UWorld Review 5/12
A 62-year-old man with amyotrophic lateral sclerosis comes to the office for follow-up. The patient was diagnosed 8 months ago after experiencing bilateral arm weakness. He notes no worsening or new physical symptoms. The patient has no mood depression or anhedonia. Vital signs are within normal limits. Cardiopulmonary examination is normal. Neurologic examination is consistent with prior evaluation; moderate atrophy and weakness of the upper extremities are present, and reflexes are 3+ in the upper and lower limbs. The patient states that he is glad that the physical examination remains unchanged but shares that he has "felt distant" from his wife since being diagnosed. Which of the following is the most appropriate response?
"Many patients with this condition experience changes with intimacy and sex; is there anything you would like to talk about?" - Patients with chronic conditions often have unaddressed psychosocial concerns. This patient was recently diagnosed with amyotrophic lateral sclerosis, which involves physical impairment. Although his clinical condition and mood are stable, he confides that he has "felt distant" from his wife. The best next step is to validate the patient's feelings (eg, "Many patients with this condition experience changes with intimacy and sex"). Then the physician should elicit the patient's specific concerns (eg, "is there anything you would like to talk about?"). The patient could be referring to a new lack of emotional intimacy with his wife or a decline in sexual well-being, which also adversely affects quality of life but may remain unaddressed due to embarrassment. For example, a common concern is decreased libido; partners of patients with physical impairment may also be worried about hurting their partners during intercourse. Therefore, physicians should have a low threshold for inquiring about emotional and sexual well-being in patients who raise relationship concerns. If the patient chooses to raise such issues, additional education on condition-specific interventions can be discussed. In addition, regular reassessment is recommended.
A 75-year-old man comes to the office due to a 2-year history of slowly worsening vision in both eyes. The symptoms are worse at night and the patient has stopped driving at night due to excessive glare from oncoming headlights. He has worked his entire life as a farmer and continues to drive tractors and other farm equipment during the day without difficulty. Medical history is unremarkable. Ocular examination shows loss of the red reflex and poor visualization of retinal detail. Acuity testing shows 20/100 vision in both eyes; visual field testing is normal. Which of the following is the most likely etiologic factor for this patient's eye condition?
Age-related oxidative injury - This patient has cataracts: progressive opacification of the lenses with chronic loss of visual acuity. Scattering of light within the lens leads to glare and halos around bright lights, especially at night. Examination reveals cloudiness in the lens, decreased detail when examining the retina, and loss of the red reflex. Transparency of the lens requires an ordered epithelial cell structure and maintenance of intracellular crystallins. Aging and environmental stressors can disrupt transparency and contribute to cataract formation through the following mechanisms: Nuclear sclerosis: new layers of epithelia form on the cortex of the lens, compacting older layers beneath Photooxidative damage and cross-linking of crystallins causes brown/yellow pigmentary changes Osmotic injury resulting in development of hydropic lens fibers that degenerate Cumulative photooxidative stress is worsened by heavy UV exposure (eg, outdoor occupations), smoking, or ionizing radiation. Likewise, osmotic injury is accelerated in patients with diabetes mellitus. A disordered balance of prooxidative versus antioxidative compounds in the lens (eg, decreased glutathione) may also contribute.
A 7-year-old boy is evaluated for fatigue. For the last year, he has been avoiding any significant outdoor activities with his peers due to poor energy and shortness of breath. He also describes occasional pounding in the chest. Physical examination shows a holosystolic murmur best heard at the lower sternal border. Echocardiography reveals apical displacement of the tricuspid valve leaflets, decreased right ventricular volume, and atrialization of the right ventricle. Moderate to severe tricuspid regurgitation is also present. If this patient's diagnosis is due to a side effect of a drug taken during pregnancy, his biological mother most likely had which of the following conditions?
Bipolar disorder - In patients with bipolar disorder, lithium is used to treat acute mania, hypomania, and bipolar and unipolar depression. Long-term treatment may also reduce the risk of suicide attempts and deaths. Lithium is potentially teratogenic; in utero exposure is associated with Ebstein's anomaly in infants. Ebstein's anomaly is characterized by apical displacement of the tricuspid valve leaflets, decreased volume of the right ventricle, and atrialization of the right ventricle.
A 43-year-old woman comes to the emergency department due to nausea and vomiting with left-sided chest pain. She states that the pain began 30 minutes ago while playing with her children. She has a history of dyslipidemia and hypertension. The patient's mother died from a myocardial infarction at age 51. Physical examination reveals mild tenderness to palpation over the left chest. An ECG and cardiac biomarkers are normal. She is scheduled for an exercise stress test. During the test, which of the following parameters is likely to be the most similar between the systemic and pulmonary circulation?
Blood flow per minute - In order to maintain blood flow through the body, the blood flow (mL/min) in the pulmonary circulation must closely match the blood flow in the systemic circulation. This is true for conditions of both exercise and rest as the circulatory system is a continuous circuit. If the flow of blood through the pulmonary circulation is less than the flow of blood through the systemic circulation, the left ventricle would soon empty completely. Alternately, if the flow of blood is significantly greater in the pulmonary circulation than it is in the systemic circulation, the left ventricle would soon be overloaded. The major exception to this is the bronchial circuit, which supplies oxygen and nutrients to the pulmonary parenchyma from the systemic circulation but drains mostly to the left atrium as opposed to the right atrium (creating a right to left shunt that acts as a partially independent circuit). However, this typically accounts for <5% of the systemic cardiac output.
A 4-day-old newborn is brought to the office for a 2-day history of progressive jaundice. He was born at term following an uncomplicated vaginal delivery. The patient has been breastfed since birth. Vital signs are normal. Examination shows scleral icterus and jaundice from the face to the upper abdomen. Laboratory results are as follows: Complete blood count Hematocrit 52% Reticulocytes 1% Liver function studies Total bilirubin 10.3 mg/dL Direct bilirubin 0.3 mg/dL Aspartate aminotransferase (SGOT) 18 U/L Alanine aminotransferase (SGPT) 24 U/L Which of the following is the most likely explanation for these findings?
Decreased UDP glucuronosyltransferase activity - This neonate most likely has benign neonatal hyperbilirubinemia, a physiologic condition characterized by an elevated indirect bilirubin level that peaks at age 2-5 days. The pathophysiology of benign neonatal hyperbilirubinemia includes the following: ↑ Bilirubin production: Fetal red blood cells (RBCs) are increased in number and have a shorter life span compared to RBCs in children and adults. Physiologic breakdown of these RBCs causes excess production of indirect bilirubin. ↓ Bilirubin clearance: Physiologically decreased levels of hepatic uridine diphosphogluconurate (UDP) glucuronosyltransferase in newborns results in decreased bilirubin conjugation and excretion into the bile. ↑ Enterohepatic circulation: Normally, bilirubin in the intestines is reduced by bacterial enzymes to allow for excretion through urine and stool. In the newborn, lack of bacterial enzymes due to relative gut sterility results in an increased bilirubin concentration remaining in the intestines. This excess bilirubin is deconjugated by intestinal beta-glucuronidase and then reabsorbed via the enterohepatic circulation. Benign neonatal hyperbilirubinemia is typically asymptomatic except for scleral icterus and jaundice. The resolution of benign neonatal hyperbilirubinemia is expected by age 1-2 weeks as UDP glucuronosyltransferase activity and gut bacteria increase, allowing increased bilirubin clearance and excretion.
