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TABLE OF CONTENTS Topics/Chapters Page Location Nephritic Syndrome and Membranoproliferative Glomerulonephritis (MPGN): Renal Pathophysiology Staph aureus: Integrated Bacteriology Review 1 Adrenal Pathophysiology and Pharmacology: Integrated Endocrinology Aortic Stenosis: Ventricular Pressure-Volume Loop Pathophysiology Visual Field Defects: Neurology and Mini Neuroanatomy Glycolysis and Glycolytic Enzyme Deficiencies: Biochemistry Simulated Post-test 14 9 23 28 37 48 Nephritic Syndrome and Membranoproliferative Glomerulonephritis Excerpts of Renal Pathophysiology Synopsis of Nephritic Syndrome and Membranoproliferative Glomerulonephritis (MPGN) Your patient is an 18 year-old woman who is seen for the complaint of occasional vomiting, back pain, swollen ankles, and oliguria. She has a 4-year history of arthritic joint pain. She previously tested positive for serum antinuclear antibody (ANA). On examination she has a blood pressure of 160/90 mmHg. Urinalysis is significant for hematuria, and serology shows high BUN and creatinine levels. To confirm your clinical suspicion, you schedule her for renal biopsy and immunofluorescence evaluation. Results of the biopsy show a tram-track appearance of the glomerular basement membrane and sub-endothelial deposits of immune complexes. 1. It is apparent that the patient has renal disease. Which of the two patterns of renal disease, nephrotic or nephritic, is supported by the given findings? _______________________________________ _______________________________________ 2. What is the classic triad of nephritic syndrome? _______________________________________ _______________________________________ 6. What are the major causes of nephritic syndrome? P____________________________________ I ____________________________________ G____________________________________ Rapidly progresses__________________ to H____________________________________ A____________________________________ M____________________________________ Hematuria! PIG Rapidly Progresses to HAM! "If slaughterhouses had glass walls, everyone would be vegetarian.” Sir Paul McCartney PETA Organization, UK *Imagine that the number “2” is in superscript to remind you of HYPER-tension! 3. What is the mechanism of severe hypertension and oliguria in nephritic syndrome? _______________________________________ _______________________________________ _______________________________________ _______________________________________ 4. Hematuria of nephritic syndrome is known as glomerular hematuria. How do we distinguish between hematuria of glomerular origin and those that originate from lower urinary tract locations? _______________________________________ _______________________________________ 5. What is the mechanism of red cell cast formation in nephritic syndrome? ________________________________________ ________________________________________ Question 7 Refers to the previous clinical vignette: 7. Which of the listed conditions that we covered with the mnemonic of “PIG RAPIDLY PROGRESSes to HAM” is the most likely cause of her symptoms? ________________________________________ ________________________________________ Hint: the tram-track appearance of the glomerular basement membrane and subendothelial deposits of immune complexes! Supplemental Drill Questions 8. What is the other commonly used term for rapidly progressive glomerulonephritis? ________________________________________ ________________________________________ 9. What is the hallmark of nephritic syndrome? ________________________________________ ________________________________________ 1. Northwestern Medical Review, Bare Minimum Pathology Review Series, 2012 10. What is the hallmark of nephrotic syndrome? ________________________________________ ________________________________________ 11. It is apparent that the procedure for collecting 24hour urine samples for measuring protein levels is quite difficult for patients as well as being more time-consuming and expensive. What is the commonly used alternative test for this purpose? ________________________________________ ________________________________________ 12. Single dipstick (spot) urinalysis tests are reported in four grades of 1+, 2+, 3+ and 4+. What does this reporting mean and what is the reason that proteinuria of more than 3.5 is known as nephrotic range proteinuria? _______________________________________ _______________________________________ 13. A patient has a single spot urine test of 2+; what does this mean? ________________________________________ ________________________________________ MPGN MPGN is an uncommon cause of nephritic syndrome that mostly affects children and young adults. There are two major types of MPGN, mesangiocapillary glomerulonephritis (known as Type I), and mesangial proliferative glomerulonephritis (known as Type II). Causes: Idiopathic or familial predispositions. Type I MPGN is due to abnormal immune response and sub-endothelial antibody and immune complex deposition. In either Type I or II, mesangial cells increase in number. Type I, as its name implies, is by far the most common and most commonly tested one on the USMLE and COMLEX examinations. Note: Type III MPGN is uncommon and is characterized by the concomitant presence of sub-endothelial and subepithelial deposits. Type I MPGN Type II MPGN AKA. Mesangiocapillary proliferative glomerulonephritis The more common type Immune complexes activate the classical complement pathway Subendothelial and mesangial deposits Thickening of the capillary walls and interposition of mesangial cytoplasm into the peripheral capillary loops Mesangial cell proliferation AKA. Mesangial proliferative glomerulonephritis No immune complexes involved Pathogenesis is related to uncontrolled activation of the alternate complement pathway Dense homogenous deposition along the glomerular basement membrane and in the mesangium Mesangial cell proliferation Dense deposits largely diminish kidney’s filtering ability 14. What is the function of mesangial cells? _______________________________________ _______________________________________ 15. What does the following diagram remind you of and how is it related to nephritic syndrome in general and MPGN in particular? _______________________________________ _______________________________________ Hint: Supreme pizza with lots of items! 16. Would you be able to identify hypercellularity of the glomeruli in light microscopy of other causes of nephritic syndrome besides poststreptococcal glomerulonephritis? ________________________________________ ________________________________________ 17. What is the basement membrane? ________________________________________ ________________________________________ 18. What is basal lamina and how does it differ from the basement membrane? ________________________________________ ________________________________________ 2. Northwestern Medical Review, Bare Minimum Pathology Review Series, 2012 19. What is the location and function of the basal lamina? _______________________________________ _______________________________________ 20. What are the 3 layers of the basal lamina and how do they help to differentiate the basement membrane from the basal lamina? _______________________________________ _______________________________________ 21. What are the major chemical ingredients of the laminal layers? ________________________________________ ________________________________________ 22. What staining technique is most helpful in highlighting the basement membrane for visualization in light microscopy because of the presence of glycoproteins (e.g. heparan sulfate)? ________________________________________ ________________________________________ Hint: The color scheme of the above picture must have been a pink-red color! 23. An 18 year-old patient with a recent history of streptococcal sore throat presents with sudden onset of hematuria and hypertension. Within 4 days his condition worsened and his 24-hour urine protein exceeded 3.5 grams. A renal biopsy was performed. Results were significant for crescentic urinary spaces. What is your most probable diagnosis? _______________________________________ Type I MPGN characteristic microscopic findings are increased number of mesangial cells, thickened basement membrane, extension of mesangium in between the epithelial and endothelial cells, narrow lumen of the vessels, and widespread mesangial and subendothelial deposits of immune complexes. Type II MPGN Type II MPGN presents with proliferation of mesangial cells, lack of subendothelial deposits, and thickened basement membrane (see the above diagram). The thickened basement membrane may be due to combined growth of mesangial matrix and basement membrane. 24. What are the two major microscopic findings of MPGN 1? ________________________________________ ________________________________________ 25. You might have heard of the term “tram track” in conjunction with MPGN; what does it really mean? ________________________________________ ________________________________________ Type I MPGN The answer will be evident soon! *The dumbbell-shaped structure in the left capillary is a red blood cell! 26. What other staining method will highlight the basement membrane? _______________________________________ 3. Northwestern Medical Review, Bare Minimum Pathology Review Series, 2012 31. Does nephritic or nephrotic pattern of MPGN present in a rapidly or slowly progressive manner? ________________________________________ ________________________________________ 32. Which of the two MPGNs is called dense deposit disease? ________________________________________ ________________________________________ Back to our original case-scenario… Your patient is an 18 year-old woman who is seen for the complaint of occasional vomiting, back pain, swollen ankles, and oliguria. She has a 4-year history of arthritic joint pain. She previously tested positive for serum antinuclear antibody (ANA). On examination she has a blood pressure of 160/90 mmHg. Urinalysis is significant for hematuria, and serology shows high BUN and creatinine levels. To confirm your clinical suspicion, you schedule her for renal biopsy and immunofluorescence evaluation. Results of the biopsy show a tram-track appearance of the glomerular basement membrane and sub-endothelial deposits of immune complexes. 