UWorld Review 5/17
A 43-year-old man is evaluated for retrosternal discomfort and dysphagia for the past several months. He smokes a pack of cigarettes daily and drinks alcohol on weekends. His BMI is 32.8 kg/m2. Physical examination is unremarkable. Esophageal manometry is performed; after a single swallow of 5 mL of water, the tracings appear as shown. Which of the following is the most likely diagnosis in the patient?
Achalasia - To initiate swallowing, the contents of the oral cavity are collected on the tongue and propelled into the pharynx, where contraction of the pharyngeal muscles pushes the material into the esophagus. The cricopharyngeus muscle contracts behind the food bolus, initiating a peristaltic wave to propel the bolus downward. When the food bolus reaches the lower esophagus, the lower esophageal sphincter (LES) relaxes to allow the material to enter the stomach. Achalasia is a motility disorder caused by reduced numbers of inhibitory ganglion cells in the esophageal wall, which creates an imbalance favoring excitatory ganglion cells. This patient's esophageal manometry shows typical findings in achalasia, including normal contraction of the upper esophageal sphincter, decreased amplitude of peristalsis in the mid esophagus, and increased tone and incomplete relaxation at the LES. Patients experience dysphagia, regurgitation, and retrosternal chest pain. Barium esophagram typically shows dilation of the esophagus with distal narrowing.
A 36-year-old woman with fistulizing perianal Crohn disease comes to the office for a follow-up appointment. Eight weeks ago, the patient began receiving intermittent injections of infliximab, a chimeric human-mouse monoclonal antibody targeted against tumor necrosis factor-alpha. She reports improvement in fistula discharge and discomfort but has experienced fever, diffuse joint pain, and an itchy rash 5-7 days after each of the recent treatments. The symptoms spontaneously resolve after 2-3 days. The patient has no other medical conditions and has no history of drug allergies. A delayed drug reaction due to formation of antibodies against foreign drug components is suspected. Which of the following mechanisms is most likely responsible for resolution of these drug reactions?
Activation of the mononuclear phagocyte system - Chimeric monoclonal antibodies such as infliximab contain amino acid sequences from human and non-human (eg, mice) sources. These proteins are processed by antigen presenting cells, displayed on class II major histocompatibility complexes, and the nonhuman components are recognized as foreign by patrolling CD4 cells. The CD4 cells then stimulate activated B-cells to undergo somatic hypermutation and class switching, which generates plasma cells that secrete high-affinity IgG antibodies against foreign components of the drug. With subsequent infusions, the foreign proteins in the medication trigger memory B cells to differentiate into plasma cells, which generate a burst of IgG against the monoclonal antibody. Binding of the IgG to the medication generates immune complexes (ICs), which are then cleared by mononuclear phagocytes in the reticuloendothelial system, as follows: Classic complement activation: The Fc portion of the bound IgG activates the classical complement system, leading to the generation of C3b on the IC. C3b binds to CR1 on erythrocytes/leukocytes, which bring the IC to reticuloendothelial mononuclear phagocytes (eg, Kupffer cells, splenic macrophages) for clearance. Direct removal: Mononuclear phagocytes bind to the Fc portion of the bound IgG using their Fc receptor (CD16) and remove the IC from the circulation. IC clearance generally proceeds without issue, but significant quantities of ICs can saturate the phagocytic system and lead to IC aggregation; IC aggregates can deposit in tissue (eg, skin, joints), where persistent complement activation can result in a type III hypersensitivity reaction called serum sickness. This is typically marked by fever, urticarial rash, and joint pain 5-14 days after exposure. Most cases resolve spontaneously over days as mononuclear phagocytes continue to remove the excess ICs.
As part of an experiment, healthy volunteers undergo a 12-hour fast and then drink a solution containing radiolabeled alanine. Consecutive blood samples are drawn every 15 minutes for the next 3 hours. Initial blood samples detect the radiolabeled alanine, but analysis of later samples shows that the radiotracer is present in blood primarily in the form of glucose. Before alanine can be converted to glucose, its amino group is transferred to which of the following?
α-Ketoglutarate - Alanine and glutamine play an important role in transporting nitrogen throughout the body. Glutamine is produced by most body tissues and is catabolized primarily by the gut and kidney for maintenance of cellular metabolism and acid-base regulation, respectively. A significant portion of the glutamine used by these tissues is converted to alanine and released into the circulation. Alanine is also released by skeletal muscle tissue during protein catabolism as part of the glucose-alanine cycle that helps remove excess nitrogen. Alanine is then transported to the liver, where it serves as a vehicle for nitrogen disposal and as a source of carbon skeletons for gluconeogenesis. In the liver, alanine is transaminated by alanine aminotransferase to pyruvate with the amino group being transferred to α-ketoglutarate to form glutamate. Almost all aminotransferase enzymes use α-ketoglutarate as the amino group acceptor. Thus, amino groups are funneled into glutamate during protein catabolism. Glutamate is further metabolized by the enzyme glutamate dehydrogenase, which liberates free ammonia and regenerates α-ketoglutarate. Ammonia then enters the urea cycle to form urea, the primary disposal form of nitrogen in humans. Urea subsequently enters the blood and is excreted in the urine.
A 44-year-old man is brought to the emergency department after police officers found him agitated and confused. During transport to the hospital, he is started on intravenous fluids with dextrose. On arrival, the patient is disoriented but cooperative. Physical examination shows bruises on the forehead, forearms, and shins. Extraocular findings include bilateral horizontal nystagmus and impaired lateral eye movements; however, the ambulance personnel state that the patient's extraocular movements were normal when they arrived on the scene. The patient also has an unsteady gait with widely spaced legs and short steps. Review of the medical record shows that he has been admitted to the hospital with alcohol intoxication several times before. This patient's neurologic findings are most likely related to deficiency of a cofactor required for which of the following reactions?
α-Ketoglutarate --> Succinyl-CoA - This patient's multiple previous hospitalizations for alcohol intoxication and easy bruising are indicative of chronic alcohol use. Patients with this condition are frequently deficient in thiamine, a necessary cofactor for several enzymes involved in glucose metabolism, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase. The administration of glucose to thiamine-deficient patients can rapidly deplete the small amount of circulating thiamine. This can result in neuronal injury within highly metabolic brain regions, leading to the classic triad of acute Wernicke encephalopathy seen in this patient: Encephalopathy (eg, confusion) Oculomotor dysfunction (eg, horizontal nystagmus) Ataxia (eg, unsteady gait)
A 54-year-old man comes to the emergency department due to worsening shortness of breath for the last 3 days. His symptoms initially occurred with exertion but are now present at rest. The patient could not sleep last night because of a suffocating cough each time he tried to lie down. He considers himself generally healthy and states, "I've never had to see a doctor for any problems." Family history is remarkable for asthma and hypertension. Blood pressure is 162/86 mm Hg, pulse is 92/min, and respirations are 26/min. An x-ray of the chest is shown in the exhibit. Which of the following is the most likely diagnosis?
