Robbins & Cotran Review of Pathology Pg. 626 31. Final Review and Assessment

1 (D) The C282Y mutation in the HFE gene can be found in one of nine individuals of Celtic heritage and causes increased absorption of dietary iron. In men about 40 years old, the increased iron stores lead to organ dysfunction, typically involving the heart (cardiomyopathy with congestive heart failure), pancreas (diabetes mellitus), skin (increased pigmentation), and joints (arthritis). In women, increased iron loss through menses delays the onset of this disease for 20 more years. A patient with β-thalassemia would have anemia, although the ineffective erythropoiesis leads to excessive iron absorption. Although this patient has diabetes mellitus and an increased glucose level, diabetes mellitus type 1 does not explain all the findings, such as the arthritis. Familial hypercholesterolemia could lead to coronary artery disease and heart failure, but it does not explain the patient's diabetes or arthritis. Rheumatoid arthritis typically leads to joint deformities and mostly involves small joints.

1 A 47-year-old white man has had increasing orthopnea and worsening pedal edema for the past 3 years. He complains of worsening arthritis involving his hands, knees, hips, and elbows. On physical examination, he has decreased range of motion of the lower legs, but no apparent joint deformities, warmth, or swelling. There is a brownish hue to his skin although it is winter, and he rarely goes outdoors. Laboratory findings show hemoglobin, 13.7 g/dL; hematocrit, 40.8%; MCV, 90 μm3; platelet count, 213,500/mm3; WBC count, 6690/mm3; Na+, 141 mmol/L; K+, 4.2 mmol/L; Cl−, 101 mmol/L; CO2, 24 mmol/L; glucose, 201 mg/dL; creatinine, 1.2 mg/dL; and calcium, 8.2 mg/dL. Which of the following underlying diseases most likely explains these findings? □ (A) β-Thalassemia minor □ (B) Diabetes mellitus type 1 □ (C) Familial hypercholesterolemia □ (D) Hereditary hemochromatosis □ (E) Rheumatoid arthritis

10 (D) The patient has pernicious anemia owing to atrophic gastritis, with lack of intrinsic factor to bind dietary vitamin B12 for absorption. This condition has led to megaloblastic anemia and subacute combined spinal cord degeneration of dorsal and lateral tracts. The anti-Smith antibody is a feature of systemic lupus erythematosus, which has many manifestations, but not typically gastritis or spinal cord degeneration. Factor V (Leiden) deficiency is a risk factor for recurrent thrombosis. Helicobacter pylori infection leads to gastritis (not typically atrophic), but not to neurologic problems. An elevated urine glucose level suggests diabetes mellitus, which may lead to peripheral neuropathy, but not to gastritis.

10 A 54-year-old man has had nausea for the past 6 months, but he does not report hematemesis. He has increasing malaise. On physical examination, he has decreased sensation to pinprick and light touch over the lower extremities bilaterally. He exhibits mild ataxia when walking. An upper gastrointestinal endoscopy study shows the absence of gastric rugal folds, but no ulceration or mass. Which of the following laboratory findings is most likely to be reported? □ (A) Positive anti-Smith antibody □ (B) Deficiency of factor V □ (C) Positive Helicobacter pylori antibody □ (D) MCV 125 μm3 □ (E) Urine glucose 4+

1 1 (E) This patient with acute myocardial infarction, cerebrovascular disease, and peripheral vascular disease has features suggestive of heterozygous familial hypercholesterolemia, in which a mutation in the gene encoding for the LDL receptor is present. Such individuals have early, accelerated atherosclerosis. The "statin" drugs are HMG CoA reductase inhibitors that suppress endogenous cholesterol synthesis and increase LDL receptor synthesis. The patient does not have findings consistent with diabetes mellitus, another disease that promotes atherosclerosis, because his hemoglobin A1c level is normal, indicating that hyperglycemia has not been present. In type 1 diabetes mellitus, there is reduced β cell mass; in type 2 diabetes mellitus, there can be a reduction in glucose transport proteins. Although glucose metabolism and lipoprotein metabolism are important liver functions, liver disease does not tend to produce atherosclerosis, and the liver can regenerate hepatocytes. Proliferation of intimal smooth muscle cells is part of the formation of arterial atheromas.

11 A 33-year-old man has experienced onset of chest pain, diaphoresis, and dyspnea over the past 6 hours. In the emergency department, he has a serum troponin I level of 6 ng/mL. Additional laboratory findings include hematocrit of 41%, hemoglobin A1c of 4.2%, total serum cholesterol of 482 mg/dL, and serum triglyceride of 160 mg/dL. Emergent coronary angiography shows 65% stenosis of the left circumflex artery and 70% stenosis of the left anterior descending artery. Angioplasty is performed. He experiences a series of transient ischemic attacks 1 year later. He also has pain in the lower extremities when walking more than 300 m. He is given a drug that inhibits hepatic HMG CoA reductase. The pathogenesis of his underlying disease is most likely related to a reduction in which of the following? □ (A) β cells □ (B) Glucose transport proteins □ (C) Hepatocytes □ (D) Intimal smooth muscle cells □ (E) LDL receptors

12 (B) These findings are characteristic of lead poisoning, which is mainly manifested by neurologic disorders, particularly in children. Lead absorption is enhanced by zinc deficiency; zinc is a trace metal. Lead inhibits heme incorporation into hemoglobin, leading to increased amounts of zinc protoporphyrin with anemia. Fluoride is added in small quantities to drinking water to reduce the prevalence of dental caries, and increased amounts produce fluorosis, which discolors the teeth. Methanol poisoning is acute and can lead to acidosis, respiratory depression, CNS depression, and blindness. Monosodium glutamate (MSG) is an additive in many foods; in some individuals, it causes an acute reaction characterized by nausea, dizziness, and flushing. Vitamin A toxicity leads to CNS findings resembling a brain tumor.

12 Several children 6 to 10 years old in the same community have been reported by the local physician to have similar symptoms. They all are doing poorly in school, which has been attributed to behavioral problems. Their parents state that these children have poor appetites, complain of nausea, and have frequent headaches. On physical examination, they have decreased sensation to touch over the lower extremities. They exhibit loss of fine motor control of movement and have a slightly ataxic gait. A representative CBC shows hemoglobin of 11.8 g/dL, hematocrit of 35.2%, MCV of 82 μm3, platelet count of 282,300/mm3, and WBC count of 4745/mm3. Examination of the peripheral blood smear shows basophilic stippling of the RBCs. Serum chemistries show Na+, 144 mmol/L; K+, 4.4 mmol/L; Cl−, 105 mmol/L; CO2, 26 mmol/L; glucose, 69 mmol/L; creatinine, 1.4 mg/dL; calcium, 7.7 mg/dL; total protein, 6.6 g/dL; albumin, 4.3 g/dL; AST, 43 U/L; ALT, 28 U/L; alkaline phosphatase, 189 U/L; and total bilirubin, 1.1 mg/dL. Excessive chronic ingestion of which of the following substances is most likely to explain these findings? □ (A) Fluoride □ (B) Lead □ (C) Methanol □ (D) Monosodium glutamate □ (E) Vitamin A □ (F) Zinc

13 (E) This patient has Wegener granulomatosis, a multisystem vasculitis that most often involves the lungs and kidneys. C-ANCA is positive in 95% of patients with Wegener granulomatosis. Anti-DNA topoisomerase I antibody can be seen in diffuse scleroderma, which produces pulmonary interstitial fibrosis and renal hyperplastic arteriolosclerosis. Anti- glomerular basement membrane antibody is seen in Goodpasture syndrome, which produces crescentic glomerulonephritis and pulmonary hemorrhage, but not necrotizing vasculitis. Anti-Jo-1 antibody accompanies polymyositis/dermatomyositis. Antimitochondrial antibody accompanies primary biliary cirrhosis. ANA is positive in many autoimmune diseases, principally systemic lupus erythematosus (SLE), which can produce a vasculitis, but not a necrotizing granulomatous vasculitis. Anti-RNP antibody is positive in cases of mixed connective tissue disease, which overlaps SLE, scleroderma, rheumatoid arthritis, and polymyositis, but it usually does not entail significant renal or pulmonary involvement.

13 A 45-year-old, previously healthy woman has had a chronic nonproductive cough for the past 2 months. During the past 3 weeks, she has had increasing dyspnea and arthralgias. One week ago, her cough was productive of blood-streaked sputum. She does not smoke. Physical examination shows temperature of 37.5°C, pulse of 77/min, respirations of 17/min, and blood pressure of 140/90 mm Hg. On auscultation, bilateral crackles are audible in the lungs. A chest radiograph shows bilateral nodular and cavitary infiltrates, but there are no masses. Laboratory findings show hemoglobin, 11.7 g/dL; hematocrit, 35.2%; platelet count, 217,000/mm3; WBC count, 6330/mm3; serum glucose, 72 mg/dL; creatinine, 2.6 mg/dL; and urea nitrogen, 25 mg/dL. Urinalysis shows specific gravity of 1.017, pH 6.5, 1+ proteinuria, 2+ hematuria, and no glucose or ketones. A transbronchial biopsy specimen shows necrotizing granulomatous vasculitis of the alveolar capillaries and small peripheral pulmonary arteries. A renal biopsy specimen shows a crescentic glomerulonephritis. Which of the following serologic test results is most likely to be positive? □ (A) Anti-DNA topoisomerase I □ (B) Anti-glomerular basement membrane antibody □ (C) Anti-Jo-1 antibody □ (D) Antimitochondrial antibody □ (E) C-ANCA □ (F) ANA □ (G) Antiribonucleoprotein antibody

14 (A) She has reactive systemic amyloidosis from her underlying granulomatous ileitis, and serum amyloid associated protein is generated by chronic inflammation. Amyloid precursor protein forms the fibril protein in the senile plaques of Alzheimer disease. Atrial natriuretic peptide can be seen with isolated atrial amyloidosis. β-Microglobulin is found with hemodialysis-associated amyloidosis. Calcitonin is a precursor to local amyloid deposition in medullary thyroid carcinomas. Excessive light chains predispose to amyloid deposition with multiple myeloma. Transthyretin can be associated with systemic senile amyloidosis.

14 A 50-year-old woman has a 20-year history of Crohn disease. Over the past 14 months, she has had increasing fatigue with worsening peripheral edema. On physical examination, she has pitting edema to her knees. Laboratory studies show hemoglobin, 13.2 g/dL; hematocrit, 40.1%; platelet count, 203,000/mm3; and WBC count, 7470/mm3. Serum urea nitrogen is 35 mg/dL, and creatinine is 3.8 mg/dL. Urinalysis shows proteinuria without hematuria, glucosuria, or ketonuria. A renal biopsy specimen shows deposits of amorphous pink material in glomeruli, arterioles, and peritubular interstitium. By electron microscopy, these pink deposits are composed of nonbranching 7.5- to 10-nm fibrils. Which of the following proteins is most likely to form these fibrils? □ (A) Amyloid-associated □ (B) Amyloid precursor protein □ (C) Atrial natriuretic peptide □ (D) β2-microglobulin □ (E) Calcitonin □ (F) Lambda light chain □ (G) Transthyretin

15 (C) The reddish purple nodular lesion is typical of Kaposi sarcoma in a patient with wasting syndrome, oral thrush, and lymphopenia characteristic of HIV infection with AIDS. Hepatitis C virus is unlikely to produce skin lesions or lymphopenia of this degree. Herpes simplex virus infections may be seen more frequently in HIV infection, but the lesions are typically vesicular and are located in the perioral or perianal regions. Hansen disease, caused by Mycobacterium leprae infection, may produce a faint reddish rash that fades, followed by hypopigmentation or anesthesia of affected skin and sometimes nodular deforming lesions developing over years. Malaria owing to Plasmodium vivax can produce anemia with a pale appearance to the skin. Staphylococcal skin infections tend to produce localized abscesses, such as furuncles and boils. Streptococcal skin infections may manifest as abscesses or as cellulitis.

15 A 40-year-old man has been bothered by oral candidiasis for the past year. On physical examination, he has muscle wasting. His weight is 70% of normal for his height and age. He has generalized nontender lymphadenopathy, but no hepatosplenomegaly. The figure shows a skin lesion on his forearm. Laboratory findings show hemoglobin, 12.2 g/dL; hematocrit, 36.5%; MCV, 85 μm3; platelet count, 188,000/mm3; and WBC count, 3460/mm3 with 78% segmented neutrophils, 4% bands, 10% lymphocytes, 6% monocytes, and 2% eosinophils. Infection with what organism is most likely to produce these findings? □ (A) Hepatitis C virus □ (B) Herpes simplex virus □ (C) HIV □ (D) Mycobacterium leprae □ (E) Plasmodium vivax □ (F) Staphylococcus aureus □ (G) Streptococcus pyogenes

16 (C) This patient has Lyme arthritis, meningitis, and carditis, and a past history of erythema chronicum migrans. The arthritis may appear weeks to a couple of years after a bite from the vector, the deer tick (Ixodes), and can be migratory and involve the large joints. Streptococci may cause an acute arthritis, although a polyarthritis with rheumatic fever owing to group A streptococcal infection can occur along with carditis. Staphylococcus aureus causes an acute suppurative arthritis. Tuberculosis tends to produce a chronic arthritis associated with osteomyelitis of the large joints, leading to ankylosis and deformity. Viral arthritis can be acute to subacute, but generally is mild. Yersinia enterocolitica can cause an enteropathic arthritis with an abrupt onset, but a year-long course in HLA-B27-positive individuals.

16 A 30-year-old man visits the physician because he has had joint pain in the right hip and left elbow and a headache for the past week. One month ago, he had similar pain in the left hip and knee, which slowly resolved. He remembers having a ringlike skin rash on his left thigh several months ago after a tick bite. On physical examination, there is joint tenderness, but no swelling or deformity of the right hip and left elbow. His heart rate is slightly irregular. What infectious agent is most likely to produce these findings? □ (A) Streptococcus pyogenes □ (B) Staphylococcus aureus □ (C) Borrelia burgdorferi □ (D) Mycobacterium tuberculosis □ (E) Parvovirus B19 □ (F) Yersinia enterocolitica

17 (E) The child has features of protein-energy malnutrition characteristic of kwashiorkor; the decreased protein intake translates to diminished albumin synthesis by the liver. The decreased plasma oncotic pressure from hypoalbuminemia leads to peripheral edema and ascites. The hair and skin changes and the muscle wasting also reflect decreased protein synthesis. An increased plasma homocysteine level is a risk factor for accelerated atherosclerosis, which could lead to heart disease and congestive failure, but this takes decades to occur and does not explain the skin and hair findings. Hyperuricemia is seen in gout, which mainly leads to arthritis. Hypercalcemia can lead to ulcer disease, pancreatitis, stone formation, cardiac arrhythmias, and mental status changes. In the absence of signs of bleeding, including skin ecchymoses, a decreased prothrombin time is unlikely. An absolute decrease in insulin indicates type 1 diabetes mellitus, which also could lead to eventual heart disease and congestive heart failure decades later.

17 A 9-year-old girl has become increasingly listless over the past year. On physical examination, she has pitting edema to the thighs, muscle wasting, a protuberant abdomen with a fluid wave, areas of scaling skin with decreased pigmentation, and patches of hair that are irregularly pigmented. No ecchymoses are noted. She is 75% of ideal body weight, but her height is normal. Which of the following laboratory findings is most likely to be present? □ (A) Hyperhomocysteinemia □ (B) Hyperuricemia □ (C) Hypercalcemia □ (D) Hypoprothrombinemia □ (E) Hypoalbuminemia □ (F) Hypoinsulinemia

18 (D) The findings are most characteristic of Alzheimer disease, which is progressive over several years. The brain is slightly decreased in size, with narrower gyri and widened sulci in all lobes except the occipital lobes. There is ex vacuo ventricular dilation. Microscopically, there are neuritic plaques with Aβ amyloid cores. Spongiform change is most likely to occur in a rapidly progressive dementia (over weeks to months), such as Creutzfeldt-Jakob disease. Intranuclear inclusions may be seen in viral infections, such as cytomegalovirus or herpes simplex virus, and these are more acute illnesses in which focal neurologic findings are more likely to be seen. Alzheimer type II cells, despite the eponym, are not part of Alzheimer disease, but are seen with increased blood ammonia levels as a consequence of hepatic failure—hepatic encephalopathy. Arteriolosclerosis can occur in association with hypertension. Loss of pigmented neurons occurs in Parkinson disease, and the loss is in the substantia nigra of the midbrain, not the neocortex. Absence of Betz cells may be seen in amyotrophic lateral sclerosis, in which there is progressive muscular weakness.

