edema is aregrossly seen on light micrOscopy. In fat necrotizing (hemorrhagic) pancreatitis, chalky-white areas of fat necrosis interspersed with hemorrhage are seen on macroscopic examination. Congenital pyloric stenosis anses secondary to hypertrophy of the pyloric muscularis mucosae, Diarrhea, weight loss, and epigastric region calcitlcations in a patient with chronic alcoholism suggest chronic pancreatitis with resulting pancreatic exocrine insufficiency and malabsorption Abetalipoproteinemia is an inherited inability to synthesize apolipoprotein B, an important component of chylomicrons Lipids absorbed in the small intestine cannot be transported and therefore accumulate in the intestinal epithelium. Lack of lipids in the cell membranes causes abnormal red blood cells (acanthocytes) and neurologic deficits. Parietal cells secrete hydrochloric acid and intrinsic factor and are primarily found in the superficialfound region of deeper gastric region glands.of Chief synthesize and secrete pepsinogen and are primarily in the gastriccells glands Pancreatic pseudocyst is a common complication of acute pancreatitis It is a collection of fluid hch in enzymes and inflammatory debns Its walls consist of granulation tissue and fibrosis Unlike true cysts, pseudocysts are not lined by epithehum Patients with Crohn’s disease affecting the terminal ileum are prone to the development of gallstones. Decreased bile acid reabsorption and its loss via feces increases the lithogenicity of bile Cholesterol precipitates and forms gallstones. Because the splenic flexure and distal sigmoid colon lie between areas of perfusion of malor arteries, they are called “watershed” areas. These two areas of the intestine are the most susceptible to ischemic damage during hypotension I low perfusion states.
PATHOLOGY-Hepatic Absorbed copper is used to form ceruloplasmin, which accounts for 90-95% of circulating copper Senescent ceruloplasmin and the unabsorbed copper are secreted into bile and excreted in stool, which is the primary route for copper elimination. Hepatitis B virus infection is associated with a serum-sickness like syndrome in the prodromal period. Hepatocyte injury in vial hepatitis is characterized by a diffuse swelling termed Thallooning degeneration’ Hepatocyte death in wal hepatitis is charactenzed by lobular architectural disruption and confluent hepatocyte necrosis, a process called “bndging necrosis In response to the hepatocellular injury and death. mononuclear inflammation develops m the sinusoids and portal tracts. Gallbladder hypomotibty often results in bile precipitation and the formation of biliary sludge. Acute acalculous cholecysttis is an acute inflammahon of the gallbladder in the absence of gallstones It is most commonly seen in the hospitalized and severely ill The Kayser-Fleischer ring is an ophthalmologic finding most strongly associated with Wilsons disease It is seen most frequently in patients with neuropsychiatric complications. Basal gangha atrophy is typically present in these patients. The diagnosis of alpha-i antitrypsin deficiency should be suspected in all patients with premature onset (< 50 years) of chronic bronchitis. emphysema. or dyspnea, as well as in nonsmokers suffering from chronic obstructive pulmonary disease (COPD) A history of neonatal hepatitis with cholestasis should heighten suspicion for A1AT deficiency. Brown pigment stones typically arise secondary to infection of the biliary tract, which results in the release of 3-glucuronEdase by injured hepatocytes and bactena The presence of this enzyme contnbutes to the hydrolysis of bibrubin glucuronides and increases the amount of unconjugated bilirubin in bile To reduce the likelihood of cholesterol precipitahon (and gallstone formation), cholesterol quantities should be kept low and bile acid quantities kept high. High levels of phosphatidyicholine. a phospholipid that renders cholesterol soluble, are also associated with decreased risk of gallstones The most common hepatic lesion is a metastasis from another pnmary site (eg, breast, lung, colon), not hepatocellular carcinoma The cIassc picture and of primary cirhosis is a middle-aged Caucasian female with a long history of pruntus fatigue biliary 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 Inhaled anesthetics, such as halothane. can be associated with a highly lethal fulminant hepatitis that cannot be histologically distinguished from acute viral hepatitis. Patients present with significantly elevated aminotransferase levels, a prolonged prothrombin time, and eosinophilia. Black pigment stones are associated with chronic extravascular hemolysis. Hepatocellular carcinoma is strongly associated with HBV infection. Integration of viral DNA into the genome of host hepatocytes triggers neoplastic changes Other risk factors for hepatocellular carcinoma include HCV, akoholic cirrhosis, aflatoxins and hemochromatosis. The most common outcome in HBV-infected adults (> 95%) is acute hepatitis with mild or subclinical symptoms that eventually completely resolve. Anorexia. nausea, and low-grade fever followed by bElirubnuria and right upper quadrant tenderness suggest acute hepatitis, which is most commonly caused by the Hepatitis A virus in young adults Acute hepatitis due to most hepatotropic viruses causes hepatocyte ballooning degeneration and apoptosis on histologic exam Cholecystectomy is recommended for those with porcelain galibladders because 11-33% of this patient population will eventually develop gallbladder carcinoma Dubin-Johnson syndrome is characterized by a defect in the hepatic excretion of bilirubin glucuronides across the canalicular membrane Grossly. the liver is stnkingly black Histological features are normal, though a dense pigment composed of epinephnne metabohtes within the lysosomes can be seen Individuals with stable. compensated cirrhosis who suddenly decompensate without apparent reason should be carefully evaluated for hepatocellular carcinoma, especially when serum AFP levels are also elevated. Primary biliary cirrhosis and graft versus host disease have similar histologic findings, including granulomatous bile duct destruction and a heavy lymphocyte-predominant poital tract infiftrate
The genetic mutation of hemochromatosis prevents expression of the HFE protein on the basolateral surface of the intestinal cells where it normally binds to the transfemn receptor and regulates transferrin/iron complex endocytosis into the cells As a result. there is unregulated expression of the iron uptake proteins and an excessive amount of iron is absorbed gastrointestinally Liver cirrhosis and hepatocellular carcinoma are two of the more ominous potential complications of this disease. Cirrhosis is microscopically charactenzed by diffuse hepatic fibrosis with replacement of the normal lobular architecture by fibrous-lined parenchymal nodules. Hepatitis B infection the antigen) hepatocellular cytoplasm to fill with theeosinophihc spheres andappearance tubules of HBsAg (the hepatitis causes B surface and take on a finely granular. commonly described as “ground glass.” Estrogen-induced cholesterol hypersecretion and progesterone-induced gallbladder hypomotility are responsible for the increased incidence of cholelithiasis in women who are pregnant or using oral contraceptives. The pathogenesis of alcohol-induced hepatic steatosis appears related primarily to a decrease in free fatty acid oxidation secondary to excess NADH production by the 2 major alcohol metabolism enzymes, alcohol dehydrogenase and aldehyde dehydrogenase Stable chronic hepatitis is the most likely outcome for a patient acutely infected with hepatitis C virus, followed closely by chronic hepatitis progressing to cirrhosis. Physiologic iron loss through menstruation and pregnancy slows the progression of hemochromatosis in women. Alpha-i antitrypsin (AIAT) is a serum protein that reduces tissue damage caused by inflammation through the inhibition of neutrophil elastase, Histologically. A1AT deficiency is associated with reddish-pink, periodic acid-Schiff-positive granules of unsecreted, polyrnerized AIAT in the periportal hepatocytes Alcoholic liver injury develops through the stages of alcoholic steatosis. alcoholic hepatitis anJ cirrhosis. Increased AST and ALT are indicators of hepatocellular damage The serum albumin level and prothrombin time reflect liver function and are of greatest prognostic Significance. A positive HIDA scan confirms cystic duct obstruction, which is necessary for a definitive diagnosis of acute calculous cholecystitis Nonobstructing biliary stones seen by ultrasound are suggestive but not diagnostic of the condition Reye syndrome occurs in children with febrile illness treated with saIicyIates It consists of hepatic failure and encephalopathy The characteristic histological finding is microvesicular steatosis of hepatocytes without inflammation and cerebral edema.
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, likely dueApoptotic to hepatitis C mfection. Acute viral hepatitis causes hepatocyte apoptosis most and necrosis. hepatocytes shrink, undergo nuclear fragmentation and become intensely eosinophilic. They may also be referred to as acidophibc bodies, Councilman bodies, and apoptotic bodies. Primary biliary cirrhosis is a chronic hver disease characterized by autoimmune destruction of the intrahepatic bile ducts and cholestasis (elevated alkaline phosphatase). The condition is most common in middle-aged women, with severe pruntus (especially at night) one of the first symptoms reported. Aipha-fetoproteinis a useful marker in the evaluation of cirrhotic patients who are at increased risk for developing hepatocellular carcinoma Regular monitoring of AFP in this patient population is recommended Cavernous hemangiorna is the most common benign liver tumor Microscopically, these tumors consist of cavernous, blood-filled vascular spaces of variable size lined by a single epithehal layer Thefatal biopsy of a suspected hemangioma is not advisable, as the procedure has been known to cause hemorrhage and is of low diagnostic yield. The hemochromatosis gene (HLA-H) is on the short arm of chromosome 6 and encodes for a molecule that appears to affect iron absorption from the gastrointestinal tract Estrogenc influence facilitates the biosynthesis of cholesterol by increasing hepatic HMG-CoA reductase actMty Suppression of cholesterol 7cz-hydroxylase actMty (by medications such as fibrates) reduces the conversion of cholesterol to bile acids, resulting in excess cholesterol secretion in bile Advanced Wilson disease is often characterized by neuropsychiatnc symptoms, including Parkinsonian-hke tremor, rigidity, ataxia. slurred speech, drooling, personality changes. depression, paranoia, and catatonia OJmost all patients with neuropsychiatric involvement will also have Kayser-Fleisc her rings, which can be identified on slit lamp examination. Aspiration of hydatid cysts is generally inadvisable, as the spilling of cyst contents within the peritoneum can cause anaphylactic shock.
Gallstone ileus is a rare type of mechanical bowel obstruction caused when a large gallstone erodes into the intestinal lumen. Pneumobiha (air in the bihary tract) is suggestive of the diagnosis.
PATHOLOGY-Neuro 1 Cerebral amyloid angiopathy is a common cause of recurrent lobar hemorrhage This type of intracranial hemorrhage has a lower mortality rate and more benégn clinical course than hemorrhagic strokes associated with hypertension Synaptophysin is a protein found in the presynaptic vesicles of neurons. neuroendocrine and neuroectodermal cells, CNS tumors of neuronal srcin frequently stain positively for synaptophysin on immunohistology Neoplasms of glial srcin (astrocytomas, ependymomas. and oligodendrogliomas) stain for GFAP Liquefactive necrosis is characterized by complete digestion and removal of necrotic tissue with formation of cystic cavity. Hypoxic CNS injury is often followed by hquefactive necrosis. Abscess formation due to bacterial or fungal infection is another example of this type of necrosis. The subthalamic nucleus is one of the components of the basal ganglia Damage to this nucleus (most often due to lacunar stroke) leads to hemibalhsm, The wwoluntary flinging movements of one side of the body (arm and/or leg) that constitutes hemiballism are always contralateral to the lesion Subarachnoid hemorrhage presents with a generakzed. excruciating headache It is classically described by patients as ‘The worst headache of my life.” Subarachnoid hemorrhage usually occurs due to rupture of saccular (berry) aneurysms or artenovenous maWormatons. Berry aneurysms of the circle of Willis are associated with autosomal dominant polycystic kidney disease The hippocampus is the area of the brain demonstrating the greatest degree of atrophy in AIzheimers disease Hippocampal atrophy on MRI is highly suggestive of the diagnosis Duchenne muscle dystrophy manifests with proximal muscle weakness and atrophy. True hypertrophy of the distal muscle is noted early in the disease as distal muscles compensate for weak proximal ones. Later, muscle fibers of the distal extremities are replaced by fat and connective tissue (pseudohypertrophy). Both myasthenia gravis and Lambert-Eaton Lambert-Eaton syndrome syndrome isare caused bywith poorunderlying sgnaI transmission at the neuromuscular junction associated malignancy Antibodies to voftage-gated presynaptic calcium channels are found in these patients
Bilateral acoustic neuromas are associated with r,eurofibromatosis type 2, an autosomal dominant condition caused by mutation of the NF-2 gene on chromosome 2Z Severe vitamin E deficiency closely resembles the clinical presentation of Friedreich ataxia Vitamin E is a lipd-solubIe vitamin that has antiox,dative properties Pituitary adenornas cause symptoms from mass effect and often produce endocrine disorders from the vanous hormones that they can produce. Prolactinomas are the most common adenoma—excess prolactin causes amenorrhea and galactorrhea. Bitemporal hemianopsia from compression of the optic chiasm is common. A cystic tumor in the cerebellum of a child is most likely a pdocytic astrocytoma Biopsy will show a welld ifferentiated neoplasm comprised of spindle cells with hair-like ghal processes that are associated with microcysts These cells are mixed with Rosenthal fibers and granular eosinophilic bodies Subacute scierosing encephahtis is a rare complication of measles infection. It occurs several years after apparent recovery from initial infecbon Oligoclonal bands of antibodies to the measles virus are found in the CSF of these patients. Antibodies to the M component of the measles virus are absent CNS involvement in syphihs (neurosyphiks) may manifest as a number of syndromes Tabes dorsalis occurs due to demyelination of dorsal columns and dorsal roots of the spinal cord Loss of proprioception and vibration senses, ataxia. and Argyll Robeftson pupil may be seen. A cerebellar hernangioblastoma in association with congenital cysts of the kidneys, liver, and/or pancreas is highly suggestive of von Hippel—Lindau disease. a rare autosomal dominant condition Note: The syndromes descnbed above are common’y tested on USMLE exams It is important to be familiar with them. Counting down from 100 by 7 or3, reciting the months of the year in reverse order, and spelling “world” backwards are quick clinical tests to assess attention and concentration Attention and concentration are tested as part of the Mini-Mental State Examination (MMSE), a wdely used screening tool for cognitive impairment The MMSE also measures onentaton to time and place, short-term memory, calculation, language, and constructional praxis. 1. Holoprosencephaly results from failure of forebrain cleavage into cerebral hemispheres. It is an example of a congenital malformation, a primary abnormality in a development process 2 Amniotic band syndrome is an example of a disruption (secondary destruction of a previously well-formed tissue or organ). 3. Congenital hip dislocabon, clubbed feet and flat facies (Potter syndrome) are examples of deformations (secondary to extnnssc compression). 4. Potter syndrome is also an example of a sequence.
Subdural hematoma occurs due to the rupture of cortical bridging veins In young patients, it results from a fall or motor vehicle accident, and manifests with gradual onset of headache and confusion In elderly patients it may occur after a minor trauma and present with a variety of neurologic symptoms. You should know how to recognize this on CT scan Meniére’sdEsease is characterized by the triad of tinnetus, vertigo and sensorineural hearing loss Its pathogenesis is related to an increased volume and pessure of endolymph in the vestibular apparatus Cluster headaches cause severe. episodic. unilateral periorbital and temporal pain associated with lacrimation, congestion ptosis Cluster headaches classically occur at the same time each day and nasal are more commonand in males. A neuron that is responding to irreversible injury is called a red neurons Characteristic changes become evident 12-24 hours after the injurious event and include shrinkage of the cell body, eosinophilia of the cytoplasm. pyknosis of the nucleus and loss of Nissl substance The infusion of glucose without thiamine in a patient with chronic thiamine deficiency precipitates encephalopathy Confusion, ataxia. and ophthalmoplegia form the thad of Wemicke encephalopathy. Hemorrhage into the mamillary bodies is characteristic Picks disease causes pronounced atrophy of the frontal lobe. Clinically, it manifests with progressive dementia, behavioral disinhibition. and speech difficulties, such as dysarthna. aphasia, and echolalia Guillain-.Barre syndrome is an acute demyelinating peripheral neuropathy. It affects young adults is usually preceded byinfiltrate a febrileare illness. demyehnation of peripheral nerves and an and endoneural inflammatory seen Segmental on light microscopy. Meningiomas are slowly growing. weli-circumscribed and benign tumors. Psammoma bodies are characteristic of meningiomas Psammoma bodies are composed of a core of dense calcification with surrounding collagen-fiber bundles Arnold-Chiari malformations are congenital abnormalities They are caused by impaired development of the posterior fossa Arnold-Chiari type I is relatively benign and may manifest in adulthood Arnold-Chiari type II is severe and is evident in the newbom Myelopathy associated wfth vitamin B2 deficiency is called subacute combined degeneration. “Combined refers to degeneration of both the ascending (dorsal columns) and descending (corticospinal tract) pathways Loss of position and vibration sensation. ataxia, and spastic paresis are common manifestations. Duchenne muscular dystrophy is an X-liriked condition. It occirs due to deletion of the dystrophin gene Dystrophin is a protein that allows interaction between extracellular connective tissue and the intracellular contraction apparatus The disease manifests in boys aged 3-6 with proximal muscle weakness and enlargement of the distal muscles.
Subarachnoid hemorrhage occurs due to rupture of saccular (berry) aneurysm or arteriovenous malformation. Severe vasospasm 4— 12 days after the initial insult is the major cause of morbidity and mortality in patients recovering from SAH Nimodipine. a selective calcium channel blocker, is often prescribed to prevent this vasospasm. Demyelination (denudation means removal of covering) of axons in the white matter is a hallmark of multiple sclerosis. The areas of demyehnation form charactenstic plaques. The symptoms of the disease depend on the plaque location. Involvement of the MLF leads to internuclear ophthalmoplegia Tremulousness is commonly the first symptom of alcohol withdrawa[ Other common symptoms are GI distress, agitation, anxiety, and autonomic disturbance Delirium tremens is the most severe manifestation of alcohol withdrawal and typically begin between 48 and 72 hours after the last drink Irreversible ischernic injury to the brain tissue results in liquefactive necrosis The infarcted CNS tissue is eventually replaced with a cystic astroglial scar In other organs, lethal Eschemic injury generally produces coagulative necrosis Fibnnoid necrosis is seen in some vasculitides Caseous necrosis results from tuberculosis Nonenzymatic f at necrosis follows local trauma to adipose tissue. Primary CNS lymphomas occur in immunosuppressed patients. such as those suffering from AiDS These tumors arise from B cells and are universally associated with EBV They are highgrade tumors with a poor prognosis. The changes in the body of a neuron aftersynthesis the axonthat has facilitates been severed called axonal reaction. This process reflects an increased protein axonare repair Enlarged, rounded cells with peripherally located nuclei and dispersed finely granular Nissi substance are seen. Hemiparesis with the arm affected more than the leg occurs due to occlusion of the middle cerebral artery (MCA). If the occluded NCA is in the dominant hemisphere (usually the left), aphasia may also occur. Neurofibrillary tangles and amyloid plaques are classic findings in Alzheimerrs dementia. Medulloblastoma is the second most common brain neoplasm of childhood It is located in the cerebellum. often at the vermis, and consists of sheets of small, blue cells, Like other PNE tumors, medulloblastomas are poorly differentiated and have a bad prognosis. Vitamin E deficiency can occur in indivdua1s suffering from fat malabsorption or abetalipoproteinemia. Deficiency of this fat-soluble vitamin is associated with increased susceptibility of the neuronal and erythrocyte membranes to oxidative stress.
