UWorld 3/12
She therefore has late (tertiary) syphilis, and her vulvar lesion is most likely a ____ _____ would be seen in primary syphilis (Choice A), and _____ occur during secondary syphilis (Choice C)
A chancre condylomata lata gumma
Auer Rods suggest
Acute Myelogenous Leukemia!
A 35-year-old woman comes to the office due to fever, headache, severe muscle aches, and sore throat for the last 4 days. Physical examination shows mild pharyngeal erythema and nasal congestion. A rapid influenza antigen test is positive. The patient's condition improves over the next several days despite receiving only symptomatic treatment. In response to the influenza virus, infected respiratory epithelial cells begin secreting increased quantities of interferons. The specific interferons secreted by these cells will most likely cause which of the following changes? A. Decreased apoptosis of infected cells (%) B. Decreased protein synthesis by infected cells (%) C. Increased class II MHC expression (%) D. Increased intracellular killing by macrophages (%) E. Increased neutrophil recruitment (%)
B. Decreased protein synthesis by infected cells (%) Type I interferons (α and β) are synthesized by most human cells in response to viral infections. Once secreted, α and β interferons bind to type I interferon receptors found on infected and neighboring cells (autocrine/paracrine signaling). This results in transcription of antiviral enzymes capable of halting protein synthesis, such as RNase L (endonuclease that degrades all RNA in the cell) and protein kinase R (inactivates eIF-2, inhibiting translation initiation). However, these enzymes become active only in the presence of double-stranded RNA, which forms in infected cells as a result of viral replication. As a result, normal metabolism and protein synthesis can continue in uninfected cells but is selectively inhibited in virally infected cells.
A 50-year-old woman with a history of systemic lupus erythematosus is admitted with fever, chills, vomiting, and burning pain when urinating. Temperature is 39.3 C (102.7 F), blood pressure is 80/50 mm Hg, pulse is 120/min, and respirations are 20/min. On examination, costovertebral angle tenderness is present. The patient is given intravenous antibiotics. Over the next several hours, she has decreased urine output despite aggressive intravenous hydration. Blood is oozing around the central venous catheter. Laboratory results are as follows: Complete blood count Hemoglobin 9.0 g/dL Platelets 68,000/mm3 Leukocytes 24,500/mm3 Coagulation studies Prothrombin time 23 sec Partial thromboplastin time 60 sec Plasma fibrinogen 100 mg/dL (150-350) Which of the following is the most likely cause of this patient's hematologic abnormalities? A. Accumulation of anticardiolipin antibodies (%) B. Accumulation of ultra-large von Willebrand factor multimers (%) C. Consumptive coagulopathy (%) D. Immune-mediated platelet destruction (%) E. Impaired hepatic synthetic activity (%)
C. Consumptive coagulopathy (%) This patient's costovertebral angle tenderness, dysuria, and leukocytosis are indicative of acute pyelonephritis complicated by septic shock (hypotension, tachycardia). Her laboratory results show a consumptive coagulopathy (thrombocytopenia, prolonged PT/PTT, low fibrinogen), which, along with bleeding from the central catheter site, are likely due to disseminated intravascular coagulation (DIC). DIC is a common complication of sepsis (particularly with gram-negative organisms) because lipopolysaccharide is a procoagulant that triggers the coagulation cascade. This leads to the formation of fibrin- and platelet-rich thrombi in the vasculature, which consumes platelets (thrombocytopenia), coagulation factors (prolonged PT/PTT), and fibrinogen. Fibrinolysis is then triggered to degrade the clots, which elevates D-dimer (a fibrin degradation product) and depletes protein C, protein S, and antithrombin. The thrombi also often shear red blood cells, leading to microangiopathic hemolytic anemia (MAHA). Most patients with acute DIC have signs of bleeding, such as oozing from vascular catheters, mucocutaneous bleeding, ecchymosis, or petechiae. End organ damage (eg, renal insufficiency, pulmonary hemorrhage) is also common
56-year-old man hospitalized in the intensive care unit is being evaluated for fever. He was admitted 8 days ago with respiratory failure and has had a complicated hospital course, including mechanical ventilation, central venous line placement, and broad-spectrum antibiotic therapy. The patient has a history of HIV and a hematologic malignancy. His last chemotherapy session was 2 weeks ago. Chest x-ray does not reveal a new infiltrate, and urine cultures are negative for infection. Blood cultures grow pseudohyphae-producing yeast species with an ability to form germ tubes. Which of the following most likely directly contributed to the development of fungemia in this patient? A. Complement deficiency (%) B. Hypogammaglobulinemia (%) C. Low eosinophil count (%) D. Low neutrophil count (%) E. Low T-lymphocyte count (%)
