8/5

What parts of hte brain are damaged in Vit B12 def

damage to the dorsal column of the spinal cord, leading to bilateral loss of position and vibration sensation. This commonly results in gait dysfunction, particularly when the patient's eyes are closed (sensory ataxia) damage to the lateral corticospinal tracts, leading to upper motor neuron signs (eg, spastic paresis) and positive Babinski sign axonal degeneration of theperipheral nerves, leading to numbness, paresthesia, and depressed motor reflexes The spinal cord damage seen with vitamin B12 deficiency is called subacute combined degeneration; "combined" refers to the degeneration of ascending pathways (dorsal columns) and descending pathways (corticospinal tract).

Flame shaped hemorrhages

hypertensive retinopathy

A 59-year-old man comes to the office due to 3 months of progressive fatigue and back pain. The back pain occurs mainly with movement or positional changes. Physical examination reveals midline tenderness over the middle and lower back. Laboratory evaluation shows a hemoglobin level of 10.2 g/dL and serum calcium level of 12 mg/dL. A bone marrow aspirate is performed, and the histopathologic findings are shown below This patient is at greatest risk for which of the following?

*Amyloidosis* This patient's bone marrow aspirate shows numerous plasma cells, which can be identified by abundant basophilic cytoplasm, well-developed Golgi apparatus (perinuclear paleness), and "clock-face" (peripheral) chromatin. A bone marrow sample with >10% plasma cells is strongly suggestive of multiple myeloma (MM), a clonal plasma cell malignancy. In MM, neoplastic plasma cells: Replicate in the bone marrow and choke out normal hematopoiesis, leading to normocytic, normochromic anemia (impaired erythropoiesis) and increased risk of infection (impaired B-cell lymphopoiesis). Secrete osteolytic cytokines, leading to bone pain, osteolytic (radiolucent) bone lesions, and hypercalcemia. Produce large quantities of monoclonal immunoglobulin (paraprotein) composed of heavy and light chains (eg, IgG, IgA) or light chains alone. Light chains can deposit in the renal tubules, leading to light-chain cast nephropathy, which is usually characterized by mild renal insufficiency and waxy, laminated urinary casts (Bence Jones). Light chains can also form insoluble fibrils and deposit in major organs, leading to amyloid light-chain amyloidosis. This can contribute to the already elevated risk of renal failure as well as heart failure and neurologic dysfunction. Amyloidosis can often be identified on biopsy using hematoxylin and eosin stain (eosinophilic extracellular deposits) or Congo red stain viewed under polarized light (apple-green birefringence).

What medication txs trigeminal neuralgia

*Carbemezepine* This case presents a classic picture of trigeminal neuralgia (tic douloureux). This condition presents with episodes of sudden and severe pain in the distribution of CN V (particularly V2 and V3). The pain is described as "stabbing" or like an "electrical shock"; it is usually unilateral, and does not last more than few seconds; but occurs repeatedly. Pain is triggered by any stimulus to CN V, for example chewing, teeth brushing, shaving or washing an affected area of the face, swallowing, or exposure to hot or cold temperatures. These painful episodes may occur for several months. In the majority of cases, trigeminal neuralgia is not caused by any structural abnormality and its pathogenesis remains unclear. Carbamazepine is the drug of choice for the treatment of trigeminal neuralgia. It is effective in pain reduction in up to 80% of patients. Like phenytoin, it inhibits neuronal high-frequency firing by reducing the ability of sodium channels to recover from inactivation. Carbamazepine can cause aplastic anemia, so CBC should be monitored regularly. Carbamazepine is a P450 inducer that increases the metabolism of many other medications, thereby decreasing their effectiveness.

Their research focuses on the inductive signals exchanged between the metanephric diverticulum and metanephric blastema that drive their differentiation into tissues forming the mature kidney. If a toxic insult occurs during early fetal development that selectively inhibits the renal structures formed by the metanephric blastema, which of the following adult derivatives will fail to develop?

*Distal convoluted tubule* Embryonic kidney development involves the sequential formation of 3 sets of nephric systems termed the pronephros, mesonephros, and metanephros. The urinary structures formed during these stages are derived from the nephrogenic cord which develops from the urogenital ridge (intermediate mesoderm). 1. The pronephros forms first and later completely regresses. 2. The mesonephros forms next from the midportion of the nephrogenic cord. -In males, it persists as the Wolffian ducts, forming the ductus deferens and epididymis. -In females, the mesonephros regresses and becomes vestigial Gartner's ducts. 3. The metanephros forms last from the caudal end of the nephrogenic cord.It gives rise to the glomeruli, Bowman's space, proximal tubules, the loop of Henle, and distal convoluted tubules. Development of the metanephros begins with formation of the metanephric diverticulum (ureteric bud) which penetrates the sacral intermediate mesoderm to induce the formation of the metanephric blastema. The reciprocal exchange of inductive signals between the metanephric diverticulum and metanephric blastema drives their differentiation into the structures that form the mature kidney. The ureteric bud ultimately gives rise to the collecting system of the kidney, including the collecting tubules and ducts, major and minor calyces, renal pelvis, and the ureters Educational objective:The metanephros (metanephric blastema) gives rise to the glomeruli, Bowman's space, proximal tubules, the loop of Henle, and distal convoluted tubules. The ureteric bud becomes the collecting system of the kidney, including the collecting tubules and ducts, major and minor calyces, renal pelvis, and the ureters.

The patient is started on a new antiepileptic medication that selectively blocks voltage-gated calcium channels. This medication most likely affects which of the following steps of neurotransmission?

*Fusion and release of neurotransmitter vesicles Neurons communicate with each other via synapses, regions where the axon terminal of a presynaptic neuron transmits chemical signals to the dendrites of a postsynaptic neuron. Binding of an excitatory neurotransmitter (eg, glutamate) to a postsynaptic neuron causes opening of ligand-gated sodium channels, leading to sodium influx and membrane depolarization. This depolarization impulse is transmitted from the dendrites through the cell body to the axon hillock, which contains a large number of voltage-gated sodium channels. Once the axon hillock becomes sufficiently depolarized, an action potential is triggered and propagates along the axon via a steady influx of sodium ions. When the action potential reaches the axon terminal, voltage-gated calcium channels open and allow the influx of calcium, which is essential for the fusion and release of neurotransmitter vesicles into the synaptic cleft. Seizures occur due to abnormal, synchronized firing of hyperexcitable neurons in the brain, and many antiepileptic medications work by modifying electrochemical transmission between neurons. Gabapentin is an anticonvulsant that works by inhibiting presynaptic voltage-gated calcium channels, whereas levetiracetam acts downstream by disrupting vesicle fusion.

A 73-year-old woman is brought to the emergency department due to right hip pain. The patient was getting out of the shower when she slipped and fell directly on her right hip. She now has pain and swelling over the lateral aspect of her hip and cannot walk without assistance. Vital signs are within normal limits. Bilateral pedal pulses are normal, and sensation is intact. This patient's x-ray shows avulsion of the tip of the greater trochanter of the femur. Examination of this patient will most likely show impaired function of which of the following muscles?

