BRS pathology

A 56-year-old man dies 24 hours after the onset of substernal chest pain radiating down his left arm to the ulnar aspect of his fingertips. Which of the following morphologic myocardial findings is an indicator of irreversible injury? (A) Cell blebs (B) Depletion of glycogen (C) Mitochondrial swelling (D) Myelin figures (E) Pyknotic nuclei

. Myelin figures, cell blebs, mitochondrial swelling, and glycogen depletion are all signs of reversible injury. Nuclear changes such as pyknosis, karyorrhexis, and karyolysis are signs of cell death and are, of course, irreversible.

A 24-year-old woman with a history of heavy and painful menstrual periods has been having difficulty conceiving despite months of trying to become pregnant. Further workup includes a bimanual pelvic examination and an ultrasound, which demonstrates a mass in the uterus that is presumed to be a leiomyoma. This mass is a (A) benign tumor of mesenchymal tissue. (B) benign tumor of surface epithelium. (C) malignant tumor of epithelial tissue. (D) malignant tumor of glandular epithelium. (E) malignant tumor of mesenchymal tissue.

A. A leiomyoma (fibroid) is a benign tumor of the smooth muscle of the uterus and thus is an example of a benign tumor of mesenchymal origin. Profuse, painful menses and infertility are major complications of this most common tumor of the female genital tract. A leiomyosarcoma is the malignant counterpart. Malignant tumors of epithelial cells are carcinomas, and these are known as adenocarcinomas if they involve glandular epithelium. Benign tumors of surface epithelium are termed papillomas.

A 29-year-old man hospitalized for acquired immunodeficiency syndrome (AIDS) is found to have pulmonary tuberculosis. Which type of necrosis is found in the granulomatous lesions (clusters of modified macrophages) characteristic of this increasingly frequent complication of AIDS? (A) Caseous (B) Coagulative (C) Enzymatic (D) Fibrinoid (E) Liquefactive

A. Caseous necrosis occurs as part of granulomatous inflammation, typified by the lesions of tuberculosis.

Following his return home from a party, a 22-year-old man develops crushing chest pain and is brought to the emergency department by ambulance. Questioning reveals no cardiac risk factors. Electrocardiographic and serum enzyme findings are consistent with acute myocardial infarction. It is suspected that the cardiac damage is related to toxicity of a drug of abuse. Which of the following drugs is most likely? (A) Cocaine (B) Ethyl alcohol (C) Heroin (D) Methyl alcohol (E) Phenacetin

A. Cocaine is associated with increased myocardial irritability and sometimes with myocardial infarction, hypertension, and cerebral vascular accident. Both ethyl alcohol and heroin are long-term contributors to heart disease but are unlikely to cause an acute event in a young patient. Methyl alcohol can lead to blindness, as well as kidney damage. Phenacetin, an analgesic related to acetaminophen, can lead to kidney damage and is no longer used in this country.

A 19-year-old intravenous drug user has regularly sought human immunodeficiency virus (HIV) testing, always with negative results. He admits to carelessly sharing needles on multiple occasions with individuals later found to be HIV-positive. He has heard that there is an inherited genetic basis for some people to be relatively "immune" to HIV infection. The genetic change that he is referring to is a mutation in a gene coding for which of the following proteins? (A) CCR5 (B) CD4 (C) gp120 (D) gp41 (E) Reverse transcriptase

A. Either of two coreceptors, CCR5 or CXCR4, is involved in the initial binding of the virus to the cell surface molecule gp120 on CD4+ cells. It is of considerable interest that certain mutations in the CCR5 gene are associated with what appears to be total resistance to infection with some common strains of HIV. Homozygotes are totally resistant, and heterozygotes develop a more slowly progressive disease.

A 24-year-old woman who had previously been uneventfully transfused receives a blood transfusion during surgery and shortly thereafter develops itching, generalized urticaria, laryngeal edema, and dyspnea with wheezing respiration. She has a past history of recurrent upper respiratory tract infections and frequent episodes of diarrhea. Laboratory studies are most likely to reveal decreased concentrations of which of the following immunoglobulins? (A) IgA (B) IgD (C) IgE (D) IgG (E) IgM

A. Isolated IgA deficiency is most often asymptomatic but can be characterized by anaphylactic reactions to transfused blood. It is critical to notify the transfusion service about a patient with possible IgA deficiency prior to giving blood products so that products can be washed to remove any immunoglobulins prior to administration. This disorder can also be associated with frequent episodes of diarrhea and recurrent infections, especially those involving mucosal surfaces. This inherited B-cell defect is due to inability of IgA B cells to mature into IgA-producing plasma cells. Interestingly, the defect leading to systemic anaphylaxis involves both IgA and IgE antibody formation. Patients lacking IgA can develop IgE antibodies against the IgA antibodies present in transfused blood. This sensitization can result in susceptibility to anaphylaxis on subsequent transfusion.

A laboratory experiment is performed to evaluate the chemotactic potential of a group of potential mediators. Which of the following substances most likely has the greatest affinity for neutrophils? (A) C5a (B) Fucosyl transferase (C) â2-Integrin (D) P-selectin (E) TNF-á

A. Several substances have chemotactic potential for neutrophils (see Table 2-1). C5a is a prominent example.

A 50-year-old woman of Eastern European Jewish ancestry has a history of recurrent fractures and easy bruising and is found to have hepatosplenomegaly and mild anemia. Serum assays reveal elevations of chitotriosidase and angiotensin-converting enzyme. Assay of cultured leukocytes most likely reveals marked deficiency of which of the following enzymes? (A) Glucocerebrosidase (B) á-1,4-Glucosidase (C) Hexosaminidase A (D) á-L-Iduronidase (E) Sphingomyelinase

A. The clinical findings are those of type I Gaucher disease, which is a manifestation of glucocerebrosidase deficiency. The disorder is most often seen in persons of European (Ashkenazic) Jewish lineage. Prominent findings include bone pain and fractures, easy bruising, hepatosplenomegaly, anemia, and thrombocytopenia. Bone marrow aspiration reveals numerous typical Gaucher cells, but specific enzyme assay is required to confirm the diagnosis. This lysosomal storage disease is relatively mild compared to a number of other such entities, such as Tay-Sachs disease and Niemann-Pick disease, which are rarely seen in adults. The disease is highly variable in its clinical manifestations, and assays of chitotriosidase and angiotensin-converting enzyme, markers of macrophage proliferation, are useful measures of the extent of disease and of its control.

A 2-year-old child has been followed for mental retardation and slow development, as well as multiple birth defects. The child has a high-pitched catlike cry. On examination, microcephaly, hypertelorism, micrognathia, epicanthal folds, low-set ears, and hypotonia are noted. Karyotypic analysis would be expected to show (A) 5p-. (B) 22q11-. (C) 45,XO. (D) 46,XY. (E) 47,XXY.

A. The clinical presentation is that of the cri du chat (or 5p-) syndrome.

A 28-year-old woman is evaluated for possible thrombophilia since she has had two episodes of deep vein thrombosis, as well as two pregnancies that terminated in spontaneous abortion. The activated partial thromboplastin time is prolonged, and she has a positive VDRL screening test for syphilis. This combination of findings is most suggestive of (A) antiphospholipid antibody syndrome. (B) disseminated intravascular coagulation. (C) factor V Leiden. (D) methylene tetrahydrofolate reductase mutation. (E) prothrombin 20210A transition.

A. The combination of a prolonged activated partial thromboplastin time (APTT), a positive VDRL test for syphilis, recurrent thromboses (arterial or venous), and spontaneous abortion is highly suggestive of the antiphospholipid antibody syndrome. As the name implies, antibodies directed at phospholipids are a characteristic finding. Because of the prolonged APTT and frequent association with systemic lupus erythematosus (SLE), the antibody has been referred to as the "lupus anticoagulant," a misleading term because affected subjects have a thrombotic rather than hemorrhagic diathesis and not all subjects have SLE. The term primary antiphospholipid antibody syndrome is used when there is no evident underlying disease. It should be contrasted to secondary antiphospholipid antibody syndrome, in which the patient has a well-defined autoimmune disorder such as SLE.

A 1-year-old boy has had repeated pyogenic infections with streptococci, staphylococci, and Haemophilus for the past 6 months. Tests for T-cell function, granulocyte function, and complement activity have all been unaffected. Serum IgG is 50 mg/dL (normal 500 mg/dL). Flow cytometry revealed absent expression of heavy-chain ì on blood lymphocytes. T lymphocytes were slightly increased in number, with a normal CD4+ to CD8+ ratio. Expected findings on examination of a lymph node biopsy from this patient include which of the following? (A) Absent germinal centers (B) Follicular hyperplasia with exuberant proliferation of immature B cells (C) Massive TH1 cell infiltration into lymphoid follicles (D) Normal lymphoid tissue development (E) Plasma cell hyperplasia

A. The diagnosis is X-linked agammaglobulinemia of Bruton. Failure of maturation of pre-B cells is associated with absence of mature B lymphocytes and plasma cells; failure of antibody synthesis; marked serum hypogammaglobulinemia; and recurrent bacterial infections, especially sinopulmonary infections. Histologic examination of lymphoid tissue reveals marked underdevelopment of germinal centers. T cells are unaffected, as are T-cell functions such as cell-mediated immunity and resistance to most viral infections. The disease is X-linked and is due to mutations in the B cell tyrosine kinase (Btk) gene.

A 1-year-old female infant is hospitalized for pneumonia. Bacterial cultures of the sputum have grown Pseudomonas aeruginosa. She has had two prior hospitalizations for severe respiratory infections. Her mother has noted that when she kisses her child, the child tastes "salty." The child has had weight loss that the mother attributes to frequent vomiting and diarrhea with bulky, foul-smelling fatty stools. The child is small for her age. Which of the following critical proteins is altered in this condition? (A) Cystic fibrosis transmembrane conductance regulator (B) Dystrophin (C) á-1,4-Glucosidase (D) á-L-Iduronidase (E) Lysyl hydroxylase

A. The diagnosis is cystic fibrosis, the most common lethal genetic disease in Caucasian populations. The disorder is due to a defect in the cystic fibrosis transmembrane conductance regulator protein, and about 70% of cases have a deletion of phenylalanine in position 508 (DF508 mutation). Affected patients often have multiple pulmonary infections and pancreatic insufficiency with steatorrhea and failure to thrive. Death is often due to respiratory failure secondary to repeated pulmonary infections, facilitated by the buildup of thick, tenacious mucus in the airways. Increased concentration of chloride in sweat and tears is characteristic, and the sweat test is an important diagnostic adjunct.

An 8-year-old child is evaluated by the pediatrician, who notes what appear to be 10 small café-au-lait spots on the child's torso. In addition, on close inspection of the eyes, the presence of Lisch nodules is noted. The patient is diagnosed with von Recklinghausen neurofibromatosis type 1. The protein that is mutated in this disorder normally (A) activates the GTPase activity of Ras. (B) cleaves cellular proteins during apoptosis. (C) functions as a regulator of the cell cycle. (D) promotes angiogenesis in the growing tumor mass. (E) promotes the cell to undergo apoptosis.