D. Low neutrophil count (22%) This patient with HIV likely has candidemia, a disseminated form of Candida infection. Candida exists as a single-celled budding yeast with pseudohyphae (C albicans also exhibits "germ tubes," hyphal structures formed when the organism is grown in a specific nutritionally rich serum). Candida is a component of normal human skin and mucous membrane flora and is an opportunistic pathogen (does not cause disseminated infection in healthy people). Host defense is provided by 2 immune system components with distinct functions: T lymphocytes (in particular TH cells) are important for prevention of superficial Candida infection (eg, oral/esophageal candidiasis, cutaneous candidiasis, Candida vulvovaginitis). Conditions such as HIV (low T-cell count) increase the risk of superficial candidiasis. Neutrophils prevent the hematogenous spread of Candida. Disseminated candidiasis (eg, candidemia, endocarditis) is more likely in patients who are neutropenic or otherwise immunocompromised (eg, cancer with chemotherapy) and in those with inherited impairments of phagocytosis. The interplay of these 2 components can be seen in patients with HIV. These patients frequently have superficial Candida infections given their low T-cell counts, but they do not typically suffer from disseminated candidiasis as a result of HIV itself. If they also have neutropenia, there is a risk for both localized and disseminated candidiasis.
34-year-old man with an unremarkable past medical history is evaluated for an enlarged lymph node in his anterior cervical chain that measures 4 cm in diameter. The patient first felt the lymph node several weeks ago and states that it has been steadily increasing in size. He is concerned about whether or not he "has cancer." The patient is referred to a specialist for surgical removal of the enlarged node. Biopsy reveals abnormal lymph node architecture and numerous lymphocytes. Which of the following, if present, would be most consistent with malignancy in this patient? A. Lymphocyte pleomorphism (%) B. Abundant mitotic figures within the lymph node (%) C. Nuclear changes in lymphocytes (%) D. Monoclonal T-cell receptor gene rearrangements (%) E. Admixture of several lymphoid cell types within the lymph node (%)
D. Monoclonal T-cell receptor gene rearrangements (%) lymphadenopathy can represent inflammatory changes within the lymph node (reactive hyperplasia) or malignant transformation. Reactive hyperplasia is a broad term that encompasses all benign, reversible enlargement of the lymphoid tissue secondary to an antigenic stimulus. The nodal response to antigenic stimuli is highly variable and can be classified as follicular hyperplasia, sinus hyperplasia, or diffuse hyperplasia. Follicular hyperplasia occurs when the follicles increase in size and number, whereas sinus hyperplasia occurs when the sinuses enlarge and fill with histiocytes. Diffuse hyperplasia is observed when the nodal architecture is diffusely effaced by sheets of lymphocytes, immunoblasts, and macrophages. When malignant transformation occurs (as in lymphomas), the normal lymph node architecture is distorted or effaced by the proliferation of malignant lymphoid cells, often to a greater extent than that seen with reactive hyperplasia. Malignancy-associated effacement of nodal architecture may be follicular or diffuse. Reactive lymphoid hyperplasia is polyclonal in that it consists of a proliferation of many different cell types within the lymph node. For each type of lymphocyte responding to an antigenic stimulus, multiple genetically-distinct cells of that variety undergo limited monoclonal expansion, leading to an overall polyclonal response. Malignant transformation, in contrast, is monoclonal in that it results from the unchecked proliferation of a single genetically unique cell from only one cell line. Evaluation for monoclonality of the lymphocyte population is important when lymphoma is suspected. The clonality of a T-cell population is assessed by molecular methods, such as PCR, that examine the rearrangement of T-cell receptor (TCR) genes. If a single allele for the V region of the T-cell receptor predominates in a lymphocytic population, monoclonal proliferation is suspected. The same principle applies when assessing B-cell clonality. Monoclonal rearrangement of the genes for immunoglobulin variable regions is suggestive of a B-cell lymphoma. Of the choices given, monoclonal TCR gene rearrangement is most indicative of malignant processes, especially in the context of appropriate clinical features (i.e., weight loss, night sweats, fever, anorexia).