Rapid correction of chronic hyponatrerrna may lead to osmotic demyelination of the axons in the central part of the pons. This condition is called central pontine myehnolysis It manifests with spastic quadriplegia and pseudobulbar palsy. Friedre,ch ataxia is characterized by cerebellar ataxia. loss of position and vibration sensation, kyphoscohosis. and hypertrophic cardiomyopathy. Foot abnormalities and diabetes mellitus are also common. Neuropathy is a frequent complication of diabetes melhtus It is caused by diabetic microangiopathy which leads to nerve schemia Mother pathogenetic factor is the accumulation of sorbitol, which leads to osmotic nerve injury. The symmetric peripheral neuropathy descnbed in this vignette is common True hydrocephalus is an increase in CSF volume and pressure that occurs due to the abnormal production, flow, or absorption of CSF. The pressure increase then causes ventricular enlargement hi hydrocephalus e.r vacuc, ventricular enlargement occxs due to brain atrophy and is not accompanied by increase in CSF presSure. Proliferation of aStrOCyteS in an area of neuron degeneration is called gIiosis It leads to the formation of a glial scar which compensates for the volume loss that occurs after neuronal death Hypertension is the most common overall cause of intraparenchymal hemorrhage, usually through the formation of small Charcot-Bouchard pseudoaneurysms in the small arterio’es that penetrate the basal ganglia and thalami, This should be contrasted with rupture of a saccular aneurysm which typically presents with subarachnoid hemorrhage. Mu(tiple sclerosis is viewed autoimmune condition. Viral of andlgG environmental factors are also considered to play a role as in an its development Increased levels in the CSF. detected as an oligoclonal band on electrophoresis, supports the immunologic theory Multiple sclerosis is an autoimmune dernyelinating disease Within the p’aques, loss of myelin sheaths and depletion of ohgodendrocytes is seen Ohgoclonal bands of lgG may be detected in cerebrospinal fluid Oligodendrocyte depletion is also seen in progressive multifocal leukoencephalopathy
PATHOLOGY-Neuro 2 CNS involvement in syphilis (neurosyphilis) may manifest as a number of syndromes Tabes dorsahs occurs due to demyehnation of dorsal columns and dorsal roots of the spinal cord Loss of propnoceptlon and vibration senses, ataxta. and Argyll Robertson pupd may be seen Syringomyelia is characterized by the formation of a cavity (syrinx) in the cervical region of the spinal cord. The syrinx damages the ventral white commissure, leading to bilateral loss of pain and temperature sensation that is limited to the affected levels (typically the arms and hands); distal sensation is preserved Destruction of the motor neurons in the ventral horns (due to extension of the syrinx) causes flaccid paralysis and atrophy of the intrinsic muscles of the hand Amold-Chiari malformations are congenital abnormalities. They are caused by impaired development of the posterior fossa Arnold-C hian type I is relatively benign and may manifest in adulthood Arnold-Chiari type II is severe and is evident in the newbom Multiple sclerosis is viewed as an autoimmune condition Viral and environmental factors are also considered to play a role in its development. Increased levels of lgG in the CSF, detected as an oligoclonal band on electrophoresis, supports the immunologic theory. Multiple sclerosis is an autoimmune demyehnating disease. Within the plaques, loss of myelin sheaths and depletion of oligodendrocytes is seen Ohgoclonal bands of lgG may be detected in cerebrospinal fluid Oligodendrocyte depletion is also seen ii progressive multifocal leukoencephalopathy. Subacute sclerosing encephalitis is a rare complication of measles infection It occurs several years after apparent recovery iwtial bands of component antibodies to the measles virus are found in the from CSF of theseinfection patients Ohgoclonal Antibodies to the M of the measles virus are absent, A cerebellar hemangiobLastoma in association with congenital cysts of the kidneys, bver. and/or pancreas is highly suggestive of von Hippel—Lindau disease, a rare autosomal dominant condibon Vitamin E deficiency can occur in individuals suffering from fat malabsorption or abetahpoproteinemia Deficiency of this fat-soluble vitamin is associated with increased susceptibility of the neuronal and eMhrocyte membranes to oxidative stress Subarachnoid hemorrhage occurs due to rupture of saccular (berry) aneurysm or artenovenous malformation, Severe vasospasm 4— 12 days after the initial insult is the major cause of morbidity and mortality in patients recovering from SAl-I. Nimodipine. a selective calcium channel blocker, is often prescribed to prevent this vasospasm Primary CNS lymphomas occur in immunosuppressed patients, such as those suffering from AIDS These tumors arise from B cells and are universally associated with EBV. They are highgrade tumors with a poor prognosis
Anemia associated with neurologic abnormalities is fairty specific to vitamin B12 deflciency Neurological damage associated with B12 deficiency includes subacute, combined degeneration of the posterior and lateral spinal columns Increased serum level of methylmalonic acid is diagnostic of vtamin B12 deficiency. A biphasic pattern (Antoni A and B areas) and S-100 positivdy indicate schwannoma Cranial nerves are covered by Schwann cells: therefore. schwannomas can arise from any cranial nerve, except CN II The acoustic neuroma, which is located at the cerebellopontine angle at CN Vill, is the most common schwannoma Melanomas are also S-tOO positive because both melanocytes and Schwann cells are derived from the neural crest. The hippocampus is the area of the brain demonstrating the greatest degree of atrophy in Alzheimer’s disease Hippocampal atrophy on MRI is highly suggestive of the diagnosis Amyotrophic lateral sclerosis (ALS) causes both upper and lower motor neuron lesions Loss of neurons of the anterior horns of the spinal cord (LMN lesion) causes muscle weakness and atrophy Demyelination of the lateral corticospinal tract (UMN lesion) leads to spasticity and hyperreflexia Elevated protein, normal glucose. and lymphocytic predominance are characteristic of viral meningitis Transtentorial (i.e., uncal) hemiation is a complication of an ipsilateral mass lesion, such as a hemorrhage or brain tumor. The first sign of uncal herniation is a fixed and dilated pupil on the side of the lesion IpsiLateral paralysis of oculomotor muscles. contralateral or ipsilateral hemiparesis, and contralateral homonymous hernianopsia with macular sparing may also occur Lacunar infarcts are small ischernic infarcis (< 15 mm in diameter). usually rivoMng the basal ganglia, pons. internal capsule, or deep white matter of the brain Lacunar infarcts occur most often due to hypertensive artenolosclerosis of small, penetrating artenoles Liquefactive necrosis is characterized by complete digestion and removal of necrotic tissue with formation of cystic cavity. Hypoxic CNS injury is often followed by liquefactive necrosis. Abscess formation due to bacterial or fungal infection is another example of this type of necrosis. Normal pressure hydrocephalus (NPH) causes the triad of urinary incontinence and ataxic gait, then dementia (wacky, wobbly & wet). NPH is a communicating hydrocephalus that occurs due to a diminished reabsorptive capacity of the arachnoid villi. CT scan of the bran shows symmetric dilation of ventricuk. Diabetic mononeuropathy often involves CN III. Nerve damage is ischemic. and only somatic nerve fibers are affected. Parasympathetic fibers of CN Ill retain function. Ptosis and a down and out” gaze in conjunction with normal light and accommodation reflexes indicate diabetic CN Ill neuropathy.
1 Holoprosencephaly results from failure of forebrain cleavage rito cerebral hemispheres lt is an example of a congenital malformation, a primary abnormality i a development process 2. Amniotic band syndrome is an example of a disruption (secondary destruction of a prevousIy well-formed tissue or organ) 3. Congenital hip dislocation, clubbed feet and flat facies (Potter syndrome) are examples of deformations (secondary to extnnsic compression). 4 Potter syndrome is also an example of a sequence. Both myastheniagravis and Lambert-Eaton syndrome are caused by poor signal transmission at the neuromuscular junction. Lambert-Eaton syndrome is associated with undertying malignancy. Antibodies to voltage-gated presynaptic calcium channels are found in these patients Severe vitamin E deficiency close’y resembles the clinical presentation of Friedreich ataxia Vitamin E is a lipid-soluble vitamin that has antioxidative properties. Epidural hematoma occurs due to tear of the middle meningeal artery It is often associated with temporal bone fracture, and is located between the bone and dura mater Clinical presentation is characterized by a “lucid interval”, followed by loss of consciousness Polymyalgia rheumatica occurs in more than half of patients with temporal arteritis It is characterized by neck, torso, shoulder, and pelvic girdle pain and morning stiffness Fatigue, fever and weight loss may also occur Monocular vision loss is a common complication of temporal arteritis In patients with Alzheimer disease. there are decreased levels of acetyicholine in the nucleus basalis of Meynert and hippocampus. Diminished activity of choline acetyftransferase in these cerebral structures is the cause. Subarachnoid hemorrhage presents with a generalized. excruciating headache It is classically described by patients as ‘The worst headache of my life.” Subarachnoid hemorrhage usuafly occurs due to rupture of saccular (berry) aneurysms or artenovenous malformations Berry aneurysms of the circle of Willis are associated with autosomal dominant polycystic kidney disease Demyelination (denudation means removal of covering) of axons in the white matter is a hallmark of multiple sclerosis The areas of demyehnatiori form characteristic plaques The symptoms of the disease depend on the plaque location. Involvement of the MLF leads to internuclear ophthalmoplegia Rapid correction of chronic hyponatremia may lead to osmo& demyelination of the axons in the central part of the pons This condition is called central pontine myeIinolysis k manifests with spastic quadriplegia and pseudobulbar palsy. Microglia move to the area of ischerriic infarct approximately 3-5 days after the onset of isc hernia and phagocytize the fragments of neurons, myelin, and necrotic debris A cystic space replaces the necrosis. and astrocytes form a glial scar along the periphery
Tremulousness is commonly the first symptom of alcohol withdrawal Other common symptoms are GI distress, agitation, anxiety, and autonomic disturbance Delinum tremens is the most severe manifestation of alcohol withdrawal and typically begin between 48 and 72 hours after the last dnnk Carpal tunnel syndrome is caused by median nerve compression. Pt is the most common example of compression (entrapment) neuropathy and is associated with repetitive wrist movements Carpat tunnel syndrome is also associated with hypothyroidism, diabetes meibtus, rheumatoid arthritis and diatysisa ssociated amyloidosis Pituitary adenornas cause symptoms from mass effect and often produce endocrine disorders from the various hormones that they can produce. Prolactinomas are the most common adenorna—excess prolactin causes amenorrhea and galactorrhea. Bitemporal hemianopsia from compression of the optic chiasm is common. Neurofibrillary tangles and amyloid plaques are classk findings in Alzheimer’s dementia Hypeftension is the most common overall cause of intraparenchymal hemorrhage, usually through the formaton of small Charcot-Bouchard pseudoaneurysms in the small arterioles that penetrate the basal ganglia and thalami This should be contrasted with rupture of a saccular aneurysm which typically presents with subarachnoid hemorrhage. Proliferation of astrocytes in an area of neuron degeneration is called gliosis It leads to the formation of a glial scar which compensates for the volume loss that occurs after neuronal death Huntington disease is inherited as an Loss autosomal dominant trait It manifests dementia and choreilorm movements. of neurons in the caudate nucleuswith and progressive putamen is characteristic. Counting down from I 00 by 7 or 3, reciting the months of the year in reverse order, and spelling world” backwards are quick clinical tests to assess attention and concentration Attention and concentration are tested as part of the Mine-Mental State Examination (MMSE), a widely used screening tool for cognitive impairment The MMSE also measures onentation to time and place, short-term memory, calculation, language, and constructional praxis. Paraneoplastic syndromes occur due to the tumor cells producing substances that frequently induce an autoimmune reaction and cause damage and degeneration of healthy organs and tissues Neurologic paraneoplastic syndromes such as paraneoplastic cerebellar degeneration are considered to be autoimmune. The pineal region is the most common location of brain gerrninomas Histologically, germinomas are similar to testicular seminomas. Classic symptoms of pineal germinomas are precocious puberty, Pannaud syndrome, and obstwctive hydrocephalus.
Accumulation of an abnormal prion protein is considered a cause of phon diseases. Characteristic microscopic findings are vacuoles in the gray matter (spongiform encephalopathy) with no inflammatory changes Creutzfeldt-Jakob disease is an example of pñon disease Friedreich ataxia is characterized by cerebellar ataxia. loss of position and vibration sensation, kyphoscoliosis, and hypertrophic cardiomyopathy. Foot abnormalities and diabetes meflitus are also common. Normal pressure hydrocephalus occurs in elderly patients It causes the triad of ataxic gait and urinary incontinence, then dementia These symptoms are explained by distortion of periventricular matter Bladder is influenced byinhibition descending fibers that run in the distendedwhite paraventricular area.control Later, loss of cortical oncortical the sacral mictuntion center causes the development of urge incontinence. Ophthalmoplegia, ataxia. and confusion form the triad of Wemicke syndrome Most of these symptoms resolve after thiamine admInistration. Korsakoff syndrome is a complication of Wemicke encephalopathy. The hallmarks of Korsakoff syndrome are permanent memory loss and confabulation Neuropathy is a frequent complication of diabetes mellitus. It is caused by diabetic microangiopathy which leads to nerve ischernia Another pathogenetic factor is the accumulation of sorbitol, which leads to osmotic nerve injury. The symmetric peripheral neuropathy described in thés vignette is common. The subthalamic nucleus is one of the components of the basal gangIia Damage to this nucleus (most often due to lacunar stroke) leads to hen-übaflsm. The involuntary flinging movements of one side of the body (arm and/or leg) that constitutes hemibalksm are always contralateral to the lesion
PATHOLOGY-Oncology Symptoms of urinary urgency, noctuna. frequency, and hesitancy associated with constant back pain in an elderly man are suggestive of metastatic prostate cancer. Asymmetric nodular enlargement of the prostate on digital rectal examination is also suggestive. Metastatic prostate cancer has a strong predilection for bones (especially the axial skeleton). The bony metastases of prostate cancer are blastic (sclerotic), and can be detected by radionuclide bone scanning. Most chemical carcinogens enter the body in an inactive state (ie, as pro-carcinogens) These 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 srcin and presents with painless “waxing and waning” Iymphadenopathy The cytogenetic change t(14;18) is charactenstic and resuIts in overexpression of the bcl-2 oncogene Hereditary breast cancer is associated with mutation of BRCA-1 and BRCA-2 These are tumor suppressor genesthe that inand gene repair cancer. and regulation of the cell cycle. Mutation of these genes increases riskfunction of breast ovarian 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. growth a starry-sky”8microscopic appearance Translocation of the c-myc oncogene onrapid the long armand of chromosome with the Ig heavy chain region on chromosome 14 produces a nuclear phosphoprotein (c-Myc) that functions as a transcription activator Cushing syndrome in a patient with small cell (oat cell) lung cancer is most likely the result of a paraneoplastic syndrome involving ectopc produchon of ACTH by the tumor cells Li-Fraumeni syndrome is an autosomal dominant predisposition to a variety of Cancers. Sarcomas and tumors of the breast. brain, and adrenal cortex are most common. This syndrome is associated with mutation of the p53 gene. The majority of bladder carcinomas are urothelial (formerly known as transitional cell) carcinomas Painless gross hematuria is the main presenting symptom Tumor penetration of the bladder wall is the maior determinant of prognosis. Proliferation signals activate CDK4 (cyclin-dependent kinase-4), resulting in hyperphosphorylation of the Rb protein, Because hyperphosphorylated Rb is inactive, cells are allowed to transition unchecked from the Gi phase to the S phase in the cell cycle
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 boneand lesions (back pain, pathologic fractures), and renal insufficiency (related to amyloid deposition 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. Peau dOrange the presence of pitting hair edema in subcutaneous breast occurs tissue accompanied by descnbes skin thickening around exaggerated folhcles. The pitting edema when neoplastic cells plug the dermal lymphatic channels.
EBV virus causes infectious mononucleosis an teenagers and young adults It is also associated with a number of malignant conditions, including Burtatt lymphoma and nasopharyngeal carcinoma TNF-a was shown to induce a wasting syndrome (cachexia) in experimental animals It is thought to mediate paraneoplastic cachexia in humans by suppressing appetite. inhibiting lipoprotein lipase and increasing insulin resistance of peripheral tissues Oral contraceptives reduce the risk of non-hereditary ovarian and endometnal cancer. Muttiparity and breast-feeding also decrease the risk ot ovarian cancer. Prognosis of colorectaladenocarcinoma is directly related to the stage of the tumor (not to the grade!)
Most tumors possess multiple cytogenetic abnormalities Activation of proto-oncogenes results in stimulation of cellular proliferation Inactivation of anti-oncogenes eliminates oversight of the cell cycle Cytokeratin is a commonly-used immunohistochemical marker of epithehai-dehved tissues. The HER2Ineu oncogene encodes for a 1 85-kD transmembrane glycoprotein that has intracellular tyrosine kinase activity and is a member of the family of epidermal growth factor receptors Overexpression of this protein is associated with increased rates of breast and ovanan cancer Integnn-mediated adhesion of cells to basement membrane and the extracellular matrix involves the binding of integrins to fibronectin, collagen, and Iaminin Kaposs sarcoma typically presents as blue-violet skin p’aques on the extremities and mucous membranes of HIV-positive patients This tumor arises from primitive mesenchymal cells and is strongly associated with human herpes virus type 8 (HHV-8) Reed-Stemberg cells are large binuceated cells with an owI’s eyes appearance that appear on a background of lymphocytic infiltrates. Reed-Stemberg cells must be present histopathologically in order to make the diagnosis of Hodgkin lymphoma. Benign lymph node enlargement in response to antigenic stimulation is associated with a polyclonal proliferation of lymphocytes. A monoclonal lymphocytic proliferation is strong evidence of nialignancy Keratin is a marler of epfthelial cell srcin The key growth factors that promote angiogenesis ii neoplastic and granulation tissue are vascular endotheleal growth factor (VEGF) and fibroblast growth factor (FGF). Proinflammatory cytolanes (like IL-I and INF.y) can indirectly promote angiogenesis throu9h increased VEGF expression The larnanin in basement membranes may pose a physical barner to the sprouting of new blood vessels Apoptosss can occur through either the intrinsic (mitochondria-mediated) pathway or the extrinsic (receptor-initiated) pathway. Both pathways converge in the activation of caspases Caspases are proteolttic enzymes that cleave cellular proteins. The avid uptake of bromodeoxyuridine by the tumor reflects the high number of tumor cells in S phase (preparing to divide) that are present in this mans brain tumor A high proliferation rate suggests a high tumor grade and, therefore, a poor prognosis. Small cell carcinoma of the lung is the most aggressive lung neoplasm. This tumor is thought to have a neuroendocrine ongin. Tumor cells express neuroendocnne markers and contain neurosecretory granules in the cytoplasm.
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 srcin They are composed of pleomorphic cells with hyperchromatic nuclei that grow in a disorganized fashion. Many abnormal mitoses and giant tumor cells may be seen.