A 34-year-old woman has recurrent throbbing headaches that occur several times a month and cause significant distress. They are accompanied by nausea and photophobia. She has had 5 emergency department visits for these headaches over the last 6 months. During office visits, her blood pressure ranges from 140/90 mm Hg to 150/95 mm Hg. Neurologic examination is unremarkable. The patient is prescribed metoprolol and is advised that the medication is expected to decrease the frequency of headaches and also lower blood pressure in the long term. Which of the following best explains this medication's effect on blood pressure?
Decreased level of circulating renin - Beta blockers are useful for treating hypertensive patients with comorbid conditions such as migraine, essential tremor, angina pectoris/prior myocardial infarction, and atrial fibrillation. Beta blockers lower blood pressure via 2 mechanisms: Reducing myocardial contractility and heart rate Decreasing renin release by the kidney Renin release is mediated in part through sympathetic stimulation of beta-1 receptors located on juxtaglomerular cells. Therefore, beta-adrenergic blocking drugs (eg, metoprolol) act to inhibit renin release, which in turn reduces the conversion of angiotensinogen to angiotensin I and reduces the levels of angiotensin II (a potent vasoconstrictor) and aldosterone (decreasing renal sodium and water retention)
A 1-day-old boy is diagnosed with hyperphenylalaninemia by newborn screening. He is placed on a special phenylalanine-restricted diet with tyrosine supplementation. The parents are extensively counseled on the boy's condition and informed of the necessary dietary restrictions. They are also instructed to return to his physician for regular follow-up visits. Several months later, laboratory test results indicate that the infant has a normal serum phenylalanine level. Careful examination, however, reveals some neurological abnormalities, including axial hypotonia and microcephaly. Further workup is notable for elevated prolactin, and his physician suspects a cofactor deficiency. Which of the following enzymes is most likely deficient in this patient?
Dihydrobiopterin reductase - This patient with phenylketonuria (PKU) most likely has a deficiency of dihydrobiopterin reductase (reduces BH2 to BH4) based on the combination of hyperphenylalaninemia and elevated prolactin. Phenylalanine is converted to tyrosine by phenylalanine hydroxylase using BH4 as a cofactor. Tyrosine is converted to DOPA via the enzyme tyrosine hydroxylase, which also uses BH4 as a cofactor. Once DOPA is synthesized, it is decarboxylated to dopamine by DOPA decarboxylase. Dopamine ultimately serves as the precursor molecule to the catecholamines epinephrine and norepinephrine. In classic PKU, supplementation of tyrosine allows for normal catecholamine production due to intact function of tyrosine hydroxylase. However, deficiency of dihydrobiopterin reductase results in both hyperphenylalaninemia from impaired phenylalanine hydroxylase activity and low dopamine levels from impaired tyrosine hydroxylase activity. Although phenylalanine levels can be controlled by dietary restriction, downstream deficiencies of neurotransmitters (eg, dopamine, norepinephrine, epinephrine, serotonin) lead to progressive neurologic deterioration in these patients. Normally, dopamine from the tuberoinfundibular system tonically inhibits prolactin release. Decreased BH4 causes lower levels of dopamine, resulting in increased prolactin levels.
A 66-year-old man with hypertension and stage IV chronic kidney disease comes to the office for follow-up. The patient has had worsened fatigue and low energy over the past several months but no chest pain or shortness of breath. He was previously nonadherent with antihypertensive therapy but has been following treatment recommendations since renal dysfunction was diagnosed 2 years ago. Blood pressure is 126/78 mm Hg and pulse is 68/min. Cardiac auscultation reveals an S4 sound. The rest of the physical examination is unremarkable. Laboratory results show normocytic, normochromic anemia with a low reticulocyte count. Serum iron studies are within normal limits. Treatment with a recombinant glycoprotein hormone is begun, and repeat laboratory testing several weeks later shows an improvement in hemoglobin level. The effects of the hormone prescribed for this patient are most likely mediated by which of the following pathways?
Janus kinase 2/signal transducers and activators of transcription - Patients with chronic kidney disease (CKD) often develop normocytic anemia as the glomerular filtration rate declines, due to an inability to generate adequate quantities of erythropoietin (EPO). EPO is a glycoprotein produced by peritubular fibroblast cells in the renal cortex in response to tissue hypoxia (as seen with anemia). Healthy individuals increase EPO production up to 10,000-fold in response to anemia, but patients with CKD have chronic renal inflammation that damages EPO-producing cells, thereby preventing an adequate EPO response. Therefore, patients with CKD are often treated with recombinant EPO agents (eg, epoetin, darbepoetin) to supplement EPO production. EPO travels from the kidney through the bloodstream to the bone marrow, where it binds to a surface receptor on erythrocyte colony-forming unit cells (erythrocyte precursors). Binding activates the Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling pathway, which induces the transcription of proteins that inhibit erythrocyte precursor apoptosis and promote survival. Binding also activates signals that increase the differentiation of erythrocyte precursors into mature erythrocytes. Together, these effects increase the production of erythrocytes and improve circulating red blood cell counts. Activating mutations affecting the JAK2 gene are associated with polycythemia vera, a chronic myeloproliferative disorder marked by the clonal proliferation of erythrocytes (leading to dramatic elevations in hematocrit).
A 46-year-old, previously healthy man develops sudden-onset, sharp, left-sided flank pain radiating to the groin. CT scan of the abdomen reveals a left ureteral calculus, which he passes spontaneously in the urine. Other, incidental findings include a left lower lobe lung nodule and foci of calcifications in the spleen. Chest imaging shows several small calcified nodules in both lungs and a calcified mediastinal lymph node. The patient has had no pulmonary symptoms and is a lifelong nonsmoker. He is a farmer who lives in Ohio and has not traveled recently. Physical examination reveals no abnormalities. Tuberculosis skin test shows a <5 mm induration at 48 hours. Repeat chest imaging 3 months later reveals no changes. Which of the following is the most likely cause of the observed findings in this patient?
Fungal infection - This patient has calcified lung, mediastinal, and splenic lesions that are stable over time and asymptomatic, raising suspicion for a contained granulomatous infection. The most likely cause is the dimorphic fungus Histoplasma capsulatum, which exists as a mold in the soil of the Ohio and Mississippi River Valleys (midwestern/central United States). The pathogen is inhaled into the lungs, where it converts to yeast form and is phagocytosed by alveolar macrophages. Macrophages cannot initially eliminate the organism due to microbial virulence factors that prevent phagolysosome formation and acidification. Therefore, H capsulatum is able to replicate within the macrophage and spread through the draining lymphatic system and (often) into the reticuloendothelial system (eg, spleen, liver). After about 2 weeks, patients with intact immunity develop a cell-mediated immune response that contains the infection within granulomas. Over time, the granulomas fibrose and calcify and can be visualized on radiographic imaging at the initial sites of infection (eg, lungs, hilar and mediastinal lymph nodes, spleen). In healthy patients, most infections with H capsulatum are asymptomatic and are therefore often discovered incidentally during evaluation for an unrelated condition (eg, nephrolithiasis).