27. Which of the following serological findings would you also expect in this patient? A. Low levels of serum complement 3 (C3) B. High levels of serum complement 3 (C3) C. High levels of IgG auto-antibody against C3 convertase that over-activates the alternative complement pathway D. Low levels of C1-esterase enzyme that overactivates the classic pathway E. Low levels of serum complement 2 (C2) 28. Formerly we said that it is postulated that complement deficiency plays an important role in the pathogenesis of MPGN. What complement deficiency is most commonly involved in this situation? ________________________________________ ________________________________________ 29. What is the prognosis of MPGN? ________________________________________ ________________________________________ 33. Although the tram-track appearance is characteristic of MPGN, it is not as apparent in one of the two types; in which type is it less apparent? ________________________________________ ________________________________________ 34. Why do we only see the tram-track appearance in the above type of MPGN? ________________________________________ ________________________________________ 35. The case scenario states that the patient had been tested positive for antinuclear antibodies; what is the significance of this piece of information? ________________________________________ ________________________________________ 36. Name important autoimmune conditions that are associated with ANA. ________________________________________ ________________________________________ 37. The gender and age of the patient may increase the suspicion of SLE as our top differential for the ANA antibodies. Assuming that the patient has SLE, is SLE nephropathy a nephrotic or nephritic syndrome? ________________________________________ ________________________________________ 38. IgA nephropathy is a non-systemic disease that is associated with mesangial IgA deposits. But several systemic diseases are also associated with mesangial IgA deposits. Name the top 4 such diseases. ________________________________________ ________________________________________ ________________________________________ 30. Which of the two patterns of nephritic or nephrotic syndrome would you expect to see in MPGN? ________________________________________ ________________________________________ 4. Northwestern Medical Review, Bare Minimum Pathology Review Series, 2012 39. Patients with ankylosing spondylitis are also presented with mesangial deposits. These patients are often young males that, in addition to IgA deposits, may also have another type of immune deposit in their glomeruli and vertebral joints. What is the name of the other immune deposits, and why is this condition more common in young males? ________________________________________ ________________________________________ 40. Dermatitis herpetiformis is also associated with IgA nephropathy. What is the relationship between herpes and dermatitis herpetiformis? ________________________________________ ________________________________________ 41. What type of deposits would you expect to see in the glomeruli of a patient with SLE nephropathy? ________________________________________ ________________________________________ 42. A patient with a history of systemic lupus erythematosus presents with MPGN and glomerular IgA deposits. Which of the two patterns of MPGN would you expect in this patient: Type I or II? ________________________________________ ________________________________________ Simplified Classic and Alternate Complement Pathways Details of the Classic Complement Pathway The classic pathway shown above is a simplified an oldest version of the classic pathway. The current view of the classic pathway includes the following steps: The classic pathway starts with an antigenantibody reaction. The antibody is either IgG or IgM. Complement 1 (C1) identifies Fc receptors of the IgG or IgM C1 is activated and forms C1qrs complex. Note that C1 is a multi-subunit protein containing three different proteins (C1q, C1r and C1s) C1qrs activates C4 Activated C4 breaks down to C4a and C4b C4b activates C2 to form C4b2a complex C4b2a complex is also known as C3 convertase C4b2a activates C3 (note that calcium is necessary for this reaction) Activated C3 breaks down to C3a and C3b fragments C3b binds to the membrane in association with C4b and C2a. Meanwhile C3a is released into the surrounding area. The resulting C4bC2aC3b is known as C5 convertase. Generation of C5 convertase is the end of the classic pathway. C5 convertase activates MAC complex. Activated MAC has lytic power and attacks cellular membranes of pathogens, makes pores in them, and mediates both pathogenesis and the prevention of immune complex diseases. 5. Northwestern Medical Review, Bare Minimum Pathology Review Series, 2012 Details of the Alternate Complement Pathway C3 is made by the liver and is abundant in the blood. The pathway is initiated by the spontaneous hydrolysis of C3, that is, C3 (H2O) formation. Binding of plasma protein Factor B to hydroxylated C3 allows Factor D to cleave Factor B into Ba and Bb fragments. Bb attaches to C3 to form C3Bb (AKA. C3 convertase). The latter cleaves many C3 complements into C3a and C3b. C3a dissipates and C3b cleaves C5 to C5a and C5b. C5a dissipates. C5b, C6, C7, and C9 together form the MAC complex. Lectin (Mannose-Binding Lectin) Pathway The lectin pathway is the third complement pathway. Mannose-binding protein is produced by the liver and can initiate the complement cascade by binding to pathogen surfaces. It binds to mannose, glucose, or other sugars or glycoprotein components of micro-organisms. It is similar to the classical complement pathway because after activation, it proceeds through the action of C4 and C2 to produce activated complement proteins further down the cascade. In contrast to the classical complement pathway, it does not recognize antibodies bound to its target. The pathway starts with mannose-binding lectin binding to certain sugars on microorganisms. 43. What is the consequence of activation of MAC complex in the nephrons? ________________________________________ ________________________________________ 46. Which of the two immunoglobulins, IgG or IgM, is more effective in binding complements and initiating the complement cascade? ________________________________________ ________________________________________ 47. Biopsy of the glomeruli and immunofluorescence studies of the deposits in renal diseases show certain patterns of distribution of immune complexes. Which of the following patterns is associated with mesangial deposits? ________________________________________ ________________________________________ Fireworks in the Sky! 48. MPGN type II at times is associated with acquired partial lipodystrophy (APL). Patients present with whitish-yellow deposits within Bruch's membrane of the retina quite commonly during their second decade of life. Over time these deposits may cause macular detachment, and central serous retinopathy. What is the term that is used to describe those whitish-yellow deposits? ________________________________________ Note: Bruch's membrane is the inner layer of the choroid, separating it from the pigmentary layer of the retina. 44. Activation of which of the two complement pathways, classic or alternate, is most likely related to etiology of IgA nephropathy and Type II MPGN? ________________________________________ ________________________________________ 45. Which of the two complement systems, classic or alternate, is more effective against the lipopolysaccharide of gram-negative bugs? ________________________________________ ________________________________________ 6. Northwestern Medical Review, Bare Minimum Pathology Review Series, 2012 Answers 1. Nephritic 2. Hypertension, Hematuria, and Oliguria 3. Immune complex injury of the glomerular capillary endothelium causes hematuria. Meanwhile, widespread damaged glomerular vessel walls will activate degranulation of the platelets and lead to thrombotic blockade of the vessels and a resulting drop in the GFR and oliguria. Drop in the GFR will aggressively activate the renin-angiotensin system, and this leads to hypertension. 4. Hematuria of glomerular origin presents with red blood cell casts, whereas the hematuria that originates after the renal pelvis does not present with casts. 5. Red cells that pass through injured fenestrations of the glomerular capillaries are damaged and assume dysmorphic shapes. Additionally, they pile up and adhere to each other with protein molecules. As such they assume a stack-like and cylindrical appearance. 6. “PIG RAPIDLY PROGRESSes to HAM!” Stands for Poststreptococcal Glomerulonephritis, IgA nephropathy, Goodpasture’s syndrome, Rapidly Progressive glomerulonephritis, Henoch-Schonlein purpura, Alport’s syndrome, and Membranoproliferative glomerulonephritis. 7. Membranoproliferative glomerulonephritis. 8. Rapidly progressive glomerulonephritis is also known as crescentic nephritis. 9. Hematuria will be lost. Note that even if a patient loses 4, 5 or more grams of protein per day it is going to be reported as 4+. 13. Pre-nephrotic range or 2 grams per day of protein loss. Note: Although the lab reporting may vary from lab to lab, below is a helpful summary table based on the recommendations of the International Society on Nephrology. Grades I II III IV Description 1+ on dipstick or 0.15–1.0 g/24 2+ to 3+ on dipstick or >1.0–3.5 g/24 h 4+ on dipstick or >3.5 g/24 h Nephrotic syndrome 14. Mesangial cells, modified smooth muscle cells, occupy a central position within the renal glomerulus. They produce cytokines and prostaglandins, mediate inflammation, produce and remove basement membrane and other matrix substances, uptake immune complexes, and by the virtue of their contraction or relaxation-ability can modify glomerular filtration rate. 15. This diagram is a cartoon version of hypercellularity of the glomeruli in poststreptococcal glomerulonephritis (PSGN). The cells (and their nuclei) are practically all types of cells; endothelial, mesangial, epithelial, neutrophils, etc. 16. Hypercellularity is a common finding of nephritic syndrome, although it may not present with a diffuse pattern as it is seen with PSGN. For instance, in Type I MPGN it is more localized to the mesangial cells. 17. Extracellular matrix found on the basal surface of and secreted by the epithelial cells. 10. Proteinuria of more than 3.5 grams per day 11. Single “Spot” urine test (simple dipstick test). Nephrotic range proteinuria is 3 grams per day or more. 12. On a single, "spot" urine collection, it is 2 grams of protein (albumin) per gram of urine creatinine. A healthy liver makes 3 grams of proteins (albumin) per day. If in nephrotic syndrome a patient loses 1 (1+), 2 (2+), or 3 (3+) grams of albumin per day, the liver compensates by making up to 3 grams per day. However, above 3 (4+) grams of protein loss, the liver’s compensatory ability 18. The basal lamina and the basement membrane are quite often used interchangeably. However, the term "basal lamina" is usually used in conjunction with electron microscopy, while "basement membrane" is usually used with light microscopy. 19. The basal lamina surrounds and lies underneath sheets of epithelial cells. In the lungs and kidneys it separates two types of cells; namely, the endothelial cells of blood vessels and epithelial cells from each other. 20. The 3 layers of basal lamina are lucida, densa, and reticularis. Some histologists believe that the basal lamina is composed of lamina densa and lamina lucida, whereas the basement membrane is composed of the lamina densa and lamina reticularis. No matter which description of basement membrane and basal lamina you subscribe to, they both have the middle layer, lamina densa, in common! 7. Northwestern Medical Review, Bare Minimum Pathology Review Series, 2012 21. Collagen Type IV glycosaminoglycan) and Heparan sulfate (a 22. Periodic Acid Schiff (PAS) 23. Rapidly progressive glomerulonephritis 24. Mesangial and subendothelial deposits of immune complexes, and increased number of mesangial cells. 