The histology described is classic for Burkitt lymphoma: diffuse medium-sized lymphocytes and a high proliferation index represented by the high____ fraction (approaching 100%)
Ki-67
Hemosiderin can be identified histologically with a Prussian-blue stain. In the liver, hemosiderin is typically seen in ____ cells (hepatic macrophages that line the walls of the sinusoids and participate in RBC breakdown). Patients receiving regular transfusions should undergo routine _____ therapy to reduce the overall iron load within the body and improve survival. Eventually, the iron burden will overwhelm the reticuloendothelial cells' capacity to sequester iron, resulting in parenchymal iron overload in the liver, myocardium, skin, and pancreas (eg, "bronze diabetes").
Kupffer iron chelation
Type I interferons (α and β) are synthesized by most human cells in response to viral infections. Once secreted, α and β interferons bind to type I interferon receptors found on infected and neighboring cells (autocrine/paracrine signaling). This results in
transcription of antiviral enzymes capable of halting protein synthesis, such as RNase L (endonuclease that degrades all RNA in the cell) and protein kinase R (inactivates eIF-2, inhibiting translation initiation). However, these enzymes become active only in the presence of double-stranded RNA, which forms in infected cells as a result of viral replication. As a result, normal metabolism and protein synthesis can continue in uninfected cells but is selectively inhibited in virally infected cells.
Contact dermatitis, granulomatous inflammation, and reactive skin testing (eg, tuberculin skin test, Candida extract skin reaction) are all examples of type IV (T Cell-mediated) delayed-type hypersensitivity reactions. When reexposed to an antigen, previously sensitized T lymphocytes proliferate and release inflammatory cytokines that promote cell-mediated cytotoxicity (CD8+ T cells) and/or macrophage recruitment and activation. The resulting tissue damage and swelling is typically evident ______ (time) after exposure.
24-48 hours
polycythemia vera This patient most likely has a mutation in which of the following types of proteins? A. Cytoplasmic tyrosine kinase (%) B. Growth-stimulating transcription factor (%) C. Intrinsic receptor tyrosine kinase (%) D. Tumor suppressor protein (%) E. Vascular growth factor (%)
A. Cytoplasmic tyrosine kinase (%) Polycythemia vera is caused by abnormal transduction of erythropoietin growth signals. The erythropoietin receptor has no intrinsic kinase activity and must interact with Janus kinase 2 (JAK2), a cytoplasmic (non-receptor) tyrosine kinase, to initiate downstream signaling. Virtually all patients with polycythemia vera have a mutation in JAK2 that causes constitutive activation of its kinase domain, resulting in clonal proliferation of myeloid cells. JAK2 mutations have also been implicated in essential thrombocythemia, primary myelofibrosis, and other myeloproliferative disorders.
57-year-old woman with autosomal dominant polycystic kidney disease develops end-stage renal disease and undergoes deceased-donor kidney transplantation. During the operation, the surgeon notices that the graft becomes cyanotic and mottled soon after its blood vessels are connected with those of the recipient. Blood flow to the graft ceases, and no urine is produced. Which of the following best explains the findings observed by the surgeon? A. Activation of recipient T lymphocytes (%) B. Antibody recognition of graft HLA components (%) C. Degranulation of recipient mast cells and basophils (%) D. Donor T lymphocyte-mediated vasculopathy (%) E. Severe renal graft atherosclerosis (%)
B. Antibody recognition of graft HLA components (%) This patient is experiencing hyperacute rejection of a renal transplant. Hyperacute rejection is an antibody-mediated reaction (ie, type II hypersensitivity) caused by preformed IgG antibodies in the recipient that are directed against donor antigens. These are commonly anti-HLA antibodies (eg, formed during prior blood transfusion or pregnancy) or ABO blood group antibodies. Hyperacute rejection is usually diagnosed in the operating room when the kidney becomes cyanotic and mottled after anastomosis of the donor and recipient blood vessels. Perfusion through the transplanted organ ceases immediately due to antibody- and complement-mediated vascular injury with subsequent thrombotic occlusion. This rapidly leads to ischemic necrosis of the glomeruli and renal cortex with little to no urine output and irreversible graft loss. To minimize the risk of hyperacute rejection, donor and recipient ABO and HLA cross-matching is performed prior to renal transplantation
