UWorld Review 5/4

A 32-year-old woman, gravida 1 para 1, comes to the office for vaginal discharge. The patient has no chronic medical conditions and takes no daily medications. Her last menstrual period was 3 weeks ago. The patient has recently become sexually active with a new partner and uses an intrauterine device for contraception. Cytology of the discharge is shown. Which of the following best describes the predominant organism causing this patient's condition?

Anaerobic gram-variable rod - Bacterial vaginosis (BV) is most commonly caused by an overgrowth of the facultative anaerobic, gram-variable rod Gardnerella vaginalis and loss of normal lactobacilli flora. A classic symptom is a thin, malodorous, grayish-white vaginal discharge. The odor becomes more prominent with the addition of potassium hydroxide (whiff test) to a sample due to the anaerobes that release amines. Wet mount microscopy of the discharge and cytologic smears characteristically show clue cells, which are vaginal squamous epithelial cells covered with multiple, small, adherent G vaginalis organisms. Treatment is with metronidazole or clindamycin.

A 60-year-old man is brought to the emergency department due to altered mental status. His wife says that he had a nagging cough that seemed to worsen over the past several months and that he began experiencing occasional dizziness earlier this week. Over the last couple of days, the patient has become increasingly confused, and today he "does not make any sense at all." He has no significant past medical history but has smoked a pack of cigarettes daily for the last 40 years. On physical examination, the patient is incoherent but has an otherwise normal neurologic examination. Laboratory results are as follows: Serum chemistry Sodium 120 mEq/L Potassium 4.0 mEq/L Blood urea nitrogen 12 mg/dL Creatinine 0.8 mg/dL Calcium 9.0 mg/dL Glucose 98 mg/dL Plasma osmolality 250 mOsm/kg Urine drug screen negative Chest x-ray reveals a mass in the right lung. Which of the following additional findings is most likely to be present in this patient?

Apparent euvolemia - The combination of hyponatremia and a lung mass is suggestive of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). ADH is normally produced in the hypothalamus and secreted from the posterior pituitary in response to changes in plasma osmolality and intravascular volume. However, small cell lung carcinomas, which are tumors of neuroendocrine origin, often release ADH independent of feedback inhibition (paraneoplastic effect). This inappropriate secretion of ADH leads to hyponatremia, decreased plasma osmolality, and elevated urine osmolality (which normally should be <100 mOsm/kg given the degree of hyponatremia). The profound hyponatremia that occurs in SIADH can cause headache, weakness, altered mental status, and seizures. In SIADH, increased ADH causes excessive water absorption by the kidneys, leading to a transient, subclinical hypervolemia. This mild increase in extracellular fluid volume suppresses the renin-aldosterone axis and stimulates the production of natriuretic peptides, leading to excretion of sodium in the urine (natriuresis). As a result, patients with SIADH have a clinically normal extracellular fluid volume and low plasma osmolality (euvolemic hyponatremia). Features of volume overload (eg, peripheral edema, pulmonary crackles, elevated jugular venous pressure) are not seen.

A 26-year-old woman comes to the office due to recent weight gain. She has eaten more than usual over the last 5 months, has gained 3.2 kg (7 lb), and feels guilty and depressed about it. Further questioning reveals that she consumes a large pizza and two large bags of chips in one sitting several times a week. Afterward, the patient feels ashamed about being unable to control her intake and fasts to make up for it. She is very distressed about being unable to lose weight despite exercising 2-3 hours a day. Vital signs are within normal limits. BMI is 23.7 kg/m2. Despite being told that her BMI is normal, the patient insists that she is overweight. Which of the following is the most likely diagnosis?

Bulimia nervosa - This patient's recurrent episodes of eating large amounts of food and sense of loss of control, together with compensatory behaviors (fasting, exercising) to prevent weight gain, is consistent with bulimia nervosa (BN). Patients with BN are excessively preoccupied with their weight and body shape. Although self-induced vomiting is the most common compensatory behavior, patients may also fast and exercise excessively or misuse laxatives, enemas, diuretics, or diet pills. In DSM-5, both binges and inappropriate compensatory behaviors must occur at least once a week for 3 months for diagnosis. Patients with BN are normal weight or overweight, in contrast to individuals with anorexia nervosa. Signs of BN in patients who vomit regularly may include hypotension, tachycardia, dry skin, menstrual irregularities, erosion of dental enamel, parotid hypertrophy, calloused knuckles, and electrolyte abnormalities (eg, hypokalemia, hypochloremia, metabolic alkalosis).

A 15-year-old girl is evaluated due to persistent fever, fatigue, and sore throat. Physical examination reveals splenomegaly and symmetric posterior cervical lymphadenopathy. Peripheral blood smear results are shown. The atypical cells seen here are most likely an activated form of which of the following?

CD8+ Cytotoxic lymphocytes - This patient's fever, fatigue, sore throat, splenomegaly, symmetric posterior cervical lymphadenopathy, and atypical lymphocytosis are characteristic of infectious mononucleosis (IM). After entering the bloodstream through the pharyngeal mucosa and tonsillar crypts, the Epstein-Barr virus (EBV) preferentially infects B lymphocytes by binding to CD21 cell surface receptors. EBV-infected B lymphocytes then activate cytotoxic T lymphocytes (CD8+) through the presentation of viral antigens on major histocompatibility complex class I molecules. These reactive (atypical) CD8+ T lymphocytes are the primary immune response to EBV and clonally expand to destroy virus-infected cells. Atypical lymphocytes make up more than 10% of the cells in a peripheral blood smear in IM, and most (>95%) of those cells are CD8+ T lymphocytes. They classically appear much larger than quiescent lymphocytes, with abundant basophilic cytoplasm and a cell membrane that conforms to the borders of neighboring cells. Although activated CD21+ B lymphocytes and CD4+ helper T lymphocytes can have a similar appearance in response to EBV infection, they make up <5% of the atypical lymphocytes in the peripheral circulation.

A 37-year-old woman comes to the office due to a two-month history of abdominal pain, salt craving, and weight loss. She also has dizziness on standing. The patient has no chronic medical conditions and takes no medications. She does not use tobacco, alcohol, or illicit drugs. Her mother and sister have hypothyroidism. Blood pressure is 100/70 mm Hg supine and 80/50 mm Hg standing. Laboratory results are as follows: Sodium 129 mEq/L Potassium 5.9 mEq/L Chloride 100 mEq/L Bicarbonate 21 mEq/L Creatinine 1.4 mg/dL Blood urea nitrogen 38 mg/dL Which of the following changes in circulating hormone levels are expected in this patient?

Cortisol: ↓ Aldosterone: ↓ Antidiuretic hormone: ↑ Norepinephrine: ↑ This patient has multiple signs and symptoms of primary adrenal insufficiency (PAI) (also known as Addison disease), including abdominal pain, weight loss, salt craving, orthostasis (dizziness on standing), and electrolyte disturbance. PAI usually results from autoimmune destruction of the bilateral adrenal cortex and is more likely to occur in patients with a personal or family history of autoimmune disease (eg, Hashimoto thyroiditis). Because all 3 layers of the adrenal cortex are affected, clinical manifestations result from a reduction in circulating mineralocorticoids, glucocorticoids, and androgens. Reduced aldosterone, the principal mineralocorticoid in the body, leads to markedly decreased sodium absorption by the renal collecting tubule principal cells with consequent retention of potassium (leading to hyperkalemia). The decrease in total body sodium results in hypovolemia and hypotension that may lead to renal insufficiency. The hypovolemia provides nonosmotic stimulus for antidiuretic hormone (ADH) secretion, which stimulates water retention and leads to hyponatremia. Cortisol, the main glucocorticoid in the body, normally inhibits ADH secretion; therefore, reduced cortisol further contributes to hyponatremia. Cortisol is also necessary for the synthesis of epinephrine in the adrenal medulla; the consequent reduction in circulating epinephrine leads to a compensatory increase in norepinephrine to increase vascular tone in an effort to maintain blood pressure.

A previously healthy 2-year-old boy is brought to the clinic with fever and mouth pain that began yesterday. He has consumed an adequate amount of fluids but refuses to eat due to the pain. The patient has no medical problems and takes no medications. Physical examination reveals swollen gums and vesicular, inflamed lesions on his hard palate and lips. He has enlarged and tender cervical lymph nodes. Which of the following is most likely responsible for this patient's condition?

DNA virus, double stranded, enveloped - Primary herpes simplex virus type 1 (HSV-1) infection is characterized by the gingivostomatitis (vesicles on the lips and hard palate, fever, lymphadenopathy) seen in this young patient. Recurrent HSV-1 infection causes lip lesions that are typically less severe due to existing cellular and humoral immunity from prior infection. HSV-1 and other herpesviruses are enveloped and possess double-stranded DNA genomes. Transmission is usually by direct contact with infected oral secretions or lesions. Inoculation occurs on mucosa or skin where the virus replicates rapidly in the host cell nucleus and causes abnormal cell division, resulting in intranuclear inclusion bodies and multinucleated giant cells visible on Tzanck smear. The vesicular lesions result from cell lysis and necrosis as well as tissue destruction, inflammation, and fluid accumulation between the dermis and epidermis.