18 A 61-year-old man has become more withdrawn and less active over the past 2 years. He spends most of his day in bed, although he seems to have minimal difficulty with movement. He has become less talkative. On physical examination, he has 5/5 motor strength in all extremities; there is no apparent tremor or ataxia. There are no focal neurologic deficits. He can remember only one of three objects after 3 minutes. His mood is depressed. His condition improves with use of Ginkgo biloba extract. One year later, he has an episode of aspiration while eating and dies 1 week later of pneumonia. At autopsy, the brain weighs 1000 g. The gross appearance is shown in the figure. Which of the following microscopic findings is most likely to be seen in the frontal cortex? □ (A) Spongiform change □ (B) Intranuclear inclusions □ (C) Alzheimer type II cells □ (D) Aβ amyloid deposits □ (E) Arteriolosclerosis □ (F) Loss of pigmented neurons □ (G) Absence of Betz cells

19 (E) The findings are most typical of gouty arthritis. Gout can lead to renal failure and to tophaceous deposits in soft tissues and joints, and it is often accompanied by hyperlipidemia. Calcium pyrophosphate dihydrate deposition disease is more common in elderly individuals and usually is asymptomatic; the knees are most often affected, and soft-tissue deposition of the crystals away from joints is unlikely. Cholesterol crystals form in joint cavities after trauma with hemorrhage. Cystine crystals can be seen in the urine in cystinosis, a rare inborn error of metabolism. Hydroxyapatite crystals may be found in joints affected by osteoarthritis, with either acute or chronic presentation.

19 A 51-year-old man has had increasing lethargy over the past year. On physical examination, his temperature is 37°C, pulse is 80/min, respirations are 15/min, and blood pressure is 145/90 mm Hg. He has deformity with increased size, and there is decreased range of motion of the first three metacarpophalangeal (MCP) joints on the right and the second two MCP joints on the left. There is a 2-cm, firm, painless nodule over the left olecranon bursa. A similar 1-cm nodule is palpated in the helix of the right ear, and another 1.5-cm nodule is palpable over the right Achilles tendon. Urinalysis shows specific gravity of 1.012, pH 5.5, 1+ hematuria, 1+ proteinuria, and no glucose. The serum urea nitrogen level is 31 mg/dL, and the creatinine is 3.2 mg/dL. The total serum cholesterol is 222 mg/dL. Aspiration of material from the nodule at the left elbow is performed. Which of the following types of crystals is most likely to be seen microscopically in this aspirate? □ (A) Calcium pyrophosphate dihydrate □ (B) Cholesterol □ (C) Cystine □ (D) Hydroxyapatite □ (E) Sodium urate

2 (F) The patient has findings consistent with systemic lupus erythematosus (SLE): photosensitivity, renal failure, body cavity effusions, pericarditis, arthralgias, myalgias, and cytopenias. The antinuclear antibody test is the most sensitive screening test for SLE, and if positive can be followed by the more specific anti-double-stranded DNA antibody test. Acetylcholine receptor antibody may be seen in myasthenia gravis, which would explain muscle weakness but not pain. Anti-DNA topoisomerase is seen in scleroderma, in which there is renal failure and skin thickening, but not photosensitivity. Anti-glomerular basement membrane antibody can be seen in Goodpasture syndrome and renal failure, but not arthralgias, myalgias, or cytopenias. Antimicrosomal (anti-thyroid peroxidase) antibody is associated with autoimmune thyroid diseases, mainly Hashimoto thyroiditis, but also Graves disease. Antimitochondrial antibody may be seen in primary biliary cirrhosis, which leads to malaise, but not to renal failure or photosensitivity.

2 A 34-year-old woman has had increasing lethargy for the past 8 months. During this time, she has experienced increased sensitivity to sunlight, and now rarely goes outdoors during the day. She has pain in her hands, elbows, knees, and feet, and muscle aches in her arms and legs. She has had increasing dyspnea for the past week. Physical examination shows no joint deformities, swelling, or redness. On auscultation of the chest, a friction rub is audible. A chest radiograph shows bilateral pleural effusions. Laboratory findings show hemoglobin, 11.6 mg/dL; hematocrit, 34.3%; MCV, 84 μm3; platelet count, 133,400/mm3; WBC count, 4610/mm3; Na+, 140 mmol/L; K+, 4 mmol/L; Cl−, 99 mmol/L; CO2, 25 mmol/L; glucose, 80 mg/dL; creatinine, 2.4 mg/dL; and calcium, 7.9 mg/dL. Which of the following additional laboratory tests would be most helpful to diagnose her underlying condition? □ (A) Acetylcholine receptor antibody □ (B) Anti-DNA topoisomerase antibody □ (C) Anti-glomerular basement membrane antibody □ (D) Antimicrosomal antibody □ (E) Antimitochondrial antibody □ (F) Antinuclear antibody

20 (D) Patients with hepatitis C infection can develop chronic hepatitis with persistently elevated liver enzymes. Some patients with hepatitis C develop a mixed cryoglobulinemia with a polyclonal increase in IgG. Renal involvement is common, with either nephrotic or nephritic features. Cryoglobulinemic vasculitis leads to skin hemorrhages and ulceration. Autoimmune hemolytic anemia can lead to a predominantly indirect hyperbilirubinemia. Although hepatocellular carcinoma may complicate hepatitis C infection, a mass lesion would be seen on CT scan, and the alkaline phosphatase level usually is elevated when an intrahepatic mass is present. Chronic liver disease may complicate hereditary hemochromatosis, but these patients usually do not have hepatitis C, and the skin has a slate color, not purpura. Multiple myeloma can increase the serum globulin and produce renal disease, but hepatitis is usually not part of myeloma; vasculitis likewise is not part of myeloma.

20 A 38-year-old woman has had malaise and arthralgias for the past 14 months. Over the past month, she has developed areas of purpura on the distal extremities. On physical examination, her temperature is 37°C, pulse is 81/min, respirations are 14/min, and blood pressure is 140/90 mm Hg. She has scleral icterus and 1- to 3-cm areas of reddish purple discoloration on her skin. Several of these areas show focal ulceration. Laboratory findings show total protein, 7.1 g/dL; albumin, 3.3 g/dL; AST, 87 U/L; ALT, 95 U/L; alkaline phosphatase, 80 U/L; total bilirubin, 4 mg/dL; and direct bilirubin, 3.1 mg/dL. Serologic test results are positive for anti-HCV and negative for anti-HBs and IgM anti-HAV. Urinalysis shows 4+ proteinuria and 1+ hematuria. CT scan of the abdomen shows a small amount of ascites, mild hepatomegaly, and no splenomegaly or lymphadenopathy. A biopsy specimen of an ulcerated skin lesion shows leukocytoclastic vasculitis involving the upper dermis. What is the most likely diagnosis? □ (A) Autoimmune hemolytic anemia □ (B) Hepatocellular carcinoma □ (C) Hereditary hemochromatosis □ (D) Mixed cryoglobulinemia □ (E) Multiple myeloma

21 (D) The delay in onset after trauma is consistent with fat embolism to brain, and the figure shows the predominantly white matter petechiae of "brain purpura." Fat embolism causing respiratory difficulty or neurologic findings typically has an onset 1 to 3 days after trauma. The exact mechanism for development of these vascular lesions is unknown, but vascular occlusion with free fatty acid release and platelet activation play a role. Because she is afebrile, an abscess is unlikely, and the CT scan did not show a focal lesion. Central pontine myelinolysis occurs when hyponatremia is rapidly corrected, leading to white matter edema most marked in the tightly packed crossing fibers of the pons. Diffuse axonal injury can occur as a result of trauma, but symptoms and signs should appear soon after the injury, and the white matter lesions are often microscopic. A ruptured aneurysm is usually not related to trauma, and most of the hemorrhage is at the base of the brain. Viral meningitis can produce brain edema, and herpes simplex viral infection can produce hemorrhage, but there is no relationship to trauma, and there should be leukocytosis in the CSF.

21 A 22-year-old woman incurs multiple blunt trauma with bilateral femoral and right humeral fractures from a fall. The fractures are treated with open reduction and internal fixation. She is in stable condition until 3 days later, when she becomes progressively delirious and then comatose. On physical examination, she is afebrile. Head CT scan shows generalized brain edema. The representative gross appearance of her brain is shown in the figure. Lumbar puncture yields clear CSF with no RBCs, one mononuclear cell, and normal protein and glucose. Her serum glucose is 102 mg/dL, and creatinine is 0.9 mg/dL. What is the most likely diagnosis? □ (A) Abscess with Staphylococcus aureus □ (B) Central pontine myelinolysis □ (C) Diffuse axonal injury □ (D) Fat embolism □ (E) Ruptured berry aneurysm □ (F) Viral meningitis

22 (E) Ulcerative colitis has a peak age of onset between 15 and 30 years. A second peak occurs between 60 and 80 years. The colonoscopic appearance is of a mucosal erythematous and finely granular surface that looks like sandpaper. Extraintestinal manifestations of ulcerative colitis can occur, including primary sclerosing cholangitis (PSC), uveitis, migratory polyarthritis, and erythema nodosum. Sixty percent to 70% of cases of PSC have concurrent inflammatory bowel disease. Dermatitis herpetiformis occurs in patients with celiac disease, both caused by gluten sensitivity. Rheumatoid arthritis is typically associated with Sjögren syndrome. Orchitis is most often a complication of mumps virus infection, particularly in adults. Thyroiditis may occur in association with other autoimmune endocrinopathies, such as Addison disease. Atrophic gastritis causes pernicious anemia and may coexist with other autoimmune disorders, such as Hashimoto thyroiditis.

22 A 64-year-old man develops a low-volume mucoid diarrhea. He has had about five bowel movements per day, accompanied by cramping abdominal pain, for the past 2 months. The stool is occasionally blood-streaked. On physical examination, he appears pale. Vital signs include temperature of 37.2°C, pulse of 84/min, respirations of 15/min, and blood pressure of 115/75 mm Hg. A colonoscopy is performed; the figure shows a representative image of the mucosa from the rectum to the lower portion of the sigmoid. The remaining colonic mucosa appears normal. Biopsy specimens of the affected colon show mucosal crypt distortion, focal crypt abscesses, and mixed inflammatory infiltrates extending to the lamina propria. Over the next 2 years, the patient develops polyarthritis with no joint deformity, and uveitis and chronic active hepatitis. Which of the following inflammatory diseases is he most likely to develop? □ (A) Dermatitis herpetiformis □ (B) Rheumatoid arthritis □ (C) Orchitis □ (D) Thyroiditis □ (E) Primary sclerosing cholangitis □ (F) Atrophic gastritis

23 (A) Translational research takes an idea from bench to bedside. The mechanism described is that of apoptosis, or individual cell death. Turning on apoptosis within cancer cells would be a useful pharmacologic effect, to cause the tumor to "self-destruct." The other listed conditions would not benefit from induction of apoptosis to a similar degree.

23 A translational research project is focused on development of a pharmacologic agent that would affect molecular signaling pathways within cells. This agent binds to type 1 TNF receptor (TNFR1), which triggers activation of intracellular caspases. For what condition is this agent most likely to be useful? □ (A) Adenocarcinoma □ (B) Atherosclerosis □ (C) Autoimmunity □ (D) Cirrhosis □ (E) Dementia □ (F) Osteoporosis

24(D) The MR image shows white matter plaques of demyelination typical of multiple sclerosis, a disease that has various neurologic manifestations. The mean age at onset is 30 years, and it rarely occurs after age 60. Optic neuritis, weakness, and sensory changes are frequent manifestations. Diabetes mellitus can produce peripheral neuropathy and retinopathy, but typically in a more symmetric fashion, and white matter plaques are not present. Graves disease can lead to hyperthyroidism with heat intolerance, but neurologic manifestations are not frequent, and diarrhea is typically present. HIV infection can lead to HIV encephalitis, which can involve white matter, although defined plaques are unlikely, and peripheral neuropathy is infrequent. Myasthenia gravis can produce generalized weakness, which becomes worse with repetitive movement and is not focal; there are no white matter changes. Systemic lupus erythematosus can cause cerebritis but without plaques of demyelination, and focal neurologic deficits are an infrequent finding.

24 Over the past 2 years, a 44-year-old man has noticed a decline in dexterity of his right hand in his work as an auto mechanic. His right hand strength is weaker than the left. He experienced painful burning sensations in the left upper extremity 1 year ago. He has been bothered by decreased visual acuity in the left eye for the past month. He is insensitive to heat, and on taking a hot shower, his vision worsens. On physical examination, he is afebrile, and his blood pressure is normal. Motor strength in the right extremity is 4/5, but 5/5 elsewhere. Vision is 20/100 in the left eye and 20/40 in the right eye. One year later, he reports chronic constipation and urinary urgency, hesitancy, and incontinence. An MR image of the brain is shown in the figure. What is the most likely diagnosis? □ (A) Diabetes mellitus □ (B) Graves disease □ (C) HIV infection □ (D) Multiple sclerosis □ (E) Myasthenia gravis □ (F) Systemic lupus erythematosus

25 (F) The patient has Wilson disease (hepatolenticular degeneration), with Kayser-Fleischer corneal rings owing to a mutation in the gene encoding for a copper-transporting ATPase. Excessive copper deposition occurs, particularly in the liver, putamen, and cornea. Psychiatric and neurologic disturbances are common in Wilson disease, and patients often develop chronic liver disease ranging from acute hepatitis to chronic hepatitis to cirrhosis. In α1-antitrypsin deficiency, there can be chronic hepatitis and pulmonary emphysema, but there are no neurologic changes. Cystic fibrosis can lead to pulmonary disease and pancreatic insufficiency. Galactosemia can lead to liver disease and cirrhosis in early childhood. In its most severe form, Gaucher disease can lead to neurologic deterioration, but it does not lead to chronic liver disease. Von Gierke disease is a form of glycogen storage disease that does not commonly progress to cirrhosis.

25 A 22-year-old woman has experienced bizarre changes in her behavior over the past year, culminating in her withdrawal from college. She is diagnosed with bipolar disorder. Over the next year, she develops neurologic manifestations that include resting and intention tremors, rigidity, chorea, dysphagia, and dysarthria. On physical examination, she has bilateral Babinski responses. There are ringlike deposits of gold-colored material involving the cornea bilaterally, but her vision is not decreased. One year later, she has an illness that lasts several weeks, with nausea, vomiting, and malaise and scleral icterus. Laboratory findings include serum AST, 100 U/L; ALT, 122 U/L; alkaline phosphatase, 105 U/L; total bilirubin, 4.5 mg/dL; glucose, 77 mg/dL; and creatinine, 0.9 mg/dL. Serologic test results for hepatitis A, B, and C are negative. This episode subsides without treatment, but she eventually develops cirrhosis. A mutation in a gene encoding for what substance is most likely to be present? □ (A) α1-Antitrypsin □ (B) CFTR □ (C) Galactose-1-phosphate uridyl transferase □ (D) Glucocerebrosidase □ (E) Glucose-6-phosphatase □ (F) Copper-transporting ATPase

26 (A) The patient has an aortic dissection that is extending proximally to envelop and partially occlude the great vessels. Proximal dissections may result in minimal or no chest pain. Blood has moved into the mediastinum, causing widening, and into the pericardial cavity, causing tamponade. Risk factors include hypertension and atherosclerosis. In addition, cystic medial necrosis makes aortic dissection a serious risk in individuals with Marfan syndrome. A bicuspid aortic valve leads to aortic valvular stenosis, but not to aortic rupture. Neoplasms involving the mediastinum, typically hematologic malignancies such as lymphomas, may produce a superior vena cava syndrome, but neoplasms virtually never invade the arterial media, and bleeding from neoplasms is produced from much smaller vessels. T akayasu arteritis can involve the aortic arch and lead to dissection, but this condition is rare and is most likely seen in women younger than 30 years old. Syphilitic aortitis may produce aortic root dilation and possible rupture, but this is much less common than aortic dissection resulting from hypertension and atherosclerosis. Thromboangiitis obliterans (Buerger disease) is an uncommon disorder that affects small to medium-sized arteries in the arms and legs of middle-aged men who smoke.

26 A 57-year-old woman experiences a sudden loss of consciousness. She has a history of untreated hypertension, and has smoked one pack of cigarettes per day for the past 40 years. On physical examination, her temperature is 37.1°C, pulse is 70/min and irregular, respirations are 18/min, and blood pressure is 90/40 mm Hg. Carotid and radial pulses are diminished compared with femoral and posterior tibial pulses. Auscultation of the chest reveals faint heart sounds; lung fields are clear. A chest radiograph shows a widened mediastinum. The chest CT scan is shown in the figure. Pericardiocentesis is performed, and there is blood in the aspirate. What condition is most likely to produce these findings? □ (A) Aortic dissection □ (B) Bicuspid aortic valve □ (C) Small-cell anaplastic carcinoma □ (D) Takayasu arteritis □ (E) Tertiary syphilis □ (F) Thromboangiitis obliterans

27 (C) The patient has findings that are consistent with emphysema. Smoking promotes gastritis. Several malignancies are related to smoking, including urinary tract transitional cell carcinoma and renal cell carcinoma. α1-Antitrypsin (AAT) deficiency can explain emphysema, but it would be panlobular, and AAT deficiency is not associated with urinary tract neoplasia. Chronic alcoholism can explain gastritis, but not emphysema or carcinoma. Aniline dyes increase the risk of transitional cell carcinoma, but not of emphysema or gastritis. Vitamin C deficiency can lead to soft-tissue hemorrhages and bone pain, but not to carcinoma or emphysema.