*Gluteus medius* The pelvic bones and femoral trochanters provide sites of attachment for the large postural and ambulatory muscles of the hip girdle. Fractures involving these attachment sites are commonly caused by high-velocity trauma (eg, motor vehicle collisions, falls from height), but may occur even with ground-level falls (eg, getting out of the shower) in patients with skeletal fragility (eg, postmenopausal osteoporosis). The greater trochanter serves as the site of insertion for the gluteus medius muscle, which originates from the ilium. The main actions of the gluteus medius are hip abduction and stabilization of the pelvis during ambulation. Damage to the point of insertion on the greater trochanter can result in lateral hip pain with gait instability (ie, positive Trendelenburg sign) and weakness of abduction.

On physical examination, there is flattening of the left nasolabial fold and drooping of the left lower lip. The patient cannot fully close his left eye. MRI of the brain reveals a well-circumscribed homogenously enhancing mass in the posterior fossa that is compressing the left facial nerve root. Which of the following additional findings is most likely present on this patient's neurologic examination?

*Increased sensitivity to sound* This patient has facial nerve (CN VII) palsy, likely due to nerve compression by a meningioma (eg, well-circumscribed, homogenously enhancing mass) in the posterior fossa. Space-occupying intracranial lesions classically present with a headache that is worse in the morning and with Valsalva (eg, bearing down, coughing) due to increased intracranial pressure. The facial nerve exits the brainstem at the pontomedullary junction and subsequently enters the internal auditory meatus and facial canal in the temporal bone. Here, it gives off branches that supply the stapedius muscle (reduces volume by dampening ossicle movement in middle ear), salivary glands (eg, sublingual, submandibular), and lacrimal glands. It also provides taste from the anterior two thirds of the tongue via the chorda tympani nerve. After exiting the skull through the stylomastoid foramen, the facial nerve courses within the parotid gland and its terminal branches innervate the muscles of facial expression. Facial nerve palsy presents with ipsilateral facial paralysis (eg, flattening of the nasolabial fold, drooping of the lower lip, inability to close the eye). There is also loss of the corneal reflex (efferent limb) due to denervation of the orbicularis oculi muscle. Paralysis of the stapedius muscle may lead to increased sensitivity to sound (hyperacusis). Since the nerve to the stapedius is one of the first branches of the facial nerve, hyperacusis indicates that the facial nerve is injured near its brainstem origin. Other features of facial nerve palsy include decreased lacrimation, salivation, and loss of taste in the anterior two thirds of the tongue.I

Upper endoscopy reveals a 4-cm mass in the middle third of the esophagus, and several biopsies are taken. Thoracic imaging reveals mediastinal lymphadenopathy. Histologic evaluation of the biopsy specimens will most likely show which of the following in this patient?

*Keratin pearls and intercellular bridges This patient with a mid-esophageal mass and mediastinal lymphadenopathy likely has squamous cell carcinoma (SCC) of the esophagus. SCC is characterized by sheets of pleomorphic squamous cells with abundant eosinophilic cytoplasm and large, bizarre nuclei with atypical mitosis; keratin formation (keratin pearls) and intercellular bridges are common. Malignant cells are often seen invading the submucosa and surrounding structures. The esophagus can be subdivided (based on anatomy and embryonic formation) into thirds; malignancies occur at different frequencies within each segment. 1.Proximal and middle third: SCC is more common, and occurs at the highest frequency in the middle third. Lymphatics drain to mediastinal nodes; metastatic disease may present with mediastinal lymphadenopathy. 2. Distal third: Adenocarcinoma is more common. Lymphatics drain caudally to the gastric and celiac nodes; metastatic disease may present with abdominal lymphadenopathy. Adenocarcinoma is characterized by invasive patches of dysplastic, mucin-producing cells that form glands. It typically occurs as a consequence of chronic gastroesophageal reflux disease and is preceded by Barrett esophagus (replacement of the normal esophagus with nondysplastic columnar intestinal cells)

A 20-year-old man is evaluated in the clinic for right arm weakness and numbness. He is a competitive baseball pitcher and says that he played a lot more innings than usual last week because his team made the playoffs. Since then, the patient has had difficulty using the right arm, particularly when lifting objects. He has no known history of head, neck, or upper extremity trauma. On physical examination, there is diminished strength on right elbow flexion and an absent biceps reflex. This patient is most likely to have sensory loss over which of the following areas?

*Lateral forearm* This patient likely has musculocutaneous nerve injury, which most commonly occurs in the setting of trauma (eg, shoulder dislocation) and strenuous upper extremity activity (eg, baseball pitching). The musculocutaneous nerve is derived from the C5-C7 spinal nerve roots and arises from the lateral cord of the brachial plexus. It innervates the major forearm flexors (eg, biceps brachii, brachialis) and coracobrachialis (flexes and adducts the arm). After innervating these muscles, the remaining fibers become the lateral cutaneous nerve of the forearm and provide sensory innervation to the skin of the lateral forearm.

He is a graduate student in chemistry and was accidentally exposed to nitrites in his research laboratory. Physical examination is notable for cyanosis that is not improved by administration of supplemental oxygen via facemask. Analysis of a sample of arterial blood drawn from this patient prior to any oxygen supplementation is most likely to reveal normal values for which of the following?

*Normal partial pressure of Oxygen in the arterial blood* Iron bound to heme is normally in the reduced ferrous (Fe2+) state. Nitrites cause poisoning by inducing the conversion of this heme iron to the oxidized ferric (Fe3+) state, leading to the formation of methemoglobin. With iron in the oxidized ferric state, methemoglobin is unable to bind oxygen. In addition, the affinity of any residual ferrous iron in the hemoglobin tetramer is increased, causing a leftward shift of the oxygen-dissociation curve. However, the partial pressure of oxygen in blood, which represents the amount of oxygen dissolved in the plasma, is unchanged. Methemoglobinemia causes dusky discoloration of the skin (similar to cyanosis), and because methemoglobin is unable to carry oxygen, a state of functional anemia is induced. Methemoglobin cannot bind to oxygen and therefore the oxygen content and oxygen carrying capacity of the arterial blood will decrease. The bound fraction of oxygen and oxygen delivery to the peripheral tissues will also decrease due to methemoglobin's inability to carry and deliver oxygen

When asked if anything improves the tremor, the patient mentions that it subsides somewhat when she drinks small amounts of alcohol. Family history is significant for similar problems in her mother. Vital signs are normal. Neurologic examination shows bilateral tremor in the upper extremities. Which of the following is the best treatment for this patiexnt?

*Proproanolol* This patient has essential tremor, the most commonly diagnosed movement disorder. Essential tremor is also referred to as familial tremor as it often follows autosomal dominant inheritance. A positive family history of tremor can sometimes assist in making the diagnosis. Essential tremor classically worsens while maintaining a particular posture (eg, when holding an object). Patients commonly report that their symptoms improve with alcohol consumption. Propranolol is the first-line treatment for essential tremor. This nonselective β-adrenergic antagonist is thought to lessen the tremor via central nervous system effects.

A study assessed the association between a new vaccine and traveler's diarrhea (TD). Researchers selected a random sample of people who intended to travel to regions where they were at increased risk for TD and who had received the new vaccine and another independent random sample of people who intended to travel to the same regions and who had not received the new vaccine. These 2 samples of travelers were assessed for the occurrence of TD during the trip and for 7 days after returning home. Which of the following measures of association are the investigators most likely to report

*Relative risk* This case describes a cohort study in which participants are initially selected based on their exposure status to a risk modifier: exposed (eg, vaccinated) or nonexposed (eg, not vaccinated). Once participants are categorized based on exposure status, the occurrence (ie, incidence) of the outcome/disease of interest (ie, traveler's diarrhea [TD]) within a specific period is determined in each group. The risk of disease is finally compared between exposed and nonexposed groups to estimate the association between exposure to a risk modifier and disease occurrence. A common measure of association in cohort studies is the relative risk (RR). The RR is calculated as follows: RR = (risk of disease in exposed) / (risk of disease in nonexposed) The exposed group could also have been defined as the unvaccinated group and the nonexposed group as the vaccinated group; in this case, the RR would be inversed (interpretation of RR depends on what is chosen to represent the exposure).