A 57-year-old man with a history of alcohol-induced cirrhosis is brought to the emergency department due to altered mental status. Over the weekend, he ate a lot of smoked meats at a local barbecue competition. Since then, he has been sleeping most of the day and is confused and disoriented when awake. On examination, he has abdominal distension with shifting dullness. The patient answers correctly when asked for his name but does not know that he is in the hospital and says the year is "1997." When asked to extend his hands as if stopping traffic, the patient makes rhythmic flapping movements. He is started on rifaximin. Which of the following is the most likely mechanism of action of this drug when used to treat this patient's current condition?

Decreased intraluminal ammonia production - This patient likely has hepatic encephalopathy (HE), a neurologic complication of cirrhosis due in part to the liver's inability to convert ammonia (a neurotoxin) to urea. Excess ammonia is shunted past the liver and crosses the blood-brain barrier, leading to altered mental status (thought due to impaired neurotransmitter release, astrocyte dysfunction, neuroinflammation, and/or edema). Asterixis, the rhythmic flapping of dorsiflexed hands, is another common manifestation of HE. A primary source of ammonia is degradation of nitrogen products by intestinal bacteria. Therefore, gastrointestinal (GI) bleeding can precipitate HE as hemoglobin breakdown leads to increased nitrogen products in the gut. Excess dietary protein intake (eg, large steak meal) is another common trigger. Others include infection, sedatives, and metabolic derangements (eg, hypokalemia). Rifaximin is a nonabsorbable antibiotic that alters GI flora to decrease intestinal production and absorption of ammonia. In patients with HE, rifaximin is generally used in addition to lactulose, which is catabolized by intestinal bacterial flora to short chain fatty acids, lowering the colonic pH and increasing conversion of ammonia to ammonium. Rifaximin is also sometimes used for traveler's diarrhea, as it inhibits bacterial RNA synthesis through binding with DNA-dependent RNA polymerase.

An investigator studies the effects of 2 different medications on the heart rate of patients with persistent atrial fibrillation. After participants receive therapeutic doses of medication for several days, their heart rates are measured for 24 hours at rest and during 10 minutes of moderate exercise. The results are compared against placebo and shown in the graphs below. Which of the following medications is most likely represented by the red line (drug 1)?

Digoxin - Persistent atrial fibrillation is usually managed with a rate-control strategy that focuses on maintaining an acceptable ventricular contraction rate during both rest (eg, <85/min) and moderate exercise (eg, <110-120/min) despite continued rapid and disorganized conduction of the atria. Pharmacologic agents that allow for rate control do so by slowing conduction through the atrioventricular (AV) node via various mechanisms: Beta blockers (eg, atenolol, metoprolol) slow AV node conduction via blockade of sympathetic tone. This mechanism allows for effective rate control both during rest and exercise. For this reason, beta blockers are often the preferred agent for rate control of atrial fibrillation. Nondihydropyridine calcium channel blockers (eg, verapamil, diltiazem) block AV nodal calcium channels to slow AV node conduction both at rest and during exercise. These drugs have similar rate control efficacy to that of beta blockers, although beta blockers are slightly superior at controlling heart rate during exercise. Digoxin slows AV node conduction via increased parasympathetic tone. This mechanism is effective at rest, when sympathetic tone is low, but it poorly controls ventricular rate during exercise, when high levels of sympathetic tone accelerate AV node conduction. For this reason, digoxin is often used only as an adjunctive agent for rate control in atrial fibrillation.

A 63-year-old man with peptic ulcer disease comes to the emergency department after several bouts of melena followed by large hematemesis. He reports nausea and feels faint. Temperature is 34.5 C (94.1 F), blood pressure is 90/46 mm Hg, pulse is 126/min, and respirations are 28/min. Physical examination reveals a lethargic man with cold extremities and sluggish capillary refill. Type O, Rh-D negative red blood cells are given as rapidly as possible via intravenous access. However, the blood transfusion rate is unacceptably slow, and the patient remains hypotensive. Which of the following will lead to the greatest improvement in flow rate?

Doubling the diameter of the intravenous catheter - This patient has brisk upper gastrointestinal bleeding and is developing hypovolemic hemorrhagic shock (ie, hypotension, cold extremities, delayed capillary refill). He requires rapid transfusion of red blood cells. His condition is unstable, so there is no time for cross-matching. Therefore, he is receiving type O, Rh-D negative blood. With blood available at the bedside, the time-limiting factor is the transfusion flow rate. The flow rate is determined by the geometry of the intravenous access. The flow of viscous fluids (eg, blood) through hollow tubes (eg, intravenous catheters) is described by Poiseuille law. Flow is proportional to pressure (P) divided by resistance. The resistance is inversely proportional to the radius (equivalent: diameter) raised to the fourth power (r4) but only directly proportional to the length (L) and viscosity of the fluid. Therefore, small changes in the radius result in large changes in flow rate: A 19% increase in radius doubles the flow rate (1.194 = 2); similarly, doubling the radius multiplies the flow rate by 16-fold (24= 16).

A 46-year-old woman comes to the office with a painful rash involving her groin and legs that has been worsening over the last 2 weeks. She was diagnosed with diabetes mellitus 6 months ago but has no other medical problems other than occasional loose stools. Physical examination shows coalescing erythematous plaques with crusting and scaling at the borders and central areas of brownish induration. Biopsy of the lesions reveals superficial necrolysis. Which of the following laboratory abnormalities is most likely to be present in this patient?

Elevated glucagon - This patient most likely has a glucagonoma, a rare tumor arising from the alpha cells of the pancreatic islets of Langerhans. Glucagonomas secrete large quantities of glucagon, so affected patients often have hyperglycemia or overt diabetes mellitus. A characteristic skin finding is necrolytic migratory erythema, an elevated painful and pruritic rash typically affecting the face, groin, and extremities. Over time, small erythematous papules coalesce to form large, indurated plaques with a central clearing that often appears brown or bronze-colored. Diagnosis is made by detecting elevated levels of glucagon in the serum.

A 34-year-old man comes to the office due to shortness of breath. He reports an episodic cough and chest tightness for the past 4 months. The patient was recently on a 2-week vacation in Arizona and reports that he had no symptoms during the trip but that they restarted when he returned home. He has no prior medical conditions and takes no medications. The patient smoked marijuana in his early 20s for several years but does not use tobacco or alcohol. He started working at a chemical manufacturing factory 7 months ago and has had no sick contacts. Temperature is 36.7 C (98 F), blood pressure is 120/80 mm Hg, pulse is 76/min, and respirations are 18/min. On physical examination, expiration is mildly prolonged and there are scattered wheezes. Office spirometry shows an FEV1/FVC of 82%, and chest radiography reveals no abnormalities. Which of the following features is most likely involved in the pathogenesis of this patient's condition?

Exposure to inhaled allergens - This patient with dyspnea, cough, and intermittent chest tightness likely has asthma. The correlation of symptom onset after starting a new job and relief while traveling is suggestive of occupational asthma (OA), which accounts for up to 25% of adult-onset asthma. OA is characterized by airway inflammation, bronchial hyperreactivity, and a variable airflow obstruction triggered by a workplace exposure. Like other forms of asthma, patients may have normal chest imaging and pulmonary function tests between exacerbations. Inciting factors in OA can be categorized as immunologic or nonimmunologic: Immunologic: Similar to atopic asthma, exposure to workplace aero-allergens induces a Th2-mediated reaction, which stimulates IgE formation and eosinophilic activation. There is often a latent period before symptoms develop during which the patient is sensitized to an allergen. Common causes include cereals, latex, and chemicals (eg, formaldehyde, amines, dyes). Nonimmunologic: Exposure to aero-irritants induces denudation of the airway mucosa, resulting in persistent airway inflammation, loss of epithelial relaxation factors, and mast cell degranulation. This typically occurs after large accidental exposures (eg, chemical spill), and symptom onset is sudden and severe. Common causes include chlorine and ammonia.

A 12-year-old boy experiences excessive bleeding following a tooth extraction. His past medical history includes episodes of painful joint swelling from minor trauma. Physical examination shows a soft and nontender abdomen with a liver span of 10 cm. The spleen is not palpable. Laboratory results are as follows: Bleeding time 5 min Activated partial thromboplastin time 25 sec Prothrombin time23 sec This patient most likely has a deficiency involving which of the following factors?

Factor VII - This patient's hemarthroses and excessive bleeding following tooth extraction are suggestive of a coagulopathy (ie, clotting factor deficiency). Coagulopathies generally present with deep-tissue bleeding into joints, muscles, and subcutaneous tissue. In contrast, platelet defects typically manifest with mucocutaneous bleeding (eg, epistaxis, petechiae). The patient's laboratory results show a normal bleeding time, normal activated partial thromboplastin time (aPTT), and a prolonged prothrombin time (PT). The normal bleeding time indicates adequate platelet function, and the normal aPTT indicates an intact intrinsic coagulation system. However, the prolonged PT indicates a defect in the extrinsic coagulation pathway. Therefore, the patient is most likely deficient in factor VII.