25. Tram-track refers to the basement membrane in MPGN, which has a tram-track appearance in light microscopy with the help of special staining techniques. With PAS staining, the capillary endothelial lamina and basement membrane show two distinct membranes in light microscopy due to mesangial interposition into the capillary, which gives the loops a tram-track appearance. Do all MPGN types have tram-tracks? Please see below for the answer. 26. Silver staining (methenamine-silver staining) is the second commonly used staining, besides PAS, for highlighting the basement membrane. With this type of staining the glomeruli will assume a silverish-bluish coloration. 27. [A]. Low levels of serum complement 3 28. C3 deficiency is very common in MPGN and is demonstrable in about 75% of the patients. 29. As you might have guessed the prognosis of MPGN is relatively poor despite optimal effects of steroids and immune suppressant therapy. The disease often progresses to end stage renal failure. 30. The best answer is either, but the nephritic pattern is by far the most common pattern. Quite often it starts with a nephritic pattern and progresses to a nephrotic pattern. 31. They both appear in a slowly progressive pattern. This is their distinguishing characteristic against rapidly progressive glomerulonephritis. 32. Type II 33. You don’t see it in Type II and you only see it in Type I MPGN. 34. In Type I the mesangium extends between the podocytes and endothelial cells, whereas in Type II we get a dense homogenous deposition along the glomerular basement membrane and in the mesangium that would not allow the double contour to express itself. In Type II you will see a thick ribbon-like pattern. 35. This supports the fact that MPGN must have an autoimmune etiology! 36. SLE, Sjogren’s, Scleroderma, Polymyositis and Rheumatoid arthritis. 37. SLE presents with either nephrotic or nephritic or a mixed pattern. But the nephrotic pattern is by far the most commonly presented pattern. 38. Henoch-Schonlein Purpura, Systemic lupus erythematosus, Ankylosing spondylitis, and Dermatitis herpetiformis. A few other noteworthy associations are celiac disease, rheumatoid arthritis, and HIV. 39. Ankylosing spondylitis is due to IgA and more importantly, HLA-B27 deposits. This condition is characteristically more common in men, and is accentuated with hyper-testosterone levels in younger men. It is postulated that testosterone facilitates interaction of HLA-B27 with the glomerular or joint tissues. 40. There is no relationship between the two conditions. The presumption of a relationship may be due to the resemblance of the skin rash of dermatitis herpetiformis with that of the rash of herpes. Interestingly, dermatitis herpetiformis is heavily associated with celiac disease and gluten sensitivity. 41. SLE nephropathy may have any combination of IgG, IgM, IgA, and C3 glomerular deposits. 42. The patient with SLE will most likely have a Type II pattern of MPGN. In Type I, immune complexes are due to IgG and IgM, and they activate the classical complement pathway. In contrast, Type II MPGN involves uncontrolled activation of the alternate complement pathway and consumption of C3. Hence, this patient most likely has Type II MPGN due to IgA deposits. 43. Ongoing activation of the complements and MAC complex in the nephrons in nephritic and nephrotic diseases can cause ongoing damage to the kidney’s filtering ability. 44. Given that IgG and IgM are involved in the initiation of the classic pathway, the IgA nephropathy and MPGN Type II must involve the alternate complement pathway. 45. The alternate pathway. 46. IgM is more effective because it has 5 immunoglobulin subunits and thus more binding surfaces. 47. [C]. This pattern resembles fireworks in the sky, or “4th of July pattern!” 48. Drusen’s deposits 8. Northwestern Medical Review, Bare Minimum Pathology Review Series, 2012 Excerpts Bare Minimum Microbiology Review Staph aureus 9. Northwestern Medical Review, Bare Minimum Microbiology, 2012 Staphylococcus aureus Gram-positive cocci, grape-like clusters, facultative anaerobic, catalase and coagulase-positive, and grows on blood agar. Reservoir: Skin and nose; Transmission: By hands is an important issue Important diseases Abscess: Protein A, coagulase, leukocidin Gastroenteritis (food poisoning): Enterotoxin Scalded skin syndrome: Exfoliatin Toxic shock syndrome: TSST Acute bacterial endocarditis Hospital Acquired pneumonia Others: Various types of skin infections; pimples, impetigo, boils, cellulitis, carbuncles, etc., meningitis, osteomyelitis, and septicemia. Important Issue: Common cause of nosocomial infections Antibiotic Resistance: (1) Beta-lactamase (Penicillinase); and (2) Altered binding site for Penicillin (MRSA) Treatment: Nafcillin (for all but MRSA), and Vancomycin for MRSA Side Effects of Vancomycin Thrombophlebitis Ototoxicity Nephrotoxicity Shock Van has TONs of Load! 1. What is the mechanism of action of penicillin? _____________________________________ 2. What is the other name for beta-lactamase? _____________________________________ 3. What is the mechanism of action of Vancomycin? _____________________________________ _____________________________________ 4. What is the bactericidal spectrum of Vancomycin? Gram _______________________________! Hint: What sign do you see on the van? 5. What is the next DOC for MRSA? _____________________________________ Indications of Vancomycin Methicillin Resistant Staph aureus Pseudomembraneous colitis Prosthetic heart valve patients who undergo oral surgery (Staph epidermidis) * May also be used for serious cases of resistant streptococcus pneumoniae. 10. Northwestern Medical Review, Bare Minimum Microbiology, 2012 6. Staphylococcus and streptococcus cultures produce either a grape-like cluster or have a chain-like appearance. Which one is which? ____________________________________ 12. What is scombroid and what are the major sources of poisoning with it? _____________________________________ _____________________________________ 7. Staph aureus is the most common cause of abscess formation. What are the characteristic immune cells within an abscess? ____________________________________ 13. How long is the incubation period of Staph aureus food poisoning? ___________________________________ 8. Of the 3 virulent mechanisms causing abscess formation by staph aureus, one is protein A which coats staph with immunoglobulin; and the second one is coagulase that converts fibrinogen to fibrin. What is the function of the third one, leukocidin? _____________________________________ 9. The key organisms that one must differentiate from Staph are Strep and Listeria. Is Strep catalase-positive or negative? _____________________________________ 10. Is Listeria catalase-positive or negative? _____________________________________ 14. How long is the incubation period of Salmonella food poisoning? ___________________________________ 15. S. aureus, among other things, is one the two must-know causes of abscess formation. What is the other important abscess producer? _____________________________________ Hint 1: Anaerobic Hint 2: Gram-negative rod Hint 3: Bowel surgery Hint 4: Metronidazole and Clindamycin 16. There are only 5 must-know anaerobic bugs for the exam; one of the five is Bacteroides fragilis (see above); what are the other four? _____________________________________ 17. What is the DOC of Bacillus fragilis? Your List of sources for Listeria should include cattle products! ____________________________________ 18. What is the virulence mechanism of Staph aureus abscess formation? Listeria is Cattle-ase positive! 11. Is enterotoxin of Staph aureus heat stable or labile? ______________________________ Food Poisoning Incubation Scombroid Up to 1 hour Staph aureus Bacillus cereus 3 – 8 hours Botulinum ½-day to 1-day Salmonella enteritidis 1 – 2 days 1. Protein A: ___________________________ 2. Coagulase: ___________________________ 3. Leukocidin: ___________________________ This is not PCL! Actually it is ACL (“A” for Protein A!) If you like PCL better, then P is for “Protein”! Note: Protein A binds to Fc-IG and coats Staph with PMNs! Rash on Palms and Soles T S oxic Shock Syndrome (Staph aureus) alded Skin Syndrome (Staph aureus) Not that many diseases can cause rash on palms and soles. Solve the puzzle by adding more bugs or diseases to the right column until you figure out the hidden word of the first column. Note that the answer will become apparent as we learn about more bugs. 11. Northwestern Medical Review, Bare Minimum Microbiology, 2012 19. What ionic situation is postulated to provide a suitable medium for production of TSS toxin? ____________________________________ ____________________________________ 20 What gram-positive rod causes flaccid paralysis and produces a heat labile toxin? _____________________________________ 21. Is salmonella toxin heat stable or labile? ____________________________________ About Scombroid Food Poisoning… Scombroid food poisoning is a seaborne illness that often results from eating decayed fish. It is one of the common types of seafood poisoning; however because of its symptoms it is often classified as or confused with type I hypersensitivity reaction (food allergy). Symptoms, often self-limited, start within 10-30 minutes of ingesting the fish and include skin flushing, erythema, abdominal cramps, nausea, diarrhea, tachycardia, wheezing and hypotension. It is proposed that histidine that is abundant in many types of fish is converted to histamine via histidine decarboxylase in meat that is stored at very low temperatures. Histamine is heat stable within normal cooking temperatures, so even properly cooked fish can be affected. Note that freezing, cooking and smoking do not destroy the scombroid toxin. A few fish commonly poisoned with scombroid include anchovy, bluefish, herring, mackerel, mahi-mahi, sardine, and yellow fin tuna. Diseases Caused By Staph aureus S OF Skin Infections Pneumonia For TP Sta p A Osteomyelitis Acute Endocarditis h aureus INS Dis eas es Food Poisoning Infective arthritis Toxic Shock Necrotizing Fasciitis Syndrome Sepsis 22. Clinical Settings for Toxic Shock Syndrome: A. _________________________________ B. _________________________________ C. _________________________________ 23. What is the number 1 cause of necrotizing fasciitis (flesh eating disease)? _____________________________________ _____________________________________ 24. What is the number 2 cause of death in noncoronary ICU patients and the 10th overall cause of death in the USA? _____________________________________ 25. What are the major criteria used for diagnosis of sepsis? _____________________________________ _____________________________________ _____________________________________ _____________________________________ Hint: SIRS! 26. X-ray of the hip of an 8-year-old boy with history of recurrent bone pain is significant for avascular necrosis of the head of the femur. In the past on three occasions the child has been diagnosed with osteomyelitis. What organism most likely might have caused this finding? ____________________________________ 27. Would you change your answer if you knew that the boy has sickle cell anemia? ___________________________________ 28. Who am I? I am a must-know cousin of Staph aureus, but I prefer to live on the skin! Often I like to dive into the bodies of 3 groups of people and roam through their bodies. Docs say I give them “bacteremia.” You may ask “who are these three?” They are the immunocompromised, hospital patients with Foley urine catheters or IV lines, and patients with prosthetic devices such as valves or joints! I just don’t know what it means, but lab technicians often say that I am a catalasepositive and coagulase-negative creature! I just hate vancomycin! Now can you tell me who am I? ________________________________ 29. There are only three must know staph family members for the exam. The most commonly tested one is Staph aureus. The second one is Staph epidermidis, which you were just introduced to. Who is the third one? __________________________________ Hint: It is the second most common cause of UTI (ranks after E. coli) in ambulatory women. Hint: It is coagulase negative! 