USMLE Step 1
Practice Test 1 for USMLE Step 1: real questions and explanations from the Varsity Tutors practice-test pool.
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During the first 2-3 days of a primary viral infection, before a robust T-cell response has developed, the host relies on a rapid innate immune mechanism to control viral replication. A key cell type involved in this early response can kill virally infected cells that have attempted to evade the immune system.
Which of the following cell types is most critical for eliminating host cells that have downregulated surface expression of MHC class I molecules?
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During the first 2-3 days of a primary viral infection, before a robust T-cell response has developed, the host relies on a rapid innate immune mechanism to control viral replication. A key cell type involved in this early response can kill virally infected cells that have attempted to evade the immune system.
Which of the following cell types is most critical for eliminating host cells that have downregulated surface expression of MHC class I molecules?
Explanation: Natural killer (NK) cells are lymphocytes of the innate immune system that provide early defense against viral infections and tumors. Their activity is regulated by a balance of activating and inhibitory signals. A key inhibitory signal is transmitted when NK cell receptors engage with MHC class I molecules on healthy host cells. Many viruses cause downregulation of MHC class I to evade recognition by cytotoxic T lymphocytes. This lack of MHC class I ('missing self') removes the inhibitory signal for NK cells, leading to their activation and the killing of the infected cell.
A researcher observes that many cancer cells have developed mechanisms to evade apoptosis. One such mechanism involves the inactivation of the p53 tumor suppressor protein, which normally induces apoptosis in response to cellular stress.
p53 carries out its pro-apoptotic function primarily by acting as a transcription factor for which of the following target genes?
Explanation: The p53 protein acts as a transcription factor that upregulates the expression of several pro-apoptotic genes. One of its key targets is the BAX gene. The BAX protein is a member of the Bcl-2 family that promotes apoptosis by increasing the permeability of the outer mitochondrial membrane, leading to the release of cytochrome c and the activation of caspases. In contrast, BCL2 is an anti-apoptotic protein, which is often downregulated by p53.
A 65-year-old man with a prosthetic heart valve is admitted with fever and malaise. Blood cultures grow methicillin-resistant Staphylococcus aureus (MRSA). He is started on intravenous vancomycin. During the first infusion, he develops diffuse erythema over his face, neck, and upper torso, along with pruritus and hypotension.
The therapeutic effect of the medication responsible for this reaction is achieved by which of the following mechanisms?
Explanation: Vancomycin is a glycopeptide antibiotic that inhibits cell wall synthesis in gram-positive bacteria by binding to the D-Ala-D-Ala terminus of peptidoglycan precursors. This sterically hinders transglycosylase and transpeptidase, preventing cell wall elongation and cross-linking. The patient's symptoms are characteristic of red man syndrome, a rate-dependent infusion reaction caused by widespread histamine release, which is a common side effect of vancomycin.
An unimmunized surgical resident sustains a deep needlestick injury from a patient who is chronically infected with hepatitis B virus (HBV). The occupational health service administers both Hepatitis B immune globulin (HBIG) and the first dose of the Hepatitis B vaccine.
Which of the following best describes the immunological rationale for this combined post-exposure prophylaxis strategy?
Explanation: This strategy combines passive and active immunization. Hepatitis B immune globulin (HBIG) contains high titers of pre-formed anti-HBsAg antibodies that provide immediate passive protection by neutralizing any virus introduced during the exposure. Concurrently, the Hepatitis B vaccine is administered to stimulate the resident's own immune system to produce a long-lasting active immune response, including antibodies and memory cells, for future protection.
A 28-year-old woman and her partner are trying to conceive. She has been using an ovulation predictor kit that measures urinary hormone levels. The kit shows a positive result, indicating an impending ovulation. This event is a critical component of the menstrual cycle, enabling potential fertilization.
The surge of which of the following hormones is directly responsible for triggering ovulation within 24-36 hours?
Explanation: The mid-cycle surge of Luteinizing Hormone (LH) from the anterior pituitary is the primary trigger for the final maturation of the dominant ovarian follicle and its rupture, a process known as ovulation. This surge is caused by a positive feedback effect of high estrogen levels from the mature follicle.