A 48-year-old woman enrolls in a clinical trial. The patient has had persistent discomfort in her lower extremities for the past 2 years. She describes an uncomfortable sensation in her legs, particularly in the evening and at night, but no pain. The symptoms are relieved with leg movement or walking. She has experienced no behavioral or mood changes. The patient intermittently experiences mild migraines, and during a recent episode she found that antiemetic therapy worsened the leg discomfort. Vital signs are normal, and physical examination shows no abnormalities. Blood cell counts, serum chemistry studies, and serum iron levels are within normal limits. Treatment with a novel agent, an alpha-2-delta calcium channel ligand, is initiated. The patient receives significant symptom relief with this therapy. The novel agent used in this trial is most similar to which of the following medications?
Gabapentin - This patient with vague lower extremity discomfort and an urge to move the legs that worsens at night has typical features of restless legs syndrome (RLS). RLS is characterized by uncomfortable sensations in the legs that are often difficult to describe and associated with an urge to move the lower extremities. Symptoms are relieved with movement (eg, walking, stretching) and are typically worse at night. As a result, patients often develop sleep-onset insomnia. The pathophysiology of RLS is incompletely understood but likely involves CNS iron deficiency (even in patients with normal serum iron levels) and abnormalities in dopaminergic transmission. Certain medications, including dopamine antagonists (eg, antipsychotics, certain antiemetics [metoclopramide]), first-generation antihistamines (eg, diphenhydramine), and antidepressants (eg, selective serotonin reuptake inhibitors [eg, sertraline], mirtazapine), are associated with worsening symptoms.Treatment includes lifestyle measures (eg, limiting alcohol and caffeine) and alpha-2-delta calcium channel ligands (eg, gabapentin, pregabalin). Dopamine agonists (eg, pramipexole) are alternate agents, but regular use can lead to augmentation of symptoms (ie, paradoxical worsening with chronic therapy) as well as the risk of impulse control disorders.
A 26-year-old woman is being evaluated for a possible inherited disorder. She has a 6-year history of generalized tonic-clonic seizures, and a year ago, she had partial loss of vision due to an occipital infarction. Her mother has chronic intermittent muscle weakness and lactic acidosis, and her maternal uncle has hemiplegia. Skeletal muscle biopsy of the patient shows ragged-appearing muscle fibers. After further evaluation, all the affected family members are found to suffer from the same inherited disease. Pedigree analysis is shown with the maternal grandmother, maternal uncle, mother, and patient being affected. None of the maternal uncle's kids are affected. Which of the following is the most likely explanation for the variability of clinical manifestations in the affected family members?
Heteroplasmy - The neuromuscular lesions, ragged skeletal muscle fibers, and lactic acidosis in these family members suggest mitochondrial encephalomyopathy. Mitochondrial disorders follow a maternal inheritance pattern because an embryo's mitochondria are inherited from the ovum only. Mitochondria are responsible for ATP production via oxidative phosphorylation, which is why mitochondrial defects tend to cause lactic acidosis and primarily affect tissues with the highest metabolic rates (eg, neural tissue, muscular tissue). Although many mitochondrial proteins are coded for in the nuclear genome, mitochondria also contain their own genome, which is vulnerable to mutations. Each cell has hundreds of mitochondria, and defects in their genome may occur in any number of the mitochondria within the cell. Heteroplasmy describes the condition of having different mitochondrial genomes within a single cell. The severity of mitochondrial diseases is often directly related to the proportion of abnormal to normal mitochondria within a patient's cells.
A 54-year-old man with HIV comes to the emergency department due to nonproductive cough, low-grade fevers, and worsening fatigue for the past month. He has also lost 3.6 kg (8 lb) over the same period. The patient does not take antiretroviral therapy consistently and has not followed up with his primary care physician for the past several months. Physical examination reveals hepatosplenomegaly. Laboratory testing shows pancytopenia and elevated liver aminotransferases. Bone marrow aspiration is performed, and light microscopy of the specimen is shown. Which of the following is the most likely cause of this patient's current condition?
Histoplasma capsulatum - Light microscopy reveals several small, ovoid bodies within a macrophage, raising strong suspicion for Histoplasma capsulatum. This dimorphic fungus is transmitted by inhalation, converts to a yeast form in the lungs, and replicates within the phagosome of macrophages. Patients with intact immunity usually have an asymptomatic or self-limited pulmonary infection that is contained over time by the cell-mediated immune response. However, those with impaired immunity (eg, advanced AIDS) are at risk for dissemination through the reticuloendothelial system due to the organism's affinity for mononuclear phagocytic cells. Common manifestations include hepatosplenomegaly, lymphadenopathy, and pancytopenia. Ulcerated lesions on the tongue are also very characteristic of disseminated histoplasmosis. Disseminated infection is often diagnosed when histopathology shows oval or round yeasts within macrophages. Culture on Sabouraud agar grows hyphae (Histoplasma is a mold at cooler temperatures). Histoplasma antigen in blood and urine can also be detected by immunoassay.
A 52-year-old, post-menopausal woman comes to the office for a follow-up appointment. Six months ago, the patient was evaluated for recurrent, brief episodes of excessive warmth and sweating, which were interfering with her usual activities. Thyroid hormone levels were normal, and the patient was subsequently diagnosed with menopausal hot flashes. Treatment with estrogen-containing hormone replacement therapy was begun with significant symptom improvement. She has no other medical conditions and takes no other medications. Which of the following most likely occurred in this patient as a result of her medication use?
Increased total T4 level - Circulating thyroid hormone consists of 2 fractions: an inert protein-bound fraction and a free fraction that is available to enter target cells via a carrier-mediated mechanism. More than 99% of circulating thyroid hormone is bound to plasma proteins, creating a large circulating reservoir of thyroid hormone. Thyroxine-binding globulin (TBG) accounts for approximately 70% of thyroid hormone binding with an additional share bound by albumin and transthyretin. An increase in estrogen activity (eg, pregnancy, oral contraceptive use, postmenopausal hormone replacement therapy) raises circulating TBG levels, causing a corresponding reduction in free T4 and T3 levels. In patients with a normal hypothalamic-pituitary-thyroid axis, this reduction will result in a transient increase in TSH, leading to increased thyroid hormone production until the additional TBG becomes saturated with thyroid hormone and free T4 and T3 levels are restored (ie, patients remain euthyroid). Therefore, an increase in the TBG level leads to an increase in total T4 and T3 (bound plus free fractions)
A 45-year-old man comes to the clinic due to recurrent palpitations accompanied by chest discomfort and shortness of breath. A year ago, he was diagnosed with paroxysmal atrial fibrillation treated with rate control using a beta blocker. Past medical history is also significant for hypertension and obesity. Echocardiogram shows left atrial enlargement, normal left ventricular ejection fraction, and no significant valvular disease. 24-hour Holter monitoring reveals bursts of atrial fibrillation associated with the patient's symptoms. He is initiated on dofetilide to maintain normal sinus rhythm. This medication exerts its main effect on which portion of the action potential curve?