A 46-year-old woman comes to the office due to sexual difficulties for the past year. The patient rarely thinks about sex anymore and frequently declines sex when her husband tries to initiate. She is attracted to her husband and worries that he assumes she is losing interest in him. Although vaginal lubrication is adequate during sex and the patient can reach orgasm, she finds that her mind wanders during the experience. She is unsure what is causing a decrease in her sex drive, although she notes that she received a promotion 3 months ago and has been working longer hours since then. The patient describes her marriage as stable and loving. She has a history of a depressive episode and currently takes bupropion. Physical examination and laboratory studies, including thyroid function tests, show no abnormalities. Which of the following is the most likely diagnosis?

Female sexual interest/arousal disorder - This patient's lack of sexual desire is most consistent with female sexual interest/arousal disorder, a sexual disorder characterized by lack of, or significantly reduced, sexual interest and/or arousal. Diagnosis requires ruling out psychological, medical, and substance/medication-related causes of sexual dysfunction (eg, depression, diabetes, chronic alcohol or drug use) and relationship problems. The diagnosis of female sexual interest/arousal disorder encompasses symptoms of decreased interest, decreased arousal, or both. This patient primarily experiences decreased interest (ie, lack of sexual thoughts; reduced initiation of sexual activity or receptivity to a partner's attempts to initiate, but adequate lubrication/orgasm). Symptoms related to arousal may include decreased excitement/pleasure in response to mental and physical sexual cues and encounters.

A 52-year-old man is brought to the office due to social withdrawal and inability to care for himself. The patient is divorced and lives alone, and he was found to be living in disarray by his daughter, who is visiting from out of state. His neighbors and friends say the patient rarely comes out of the house or contacts them. During previous visits, his daughter noticed fidgety movements of his hands, but now he has marked jerky movements of his extremities with frequent facial grimaces. He has a history of depression with frequent angry outbursts that led to his divorce several years ago. The patient has no other medical conditions and does not use tobacco, alcohol, or illicit drugs. He was adopted and his family history is unknown. On physical examination, the patient is forgetful and has slowed mental processing. Involuntary, spasmodic movements of the hands and facial muscles are present. Deep tendon reflexes and sensation are normal. The loss of neurons supplying which of the following neurotransmitters is most specific for this patient's disease process?

GABA - This patient with behavioral abnormalities (eg, mood changes, withdrawal), cognitive impairment, and chorea (eg, jerky, fidgety, involuntary movements) most likely has Huntington disease (HD). HD is a neurodegenerative disorder inherited as an autosomal dominant trait and classically manifests between ages 30 and 50. Excessive CAG trinucleotide repeats cause a gain-of-function mutation that leads to the accumulation of abnormal huntingtin protein in neural cells. The inhibitory GABAergic neurons in the caudate nuclei (striatum) are especially vulnerable and atrophy early in the course of the disease. These neurons play an important role in regulating both emotional and motor impulses from the cerebral cortex, and their loss is central to the behavioral and movement changes in HD. As HD progresses, neuronal atrophy becomes more widespread. Patients display features of advanced dementia (eg, memory loss, facial agnosia, incontinence) with bradykinesia and near-total absence of voluntary movement.

A 71-year-old woman is brought to the emergency department with suicidal ideation. Medical history includes major depressive disorder as well as chronic knee and back pain due to injuries sustained in a motor vehicle collision. Developmental history is significant for physical abuse as a child. Family history is significant for bipolar disorder and completed suicide in her father. The patient reports increasing depression since losing her job a year ago and separating from her husband of 40 years 6 months ago. She has a history of 2 prior hospitalizations for depression and a previous suicide attempt. The patient is recovering from alcohol use disorder and attends weekly Alcoholics Anonymous meetings at her church. Although she lives alone, she is close to her daughter, who lives nearby. The patient reports that she owns a firearm that is kept in a locked cabinet. Which of the following is the strongest risk factor for completed suicide in this patient?

History of suicide attempts - A comprehensive suicide risk assessment involves considering both risk and protective factors. This patient has multiple risk factors for suicide, including her marital status, unemployment, psychiatric illness, past suicide attempt, family history of suicide, chronic pain, childhood abuse, and access to a firearm. Of these risk factors, a history of attempted suicide is the strongest single factor predictive of completed suicide. Patients with previous suicide attempts are 5-6 times more likely to make another attempt. Studies suggest that 1 out of 100 people who survive a suicide attempt will complete suicide within a year. This is 100 times the risk seen in the general population. Protective factors in this patient include her status as a parent with a connection to her daughter, participation in her church, and sobriety (as alcohol and other drugs have disinhibiting effects that increase the risk of acting on suicidal impulses).

A 65-year-old man with benign prostatic hyperplasia has moderately severe symptoms and is started on finasteride. After six months of treatment with finasteride, his symptoms improve markedly and his prostate has regressed in size. Which of the following histological patterns was most likely present at the time of initiation of treatment?

Hyperplasia of the prostate with predominance of epithelial components - Finasteride is a 5-alpha reductase inhibitor and it inhibits the conversion of testosterone to dihydrotestosterone. It acts on the epithelial components of the prostate gland and produces improvement of symptoms as well as reduction in the size of the gland. There are various histological patterns of BPH. Some patients have predominant epithelial hyperplasia and others have predominant stromal hyperplasia. Those with stromal hyperplasia may have collagen or smooth muscle predominance. Patients with epithelial predominance best respond to treatment with finasteride.

A 36-year-old woman comes to the clinic for evaluation of a 4-month history of nonproductive cough and exertional dyspnea. Her only other medical problem is frequent heartburn, for which she takes over-the-counter antacids. Temperature is 37.1 C (98.8 F), blood pressure is 126/74 mm Hg, pulse is 88/min, and respirations are 20/min. Examination shows bilateral crackles and normal heart sounds. The remainder of the examination is unremarkable. Chest imaging shows bilateral interstitial opacities. Bronchioalveolar lavage reveals >50% of cells being lymphocytes. Which of the following is the most likely diagnosis?

Hypersensitivity pneumonitis - This patient with several months of nonproductive cough and exertional dyspnea as well as a lymphocyte-predominant bronchoalveolar lavage (BAL) most likely has hypersensitivity pneumonitis (HP). HP results from an exaggerated immunologic response that some individuals develop to an inhaled antigen (eg, mold, animal protein). Those most commonly affected include farmers (ie, farmer's lung due to exposure to moldy hay) and bird keepers (ie, bird fancier's lung due to exposure to avian proteins). The presentation of HP can be acute or chronic. Acute disease usually involves recurrent episodes of abrupt-onset cough, dyspnea, fever, chills, and fatigue that correlate with intermittent antigen exposure. Chronic disease likely results from chronic, long-term antigen exposure, and presents with gradually progressive cough, dyspnea, fatigue, and weight loss over a period of several months. Lung crackles are present with both acute and chronic disease. Chest x-ray in acute disease is frequently normal, whereas diffuse reticular interstitial opacities are present with chronic disease as a network of interstitial inflammation and fibrosis develops. Normally, the leukocytes in alveolar fluid consist of approximately 85% alveolar macrophages, 10% lymphocytes, and a small percentage of neutrophils and eosinophils. With both acute and chronic HP, BAL usually shows high relative lymphocyte count (eg, >20%, often >50%), which helps support the diagnosis. Other causes of high relative lymphocyte count in BAL include sarcoidosis, lymphoma, and chronic fungal or mycobacterial infection.

An 18-year-old previously healthy woman is brought to the emergency department with 2 days of fever, headache, and lethargy. She has also had nausea and several episodes of vomiting. Her temperature is 38.9 C (102 F), blood pressure is 110/60 mm Hg, and pulse is 108/min. On physical examination, the patient is diaphoretic, delirious, and has a petechial rash on the trunk and extremities. Signs of meningeal irritation are present. CT scan of the head reveals no mass lesions. She is scheduled for a lumbar puncture for cerebrospinal fluid analysis. During this procedure, which of the following anatomical landmarks helps locate the optimal site for needle insertion?

Illiac crest - This patient with fever, headache, delirium, petechial rash, and meningismus likely has meningococcal meningitis. The diagnosis is typically confirmed with lumbar puncture and cerebrospinal fluid (CSF) analysis after neuroimaging excludes a mass lesion. The spinal cord extends from the medulla to the inferior border of the L1 vertebra in adults (L2/L3 in neonates and infants). The conus medullaris is the tapered lower part of the spinal cord, which subsequently branches out into spinal nerves forming the cauda equina. The pia mater surrounding the spinal cord projects downward to form the filum terminale, which is a filament connecting the conus medullaris to the posterior coccyx. The dura extends below the spinal cord termination level to form a sac containing the CSF, nerve roots, and cauda equina. The dura ends at S2 and fuses with the filum terminale to connect to the coccyx. Lumbar puncture is performed with the patient in the recumbent (preferred for accurate opening pressure measurement) or sitting position. The optimal location for needle insertion is the L3/L4 or L4/L5 space as this is well below the spinal cord termination site. The L4 vertebral body lies on a line drawn between the highest points of the iliac crests, which can be visually identified and confirmed by palpation.