A 78-year-old woman comes to the office due to tenderness and easy bleeding of the gums when she brushes her teeth. The patient has brushed her teeth twice a day for as long as she can remember and has not experienced these symptoms before. Physical examination shows swollen gingiva that bleed on probing. Her skin findings show perifollicular hemorrhages and coiled hair. Further questioning reveals that the patient lives alone and that her diet consists primarily of tea and toast. Her symptoms are most likely caused by hypoactivity of an enzyme found in which of the following compartments?

*Rough ER* This patient likely has vitamin C deficiency (scurvy). In the United States, vitamin C deficiency is seen primarily among malnourished populations, including alcoholics, the poor, and the elderly. The symptoms of scurvy reflect impaired formation of collagen and include gingival swelling/bleeding, petechiae, ecchymoses, and poor wound healing. Perifollicular hemorrhages and coiled (corkscrew) hairs are also commonly seen. Collagen synthesis is a complex process that begins with the transcription of collagen genes in the nucleus (Choice E). Collagen α-chains are then synthesized by rough endoplasmic reticulum (RER)-bound ribosomes and directed into the cisternae of the RER. Within the RER, specific proline and lysine residues are post-translationally hydroxylated to hydroxyproline and hydroxylysine by prolyl hydroxylase and lysyl hydroxylase, respectively. Vitamin C is a required cofactor for this post-translational modification. Defective hydroxylation of these residues severely diminishes the amount of collagen secreted by fibroblasts and impairs triple helix stability and covalent crosslink formation.

In an experiment, laboratory animals are subjected to a toxic insult that specifically targets the protein kinesin. Which of the following is most likely to be absent from tissues on histological examination as a result?

*Secretory vesicles in nerve terminals* Kinesin is a microtubule associated motor protein whose function is anterograde transport of intracellular vesicles and organelles toward the plus (rapidly growing) ends of microtubules. Kinesin uses energy derived from ATP hydrolysis to move along the microtubule. The plus ends of microtubules typically lie at sites distant from the nucleus; thus, in neurons, kinesin carries vesicles and organelles away from the cell body and toward the nerve terminal. A targeted toxic insult to this protein would be expected to impair anterograde transport resulting in a deficiency of synaptic vesicles at the nerve terminal.

newborn is taken to the neonatal intensive care unit after delivery due to respiratory distress. The neonate was born full-term, and there were no significant complications during pregnancy or delivery. Once the patient is stabilized, a detailed physical examination is performed. The neonate has an underdeveloped mandible and hypoplastic zygomatic bones. Genetic testing confirms a gene mutation that results in abnormal development of the first and second pharyngeal arches. Which of the following structures is also likely abnormal in this patient?

*Stapes* The developing embryo has 6 pharyngeal or branchial arches, all but the fifth arch contribute to adult structures. The mesoderm forms muscular and vascular elements, and neural crest cells form the bony and cartilaginous structures. Each arch is also innervated by a specific cranial nerve (CN). The first pharyngeal arch is associated with the trigeminal nerve (CN V). Its bony derivatives include the maxilla, zygoma, mandible, incus, and malleus; its muscular derivatives include the muscles of mastication (eg, masseter, temporalis). The second pharyngeal arch is associated with the facial nerve (CN VII) and gives rise to the styloid process of the temporal bone, lesser horn of the hyoid, and stapes. Muscular derivatives of the second arch include the muscles of facial expression. This neonate's presentation is consistent with Treacher-Collins syndrome (TCS), a genetic disorder resulting in the abnormal development of the first and second pharyngeal arches. The craniofacial abnormalities (eg, mandibular, maxillary, and zygomatic bone hypoplasia) often result in airway compromise and feeding difficulties. In addition, absent or abnormal ossicles (eg, incus, malleus, stapes) lead to profound conductive hearing loss.

The patient reports no change in motor symptoms, and the disease has been well controlled with anti-Parkinson medication. However, his wife is very concerned about a change in behavior, reporting that he recently started gambling and has lost a significant amount of their savings. The patient drives several hours multiple times a week to gamble at a casino in a neighboring state. His only other medical condition is major depressive disorder for which he takes sertraline. The patient does not use tobacco, alcohol, or illicit drugs. Vital signs are within normal limits. Physical examination shows a mild resting hand tremor and minimal rigidity. Which of the following is most likely responsible for this patient's recent change in behavior?

*Stimulation of Central Dopamine receptors* Parkinson disease (PD) is caused by loss of dopaminergic neurons in the basal ganglia, resulting in symptoms of bradykinesia, tremor, and rigidity. Dopaminergic medications used to treat PD have been associated with the abrupt onset of impulse control disorders, including pathological gambling, compulsive buying, and compulsive sexual behavior. Dopamine agonists (eg, pramipexole) as a class are most frequently associated with this adverse effect. These drugs act by binding to central dopamine receptors and stimulating dopamine activity in the ventral striatum (includes the nucleus accumbens, which is involved in motivation and reward pathways) and substantia nigra. Patients on dopamine agonist therapy should be monitored for dysfunctional impulse control. Gradual taper of the offending agent results in improvement in most cases.

Old woman with urinary urgency and incontinence. She's forgetful and has difficult planning and executing various activities. Patient feels unsteady with walking. Neurological examination shows impaired attention and short-term memory. MRI of the brain reveals chronic white matter changes. There is diffuse ventriculomegaly with no sulcal enlargement. Which of the following is the most likely underlying cause of this patient's urinary incontinence?

*Stretching of descending cortical fibers* This patient with impaired memory and cognition, unsteady gait, and urinary incontinence has ventriculomegaly without sulcal enlargement on MRI, which is characteristic of normal pressure hydrocephalus (NPH). NPH can occur due to decreased absorption of cerebrospinal fluid (CSF) by the arachnoid granulations (eg, fibrosis from previous cerebral inflammation or bleeding) with gradual accumulation of CSF in the ventricular system. The lateral ventricles expand, resulting in normal intracranial pressure and stretching the descending cortical fibers (corona radiata). Interruption of these pathways, along with impairment of cortical and subcortical function, leads to the classic triad of NPH symptoms (dementia, gait disturbance, urinary incontinence). The cerebral cortex (through the pontine micturition center) regulates the micturition reflex, which is an autonomic spinal reflex mediated by the neurons in the sacral spinal cord. In NPH, the lack of cortical inhibition results in detrusor muscle hyperactivity. This leads to urinary urgency, which can be worsened by gait abnormalities that limit a patient's ability to quickly get to a bathroom (urge incontinence). Progressive frontal lobe impairment leads to the inability to recognize urinary urge, uncontrolled urination, and a lack of concern as the disease progresses.

A 32-year-old woman comes to the emergency department due to severe headache, nausea, and vomiting for the past several hours. The headache is pounding and localized to the left side. She also describes bright spots in her vision prior to headache onset. The patient has had similar episodes occasionally since adolescence. Physical examination shows normal pupils and fundi, but the patient has discomfort to bright light. There is no facial droop, extremity weakness, or sensory loss. The patient is treated with metoclopramide and diphenhydramine. Which of the following is the most likely reason diphenhydramine was used in this patient?