PATHOLOGY-Pulmonology Small cel carcinoma is the most aggressive type ol lung cancer Most patients have distant metastases at the time of diagnosis Surgery is usually not a treatment option, even when the disease is localized This tumor is sensitive to chemotherapy and radiation Secondary (reactivation) tuberculosis occurs in patients who have been previously infected with tuberculosis Primary tuberculosis causes the formation of Ghon foci in the lower lung fields Reactivation tuberculosis occurs in immunosuppressed patients, and is characterized by apical cavitary lesions and hemoptysis. Prolonged, substernal and STinfarction. segment elevation leads I and V3-V6 strongly suggestive burning of anterolateral leftpain ventricle Commoninconsequences of leftis ventricle infarction include left ventricular failure, cardiogenic acute pulmonary edema, pulmonary venous hypertension (congestion), and transudate of plasma into the lung interstitium and alveoli. Sarcoidos,s is a disease that is characterized by hilar adenopathy, pulmonary disease, and constitutional symptoms Histologically, non-caseating granulomas are seen, helping to distinguish sarcoidosis from tuberculosis infection Patients with a long history of asbestos exposure are at risk for developing asbestosis, bronchogenic carcinoma and mesothelioma Bronchogenic carcinoma is the most common malignancy in this population, while mesothelioma is the second Bronchioloaiveolar carcinoma is a subtype of lung adenocarcinoma This uncommon tumor occurs in non-smokers and arises from alveolar epithelium It is located in the penpheral parts of the lun9 and is often multifocal On microscopc examination, it is composed of tall, columnar cells that line the alveolar septa without evidence of vascular or stromal invasion. The incidental chest x-ray finding of fibrocalcific panetal pleural plaques in the posterolateral mid-lung zones and over the diaphragm are highly suggestive of asbestosis.
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 fibrosis. cystic airspace enlargement (honeycomb lung) are charactenstic of idiopathic pulmonary Use of concentrated oxygen therapy for neonatal respiratory distress syndrome may be complicated by retinopathy of prematurity This abnormal retinal neovascularization is a major cause of blindness in developed nations. Sarcoidosis most commonly affects young black women and presents with malaise, cough and varied cutaneous findings including erythema nodosum. Chest X-ray reveals bilateral hilar lymphadenopathy. Transbrorichial biopsy showing non-caseating granulomas is necessary for diagnosis. Leukotriene B stimulates neutrophil migration to the site of inflammation. Other significant chemotactic agents include 5-HETE (the leukotriene precursor) and complement component C5a. Tissue damage and resuftant abscess formation is pnmanly caused by lysosomal enzyme release from neutrophds and macrophages.
Malignant mesothelioma is a rare neoplasm that arises from the pleura or pehtoneum It is strongly associated with asbestos exposure. Hemorrhagic pleural effusions and pleural thickening are characteristic. Electron microscopy is the gold standard for diagnosis, revealing tumor cells with numerous, long, slender microvilli and abundant tonofilaments. Erytherna nodosum, arthralgias. hilar Iyrnphadenopathy, and elevated serum ACE levels are common findings in sarcoidosis There may be evidence of liver involvement on histologic examination in up to 75% of cases Needle biopsy of the liver frequently demonstrates scattered noncaseating granulomas Sepsis shock are as two‘shock major lung’). risk factors forproduces developing adult respiratory distress interstitial syndrome (ARDS,and also known ARDS non-cardiogenic pulmonary and intra-atveolar edema, inflammation, and alveolar hyatine membranes Tumors located in the lung apex (superior sulcus) are called Pancoast tumors. Pancoast syndrome is characterized by ipsitateral Homer’s syndrome, rib destruction, atrophy of hand muscles, and pain in the distribution of C8. Ti. and T2 nerve roots An obstructive lesion in a mainstern bronchus can prevent ventilation of an entire lung, leading to lung collapse Characteristic findings on chest x-ray include unilateral pulmonary opacification and deviation of the mediastinum toward the opacified lung. Intrathoracic spread of bfonchogenic carcinoma may lead to compression of the superior vena cava causing impaired venous return from the upper part of the body Signs and symptoms include facial swelling and headache. Cystic fibrosis (CF) is a A common cause of can congenital of the anomaly vas deferens, resuLting in azoospermia. diagnosis of CF be madebilateral based onabsence this urogenital with an abnormal sweat chloride test or an abnormal nasal transepithehal potential difference. Adenocarcinoma Es the most common lung cancer in the general population ft is also the most common subtype in women and nonsmokers It is located peripherally and consists of tumor cells that form glandular or papillary structures In lobar pneumonia. the inflammation involves an entire lobe of the lung. The course of the disease includes four morphologic stages: congestion, red hepatization1 gray hepatization and resolution Peptostreptococciand Fusobacterià are anaerobèc bacteria normally found in the oral cavity They cause lung abscesses associated with aspiration R’sk factors for such abscesses include alcoholism, seizure disorder, CVA and dementia.
Patients with sarcoidosis or other granulomatous diseases are prone to developing hypercalcemia secondary to high levels of active vitamin 0 (calcitriol).
Intermittent respwatory symptoms in a patient with a normal CXR, occasional sputum eosinophils, and reduced FEV1 suggest a diagnosis of asthma Extnnsic allergic asthma provoked by inhaled allergens such as animal dander is the most common type Acute necrotizing pancreatitis is a major risk factor for progression to adult respiratory distress syndrome (ARDS). Diffuse injury to the alveolocapillary membrane resu*s in interstitial and intraalveolar edema, acute inflammation, and alveolar hyahne membranes Hyahne membranes result from alveoocapitlary membrane leakage and consist of fibnn exudate and plasma 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 Thi and Th2 lymphocytes. Environmental irritants, such as smoking, trigger bronchospasm in predisposed IndMduals Fat embolism syndrome should be strongly suspected in a patient with severe long bone and/or peMc fractures who then develops acute-onset neurologic abnormalities, hypoxemia, and a petechial rash. Occlusion of the pulmonary microvessels by fat globules is an early histologic finding of this syndrome. Chronic rejection can occur to years following transplantation. In obliterans lung transplantation, the immune reaction affectsmonths the small airways, causing bronchiohtis syndrome Symptoms include dyspnea and wheezing. Rupture of apical subpleural blebs is the most common cause of primary spontaneous pneumothorax. These blebs may arise due to distal acinar (paraseptal) emphysema Tall, thin, young adult males are most commonly affected Other types of emphysema may predispose to a secondary spontaneous pneumothorax. Compensatory and obstructive hypennflation cause distention of normal lung parenchyma and would be unlikely to cause pneumothorax. al-antitrypsin deficiency is associated with chronic panacinar emphysema. which is preferentially localized to the lower pulmonary lobes. Centnacinar emphysema has a predominantly upper lung lobe distnbution and is strongly associated with chronic smoking. Small cell carcinoma is strongly associated with smoking and usually is centrally located. This tumor arises from the primitive cells of the basal layer of the bronchial epithelium Immunohistochemical stains are frequently positive for neuroendocrine markers, such as neuron specific enolase, chromogranin and synaptophysin
Dry cough, pulmonary infiltrates, and hilar adenopathy in an African American female strongly suggest sarcoidosis. This diagnosis may be confirmed by the finding of non-caseating granulomas on lung biopsy. The tissue destruction caused by Al &,bercc.*sis infection is the direct resuk of host immune activation and inflammation through a type IV delayed-type hypersensitivity reaction The characteristic pathologic lesion consists of granulomatous inflammation and caseous necroSis. Lung abscess is a common comphcation of aspiration pneumonia, Aspiration pneumonia occurs in individuals with impaired consciousness or decreased ability to swallow (alcoholics, demented, chronically patients). The anaerobic bactena of the gingivodental sulcus are the most common cause of ill lung abscesses. Pulmonary tuberculosis is a disease passed from person to person through the transmission of aerosolized respiratory secretions that contain Mycobact er/urn tubercuksis Organisms. The smaller droplets deposit organisms in the alveoli of lower lung fIelds These organisms are engulfed by alveolar macrophages that allow for intracellular bacterial proliferatIon. Primary infection by M tuberculosis occurs after inhaling the organism in the aerosolized respiratory secretions of an infected person Initial M tuberculosis infection is characterized by a Ghon complex, which consists of a lower lobe lung lesion (Ghon focus) and ipsilateral hilar adenopathy Recurrent sinopulmonary infections and exocnne gland fibrotic atrophy in a young Caucasian are suggestive of cystic fibrosis (CF), CF can lead to pancreatic insufficiency, fat malabsorption. and a deficiency of vitamins A, 0, E and K. Vitamin A maintains ordedy differentiation of specialized and epitheha, including the pancreatic mucus-secreting columnar epitheha of the ocular A conjunctiva, respiratory urinary tracts, and and other exocnne ducts Avitaminosis can cause squamous metaplasia of such epethelia to a keratinizing epithelium. PathOphySIOIOgiCaHy, deep venous thrombosis arises due to Virchows triad of endothelial injury, venous stasis, and a hypercoagulable state. Of the pneumoconioses that can cause exertional dyspnea and interstitial densities on chest x-ray, silicosis is the only one that produces eggshell calcifications of hilar nodes and birefringent particles surrounded by fibrous tissue on histologic exam Asbestosis is associated with calcified pleural plaques and ferruginous bodies Berylliosis and hypersensitivity pneumonitis may produce noncaseating granulomas Coal mine?s lung is associated with penlymphatic accumulations of coal dust-laden macrophages
PATHOLOGY-Renal Membranous glomerulopathy is one of the most common causes of nephrotic syndrome in adufts, It can occur secondary to underlying malignant tumors, infections, and certain medications Diffuse increased thickness of the glomerular basement membrane on light microscopy (without increased cellularity), “spike and dome” appearance on methenamine silver stain, and granular deposits on immunofluorescence are diagnostic lschemic ATN is one of the most common causes of intrinsic renal failure (acute renal failure) in hospitalized patients. Renal ischernia triggers hypoxic changes in tubular epithelial cells (especially in proximal tubules and the thick ascending limb of Henles loop), decreasing their functional capacity Muddy brown casts are pathognomonic for ATN. The most common renal malignancy is clear cell carcinoma, which arises from renal tubular cells. Routine histological staining of this tumor shows rounded or polygonal cells with abundant clear cytoplasm. These cells have this appearance because they are packed with glycogen and lipids On any histologic preparation. clear cells” are generaity those with a high glycogen or lipid content Henoch-Schônlein purpura (HSP) generally affects young children and is classically preceded by an upper respiratory infection This IgA-mediated hypersensitivity (leukocytoclastic) vasculitis commonly causes abdominal pain, joint pain, lower extremity palpable purpura and hematuria Poststreptococcal glomerulonephntis occurs most frequently in cMdren, but adults can be affected, too. Immunofluorescence microscopy shows granular deposits of lgG. 1gM, and C3 in the mesangium and basement membranes, producing a ‘starry sky’ appearance. Idiopathic membranous nephropathy is associated with circulating IgG4 antibodies to the phospholipase A2 receptor, which might play a role in the development of the disease Age is an important prognostic factor in poststreptococcal glomenilonephritis 95% of affected children, but only 60% of affected adults. recover completely During the recovery phase (polyuric phase) of acute tubular necrosis, patents can become dehydrated and can develop severe hypokalemia due to high volume. hypotonic urine ANCA-associated RPGN is also ca$ed pauci immune GN due to the absence or scarcity of Ig and C3 deposits Pahents present with renal failure, pulmonary symptoms (cough, dyspnea, hemoptysis), and upper respiratory tract symptoms (epistaxis. mucosal ulceration, chroruc sinusitis). Crescents are found on light microscopy. The histological picture of poststreptococcal glomerulonephritis includes I2 Enlarged. hypercellular glomeruh “Lumpy-bumpy” granular depositsonoflight lgGmicroscopy and C3 on immunofluorescence 3. 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. Goodpasture syndrome is caused by anti-GBM antibodies that react with a component of the alpha3-chain of collagen type IV. Patients typically present with rapidly progressive glomerulonephritis resulting in acute renal failure and hemoptysis due to pulmonary hemorrhage Mti-GBM antibodies react with the a3 chain of collagen type IV, found in the glomerular basement membrane Anti-GBM antibodies are found in Goodpasture syndrome, a condition characterized by pulmonary hemorrhages (hemoptyss) and rapidly progressive glomerulonephr*is (RPGN) On light microscopic examination, there is glomerular crescent formation On immunofluorescence, linear deposits of lgG and C3 along the glomerular basement membrane are characteristic Autosomal dominant polycystic kidney disease manifests in patients 40-50 years old with enlarged kidneys, hypertension, and renal failure. In newborns, the kidneys are of normal size, and the cysts are too small to be detected on abdominal ultrasonography. As the cysts enlarge. they compress the renal parenchyma and cause symptoms The ureters are at hsk of injury during pelvic surgeries Hysterectomies are especially risky because the ureters course just posterior to the utenne arteries, which are ligated in this procedure Most patents with ATN experience tubular re-epithelization and regain renal function When ATN is associated with multi-organ failure, renal function may be permanently impaired (foci of interstitial scarring can be seen on light microscopy). Crescent formation on light microscopy is diagnostic for rapidly progressive glomerulonepliritis. Crescents consist of glomerular parietal cells monocytes, macrophages as well as abundant fibrin Crescents eventually become sclerotic, disrupting glomerutar function and causing irreversible renal injury Granulomatosis with poiyangiitis (Wegeners) is a cause of rapidly progressive (crescentic) glomerulonephritis (RPGN) type 3 (pauci-immune). The symptoms of nephntis are accompanied by signs of upper and lower respiratory tract involvement. Crescents on bght microscopy, the absence of deposits on immunofluorescence, and elevated serum c-ANCA are diagnostic Minimal change disease (MCD) presents as a nephrotic syndrome in children between 2-8 years ol& The pathognomonic finding is a diffuse effacement of the foot processes of podocytes found
on electron microscopy Light microscopy shows normal glomeruh and immunofluorescence fails to reveal any immunoglobulin or complement deposits. Renal function is also norma[ An important feature of this condition is its rapid response to corticosteroid therapy. Acute renal allograft rejection can be an anhbodymediated or cell-mediated pcocess The latter of the two is associated with lymphocytic infiltration of the renal parenchyrna Anti-CD3 antibodies such as muromonab-CD3 (OKT3) inhibit T-lyrnphocytes. which is useful in the treatment of acute rejection in patients with kidney, heart, and liver transplants. Transitional cell carcinoma bladder typically presents as gross hematuna m an elderly man, A history of smokingofortheoccupational exposure to rubber, plastics, aromatic aminecontaining dyes, textiles, or leather increases the nsk of developing transitional cell carcinoma. NephntiC syndrome is manifested by hypertenson. mild proteinuna (<1 g/day), RBC casts or dysmorphic red cells in the urine, and azotemia. In contrast, the nephrotic syndrome is manifested by heavy proteinuria (>3.5 glday), lipiduria, absence of RBC casts in the urine, and usua*y normal renal function. Painless hematuna 2-3 days following an upper respiratory tract infection is suggestive of IgA nephropathy (Berger disease). Diagnosis is made via the detection of IgA deposits in the mesangium of glomerub on immunofluorescence microscopy. When IgA nephropathy is accompanied by extrarenal symptoms (e.g., abdominal pain, purpuric skin lesions), the diagnosis is Henoc h-Sc honlein purpura. ADPKD is one of the most common inherited disorders in humans It is the most frequent genetic cause of of inheritance renal failureisinautosomal adults, accounting 10% PKDAD). of patients on dialysis in the United States Its mode dominantfor (ADult Hemolybc-uremic syndrome (HUS) is a common cause of acute renal failure ii children k is associated with shiga toxin-producing organisms like E cok0157:H7 and Shigeffa dysentenàe HUS is characterized by the triad of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia Medullary sponge kidney (MSK) is a relatively common and benign congenital disorder characterized by cystic dilatations of the medullary collecting ducts Cysts usually do not involve the renal cortex Kidney stones are the most common complication of the disease Patients with MSK do not typically develop chronic renal failure Microalbuminuna detection is the preferred method for diagnosing incipient diabetic nephropathy, the leading cause of end stage renal disease in the United States Easy fatigabihty. constipation, back pain, and azotemia in an elderly patient are the classic constellation of findings for multiple myeloma. On kidney biopsy, large eosinophilic casts composed of Bence-Jones proteins are seen in the tubular lumens.
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) srcinate 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.
PATHOLOGY-Reproductive Anovulation is common during the first five to seven years after menarche and the last ten years before menopause, and manifests with marked menstrual cycle vanabihty Granulosa cell tumors are sex-cord strornal tumors that secrete estrogen. Prolactinomas are the most common pfluitary adenomas The excess prolactin produced by these tumors can cause galactorrhea and amenorrhea Visual changes may also occur due to compression of the optic chiasm CenAcal epitheliahnfection with human papilloma virus (HPV), especially HPV 16 and HPV 18. is the strongest known risk factor for development of CIN and invasive cervical carcinoma Early age at first intercourse and multipe sexual partners increase the incidence of HPV infection. A uniformly enlarged uterus with normal appearing endometrial tissue within the myometrium indicates a diagnosis of adenomyosis Menorrhagia and dysmenorrhea are common presenting syrnptoms PCOS is clinicaHy charactenzed by obesity, hyperandrogenism, ohgomenorrhea, nfertility, and enlarged ovanes with multiple cysts Patients with PCOS who desire fertility are treated with clomiphene. which is an estrogen receptor modulator that decreases negative feedback inhibition on the hypothalamus by circulating estrogen and thereby increases gonadotropin production. Granulosa cell tumors are estrogen-secreting primary ovarian tumors. The hyperestrogenemic state that results can cause endometnal hyperplasia and abnormal uterine bIeeding it also predisposes to endometrial adenoc arc inoma Pre-eclampsia is the triad of hypertension. proteinuria and edema. Eclampsia is pre-eclampsia with seizures Pre-eclampsia may also progress to HELIP syndrome (Hemolytic anemia, Elevated Liver enzymes, and Low PlateletS). Ovarian malignancy is the most likely explanation for an adnexal mass in an elderly female Approximately 90% of ovarian malignancies srcinate from the ovars surface epithehum CA-125 is produced by malignant ovarian epithelial tumors and can be used as a serum marker of this condition. Comedocarcinoma (DCIS) is characterized by solid sheets of pleomorphic, high-grade cells with central necrosis A positive ‘whifr test — production of a fishy odor on addition of potassium hydroxide (KOH) to vaginal discharge — is a sign of bacterial vaginosis. Clue cells on saline wet mount microscopy also suggest this diagnosis.
PATHOLOGY-Skeletal Pathologic atrophy generally occurs secondary to one of the following mechanisms: decreased physical workload, loss of innervation, decreased blood supply, inadequate nutrition, absent endocrine stimulation aging, or pressure Enthesopathies (inflammation at sites of tendon insertion) are common in ankyosing spondyhtis Involvement of the costovertebral and costosternal junctions may cause Iimation of chest movements, resulting in hypoventilation. Osteogenesis imperfecta results from defective synthesis of type 1 collagen. Clinical findings include a history of fractures after only minimal trauma abnormal (blue) sclerae, and small, malformed teeth. In most patients, osteogenesis imperfecta is transmitted by autosomal dominant inheritance • The most common defect in achondroplasia is an activating mutation of the fibroblast growth factor receptor-3 at the epiphyseal growth plate which inhibits growth at the epiphyseal growth plate. The result is short, thick tubular long bones in the appendicular (limb) skeleton and normal axial (spine) length • Short stature in growth hormone I IGF-1 deficiency is proportional; that is, the axial and appendicular skeleton are proportionate Parvoviws B 19 causes erythema infectiosum (fifth disease) in children and arthritis in adults Parvovirus arthritis can mimic rheumatoid arthritis, but is unique in that it is usually self resoMng In the United States. vitamin C deficiency is most C often seen in severely malnourished individuals (the homeless, alcoholics, drug (scurvy) users). Vitamin is necessary for the hydroxylation of proline and lysine residues in pro-collagen. Patients with vitamin C deficiency demonstrate perifollicular hemorrhages. easy bruising and gum disease. Additionally, in children, bony deformities and subperiosteal hemorrhages are characteristic. Severe injury to living tissue can cause necrosis. There are several morphologic types of necrosis. Coagulative necrosis is the most common Osteoarthrrtis usually involves the distal interphalangeal joints whereas rheumatoid arthntis typically affects the metacarpophalangeal and proximal interphalangeal joints Fibromyalgia is a chronic disorder with unclear etiology that presents most commonly in women 20 to 50 years of age with diffuse musculoskeletal pain, insomnia and emotional disturbances During wound heahng, excessive matrix metalloproteinase activity and myotibroblast accumulation the wound margins produce of the wound andinsurrounding tissues, can mostresult ofteninoncontracture the palms.Contractures soles. anterior thorax,deformities or at serious bum sites.
Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disorder presenting wfth proximal muscle weakness, cranial nerve involvement, and autonomic symptoms Approximately half of all patients with LEMS also have a malignancy (classically, small-cell lung cancer) • Metaphysis of long bones are typic ally affected by hernatogenous osteomyehtis due to rich vascularization and capdlary fenestrae • Staphylococcus aureus and Strtococcuspyogenes(Group A Strep) are the first and second most common causes of this disease, respectively, and hematogenous osteomyelitis most frequently affects children and young adults • Pseudomonas aeiz.çzinosa frequently plays a role in osteomyelitts resulting from chronic wounds such as in diabetics Digital clubbing is often associated w4h prolonged hypoxia It can be found m patients with large-cell lung cancer, tuberculosis, cystic fibrosis, and suppurative lung diseases such as empyema, bioncheectasis. and chronic lung abscesses. Osteoporosis (porous bones) represents loss of “total bone mass” that results in trabecular thinning. Subperiosteal resorption with cystic degeneration is characteristic of hyperparathyroidism Vitamin D deficiency result in “excessive unmineralized osteoid. resulting in low mineral densy. Osteopetrosis is characterized by “the persistence of pnmary, unminerahzed spongiosa in the medullary canals.” Dactyhtis (painful swelling of hands and feet) is a common presentation of sickle cel disease in young children. It is one of many vasoocclusive symptoms that occur in this condition In the case of hemolysis, haptoglobin levels decrease by binding to free hemoglobin, and the complex is hepatically cleared Gottron papules are flat-topped violaceous papules over the joints of the fingers This cutaneous symptom, along with a heliotrope rash. is characteristic for dermatomyositis Avascular necrosis of the femoral head is associated with sickle cell disease, steroid therapy, SLE and alcoholism. It presents with acute onset of hip pain that is exacerbated by weight bearing. No swelling, erythema or temperature change is seen. MRI is the diagnostic modality of choice. Presbyopia and skin wrinkles are age-related changes. Presbyopia occurs due to sclerosis of the lens Decreased synthesis and increased breakdown of collagen and elastin contnbute into development of skin wrinkles CREST syndrome (limited scleroderma) manifests with calcinosis. Raynaud’s phenomenon, esophageal dysmotility, scierodactyly and telangiectasias. Anti-centromere antibodies are found in about 40% of patients with CREST syndrome. Anti-DNA topoisomerase I (Scl-70) antibodies are highly specific for systemic sclerosis.
The presence of rhomboid-shaped calcium pyrophosphate crystals is diagnostic of pseudogout These crystals are positively birefringent under polarized light The knee joint is involved in more than 50% of cases. The histological hallmark of rickets is an increase in unminerahzed osteoid matrix and widened osteoid seams. Clinically, there are many notable features. including bowed legs, a rachitic rosary, Harrison’s sulci, craniotabes, and growth retardation. A psoas abscess can occur as the result of hernatogenous or lymphatic seeding from a distant site or by spread from an adjacent site. Patients can present with fever, back or flank pain, inguinal mass, and(psoas difficulty extended sign) walking Inflammation of the psoas muscle causes pain when the hip is Dystonia is a syndrome of prolonged. repetitive muscle contractions This condition may be the result of impaired function of the basal gangha Cervical dystonia (spasmodic torticollis), blepharospasm, and writer’s cramp are the most common types of focal dystonia Hypercalcernia in sarcoidosis is caused by increased extrarenal formation of 1 25-dihydroxy vitamw D by activated macrophages The hypercakemia of sarcosdosas suppresses PTH secretion Reactive arthritis is an HLA-B27 spondyloarthropathy that can occur following infection by Chiamydia. Campylobacter, Salmonella. Shigella or Yersinia. It is an asymmetric large joint arthritis with sterile synovial fluid on joint aspiration. Gout results from the deposition of monosodium urate, not uric acid, in the joints and soft tissues. Under polarized light, monosodium urate crystals appear needle-shaped and negatively birefringent The subcutaneous deposition of monosodium urate leads to the formation of tophi Shaken baby syndrome is the combination of subdural hematoma with bilateral retinal hemorrhages in an infant Any suspicion of child abuse should be reported to state protective agencies
PATHOLOGY-Vascular Marked, one-sided kidney atrophy is suggestive of renal artery stenosas (RAS) It occurs in elderty individuals due to atherosclerotic changes in the artenal intima or in women of chddbeanng age due to fibromuscular dysplasia Hypertension and an abdominal bruit are present Familial hypercholesterolemia. one of the most common autosomal dominant disorders, is the result of heterozygous or homozygous LDL receptor gene mutations, which cause hepatocyte under-expression of functional LDL receptors. This condition can lead to accelerated atherosclerosis and early-onset coronary artery disease. Intermittent muscle pain reproducibly caused by exercise and relieved by a brief period of rest defines claudication, Claudication is almost always the result of atherosclerosis of larger, named arteries The obstruction of blood flow in these arteries is the result of fixed stenohc lesions produced by atheromas, which are lipid-filled intimal plaques that bulge into the artenal lumen The stenoses prevent sufficient increases in blood flow to exercising muscles, resulting in ischemic muscle pain. Hyperplastic arteholosclerosis in renal arterioles can result from and perpetuate malignant hypertension The pathological lesion is an onion-like concentnc thickening of artenolar walls in the renal vasculature and elsewhere. Severe retrosternal pain that radiates to the back is the classic presentation of an aortic dissection An intimal tear is thought to be the initiating process in a dissecting aortic aneurysm. The dissection can extend through the media along the aorta, both proximally and distally The intramural hematoma dissects through the media and can compress major arterial branches. Unilateral renal artery stenosis is a cause of secondary hypertension in two to five percent of hypertensive patients The kidney affected by the stenosis may become atrophied due to oxygen and nutrient deprivation. Small vessel leukocytoclastic angiltis associated with IgA and C3 deposition is typical of HSR HSP is most common in children 3 to 11 years old and is most often related to a recent infection Most children present with palpable skin lesions, with or without abdominal pain and arthralgias Although usually self-limiting, patients afflicted with HSP should be observed carefully because glomerulonephritis and even end-stage renal disease are possible complications. Takayasu arteritis and temporal arterdis involve artenal vessels of different sizes and locations (aorta and proximal aortic arterial branch involvement versus more distal carotid artery branch involvement, respectively), and have different clinical presentations Even so. they may share a common pathologic morphology, consisting of granulomatous inflammation of the media. Xanthelasmas. type of xarithoma. are yellowish maculeslpapules found the medial eyelids. They are dermala accumulations of macrophages containing cholesterol andon 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. GCAis characterized by granulomatous inflammation of the media, with fragmentation of the internal elastic lamina of medium and small branches of the carotid artery. GCA is most common in patients older than 50. and jaw claudication is the most specific symptom. Irreversible blindness due to ophthalmic artery occlusion is a severe complication of GCA, and can be prevented by immediate prednisone therapy. Patients with adult-type coarctation of the aorta commonly die of hypertension-associated complications, including left ventricular failure, ruptured dissecting aortic aneurysm, and intracranial hemorrhage. These patients are at increased risk for ruptured intracranial aneurysms because of the increased incidence of congenital berry aneurysms of the Circle of Willis as well as aortic arch hypertension Hepatic angiosarcoma is associated with exposure to carcinogens such as arsenic, thorotrast, and polyvinyl chloride Tumor cells express CD 31, an endothelial cell marker Abdominal pain due to acute pancreatitis is the most likely presentation for hyperchylomicronemia (hypertriglyceridemia). Patients with this disorder are not usually at increased risk for premature coronary artery disease. Skin xanthomas may be present in hypertriglyceridemia. but tubular/tendon xanthomas and xanthelasmas are present with hypercholesterolemia (high LDL). Cutaneous, strawberry4ype capillary hemangiomas are common. benign, congenital tumors, which are composed of unencapsulated aggregates of closely packed, thin-walled capillanes Initially, strawberry hemangiomas grow in proportion to the growth of the child, before eventually regressing In 75-95% of cases, the vascular tumor will regress completely by age 7 Cherry hemangiomas are small. red. cutaneous papules common in aging adults They do not regress spontaneously and typically increase in number with age Light microscopy of these lesions shows piohferabon of capillanes and post-capdlary venules in the papillary dermis The malor cause of AAA is atherosclerosis Atherosclerotic atheromas can sufficiently progress to weaken the underlying media of the aortic wall. Asnificantrnrnatched defect on ventilation-perfusion scan is a specific finding for a pulmonary embolism, which is usually the result of a deep vein thrombosis and part of a continuum of the same disease known as pulmonary thromboembolism. A benign glomus tumor (glomangioma) can produce a very tender, small (a few millimeters in diameter); red-blue lesion under the nail bed. This type of tumor onginates from the modified smooth muscle cells that control the thermoregulatory functions of dermal glomus bodies.
ChurgStrauss syndrome is an idiopathic systemic vasculitis associated with adult-onset asthma, eosinophilia, and p-ANCA. Additional clinical criteria for this diagnosis include a history of allergy, mono- or polyneuropathy, migratory/transient pulmonary infiltrates, and paranasal sinus abnormalities. Persistent lymphederna (with chronic dilatation of lymphatic channels) predisposes to the development of lymphangiosarcoma. a rare malignant neoplasrn of the endothekal lining of lymphatic channels This cancer may arise approximately 10 years after radical mastectomy with axiflary lymph node dissection for breast cancer Myxomatous changes in the media ol large arteries are found m cystic medial degeneration. which predisposes to the development of aortic dissechons and aortk aneurysms Medial degeneration is frequently seen in younger individuals with Marfan syndrome. Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia) is an autosomal dominant condition marked by the presence of telangiectasias in the skin as well as the mucous membranes of the lips, oronasopharynx, respiratory tract, gastrointestinal tract, and urinary tract Rupture of these telangiectasias may cause epistaxis, gastrointestinal bleeding, or hematuria Incompetent venous valves in the lower extremities allow retrograde blood flow from deep to superficial veins. This increases the pressure in the superficial veins, leading to their dilation (vancose veins). The resulting chronic venous insufficiency causes stasis dermatitis, which manifests as erythema and scaling with progressive dermal fibrosis and hyperpgmentation. PAN is segmental. transmural. necrotizing inflammation of medium- to small-sized arteries Renal artery involvement is often prominent Vessels the kidneys, heart liver, and gastrointestinal tract are most commonly involved in of 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.
Pulmonary embolism is common in hospitalized patients. Large emboli lodge in the pulmonary artery bifurcation. Smaller emboh occlude the peripheral branches of the pulmonary artery, producing wedge-shaped, red Themorrhagic” infarcts This condition is precipitated by hypercoagulability and can be prevented by the anticoagulant heparin A paraneoplastic syndrome of hypercoagulability may be seen in some patients with cancer, especially adenocarcinomas of the pancreas, colon, or lung Superficial venous thromboses may thus appear in one site and then resolve, only to recur in another site, producing “Trousseau’s syndrome.” or migratory superficial thrombophlebitis—an indication of visceral cancer. Temporal cell) form arteritis is characterized by in granulomatous inflammation of the media, is the most(giant common of systemic vascuhtis adults It predominantly involves mediumand to smaller branches of the carotid artery, especially the temporal artenes, The resulting headache, facial pain, jaw claudication, and visual deterioration generally respond well to glucocorticoid therapy. Hypertension is the single most important nsk factor for the development of intimal tears leading to aortic dissections. In addition to hypertension, smoking, diabetes, and hypercholesterole.ma are all major nsk factors for atheroscleios,s, which predisposes to aortsc aneurysm formahon more than to aortic dissection. Necrotizing vasculitis of the upper and lower respiratory tract (causing nasal ulcerations, sinusitis, hemoptysis) and rapidly progressive glomerulonephritis—producing a variable degree of renal failure—is characteristic of granulomatosis with polyangutis (Wegeners) This disease is associated with C-ANCAs, Necrotizing vasculitisand of rapidly the upper and lower respiratory tract (causing nasal ulcerations, sinusitis, hemoptysis) progressive glomerulonephritis—producing a variable degree of renal failure—is characteristic of granulomatosis with polyangiltis (Weqener’s). This disease is associated with C-ANCAs, which may target neutrophil proteinase 3. Among the arterthdes. transmural inflammation with fibhnOid necrosis is most characteristic of PAN Fever. malaise, weight loss, abdominal pain, and melena are frequent symptoms of PAN. PAN is associated with hepatitis B infection in 10 to 30% of cases Varicose veins are dilated. tortuous veins resulting from prolonged increases in intraluminal pressure and loss of vessel wall tensile strength Incompetent venous valves, venous stasis/congestion, edema, and an increased incidence of superficiaI venous thrombosismay result However, thromboembolism is a very infrequent complication of vancose veins Venous stasis ulcers are very common and often occur over the medial malleolus Tertiary syphilis can result in thoracic aortic aneurysm. It the aneurysm compress adjacent structures and dilates the aortic valve ring, a murmur and mediastinal widening might be present, as in this pabent. The pathogenesis of such an aneurysm begins with vasa vasorum endarteritis and obhteration, resufting in inflammation, ischemia, and weakening of the aortic adventitia. FTA.-ABS is a test specific for syphilis.
PATHOPHYSIOLOGY-Cardiology+Renal
The major determinant of the ratio of forward4o-regurgitant left ventricular (LV) output in patients with mitral regurgitation (MR) is LV afterload. An increase in steady state LV afterload tends to decrease this ratio. An increase in steady state LV end diastolic volume may contribute to or worsen MR. Decreased cardiac output triggers a number of compensatory mechanisms. Renin-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 is defined by a decrease in systolic blood pressure of greater than 10 mmHg with inspiration, and occurs in the setting of acute cardiac tamponade, constrictive pericarditis, severe obstructive lung disease, and restrictive cardiomyopathy. Pulsus paradoxus can occur in the setting of severe obstructive pulmonary disease such as asthma Beta-adrenergc agonists control acute asthma exacerbations by causing bronchial smooth muscle relaxation via increased intracellular cAMP In patients with chronic aortic stenosis (AS) and concentric left ventricular hypertrophy: 1 The loss of the contribution of atnal contraction to ventricular tilling that occurs with acute atrial fibrillation (AF) can reduce left ventricular peload and cardiac output sufficiently to result in dangerous systemic hypotension, and 2. Acute AF might also increase steady state pulmonary Venous pressures sufficiently to cause acute pulmonary edema. Collateral microvessels form adjacent pathways for blood flow to areas distal to an occluded vessel Adenosine and dipyridamole are selective vasoddators of coronary vessels that can cause coronary steal, a phenomenon in whsch blood flow m ischemic areas is reduced due to artenolar vasodilabon in nonischemic areas Coronary steal can lead to hypoperfusion and worsening of existing ischemia Loss of cardiomyocyte contractility occurs within 60 seconds after the onset of total ischemia. When ischernia lasts less than 30 minutes, restoration of blood flow leads to reversible contractile dysfunction (myocardial stunning), with contractility gradually returning to normal over the next several hours to days However, after about 30 minutes of total ischemia, ischemic injury becomes irreversible. Under normal circumstances, the right ventñcular (RV) thickness is between 3-4mm during diastole, significantly thinner than the left ventricular wall thickness (1 cm). RVH is a feature of cor pumonale. a condition caused by pulmonary hypertension resulling from disease of the lung parenchyma or the pulmonary vasculature. In young females between the ages of 20 and 40. primary pulmonary hypertension may be responsible for cor pulmonale.
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 (decreased LVEDP andcontractile LVEDV toperformance imp1ove stroke volumeejection fraction) and requires an increase in both 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. the first peak is the a wave. which is generated by atrial contraction This is notably absent in patients with atnal fibrillatIon. Calcthcation and thickening of the pencardium > 4 mm are common features of constrictive pencarditis on CT Clinical findings include slowty pogressrve dyspnea, peripheral edema, and ascites In the kidney, angiotensin II preferentially constricts the efferent arteriole, thereby maintaining the GFR ACE-inhibitors promote efferent arteriolar dilation, causing GFR reductions. Paradoxical thromboembolism occurs when a blood clot from the venous system crosses directly into the arterial circulation via an abnormal connection between right arid left cardiac chambers, such as an ASD or ventricular septal defect, Auscultatory findings in an ASD include a wide and fixed sphtting of S2. Additional associations between auscultatory findings and cardiac lesions are as follows 1 Systolic ejection murmur accentuated by standing hypertrophic obstructive cardiomyopathy 2. Early diastolic decrescendo murmur decreased by amyl nitrite: aortic regurgitation 3. Late diastolic murmur eliminated by atnal fibrillation: mitral (and/or tricuspid) stenosis
Brain Natnuretic Peptide (BNP) is elevated in patients with heart failure and is often used as a laboratory test in the clinical setting to determine a patient is siifering from a CHF exacerbation It is released by the ventncles when they are stretched as they often are in CHF from systolic dysfunction ft acts along with ANP to cause vasodilatation (decreased preload) and diuresis Both ANP and BNP activate guanytate cyclase. which induces an increase of intracellular cycbc GMP The murmur of AR is a diastolic decrescendo murmur, heard loudest in early diastole when the pressure gradient between the aorta and the left ventncle is maximal The murmur of AR is typically best heard at the left sternal border, with the patient leaning forward and at end expirahon In patients with TOF, the degree of RV outflow tract obstruction is the major determinant of the degree of nght4o-Ieft intracardiac shunting, and thus of hypoxemEc symptom severity. Left ventricular dysfunction can lead to increased pulmonary arterial pressure due to reactive vasoconstriction secondary to pulmonary venous congestion. Reactive changes in the pulmonary vasculature (e.g., endothelial dysfunction resulting in further vasoconstriction) also contribute to pulmonary hypertension Cardiac (or pencardial) tamporiade presents clinically with hypotension, tachycardia, and an elevated central venous pressure that produces jugular venous distension (JVD). Heart sounds may be muffled on cardiac auscultation and systolic blood pressure may drop more than 1 OmmHg on wispiration (pulsus paradoxus). In a patient with mitral regurgitation (MR). the most reliable auscultatory finding indicating a high regurgitant volume (severe MR) and left ventricular volume overload is a left sided S3 gallop Intensity of aS4holosystolic murmur due to MR may not of correlate well towith volume A left sided would suggest end stage decompensation severe MR left regurgitant ventncular failure, however, many patients with severe MR may not have developed left heart failure Isolated mitral stenosis (MS) elevates the left atrial end diastolic pressure and can therefore cause an elevated pulmonary capillary wedge pressure (PCWP), pulmonary hypertension, pulmonary vascular sclerosis and decreased compliance, nght venincular dilatation, and functional tncuspid regurgitation Note that in patients with isolated MS, PCWP does not reflect the left ventricular end diastolic pressure, which may be normal. Acute hemodynamic changes can produce functional heart murmurs, in the absence of any fixed valve lesion Dilatation of the left venincle in response to increased preload can result in functional mitral regurgitation, which can be eliminated by preload reduchon and reduced by afterload reduction Aortic stenosis (AS) may cause exertional syncope The murmur of AS is a systolic ejection-type, crescendo-decrescendo murmur that starts after the first heart sound and typically ends before the A2 component of the second heart sound. The intensity of the AS murmur is proportional to the magnitude of the left ventricle-to-aorta pressure gradient during systole.