A 25-year-old man is brought to the emergency department after being found unresponsive. He has a history of schizoaffective disorder and previous suicide attempts by prescription medication overdose. The patient was recently started on haloperidol and sertraline. Temperature is 40.6 C (105 F), blood pressure is 180/98 mm Hg, and pulse is 112/min. On examination, the patient is obtunded and diffusely rigid without clonus. Laboratory studies show serum creatinine of 3.2 mg/dL, creatine kinase of 75,000 U/L, and leukocytes of 16,000/mm3. The antidote for this patient's current condition most likely has which of the following mechanisms of action?

Inhibition of calcium ion release from sarcoplasmic reticulum of skeletal muscle - This patient has neuroleptic malignant syndrome (NMS) likely caused by an overdose of haloperidol. NMS is a life-threatening adverse reaction most commonly resulting from the use of antipsychotics (neuroleptic) medications, which block dopamine receptors in the brain. NMS presents clinically with diffuse muscle rigidity, high fever, autonomic instability (hypertension, tachycardia), and altered sensorium. Laboratory findings include creatine kinase elevation due to rhabdomyolysis, which can result in acute renal failure. The mainstay of treatment is to discontinue the causative agent and provide supportive care (eg, intravenous hydration). In severe cases, dantrolene can be administered, which antagonizes ryanodine receptors and inhibits calcium release from the sarcoplasmic reticulum. Bromocriptine, a dopamine agonist, has also shown clinical benefit in NMS.

A 71-year-old man comes to the emergency department due to sudden-onset vision loss in his left eye for one hour. He has a history of coronary artery disease, hypertension, and type 2 diabetes mellitus. Blood pressure is 145/80 mm Hg and pulse is 72/min. On examination, the patient can see only hand motions through the left eye. Funduscopic evaluation of the eye shows a cherry-red spot in the macula with surrounding retinal whitening. Cranial nerve examination is otherwise unremarkable. There is a left-sided neck bruit on cardiovascular examination. Which of the following is the most likely path of the embolus causing this patient's symptoms?

Internal carotid artery, ophthalmic artery, retinal artery - Retinal artery occlusion (RAO) is an important cause of acute, painless, monocular vision loss. Thromboembolic complications of atherosclerosis in the internal carotid are the most common cause of RAO. The retinal artery is one of the first branches of the ophthalmic artery, which receives its supply from the internal carotid. The retinal artery then travels within the retinal nerve to supply the inner retina and the surface of the optic nerve.

A 33-year-old woman comes to the office due to swelling affecting her extremities. Over the last 12 months her fingers, arms, and legs have become progressively swollen and somewhat itchy. Physical examination shows diffuse skin thickening extending proximally to the arms, thighs, and trunk. A skin biopsy is performed. Histologic sections show expansion of the dermal layer with atrophy of the intradermal adipose tissue and dermal appendages. High-power images of the dermis demonstrate extensive deposition of dense, eosinophilic connective tissue. This patient is most at risk for which of the following conditions?

Interstitial lung disease - This patient has diffuse skin thickening consistent with systemic sclerosis (SS), an autoimmune disease characterized by widespread fibrosis of multiple organ systems. Early symptoms often include swelling of the fingers and mild pruritus. A characteristic skin biopsy finding is dermal layer expansion due to diffuse deposition of collagen (eosinophilic connective tissue), resulting in atrophy of the intradermal adipose tissue and dermal appendages (ie, hair follicles, glands). Up to 80% of patients with SS develop pulmonary complications: Interstitial lung disease is the most common pulmonary complication of diffuse cutaneous SS (ie, skin involvement extending proximal to the wrist that may affect the trunk). Pulmonary hypertension is the most common pulmonary complication of limited cutaneous SS (ie, skin involvement is mainly in the hands and/or face), which is often associated with CREST syndrome.

A 35-year-old man comes to the office due to a painful tongue sore. For the past 2 weeks he has had a fever and has experienced myalgias and arthralgias. He has no known medical problems. The patient works as a driver for a local delivery service. He had unprotected sex with a stranger approximately 1 month ago. Physical examination shows a rash over his trunk and cervical lymphadenopathy. An ulcer is located on the median sulcus of the tongue and is 2 cm anterior to the foramen cecum. Blood is drawn for an HIV test. The pain sensation from his ulcer is most likely carried by which of the following nerves?

Mandibular division of the trigeminal nerve -Acute HIV can present with rash, lymphadenopathy, fever, and painful oral ulcers on the tongue. Innervation of the tongue is complex, as there are motor, general sensory, and gustatory (taste) components. Motor innervation of the tongue is provided by the hypoglossal nerve (cranial nerve [CN] XII) with the exception of the palatoglossus muscle, which is innervated by the vagus nerve (CN X). General sensory innervation of the tongue (including touch, pain, pressure, and temperature sensation) is provided by:Anterior 2/3 of the tongue: mandibular branch of trigeminal nerve (CN V3)Posterior 1/3 of the tongue: glossopharyngeal nerve (CN IX)Posterior area of the tongue root: vagus nerve (CN X) Gustatory innervation (taste buds) is as follows:Anterior 2/3 of the tongue: chorda tympani branch of facial nerve (CN VII)Posterior 1/3 of the tongue: glossopharyngeal nerve (CN IX)Posterior area of the tongue root and taste buds of the larynx and upper esophagus: vagus nerve (CN X) Any lesion anterior to the terminal sulcus and foramen cecum, including this patient's oral ulcer, would be located on the anterior 2/3 of the tongue. Pain from this region (as well as sensations of touch, pressure, and temperature) is transmitted by the mandibular branch of the trigeminal nerve.

An unresponsive 62-year-old man is brought to the emergency department after sustaining multiple injuries in a major motor vehicle accident. He is obtunded but responds to painful stimuli. His blood pressure is 160/90 mm Hg, pulse is 72/min, and respirations are 10/min. A few hours after initial treatment and stabilization, he develops severe tachypnea and decreased oxygenation. His chest x-ray shows evidence of pulmonary edema. He is rapidly intubated and given oxygen but acutely worsens and dies a few hours later, despite aggressive measures. Which of the following drugs could have caused this patient's condition?

Mannitol - This patient presents after trauma and was likely treated with mannitol, an osmotic diuretic often used in the management of cerebral edema and increased intracranial pressure. Mannitol works by rapidly increasing plasma or tubular fluid osmolality, which causes water to move from the interstitial space into the vascular space or tubular lumen. In the kidneys, osmotic diuretics primarily work in the proximal tubule and the loop of Henle to produce diuresis. In the brain, water redistribution from the tissues into the plasma helps to reduce cerebral edema and intracranial pressure. Common side effects of osmotic diuretics include headache, nausea, and vomiting. Overaggressive treatment with osmotic diuretics can lead to excessive volume depletion and eventual hypernatremia in certain patients. One of the more severe toxicities of aggressive osmotic diuretic therapy is pulmonary edema, caused by the rapid rise in volume that can also increase the overall hydrostatic pressure in the vasculature. The continued rise in plasma osmolality causes more water and potassium to move out of the cells and brain. This leads to further volume expansion (and possibly worsening pulmonary edema), dilutional hyponatremia and metabolic acidosis, and hyperkalemia. Therefore, osmotic diuretics should be cautiously used in high-risk patients, such as those with congestive heart failure (CHF) or preexisting pulmonary edema.

A 46-year-old woman comes to the office due to episodes of headaches, nausea, sweating, and feeling like she is going to pass out. The patient has had 3 such episodes in the past 2 weeks, with symptoms occurring when she skips a meal. During the most recent episode, her fingerstick glucose was 50 mg/dL. She was diagnosed with type 2 diabetes mellitus 3 years ago and was initially treated with metformin monotherapy; glyburide was added to her regimen 3 months ago due to inadequate glycemic control. The patient has no other medical conditions. Vital signs are within normal limits, and physical examination shows no abnormalities. Laboratory results show hemoglobin A1c is 6.7%. The medication most likely causing this patient's current symptoms works by targeting which of the following?

Membrane ion channels - This patient has symptomatic hypoglycemia following initiation of a sulfonylurea medication (ie, glyburide) for diabetes mellitus. Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing depolarization and L-type calcium channel opening. The increased Ca2+ influx stimulates beta cell insulin release independent of blood glucose concentrations. Sulfonylureas continue to stimulate insulin secretion even when blood glucose levels are normal, which can lead to hypoglycemia. The longer-acting sulfonylureas (eg, glyburide) are more prone to causing hypoglycemia than shorter-acting drugs (eg, glipizide). Meglitinides (eg, repaglinide, nateglinide) are short-acting drugs that are functionally similar to sulfonylureas.

A 44-year-old man with progressive dyspnea is diagnosed with dilated cardiomyopathy. Despite optimal medical therapy, he continues to have symptoms and disease progression is noted. He undergoes cardiac transplantation after a suitable donor becomes available. Permission is obtained from the patient to study his diseased heart for intracellular calcium regulation. Microelectrodes placed into cardiac muscle cells detect a rapid decrease in cytoplasmic calcium level immediately preceding relaxation. Which of the following proteins is most likely responsible for the observed change in electrolyte levels?