Acute decompensated heart failure - This patient has progressive dyspnea and orthopnea (cough when lying down), along with chest x-ray findings of prominent pulmonary vessels, patchy bilateral airspace opacities, blunting of the costophrenic angles (pleural effusions), and a fissure sign (created by fluid trapped between the right upper and middle lobe). These findings are consistent with acute decompensated heart failure (ADHF); chronic hypertension is a common cause of heart failure due to concentric left ventricular hypertrophy and resulting diastolic dysfunction. In ADHF, increased atrial and ventricular filling pressures are transmitted to the pulmonary vasculature, causing fluid transudation into pulmonary interstitial and alveolar spaces (cardiogenic pulmonary edema). The chest x-ray may also show Kerley B lines—short, horizontal lines perpendicular to the pleural surface that represent edema of the interlobular septa. Cardiomegaly (cardiac-to-thoracic width ratio >50%) is also common in heart failure, but it is difficult to assess on anteroposterior view due to magnification of the heart.
A 40-year-old woman is evaluated for intermittent headaches, insomnia, diaphoresis, and unintentional weight loss over the past several months. The patient has no other medical problems and takes no medications. She does not use tobacco, alcohol, or illicit drugs and has no significant family history. The patient is found to have a neoplastic mass producing excessive amounts of hormones that are causing her symptoms. Surgical resection of the abnormal tissue is performed with no operative complications. Microscopic examination of the tumor cells shows electron-dense, membrane-bound secretory granules. Immunohistochemistry is positive for synaptophysin, chromogranin, and neuron-specific enolase. The abnormal tissue most likely originated from which of the following?
Adrenal medulla - Pheochromocytoma is a tumor of the chromaffin cells of the adrenal medulla characterized by excess production of catecholamines (norepinephrine, epinephrine, dopamine). Fluctuating catecholamine release results in increased vascular tone and hypertension, often associated with episodic headache, diaphoresis, and palpitations. The diagnosis is confirmed by detecting elevated levels of urinary and plasma catecholamines and metanephrines (catecholamine breakdown products). Histopathology shows a highly vascular tumor with nests of spindle-shaped or polygonal cells. The neurohormonal character of the cells is confirmed with stains for synaptophysin, chromogranin, and neuron-specific enolase, and electron microscopy may show dense membrane-bound granules containing catecholamines.
Physiologists are studying the forces governing glomerular ultrafiltration using a single nephron in an intact kidney of an experimental animal. Hydrostatic pressure in the glomerular capillary and Bowman space is measured using micropipette transducers. Colloid osmotic pressure in the glomerular capillary is estimated using the difference in plasma protein concentration in the afferent and efferent arterioles. The glomerular surface is assumed to be functionally intact with negligible filtration of plasma proteins into the Bowman space. From the data obtained, net filtration pressure is calculated at 10 mm Hg. A substance is instilled into the renal artery, and measurements are repeated. The net filtration pressure after the intervention is 20 mm Hg. Which of the following substances was most likely used in this experiment?
Angiotensin II agonist - The net filtration pressure is a result of pressure gradients formed by Starling forces and is calculated by subtracting the oncotic pressure gradient from the hydrostatic pressure gradient (ie, net filtration pressure = [Pc − Pi] − [πc − πi]): The hydrostatic pressure gradient (Pc − Pi) is the difference between the hydrostatic pressure in the intraglomerular capillaries and Bowman's space. Hydrostatic pressure in the capillaries is higher than in Bowman's space, and provides the driving force for fluid efflux from the capillaries. The oncotic pressure gradient (πc − πi) is the difference between the oncotic pressure in the intraglomerular capillaries and Bowman's space. Oncotic pressure is driven chiefly by large plasma proteins (eg, albumin), which do not freely filter across the glomerular capillary basement membrane due to both a size and a charge barrier. The high oncotic pressure in the capillaries counteracts the capillary hydrostatic pressure and decreases net fluid efflux from the capillaries. This patient's net filtration pressure has increased from 10 to 20 mm Hg after infusion of a substance. Increased net filtration pressure occurs due to either an increase in the hydrostatic pressure gradient or a decrease in the oncotic pressure gradient. Of the available options, only an angiotensin II agonist would increase the net filtration pressure. Angiotensin II preferentially constricts the efferent arteriole, resulting in an increased hydrostatic pressure gradient and increased net filtration pressure.
A 23-year-old woman comes to the emergency department due to right wrist pain after a fall. The patient fell onto her outstretched hand while walking across the floor at a gym where she exercises regularly. She has no significant medical history and takes no medications. The patient says she has tried several diets to lose weight and is currently consuming a vegan diet. Her last menstrual period was 3 months ago. She does not use tobacco, alcohol, or illicit drugs. Temperature is 36.1 C (97 F), blood pressure is 90/58 mm Hg, and pulse is 50/min. BMI is 18.3 kg/m2. Weight is 50 kg (110.2 lb) and height is 165 cm (5 ft 5 in). Physical examination shows tenderness and swelling over the distal radius. The parotid glands are enlarged and there are fine, soft hairs on her extremities. Urine pregnancy test is negative. X-rays reveal a nondisplaced fracture of the right distal radius and generalized radiolucency of the bone. Which of the following is the most likely diagnosis?
Anorexia nervosa - This patient has a fragility fracture (ie, fracture due to low-energy trauma) and radiolucency of bone on x-ray, suggesting osteoporosis. In light of her restricted diet, thin body habitus, and cessation of menses, this is likely due to a low-estrogen state and functional hypothalamic amenorrhea (excessive exercise or weight loss suppresses secretion of GnRH, leading to decreased release of FSH and low estrogen levels). She also has vital sign abnormalities (eg, bradycardia, low body temperature) and lanugo (ie, fine, downy body hair) that together raise suspicion for anorexia nervosa (AN). AN is characterized by restriction of energy intake below that needed to maintain normal body weight (BMI typically <18.5 kg/m2), leading to an emaciated body habitus and clinical features of starvation. Patients with AN have a distorted body image and an intense fear of gaining weight or becoming fat. Common behaviors include excessive caloric restriction, intensive exercise, and binge eating/purging (eg, self-induced vomiting, misuse of laxatives or diuretics).