27 A 62-year-old woman who has had a chronic cough for years becomes short of breath after climbing a single flight of stairs. A chest radiograph performed 1 year ago showed increased lucency of upper lung fields and bilateral flattening of the diaphragmatic leaves. She has had nausea and vague abdominal discomfort for 6 months. Biopsy specimens from an upper gastrointestinal endoscopic study show a chronic nonspecific gastritis with no detectable Helicobacter pylori organisms. During the past month, she has passed red-colored urine on several occasions. Cystoscopic examination shows a 3-cm exophytic mass in the dome of the bladder, and biopsy specimens show a transitional cell carcinoma. What is the most likely risk factor for this spectrum of findings? □ (A) α1-Antitrypsin deficiency □ (B) Chronic alcoholism □ (C) Cigarette smoking □ (D) Exposure to aniline dye □ (E) Vitamin C deficiency

28 (B) Hemoglobin A1c elevation occurs in diabetes mellitus. The patient has complications of diabetes mellitus type 2 that are typical of obesity: a "diabetic foot" as a consequence of peripheral neuropathy and decreased sensation, advanced atherosclerosis with carotid arterial occlusion, and an atherosclerotic aortic aneurysm. Autonomic dysfunction with neuropathy can lead to erectile dysfunction. Cushing disease owing to an ACTH-secreting pituitary adenoma leads to truncal obesity and skin that is easily bruised and possibly to secondary diabetes mellitus, but not to advanced atherosclerosis. Hyperchromocysteinemia is a risk factor for atherosclerosis, but not for neuropathy. The oligoclonal bands of IgG are characteristic for multiple sclerosis, which usually has more focal CNS involvement. Anti-parietal cell antibodies occur in pernicious anemia with vitamin B12 deficiency, which can lead to decreased sensation in the lower extremities, but not to atherosclerotic complications.

28 A 59-year-old man comes to the physician seeking a prescription for sildenafil after seeing television advertisements regarding erectile dysfunction. He is 168 cm (5 ft 6 in) tall and weighs 93 kg (body mass index 33). On physical examination, there are bilateral carotid bruits and a midline palpable abdominal pulsatile mass. Decreased hair is noted over the lower extremities, and a 1-cm shallow ulceration is present in the skin over the right first metatarsal head. He has decreased sensation to light touch and pinprick in the lower extremities. Laboratory findings include hemoglobin, 12.9 g/dL; hematocrit, 42%; WBC count, 8950/mm3; Na+, 140 mmol/L; K+, 4.2 mmol/L; Cl−, 105 mmol/L; CO2, 26 mmol/L; glucose, 144 mg/dL; and creatinine, 1.7 mg/dL. Which of the following laboratory findings is most likely to be present in this man? □ (A) Plasma ACTH 119 pg/mL □ (B) Hemoglobin A1c 8.8% □ (C) Plasma homocysteine 23 μmol/L □ (D) Cerebrospinal fluid oligoclonal IgG bands □ (E) Serum anti-parietal cell antibodies

29 (A) The patient has Addison disease with bilateral atrophy of the adrenal cortex, which is most often idiopathic and leads to electrolyte changes owing to loss of mineralocorticoid secretion, mainly aldosterone; when atrophy is marked, glucocorticoid secretion is diminished. Increased ACTH precursor hormones, resulting from loss of feedback from cortisol production, stimulate skin melanocytes. Stress, including infections, may precipitate an addisonian crisis. Loss of islets of Langerhans is a feature of type 1 diabetes mellitus, with hyperglycemia and possible ketoacidosis as complications. Loss of releasing or inhibiting hormones from the hypothalamus affects the pituitary and leads to multiple endocrinopathies, but not specifically to loss of ACTH. Parafollicular cells of the thyroid produce calcitonin, which plays a minor role in calcium homeostasis. The pineal gland produces melatonin, which is involved in circadian rhythms, but not in significant disease states. Loss of thyroid hormone from follicular epithelium leads to hypothyroidism typified by modest weight gain, coarse and dry skin, and constipation, but without significant electrolyte disturbances.

29 A 42-year-old woman has had increasing weakness, nausea, vomiting, watery diarrhea, and a 5-kg weight loss over the past 7 months. She has generalized muscle weakness, muscle wasting, and increased skin pigmentation on physical examination. After an upper respiratory tract infection lasting 1 week, she develops abdominal pain and faintness and lapses into a coma. On admission to the hospital, her temperature is 36.9°C, pulse is 83/min, respirations are 17/min and shallow, and blood pressure is 80/40 mm Hg. Laboratory findings show hemoglobin, 13.6 g/dL; hematocrit, 43.8%; WBC count, 5420/mm3; Na+, 129 mmol/L; K+, 3.5 mmol/L; Cl−, 95 mmol/L; CO2, 23 mmol/L; glucose, 48 mg/dL; and creatinine, 0.6 mg/dL. Atrophy of which of the following tissues is most likely to be present? (A) Adrenal cortex □ (B) Islets of Langerhans □ (C) Hypothalamus □ (D) Parafollicular cells □ (E) Pineal gland □ (F) Thyroid epithelium

3 (A) The findings listed describe myasthenia gravis with complications of thymoma, including the rare finding of pure RBC aplasia, which is characterized by selective suppression of the erythroid lineage in the bone marrow. This curious entity is sometimes associated with a thymic tumor. In about half of such cases, removal of the thymic tumor relieves the RBC aplasia, suggesting some autoimmune mechanism as the cause of the aplasia. The chest CT scan shows a mass posterior to the sternum just below the clavicles. Thymic disorders are common in myasthenia gravis, either thymic hyperplasia or thymoma (as in this case). Antibodies against the acetylcholine receptor disrupt the function of the myoneural junction. Anti-DNA topoisomerase is seen in scleroderma, in which there is renal failure and skin thickening, but not muscle weakness after use. Anti-glomerular basement membrane antibody can be seen in Goodpasture syndrome, a form of rapidly progressive glomerulonephritis, often with pulmonary hemorrhage. Antimitochondrial antibody may be seen in primary biliary cirrhosis. ANA is characteristic of many systemic autoimmune diseases, most often systemic lupus erythematosus, which can be accompanied by myalgias, but not by muscle weakness with repetitive movement.

3 A 50-year-old woman sees her physician because of a 3-month history of fatigue on exertion and dizziness. She has recently experienced syncopal episodes. She has trouble keeping her eyes open toward the end of the day and has double vision. She has no muscle aches or pains. On physical examination, she is afebrile, with a pulse of 88/min, respirations of 19/min, and blood pressure of 115/75 mm Hg. She exhibits marked pallor, but no hepatosplenomegaly or lymphadenopathy. There is decreased motor strength with repetitive motion, but no apparent muscle atrophy, joint deformity, pain, or redness. Laboratory findings show hemoglobin of 6.6 g/dL, hematocrit of 19.9%, platelet count of 199,800/mm3, WBC count of 4780/mm3, and reticulocyte count of 0.1%. The MCV, MCHC, and serum ferritin level are normal. A bone marrow biopsy specimen of aspirate shows normal cellularity, but the cells of the erythroid series, such as pronormoblasts, normoblasts, and later stages, are greatly reduced. Other elements are normal in number and differentiation. The figure shows a chest CT scan. Which of the following would be most helpful serologic laboratory tests in diagnosing her underlying condition? □ (A) Acetylcholine receptor antibody □ (B) Anti-DNA topoisomerase □ (C) Anti-glomerular basement membrane antibody □ (D) Antimitochondrial antibody □ (E) Antinuclear antibody

30 (A) The patient has hyperprolactinemia caused by a prolactinoma, which is the most common tumor of the anterior pituitary. Macroadenomas produce homonymous hemianopsia and can secrete prolactin to cause gynecomastia. A carcinoid tumor can produce various hormones, but not prolactin. Medullary thyroid carcinomas can produce calcitonin, which has a minimal effect on calcium homeostasis. Pheochromocytomas can produce excess catecholamines, most often manifested by hypertension. Renal cell carcinomas can be accompanied by various paraneoplastic syndromes, most often polycythemia, hypercalcemia, and Cushing syndrome, but not hyperprolactinemia. Likewise, small-cell anaplastic ("oat cell") lung cancers can produce paraneoplastic syndromes, most often Cushing syndrome and the syndrome of inappropriate antidiuretic hormone secretion.

30 A 39-year-old man goes to the physician because he has experienced diminished libido for the past 4 months. Review of systems indicates that he has had frequent headaches over the past 2 months. On physical examination, he has gynecomastia bilaterally, normal-sized testes in the scrotum, and difficulty with peripheral vision. His visual acuity is 20/20 bilaterally. Laboratory findings show Na+, 141 mmol/L; K+, 4.1 mmol/L; Cl−, 102 mmol/L; CO2, 25 mmol/L; glucose, 75 mg/dL; and creatinine, 1.2 mg/dL. Which of the following neoplasms is most likely to be diagnosed? □ (A) Adenohypophyseal adenoma □ (B) Carcinoid tumor □ (C) Medullary carcinoma □ (D) Pheochromocytoma □ (E) Renal cell carcinoma □ (F) Small-cell anaplastic carcinoma

31 (E) The child has Down syndrome and has developed leukemia as a complication. The 45,X karyotype is seen in Turner syndrome only in females. The normal 46,XY karyotype is unlikely with the constellation of anomalies present in this case. Trisomies 13 and 18 are far less likely than trisomy 21 to be associated with long-term survival; affected children are more likely to have severe anomalies. The 47,XXY karyotype of Klinefelter syndrome is associated with nearly normal- appearing males of normal intelligence. Triploidy with 69 chromosomes is associated with partial hydatidiform mole and with stillbirth.

31 A boy born to a 40-year-old woman, who had an uncomplicated pregnancy, is noted at birth to be at the 70th percentile for height and weight. On physical examination, the infant has bilateral palmar transverse creases and absent distal flexion creases on the fifth digits. The palpebral fissures are oblique. He has brachycephaly. On auscultation of the chest, a holosystolic murmur is audible. During childhood, mental retardation is exhibited, but the child is able to perform activities of daily living. At age 17, the boy has a series of severe upper respiratory tract infections. CBC shows hemoglobin, 10.2 g/dL; hematocrit, 30.5%; MCV, 89 μm3; platelet count, 103,000/mm3; and WBC count, 19,200/mm3 with 14% segmented neutrophils, 6% bands, 22% lymphocytes, 13% monocytes, and 45% blasts. What karyotype is most likely to be present in this boy? □ (A) 45,X □ (B) 46,XY □ (C) 47,XY,+13 □ (D) 47,XY,+18 □ (E) 47,XY,+21 □ (F) 47,XXY □ (G) 69,XYY

32 (D) About 10% of individuals with autosomal-dominant polycystic kidney disease (ADPKD) have a berry aneurysm of the circle of Willis, which may be complicated by rupture and hemorrhage into the subarachnoid space. The cysts of ADPKD may appear in the liver, and rarely in the pancreas. The cysts in *adult-onset medullary cystic disease* are centrally located in the kidney. Although renal failure does occur in middle age, similar to ADPKD, the kidneys are small and shrunken, and there are no cysts in other organs. Abnormal renal resorption of amino acids, including cystine, may lead to formation of cystine crystals and stones in the urine; maple syrup urine disease and severe liver disease may cause such a finding. Diabetic nephropathy includes nephrosclerosis, glomerulosclerosis, pyelonephritis, and papillary necrosis, but not cystic disease. Polyarteritis nodosa may produce small microaneurysms of arteries, typically in the kidneys, and may affect multiple organs, but cystic disease is not seen. Wegener granulomatosis is a form of vasculitis that can affect multiple organs, principally the kidneys and lungs, but it does not produce cystic disease. Wilson disease, or hepatolenticular degeneration, leads to chronic liver disease and putaminal degeneration, not cystic disease.

32 A 52-year-old woman has noticed increasing thirst and urine output for the past 6 months. She has become more lethargic and has had decreased mental agility during that time. She has had flank pain on the right during the past month. On physical examination, her temperature is 37°C, pulse is 77/min, respirations are 14/min, and blood pressure is 150/95 mm Hg. There are bilateral palpable masses in the abdomen. The figure shows an abdominal CT scan. Urinalysis shows specific gravity of 1.010, pH 6.5, 2+ proteinuria, 2+ hematuria, and no glucose or ketones. Laboratory findings show hemoglobin of 10.4 g/dL, hematocrit of 31.3%, glucose of 102 mg/dL, AST of 30 U/L, ALT of 21 U/L, creatinine of 5.5 mg/dL, and urea nitrogen of 53 mg/dL. One year later, she develops a sudden, severe headache. CT scan of the head shows a subarachnoid hemorrhage at the base of the brain. What is the most likely diagnosis? □ (A) Adult-onset medullary cystic disease □ (B) Cystinosis □ (C) Diabetes mellitus type 2 □ (D) Autosoma-dominant polycystic kidney disease □ (E) Polyarteritis nodosa □ (F) Wegener granulomatosis □ (G) Wilson disease

33 (E) This patient has findings of "classic" polyarteritis nodosa, and in about one third of cases, HBsAg is positive. The mesenteric artery angiogram reveals focal distal *occlusions and microaneurysms of branches of the superior mesenteric artery*. Antimitochondrial antibody is seen in primary biliary cirrhosis. P-ANCA is associated with "microscopic" polyarteritis, but not with classic polyarteritis. The ANA test result is positive in a wide variety of autoimmune diseases, principally systemic lupus erythematosus, which can affect the kidney with glomerulonephritis, not typically vasculitis. Cryptococcal antigen can be detected in CSF of patients with meningitis, usually immunocompromised patients. Histoplasma capsulatum antibody may be detected in individuals with prior exposure to this agent, which mainly causes pulmonary disease. The p24 antigen of HIV is used in testing for congenital infection; HIV does not produce a florid acute vasculitis.

33 A 35-year-old man has had bouts of severe, diffuse abdominal pain over the past 4 months. These bouts have been accompanied by fever, malaise, and myalgias. During one bout, he sees the physician. On physical examination, his temperature is 37.7°C, pulse is 81/min, respirations are 16/min, and blood pressure is 145/90 mm Hg. There is diffuse abdominal tenderness, but no masses, and bowel sounds are present. A stool sample is positive for occult blood. Laboratory findings show serum glucose of 73 mg/dL, amylase of 44 U/L, AST of 54 U/L, ALT of 23 U/L, creatinine of 2.4 mg/dL, and urea nitrogen of 22 mg/dL. A renal biopsy specimen shows acute transmural vasculitis of medium-sized arteries; the glomeruli and tubules are unremarkable. Mesenteric artery angiography is performed; the figure shows the appearance of the angiogram. Which of the following serologic tests is most likely to be positive in this patient□ (A) Antimitochondrial antibody □ (B) C-ANCA □ (C) ANA □ (D) Cryptococcus neoformans antigen □ (E) HBsAg □ (F) Histoplasma capsulatum antibody □ (G) p24 antigen

34 (D) Vitamin C deficiency is manifested by a decrease in synthesis of collagen peptides from inadequate hydroxylation of procollagen. Diminished collagen synthesis affects bone matrix formation, vascular integrity, and epithelial function. There is bleeding into joints and soft tissues with minimal trauma. Mutation of the CFTR gene leads to cystic fibrosis, and malabsorption in cystic fibrosis primarily affects the fat-soluble vitamins A, D, E, and K, with bone changes marked by inadequate mineralization. Hemophilia A, which in some cases can be due to an acquired inhibitor of factor VIII, leads to hemorrhage into soft tissues with hemarthroses and joint deformities, but this condition is typically X-linked and unlikely to affect girls, and skin and bone are not primarily involved. Mutations in a collagen gene can lead to osteogenesis imperfecta, resulting in multiple fractures with deformity. The lack of fractures in this case makes a diagnosis of trauma less likely, and the skin and epiphyseal changes are not seen with trauma.

34 A 14-year-old girl who has been in foster care for the past 11 years has not been with one caregiver for more than 1 year at a time. She is brought to the physician by the most recent caregiver, who obtained custody of the child 1 week ago. On physical examination, there are ecchymoses of the trunk, extremities, and gingiva. A hyperkeratotic, papular rash, with 0.4-cm lesions ringed by hemorrhage, is present in a similar distribution. The child has pain on movement of the arms and legs. There is abnormal depression of the sternum with prominence of the ribs and the costochondral junctions. Radiographs of the arms and legs show bowing of the long bones and widening of the metaphyses, with normal calcification. There is a right femoral subperiosteal hematoma. No fractures are noted. CBC shows hemoglobin of 10.8 g/dL, hematocrit of 32.4%, MCV of 77 μm3, platelet count of 201,300/mm3, and WBC count of 5730/mm3. What most likely explains these findings? □ (A) CFTR gene mutation □ (B) Inhibitor of procoagulant factor VIII □ (C) Collagen gene mutation □ (D) Vitamin C deficiency □ (E) Multiple blunt trauma

35 (A) This girl has Stevens-Johnson syndrome (SJS), a severe form of erythema multiforme that can complicate infections and drug therapy. Sulfonamides, allopurinol, phenytoin, and carbamazepine are the most likely drugs to be associated with SJS. Cytotoxic (CD8+) lymphocytes mediate SJS through epidermal cell necrosis. Eosinophils are common in allergic reactions, including drug allergies, but most of these reactions are accompanied by urticaria and erythema of short duration, without blistering or desquamation. Langerhans cells and macrophages are antigen-presenting cells in the epidermis and dermis that do not directly cause toxic damage to surrounding cells. Neutrophilic exudates are not a feature of SJS, although a leukocytoclastic vasculitis with purpura is a form of drug reaction. Natural killer cells are part of innate immunity and do not participate directly in drug reactions.