Na+/Ca2+ exchanger - Intracellular calcium regulation plays an important role in excitation-contraction coupling. Voltage-dependent calcium channels (L-type) are activated during phase 2 of cardiac action potential (depolarization) and permit influx of calcium into the cardiac myocytes. This initial calcium influx is sensed by the ryanodine receptors in the sarcoplasmic reticulum, which triggers further release of Ca2+ (calcium-induced calcium release) into the cytoplasm, thereby increasing intracellular calcium concentration 100-fold. The calcium released from the sarcoplasmic reticulum diffuses through the myofilament network and binds to troponin C. Tropomyosin is then moved out of the way so that actin and myosin can interact, leading to muscle contraction. The final stage of excitation-contraction coupling is myocyte relaxation, which occurs subsequent to calcium efflux from the cytoplasm. Intracellular calcium is removed primarily via an Na+/Ca2+ exchange pump (NCX) and sarcoplasmic reticulum Ca2+-ATPase pump (SERCA). NCX uses the large extracellular Na+ concentration gradient to help pump Ca2+ out of the cell and, in the process, removes one intracellular Ca2+ in exchange for 3 extracellular Na+ ions. In contrast, SERCA is a Ca2+-ATPase pump that actively transfers Ca2+ from the cytosol to the lumen of sarcoplasmic reticulum at the expense of ATP hydrolysis.

A 24-year-old man is brought to the emergency department due to seizures. He has had 2 days of worsening fever, headache, and vomiting. Physical examination shows signs of meningeal irritation. The patient rapidly becomes comatose and dies 48 hours later despite aggressive medical care. Autopsy examination shows congested leptomeninges with fibrinopurulent exudate (not shown). Microscopy reveals numerous ameba in the exudate and brain tissue. Which of the following is the most likely portal of entry of this pathogen into the CNS?

Olfactory nerve -Primary amebic meningoencephalitis is a rare, highly fatal condition caused by the free-living, flagellated protozoan Naegleria fowleri. This pathogen resides in warm fresh water (30-45 C) and moist soil. Humans are primarily exposed when the organism comes into contact with nasal mucosa during recreational water activities (eg, swimming, diving, water skiing, unchlorinated hot tub bathing). Although serologic evidence of exposure is widespread, only a small number of individuals develop invasive disease (~300 known cases). Patients typically have rapidly progressive meningeal signs, cranial nerve deficits, and confusion. Cerebrospinal fluid analysis with wet mount can usually identify motile trophozoites. Although treatment should be attempted, almost all patients die within 2-3 days.

A 47-year-old man with known coronary artery disease comes to the emergency department with chest tightness, sweating, and palpitations. His symptoms began abruptly 2 hours ago while he was at work. Six months ago, the patient underwent percutaneous angioplasty of the right coronary artery. Past medical history also includes anxiety and panic attacks. Blood pressure is 180/90 mm Hg and pulse is 110/min with a regular rhythm. An esmolol infusion produces rapid symptom relief and heart rate slowing. Which of the following portions of the ECG will be affected most significantly by the medication?

PR interval - On an ECG, the P wave represents atrial depolarization and the QRS complex represents ventricular depolarization. The PR interval is the period from the beginning of atrial depolarization (start of P wave) to the beginning of ventricular depolarization (start of QRS complex). The longer the PR interval, the longer it takes for an electrical stimulus to travel from the SA node to the ventricles via the AV node, bundle of His, and fascicular branches. Drugs that slow AV nodal conduction, such as beta blockers, will prolong the PR interval. Beta blockers (except sotalol, which also has class III properties) do not have any specific effects on QRS or QT interval durations.

A 65-year-old woman is enrolled in a clinical trial to test a new medication for rheumatoid arthritis. The patient's condition has been poorly controlled despite prolonged treatment with multiple disease-modifying antirheumatic drugs. The new medication is a CTLA4-Ig fusion protein that prevents CD28 from binding to CD80/86 on antigen-presenting cells. A month after treatment begins, the patient reports a significant reduction in joint pain and stiffness. Laboratory results reveal reduced levels of C-reactive protein and IL-2. Which of the following is the most likely underlying cause of this patient's treatment response?

Peripheral tolerance - Abatacept, a disease-modifying antirheumatic drug, is a fusion of CTLA4 with the Fc portion of IgG (CTLA4-Ig). CTLA4 is a naturally occurring immune checkpoint receptor that is upregulated on the surface of active T cells. It acts as a brake for the adaptive immune response by preventing the conversion of antigen-specific naive T cells into effector T cells. The activation of cytotoxic T cells requires 2 stimulatory signals. First, the T cell must bind to a specific antigen on the class I major histocompatibility complex (MHC) of an antigen-presenting cell (APC); then, the bound T cell must be costimulated by an interaction between the T cell surface receptor CD28 and the APC cell surface ligand CD80/86. T cells that bind an antigen on an APC but are not costimulated undergo anergy, a form of peripheral immune tolerance marked by a lack of T-cell response to cytokine, ligand, or antigen stimulation (T-cell inactivation). Because CTLA4 binds to CD80/86 with greater affinity than CD28, administration of exogenous CTLA4 (eg, abatacept) reduces the availability of ligands necessary for T cell costimulation, which dramatically increases T cell anergy in areas of active inflammation.

Physiologists conduct a series of experiments on hypophysectomized animals to investigate the effects of cortisol on vascular reactivity. Their initial tests show that administration of cortisol alone does not elicit a vascular response. Next, the researchers measure vascular reactivity to an infusion of norepinephrine both with and without pretreatment with cortisol. The results of their experiments are shown. Which of the following pharmacologic principles best describes the effect of cortisol in this experiment?

Permissiveness - Although cortisol has no direct vasoactive properties, it augments the vasoconstrictive effects of catecholamines and angiotensin II. The above graph shows that the administration of norepinephrine produced a limited degree of vasoconstriction that was markedly increased following pretreatment with cortisol. This phenomenon is termed permissiveness; it occurs when a hormone has no direct effect on a physiologic process but allows another hormone to exert its maximal effect on that process. Cortisol exerts its potentiating effect on vasoconstriction in part through upregulation of alpha-1 adrenergic receptors on vascular smooth muscle cells. In adrenal insufficiency, low cortisol levels can contribute to hypotensive crisis by decreasing vascular responsiveness to norepinephrine and angiotensin II. Cortisol also has a permissive effect on catecholamine-mediated bronchodilation and glucagon-mediated release of glucose from the liver.

A 50-year-old man with polycystic kidney disease comes to the office due to constant, deep pain in his shoulders, arms, and legs. Medical history includes long-standing hypertension treated with ramipril. Blood pressure is 150/85 mm Hg and pulse is 78/min. Cardiopulmonary examination is normal. Abdominal examination shows large, palpable renal masses. Trace bilateral lower-extremity edema is present. Laboratory results from 2 years ago showed a blood urea nitrogen level of 25 mg/dL and a creatinine level of 2.3 mg/dL. Current laboratory results are as follows: Sodium 136 mEq/L Potassium 4.8 mEq/L Chloride 104 mEq/L Bicarbonate 22 mEq/L Blood urea nitrogen 66 mg/dL Creatinine 5.5 mg/dL Calcium 7.5 mg/dL Which of the following metabolic states is most likely present in this patient?

Phosphate: ↑ Parathyroid hormone: ↑ Calcitriol: ↓ This patient's presentation is consistent with metabolic bone disease due to chronic kidney disease (CKD). CKD decreases the glomerular filtration rate (GFR), which decreases the filtered phosphate load and causes elevated serum phosphate levels. Hyperphosphatemia reduces serum free calcium and stimulates osteocytes and osteoclasts to release fibroblast growth factor-23 (FGF-23), a circulating peptide that decreases proximal tubule phosphate reabsorption. Elevated levels of phosphate and FGF-23 also reduce calcitriol synthesis by inhibiting the proximal tubular expression of 1-alpha-hydroxylase, resulting in decreased intestinal calcium and phosphate absorption. This worsens hypocalcemia but does not significantly improve hyperphosphatemia due to the low GFR, which is the limiting factor for phosphate excretion in patients with advanced CKD. Hypocalcemia and hyperphosphatemia also increase parathyroid hormone (PTH) secretion, which stimulates osteoclasts to increase bone turnover. Long-term elevation in PTH (secondary hyperparathyroidism) can eventually lead to friable bones and osteitis fibrosa. Affected patients can develop weakness, bone pain, and fractures.

A 30-year-old man comes to the emergency department with a 4-day history of progressively worsening abdominal pain and bloody diarrhea. He was started on mesalamine therapy 6 months ago after being diagnosed with ulcerative colitis but has been noncompliant with treatment. His temperature is 38.8 C (102 F), blood pressure is 100/70 mm Hg, and pulse is 130/min. The patient is lethargic and has dry mucous membranes. There is marked abdominal distension and tenderness without rebound or guarding. Rectal examination shows guaiac-positive, maroon-colored, liquid stool. Which of the following is the best next step in this patient's workup?

