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A 55-year-old man is referred for a screening chest x-ray due to a 20-pack-year history of smoking. A 2-centimeter pulmonary nodule is identified in the left lower lobe. Surgical excision is performed. Grossly, the lesion is tan-colored, well-encapsulated, and firm. Microscopic examination reveals a heterogeneous collection hyaline cartilage, fat, respiratory epithelial cells, and smooth muscle. Which of the following would most likely have occurred if this lesion had not been removed?
A) Spread throughout lung
B) Metastasis to liver
C) Slow growth over years
D) Cushing's syndrome
E) SIADH
Answer C (correct answer): This man has a pulmonary hamartoma, a benign lesion that is responsible for about 10% of pulmonary nodules. They are the most common benign tumor of the lung. Hamartomas contain disorganized but normal tissue from the organ in which they are found. In the case of lung hamartomas, these lesions typically contain fat, epithelial cells, fibrous tissue, and cartilage. In some cases, calcification is present which helps with identification by x-ray or CT scan. Hamartomas grow slowly over years and carry an excellent prognosis which is why they are classified as benign.
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Researchers are evaluating four different lines of epithelial cells from human breast tissue. Which of the following characteristics suggest the malignant potential of these cells?
A) Resistance to natural killer cells
B) Strong response to growth inhibitors
C) Strong dependence on growth promoters
D) Inability to invade basement membranes
E) Increased p53 gene activity
Answer A (correct answer): There are several well-described hallmarks seen among all malignant neoplasms. These include the ability to evade cell death by the immune system. Natural killer cells were first identified as lymphocytes capable of killing tumor cells without prior exposure (i.e., without being sensitized, as is required for B and T cells). They recognize antigens expressed on many tumor cells and subsequently destroy the cell. To have malignant potential, cells must possess some ability to avoid this natural defense mechanism.
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A 42-year-old man is evaluated for a rash. He has end-stage renal disease requiring hemodialysis three times per week. He complains of a painful skin lesion that has progressed over the past few weeks (image below). Which of the following contributed to development of this finding?
A) Hypercalcemia
B) Hyperphosphatemia
C) Elevated BUN
D) Hypomagnesemia
E) Hypokalemia
Answer B (correct answer): This man has calciphylaxis, a rare, dangerous skin complication of chronic renal failure. Patients with chronic renal failure develop hyperphosphatemia due to inability to excrete phosphate in the urine. Serum phosphate binds to calcium, pulling calcium from the circulation and causing hypocalcemia. Calcium-phosphate crystals deposit in the walls of blood vessels of the skin. This can lead to ischemic necrosis of the skin, which presents as described in the question. Renal failure patients are prescribed “phosphate binders,” drugs that lower serum phosphorus to prevent hyperphosphatemia and calciphylaxis.
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A 62-year-old woman with a history of rheumatoid arthritis has an elective hysterectomy for the treatment of uterine fibroids. A five-centimeter pelvic skin incision is made and then sutured at the completion of the procedure. Four days after surgery, her abdominal incision shows minimal granulation tissue formation. She is afebrile and there is no pus in the wound. The skin edges have separated between two of the sutures. Which of the following most likely explains this woman’s wound findings?
A) Thrombocytopenia
B) Glucocorticoid therapy
C) Wound infection
D) Zinc deficiency
E) Copper deficiency
Answer B (correct answer): This woman has delayed wound healing, a common problem in clinical medicine. Four days after surgery she has minimal granulation tissue and her wound shows evidence of dehiscence. There are many causes of delayed wound healing but the most common include infection, diabetes, glucocorticoid therapy, and poor nutritional status. In this woman with a history of autoimmune disease, glucocorticoid therapy is most likely. Steroids have a number of anti-inflammatory effects including inhibition of neutrophil migration. This delays the wound healing process.
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A 6-year-old boy is brought to the pediatrician for evaluation of a scratch. The mother states the boy was scratched on the face by another child on the playground. Examination reveals a two-centimeter laceration on the left cheek. The mother is advised to keep the wound clean. Two weeks later, the child returns to the clinic and the cheek appears normal. Which of the following was most important for healing of this boy’s skin?
A) Angiogenesis
B) Fibroblast proliferation
C) Intact basement membrane
D) Type III collagen deposition
E) Type I collagen deposition
Answer C (correct answer): This boy’s wound has healed with no scar formation. This occurs in tissues capable of regeneration like the skin if the basement membrane remains intact and basal layer stem cells are not destroyed. Superficial skin wounds often heal with no scar because these wounds do not disrupt the basement membrane and the skin is capable of regeneration.
Special Note: Many tissues can heal with no scar including the skin after superficial lacerations, the gastrointestinal mucosa after an ulcer, or the lungs after pneumonia. In all of these cases, the tissues have regenerative capacity, and the injury does not destroy the basement membrane and stem cells. None of the typical scar processes will occur when this happens.
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A general surgeon is researching the causes of wound failure in skin wounds after emergency surgery. Using a novel technique, he estimates wound mechanical strength as a function of days following the injury. In the graph below, at which point is vascular endothelial growth factor (VEGF) activity likely to be highest?
A) Day 1
B) Day 5
C) Day 9
D) Day 11
E) 1 month
Answer B (correct answer): Wound strength depends on the amount and quality of collagen deposition. In the first few days after injury, no collagen is present and wounds are prone to failure. During this time, sutures, staples, or other devices are used to maintain skin approximation. When collagen deposition begins around days 3 to 5, wound strength steadily increases. Over time, type III collagen is replaced with stronger type I collagen which further increases wound integrity. By several weeks, collagen synthesis is complete. In later phases of wound healing (weeks to months), other collagen modifications occur including crosslinking. These further increase wound strength although the wound will never reach the strength of uninjured tissue.