Late repolarization - The typical myocardial action potential of "nonpacemaker" or cardiac myocytes includes several phases: Phase 0 (rapid depolarization) - occurs when the resting membrane potential reaches threshold; it is characterized by rapid sodium entry into the cell due to activation and opening of voltage-dependent sodium channels. Class I antiarrhythmic drugs (eg, procainamide, flecainide, lidocaine) block these sodium channels and inhibit the initial depolarization phase (phase 0) of the action potential. Phase 1 (early repolarization) - caused primarily by activation of transient outward potassium currents along with a rapid decline in inward sodium current. This phase is not modulated to an appreciable extent by antiarrhythmic medications. Phase 2 (plateau phase) - Stable membrane potential due to a balance of "late" inward calcium current and outward potassium current. Calcium channel blockers (verapamil, diltiazem) are class IV antiarrhythmic drugs that inhibit the L-type calcium channels during this phase. These medications slow the sinus rate, prolong conduction through the atrioventricular node, and depress myocardial contractility (negative inotropic effect). Phase 3 (late repolarization) - characterized by the opening of potassium channels and the efflux of potassium ions from the cell (delayed rectifier potassium currents IKr and IKs) in conjunction with the decay of inward calcium current. Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide) predominantly block potassium channels and inhibit the outward potassium current during this phase, leading to prolongation of repolarization, action potential duration, and the QT interval on ECG. These medications are often used for maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation. Phase 4 (recovery) - normal resting membrane potential is between −80 and −95 mV and is generated by open potassium channels (inward rectifier current). Antiarrhythmic drugs do not affect phase 4 of the myocyte action potential, but beta blockers and calcium channel blockers can slow diastolic depolarization (phases 4 and 0) in pacemaker cells by decreasing the slope of depolarization.
A 64-year-old man is evaluated for worsening cough and shortness of breath. The patient has a history of hypertension and type 2 diabetes mellitus. He smokes a pack of cigarettes daily and drinks alcohol occasionally. Temperature is 38 C (100.4 F), blood pressure is 140/82 mm Hg, and pulse is 92/min. Lung auscultation reveals abnormal breath sounds. Chest x-ray is shown. Which of the following is the most likely cause of the observed pulmonary findings in this patient?
Leakage of protein-rich fluid in the alveolar air space - This patient has cough, shortness of breath, fever, and a right lower lobe infiltrate on chest x-ray, indicating lobar pneumonia likely due to a community-acquired pathogen (eg, Streptococcus pneumoniae). Lobar pneumonia is characterized by a step-wise inflammatory response, as follows: Congestion (day 0-2) - Neutrophils respond to bacterial components (eg, peptidoglycan) by releasing cytokines that increase the permeability of the pulmonary capillary endothelium, which allows circulating immune cells to more easily migrate to the area. Increased capillary permeability also leads to the accumulation of erythrocytes and abundant proteinaceous fluid in the alveolar space, resulting in the affected lobe becoming heavy and red. Red hepatization (day 2-4) - The proteinaceous fluid transforms into fibrin strands, resulting in a confluent exudate of fibrin, neutrophils, and erythrocytes. On gross examination, the lobe appears liver-like: Red, firm, and airless. Gray hepatization (day 4-7) - Red cell disintegration along with increased leukocyte infiltration causes the lung to appear gray rather than red. Neutrophils begin to be replaced by macrophages that begin the repair process. Resolution (>7 days) - Macrophages secrete digestive enzymes that liquefy the fibrinous exudate, which is reabsorbed, expectorated, or phagocytized by macrophages. The lung parenchyma regains its normal appearance by approximately 3 weeks. Besides lobar pneumonia, there are 2 other major morphologic categories of pneumonia. Bronchopneumonia is an infection of the terminal bronchioles that results in patchy consolidation of a number of lobules. Interstitial pneumonia is an infection of the interstitial tissue of the lung with minimal or no alveolar infiltrate; atypical pneumonias (eg, Mycoplasma pneumoniae, Chlamydia pneumoniae) are often associated with an interstitial infiltrate
A 54-year-old man is brought to the office by his friend because of worsening memory impairment over the past several months. The patient is also withdrawn and not focused during conversations. He is slow to answer questions or carry out instructions. The patient has a prolonged history of HIV infection and has had several opportunistic infections due to inconsistent antiretroviral medication use. On physical examination, he is alert and oriented. Muscle strength, deep tendon reflexes, and sensation are normal. MRI of the head shows diffuse cerebral atrophy with no focal mass lesions or areas of demyelination. Viral proliferation in which of the following central nervous system cells is most likely involved in this patient's disease process?
Macrophages - In the context of a long history of HIV infection, this patient's memory impairment, subcortical dysfunction (ie, inattention, impaired psychomotor speed), and cerebral atrophy on MRI of the head are consistent with HIV-associated dementia (HAD). HAD is characteristically a subcortical dementia with prominent mood, attention, memory, and psychomotor dysfunction. It is uncommon in patients receiving antiretroviral treatment but can occur in those with inconsistently treated, advanced HIV infection. Although HIV-1 preferentially infects and replicates in CD4+ helper T cells in peripheral blood, CNS infection is associated with a change in viral tropism (ie, ability to infect different cell types) to microglia and macrophages, which allows the virus to penetrate deeper into the brain parenchyma. This macrophage tropic (M-tropic) version of the virus becomes "compartmentalized" in the CNS and evolves independently from the strain found in the blood.
A 54-year-old woman comes to the office due to right upper limb weakness and fatigue. She has no problem during most activities but develops symptoms when attempting to raise her arm overhead. The patient first noticed the symptoms after a recent hospitalization. On examination, there is no sensory loss in the upper extremities, but she has difficulty abducting her right arm past the horizontal position. The patient is instructed to press her outstretched arms against a wall, and the medial border of the right scapula lifts off the thoracic wall and becomes prominent. This patient was most likely hospitalized for which of the following conditions?
Mastectomy with axillary lymph node removal - This patient has paralysis of the serratus anterior muscle due to long thoracic nerve injury. The serratus anterior originates on the surface of the first 8 ribs and inserts on the medial border of the scapula. It functions to stabilize and rotate the scapula upward. The deltoid and supraspinatus muscles abduct the arm up to the horizontal position, after which the serratus anterior and trapezius are required to rotate the glenoid cavity superiorly, thereby allowing complete abduction of the arm over the head. Innervation of the serratus anterior is from the long thoracic nerve, which arises from the C5-C7 nerve roots via the brachial plexus and follows a lengthy course along the lateral chest wall. Injury to the nerve can occur during penetrating trauma or iatrogenically during axillary lymph node dissection or chest tube insertion. Paralysis of the serratus anterior causes scapular winging due to inability of the serratus to hold the scapula against the thorax. Patients will also show weakness in abducting the arm above horizontal due to impaired rotation of the scapula.