12. Northwestern Medical Review, Bare Minimum Microbiology, 2012 Catalase NEgative Catalase Positive Answers 1. Penicillins bind to penicillin binding proteins (cell wall transpeptidases) and inhibit cross-linkage of the peptidoglycan units of the bacterial cell wall. 2. Penicillinase Staph StrEp Fibrinogen Coagulase 4. Gram-positive! Fibrin Positive Negative 3. Vancomycin inhibits cell wall synthesis in Gram-positive bacteria. In contrast to penicillins that inhibit cross linkage of the peptidoglycan subunits, it acts by binding to precursors of peptidoglycan subunits rather than by interacting with the transpeptidases. It is proposed that it inhibits incorporation of N-acetylmuramic acid and N-acetylglucosamine peptide subunits into the peptidoglycan matrix. S. Aureus S. Epidermidis S. Saprophyticus Which one is catalase nEgative—Staph or Strep? StrEp! StAph is CAtAlAse positive! 5. The next DOC for MRSA is trimethoprim-sulfamethoxazole (Bactrim). Lately, there has also been emergence of Vancomycin-Resistant Staph Aureus (VRSA). A few newly developed antibiotics that can act on them are Linezolid, and daptomycin. 6. Staph is grape-like and Strep is chain-like! 7. PMNs! 8. Leukocidin is leukocidal and destroys PMNs! 9. Strep is catalase-negative and listeria is catalase positive 10. Listeria is catalase-positive! 11. Staph toxin is heat stable! 12. See the note about scombroid poisoning 13. 3 to 8 hours! 14. Salmonella food poisoning incubation is 1 to 2 days! 15. Bacteroides fragilis! 16. The other strict anaerobes are the four clostridial members (tetani, botulinum, perfringens and difficile) 17. Clindamycin and metronidazole CATA Co. 18. Protein A attracts PMNs; coagulase coagulates blood; and leukocidin kills the neutrophils! all staff members In our company love cats! Staff is Catalase Positive! 30. What are the top 3 bacterial causes of sepsis as a result of skin infections? ____________________________________ ____________________________________ ____________________________________ 31. Among -lactamase resistant penicillins that can act on Staph aureus (NO MDs!) Nafcillin is by far most preferable over Methicillin; why? ____________________________________ ____________________________________ 32. The treatment strategy of staph aureus and Staph epidermidis endocarditis is similar because of what important issue? ____________________________________ ____________________________________ Note: Answer for “rash on palms and soles” will progressively become more apparent as further bacteria are covered and we add in more words into the puzzle during the course! 19. Hypomagnesemia! It is postulated that tampons absorb various ions including magnesium. Note: Staph aureus is a normal vaginal flora in 8-10% of females. But heavy growth is unusual. 20. Clostridium botulinum causes flaccid paralysis 21. Salmonella toxin is heat labile 22. The 3 settings for TSS are tampons, nose-packing and wound dressing! 23. Strep pyogenes is the number one cause of necrotizing fasciitis. Other major causes are Staph aureus, Clostridium perfringens and Bacteroides fragilis! 24. Sepsis is the number 2 cause of death in non-coronary ICU and 10th overall cause of death in the USA. Note: Recent data suggest that sepsis is the number one cause of death in noncoronary ICU 25. Criteria for diagnosis of sepsis: Presence of infection plus 2 or more signs of Systemic Inflammatory Response Syndrome (SIRS): Tachycardia; Hypo or hyperthermia; Tachypnea (hypocapnia); and WBC less than 4000 or more than 12000/mm3! 26. The most likely infectious cause of osteomyelitis is Staph aureus (also see answer to question 27). 27. Children with sickle cell disease due to splenetic malfunction or splenectomy are uniquely susceptible to frequent osteomyelitis as a result of salmonella infections. Note: The cause of avascular necrosis is often vascular and aseptic; but it is postulated that frequent infections and resultant inflammation of the bone may cause stenotic damages to the vasculature, leading to avascular necrosis of the hip and femoral head! 28. Staphylococcus epidermidis! 29. Staphylococcus saprophyticus! 30. Top 3 causes of sepsis as a result of skin infections are Strep pyogenes, Staph aureus, and Pseudomonas! 31. Meticillin causes serious nephrotoxicity 32. Most Staph epidermidis strains are currently MRSA-like and they are resistant to nafcillin! 13. Northwestern Medical Review, Bare Minimum Microbiology, 2012 Excerpts ENDOCRINOLOGY Adrenal Pathophysiology and Pharmacology Part 1 of 3 14. Excerpts of Triology; Northwestern Medical Review, 2012 HYPOTHALAMIC-PITUITARY-ADRENAL AXIS Positive CRH Releasing Factors Stress (via reticular formation); severe hypoglycemia; anxiety/fear (via Amygdaloid nucleus); increased ACh and serotonin; pain (via ascending pathways); circadian rhythms (via suprachiasmatic nucleus). Negative CRH Releasing Factors • Increased GABA • Increased enkephalins • Increased opioids Hypothalamus (CRH Cells) CRH Anterior Pituitary ACTH Adrenal Cortex Cortisol CRH via cAMP stimulates synthesis of POMC (Proopiomelanocortin) which splits into ACTH, MSH and endorphin. STEROID BIOSYNTHETIC PATHWAYS IN ADRENAL GLAND Cholesterol Desmolase Pregnenolone Hydroxysteroid Dehydrogenase Progesterone Steroid Biosynthesis 17-hydroxylase 17-OH Progesterone ----------21-hydroxylase----------Deoxycorticosterone Deoxycortisol --------11-hydroxylase----------- Corticosterone Aldosterone Mineralosteroids Cortisol Glucosteroids Androstenedione Testosterone Estradiol Sex Steroids 15. Excerpts of Triology; Northwestern Medical Review, 2012 ACTH Effects on the Adrenal Gland ACTH acts on the adrenal cortex and causes hypertrophy of zona fasciculata and zona reticularis—sites of cortisol and androgen precursor’s synthesis. ACTH up-regulates ACTH receptors Increases cholesterol uptake via HDL/LDL receptors (increases adrenal free cytoplasmic cholesterol levels). Increases desmolase activity. Hence, increases cholesterol conversion to pregnenolone. Increases cytochrome P450 enzymes and causes an increased conversion of pregnenolone to cortisol and aldosterone. Steroids Zona glomerulosa lacks 17 -hydroxylase, and it is the only zone that contains aldosterone synthase Zona glomerulosa has no enzymatic pathway to synthesize cortisol, DHEA (dehydroepiandrosterone) and androstenedione Male and female gonads lack 11 and 21 hydroxylase. Thus, gonads cannot produce corticosterone, cortisol or aldosterone. DHEA and androstenedione can be converted to testosterone in gonads. Adrenal’s testosterone synthesis is insignificant Gonads only possess enzymes that are required for androgens (e.g. testosterone) and estrogen synthesis. ZONA GLOMERULOSA CORTEX (Mineralocorticoids-Aldosterone) ZONA FASCICULATA (Glucocorticoids--Cortisol) ZONA RETICULARIS (Gonadocorticoids--Sex steroids) MEDULLA (epinephrine, norepi.) • Salt • Sugar • Sex • Stress The deeper you go the more excited you get! Zona Glomerulosa makes the hormones that act on the glomeruli—e.g. aldosterone! In humans, sex starts with retinal stimulation! Hence, zona reticulosa for sex hormones! Cortisol is the stress hormone. Its blood level rises just before waking up, and just before getting ready to confront everyday’s challenges! Cortisol Binds to plasma proteins—Transcortin and albumin Plasma levels are high immediately prior to waking and lowest around mid-night Produced in Zona Fasciculata and Reticularis Release is stimulated by ACTH and epinephrine Signal transduction is via nuclear receptors (gene transcription). Metabolic Effects of Cortisol Prepares body for stress by metabolizing fuels Catabolism of muscle protein to provide substrate for liver gluconeogenesis. Increases plasma glucose Cortisol Effects on the Liver Increases amino acid (AA) uptake and gluconeogenesis. Increases glucose export (glucagon like!) Increases glycogen synthesis (insulin like!) Over all it has anabolic effect Cortisol Effects on the Muscle Decreases glucose uptake, increases proteolysis and increases AA export (amino acids go to liver), decreases protein synthesis. Glucagon-like effect Catabolic role Fasting drops blood sugar. Hence, zona fasciculata for blood-sugar-raising hormone, that is, cortisol! 16. Excerpts of Triology; Northwestern Medical Review, 2012 Cortisol and the Adipose Tissues Decreases glucose uptake, increases lipolysis, increases free fatty acid (FFA) export (FFAs go to the liver and they are converted to acetylcholine, the precursor of ketone bodies) and increases plasma glycerol level. Catabolic role Anti-Inflammatory Roles of Cortisol Strong inhibition of the entire inflammatory response Prevents transplant rejection Decreases neutrophil recruitment, and prostaglandin and leukotriene synthesis by inhibiting phospholipase A2 Decreases T-cell count, and inhibits production of interleukin-2. Decreases capillary permeability, and inhibits histamine release from mast cells. Shrinks the lymphoid mass and drops the lymphocytic count. Hence, it is desirable in treatment of lymphomas. Note: Patients with Cushing’s syndrome present with shrunken lymphoid mass. Prednisone (a glucocorticosteroid) is one of the commonly used drugs in treatment of Hodgkin’s lymphoma. Potency of Various Steroids All steroids have both mineralo and glucocorticoid effects. Cortisol and cortisone have equal mineralo and glucocorticoid effects. Dexamethasone by far is the most potent glucocorticosteroid, and fludrocortisone is the most selective mineralocorticoid. Fludrocortisone is Fluidocortisone! Glucocorticoid (Cortisol) Side Effects Hypokalemic alkalosis (mineralocorticoid effects) Glycosuria (Cushing’s diabetes) Increased susceptibility to infection Peptic ulcers Myopathy Osteoporosis Cushing’s symptoms and hypertension ACTH suppression 2. The management of myasthenia gravis requires corticosteroid therapy. However, at times the patients are presented with worsening symptoms; why? _______________________________________ _______________________________________ Phospholipase A2 Corticosteroids Arachidonic Acid Cyclooxygenase Lipoxygenase NSAIDS Decreasing Order Membrane Phospholipid Potency of Glucocorticoids Dexamethasone Cortisol Corticosterone DECORTIzation order! Leukotrienes Increase Bronchial Tone Prostacyclin Prostaglandins Thromboxane • PGI2 • Decrease vascular & bronchial tone • Increase Platelet aggregation • Decreases Platelet aggregation • Increase Uterine Tone & bronchial tone • Increase vascular & bronchial tone • Decreases vascular, uterine & bronchial tone Please refer to chapter on eicosanoids and NSAIDs for more information on the above diagram. 