Vascular endothelial growth factor (VEGF) is critical for angiogenesis which occurs after about 3 days for up to one or two weeks. Growth of new blood vessels brings fibroblasts to the wound so these cells can begin secreting collagen.
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A 62-year-old man is evaluated for coronary artery disease. Five months ago, he underwent four vessel coronary artery bypass grafting (CABG) surgery for symptoms of angina. Since the operation, he has completed six weeks of cardiac rehabilitation therapy. He denies any exertional chest pain. His medications include aspirin, metoprolol, and atorvastatin. Blood pressure and pulse are within normal limits. Examination of the chest reveals a sternal incision that is clean and dry with no warmth, tenderness, or redness. Which of the following processes is occurring in this man’s scar at this time?
A) Granulation tissue formation
B) Type II collagen synthesis
C) Angiogenesis
D) Collagen cross-linking
E) No activity at this time
Answer D (correct answer): This man’s chest incision has healed by primary intention which progresses through several phases over the days, weeks, and months following surgery. When the wound edges are sutured together, the following 24 hours are dominated by clot formation and neutrophil invasion within the wound. From about three days to about one week, neutrophils are replaced by macrophages (for debris phagocytosis) and “granulation tissue” fills the wound space meaning thick fluid with protein and cells. During this time angiogenesis occurs, fibroblasts infiltrate the wound, and collagen synthesis begins. After one month, inflammatory cells are absent and only fibroblasts remain. Collagen synthesis is complete after several weeks, but collagen remodeling continues for up to six months to one year after injury. The changes that occur during remodeling include cross-linking of collagen.
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A 14-year-old girl is evaluated one week after an appendectomy. She had intense abdominal pain one week ago when she was diagnosed with acute appendicitis. Her recovery from surgery was uneventful and her abdominal pain has resolved. She is eating normally and reports normal bowel habits. She denies fever, chills, or sweats. Abdominal exam reveals a 5-cm incision that is clean, dry, and intact. There is minimal redness at the edges of the wound. Which of the following processes is occurring in the wound at this time?
A) Granuloma formation
B) Neutrophil infiltrate
C) Angiogenesis
D) Collagen cross-linking
E) Clot formation
Answer C (correct answer): This girl’s incision has healed by primary intentionwhich progresses through several phases over the first few days, weeks, and months. When the wound edges are sutured together, the following 24 hours are dominated by clot formation and neutrophil invasion within the wound. From about three days to about one week, neutrophils are replaced by macrophages (for debris phagocytosis) and granulation tissue fills the wound space. During this time angiogenesis occurs, fibroblasts infiltrate the wound, and collagen synthesis begins. After one month, inflammatory cells are absent and only fibroblasts remain. Collagen synthesis is complete after several weeks, but collagen remodeling continues for up to six months to one year after injury.
This girl is one week out from surgery. Her wound is in the fibroblast proliferative phase where angiogenesis occurs.
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Scientists are evaluating the immune response to tissue damage among epithelial cells. They characterize a protein complex that assembles in the cytosol when cells are exposed to high levels of uric acid. This assembly most likely leads to the cellular release of which of the following?
A) C5a
B) IgG
C) IL-1
D) IL-5
E) IFN-gamma
Answer C (correct answer): The question stem is describing the inflammasome, a multi-protein complex that assembles in the cytoplasm of cells in response to cellular damage or infection. Many cell types including epithelial cells contain proteins called “NOD-like receptors” (NLRs) within the cytoplasm. These receptors are similar to toll-like receptors which are found on the cell membrane surface. NLRs bind numerous components of necrotic or dying cells including uric acid, excess ATP, or free DNA (collectively called damage-associated molecular patterns or DAMPs). They have also been shown to bind some components of bacteria (called pathogen-associated molecular patterns or PAMPs). These substances may be taken up from the extracellular environment and bound to cytoplasmic NLRs. Once activated, many NLRs assemble into a multi-protein complex called the inflammasome. This structure activates the enzyme caspase-1 that generates IL-1 to initiate an inflammatory response. This is sometimes called the “NLR-inflammasome pathway” of initiating inflammation. It may play a role in some autoimmune diseases.
Key point: Toll-like receptors are found on cell membranes and within endosomes. NLRs perform a similar function but are intracellular.
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Scientists identify a surface receptor on macrophages that binds molecular patterns found only in bacteria. Once activated, the receptor triggers the release of cytokines. Further evaluation shows that this receptor is also activated by some components of human cells. Activation by human cellular components is helpful for the immune response to which of the following?
A) Vaccination
B) Necrosis
C) Candida
D) Schistosoma
E) Staph Aureus
Answer B (correct answer): The question is describing toll-like receptors (TLRs), a key component of the innate immune response. TLRs are an example of “pattern recognition receptors” and are found on the surface of macrophages and other cells. They recognize pathogen-associated molecular patterns (PAMPs), small molecular structures found only on pathogens like bacteria. When a PAMP binds a TLR on a macrophage, the cell becomes activated. In this primed state, it releases cytokines to activate the inflammatory response.
As TLRs were studied, evidence emerged that these receptors also bind some components of normal human cells (i.e., non-foreign substances). These cellular components are called damage-associated molecular patterns (DAMPs) and are important for initiating the inflammatory response to necrosis. Many DAMPs have been described including proteins of the nucleus, heat shock proteins (normally found in the cytoplasm), ATP, uric acid, RNA, and DNA. When necrosis occurs, these bind to TLRs to initiate inflammation.