*TO prevent abnormal motor reaction* This patient with a normal neurologic examination has unilateral headache associated with nausea and vomiting, photophobia, and a visual aura (eg, flashing lights), features that are consistent with migraine headache. Severe migraine headache with nausea and vomiting is typically treated with a serotonin 1B/1D agonist (ie, triptans) or a dopamine receptor blocker (eg, metoclopramide, prochlorperazine) to abort the migraine and treat associated nausea and vomiting. Dopamine receptor blockers have both antiemetic and analgesic effects on migraine headaches by antagonizing central dopamine D2 receptors in the midbrain and striatum. Dopamine receptor blockade in the basal ganglia can also cause excess cholinergic activity that manifests as significant extrapyramidal symptoms, such as acute dystonic reaction (eg, torticollis, oculogyric crisis). Therefore, diphenhydramine can be co-administered with metoclopramide or prochlorperazine to prevent such reactions due to its anticholinergic activity.

It is determined that the patient is experiencing a medication-induced dystonic reaction due to motor neuron hyperactivity. The persistent myocyte stimulation causes a substance to be released from the sarcoplasmic reticulum. This substance most likely binds to which of the following proteins to cause this patient's symptoms?

*TROPONIN* The sarcoplasmic reticulum (SR) is a modified endoplasmic reticulum within skeletal muscle cells. The SR forms a network of tubules with terminal cisterns that are in close contact with the T tubules (cytoplasmic membrane invaginations), allowing the membrane depolarization signal to reach the SR. The Ca2+-ATPase pump in the SR membrane actively sequesters calcium to keep intracellular concentrations low. Cell membrane depolarization causes calcium release from the SR into the cytoplasm via the SR ryanodine receptor. Actin filaments, troponin complex (troponins C, T, and I), and tropomyosin form the thin filaments of muscle fibers. In the resting state, tropomyosin covers the myosin binding sites on the actin filaments. On release from the SR, calcium binds to troponin C on the thin filaments (Choices A and C). This induces a conformation change in the troponin complex, causing it to displace tropomyosin and expose the myosin binding sites on the actin filaments. Myosin makes up the thick filaments of skeletal muscle. ATP is bound by the myosin head and cleaved to form ADP and inorganic phosphate ion, which are retained at the myosin head. When the myosin head binds to an actin filament, a conformational change causes the myosin to pull the actin filament, leading to muscle contraction and ADP release. A new ATP molecule then is bound to the myosin head, causing release of the actin filament. The cycle then repeats until calcium is displaced from troponin C and the myosin binding sites are again covered (Choice B). The pulse of elevated intracellular calcium lasts only a fraction of a second before the calcium is resequestered within the SR.

A 45-year-old man comes to the physician because of involuntary movements and behavioral disturbance. He has frequent, jerky, irregular movements of his upper extremities that have progressively worsened over the past month. His family and friends also say that he has become increasingly irritable over the past year. Genetic testing shows a mutation affecting the huntingtin protein that causes transcriptional repression of a number of other genes. Which of the following mechanisms is most likely responsible for the decreased gene expression seen in this patient?

*histone deacetylase* Huntington disease is an autosomal-dominant neurodegenerative disease caused by an increase in the number of CAG trinucleotide repeats in the gene that codes for the huntingtin protein. Expansion of the protein's polyglutamine region results in a gain-of-function that leads to pathological interaction with other proteins, including various transcription factors. Transcriptional repression (silencing) is one of the mechanisms by which mutated huntingtin is thought to cause disease. Regulation of transcription occurs in part due to the presence of histones, small proteins that complex with DNA to help compact the strands. Histones can undergo a variety of modifications (eg, methylation, acetylation, phosphorylation) that affect the accessibility of the genome for transcription. Acetylation of histones weakens the DNA-histone bond and makes DNA segments more accessible for transcription factors and RNA polymerases, enhancing gene transcription. In Huntington disease, abnormal huntingtin causes increased histone deacetylation, silencing the genes necessary for neuronal survival. As a result, one of the treatment options under investigation includes histone deacetylase inhibitors that help upregulate survival genes.

Noncontrast head CT reveals an acute hemorrhage in the cerebellar vermis without mass effect or midline shift. Which of the following neurologic findings is most likely to be present during this patient's physical examination?

*truncal ataxia* The cerebellar vermis modulates axial/truncal posture and coordination via connections with the medial descending motor systems (eg, anterior corticospinal, reticulospinal, vestibulospinal, and tectospinal tracts). Consequently, acute lesions to this region (eg, due to hemorrhage) typically result in truncal ataxia, characterized by a wide-based, unsteady gait. Patients may also develop vertigo and nystagmus due to involvement of the inferior vermis and the flocculonodular lobe (vestibulocerebellum), which modulate balance and ocular movements via connections with the vestibular nuclei and medial longitudinal fasciculus. Other features of cerebellar hemorrhage include nausea and occipital headache. Most cases are caused by hypertensive vasculopathy, but this patient's recent diagnosis of lung adenocarcinoma should also raise concern for hemorrhagic metastasis.

A short systolic murmur is heard at the apex. Bilateral crackles are present on lung auscultation. Bedside echocardiography reveals a flail posterior mitral leaflet due to chordal rupture and severe mitral regurgitation. Which of the following best reflects this patient's left ventricular hemodynamics compared to the normal heart? Afterload: Inc/Dec? Preload: Inc/Dec? EF: Inc/Dec?

Afterload: Dec Preload: Inc EF: Inc This patient has acute mitral regurgitation (MR) due to a spontaneous chordae tendineae rupture. In acute MR, the left atrium (LA) is of normal size and compliance and is suddenly exposed to a large volume of regurgitant blood from the left ventricle (LV). This leads to very high LA pressures and subsequent pulmonary edema. In addition, because the LV must accommodate the regurgitant blood volume along with normal pulmonary venous return, there is increased LV end-diastolic volume (preload). Meanwhile, the incompetent mitral valve forms a low-resistance regurgitant pathway for blood to flow into the LA during ventricular systole, decreasing LV afterload. The decreased afterload leads to increased LV ejection fraction (via increased stroke volume); however, much of the stroke volume is lost to regurgitation into the LA, resulting in overall decreased forward stroke volume and reduced cardiac output (manifesting as hypotension and cardiogenic shock). In chronic MR, compensatory LA enlargement allows the LA to receive the regurgitant volume at lower filling pressures, preventing pulmonary edema from developing. Chronic volume overload also causes the LV to undergo substantial enlargement due to eccentric hypertrophy. Early on, the larger ventricular volume helps maintain forward stroke volume even in the setting of substantial regurgitant flow. However, with prolonged hemodynamic overload, progressive eccentric remodeling of the LV becomes maladaptive, resulting in an overwhelming increase in wall stress with eventual contractile dysfunction. The impaired contractility culminates in decompensation of chronic MR with reduced forward stroke volume (decreased cardiac output) and increased left-sided filling pressures (pulmonary edema).

Connect each pharyngeal arch to the associated nerve

Arch 1: Trigeminal N (V) Arch 2: Facial N (VII) Arch 3: Glossopharyngeal N (IX) Arch4&6: Vagus (X)

A 34-year-old woman comes to the office for evaluation of recurrent transient pulmonary infiltrates. The patient has a history of bronchial asthma and has had several exacerbations over the past few years, particularly during the winter months. Her medications include albuterol as needed and medium-dose inhaled glucocorticoids. Complete blood count shows eosinophilia. A chest CT scan reveals proximal bronchiectasis. This patient's condition is most likely related to colonization with which of the following?