A. The normal function of NF-1 is to promote the intrinsic GTPase function of the Ras oncogene. When the Ras protein is bound to GTP, the growth-promoting function of the molecule is "ON." On hydrolysis of the GTP to GDP, Ras is converted to an inactive state. GAPs, such as NF-1, suppress cell growth by stimulating GTP hydrolysis. Patients with a mutation in NF-1 are susceptible to fibrosarcomas as a result of loss of function of this GAP. The molecule Bax is pro-apoptotic and antagonizes Bcl-2. Vascular endothelial growth factor promotes tumor angiogenesis. The protein p53 regulates the cell cycle if DNA damage is detected. Lastly, caspases function to cleave cellular proteins once apoptosis is triggered.

A 45-year-old woman is seen because of varied complaints. She has been troubled by small painful lumps under the skin of her fingers, some of which have ruptured and leaked a chalky white substance. She also complains of painful episodes in her fingers and toes, which blanch and turn blue on exposure to cold. In addition, questioning reveals increasing "heartburn" and difficulty swallowing. Examination reveals thickening of the skin of the fingers and toes, resulting in a claw-like appearance. Telangiectatic clusters of vessels, appearing as small focal red lesions, are observed in the skin of the face, upper trunk, and hands, and on the mucosal surface of the lips. Antibodies to which of the following are most characteristic of the findings presented by this patient? (A) Centromeric proteins (B) Histidyl-t-RNA synthetase (Jo-1) (C) Histones (D) Mitochondria (E) Native DNA

A. The patient exhibits the cardinal findings of the CREST syndrome, a less severe variant of systemic sclerosis (scleroderma) characterized by Calcinosis, Raynaud phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasia. Although a number of antinuclear antibodies can be found in this disorder, the most characteristic is directed at centromeric proteins (the antibody is often referred to as anticentromere).

During a routine physical examination, a 41-year-old woman is noted to have blueblack pigmented patches in the sclerae and gray-blue discoloration of the ear cartilages. The extensor tendons of the hands exhibit similar discoloration when she is asked to "make a fist." On questioning, the patient vaguely remembers hearing her mother say that the patient had dark discoloration on her diapers when she was an infant. Her only current complaint is slowly increasing pain and stiffness of the lower back, hips, and knees. A urine sample darkens on standing. These findings are characteristic of a deficiency of which of the following enzymes? (A) Homogentisic oxidase (B) Hypoxanthine-guanine phosphoribosyltransferase (C) L-Iduronosulfate sulfatase (D) Ketoacid decarboxylase (E) Phenylalanine hydroxylase

A. The patient has homogentisic oxidase deficiency, a rare inborn error of metabolism (actually the first such disorder described by Garrod in 1902), clinically manifest by alkaptonuria and ochronosis. The term alkaptonuria refers to urinary excretion of unmetabolized homogentisic acid imparting a dark color to urine on standing. The term ochronosis refers to pigment deposition in multiple tissues, most prominently in cartilage and connective tissue. Most symptoms result from joint involvement, which can lead to disabling arthritis as patients age. Other affected structures include the eyes, larynx and bronchi, heart and vessels, prostate, and sweat glands.

A 74-year-old woman presents to her primary care physician with malaise, proximal muscle pain, morning stiffness, and claudication of the jaw, along with occasional visual impairment. On examination, palpation along the lateral aspect of the head elicits tenderness. This is likely a result of (A) giant cell arteritis. (B) hypersensitivity vasculitis. (C) Kawasaki disease. (D) Takayasu arteritis. (E) Wegener granulomatosis.

A. This is the typical presentation of temporal, or giant cell, arteritis. Along with involvement of the branches of the carotid artery, such as the temporal or ophthalmic arteries, there is a close association with a complex of symptoms of proximal muscles termed polymyalgia rheumatica. Hypersensitivity vasculitis manifests with palpable purpura and is associated with drugs, food, or infectious agents. Takayasu arteritis involves the vessels of the aortic arch, whereas Kawasaki disease involves the coronary arteries. Wegener granulomatosis involves vessels of the respiratory tract and kidney.

A 4-year-old Inuit child from northern Alaska is brought to the pediatrician because of concern about progressive bowing of the legs and enlargement of the costochondral junctions (rachitic rosary). The underlying defect in this disorder is a defect in (A) calcification of osteoid matrix. (B) fibrillin. (C) formation of osteoid matrix. (D) hydroxylation of proline residues in collagen. (E) type I collagen.

A. Vitamin D is required for calcification of osteoid matrix, and defective calcification leads to bowing of the legs and the abnormalities in the costochondral junctions known as the rachitic rosary. Mutations in genes involved in the synthesis of type I collagen lead to osteogenesis imperfecta, and defects in fibrillin lead to Marfan syndrome. Defects in hydroxylation of proline residues occur both in the Ehlers-Danlos syndrome and in vitamin C deficiency, leading to defects in the synthesis of osteoid matrix.

A 20-year-old man presents with yellowing of the sclerae, skin, and oral mucosa. Which of the following accumulations underlies these findings? (A) Bilirubin (B) Hemosiderin (C) Lead (D) Melanin (E) Silver

A. Yellowing of the sclerae, skin, and oral mucosa are all characteristic of jaundice, the accumulation of bilirubin, the catabolic product of the heme moiety of hemoglobin. Jaundice can occur by diverse mechanisms: hemolytic (see Chapter 11), hepatocellular (see Chapter 16), or obstructive (see Chapter 16).

During a laboratory exercise on coagulation testing, a 23-year-old medical student is found to have a prolonged bleeding time. She has had a long history of "easy bleeding," with frequent bleeding of the gums, epistaxis, cutaneous bleeding, and menorrhagia. Further testing revealed a deficiency of von Willebrand factor. Which of the following thrombogenic processes involving platelets is most directly impaired? (A) Adhesion (B) Conformational change with activation of phospholipid surface (C) Formation of fibrinogen bridges (D) Release reaction (E) Stabilization of platelet plug

A. von Willebrand factor is required for platelet adhesion to the subendothelium of damaged blood vessels. See further discussion of von Willebrand disease in Chapter 13.

A 36-year-old man dies during cardiac surgery. He had a history of long-standing rheumatic heart disease with mitral stenosis. At autopsy, the pathologist reports findings consistent with mitral stenosis and noted the presence of "heart failure cells." This finding results from (A) activation of the coagulation cascade. (B) chronic passive congestion of the lungs. (C) hypoxic myocardial injury. (D) myocardial hyperemia.

B. "Heart failure cells" are intra-alveolar hemosiderin-laden macrophages and are indicative of marked chronic passive congestion of the lung. Red cells leak from congested alveolar capillaries into the alveoli, where they are engulfed and degraded by macrophages.

A 70-year-old man seeks medical attention because of shortness of breath on minimal exertion. A posteroanterior chest radiograph reveals blunting of the right costophrenic sulcus interpreted as a rightsided pleural effusion. The aspirated fluid is straw colored and clear. The protein concentration is low, and the specific gravity is 1.011. Microscopic examination reveals an occasional mesothelial cell. Which of the following is the most likely cause of the effusion? (A) Decreased oncotic pressure (B) Left ventricular heart failure (C) Mesothelioma (D) Pneumonia (E) Tuberculosis

B. A clear, straw-colored fluid with low protein and low specific gravity is a transudate, and the term hydrothorax refers to the accumulation of a significant volume of transudate within the pleural cavities (to be detected by chest radiograph, about 200 to 400 mL of pleural fluid must be present). The most common cause of hydrothorax is cardiac failure, which may be either unilateral or bilateral (bilateral is more common). It is incumbent on the clinician to distinguish pleural transudates from exudates, because the causes of each are quite different.

A pathologist examines a renal biopsy from a 45-year-old man with nephrotic syndrome and requests a Congo red stain to confirm the nature of an amorphous acidophilic extracellular hyaline substance localized within the mesangial matrix of the glomeruli. A positive test confirms the presence of (A) á1-antitrypsin. (B) amyloid. (C) copper. (D) glycogen. (E) hemosiderin.

B. A positive Congo red test confirms the presence of amyloid. Apple green birefringence is observed under polarized light.

A 25-year-old woman with membranous glomerulonephritis receives a kidney transplant. The donor is her HLA-matched sister. She does well initially, but after several weeks, there is a progressive increase in serum creatinine. Assuming that this represents acute cellular rejection, an infiltrate with which of the following types of inflammatory cells is most likely to be a prominent finding on renal biopsy? (A) Eosinophils (B) Lymphocytes (C) Mast cells (D) Monocytes-macrophages (E) Neutrophils

B. Acute cellular rejection is characterized by an infiltrate of both CD4+ and CD8+ lymphocytes. Acute rejection occurs over a variable time period, ordinarily days to weeks to months after transplant.

A 64-year-old man undergoes a total gastric resection for adenocarcinoma of the stomach. He has done well for 4 years but now presents with profound anemia, fatigue, and vague neurologic complaints. Position and vibration sensation are markedly diminished, and hyperreflexia is pronounced. Laboratory studies, including examination of the bone marrow, reveal pancytopenia and other findings compatible with a megaloblastic anemia. He is likely suffering a deficiency of which essential vitamin? (A) Folate (B) Vitamin B12 (C) Vitamin C (D) Vitamin D (E) Vitamin K

B. Both folate and vitamin B12 deficiency lead to megaloblastic anemia, secondary to impaired DNA replication. In marked contrast to folate deficiency, vitamin B12 deficiency causes neurologic dysfunction associated with damage to the lateral and dorsal spinal columns. The history of gastric resection is consistent with a deficiency of intrinsic factor, which is required for absorption of vitamin B12 in the terminal ileum.

A 78-year-old man is found in his closed room unresponsive in bed after the first cold day of winter. There is a kerosene heater still on from the previous night. On attempts to arouse him, officers note the cherry hue of his lips, cheeks, and mucous membranes. The likely mechanism of his death was (A) accidental ingestion of ethylene glycol. (B) binding of carbon monoxide to hemoglobin. (C) hepatic necrosis with fatty change. (D) inhibition of hemoglobin production. (E) inhibition of incorporation of iron into hemoglobin.

B. Carbon monoxide (CO) binds to hemoglobin with approximately 200 times greater affinity than oxygen, preventing delivery of oxygen to tissues. In addition, CO is an inhibitor of cytochrome oxidase, impairing cellular respiration. Ethylene glycol (antifreeze) is associated with kidney damage and the formation of birefringent calcium oxalate crystals in the urinary tract. Hepatic necrosis and fatty change result from carbon tetrachloride poisoning. Lead inhibits a key enzyme in hemoglobin synthesis as well as iron incorporation in hemoglobin.