35 A 10-year-old girl has a respiratory tract infection and is treated with trimethoprim-sulfamethoxazole. Three days later, she develops a sore throat, malaise, fever, and a macular skin rash on the trunk and extremities. Some of the skin lesions have a central raised area of more pronounced erythema. Within a few days, there are erosions of the oral mucosa and small blisters developing on purpuric skin macules. The blisters enlarge slightly and then show epidermal detachment. The total body surface area involved with blistering and detachment is less than 10%. This disease process is most likely mediated by what inflammatory cell type? □ (A) CD8+ lymphocytes □ (B) Eosinophils □ (C) Langerhans cells □ (D) Macrophages □ (E) Neutrophils □ (F) Natural killer cells

36 (E) The patient has toxic shock syndrome. Some strains of Staphylococcus aureus produce exotoxins, acting as "superantigens," such as TSST-1, which are T-cell mitogens able to stimulate more than 10% of the body's T cells, provoking an exuberant and dysregulated immune response characterized by release of the cytokines that mediate cell injury. Bacillus anthracis can cause anthrax, a serious illness with pneumonia and meningitis as the predominant findings. Clostridium perfringens is known to cause wound infections with gas gangrene. Enterococcus generally does not cause such a rapidly progressing illness. Listeriosis is associated with food poisoning and can cause life-threatening disease, but typically without desquamation. Vibrio cholerae organisms elaborate a toxin that causes severe watery diarrhea and little else.

36 Within the past 24 hours, a 26-year-old, previously healthy woman has developed a high fever and generalized diffuse erythematous macular rash resembling a sunburn. She is menstruating, and her menstrual cycles are regular. She has nausea, vomiting, abdominal pain, diarrhea, myalgias, sore throat, headache, and dizziness. On physical examination, her temperature is 39.4°C, pulse is 101/min, respirations are 18/min, and blood pressure is 90/40 mm Hg. She has oropharyngeal and conjunctival hyperemia. The vaginal mucosa is erythematous. A tampon is present in the vaginal vault. She is disoriented, but there are no neurologic deficits. Laboratory findings show hemoglobin, 13.5 g/dL; hematocrit, 41.4%; platelet count, 100,000/mm3; WBC count, 11,200/mm3; glucose, 70 mg/dL; creatinine, 2.5 mg/dL; total bilirubin, 2.4 mg/dL; AST, 82 U/L; and ALT, 29 U/L. A chest radiograph shows no abnormal findings. She receives supportive therapy of nafcillin with clindamycin and improves, but skin and mucous membrane desquamation is noted 10 days later. These findings are most likely produced by an exotoxin elaborated by which of the following organisms? □ (A) Bacillus anthracis □ (B) Clostridium perfringens □ (C) Enterococcus □ (D) Listeria monocytogenes □ (E) Staphylococcus aureus □ (F) Vibrio cholerae

37 (C) The child has Letterer-Siwe disease, an acute disseminated form of Langerhans cell histiocytosis. Acute lymphoblastic leukemia generally produces an elevated WBC count, and cutaneous and skeletal manifestations are rare. Gaucher disease, an autosomal recessive condition resulting from diminished glucocerebrosidase activity, has cells with cytoplasm that resembles crinkled tissue paper, and the course is not as aggressive. Leishmania donovani can cause visceral leishmaniasis, but the amastigotes infiltrating the marrow are not positive for CD1a, and the course is usually not as aggressive. Multiple myeloma is seen in older adults, and although lytic bone lesions are common, they are caused by infiltrates of plasma cells. Forms of myelodysplastic syndrome are seen in older adults, with myeloid cells that do not mark for CD1a and numerous ringed sideroblasts in the marrow; some cases progress to acute myelocytic leukemia.

37 A 21-month-old child has had recurrent otitis media complicated by mastoiditis for the past 3 months. On physical examination, there is a seborrheic eruption on the skin of the trunk and scalp. Hepatosplenomegaly and generalized nontender lymphadenopathy are present. A chest radiograph shows bilateral 0.5- to 2-cm pulmonary nodules, and there is a 1-cm lesion on the right clavicle and a 1.5-cm lesion on the left seventh rib, both osteolytic. Laboratory findings show hemoglobin of 10.4 g/dL, hematocrit of 31.2%, platelet count of 93,400/mm3, WBC count of 5780/mm3, glucose of 72 mg/dL, and creatinine of 0.5 mg/dL. A bone marrow biopsy specimen shows reduced hematopoiesis with increased numbers of large cells having oval vesicular nuclei and vacuolated cytoplasm that mark immunocytologically for CD1a. What is the most likely diagnosis? □ (A) Acute lymphoblastic leukemia □ (B) Gaucher disease □ (C) Langerhans cell histiocytosis □ (D) Leishmaniasis □ (E) Multiple myeloma □ (F) Myelodysplastic syndrome

38 (B) The findings are consistent with an adrenogenital syndrome, characterized by 21-hydroxylase deficiency and salt wasting owing to a block in cortisol synthesis and an increase in ACTH secretion stimulating increased androgen production. The rare anaplastic thyroid carcinoma is a neoplasm seen in adults with no hormonal effect. Islet cell adenomas may secrete various hormones, often insulin, glucagon, or somatostatin, which do not produce virilizing signs. Medullary carcinoma of the thyroid is a tumor in adults that can produce calcitonin. Neuroblastomas can be seen in young children, but their hormonal output may produce only hypertension. Pituitary adenomas may destroy remaining pituitary function and lead to hypopituitarism, but a microadenoma is unlikely to do this, and the features in this case suggest increased ACTH secretion. Craniopharyngiomas are typically seen in adolescence to young adulthood and are destructive lesions without hormonal output.

38 A 4-year-old girl has become increasingly listless over the past year. The child is at the 25th percentile for height and weight. On physical examination, there is pubic hair and clitoral and breast enlargement. There is no hepatomegaly, splenomegaly, or lymphadenopathy. The neurologic examination is unremarkable. Laboratory findings show hemoglobin, 13.7 g/dL; hematocrit, 41.8%; WBC count, 7120/mm3; Na+, 128 mmol/L; K+, 4.8 mmol/L; Cl−, 99 mmol/L; CO2, 21 mmol/L; glucose, 69 mg/dL; and creatinine, 0.5 mg/dL, and ACTH of 95 pg/mL with loss of diurnal rhythm of secretion. What disease process is most likely associated with these findings? □ (A) Anaplastic carcinoma of the thyroid □ (B) Bilateral adrenal hyperplasia □ (C) Islet cell adenoma □ (D) Medullary carcinoma of the thyroid □ (E) Neuroblastoma of the adrenal □ (F) Pituitary microadenoma □ (G) Suprasellar craniopharyngioma

39 (D) This infant has the acute neuronopathic form of Gaucher disease (type II), which is uniformly fatal in children and is much less common than the milder type I, which has prolonged survival into adulthood. The *marrow is infiltrated by large cells with abundant pale cytoplasm with the appearance of crumpled tissue paper.* α-l-Iduronidase deficiency is seen in Hurler syndrome, characterized by progressive features of corneal clouding, coarse facial features, and mental retardation. α-1,4-Glucosidase deficiency is present in Pompe disease, a glycogen storage disease that causes marked cardiomegaly. Arylsulfatase A deficiency is present in metachromatic leukodystrophy and causes CNS degeneration without visceral organ involvement. Glucose-6-phosphatase deficiency characterizes von Gierke disease; affected individuals have hepatomegaly and hypoglycemia. Tay-Sachs disease with cherry red maculae and progressive neurologic deterioration occurs as a result of diminished hexosaminidase A; hexosaminidase B deficiency leads to Sandhoff disease. Sphingomyelinase deficiency leads to Niemann-Pick disease, with foamy-appearing macrophages filling tissues of the mononuclear phagocyte system.

39 A 10-month-old infant is not meeting developmental milestones and is below ideal weight and height. The parents noted an episode of convulsions 1 week ago. On physical examination, the infant has hepatosplenomegaly and generalized nontender lymphadenopathy. There is tenderness on palpation of the right upper extremity. No focal neurologic deficits are present, but the infant's attention and movement are diminished. A radiograph of the right arm shows a healing fracture. Laboratory findings show hemoglobin of 9.7 g/dL, hematocrit of 28.4%, platelet count of 76,700/mm3, WBC count of 4200/mm3, glucose of 78 mg/dL, and creatinine of 0.4 mg/dL. A bone marrow biopsy is done; the figure shows the microscopic appearance of the biopsy specimen. The infant is most likely to have the near absence of which of the following enzymes? □ (A) α-l-Iduronidase □ (B) α-1,4-Glucosidase □ (C) Arylsulfatase A □ (D) Glucocerebrosidase □ (E) Glucose-6-phosphatase □ (F) Hexosaminidase A □ (G) Hexosaminidase B □ (H) Sphingomyelinase

4 (A) This patient has findings associated with Goodpasture syndrome, in which there is antibody directed against the glomerular basement membrane, which also acts on basement membrane in the lung to produce pulmonary hemorrhage and hemoptysis. Cytotoxic CD8+ lymphocytes are part of a cell-mediated immune response effective in eliminating intracellular infections such as influenza. Circulating immune complexes are more likely to be seen in autoimmune diseases, such as systemic lupus erythematosus. Macrophage activation is more typical of chronic inflammation and granulomatous inflammation with type IV hypersensitivity. Release of mediators such as histamine from mast cells is typical of anaphylaxis with type I hypersensitivity.

4 A 24-year-old, previously healthy man who smokes one pack of cigarettes per day and who works as a histotechnologist has developed a cough with bloody sputum over the past 2 days. He has increasing lethargy and nausea. A chest radiograph shows diffuse infiltrates most pronounced in the lower lobes. Laboratory findings show hemoglobin, 13.7 g/dL; hematocrit, 40.6%; MCV, 91 μm3; platelet count, 361,000/mm3; WBC count, 7385/mm3; Na+, 144 mmol/L; K+, 4.3 mmol/L; Cl−, 103 mmol/L; CO2, 26 mmol/L; creatinine, 3.8 mg/dL; urea nitrogen, 36 mg/dL; and glucose, 75 mg/dL. An abdominal ultrasound scan shows normal-sized kidneys. A renal biopsy specimen shows a crescentic glomerulonephritis. Which of the following mechanisms most likely produced this patient's pulmonary disease? □ (A) Antibody directed against basement membrane collagen □ (B) Apoptosis induced by CD8+ lymphocytes □ (C) Complement activation by circulating antigen-antibody complexes □ (D) Macrophage activation by CD4+ lymphocytes □ (E) Release of inflammatory mediators from mast cells

40 (C) This man has celiac disease complicated by dermatitis herpetiformis. The jejunal biopsy specimen shows mucosal flattening and increased intraepithelial lymphocytes. Individuals who have HLA-DQ2 or HLA-DQ8 are more likely to develop these findings. With a gluten-free diet, the skin lesions resolve in some patients. Antibodies to desmoglein 3, a desmosome protein, are present in pemphigus vulgaris, a vesicular disease of older adults without gastrointestinal tract involvement. Antibodies to double-stranded DNA are highly specific for systemic lupus erythematosus (SLE), which produces erythematous rashes without vesicles. Antihistone antibodies are most characteristic of drug-induced SLE. Anti- RNP antibodies are seen in mixed connective tissue disease, which has elements of SLE, scleroderma, rheumatoid arthritis, and polymyositis. Antibodies to type IV collagen are seen in Goodpasture syndrome, which does not involve skin rashes.

40 A 39-year-old man states that he has had watery diarrhea and flatulence for the past 8 months. He also reports increasing fatigue and a 4-kg weight loss. He has had urticarial plaques on extensor surfaces of the elbows and knees and on the upper back for the past month. Some of the plaques have small, grouped vesicles. A biopsy specimen of one of the skin lesions shows neutrophils at the tips of dermal papillae with overlying basal cell vacuolization. Under immunofluorescence microscopy, granular IgA deposits appear at the tips of dermal papillae. The figure shows the microscopic appearance of a jejunal biopsy specimen. More than 20 years later, the patient has a T-cell lymphoma of the jejunum. Antibody to which of the following is most likely to produce this disease □ (A) Desmoglein 3 □ (B) Double-stranded DNA □ (C) Gliadin □ (D) Histone □ (E) Ribonucleoprotein □ (F) Type IV collagen

41 (A) The patient has multiple endocrine neoplasia type I (MEN I) with a gastrinoma (arising either in the islets or in the small intestine), a parathyroid lesion (adenoma or hyperplasia), and a prolactinoma. Medullary carcinoma and pheochromocytoma are more typical of MEN II with RET gene mutation. Non-Hodgkin lymphomas are more typical of syndromes in which an immunodeficiency state is present, such as AIDS and large-cell lymphoma with BCL-6 mutation. Osteomas may be seen in Gardner syndrome with the adenomatous polyposis coli (APC) gene. Renal cell carcinoma may be seen in von Hippel-Lindau disease owing to mutation in the VHL gene.

41 For the past month, a 33-year-old woman has had burning epigastric pain and nausea and vomiting. An upper gastrointestinal endoscopic study shows multiple 1-cm shallow gastric antral and proximal duodenal ulcerations. She is treated with omeprazole and improves. One year later, she has an episode of severe, colicky lower abdominal pain and hematuria and passes a calcium oxalate calculus. She notes galactorrhea 1 month later, and over the next 2 months ceases to menstruate. She is given a dopamine agonist and improves. Laboratory findings show Na+, 140 mmol/L; K+, 4 mmol/L; Cl−, 101 mmol/L; CO2, 25 mmol/L; calcium, 11.1 mg/dL; phosphorus, 2.4 mg/dL; and creatinine, 1.1 mg/dL. Which of the following gene mutations with associated neoplasms is most likely to develop in this patient? □ (A) MEN1—islet cell adenoma □ (B) RET—medullary carcinoma □ (C) BCL6—non-Hodgkin lymphoma □ (D) APC—osteoma □ (E) RET—pheochromocytoma □ (F) VHL—renal cell carcinoma

42 (A) Caplan syndrome includes pneumoconiosis (with progressive massive fibrosis producing restrictive lung disease) coupled with rheumatoid arthritis. Carney syndrome includes atrial and extracardiac myxomas, irregular pigmentation, and endocrinopathies. Churg-Strauss syndrome is a form of pulmonary vasculitis with allergic manifestations. Felty syndrome includes rheumatoid arthritis with splenomegaly and secondary hypersplenism (anemia, leukopenia, thrombocytopenia). Hamman-Rich syndrome is idiopathic pulmonary interstitial fibrosis. Kartagener syndrome includes absence of ciliary dynein arms leading to bronchiectasis, and situs inversus is present. In Trousseau syndrome, hypercoagulability results from a paraneoplastic effect, and pulmonary thromboembolism is often present.

42 A 60-year-old man has pain in his hands and feet on arising in the morning. The pain persists for almost 2 hours and is aggravated by movement. He would rather stay in bed. He has weakness, easy fatigability, and anorexia, and reports a 6- kg weight loss over the past 2 years. On physical examination, his temperature is 37.4°C, pulse is 74/min, respirations are 20/min, and blood pressure is 110/70 mm Hg. There is warmth, tenderness, and limitation of motion of the joints of his hands. He develops joint deformities over the next 5 years. A chest radiograph shows extensive interstitial lung disease and a prominent right-sided heart border. Spirometry reveals decreased FEV1 and FVC. Additional findings include 1-cm, firm, subcutaneous nodules over the olecranon bursae and Achilles tendons. What is the most likely diagnosis? □ (A) Caplan syndrome □ (B) Carney syndrome □ (C) Churg-Strauss syndrome □ (D) Felty syndrome □ (E) Hamman-Rich syndrome □ (F) Kartagener syndrome □ (G) Trousseau syndrome

43 (F) The patient has mixed connective tissue disease, which has overlapping features of systemic lupus erythematosus (SLE), scleroderma, polymyositis, and rheumatoid arthritis. ANCA is most likely to be seen in vasculitides such as Wegener granulomatosis or microscopic polyarteritis. Antibodies to cyclic citrullinated peptide (anti-CCP) have greater than 99% specificity for rheumatoid arthritis, and these patients are more likely to have severe disease. Antihistone antibodies are most characteristic of drug-induced SLE. Anti-Smith antibodies are very specific for SLE. Thyroid peroxidase antibodies are seen in autoimmune thyroid disorders, such as Hashimoto thyroiditis and Graves disease.