Plain abdominal x-ray - This patient with abdominal pain/distension, bloody diarrhea, fever, and signs of shock (eg, hypotension, tachycardia) in the setting of untreated ulcerative colitis likely has toxic megacolon. This is a common life-threatening complication of inflammatory bowel disease and is seen more frequently in ulcerative colitis than in Crohn disease. Toxic megacolon can also be associated with Clostridium difficile infection and other forms of infectious colitis. Severe, occasionally transmural inflammation causes release of inflammatory mediators, bacterial products, and increased nitric oxide, which contribute to colonic smooth muscle paralysis. Rapid colonic distension ensues, thinning the intestinal wall and making it prone to perforation. Plain abdominal x-ray is the preferred diagnostic imaging study as it may show colonic dilation (as seen above) with multiple air-fluid levels (not seen in this image). Free air may also be visualized in the setting of intestinal rupture, which presents with generalized peritonitis (eg, abdominal rebound tenderness/guarding). Barium enema and colonoscopy are normally contraindicated in patients with suspected toxic megacolon as these may cause perforation.

A 48-year-old woman comes to the office 10 days after undergoing breast reduction surgery. She feels well overall and is taking acetaminophen as needed for pain control. Vital signs are normal. Examination of the breasts reveals intact surgical incisions without drainage; the incisions are pink, shiny, and slightly warm. The surrounding skin has mild edema but no erythema. Which of the following wound healing processes is most likely occurring at this time?

Proliferation of vascular endothelial cells - Ten days after surgery, this patient's intact, healing surgical incisions are most likely undergoing a type of neovascularization called angiogenesis, the process by which new blood vessels sprout and grow into the wound from surrounding, uninjured vessels. Angiogenesis primarily occurs during the proliferation phase of wound healing, which begins around day 3 (overlapping with the end of the inflammatory phase) and lasts approximately 5 weeks. During the proliferation phase, fibroblasts multiply and synthesize ground substance and type III collagen, which form an amorphous gel into which new capillaries can grow. In addition, fibroblasts secrete fibroblast growth factor and vascular endothelial growth factor, which stimulate endothelial cell proliferation, migration, and differentiation—leading to the formation of new capillaries. By increasing the number of capillaries within the healing surgical incision, angiogenesis increases blood flow to the area, causing the pink and slightly warm characteristics of the wound at this stage. The incision's newly formed epithelium (ie, reepithelialization) typically has a shiny appearance as well.

A 27-year-old woman comes to the office for a health maintenance examination. The patient has no chronic medical conditions and no family history of cancer. She has had several sexual partners and takes oral contraceptive pills for birth control. Vital signs are normal. Physical examination, including pelvic examination, is normal. A Pap test is performed and shows a squamous intraepithelial lesion that is positive for human papillomavirus. A cervical biopsy is performed and reveals low-grade dysplasia. Which of the following features best distinguishes this patient's lesion from cervical malignancy?

Reversibility of changes - Human papillomavirus (HPV) infection of the cervical squamous epithelium can lead to dysplasia (ie, cervical intraepithelial neoplasia [CIN]), a premalignant lesion. Squamous dysplasia is characterized by a breakdown in the normal, organized progression from tall cells in the basal layer to flattened cells on the epithelial surface. Individual dysplastic cells are often pleomorphic (ie, differing in shape and size), have enlarged and hyperchromatic (ie, dark staining) nuclei, and are associated with numerous mitotic figures (normally found only in the basal layer). The grade of CIN describes the degree of epithelial disruption: Low-grade CIN: Dysplasia involves the lower third of the epithelium (ie, CIN 1) High-grade CIN: Dysplasia has advanced beyond the lower third of the epithelium (sometimes involving the entire thickness) but does not penetrate the basement membrane (ie, CIN 2 or 3) In contrast to malignancy (eg, invasive carcinoma), dysplastic changes (if mild to moderate) may reverse when the causal factor is withdrawn. Most cases of low-grade CIN regress spontaneously once the HPV infection is cleared by the immune system.

A newborn girl is evaluated in the neonatal intensive care unit for difficulty breathing. The patient was born at term via spontaneous vaginal delivery. Since birth, she has had difficulty breathing with loud snoring sounds and intermittent oxygen desaturations. She has been unable to breastfeed due to her breathing problems. Breathing improves significantly when the patient is placed in a prone position. On examination, there is a small mandible, posteriorly displaced tongue, and U-shaped cleft palate. The abnormalities described represent an example of which of the following?

Sequence - This patient has a small mandible, posteriorly displaced tongue, and U-shaped cleft palate, which is consistent with Pierre Robin sequence. A sequence occurs when a single developmental defect causes a cascade of additional malformations. In Pierre Robin sequence, hypoplasia of the mandibular prominence leads to micrognathia. Severe micrognathia causes posterior displacement of the tongue (glossoptosis), which blocks fusion of the palatine shelves, resulting in a cleft palate that is characteristically U-shaped. Difficulty breathing occurs because the tongue prolapses into the posterior oropharynx, blocking airflow. Breathing improves when the patient is in a prone position because gravity pulls the tongue anteriorly, opening the airway.

A 5-month-old boy is brought to the office by his parents who are concerned that he has developmental delay. He has 3 older siblings, and the parents report that his siblings were much more active and interactive at the boy's age. The family has just moved to the United States from South America and did not have consistent primary care previously. Physical examination shows that the boy is unable to roll from front to back or back to front and does not seem to recognize his parents. Comprehensive laboratory evaluation reveals impaired tetrahydrobiopterin synthesis. Which of the following is most likely deficient in this patient?

Serotonin - Tetrahydrobiopterin (BH4) is a cofactor in the synthesis of serotonin (a major neurotransmitter), tyrosine (a precursor of DOPA), and DOPA (the antecedent of the neurotransmitters dopamine, norepinephrine and epinephrine). Dihydropteridine reductase enzymatically reduces dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4). Serotonin (5-hydroxytryptamine, or 5HT) is formed through hydroxylation and decarboxylation of the amino acid tryptophan. Most cases of phenylketonuria are due to phenylalanine hydroxylase deficiency. Less commonly, the etiology is due to BH4 deficiency secondary to dihydropteridine reductase deficiency. The consequences of defective phenylalanine and tryptophan metabolism are phenylalanine accumulation and low levels of serotonin and other neurotransmitters, respectively. The combination of high phenylalanine levels, which may disrupt neuronal and glial development, and low serotonin and other neurotransmitters results in progressive neurologic deterioration in untreated patients. Manifestations include developmental delay, hypotonia, dystonia, and seizures. Treatment includes both a low phenylalanine diet and BH4 supplementation.

A 34-year-old woman comes to the physician for a follow-up visit. She was diagnosed with rheumatoid arthritis 3 months ago and started on methotrexate therapy. Despite treatment, she continues to have several hours of morning stiffness daily and frequently awakens at night due to joint pain. Physical examination shows swelling and tenderness in the joints of her hands and wrists. Etanercept is subsequently added to her treatment regimen. This medication is best characterized as which of the following?

Soluble receptor decoy protein - Etanercept is a tumor necrosis factor-alpha (TNF-α) inhibitor added to methotrexate to treat moderate-to- severe rheumatoid arthritis in patients who have failed methotrexate alone. It is a fusion protein linking a soluble TNF-α receptor to the Fc component of human immunoglobulin G1 (IgG1). Etanercept reduces the biological activity of TNF-α by acting as a decoy receptor: the TNF-α receptor component acts like a sponge to bind TNF-α and keep it away from functional TNF-α receptors, while the Fc component stabilizes the complex. Pharmaceutical companies provide the prefix of the names for biological agents; the suffix indicates whether the medication is a monoclonal antibody (mab), a receptor molecule (cept), or a kinase inhibitor (nib). Monoclonal antibodies, which are the largest group of biological agents, also include in their names the type of target (eg, bacterial or immune system) and their origin (eg, human or mouse).

A 64-year-old man comes to the emergency department after an episode of hematemesis. He also reports dark stools and abdominal pain for the past several days. The patient has a history of chronic pancreatitis. Abdominal examination shows epigastric tenderness to palpation. Rectal examination is notable for black, guaiac-positive feces. Upper gastrointestinal endoscopy reveals a bleeding spot within a cluster of enlarged tortuous veins in the gastric fundus. The rest of the stomach and esophagus appears normal. Increased pressure in which of the following vascular structures is the most likely cause of this patient's condition?

Splenic vein - Gastric varices are dilated submucosal veins that can cause life-threatening bleeding in the upper gastrointestinal tract. The varices are commonly due to portal hypertension, which can be a complication of cirrhosis. Gastric varices can also be seen with splenic vein thrombosis due to chronic pancreatitis, pancreatic cancer, and abdominal tumors. The splenic vein runs along the posterior surface of the pancreas and can develop a blood clot from pancreatic inflammation. The short gastric veins drain the fundus of the stomach into the splenic vein. Splenic vein thrombosis can increase pressure in the short gastric veins and cause gastric varices only in the fundus. The rest of the stomach and esophagus are usually not affected.