A 2-year-old boy presents with recurrent infections involving multiple organ systems. Extensive investigation results in a diagnosis of chronic granulomatous disease of childhood. Which of the following most closely characterizes the abnormality in this patient's phagocytic cells? (A) Decreased killing of microorganisms because of enhanced production of hydrogen peroxide (B) Deficiency of NADPH oxidase activity (C) Impaired chemotaxis and migration caused by abnormal microtubule formation (D) Inability to kill streptococci (E) Increased myeloperoxidase-halidemediated killing of catalase-positive organisms when compared with catalase- negative organisms

B. Chronic granulomatous disease of childhood, a condition characterized by repeated infections and most commonly X-linked inheritance, is marked by failure of the myeloperoxidase-halide system of killing within phagocytic cells. It is caused by the deficiency of NADPH oxidase activity. This results in a secondary deficiency of reactive oxygen metabolites, including H2O2, which, along with halide ions, functions as a substrate for myeloperoxidase. A hallmark of the disorder is the failure of intracellular killing of catalase-positive organisms, exemplified by staphylococci. These organisms are ingested but not killed. The impaired phagocytic cell is incapable of producing H2O2, and any H2O2 produced by the microorganism itself is inactivated by endogenous catalase. In contrast, catalase-negative microorganisms, such as streptococci, are ingested and killed. They too produce endogenous H2O2, which is thus available as one of the substrates for myeloperoxidase. In a sense, the microorganisms assist in their own killing.

A 38-year-old woman is receiving radiation therapy to her abdomen as adjuvant therapy for the treatment of cervical cancer. The radiosensitivity of organs or tissues within the treatment field is a limiting factor in determining the dose of radiation that can be administered. Which of the following is most susceptible to radiation damage? (A) Bone (B) Gastrointestinal mucosa (C) Peripheral nervous tissue (D) Renal parenchyma (E) Skeletal musculature of the abdomen

B. Gastrointestinal mucosal cells are examples of labile cells, and thus are among the most radiosensitive of the tissues or organs listed in the question. The symptoms associated with damage to these cells (nausea, diarrhea, and malabsorption) are likely to limit the total dose of radiation the patient can receive. The other tissues listed are relatively radioresistant and are unlikely to limit the amount of radiation a patient can receive.

A 22-year-old woman with acute myeloblastic leukemia receives an allogeneic bone marrow transplant with apparent successful engraftment. Three weeks later, early jaundice, as well as a generalized maculopapular rash, is noted. Profuse diarrhea follows. A skin biopsy reveals vacuolar changes, necrotic epidermal cells, and a lymphocytic infiltrate. These findings are most likely caused by (A) antibody-dependent cellular cytotoxicity. (B) attack on host epithelial cells by donor CD8+ T cells. (C) contamination of the donor transplant cells with hepatitis C virus. (D) IgE and mast cell-mediated anaphylactic hypersensitivity. (E) secretion of IL-2 and interferon-ã by TH1 cells.

B. Graft-versus-host disease is most often manifested by clinical findings related to the three principal target organs: the skin, liver, and gastrointestinal tract. The skin manifestations are often initiated by a pruritic rash. Elevation of bilirubin and liver enzymes signals the hepatic involvement. Effects on the ileum and colon present as diarrhea and abdominal pain. The lesions are caused by donor lymphocytes, with targeting of host epithelial cells by CD8+ T cells.

A 45-year-old man is referred because of a recent diagnosis of hereditary hemochromatosis. Which of the following is a correct statement about this disorder? (A) Damage to organs results from abnormal deposition of lead (B) It can progress to liver cirrhosis, diabetes mellitus, and skin pigmentation (C) Most cases are due to spontaneous mutations (D) Skin hyperpigmentation is due to bilirubin accumulation (E) The TIBC is characteristically increased

B. In advanced form, primary (hereditary) hemochromatosis is characterized by the triad of cirrhosis, diabetes, and hyperpigmentation, or so-called bronze diabetes. The disease is most often caused by a mutation in the Hfe gene on chromosome 6 and is characteristically familial rather than sporadic. The manifestations of the disorder are the result of iron overload and deposition of hemosiderin in tissues such as the liver, pancreas, skin, joints, and pituitary. Laboratory abnormalities of note include increased serum iron and decreased TIBC. The skin hyperpigmentation is due largely to increases in melanin and to lesser accumulations of hemosiderin.

Which of the following peripheral blood findings is associated with lead poisoning? (A) Megaloblastic anemia (B) Basophilic stippling (C) Microangiopathic changes (D) Lead line (E) Leukocytosis

B. Lead poisoning leads to basophilic stippling of erythrocytes and a hypochromic, microcytic anemia. Megaloblastic anemias are seen in folate and B12 deficiencies. Lead lines are seen in the oral mucosa, not within peripheral blood cells. Microangiopathic changes are characteristic of disseminated intravascular coagulation and other disorders with mechanical disruption of RBCs, while leukocytosis can be seen in a variety of reactive and neoplastic hematologic conditions.

An 18-year-old young man with known cystic fibrosis presents to the physician with his third episode of kidney stones in the past year. In addition, he has begun to complain of difficulty seeing at night. Such changes can be attributed to a deficiency of which vitamin? (A) Pyridoxine (B) Vitamin A (C) Vitamin B1 (D) Vitamin B12 (E) Vitamin D

B. Patients with cystic fibrosis often have impaired exocrine pancreas function, resulting in a deficiency of fat-soluble vitamins. Of the fat-soluble vitamins, vitamin A deficiency results in night blindness, xerophthalmia, keratomalacia, and squamous metaplasia of the urinary tract, contributing to the formation of recurrent renal calculi.

An 18-year-old patient presents with renal cell carcinoma. Given that this is typically a tumor of older adults, what translocation might you expect to find? This translocation is also seen in which mesenchmyal malignancy? (A) t(X;18), synovial sarcoma (B) t(X;17), alveolar soft part sarcoma (C) t(9;22), leiomyosarcoma (D) t(14;18), leiomyosarcoma (E) t(15;17), synovial sarcoma

B. Pediatric renal cell carcinomas often demonstrate translocations involving Xp11, with t(X;17) representing the most common anomaly. This translocation is also seen in alveolar soft part sarcoma, a fact which illustrates the lack of specificity of translocations in some instances. The t(X;18) translocation is associated with synovial sarcoma, while the other translocations listed are seen in hematologic malignancies

A 27-year-old man who was badly burned in an industrial accident requires multiple skin grafting. While in the intensive care unit, he is found to have blood in his stools, and endoscopy confirms the presence of many small ulcers in his stomach. This complication is referred to as (A) aplastic anemia. (B) Curling ulcer. (C) Cushing ulcer. (D) Reye syndrome. (E) Stevens-Johnson syndrome.

B. Punctate ulcers associated with extensive burn injuries are known as Curling ulcers. A similar phenomenon occurs in patients with head trauma, in which the lesions are known as Cushing ulcers. Aplastic anemia can result from an idiosyncratic reaction in patients taking the antibiotic chloramphenicol. Likewise, sulfonamides can cause a necrotizing eruption around mucous membranes in some individuals. Reye syndrome is associated with extensive microvesicular fatty change of the liver in children taking aspirin during an acute viral illness. The Stevens-Johnson syndrome is characterized by erosions and crusts of the lips and oral mucosa as a component of an extensive form of erythema multiforme, a maculopapular, vesiculobullous eruption often related to drugs (such as sulfonamides), neoplasia, or connective tissue disorders.

A bedridden elderly patient experiences the sudden onset of pleuritic pain and hemoptysis. The underlying lesion that led to this complication was most likely located in which of the following sites? (A) Hepatic veins (B) Lower extremity veins (C) Pelvic veins (D) Portal vein (E) Pulmonary veins

B. The clinical description is characteristic of pulmonary infarction, which, in turn, most often results from thromboembolism originating from thrombosis in the lower extremity veins. Because venous thrombosis is associated with impaired blood flow, this condition is particularly characteristic of immobilization, which is often seen in elderly, debilitated, or chronically bedridden persons.

A 45-year-old woman is investigated for hypertension and is found to have enlargement of the left kidney. The right kidney is smaller than normal. Contrast studies reveal stenosis of the right renal artery. The size change in the right kidney is an example of which of the following adaptive changes? (A) Aplasia (B) Atrophy (C) Hyperplasia (D) Hypertrophy (E) Metaplasia

B. The decreased size is due to restriction of the blood supply, one of the causes of atrophy. The increase in size of the opposite kidney is referred to as compensatory hypertrophy. Unilateral renal artery stenosis is a well-known cause of secondary hypertension. In this setting, increased renin excretion and stimulation of the renin- angiotensin system results in a form of hypertension that is potentially curable by surgical correction of the underlying vascular abnormality.

Fluid is aspirated from the grossly distended abdomen of a 47-year-old chronic alcoholic man. The fluid is straw colored and clear and is found to have a protein content (largely albumin) of 2.5 g/dL. Which of the following is a major contributor to the fluid accumulation in this patient? (A) Blockage of lymphatics (B) Decreased oncotic pressure (C) Decreased sodium retention (D) Increased capillary permeability (E) Inflammatory exudation

B. The patient has cirrhosis of the liver secondary to chronic alcoholism. A prominent manifestation of this disorder is decreased hepatic synthesis of albumin, the most significant contributor to plasma oncotic pressure. In addition, ascites is associated with increased sodium and water retention because of stimulation of the renin- angiotensin system. Also, hydrostatic forces (because of intrahepatic scarring and partial obstruction of the portal venous return) result in fluid transudation and increased secretion of hepatic lymph.

A 3-year-old boy is brought by his parents to the emergency department because they are concerned that he has had a high fever for several days. On examination, the boy has conjunctival and oral erythema. He has palpable cervical lymphadenopathy and erythema of his palms and soles. What is a potential life-threatening complication of this disorder? (A) Aneurysm of the abdominal aorta (B) Aneurysm of the coronary arteries (C) Dissection of the thoracic aorta (D) Ischemia and gangrene of the extremities (E) Rupture of a berry aneurysm

B. The patient presents with mucocutaneous lymph node syndrome, or Kawasaki disease. It is often a self-limiting condition, although as many as 20% of patients develop an aneurysm of the coronary vessels. Dissection of the thoracic aorta is associated with hypertension. Rupture of a berry aneurysm can result in a subarachnoid hemorrhage. Aneurysm of the abdominal aorta is associated with atherosclerosis. Ischemia and gangrene can be a result of Buerger disease.

A 56-year-old man dies of a 15-year progressive illness characterized by athetoid movements and deterioration leading to hypertonicity, fecal and urine incontinence, anorexia and weight loss, and eventually dementia and death. The disease is known to have an autosomal dominant mode of inheritance and to be due to an abnormality in a gene on chromosome 4 that is altered by increased numbers of intragenic trinucleotide repeats. In addition, this disorder has an earlier onset and is more debilitating in successive generations, a phenomenon that might be due to (A) a shift from trinucleotide repeats to pentanucleotide repeats. (B) an increase in the number of trinucleotide repeats in successive generations. (C) defects in membrane receptors and transport systems. (D) imprinting variability in successive generations. (E) increased medical awareness of the condition.