Aspergillus fumigatus is a low virulence fungus that generally does not cause significant infections except in immunocompromised or debilitated patients. It may, however, colonize the bronchial mucosa. Patients with asthma or cystic fibrosis in particular may develop an allergic hypersensitivity reaction to the fungus. The result is allergic bronchopulmonary aspergillosis (ABPA), which occurs in 5%-10% of corticosteroid-dependent asthmatics. Patients with ABPA have very high serum IgE levels, eosinophilia, and IgE plus IgG serum antibodies to Aspergillus. There is intense airway inflammation and mucus plugging with exacerbations and remissions. Repeated exacerbations may produce transient pulmonary infiltrates and proximal bronchiectasis.

A 34-year-old woman comes to the office due to a 3-day history of watery diarrhea. The patient has no fever. She has no other medical conditions and takes no medications. Blood pressure is 120/80 mm Hg and pulse is 90/min. Examination shows mild abdominal discomfort but is otherwise normal. Compared to normal laboratory values, which of the following findings are most likely present in this patient? Blood pH: high/low PaCO2: High/low Serum bicarb: High/Low

Blood pH: low PaCO2: low Serum bicarb: Low This patient with several days of diarrhea is expected to have primary metabolic acidosis, with low blood pH (<7.35), low serum bicarbonate (HCO3−) (<24 mEq/L), and compensatory low partial pressure of carbon dioxide in arterial blood (PaCO2) (<40 mm Hg). Severe diarrhea involves substantial loss of HCO3− in the stool, leading to nonanion gap metabolic acidosis. The reduced blood pH increases ventilatory drive to facilitate CO2 removal by the lungs, creating a compensatory respiratory alkalosis.

A 3-week-old baby boy is brought to the emergency department with fever, irritability, and poor feeding. Examination of the cerebrospinal fluid shows a leukocyte count of 600 cells/µL(80% neutrophils), protein of 160 mg/dL, and glucose of 20 mg/dL. Blood cultures grow gram-negative rods that form pink colonies on MacConkey agar. Which of the following is the most important bacterial virulence factor for the development of this patient's condition?

Capsule This patient has meningitis secondary to E coli infection. E coli is a motile, gram-negative, facultative anaerobic rod that is able to ferment both lactose and glucose. It grows well on blood, MacConkey, and eosin methylene blue agar plates. MacConkey agar is a selective and differential medium used to isolate gram-negative organisms from contaminants in clinical specimens. The bile salts and crystal violet present in MacConkey agar prevent the growth of gram-positive organisms. Organisms that ferment lactose (eg, E coli, Klebsiella, Enterobacter) cause a local drop in pH, resulting in colonies with a pink-red appearance. Non-lactose fermenting organisms remain colorless. E coli can invade the blood stream of infants from the nasopharynx or gastrointestinal tract and can then travel hematogenously to the meninges. The K1 capsular antigen is present in 20%-40% of intestinal E coli isolates and is considered the major virulence factor among E coli strains that cause neonatal meningitis. Bacterial capsules are important for most meningeal pathogens. They help facilitate survival in the blood by preventing recognition of bacterial antigens, complement deposition, and subsequent phagocytosis. The K1 capsule is immunogenic and anti-capsular antibodies are protective against repeat infection. Group B Streptococcus is the most common cause of neonatal meningitis (0-3 months) in the United States, followed by Escherichia coli and Listeria monocytogenes. In older infants (>3 months) and adults, the most common pathogens are Streptococcus pneumoniae and Neisseria meningitidis.

Abdominal x-ray reveals no calcifications, but abdominal ultrasound shows a small, non-obstructing gallstone. The patient prefers nonoperative management. Which of the following would best treat this patient's condition?

Cholesterol gallstones are the most common type of gallstone. They are primarily composed of cholesterol monohydrate crystals but can contain variable amounts of calcium salts, bilirubin, and mucin. Normally, bile acids and phospholipids solubilize the cholesterol to prevent stone formation. Decreased amounts of bile acids and phospholipids can cause the bile to become supersaturated with cholesterol, allowing it to crystallize and form cholesterol gallstones. Risk factors for stone formation include increasing age, obesity, excessive bile salt loss (eg, terminal ileum disease), and female sex. Cholecystectomy is the preferred treatment for symptomatic gallstones. However, medical therapy is an option in patients refusing surgery or with high surgical risk. Administration of hydrophilic bile acids (eg, ursodeoxycholic acid) reduces cholesterol secretion and increases biliary bile acid concentration. This improves cholesterol solubility and promotes gallstone dissolution. Although the response to medical therapy is good in patients with mild symptoms and small stones, there is a high rate of gallstone recurrence.

What is the MOA of the drug used for absence serizures

Ethosuximide blocks T-type calcium channels in thalamic neurons. It is a first-line treatment for absence seizures.

Is the Rabies vaccine live or inactivated?

Inactivated Restlessness, agitation, and dysphagia progressing to coma within weeks of exploring a bat cave is concerning for rabies encephalitis. Although bats (and, almost as commonly, raccoons) are among the main sources of rabies in the United States, many patients with bat rabies are not aware that they had been bitten. Once in a wound, the virus travels retrograde via peripheral nerves to the dorsal root ganglia and then to the brain, where replication occurs. The virus then spreads to other organs through neural pathways. Common manifestations include a nonspecific, flu-like prodrome followed by an acute neurologic syndrome with agitation, persistent fever, variable consciousness, and painful spasms with swallowing or inspiration (causing dysphagia, hydrophobia, and aerophobia). Generalized flaccid paralysis and coma ensue, with most patients dying within weeks. Prophylactic vaccination is recommended for individuals at high exposure risk (eg, veterinarians, cave explorers, laboratory workers handling infected tissues, travelers to countries where rabid dogs are prevalent). Postexposure prophylaxis (a medical emergency) generally includes rabies immune globulin and vaccination; it is not effective after symptom onset. The approved rabies vaccines consist of various rhabdovirus strains grown in tissue cell culture and inactivated by beta-propiolactone.

A 62-year-old woman is admitted to the hospital for a living-donor kidney transplant. She has a history of end-stage kidney disease due to diabetic nephropathy and has been undergoing hemodialysis for the last 2 years. The transplant surgery is performed without complication, and the patient demonstrates good urine output afterward. To help prevent rejection, she is given a medication that inhibits the conversion of inosine monophosphate to guanosine monophosphate primarily in lymphocytes, causing reduced proliferation of activated lymphocytes. Which of the following medications is most likely being used in this patient?

Mycophenolate is an immunosuppression drug used to prevent organ transplant rejection. It functions via the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH), an enzyme in the de novo purine synthesis pathway. The utility of mycophenolate as an immunosuppressant is aided by its relatively specific suppression of lymphocyte proliferation compared with other hematopoietic cell lines (eg, neutrophils, erythrocytes). This relative lymphocyte specificity is driven by 2 factors: Activated lymphocytes have a nearly absent purine salvage pathway and therefore are mostly dependent on de novo purine synthesis. Other hematopoietic cell lines have a more robust purine salvage pathway and can better compensate for inhibition of the de novo pathway. There are 2 subtypes of the IMPDH enzyme: - -Lymphocytes primarily contain type 2 IMPDH, whereas other cell lines contain a greater proportion of type 1. ---Mycophenolate binds to and inhibits type 2 IMPDH with a higher affinity than type 1. Common adverse effects of mycophenolate include lymphopenia and gastrointestinal disturbances (eg, diarrhea).