A 6-month-old boy is evaluated in the clinic due to delayed motor development. The mother reports that the boy is weaker than other children his age. He can barely lift his head up when prone and is unable to roll to the side. Physical examination shows generalized hypotonia and decreased deep tendon reflexes. Further evaluation reveals mutation of a protein involved in the assembly of small nuclear ribonucleoproteins (snRNPs) in motor neurons. This patient most likely has impaired function of which of the following cellular elements?

Spliceosomes - This infant with delayed motor development and flaccid paralysis (eg, hypotonia, decreased deep tendon reflexes) likely has spinal muscular atrophy. This condition is caused by mutations in the survival motor neuron (SMN1) gene, which encodes a protein involved in assembly of small nuclear ribonucleoproteins (snRNPs) in lower motor neurons. Defective snRNP assembly results in impaired spliceosome function and degeneration of anterior horn cells in the spinal cord. RNA molecules that carry out functions without first being translated into proteins are called non-coding RNAs. These include small nuclear RNA (snRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). snRNA is transcribed by RNA polymerase II and associates with specific proteins to form snRNPs. A collection of snRNPs and other proteins on pre-mRNA is referred to as a spliceosome. Spliceosomes remove introns from pre-mRNA by cleaving the 5' end of intron 1 (splice donor site) and joining that end to the branch point. The freed 3'-OH of exon 1 then forms a phosphodiester bond with the 5'-phosphate at the splice acceptor site, joining exons 1 and 2.

A 34-year-old woman who recently emigrated from Russia comes to the physician due to weakness, exertional dyspnea, and orthopnea. On cardiac auscultation, a snap followed by a rumbling diastolic murmur is heard over the cardiac apex. The snap most likely occurs nearest to which of the following points on the cardiac pressure-volume loop?

The bottom left corner - The left ventricular (LV) pressure-volume loop follows the cardiac cycle through left ventricular contraction, ejection, relaxation, and refilling, as follows: Isovolumetric contraction: The cardiac cycle begins with initiation of left ventricular contraction and closure of the mitral valve at point 1; an S1 is heard at this time, marking the end of diastole. Although intraventricular pressure increases after point 1, initially, no blood leaves the ventricle because both the aortic and mitral valves are closed. At point 2, LV pressure overcomes systemic diastolic pressure and the aortic valve opens. Ventricular ejection: LV volume decreases as blood is ejected into the aorta. The peak of the ejection curve denotes systolic blood pressure and represents the high point of LV afterload. LV ejection ends at point 3 with aortic valve closure and an S2 is heard. The horizontal distance between point 2 (or point 1) and point 3 represents the stroke volume. Isovolumetric relaxation: LV pressure rapidly falls from point 3 to point 4. No blood leaves or enters the left ventricle during this time because both the aortic and mitral valves are closed. Ventricular filling: The mitral valve opens at point 4 and diastolic filling of the left ventricle begins. LV volume and pressure gradually increase until mitral valve closure occurs again at point 1 and the cycle begins anew. Extra heart sounds (ie, an S3 or S4) may be heard during diastolic filling between point 4 and point.

Nephrologists at a research hospital are investigating the physiologic changes that occur in diabetes insipidus. The group develops a technique that permits sampling of tubular urine in experimental animals with physiology similar to that of humans. The animals then undergo hypophysectomy, after which tubular fluid samples are obtained from multiple sites throughout the nephron. In the absence of antidiuretic hormone, fluid from which of the following sampling sites is most likely to have the highest osmolarity?

The bottom of the loop of Henle - Tubular fluid osmolarity varies along the different segments of the nephron depending on each segment's permeability to water, the osmolarity of the renal interstitium, and the presence or absence of antidiuretic hormone (ADH): In the proximal tubule, water is passively reabsorbed along with active transport of solutes into the interstitium. Fluid in the proximal tubule lumen is therefore isoosmotic with plasma. The descending limb of the loop of Henle is permeable to water, but not solutes. As this segment of the nephron descends into the medullary interstitium, water moves down its concentration gradient from the lumen into the highly osmotic medulla. No reabsorption of electrolytes occurs in this segment, so the fluid in the lumen becomes hypertonic. However, tubular fluid will be the most concentrated at the bottom of the loop of Henle where interstitial osmolality is the greatest. The thick ascending limb of the loop of Henle is impermeable to water. In this portion of the nephron, electrolytes are actively resorbed by the Na+/K+/2Cl- cotransporter, causing the osmolarity of the tubular fluid to decrease and become hypotonic. Reabsorption of solutes continues to occur in the distal convoluted tubule through the action of the NaCl symporter. Because the early distal convoluted tubule is impermeable to water, tubular fluid increases in hypotonicity in this segment of the nephron. The water permeability of the collecting ducts depends on the presence of ADH. In the absence of antidiuretic hormone (ADH) (eg, overhydration, diabetes insipidus), the collecting ducts are impermeable to water, even when passing through high-osmolarity regions within the medullary concentration gradient. As solutes continue to be removed, tubular fluid in this segment can become as hypotonic as 50 mOsm/L, producing a very dilute urine.

A 36-year-old woman comes to the office due to frequent urination since an exacerbation of multiple sclerosis 2 months ago. Most of her symptoms, including dizziness, leg weakness, and numbness, have improved with corticosteroid treatment. However, she has continued difficulty holding urine, and on several occasions has passed a small amount of urine while trying to reach the bathroom. She has no urine leakage during coughing or sneezing. The patient has no other medical problems. Her abdomen is soft and nontender. Neurological examination shows hyperreflexia and increased tone in the lower extremities. Her postvoid residual volume is low. Glucose, serum 160 mg/dL Urinalysis Blood negative Leukocyte esterase negative Bacteria none White blood cells 3-4/HPF Which of the following is the most likely explanation for her urinary symptoms?

Uninhibited bladder contraction - This patient's presentation is consistent with urge incontinence, which is due to detrusor overactivity causing a sudden and/or frequent urge to urinate and empty the bladder. The micturition reflex is an autonomic spinal reflex mediated by both sensory and motor fibers from nerve centers at the S2-S4 levels. Parasympathetic stimulation causes detrusor muscle contraction and internal urethral sphincter relaxation. Sympathetic fibers cause internal sphincter contraction and also help with sensing a full bladder. Multiple sclerosis (MS) is likely an autoimmune disease that causes varying degrees of demyelination, inflammation, and gliosis in the central nervous system (eg, optic nerves, spinal cord, brainstem, periventricular white matter, and cerebellum). Regions in the pons and cerebral cortex partially inhibit the micturition reflex and also regulate contraction/relaxation of the external urethral sphincter. Spinal cord lesions above the sacral region cause a loss of higher center control of micturition and lead to detrusor hyperreflexia and urge incontinence. Patients typically develop a frequent urge to urinate and pass a small amount of urine. As the disease progresses, the bladder can become atonic and dilated leading to overflow incontinence.

A 35-year-old man who works as a nurse at a local hospital is brought to the emergency department due to confusion and lethargy. His temperature is 36.7 C (98 F), blood pressure is 86/48 mm Hg, pulse is 120/min, and respirations are 12/min. Arterial blood gas results show pH 7.54, PaCO2 49 mm Hg, and PaO2 85 mm Hg. Which of the following laboratory studies would be the most useful in determining the cause of this patient's acid-base abnormality?

Urine chloride - This patient's arterial pH >7.45 is consistent with alkalemia. The PaCO2 is elevated (>40 mm Hg), indicating a respiratory acidosis, which does not explain the alkalemia. Therefore, primary metabolic alkalosis with respiratory compensation is most likely present. When the etiology of metabolic alkalosis is unknown, assessment of volume status and measurement of urine chloride can be helpful. Because low Cl- impairs renal excretion of HCO3-, total body chloride depletion often plays an important role in the pathogenesis of metabolic alkalosis. Etiologies of metabolic alkalosis that involve temporary chloride depletion (hypovolemia) will demonstrate low urine chloride and are amenable to treatment with Cl- repletion (saline responsive). These etiologies include: Nasogastric suctioning or severe vomiting, which involve loss of H+ and Cl- (ie, hydrochloric acid) from the stomach. Loop or thiazide diuretic overuse, which involve loss of Cl- and retention of HCO3- by the kidneys. Of note, urine chloride will be high with recent use but drops to low levels once the diuretic effect wanes. Metabolic alkalosis can also occur in the absence of significant chloride depletion. Conditions of mineralocorticoid excess (eg, primary hyperaldosteronism) cause metabolic alkalosis primarily due to aldosterone-mediated H+ loss from the kidneys. These patients have hypervolemia (eg, hypertension), resulting in a pressure natriuresis with high urine chloride levels; the metabolic alkalosis does not correct with Cl- repletion (saline unresponsive) due to the persistent mineralocorticoid effect. Certain renal tubular channelopathies (eg, Bartter and Gitelman syndromes) represent a special case. Although affected patients are hypovolemic and total body chloride is low, high urine chloride is present because the defect persistently impairs renal Cl- reabsorption.