A 79-year-old woman comes to the office due to bleeding from an ulcerative lesion on her right nipple that she first noticed several months ago. The lesion is itchy and is slowly increasing in size. Examination shows a crusty, thickened, erythematous, and ulcerated nodule with evidence of hyperpigmentation. Changes extend to the surrounding areola. Excisional biopsy reveals relatively well-circumscribed aggregates of large, polygonal, pleomorphic cells with abundant mitotic activity and surrounding necrosis. S-100 and HMB-45 stains are diffusely positive. Which of the following is the most likely diagnosis?
Melanoma - This older patient has a crusted, ulcerated, hyperpigmented nodule on the nipple and areola. Biopsy was performed to differentiate Paget disease of the breast, an adenocarcinoma of the areolar epithelium, from nodular malignant melanoma. Histopathology revealed poorly differentiated cells with abundant mitotic activity and necrosis. Subsequent immunostaining was positive for S-100 (a protein expressed in cells derived from the neural crest such as melanocytes) and HMB-45 (a marker for immature melanosomes found in melanocytic tumors) indicating melanoma. Immunostaining is often used to assist the diagnosis of melanoma because histopathologic features are sometimes insufficient to confirm the diagnosis. Tumor cells that stain positive for multiple melanocyte markers (as in this case) are very likely to be melanoma. S-100 is positive in >95% of melanoma tumors, and HMB-45 is both highly sensitive (>95%) and highly specific (~100%) for the malignancy.
A 76-year-old man comes to the office with a 2-month history of progressive low back pain. The pain is relatively constant and nagging and is unrelieved by rest or position changes. It is especially bad at night and interferes with sleep. The patient has taken acetaminophen and ibuprofen without relief. Medical history is significant for hypertension and osteoarthritis affecting the knees and hands. The patient used intravenous drugs occasionally when he was younger but not for >30 years. Which of the following processes is most likely responsible for this patient's back pain?
Neoplastic - Back pain is common, and the majority of cases are due to benign skeletal (eg, osteoarthritis, spinal stenosis, disc herniation) or muscular (eg, muscle strain) conditions. The most common causes of back pain generally worsen with activity and improve with rest, postural modifications (eg, spinal stenosis worsens with back extension and is relieved with flexion), and analgesic therapy. However, this patient's constant back pain that fails to improve with positional changes, rest, or analgesics is concerning for a more serious condition (infection, malignancy). This pattern of pain in an older patient (age >50) without a recent history of intravenous drug use should raise suspicion for a neoplastic process, particularly if the pain is worse at night (nocturnal pain). Other features that raise concern for malignancy include a personal history of cancer, weight loss, neurologic deficits (eg, weakness), and point tenderness on the spinous processes. Malignancies with a propensity for bony metastasis include Prostate, Breast, Kidney, Thyroid, and Lung (mnemonic: Pb KTL, or "lead kettle"). Prostate cancer is the most common malignancy in older men and frequently metastasizes to the axial skeleton and femur.
Pharmacology researchers are developing a new antivenom to treat coral snakebites. They immunize horses with snake venom, extract IgG-containing plasma, and then administer the plasma to humans who have been bitten by a coral snake. This therapy neutralizes the venom and improves the patient's symptoms. In order to produce venom-selective antibodies, the researchers select a single venom-specific plasma cell from the immunized horse and induce it to proliferate and produce large amounts of venom-specific IgG. However, they find that the antibody produced by the single plasma cell is less effective at neutralizing the venom than the IgG-containing plasma. A decrease in which of the following best explains the reduced efficacy of the immunoglobulin produced by the single plasma cell?
Number of antigen epitopes recognized - Exposure to a pathogen or foreign substance (eg, venom) generates innate and adaptive immune responses. The humoral component of the adaptive immune response culminates when activated CD4 cells prompt antigen-specific B cells to undergo somatic hypermutation and class switching, thereby generating a pool of highly specific IgG antibodies that neutralize several different epitopes on the antigen. This is considered a polyclonal response because a number of different clonal plasma cells each produce a specific antibody that targets a different epitope on the antigen. In contrast, monoclonal antibodies are derived from a single population of plasma cells and bind only a single epitope on the antigen. Naturally occurring monoclonal antibodies are typically seen in pathologic conditions such as plasma cell dyscrasias (eg, multiple myeloma). In the laboratory setting, myeloma cells can be fused to antigen-specific plasma cells to generate a large amount of monoclonal antibody against a particular antigen. However, because monoclonal antibodies bind only a single epitope type on an antigen, they typically generate a less potent immune response than polyclonal antibodies, which bind multiple different epitope types on an antigen.
A 72-year-old man is brought to the emergency department due to diarrhea and vomiting for the last 24 hours. The patient's daughter states that he has been unable to take in much fluid during this time. He has hypertension treated with hydrochlorothiazide, which he has not taken since the onset of symptoms. Blood pressure is 90/60 mm Hg and pulse is 105/min. Examination shows dry mucous membranes. Urinalysis reveals concentrated urine with a specific gravity of 1.030. Which of the following changes in renal plasma flow (RPF), glomerular filtration rate (GFR), and filtration fraction (FF) are most likely to be present in this patient as compared with the normal state?
RPF: ↓↓ GFR: ↓ FF: ↑ Filtration of fluid through the glomeruli depends on the renal plasma flow (RPF) and the glomerular filtration rate (GFR). The GFR is the volume of fluid filtered from the renal glomerular capillaries into the Bowman capsule per unit of time. The RPF is the volume of plasma delivered to the kidney per unit of time. The filtration fraction (FF) is the ratio of GFR to RPF (FF = GFR/RPF). On average, approximately one-fifth of the plasma that passes through the glomerular capillaries is filtered into the Bowman capsule. This patient is severely hypovolemic due to profuse diarrhea and vomiting. The decline in circulating blood volume is sensed by arterial and cardiac baroreceptors and triggers increased systemic arteriolar vasoconstriction. Renal vasoconstriction further lowers the RPF, which is already decreased due to the decline in circulating blood volume. Decreased RPF causes glomerular perfusion pressure to drop, lowering the GFR and reducing distal tubule sodium delivery. This stimulates secretion of renin and increased angiotensin II production. Angiotensin II preferentially constricts the efferent glomerular arteriole, which increases hydrostatic pressure in the glomerular capillaries to maintain GFR (autoregulation). Due to this compensatory mechanism, the decrease in GFR is less pronounced than the decrease in RPF, resulting in an increased FF. As RPF continues to decline, increasing glomerular oncotic pressure will eventually overwhelm the compensatory increase in hydrostatic pressure, leading to a precipitous drop in GFR and subsequent renal failure.
An 8-hour-old boy is being assessed for a murmur in the newborn nursery. The patient was born at 37 weeks via cesarean delivery. Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. He was noted to have a harsh ejection systolic murmur of 4/6 intensity during initial newborn examination. Brachial and femoral pulses are 2+ with no delay. While the patient is breastfeeding for the first time, his face, lips, hands, and feet become cyanotic. The murmur cannot be heard during the cyanotic episode. Which of the following oxygen saturation percentages are most likely present during the cyanotic episode?