What is the role if the pilli in N. meningitidis

Neisseria meningitidis is commonly isolated from the oropharynx and nasopharynx of asymptomatic carriers. Colonization rates are variable but highest in close contact populations (eg, military recruits, university students). Transmission of meningococci usually occurs through exposure to respiratory droplets or direct contact with respiratory secretions. The pili on the capsular surface of N meningitidis are primarily responsible for attachment to and colonization of the nasopharyngeal epithelium. Pili also play a role in bacterial movement and epithelial penetration during invasion. Pili undergo high rates of antigenic variation (due to on-off gene switching and horizontal gene transfer), which limits the effectiveness of vaccines against this target. Other prominent N meningitidis virulence factors include IgA protease (destroys mucosal antibodies that would otherwise inhibit epithelial colonization), capsular polysaccharides (prevent phagocytosis and phagolysosome destruction), lipo-oligosaccharide (an endotoxin that is the major source of toxicity), and Opa-proteins (aid in endothelial attachment and invasion).

What is the inheritance pattern of NF1 and what are symptoms

Neurofibromatosis type 1 (NF-1). This autosomal dominant condition is caused by a mutation in the NF1 gene, located on chromosome 17. NF-1 has high penetrance (most patients who inherit the gene develop the disease), but the presentation is highly variable. All or none of the following symptoms may be present in an individual who suffers from NF-1: Skin: Café-au-lait spots (arrows) are hyperpigmented lesions with either smooth or irregular borders. The presence of axillary or inguinal freckles is another cutaneous feature of NF-1. Neurofibromas: Short, sessile, or pedunculated lesions that vary in size. They are commonly multiple and distributed throughout the body. Eye: Optic nerve gliomas may occur and cause visual loss. Lisch nodules are pigmented, asymptomatic hamartomas of the iris. Bony abnormalities: These include sphenoid dysplasia, congenital pseudoarthrosis, and scoliosis. Other associated tumors: Meningiomas, astrocytomas, gliomas, and pheochromocytomas. This patient's headaches and left leg weakness are probably the result of a brain tumor.

A 14-year-old boy comes to the office with his mother due to progressive anterior knee pain affecting the left leg for the past 2 months. The pain started as a mild ache toward the end of a hiking trip. The patient reports no fever, night sweats, or trauma to the knee. On physical examination, he has a normal gait. The hips, knees, and ankles have full range of motion. An area of mild swelling tender to palpation is located about 3 cm below the inferior border of the patella. An x-ray of the left knee is shown in the exhibit. Overuse of which of the following muscles most likely contributed to this patient's condition?

QUADRICEPS FEMORIS This patient has Osgood-Schlatter disease (OSD), a common cause of knee pain in adolescents due to overuse of the quadriceps muscle group (ie, rectus femoris, vastus intermedius, vastus lateralis, vastus medialis). The quadriceps is located in the anterior thigh and is responsible for knee extension. Its tendon initially inserts at the superior pole of the patella. The tendon envelops the patella and continues as the patellar ligament, which then inserts at the tibial tubercle. As a result, contraction of the quadriceps (eg, hiking, running) creates traction on the tibial tubercle. In skeletally immature children, the tibial tubercle forms as a secondary ossification center (apophysis) of the tibia, and the cartilaginous nature of the developing tibial tuberosity makes it more prone to injury compared to fully ossified bone in adults. Repetitive quadriceps contraction results in chronic avulsion/fragmentation of the tubercle, with corresponding tenderness and swelling, as seen in this patient.

A 68-year-old man comes to the office for gradually increasing shortness of breath. He initially experienced symptoms with exertion but now feels short of breath at rest. The patient has smoked 2 packs of cigarettes per day for 40 years. Blood pressure is 138/78 mm Hg, pulse is 80/min, and respirations are 22/min. The chest x-ray shows hyperinflation (flattened diaphragm, narrowed mediastinum). Which of the following measures is most likely increased in this patient?

RV/TLC ratio This is consistent with chronic obstructive pulmonary disease (COPD). COPD causes air trapping and hyperinflation of the lungs, so these patients breathe at higher baseline lung volumes (higher functional residual capacity). The volume of air in the lungs that is not respired, the residual volume (RV), is substantially increased. The total lung capacity (TLC) increases as well, but to a lesser extent than RV. Therefore, the fraction of air in the lungs that is not involved in respiration, the RV/TLC ratio, is also increased. A high RV/TLC ratio correlates with poor outcomes in patients with COPD. Diffusing capacity of the lung for carbon monoxide (DLCO) is decreased in COPD due to emphysematous destruction of the alveolar-arterial membrane. Both forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) are decreased in COPD due to airway obstruction. Because FEV1 is decreased more than FVC, the FEV1/FVC ratio is also decreased (<0.7 in COPD).

A 25-year-old woman comes to the office due to arthralgias in her hands for the last several months. The pain frequently involves her wrists and proximal finger joints bilaterally, and alternates between being worse in the wrists versus in the hands. The patient has no other medical problems and takes no medications. CBC shows pancytopenia, thrombocytopenia, leukopenia. Eval shows proteinuria and RBC casts. What is the ddx?

SLE This patient has chronic migratory arthralgias, pancytopenia, and evidence of glomerulonephritis (ie, proteinuria, red cell casts). These findings are suspicious for systemic lupus erythematosus (SLE), an idiopathic autoimmune disorder that is most common in women. Hematologic abnormalities are common in SLE. The most common cause of anemia is chronic inflammation (anemia of chronic disease); however, pancytopenia (as seen in this patient) can also occur due to autoantibodies against blood cell antigens (ie, type II hypersensitivity). Autoimmune hemolytic anemia in SLE is caused by IgG antibodies against erythrocytes; manifestations include spherocytosis, a positive direct Coombs test, and extravascular hemolysis. Antiplatelet antibodies in SLE can cause thrombocytopenia resembling immune thrombocytopenic purpura. Leukopenia can also occur, primarily due to antibody-mediated destruction of neutrophils. Lupus nephritis is caused by immune complex deposition (ie, type III hypersensitivity) in the mesangium, subendothelial, and/or subepithelial spaces. Histopathology is variable but diffuse proliferative glomerulonephritis (class IV) is the most common pattern.

In the hospital, he has several brief, back-to-back generalized tonic-clonic seizures and never fully regains consciousness between episodes. Intravenous lorazepam 2 mg is administered, and the seizures stop. Intravenous infusion of another drug is started simultaneously to prevent seizure recurrence. Which of the following is the most likely mechanism of action of the second drug infused in this patient?

Status epilepticus is a single seizure lasting >5 minutes or the occurrence of multiple discrete seizures with incomplete recovery of consciousness between episodes. Common causes include structural brain injury (eg, stroke, tumor, head trauma), infection, metabolic abnormalities (eg, hypoglycemia), and medication noncompliance in individuals with known epilepsy. Prompt evaluation and treatment is necessary as the condition is life-threatening and associated with a number of systemic complications (eg, cardiac arrhythmias, hypoventilation/hypoxia, disabling neurologic deficits). Intravenous lorazepam is a benzodiazepine that potentiates the effects of the inhibitory neurotransmitter GABA in the central nervous system. It is the initial drug of choice for treatment of status epilepticus due to its efficacy and rapid onset of action. Intravenous phenytoin (or fosphenytoin) is a long-acting anticonvulsant that is administered concurrently to prevent the recurrence of seizure activity, regardless of patient responsiveness to lorazepam. Phenytoin inhibits neuronal high-frequency firing in the cortex by reducing the ability of sodium channels to recover from inactivation.