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A 72-year-old woman is evaluated for fever, chills, and dysuria. Ten years ago, she received chemotherapy and radiation for the treatment of breast cancer. Three days ago, she noted burning on urination. She began drinking cranberry juice at the recommendation of a friend. For the past 24 hours, she has felt feverish with chills, rigors, and sweating. Her temperature is 102.1ºF. Pulse is 110/min and blood pressure is 100/70 mmHg. Urinalysis shows numerous white cells and bacteria. White blood cell count is 54,000/mm<sup style="color: rgb(0, 0, 0);">3 </sup>(normal <11,000) with 80% neutrophils and 15% bands. Which of the following is the most likely cause of her elevated white blood count?
A) Leukemia
B) Myeloproliferative disorder
C) Leukemoid reaction
D) Occult lymphoma
E) Polycythemia vera
Answer C (correct answer): This woman has pyelonephritis, a bacterial infection of the kidney. This often begins as a urinary tract infection with typical symptoms like dysuria. Bacteria “ascend” into the kidneys invoking a systemic response to infection including fever, chills, and elevated white blood cell (WBC) count. This woman’s WBC count is very high, at the level seen in malignancies like leukemia. However, the high WBC is occurring in the setting of focal infectious symptoms (dysuria) with immature neutrophils (band forms) in the blood. This is consistent with a leukemoid reaction, a physiologic response to infection.
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A 38-year-old woman presents with abdominal pain. For the past three days, she has had fatigue, nausea, and right upper quadrant abdominal pain. She recently engaged in sexual activity with a new partner without using condoms. Her sclera are icteric. Abdominal palpation elicits tenderness in the right upper quadrant. Serum testing shows increased AST and ALT. Hepatitis B surface antigen is positive. Which of the following is the major cause of damage to this woman’s liver?
A) Coagulative necrosis
B) Liquefactive necrosis
C) Caseous necrosis
D) Fat necrosis
E) Apoptosis
Answer E (correct answer): This woman has acute hepatitis B infection. The major cause of liver damage in hepatitis B is apoptosis of hepatocytes caused by CD8+ T cells. Acute viral hepatitis leads to a lymphocyte infiltrate in the liver, very different from the acute inflammatory infiltrates containing neutrophils seen in bacterial infections. In acute hepatitis, scattered areas of “spotty necrosis” may occur but apoptosis is the major process damaging liver cells. Biopsy may show microscopic evidence of apoptosis including shrunken hepatocytes with “intensely eosinophilic” cytoplasm and fragmented nuclei.
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A 72-year-old man receives a diagnosis of prostatic adenocarcinoma after his primary care physician notes a prostate nodule on digital rectal exam. He is treated with external beam radiation therapy which leads to a decrease in tumor burden. Which of the following contributed to tumor cell death in this patient?
A) p53 activation
B) BAX inhibition
C) BCL2 activation
D) Hormone withdrawal
E) Catalase activation
Answer A (correct answer): Radiation therapy causes DNA damage in malignant cells. DNA damage leads to phosphorylation of the p53 protein, a major regulator of the cell cycle. Phosphorylated p53 will lead to cell cycle arrest (see video on cell cycle in the cell biology section). During this time, DNA repair may occur. If DNA repair is not possible, activated p53 can also <a href="https://www.ncbi.nlm.nih.gov/pubmed/25980443" rel="noopener noreferrer" target="_blank" style="color: rgb(64, 145, 198);">trigger the pro-apoptosis factors, BAK and BAX</a>. This leads to apoptosis of cancer cells and a decrease in cancer cell burden.
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A 6-year-old boy develops acute lymphoblastic leukemia with CD10+ pre-B cells. He is treated with glucocorticoids, vincristine, daunorubicin, and cytarabine and achieves remission. Two years later, he develops fatigue and malaise. Peripheral white blood count is 100,000/mm3 with lymphoblasts on peripheral smear. He is treated with glucocorticoids with no reduction in white cell count. Glucocorticoids are ineffective because this boy’s cancer cells are resistant to which of the following?
A) Cell surface receptor binding
B) DNA cross linking
C) Caspase activation
D) FAS-FAS ligand binding
E) Membrane lipid peroxidation
Answer C (correct answer): Glucocorticoids induce apoptosis in lymphocytes through activation of caspase enzymes. This is one of the mechanisms of glucocorticoids as anti-inflammatory drugs. This effect is also beneficial in many forms of malignancy including some leukemias as glucocorticoids can induce apoptosis of malignant cells. In this boy, leukemic cells have become resistant to the pro-apoptotic effects of glucocorticoids.
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A 72-year-old woman develops fevers, chills, and cough. Chest x-ray shows a right lower lobe infiltrate. Sputum culture grows lancet-shaped gram-positive cocci. She is started on therapy with levofloxacin. Her symptoms persist and a bronchoalveolar lavage is performed. Analysis shows neutrophils and bacteria. Which of the following enzymes initiates bacterial killing in these neutrophils?
A) NADPH oxidase
B) Superoxide dismutase
C) Myeloperoxidase
D) Catalase
E) Glutathione peroxidase
Answer A (correct answer): This woman has a pulmonary infection with streptococcus pneumoniae. Neutrophils are drawn to the site of infection in the lungs as part of the acute inflammatory response. The major role of neutrophils is phagocytosis of bacteria. Once engulfed, bacterial killing occurs via the respiratory burst within phagosomes of neutrophils. The first step in the respiratory burst is catalyzed by NADPH oxidase.