An accessory AV conduction pathway (Wolff-Parkinson-White syndrome) can manifest clinically as recurrent paroxysmal supraventricular tachycardia in an otherwise healthy individua[ The baseline ECG generally shows a triad of abnormalities corresponding to ventricular pre-excitation: a shortened PR-interval, a delta wave at the start of the QRS complex. and a widened QRS intervaL Wide, fixed splitting of the second heart sound is a characteristic auscultatory finding in patients with ASD A hemodynamically significant ASD can produce chronic pulmonary hypertension as a result of left-to-right intracardiac shunting Eisenmenger syndrome is the late-onset reversal of a left-to-right shunt due to pulmonary vascular sclerosis resulting from chronic pulmonary hypertension. of the ASD maysyndrome be required to prevent irreversible pulmonary vascular sclerosis and aClosure permanent Eisenmenger The major long-term hemodynamic compensatory response to the volume overload of aortic regurgitation includes an increase in left ventncular preload (LV end-diastohc volume) in association with eccentric left ventricular hypeitrophy A significant increase in blood oxygen saturation between 2 nght-sided vessels or chambers indicates the presence of a left-to-right shunt. If such an oxygen step-up occurs between the right atrium and right ventricle, a ventricular septal defect (VSD) is most likely responsible VSD is the most common congenital heart disease, and a small VSD produces a holosystohc murmur that is loudest over the left mid-sternal border. The triad of muffled heart sounds. elevated jugular venous pressure. and profound hypotension indicates pericardial tamponade Rupture of the ventricular free wall as a consequence of an acute transmural Ml can cause tamponade Rupture usually occurs 3 to 7 days after the onset of total ischemia, coagulative necrosis, neutrophil infiftration, and enzymatic lysas of connective tissue havewhen sufficiently weakened the infarcted myocardium. In patients with TOF. squatting increases SVR and decreases right-to-’eft shunting, thereby increasing pulmonary blood flow Squatting thus counteracts arterial desaturation during hypoxemic speIIs Patients with mitral stenosis due to abnormal mitral valves may have an opening snap in early diastole shortty after the aortic component of the second heart sound (A2) The opening snap occurs shortly after the mitral valve opens. Patients with acute mitral regurgitation have near-normal left atrial (LA) compliance. Therefore, they tend to develop marked pulmonary hypertension and pulmonary edema Patients with chronic mitral regurgitation acquire an adaptive increase in LA volume and compliance Thus, they are less prone to pulmonary hypertension/edema but are more prone to atrial fibrillation and mural thromboembolism 1. Both ventricular hypertrophy and volume overload cause release of both ANP and BNP from the ventricular myocytes to facilitate natriuresis and diuresis 2. Reperfusion injury is thought to result from generation of oxygen-free radicals.
• 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-OSthat interval shorter this more severe the(intensity stenosis Other auscultatory findings may The accompany MS interval, include the a diastolic rumble 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.
Pathophysiology-Endcrine+Vascular+Neuro Glucagon increases serum glucose by increased production of glucose from the liver Glucagon stimulates insulin secretion from the pancreas However, patients with type 1 diabetes rarely have significant residual beta cells. Unlike epinephnne. glucagon has an insignificant effect on skeetal muscle cells and adipocytes Reduced gallbladder contractility. due to decreased cholecystokinin secretion, is responsible for biliary stones in patients with somatostatinoma. Most patients with diabetic ketoacidosis have normal to increased serum potassium levels despite low intracellular potassium. Replacement of potassium is a crucial step in management of patients with diabetic ketoacidosis. Atherosclerosis is inthated by repetitive endothelial cell injury, which leads to a chronic inflammatory state in the underlying intima of large elastic artenes as well as large and 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). One-aipha-hydroxylation transforms calcidiol to calcithol in the renal tubules In D chronic kidney disease, the conversion of 25-hydroxy vitamin D to I ,25-dihydroxy vitamin is impaired, leading to decreased circulating levels of I ,25-dihydroxy vitamin D. Low levels of the active form of vitamin D cause an increase in circulating PTH, called “secondary hyperparathyroidism Note that 24,25-dihydrocholecalcderol is an inactive substance DUnrig a water deprivation test. most patients with primary polydipsia will demonstrate a significant increase in urine osmolality. Additionally, patients with primary polydipsia will have low serum sodium levels and osmolality. Restriction of water intake normahzes unne output in patients with primary polydipsia Increase in levels of thyroid binding globulin lead to increase wi circulating total T4 and total T3 However, the level of free thyroid hormone is normal. Increase in TBG is typically seen m pregnancy, with use of oral contraceptives, or with hormone replacement therapy Sertoli cells maintain spermatogenesis. release inhibin, and secrete Mullerian inhibiting factor during male embryogenesis. Inhibin provides negative feedback on FSH secretion by the anterior pituitary
I 7ahydroxyiase deficiency impairs the synthesis of androgens. estrogens. arid cortisol but does not inhibit mineralocorticoid production Boys appear phenotypically female at birth, but gills develop normal genitalia Patients typically present with hypogonadism, hypertension, and hypokalemia Frothy or foamy urine may be caused by proteinuna Heavy proteinuria, as in nephrotic syndrome, can cause regional or generalized interstitial edema because the decrease in serum albumin and total protein concentrations lowers the plasma oncotic pressure and increases net plasma filtration in capillary beds Acetyicholine from presynaptic at theterminal. neuromuscular junction upon the influxrelease of extracellular calciumterminal into thevesicles presynaptic Calcium influx depends into the nerve terminal occurs following neuronal depolarization and opening of voftage-gated calcium channels The syndrome of inappropnate antidiuretic hormone secretion (SLADH) is characterized by low plasma sodium and osmolality. inappropriately concentrated unne, increased unnary sodium, and clinically normal body fluid volume An important cause of SIADH is a paraneoplastic effect secondary to small cell carcinoma of the lung. Adrenal adenoma and carcinoma will have low levels of ACTh in combination with the clinical features of Cushing syndrome ACTH levels are elevated in pituitary adenomas, and are suppressed by high-dose, but not low-dose, dexamethasone Serum ACTI-I levels are generally markedly elevated in ectopic ACTH production by malignant tumors; even high-dose dexamethasone does not suppress these levels Depression of cause the entire hypothalamus-pituitary-adrenal axis is the most common of adrenal insufficiency Adrenal crisis canbybeglucocorticoid precipitated intherapy these patients under stressful situations (i. e., infections or surgery) if their glucocorticoid dose is not appropnately increased Serum TSH level is the single most important screening test m diagnosing pnmary hypothyroidism Although TSH is not elevated in patients with hypothyroidism in central hypothyroidism, central hypothyroidism is uncommon. Secondary hyperparathyroidism is seen in patients with chronic renal failure These patients have an elevated serum PTH, accompanied by normal to low serum calcium levels, and high serum phosphorus levels. Circulating 1 ,25-dihydroxy vitamin D levels are low due to the deficiency of 1-alpha hydroxylase, an enzyme that resides in the kidneys. Pufferfish poisoning is caused by tetrodotoxin, a neurotoxin produced by microorganisms associated with the fish Tetrodotoxin binds to vottage-gated sodium channels in nerve and cardiac tissue, preventing sodium influx and depolarization. The likelihood of acute plaque change (especially rupture) producing an acute coronary syndrome via supenmposed thrombosis and/or thromboembohsm is most related to plaque
stabibty Plaque stability depends significantly on mechanical strength of the fibrous cap Inflammatory macrophages in the intima may reduce plaque stability by secreting metalloproteinases, which degrade collagen An age-related decrease in compliance (increased stiffness) of the aorta and its proximal major branches often causes isolated systolic hypertension (ISH) Patients with clasc, salt-wasting 21-hydroxylase deficiency have deficient cortisol and aldosterone synthesis combined with adrenal androgen overproduction. Male infants have normal genitalia and present 1-2 weeks after birth with vomiting, hypotension. hyponatremia. and hyperkalemia Females present at birth with ambiguous genitalia The diarrhea caused by cehac disease can lead to vTtamin D deficiency through malabsorption Patients with vitamin D deficiency have decreased serum phosphorus. increased serum parathyroid hormone (secondary hyperparathyroidism), and low serum calcium. They may also have symptoms such as bone pain and muscle weakness. Anytime a patient has bitemporal hemianopsia, a pituitary tumor should be suspected. The most common functional pituitary tumor is a prolactinoma Secreting prolactinomas thhibit the entire axis of GnRH-LHIFSH-sex hormones, causing impotence in men and amenorrhea in women of reproductive age (hypogonadotropic amenorrhea). Reperfuson injury is thought to occur secondary to oxygen free radical generation, mitochondrial damage, and inflammation. Sex hormones promote both growth and epiphyseal plate closure: hence, precocious puberty may resuLt in a shorter stature, despite an initial growth spurt Gigantism is caused by excessive pituitary production of growth hormone, these patients achieve enormous heights because, unlike excessive sex steroids, excessive IGF-1 does not lead to premature closure of the epiphysis Hyperproactinernia causes hypogonadism, which leads to reduced estrogen in women Low estrogen due to any cause is risk factor for accelerated bone loss. When the central venous piessure (CVP) is increased, as in right heart failure, the interstitial fluid pressure rises due to an increase in net plasma filtration, As the interstitial fluid pressure increases, so does lymphatic drainage Increased lymphatic drainage can compensate for moderate CVP elevations to prevent the development of clinically apparent interstitial edema With large CVP elevations, the net capillary filtration increases in excess of the lymphatic reabsorptive capacity and overt edema develops More than a 10% increase in urine osmolality following administration of vasopressin dunng a water deprivation test suggests central D[ A urine osmolality increase above 50% is strongly suggestive of complete central Dl.
The dominant effect of the hypothalamus on prolactiri secretion is inhibitory via dopamine production Prolactin regulation by dopamine is a commonly tested concept on USMLE Step 1 In response to calcium loading. PTh decreases. cakitonin increases, and the renal synthesis of the active form of vitamin D decreases The adrenal cortex consists of three distinct zones: the outer zona glomerulosa. the middle zona fasciculata, and the inner zona reticularis (remember GFR) The zona glomerulosa synthesizes mineralocorticoids (e.g. aldosterone), the zona fasciculata predominantly produces cortisol, and the zona reticulans predominantly produces androgens 21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia. Affected female infants present at birth with ambiguous (virilized) genitaha Male infants have normal genitalia and present later with salt-wasting or precocious puberty. A high serum level of 17hydroxyprogesterone is diagnostic. An ACTH surge with a resultant increase in steroid half-product’ excretion is a normal reaction to metyrapone administration, because metyrapone blocks the last step of cortisol synthesis Patients with type I diabetes mellitus are prone to develop other autoimmune endocrinopathies, including Hashimoto thyroiditis, Graves’ disease. and Mdison’s disease (hypoadrenocorticism). These patients are at increased risk for other non-endocnne autoimmune disorders as well, including vitiligo and pernicious anemia. Low bone density is a well-known complication of hyperprolactinemia that is associated with prolactin-induced hypogonadism (i.e.. low estrogen), Vaginal dryness is another very common manifestation of estrogen deficiency. ACTH is the major trophic hormone of the zona fasciculata and reticularis, whereas the zona glomerulosa is primarily regulated by angiotensin I. Prolonged ACTH stimulation causes hyperplasia of the zona fasciculata and reticulans, resulting in excessive cortisol production (Cushing syndrome). FFA and serum tnglycendes are bebeved to increase insulin resistance in overweight individuals. 1 1-hydroxylase deficiency typically results in excessive adrenal androgen and riNneralocorticoid (11- deoxycorticosterone) production. Females are born wdh ambiguous genitalia, and affected individuals develop hypertension and hypokalemia early in life Visceral obesity as measured by waist-to-hip ratio is an important determinant of insulin resistance. If a hypersecrehng-adrenal tumor has the functionality of the outer. intermediate, or inner layers of the adrenal cortex, the hormone(s) released and clinical syndrome produced will be aldosteronelConns syndrome, cortisoLlCushings syndrome, and androgens/hirsutism and vinkzation, respectiveIy
Morphine tolerance is a common problem in the treatment of pain. The exact mechanism of tolerance is unknown but may involve increased phosphorylation of opioid receptors, increased adenylyl cylcase activity, or increased nitric oxide levels Activation of NMDA receptors by glutamate is believed to enhance morphine tolerance by increasing phosphorylation of optoid receptors and increasing nitric oxide evels NMDA receptor blockers, like ketamine. block the actions of glutamate and effectively decrease morphine tolerance Subpenosteal thinning is a characteristic feature of hyperparathyroidism Radiologically, this thinning appears as subperiosteal erosions in the medial sides of the second and third phalanges of the hand, and as a granular, salt-and-peppe?’ appearance of the calvarium. In the pathogenesis of atherosclerotic plaques. release of platelet-derived growth factor (PDGF) by locally adherent platelets, endothelial cells, and macrophages promotes the migration of smooth muscle cells from the media into the intima and their subsequent prohferation 1. Growth hormone increases linear growth by stimulating the production of IGF-1 from the liver 2. Defective growth hormone receptors will lead to decrease in linear growth and is called Laron dwarfism. It is characterized by hágh serum levels of growth hormone in the piesence of low IGF-1 leve1s The vascular reaction to endothelial and intimal injury is intimal hyperplasia and fibrosis, predominantly mediated by reactive smooth muscle cells that migrate from the media to the intima During hyperglycemia. excess plasma glucose is converted to sorbitol by aldose reductase Sorbitol injury accumulates within some cells and attracts water into these of tissues leading osmotic cellular This mechanism is implicated in the pathophysiology cataracts andtopenpheral neuropathy in diabetes
Pathophysiology-GIT+Pulm+Haem+Hepa+Skeletal After vasectomy, viable sperm remain in the portion of the vas deferens proximal to the ligation Twenty percent of patients still have viable sperm in their ejaculate after 3 months and at least 20 ejaculations Aromatase converts androgens into estrogens in the ovaries, testes, placenta and other peripheral tissues Genetic deficiency of this enzyme leads to an inability to synthesize estrogens It presents with maternal vinlization during pregnancy and masculinization of the female fetus Trypsin activates all proteolytic pancreatic enzymes including itself I activated prematurely (i.e. before reaching the duodenal lumen), it can cause autodigestion of the pancreatic tissue A number of inhibitory mechanisms exist to prevent premature activation of trypsin A gene mutation that renders trypsinogen insensitive to inhibhon causes hereditary pancreat.tis
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. ViPomas are non-beta cell pancreatic islet cell tumors that hypersecrete VIP ViP increases intestinal chloride loss into the stool, which causes excess losses ol the accompanying water, sodium and potassium as well. ViP also inhibits gastric acid secretion. Somatostatin inhibits the secretion of VIP and is used to treat the symptoms of ViPoma In cystic fibrOSis, abnormalities of the CFTR transmembrane protein reduce luminal chloride secretion and increase sodium and net water absorption, resulting in dehydrated mucus and a widened, negative transepithelial potential difference These electrolyte changes occur in most exocrine glands (other than sweat glands). Duodenal ulcers are not associated with an increased risk of carcinoma in the same location. In contrast, esophageal, gastric, and colorectal cancers are frequently identified as ulcerative lesions on endoscopy Cheyne-Stokes respiration describes cyclic breathing in which apnea is followed by gradually increasing tidal volumes, and then gradually decreasing tidal volumes until the next apneic period It is commonly seen in advanced congestive heart faifure Lactase-deticient individuals have increased stool osmotic gap, increased breath hydrogen content, and decreased stool pH upon lactose challenge. Airway challenge testing with methachohne is a highly sensitive but nonspecific measure that can detect the degree of bronchial hyperreactivity in patients suspected of having asthma A negative methacholine challenge test can help to exclude (rule out) the diagnosis Chest x-ray, blood eosinophil count, serum IgE level, and skin reactivity to vanous allergens are less sensitive, normal findings on these tests cannot exclude the diagnosis Hepatic encephalopathy appears to be secondary to increased levels of ammonia in circulation Frequently, hepatic encephalopathy is precipitated by a stressor that alters the ammonia balance (eg, gastrointestinal bleeding)
Gilbert syndrome is the likely diagnosis in patients with no apparent liver disease who have mild unconjugated hyperbilirubinemia that appears provoked by one of the classic triggers. Arterial PaCO. is a direct indicator of the status of alveolar ventilation Hypocapnia implies ongoing alveolar hyperventilation Upper airway obstruction, reduced ventilatory drive, respiratory muscle fatigue, and decreased chest wall compliance are possible causes of alveolar hypoventilation and cause hypercapnia Renal calculi occur when there is an imbalance of the factors that facilitate and prevent stone formation. Increased concentrations of calcium, phosphate. oxalate. and uric acid promote salt crystallization, whereas increased citrate and high fluid intake help prevent calculi formation. The RANK receptor/RANK-Ugand interaction is essential for the formation and differentiation of osteoclasts. The over-expression of RANK receptors in hypoestrogenic states causes increased bone resorpUon due to increased osteoclastic activity. In short, low estrogen means a lower bone mass. Patients with osteoporosis have low bone mass. resulting in increased susceptibihty for fragihty fractures In primary osteoporosis (osteoporosis not caused by a medical disorder), serum calcium, phosphorus, and PTH levels are typically normal. Patients with CF produce eccrine sweat that contains high concentrations of sodium and chloride compared to normal individuals Although numerous substances are thought to play a role in the pathogenesis of allergic asthma, only leukotrienes (LTC4, LTD4, and LTE4) and acetyicholine have pharmacologc receptor antagonists that offer clear therapeutic benefit. Metabolic alkalosis is characterized by a high arterial blood pH. HCO3 and pCO2. It is most commonly caused by vomiting, NG suction, diuretic use or hyperaldosteronism Measuring the urinary chloride concentration and determining the patienUs volume status helps to identify the cause of metabolic alkalosis Hyperestrinism in alcohohc cirrhosis arises due to decreased catabolism of estrogens as well as increased sex hormone-binding globulin (which decreases the free testosterone-to-estrogen ratio). This imbalance leads to gynecomastia, testicular atrophy, decreased body hair, and spider angiomata Emphysema most commonly results from chronic smoking. but can also occur in genetically predisposed individuals with alpha-i antitrypsin deficiency Patients with emphysema have a decreased FEV1/FVC ratio, increased total lung volume, and decreased diffusing capacity Sunlight exposure catalyses the first reaction in the chain of active vitamin D synthesist 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. Chronic obstwctive pulmonary disease (COPD) in a heavy smoker may consist of both emphysema and chronic bronchitis and thus may present with both progressive exertional dyspnea (characteristic of emphysema) and frequent respiratory infections (charactenstic of chronic bronchitis) On pulmonary function testing, all COPD yields a decreased FEV1!FVC ratio Emphysema also tends to increase TLC and RV In contrast, restrictive lung diseases can cause reduced lung volumes and increased FEV1/FVC. Decreased esophageal body peristalsis and poor relaxation of the LES on manometry are typical for achalasia Achalasia presents with progressive dysphagia chest pain, food regurgitation and aspiration Barium swallow shows a dilated esophagus and a “bird’s beak deformity of the LES D-xylose is a monosaccharide: thus. its absorption does not require pancreatic enzymes and is not affected by pancreatic insufficiency. Oral administration of a fixed dose of D-xylose can be used to differentiate between malabsorption of pancreatic versus gastrointestinal mucosal etiology. Paroxysmal breathlessness and wheezing in a young patient that is unrelated to ingestion of aspirin, pulmonary infection, inhalation of irritants, stress, and/or exercise should raise a strong suspicion for extrinsic allergic asthma. Classic sputum findings include easinophils and 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 srcinate from hematopoietic progenitor cells. RANK-L and M-CSF play an important role in osteoclast differentiation Paget’s disease of the bone is caused by excessive osteoclastic resorption. Major basic protein released by eosinophils normally functions to kill helminths. It is also thought to contribute to the bronchial epithelial damage sustained by patients with atopic (extrinsic allergic) asthma A normal bleeding time indicates adequate platelet hemostatic function. A normal aPTT indicates an intact intnnsic coagulation system. A prolonged PT indicates a defect in the extrinsic system at a step not shared with the intrinsic system. Remember the risk factors for osteoporosis: 1 Smoking 2. Menopause 3. Corticosteroid therapy 4 Physical inactivity 5. Caucasian race (immutable) 6. Low total body weight 7. Aicohol use Digestive disorders such as cholestasis can cause malabsoiption and nutritional deficiencies of the fat-soluble vitamins This may result in osteomalacia, which is frequently associated with vitamin D deficiency The hypercalcernia associated with squamous cell lung cancer, and several other tumors, is usually due to over-production of parathyroid hormone-related peptide and is termed the ‘humoral hypercalcemia of malignancy” Systemic mastocytosis is characterized by the abnormal proliferation of mast cells and increased histamine secretion Histamine increases the production of gastric acid by parietal cells Gastric hypersecretion, therefore, is a common occurrence r systemic mastocytosis Intectous esaphagths is common in HIV-positive patients The most common cause s Candida a/b/cans. although CMV and HSV-1 are also frequently implicated Diagnosis relies on endoscopic and microscopic findings. 5a-reductase converts testosterone to dihydrotestosterone (DHT). DHT mediates development of the external genitaha in the male fetus Male neonates with 5cs4eductase deficiency are born with feminized external genitalia that typically masculinize at puberty. Small phallus and hypospadias are commonly found