B. The phenomenon of earlier and more severe manifestations of a disorder in successive generations (anticipation) is a characteristic of many trinucleotide repeat disorders, the best known examples of which are fragile X syndrome (discussed in this chapter) and Huntington disease (described in this clinical scenario and further discussed in Chapter 23). The degree of expansion is closely related to the gender of the parent with the genetic abnormality. In the fragile X syndrome, expansion occurs during oogenesis. In Huntington disease, expansion occurs during spermatogenesis. Even though trinucleotide repeats almost always involve guanine and cytosine (G and C), the third nucleotide is different in the two conditions: CGG in fragile X syndrome and CAG in Huntington disease.

A 46-year-old woman with prominent splenomegaly presents with a 3-month history of malaise, easy fatigability, weakness, weight loss, and anorexia. A complete blood count and differential demonstrates a white blood cell count of 250,000/mm3 (normal 3,000 to 10,000/mm3) with a predominance of myelocytes, metamyelocytes, band cells, and segmented neutrophils. Cytogenetic analysis is most likely to reveal which of the following translocations? (A) t(8;14) (B) t(9;22) (C) t(11;22) (D) t(14;18) (E) t(15;17)

B. The translocation t(9;22) is the characteristic translocation associated with chronic myelogenous leukemia, forming the so-called "Philadelphia chromosome." The resultant fusion protein, p210, has increased tyrosine kinase activity that contributes to the uncontrolled proliferation in this form of leukemia. The translocation t(14;18) is seen in follicular lymphoma; t(8;14) in Burkitt lymphoma; t(15;17) in the M3 variant of acute promyelocytic leukemia (AML); and t(11;22) in Ewing sarcoma, a relatively uncommon tumor of bone.

A routine complete blood count performed on a 22-year-old medical student reveals an abnormality in the differential leukocyte count. She has been complaining of frequent sneezing and "watery" eyes during the past several weeks and reports that she frequently had such episodes in the spring and summer. Which of the following cell types is most likely to be increased? (A) Basophils (B) Eosinophils (C) Lymphocytes (D) Monocytes (E) Neutrophils

B. This type of reaction is primarily mediated by the release of histamine from tissue mast cells, and the associated cellular infiltrate and peripheral blood findings represent mobilization and increased numbers of eosinophils. The symptoms reported are those of seasonal rhinitis, better known as "hay fever," a manifestation of type I hypersensitivity (see Chapter 5).

A 78-year-old Navy veteran with a 600-pack-per-year history of cigarette smoking presents with cancer. During his military career, he was involved in fireproofing naval combat ships with asbestos insulation. Given his environmental exposure to both tobacco and asbestos, to which cancer do both of these carcinogens contribute? (A) Bladder cancer (B) Bronchogenic cancer (C) Cancer of the throat (D) Esophageal cancer (E) Mesothelioma

B. Tobacco contributes to the development of many cancers, including those of the bladder, lung, throat, and esophagus. Asbestos exposure carries a risk of lung cancer, as well as mesothelioma, a cancer of the pleura. Tobacco and asbestos function as cocarcinogens in the pathogenesis of lung cancer, with an approximately 50-fold greater risk of developing bronchogenic cancer of the lung than in those without such exposure.

An 8-year-old boy is referred to the dermatologist for numerous "suspicious" pigmented lesions on the face and neck. Further history reveals that the patient has had difficulty seeing out of his right eye; he is referred to the ophthalmologist, who diagnoses an ocular melanoma. Based on the patient's symptoms, the diagnosis of xeroderma pigmentosum is considered. This condition results from (A) aberrant expression of a receptor tyrosine kinase. (B) an inborn defect in DNA repair. (C) chemical carcinogenesis. (D) DNA viral infection. (E) retroviral infection.

B. Xeroderma pigmentosum is a hereditary DNA defect with a deficiency in the ability to repair ultraviolet (sunlight)-induced thymidine dimers. Faulty repair leads to increased sun sensitivity, with a predilection to develop skin lesions and skin cancers on exposed skin, as well as ocular melanomas. Aberrant expression of the gene for a receptor tyrosine kinase, such as the Her-2/neu gene product, can cause breast cancer. A retrovirus is responsible for the development of T-cell leukemia/lymphoma. The DNA virus human papillomavirus can cause cervical cancer.

A 14-year-old girl with amenorrhea is concerned because of the delayed onset of menses. She has shortened stature and a wide, webbed neck; broad chest; and secondary sexual characteristics consistent with those of a much younger girl. Which of the following chromosomal changes is most consistent with these findings? (A) 5p- (B) 22q11- (C) 45,XO (D) 46,XY (E) 47,XXY

C. Although most patients with Turner syndrome have a 45,XO karyotype, the syndrome is thought to be caused by the absence of one set of genes from the short arm of one X chromosome, and a variety of chromosome abnormalities may be found. Many patients are mosaics (e.g., 45,XO/46,XX or 45,XO/47,XXX), and the phenotype is highly variable. A deletion of the SHOX gene can cause an identical phenotype and may be considered to be a variant of Turner syndrome.

A 23-year-old man presents with fever, weight loss, malaise, abdominal pain, and myalgias. Workup reveals that the patient has polyarteritis nodosa. Which of the following is associated with this form of vasculitis? (A) Arsenic (B) Chlamydia pneumonia (C) Hepatitis B virus (D) Human herpesvirus 8 (E) Human immunodeficiency virus

C. Although the significance remains unclear, 30% of patients with polyarteritis nodosa have serum antibodies to the hepatitis B virus. Arsenic is associated with the development of angiosarcoma. Chlamydia pneumonia has been implicated in the development of atherosclerosis. KSHV, HHV-8, causes Kaposi sarcoma in individuals infected with human immunodeficiency virus.

A 45-year-old man presents with abdominal pain and hypertension. On physical examination, he is found to have an abdominal mass. Further workup confirms the diagnosis of adult polycystic kidney disease. Which of the following vascular complications is associated with this condition? (A) Arteriovenous fistula (B) Atherosclerotic aneurysm (C) Berry aneurysm (D) Dissecting aneurysm (E) Luetic aneurysm

C. Berry aneurysms, which occur in 10% to 15% of patients with adult polycystic kidney disease, are small saccular lesions that develop at the site of congenital weakness of cerebral arteries, especially those of the circle of Willis. Rupture of these aneurysms is the most common cause of subarachnoid hemorrhage. Arteriovenous fistulas are often secondary to trauma. Dissecting aneurysm is associated with hypertension or with diseases affecting the vascular media, most notably Marfan syndrome. Syphilitic (luetic) aneurysm is associated with tertiary syphilis.

A 50-year-old man who works for a chemical company is being held on charges of murdering his wife. When the police found the woman's body, they noted no signs of physical injury but detected a scent of bitter almonds. A small sample of cyanide was recently reported missing from the husband's workplace. Based on these investigational findings, a justifiable working hypothesis for the forensic pathologist is that the death resulted from (A) acute tubular necrosis. (B) induction of direct DNA damage. (C) inhibition of intracellular oxidative phosphorylation. (D) inhibition of the oxygen-carrying capacity of hemoglobin. (E) rhabdomyolysis.

C. Cyanide is an inhibitor of the electron transport chain (ETC) within the mitochondria. Inhibition of the ETC results in the inhibition of intracellular oxidative phosphorylation, with depletion of cellular energy stores and, ultimately, death. Acute tubular necrosis can occur under many circumstances, as in cases of rhabdomyolysis secondary to crush injury. Inhibition of the oxygen-carrying capacity of hemoglobin can result from carbon monoxide poisoning. Induction of direct DNA damage can result from radiation exposure.

A newly described neurologic disorder is found to affect multiple family members in three generations that were available for study. In the first generation, two sisters and one brother were affected. In the second generation, all of the children of the first-generation sisters were affected, but none of the descendants of the first- generation son. In the third generation, all of the children of the affected second- generation women were affected, but none of the descendants of the secondgeneration men. The mode of inheritance exemplified here is (A) autosomal dominant. (B) autosomal recessive. (C) mitochondrial. (D) X-linked dominant. (E) X-linked recessive.

C. In mitochondrial inheritance, inheritance is entirely maternal in transmission. Affected males do not transmit the trait to any of their children, and affected females transmit the trait to all of their children. Abnormalities of mitochondrial inheritance typically involve genes that code for enzymes of oxidative phosphorylation.

As part of a fourth-year elective, a medical student rotating through a medical genetics service is assigned to counsel a patient who is concerned about a family history of hypertension. To be properly prepared for the counseling session, the student reviews course notes on modes of inheritance of various disorders. Knowledge of which of the following modes of inheritance is most pertinent to the upcoming discussion with the patient? (A) Autosomal dominant (B) Autosomal recessive (C) Multifactorial (D) X-linked dominant (E) X-linked recessive

C. Multifactorial disorders are among the most common familial abnormalities and are much more common than monogenic disorders. They include a number of common entities, such as ischemic heart disease, diabetes mellitus, hypertension, gout, schizophrenia, bipolar disorder, and neural tube defects.

A 45-year-old man with a long history of alcoholism presents with severe epigastric pain, nausea, vomiting, fever, and an increase in serum amylase. During a previous hospitalization for a similar episode, computed tomography scanning demonstrated calcifications in the pancreas. A diagnosis of acute pancreatitis superimposed on chronic pancreatitis was made. In this condition, which of the following types of necrosis is most characteristic? (A) Caseous (B) Coagulative (C) Enzymatic (D) Fibrinoid (E) Liquefactive

C. Pancreatic enzymatic fat necrosis represents autodigestion by proteolytic and lipolytic enzymes released from damaged parenchymal cells of the pancreas. Fatty acids liberated by the digestion of fat form calcium soaps, a process referred to as saponification. The precipitated calcium in the soaps can be visualized by radiologic imaging.

The parents of a 17-year-old boy with Down syndrome seek counseling because they are concerned that their son may develop a life-threatening disorder known to be associated with his chromosomal abnormality. The physician should be prepared to discuss which of the following disorders in terms of its association with Down syndrome? (A) Berry aneurysm of the circle of Willis (B) Creutzfeldt-Jakob disease (C) Lymphoblastic leukemia (D) Medullary carcinoma of the thyroid (E) Osteosarcoma

C. Patients with Down syndrome are at increased risk of lymphoblastic leukemia. In addition, there is common occurrence of congenital heart disease, especially defects of the endocardial cushion (atrioventricular valve malformations and atrial and ventricular septal defects), and increased susceptibility to infection. Many patients with Down syndrome who are older than 35 years of age show clinical signs, symptoms, and pathologic findings of Alzheimer-type dementia, with an incidence much higher than in the general population.

A 28-year-old woman is found to have pulmonary sarcoidosis. Flow cytometric analysis of T cells isolated from the alveoli and lung interstitium reveals the presence of large numbers of T helper (TH1) cells. These cells are known to secrete which of the following substances? (A) Complement component C5A (B) Elastase and lysyl-hydroxylase (C) Interleukin-2 (IL-2) and interferon-ã (D) IL-8 and transforming growth factor-â (E) Leukotrienes C4 and C5

C. T helper (TH1) cells secrete IL-2 and interferon-ã, which in turn facilitate T-cell expansion and macrophage activation.

