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Mail Box # Name SS#: GGG GGG-GG-GGGG INSTRUCTIONS FOR SBPM EXAM February 7th, 2000 TIME ALLOTTED: THREE HOURS GGG Your Mail Box Number Please follow the instructions carefully: 1. Write your name, social security number and your three digit mail box number on the top of this page 2. Write your mail box number only on every sheet of paper that you use. 3. Please answer in the spaces provided. We will not read additional material on the back or on another page. 4. Write clearly and legibly. If we can not read your answer we can not award you credit. You may use diagrams to answer the questions. 5. Before you start to write think deeply about the main point of the question and use scratch paper to outline your answer. 6. Follow the directions carefully for each section. When you know a specific mechanism, put it into the answer!! Questions During the Exam: we will not answer any questions during the exam. If a question is unclear or ambiguous please do the following: 1. Answer the question as best you can after stating the assumptions you made to answer the question. 2. Submit an e-mail note to me ([email protected]) explaining explicitly what was unclear about the question. Mail Box # GGG 1. An elderly patient presents to the hospital with jaundice and is found to have a carcinoma of the head of the pancreas. Briefly describe the specific changes from normal in the bile pigments of plasma, urine, and feces in this patient. Patients in this clinical situation classically have painless jaundice due to obstruction of the common bile duct. Among other signs (including pruritis from the bile salts in the skin, abdominal pain, and weight loss) they also have dark urine and acholic (clay-colored) stool. Because of the obstruction, total bilirubin will rise, with a much greater contribution to the rise consisting of conjugated bilirubin because the dysfunction is largely extrahepatic (not within the liver). Less conjugated bilirubin will reach the intestine and thus the patient will have lower levels of bilirubin, urobilinogen, and stercobilin (the latter two created by bacteria) in the feces. The lack of stercobilin makes the feces appear grey. As there is little urobilinogen to recirculate into the blood, little urobilin will be made and excreted by the kidney. However, water soluble conjugated bilirubin will be excreted and can be found in the urine, darkening its color. 2. What effect does omeprazole, an inhibitor of H+/K+–ATPase, have on gastrin and secretin secretion? Omeprazole is a an inhibitor of the gastric parietal cell proton pump and is used to manage peptic ulcer disease by lowering the levels of acidity in the stomach. Gastrin secretion from G cells is inhibited by protons in the stomach lumen (protons stimulate somatostatin release from antral D cells and somatostatin blocks gastrin release). Thus, omeprazole will cause high gastrin levels. Secretin release is stimulated by protons in the proximal small intestine in order to signal production of bicarbonate to neutralize acidity. Thus, omeprazole will cause lower secretin levels. What's more, secretin inhibits the release and action of gastrin, magnifying the direct effect of the lower acid levels on gastrin production even more. 3. Why do patients with lactase deficiency get diarrhea after consuming milk? Lactase is a disaccharidase located on the brush border that converts lactose to glucose and galactose, which are then absorbed. In a patient with lactase deficiency, starches in dairy products are still broken down by amylase creating a large supply of lactose disaccharides. These cannot be broken down further and thus are not absorbed and remain in the lumen as osmotically active particles, retarding net water absorption. Furthermore, the lactose is taken up by bacteria which convert the sugar into, among other things, free fatty acids and carbon dioxide gas. This contributes to the osmotic potential and gassy symptoms. Lactase deficiency can be caused by a congenital absence or defective synthesis of the enzyme as well as bacterial overgrowth or other infections of the brush border. Symptoms include gas, watery diarrhea, and bloating after eating dairy products. Yogurt, which contains low levels of lactose because it is broken down by bacteria, is one dairy product that does not bring on such symptoms. 4. “Bacterial overgrowth” of the small intestine often leads to fat malabsorption. Why? Bile salts are responsible for stabilization of the emulsion, remove the products of the reaction via mixed micelles, and lowering the optimum pH of lipase, thus preparing fats to be absorbed by the brush border of the small intestine. The cholyl amidases of bacteria in the terminal ileum and colon break down primary bile salts (conjugated bile from the liver) into deconjugated and dehydroxylated forms. Secondary bile salts (lithocholate, deoxycholate) differ from primary ones in that they have a higher pKa, making them more permeable to the gut wall (a greater percentage of molecules will exist in the undissociated form which can permeate the mucosal cell membranes of the terminal ileum by passive diffision) and less effective at digestion. Bacterial overgrowth thus accelerates bile salt deconjugation, making bile salts less effective at and less available for digestion. Mail Box # GGG 5. Why do GI doctors universally loathe the non-steroidal anti-inflammatory agent Advil© Advil is a non-steroidal anti-inflammatory drug (NSAID), which inhibits prostaglandin production via nonspecific inhibition of the cyclooxygenase (COX) enzymes. Prostaglandins contribute to mucosal defense by stimulation of