43 A 40-year-old man has noticed worsening myalgias and increasing difficulty swallowing over the past 2 years. When exposed to cold, the skin of his hands turns white. On physical examination, he has an erythematous rash extending across the bridge of his nose. There is swelling and warmth in the joints of his hands. Laboratory findings show hemoglobin, 12.2 g/dL; hematocrit, 36.5%; platelet count, 180,000/mm3; WBC count, 4510/mm3; serum glucose, 72 mg/dL; total bilirubin, 1 mg/dL; AST, 41 U/L; ALT, 19 U/L; alkaline phosphatase, 69 U/L; creatine kinase, 483 U/L; and creatinine, 1.3 mg/dL. The presence of antibodies to which of the following is most characteristic of his condition? □ (A) ANCA □ (B) Cyclic citrullinated peptide □ (C) Histone □ (D) Smith □ (E) Thyroid peroxidase □ (F) U1-RNP

44 (C) This man has features of acute cocaine toxicity with hyperthermia and chronic cocaine use with coronary arteriopathy and cerebral hemorrhagic strokes. The brown discoloration from hemosiderin deposition in the left anterior frontal lobe suggests a subacute to remote hemorrhage. Cocaine is a powerful vasoconstrictor. Similar to cocaine, amphetamine and methamphetamine are "uppers," or stimulants; however, they do not typically produce arterial changes. Barbiturates are "downers," or depressants. Ethanol is a depressant that can produce liver disease, but the cardiac effect is obscure and results in dilated cardiomyopathy. Heroin is an opiate narcotic that has minimal effects itself, but the typical route of administration is intravenous, and this can lead to numerous infectious complications, such as hepatitis, endocarditis, meningitis, and AIDS. Marijuana is a mild tranquilizer. Phencyclidine is a schizophrenomimetic that causes erratic behavior, but not obvious tissue effects.

44 A 19-year-old man is found unconscious by his roommate and taken to the emergency department. On physical examination, temperature is 41.2°C, pulse is 103/min, respirations are 18/min and shallow, and blood pressure is 145/100 mm Hg. He develops an intractable cardiac dysrhythmia and dies. At autopsy, the heart is slightly enlarged; microscopically, the distal coronary arteries are thickened. Sections of the brain show a 2-cm area of hemorrhage in the right superior parietal lobe and a 0.5-cm hemorrhage in the medulla. There is a partially cystic, 1-cm area with brown discoloration in the left anterior frontal lobe. What drug was this patient most likely using regularly? □ (A) Amphetamine □ (B) Barbiturate □ (C) Cocaine □ (D) Ethanol □ (E) Heroin □ (F) Marijuana □ (G) Methamphetamine □ (H) Phencyclidine

45 (B) Thromboembolic events and hepatic adenoma are rare complications of oral contraceptive use. Allopurinol and sulfonamides are associated with hepatic granuloma formation. Aspirin use in children has been associated with Reye syndrome with microvesicular steatosis. Isoniazid has been associated with acute or chronic hepatitis. Phenacetin and acetaminophen use have been associated with analgesic nephropathy, and excessive acetaminophen use may produce acute massive hepatic necrosis. The combination of prednisone and cyclophosphamide is used in aggressive immunosuppressive therapy and results in an immunocompromised state with increased risk of infection.

45 A 44-year-old woman has noted dull right upper quadrant pain for the past year. On physical examination, there is right upper quadrant tenderness on palpation. Abdominal CT scan shows a 5-cm, circumscribed mass in the superior right lobe of the liver. The figure shows the representative gross appearance of a similar mass. She experiences sudden onset of dyspnea with diaphoresis 1 month later. Multiple peripheral perfusion defects are seen on a pulmonary ventilation/perfusion scan. Which of the following combinations of pharmacologic agents taken by this patient regularly is most likely to be associated with these findings? □ (A) Allopurinol and sulfamethoxazole □ (B) Ethynyl estradiol and norethindrone □ (C) Ibuprofen and acetylsalicylic acid □ (D) Isoniazid and rifampicin □ (E) Phenacetin and acetaminophen □ (F) Prednisone and cyclophosphamide

46 (E) This woman has features seen in chronically bedridden individuals. There is a large saddle thromboembolus in the pulmonary arterial trunk. Antiphospholipid syndrome can include thromboembolic events, but osteoporosis, decubital ulcers, and muscle wasting are not features. Aplastic anemia leads to high-output congestive heart failure, bleeding diathesis from thrombocytopenia, and risk of infections. Chronic alcoholism produces chronic liver disease that predisposes to bleeding problems, not thrombosis. Blunt trauma is marked by contusions and fractures. Malnutrition could account for decreased bone density from osteomalacia, poor wound healing with skin ulceration, and muscle wasting, but coagulopathy with bleeding is more likely to occur than thromboembolism.

46 A 90-year-old woman died suddenly. Autopsy shows a 5-cm skin ulceration extending to the sacrum. She had diffuse muscle wasting; a microscopic section shows decreased size of muscle fibers without inflammation or fibrosis. Her bones show marked osteoporosis, and there is vertebral column kyphosis. A finding on examination of the lungs is shown in the figure. There is a right lower lobe pneumonia. Which of the following conditions most likely predisposed this patient to the pathologic findings seen at autopsy? □ (A) Antiphospholipid syndrome □ (B) Aplastic anemia □ (C) Chronic alcoholism □ (D) Elder abuse with blunt trauma □ (E) Immobilization □ (F) Malnutrition

47 (E) The findings are those of subacute bacterial endocarditis, and the needle track in the left arm suggests intravenous drug use as the risk factor. These individuals can have right-sided and left-sided valvular lesions. The vegetations are likely to embolize, and the septic emboli can lead to infection or infarction of multiple organs from left-sided lesions and of the lungs from right-sided lesions. The pulmonary nodule is likely a lung abscess. The patient probably has acute pyelonephritis from hematogenous infection. Candida albicans is a cause of endocarditis in immunocompromised individuals. Cryptococcus neoformans is a rare cause of endocarditis in immunocompromised individuals. Escherichia coli is a likely cause of ascending urinary tract infections with pyelonephritis, but it is an uncommon cause of endocarditis. Listeriosis most often results from food or water contamination and can lead to sepsis with meningitis, but rarely endocarditis. Streptococcal infections are more likely to cause endocarditis in individuals with preexisting valvular heart disease, and viridans streptococci is most often implicated. Yersinia enterocolitica can produce enterocolitis, not endocarditis (this organism can persist in stored blood and cause transfusion-related sepsis).

47 A 29-year-old man has had a low-grade fever for the past 2 weeks. He has had increasing fatigue and a 2-kg weight loss during this time. On physical examination, his temperature is 37.5°C, pulse is 80/min, respirations are 17/min, and blood pressure is 150/70 mm Hg. His spleen tip is palpable, and there is left upper quadrant tenderness. There is bilateral costovertebral angle tenderness. A diastolic murmur is heard at the left sternal border. Subungual hemorrhages are noted on the digits of his hands. A needle track is present in the left antecubital fossa. Laboratory findings show hemoglobin, 13.6 g/dL; hematocrit, 41.8%; platelet count, 228,000/mm3; WBC count, 11,200/mm3; glucose, 66 mg/dL; AST, 101 U/L; ALT, 28 U/L; alkaline phosphatase, 89 U/L; amylase, 45 U/L; and total bilirubin, 0.9 mg/dL. Urinalysis shows 1+ hematuria, and WBCs and WBC casts. A chest radiograph shows a 3-cm nodule with an air-fluid level in the right upper lobe. What organism is most likely to be cultured from his blood? □ (A) Candida albicans □ (B) Cryptococcus neoformans □ (C) Escherichia coli □ (D) Listeria monocytogenes □ (E) Staphylococcus aureus □ (F) Streptococcus pyogenes □ (G) Yersinia enterocolitica

48 (E) The patient has thrombotic thrombocytopenic purpura (TTP) with the classic pentad of neurologic changes, fever, thrombocytopenia, microangiopathic hemolytic anemia, and decreased renal function. The pathogenesis of TTP is related to release of von Willebrand factor (vWF). Monomers of vWF are linked by disulfide bonds to form multimers with various molecular masses that range to millions of daltons. A vWF-cleaving metalloproteinase in plasma normally prevents the entrance into the circulation (or persistence) of unusually large multimers of vWF. The metalloproteinase is referred to as ADAMTS 13 (a disintegrin and metalloproteinase, with thrombospondin-1-like domains). In most patients with TTP, plasma ADAMTS 13 activity is less than 5% of normal. The patient's hemoglobin concentration is not low enough to justify transfusion of RBCs. Giving platelets to a patient with TTP would "add fuel to the fire" because the platelets would cause more thrombi to form, resulting in further organ damage. Simple pressor agents, such as dobutamine, are not primary therapy. Surgery is not indicated because the injury is occurring in the small vasculature of many organs. Prednisone may be given to a subset of patients who do not respond to plasmapheresis.

48 A 41-year-old woman has had headaches with blurred vision for the past 3 days. Over the past day, she has developed increasing mental confusion. On admission to the hospital, her temperature is 37.9°C, pulse is 104/min, respirations are 25/min, and blood pressure is 70/40 mm Hg. On physical examination, she has petechial hemorrhages over her arms and trunk. A stool sample is positive for occult blood. Laboratory findings show hemoglobin of 9.1 g/dL, hematocrit of 27.2%, MCV of 92 μm3, RDW of 19%, platelet count of 8900/mm3, and WBC count of 8950/mm3. The peripheral blood smear shows schistocytes. A serum electrolyte panel shows Na+, 147 mmol/L; K+, 5 mmol/L; Cl−, 105 mmol/L; CO2, 26 mmol/L; creatinine, 3.3 mg/dL; urea nitrogen, 32 mg/dL; and glucose, 80 mg/dL. Ultra-large multimers of von Willebrand factor are present in plasma. What therapy should she receive emergently? □ (A) 2 U of packed RBCs □ (B) 6-pack of platelets □ (C) Dobutamine □ (D) Exploratory laparotomy □ (E) Plasmapheresis □ (F) Prednisone

49 (C) The patient has Budd-Chiari syndrome, a rare condition that can complicate pregnancy or the postpartum state. Hepatic venous occlusion leads to hepatomegaly with severe centrilobular congestion and necrosis, much more pronounced than the typical "nutmeg" liver of chronic passive congestion with right-sided heart failure. Biliary tract obstruction with choledocholithiasis would increase the serum bilirubin to a greater degree than in this patient, and hepatomegaly is unlikely. Hepatic adenomas, which can be associated with use of oral contraceptives, are mass lesions, usually several centimeters in size. At 12 weeks' gestation, with a fetus present, choriocarcinoma is very unlikely, and a marked increase in liver enzymes is unlikely. Acute fatty liver of pregnancy with microvesicular steatosis produces a more uniform density with hepatomegaly, a condition that is seen in the third trimester of pregnancy.

49 A 30-year-old woman has noted a 5-kg weight gain over the past 3 months; she has not had a menstrual period during that time. She has experienced upper abdominal pain for the past month. Physical examination shows abdominal enlargement with apparent ascites. There is no peripheral edema. She has a positive pregnancy test. Additional laboratory findings show hemoglobin, 13.2 g/dL; hematocrit, 39.7%; WBC count, 12,300/mm3; glucose, 80 mg/dL; AST, 581 U/L; ALT, 611 U/L; total bilirubin, 1.3 mg/dL; total protein, 6.2 g/dL; and albumin, 3.5 g/dL. An abdominal ultrasound scan shows hepatomegaly with heterogeneous echogenicity, and there is an intrauterine gestation with a fetus estimated at 12 weeks' size. What pathologic finding is most likely to be present? □ (A) Choledocholithiasis □ (B) Chronic passive congestion □ (C) Hepatic venous thrombosis □ (D) Hepatocellular adenoma □ (E) Metastatic choriocarcinoma □ (F) Microvesicular steatosis

5 (F) This patient's findings of ascites, edema, and splenomegaly together with laboratory evidence of hepatic dysfunction suggest a hepatic disorder with portal hypertension, and the most common cause is hepatic cirrhosis from chronic alcohol abuse. Decreased estrogen metabolism results in testicular atrophy. The findings of right-sided and left-sided congestive heart failure are associated with alcoholic dilated cardiomyopathy. Macrocytic anemia is common, and the AST is slightly higher than the ALT, features typical of chronic alcoholism. Addison disease resulting from adrenal atrophy would not produce hypoalbuminemia or liver enzyme elevations, and the glucose level is often lower. Aortic stenosis may explain the pulmonary edema. Autoimmune gastritis may lead to gastric mucosal atrophy, loss of parietal cells, and megaloblastic anemia, but not to hepatic abnormalities. In chronic glomerulonephritis severe enough to produce a hepatorenal syndrome, the renal failure would be much worse and would be indicated by a high serum creatinine. Dilated cardiomyopathy is a type of cardiomyopathy typical of chronic alcoholism.

5 A 56-year-old man has noticed increasing abdominal girth and decreased libido for the past 7 months. Physical examination shows an enlarged abdomen with a fluid wave, but no tenderness or masses; the spleen tip is palpable. Bibasilar crackles are audible on auscultation of the chest. There is 1+ pitting edema to the knees. The testes are smaller than normal, but without masses. Laboratory findings show hemoglobin, 12.2 g/dL; hematocrit, 36.9%; MCV, 103 μm3; platelet count, 189,400/mm3; WBC count, 5762/mm3; Na+, 138 mmol/L; K+, 3.9 mmol/L; Cl−, 98 mmol/L; CO2, 24 mmol/L; creatinine, 1.1 mg/dL; glucose, 88 mg/dL; total protein, 5.7 g/dL; albumin, 2.7 g/dL; AST, 167 U/L; ALT, 69 U/L; alkaline phosphatase, 48 U/L; total bilirubin, 1.5 mg/dL; and prothrombin time, 23 seconds. What is the most likely diagnosis? □ (A) Adrenal atrophy □ (B) Aortic valvular stenosis □ (C) Autoimmune gastritis □ (D) Chronic glomerulonephritis □ (E) Hypertrophic cardiomyopathy □ (F) Micronodular cirrhosis

50 (B) In common variable immunodeficiency (CVID), there are normal numbers of T cells with normal to low numbers of B cells, and there is hypogammaglobulinemia with decreased IgG and possibly other immunoglobulin types. CVID occurs in young adults of both sexes, causing increased bacterial infections and giardiasis and recurrent herpes simplex (and herpes zoster) infections. The mechanisms are diverse and include failure of B-cell maturation to plasma cells, excessive T-cell suppression, and defective T-helper cell function. A selective abnormality of T-cell activation, as shown by decreased synthesis of interleukins (IL-2, IL-4, and IL-5), has been identified in some cases. Other patients have T-cell and B-cell autoantibodies or a decreased CD4+-to-CD8+ ratio. Mutations in genes encoding NADPH oxidase proteins produce chronic granulomatous disease and recurrent infections with Aspergillus, Staphylococcus, Serratia, Nocardia, and Pseudomonas. In hyper-IgM syndrome, mutations in the CD40 ligand induce failure in B cells, with low IgG, IgA, and IgE levels, but increased IgM; in infancy and childhood, there is increased risk of severe infections with bacterial and viral agents and opportunistic agents, such as Pneumocystis jiroveci. Mutations in CD18, the common β chain of integrins, which aid in binding of leukocytes, lead to leukocyte adhesion deficiency with leukocytosis, but with absence of suppurative inflammation in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria. In severe combined immunodeficiency (SCID), half of cases result from an X-linked mutation for the common γ chain of IL-2, a receptor for many cytokines needed for T-cell development, and the other half of cases result from autosomal recessive mutation in adenosine deaminase with accumulation of purine metabolites toxic to T cells. In SCID, although T cells are primarily involved, there is secondary impairment of B-cell function, so that affected individuals have diminished IgG levels and no IgA or IgM, and decreased T-cell function, resulting in increased susceptibility to virtually all infectious organisms.

50 A 25-year-old man has had increasingly frequent infections over the past 5 years. His most recent respiratory infection was due to Streptococcus pneumoniae. He now has watery diarrhea. On physical examination, he is below ideal weight. There is a vesicular rash in the T10 dermatomal distribution on the left. Laboratory findings include hemoglobin, 14.3 g/dL; hematocrit, 43.2%; platelet count, 290,600/mm3; and WBC count, 7200/mm3 with 55% segmented neutrophils, 2% bands, 35% lymphocytes, 6% monocytes, and 2% eosinophils. Quantitative immunoglobulins include IgA of 22 mg/dL, IgG of 175 mg/dL, and IgM of 40 mg/dL. Lymphocyte subsets by flow cytometry show CD4+ cells (absolute) of 630/μL, CD8+ cells (absolute) of 785/μL, B cells of 280/μL, and T cells of 2010/μL. A stool culture is negative for bacterial pathogens, but a stool culture for ova and parasites shows Giardia lamblia cysts. What is the most likely diagnosis? (A) Chronic granulomatous disease □ (B) Common variable immunodeficiency □ (C) Hyper-IgM syndrome □ (D) Leukocyte adhesion deficiency □ (E) Severe combined immunodeficiency

51 (F) The patient has myotonic dystrophy, a form of muscular dystrophy in which there are increased CTG repeat sequences in the gene. Weakness in skeletal, cardiac, and smooth muscle develops, and cataracts, dementia, gonadal atrophy, and hypogammaglobulinemia. Deficiency of α-1,4-glucosidase leads to Pompe disease in infancy. Absence of dystrophin characterizes Duchenne muscular dystrophy, which affects young boys. The FGFR3 mutation is seen in achondroplasia, a form of short-limbed dwarfism. Mutations in the mitochondrial oxidative phosphorylase genes (mitochondrial myopathies) can produce neurodegenerative disorders and hearing loss, in addition to myopathy. Myophosphorylase is diminished in McArdle disease, which causes muscle pain on strenuous exercise. The neurofibromin gene is mutated in neurofibromatosis type 1, which does not have myopathy as a feature.