A 70-year-old man presents with the sudden onset of left-sided weakness, spasticity, and hyperactive and pathologic reflexes. The most serious consequences of this disorder are the result of damage to which of the following cell types? (A) Labile cells (B) Multipotent adult progenitor cells (C) Permanent cells (D) Stable cells

C. The clinical findings are those of "stroke," or cerebrovascular disease. This group of entities encompasses injury to the brain caused by disorders of the cerebral vasculature, such as thrombosis, embolism, and hemorrhage (see Chapter 3). The most important consequence is damage to neurons, because neurons are considered to be "permanent" cells, incapable of division and replication (however, this has been recently challenged as the result of provocative stem cell research). Permanent cells are exemplified by neurons and myocardial cells. Labile cells, such as cells of the epidermis and gastrointestinal mucosa, divide throughout the life of the individual. Stable cells, such as hepatocytes and renal tubular cells, do not divide regularly but have the capacity to divide and regenerate as needed.

A 20-year-old woman presents with malar rash, arthralgias, low-grade fever, and high titer antibodies to double-stranded DNA and to the Sm (Smith) antigen. Which of the following forms of hypersensitivity is the primary mechanism of the abnormalities found in this disorder? (A) Type I (immediate or anaphylactic) hypersensitivity (B) Type II (antibody-mediated or cytotoxic) hypersensitivity (C) Type III (immune complex-mediated disorders) hypersensitivity (D) Type IV (cell-mediated) hypersensitivity

C. The diagnosis is systemic lupus erythematosus, and the most characteristic lesions are mediated by immune complex deposition (type III hypersensitivity). In this form of hypersensitivity, antibody combines with antigen, resulting in antigen- antibody complexes. Insoluble aggregates of immune complex are deposited in vessel walls, serosal surfaces, and other extravascular sites, and complement is bound. The antigen-antibody-complement complexes are highly chemotactic for neutrophils, which release lysosomal enzymes and other mediators of tissue damage (prostaglandins, kinins, and free radicals).

A 50-year-old right-handed man with a long history of rheumatic heart disease with mitral stenosis and atrial fibrillation is brought to the emergency department after collapsing to the floor at home. He is unable to speak or walk and has right hemiplegia with a right extensor plantar response. These findings most likely result from embolism to which of the following arteries? (A) Anterior cerebral (B) Anterior communicating (C) Middle cerebral (D) Posterior communicating (E) Superior cerebellar

C. The findings are consistent with occlusion of the middle cerebral artery, the most common site of arrest of arterial emboli in branches of the carotid artery. Such emboli usually arise from a mural thrombus in the left atrium or left ventricle. Left atrial mural thrombi are especially associated with mitral stenosis with atrial fibrillation. Mural thrombi in the left ventricle are caused by myocardial infarction. Thrombi at the junction of the internal and external carotid arteries are a cause of thrombotic brain infarcts and can also be a site of origin of emboli.

A 23-year-old man undergoes surgery for fractures of the pelvis and left femur resulting from a high-speed motor vehicle accident. The following day he develops dyspnea, speech difficulties, and a petechial skin rash. Which of the following types of embolism is the likely cause of these findings? (A) Air (B) Amniotic fluid (C) Fat (D) Paradoxical (E) Thrombotic

C. The patient has fat embolism syndrome, which is characterized by pulmonary distress, cutaneous petechiae, and various neurologic manifestations. Fat embolism is a well-known complication of fractures of long bones, such as the femur, and other bones with abundant fatty marrow. On fracture, marrow fat can enter the circulation, and small fat droplets can lodge in the vessels of the skin, lung, and microvasculature of the brain, resulting in the clinical manifestations of this disorder.

A 20-year-old woman has a robertsonian translocation involving chromosome 21 and a second acrocentric chromosome. What is the theoretic likelihood of a functional trisomy 21 if one of her ova is fertilized by a normal sperm? (A) 1 in 1 (B) 1 in 2 (C) 1 in 3 (D) 1 in 4 (E) 1 in 1500

C. Theoretically, a person who carries a robertsonian translocation with chromosome 21 and a second acrocentric chromosome has a 1 in 3 chance of having a child with trisomy 21; however, the risk of a live birth of a child with Down syndrome is actually much less, presumably because of a high incidence of spontaneous abortion of such fetuses. The important point is that a robertsonian translocation predisposes to a hereditable form of Down syndrome. The risk is not related to maternal age and is much higher than the risk in the general population, which is 1 in 1500 for women 20 years of age and younger, increasing to 1 in 25 in women older than 45 years of age.

A 40-year-old woman presents with endometrial carcinoma. Her family history reveals that her mother died of endometrial cancer at age 50, while her 42-year-old brother was recently diagnosed with colon cancer. You begin to suspect a familial cancer syndrome. What gene is most likely to be mutated in this family? (A) WT-1 (B) APC (C) MSH2 (D) p53 (E) BRCA-1

C. This family likely has hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, or Lynch syndrome. Often, gynecologic malignancies (usually endometrial, although patients are also prone to ovarian tumors) are diagnosed before colorectal tumors in female patients with HNPCC. This syndrome is due to defects in DNA mismatch repair genes, with MLH1, MSH2, MSH6, and PMS2 representing the primary culprits. WT-1 mutations predispose patients to Wilms tumors and a variety of other defects, while APC is mutated in familial adenomatous polyposis (FAP). Germline mutations in p53 are seen in Li Fraumeni syndrome, while BRCA-1 mutations predispose women to breast carcinoma.

A 35-year-old African-American man is transported to the emergency department because of an unrelenting, severe, excruciating headache. His blood pressure is 245/150 mm Hg, and bilateral papilledema is evident on ophthalmoscopic examination of the retina. Despite all interventions, including administration of nitroprusside, the patient dies. At autopsy, which of the following is a likely finding? (A) Immune complex vasculitis of the glomeruli (B) Longitudinal intraluminal tears of the ascending aorta (C) Multiple punctuate hemorrhages on the surface of both kidneys ("flea-bitten kidneys") (D) "Tree-bark" appearance of the ascending aorta (E) Unilateral renal artery stenosis

C. This is a typical presentation for a patient with malignant hypertension. The kidneys appear "flea-bitten" because of multiple petechial hemorrhages on the surface. Microscopically, the glomeruli display fibrinoid necrosis and hyperplastic arteriolosclerosis. Immune complex vasculitis of the glomeruli is typical of polyarteritis nodosa. Longitudinal intraluminal tears of the ascending aorta occur with dissecting aneurysm. A "tree-bark" appearance of the ascending aorta results from tertiary syphilis. Unilateral renal artery stenosis can result from fibromuscular dysplasia.

A 3-year-old child is brought to the emergency department because of a week-long history of abdominal discomfort, irritability, and weakness. A complete blood count and blood smear demonstrate microcytic hypochromic anemia with basophilic stippling of the red blood cells. Further history reveals that the family lives in an old apartment complex. The most likely cause of the hematologic findings is (A) binding of carbon monoxide to hemoglobin. (B) inhibition of cytochrome oxidase. (C) inhibition of hemoglobin production. (D) iron deficiency. (E) iron intoxication.

C. This is a typical presentation of lead poisoning. Lead inhibits hemoglobin synthesis by inhibiting both aminolevulinic acid dehydratase and ferroketolase. This inhibits not only the synthesis of hemoglobin but also the incorporation of iron into the molecule. Cyanide and carbon monoxide (CO) inhibit cytochrome oxidase. CO also binds to hemoglobin, preventing adequate oxygen transport. Iron deficiency can lead to similar hematologic findings.

A 2-year-old boy has eczema and thrombocytopenia. There is also a history of recurrent infection. His brother has similar abnormalities, but none of his three sisters is affected. Patients with this disorder are known to have impaired antibody response to which of the following types of antigen? (A) Deoxyribonucleic acid (B) Phospholipid (C) Polysaccharide (D) Ribonucleic acid (E) Steroid

C. Wiskott-Aldrich syndrome is an X-linked disorder characterized by eczema, thrombocytopenia, recurrent infections, and poor antibody response to polysaccharide antigens. Bloody diarrhea is also common. Death before 6 years of age occurs frequently and is most often due to bleeding, infection, or malignancy (most often lymphoma).

A 32-year-old man is involved in a highspeed motor vehicle accident and brought by ambulance to a Level I trauma center because of the severity of his injuries. On arrival, it is determined that he is bleeding internally, and he is taken immediately to surgery, where the surgeons find that the source of his bleeding is a severe liver laceration. A laceration is a (A) bruise caused by disruption of underlying blood vessels. (B) clean cut by a sharp object. (C) deep tubular wound produced by a sharp, thin object. (D) jagged tear, often with stretching of the underlying tissue. (E) superficial tearing away of epidermal cells.

D. A laceration, especially of internal organs, is common in cases of blunt trauma, as in a motor vehicle accident. By definition, a laceration is a jagged tear, often with stretching of the underlying tissue. An incision is a clean cut by a sharp object, as in a clean cut by a surgeon. A contusion is a bruise caused by disruption of underlying blood vessels. A puncture is a deep tubular wound produced by a sharp, thin object. An abrasion is a superficial tearing away of epidermal cells.

An abused child is found living in the basement of his parents' home after they are arrested on drug charges. In addition to being severely malnourished, the child is found to have bleeding gums and easy bruisability, along with numerous poorly healing skin ulcerations. Assuming that these findings resulted from vitamin C deficiency, what is the likely mechanism of these findings? (A) Defective DNA synthesis (B) Defective production of ã-aminobutyric acid (C) Impaired carboxylation of coagulation factors II, VII, IX, and X (D) Impaired hydroxyproline and hydroxylysine production (E) Impaired renal 1á-hydroxylase

D. Because vitamin C is a required cofactor for the synthesis of hydroxyproline and hydroxylysine, which are both required for collagen synthesis, vitamin C deficiency can lead to impaired capillary formation, with consequent bleeding, and impaired wound healing. Both vitamin B12 and folic acid are required for DNA synthesis. Pyridoxine is required for GABA synthesis. Vitamin K is required for carboxylation of clotting factors. Patients with vitamin D-resistant rickets have a deficiency of renal 1á-hydroxylase.

A 73-year-old man develops severe, intractable diarrhea during hospitalization for bacterial pneumonia caused by a multidrug- resistant organism. What organism is most likely responsible for his gastrointestinal symptoms? (A) MRSA (B) Streptococcus pneumoniae (C) Candida (D) Clostridium difficile (E) Clostridium botulinum

D. C. difficile causes diarrhea in patients in whom competing colonic flora has been obliterated by antibiotics. Candidal infections are also common in patients on antibiotics but typically manifest with oral or vaginal candidiasis, rather than diarrhea. MRSA is a growing problem both in the hospital and in the community but does not typically cause diarrhea (although it could well be the cause of the patient's drug-resistant pneumonia!). C. botulinum causes botulism, a rare but sometimes fatal paralytic disorder, and is not associated with diarrhea.