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A 21-year-old man presents for evaluation of dark urine. He is in generally good health with no chronic medical conditions. Three days earlier, he developed cough and wheezing. He was prescribed an antibiotic by his primary care provider and his pulmonary symptoms resolved. Today, he noted dark brown urine on his morning void. Exam demonstrates scleral icterus. Hemoglobin is 10 mg/dL (normal 12-15). Total serum bilirubin is 5mg/dL (normal 0.3-1.0). Testing of red cell hemolysate demonstrates decreased nicotinamide adenine dinucleotide phosphate (NADPH) generation. Decreased amounts of which of the following substances in red blood cells may be responsible for this man's presentation?
A) Hydrogen peroxide
B) Glutathione
C) Nicotinamide adenine dinucleotide
D) Adenine triphosphate
E) Superoxide
Answer B (correct answer): This man has acute hemolytic anemia caused by glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common inherited red cell enzyme disorder. This condition is caused by an inherited defect in the gene encoding the enzyme G6PD, which generates nicotinamide adenine dinucleotide phosphate (NADPH) as part of the HMP shunt. In the absence of normal G6PD function, red cells have a limited supply of glutathione and are vulnerable to free radical damage. Diagnosis can be made by demonstrating decreased production of NADPH among red cells.
Glutathione is an antioxidant that protects red cells against free radical damage from hydrogen peroxide (H2O2). In patients with G6PD deficiency, underproduction of NADPH causes conversion of glutathione to glutathione disulfide (see slide above from HMP shunt video in biochemistry). When glutathione levels become depleted, red cells cannot metabolize H2O2 which leads to free-radical-induced hemolysis.
Many foods (fava beans) and drugs (some antibiotics) generate free radicals in red cells. Ingestion of these substances may lead to oxidative damage and acute hemolysis in G6PD deficient patients.
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A 45-year-old man with a history of systemic lupus erythematous is evaluated for groin pain. For the past ten years he has required glucocorticoid therapy for lupus. For the past two months, he finds it difficult to bear weight on his left side due to constant, throbbing groin pain. On exam, pain is elicited with any motion of the left hip. MRI shows diffuse left femoral head edema with degenerative changes. Which of the following would be expected on biopsy of the femoral head?
A) Karyorrhexis
B) Liquefactive necrosis
C) Cellular shrinkage
D) Dysplasia
E) Neoplasia
Answer A (correct answer): This man has <a href="https://radiopaedia.org/articles/avascular-necrosis" rel="noopener noreferrer" target="_blank" style="color: rgb(64, 145, 198);">avascular necrosis</a> (osteonecrosis) of the femoral head, a common problem in patients with lupus especially those who take steroids. Vascular damage to the bone blood supply leads to necrosis of bone marrow elements and ultimately mechanical failure of the hip joint. The process is progressive with joint failure usually occurring within a few years necessitating hip replacement surgery. Some cases of osteonecrosis have an obvious cause of ischemic damage (e.g., femoral neck fracture). In most cases, however, the exact cause is unknown. Many of these cases are associated with lupus or glucocorticoid therapy via a poorly understood mechanism.
On biopsy, cells of the femoral neck will show typical changes of necrosis including karyorrhexis (fragmented nuclei). Other nuclear abnormalities that may be seen include karyolysis (loss of basophilic/dark color of nuclei) and pyknosis (nuclear shrinkage).
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A 16-year-old girl is brought to the pediatrician by her mother. The girl has been trying to lose weight to fit in with her peers at school. The mother has hypothyroidism and discovered that her daughter has been taking her levothyroxine pills for the past two months to increase her metabolism. The girl has no history of thyroid disease or chronic medical conditions, and she takes no medications. Which of the following is most likely occurring in this girl’s thyroid gland?
A) Atrophy
B) Hyperplasia
C) Hypertrophy
D) Metaplasia
E) Dysplasia
Answer A (correct answer): Levothyroxine is a synthetic form of the thyroid hormone thyroxine (T4). Serum thyroid hormone levels are regulated through the anterior pituitary release of thyroid-stimulating hormone (TSH). By taking her mother’s levothyroxine, this girl has suppressed the release of TSH and therefore removed normal stimulation of the thyroid gland. In the absence of stimulation, the thyroid gland will undergo atrophy, a common cellular adaptation to the removal of a hormone stimulus.
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A 51-year-old woman is evaluated for abnormal uterine bleeding. Her menstrual periods occurred at regular 28-day intervals until 6 months ago. Since then, her cycles have been longer than usual. She has also noted frequent spotting. Her last menstrual period was two months ago. She is in excellent health and runs three marathons per year. She has no chronic medical conditions and takes no medications. Weight is 130 lbs and height is 5 feet 5 inches. Blood pressure and pulse are within normal limits. The adnexa and uterus are without swelling and non-tender on exam. Serum hCG level is within normal limits. Endometrial biopsy is performed. Which of the following is most likely to be found?
A) Acute inflammation
B) Chronic inflammation
C) Hyperplasia
D) Carcinoma
E) Atrophy
Answer C (correct answer): This woman has dysfunctional uterine bleeding during perimenopause. Menopause is the cessation of ovulation and occurs at an average age of 51 years. As women approach menopause, the time between menstrual periods often increases and becomes irregular. In addition, women may experience an “anovulatory cycle” meaning a cycle with no ovum released from the ovaries. When this occurs, the ovary does not produce progesterone and the uterus is exposed to “unopposed estrogen” which stimulates endometrial hyperplasia. Hyperplasia leads to intermittent shedding of the endometrium resulting in irregular bleeding.
Reference: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576794/" rel="noopener noreferrer" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576794/</a>
After several years of irregular periods and bleeding, this woman will eventually experience menopause defined as 12 months of amenorrhea.