A 4-year-old girl with a history of recurrent urinary tract infections is found to have bilateral vesicoureteral reflux on a voiding cystourethrogram. Over several years, she develops hypertension and her renal function begins to decline. A renal ultrasound shows bilateral small, scarred kidneys with blunted calyces.
The progressive renal damage in this patient is primarily due to which of the following processes?
Explanation: This patient's history of vesicoureteral reflux (VUR) and recurrent UTIs is characteristic of chronic pyelonephritis. VUR allows infected urine to reflux from the bladder into the kidneys, leading to recurrent episodes of acute pyelonephritis. Each infection causes an inflammatory response in the renal parenchyma, particularly the tubulointerstitium. Over time, this recurrent inflammation leads to scarring, fibrosis, and tubular atrophy, resulting in cortical scarring (especially at the poles), blunted calyces, and progressive chronic kidney disease. This process is known as reflux nephropathy. A, B, and D describe other causes of CKD (glomerulonephritis, renovascular disease, and polycystic kidney disease, respectively).
During a routine 20-week anatomy scan, a fetus is determined to be female. The sonographer observes normal-appearing ovaries and internal female reproductive structures. The genetic basis for this development is a 46,XX karyotype.
In the absence of the SRY gene product, which of the following developmental events occurs in a 46,XX fetus?
Explanation: In a fetus with a 46,XX karyotype, there is no SRY (sex-determining region on Y chromosome) gene. In the absence of the SRY protein, the indifferent gonads develop into ovaries. The ovaries do not produce anti-Müllerian hormone (AMH) or testosterone. The absence of AMH allows the Müllerian (paramesonephric) ducts to develop into the internal female structures: fallopian tubes, uterus, and the upper part of the vagina. The absence of testosterone causes the Wolffian ducts to degenerate.
A 50-year-old man undergoes a screening colonoscopy. A large polyp is found and removed. Histologic analysis shows features of a pre-malignant adenoma. Molecular studies on the polyp's cells reveal silencing of the mismatch repair gene MLH1. The DNA sequence of the gene is unaltered. Further analysis shows the chromatin surrounding the MLH1 promoter is highly condensed.
Which of the following patterns of histone modification is most consistent with the condensed chromatin state and silencing of the MLH1 gene?
Explanation: Histone acetylation, mediated by histone acetyltransferases (HATs), neutralizes the positive charge of lysine residues, relaxing the chromatin structure into euchromatin, which is accessible to transcription machinery. Conversely, histone deacetylation, carried out by histone deacetylases (HDACs), restores the positive charge, leading to a more condensed chromatin structure (heterochromatin) and transcriptional repression. Therefore, decreased acetylation is a hallmark of silenced genes.
A 45-year-old woman underwent a splenectomy 5 years ago following a motor vehicle accident. She presents to the emergency department with a 1-day history of high fever, chills, and altered mental status. Her blood pressure is 80/50 mm Hg. Blood cultures are drawn and rapidly grow gram-positive cocci in pairs.
The patient's asplenic state primarily increases her susceptibility to this type of infection due to which of the following?
Explanation: The spleen plays a crucial role in filtering the blood and removing pathogens, particularly encapsulated bacteria like Streptococcus pneumoniae (gram-positive cocci in pairs). The splenic macrophages are highly efficient at phagocytosing bacteria that have been opsonized by antibodies and complement. In asplenic patients, this critical clearance mechanism is lost, leading to a high risk of overwhelming sepsis from encapsulated organisms.
A 9-month-old infant, who has a medical contraindication to receiving the MMR vaccine, lives in a community where the vaccination coverage for MMR is 98%. Despite a regional outbreak of measles, the infant does not contract the disease.
The infant's protection from measles in this scenario is best explained by which of the following principles?
Explanation: Herd immunity (or community immunity) occurs when a large proportion of a community is immune to a disease, making the spread of the disease from person to person unlikely. This high level of immunity provides indirect protection to individuals who are not immune, such as infants too young to be vaccinated, or those with contraindications. At 9 months, maternal IgG antibodies have waned significantly and would not provide reliable protection.
A 72-year-old patient in the intensive care unit on mechanical ventilation develops pneumonia. A sputum culture grows Klebsiella pneumoniae. Despite treatment with imipenem, the patient's condition worsens. The isolate is found to be resistant to all beta-lactams, including carbapenems.