A 34-year-old man is brought to the hospital by ambulance after being involved in a motor vehicle collision. He was an unrestrained passenger and sustained considerable trauma. On arrival to the emergency department, he is hypotensive and bleeding from several sites. The patient receives an emergency blood transfusion as part of the resuscitation efforts. Abdominal ultrasound reveals splenic laceration and blood in the peritoneal cavity. En route to the operating room, the patient develops difficulty breathing, chills, and pain in the chest and back. Urine drainage from the Foley catheter was initially clear but now appears brown in color. Which of the following is the most likely cause of this patient's new findings? A. CD8+ lymphocyte-mediated cytotoxicity (%) B. Complement-mediated cell lysis (%) C. Endotoxin-induced TNF-α surge (%) D. IgE-mediated reaction to serum proteins (%) E. Vascular deposition of immune complexes (%)
B. Complement-mediated cell lysis (%) This patient is most likely experiencing an acute hemolytic transfusion reaction. This condition presents with fever and chills, hypotension, dyspnea, chest and/or back pain, and hemoglobinuria (red- to brown-colored urine). Patients may also develop disseminated intravascular coagulation and renal failure. Acute hemolytic reactions occur within minutes to hours of starting a blood transfusion and are most often due to ABO incompatibility between the donor and recipient. These reactions can be fatal and require immediate cessation of the transfusion when the diagnosis is suspected. Acute hemolytic transfusion reactions are an example of an antibody-mediated (type II) hypersensitivity reaction. Anti-ABO antibodies (mainly IgM) in the recipient bind the corresponding antigens on transfused donor erythrocytes, leading to complement activation. Anaphylatoxins (C3a and C5a) cause vasodilatation and symptoms of shock, while formation of the membrane attack complex (C5b-C9) leads to complement-mediated cell lysis. Hemolytic disease of the newborn due to Rh-incompatibility is another example of type II hypersensitivity.
bullous pemphigoid on microscopy
BP is caused by antibodies against hemidesmosomes along the basement membrane of the dermal-epidermal junction. These autoantibodies result in a destructive inflammatory cascade that causes the entire epidermis to separate from the dermis, forming subepidermal, nonacantholytic blisters. Immunofluorescence shows IgG and/or C3 deposits in a linear pattern along the basement membrane.
35-year-old woman comes to the physician complaining of weakness, fatigue, and pallor. She denies heavy menses or melena. Physical examination is unremarkable except for conjunctival pallor. Laboratory results are as follows: Complete blood count Hemoglobin 7.2 g/dL Erythrocyte count 1.8 million/µL Mean corpuscular volume 90 fL Reticulocytes 0.1% Platelets 280,000 /µL Leukocyte count 6,700 cells/µL Iron studies and serum B12 and folic acid levels are within normal limits. Bone marrow biopsy shows absence of erythroid precursors but preserved myeloid and megakaryocytic elements. Further workup would most likely show which of the following? A. Hepatocellular carcinoma (%) B. Renal cell carcinoma (%) C. Thymic tumor (%) D. Cerebellar hemangioblastoma (%) E. Uterine fibroid (%)
C. Thymic tumor (23%) Pure red cell aplasia is a rare form of marrow failure characterized by severe hypoplasia of marrow erythroid elements in the setting of normal granulopoiesis and thrombopoiesis. Pure red cell aplasia is associated with thymoma, lymphocytic leukemias, and parvovirus B19 infection. This patient's pallor and fatigue suggest that she is suffering from anemia, which is confirmed by her low erythrocyte count, low percentage of reticulocytes (decreased RBC production), and low hemoglobin. Importantly, her white blood cell and platelet counts are within normal limits and their bone marrow precursors appear normal as well. The most likely diagnosis is pure red cell aplasia (PRCA), a rare form of marrow failure characterized by severe hypoplasia of marrow erythroid elements in the setting of normal granulopoiesis and thrombopoiesis.