51 A 44-year-old man has had worsening exercise tolerance and peripheral edema during the past 5 years. He has noted increasing central opacifications that interfere with vision. He has frontal baldness. During the past 2 years, he has had progressive memory loss with decreasing ability to perform activities of daily living. On physical examination, there is significant atrophy of masseter, temporalis, scalene, deltoid, trapezius, and sternocleidomastoid muscles. There is bilateral testicular atrophy. A 2-hour glucose tolerance test shows serum glucose of 156 mg/dL. Serum quantitative immunoglobulins show IgG of 450 mg/dL, IgA of 303 mg/dL, and IgM of 197 mg/dL. His condition worsens over the next 3 years, with increasing muscular weakness, and he dies of bronchopneumonia. An abnormality in which of the following gene products is most likely to be present? (A) α-1,4-Glucosidase □ (B) Dystrophin □ (C) Fibroblast growth factor receptor 3 □ (D) Mitochondrial oxidative phosphorylase □ (E) Myophosphorylase □ (F) Myotonin protein kinase □ (G) Neurofibromin

52 (E) This patient has microvesicular steatosis characteristic of Reye syndrome, which rarely occurs now because the link between aspirin use in children following a fever and hepatic injury has been recognized; it is caused by severe mitochondrial dysfunction in the brain and liver. Biliary atresia with marked hyperbilirubinemia becomes apparent in the neonatal period. Hepatic venous thrombosis leads to Budd-Chiari syndrome, which is typically a disease of adults that complicates such conditions as polycythemia or pregnancy. Hepatoblastomas may be congenital, but they are mass lesions unlikely to be associated with such marked increases in liver enzymes. Intrahepatic lithiasis is unlikely to occur in children and is unlikely to produce marked increases in liver enzymes. Neonatal giant-cell hepatitis can produce findings of acute hepatitis in neonates, not in children.

52 A 4-year-old girl has abrupt onset of vomiting, which remains protracted for 24 hours. On arrival at the emergency department, the child is lethargic and febrile to 37.7°C. The parents state that she had a mild upper respiratory tract illness 3 days ago, but was improving, and the only medication she received was acetylsalicylic acid (aspirin). On physical examination, there is poor skin turgor, the lungs are clear, the abdomen is nontender, and the heart rate is regular. Laboratory findings show Na+, 150 mmol/L; K+, 4.5 mmol/L; Cl−, 93 mmol/L; CO2, 30 mmol/L; glucose, 60 mg/dL; creatinine, 1.1 mg/dL; amylase, 25 U/L; AST, 386 U/L; ALT, 409 U/L; alkaline phosphatase, 120 U/L; total bilirubin, 1.1 mg/dL; ammonia, 80 μmol/L; and prothrombin time, 26 seconds. The child becomes comatose. What pathologic finding is most likely present in this patient? (A) Common bile duct atresia □ (B) Hepatic vein thrombosis □ (C) Hepatoblastoma □ (D) Intrahepatic duct lithiasis □ (E) Microvesicular steatosis □ (F) Multinucleated giant cells

53 (E) This patient has findings that strongly suggest a ruptured ectopic pregnancy—hence human chorionic gonadotropin levels would be increased. Gonococcal and chlamydial infections are risk factors for pelvic inflammatory disease, which increases the risk of ectopic pregnancy. An increase in carcinoembryonic antigen is seen in some gastrointestinal tract neoplasms, but this patient is young to have such malignancies. Amebiasis would produce a bloody diarrhea, and perforation of the colon is uncommon. Factor XIII, which stabilizes fibrin clots, can be deficient, but this is extremely rare. Bleeding is first observed in the neonatal period; older patients may have poor wound healing, intracerebral hemorrhage, infertility (men), and abortion (women). Decreased follicle-stimulating hormone is typical of pituitary failure, which does not explain the bleeding. A ruptured ectopic pregnancy may lead to disseminated intravascular coagulopathy with increased partial thromboplastin time and prothrombin time, but the normal platelet count in this patient suggests that this has not yet occurred. Schistosomiasis resulting fromSchistosoma haematobium can produce hematuria, but the bladder is not perforated.

53 A 22-year-old woman has sudden onset of severe lower abdominal pain. Her medical history is remarkable for Chlamydia trachomatis cervicitis. On physical examination, her temperature is 36.9°C, pulse is 90/min, respirations are 17/min, and blood pressure is 90/50 mm Hg. There is lower abdominal tenderness, but no palpable masses. No vaginal bleeding is present. The rectal examination is unremarkable, and a stool sample is negative for occult blood. Bowel sounds are reduced. An abdominal ultrasound scan is performed, and the uterus appears normal in size with no masses visualized, but there is a right adnexal mass. Culdocentesis is performed, and there is blood in the aspirate. Laboratory findings show hemoglobin of 9.5 g/dL, hematocrit of 28.6%, platelet count of 269,300/mm3, and WBC count of 9110/mm3. Which of the following laboratory findings is most likely to be present? (A) Carcinoembryonic antigen increase □ (B) Entamoeba histolytica cysts in stool □ (C) Factor XIII deficiency □ (D) Follicle-stimulating hormone decrease □ (E) Human chorionic gonadotropin elevation □ (F) Partial thromboplastin time prolonged □ (G) Schistosoma haematobium eggs in urine

54 (C) The findings point to prolonged and sustained systemic hypertension that has led to left ventricular hypertrophy, hypertensive retinopathy, and chronic renal failure with arteriolosclerosis. The figure shows lacunar infarcts in basal ganglia. The location of the cerebral hemorrhage is classic for hypertension. Chronic alcohol abuse can lead to hepatic failure and to dilated cardiomyopathy with congestive heart failure, but renal failure is unlikely, and CNS hemorrhages are often related to trauma secondary to falls. Diabetes mellitus can lead to renal failure, ischemic heart disease, and strokes, but the retinal changes are those of background and proliferative retinopathy, and the location in the brain is not characteristic for ischemic or embolic strokes. Rheumatic heart disease can lead to congestive failure and to risk for embolization with strokes, and to prerenal azotemia, but there are usually no funduscopic findings. Sickle cell disease can produce retinopathy similar to diabetes mellitus; cardiac failure and renal failure are possible complications, but this patient is too old for such complications. SLE can lead to chronic renal disease and hypertension, but he has no diagnostic findings for SLE.

54 A 68-year-old man has had headaches with increasing fatigue and dyspnea for the past 2 years. On physical examination, there are crackles at the lung bases. Funduscopy shows retinal arteries with a "silver wire" appearance. The figure shows the representative appearance of his brain. A chest x-ray shows a prominent left heart border. He then has sudden loss of consciousness, and head CT scan now shows a right putamen hematoma. Laboratory studies show serum glucose of 77 mg/dL, creatinine of 2.5 mg/dL, and total cholesterol of 181 mg/dL. What underlying conditions does he most likely have? □ (A) Chronic alcohol abuse □ (B) Diabetes mellitus □ (C) Essential hypertension □ (D) Rheumatic heart disease □ (E) Sickle cell anemia □ (F) Systemic lupus erythematosus

55 (D) This patient is morbidly obese with complications, including obesity hypoventilation syndrome, glucose intolerance, probable sleep apnea, cholelithiasis, and osteoarthritis. Macrovesicular steatosis with hepatomegaly is seen in obesity and may progress to cirrhosis. Weight gain owing to hypothyroidism, which could occur in Hashimoto thyroiditis, is modest and does not lead to morbid obesity. An "obesity cardiomyopathy" resembles dilated cardiomyopathy. Laryngeal papillomatosis, which produces airway obstruction (without snoring), occurs more often in children and is not associated with obesity. The blood gas findings in this case could be seen in emphysema, which is not a complication of obesity; panlobular emphysema is much less common than the centrilobular emphysema associated with smoking. Rheumatoid arthritis tends to involve small joints first, and there is no relationship to obesity.

55 A 49-year-old man has had increasing knee and hip pain for the past 10 years. The pain is worse at the end of the day. During the past year, he has become increasingly drowsy at work. His wife complains that he is a "world class" snorer. During the past month, he has experienced bouts of sharp, colicky, right upper abdominal pain. On physical examination, his temperature is 37°C, pulse is 82/min, respirations are 10/min, and blood pressure is 140/85 mm Hg. He is 175 cm (5 ft 8 in) tall and weighs 156 kg (body mass index 51). Laboratory findings show glucose of 139 mg/dL, total cholesterol of 229 mg/dL, and HDL cholesterol of 33 mg/dL. An arterial blood gas measurement shows pH of 7.3, Pco2 50 mm Hg, and Po2 70 mm Hg. What condition is most likely present? □ (A) Hashimoto thyroiditis □ (B) Hypertrophic cardiomyopathy □ (C) Laryngeal papillomatosis □ (D) Nonalcoholic steatohepatitis □ (E) Panlobular emphysema □ (F) Rheumatoid arthritis

5 6 (A) One hypothesis regarding the death of Napoleon Bonaparte is that he was the victim of arsenic poisoning perpetrated by former enemies. The FBI analyzed a hair sample in 1995 and found increased arsenic levels, but the amount was equivocal. Another hypothesis is that the wallpaper at Longwood House, where he lived, contained copper arsenate and became moldy, releasing arsine vapor. A third hypothesis suggests that he died of the effects of gastric cancer, not related to arsenic ingestion, substantiated by an observation at autopsy of lymphadenopathy adjacent to the stomach. Chronic arsenic exposure has been associated with a greatly elevated risk of skin cancer and possibly of cancers of the lung, liver (angiosarcoma), bladder, kidney, and colon. Beryllium acutely produces a pneumonitis, and long- term exposure leads to non-necrotizing granulomas, similar to sarcoidosis. Chromium or nickel exposure may lead to respiratory tract cancers. Cobalt poisoning can produce pulmonary interstitial fibrosis. Lead poisoning can produce abdominal pain, anemia, neuropathy, and decreased mental sharpness, but it is not associated with malignancies.

56 A 51-year-old man living on the island of St. Helena has had a downturn in his political fortunes. Over the past 3 years, and particularly over the past year, he has had increasing bouts of abdominal pain, anorexia, nausea, vomiting, dysuria, lethargy, spiking fevers, diarrhea, constipation, excessive weakness, heavy perspiration, and weight loss. He is given a large dose of calomel (a mercury-containing compound) a few days before his death May 5, 1821, a treatment that has since vanished for good reason. An autopsy shows hepatomegaly (with steatosis?) and ulceration with thickening of the stomach. The autopsy report does not record skin and nail changes, such as hyperkeratosis and hyperpigmentation. If those changes had been present, and squamous cell carcinoma of the skin, the findings would have been most suggestive of chronic poisoning with which of the following metals? □ (A) Arsenic □ (B) Beryllium □ (C) Chromium □ (D) Cobalt □ (E) Lead □ (F) Nickel

57 (D) Risk factors for HELLP (hemolysis with elevated liver enzymes and low platelets) syndrome, a variant of severe preeclampsia, include nulliparity, advanced maternal age, diabetes mellitus, preexisting hypertension, a prior history of preeclampsia, and renal disease. Patients with HELLP syndrome may progress to disseminated intravascular coagulation. Emergent delivery is indicated. Abruptio placentae is an acute event marked by severe abdominal pain and vaginal bleeding. Hepatic vein thrombosis in Budd-Chiari syndrome can produce liver necrosis with elevated enzymes; pregnancy is a risk factor, but this does not explain the neurologic and renal findings. Likewise, a dilated cardiomyopathy that can occur in pregnancy does not explain these findings. In hydatidiform mole, preeclampsia is more likely, but 30 weeks is a long time to have it, and a fetus would not be present. Acute fatty liver of pregnancy may resemble Reye syndrome (a disease that occurs in children) and may be preceded by preeclampsia. Sheehan syndrome is postpartum pituitary necrosis leading to hypopituitarism.

57 A 37-year-old primigravida at 30 weeks' gestation has noted increasing pedal edema for the past 2 weeks. During the past week, she has developed headaches and confusion, and she has decreased urine output. She exhibited seizure activity and then lapsed into a coma. On physical examination, her temperature is 36.8°C, pulse is 82/min, respirations are 18/min, and blood pressure is 145/95 mm Hg. Her heart rate is regular, and lung fields are clear. The abdomen is soft, and bowel sounds are present. There is pitting edema to the thighs. No vaginal bleeding is noted, and the cervix is not effaced. Laboratory findings show hemoglobin, 11.9 g/dL; hematocrit, 35.8%; platelet count, 73,000/mm3; WBC count, 8180/mm3; glucose, 151 mg/dL; total protein, 6.6 g/dL; albumin, 3.2 g/dL; total bilirubin, 2.3 mg/dL; AST, 78 U/L; ALT, 93 U/L; alkaline phosphatase, 253 U/L; and prothrombin time, 32 seconds. Urinalysis shows specific gravity of 1.024, pH 6, 4+ proteinuria, 1+ glucosuria, and no blood. An ultrasound examination shows a viable 30-week fetus. What condition is most likely present in this patient? □ (A) Abruptio placentae □ (B) Budd-Chiari syndrome □ (C) Dilated cardiomyopathy □ (D) HELLP syndrome □ (E) Hydatidiform mole □ (F) Reye syndrome □ (G) Sheehan syndrome

58 (C) The combination of nongonococcal urethritis, arthritis, and conjunctivitis suggests Reiter syndrome, one of the spondyloarthropathies; the changes in the spine can resemble ankylosing spondylitis and can be equally debilitating. ANCA is indicative of forms of vasculitis, such as Wegener granulomatosis. The ANA test result is positive in many autoimmune diseases, such as systemic lupus erythematosus (SLE), but it is not a feature of spondyloarthropathies. Lyme disease can include large joint arthritis, but not urethritis or conjunctivitis. PPD is positive in prior tuberculosis infection, which may include a large joint arthritis. RPR is a screening test for syphilis, which can include arthritis of large joints (Charcot joint) in the tertiary form, but it takes decades to develop. Rheumatoid factor is a feature of rheumatoid arthritis, which initially manifests more commonly in small joints of the hands and feet. U1-RNP is a marker for mixed connective tissue disease, which has features of rheumatoid arthritis, scleroderma, polymyositis, and SLE; arthralgias are not accompanied by joint destruction or deformity.

58 A 29-year-old man sees his physician because of burning pain on urination that has persisted for 3 days. There is a urethral discharge. A sample of the exudate is positive by ELISA for Chlamydia trachomatis. The man has increasing stiffness of the knees and ankles and lower back pain 3 weeks later. A radiograph of the lumbar spine shows narrowing with sclerosis of the sacroiliac joints. One month later, he develops painful erythema of the penile glans, and the conjunctivae are red. A follow-up examination shows a slightly irregular heart rate and a murmur suggestive of aortic regurgitation. The back pain continues off and on for 5 more months. Which of the following test results is most likely to be positive?□ (A) ANCA □ (B) ANA □ (C) HLA-B27 antigen □ (D) Lyme disease □ (E) Purified protein derivative □ (F) Rapid plasma reagin □ (G) Rheumatoid factor □ (H) U1-RNP

59 (F) Von Hippel-Lindau disease is rare and results from acquired or inherited mutation in a tumor suppressor gene. Beckwith-Wiedemann syndrome includes Wilms tumor, hemihypertrophy, and adrenal cytomegaly. The MET oncogene is mutated in papillary renal carcinomas (not associated with other tumors elsewhere) and in Denys-Drash syndrome, which also includes Wilms tumor plus gonadal dysgenesis and nephropathy. Gardner syndrome has the same mutation in the adenomatous polyposis coli (APC) gene as familial polyposis, but also has osteomas, epidermal cysts, and fibromatoses. Neurofibromatosis type 2 includes schwannomas, meningiomas, gliomas, and ependymomas. Tuberous sclerosis is one of the phakomatoses with cortical hamartomas called tubers, renal angiomyolipomas, cardiac rhabdomyomas, and subungual fibromas.