A 44-year-old man who was recently diagnosed with idiopathic membranous nephropathy after developing edema comes to the office due to a sudden onset of left flank pain and gross hematuria. The patient has no other medical problems. He is taking furosemide and ramipril. Blood pressure is 135/85 mm Hg and pulse is 88/min. On examination, there is left flank tenderness. The patient's edema has improved from the previous visit. There is a left-sided varicocele that the patient has not noticed before. Urinalysis shows increased proteinuria and new hematuria. Serum lactate dehydrogenase is elevated. Urinary loss of which of the following substances most likely predisposed this patient to his acute condition?
Antithrombin III - This patient with membranous nephropathy, flank pain, hematuria, and left varicocele likely has renal vein thrombosis (RVT) as a result of nephrotic syndrome. Due to increased glomerular capillary wall permeability in nephrotic syndrome, many important substances are lost in the urine, causing a number of complications. Loss of anticoagulant factors, especially antithrombin III, leads to a hypercoagulable state, of which RVT can be a manifestation. Patients with RVT can develop sudden-onset abdominal or flank pain and gross hematuria with elevated lactate dehydrogenase as a result of renal infarction. Left-sided varicoceles are relatively common in healthy pubertal men as the aorta and superior mesenteric artery can compress the left renal vein ("nutcracker effect"), resulting in increased intravascular pressure in the left gonadal vein with retrograde blood flow and varicocele formation. However, a new-onset left varicocele associated with ipsilateral flank pain and hematuria should raise suspicion for RVT causing impaired left gonadal venous drainage.
A 56-year-old construction worker comes to the office after receiving a letter from his employer advising him of significant exposure to asbestos during a building project 25 years ago. He is currently asymptomatic and feels well. Medical conditions include hypertension and osteoarthritis, for which he takes amlodipine daily and ibuprofen as needed. The patient quit smoking 10 years ago and does not use alcohol or illicit drugs. Physical examination is within normal limits. Chest imaging is normal. He is concerned about his risk of developing cancer. Due to his occupational exposure, this patient is at greatest risk of malignancy arising from which of the following?
Bronchial epithelium -Asbestos is a fiber composed of hydrated magnesium silicates commonly used in the shipbuilding, construction, and textile industries. Inhalation of fine asbestos fibers causes epithelial cell injury, activation of macrophages, and chronic interstitial inflammation and fibrosis. The major clinical manifestations of asbestos exposure include the following: Pleural disease includes pleural effusions and pleural plaques. Pleural plaques are a hallmark of asbestos exposure that typically affect the parietal pleura along the lower lungs and diaphragm. The plaques are composed of discrete circumscribed areas of dense collagen that frequently become calcified. Asbestosis is characterized by progressive pulmonary fibrosis that is most predominant in the lower lobes and by the presence of asbestos bodies (golden-brown beaded rods with translucent centers). Bronchogenic carcinoma is the most common malignancy associated with asbestos exposure. Smoking and asbestos exposure have a synergistic effect on the development of lung carcinoma, increasing the risk from 6-fold in nonsmoking patients with asbestos exposure to 60-fold in asbestos-exposed patients who smoke regularly. Malignant mesothelioma is a rare malignancy of the pleura for which asbestos is the only known environmental risk factor. It is less common than bronchogenic carcinoma in asbestos-exposed patients. However, mesothelioma is more specific for heavy asbestos exposure.
Atherosclerotic lesions of the coronary arteries can limit blood flow to the myocardial regions supplied by the affected vessels. In some patients, certain medications can cause a redistribution of blood flow away from the ischemic areas, exacerbating existing myocardial ischemia. Which of the following drug effects is most likely to produce this phenomenon?
Coronary arteriolar dilation - Hemodynamically significant atherosclerotic lesions (>70% occlusion) reduce the amount of blood supplied by a coronary vessel to the corresponding myocardial territory. In response, the myocardium releases locally acting, endogenous substances (eg, adenosine, nitric oxide) that cause dilation of coronary arterioles, leading to a downstream reduction in vascular resistance and recruitment of additional blood flow to that region. Arterioles that supply areas of significantly ischemic myocardium can become maximally dilated at rest, limiting their capacity to further increase blood flow. Pharmacologic stress agents (eg, adenosine, dipyridamole) are used during myocardial perfusion imaging to simulate exercise-induced coronary arteriole dilation and assist in identifying areas of ischemic myocardium. Most of the time, administration of these drugs will result in a significant increase in blood flow to nonischemic myocardium and no change in blood flow to ischemic myocardium (because additional blood flow is recruited proximally). In some patients with extensive coronary artery disease, the recruitment of additional upstream blood flow is limited due to proximal atherosclerotic disease (reduced coronary flow reserve). In such a setting, these drugs can cause an absolute decrease in blood flow to ischemic myocardium, as most of the limited blood supply is redirected toward the newly vasodilated areas of nonischemic myocardium. This redistribution of blood flow leading to worsening ischemia is referred to as coronary steal.
A 34-year-old man comes to the office due to progressive low back pain for several years. The patient reports that the stiffness and pain are worst in the morning but gradually improve during the day. Lately, he has been taking over-the-counter ibuprofen, which provides some relief. Laboratory evaluation shows a positive HLA-B27 antigen. X-ray imaging reveals fusion of the sacroiliac joints. Which of the following is most helpful to monitor disease progression in this patient?
Degree of chest expansion - The symptoms of low back pain and morning stiffness in a young man suggest ankylosing spondylitis (AS), a chronic inflammatory condition associated with the HLA-B27 serotype. AS is characterized by stiffness and fusion (ankylosis) of the axial joints. The sacroiliac and apophyseal joints of the spine are the most commonly affected, leading to restricted spinal mobility. Many patients also develop peripheral arthritis and enthesitis, which is defined as pain, tenderness, and swelling at the sites of tendon insertion into bone (eg, Achilles tendon insertion). In addition, AS can cause complications in extraskeletal systems: Respiratory: Involvement of the thoracic spine and enthesopathies of the costovertebral and costosternal junctions can limit chest wall expansion, leading to hypoventilation. Chest expansion should be monitored regularly in patients with AS. Cardiovascular: The most common cardiovascular complication of AS is ascending aortitis, which can lead to dilation of the aortic ring and aortic insufficiency. Eye: Anterior uveitis develops in some patients with AS and presents with pain, blurred vision, photophobia, and conjunctival erythema.