24-year-old man comes to the urgent care clinic due to painful swelling in his left groin. The patient noticed the swelling 2 days ago, and it has progressively become more tender and painful. He has no chronic medical conditions, but he recently sustained a puncture wound to the sole of his left foot. Physical examination shows an enlarged, tender, and nonfluctuant left inguinal lymph node with erythematous overlying skin. There is a small puncture wound on the sole of the left foot, which expresses pus upon mild pressure. Which of the following histologic findings is most likely responsible for this patient's groin mass? A. Atypical B-cell proliferation (%) B. Diffuse granulomatous reaction (%) C. Extensive lymph node necrosis (%) D. Marked paracortical cell expansion (%) E. Formation of multiple germinal centers (%)
E. Formation of multiple germinal centers (39%) This patient sustained a puncture wound and subsequently developed inflammatory lymphadenopathy in a draining lymph node, suggesting bacterial infection with lymphadenitis. Lymph nodes serve as sentinel sites for generation of the adaptive immune response. Large, unprocessed foreign antigens are displayed by follicular dendritic cells in the draining lymph node. B cells recognize, bind to, and process the large antigens into smaller peptides that can be displayed on major histocompatibility II receptors to naïve T cells. T cells subsequently differentiate into T-helper cells and secrete cytokines that promote the survival and proliferation of the antigen-specific B cells, leading to the generation of germinal centers. Germinal centers are the sites where B cells compete for survival based upon the ability to bind with high affinity to a foreign antigen. Within these regions, B cells rapidly proliferate and undergo somatic hypermutation (immunoglobulin mutation); this dramatically expands the B cell population capable of binding with high affinity to antigens from the infecting microorganism. Antigen-specific B cells eventually evolve into plasma cells that secrete high affinity antibodies against the invading pathogen. Because the formation of germinal centers results in significant cellular recruitment, patients generally develop lymph node swelling (lymphadenopathy) in the draining lymph node. In addition, the release of large quantities of cytokines frequently causes pain and inflammation in that area.
A 55-year-old man is admitted to the hospital due to abdominal discomfort and black stools. Medical history includes asthma and hypertriglyceridemia, for which the patient takes the appropriate medications. He has smoked a pack of cigarettes daily for 30 years and used intravenous drugs in the past. The patient is treated empirically with a proton pump inhibitor; upper gastrointestinal endoscopy does not reveal a source for the pain or bleeding. Symptoms resolve without further intervention, and he is discharged. Several weeks later, the patient returns to the emergency department with fever, weight loss, and muscle pain. After initial evaluation, muscle biopsy demonstrates transmural inflammation of medium-sized arteries with areas of amorphous, eosin-staining arterial wall necrosis. Areas of disruption of the internal elastic lamina are also present. Which of the following is the most likely predisposing factor for this patient's current condition? A. Antibiotic use (%) B. Asthma (%) C. Hypertriglyceridemia (%) D. Smoking (%) E. Viral hepatitis (%)
E. Viral hepatitis (%) apparently this is Polyarteritis Nodosa This patient's biopsy is consistent with polyarteritis nodosa (PAN), a systemic vasculitis of medium-sized muscular arteries. Patients with PAN typically present with weeks or months of constitutional symptoms (eg, malaise, weight loss, myalgia, fever) and signs of tissue ischemia in the kidneys, skin, gastrointestinal tract, and/or neurologic system. Bleeding complications may occur due to the formation of microaneurysms from arterial wall weakening. Biopsy of affected areas generally reveals segmental, transmural inflammation with fibrinoid necrosis (amorphic, eosinophilic material in vessel wall) and disruption of the internal and external elastic laminae.
Up to 90% of Burkitt lymphoma cases are associated with translocation of the c-Myc gene on chromosome 8, usually onto the ____ region of chromosome 14 [t(8;14)]. This translocation leads to overexpression of the c-Myc oncogene and tumor growth. Burkitt lymphoma is a high-grade lymphoma. Although it is very aggressive, the tumor responds well to short-term, intensive high-dose chemotherapy. Patients with limited disease have an excellent prognosis.
Ig heavy chain
This patient's bone marrow aspirate has numerous plasma cells, which are distinguished by the presence of abundant basophilic cytoplasm, perinuclear paleness (large Golgi apparatus), and nuclei with "clock-face" (peripheral) chromatin. The presence of >10% plasma cells in the bone marrow raises strong suspicion for multiple myeloma (MM).