A 68-year-old man has a long history of prostate cancer that was metastatic at the time of diagnosis. Over the past 2 months, he has had significant weight loss, loss of appetite, and loss of energy. His current spectrum of conditions can be attributed to which of the following? (A) Platelet-derived growth factor (B) Fibroblast growth factor (C) Interleukin-2 (D) Tumor necrosis factor-á (E) Vascular endothelial growth factor

D. Cachexia, or wasting due to cancer, manifests with weakness, weight loss, anorexia, anemia, and infection. The principal cytokine responsible for such changes is tumor necrosis factor-á (TNF-á). Both platelet-derived growth factor and fibroblast growth factor are involved in wound healing. Interleukin-2 (IL-2) is an immunostimulating cytokine produced by activated T cells. Vascular endothelial growth factor is important in the proliferation of blood vessels in a growing tumor.

A 4-year-old girl is brought by her mother to the emergency department after the girl was "placed in a hot bath." The patient appears to have extensive blistering of the thighs and buttocks, with slight damage to the underlying dermis. Her burns are best described as (A) first-degree burns. (B) fourth-degree burns. (C) full-thickness burns. (D) second-degree burns. (E) third-degree burns.

D. First- and second-degree burns are both partial-thickness burns. Because the findings in this patient reveal both epithelial and dermal involvement, the burns are, by definition, second-degree in type. Both third- and fourth-degree burns are classified as full-thickness burns; they entail total destruction of dermis and epidermis along with underlying skin appendages that normally serve as a source of cells for regeneration. As such, these wounds require skin grafting.

A 60-year-old man with unstable angina (a form of acute coronary syndrome) is treated with an intravenously administered glycoprotein IIb-IIIa inhibitor. The mechanism of action of this agent is the ability to (A) dilate coronary arteries. (B) inhibit atherogenesis. (C) inhibit platelet adhesion. (D) inhibit platelet aggregation. (E) lyse thrombi.

D. Glycoprotein IIb-IIIa inhibitors prevent the action of the corresponding platelet surface receptor glycoprotein complex, which is required for formation of fibrinogen bridges between adjacent platelets.

A 63-year-old woman discovers a lump in her right breast. Mammography confirms the presence of a suspicious "lump," and a needle core biopsy is performed to determine whether the mass is malignant. The pathology report confirms that the mass is indeed cancerous and that the tissue demonstrates amplification of the Her-2/neu oncogene. The gene product of Her-2/neu is what kind of protein? (A) GTPase (B) GTPase-activating protein (C) Nuclear transcription factor (D) Receptor tyrosine kinase (E) A retinoic acid receptor protein

D. Her-2/neu, also known as c-erbB2, is a receptor tyrosine kinase related to epidermal growth factor receptor and is amplified at the DNA level and overexpressed at the protein level in some breast cancers. Ras is a GTPase that is mutated in a number of cancers. NF-1 is a GTPase-activating protein (GAP) aberrantly expressed in neurofibromatosis. An aberrant version of a retinoic acid receptor is expressed in M3 AML.

A 56-year-old man recovered from a myocardial infarction after his myocardium was entirely "saved" by immediate thrombolytic therapy. If it had been possible to examine microscopic sections of his heart during his ischemic episode, which of the following would be the most likely cellular change to be found? (A) Karyolysis (B) Karyorrhexis (C) Pyknosis (D) Swelling of the endoplasmic reticulum

D. If infarction is averted by immediate thrombolytic therapy, indicators of necrosis, such as karyorrhexis, pyknosis, and karyolysis, which represent irreversible changes, would not be expected. Swelling of the endoplasmic reticulum from increased cell water, one of the earliest ultrastructural changes observed in injured cells, is reversible and would be expected.

A 19-year-old young woman who emigrated from Taiwan 8 years ago presents with fever, malaise, myalgias, and arthritis and "coldness" in her upper extremities. She has a weak radial pulse bilaterally, and a magnetic resonance angiogram demonstrates nearly 75% stenosis of the main arteries originating from the aorta. She likely has which of the following rheumatologic conditions? (A) Buerger disease (B) Kawasaki disease (C) Raynaud disease (D) Takayasu arteritis (E) Temporal arteritis

D. Inflammation and stenosis of branches of the aortic arch is known as Takayasu arteritis, or "pulseless disease." It most commonly occurs in young Asian females. Buerger disease usually affects young Jewish males and involves the arteries of the extremities. The disease is exacerbated by smoking and can lead to gangrene of the extremities. Kawasaki disease affects the branches of the coronary arteries. Raynaud disease is due to vasospasm of small vessels of the fingers and toes, leading to cyanosis and pallor of the affected tissues. Temporal arteritis is usually encountered in older patients and affects the branches of the carotid artery, most commonly the temporal artery.

A 52-year-old recent Asian immigrant is brought to the emergency department after experiencing several convulsions. Further history reveals that she has been diagnosed with tuberculosis and has recently been started on a multidrug regimen that includes isoniazid. Which of the following is the likely cause of her convulsions? (A) Vitamin B1 (thiamine) deficiency (B) Vitamin B2 (riboflavin) deficiency (C) Vitamin B3 (niacin) deficiency (D) Vitamin B6 (pyridoxine) deficiency (E) Vitamin C (ascorbic acid) deficiency

D. Isoniazid is a competitive inhibitor of pyridoxine (vitamin B6), which is required for the synthesis of the inhibitory neurotransmitter ã-aminobutyric acid. Riboflavin deficiency is rare and can result in cheilosis, glossitis, and other epithelial changes. Niacin deficiency results in pellagra. Pyridoxine deficiency can manifest with convulsions. Vitamin C deficiency results in defects in collagen synthesis. Thiamine deficiency results in neuropathy, cardiomyopathy, and mental status changes.

A 23-year-old man known to have acquired immunodeficiency syndrome (AIDS) is seen by his primary care physician. The patient is concerned by the development of multiple red-to-purple skin plaques that have become nearly confluent on his arms and legs. The skin disorder is most likely (A) angioedema. (B) angiosarcoma. (C) erythema multiforme. (D) Kaposi sarcoma. (E) multiple telangiectasias of Osler-Weber- Rendu syndrome.

D. Kaposi sarcoma is a malignant vascular tumor that occurs in men infected with the Kaposi sarcoma herpesvirus (KSHV), often as a complication of AIDS. Angiosarcoma is a malignant tumor of blood vessels associated with thorium dioxide (Thorotrast); arsenic; or in the case of angiosarcoma of the liver, polyvinyl chloride. Polyarteritis nodosa is a vasculitis sometimes associated with hepatitis B infection. Serum sickness is due to deposition of antigen-antibody complexes.

A forensic pathologist is asked to evaluate a fatal gunshot wound involving the left thorax of a 27-year-old man, a known drug dealer. Even though a gun and suicide note were found next to the body, the pathologist has concluded that the wound was probably not self-inflicted. Which of the following findings is most supportive of that conclusion? (A) The entrance wound is smaller than the exit wound. (B) The entrance wound is stellate-shaped. (C) The exit wound is irregularly shaped. (D) There is no stippling of the skin, and the wound is oval with clean margins. (E) There is stippling of the skin from unburned gunpowder.

D. Lack of stippling is a characteristic of gunshot wounds inflicted from long distances. In addition, the wounds are often oval with clean margins. Such evidence is more consistent with a homicide than a "staged" suicide. In general, entrance wounds are smaller than exit wounds, which are often irregularly shaped. Stellate-shaped wounds are associated with wounds over bony areas. Wounds from close range, as in a suicide, would be expected to have stippling and tattooing of skin caused by unburned gunpowder.

A 19-year-old college sophomore is referred by his ophthalmologist because of the finding of ectopia lentis (dislocation of the lens), which has resulted in visual difficulties that have interfered with his performance on the varsity basketball team. The patient is very tall, with long limbs and long, slender, spiderlike fingers. His chest has a "caved-in" appearance, and he also has a modest degree of scoliosis. A midsystolic "click" is heard, and an echocardiogram reveals mitral valve prolapse. The most likely diagnosis is (A) Ehlers-Danlos syndrome. (B) Fabry disease. (C) Hurler syndrome. (D) Marfan syndrome. (E) Pompe disease.

D. Marfan syndrome, an autosomal dominant disorder caused by mutations of the fibrillin gene on chromosome 15, is a frequent cause of ectopia lentis. Other cardinal features include skeletal and cardiovascular abnormalities. Patients are tall and thin, with notably long limbs and digits. An anterior chest deformity known as pectus excavatum is sometimes seen, and vertebral abnormalities include scoliosis and lordosis. In addition, a highly arched palate and crowding of the teeth may occur. Cardiovascular complications include mitral valve prolapse and mitral regurgitation. Cystic medial necrosis can lead to dilation of the aortic root and aortic regurgitation. Life-threatening complications are aortic aneurysm and aortic dissection.

A 60-year-old woman with breast cancer and widespread bony metastases is found to have calcification of multiple organs. The calcifications are best described as (A) dystrophic with decreased serum calcium. (B) dystrophic with increased serum calcium. (C) metastatic with decreased serum calcium. (D) metastatic with increased serum calcium.

D. Metastatic calcification, or deposition of calcium in previously normal tissue, is caused by hypercalcemia. In this patient, tumor metastases to the bone with increased osteolytic activity caused mobilization of calcium and phosphate, resulting in hypercalcemia. Metastatic calcification should be contrasted with dystrophic calcification, in which the serum calcium concentration is normal and previously damaged tissues are the sites of deposition.

In a laboratory exercise for medical students, an unknown compound is studied. The students are informed that the compound has been isolated from endothelial cells and that its synthesis can be inhibited by aspirin. In the laboratory, the students demonstrate that the compound is a potent vasodilator and platelet antiaggregant. Given these findings, the substance is most likely which of the following mediators? (A) 5-HPETE (B) LTC4 (C) LXA4 (D) PGI2 (E) TxA2

D. PGI2 is a prostaglandin that is synthesized and expressed primarily in endothelial cells. It is a product of the cyclooxygenase pathway of arachidonic acid metabolism, which is inhibited by aspirin. PGI2 is a potent vasodilator and platelet antiaggregant. These properties are often contrasted with those of TxA2, which is primarily synthesized in platelets and is a vasoconstrictor and platelet aggregant. The other compounds are products of the lipoxygenase pathway of arachidonic acid metabolism, which is not inhibited by aspirin.

Within minutes of a bee sting, a 23-year-old woman develops generalized pruritus and hyperemia of the skin, followed shortly by swelling of the face and eyelids, dyspnea, and laryngeal edema. This reaction is mediated by (A) antigen-antibody complexes. (B) cytotoxic T cells. (C) IgA antibodies. (D) IgE antibodies. (E) IgG antibodies.

D. The clinical description is characteristic of systemic anaphylaxis, an IgE-mediated type I hypersensitivity reaction. In type I hypersensitivity, reaction of antigen with preformed IgE antibodies fixed by Fc receptors to the surface of basophils or tissue mast cells results in cytolysis and degranulation of these cells, with release of histamine and other mediators.