Right Atrium: 75 Right Ventricle: 75 Pulmonary Artery: 75 Pulmonary Veins: 98 Left Atrium: 98 Left Ventricle: 80 This infant has a harsh systolic ejection murmur that disappears during an episode of cyanosis, an expected finding with tetralogy of Fallot (ToF). The major defects in ToF are right ventricular outflow tract (RVOT) obstruction and a ventricular septal defect (VSD); the murmur is created by blood flow through the narrowed RVOT, not the VSD. The degree of RVOT obstruction is the major driver of symptoms in ToF because it determines the direction and magnitude of shunting through the VSD. A certain degree of RVOT obstruction is fixed, but some degree is dynamic and can change based on activity (eg, feeding, squatting) that alters the underlying hemodynamics. Many patients have left-to-right or neutral shunting at rest (and are acyanotic), but they develop cyanosis ("tet" episodes) when a dynamic increase in RVOT obstruction (eg, precipitated by crying or feeding) leads to increased right-to-left shunting through the VSD. During such an episode, decreased blood flow through the RVOT causes the systolic murmur to disappear. In addition, oxygen saturation (SaO2) in the left ventricle is reduced (eg, <90%) due to mixing with deoxygenated blood from the RV. The SaO2 in the left atrium (LA) remains normal as the LA continues to receive oxygenated blood from the pulmonary veins.
A 63-year-old man is brought to the emergency department due to an episode of syncope. The patient was recently discharged back to a nursing home after being hospitalized for a urinary tract infection. He has a history of coronary artery disease and takes aspirin, clopidogrel, and atorvastatin. His other medical conditions include type 2 diabetes mellitus and hypertension. The patient does not use tobacco, alcohol, or illicit drugs. Blood pressure is 68/32 mm Hg and pulse is 118/min. Invasive hemodynamic monitoring reveals an elevated right atrial pressure of 17 mm Hg and a pulmonary capillary wedge pressure of 7 mm Hg (normal: 8-10 mm Hg). Which of the following is the most likely cause of this patient's current condition?
Right ventricular infarction - This patient is in shock (eg, severe hypotension, end organ dysfunction [syncope]) due to an unknown cause. Hemodynamic monitoring (eg, pulmonary artery catheterization) shows decreased pulmonary capillary wedge pressure (PCWP) and increased right atrial pressure (RAP), which indicate impaired blood flow from the right ventricle to the left side of the heart (right-sided heart failure). Common causes of right-sided heart failure include obstruction of pulmonary circulation (eg, pulmonary arterial hypertension, pulmonary embolism) and right ventricular infarction (likely in this patient due to multiple cardiovascular risk factors). In right ventricular infarction, the right ventricle is unable to effectively pump blood forward into the pulmonary arteries, causing increased pressure in the right atrium (ie, elevated central venous pressure). The decreased right ventricular outflow also lowers PCWP (an indicator of left-sided preload), which subsequently reduces cardiac output and causes hypotension. A reflexive increase in heart rate is mostly intact in this patient, though it is often impaired in right ventricular infarction due to frequent ischemic involvement of the conduction system.
An 18-year-old man is brought to the clinic by his mother due to increasingly bizarre behavior over the past 2 months. The patient is in his first semester at an out-of-state college and has had difficulty adjusting to being away from home. For the past few weeks, he has not been attending classes, and he no longer socializes with friends. The patient spends most of his time alone in his dorm room and eats very little because he believes the cafeteria food is poisoned. He has no significant medical or psychiatric history and does not use alcohol or illicit drugs. Physical examination is unremarkable. On mental status examination, he appears disheveled with unwashed hair, makes poor eye contact, and shouts "leave me alone" in response to unseen people. Which of the following is the most likely diagnosis in this patient?
Schizophreniform disorder - This patient's 2-month history of progressive social withdrawal, paranoid ideation, and auditory hallucinations suggests schizophreniform disorder. These patients exhibit the same symptoms as individuals with schizophrenia (delusions, hallucinations, disorganized speech and behavior, negative symptoms) but for a shorter duration (≥1 month and <6 months). Functional decline, although often present, is not required for diagnosis. As with all psychotic disorders, diagnosis requires ruling out medical and substance-induced etiologies. Schizophreniform disorder is often a provisional diagnosis that requires longitudinal monitoring, as approximately two-thirds of patients with this disorder are eventually diagnosed with schizophrenia or schizoaffective disorder.
A 43-year-old immigrant from Southern Asia suffers from a cough that has lasted for several months duration. He comes to the clinic today because of recent onset hemoptysis. On further evaluation, he reports a 15-lb weight loss over the past four months. Sputum cultures grow acid-fast bacilli that are susceptible to most antimycobacterial drugs in vitro. Isoniazid monotherapy in this patient would most likely result in:
Selective survival of bacterial cells secondary to gene mutation - This patient most likely has active tuberculosis, which should never be treated with drug monotherapy due to the rapid emergence of antibiotic resistance in M. tuberculosis. Isoniazid resistance specifically occurs by two selective gene mutations. The first is a decrease in bacterial expression of the catalase-peroxidase enzyme that is required for isoniazid activation once the drug enters the bacterial cell. The second mechanism of resistance occurs through modification of the protein target binding site for isoniazid. Treatment of active tuberculosis is accomplished by combining multiple antibiotics to avoid selecting for resistant strains. Commonly used drug regimens include isoniazid and rifampin in addition to streptomycin, ethambutol, and/or pyrazinamide. Isoniazid monotherapy may be used for patients who have a positive PPD and a negative chest x-ray (i.e., no evidence of clinical disease).
A 3-month-old boy is brought to the office due to fussiness, poor weight gain, and polyuria. Urine volume is 700-800 mL/day. The patient's maternal grandfather has polydipsia and polyuria. Serum sodium is 151 mEq/L. Genetic testing reveals a vasopressin-2 receptor mutation. Which of the following additional findings is most likely to be seen in this patient?
Serum osmolality: high Urine osmolality after water deprivation: low Change in urine osmolality with desmopressin administration: no change This patient with a vasopressin-2 (V2) receptor mutation has polyuria and hypernatremia, findings which are consistent with congenital nephrogenic diabetes insipidus (DI). V2 receptors are located in the renal cortical collecting ducts. When serum osmolality rises (eg, water deprivation, dehydration), there is increased release of antidiuretic hormone (ADH, vasopressin) which activates V2 receptors to reabsorb water into the systemic circulation. Water reabsorption leads to concentrated urine (low urinary volume, high urine osmolality) and lower serum osmolality. Mutations that impair normal V2 receptor function result in nephrogenic DI (ADH resistance). Following water deprivation, the collecting ducts are unable to reabsorb water despite high circulating ADH levels, leading to ongoing urinary water losses. Therefore, nephrogenic DI manifests with large volumes of abnormally dilute urine (ie, polyuria with low urine osmolality), high serum osmolality (ie, hypernatremia), and dehydration. High serum osmolality, polyuria, and dilute urine also occur in central DI, which is caused by deficient ADH production by the hypothalamus. As with nephrogenic DI, urine remains abnormally dilute after water deprivation. However, challenge with desmopressin (an analogue of ADH) can differentiate between central and nephrogenic DI: In nephrogenic DI, desmopressin cannot correct the underlying ADH resistance. Therefore, urine osmolality remains unchanged (eg, low). In central DI, desmopressin corrects the underlying ADH deficiency. Therefore, urine osmolality increases following administration.