bicarbonate and mucus secretion and inhibition of acid secretion. This is why Tylenol, an analgesic that does not work through inhibition of cyclooxygenase, is given to ulcer patients for pain relief. This is also why selective COX-2 inhibitors have such potential; they still work at analgesics and it is believed the COX-1 enzyme is the main contributor to protection of the gastric mucosa. Mail Box # GGG 6. A patient ingests a piece of meat whose amino acids are tagged with radioactive nitrogen. We sample their blood and find nitrogen (in the form of urea produced in the liver). Describe the individual steps that result in the components of the steak ending up in the blood. Discuss acid denaturation, action of pepsin, pancreatic proteases and finally the peptidases attached to the luminal membrane of the enterocytes. Then, there is absorption via Na+-coupled amino acid transporters. 7. A patient undergoes an x-ray test that requires putting dye into his colon. The finding are not clear and he needs another test. Approximately how long must he wait until the dye from the old test is cleared from his colon and why? About a week: see Motility sections and discussion of transit time. 8. In treating a patient’s ulcer, a surgeon performs a “gastro-jejunal by-pass” where there is a passage made from the stomach to the early jejunum. What would be two consequences of this procedure and why? This is open ended with a number of ideas all of which would probably be correct: Acid damage to the jejunum because of the failure to neutralize the pH of the gastric contents; lipid malabsorption because of pancreatic lipase is inactivated at a low pH. There are many right answers (as long as they can be explained so that they make sense!). 9. Patients with Crohn’s disease (inflammatory disease of the bowel) often get “terminal ileitis”, inflammation of the terminal ileum. Describe two of the consequences of this complication? In other words: What does the ileum (specifically the ileum and not the jejunum or colon) do?! B12 deficiency (site of its absorption) and bile salt loss (interruption with the enterohepatic circulation). 10. A patient is found to have iron-deficiency (anemia). Describe three different mechanisms that could lead to iron deficiency. Lack of absorption because of an abnormality of the duodenum; low acidity which impairs Fe++ absorption by preventing the formation of insoluble complexes, and vitamin C deficiency (vitamin C maintains Fe in ferrous state which is more easily absorbed). Mail Box # GGG 11. What would be the best blood test of pancreatitis (inflammation of the pancreas with leakage of pancreatic secretions into the blood), and why? The principles of a "perfect" blood test for a particular condition include the following: the tested parameter should 1) be easy to detect and measure, 2)have high sensitivity (i.e. few false negatives), and 3)have high specificity (i.e. few false positives). For these reasons, the best blood test for pancreatitis is something specific to the organ that should not ordinarily be found in the blood in large quantities. Pancreatic proteases, amylase, and lipase, as exocrine pancreatic secretions, fit this description. Too many things can affect the blood bicarbonate concentration in order for it to be a valid test of pancreatitis. In clinical practice, amylase and lipase levels are used; it should be noted that salivary amylase also reacts in the assay, and therefore lipase levels are more specific for pancreatic inflammation. 12. Patients who take “sympathomimetics” (mimic the sympathetic nervous system) may get constipated. Describe two different mechanisms by which these drugs could cause difficulty in moving stool through the colon? (Hint: think water and transit time) Sympathomimetic drugs can lead to constipation via two mechanisms: 1) through enterocyte receptors for NE and other mediators, electro-neutral reabsorption of NaCl is stimulated and electrogenic secretion of Cl and HCO3 is inhibited. This leads to higher net fluid absorption, and a harder stool that is more difficult to move antegrade and 2) sympathetic stimulation inhibits intestinal peristalsis, increasing stool transit time; not only does this increase intervals between stools in its own right, it allows more contact time with colonic mucosa, more fluid absorption, and again harder stools. 13. How does enamel differ from typical bone? The enamel is different from bone both morphologically and functionally. Structurally, the enamel contains much more hydroxyapatite crystal than bone (and is therefore more brittle) and no collagen. Its matrix is organized in sheaths around hydroxyapatite prisms, and contains enamelin and tuft protein. During development the enamel matrix contains amelogenin, which is laid down and then resorbed by ameloblasts. These cells then die when the tooth erupts. Therefore, mature enamel is acellular and cannot be remodeled during life like bone; it only undergoes physiochemical changes. 