Cricopharyngeal muscle dysfunction is a condition caused by diminished relaxation of pharyngeal muscles dunng swallowing The subsequently increased intraluminal pressure in the oropharynx causes the mucosa to herniate through the wall at a point of muscle weakness, forming a Zenker diverticulum Clinically, patients (elderly) present with oropharyngeal dysphagia, coughing, choking, and recurrent aspiration Reduced expiratory airflow velocity, decreased bdal volume, and increased residual volume together characterize chronac obstructive pulmonary disease (COPD) Chronic bronchitis and/or emphysematous destruction of interalveolar walls may be responsible In companson, restnctive lung disorders tend to decrease all lung volumes without significantly affecting expiratory flow rates COPD can cause hypoxia sufficient to stimulate increased erythropoietin production by the cortical cells of the kidney
PHARMACOLOGY-Cardiology Bipolar disorder is commonly treated with lithium, an anti-manic medication Lhium has been linked to cases of Ebstein’s anomaly in infants exposed in utero Ebsteins anomaly is characterized by apical displacement of the tncuspid valve leaflets, decreased right ventricular volume, and atrialization of the right ventricle Clearance (CL) determines the dose rate required to maintain a steady-state plasma concentration (CpJ: Maint.nanc. dos. • Cp x CL I [Bloavaflability fraction] The bioavailabihty fraction = 1 if administered intravenously 1 Warfarin inhibits the carboxylahon of vitamin K-dependent coagulation factors II, VII, IX, and X. Prothrombin time should be monitored regularly during treatment with this medication. The most common adverse effect is bleeding 2. Activated partial thromboplastin time (aPTT) is used for monitonng unfractionated heparin Class Ill antiarrhythmics such as amiodarone, sotalol, ibutilide and dofetilide will slow potassium efflux from the ventricular myocyte, prolong repolarization and prolong the refractory penod. Nitrate drugs mimic the action of endothelial derived relaxing factor (nitric oxide, NO) They are transformed to NO at the vascular smooth muscle cell membrane which leads to increased cGMP, decreased intracellular calcium and myosin dephosphorylation. The best treatment of chronic dry cough caused by an ACE inhibitor is replacement of this drug with an angiotensin receptor blocking drug (ARB), such as losartan Remember that ARBs are also beneficial for both hypertension and do. diabetic nephropathy and do not interfere with the catabolism of bradykinin as ACE inhibitors receptors are found in cardiac tissue and on renal juxtaglomerular cells, but not on vascular smooth muscle. Blockade of the , receptor leads to decreasing cAMP levels in cardiac and renal tissue without affecting cAMP levels in vascular smooth muscle. Daptomycin is a lipopeptide antibiotic with activity limited to Gram-positive organisms, including methicillin-resistant Staphylococcus aureus It causes depolarization of bacterial cellular membrane and inhibition of DNA RNA. and protein synthesis. Daptomycin is associated with increased CPK levels and an increased incidence of myopathy Amiodarone along with the class IA and the remainder of the class Ill antiarrhythmic agents will cause a prolongation of the QT interval on the EKG. These drugs have this effect because they all phase 3 repolarization the ventncular myocardium Amiodarone doesslow not predispose to torsade deinpointes as the remainder of these agents do is unique in that it
Patients taking daály maintenance nitrates need to have a nitrate-free period every day to avoid tolerance to the drug Lidocaine is a class lB antiarrhythmic agent which very specifically binds rapidly depolarizing and depolarized cells lschemic myocardium is depolarized tissue: this is why ocaine is specific for ischernic tissue and is the agent of choice for prevention and treatment of post-myocardial infarction arrhythmias Currently amiodarone has replaced the lidocaine in the management of ventricular tachycardia Nitrates can lead to a reflex tachycardia by causing a relative hypotension that the body responds to with catecholamirie adrenergic blockers with release nitrates This adverse effect can be prevented by administering betaIt is important to know the difference in the cardioselectivity and vascular selectivity of the 3 classes of calcium channel blockers, Verapamil has the most effect on the heart while nifedipine is most selective for the peripheral vasculature with diltiazem having an effect somewhere in between The most frequent adverse reactions noted with verapamil are constipation and gingival hyperplasia, though they also are known to cause bradycardia as well as first. second or third degree AV nodal block in 1-2% of patients treated.
Class I antiarrhvthmics
1A nterrnediate bindrng to Na but also blocks K :hannels
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1B
ate of binding and release is so raped no :hange (fl is seen Since they APD j, also block la window current, they APD
1C
very tight binding and slow release
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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 andpessure the associated deterioration of ventricular contractile reducing blood A beta-blocker would also be beneficial for these function, patients. m addition to
In this case, digoxin toxicity manifested as changes in color vision and anorexia Digoxin toxicity can also cause ventricular dysrhythmias. headache, fatigue and confusion Isoproterenol is an agonist at both 31 and 32-adrenergic receptors and has little or no 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 is the inhibition of the Na-K-ATPase in cardiac pacemaker cells leading to AV nodal blockade (increased diastolic filling time for greater contraction by the Frank-Starling mechanism) and increased contractility from increased intracellular calcium Procainamide and hydralazine have the highest risk of causing drug-induced lupus erythematosus (DuE), which is charactenzed by the development of lupus-like symptoms in addition to positive ANA and anti-histone antibodies Unlike with SLE, anti-dsDNA antibodies are rarely seen Using nitrates together with phosphodiesterase (PDE) inhibitors used for erectile dysfunction and pulmonary hypertension causes a profound systemic hypotension because they both increase intracellular cGMP which causes vascular smooth muscle relaxation. Their use together is absolutely contraindicated Sotalol has both beta-adrenergic blocking properties and class 3 antiarrhythmic (K channel blocking) properties. It prolongs both the PR interval and the QT interval. Adenosine is a rapidly acting antiarrhythmic used to quickly convert people out of PSVT (drug of choice) It is also rapidly cleared and has a half-life of only less than 10 seconds It commonly causes chestthis burning (bronchospasm), flushing high grade block as adverse reactions (remember, is the drug used for chemical stressand tests!) Thiazide diuretics cause elevations in the serum LDL, calcium, unc acid and glucose levels They lower serum potassium. serum sodium and blood pressure Class 3 antiarrhythmic agents block potassium efflux from cardiac myocytes and prolong phase 3 of the myocyte action potential. It is important that students know the correlation between the EKG waves and the cardiac cycle, and how drugs that act on the heart affect both of these. Beta-blockers, includmg esmolol, slow AV conduction Delayed conduction through the AV node causes PR interval prolongation. Digoxin will increase cardiac contractility by blocking the Na-K-ATPase in cardiac myocytes leading to an increased intracellular calcium concentration, and it will decrease AV nodal conduction by a mechanism of increased parasympathetic tone Phosphodiesterase inhibitors lead to increased cardiac contractility via increased intracellular cAMP concentration. cAMP promotes increased intracellular calcium in cardiac myocytes and is normally metabolized by phosphodiesterases k vascular smooth muscle, increases in cAMP
cause vasodilation, a well-known side effect of phosphodiesterase inhibitors which can occasionally limit their use in hypotensrve patients. The QRS complex corresponds to ventricular depolarization and phase 0 on the action potential graph. Ventncular myocyte depolarization is mediated by inward sodium movement and can be modulated by class I antiarrhythmics. The anthracycline chemotherapeutic agents (doxowbicw, daunorubicm. epirubicin and idarubicin) form free radicals in the myocardium. Their most severe side effect is a cumulative dose-related dilated cardiomyopathy. It presents with symptoms of left and right ventricular CHF. Nifedipine causes peripheral vasodilatation which may result in reflex tachycardia Therefore this antihypertensive drug is useful for patients with bradycardia. Beta-blockers inhibit the production and release of rerun from renal juxtaglomerular cells through antagonism of 131 receptors on these cells Inhibition of renan release causes suppression of the renin-angiotensina ldosterone pathway, which results in decreased vasoconstnction and decreased renal sodium and water retention All nitrates, both long and short acting. are most commonly associated with the side effects of headache and facial flushing. These reactions occur because of the vasodilatory properties of nitrates in the meninges and skin. Nitroglycerin is primarily a venoddator It decreases preload which decreases myocardial oxygen demand and thereby treats angina pectons. Nitroglycenn and Isosorbide dinitrate undergo considerable first-pass metabolism in the liver when taken by the oral route. Interestingly, isosorbide mononitrate is nearly 100% bioavailable when taken by the oral route. Torsades de pointes is a form of ventricular tachycardia with characteristic ECG findings that is always associated with an underlying prolongation of the QT riterval. It is most commonly precipitated by pharmacologic agents that prolong the QT interval such as some antiarrhythmics, TCAs and others. Clopidogrel is an antiplatelet agent that works by inhibiting the platelet surface ADP receptor It is as efficacious as aspirin in the pcevention of thromboernbolic disease. Dobutamine is a relatively selective 31-adrenergic agonist that increases heart rate, contractility, conduction velocity, and myocardial oxygen consumption Sublingual or aerosohzed nitroglycehn is a rapidly acting agent taken by patients with stable angina pectoris as needed to rapidly relieve their symptoms, Nitrates act primanly as venodilators causing a decrease in cardiac work by decreasing left ventncular fiNing volume o preload.
Digitalis (digoxin) is a commonly used drug with a well-characterized side effect profile making it a favorite testing item among question writers ft leads to AV block and ventricular tachyarrhythmias Hyperkalemia is frequently found in acute digoxin toxicity However, please note - hypokalemia increase patient susceptibility to the toxic effects of digoxin. The class IA antiarrhythmacs (quindine. procainamide, and disopyramide) are sodium channel blocking agents that slow phase 00! the ventncular myocyte action potential and prolong repolarization as well as the refractory period of these cels ôJI diuretics except for the potassium-sparing class cause potassium loss They do this by increasing volumevolume delivered toexpense the collecting duct, where aldosterone then attempts to reclaim the the additional at the of potassium. êJl of the potassium-spanng diuretics act at the collecting duct Direct arteriolar vasodilators like hydralazine and minoxidd are effective antihypertensives Because they cause significant arterial vasoddation, they also cause reflex sympathetic activation resulting in tachycardia and edema To counteract these compensatory effects, these agents are often given in combination with sympatholytics and diuretics. Patients who have overdosed on beta blockers should be treated with glucagon, which increases heart rate and contractility independent of adrenergic receptors Glucagon activates G-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 atenolol) can have additive negative chronotropic effects yielding severe bradycardia and (eg, 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 Acyclovir, the acyclovir prodrug vaiacyclovir, famciclovir, and ganciclovir are all nucleoside analogues that require both herpes viral and cellular kinases for conversion to their active nucleoside triphosphate form. Cidofovir is a nucleoside monophosphate (ie, a nucleotide) that requires only cellular kinases for activation The acute effects of corticosterods on the CBC inck,de increased neutrophil count. and decreased lymphocyte, monocyte, basophd, and eosinophil increase from 0dargition of neutrophils previousty attachedcounts to the The vessel wal in neutrophd count results The desmopressan analog DDAVP is used in patients with von Willebrand disease because it induces endothelial procoagulatory protein release (including vWF). Remember, that desmopressin tablets can also be used for the treatment of enuresis. Isotretinoin is used to treat severe acne refractory to topical therapies. Its main adverse effects are hypertriglyceridemia and teratogenicity. Pregnancy is an absolute contraindication to its use Sexually active females should be advised to use two forms of contraception and to have monthly pregnancy tests. 1. TZDs decrease insulin resistance by binding to peroxisome prohierator activated receptor gamma (PPAR-gamma), which is a transcriptional regulator of genes involved in glucose and lipid metabolism. 2. Adiponectin levels are low in type 2 diabetes, and treatment with TZDs increases the levels of adiponectin. Anastrozole is a selective inhibitor of aromatase. the enzyme responsible for the conversion of androgens to estrogens Ketoconazole is an antifungal agent that decreases androgen synthesis by inhibiting multiple enzyme pathways involved En the synthesis of androgens. lnhibion of the epidermal growth factor and HER2Jneu pathways by trastuzumab leads to the apoptosis of breast cancer cells Activation of the HER2Ineu receptor leads to activation of tyrosine lanase. Thionamides (e.g.. methimazole and propyithiouracil) act as antithyroid medications by decreasing the formation of thyroid hormones via inhibition of the enzyme thyroid peroxidase Propyithiouracil also decreases the peripheral conversion of T4 to T3 Thiazolidinediones bind to peroxisome prohferatoractivated receptor-gamma (PPAR-y), a receptor that belongs to the steroid and thyroid superfamily of nuclear receptors. Diabetic ketoacidosis (DKA) presents as volume depletion (hypotension and tachycardia) with ketones and glucose in the unne It occurs most commonly in type 1 diabetics Regular insulin is preferred for the acute treatment of DKA.
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. The secretion of prolactin is controlled by the inhibitory effect of hypothalamic dopamine Hyperprolactinemia causes hypogonadism by inhibiting the release of gonadotroph releasing hormone from the hypothalamus Risperidone and other antipsychotics cause hyperprolactinemia by their antidopaminergic action. The mechanism of action of 13 receptor blockers i thyrotoxicosis is dual: there is a decrease in the effect of sympathetic adrenergic impulses reaching target organs and a decrease in the rate of peripheral conversion ofT4toT3. Fluid retention, with resultant weight gain and edema. is a common side effect of thiazolidinedione therapy. This excess fluid can exacerbate underlying congestive heart failure. Terbinafine is used for treatment of dermatophytosis. It inhibits synthesis of fungal membrane ergosterol by suppressing the enzyme squalene epoxidase. Diabetic patients often need 2 types of insuhn. a basal long-acting insulin and a postprandial short-acting insulin. The best basal long-acting insulins are glargine and detemir insulin (administered as once-a-day shots) NPH is good for about 18 hours (shots given twice a day) The best short-acting insulins are lispro, aspart, and glulisine (shots given 3 times a day with meals). They have a very rapid onset of action with peak effects coinciding with peak postprandial hyperglycemia. Flutamide is a non-steroid anti-androgen that competes with testosterone and DHT for testosterone receptors It is used for treatment of prostate cancer in combination with GnRH agonists High-dose glucocorticoids such as prednisone are used to control severe Graves’ ophthalmopathy They are helpful in decreasing the severity of inflammation and decreasing extraocular voIume Conventional antithyroid drugs do not improve ophthalmopathy Glucocorticoids are predominantly catabolic, causing muscle weakness, skin thinning, impaired woundh ealing, osteoporosis, and immunosuppression However, they ricreasekver protein synthesis, specifically the enzymes involved in gluconeogenesis and glycogenesis This, along
with peripheral antagonism of the effects of insulin, contnbutes to the development of hyperglycemia Tamoxifen and raloxifene are called “selective estrogen receptor modulators (SERMs)” because of their tissue-selective estrogen agonist and antagonist properties Tamoxifen is useful for the treatment of osteoporosis and breast cancer. However, it is associated with an increased incidence of endometrial cancer and thromboembolic disease. Nafcilhn, methiciHin and oxacillin are penicdlinase-resistant pemcdhns active against isolates of S aureus and S epdetmidis that are resistant to other peniciflins They are not effective against MRSA. however FinasterideisaS-aipha-reductase inhibitor that suppresses peripheral conversion of testosterone to dihydrotestosterone ft is used for treatment of benign prostatic hyperplasia and androgenetic alopecia Local cutaneous adverse effects of chronic topical corticosteroid administration include atrophy/thinning of the dermis that is associated with loss of dermal collagen, drying, cracking, andlor tightening of the skin, telangiectasias. and ecchymoses Agranulocytosis is a rare but very serious comphcation of antithyroid drugs A WBC count with a differential is necessary in any pabent receMng eher methimazole or PTU who presents with a fever Administration of potassium iodide may prevent thyroid absorption of radioactive iodine isotopes by competitive inhibition. 1 Anion inhibitors (perchiorate. pertechnetate) block iodide absorption by the thyroid gland via competitive inhib4ion 2. Thionamides (methemazole and propylthiouracd) decrease the formation of thyroid hormones by inhibiting thyroid peroxidase 3. Iodide salts inhabit synthesis as well as release of thyroid hormones. 1. Because troghtazone was withdrawn from the market due to hepatotoxicity, periodic liver function tests are now recommended in all patients treated with thiazohdinediones 2. The other important side effect of TZDs includes fluid retention, which can exacerbate congestive heart failure in patients with underlying cardiac dysfunction. Loss of consciousness brought about by severe hypoglycemia is typically treated with intramuscular glucagon in the non-medical setting and with intravenous dextrose in the medical setting Metformin is absolutely contraindicated in patients with renal failure, due to a risk of lactic acid accumuIation In fact, metformin is contraindicated in any situation that might precipitate lactic acidosis, such as liver dysfunction, congestive heart failure, alcoholism, and Sepsis.