A 16-year-old boy is brought to the emergency department due to severe retrosternal burning pain and odynophagia for the past 12 hours. The patient has had no fever, sore throat, nausea, vomiting, or abdominal pain. Medical history includes nodulocystic acne, for which he began taking oral doxycycline a week ago. Vital signs are within normal limits. Physical examination shows a normal oropharynx, clear lungs, normal heart sounds, and a nontender abdomen. Upper gastrointestinal endoscopy reveals a small, punched-out ulcer in the proximal esophagus and normal-appearing gastroduodenal mucosa. Doxycycline is presumed to be the culprit. This medication most likely led to this patient's current condition through which of the following mechanisms?
Drug-induced direct mucosal injury - Pill esophagitis occurs when caustic medications come in contact with the esophageal mucosa for a prolonged time, leading to direct mucosal injury. Common culprits include tetracyclines (eg, doxycycline), bisphosphonates (eg, alendronate), potassium chloride, and nonsteroidal anti-inflammatory drugs. This complication usually develops in locations where the esophageal lumen is compressed by other anatomic structures. The aortic arch and carina may impede the movement of pills through the proximal esophagus, whereas the gastroesophageal junction or severe left atrial enlargement can lead to pills lodging in the distal esophagus. Pill esophagitis causes odynophagia and retrosternal chest pain and is usually diagnosed by upper gastrointestinal endoscopy, which reveals discrete ulcerations at the location of medication-induced caustic injury. To avoid this complication, patients should remain upright after swallowing high-risk medications and consume plenty of water to facilitate rapid passage through the esophagus.
A 33-year-old, previously healthy woman comes to the emergency department due to sudden-onset shortness of breath and left-sided chest pain. The symptoms began an hour ago while she was doing yard work, and she nearly passed out at symptom onset. The patient takes no medications or supplements other than ibuprofen for occasional headaches. She does not use tobacco, alcohol, or illicit drugs. Temperature is 37.1 C (98.8 F), blood pressure is 84/58 mm Hg, pulse is 122/min, and respirations are 24/min. Pulse oximetry is 86% on room air. On physical examination, the patient is in moderate distress. The jugular veins are distended. Heart sounds are rapid and regular with no murmurs. Lungs are clear to auscultation bilaterally with no crackles or wheezes. Arterial blood gas results are pH 7.52, PaCO2 28 mm Hg, and PaO2 54 mm Hg. Which of the following is most likely to be seen on bedside echocardiography?
Enlarged right ventricular cavity - This patient most likely has an acute pulmonary embolism (PE). The classic presentation is acute-onset chest pain and shortness of breath that may be accompanied by syncope or near-syncope. Patients usually have tachycardia, tachypnea, jugular venous distension, and clear lungs. Arterial blood gas typically show hypoxemia and acute respiratory alkalosis due to hyperventilation. Up to 30% of cases may present with no apparent risk factors (eg, hypercoagulability). Massive PE can lead to hypotension and obstructive shock. There is a rapid increase in pulmonary arterial resistance that leads to an increase in pulmonary arterial and right ventricular (RV) pressure. The rapid pressure increase causes RV cavity enlargement due to increased RV wall tension and cardiac muscle stretching. RV myocardial oxygen demand increases and coronary artery perfusion decreases, leading to a supply/demand mismatch and RV ischemia. Consequent RV dysfunction then leads to an inability to pump blood through the pulmonary circulation, resulting in decreased left-sided preload and decreased cardiac output. Such RV failure caused by an increase in pulmonary vascular resistance is sometimes called cor pulmonale.
A 58-year-old man comes to the emergency department due to sudden right-sided weakness. He has no sensory loss, problems speaking/swallowing, or difficulty with balance. The patient was previously told that he has elevated blood pressure, but he does not routinely follow up with his physician. He takes no medications. Examination shows intact cranial nerves and sensory function. The patient has 3/5 muscle strength on the right side. Initial CT scan without contrast reveals no abnormalities. Four weeks later, repeat brain imaging shows a 9-mm, fluid-filled cavitary lesion in the left internal capsule. This patient's condition is most likely caused by which of the following?
Hypertensive arteriolar sclerosis - This patient has pure motor hemiparesis and a small cavitary lesion in the internal capsule, characteristic of a lacunar infarct. This type of stroke affects the small penetrating arterioles that supply the deep brain structures (eg, basal ganglia, pons) and subcortical white matter (eg, internal capsule, corona radiata). Lacunar infarcts are primarily associated with chronic hypertension, which promotes lipohyalinosis, microatheroma formation, and hardening/thickening of the vessel wall (hypertensive arteriolar sclerosis). This leads to progressive narrowing of the arteriolar lumen and predisposes to thrombotic vessel occlusion, which causes characteristic clinical syndromes, depending on the portion of the brain affected: Posterior limb of the internal capsule and/or basal pons - pure motor hemiparesis or ataxia-hemiplegia syndrome (ie, ipsilateral limb ataxia out of proportion to motor deficit) Genu/anterior limb of the internal capsule and/or basal pons - dysarthria-clumsy hand syndrome (ie, dysarthria and dysphagia with clumsiness of one hand) Ventroposterolateral or ventroposteromedial thalamus - pure sensory stroke In the acute setting, CT imaging may not reveal the expected hypodensity of ischemic stroke due to the small infarct size (usually <15 mm). After several weeks, these necrotic lesions turn into cavitary spaces filled with cerebrospinal fluid and surrounded by scar tissue called lacunas.
A 60-year-old woman is being evaluated for abnormal renal function. She is found to have a serum creatinine of 2.2 mg/dL on routine laboratory monitoring; her creatinine level a year ago was 1.2 mg/dL. The patient has a history of nonischemic cardiomyopathy and systolic heart failure and has been on a stable medical regimen for the past 2 years. She has no dyspnea, fever, rash, or lower extremity swelling but has been taking ibuprofen for 2 weeks due to left knee osteoarthritis. Urinalysis reveals the following: Protein none White blood cells none Red blood cells none Sediment none Ibuprofen is discontinued, and her kidney function returns to normal in a week. Which of the following best explains this patient's transient deterioration in renal function?