Which of the following is the most likely mechanism of resistance in this isolate?
Explanation: Resistance to carbapenems (e.g., imipenem, meropenem) in Klebsiella pneumoniae is most commonly due to the production of carbapenemases, such as Klebsiella pneumoniae carbapenemase (KPC). These enzymes are beta-lactamases that can hydrolyze a broad spectrum of beta-lactam antibiotics, including the carbapenems, rendering them ineffective.
A 52-year-old woman presents to the emergency department with a deep, contaminated laceration on her leg after a gardening accident. Her immunization records show her last tetanus booster was 15 years ago. She is given a dose of the tetanus toxoid vaccine.
The protective immunity generated by this vaccine works primarily by which of the following mechanisms?
Explanation: The clinical manifestations of tetanus are caused by a potent neurotoxin (tetanospasmin) produced by Clostridium tetani, not by the bacterium itself. The tetanus vaccine contains a toxoid, which is an inactivated form of the toxin. The vaccine induces the production of neutralizing antibodies that bind to the circulating neurotoxin and prevent it from reaching its target in the central nervous system, thereby preventing the symptoms of tetanus.
A 40-year-old woman with end-stage renal disease receives a kidney transplant. Her maintenance immunosuppression includes belatacept, a newer agent that interferes with T-cell activation. This drug is a fusion protein that binds to specific molecules on antigen-presenting cells, preventing them from interacting with T-cells.
Belatacept prevents T-cell activation by blocking which of the following crucial signaling pathways?
Explanation: Belatacept is a costimulation blocker. It is a fusion protein consisting of the extracellular domain of CTLA-4 linked to the Fc portion of IgG1. It binds with high affinity to CD80 (B7.1) and CD86 (B7.2) on antigen-presenting cells. This blocks these molecules from binding to their natural ligand, CD28, on T-cells. The CD28-B7 interaction provides a critical 'second signal' (costimulation) required for full T-cell activation. By blocking this signal, belatacept induces a state of T-cell anergy or apoptosis, preventing an effective immune response against the graft.
A 48-year-old man notes that his rings and shoes have become too tight over the past few years. His wife mentions that his facial features have become coarser and he snores loudly. He has also been diagnosed with hypertension and type 2 diabetes mellitus. Physical examination reveals large hands and feet, frontal bossing, and a prognathism. His serum insulin-like growth factor 1 (IGF-1) level is markedly elevated.
The hormone responsible for this patient's condition exerts which of the following metabolic effects?
Explanation: This patient has acromegaly, caused by a growth hormone (GH)-secreting pituitary adenoma. While GH promotes linear growth (via IGF-1), it also has significant metabolic effects. GH is a counterregulatory hormone that antagonizes insulin's effects. It decreases peripheral glucose uptake and increases hepatic gluconeogenesis, leading to hyperglycemia and insulin resistance. This explains the high incidence of diabetes mellitus in patients with acromegaly.
A 25-year-old woman presents with a lifelong history of severe mucocutaneous bleeding, including recurrent epistaxis and prolonged bleeding after minor cuts. Her platelet count is normal. Platelet aggregation studies are performed. The addition of ADP, collagen, and epinephrine to her platelet-rich plasma fails to induce aggregation. However, the addition of ristocetin causes normal platelet agglutination.
The defective protein in this patient's platelets is most likely which of the following?
Explanation: This patient's clinical and laboratory findings are characteristic of Glanzmann thrombasthenia, an autosomal recessive disorder of platelet function. The key finding is the failure of platelets to aggregate in response to multiple agonists (ADP, collagen, epinephrine), while agglutination in response to ristocetin is normal. This pattern points to a defect in the final common pathway of platelet aggregation, which is the cross-linking of adjacent platelets by fibrinogen. This cross-linking is mediated by the glycoprotein IIb/IIIa receptor. Ristocetin-induced agglutination is normal because it depends on the interaction between vWF and the GpIb receptor, which is intact in this disorder.
During a neurophysiology laboratory, students record intracellularly from a motor neuron while stimulating various afferent inputs. Stimulation of Ia afferents from the muscle spindle produces a large, fast excitatory postsynaptic potential, while stimulation of Ib afferents from the Golgi tendon organ produces a slower, smaller inhibitory postsynaptic potential. Which of the following best explains the difference in time course between these two synaptic responses?