The ideal treatment for patients in adrenal crisis is administration of stress-dose corticosteroids. Response to vasopressors in the presence of adrenal insufficiency is generally suboptimal. TZDs activate PPAR-gamma. whkh is the nuclear receptor that alters the transcription of genes responsible for glucose and lipid metabolism Thiazohdined*ones (TZDs) exert their 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. 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: 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 oralTheir contraceptives by endometnum decreasing synthesis of FSH and LH in the anterior pituitary effects on inhibit cervicalovulation mucus and 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. 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 dose-response expectedshift for the effect of in a reversible competitive antagonist added to log a full agonist are:curve 1) a parallel to the nght 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 in the results duodenum anddeficiency proximal anemia jejunumMalabsorption Bypass of this segment of smalloccurs bowel predominantly by gastrojejunostomy in iron 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 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 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 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
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 viaandintracellular nevirapine, efavirenz, delavirdine phosphorylation. The more common NNRTIs include
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 and cornea. remove excess looselynucleus, bound serum copper.Chelation therapy with penicillamine is indicated to
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 agents contraindication to bothareNSAIDs and coichicine, such as patients with renal failure Uricosuric and allopurinol 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.
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 srcin (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 Manyaffected patients by treated with coichicine also develop diarrhea as the gastrointestinal mucosa is adversely 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 lsoniazidon is whether metabolized with acetylators which a patient is able toofacetylate depends theyby areacetylation. geneticallyThe “fasrspeed or slow” The presence fast anddrugs 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
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 that is augmented by neostigmine I block but reversed bylargely neostigmine duringblocker phase II block The duration of paralysis during causedphase by succinylchohne depends 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 tocysteine the sulfhydryl groups. NAC also acts as a glutathione substitute and binds the toxicprovides metaboifte. Cokhicine affects tubulin polymehzation into microtubules. Important side effects of colchácines are nausea, abdominal pain, and diarrhea. As a selective estrogen receptor modulator (SERM). raloxifene binds to estrogen receptors and exhibits tissue-specific behavior that either imitates or antagonizes the effects of natural estrogen In bone, the estrogen agonist effects of raloxifene predominate and osteoporosis is inhibited In mammary tissue, the estrogen antagonist effects of raloxifene predominate and protection is provided against estrogen receptor- positive breast cancer. Acute extrapyrarnidal symptoms (eg, dystonic reactions. akathisia, and parkinsonism) are related to an imbalance between dopamine (D2) and muscarinic (M1) activity in the nigrostriatal tract Traditional-high potency antipsychotics (haloperidol. fluphenazine) strongly block D. receptors and are the most likely to cause extrapyramidal symptoms. A decrease in the intravascular fluid volume stimulates aldosterone secretion and leads to increased excretion of potassium and hydrogen ions in the urine This results in hypokalemic
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 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(TCAs). inhibitorSexual (SSRIs) that has is a abetter side effect profile compared to tricyclic antidepressants dysfunction 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 microscopy liver injury by halothane metabolites andhepatic formation of autoantibodies against liver proteins Light shows massive centnlobular necrosis Co-administration of an SSRI and MAO inhibitor can produce excessive serotonin levels secondary to decreased reuptake and decreased metabolism Excessive serotonin evels can lead to the development of a potentially fatal condition known as serotonin syndrome To avoid the risk faq’ serotonin syndrome, it is recommended to wait at least 14 days after MAO inhibitor discontinuation before initiating SSRI therapy This should allow sufficient time for the regeneration of MAO Tngeminal neuralgia presents with brief episodes of sudden and severe electric shock-like or stabbing pain in the disthbution of CN V (particularly V2 and V3) Carbamazepine is the drug of choice References: Trigemmal neuralgia and Its management 2. Drug therapy of trigeminal neuralgia Minimal alveolar concentration is the best measure of potency of an inhaled anesthetic (actually ED50). The less MAC is required for anesthesia, the more potent the inhalation anesthetic is.
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 serotonergic drugs can induce serotonin syndrome when used concomitantty with other References: 1 Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Benzodiazepines substitute for the action of alcohol on GABA receptors and are indicated for the treatment of alcohol withdrawal Long-acting benzodiazepines (chiordiazepoxide, diazepam) are first-line medications Short-acting benzodiazepines (lorazepam. oxazepam) are preferred in patients with advanced liver dysfunction. The “on-off’ phenomenon is an unpredictable and dose-independent characteristic of advanced Parkinson disease-there is no clear etiology this phenomenon On the other hand, the “wearing off” phenomenon of Parkinson disease is due to progressive destruction of striatonigral dopaminergic neurons over a period of time Zolpidem is a short-acting hypno& medication chemically unrelated to benzodiazepines It has the same mechanism of action as benzodiazepines, but a much lower risk of tolerance and dependence
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 and up to 50% of latency patientstotreated with SSRIs. Symptoms include decreased libido. anorgasmia, increased ejaculation Bupropion is an excellent alternative Body temperature greater than 40 C is called hyperpyrexia and may lead to permanent brain damage if left untreated Emergent treatment of hyperpyrexia should consist of increasing body heat loss (cooling) and decreaseng the hypothalamic set pomt (antipyretics). Facilitating body heat loss takes precedence because it is effective immediately as opposed to antipyretics which take time to act disease due to increased intraocu’ar pressure. develops due to decreased outflow or increased production of aqueous humor Timolol and other beta-blockers decrease aqueous humor production by the ciliary epithelium Cholinergic agonists bind to muscahnic receptors on endothelial cells and promote release of NO (EDRF). NO activates guanylate cyclase and diminishes endothehum calcium concentration This produces vasodilatation. The use of opioids can lead to the development of tolerance or a decrease in opioid effectiveness and physiological response with continued use Tolerance to opioid induced constipation and miosis does not readily occur. To prevent bowel complications, it is recommended to treat patients prophylactically with adequate fluid intake and daily laxatives. Traditional high potency agents are more likely to cause extrapyramidal symptoms and less likely to cause ariticholinergic and antihistamine side effects. In contrast, low potency antipsychotics more likely to cause ant)cholinergic and anti histamine side effects, (Mency = Extrafy’ramidal) Exacerbation of myasthenia graves in a patient treated wdh cholinesterase inhib4ors occurs due to myasthenic or cholinergic crisis The edrophonium (Tensdon) test helps to differentiate these two conditions Clinical improvement after edrophonium administration indicates that the patient is undertreated (myasthenic crisis) Unlike other traditional antipsychotks, which act on D2 receptors. clozapine acts on D4 receptors Due to the nsk of life-threatening agranulocytosis with clozapine, the FDA requires periodic
monitoring of the white blood cell count (WBC) for the duration of treatment The other impoflant side effect of clozapine is seizures The tertiary amine physostigmine can reverse both the CNS and peripheral symptoms of severe atropine toxicity. The antichohnesterase agents neostigmine and edrophonium have a quatemary ammonium structure that limits CNS penetration Exposure to certain insecticides can cause organophosphate poisoning The resultant cholinesterase inhibition is profound and prolonged because organophosphates bind wreversably to cholinesterase This causes a state of chohnergic excess, marked by excessive salivation, lacnmation, diaphoresis, urinary incontinence, diarrhea, emesis, miosis and bradycardia Sodium bicarbonate is the single most effective agent in treating TCA-associated cardiac abnormalities Methadone is the drug of choice for treating heroin addiction and abuse It is a very potent. long acting opiate with good oral bioavadablity Its long half-life allows for prolonged effects to suppress withdrawal symptoms in heroin dependent patients The symptoms of schizophrenia include the following: 1, Positive symptoms hallucinations (usually auditory), delusions, and disorganized speech and behavior 2. Negative symptoms a decrease in emotional range, poverty of speech, and loss of interest in living The symptoms of schizophrenia include the following: 1. Positive symptoms: hallucinations (usually auditory), delusions, and disorganized speech and behavior. 2, Negative symptoms: a decrease in emotional range, poverty of speech, and loss of interest in living. Unlike first-generation neuroleptics, second-generation (atypical) agents (clozapine, risperidone, olan.zapine, quetiapine) improve both positive and negative symptoms of schizophrenia References: 1. Pharmacological approaches to the management of schizophrenia. 1 Phenytoin, carbamazepine and vaiproic acid inhts neuronal high-frequency flung by reducing the abdity of sodium (Na’)channels to recover from mactivation 2 Ethosuximide is believed to block T-type calcium channels in thalamic neurons causing hyperpolanzation and is approved for the treatment of absence seizures The autonomic nervous system utilizes three types of signal pathways: cAMP. lP3, and ion channels. Nicotinic receptors are hgand-gated ion channels that open after binding acetyIchoIine This results in an immediate influx of Na and C& into the cell and an outfiux of K from the cel References: 1. Neuromuscular junction in health and disease.
Second-generation antihistamin s htce fexofenadine have minimal sedative a d antimuscannic effects 1. Buspirone is a selective agon ist of the 5HT1A receptor and is a safe and e fective treatment for generalized anxiety disorder t has no muscle relaxant or anticonvulsant prop erties 2 Buspirone is an anti-anxiety gent that is useful in patients wrth a history of abuse of antianxiety drugs due to its reduced potential for abuse compared to benzodiazepine s Atropine is indicated for the tre tment of bradycardia as it decreases vagal infl uence on the SA and AV nodes. A common side effect is increased intraocular pressure It may precipitate acute closed-angle glaucoma in suscep tible individuals.
PHARMACOLOGY-Neu o 2 Lithium is almost exclusively xcreted by the kidneys. with filtrahon and esorption in the proximal tubules following sod ium reabsorption. Renal injury, toxins, and d rugs that lead to increased proximal tubular abs rption of sodium (eg. NSAIDs, thiazide diu retics, and ACE inhibitors) also increase lithium levels and elevate the nsk of lithium toxicity. Hemodialysis is the most effective way of acutel reducing the blood lithium level F References: 1 Clinical relevance of drug inte actions with lithium As opposed to the serotonin sy ndrome. the Neuroleptic Malignant Syndrome is distinguished clinically by an absence of m yoclonus and by the presence of ngidity D pamine agonists (bromocriptine) and)or direct m scle relaxants (dantrolene) have been used to d ecrease mortality rates associated with the neurole ptic malignant syndrome (NMS), but there is n o way to prevent NMS Penicdhns and cephalosponns fu nction by i rreversdly binding to p enicillin-bind ing proteins such as transpeptidases.
Lamotrigine is a newer anticonv cause skin rash Because this ras immediately at the first sign of r F References: 1. Predictors of Lamotrigine-ass 2. The new anti.pil.ptic drugs 3. Rash In adult and pediatric pa
lsant used for the treatment of refractory parti l seizures It may is life threatening in children, the drug shoul be discontinued sh ciated rash. ients treated with lamotngine
Sexual dysfunction is seen in p to 50% of patients treated with SSRIs S mptoms include decreased libido, anorgasmia, a nd increased latency to ejaculation Bupropio 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 white blood cell count (WBC) for the duration of treatment The other important side effectofofthe 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 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 anreuptake SSRI and MAO inhibitor can produce excessive secondary to decreased and decreased metabolism Excessive serotoninserotonin levels canlevels 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. Antimuscarinic agents and antihistamines with antimuscarinic action are most effective for motion sickness prevention
The onset of action of a gas ane thetic depends on its solubility in the blood (bl ood/gas partition coefficient). Drugs with high bl od/gas partition coefficients are more soluble in the blood and demonstrate slower onset of acti n and slower equilibration with the brain A majonty of opioid narcot,cs re selective mu receptor agonists that work b y binding to mu receptors and mimicking the e fects of endogenous opioid peptides Pentazo ine is an opioid narcotic specificalty designed o produce analgesic effects with little to no abuse potential Pharmacc4ogically, it works thr ough partial agonist activity and weak antagon ist activity at mu receptors. Because of its weak a tagonistic effects, it can cause withdrawal sym ptoms in patients who are dependent or tolerant to morphine oi other opioids
1. Selegiline is an inhibitor o MAO. type B and can prevent MPTP-ind ced damage of dopaminergic neurons 2 Selegiline is used clinically to elay the progression of Parkinson disease 3, Many neurologists favor t he use of combinations of selegihne, anti hohnergics. and amantadine until they no longe provde control of symptoms Only then is le odopa/carbidopa introduced Buspirone is considered a first li ne treatmentbut forthe generalized anxietyisdisorder. ependence not occur with chronic buspiron treatment, clinical response often de ’ayed for up does to 2 weeks of regular use and is not e ffective when used on an as-needed basis Cholinomimetics are ind icated i non-obstructive urinary retention, paralytic ile s, and glaucoma Their side effects include nause , vomiting, abdominal cramps, diarrhea, dysp ea and increased secretions (sweating, lacrimation and saIivation) .ILIl.ISI II V V. Commonly used drugs such as the analgesic tramadol. the antiernetic onda nsetron, and the antibiotic linezolid can induc serotonin syndrome when used concomit ntly with other serotonergic drugs. R.f.r.nc.s: 1. Risk of serotonin syndrom with concomitant administration of linezol d and serotonin agonists. 1 Antimuscannic are usua llyfor preferred in patients with medication-induce Parkinsonism 2. Levodopa is agents contraindicate drug-induced Padansonism because it d 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. 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 associatedwith withbleomycin chemotherapeutic agents include fibrosis and flagellate skin discoloration use; congestive heart pulmonary 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. 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 anaerobic bacteria In aspiration pneumonia: when should they be treated and whatimportant Is optimalare therapy. 2. Etiology and outcome of community-acquired lung abscess. 3, Aspiration pneumonia and primary lung abscess: diagnosis and therapy of an aerobic or an anaerobic infection? Antimuscannic agents (ipratropium) only reverse vagally-mediated bronchoconstriction Methyixanthines like theophylline and aminophylline cause bronchial dilatation by decreasing phosphodiesterase enzyme activity, thereby increasing intracellular cAMP. MycobacteriUm avium is a common opportunsbc pathogen that causes disseminated disease (MAC) in HIV+ patients Weekly azithromycin is used as prophylaxis in patients at risk for MAC (eg, HIV+ patients with CD4 counts less than 50 cells/mL). References: 1. Infections due to non-tub.rculous mycobactena (NTM). 2. The pathophysiology of disseminated Mycobacterium avium complex disease in AIDS.
• The aminoglycoside streptomycin inhibits protein synthesis by inactivating the 30S (small) ribosomal subunit
• Decreased activity of bactenal catalase-peroxidase is one mechanism of mycobactenal resistance to isoniazid • Structural alteration of enzymes involved in RNA synthesis (DNA-dependent RNA polymerase) is the mechanism through which organisms become resistant to ntampin Cromolyn and nedocromd are mast cell stabihzing agents They inhibit mast cell degranulation independent of stimuli present These are less effective than inhaled glucocorticoids. and are considered second-line for the treatment of allergic rtiinitis and bronchial asthma References: 1. The effects of anti-asthma drugs on mediator release from cultured human mast cells. 2. Mast-cell stabilising agents to prevent .xercis.4nduc.d bronchoconstriction. Bosentan is a competitive antagonist of endothelin receptors used for treatment of primary (idiopathic) pulmonary arterial hypertension. Isoniazid is an antimycobacterial agent that specificaWy inhibits the synthesis of mycolic acids. Mycolic acids are essential components of the unique mycobacterial peptidoglycan cell wall. Without mycolic acids, the mycobactena lose their acid-fastness and become unable to synthesize new cell walls or multiply Every patient using inhaled corticosteroids should be instructed about oral rinsing to prevent oropharyngeal candidiasis. References: 1. Salivary IgA and oral candidlasis In asthmatic patients treated with Inhaled corticosterold. 2. Influence of mouth washing procedures on the removal of drug residues following inhalation of corticosteroids. 3. Oesophageal candidiasis in elderly patients: risk factors, prevention and management. Rifampin is the preferred prophylaxis for persons who have been definthvely exposed to IV mening#ichs Rifampin can eliminate the camer state as well as prevent active infection in those who have been exposed to N ,nen,ngitidis Rifampan as also used as a component of multi-agent therapy for both typical and atypical mycobactenal pulmonary infections, leprosy, and staphylococcal endocardatis When used alone, bacteria rapidly acquire resistance to nfamp*n through spontaneous genetic mutations of the bacterial DNA-dependent RNA potymerase The main groups of antifungal drugs are the polyenes, azoles, echinocandins and pyrimidines The polyene antifungals (amphotencin B and nystatin) act by binding ergosterol in the fungal cell membrane Azoles inhibit the synthesis of ergosterol by the fungal cytochrome P450 enzymes They also suppress the human P450 system, resulting in many drug-drug interactions Cortácosteroids have the strongest and most predictable effects on the inflammatory component of asthma References: 1. Evidence-based selection of inhaled corticosteroid for treatment of chronic asthma.
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 (metoprolol, atenolol. acebutolol, and esmolol) are preferred in patients with COPD f3-blockers and/or asthma Seizures are the major cause of morbidity and mortality from theophylline intoxication Tachyarrhythmias are the other major concern. Seizures are the major cause of morbidity and mortality from theophylline intoxication Tachyarrhythmias are the other major concern References: 1 Role of extracorporeal drug removal in acute iheophylline poisoning. A review. 2. First-line therapy for theophylline-associated seizures. Ethambutol is an antimycobactenal agent that inhibits carbohydrate polymeñzation, thereby preventing peptidoglycan cell wall synthesis One unique adverse effect of ethambutol is optic neuritis, which typically presents in conjunction with decreased visual acuity, central scotoma and color blindness Active tuberculosis is never treated with drug monotherapy due to the fast emergence of mycobacterial antibiotic resistance from rapid. selective gene mutations. Isoniazid monotherapy may be used for patients who have a positive PPD and a negative chest x-ray (ie, no evidence of clinical disease) R.f.r.nc.s: 1. The catalas.-p.roxldas. gene and isoniazid r.sistanc. of Mycobact.num tub.rculosis. 2. Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Arnphotencln t3 binds tfle ergosterol ot tungal cell memoranes to exert its antitungal ettects However, it also binds cholesterol to some degree, causing toxicity to human tissues, The most important adverse effects of amphotencin B are nephrotoxicity, hypokalemia. and hypomagnesemia Of the first-line agents for MycabacteriUm tuberculosis, only pyrazinamide requires an acidic environment (as is present within macrophage phagotysosomes) to exert antimicrobial effects Isoniazid, fliampin, and ethambutol are more active than PZA against extraceflular mycobacteria
PHARMACOLOGY-Renal Spironolactone is an aldosterone antagonist commonly used in treating class Ill and IV heart failure patients. Since it is structurally similar to steroids. spironolactone can cause endocrine effects including gynecomastia, decreased libido, and impotence. Gynecomastia occurs in approximately 10 % of patients. Eplerenone is a newer and more selective aldosterone antagonist that may produce less endocrine effects. Mannitol is an osmotk diuretic that works by increasing plasma or tubular fluid osmolality Increased plasma and fluid osmolality causes extraction of water from the interstitial space into the vascular space or tubular lumen, with subsequent diuresis. h, the brain, water redistribution from the tissues into the plasma helps reduce edema and intracranial pressure in the setting of cerebral edema. One of the more severe toxicibes of aggressive osmotic diuretics is pulmonary edema R.f.r.nc.s: 1 Mannitol revisited Digoxin is a cardiac glycoside that is predominantly cleared by the kidneys. Elderly patients typically exhibit age-related renal insufficiency, even in the presence of normal creatinine levels. The dose of digoxin must be reduced in these patients in order to prevent toxicity. Calcineuhn is an essential protein in the activation of IL-2, which promotes the growth and differentiation of T ceIls Immunosuppressants such as cyclosporine and tacrohmus wOrk by inhibiting calcineurin activation Amphotericin B is a polyene antifungal notorious for its renal toxicity Severe hypokalemia and hypomagnesemia are commonly seen during therapy, and often require daily supplementation. Acyclovir can cause crystalline nephropathy if adequate hydration is not also provided. Thiazide diuretics work by blocking Na”-Ci’ symporters in the distal convoluted tubules, causing enhanced Na, Cl, and water excretion. Since only a small amount of filtered Na” reaches the distal tubules, thiazides are not as efficacious as loop diuretics. Unlike loop diuretics, thiazides can cause hypercalcemia Common side-effects of ACE-inhibftors include decreased glomerular filtration rate (GFR), hyperkalemia. and cough Angioedema is a rare, but hie-threatening. side-effect. Thiazide diuretics are the only diuretics that increase calcium reabsorption from the nephron. They are indicated in patients with nephrolithiasis secondary to hypercalciuria and contraindicated in hypercalcemia. Carbonic found infor high concentrations in theAcetazolamide proximal tubuleisand is responsible for catalyzinganhydrase reactions is necessary NaHCO3 reabsorption 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.