Impaired afferent arteriolar vasodilation - This patient developed acute kidney injury after taking ibuprofen. Nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen, aspirin, naproxen) exert their anti-inflammatory, analgesic, and antipyretic effects through the inhibition of the cyclooxygenase enzymes. These enzymes are the rate-limiting step in the formation of prostanoids (ie, prostaglandins, thromboxane), which are involved in mediating pain and inflammation. Prostaglandins also help maintain renal perfusion by dilating the afferent arteriole, particularly in patients with intravascular volume depletion (eg, congestive heart failure, diarrhea, excessive diuresis) or chronic kidney disease. In such patients, increased prostaglandin synthesis is necessary to preserve renal blood flow and maintain glomerular filtration rate. In at-risk patients, inhibition of afferent dilation with NSAIDs results in reduced glomerular filtration and prerenal azotemia with elevations in creatinine and blood urea nitrogen (ratio >20:1). NSAID-induced acute kidney injury is often diagnosed incidentally on laboratory tests performed for other reasons, and patients are generally asymptomatic. Urinalysis is typically bland without proteinuria, hematuria, or casts. Prolonged NSAID use can cause chronic kidney disease (analgesic nephropathy) due to papillary necrosis and chronic interstitial nephritis.
A 43-year-old man visiting the United States from Thailand comes to the emergency department due to 10 days of hemoptysis. He also has had night sweats but reports no fever or weight loss. Temperature is 37.7 C (99.9 F), blood pressure is 118/68 mm Hg, pulse is 86/min, and respirations are 18/min. Physical examination shows right-sided rhonchi and crackles. Chest x-ray shows an infiltrate in the right upper lobe. Sputum samples from 3 consecutive days are also obtained. After 72 hours of tuberculin skin test (TST) placement, there is no induration at the site; however, 2 of 3 sputum sample smears reveal acid-fast bacilli. Which of the following best explains the negative TST in this patient?
Inadequate lymphocytic response - This patient from Thailand has hemoptysis, night sweats, right upper lobe infiltrate, and positive sputum acid-fast bacillus stain, raising strong suspicion for active pulmonary TB. Tuberculin skin testing (TST) is generally positive in patients with active TB because differentiated lymphocytes recognize injected tuberculin antigens and trigger a strong type IV (cell-mediated) hypersensitivity response, leading to a large wheal of induration within 48-72 hours. However, approximately 25% of patients with active TB have false negative TST (T cell anergy). In these individuals, an impaired lymphocyte response results in minimal or no induration after exposure to tuberculin antigens. Because a weak cell-mediated response increases the risk of severe disseminated TB, patients with active disease who have TST anergy are at much greater risk for TB-related morbidity and mortality. A false-negative TST can also be seen with recent infection (it takes approximately 8 weeks for the cell mediated response to fully form), immunocompromise (eg, HIV), improper injection technique, and natural waning of immunity to latent infection. Because active TB requires a microbial diagnosis (eg, identifying the organism on sputum sample), neither TST nor interferon-gamma release assay can be used to diagnose or exclude the disease.
A group of researchers collected demographic and clinical data from multiple hospitals across the nation to determine epidemiological features of nosocomial bloodstream infections. In this study, a nosocomial bloodstream infection was diagnosed if blood cultures drawn 48 hours after admission yielded a pathogenic organism. Analysis of the data collected over several decades shows that staphylococci are increasingly responsible for the identified cases. An increased use of which of the following is most likely the underlying cause of the observed trend?
Intravascular catheters - Approximately 250,000 nosocomial bloodstream infections (BSIs) are estimated to occur in the United States each year. Prior to the 1980s, the leading cause was gram-negative aerobic organisms such as Escherichia coli that spread from primary infections in the genitourinary or gastrointestinal tract. However, the increasing use of intravascular catheters, which provide a portal of entry for skin flora to reach the bloodstream, has led to a shift in the underlying microbiology of BSI; most cases are now caused by skin commensals such as coagulase-negative staphylococci and Staphylococcus aureus. BSI is most common in those who have long-term (>12 days) central venous access as this provides sufficient time for skin flora to colonize the internal/external lumen of the catheter, to replicate within a biofilm of host (fibrin) and bacterial (glycoprotein) components, and to subsequently spread to the bloodstream. BSI should be suspected when a patient with an intravascular catheter develops new-onset fever or bacteremia.
A 65-year-old hospitalized man is evaluated for decreased urine output and increased serum creatinine. The patient was admitted for 3-vessel coronary artery disease and underwent coronary artery bypass grafting surgery yesterday. Other medical conditions include type 2 diabetes mellitus and hypertension. He received a dose of intravenous vancomycin prior to the surgery for prophylaxis of surgical infection. The patient has also been receiving 100 mL/hour of intravenous normal saline for the past 24 hours. He is afebrile. Blood pressure is 130/80 mm Hg and pulse is 80/min. Examination shows bibasilar crackles. The abdomen is soft. Urine output over the past 6 hours is 100 mL. Laboratory results are as follows: Day of admission Blood urea nitrogen 20 mg/dL Serum creatinine 1.3 mg/dL Today Blood urea nitrogen 35 mg/dL Serum creatinine 2.5 mg/dL Urine sediment microscopy is shown in the exhibit. Which of the following is the most likely cause of this patient's current condition?
Ischemic tubular necrosis - This patient with acute kidney injury has muddy brown casts on urine microscopy; in the setting of recent major surgery this presentation suggests acute tubular necrosis (ATN) due to intraoperative renal ischemia. Surgeries complicated by significant blood loss or those requiring the use of cardiopulmonary bypass (eg, coronary artery bypass grafting) or aortic clamping can cause renal hypoperfusion. The risk is increased in the elderly and those with a history of chronic kidney disease, diabetes, or congestive heart failure. ATN is characterized by the presence of muddy brown granular casts composed of sloughed renal tubular epithelial cells. Patients have increased serum creatinine, blood urea nitrogen/ creatinine ratio <20:1 (indicating intrinsic renal pathology), and oliguria (low urine output). Histologically, flattened tubular epithelial cells with cellular necrosis and loss of the brush border are seen.
A 22-year-old woman comes to the emergency department with fevers and arthralgias. She recently had unprotected sexual intercourse with a new male partner. Her temperature is 38.4 C (101.1 F), blood pressure is 118/76 mm Hg, pulse is 102/min, and respirations are 16/min. Examination shows several pustules on the dorsal aspects of her forearms. Her right wrist and ankle are tender on palpation. Gram-negative bacteria isolated from this patient's blood produce an enzyme that splits the IgA molecule at the hinge region. Which of the following is likely to be the most important role of this bacterial enzyme in the course of the infection?