In MM, neoplastic plasma cells crowd the bone marrow, leading to impairments in normal hematopoiesis. B-cell development is particularly affected, which reduces plasma cell diversity and limits the generation of targeted immunoglobulins against infectious agents. Therefore, patients with MM have increased risk of recurrent bacterial infections, particularly of the urinary tract, lungs, and sinuses. Although patients with MM have high levels of circulating monoclonal immunoglobulin, monoclonal immunoglobulin does not provide immunity against a diverse range of pathogens. MM is also associated with normocytic anemia (due to ineffective erythropoiesis), bone pain (due to osteolytic lesions), hypercalcemia, and renal insufficiency (due to clogging of the tubules with immunoglobulin light chains).
A 67-year-old man comes to the office due to slowly worsening pain in both legs. He has had no trauma, fever, or chills. The pain is deep and aching, is present throughout the day, and increases with weight bearing. Vital signs are normal. Examination shows bilateral bowing of the legs with palpable warmth over the anterior shins but no redness. The remainder of the examination shows no abnormalities. Imaging studies reveal bone expansion, with cortical and trabecular thickening affecting both the tibia and fibula. What is this? Which of the following patterns of serum laboratory values is most likely in this patient?
Pagets This patient with skeletal pain, deformity (ie, bowing of the legs), and focal warmth has Paget disease of bone (osteitis deformans). Paget disease is a chronic disorder characterized by excessive and disordered bone formation. The affected bone becomes weakened, which can lead to bone pain, bowing, fracture, or arthritis of adjacent joints. Increased blood flow in pagetic lesions can be apparent as local warmth or bruits and can occasionally lead to high-output heart failure. Patients with Paget disease frequently have an elevated serum alkaline phosphatase level due to increased formation of new bone. However, calcium, phosphorus, and parathyroid hormone levels are normal, as calcium homeostasis remains intact by the disease process. X-rays are usually diagnostic, showing mixed lytic-sclerotic lesions, thickening of cortical and trabecular bone, and bony deformities
35-year-old woman comes to the emergency department due to an itchy rash that appeared earlier this morning. She recently returned from a family vacation at a resort in Cancun. Two days ago, the patient's husband developed similar symptoms. The patient has no significant past medical history and takes no medications. She has no known allergies. Her temperature is 37.6 C (99.7 F). On examination, there is a diffuse, pruritic, papulopustular rash that is most noticeable on the trunk and extremities. Microbiologic analysis of a pustular fluid sample demonstrates oxidase-positive gram-negative rods that produce pigment on culture medium. Which of the following is the most likely source of this patient's infection? A. Food (%) B. Human contact(%) C. Insects (%) D. Pets (%) E. Pool water (%) F. Soil (%)
Pseudomonas!! Hot tub folliculitis! The clinical syndrome described is consistent with "hot tub folliculitis," a superficial pseudomonal infection of the hair follicle. This condition, characterized by a pruritic, papulopustular rash, is most commonly seen with outbreaks from public or hotel swimming pools or hot tubs where the chemicals in the pool water have not been maintained at appropriate concentrations, thereby allowing Pseudomonas aeruginosa proliferation. P aeruginosa is ubiquitous in nature. Many P aeruginosa infections often begin with exposure to a water source or creation of a moist environment (ie, swimmer's ear, hot tub folliculitis, burn wound). P aeruginosa is a motile gram-negative rod that is oxidase-positive, produces green pigment (pyocyanin, pyoverdin) during culture, and is nearly always implicated in "hot tub folliculitis
This patient has Dupuytren contracture (DC), a condition caused by progressive fibrosis of the superficial palmar fascia. The disease typically involves the fascia at the base of the middle, ring, and little fingers. Although the etiology of DC is unknown, risk factors include age >50, male sex, family history, and Northern European ancestry. DC is thought to be caused by overstimulation of the______ pathway, which regulates cellular proliferation. Initial findings include painless fascial thickening with puckering of the skin just proximal to the affected metacarpophalangeal joint(s). As fibrosis continues, pathognomonic fascial nodules form along the flexor tendons composed of proliferating fibroblasts and disordered type III collagen. The nodules eventually coalesce into palpable fibrotic cords that tether the flexor tendon to the palmar fascia, leading to loss of finger extension (ie, contractures) at the metacarpophalangeal and proximal interphalangeal joints
Wnt-signaling
HURLER V HUNTER SYNDROME
This patient most likely had Hurler syndrome (type I mucopolysaccharidosis), an autosomal recessive disorder characterized by severe intellectual disability, corneal clouding, and coarse facial features (eg, frontal bossing, broad nose, flat midface). Hepatosplenomegaly and heart disease are also typical findings. Mucopolysaccharidoses are lysosomal storage disorders resulting from the defective metabolism of glycosaminoglycans (GAGs). GAGs are long, unbranched polysaccharides that are an important component of the ground substance within the extracellular matrix of connective tissues. Hurler syndrome is caused by a deficiency of alpha-L-iduronidase, which hydrolyzes dermatan and heparan sulfate. Hunter syndrome, a less severe disease than Hurler syndrome, also results in an accumulation of dermatan and heparan sulfate but characteristically does not cause corneal clouding. Patients with Hurler syndrome have a shortened life expectancy. Death, typically in early childhood, is usually caused by cardiac complications (eg, myocardial infarction); this child's death from coronary artery disease was likely due to deposition of dermatan and heparan sulfate within the vessels.