Explanation: This question tests your understanding of spinal reflex circuits and synaptic transmission. When analyzing differences in synaptic response timing, focus on the circuit pathways and neurotransmitter systems involved. The key difference lies in the synaptic pathways these afferents use. Ia afferents from muscle spindles make direct monosynaptic connections with motor neurons, releasing glutamate that produces fast excitatory postsynaptic potentials (EPSPs). In contrast, Ib afferents from Golgi tendon organs work through polysynaptic pathways - they synapse onto inhibitory interneurons, which then release GABA onto the motor neuron, creating the slower inhibitory postsynaptic potential (IPSP). This extra synaptic step introduces synaptic delay, making the response slower. Choice A correctly identifies this circuit difference and the appropriate neurotransmitters involved. Choice B incorrectly focuses on conduction velocity - while both Ia and Ib fibers are heavily myelinated with fast conduction, this doesn't explain the different response kinetics once the signal reaches the spinal cord. Choice C is wrong because both pathways use chemical synapses, not electrical ones. Choice D misidentifies the receptor types - both glutamate and GABA typically act on ionotropic receptors in these circuits, not metabotropic ones. Remember that synaptic timing differences in the CNS usually result from circuit complexity (mono- vs. polysynaptic pathways) rather than conduction velocity or receptor types. The stretch reflex (Ia pathway) is monosynaptic for speed, while the inverse stretch reflex (Ib pathway) uses interneurons for integration and inhibition.
A public health report compares the annual incidence of influenza in two cities. In City A, a bar chart shows that 15% of the population contracted influenza. In City B, the corresponding bar is at 10%. An asterisk above the bars indicates a statistically significant difference, with a reported p-value of 0.03.
Which of the following is the most appropriate conclusion?
Explanation: The data shows an absolute difference of 15% - 10% = 5 percentage points. The p-value of 0.03 is less than the conventional alpha of 0.05, which means this difference is unlikely to be due to random chance and is considered statistically significant. While the relative difference is 50% ([15-10]/10), expressing it as an absolute difference of 5 percentage points is also correct and directly stated. This option correctly combines the observed difference with its statistical significance. The data does not provide information about vaccination rates.
A 75-year-old man presents with a 2-year history of cognitive decline, recurrent, well-formed visual hallucinations of people in his room, and motor symptoms including rigidity and bradykinesia. His family reports that his cognitive function fluctuates significantly from day to day. Last year, he was given haloperidol for his hallucinations and developed severe parkinsonism.
The neuropathological diagnosis for this condition is confirmed by finding eosinophilic intracytoplasmic inclusions composed of alpha-synuclein within which of the following?
Explanation: This clinical picture, including fluctuating cognition, visual hallucinations, and parkinsonism, is classic for Dementia with Lewy Bodies (DLB). The core pathological feature of DLB is the presence of Lewy bodies, which are abnormal aggregates of alpha-synuclein protein, within neurons. While Lewy bodies are also found in the substantia nigra in Parkinson's disease, their widespread presence in cortical neurons (frontal, temporal, cingulate) is characteristic of DLB and underlies the cognitive and psychiatric symptoms.
A 29-year-old woman presents to her primary care physician with complaints of fatigue, weakness, and feeling cold all the time. She also notes occasional cravings for ice chips. She has a history of heavy menstrual periods. Physical examination reveals pale conjunctivae and spoon-shaped nails (koilonychia). A CBC shows microcytic, hypochromic anemia.
This patient's condition is due to a deficiency of a mineral that is essential for the function of which of the following proteins?
Explanation: The patient's symptoms (fatigue, pallor), signs (koilonychia), pica (ice craving), and laboratory findings (microcytic anemia) are all characteristic of iron deficiency anemia, often caused by heavy menstrual bleeding. Iron is a fundamental component of the heme molecule within hemoglobin, which is responsible for oxygen transport in the blood. Insufficient iron impairs heme synthesis, leading to small, pale red blood cells and anemia.
A 45-year-old park ranger is bitten by a raccoon. The animal escapes and cannot be tested for rabies. The ranger has no history of rabies vaccination. In the emergency department, he receives both rabies immune globulin (RIG) and the first dose of the rabies vaccine.