Anovulatory bleeding is common in women approaching menopause and girls who recently began menstruating. In the first few years after menarche, anovulation is the most common cause of irregular bleeding. This occurs because the hypothalamic-pituitary axis has not yet matured to support regular menstrual cycles
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A 55-year-old man is referred for a screening chest x-ray due to a 20-pack-year history of smoking. A 2-centimeter pulmonary nodule is identified in the left lower lobe. Surgical excision is performed. Grossly, the lesion is tan-colored, well-encapsulated, and firm. Microscopic examination reveals a heterogeneous collection hyaline cartilage, fat, respiratory epithelial cells, and smooth muscle. Which of the following would most likely have occurred if this lesion had not been removed?
A) Spread throughout lung
B) Metastasis to liver
C) Slow growth over years
D) Cushing's syndrome
E) SIADH
Answer C (correct answer): This man has a pulmonary hamartoma, a benign lesion that is responsible for about 10% of pulmonary nodules. They are the most common benign tumor of the lung. Hamartomas contain disorganized but normal tissue from the organ in which they are found. In the case of lung hamartomas, these lesions typically contain fat, epithelial cells, fibrous tissue, and cartilage. In some cases, calcification is present which helps with identification by x-ray or CT scan. Hamartomas grow slowly over years and carry an excellent prognosis which is why they are classified as benign.
Researchers are evaluating four different lines of epithelial cells from human breast tissue. Which of the following characteristics suggest the malignant potential of these cells?
A) Resistance to natural killer cells
B) Strong response to growth inhibitors
C) Strong dependence on growth promoters
D) Inability to invade basement membranes
E) Increased p53 gene activity
Answer A (correct answer): There are several well-described hallmarks seen among all malignant neoplasms. These include the ability to evade cell death by the immune system. Natural killer cells were first identified as lymphocytes capable of killing tumor cells without prior exposure (i.e., without being sensitized, as is required for B and T cells). They recognize antigens expressed on many tumor cells and subsequently destroy the cell. To have malignant potential, cells must possess some ability to avoid this natural defense mechanism.
A 42-year-old man is evaluated for a rash. He has end-stage renal disease requiring hemodialysis three times per week. He complains of a painful skin lesion that has progressed over the past few weeks (image below). Which of the following contributed to development of this finding?
A) Hypercalcemia
B) Hyperphosphatemia
C) Elevated BUN
D) Hypomagnesemia
E) Hypokalemia
Answer B (correct answer): This man has calciphylaxis, a rare, dangerous skin complication of chronic renal failure. Patients with chronic renal failure develop hyperphosphatemia due to inability to excrete phosphate in the urine. Serum phosphate binds to calcium, pulling calcium from the circulation and causing hypocalcemia. Calcium-phosphate crystals deposit in the walls of blood vessels of the skin. This can lead to ischemic necrosis of the skin, which presents as described in the question. Renal failure patients are prescribed “phosphate binders,” drugs that lower serum phosphorus to prevent hyperphosphatemia and calciphylaxis.
A 62-year-old woman with a history of rheumatoid arthritis has an elective hysterectomy for the treatment of uterine fibroids. A five-centimeter pelvic skin incision is made and then sutured at the completion of the procedure. Four days after surgery, her abdominal incision shows minimal granulation tissue formation. She is afebrile and there is no pus in the wound. The skin edges have separated between two of the sutures. Which of the following most likely explains this woman’s wound findings?
A) Thrombocytopenia
B) Glucocorticoid therapy
C) Wound infection
D) Zinc deficiency
E) Copper deficiency
Answer B (correct answer): This woman has delayed wound healing, a common problem in clinical medicine. Four days after surgery she has minimal granulation tissue and her wound shows evidence of dehiscence. There are many causes of delayed wound healing but the most common include infection, diabetes, glucocorticoid therapy, and poor nutritional status. In this woman with a history of autoimmune disease, glucocorticoid therapy is most likely. Steroids have a number of anti-inflammatory effects including inhibition of neutrophil migration. This delays the wound healing process.
A 6-year-old boy is brought to the pediatrician for evaluation of a scratch. The mother states the boy was scratched on the face by another child on the playground. Examination reveals a two-centimeter laceration on the left cheek. The mother is advised to keep the wound clean. Two weeks later, the child returns to the clinic and the cheek appears normal. Which of the following was most important for healing of this boy’s skin?
A) Angiogenesis
B) Fibroblast proliferation
C) Intact basement membrane
D) Type III collagen deposition
E) Type I collagen deposition
Answer C (correct answer): This boy’s wound has healed with no scar formation. This occurs in tissues capable of regeneration like the skin if the basement membrane remains intact and basal layer stem cells are not destroyed. Superficial skin wounds often heal with no scar because these wounds do not disrupt the basement membrane and the skin is capable of regeneration.
Special Note: Many tissues can heal with no scar including the skin after superficial lacerations, the gastrointestinal mucosa after an ulcer, or the lungs after pneumonia. In all of these cases, the tissues have regenerative capacity, and the injury does not destroy the basement membrane and stem cells. None of the typical scar processes will occur when this happens.
A general surgeon is researching the causes of wound failure in skin wounds after emergency surgery. Using a novel technique, he estimates wound mechanical strength as a function of days following the injury. In the graph below, at which point is vascular endothelial growth factor (VEGF) activity likely to be highest?
A) Day 1
B) Day 5
C) Day 9
D) Day 11
E) 1 month
Answer B (correct answer): Wound strength depends on the amount and quality of collagen deposition. In the first few days after injury, no collagen is present and wounds are prone to failure. During this time, sutures, staples, or other devices are used to maintain skin approximation. When collagen deposition begins around days 3 to 5, wound strength steadily increases. Over time, type III collagen is replaced with stronger type I collagen which further increases wound integrity. By several weeks, collagen synthesis is complete. In later phases of wound healing (weeks to months), other collagen modifications occur including crosslinking. These further increase wound strength although the wound will never reach the strength of uninjured tissue.