1. What non-steroid hormone has intra-nuclear transduction? ______________________________________ Anti-Steroids Aminogluthemide Inhibits P-450 and in turn inhibits desmolase activity It is used in (1) Cushing’s treatment and (2) to reduce estrogen level in breast cancer Ketoconazole: Desmolase inhibitor and antifungal. Reduces all steroids. Spironolactone: Diuretic used for treatment of hypertension and primary hyperaldosteronism. Note: Aromatase converts androgens to estrogens and promotes estrogen formation. 17. Excerpts of Triology; Northwestern Medical Review, 2012 ADRENOCORTICAL DISEASES (PART I) Duration of Action of Glucocorticoids Short Acting Glucocorticoids Hydrocortisone and cortisone Duration of action: 8-12 hours Intermediate Acting Glucocorticoids Prednisone, prednisolone, triamcinolone 18 - 36 hours Long Acting Glucocorticoids Betamethasone, dexamethasone, paramethasone 1 - 3 days hours Potency of Various Steroids All steroids have both mineralocorticoid and glucocorticoid effects Cortisol has equal mineralo and glucocorticoid effects Dexamethasone is by far the most potent glucocorticoid, and fludrocortisone is the most selective mineralocorticoid. Case for the Next 3 Questions A 17-year-old girl is being admitted to the OB/GY clinic for the complaint of amenorrhea. Examination reveals lack of development of secondary sex characteristics. Blood pressure is 180/110; result of funduscopy is normal; she has no lymphadenopathy or hepatosplenomegaly. Blood analysis indicates hypokalemia, hypernatremia, metabolic alkalosis, and suppressed renin. Urinary analysis confirms a high level of urinary gonadotropins. 6. Suppression of rennin in this patient is due to which of the following options? (A) (B) (C) (D) (E) Negative aldosterone feedback Insensitivity of kidney to aldosterone Lack of adrenal development Lack of ACTH Insensitivity of JG cells 7. Which of the following hormones is expected to increase in this patient’s plasma? (A) Deoxycortisol and cortisol (B) Deoxycorticosterone and corticosterone (C) Progesterone and deoxycortisol (D) Androstenedione and corticosterone (E) Aldosterone and cortisol 3. Three steroids with noticeable mineral effects: A_____________________________________ F_____________________________________ D_____________________________________ 8. Which of the following deficiencies is the most likely cause of this patient’s problems? (A) (B) (C) (D) (E) 4. What are the top two side effects of mineralocorticoids? _____________________________________ _____________________________________ 5. Cushing’s and Addison’s disease have opposing effects on the level of eosinophils. Which one causes eosinophilia and which one causes eosinopenia? _______________________________________ 11-hydroxylase 21-hydroxylase 17-hydroxylase Desmolase Hydroxysteroid dehydrogenase Hydroxysteroid Dehydrogenase Deficiency Congenital adrenal hyperplasia Lack of steroids removes negative feedback over the pituitary and ACTH production stays uninhibited. Constant ACTH production causes hypertrophy of the adrenal cortex. Pregnenolone is not converted to all other subsequent steroids. All pathways; mineralocorticoids, corticosteroids and glucocorticosteroids 18. Excerpts of Triology; Northwestern Medical Review, 2012 The second most fatal steroid biosynthetic deficiency. Early death Note: Desmolase deficiency is by far the most fatal steroid deficiency. Many patients die in early infancy. Cholesterol Desmolase Pregnenolone Hydroxysteroid Dehydrogenase Deficiency of hydroxysteroid dehydrogenase is associated with ----------21-hydroxylase----------increase in pregnenolone and total deficiency of all steroids and products after the affected step. 21-Hydroxylase Deficiency The most common deficiency. Congenital adrenal hyperplasia Deficiency of both mineralocorticoids and glucocorticoids. Due to lack of feedback over pituitary there is a high level of ACTH in the plasma. Pathways are shunted to sex steroid production There is a high level of androgens Adrenal virilism. Male phenotype exaggerated. Female patients present with masculine characteristics such as enlarged clitoris Salt loss and hypotension Cholesterol Desmolase Pregnenolone Hydroxysteroid Dehydrogenase Progesterone Progesterone 17-hydroxylase 17-Hydroxylase Deficiency Autosomal recessive defect Congenital adrenal hyperplasia Conversion of progesterone to subsequent sex hormones and glucocorticoids is affected. Female characteristics are preserved, but secondary developments are affected. Pathways are shunted to further mineralocorticoids production. Increased mineralocorticoids leads to sodium and water retention and hypertension Due to lack of androgens (i.e. development of zona reticularis) female phenotype is exaggerated. For instance males have shrunken external genitalia. Cholesterol Desmolase 17-OH Progesterone Androstenedione 21-hydroxylase Deficiency Estradiol Zonal Glomerulosa Pregnenolone Hydroxysteroid Dehydrogenase Progesterone 17-hydroxylase ---------------- 21-hydroxylase ---------------- Testosterone Zona Fasciculata www.northwesternmedicalreview.com 11-Hydroxylase Deficiency Autosomal recessive deficiency that causes deficiency of corticosterone, aldosterone and cortisol. Increased level deoxycorticosterone leads to salt and fluid retention, and hypertension. Hypertension is due to accumulation of deoxycorticosterone that has a very strong mineralocorticoids effect. Like 21--hydroxylase leads to adrenal virilism (AKA. adrenogenital syndrome) and masculinization. More common in males. Less common than 21-hydroxylase deficiency Deoxycorticosterone ---------------- 11-hydroxylase ---------------Corticosterone 17-hydroxylase Deficiency Aldosterone Zonal Glomerulosa Zona Fasciculata www.northwesternmedicalreview.com Zona Reticularis Zona Reticularis 19. Excerpts of Triology; Northwestern Medical Review, 2012 Cholesterol Desmolase Pregnenolone But the most commonly remembered one on the history of the exam (i.e. the most commonly tested one) has been the 17-hydroxylase deficiency! Progesterone 17-hydroxylase 17-OH Progesterone Testosterone 11-hydroxylase deficiency Zonal Glomerulosa Drill and Self-Study Questions Androstenedione Deoxycorticosterone Zona Fasciculata www.northwesternmedicalreview.com Estradiol Zona Reticularis Blackjack Makes You Happy (Hypotensive!) 9. In the following two pedigree diagrams the solid squares and circles indicate genetically affected individuals. Which one of them is most likely affected with 17-hydroxylase deficiency? A. B. C. D. E. A B C A and B B, C and D About the Black Jack Mnemonic! The top three tested congenital steroid deficiencies are 21, 17 and 11-hydroxylase deficiencies. All three conditions are associated with hypertrophy of the adrenals due to high levels of ACTH (lack of suppression). The highest number among the three is 21. This number happens to be the highest and mostly desired number in black jack as well. It is the only number that if you get it in the game you would be happy (hypotensive). The other two numbers in the game, quite often will make the players hypertensive; especially if the dealer shows a 10 or 9 up! In short, 11 and 17 hydroxylase deficiencies are associated with hypertension whereas 21-hydroxylase is associated with hypotension. Important Note: Hypertension is the top most important distinguishing characteristic between 11 and 21-hydroxylase deficiencies. At the same time, the most common deficiency among all congenital adrenal deficiencies is the 21-hydroxylase deficiency. 10. A newborn presents with ambiguous external genitalia. The genitalia seem more like an enlarged clitoris than penis. There is a scrotum– like structure that has resulted from labial fusion. Ultrasound confirms normal ovarian development and presence of bilaterally enlarged adrenal glands. Karyotyping indicates a 46 XX karyotype. Of the following conditions which one is the most likely cause of these findings? A. 11 alpha-hydroxylase deficiency B. 17 alpha-hydroxylase deficiency C. 21 alpha-hydroxylase deficiency D. Desmolase deficiency E. Turner’s syndrome 20. Excerpts of Triology; Northwestern Medical Review, 2012 11. At age 10 the patient is admitted to the hospital for complete physical evaluation. Which of the following lab findings would be the most remarkable finding in the patient? A. High level of cortisol B. Low level of ketosteroids C. Low blood pressure D. Low level of rennin E. Low level of ACTH 12. Addison’s disease causes eosinophilia and darkened mucosa. What are the major causes of eosinophilia? _____________________________________ _____________________________________ 13. Wegener’s Granulomatosis also causes eosinophilia. What are some of the main characteristics of this disease? _____________________________________ _____________________________________ 14. What is the name of the condition that is associated with eosinophilia, fibrotic thickening of heart valves and restrictive cardiomyopathy? _____________________________________ _____________________________________ Answers 1. The only other hormone other than steroids with intracellular transduction is thyroxine. 2. Steroid-induced myopathy is the problem associated with myasthenia treatment. Despite this finding corticosteroids are the mainline medications. Note: MG is an autoimmune disease and often is associated with thymoma. 3. The 3 steroids that have mineralocorticoid effect are: aldosterone, fludrocortisone and deoxycorticosterone. 4. Side effects of mineralocorticoids are hypokalemia and congestive heart failure (CHF) due to volume overload! 5. Cushing’s (hypocortisolism) depresses immune functions and causes eosinopenia. Addison (lack of steroids) does the opposite (eosinophilia). 6. Option [A] is correct. 7. Option [B] is correct. 8. Option [C] is correct. 9. The correct answer is [A]. 11, 21 and 17 alphahydoxylase deficiencies are all autosomal recessive conditions. Only the pedigree I is illustrative of autosomal recessive conditions. Hence, the female person marked “A” is the one who is affected with the deficiency. Please note that it is very unlikely for patients with 17-hydoxylase deficiency to get pregnant. But with rigorous hormonal therapy (e.g. estrogen and glucocorticosteroid therapy, and in vitro fertilization) this may not be impossible. Also note that the pedigree II is illustrative of dominant genetic conditions. The person “B” in this pedigree has randomly acquired a mutated dominant gene. 10. The correct answer is [C]. Patients with 21 hydroxylase deficiency present with adrenal virilism. As a result females present with ambiguous and enlarged clitoris, and males present with exaggerated genitalia and precocious puberty. These patients characteristically are hypotensive as a result of lack of development of zona glomerulosa or production of mineralocorticoids. Note that as result of low aldosterone and blood volume and pressure, the rennin level is going to be high in these patients. Also as a result of lack of cortisol, the level of ACTH is also high in the patient. Also note that ketosteroids are the byproducts of metabolism of androgens such as testosterone or dihydrotestosterone. The patients with 21-hydroxylase deficiency have a very high level of androgens that raises the levels of ketosteroids in their serum and urine. 