14. Describe a simple feedback loop in which the presence of digested material in the intestine would stimulate the peristaltic contraction of smooth muscle in that particular area. The presence of a food bolus in a particular section of the intestine causes distension of the mucosa in that area. Enterochromaffin cells sense this distension (like a baroreceptor) and release serotonin, which is picked up by sensory neurons in the submucosal plexus of the enteric nervous system. These neurons project to interneurons in the myenteric plexus, which eventually leads to contraction of the smooth muscle layers proximal to the bolus andrelaxation distal. These contractions propel the bolus distally and lead to decreased distension of the mucosa and shut-off of the feedback loop in that area. Mail Box # GGG 15. A patient ingests triglycerides who glycerol backbones are tagged with radioactive carbon. We sample the patient’s blood and find tracer carbon in circulating triglycerides. Describe the individual steps that result in the ingested triglyceride appearing as a blood triglyceride. The first few steps of triglyceride digestion increase the surface area for pancreatic enzymes to act. The fat is emulsified by mixing in the stomach and coating with phospholipids; gastric lipase acts on the triglycerides to cleave off fatty acids and stabilize the emulsion. Pancreatic secretions act on the mixture in the duodenum; pancreatic lipase, functionally optimized by the presence of HCO3 and co-lipase, cleaves TG into fatty acids (FA) and monoglycerides (MG). Bile salts help to stabilize the emulsion further, but more importantly form micelles to solubilize the hydrophobic FA and MG. The FA and MG diffuse across the enterocyte membrane, where they are re-esterified and packaged with other lipids into chylomicrons. The chylomicrons are released into intestinal lymphatics (lacteals). The lymph (and radioactive TG, in this question) enters the circulation via the thoracic duct. (Note that the above process occurs for TG with long-chain FA. Medium-chain FA are more soluble and may be absorbed directly into the portal circulation) Mail Box # GGG HISTOLOGY 1. A. #101A PAS small intestine; B. #32 upper esophagus; C. #39 colon. For each of the following structures or functions, provide the letter or letters (or none) of the panel in which they are found. a. skeletal muscle b. enteric nervous system c. absorption d. stratified squamous non-keratinized epithelium e. smooth muscle f. esophagus g. stomach h. colon i. villi answers: a. B, b. A, B, C; c. A, C; d. B; e. A, B, C; f. B; g. none; h. C; i. A 2. A. EM chief cell; B. #34 stomach (#1 EM chief cell, #2 mucus neck cell, #3 parietal cell; C. EM Parietal cell. a. b. c. d. e. f. g. h. In panel B, identify the cell type numbered: 1. 2. 3. Provide one function for each of the numbered cell types: 1. 2. 3. The cell in Panel A is the same as #_________ in Panel B. Name one ultrastructural component that serves a specific function in this cell. What is that function? The cell in Panel C illustrates #_________ in Panel B. Name one ultrastructural component that serves a specific function in this cell. What is that function? Answers: a. 1. chief cell, 2. mucus neck cell, 3. parietal cell, b. 1. protein synthesis, production of zymogen (digestive enzymes), 2. undifferentiated cells, gives rise to other cell types, secrete soluble mucus, 3. produces acid (HCl), produces intrinsic factor; c. #1; d. RER, secretory granules; e. RER: protein synthesis, secretory granules: storage for regulated secretion; f. #3; g. mitochondria, canaliculi, tubulovesicular membrane system; h. mitochondria: provide energy for HCl transport; canaliculi: provides surface area for release of HCl; tubulovesicular membrane system: insert into plasma membrane for increased secretion at cell surface. 3. #48 recto-anal junction. A. anal canal - stratified cuboidal and stratified squamous keratinized epithelium; B. recto-anal junction; C. stratified cuboidal epithelium. a. The three panels A,B,C are from one portion of the gastrointestinal tract. Name the portion.__________________________________. b. Arrange the three panels in anatomical sequence, rostral to caudal. ___ ___ ___. c. Explain your reason for arranging the panels in this order. answers: a. rectoanal junction; b. B,C,A; c. simple columnar epithelium of the rectum shown in Panel B is most rostral portion shown; This is followed by stratified cuboidal epithelium in Panel C which is followed by the most terminal portion of the canal lined by stratified squamous keratinized epithelium shown in Panel A. Mail Box # GGG 4. A. Pancreatic acinus; B. Sublingual gland- mixed acinus, mucous acinus pointer on serous demilune; C. #40 Parotid. Answer TRUE or FALSE: a. Panel A is a micrograph of the pancreas. b. In Panel A cells are serous secreting. c. In Panel B the cells at the pointer secrete directly into capillaries. d. In Panel B there are both mucus and serous secreting cells. e. Panel C is the liver. f. Cholecystokinin (CCK) acts upon cells in panel A. g. The cells in Panel B are under both neural and hormonal control. Answers: a. True; b. True; c. False; d. True; e. False; f. True; g. True. 5. A. #114 Parotid - arrows on striated ducts; B. Dental #75 Sublingual gland, arrow on excretory duct; C. #43, exocrine pancreas, pointer on intercalated duct. a. b. c. d. e. The structures at the arrows in Panel A are specialized for what function? In Panel A, what is responsible for the eosinophilic staining of these structures? In Panel B, what is the function of the large structure at the arrow? In Panel C, name the structure at the arrow. In Panel C, name the product secreted by the structure at the arrow. answers: a. fluid and electrolyte transport, absorbs Na+; b. Palisading mitochondria; c. conduit; d. intercalated duct; e. HCO36. A. #47 Liver, 1=bile canaliculus, 2=Space of Disse; B. EM bile canaliculus, pointers on tight junctions; C. #45, liver, 3=bile duct, 4=portal vein, 5=hepatic artery. a. b. c. d. e. Name the organ. In Panel A, name the structure labeled #1. Which structure (#1 or #2) in Panel A is shown at the EM level in Panel B? In Panel B, name the structure at the arrows. Provide the number of the structure in Panel C into which the contents of #1 are delivered. answers: a. liver; b. bile canaliculus; c.#1; d. tight junctions; e. #3.