Vascular endothelial growth factor (VEGF) is critical for angiogenesis which occurs after about 3 days for up to one or two weeks. Growth of new blood vessels brings fibroblasts to the wound so these cells can begin secreting collagen.
A 62-year-old man is evaluated for coronary artery disease. Five months ago, he underwent four vessel coronary artery bypass grafting (CABG) surgery for symptoms of angina. Since the operation, he has completed six weeks of cardiac rehabilitation therapy. He denies any exertional chest pain. His medications include aspirin, metoprolol, and atorvastatin. Blood pressure and pulse are within normal limits. Examination of the chest reveals a sternal incision that is clean and dry with no warmth, tenderness, or redness. Which of the following processes is occurring in this man’s scar at this time?
A) Granulation tissue formation
B) Type II collagen synthesis
C) Angiogenesis
D) Collagen cross-linking
E) No activity at this time
Answer D (correct answer): This man’s chest incision has healed by primary intention which progresses through several phases over the days, weeks, and months following surgery. When the wound edges are sutured together, the following 24 hours are dominated by clot formation and neutrophil invasion within the wound. From about three days to about one week, neutrophils are replaced by macrophages (for debris phagocytosis) and “granulation tissue” fills the wound space meaning thick fluid with protein and cells. During this time angiogenesis occurs, fibroblasts infiltrate the wound, and collagen synthesis begins. After one month, inflammatory cells are absent and only fibroblasts remain. Collagen synthesis is complete after several weeks, but collagen remodeling continues for up to six months to one year after injury. The changes that occur during remodeling include cross-linking of collagen.
A 14-year-old girl is evaluated one week after an appendectomy. She had intense abdominal pain one week ago when she was diagnosed with acute appendicitis. Her recovery from surgery was uneventful and her abdominal pain has resolved. She is eating normally and reports normal bowel habits. She denies fever, chills, or sweats. Abdominal exam reveals a 5-cm incision that is clean, dry, and intact. There is minimal redness at the edges of the wound. Which of the following processes is occurring in the wound at this time?
A) Granuloma formation
B) Neutrophil infiltrate
C) Angiogenesis
D) Collagen cross-linking
E) Clot formation
Answer C (correct answer): This girl’s incision has healed by primary intentionwhich progresses through several phases over the first few days, weeks, and months. When the wound edges are sutured together, the following 24 hours are dominated by clot formation and neutrophil invasion within the wound. From about three days to about one week, neutrophils are replaced by macrophages (for debris phagocytosis) and granulation tissue fills the wound space. During this time angiogenesis occurs, fibroblasts infiltrate the wound, and collagen synthesis begins. After one month, inflammatory cells are absent and only fibroblasts remain. Collagen synthesis is complete after several weeks, but collagen remodeling continues for up to six months to one year after injury.
This girl is one week out from surgery. Her wound is in the fibroblast proliferative phase where angiogenesis occurs.
Scientists are evaluating the immune response to tissue damage among epithelial cells. They characterize a protein complex that assembles in the cytosol when cells are exposed to high levels of uric acid. This assembly most likely leads to the cellular release of which of the following?
A) C5a
B) IgG
C) IL-1
D) IL-5
E) IFN-gamma
Answer C (correct answer): The question stem is describing the inflammasome, a multi-protein complex that assembles in the cytoplasm of cells in response to cellular damage or infection. Many cell types including epithelial cells contain proteins called “NOD-like receptors” (NLRs) within the cytoplasm. These receptors are similar to toll-like receptors which are found on the cell membrane surface. NLRs bind numerous components of necrotic or dying cells including uric acid, excess ATP, or free DNA (collectively called damage-associated molecular patterns or DAMPs). They have also been shown to bind some components of bacteria (called pathogen-associated molecular patterns or PAMPs). These substances may be taken up from the extracellular environment and bound to cytoplasmic NLRs. Once activated, many NLRs assemble into a multi-protein complex called the inflammasome. This structure activates the enzyme caspase-1 that generates IL-1 to initiate an inflammatory response. This is sometimes called the “NLR-inflammasome pathway” of initiating inflammation. It may play a role in some autoimmune diseases.
Key point: Toll-like receptors are found on cell membranes and within endosomes. NLRs perform a similar function but are intracellular.
Scientists identify a surface receptor on macrophages that binds molecular patterns found only in bacteria. Once activated, the receptor triggers the release of cytokines. Further evaluation shows that this receptor is also activated by some components of human cells. Activation by human cellular components is helpful for the immune response to which of the following?
A) Vaccination
B) Necrosis
C) Candida
D) Schistosoma
E) Staph Aureus
Answer B (correct answer): The question is describing toll-like receptors (TLRs), a key component of the innate immune response. TLRs are an example of “pattern recognition receptors” and are found on the surface of macrophages and other cells. They recognize pathogen-associated molecular patterns (PAMPs), small molecular structures found only on pathogens like bacteria. When a PAMP binds a TLR on a macrophage, the cell becomes activated. In this primed state, it releases cytokines to activate the inflammatory response.
As TLRs were studied, evidence emerged that these receptors also bind some components of normal human cells (i.e., non-foreign substances). These cellular components are called damage-associated molecular patterns (DAMPs) and are important for initiating the inflammatory response to necrosis. Many DAMPs have been described including proteins of the nucleus, heat shock proteins (normally found in the cytoplasm), ATP, uric acid, RNA, and DNA. When necrosis occurs, these bind to TLRs to initiate inflammation.