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 blockers is accumulation substance P. or prostaglandins. Because angiotensin receptor (ARB5) of do bradykinin. not affect ACE activity, they theoretically should not cause cough Niacin and fibrates are the most effective agents for the treatment of hypertnglyceridemia This is a very common clinical issue given the prevalence of diabetes in the US population. and the ACE-I class of drugs together with the ARB class of drugs have been shown to decrease the progression of diabetic nephropathy. First-dose hypotension is an adverse effect and concern when initiating ACE inhibitors Predisposing risk factors for first-dose hypotension include hyponatremia, hypovolemia secondary to diuretics, low baseline blood pressure, high renin or aldosterone levels, renal impairment, and heart failure To minimize the risk for first-dose hypotension, identify patients at nsk, initiate therapy at low dosages, and follow with cautious dosage titration and blood pressure monitoring Myopathy is a well-known side effect of some hypolipidemic drugs (especially statins) Simvastatin decreases and cholestyramine increases hepabc cholesterol production
independently Combination ther apy results in a net decrease m hepatic choleste rol synthesis and plasma LDL level Agents that increase epatic cholesterol synthesis (eg., fibrates and b le acid—binding agents) are associated with an in reased risk of gallstones. References: 1 0. ?rvIe of pharma: olocjic the ap r L irnen r Simvastatin decreases and chole tyramine increases hepabc cholesterol producti on independently Combination ther apy results in a net decrease m hepatic choleste rol synthesis and plasma LDL level Agents thatwith increase synthesis (eg., fibrates and b le acid—binding agents) are associated an in epatic reasedcholesterol risk of gallstones. References: 1 0. ?rvIe of pharma: olocjic the ap r L irnen r Fatty oxidation inhibitors are n ewer agents that inhibit fatty acid oxidation and shift energy production to glucose oxidation, thus promoting oxygen efficiency. This not o ly decreases the amount of oxygen needed to s pport cardiac function, but also decreases pot entially toxic fty acid metabobte production. Charactehstcs of a drug such s high molecular weight. high plasma prote in binding, high charge. and hydr ophihcity tend t o trap the drug in the plasma compatment resu ting in a low Vd (3-5 L). al -adrenergic agonists increase both systolic and diastolic blood pressure via s timulation of ala drenoreceptors in the vascular w alls Elevated systemic blood pressure is associ ted with a reflex increase in vagal influence on t he heart This results in decreased heart rate, ontractility, and conductance References: 1 Sympathetic neural mechanis s in human cardiovascular health and disease. 2. N.ural control of the circulatio n.
Low doses of dopamine stimula te Di receptors in the renal and mesentenc vas ulature resulting in vasodilation and increased lood flow to these sites. Higher doses of d pamine increase cardiac contractility by stimulati on of beta-i adrenergic receptors, and still high er doses produce generalized vasoconstriction by n 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. 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 resinsacid are derivatives unique among hypohpidemic agents for m hypertriglycendemia that they rncrease blood triglyceride levels Fibnc are the first-line treatment References: 1. Hypertriglyceridemia: a contraindication to the use of bile acid binding resins. 2. An overview of lipid-lowering drugs. Most statins are metabolized by cytochrome P-450 3A4, with the exception of pravastatin Concomitant administration of drugs that inhibit statin metabobsin (e.g. macrohdes) is associated with increased incidence of statin-induced myopathy and rhabdomyolysis Acute renal failure is a possible sequela of rhabdomyolysis R•f•r• nc.s: 1. Risk management of simvastatin or atorvastatin interactions with CYP3A4 inhibitors. ACE inhibitors block the effect of ACE. decreasing angiotensin II and aldosterone levels. By decreasing angiotensin II levels. ACE inhibitors directly interrupt negative feedback loops, thus increasing renin and angiotensin I levels. Without effective ACE, bradykinin metabolism decreases and bradykinin levels will inCrease.
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 isthe number of antagonist, receptors availab’e binding Because phenoxybenzamine an irreversible even very for highnorepinephrine concentrations of norepinephnne cannot overcome its inhibitory effects. 1 Alpha 1 -blockers such as Doxazosin. Prazosin and Terazosin are useful for the treatment of both benign prostatic hyperplasia and hypertension 2. Patients with coronary artery disease and heart failure along with hypertension will benefit from cardioselective beta-blockers 3. Hydrochlorothiazide is presently the first-line medication for the treatment of essential hypertension in the general population. Niacin can potentiate the effects of some anti-hypertensive medications because of its vasodilatory effects. Dose adjustment may be required Niacin also causes insulin resistance and oftentimes necessitates an increase in diabetes medications References: 1. Treatment of diabetic dyslipidemia. 2. Does nicotinic acid (niacin) lower blood pressure? Streptokinase is a thrombolytic agent that acts by converting plasminogen into plasmin, which subsequently degrades fibrin Its most common side effect is hernorrhage Streptokinase is a foreign protein derived from Streptococci and can induce hypersensitivity reactions. Fenoldopam is a newer parenteral agent that is classified as a selective dopamine-1 receptor agonist. It causes artenolar dilation and natnuresis leading to decreased systemic vascular resistance and blood pressure reduction. Since fenoldopam is the only intravenous agent that improves renal perfusion, it may be exceptionally beneficial in hypertensive patients with concomitant renal insufficiency. Norepinephrine stimulates cardiac 31 adrenoreceptors. which utilize the cAMP signal transduction pathway. Stimulation of these receptors by norepinephrine causes increases in cAMP concentration within cardiac myocytes. References: 1. Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension.
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 to thiocyanate by liver rhodanase Thus, one majoris disadvantage its use involves theconversion risk for developing cyanide toxicity Sodium thiosulfate used to treatofcyanide toxicity and works by donating sulfur to hver rhodanase to enhance conversion of cyanide to thiocyanate 1. Patients with familial hypoalphalipoproteinemia (low HDL) are at increased risk of developing premature coronary artery disease Niacin (vitamin B3) is the best agent currently available to increase HDL cholesterol levels 2. Statins and ezetimibe are mainly used for hypercholesterolemia (high LDL). High LDL is a risk factor for atherogenesis 3, Fibnc acid derivatives are mainly used for hyperinglycendemia Remember that severe hypertnglyceridernia can cause pancreatitis Ref erences: 1, High- density lipoprotein therapy: is there hop.’ 1. The cutaneous flushing associated with ruacin is mediated by prostaglandins and can be prevented with aspirin pre-treatment 2. Capsaicin reduces pain by decreasing the level of substance P in the penpheral nervous system References: 1. Niacin use and cutaneous flushing: mechanisms and strategies for prevention.
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.
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 tachycardia is a common dysrhythmia that frequently in patients withsupraventncular no other heart disease The cause is typically a re-entrant circuit in the occurs AV node Episodes are usually treated with adenosine in the hospital setting. but vagal maneuvers such as carotid sinus massage and Valsalva can also be used Only 10% of total perfusion through the myocardial capillaries of the LV occurs during systole, while the majority of left ventricular blood flow occurs during diastole. The systolic reduction in coronary blood flow is greatest in the subendocardial myocardium of the LV. Metabolic acidosis is characterized primarily by a decrease in serum bicarbonate and a decrease in pH. The PaCO. will also decrease as a resuft of respiratory compensation for the primary metabolic acidosis The treatment of choice for diabetic ketoacidosis is intravenous hydration with normal saline and insulin. These therapies will result in decreases in the serum glucose, osmolality, and potassium, as well as increases in serum bicarbonate and sodium Most of the blood supply to the heart occurs during diastole and the duration or length of diastole is a critical factor in determining coronary blood flow.
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 in sinus walls, leading to vasodilatation. a decrease in heart rate and contractility, and a decrease 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 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 s harp decrease in cardiac output due to loss of f nction of a zone of myocardium On a cardiac fun ction curve. myocardial infarction would decre se both the slope and the maximal height of the li e.
Pregnant women > 20 weeks g station can experience compression of the inf rior cava by the gravid uterus while in the supin position This reduces venous return and cardi ac output. which can result in hypotension and sy cope. Verapamil is a calcium channel locker that slows depolarization of cardiac slo -response tissue (sinoatrial and atrioventncularodes) by decreasing the calcium ion influx t at occurs during phase 0 and the latter part of hase 4. Verapamil also decreases the amoun t of intracellular calcium available within cardio myocytes (fast-response tissue), which can reduce myocardial contractihty The pulmonary capillary wedge pressure (PCWP) measures the left atrial end iastolic pressure (LAEDP). Under normal conditi ons, the LAEDP is nearly equal to the LV end- iastolic pressure (LVEDP). Mitral stenosis elevat s the LAEDP and PCWP relative to the LVED Carrier-mediated transport incl udes facihtated diffusion and active transpo it Movement of substrate across the cell memb ane by these mechanisms depends on the pr sence of carrier proteins in the membrane. Trans ort mechanisms utilizing proteins are able to b saturated In patients with heart failure. compensatory activation of the renin-angiot nsin-akiosterone pathway and sympathetic ner ous system results in increased afterload (from excessive vasoconstnction), excess fluid re tention, and deleterious cardiac remodeling. Atnal fibrillation occurs due to irregular. chaotic electrical activity within the tria While some of the atrial impulses are tran mitted to the ventricles, most are not due t o the AV nodal refractory period. The Fick principle can be used o calculate the cardiac output It states that the cardiac output is equal to the oxygen consumptio by the tissues divided by the arteriovenous ox gen difference Any significant acute change in heart rate or rhythm or the force of ventricular contraction may cause palpitations. An irregularl y irregular tachyarrhythmia in a c onscious pati nt is most likely atrial fibrillation, the most com on chronic arrhythmia In AF. the EKG show s absent p waves and irregularly spaced ventricula r contractions evidenced by a variable R-R inte val The cardiac myocyte action po tential consists of rapid depolarization (phase 0), initial rapid repolarization (phase 1), plateau (phase 2), lat rapid repolarization (phase 3), and resting po tential (phase 4). The action potential is associated with inc reased membrane permeability to Na and Ca 4 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 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 be precipitated diabetic patient after vigorous exercise due the to increased glucose uptake can by muscles as well in asarapid subcutaneous insulin absorption when injection occurs in a limb that is subsequently exercised Mu receptors are G protein-hnked receptors whose actions are mediated through various secondary messenger pathways. One identified pathways involves increased potassium efflux. Binding of morphine to mu receptors results in G protein-coupled activation of potassium conductance. Potassium efflux increases and causes hyperpolarization of postsynaptic neurons effectively blocking pain transmission. Volume contraction and volume expansion can be dMded into isoosmotic, hypoosmotic and hyperosmotic forms. The loss of free water with retention of electrolytes is seen in diabetes insipidus and in excessive sweating without fluid and solute replacement. These conditions cause hyperosmotic volume contraction. Insulin opposes glucagon action. Glucagon stimulates glycogenolysis, gluconeogenesis, lipolysis and body production whileand insulin increases glucose. amino acid and potassium uptake by cells,ketone inhibits ketoacid formation 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 and unique neurophysins of production the cellofbodies of the paraventricular supraoptic nuclei tofrom theirtheir site ofsite release in the axoninterminals the posterior pituitary Point mutations in neurophysin II underlie most cases of hereditary hypothalamic diabetes insipidus. a disorder resulting from insufficient ADH C peptide can be used as a marker of the total rate of endogerious 13—cell insulin secretion under steady-state conditions. Sulfonylureas increase the rate of insulin secretion and C peptide levels in patients with type 2 diabetes. The length constant is a measure of how far along an axon an electrical impulse can propagate. A low-length constant reduces the distance an impulse can travel. Myelination increases the ‘ength constant and decreases the time constant, both of which improve axonal conduction speed. Demyelination thus impairs stimulus transmission. Inhibin B is produced by the Sertoli cells and is the physiological inhibitor of FSH secretion LH concentration is controlled primarily by testosterone feedback Patients undergoing total gastrectomy require lifelong vaamin B, supplementation due to the poor B12 absorption that occurs with intrinsic factor deficiency Elevated systemic T3 and T4 (via intracellular conversion to T3) cause negative feedback on the hypothalamus and anterior pituitary leading to decreased TSH production and release T4 can be converted in the peripheral tissues to the more active T3 or to the inactive rT3. T3 cannot be converted to rT3 or to T4 Exogenous T3 administration causes decreased TSH levels, which act upon the thyroid gland to reduce endogenous T4 production (and thus reduce peripheral conversion to rT3) Energy is supplied by the metabolism of protein. fat and carbohydrates Metabolism of 1 g of protein or carbohydrate produces 4 cal of energy. while metabolism of 1 g of fat produces 9 cal. Neurophysins are proteins involved in the posttranslational processing of oxytocin and vasopressin These hormones and their respective neurophysins are produced within the neuronal cell bodies of the paraventricular and supraoptic nuclei and they are released into the circulation from axon terminals in the posterior pituitary gland
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 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 acidsand are absorption necessary for lipidpatients absorption typically has little effect on lipid digestion though mayCholecystectomy 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 inhibitors cause adverse effects to muscarinic overstimulation, whichCholinesterase can be ameliorated by usemay of an antimuscarinic agentrelated like scopolamine During skeletal muscle contraction, calcium is released from the sarcoplasmic reticulum arid binds troponin C thereby allowing the binding of actin to myosin During the skeletal muscle contraction cycle. ATP binding to myosin causes release of the myosin head from its binding site on the actin filament. The H band is the region of the sarcomere containing only myosin thick filaments It is the part of the A band on either side of the M line where myosin thick filaments do not have any overlapping actin thin filaments. Once specific channels are open. ions will flow across the membrane to bring the resting membrane potential toward their equilibrium potential. T-tubules are invaginations of sarcoplasmic the sarcolemma that extend eachthe muscle fiber transmit depolarization signals to the reticulum and into trigger release ofThey 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 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 space. is thevolume. product of the respiratory rate and the difference between the tidal volumedead and the deadItspace 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 resting state pressure equals zero At the FRC, the intrapleural pressurethe is negative with awhere value the of -5airway 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 with systemic hypertension Prolonged, untreated obstructive sleep apnea can also associated 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 srcinating from the bronchial arteries mixes with oxygenated blood in the pulmonary veins Stimulation of the vagus nerve branches that supply the lung would cause bronchoconstriction and increased bronchial mucus secretion. These effects increase airway resistance and the work of breathing. Anticholinergic agents such as tiotropium and ipratropium work to counteract these effects. Pulmonary vascular resistance (PVR) is lowest at the functional residual capacity Inhalation increases PVR due to the pressure placed on pulmonary vessels by the expanding alveoli Forced exhalation increases PVR due to the collapsing positive pressure placed on the lung parenchyma Total body iron content is regulated through hepeidin’s effects on the absorption of dietary iron by intestinal epithelial cells and the release of iron by macrophages Hospitalized and postoperative patients are at risk for pulmonary embolism, which presents with tachypnea, tachycardia, cough and pleuritic chest pain Hypoxemia in patients with pulmonary embolism develops due to ventilation-perfusion mismatch Erythrocytosis is defined as a hematocrit level > 52% in men and > 48% in women Measurement of red blood cell mass is necessary to distinguish absolute from relative erythrocytosis. A normal red blood cell mass indicates plasma volume contraction as the cause of polycythemia
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 difference betweenThe thearterial alveolarPC2 andis arterial P02with (A-aangradient) can help determine thethe cause of hypoxemia measured 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 high HCO; (> 30). respiratory acidosis is characterized by a low normal pH, a high pCO and a 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 citrate (atheir substance storedparesthesias blood) Citrate chelates calcium and magnesium andof may reduce plasma added levels, to causing 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. Normal renal handling of plasma glucose is characterized by complete reabsorption of low filtered at low plasma concentrations. Increasing fractional excretion of glucose is observedloads 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 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 a intercalated component cells of the renin-angiotensin-aldosterone system that acts on the principal cellsisand 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 comm on cause of secondary hyperparathyroidism. T ypical laboratory abnormalities include high PTH, low calcium, high phosphate. and low calcitrio . Educational Objective: The con entrations of PAH. creatinine. inulin, and urea increase as fluid wns along the proximal tubule, hile the concentrations of bicarbonate, glucose, and amino acids decrease Paraaminohippuric acid (PAH) s freely tittered from the blood in the glomer lar capillaries to the tubular fluid in Bowman’s s pace. It is also secreted from the blood into th tubular fluid by the cells of the proximal tubule y a carrier protein-mediated process. The secre tion of PAl-I can be saturated at high blood conce
trations
Dehydration leads to a decr eas in renal plasma flow (RPF) and a decrease i n the glornewlar filtration rate (GFR). Compensa tory activation of the renin-angiotensin mecha nism in response to hypotension leads to constric ion of the efferent (outgoing) arteriole to main tain GFR as best as possible The filtration fractio n, which is equal to the GFR divided by the PF, increases in hypovolemia as the RPF drops proportionately more than the GFR due to th aforementioned compensatory mechanism Selective vasoconstnction of th efferent arteriole (up to certain extent) incr ases hydrostatic pressure in the glomerular capil laries, and therefore increases the glomerular filtration rate As efferent arteriolar constriction ontinues to increase, the glomerular filtratio n rate begins to decrease due to a flow-mediat d rise in oncotic pressure in the glomerula capillaries The filtration fraction always increas s with increasing efferent arteriole constriction. Furosemide is a loop diuretic tha t works by inhibiting Na-K-2C1 symporters in he loop of Henle effectivelyprostaglandin causing increased a. stimulating Cl, and fluid excretion Additionally, p diuretics also stimulate release By renal prostaglandin release, lolo op diuretics also increase renal blood flow leadin to increased GFR and enhanced drug delivery Thus concurrent use of NSAIDs with loop diureti s can result in a decreased diuretic response.
The filtration fraction (FF) can e calculated if the glomerular filtration rate ( flow (RBF), and hematocrit (Hct ) are known: FF = GFR)j(1 - HctXRBF)]. Dehydration stimulates ADH permeability to water Thus, in concentrated fluid in the nephro convoluted tubule contain the m
FR), renal blood
ecretion ADH acts on the collecting ducts, increasing their the presence of ADH, the collecting ducts ontain the most , while the thick ascending limb of the loop o Henle and distal st dilute fluid.
Increases in the capillary hydr static pressure or the Bowman’s space onco tic pressure will increase GFR, while increases in capillary oncotic pressure or Bowman’s s pace hydrostatic pressure will decrease GFR The filtration fraction (FF) can be calculated by dM ding the GFR by the renal plasma flow (RPF). Inc reases in GFR or decreases in RPF will increas 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. 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 the and onset of menses). Progesterone released by the corpus luteum causes the utenne glandsand to coil 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