A 45-year-old man comes to the office due to a week of purulent nasal discharge, headache, sore throat, and nonproductive cough. He has no significant past medical history except for an episode of infectious mononucleosis at age 22. The patient smokes a pack of cigarettes daily. His temperature is 38 C (100.4 F). He has maxillary sinus tenderness, pharyngeal erythema, and tender anterior cervical lymphadenopathy. Laboratory results are as follows: Leukocytes 58,000/mm3 Neutrophils 42% Myelocytes 30% Metamyelocytes 8% Band forms 1% Blast cells 1% Eosinophils 6% Basophils 4% The leukocyte alkaline phosphatase score is low. Which of the following is the most likely diagnosis? A. Acute lymphoblastic leukemia (%) B. Acute myelogenous leukemia (%) C. Burkitt lymphoma (%) D. Chronic lymphocytic leukemia (%) E. Chronic myelogenous leukemia (%) F. Diffuse large B-cell lymphoma (%) G. Follicular lymphoma (%) H. Fungal superinfection (%) I. Leukemoid reaction (%) J. Parasitic superinfection (%)
This patient with sinusitis is found to have a markedly elevated white blood cell (WBC) count with an increase in myeloid precursor forms on peripheral blood smear. The differential diagnosis is chronic myelogenous leukemia (CML) (uncontrolled mature granulocyte production, mostly neutrophils but also basophils and eosinophils) or leukemoid reaction (over-exuberant WBC response associated with bacterial infection or malignancy, among others). Both cause an elevated WBC count (>50,000/mm3) with an increase in precursor forms (eg, bands, metamyelocytes, myelocytes). However, the enzyme leukocyte (neutrophil) alkaline phosphatase is decreased in CML (as seen in this patient) because the WBCs are cytochemically abnormal; by contrast, it is normal or elevated in a leukemoid reaction (Choice I). Other clues to the diagnosis of CML are the predominance of myelocytes compared to more mature forms such as metamyelocytes ("myelocytic bulge") and the absolute basophilia and eosinophilia. CML is confirmed by demonstration of the Philadelphia chromosome (translocation between chromosomes 9 and 22) or the BCR-ABL1 fusion gene or mRNA. Immature blast cells (eg, myeloblasts, promyelocytes) are typically <2%. Management generally includes a tyrosine kinase inhibitor.
The major clinical manifestations of factor V Leiden include
deep vein thrombosis (DVT), cerebral vein thrombosis, and recurrent pregnancy loss. Because pulmonary thromboembolism occurs in approximately 50% of all individuals with untreated DVTs, the young woman presented here is at significant risk of developing a pulmonary thromboembolism at some point in her lifetime. Factor V Leiden is the most common cause of inherited thrombophilia, with the heterozygote prevalence of this genetic mutation ranging from 1-9% in Caucasian populations worldwide. Heterozygote carriers of factor V Leiden have five to ten times the risk of developing a thrombosis, while homozygote carriers of factor V Leiden have fifty to one hundred times the risk of developing a thrombosis. Factor V Leiden causes thrombophilia through two pathophysiological mechanisms. In normal hemostasis, activated protein C (APC) restricts clot formation by proteolytically inactivating factors Va and VIIIa. Factor Va Leiden has reduced susceptibility to cleavage by APC, however. Because factor Va is a cofactor in the conversion of prothrombin to thrombin, persistently circulating factor Va Leiden results in increased thrombin production. Additionally, factor V Leiden is unable to support APC anticoagulant activity. This combination of increased coagulation and decreased anticoagulation produces the hypercoagulable state seen in those with factor V Leiden
The primary treatment for diphtheria is
diphtheria antitoxin (passive immunization), which inactivates circulating toxin. Antibiotics should also be administered to reduce continued production of toxin.