A 72-year-old woman is evaluated for fever, chills, and dysuria. Ten years ago, she received chemotherapy and radiation for the treatment of breast cancer. Three days ago, she noted burning on urination. She began drinking cranberry juice at the recommendation of a friend. For the past 24 hours, she has felt feverish with chills, rigors, and sweating. Her temperature is 102.1ºF. Pulse is 110/min and blood pressure is 100/70 mmHg. Urinalysis shows numerous white cells and bacteria. White blood cell count is 54,000/mm<sup style="color: rgb(0, 0, 0);">3 </sup>(normal <11,000) with 80% neutrophils and 15% bands. Which of the following is the most likely cause of her elevated white blood count?
A) Leukemia
B) Myeloproliferative disorder
C) Leukemoid reaction
D) Occult lymphoma
E) Polycythemia vera
Answer C (correct answer): This woman has pyelonephritis, a bacterial infection of the kidney. This often begins as a urinary tract infection with typical symptoms like dysuria. Bacteria “ascend” into the kidneys invoking a systemic response to infection including fever, chills, and elevated white blood cell (WBC) count. This woman’s WBC count is very high, at the level seen in malignancies like leukemia. However, the high WBC is occurring in the setting of focal infectious symptoms (dysuria) with immature neutrophils (band forms) in the blood. This is consistent with a leukemoid reaction, a physiologic response to infection.
A 38-year-old woman presents with abdominal pain. For the past three days, she has had fatigue, nausea, and right upper quadrant abdominal pain. She recently engaged in sexual activity with a new partner without using condoms. Her sclera are icteric. Abdominal palpation elicits tenderness in the right upper quadrant. Serum testing shows increased AST and ALT. Hepatitis B surface antigen is positive. Which of the following is the major cause of damage to this woman’s liver?
A) Coagulative necrosis
B) Liquefactive necrosis
C) Caseous necrosis
D) Fat necrosis
E) Apoptosis
Answer E (correct answer): This woman has acute hepatitis B infection. The major cause of liver damage in hepatitis B is apoptosis of hepatocytes caused by CD8+ T cells. Acute viral hepatitis leads to a lymphocyte infiltrate in the liver, very different from the acute inflammatory infiltrates containing neutrophils seen in bacterial infections. In acute hepatitis, scattered areas of “spotty necrosis” may occur but apoptosis is the major process damaging liver cells. Biopsy may show microscopic evidence of apoptosis including shrunken hepatocytes with “intensely eosinophilic” cytoplasm and fragmented nuclei.
A 72-year-old man receives a diagnosis of prostatic adenocarcinoma after his primary care physician notes a prostate nodule on digital rectal exam. He is treated with external beam radiation therapy which leads to a decrease in tumor burden. Which of the following contributed to tumor cell death in this patient?
A) p53 activation
B) BAX inhibition
C) BCL2 activation
D) Hormone withdrawal
E) Catalase activation
Answer A (correct answer): Radiation therapy causes DNA damage in malignant cells. DNA damage leads to phosphorylation of the p53 protein, a major regulator of the cell cycle. Phosphorylated p53 will lead to cell cycle arrest (see video on cell cycle in the cell biology section). During this time, DNA repair may occur. If DNA repair is not possible, activated p53 can also <a href="https://www.ncbi.nlm.nih.gov/pubmed/25980443" rel="noopener noreferrer" target="_blank" style="color: rgb(64, 145, 198);">trigger the pro-apoptosis factors, BAK and BAX</a>. This leads to apoptosis of cancer cells and a decrease in cancer cell burden.
A 6-year-old boy develops acute lymphoblastic leukemia with CD10+ pre-B cells. He is treated with glucocorticoids, vincristine, daunorubicin, and cytarabine and achieves remission. Two years later, he develops fatigue and malaise. Peripheral white blood count is 100,000/mm3 with lymphoblasts on peripheral smear. He is treated with glucocorticoids with no reduction in white cell count. Glucocorticoids are ineffective because this boy’s cancer cells are resistant to which of the following?
A) Cell surface receptor binding
B) DNA cross linking
C) Caspase activation
D) FAS-FAS ligand binding
E) Membrane lipid peroxidation
Answer C (correct answer): Glucocorticoids induce apoptosis in lymphocytes through activation of caspase enzymes. This is one of the mechanisms of glucocorticoids as anti-inflammatory drugs. This effect is also beneficial in many forms of malignancy including some leukemias as glucocorticoids can induce apoptosis of malignant cells. In this boy, leukemic cells have become resistant to the pro-apoptotic effects of glucocorticoids.
A 72-year-old woman develops fevers, chills, and cough. Chest x-ray shows a right lower lobe infiltrate. Sputum culture grows lancet-shaped gram-positive cocci. She is started on therapy with levofloxacin. Her symptoms persist and a bronchoalveolar lavage is performed. Analysis shows neutrophils and bacteria. Which of the following enzymes initiates bacterial killing in these neutrophils?
A) NADPH oxidase
B) Superoxide dismutase
C) Myeloperoxidase
D) Catalase
E) Glutathione peroxidase
Answer A (correct answer): This woman has a pulmonary infection with streptococcus pneumoniae. Neutrophils are drawn to the site of infection in the lungs as part of the acute inflammatory response. The major role of neutrophils is phagocytosis of bacteria. Once engulfed, bacterial killing occurs via the respiratory burst within phagosomes of neutrophils. The first step in the respiratory burst is catalyzed by NADPH oxidase.