11. Option [C] is the correct answer. The karyotype of 46XX indicates that the patient has acquired congenital adrenal virilism (masculinization) as a result of too much androgens or over-activity of zona reticularis. Note, that the option “A” in question 10 may also cause the very same symptoms. But by far 21hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia, and between the two options in question 10 it seems to be the more probable answer. Note that 11 hydroxylase deficiency in contrast to 21 hydroxylase causes hypertension. 12. “NAACP“is the mnemonic for major causes of eosinophilia (see the next mnemonic)! 21. Excerpts of Triology; Northwestern Medical Review, 2012 Causes of Eosinophilia Note: Eosinophilia is often associated with skin hypersensitivity reactions that color the skin. In Addison’s, ACTH is high and as such MSH is high 13. About Wegener’s Granulomatosis… (Please review the chapter on vascular pathology for more information) Granulomatous inflammation of arterioles, capillaries and venules. Triad of Wegener’s: (1) Focal lung vasculitis; (2) Necrotizing pulmonary granuloma; and (3) Necrotizing glomerulitis. Fifth decade onset. 80% of patients die in year one if not treated Immunosuppression (with cyclophosphamide) has saved more than 90% of the victims. C-ANCA (antineutrophilic cytoplasmic autoantibodies) is present in more than 90% of patients. It is a good disease marker. 14. Loeffler’s endocarditis (A.K.A. endomyocardial fibrosis) (Please review Bare Minimum Pathology Book for more information) **End of Adrenal Endocrinology Part I** 22. Excerpts of Triology; Northwestern Medical Review, 2012 Excerpts Triology Book Physiology and Pharmacology with Relevant Pathology Aortic Stenosis: Ventricular Pressure-Volume Loop Pathophysiology 23. Excerpts of Triology; Northwestern Medical Review, 2012 Pressure-Volume Loop: Aortic Stenosis (AS) A 77-year-old woman is presented with syncope during her routine daily exercise. Her history is significant with several other episodes of syncope within the past 6 months. She has a systolic murmur that is best heard at the right upper sternal border. There is radiation of the murmur into the neck. Which of the following options is the most probable diagnosis? (A) Mitral stenosis (B) Mitral regurgitation (C) Tricuspid regurgitation (D) Aortic stenosis (E) Aortic insufficiency 1. What is the second most common valvular anomaly and the second most commonly tested valvular defect? ________________________ Note: Over time the loop may tilt a little to the right. But concentric hypertrophy will oppose its overexpansion! 2. What happens to stroke volume in AS and what portion of the shaded diagram in the left represents it? _______________________________________ _______________________________________ 3. What will happen to end-systolic ventricular volume (afterload) in AS? _______________________________________ _______________________________________ 4. Do you expect the velocity of fiber–shortening increase or decrease in AS, or any condition that increases the afterload? _______________________________________ _______________________________________ 5. What is the expected end diastolic volume in AS, and how does this affect the force of contraction? _______________________________________ _______________________________________ The above shaded P-V loop represents mild to severe aortic stenosis. Compared to normal heart, the ventricular pressure rises sharply in systole; meanwhile less volume is ejected into the aorta. Impairment of Cardiac Output Aortic stenosis (AS) impairs ventricular emptying due to high outflow resistance. A large pressure gradient (see the next picture) is required to push blood through the valve; this raises the peak (or end-systolic pressure or the afterload). Notice the wide difference between intraventricular pressures of 200/30 mmHg versus intra-aortic pressures of 90/70 in AS. 6. What is the key adaptive (structural cardiac remodeling) response to AS? _______________________________________ _______________________________________ 7. What is the expected systemic blood pressure in AS? _______________________________________ _______________________________________ 8. What is an important clinical finding in AS? _______________________________________ 9. What type of dysfunction would you expect to see in AS; systolic or diastolic? _______________________________________ 24. Excerpts of Triology; Northwestern Medical Review, 2012 10. Patients with AS are presented with angina. What is the pathophysiology of angina in AS? _______________________________________ 11. What is a reasonable explanation for syncope of the AS patients during exercise? _______________________________________ _______________________________________ 12. The following diagram shows the characteristic auscultation findings of the heart of a patient diagnosed with AS. What is this finding? _______________________________________ 13. What are the two unique auscultation findings in paradoxical split? _______________________________________ _______________________________________ “A” is always before “P” Except in PA radoxical split; wherein P2 is before A 2 (as in the word “Paradox”)! 14. What are the top 3 causes of paradoxical split? _______________________________________ _______________________________________ _______________________________________ 15. In which of the above conditions the afterload decreases? _______________________________________ _______________________________________ This astronaut was the captain in charge of the last NMR-space mission that was aborted prematurely. Since then NMR has categorically halted all extraterrestrial missions. Why? Hint: Watch the last 30 seconds of the videotape that accompanies this lecture. _______________________________________ _______________________________________ Bicuspid valves calcify at an earlier age compared to trileaflet valves. Age of onset of symptoms in calcified valves is 45 for bicuspid and 75 years for trileaflet valves. 17. What is the best way to evaluate the function of the stenotic valve? _______________________________________ _______________________________________ 18. What aortic valve size (area) is considered severe stenosis? _______________________________________ 19. Normally aortic and pulmonary valves have three leaflets (cusps). Why do they call them semilunar valves? _______________________________________ _______________________________________ 20. Do you expect patients with aortic stenosis to have wide or narrow pulse pressures? _______________________________________ 21. What is the best location to auscultate the aortic valvular sounds? _______________________________________ 22. List the must-know clinical findings and keywords of aortic stenosis: _______________________________________ _______________________________________ _______________________________________ _______________________________________ _______________________________________ _______________________________________ Why do patients with aortic stenosis look so SAD? 16. List the common causes of AS from the most to the least common? _______________________________________ 25. Excerpts of Triology; Northwestern Medical Review, 2012 Answer: They look sad because “sad” stands for: S yncope A ngina D yspnea! 23. Aortic stenosis is more common in elderly women as a result of age-related calcification of the valve. However, prevalence of the disease in young-age is more common in males and it is associated with bicuspid (instead of tricuspid) aortic valves. What would be a reasonable explanation for this finding? _______________________________________ _______________________________________ Note: AS reminds you of Astronaut and the rocket reminds you of the shape of the P-V loop in AS. Also, the tip of the rocket reminds you of the ventricular pressure that propels the rocket! 26. Excerpts of Triology; Northwestern Medical Review, 2012 ANSWERS 1. The second most common Valvular defect is aortic stenosis. This also happens to be the answer to the cited case scenario. 2. The stroke volume is represented by the width of the loop and it is decreased in AS. 3. End-systolic ventricular volume increases in AS! 4. Increased afterload slows the velocity of myocytic shortening. Because the period of time available for ejection is fixed at about 200 msec, a decrease in fiber shortening velocity drops the volume ejection and as a result more blood remains in the ventricle after systole. 5. As a result of increase in end-systolic volume the excess residual blood is added to the incoming venous blood and raises the EDV. This raises the preload and as a result (via Starling Law) the force of contraction. Note that left ventricular concentric hypertrophy will limit the over-expansion of the enddiastolic volume (to the right). to exercise and as a result blood perfusion to their brains is drastically affected. 12. Paradoxical split of the second heart sound. 13. Systolic crescendo-decrescendo murmur and paradoxical split. 14. Top three causes of paradoxical split: Aortic stenosis, left bundle branch block, and systemic hypertension. 15. In aortic stenosis and systemic hypertension 16. Age-related calcification of the valve, congenital bicuspid valve, and acute rheumatic fever 17. The best way to evaluate the function of a stenotic valve: Electrocardiography. 6. Concentric ventricular hypertrophy! 18. Less than 1 cm2 7. As a result of a fall in stroke volume, the arterial pressure drops substantially in AS. 19. Cross-section of the valves (the three leaflets) has semilunar appearance. 8. Syncope and faintness is a common clinical finding in AS. 9. Diastolic dysfunction due to hypertrophied left ventricle 20. Pulse pressure is equal to systolic minus diastolic pressure. As a result of low systolic pressure, AS patients have a narrow pulse pressure 10. Angina of AS is due to left ventricular hypertrophy and as result increased oxygen demand of the heart. 11. AS causes a low cardiac output. During exercise vasodilation of the skeletal muscles decreases peripheral vascular resistance. In normal individuals this decreased resistance is compensated for by an increase in the cardiac output. Patients with severe AS cannot increase their cardiac output in response 21. Second intercostal space to right of the sternum. aoRTic = RighT ! 22. Must-know clinical findings of AS: Paradoxical split, Systolic crescendo-decrescendo murmur, narrow pulse pressure, dyspnea upon exertion, and syncope (faintness) 23. Congenital bicuspid aortic valve is inherited in an xlinked fashion. Also it has more tendencies for calcification! 