A 65-year-old man who has a long history of hypertension presents to the emergency department with tearing chest pain that radiates to the back. An electrocardiogram is normal, as are cardiac enzymes. A "stat" chest radiograph demonstrates widening of the mediastinum. Which of the following is the most likely? (A) Arteriovenous fistula (B) Atherosclerotic aneurysm (C) Berry aneurysm (D) Dissecting aneurysm (E) Syphilitic aneurysm

D. The clinical presentation of a dissecting aortic aneurysm mimics that of a myocardial infarction; however, electrocardiographic changes and increased concentration of cardiac enzymes are notably absent. The mediastinum is often widened by radiographic examination. Although there is an association with hypertension and disorders of connective tissue (e.g., Marfan syndrome and Ehlers-Danlos syndrome), there is no association with atherosclerosis. The presentation exemplified by this scenario is a true surgical emergency!

A 54-year-old Native American living on a reservation in southwest Arizona presents to a clinic with impaired memory; diarrhea; and a rash on the face, neck, and dorsum of the hands. It is likely that this patient has a deficiency of which of the following nutrients? (A) Ascorbic acid (B) Folic acid (C) Homocysteine (D) Niacin (E) á-Tocopherol (vitamin E)

D. The clinical scenario depicts the classic findings of pellagra, or niacin deficiency, with diarrhea, dementia, and dermatitis. Niacin is synthesized from the essential amino acid tryptophan, which is particularly deficient in corn-based diets. Vitamin C deficiency results in scurvy. Folic acid deficiency often manifests with anemia. Decreased levels of homocysteine, an amino acid, have been associated with cardiovascular disease. Vitamin E deficiency is rare and can result in neurologic abnormalities.

A 14-year-old boy is brought by his family to your clinic in Utah with a long history of recurrent epistaxis. His father also reports such a history. Of the following, which is the most likely condition consistent with these findings? (A) Cavernous hemangioma (B) Glomangioma (C) Hemangioendothelioma (D) Osler-Weber-Rendu syndrome (E) Varicose veins

D. The hemorrhagic phenomena in this patient likely represent recurrent rupture of the convolutions of venules and capillaries in the mucous membranes of the nose, as occurs in the Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia). This disorder is inherited as an autosomal dominant condition and also affects the vessels of the gastrointestinal tract. Characteristic lesions can often be seen on the lips, conjunctivae, and mucous membranes of the nose or mouth. Cavernous hemangioma is a common lesion. On occasion, it can be seen as a component of the von Hippel-Lindau syndrome. A glomangioma is a benign tumor of blood vessels on the fingers or toes. A hemangioendothelioma is a rare malignant tumor of blood vessels. Varicose veins are a manifestation of incompetency of the valves in the superficial veins of the legs of older patients.

A 26-year-old African-American woman has bilateral hilar adenopathy, and radiography reveals multiple reticular densities in both lung fields. A bronchoscopic biopsy reveals granulomatous inflammation with multiple giant cells of the Langhans type and no evidence of caseous necrosis. Which of the following is the most likely diagnosis? (A) Aspergillosis (B) Coccidioidomycosis (C) Histoplasmosis (D) Sarcoidosis (E) Tuberculosis

D. The histologic hallmark of sarcoidosis is the finding of noncaseating granulomatous inflammation. Although this finding is not entirely specific, a non-necrotizing granulomatous response of the lung is rarely seen in patients with tuberculosis or deep-seated fungal infections. These infections usually have a necrotizing component.

While working with an international group of physicians to administer polio vaccines, a medical student sees several children with abdominal distention and pale streaks in the hair and skin. Cursory physical examination reveals significant hepatomegaly. The children likely suffer from (A) anorexia. (B) beriberi. (C) bulimia. (D) kwashiorkor. (E) marasmus.

D. These children suffer from kwashiorkor, a form of protein-calorie malnutrition that is associated with a protein-poor diet. Kwashiorkor should be distinguished from the relative deficiency of all calories known as marasmus. Anorexia and bulimia are psychiatric eating disorders that are significantly more prevalent in developed countries. Beriberi is due to deficiency of thiamine.

A 50-year-old chronic alcoholic is seen in the emergency department with ataxic gait, confusion, confabulation, and nystagmus. This constellation of findings is the classic presentation of (A) Fetal alcohol syndrome. (B) Li-Fraumeni syndrome. (C) Lynch syndrome. (D) Wernicke-Korsakoff syndrome. (E) Wiskott-Aldrich syndrome.

D. Wernicke-Korsakoff syndrome presents with the classic triad of ataxia, confabulation, and ophthalmoplegia and is seen in alcoholics secondary to a deficiency of the vitamin thiamine. Fetal alcohol syndrome occurs in infants born to mothers who consume alcohol during pregnancy and results in microcephaly, mental retardation, and facial and cardiac defects. Li-Fraumeni syndrome and the Lynch syndrome are both familial defects in DNA repair that lead to a propensity to develop particular cancers. Wiskott-Aldrich syndrome is an inborn immune defect presenting with eczema, thrombocytopenia, and recurrent infections.

A 57-year-old man is admitted to the hospital for treatment of chronic pancreatitis. In patients with chronic pancreatitis, deficiency of which of the following vitamins is most likely? (A) Folic acid (B) Vitamin B2 (riboflavin) (C) Vitamin B6 (pyridoxine) (D) Vitamin B12 (cobalamin) (E) Vitamin D

E. Deficiency of fat-soluble vitamins (vitamins A, D, E, and K) can occur in chronic pancreatitis due to loss of exocrine pancreas function. Vitamin B12 (cobalamin), folic acid, vitamin B2 (riboflavin), and vitamin B6 (pyridoxine) are all water-soluble vitamins. It should be noted that most patients with chronic pancreatitis also are alcoholics and that alcoholics often have multiple nutritional deficiencies, including lack of watersoluble vitamins.

A woman from a rural Appalachian community who had recently given birth to a newborn boy at home with the aid of a midwife now brings her infant to the hospital because of continued bleeding and oozing from the umbilical stump. It is likely that the bleeding problem is secondary to a deficiency of which of the following vitamins? (A) Folic acid (B) Vitamin A (C) Vitamin D (D) Vitamin E (E) Vitamin K

E. Deficiency of vitamin K results in abnormal bleeding, based on the requirement of the vitamin for ã-carboxylation of clotting factors II, VII, IX, and X. Because newborns have inadequate intestinal flora, the primary source of vitamin K, vitamin K deficiency is relatively common and is estimated to occur in approximately 3% of neonates. The resultant bleeding disorder is termed hemorrhagic disease of the newborn. Folic acid deficiency during early embryogenesis can result in neural tube defects. Vitamin A deficiency results in changes in vision and defects in epithelial cell function. Vitamin D deficiency in children results in rickets.

A 54-year-old woman who has been diagnosed with early-stage breast cancer undergoes surgery for a lumpectomy to remove a small tumor detected by mammography. The pathology report confirms the early stage of the cancer and further comments on the fact that there is significant desmoplasia in the surrounding tissue. The term desmoplasia refers to (A) an irregular accumulation of blood vessels. (B) maturation and spatial arrangement of cells. (C) metastatic involvement of surrounding tissue. (D) normal tissue misplaced within another organ. (E) proliferation of non-neoplastic fibrous connective tissue.

E. Desmoplasia refers to proliferation of non-neoplastic fibrous connective tissue within a tumor and is quite common in cases of breast cancer. An irregular accumulation of blood vessels is known as a hemangioma. An area of tissue misplaced within another organ is known as a choristoma.

A 62-year-old woman with a long history of rheumatoid arthritis was recently placed on therapy with methotrexate (a folic acid antagonist). The physician should be on the alert for which of the following side effects of this newly added medication? (A) Defective osteoid matrix production (B) Hemorrhagic lesions of the mamillary bodies (C) High-output heart failure (D) Impaired wound healing (E) Megaloblastic anemia

E. Folate is required for DNA replication in rapidly dividing cells, such as red blood cell precursors, and a deficiency results in megaloblastic anemia. Hemorrhagic lesions of the mamillary bodies and high-output heart failure occur with thiamine deficiency. Impaired wound healing and defective osteoid matrix production result from vitamin C deficiency.

A 27-year-old woman has recently been diagnosed with a glioma (a malignant brain tumor). Further family history reveals that her 4-year-old son has been diagnosed with leukemia and has been undergoing chemotherapy. In addition, the patient's mother died at 36 years of age due to metastatic breast cancer. Li-Fraumeni syndrome is suspected, given the familial clustering of this group of malignancies. The gene mutated in Li-Fraumeni syndrome normally functions in what capacity? (A) Activates the GTPase activity of the gene product of the Ras oncogene (B) Excises ultraviolet light-induced thymidine dimers (C) Functions as a cytoplasmic tyrosine kinase (D) Functions as a transmembrane tyrosine kinase (E) Halts the cell cycle if DNA damage is detected

E. Li-Fraumeni syndrome is a hereditary syndrome characterized by sarcomas, breast cancer, leukemia, and brain tumors. Xeroderma pigmentosum results from a defect in repair of UV damage. Numerous transmembrane tyrosine kinases, such as Her-2/neu, are implicated in numerous cancers. C-abl codes for a cytoplasmic tyrosine kinase that forms a fusion protein with bcr in chronic myelogenous leukemia. NF-1, mutated in neurofibromatosis, normally activates the GTPase activity of the gene product of the Ras oncogene. The gene p53, the "guardian of the genome," arrests the cell cycle in G1 in the event that DNA damage is detected.

A 64-year-old woman presents with fever, chills, headache, neck stiffness, vomiting, and confusion. The Kernig sign (passive knee extension eliciting neck pain) and Brudzinski sign (passive neck flexion eliciting bilateral hip flexion) are both positive. Examination of the cerebrospinal fluid reveals changes consistent with bacterial meningitis, and brain imaging demonstrates a localized abscess. Which of the following types of necrosis is most characteristic of abscess formation? (A) Caseous (B) Coagulative (C) Enzymatic (D) Fibrinoid (E) Liquefactive

E. Liquefactive necrosis is characteristic of ischemic injury in the CNS and suppurative infections that cause abscess formation (see Chapter 2). The changes in the cerebrospinal spinal fluid characteristic of bacterial meningitis are detailed in Chapter 3.

A 1-year-old girl with an inborn error of metabolism resulting in a lysosomal storage disease receives a hematopoietic stem cell transplant intended to replace her macrophage population. The gene of interest has a "marker" small nucleotide polymorphism within a noncoding intron of the affected gene in which an A (patient gene) is substituted for a G (donor gene). She does quite well for the first 3 weeks. She tests positive for the missing enzyme, her previously abnormally enlarged organs begin to diminish in size, and assay of peripheral blood lymphocytes reveals increasing numbers of cells with the G polymorphism. However, the attending physicians are now concerned because repeated genetic testing reveals a progressive increase in lymphocytes with the A polymorphism. Which of the following is the best explanation for this finding? (A) Generalized immune complex formation (B) Graft-versus-host disease (C) Immune paralysis (D) Immune tolerance (E) Rejection of the stem cell transplant

E. Rejection of the stem cell transplant is occurring, as evidenced by reappearance of the marker for the patient's original gene. Small nucleotide polymorphisms are the most frequent form of DNA variation. As the name implies, they are typically small in size, often a single nucleotide. They may occur in any portion of the gene, even in intergenic regions of the genome, and are of increasing importance as genetic markers, as illustrated by the example presented here.