A 28-year-old man is hospitalized following a motor vehicle collision complicated by severe hemorrhage. Over the next 8 hours his urine output is markedly decreased. Laboratory results reveal elevated blood urea nitrogen. The patient is given aggressive intravenous fluid hydration. After 24 hours of therapy, urine output is increased and blood urea nitrogen declines toward normal. Which of the following additional laboratory abnormalities suggests that this patient's initial oliguria is a compensation for volume contraction?

Urine sodium <20 mEq/L - This patient developed symptoms of acute renal failure (ARF) (eg, low urine output, high blood urea nitrogen) after a massive hemorrhage. ARF can be classified according to 1 of 3 etiologies: Prerenal: Caused by decreased renal perfusion; the nephrons remain intact and tubular function is preserved. Etiologies include volume loss (eg, hemorrhage), low-output states (eg, myocardial infarction, congestive heart failure), or systemic vasodilation (eg, sepsis). Intrinsic: Caused by tubular epithelial or glomerular damage; resorptive capacity is lost. Etiologies include acute tubular necrosis (due to renal ischemia or nephrotoxins) or glomerular diseases (eg, glomerulonephritis, nephrotic syndrome). Postrenal: Caused by urinary tract obstruction with normal nephron capacity. Etiologies include bilateral calculi, enlarged prostate, or a renal tumor in an individual with a sole functional kidney. This patient with severe blood loss was at risk for prerenal and intrinsic renal failure; however, his rapid improvement with hydration suggests a prerenal (hypovolemic) etiology. His laboratory results reflect intact renal tubular function, with compensatory mechanisms to restore blood volume. Increased tubular sodium reabsorption results in low urine sodium (<20 mEq/L) and low fractional excretion of sodium (FENa), whereas increased water reabsorption leads to high urine osmolarity. Urea reabsorption also increases to help concentrate the urine, resulting in increased serum levels of urea; creatinine continues to be excreted, resulting in the characteristic BUN/creatinine ratio >20. In contrast, intrinsic ARF reflects tubular epithelium damage and loss of renal reabsorptive capacity. Water, sodium, and urea are excreted in the urine, leading to lower urine osmolarity, higher urinary sodium, higher urinary FENa, and a normal serum BUN/creatinine ratio.

A 22-year-old man comes to the office due to recurrent blistering on the back of his hands and forearms for the past several years. The patient usually develops small itchy spots but lately has had large blisters that heal with hyperpigmentation after rupturing. He has used over-the-counter topical hydrocortisone and emollients, but the symptoms have not improved. The patient works as a night security guard and has had no exposure to chemicals or animals. He drinks 2-3 cans of beer daily. Physical examination shows vesicles and erosions on the dorsum of both hands. Which of the following enzymes is most likely deficient in this patient?

Uroporphyrinogen decarboxylase - This patient most likely has porphyria cutanea tarda (PCT), the most common disorder of porphyrin (eg, heme) synthesis. Enzyme deficiencies in the early steps in porphyrin synthesis cause abdominal pain and neuropsychiatric manifestations (due to metabolite buildup) without photosensitivity. Late step (ie, following porphobilinogen [PBG] conversion) derangements (eg, PCT) cause photosensitivity, which is thought to be due to the accumulation of porphyrinogens that react with oxygen on excitation by ultraviolet (sun) light. PCT is caused by uroporphyrinogen decarboxylase (UROD) deficiency, which is either inherited or (more commonly) acquired, manifesting in the presence of iron and of susceptibility factors (eg, alcohol [as in this patient], smoking, halogenated hydrocarbons, hepatitis C, HIV). Photosensitivity presents as vesicle and blister formation on sun-exposed areas as well as edema, pruritus, pain, and erythema. Deficiencies in coproporphyrinogen oxidase, protoporphyrinogen oxidase, or ferrochelatase can also result in photosensitivity.

A 75-year-old man is brought to the office for evaluation due to memory loss and increasing confusion for 6 months. The patient is unable to manage his finances and occasionally gets lost in his neighborhood, needing to ask for directions. On examination, he can recall only 1 of 3 objects after 5 minutes. The patient performs poorly on cognitive assessment testing. Cranial nerves and gait are normal. T2-weighted MRI reveals multiple white matter abnormalities (hyperintensities) within the left frontal, bilateral parietal, and occipital white matter. Also noted are subcortical gray matter hyperintensities in the bilateral thalamus. Which of the following is the most likely diagnosis?

Vascular dementia - This patient has had a relatively abrupt cognitive decline with prominent executive dysfunction (eg, managing finances, getting lost). Neuroimaging reveals scattered lesions in the white matter and subcortical gray matter, especially the thalamus. This is consistent with vascular dementia (VaD), which often occurs due to one of the following mechanisms: Atherosclerosis of large vessels (eg, basilar arteries, carotid arteries, circle of Willis): Plaque accumulation narrows the lumen; plaque rupture can lead to thrombosis and thromboembolism, often causing a clinical stroke, resulting in localized neurologic deficits. MRI would reveal a discrete cortical infarct. Small-vessel disease, which includes the development of microatheromas; small-vessel degeneration with eosinophilic, lipid-rich accumulations in the vessel wall; and arteriolosclerosis (ie, thickening and stiffening of arteriole walls): Small-vessel disease can lead to microaneurysm formation, obstruction, or breakage of the vessel walls. It more often impacts subcortical regions (eg, thalamus, basal ganglia) because there is less arteriole collateralization in these regions compared to the cerebral cortex. MRI often reveals signs of multiple small infarcts or microbleeds in these areas. Cerebral amyloid angiopathy: Beta-amyloid deposits in the walls of small to medium cerebral arteries and leads to increased fragility of the vessels. Although the most common manifestation is spontaneous, lobar intracranial hemorrhage, it can also cause multiple small infarcts and present as VaD.

A 7-year-old boy is brought to the emergency department due to fever, headache, vomiting, and confusion. He has no prior medical conditions and is up to date with immunizations. The patient has not traveled recently, and his parents report no exposure to individuals with similar symptoms or ingestion of anything out of the ordinary. They have recently noticed several dead birds around their neighborhood. Temperature is 39 C (102.2 F). Physical examination shows neck rigidity and right lower extremity weakness with fasciculations. Cerebrospinal fluid analysis shows a leukocyte count of 200/mm3 with 20% neutrophils and 80% lymphocytes. Which of the following is the most likely pathogen responsible for this patient's condition?

West Nile virus - West Nile virus is an enveloped RNA virus that is found in warm climates worldwide. The virus replicates extensively within birds and is passed to mosquitos (Culex species) during blood feeding. Viral accumulation in mosquito salivary glands can lead to human transmission. Most infected patients develop low-level viremia that is neutralized within a week by the humoral immune response; these individuals typically remain asymptomatic. However, a minority of patients (particularly the young, elderly, or immunosuppressed) are unable to mount an effective immune response and develop significant clinical manifestations, including: West Nile fever - a self-limited, flu-like illness that is often associated with a maculopapular rash Neuroinvasive disease - the virus is neurotropic and often causes meningitis (eg, fever, headache, neck stiffness), encephalitis (eg, confusion, tremors, seizures), and/or flaccid paralysis (eg, asymmetric weakness of limbs, fasciculations). Cerebrospinal fluid usually shows a lymphocytic pleocytosis. Most patients recover completely with supportive care, but some with neuroinvasive disease have long-term neurologic sequelae or die.

A 21-year-old woman comes to the office for evaluation of urinary frequency and urgency for the past 2 days. She has also noticed scant vaginal discharge. The patient has never had these symptoms before. She has no chronic medical conditions, and she takes a combination oral contraceptive pill daily. The patient has been sexually active with multiple partners over the last year. She is a college student and does not use tobacco, alcohol, or illicit drugs. A urine sample is obtained for urinalysis and culture. Which of the following additional findings would be most suggestive of a diagnosis of pyelonephritis?

White blood cell casts - This patient has urinary frequency and urgency consistent with a urinary tract infection (UTI). Women are more susceptible to UTIs because the female urethra is closer to the rectum and shorter than the male urethra. Sexual intercourse is often a precipitating factor because it introduces enteric bacteria to the periurethral area, leading to ascending infection of the bladder. UTIs are categorized into either upper (eg, pyelonephritis) or lower (eg, cystitis) infections based on the ascension of bacteria through the urinary tract. Pyelonephritis and cystitis can share concomitant clinical features including dysuria, suprapubic pressure, and hematuria. Urinalysis with microscopy is often performed to confirm the diagnosis of UTI, but both upper and lower UTIs can show hematuria, pyuria (presence of urine white blood cells [WBCs]), and bacteriuria. However, the presence of WBC casts on urinalysis differentiates between upper and lower UTIs and can confirm the diagnosis of pyelonephritis. This is because WBC casts are formed only in renal tubules, where WBCs precipitate with Tamm-Horsfall protein secreted by tubular epithelial cells. WBC casts can also be seen with other intrarenal disorders (eg, acute interstitial nephritis), but urinary frequency and urgency are not typically present.