27. Excerpts of Triology; Northwestern Medical Review, 2012 Excerpts Bare Minimum Neurology and Neuroanatomy Review Visual Field Defects 28. Northwestern Medical Review, Bare Minimum Review Series, 2012 LESIONS OF THE VISUAL PATHWAY Normally damage to the brain cortex causes contralateral deficits in the extremities. This is not, however, true of the visual system. Unilateral damage to the visual cortex is manifested by characteristic partial loss of vision in both eyes. Neither of the eyes is able to see the contralateral visual field with respect to the location of lesions. As we will see later this unique pattern also holds true for the oculomotor muscles. In this case either of the eyes will have difficulty in moving to the contralateral position. Left T The next drawing illustrates the visual field (field of view) through the left and right eyes. To better understand the diagram and concepts that will follow hereafter it would be helpful to suppose that you are looking over the head of the perceiver and through his/her eyes. The visual field would then be what the perceiver actually would be able to see in front of him or her. N T Right Visual Field Temporal Retina Nasal Retina Fovea Optic Nerve Chiasm Optic Tract Lateral Geniculate Parietal Lobe Optic Radiation (From Superior Retina) Temporal Lobe Optic Radiation (From Inferior Retina) Calcarine Fissure Following diagram depicts report of the patient to her physician about how she sees the world (i.e. visual field) through her right eye. “DOC a pie is missing on the lower inner side of whatever I look at!” Visual Cortex This tumor most frequently occurs in the convexities of the cerebral hemisphere, parasagittal/falx-cerebri, olfactory area, and supra-sellar region. It arises from the arachnoid’s layer. It is more common in woman (3:2 female-male ratio); and often happens between ages 20 to 60. It is the second most common primary brain tumor. It is benign and grows slowly Histologically it is characterized by uniform whorling pattern and calcified psammoma bodies. Surgical removal is quite successful. Associated with bitemporal heteronymous hemianopia. This tumor is ___________________________ Note: Suprasellar means above the sella turcica (literally Turkish Saddle). It is the saddle-shaped depression in the sphenoid bone that houses pituitary gland. 29. Northwestern Medical Review, Bare Minimum Review Series, 2012 About Calcarine Fissure The calcarine fissure (or calcarine sulcus) is an anatomical landmark located at the caudal and medial surface of the occipital lobe and divides the visual cortex into upper and lower parts. Visual information that originates on the upper retina is projected to the visual cortex above the calcarine, and those that originate in the inferior retina, to the inferior part of the calcarine fissure. Common Primary Brain Tumors 1. The most common primary brain tumor is: _______________________________________ 8. In the above diagram, circular structures that are labeled “A” and “B” represent tumors of the brain. One of the two tumors belongs to a 5-year-old child and the other to a 70-year-old man. Which one is which? _______________________________________ _______________________________________ 9. Also called “Blue Cell Tumor”, this brain tumor commonly occurs in children. The most common location for it is the midline of cerebellum. It may spread into the CSF. What is this tumor? _______________________________________ 2. The second most common primary brain tumor is: _______________________________________ 3. The third most common primary brain tumor is: _______________________________________ 4. Gliomas are tumors that originate in the brain or spine. They are named according to the types of cells that they originate from. What are the four main cell types of gliomas? _______________________________________ Pathways that originate in the superior or inferior retina are projected to the superior or inferior aspects of the calcarine fissure respectively! Parietal Lobe Radiations _______________________________________ (From Superior Retina) 5. What is the most common astrocytoma? _______________________________________ 6. Name the two most important nerve sheath tumors? _______________________________________ 7. In the diagram below the exaggerated (caricature) crescent structure (labeled “?”) is a fold of dura mater forming a roof over the posterior cranial fossa, and separating the cerebellum from the basal surface of the occipital and temporal lobes of the cerebral cortex. What is the term that correctly describes this structure? _______________________________________ Temporal Lobe Radiations (From Inferior Retina) Inferior to Calcarine Fissure About Psammoma Bodies AKA. Sand bodies Mineralized (calcium deposit) bodies composed usually of a central capillary surrounded by concentric whorls They can occur in benign and malignant epithelial tumors (such as papillary ovarian or thyroid carcinoma, and meningiomas) Papillary carcinoma of the thyroid Serous ovarian cystadenocarcinoma / Sand tumor Adenocarcinoma of ovary Meningioma Mesothelioma Omatous-like lesions Malignant or benign Adenocarcinoma 30. Northwestern Medical Review, Bare Minimum Review Series, 2012 Doc, what’s happening to me; I can’t see my shoes; I can’t see my belt; and I can’t even see my “youknow-what!”. I can’t see anything from my nose to toes! Doc: “We will get back to you a little later, just be patient for now!” Note: The simplified method of illustrating the visual pathways, above, is very helpful in learning the lesions of the pathways hereafter. Beauty is in the eye of beholder! World through Bitemporal Heteronymous Hemianopsic eyes Human mind is a powerful tool. Quite often it fills up the perceptual gaps as it pleases ! 12. This patient has a tumor that has severed the temporal retinal pathways on the rightside and has spared the decussating fibers. Name and draw the visual defect of the patient. ________________________________________ ________________________________________ 10. Name the term used to describe the above visual finding in lesions of chiasm? _______________________________________ 11. What are a few major causes of the above finding? ________________________________________ _______________________________________ Constructing Simplified Visual Pathways 13. In the following diagram there are two lesions (severance of pathways); one before, and the other after the lateral geniculate body. In either condition the patient reports similar visual field deficits. What is the descriptive term for this condition, and how would you illustrate it by filling out the diagram below? _______________________________________ _______________________________________ 31. Northwestern Medical Review, Bare Minimum Review Series, 2012 14. A patient with pituitary adenoma has lesions of the visual pathway at the level of chiasm that has uniquely spared the decussating fibers. Name and draw the visual defect of the patient. _______________________________________ _______________________________________ 18. A patient with recent history of deep vein thrombosis presents with thrombosis of the basilar artery at the bifurcation of the two posterior cerebral circulations. As a result he has bilateral damage to his visual cortex (as it is shown in the diagram). Name and draw his visual field defect? _______________________________________ _______________________________________ 15. What lesions cause homonymous defects? _______________________________________ _______________________________________ Note: Patients with end stage glaucoma in one or both eyes may present with unilateral or bilateral macular sparing. 16. What is the distinctive difference between severing projection pathways at the position (A) and severing them after the lateral geniculate (B)? _______________________________________ _______________________________________ 17. A patient has been diagnosed with metastatic brain tumors. The tumors have severed his visual pathways as it is shown in the diagram. Name and draw his visual field defect? _______________________________________ 19. What is the following picture all about? _______________________________________ _______________________________________ Note: As a general rule lesions that are located farther away from the lateral geniculate bodies and closer to the visual cortex are presented with a more prominent macular sparring. 32. Northwestern Medical Review, Bare Minimum Review Series, 2012 Superior and Inferior Visual Fields Above diagram shows location of the lesion in the temporal lobe of the patient in the former question in a lateral view of the brain. 21. We have talked so many times about lateral geniculate nucleus or body (LGN). What is this organ; what is its function and where is it located? _______________________________________ Superior visual field information is projected onto the inferior retina, and the inferior field information onto the superior retina The neurons that originate in the superior or inferior retina maintain their topographic positions throughout the visual pathway until they reach the visual cortex. Superior retinal neurons pass through the parietal lobes and end on the superior aspects of the calcarine fissure. Inferior retinal neurons pass through the temporal lobes and end on the inferior aspect of the calcarine fissure From retina through the lateral geniculate bodies the superiorly and inferiorly located neurons are so close to each other that a lesion will sever both of them together. Past the lateral geniculate, the optic radiations through the parietal or temporal lobes are spatially apart from each other. As a result a lesion may selectively sever one of the two radiations and spare the other. 20. You are evaluating a patient with lesion of the left temporal lobe due to vascular thrombosis. What is the name of the characteristic visual field defect of the patient, and how would you draw it? _______________________________________ _______________________________________ _______________________________________ 22. Draw and name the visual defect that results from severance of the temporal radiations in this picture _______________________________________ _______________________________________ 23. Draw and name the visual defect that results from bilateral severance of the parietal lobe radiations in this picture. _______________________________________ _______________________________________ 24. What type of cerebral lesions will cause the following visual field finding? _______________________________________ _______________________________________ 33. Northwestern Medical Review, Bare Minimum Review Series, 2012 25. Using the following diagram and lesions draw and name the visual defect of the following patient? 30. A patient is presented with the following visual field defect pattern. Which of the following options better explains this finding? A. Right eye blindness and bitemporal heteronymous hemianopia B. Bitemporal heteronymous hemianopia and left homonymous hemianopia C. Neither of the above D. Both of the above _______________________________________ _______________________________________ 26. What lesions of the visual pathways cause homonymous defects? _______________________________________ _______________________________________ Use the word “hetero” if the defect seen by the left and right eyes are not to the same side of the visual field (i.e. one is to the left and one to the right). Use the word “homo” if the visual field defects of the left and right eyes are to the same side (i.e. either on the left or right. 