What is the primary purpose of administering the rabies immune globulin in this situation?
Explanation: Rabies immune globulin (RIG) is a preparation of concentrated, pre-formed anti-rabies antibodies. Its purpose is to provide immediate, passive immunity by binding to and neutralizing the rabies virus before it can enter the central nervous system. This temporary protection bridges the gap until the patient's own immune system can generate a protective active immune response, stimulated by the concurrently administered rabies vaccine.
A 58-year-old man with a 30-pack-year smoking history, type 2 diabetes mellitus, and hyperlipidemia is evaluated for stable angina. A coronary angiogram reveals significant stenosis in his left anterior descending artery. The patient's condition is attributed to atherosclerosis.
The initial event in the pathogenesis of this patient's coronary artery disease is most likely which of the following?
Explanation: The pathogenesis of atherosclerosis begins with chronic endothelial injury. Risk factors such as smoking, hypertension, hyperglycemia, and hyperlipidemia damage the endothelium. This initial injury increases endothelial permeability, leukocyte adhesion, and thrombotic potential, setting the stage for all subsequent events, including lipid entry, macrophage accumulation (foam cells), and smooth muscle cell proliferation.
A 40-year-old woman presents with symptoms of hyperthyroidism. Her laboratory tests show elevated T3 and T4 levels with a suppressed TSH. She is diagnosed with Graves' disease. The pathophysiology involves autoantibodies that bind to and activate TSH receptors on thyroid cells, leading to uncontrolled thyroid hormone production. The TSH receptor is a G-protein coupled receptor that, when activated, initiates a signaling cascade.
Activation of the TSH receptor ultimately leads to increased thyroid hormone synthesis primarily through stimulation of which of the following cellular processes?
Explanation: TSH receptor activation leads to increased cAMP levels and PKA activation, which phosphorylates and activates transcription factors such as CREB. These transcription factors bind to cAMP response elements in the promoters of genes encoding thyroid hormone synthesis enzymes, including thyroid peroxidase (TPO) and thyroglobulin. This results in increased transcription of these essential enzymes, leading to enhanced thyroid hormone production.
A researcher is purifying a mixture of proteins at a buffered pH of 7.4. The mixture contains albumin (pI = 4.7) and myoglobin (pI = 7.0). The researcher uses a chromatography column containing a positively charged diethylaminoethyl (DEAE) cellulose resin.
Under these conditions, which of the following is the most likely outcome?
Explanation: This is an example of anion-exchange chromatography, where a positively charged resin (DEAE) binds negatively charged molecules. At pH 7.4, both proteins will have a net negative charge since the pH is above their respective pIs. However, albumin (pI = 4.7) will be much more negatively charged than myoglobin (pI = 7.0) at this pH. The further a protein's pI is from the buffer pH, the greater its net charge. Therefore, albumin will bind much more strongly to the positively charged column.
A 19-year-old male college student presents to the emergency department with a high fever, severe headache, nuchal rigidity, and a petechial rash. A lumbar puncture confirms a diagnosis of meningococcal meningitis caused by Neisseria meningitidis. His medical history is significant for a similar episode one year prior. A deficiency in which of the following would most likely explain his recurrent infections with this specific pathogen?
A deficiency in which of the following would most likely explain his recurrent infections with this specific pathogen?
Explanation: Deficiencies in the terminal complement components (C5b, C6, C7, C8, C9), which form the membrane attack complex (MAC), confer a specific susceptibility to recurrent infections with encapsulated bacteria of the Neisseria species (N. meningitidis and N. gonorrhoeae). The MAC is essential for lysing these particular organisms.
A 40-year-old woman presents with numerous benign skin tumors, oral papillomas, and a history of a multinodular goiter. She was recently diagnosed with breast cancer. Her constellation of findings is suggestive of Cowden syndrome.
This patient's condition is caused by a loss-of-function mutation in a gene whose product directly antagonizes the action of which signaling enzyme?
Explanation: Cowden syndrome is caused by a germline mutation in the PTEN tumor suppressor gene. The PTEN protein is a phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-bisphosphate (PIP2). This action directly opposes the function of phosphoinositide 3-kinase (PI3K), thus downregulating the pro-survival and pro-proliferative PI3K/AKT/mTOR signaling pathway.