It facilitates mucosal adherence of bacteria - This patient likely has disseminated gonorrheal infection (triad of arthritis, dermatitis, and tenosynovitis in a sexually active woman) due to Neisseria gonorrhoeae. In mucosal regions as well as in secretions, IgA exists in its secretory form, composed of an IgA dimer (joined by a peptide J chain) and a peptide secretory component. IgA antibodies usually bind to pili and other membrane proteins involved in bacterial adherence to mucosa, thus inhibiting mucosal colonization by the microorganism. Certain bacteria (eg, N gonorrhoeae, N meningitidis, Streptococcus pneumoniae, Haemophilus influenzae) produce IgA proteases that cleave IgA at its hinge region (yielding Fab and compromised Fc fragments), thus decreasing its effectiveness. This facilitates bacterial adherence to mucosa (possibly due to easier bacterial access to mucosal surface or immune disguise by binding to released Fab fragments, among others).
A 43-year-old man is hospitalized due to severe epigastric pain radiating to his back. He does not drink alcohol. Temperature is 37.9 C (100.2 F), blood pressure is 114/68 mm Hg, and pulse is 85/min. BMI is 34 kg/m2. The patient appears restless. Physical examination shows significant epigastric tenderness. Laboratory results are as follows: Serum chemistry Glucose 120 mg/dL Creatinine 1.2 mg/dL Cholesterol 290 mg/dL Triglycerides 1,200 mg/dL Amylase 400 U/L Administration of intravenous fluids and analgesics is begun. In addition, insulin is administered to rapidly reduce the elevated lipid levels. This medication is likely to improve this patient's condition by stimulating which of the following enzymes?
Lipoprotein lipase - This patient has acute pancreatitis presenting with abdominal pain, epigastric tenderness, and an elevated serum amylase level. In addition, he has severe hypertriglyceridemia, which is the likely cause of his pancreatitis. Triglyceride-induced pancreatitis (TIP) is usually seen in patients with triglyceride levels >1,000 mg/dL. The risk is elevated in patients with diabetes mellitus, obesity, or excessive alcohol use. TIP is initiated by impaired blood flow in pancreatic capillaries due to excessive concentrations of chylomicrons and VLDL particles. The resulting tissue ischemia releases pancreatic lipases into the plasma, hydrolyzing triglycerides to yield very high local concentrations of inflammatory free fatty acids. Management of TIP requires rapid lowering of triglyceride levels, often with an insulin infusion. Insulin upregulates lipoprotein lipase, which hydrolyzes triglycerides in chylomicrons and VLDL; the liberated fatty acids are largely taken up and esterified in adipose tissue, and plasma triglyceride levels are lowered. In addition, insulin reduces the activity of hormone-sensitive lipase in adipose tissue, suppressing the release of fatty acids.
A 38-year-old man is evaluated for bloody stools, weight loss, and anemia. The patient's past medical history is unremarkable, and he does not take any medications. He uses tobacco and drinks alcohol "socially." The patient's father died of colon cancer at age 40. His younger sister suffers from endometrial cancer. Examination is remarkable for minimal right-sided abdominal tenderness without guarding to deep palpation. Stool is positive for occult blood. Colonoscopy shows a right-sided ulcerative colon mass. No polyps are noted. Biopsy of the mass reveals adenocarcinoma. A mutation in which of the following genes is most likely responsible for this patient's condition?
MSH2 - This case is typical of hereditary nonpolyposis colon cancer (HNPCC), or Lynch syndrome, an autosomal dominant genetic predisposition to colon cancer. In patients with HNPCC, colon cancer occurs at a young age (age <50). Family history reveals a high incidence of colon cancer and, occasionally, extraintestinal (eg, endometrial) cancers in first-degree relatives. With HNPCC, there is an inherited mutation in one of the genes responsible for DNA mismatch repair (eg, MSH2, MLH1). The products of these genes proofread DNA during replication. Patients with HNPCC inherit a mutation in an allele, and mutation of the second allele occurs during adult life. When 2 dysfunctional copies are present, malignancies will develop readily.
A 48-year-old woman comes to the emergency department due to back pain after minor trauma. She has no leg weakness or numbness. Review of systems is positive for recent-onset hot flashes and irregular menses; her most recent menstruation was 2 weeks ago. The patient has a long history of hypothyroidism treated with levothyroxine and rheumatoid arthritis treated with methotrexate. She has also taken oral prednisone for frequent symptom flares. The patient does not use tobacco, alcohol, or illicit drugs, and she consumes a balanced diet. Physical examination shows point tenderness over the midthoracic spine. The straight-leg raising test is negative, and neurologic examination of the lower extremities shows no abnormalities. Spine imaging is shown. Which of the following contributed most to this patient's current condition?
Medication adverse effect - This patient has a fragility fracture of a thoracic vertebra (ie, fracture due to a force significantly less than that required to fracture a normal bone). A fragility fracture suggests underlying bone pathology, often due to metastatic malignancy or intrinsic bone disease. In this patient, who has had frequent exposure to systemic glucocorticoids (eg, prednisone), this likely represents osteoporosis. Chronic or recurrent glucocorticoid use, as is occasionally needed for patients with rheumatoid arthritis, is associated with an increased risk for osteoporosis. Osteoporosis can also occur due to systemic absorption of topical glucocorticoids (eg, inhaled glucocorticoids used in the treatment of asthma). Glucocorticoids promote osteoporosis by inhibiting proliferation and differentiation of osteoblast precursor cells, promoting osteoclast differentiation and activity, and suppressing intestinal calcium absorption and renal calcium reabsorption.
A 17-year-old boy is brought to the office due to occasional blood in the urine. The first episode occurred 1 year ago during a flulike illness, and resolved spontaneously. The patient had a similar episode about 6 months ago, which also seemed to resolve. He has no other medical conditions and does not use tobacco or alcohol. There is no history of blood or kidney disorders in the family. Vital signs are normal. On laboratory evaluation, blood urea nitrogen level is 14 mg/dL and creatinine is 0.8 mg/dL. Urinalysis results are as follows: Specific gravity 1.013 Protein +2 Blood trace Glucose negative Ketones negative Leukocyte esterase negative Nitrites negative White blood cells 1-2/hpf Red blood cells 20-30/hpf A renal biopsy is performed. Which of the following findings is most likely to be seen on microscopic evaluation?
Mesangial deposition of IgA - This patient likely has IgA nephropathy (Berger disease), the most common cause of glomerulonephritis. It typically affects older children and young adults and presents with painless hematuria that is often accompanied by an upper respiratory tract infection. The hematuria lasts for several days and then subsides temporarily, returning every few months or with another upper respiratory infection (synpharyngitic hematuria). Complement levels are usually normal. Renal biopsy will show mesangial hypercellularity with mesangial IgA deposits seen by immunofluorescence.When IgA nephropathy is accompanied by extrarenal symptoms (eg, abdominal pain, arthralgias, purpuric skin lesions), the syndrome is called Henoch-Schönlein purpura.