A 7-month-old boy has had multiple bouts of otitis media, sinusitis, bronchitis, oral candidiasis, and multiple viral infections. Cessation of the recurrent infections follows successful engraftment of a bone marrow transplant. The basis of the clinical improvement is (A) direct transfusion of antibody-producing B cells. (B) direct transfusion of donor CD4+ and CD8+ lymphocytes. (C) donor suppression of recipient cytotoxic T cells. (D) infusion of donor-derived cytokines. (E) maturation of donor lymphoid progenitor cells.

E. Severe combined immunodeficiency disease is characterized by failure to thrive and increased susceptibility to bacterial, fungal, and viral infections. Laboratory studies reveal decreased numbers of both B cells and T cells and deficiency of immunoglobulins. The treatment of choice is bone marrow (or other sources of hematopoietic stem cells) transplantation and is based on maturation of donor lymphoid progenitor cells.

A 16-year-old boy presents with a 24-hour history of severe abdominal pain, nausea, vomiting, and low-grade fever. The pain is initially periumbilical in location but has migrated to the right lower quadrant of the abdomen, with maximal tenderness elicited at a site one-third of the way between the crest of the ileum and the umbilicus (McBurney point). The leukocyte count is 14,000/mm3, with 74% segmented neutrophils and 12% bands. Surgery is performed. Which of the following describes the expected findings at the affected site? (A) Fistula (abnormal duct or passage) connecting to the abdominal wall (B) Granulation tissue (new vessels and young fibroblasts) with a prominent infiltrate of eosinophils (C) Granulomatous inflammation with prominent aggregates of epithelioid cells and multinucleated giant cells (D) Massive infiltration of lymphocytes and plasma cells (E) Prominent areas of edema, congestion, and a purulent reaction with localized areas of abscess formation

E. The clinical findings are typical of acute appendicitis, another example of severe acute inflammation. Because the danger of perforation is great, early appendectomy is the treatment of choice. Suppurative or purulent inflammation is characterized by the prominent areas of edema resulting from increased vascular permeability, congestion, and a purulent (pus-containing) exudate consisting of necrotic cells and large numbers of neutrophils. In addition, other signs of acute inflammation, such as congestion, are prominent. The patient responds with the sensation of pain (induced by increased hydrostatic pressure in tissue and by chemical mediators such as bradykinin) and the acute phase reaction (in this instance, fever and neutrophilic leukocytosis with a "shift to the left").

A screening test for phenylketonuria (PKU) is performed on umbilical cord blood from a fair-skinned blond, blue-eyed infant born to dark-complexioned parents. The test is reported as negative, and no dietary restrictions are imposed. At 1 year of age, the child is seen again, this time with obvious signs of severe mental retardation, and a diagnosis of PKU is made. The diagnosis was missed at birth because (A) cord blood is not a good source of fetal blood. (B) the screening (Guthrie) test has low sensitivity. (C) the test should have been performed on maternal blood. (D) the test should have been performed on urine rather than blood. (E) the test was performed too early.

E. The concentration of phenylalanine in affected infants is usually normal at birth and increases rapidly during the first days of life. False-negative results are common immediately after birth but are rare on the second and third days of life. Consequently, the blood sample for phenylketonuria is usually taken from the infant's heel within 2 to 3 days after birth. If the test is performed too early, the diagnosis could be missed.

An 86-year-old man with a history of recurrent urinary tract infection presents with fever, tachypnea, tachycardia, mental obtundation, and reduced blood pressure. Which of the following forms of shock is most likely? (A) Anaphylactic shock (B) Cardiogenic shock (C) Hypovolemic shock (D) Neurogenic shock (E) Septic shock

E. The diagnosis is septic shock, most likely a result of gram-negative sepsis originating from a urinary tract infection. Gram-negative organisms contain lipopolysaccharide in the outer membrane, which triggers the release of cytokines, such as tumor necrosis factor, resulting in a cascade of events culminating in increased capillary permeability and redistribution of circulatory volume into the interstitium. Anaphylactic shock is a result of a type I hypersensitivity. Cardiogenic shock often results from myocardial infarction. Hypovolemic shock is a result of blood or fluid loss. Neurogenic shock can result from spinal cord injuries.

Two days following a cholecystectomy, a 32-year-old hospitalized woman has sudden onset of dyspnea, pleural pain, and cough productive of frothy, blood-tinged sputum. Ventilation-perfusion scintigraphy indicates a perfusion defect. If it were possible to examine a portion of the affected lung, which of the following would most likely have been found? (A) Air embolism (B) Anemic (white or pale) infarct (C) Disseminated intravascular coagulation (DIC) (D) Generalized thrombosis (E) Hemorrhagic (red) infarct

E. The history is that of pulmonary embolism and infarction, a danger of immobilization, and the postoperative state. The infarct consists of an area of coagulative necrosis with superimposed hemorrhage, a combination referred to as a hemorrhagic, or red, infarct. Red infarcts are typical of tissues with a redundant arterial blood supply. Prominent examples are the lung with its double circulation from the pulmonary and bronchial arteries and the gastrointestinal tract with its multiple anastomoses between branches of the mesenteric artery. When a portion of the blood supply is obstructed, other portions remain patent, which can lead to hemorrhage into the infarcted area.

A 26-year-old woman dies after a short illness beginning in the late stages of labor. At autopsy, blood vessels in the lungs contained fetal debris (e.g., squamous cells, vernix, mucin), as did other vessels of multiple organs. Review of the clinical history reveals that she had become acutely ill with dyspnea, hypotension, and seizures, and a chest radiograph had demonstrated evidence of pulmonary edema. This was all followed by prolonged hemorrhage from the vagina and generalized bleeding from multiple other sites. The changes that were found within multiple blood vessels most likely are (A) bone marrow emboli. (B) fat emboli. (C) gas emboli. (D) septic emboli. (E) widespread thrombosis.

E. The history is typical of amniotic fluid embolism, one of the major obstetric causes of disseminated intravascular coagulation (DIC). Other obstetric complications associated with DIC include retained dead fetus and abruptio placentae (premature separation of the placenta). Nonobstetric causes include neoplasms or tissue damage from infection, immunologic mechanisms, or trauma. Neoplastic causes include tumors of the lung, pancreas, prostate, and stomach, and FAB M3 acute myeloblastic (promyelocytic hypergranular) leukemia. Tissue damage can result from trauma such as lung surgery, from hemolysis or hemolytic transfusion reactions, and from inflammatory causes, such as gram-negative sepsis and immune complex disease.

A 58-year-old man with a 700-pack-peryear smoking history presents to the emergency department with shortness of breath and hemoptysis. Portable chest radiography demonstrates a large mass centrally located within the left lung field. The serum calcium is 13.0 mg/dL (normal 8.5 to 10.2). The metabolic abnormality described here is likely due to elaboration of which substance? (A) Adrenocorticotropic hormone-like substance (B) Antidiuretic hormone (C) Carcinoembryonic antigen (D) Erythropoietin (E) Parathyroid-related hormone

E. The man is likely to have a lung tumor, given his clinical presentation and the radiographic results. The patient's hypercalcemia is likely due to a paraneoplastic syndrome, such as that due to the elaboration of parathyroid-related hormone (PTrH). PTrH is produced by squamous cell carcinoma, whereas adrenocorticotropic-like substance and antidiuretic hormone are produced by yet another form of lung cancer—small cell carcinoma of the lung. Carcinoembryonic antigen is an oncofetal antigen produced by colon cancer cells. Erythropoietin causes secondary polycythemia and is related to renal cell carcinoma.

A 72-year-old man presents with a 3-day history of progressively worsening productive cough, fever, chills, and signs of toxicity. Prominent physical findings include signs of consolidation and rales over the right lung base. Sputum culture is positive for Streptococcus pneumoniae. An intra-alveolar exudate filling the alveoli of the involved portion of the lung is present. Which of the following types of inflammatory cells is most likely a prominent feature of this exudate? (A) Basophils (B) Eosinophils (C) Lymphocytes (D) Monocytes-macrophages (E) Neutrophils

E. The patient has bacterial pneumonia due to Streptococcus pneumoniae, a classic example of severe acute inflammation. In the early stages of acute inflammation, the neutrophil is the most prominent inflammatory cell. It is noteworthy that, in many instances, bacterial infections are characterized by neutrophilic infiltrates. It is also noteworthy that S. pneumoniae (also known as the "pneumococcus") is the most common etiologic agent of lobar pneumonia (see Chapter 14).

An impending myocardial infarction was successfully averted by thrombolytic ( clot-dissolving) therapy in a 55-year-old man. Which of the following biochemical events most likely occurred during the period of hypoxia? (A) Decreased hydrogen ion concentration (B) Increase in oxidative phosphorylation (C) Loss of intracellular Na+ and water (D) Stimulation of ATP synthesis (E) Stimulation of anaerobic glycolysis and glycogenolysis

E. The sequence of events in hypoxic cell damage is as follows: Hypoxia results in failure of oxidative phosphorylation, with resultant depletion of ATP and increase in adenosine monophosphate and adenosine diphosphate. Anaerobic glycolysis and glycogenolysis are stimulated (not inhibited) through increased phosphofructokinase and phosphorylase activities, respectively. This results in an accumulation of cell lactate, with a decrease in intracellular pH and depletion of cellular glycogen stores. Decreased availability of ATP also results in failure of the Na+K+-ATPase pump, which then leads to increased cell Na+ and water and decreased cell K+.

An HIV-positive intravenous drug user is suspected of having active tuberculosis, and a tuberculin (Mantoux) intradermal skin test is performed. After 48 hours, 10 cm of induration is observed. Which of the following are involved in this form of hypersensitivity reaction? (A) B cells and antibodies (B) Basophils and IgE (C) Immune complexes and complement (D) Plasma cells and IgM (E) T cells and macrophages

E. The tuberculin test is a classic example of delayed hypersensitivity, a form of cell-mediated hypersensitivity involving CD4+ T cells and macrophages. Native CD4+ T cells are converted to TH1 cells that secrete cytokines, especially interferon-ã, which is a central mediator of delayed hypersensitivity. Among the many actions of interferon-ã, the most important is the activation of macrophages.

A 56-year-old man is surgically treated by a four-vessel coronary artery bypass graft procedure and placed on prophylactic daily aspirin therapy. Aspirin has been shown to prevent recurrent myocardial infarction through its ability to inhibit the synthesis of (A) adenosine diphosphate (ADP). (B) leukotriene B4 (LTB4). (C) nitric oxide (NO). (D) prostaglandin I2 (PGI2). (E) thromboxane A2 (TxA2).

E. Thromboxane A2 (TxA2) promotes platelet aggregation, as does ADP. Aspirin irreversibly inhibits the enzymes cyclooxygenase 1 and 2 and thereby the synthesis of TxA2, thus inhibiting platelet aggregation, which is thought to be an important early step in atherogenesis. A negative but apparently unimportant consequence of aspirin prophylaxis is the parallel inhibition of synthesis of the antiaggregant endothelial PGI2, also a product of the cyclooxygenase pathway.