A 54-year-old woman is evaluated in the clinic due to easy fatigability. Her medical history is significant for gastrectomy due to a nonhealing gastric ulcer. Physical examination shows a shiny tongue and pale palmar creases. Her gait is unstable when her eyes are closed, and vibration sense is markedly decreased over the lower extremities. There is mild symmetrical loss of strength affecting the proximal lower extremity muscles. Blood hemoglobin level is 7.2 g/dL and white blood cell count is 3,600/mm3. Stool tests for occult blood are repeatedly negative. Which of the following spinal cord lesions is most likely present in this patient?

Subacute Combined Degeneration This patient is most likely suffering from subacute combined degeneration of the spinal cord, a condition that results from chronically low levels of vitamin B12 (cobalamin). Low cobalamin levels may occur due to pernicious anemia (autoimmune gastritis with deficient intrinsic factor), gastrectomy, ileal resections, infection by the tapeworm Diphyllobothrium latum, and strict vegan diets containing no animal products for a prolonged period (4-5 years). Anemia along with neurologic abnormalities is typical of vitamin B12 deficiency. Vitamin B12 is an important cofactor in DNA synthesis; therefore, hematologic manifestations of vitamin B12 deficiency include megaloblastic anemia and pancytopenia. Elevated levels of methylmalonic acid also result in myelin synthesis abnormalities. Neurologic damage associated with vitamin B12 deficiency classically includes subacute combined degeneration of the dorsal columns (loss of position and vibration sensation, sensory ataxia [positive Romberg sign]), lateral corticospinal tracts (spastic paresis), and spinocerebellar tracts (contributes to ataxia). Patients may also develop atrophic glossitis, which appears as a smooth, shiny, erythematous tongue.

PSGN EM

Subepithelial (humps), intramembranous, subendothelial and mesangial deposits

34-year-old Russian immigrant comes to the physician with a 2-month history of exertional dyspnea and progressive lower extremity swelling. He also reports abdominal distension and decreased appetite. The patient has gained 4.5 kg (10 lbs) over the last 2 months. Past medical history is significant for hypertension and recurrent lung infections requiring prolonged antibiotic therapy. He has no history of coronary artery disease. The patient has smoked a pack of cigarettes daily for the past 15 years. He undergoes noninvasive cardiac testing followed by cardiac catheterization. A jugular venous pressure tracing is shown on the slide below.

The above CT image shows thickening and calcification of the pericardium suggestive of constrictive pericarditis. Although the pericardium is normally only 1-2 mm thick, it can range in thickness from 4-20 mm in patients with constrictive pericarditis. Patients with this condition typically have slowly progressive dyspnea, chronic edema, and ascites. A rapid y-descent that becomes both deeper and steeper during inspiration is often observed on the jugular venous pressure tracing. Possible causes include radiation therapy to the chest, cardiac surgery, and tuberculosis (which is possibly the cause in this patient who is an immigrant from an endemic region).

Describe an S4

The auscultatory findings in this case demonstrate an extra low frequency heart sound at the end of diastole just before S1 known as S4. This fourth heart sound is often heard in older adults due to an age-related decrease in left ventricular compliance, and in such cases is a relatively benign finding. However, the louder the sound, the more likely it is due to a pathologically stiff left ventricle, which occurs in restrictive cardiomyopathy and in left ventricular hypertrophy following prolonged hypertension (likely the cause in this case). Unlike the S3 sound, auscultation of an S4 in younger patients is always pathologic. It is thought that the S4 coincides with atrial contraction and is produced by the resultant onrush of blood striking a stiff left ventricle.

A 26-year-old woman, para 0, comes to the office for follow-up of irregular menstrual periods. She has a period every 15-90 days that lasts 2-14 days and ranges from spotting to quarter-sized clots. The patient and her husband have been trying to conceive, but it has been difficult to time intercourse given her erratic menstrual cycles. She has been exercising and losing weight and now has a BMI of 32 kg/m2. Gynecologic examination shows normal external genitalia, a small mobile uterus, and normal adnexa. Endometrial sampling reveals coiled glands filled with carbohydrate-rich mucus, edematous stroma, and tortuous spiral arteries. At which time point on the graph below was the endometrial sampling most likely obtained?

The uterine endometrium is a highly specialized mucosa that undergoes histologic transformation during the menstrual cycle in preparation for zygote implantation. The upper layer of the endometrium (the stratum functionale) consists of lamina propria studded with tubular glands, spiral arteries, and dilated capillaries. Histologic examination of these components with an endometrial biopsy allows for endometrial dating and evaluation for pathological processes. A normal menstrual cycle lasts for 21-35 days (28+/-7 days). The proliferative phase is the first half of the menstrual cycle (days 1-14), beginning with the first day of menses and ending with ovulation. During this time, estrogen stimulates proliferation of the stratum functionale. Normal proliferative endometrium consists of nonbranching, nonbudding, uniform glands evenly distributed throughout a uniform stroma. In the midproliferative phase, the glands are tubular, narrow, and lined with pseudostratified, elongated, mitotically active epithelial cells. The stratum functionale contains compact, nonedematous stroma. The uterine glands have increased in length and girth but still remain relatively straight. No secretions are present in the glandular lumens. The endometrium thickens, but the coiled spiral arteries remain limited to the deeper layers. At the end of the proliferative phase, ovulation occurs. Endometrial biopsy at ovulation shows a late proliferative endometrium with coiled glands and occasional cytoplasmic vacuoles in the glandular epithelium The secretory phase is the second half of the menstrual cycle (days 15-28), which follows ovulation. During this time, progesterone secreted by the corpus luteum in the ovary promotes the development of secretory endometrium. The glands increase in size and become more coiled, and the cells lining the glands acquire large cytoplasmic vacuoles. Glycogen-rich mucus is released into the glandular lumens. The stroma becomes increasingly edematous, and the prominent spiral arteries extend to the endometrial surface. The endometrial biopsy taken in this patient is consistent with the mid-secretory phase.

A 2-day-old girl is in the newborn nursery with persistent crying, tremors, tachypnea, sneezing, and diarrhea. She was born vaginally and had been breastfeeding well until several hours ago when she became tachypneic. Her mother has poorly controlled schizophrenia and did not receive prenatal care. The patient's mother also had a positive hepatitis C antibody test during postnatal laboratory testing. On physical examination, the girl has increased tone in all extremities. She is irritable during examination but quiets when swaddled. Chest radiograph shows normal lung fields. Which of the following is the most appropriate pharmacotherapy for treatment of the newborn's symptoms?