A 63-year-old man is brought to the emergency department due to an episode of syncope. The patient was recently discharged back to a nursing home after being hospitalized for a urinary tract infection. He has a history of coronary artery disease and takes aspirin, clopidogrel, and atorvastatin. His other medical conditions include type 2 diabetes mellitus and hypertension. The patient does not use tobacco, alcohol, or illicit drugs. Blood pressure is 68/32 mm Hg and pulse is 118/min. Invasive hemodynamic monitoring reveals an elevated right atrial pressure of 17 mm Hg and a pulmonary capillary wedge pressure of 7 mm Hg (normal: 8-10 mm Hg). Intravenous fluids and vasopressors are administered, but the patient remains hypotensive and dies 3 hours later. Autopsy examination is performed and reveals bilateral hippocampal necrosis. Which of the following areas of the colon would be most likely to also demonstrate necrosis?
Splenic flexure - This patient's bilateral hippocampal necrosis is characteristic of the effects of global cerebral ischemia due to systemic hypotension. The hippocampus is particularly vulnerable during shock because of the high metabolic demand of its CA1 pyramidal neurons. Watershed areas located between the distal terminal branches of 2 different vascular territories (border zones) are also susceptible to ischemia because they have a low baseline perfusion pressure and poorly tolerate sustained decreases in systemic blood pressure. Important watershed areas in the body include: Gastrointestinal (colon) Splenic flexure: the border zone supplied by branches of the superior mesenteric artery and inferior mesenteric artery Rectosigmoid junction: the border zone supplied by the sigmoid arteries and the superior rectal arteries Brain: the borders of the areas supplied by the anterior cerebral artery, middle cerebral artery, and posterior cerebral artery
A 38-year-old woman is brought to the emergency department after a motor vehicle collision. She sustained no injuries in the collision but is adamant that she did not see the car that hit her along the front side of her vehicle. The patient also reports that she has been having daily headaches and has not menstruated in 4 months. On physical examination, there is bitemporal hemianopsia but no other abnormalities. MRI of the brain is shown. This patient's lesion most likely originates from which of the following embryonic layers?
Surface ectoderm - Bitemporal hemianopsia, amenorrhea, and enlargement of the pituitary gland on brain imaging are suggestive of a prolactin-secreting pituitary adenoma. Prolactinomas develop from lactotroph cells in the anterior pituitary (adenohypophysis). All tissues can be traced back to 3 primary germ layers: ectoderm, mesoderm, and endoderm. These germ layers form during the process of gastrulation, which occurs during week 3 of embryogenesis. Gastrulation is initiated by formation of the primitive streak, a thickening of the epiblast cell layer that appears at the caudal end of the embryo and grows cranially. Epiblast cells then undergo an epithelial-to-mesenchymal transition, causing them to lose their cell-cell adhesion properties. This allows them to migrate downward through the primitive streak to form the mesoderm and endoderm layers. The remainder of the epiblast layer forms the ectoderm. About 2 days after gastrulation begins, some of the epiblast cells migrate cranially through the primitive node (the cephalic end of the primitive streak) to form a midline cellular cord known as the notochord. The notochord induces the overlying ectoderm to differentiate into the neuroectoderm and form the neural plate. The neural plate gives rise to the neural crest and neural tube cells, while the remainder of the ectoderm becomes the surface ectoderm. The anterior pituitary is derived from the Rathke pouch, an evagination of the surface ectoderm that lines the fetal oral cavity. In contrast, the posterior pituitary (pars nervosa and pituitary stalk) is derived from the infundibulum, an extension of neuroectoderm from the diencephalon.
A 25-year-old man comes to the hospital due to worsening abdominal pain, distension, and nausea and vomiting for 3 days. He has a 4-year history of recurrent abdominal pain associated with diarrhea, low-grade fever, and easy fatigability. The symptoms usually occur after stress and resolve spontaneously in a few days. However, this time, the patient's symptoms persisted and worsened. He has no other medical problems and takes no medications on a regular basis. Temperature is 38.2 C (100.8 F), blood pressure is 110/70 mm Hg, pulse is 104/min, and respirations are 16/min. BMI is 19 kg/m2. Examination shows a tender mass in the right lower quadrant of the abdomen. Imaging is consistent with small-bowel obstruction. Laparotomy reveals that the abdominal mass is composed of inflamed small bowel, adherent and indurated mesentery, and enlarged abdominal lymph nodes. The affected region of the small bowel is resected. Which of the following is most likely to be seen on histologic examination of this patient's intestine?
Thickening of the muscularis mucosae -This patient with recurrent abdominal pain and diarrhea likely has Crohn disease (CD) complicated by small-bowel obstruction. CD is an inflammatory bowel disease that occurs most commonly in young adults. It typically presents as recurrent episodes of abdominal pain associated with diarrhea, low-grade fevers, and fatigue; symptoms may worsen during periods of stress. The inflammation can affect any part of the gastrointestinal tract from the mouth to the anus and is typically patchy with interspersed areas of normal bowel (skip lesions). CD is characterized by transmural inflammation (all layers of the bowel wall are involved), which predisposes to several complications: Strictures occur as a result of bowel wall edema, fibrosis, and hypertrophy (thickening) of the muscularis mucosae, which narrows the intestinal lumen. This can progress to bowel obstruction. Fistulas occur when ulcers penetrate the entire thickness of the intestinal wall, leading to a sinus tract that communicates between multiple organs (eg, enterovesicular, enterovaginal, enteroenteric). Abscesses form when sinus tracts become walled off. They can also perforate, leading to diffuse peritonitis.
A newborn boy is found to have a serum TSH above and serum thyroxine below the normal range for his age. The patient was born at 39 weeks gestation via spontaneous vaginal delivery. His mother has no medical conditions. On examination, the patient's length and weight are normal, and he has no apparent congenital abnormalities. Ultrasound of the neck shows a normal-sized thyroid gland in the appropriate location. Which of the following is the most likely cause of this patient's condition?
Thyroid gland resistance to TSH - This patient has an elevated serum TSH and decreased thyroxine (T4) level, findings consistent with primary hypothyroidism. The most common congenital causes are thyroid dysgenesis (eg, ectopy, hypoplasia) and TSH resistance. Less common, transient etiologies are usually due to maternal conditions (eg, iodine excess, antithyroid medications). Given that this patient's thyroid is normal in size and location and the mother has no medical conditions, the most likely cause is thyroid gland resistance to TSH. TSH is normally produced by the anterior pituitary and binds to TSH receptors on follicular thyroid cells to stimulate T4 production. In TSH resistance, a mutation in the TSH receptor gene leads to thyroid insensitivity to TSH and reduced synthesis of T4. Low T4 leads to positive feedback to the pituitary, further increasing TSH levels. Newborns are usually asymptomatic due to placentally transferred maternal T4 (although thyroid hormones do not readily cross the placenta, enough T4 can usually cross to prevent development of overt symptoms); diagnosis is typically via newborn screening. Treatment is lifelong levothyroxine.