A 56-year-old woman is brought to the emergency department after a generalized tonic-clonic seizure witnessed by her husband. The patient has no history of seizures or other medical conditions but has been having recurrent headaches for the past several months. Physical examination shows mild weakness with increased deep tendon reflexes in the left upper extremity. MR imaging of the brain reveals a large mass in the right frontal lobe. Stereotactic biopsy of the mass yields hypercellular white matter with extensive astrocytic aberration, microvascular proliferation, and areas of necrosis lined by tumor cells. Molecular studies of the abnormal cells are most likely to demonstrate which of the following findings?
Overexpression of epidermal growth factor receptor - This patient's seizure, headache, motor weakness, and brain mass composed of abnormal astrocytes with necrosis and microvascular proliferation raises strong suspicion for glioblastoma (GBM), a highly aggressive tumor that stems from glial or pluripotent neural stem cells. A number of characteristic oncogenic mutations are usually present in GBM, but >95% of cases are associated with the overexpression of epidermal growth factor receptor (EGFR) on the surface of neoplastic cells. EGFR is a tyrosine-kinase signal transduction system that conducts external growth signals into the nucleus, thereby promoting cellular survival and proliferation. Mutations that enhance this pathway (eg, overexpression of EGFR or EGFR-ligand) are associated with uncontrolled cellular proliferation and are seen in GBM and other cancer types (eg, non-small cell lung cancer, breast cancer, prostate cancer). Therefore, drugs that inhibit the EGFR/EGFR-ligand interaction (eg, erlotinib) are often used as part of treatment.
A 61-year-old woman comes to the office due to a neck lump. She is otherwise in good health and has no other symptoms. Temperature is 36.7 C (98.1 F), blood pressure is 115/70 mm Hg, and pulse is 78/min. On physical examination, there is a nontender, firm nodule in the left lobe of the thyroid. Laboratory results show a normal serum TSH level. Thyroid ultrasonography reveals a 2-cm, hypoechoic thyroid nodule with increased central blood flow. Fine-needle aspiration biopsy shows clusters of cells with large, overlapping nuclei containing finely dispersed chromatin. Numerous intranuclear inclusion bodies and grooves are also seen. Which of the following is the most likely diagnosis?
Papillary carcinoma - The 4 main types of primary thyroid carcinoma include papillary, follicular, medullary (derived from the parafollicular, calcitonin-secreting C cells), and anaplastic. The papillary type is most common, accounting for >70% of cases. Risk factors include a positive family history of thyroid cancer and radiation exposure, especially in childhood. Papillary carcinoma cells are characteristically large with overlapping nuclei containing finely dispersed chromatin, giving them an empty or ground-glass appearance (sometimes termed Orphan Annie eye nuclei after a cartoon character whose eyes were drawn without pupils or irises). Numerous nuclear grooves as well as intranuclear inclusions composed of cytoplasm (ie, pseudoinclusions) can be seen due to invagination of the nuclear membrane. Psammoma bodies (laminated calcium deposits) may also be found within the tumor.
An outbreak of diarrheal illness occurs in a community after a massive hurricane. The affected patients experience voluminous, watery diarrhea that quickly leads to severe dehydration. Stool examinations of these patients yield oxidase-positive, curved, highly motile, gram-negative rods. Epidemiologic study reveals the source as a contaminated water supply. Which of the following patient populations would be most susceptible to developing this illness?
Patients taking proton pump inhibitors - Vibrio cholerae is a comma-shaped, oxidase-positive, highly motile, gram-negative rod that is acquired after ingesting contaminated food or water. The infection is not invasive and does not disseminate outside of the gastrointestinal tract. However, the elaboration of the cholera enterotoxin leads to severe, watery diarrhea that can cause death from electrolyte imbalance and dehydration within 12 hours of symptom onset. Cholera is endemic in southern Asia and parts of Africa and Latin America, where seasonal outbreaks are common (peaks occur prior to and after rainy seasons). In the United States, the disease is rare and occurs mainly in patients who ingest contaminated seafood from the Gulf Coast. V cholerae must survive the acidic environment of the stomach to reach the small intestine and cause disease. Because the organism is very acid-sensitive, a high burden of V cholerae is generally required to cause clinical symptoms (>1010 organisms from contaminated water or >106 organisms from contaminated food). However, those with inadequate gastric acid production (achlorhydria) can develop the disease with much smaller infectious doses as there is insufficient acid to kill the bacteria. Patients on long-term proton pump inhibitor therapy (eg, omeprazole) have pharmacologically induced achlorhydria; it can also be seen in those with gastritis.
A group of investigators is studying the regulation of catecholamine synthesis in response to severe stress. In the experiments, subject rats are randomly assigned to either an experimental or a control group. The experimental rats undergo resection of the pituitary gland, and the control rats undergo craniotomy without pituitary resection. The experimental animals are subsequently found to have decreased production of epinephrine by the adrenal medulla and cortisol from the adrenal cortex compared with the control animals. Decreased activity of which of the following enzymes is most likely responsible for the lower epinephrine in the experimental animals?
Phenylethanolamine-N-methyltransferase - The 3 main circulating catecholamines are dopamine, norepinephrine, and epinephrine. Norepinephrine and dopamine are produced in the central as well as the peripheral nervous system, whereas epinephrine is predominantly produced in the adrenal medulla. The first step in the synthesis of catecholamines is the conversion of tyrosine to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. This is the rate-limiting step in the synthesis of catecholamines. DOPA is converted to dopamine by dopa decarboxylase, which is then converted to norepinephrine by dopamine beta-hydroxylase. In the adrenal medulla, norepinephrine is rapidly converted to epinephrine by phenylethanolamine-N-methyltransferase (PNMT). Expression of PNMT in the adrenal medulla is upregulated by cortisol. Because the venous drainage of the adrenal cortex passes through the adrenal medulla, cortisol concentrations in the medulla can be very high, and PNMT is expressed at a high level. However, following pituitary resection, the loss of ACTH leads to decreased synthesis of cortisol in the adrenal cortex. The result is decreased PNMT activity and reduced conversion of norepinephrine to epinephrine.