A 21-year-old man presents for evaluation of dark urine. He is in generally good health with no chronic medical conditions. Three days earlier, he developed cough and wheezing. He was prescribed an antibiotic by his primary care provider and his pulmonary symptoms resolved. Today, he noted dark brown urine on his morning void. Exam demonstrates scleral icterus. Hemoglobin is 10 mg/dL (normal 12-15). Total serum bilirubin is 5mg/dL (normal 0.3-1.0). Testing of red cell hemolysate demonstrates decreased nicotinamide adenine dinucleotide phosphate (NADPH) generation. Decreased amounts of which of the following substances in red blood cells may be responsible for this man's presentation?
A) Hydrogen peroxide
B) Glutathione
C) Nicotinamide adenine dinucleotide
D) Adenine triphosphate
E) Superoxide
Answer B (correct answer): This man has acute hemolytic anemia caused by glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common inherited red cell enzyme disorder. This condition is caused by an inherited defect in the gene encoding the enzyme G6PD, which generates nicotinamide adenine dinucleotide phosphate (NADPH) as part of the HMP shunt. In the absence of normal G6PD function, red cells have a limited supply of glutathione and are vulnerable to free radical damage. Diagnosis can be made by demonstrating decreased production of NADPH among red cells.
Glutathione is an antioxidant that protects red cells against free radical damage from hydrogen peroxide (H2O2). In patients with G6PD deficiency, underproduction of NADPH causes conversion of glutathione to glutathione disulfide (see slide above from HMP shunt video in biochemistry). When glutathione levels become depleted, red cells cannot metabolize H2O2 which leads to free-radical-induced hemolysis.
Many foods (fava beans) and drugs (some antibiotics) generate free radicals in red cells. Ingestion of these substances may lead to oxidative damage and acute hemolysis in G6PD deficient patients.
A 45-year-old man with a history of systemic lupus erythematous is evaluated for groin pain. For the past ten years he has required glucocorticoid therapy for lupus. For the past two months, he finds it difficult to bear weight on his left side due to constant, throbbing groin pain. On exam, pain is elicited with any motion of the left hip. MRI shows diffuse left femoral head edema with degenerative changes. Which of the following would be expected on biopsy of the femoral head?
A) Karyorrhexis
B) Liquefactive necrosis
C) Cellular shrinkage
D) Dysplasia
E) Neoplasia
Answer A (correct answer): This man has <a href="https://radiopaedia.org/articles/avascular-necrosis" rel="noopener noreferrer" target="_blank" style="color: rgb(64, 145, 198);">avascular necrosis</a> (osteonecrosis) of the femoral head, a common problem in patients with lupus especially those who take steroids. Vascular damage to the bone blood supply leads to necrosis of bone marrow elements and ultimately mechanical failure of the hip joint. The process is progressive with joint failure usually occurring within a few years necessitating hip replacement surgery. Some cases of osteonecrosis have an obvious cause of ischemic damage (e.g., femoral neck fracture). In most cases, however, the exact cause is unknown. Many of these cases are associated with lupus or glucocorticoid therapy via a poorly understood mechanism.
On biopsy, cells of the femoral neck will show typical changes of necrosis including karyorrhexis (fragmented nuclei). Other nuclear abnormalities that may be seen include karyolysis (loss of basophilic/dark color of nuclei) and pyknosis (nuclear shrinkage).
A 16-year-old girl is brought to the pediatrician by her mother. The girl has been trying to lose weight to fit in with her peers at school. The mother has hypothyroidism and discovered that her daughter has been taking her levothyroxine pills for the past two months to increase her metabolism. The girl has no history of thyroid disease or chronic medical conditions, and she takes no medications. Which of the following is most likely occurring in this girl’s thyroid gland?
A) Atrophy
B) Hyperplasia
C) Hypertrophy
D) Metaplasia
E) Dysplasia
Answer A (correct answer): Levothyroxine is a synthetic form of the thyroid hormone thyroxine (T4). Serum thyroid hormone levels are regulated through the anterior pituitary release of thyroid-stimulating hormone (TSH). By taking her mother’s levothyroxine, this girl has suppressed the release of TSH and therefore removed normal stimulation of the thyroid gland. In the absence of stimulation, the thyroid gland will undergo atrophy, a common cellular adaptation to the removal of a hormone stimulus.
A 51-year-old woman is evaluated for abnormal uterine bleeding. Her menstrual periods occurred at regular 28-day intervals until 6 months ago. Since then, her cycles have been longer than usual. She has also noted frequent spotting. Her last menstrual period was two months ago. She is in excellent health and runs three marathons per year. She has no chronic medical conditions and takes no medications. Weight is 130 lbs and height is 5 feet 5 inches. Blood pressure and pulse are within normal limits. The adnexa and uterus are without swelling and non-tender on exam. Serum hCG level is within normal limits. Endometrial biopsy is performed. Which of the following is most likely to be found?
A) Acute inflammation
B) Chronic inflammation
C) Hyperplasia
D) Carcinoma
E) Atrophy
Answer C (correct answer): This woman has dysfunctional uterine bleeding during perimenopause. Menopause is the cessation of ovulation and occurs at an average age of 51 years. As women approach menopause, the time between menstrual periods often increases and becomes irregular. In addition, women may experience an “anovulatory cycle” meaning a cycle with no ovum released from the ovaries. When this occurs, the ovary does not produce progesterone and the uterus is exposed to “unopposed estrogen” which stimulates endometrial hyperplasia. Hyperplasia leads to intermittent shedding of the endometrium resulting in irregular bleeding.
Reference: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576794/" rel="noopener noreferrer" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576794/</a>
After several years of irregular periods and bleeding, this woman will eventually experience menopause defined as 12 months of amenorrhea.
Anovulatory bleeding is common in women approaching menopause and girls who recently began menstruating. In the first few years after menarche, anovulation is the most common cause of irregular bleeding. This occurs because the hypothalamic-pituitary axis has not yet matured to support regular menstrual cycles
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