This newborn is showing signs of neonatal abstinence syndrome (NAS) due to withdrawal from opiates. NAS can result from illicit maternal drug use or prescribed opiate use (ie, a drug treatment program). At-risk newborns include those born to mothers with poor mental health, no prenatal care, and hepatitis C infection, as in this case. NAS typically presents a variety of manifestations, as shown in the Table. This newborn's crying, tremors, tachypnea, sneezing, irritability, and diarrhea are classic for NAS. Jittery movements are also common in affected newborns. The onset of symptoms depends on the type of opiate(s) used and how recently used by the mother before delivery. Generally, newborns exposed to drugs with shorter half-lives (eg, heroin) are symptomatic at age 1-2 days; those exposed to drugs with longer half-lives (eg, methadone) may present later. The treatment of choice for acute opioid withdrawal in neonates is opiate replacement, usually morphine or methadone. The dose is gradually increased until symptoms are controlled, and then the patient is weaned off over several weeks.

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

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

The patient has taken daily subcutaneous, low-molecular-weight heparin and as-needed acetaminophen since the surgery 5 days ago. Her left posterior calf is tender and swollen to the knee. Three days ago, complete blood count was normal, but platelet count is now 70,000/mm3. Peripheral blood smear shows decreased platelet number but no other abnormalities. Which of the following is the most likely cause of this patient's thrombocytopenia?

This patient on low-molecular-weight heparin developed thrombocytopenia and deep venous thrombosis (calf pain/swelling), raising strong suspicion for heparin-induced thrombocytopenia (HIT) type 2. In HIT type 2, heparin induces a conformational change in platelet-factor 4, leading to the formation of a neoantigen. IgG antibodies form against the neoantigen (heparin-platelet factor 4), which results in antibody aggregation on the platelet surface. Patients generally develop manifestations 5-10 days after heparin initiation. Thrombocytopenia is the hallmark feature due to the clearance of antibody-coated platelets by splenic macrophages. Antibody aggregation on the platelet surface also results in wide-spread platelet aggregation, which worsens the thrombocytopenia and significantly increases the risk of venous and arterial thrombosis. Patients with HIT-type 2 should immediately stop heparin and be initiated on a nonheparin anticoagulant (eg, argatroban) to help prevent/treat thrombosis. HIT type 1 is a non-immune-mediated condition caused by platelet clumping. Thrombocytopenia is typically mild (nadir ~100,000/mm3), and most cases arise within 2 days of heparin administration. It does not cause thrombosis and is not considered clinically significant; therefore, heparin can be continued.

A 65-year-old man comes to the emergency department due to acute-onset, severe right flank pain; nausea; and vomiting for the past hour. His medical conditions include prostate cancer and membranous nephropathy. Blood pressure is 148/60 mm Hg and pulse is 95/min. There is right costovertebral angle tenderness. Contrast-enhanced CT scan reveals a wedge-shaped perfusion defect in the right kidney. The affected renal tissue is most likely to develop which of the following histologic changes over the next several days?

This patient with multiple risk factors for hypercoagulability (ie, malignancy, membranous nephropathy) has flank pain, hematuria, and a wedge-shaped perfusion defect in the right kidney. This presentation is consistent with a renal infarction, likely from thromboembolic disease. Prolonged ischemia (as seen in infarcted tissue) results in irreversible cellular injury and cellular necrosis. Necrosis is an uncontrolled process of cell death that results in denaturation of cellular proteins and enzymatic digestion of cellular components. Unlike apoptosis, necrosis leads to a loss of membrane integrity and leakage of proinflammatory intracellular material that can injure the surrounding tissue. Necrosis occurs in several distinct morphologic patterns. In most organs, irreversible ischemic injury typically results in coagulative necrosis. Because the digestive enzymes denature before they can significantly disrupt tissue integrity, the cellular architecture is maintained but nuclei are absent. A major exception is tissue within the CNS, in which ischemia (eg, stroke) causes liquefactive necrosis with digestion of cellular constituents and liquefaction of necrotic tissue

A 73-year-old man comes to the clinic with epigastric pain that starts 30-40 minutes after meals and does not respond to antacids. The pain is non-radiating and is graded 6/10 in intensity. The patient has lost more than 4.5 kg (10 lb) over the last few months, which he attributes to eating less due to his fear of the pain. He has no vomiting, diarrhea, or urinary symptoms. His past medical history is significant for hypertension, hyperlipidemia, coronary artery bypass grafting, and right-sided carotid endarterectomy. He has smoked a pack of cigarettes daily for 32 years. Upper gastrointestinal endoscopy shows no abnormalities. The underlying pathophysiology of this patient's disease process is most similar to which of the following conditions?

This patient's postprandial epigastric pain and associated food aversion/weight loss in the setting of generalized atherosclerosis (eg, coronary and carotid artery disease) is consistent with chronic mesenteric ischemia. When atherosclerosis involves the mesenteric arteries, the bowel can suffer from diminished blood supply. Intestinal hypoperfusion, which can be very painful, is especially pronounced within an hour after meals when more blood is needed for the digestion/absorption of nutrients (intestinal angina). This is analogous to stable cardiac angina, chest pain that occurs with physical exertion due to increased myocardial oxygen demand. The diagnosis can be made with duplex ultrasonography or angiography showing high-grade stenosis in the celiac and mesenteric arteries.

A 9-year-old girl is brought to the office due to 2 days of face and eye puffiness. The patient was treated for a rash on her leg with an antibiotic about 3 weeks ago. Temperature is 37.2 C (99 F) and blood pressure is 150/90 mm Hg. On physical examination, there is generalized edema but no rash. Urinalysis reveals proteinuria and hematuria. An electron microscopy image representative of this patient's disease process shows a lumpy bumpy appearance. What is likely deposited here that causes this appearance?

This pediatric patient with hypertension, hematuria, proteinuria, and edema has a nephritic syndrome. The onset 3 weeks after a bacterial skin infection suggests poststreptococcal glomerulonephritis (PSGN), an immune complex-mediated disease that occurs 2-4 weeks after exposure to group A beta-hemolytic Streptococcus (eg, impetigo, pharyngeal infection). Acute kidney injury is common and leads to fluid and salt retention, often resulting in edema and hypertension. The immune complexes in PSGN are deposited along the glomerular basement membrane (GBM) and are visible on electron microscopy as large, dome-shaped, subepithelial, electron-dense deposits ("humps"). These can be further visualized on immunofluorescence as granular deposits of IgG, IgM, and C3 along the GBM and glomerular mesangium ("lumpy-bumpy" appearance). On light microscopy, the glomeruli are enlarged and hypercellular due to leukocyte infiltration.

A 16-year-old boy is evaluated for progressive gait instability, dysmetria, and dysarthria for the past several years. He is worried as his brother died of a neurologic disease at age 21. Physical examination of the lower extremities reveals bilateral motor weakness and loss of deep tendon reflexes, joint position, and vibration sense. MRI of the brain and spine shows degeneration of the posterior columns and spinocerebellar tracts. Which of the following conditions has clinical manifestations that closely resemble this patient's disease?

Vitamin E is a lipid-soluble, antioxidant vitamin that is widely available in the diet. Vitamin E deficiency is rare but may occur in patients with fat malabsorption and abetalipoproteinemia. The most notable manifestations include hemolysis and neurologic dysfunction (due to free radical damage of cell membranes). Neurologic symptoms of vitamin E deficiency closely mimic Friedreich ataxia (an autosomal recessive degenerative condition) as many of the same areas in the nervous system are affected. Specifically, patients with either condition may have ataxia (due to degeneration of spinocerebellar tracts), loss of position and vibration sense (due to degeneration of the dorsal columns), and loss of deep tendon reflexes (due to peripheral nerve degeneration). Vitamin B12 deficiency may also present similarly due to subacute combined degeneration of the dorsal and lateral spinal columns.