A 24-year-old man comes to the emergency department due to a painful erection for the past 6 hours. He has never had this condition before and says it is unrelated to sexual excitement. Medical history is significant for treatment-resistant major depressive disorder, obsessive-compulsive disorder, and insomnia. The patient has smoked a pack of cigarettes a day for 2 years and drinks 1 or 2 cans of beer daily. Examination reveals engorged corpora cavernosa but otherwise shows no abnormalities. Which of the following drugs is the most likely cause of this patient's condition?
Trazodone - Trazodone is a sedating antidepressant used off-label most often as a hypnotic to treat insomnia associated with depression or antidepressant treatment. It has been associated with the rare but serious side effect of priapism (ie, persistent erection of the penis for >4 hours that is not associated with sexual excitement). Priapism is a medical emergency that, if left untreated, can result in permanent damage to penile tissue and erectile dysfunction. Priapism occurs most often in young adult men. Trazodone is a serotonin modulator (it antagonizes postsynaptic serotonin receptors and inhibits serotonin reuptake) that has minimal effects on norepinephrine and dopamine. Additional properties include alpha-adrenergic blockade—which may account for the side effects of orthostatic hypotension and priapism—and histamine H1 receptor antagonism, which contributes to its sedating effect. Trazodone should be used with caution in patients with conditions that predispose to priapism (eg, sickle cell disease).
A 51-year-old woman comes to the office for a follow-up visit. Three weeks ago, she had a screening mammogram that was suspicious for malignancy. An ultrasound-guided needle aspiration was performed and showed invasive ductal carcinoma. The patient underwent a lumpectomy with axillary dissection and was found to have no metastatic disease. Immunohistochemical analysis of the tumor specimen was significant for the following: Estrogen receptor Positive Progesterone receptor Positive Human epidermal growth factor receptor 2 Positive Adjuvant therapy with a monoclonal antibody is started. Which of the following is the most likely target of this drug?
Tyrosine kinase receptor - This patient has localized invasive ductal breast carcinoma that shows estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) positivity. Trastuzumab is a monoclonal antibody used in the management of patients with HER2-positive breast cancer. It binds to a portion of the extracellular domain of HER2 and prevents activation of a transmembrane tyrosine kinase. This downregulates cellular proliferation and promotes apoptosis. Approximately 20% of all invasive breast cancers overexpress HER2; this can also be found in other solid tumors (eg, stomach, lung, ovary).
A 52-year-old man comes to the emergency department due to several days of vague chest pain and cough. He immigrated to the United States from Taiwan 20 years ago. Temperature is 37.1 C (98.8 F). Physical examination reveals a decrescendo-type diastolic murmur over the right sternal border. Pulmonary auscultation reveals normal breath sounds with no wheezes or rales. Abdominal examination shows no organomegaly. Serum fluorescent treponemal antibody absorption testing is positive. Chest x-ray reveals mediastinal widening. The pathologic process most likely responsible for this patient's symptoms starts as which of the following?
Vasa vasorum obliteration - This patient's murmur is characteristic of aortic regurgitation, which, in the presence of mediastinal widening, suggests an aortic aneurysm that has dilated the aortic annulus. The positive serology for syphilis (positive fluorescent treponemal antibody absorption [FTA-ABS] test) suggests a "luetic" aneurysm, consistent with tertiary syphilis. Tertiary syphilis begins with vasa vasorum endarteritis and obliteration, resulting in inflammation, ischemia, and weakening of the adventitia. Aneurysmal dilation of the thoracic aorta results and can extend to involve the aortic valve ring. Syphilitic aneurysms are uncommon in the United States.
A 34-year-old man comes to the office due to heart palpitations that are particularly prominent at night. With moderate exertion he also experiences head-pounding accompanied by involuntary head-bobbing. The patient recently emigrated from Southeast Asia and remembers being diagnosed with a heart murmur years before, but he cannot recall the type of murmur and has never received any treatment. He has no other medical conditions and takes no medications. He does not use tobacco, alcohol, or illicit drugs. The patient's father has coronary artery disease and his mother has type 2 diabetes mellitus. Based on this patient's history, which of the following findings is most likely to be present on further evaluation?
Widening of the pulse pressure - This patient has a number of clinical findings that are characteristic of chronic aortic regurgitation (AR). Failure of the aortic valve to tightly seal off the aorta from the left ventricle at the end of systole leads to rapid loss of aortic pressure and an overall decrease in diastolic blood pressure. In addition, the left ventricle undergoes eccentric hypertrophy to initially compensate for an increase in left ventricular end-diastolic volume, which leads to increased stroke volume and cardiac output. Because pulse pressure (the difference between diastolic and systolic blood pressure) is proportional to stroke volume, the compensatory increased stroke volume on top of reduced diastolic pressure causes the characteristic widened pulse pressure seen with AR. This high-amplitude pulsation with rapid diastolic collapse is responsible for the unusual pulsation findings in AR. Forceful pulsations in the intracranial arteries can cause head bobbing with each heart beat (de Musset sign), and patients may experience palpitations due to forceful left ventricular contraction. In addition, physical examination can show abrupt distension and collapse of the carotid arteries (Corrigan sign) and peripheral arteries ("water-hammer" pulse), and reveal "pistol-shot" femoral pulses (Traube sign) on auscultation.
Molecular biologists undertake a series of experiments designed to classify proteins involved in various intracellular signaling pathways. During one of the experiments, a protein mixture obtained from a cell culture is separated by gel electrophoresis and subsequently transferred to a filter membrane. Labeled double-stranded DNA probes are then used to detect a specific protein of interest in the sample. Which of the following proteins is most likely to be detected by this method?
c-Jun - The Southern, Western, Northern, and Southwestern blot procedures are powerful techniques used to analyze and identify DNA fragments, proteins, mRNA, and DNA-bound proteins, respectively. The same basic technique underlies all of the blot procedures. First, the unknown sample is separated by gel electrophoresis. Separation occurs based on a molecule's size and charge. The separated molecules form bands on the gel that are then blotted onto a nitrocellulose membrane and incubated with a labeled probe to identify the specific DNA fragment, RNA molecule, or protein of interest. Southwestern blots are used to identify and isolate proteins that bind DNA. In this technique, the target protein binds to a labeled, double-stranded DNA probe that is homologous to the protein's regulatory sequence. Of the molecules listed, c-Jun is the only DNA-binding protein. c-Jun and c-Fos are nuclear transcription factors that directly bind DNA via a leucine zipper motif. The genes that code for c-Jun and c-Fos are proto-oncogenes, genes that can become oncogenes following a mutation or with constitutive expression.