Acanthosis Nigricans is associated with a number of diseases. Depending on the underlying condition, it is divided into benign and malignant forms. Benign AN is commonly associated with insulin resistance. Increased levels of insulin and insulin-like growth factors stimulate epidermal and dermal proliferation. Malignant AN is associated with underlying neoplasms, especially of the _____
gastrointestinal and genitourinary tracts. The sudden appearance of such skin changes in middle-aged or elderly patients is suggestive of underlying malignancy. Gastric adenocarcinoma is the most common cause of malignant AN.
Patients with chronic hemolytic anemia (eg, beta thalassemia major) depend on recurrent red blood cell (RBC) transfusions to maintain an adequate hemoglobin level. Iron overload (hemosiderosis) from increased iron absorption is a common complication resulting from both the primary condition (eg, hemolysis) and its treatment (frequent RBC transfusions). Circulating iron is carried by transferrin. Once deposited in cells, iron binds to apoferritin to form ferritin micelles. Because iron is utilized poorly in patients with thalassemia and cannot be excreted actively, the ferritin micelles accumulate in macrophages of the reticuloendothelial system. The resulting iron-storage complex is known as ____ and microscopically appears as brown or yellowish-brown pigments in either granular or crystalline form.
hemosiderin
The mechanism of action of isoniazid (INH) is the inhibition of mycolic acid synthesis by M tuberculosis. INH accomplishes this through an incompletely understood method. However, it is known that INH must be processed by
mycobacterial catalase peroxidase for the drug to be activated within the bacteria, and that INH requires a specific protein sequence in its enzyme target (necessary for mycolic acid synthesis). For this reason, mycobacterial resistance to INH could be accomplished through non-expression of the catalase-peroxidase enzyme or through genetic modification of the INH binding site on the mycolic acid synthesis enzyme.
Disseminated gonococcal infection occurs when Neisseria gonorrhoeae spreads from the genitourinary tract to the bloodstream. It typically presents with the triad of ______. The diagnosis is confirmed when the organism is isolated on Thayer-Martin media, chocolate agar infused with antibiotics
polyarthralgia, tenosynovitis, and dermatitis (painless pustules on the extremities) or purulent arthritis A 26-year-old woman comes to the office due to fever, malaise, and joint pain. A week ago, the patient had pain in the small joints of her right hand, which improved spontaneously but was quickly followed by pain in the right ankle and left wrist. She has no prior medical problems and takes no medications. Temperature is 38 C (100.4 F), blood pressure is 124/82 mm Hg, and pulse is 90/min. The extremity joints are not erythematous or swollen, but tenderness is present along the tendons of the left wrist and right ankle. Several small, nontender pustules are seen on the extremities.
The Epstein-Barr virus genome is identified in approximately 50% of _____ and almost all _____ occurring in the setting of HIV infection. A high mitotic index is typical of Burkitt lymphoma.
systemic B-cell lymphomas primary CNS lymphomas
Acute intermittent porphyria attacks are due to
the accumulation of aminolevulinate (ALA) and porphobilinogen (PBG), resulting from inherited PBG deaminase deficiency combined with ALA synthase induction (typically due to certain medications, alcohol use, or a low-calorie diet). Management with glucose or hemin inhibits ALA synthase activity. Biochemistry Subject Hematology & Oncology System Heme metabolism Topic This patient with neurologic symptoms (eg, tingling, difficulty concentrating) and recurrent episodes of nonspecific abdominal pain likely has acute intermittent porphyria (AIP), an autosomal dominant disease characterized by porphobilinogen (PBG) deaminase deficiency. Management of AIP attacks includes infusion of hemin, which downregulates hepatic aminolevulinate (ALA) synthase (rate-limiting enzyme in hepatic pathway of heme synthesis).