59 A 19-year-old man has been having headaches for the past month. On physical examination, his temperature is 37°C, pulse is 77/min, respirations are 14/min, and blood pressure is 160/95 mm Hg. On funduscopic examination, there are bilateral retinal angiomas. Abdominal CT scan shows a 3-cm mass involving the right adrenal gland. Laboratory testing shows increased urinary catecholamines. The mass is removed surgically. He develops a movement disorder 5 years later with incoordination and ataxia. MRI of the brain shows a 2-cm mass in the left cerebellar hemisphere and a 1-cm mass in the vermis. These are removed surgically. Six years later, he has right flank pain with hematuria; his abdominal CT scan is shown in the figure. His hemoglobin concentration is 20.3 g/dL, and hematocrit is 60.9%. Which of the following gene mutations and associated neoplasms does he most likely have? □ (A) WT-1—Beckwith-Wiedemann syndrome □ (B) MET—Denys-Drash syndrome □ (C) APC—Gardner syndrome □ (D) NF2—Neurofibromatosis type 2 □ (E) TSC-1—Tuberous sclerosis □ (F) VHL—von Hippel-Lindau disease

6 (C) Elusive as the yeti, the "paradoxical" embolus explains her findings. She has thrombophlebitis with pulmonary embolism as a result of prolonged bed rest owing to her viral pneumonia. Her chronic obstructive pulmonary disease has led to cor pulmonale with enlarged right heart, reversing the shunt across an atrial septal defect, allowing a thromboembolus arising in the venous circulation to reach the systemic arterial circulation in the brain. A constrictive pericarditis yields a "paradoxical pulse" from impaired cardiac filling and greater than normal decline in systolic arterial pressure on inspiration; this is not associated with thromboembolism. A dilated cardiomyopathy should lead to global cardiac enlargement, not just enlargement of the right heart, and although mural thrombosis with embolism can occur, there is usually no association with thrombophlebitis. Infective endocarditis can lead to embolization, but in her case there is no fever of infection. Rheumatic heart disease can affect one or more valves, and often leads to left atrial enlargement with mural thrombosis and embolism, but the left atrial border would be prominent, and the pulmonic valve is almost never involved.

6 A 72-year-old woman with chronic bronchitis from cigarette smoking has been bedridden because of influenza virus infection for the past 2 weeks. She experiences sudden, severe dyspnea with chest pain. On examination, her temperature is 37°C, pulse is 104/min, respiratory rate is 26/min, and blood pressure is 100/60 mm Hg. Her left leg is swollen and painful on raising. She appears cyanotic. A systolic ejection sound and diastolic murmur are auscultated over the pulmonic region. A chest x-ray shows a prominent right heart border. Echocardiography shows blood flow from the right to left atrium. Laboratory studies show an elevated D-dimer. She then develops right leg weakness. MRI of the brain shows early infarction within the left hemisphere. Which of the following cardiac conditions best explains these findings? □ (A) Constrictive pericarditis □ (B) Dilated cardiomyopathy □ (C) Eisenmenger complex □ (D) Infective endocarditis □ (E) Rheumatic heart disease

60 (A) The patient has features of CREST syndrome, or limited scleroderma. Because her disease has not progressed to include serious pulmonary fibrosis or renal disease, she is less likely to have diffuse scleroderma, which is associated with the anti-DNA topoisomerase antibody. Gliadin antibodies are seen in celiac disease, which is marked by malabsorption, not esophageal dysmotility. Antimicrosomal (anti-thyroid peroxidase) antibodies are seen in autoimmune thyroid diseases, such as Hashimoto thyroiditis and Graves disease. Antimitochondrial antibody appears most frequently in primary biliary cirrhosis. ANCA can be a marker for various forms of vasculitis.

60 A 43-year-old woman has had increasing difficulty swallowing over the past year. She notices that her hands turn white and are painful on exposure to cold. She remarks, "I may be getting older, but at least I don't have any wrinkles on my face or hands yet." On physical examination, her temperature is 37°C, pulse is 68/min, respirations are 14/min, and blood pressure is 115/75 mm Hg. The skin of her face and hands appears taut and shiny. A punch biopsy specimen of the skin of the hand shows dermal collagenous fibrosis and focal calcification. She receives yearly esophageal dilation for the next 20 years, during which time she develops no serious illnesses. Which of the following serologic test results is most likely to be positive? □ (A) Anticentromere antibody □ (B) Anti-DNA topoisomerase antibody □ (C) Antigliadin antibody □ (D) Antimicrosomal antibody □ (E) Antimitochondrial antibody □ (F) ANCA

61 (B) The patient has features of Wernicke disease and beriberi, both resulting from thiamine deficiency, which can accompany chronic alcoholism. Vitamin A deficiency leads to night blindness, keratomalacia, and respiratory tract difficulties owing to epithelial disorders. Pure vitamin B2 deficiency is rare and is marked by findings such as neuropathy and cheilosis. Niacin deficiency leads to pellagra with dementia, diarrhea, and photodermatitis. Vitamin B12 deficiency leads to subacute combined degeneration of the spinal cord; MCV in this case is not in the range to cause macrocytosis. Vitamin C deficiency leads to scurvy with anemia, loose teeth, hematomas, and poor wound healing. Vitamin D deficiency in an adult leads to osteomalacia with risk of fractures. Vitamin E deficiency is rare and produces spinal cord changes similar to those of vitamin B12 deficiency.

61 A 56-year-old man has had increasing lower leg swelling during the past 6 months. Also, he has had so much difficulty breathing at night that he sleeps propped up on two pillows. On physical examination, his temperature is 37.1°C, pulse is 80/min, respirations are 17/min, and blood pressure is 110/70 mm Hg. On auscultation of the chest, bilateral crackles are audible at the lung bases. The liver span is increased. There is 2+ pitting edema to the thighs. Laboratory findings show hemoglobin, 13.4 g/dL; hematocrit, 40.2%; MCV, 88 μm3; platelet count, 229,300/mm3; and WBC count, 6715/mm3. He develops an acute psychosis 1 year later. He dies of aspiration pneumonia. At autopsy, there is anterior vermian atrophy and petechial hemorrhages with brown discoloration in the periaqueductal gray matter and shrunken mamillary bodies. A chronic deficiency of which of the following vitamins would most likely explain these findings? □ (A) Vitamin A (retinoic acid) □ (B) Vitamin B1 (thiamine) □ (C) Vitamin B2 (riboflavin) □ (D) Vitamin B3 (niacin) □ (E) Vitamin B12 (cobalamin) □ (F) Vitamin C (ascorbic acid) □ (G) Vitamin D (cholecalciferol) □ (H) Vitamin E (α-tocopherol)

62 (B) The patient has Pneumocystis jiroveci pneumonia. The spectrum of opportunistic infections, wasting syndrome, and lymphopenia suggest AIDS complicating HIV infection. This spectrum of findings is not typical of autoimmune diseases, which usually are accompanied by opportunistic infections in patients receiving immunosuppressive therapy (e.g., patients with systemic lupus erythematosus [SLE] who have a positive ANA test result). SLE-like disease is seen in C2 deficiency. B-cell function tends to be preserved in HIV infection, so marked hypogammaglobulinemia is unlikely to be present. The neutrophil oxidative burst assay is used to test for chronic granulomatous disease, an immunodeficiency condition in which bacterial infections are more likely to appear in children. RPR is a screening test for syphilis, which is a sexually transmitted disease that is not accompanied by immunodeficiency.

62 A 32-year-old woman has had increasing malaise and a 10-kg weight loss over the past 6 months. Physical examination shows muscle wasting, and there is a tan-yellow, plaquelike coating on her tongue. Laboratory testing shows hemoglobin, 12.6 g/dL; hematocrit, 37.8%; MCV, 85 μm3; platelet count, 188,300/mm3; and WBC count, 4320/mm3 with 73% segmented neutrophils, 3% bands, 9% lymphocytes, 14% monocytes, and 1% eosinophils. A scraping of the material from her tongue microscopically shows budding cells with pseudohyphae. She develops watery diarrhea 6 months later; a stool specimen contains cysts of Cryptosporidium parvum. She then develops a fever, cough, and severe dyspnea. Bronchoalveolar lavage is done; the figure shows the microscopic findings. Which of the following laboratory findings is most likely to be present? □ (A) ANA titer 1:1024 □ (B) CD4+ lymphocyte count 111/μL □ (C) Complement C2 undetectable □ (D) IgG 88 mg/dL □ (E) Neutrophil oxidative burst assay less than 5% □ (F) Positive RPR

63 (A) Metabolic acidosis, tinnitus, platelet function abnormalities, and gastritis with ulceration are typical effects of excessive aspirin ingestion. Acetaminophen in large quantities may produce hepatotoxicity. Adalimumab, a monoclonal antibody directed against tumor necrosis factor, and methotrexate are drugs used to treat rheumatoid arthritis and do not have antiplatelet effects. Oxycodone is an opiate, and propoxyphene is a non-narcotic analgesic; these drugs do not have significant effects on the gastrointestinal tract or on platelets.

63 A 73-year-old man has had bilateral knee and hip pain for the past 25 years and has taken a medication for this pain for the past 5 years. During the past year, he has noticed increasing frequency of headaches, dizziness, tinnitus, confusion, and nausea. He states that bruises form on his skin with minimal trauma. One week ago, he experienced an episode of hematemesis. On physical examination, his temperature is 37.1°C, pulse is 73/min, respirations are 18/min, and blood pressure is 130/80 mm Hg. There are scattered petechiae on his arms and legs and an area of purpura on his right thigh. His heart rate is regular, and the lungs are clear. No neurologic deficits are noted. Laboratory findings show hemoglobin, 11.1 g/dL; hematocrit, 33.1%; MCV, 72 μm3; platelet count, 317,200/mm3; WBC count, 5915/mm3; Na+, 139 mmol/L; K+, 3.9 mmol/L; Cl−, 98 mmol/L; CO2, 19 mmol/L; glucose, 76 mg/dL; and creatinine, 1.1 mg/dL. The partial thromboplastin time is 27 seconds, and the prothrombin time is 13 seconds. Platelet function analysis shows decreased aggregation in response to ADP and collagen stimulation. An upper gastrointestinal endoscopy shows gastric mucosal erythema and a 1.8-cm, sharply demarcated, shallow, antral ulceration. Long-term use of which of the following pharmacologic agents is most likely to produce these findings? □ (A) Acetylsalicylic acid □ (B) Acetaminophen □ (C) Adalimumab □ (D) Methotrexate □ (E) Oxycodone □ (F) Propoxyphene

64 (B) Choriocarcinoma is the most aggressive, and the least common, form of molar pregnancy. It can metastasize widely, particularly to the lungs and vagina, and also to the brain, liver, and kidney. The neoplasm is composed of a malignant-appearing syncytiotrophoblast and forms a soft, hemorrhagic mass that can rupture and bleed. In addition, the amount of human chorionic gonadotropin (hCG) produced by a choriocarcinoma is marked; hCG shares the same α- subunit as other glycoprotein hormones, such as thyroid-stimulating hormone (TSH), and may enhance the effect of TSH. Many choriocarcinomas respond to chemotherapy. Endometrial adenocarcinoma is most often seen in postmenopausal women. Clear cell carcinomas of the vagina most often appear in young women whose mothers were given diethylstilbestrol (DES) during pregnancy. A leiomyosarcoma is an uncommon lesion in women and usually produces a large uterine mass. Likewise, a malignant mixed müllerian tumor is a rare neoplasm seen in women. Sarcoma botryoides is a neoplasm found in girls younger than 5 years old.

64 For the past month, a 16-year-old girl has had increasing heat intolerance, with nervousness and a fine tremor. She has had irregular menstrual cycles since menarche 2 years ago and has not menstruated for 3 months. She has not used contraceptives. One week ago, she noticed a small amount of vaginal bleeding and now has sudden onset of severe abdominal pain. On physical examination, her temperature is 36.9°C, pulse is 105/min, respirations are 17/min, and blood pressure is 80/40 mm Hg. There is marked right upper quadrant abdominal tenderness, and bowel sounds are reduced. A stool sample is negative for occult blood. Brownish fluid is noted in the vaginal vault, emanating from a reddish brown, 2- cm mass in the vault. An abdominal ultrasound examination shows several 3- to 6-cm masses in the liver, and the uterus appears enlarged, with a 5-cm mass. An anteroposterior chest radiograph shows several 1- to 3-cm nodules in the lungs. Paracentesis is done, and there is blood in the aspirate. The figure shows the microscopic appearance of a biopsy specimen of the vaginal mass. She is given methotrexate and actinomycin D and improves. What neoplasm would most likely produce these findings? □ (A) Adenocarcinoma □ (B) Choriocarcinoma □ (C) Clear cell carcinoma □ (D) Leiomyosarcoma □ (E) Malignant mixed müllerian tumor □ (F) Sarcoma botryoides

65 (C) She has rheumatoid arthritis with anemia of chronic disease. Despite abundant stored iron such anemias are caused by impaired transfer of iron from macrophages to developing erythroid cells. Hepcidin is synthesized in the liver and normally released in response to increased intrahepatic iron levels. Hepcidin inhibits ferroportin function in macrophages and thus prevents transfer of iron. Hepcidin production in the liver is increased in chronic inflammatory states by the action of inflammatory mediators such as IL-6. C-reactive protein and IL-1β are also acute phase reactants but they do not affect hepcidin levels. IgG plays no role in iron metabolism. GM-CSF can cause increased production of normal macrophages.

65 A 43-year-old woman has had easy fatigability along with pain and stiffness of both wrist joints and other small joints of the hands for the past 7 years. The stiffness is marked in the morning and abates as the day goes by. X-rays of her hands reveal narrowing of the proximal interphalangeal and metacarpophalangeal joint spaces from synovitis and erosion of the cartilage. Laboratory tests show Hgb 8.4 g/dL, Hct 23.5, MCV 65 fL, and MCH 23 pg. Her peripheral blood smear shows hypochromic, microcytic red blood cells. Her serum iron and iron binding capacity levels are low and the ferritin level elevated. A high level of which of the following is most likely related to the causation of anemia in this woman? □ (A) C-reactive protein □ (B) GM-CSF □ (C) Hepcidin □ (D) IgG □ (E) IL-1β

66 (F) The findings are consistent with tertiary syphilis; specifically, syphilitic aortitis from endarteritis obliterans of the vasa vasorum, which is most marked in the proximal aorta. In addition, the patient has findings of neurosyphilis, with tabes dorsalis and general paresis. A positive VDRL test result on CSF aids in diagnosis. None of the remaining organisms listed produces aortic disease. Neuroborreliosis from Lyme disease can produce aseptic meningitis, encephalopathy, and polyneuropathy. Coxsackievirus B can produce meningoencephalitis and myocarditis. HIV can produce encephalitis characterized by dementia and motor and sensory deficits. Hansen disease, caused by Mycobacterium leprae infection, mainly affects the peripheral nerves. Tuberculosis can produce meningoencephalitis or a mass known as a tuberculoma; obstructive hydrocephalus may occur in chronic meningitis. West Nile virus is most likely to produce severe meningoencephalitis in elderly individuals.

66 A 70-year-old man has had increasing exercise intolerance and difficulty breathing for the past year. His family has noted memory loss and decreased ability to perform activities of daily living for the past 2 years. On physical examination, his temperature is 37.1°C, pulse is 70/min, respirations are 18/min, and blood pressure is 140/80 mm Hg. On auscultation of the chest, rales are audible in the lung bases, and there is a diastolic murmur. He has a marked decrease in sensation to light touch and pinprick over the lower extremities. His gait is ataxic, with the feet widely spaced. He cannot name any of three objects after 3 minutes. He thinks he is an astronaut returned from Mars. An echocardiogram shows aortic regurgitation with a widened aortic root and arch. MRI of the brain shows mild diffuse cortical atrophy and meningeal thickening. Infection with what organism would most likely produce these findings? □ (A) Borrelia burgdorferi □ (B) Coxsackievirus B □ (C) HIV □ (D) Mycobacterium leprae □ (E) Mycobacterium tuberculosis □ (F) Treponema pallidum □ (G) West Nile virus

67 (D) This girl has McCune-Albright syndrome, an acquired somatic gene defect that occurs during embryogenesis and leads to excessive cyclic AMP production that fuels endocrine gland activity. As a result, growth hormone-secreting pituitary adenomas, hyperthyroidism, adrenal hyperplasia, and sexual precocity can occur. There are café-au-lait spots. The bone lesions are polyostotic fibrous dysplasia. Most cases of fibrous dysplasia are solitary (monostotic) and unaccompanied by syndromic features. Albers-Schönberg disease is rare and leads to a form of osteopetrosis known as marble bone disease (the manatee normally has similar bone). Congenital adrenal hyperplasia, most often resulting from an inherited defect in 21-hydroxylase, can lead to sexual precocity, but not to bone lesions. Ollier disease is enchondromatosis (cartilaginous tumors in metaphyseal regions of long bones); if soft-tissue hemangiomas also are present, it is called Maffucci syndrome. Paget disease of bone (osteitis deformans) affects older individuals with monostotic or polyostotic lesions, which initially may be lytic, but then become sclerotic; there are no endocrinopathies.