A 26-year-old woman is evaluated for joint pain affecting the elbows, knees, and ankles for the past month. She has also experienced a dry cough and mild shortness of breath over the last 6 months. She is sexually active and takes oral contraceptives. Temperature is 37.2 C (99 F), blood pressure is 120/70 mm Hg, pulse is 84/min, and respirations are 16/min. On physical examination, the lungs are clear to auscultation. There is mild swelling and tenderness of the elbows, knees, and ankles. The lower extremities are tender to palpation and have scattered erythematous nodules. Chest x-ray reveals lung nodules and hilar fullness. Transbronchial biopsy shows large epithelioid cells, occasional giant cells, and no areas of necrosis. Which of the following pharmacotherapies is most appropriate for the initial treatment of this patient?
Prednisone - This young patient has arthralgias, dyspnea, cough, and erythema nodosum (tender, subcutaneous, lower extremity nodules). This, in conjunction with lung nodules and hilar fullness on x-ray, is highly suggestive of sarcoidosis, an inflammatory disease characterized by granuloma formation in multiple tissues. Diagnosis is confirmed by biopsy showing noncaseating granulomas composed of epithelioid cells (activated macrophages) and giant multinucleated cells without central necrosis. Typical manifestations include hilar adenopathy, pulmonary infiltrates (eg, nodules, interstitial lung disease), skin (eg, erythema nodosum) and ocular (eg, anterior uveitis) involvement, polyarthritis, and constitutional symptoms (eg, fatigue, weight loss). Many patients with sarcoidosis do not require treatment; however, those with significant symptoms (eg, dyspnea, chest pain) or progressive pulmonary disease (ie, worsening opacities/fibrosis or pulmonary function tests) should be treated. Oral glucocorticoids (eg, prednisone) are the initial treatment of choice.
Researchers are studying treatment of osteoporotic fractures. Subjects with pelvic fractures due to osteoporosis are divided into 2 groups. The control group receives physical therapy along with calcium and vitamin D supplementation. The experimental group receives a parathyroid hormone analogue in addition to the standard therapy. It is found that the subjects who receive hormonal treatment have a shorter time to fracture healing and improved functional outcome. The benefits of the investigational medication are attributed to increased osteoblastic activity. An elevated level of which of the following markers is most likely to reflect the medication effect in these subjects?
Serum alkaline phosphatase - Bone is continually broken down and reformed by the process known as bone remodeling, which consists of the coordinated activity of osteoblasts (responsible for bone formation) and osteoclasts (responsible for bone resorption). The subjects in this study are receiving a recombinant parathyroid hormone analog (eg, teriparatide), which promotes bone formation by stimulating maturation of pre-osteoblasts into osteoblasts. Osteoblasts synthesize bone matrix and express alkaline phosphatase (AlkP), which promotes normal bone mineralization by increasing local concentrations of inorganic phosphorus. Serum AlkP levels correlate with osteoblastic activity. However, total serum levels are nonspecific, as AlkP is also produced by the hepatobiliary tree, intestine, and placenta and may be elevated due to other causes (eg, pregnancy, biliary obstruction). If the source of AlkP is uncertain, AlkP isoenzymes (ie, liver, placental, intestinal, bone) can be differentiated with additional laboratory techniques (eg, electrophoresis, immunoassay). Other markers of osteoblast activity include N-terminal propeptide of type 1 procollagen (PINP), which is released during post-translation cleavage of type 1 procollagen before its assembly into mature type 1 collagen fibrils.
An 87-year-old woman comes to the office to discuss treatment for colon cancer, which was recently diagnosed by colonoscopy. CT scan was negative for metastatic disease. The patient has no other medical conditions, and family history is unremarkable. She does not drink alcohol. Vital signs are normal. A chemotherapy regimen containing a medication that is primarily metabolized by the liver is chosen for therapy. Because of the patient's age, the physician is considering adjusting the dose to prevent adverse effects. Which of the following parameters is likely to be the most similar between this patient and a healthy 40-year-old individual?
Serum aminotransferase levels - A number of age-related changes take place in the liver that impair its ability to metabolize drugs. These changes place elderly individuals, such as this patient, at higher risk for drug-related toxicity. Normal age-related changes include the following: Decreased liver mass, which is largely explained by the decrease in hepatic blood flow that occurs with aging, can impair metabolism because the liver is unable to take up as much drug from the systemic circulation as it once could. Decreased cytochrome P-450 expression and concentration slows the rate of hepatic metabolism of numerous drugs (eg, some antineoplastic agents). Reduced rate of hepatic regeneration impairs the liver's ability to recover after injury. Although the liver's metabolic capabilities generally decline with age, aminotransferase levels are unchanged in healthy elderly individuals. Elevations in liver enzymes should therefore raise suspicion for undiagnosed hepatic disease or hepatotoxin exposure. Small variations may be seen in bilirubin, alkaline phosphatase, and gamma-glutamyltransferase levels, but they are generally minimal.
Membrane potential changes in an isolated cardiac muscle cell are recorded along with ion movements across the cell membrane. Which of the following ion sequences corresponds to the regions 1, 2, and 3 of the graph?
Sodium, calcium, potassium - The action potential of ventricular and non-nodal conduction cells within the heart consists of four phases. Phase 4: Resting potential (diastole). Resting potential is determined largely by membrane permeability to K+ ions when in the resting state. The resting potential of cardiac myocytes is approximately -90mV, while the resting potential of skeletal myocytes is approximately -75mV. The highly negative resting potential of cardiac myocytes reduces the risk of arrhythmias, as a larger stimulus is needed to excite the cells. Phase 0: Rapid depolarization. As in skeletal myocytes, the action potential onset occurs when voltage-gated Na+ channels open and Na+ ions rush into the cell. Phase 1: Initial rapid repolarization. This phase is associated with the rapid closure of Na+ channels. Phase 2: Plateau. This phase is a distinctive feature of the cardiac action potential not seen in other tissues. It is characterized by the opening of L-type dihydropyridine-sensitive Ca++ channels and the closure of some K+ channels. Consequently, the membrane becomes highly permeable to Ca++ ions and minimally permeable to K+ ions. Phase 3: Late rapid repolarization. This phase features closure of Ca++ channels and the opening of K+ channels. Efflux of K+ from the cell restores the membrane resting potential. In sum, the cardiac myocyte action potential includes the following three key events: Na+ ion influx (corresponding to the red curve on the ion conductivity graph); Ca++ ion influx (corresponding to the blue curve on the ion conductivity graph); and decreased K+ permeability during the action potential upstroke (corresponding to the green curve on the ion conductivity graph).