67 A 9-year-old girl has been bothered by right lower leg pain for the past 3 months. On physical examination, she is at the 150th percentile for height. She has a 4 × 5 cm, dark café-au-lait spot with a serpiginous border on her right hip, and a similar 3 × 6 cm spot on the posterior aspect of her right shoulder. She has significant breast and pubic hair development. A radiograph of the lower leg shows a 3-cm, circumscribed, lucent lesion involving the intramedullary right tibial diaphysis, with expansion of surrounding bone. A biopsy specimen of the lesion has the microscopic appearance shown in the figure. Abdominal CT scan shows bilateral adrenal enlargement. MRI of the brain shows a gadolinium-enhancing, 1.5-cm mass in the sella turcica. What is the most likely diagnosis? □ (A) Albers-Schönberg disease □ (B) Congenital adrenal hyperplasia □ (C) Maffucci syndrome □ (D) McCune-Albright syndrome □ (E) Ollier disease □ (F) Osteitis deformans

68 (F) The sudden nature of the death requires investigation by the medical examiner (coroner), who would notify the local law enforcement agency on discovery of the findings in this case. The pattern of injuries is consistent with vigorous shaking of the infant. Because an infant's head is larger in proportion to its body compared with an adult, it cannot counter the shaking with neck musculature. Grasping the arms of the infant strongly and pressing or hitting the head against a hard surface increases the risk of internal injuries, including fractures. Axonal retraction balls are a feature of marked stretching and tearing with acceleration-deceleration forces. α-Thalassemia major leads to severe anemia with hydrops noted at birth; α-thalassemia minor leads to mild anemia. Congenital syphilis produces osteochondritis with skeletal deformities, not fractures, and without a bleeding tendency. Edwards syndrome is trisomy 18, which is characterized by multiple external anomalies, such as overlapping fingers, cleft lip, and omphalocele. Hemophilia A could account for hemorrhages in a child or adult, but not fractures. Osteogenesis imperfecta can account for fractures, but not hemorrhages. In sudden infant death syndrome, there would be no signs of trauma. Thanatophoric dysplasia is a lethal form of short-limbed dwarfism.

68 A 4-month-old boy was born at term to an 18-year-old woman, G1, P0, after a normal pregnancy. The woman returned home from work one evening and was told by her boyfriend, who is staying at her home, that the infant died suddenly. An autopsy shows no external anomalies. The infant's height and weight are at the 40th percentile. Internal examination reveals subarachnoid hemorrhage at the vertex and subdural hemorrhage over the right parietal lobe. The right eye shows petechial hemorrhages at the ora serrata. There is a soft-tissue hemorrhage in the right upper arm. There is a recent fracture of the occipital bone. A section of the frontal cortex shows axonal retraction balls in white matter tracts. What is the most likely diagnosis? □ (A) α-Thalassemia □ (B) Congenital syphilis □ (C) Edwards syndrome □ (D) Hemophilia A □ (E) Osteogenesis imperfecta □ (F) Shaken baby syndrome □ (G) Sudden infant death syndrome □ (H) Thanatophoric dysplasia

69 (A) He has features of Marfan syndrome and although the primary defect is mutation in the fibrillin-1 gene and hence poor formation of microfibrils, there is an important secondary effect on transforming growth factor-β (TGF-β) bioavailability. Normally microfibrils sequester TGF-β but in Marfan syndrome abnormal microfibrils allow excessive TGF-β signaling which is responsible for the cardiac symptoms. Bone marrow transplants are useful in those diseases where the primary defect is in the hematopoietic cells, or the marrow cells can deliver normal genes to the affected tissues. Even if one could transduce the fibrillin-1 gene into T cells, the protein cannot be delivered to the extracellular matrix. Marfan syndrome does not have abnormal lysosomes, and the vascular disorders are not the result of atherosclerosis accelerated by dietary factors.

69 A 35-year-old man presents with increasing breathlessness on exertion. On physical examination his height is 208 cm (82 in) with long arms and tapering fingers. His joints are exceptionally flexible. He also has bilateral subluxation of crystalline lenses. Echocardiography reveals mitral valve prolapse and an aneurysm in his ascending aorta. Which of the following experimental therapies is likely to be beneficial in treating this man? □ (A) Anti-TGF-β antibody □ (B) Bone marrow transplantation □ (C) Low-calorie, low-cholesterol diet □ (D) Lysosomal stabilizing agents □ (E) Transduction of fibrillin-1 gene into T cells

7 (E) The patient has findings that are consistent with sickle cell anemia (hemoglobin SS) with abdominal crisis and vertebral bone marrow infarction. The haptoglobin is low as a result of sickle cell crisis with hemolysis. The continued hemolysis leads to formation of pigmented gallstones. "Autosplenectomy" is a consistent finding. There is a predisposition to aseptic necrosis and osteomyelitis, particularly with Salmonella. The MCV is high because of reticulocytosis, and the RDW is quite high because of sickling and hemolysis. An elevated amylase level could be seen in acute pancreatitis, which could occur with gallstones, but this would not explain the anemia or the undetectable spleen. Antiphospholipid syndrome (APS) with anticardiolipin antibodies leads to thrombosis, but the abdomen is not the typical location, and the anemia is not explained by APS. Pancreatitis can complicate hypercalcemia and hypertriglyceridemia, but this does not explain the anemia or undetectable spleen. An increased serum ferritin level indicates increased iron stores, which is most typical of hemochromatosis. This condition could complicate β-thalassemias, but not sickle cell disease, unless the patient has received many blood transfusions.

7 A 20-year-old man has sudden onset of severe abdominal and back pain and dyspnea. His medical history indicates similar episodes over a 12-year period. He had osteomyelitis of the left hip 1 year ago; the bone culture was positive for Salmonella enteritidis. On physical examination, his lungs are clear to auscultation, but he has tachycardia. Palpation of the abdomen reveals diffuse tenderness with rigidity of abdominal musculature, but no apparent masses. CT scan of the chest shows prominent pulmonary veins, but no infiltrates. Abdominal CT scan shows the presence of multiple 0.5- to 1-cm stones in the gallbladder, a very small spleen, and prominent hepatic veins. An abdominal radiograph shows no free air. CBC shows hemoglobin of 10.2 g/dL, hematocrit of 30.9%, MCV of 99 μm3, RDW of 22, platelet count of 189,300/mm3, and WBC count of 6320/mm3. What additional laboratory test finding is most likely to be reported? □ (A) Amylase 694 U/L □ (B) Positive anticardiolipin antibody □ (C) Calcium 12.3 mg/dL □ (D) Ferritin 710 ng/mL □ (E) Haptoglobin 1 mg/dL □ (F) Triglyceride 1140 mg/dL

70 (E) Vitamin A deficiency leads to epithelial disorders affecting the cornea, skin, respiratory tract, and urinary tract. *Squamous metaplasia* (shown) in the respiratory tract increases the risk of infection; desquamation of keratin debris forms the nidus of urinary tract calculi. Hyperkeratosis and follicular plugging affect the epidermis. Cystic fibrosis leads to an increased risk of respiratory tract infections, particularly infections caused byPseudomonas, from widespread bronchiectasis; the skin and eye are not affected. Congenital syphilis can produce bone deformities and gummas. HIV infection can be complicated by opportunistic infections, including infections of the respiratory tract, but keratomalacia is not a feature of HIV infection. Kartagener syndrome can lead to bronchiectasis from an altered respiratory tract epithelium in which the ciliary dynein arms are absent, and there is situs inversus; eye and skin changes are not present.

70 A 5-year-old child who has received no medical care since birth has had gradual onset of markedly decreased vision bilaterally. The child also has a history of increased respiratory tract infections caused by Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, and rubeola. The figure shows the representative microscopic appearance of the bronchial mucosa. The child also has passed several urinary tract calculi. On physical examination, generalized papular dermatosis is noted. The child has xerophthalmia, and there is marked keratomalacia with corneal clouding. Bilateral crackles are audible in the lungs on auscultation. What disease process would most likely lead to these findings? □ (A) Cystic fibrosis □ (B) Congenital syphilis □ (C) HIV infection □ (D) Kartagener syndrome □ (E) Vitamin A deficiency

71 (E) The pattern of metastases with seeding of the peritoneal cavity along with the microscopic and serum tumor markers are most characteristic for an ovarian serous cystadenocarcinoma, the most common malignant neoplasm arising in the ovary. Ileal adenocarcinomas are rare and would probably lead to bowel obstruction. Carcinoid tumors are unlikely to be widely metastatic. Endometrioid carcinomas arise in the ovary. A malignant mesothelioma is a rare complication of asbestosis. It is unlikely that a cystadenocarcinoma would recur 10 years later. Cystadenomas are benign.

71 A 47-year-old woman has had increasing abdominal enlargement, with no significant pain, and diarrhea for the past 3 months. She goes to the physician, who performs a cursory physical examination and obtains a stool culture that is negative. The diagnosis is irritable bowel syndrome. She continues to have increasing abdominal enlargement over the next month, reaching the size of a 5-month pregnancy. She sees another physician, who finds a fluid wave on examination of the abdomen. Abdominal CT scan shows massive ascites and scattered 0.5- to 1.5-cm cystic to solid nodules on the surfaces of the bowel and abdominal wall. Paracentesis yields a yellow, slightly cloudy fluid with a high protein content. Cytologic examination of the fluid shows clusters of malignant cells. Laboratory studies show a positive CA 125 and a negative carcinoembryonic antigen test result. What is the most likely neoplasm? □ (A) Adenocarcinoma of the ileum □ (B) Carcinoid tumor □ (C) Endometrioid carcinoma □ (D) Malignant mesothelioma □ (E) Serous cystadenocarcinoma □ (F) Mucinous cystadenoma

72 (E) The child had rabies, an infectious disease in which the virus travels from the site of an infected animal bite up nerves to the CNS. Pathognomonic Negri bodies are cytoplasmic inclusions found in the hippocampal pyramidal cells and cerebellar Purkinje cells. Anterior horn cell loss is characteristic of poliovirus infection. Gummatous necrosis is seen in syphilis. Multinucleated giant cells can be seen in herpesvirus, HIV, and tuberculosis. Necrotizing vasculitis can be seen in aspergillosis. Toxoplasmosis yields pseudocysts with bradyzoites. A spongiform encephalopathy is characteristic of the prion disease Creutzfeldt-Jakob disease.

72 A 12-year-old boy develops fever, accompanied by occasional headaches, malaise, fatigue, and nausea after being bitten by a dog. One day later, he experiences episodes of rigidity, hallucinations, breath holding, and difficulty swallowing because of uncontrollable oral secretions. Dr. Louis Pasteur is called upon. "The death of this child appearing to be inevitable, I decided, not without lively and sore anxiety, as may well be believed, to try ... the method which I had found constantly successful with dogs. Consequently, 60 hours after the bites [the child] was inoculated under a fold of skin with half a syringeful of the spinal cord of a rabbit. In the following days, fresh inoculations were made. I thus made 13 inoculations." The boy survived. Which of the following pathologic findings is most characteristic of the boy's disease? □ (A) Anterior horn cell loss □ (B) Gummatous necrosis □ (C) Multinucleated giant cells □ (D) Necrotizing vasculitis □ (E) Negri bodies □ (F) Pseudocysts with bradyzoites □ (G) Spongiform encephalopathy

73 (C) This patient has a classic history for atopic bronchial asthma that usually begins in childhood. Although many of the symptoms of bronchial asthma can be related to type I hypersensitivity, this disease is fundamentally T cell-mediated chronic inflammation of the bronchial wall. The TH2 type CD4+ T cells drive type I hypersensitivity by favoring IgE production and eosinophil recruitment. The dominance of TH2 helper cells is accompanied by down-regulation of the TH1 helper cells because the CD4+ T-cell differentiation is skewed toward TH2 cells. Neutrophils, eosinophils, and macrophages also can be present in the inflammatory exudates, but these cells all are recruited secondarily to the TH2 response. ADAM-33, a metalloproteinase, has been linked to the airway remodeling seen in bronchial asthma. Specifically, certain polymorphisms of the ADAM-33 gene are associated with proliferation of bronchial smooth muscle cells and fibroblasts. There is, however, no evidence that ADAM-33 contributes to the immunological alterations seen in bronchial asthma.

73 An 18-year-old woman has had recurrent acute attacks of dyspnea for the past 10 years. Between these attacks, she has no medical problems. She is brought to the emergency department within an hour of onset of the latest episode. On physical examination, her temperature is 37.4°C, pulse is 110/min, respiratory rate is 18/min, and blood pressure is 110/70 mm Hg. Expiratory wheezes are auscultated over the chest bilaterally. A chest x-ray shows bilateral radiolucency with no masses or infiltrates. Pulmonary function studies show severe limitation of airflow, which is relieved on injection of epinephrine. Sputum cytologic examination shows abundant mucus with an inflammatory infiltrate dominated by eosinophils, but mixed with neutrophils and macrophages. Which of the following immunological mechanisms is of primary importance in the pathogenesis of her disease? □ (A) Activation of neutrophils and macrophages by IL-8 □ (B) Chemoattraction of eosinophils by exotoxin □ (C) Proliferation of the TH2 subset of CD4+ T cells □ (D) Recruitment of monocytes by interferon-γ □ (E) Stimulation of bronchial smooth muscle cells by ADAM-33

74 (D) This family has fragile-X syndrome. Anticipation occurred, with premutations of limited triple repeat expansions present in the first two generations, while later generations had full mutations with larger CGG expansions. The FMR1 gene encodes for familial mental retardation protein (FMRP) expressed most abundantly in brain and testis, accounting for macro-orchidism in the latter. Absence of this protein in brain leads to increased mRNA translation that affects synaptic junctions and their function. The FMRP protein is widely expressed in other tissues such as those listed, but their function is not as markedly affected as brain and testis.

74 A family pedigree reveals first and second-generation female relatives with premature menopause and male relatives with a progressive neurodegenerative disorder starting by their sixth decade. There are more males than females exhibiting mental retardation from childhood by the fourth generation. Genetic analysis of affected persons reveals CGG repeat expansions in a gene encoding for a protein that binds mRNA transcripts in neurons and shuttles them to the synapses. An abnormality involving which of the following organs is most likely to be present in affected males? □ (A) Adrenal □ (B) Pancreas □ (C) Pituitary □ (D) Testis □ (E) Thyroid

75 (All are correct) We hope that you have advanced your knowledge and are now better able to help others in your health science career. Go make the world a better place for everyone!

75 As a student in the health sciences, you have just finished this review book, learning to apply your knowledge base in pathology to clinical and experimental scenarios of human disease states. Which of the following represents your best application of this knowledge? □ (A) Collegial consultation □ (B) Compassionate care □ (C) Differential diagnosis □ (D) Lifelong learning □ (E) Patient education □ (F) Research projects

8 (F) This patient has type 1 diabetes mellitus with ketoacidosis, which is the setting for infection by Mucor in the paranasal sinuses, an otherwise unusual infection. T-cell and B-cell function is generally maintained in diabetes mellitus, although neutrophilic function may be depressed, so bacterial infections (staphylococcal, streptococcal, and coliform organisms) most often complicate diabetes mellitus. Actinomycosis can produce chronic subcutaneous abscesses, usually in the neck, lung, or abdomen, and usually following trauma or tissue devitalization. Cutaneous anthrax is rare and produces a localized eschar or ulcerated region. Cytomegalovirus and cryptococcal infections are typically seen in immunocompromised individuals with diminished cell-mediated immunity. Clostridium perfringens appears in the setting of soft-tissue infections with gas gangrene. Pseudomonas infections are frequent nosocomial infections of the urinary and respiratory tracts.

8 A 24-year-old woman has developed right-sided facial pain over the past 24 hours. During that time, she has become lethargic and obtunded. Her medical history shows a 5-kg weight loss over the past 6 months, despite increasing caloric intake. On physical examination, there is swelling with marked tenderness over the right maxilla, exophthalmos on the right side, diffuse abdominal pain, poor skin turgor, and dry mucous membranes. Her temperature is 37.7°C. She has tachycardia, but no murmurs, and tachypnea; the lung fields are clear. Laboratory findings show hemoglobin, 13.1 g/dL; hematocrit, 39.4%; Na+, 131 mmol/L; K+, 4.6 mmol/L; Cl−, 92 mmol/L; CO2, 9 mmol/L; glucose, 481 mg/dL; and creatinine, 1 mg/dL. An arterial blood gas measurement shows pH 7.2, Po2 98 mm Hg, Pco2 28 mm Hg, and HCO3− 10 mmol/L. Fine- needle aspiration of the right maxillary region is performed. What organism is most likely to be present in this aspirate? □ (A) Actinomyces israelii □ (B) Bacillus anthracis □ (C) Cytomegalovirus □ (D) Clostridium perfringens □ (E) Cryptococcus neoformans □ (F) Mucor circinelloides □ (G) Pseudomonas aeruginosa

9 (A) The patient has findings consistent with cystic fibrosis; agenesis of the vas deferens is a common finding and leads to infertility. With good medical care, patients with cystic fibrosis are living longer, and childbearing becomes an issue. Disorders of fibroblast growth factor receptor (FGFR) can include dwarfism. Glucose-6-phosphatase deficiency results in hemolysis on exposure to oxidants such as antimalarial drugs (e.g., primaquine). The HFE gene is abnormal in hereditary hemochromatosis; however, the patient is young for the onset of this disease. NF1 (neurofibromatosis) is associated with the appearance of various neoplasms, including neurofibromas, pheochromocytomas, and gliomas. p53 is a tumor suppressor gene, and loss of both alleles can promote the appearance of various malignancies, mainly carcinomas.

9 A 30-year-old man is infertile and has a low sperm count. He also has chronic diarrhea with elevated quantitative stool fat. He has had recurrent, severe respiratory tract infections since early childhood. As a neonate, he had bowel obstruction from meconium ileus. He is most likely to have an abnormality involving which of the following genes? □ (A) CFTR □ (B) FGFR □ (C) G6PD □ (D) HFE □ (E) NF1 □ (F) p53