27. Which of these two findings is a heteronymous and which one a homonymous defect? _________________________ _________________________ 28. This picture is the left eye report of a 25-year-old female patient during her ophthalmologic examination. Name the visual defect and the most likely disease that she is suffering from? _______________________________________ _______________________________________ 29. What is the mechanism of macular sparing? _______________________________________ _______________________________________ 34. Northwestern Medical Review, Bare Minimum Review Series, 2012 Answers 1. The top most common Glioblastoma multiforme 2. The second most common: Meningioma 3. The 3rd most common: schwannoma. 4. The four main cells types and tumors are ependymomas (ependymal cells), astrocytomas (astrocytes), oligodendrogliomas (oligodendrocytes) and nerve sheath tumors. 5. The most common (and most aggressive) astrocytoma is glioblastoma multiforme. 6. The two major nerve sheath tumors are neutrofibromas and schawannoma 19. “This is the picture of a pie in the sky!” 7. The crescent structure is tentorium cerebelli 20. Right superior (upper) quadrantanopia. Pie in the sky! 8. Adult tumors are often supra-tentorial (i.e. “A”) whereas children tumors are often infra-tentorial (i.e. “B”). 9. “Blue Cell” brain tumor of children is medulloblastoma. 10. Bitemporal heteronymous hemianopia! 11. Pituitary Adenomas, craniopharyngiomas, and meningiomas. 12. Right nasal heteronymous hemianopia. Common causes are calcified right internal carotid arteries and compression of the chiasm. 13. Left homonymous hemianopia 18. The patient with bilateral damage to visual cortex due to lack of circulation presents with has bilateral macular sparing (AKA. bilateral homonymous hemianopia with macular sparing) 21. The left and right lateral geniculate nuclei (LGN) are within the thalamus and they are the primary relay centers for visual information from the retina. Each LGN receives information from one half of the visual field. For example, the left LGN receives information from ganglion cells of the temporal retina of the left eye plus information from the nasal retina of contralateral (right) eye. The nerves that originate in the retina have long axons that extend, uninterrupted, through the optic nerve, chiasm and optic tract and reach to the LGN. In the LGN they synapse with the second set of neurons that extend to the visual cortex. 22. Bilateral superior hemianopia or superior homonymous hemianopia. Of course, there may also be a macular sparing. 14. Binasal heteronymous hemianopsia 23. Inferior (Lower) (Homonymous) hemianopia 15. Lesions after the chiasm (and excluding chiasm cause homonymous defects. Lesions before the chiasm cause heteronymous defects 16. Both lesions cause right homonymous hemianopia. However, the lesion in “B” causes right homonymous hemianopia with macular sparing. 24. Vascular damage to the occipital visual cortex (example bilateral occlusion of the posterior cerebral circulation) 25. Right inferior (homonymous) quadrantanopia and left superior quadrantanopia. 17. He has bilateral macular sparing (AKA. bilateral homonymous macular sparing). 35. Northwestern Medical Review, Bare Minimum Review Series, 2012 26. Lesions anywhere behind the chiasm; optic tract, lateral geniculate, optic radiations, and visual cortex cause homonymous defects! 27. 28. This condition, often unilateral, is called central scotoma seen in optic neuritis and it may also result from optic disc swelling. It is commonly associated with multiple sclerosis. 29. Due to the large size of foveal representations in the cortex, the areas that are devoted to central vision (central parts of the visual field) are less likely to be affected. Additionally, it is shown that the occipital lobe receives a dual blood supply. Even though the posterior cerebral artery is the main supply, a branch of middle cerebral artery also supplements the occipital pole areas that are topographically represented by the macula. 30. The best option is “D”. When you superimpose the following two diagrams you will generate the picture that is shown in the tested item. 36. Northwestern Medical Review, Bare Minimum Review Series, 2012 Carbohydrate Metabolism Synopsis of Glycolytic Enzyme Deficiencies The video that accompanies the texts in this segment begins on page 44. However, a quick review of the rest of the materials is highly recommended prior to watching the video. 37. Northwestern Medical Review, Bare Minimum Review Series, 2012 Glycolytic Pathway Glycogen Glucose 1-phophate Glucose Glucose 6-phosphate Fructose 6-phosphate Fructose 1,6 bisphosphate Dihydroxyacetone phosphate Glyceraldehyde 3-phosphate 1, 3-Diphosphoglycerate 3-Phosphoglycerate 2-Phosphoglycerate Phosphoenolpyruvate Lactate LACTATE Pyruvate Cytoplasm Acetyl-CoA Mitochondria *Stars indicate key controlling enzymes and steps of glycolysis. The light-color star connecting pyruvate to acetyl CoA is not a glycolytic step. It marks the pyruvate dehydrogenase enzyme (PDH) that is required for aerobic respiration of glucose. Glucose 6-Phosphate Glycogen phosphorylase catalyzes conversion of glycogen to glucose 1-phosphate. Hexokinase and/or glucokinase catalyze conversion of glucose to glucose 6-phosphate. The two glucose phosphates—glucose 1phosphate and glucose 6-phosphate, are readily interchangeable—using phosphoglucomutase as their catalyst. Inhibited by the product (G-6-P); hence, it works better if products are utilized quickly (e.g. fasting conditions). Glycogen Glucose Hexokinase Phosphorylase G-6-Phosphatase Phosphoglucomutase Hexokinase (HK) Most tissues have hexokinase Broad Specificity (acts on most sugars). Affinity for glucose is high (low Km); it works maximally during fasting glucose conditions. Helps to provide G6P to tissues during low blood glucose levels. Low Vmax (cannot phosphorylate high glucose quantities). It has low capacity for working on glucose. Glucose 1-P Glucose must first be converted to glucose 6-P before descending down the glycolytic pathway. 38. Northwestern Medical Review, Bare Minimum Review Series, 2012 Glucose 6-P Glycolytic Pathway Note: Normally about 10-20% of red cell glycolytic pathways are shunted toward 2,3 DPG formation. This is an important shunt in the red cells and it is normally stimulated on the tissue sides as a result of accumulation of metabolic byproducts such as CO2 and hydrogen ions that drop the pH. Glucose Hexokinase Glucose 6-P Glyceraldehyde 3-P Note: Addition of phosphate to hexoses would trap glucose within the cells. It also energizes the molecule in preparation for further enzymatic activities. As we will see later in the absence of alternative pathways to utilize the phosphorylated sugars, this trapping will increase the osmotic pressure and lyses or damages the cells. Glucokinase Glucokinase is the unique liver brand of hexokinase. Shows affinity for glucose when glucose level is very high (high Km). Handles huge incoming venous portal glucose after meals (high vmax). It has high capacity for working on glucose. Synthesis is stimulated by insulin. As opposed to hexokinase, it is not inhibited by glucose 6-phophate. Note: The only other cells in the body with glucokinase are the pancreatic beta-cells. 1. Why do people not get hyperglycemic after carbohydrate meals? ______________________________________ ______________________________________ Hexokinase (HK) Deficiency Autosomal recessive disease Hemolytic anemia Decreased formation of 1, 3 DPG (1,3 diphosphoglycerate). 1,3 DPG is normally converted to 2,3 DPG by a mutase in the red cells. Hence, in hexokinase deficiency the 2,3 DPG level is decreased. Hexokinase deficiency is associated with downstream deficiency of 1,3 DPG and as a result a deficiency of 2,3 DPG in the red cells! 1,3 Diphosphoglycerate 3 Phosphoglycerate Mutase Red Cells Phosphatase O2 + Hb 2,3 Diphosphoglycerate HbO2 Pyruvate 2,3 Diphosphoglycerate Most abundant organic phosphate source of RBC Regulates binding of oxygen to hemoglobin If absent, Hb (hemoglobin) shows a high affinity for oxygen; if present, Hb unloads oxygen. HbO2 (oxyhemoglobin) + 2,3DPG Hb2 (deoxyhemoglobin) + O2 + 3PG 2,3DPG level in RBC increases in chronic hypoxia, COPD, asthma, and high altitude. Note: It is postulated that acidity of blood at the tissue level redirects part of red blood cell glycolytic pathways toward 2,3 DPG formation via activating a mutase that converts 1,3 DPG to 2,3 DPG. As a result red cells unload their oxygen to the tissues and become deoxygenated. Deoxyhemoglobin, on the other hand, is a perfect buffer and it buffers the acids. As a result of drop in the acidity a phosphatase enzyme gets activated and converts 2,3 DPG to 3phopshoglycerate (i.e. back to the main glycolytic pathway). Also note that in the lung vasculature due to lower levels of 2,3 DPG and less acidity of the blood hemoglobin can more aggressively load oxygen. The same mechanism also explains why in COPD and asthma (which are associated with respiratory acidosis and high CO2 levels) there is a higher level of 2,3 DPG in red cells. 39. Northwestern Medical Review, Bare Minimum Review Series, 2012 Findings in Hexokinase (HK) Deficiency Low 2,3-DPG of the red cells causes high oxygen affinity of hemoglobin for oxygen. At the same time it makes unloading of oxygen to tissues very difficult. This leads to left shift of the hemoglobin oxygen dissociation curve and tissue anoxia (or tissue hypoxia). Lack of ATP formation due to failure of glycolytic pathways cause hemolytic anemia. Generalization All glycolytic enzymes share one aspect in common; their deficiency is associated with hemolytic anemia! Autosomal Recessive and Dominant Defects Recessive Dominant 3. Why does failure of the Na+/K+-ATPase pump cause hemolysis of the red cells? ______________________________________ ______________________________________ 4. What is the only source of energy for the red cells and why? ______________________________________ ______________________________________ Findings in Hemolytic Anemia Premature RBC destruction Accumulation of hemoglobin catabolic products (e.g. bilirubin). Marked erythropoiesis and reticulocytosis. Lab Characteristics of Hemolytic Anemia Hemoglobinemia, hemoglobinuria and Hemosiderinuria (Iron overload) Normocytic anemia (acute cases) Jaundice (conjugated hyperbilirubinemia) Reduced serum haptoglobin. Haptoglobin is made by the liver and binds free hemoglobin and the bound form is removed by the reticuloendothelial system and spleen. Often cause enzyme deficiencies (e.g. hexokinase or glucose 6 phosphate dehydrogenase deficiencies) Often cause structural protein defects (e.g. collagen in Marfan’s, or spectrin in hereditary spherocytosis) 100% penetrance (i.e. all patients exhibit all symptoms) Partial penetrance (i.e. not all patients exhibit all symptoms) Early age of onset (e.g. infancy to early childhood) Variable age of onset (early childhood through middle ages) Both parents must be carriers for the defective gene One of the parents must have the disease 5. In what form is iron absorbed from the GI? ______________________________________ Often more serious Often less serious 6. How is iron transported in the blood? ______________________________________ 2. A patient is diagnosed with hexokinase deficiency. What is the most likely age of the patient? A. B. C. D. E. 7. What is the name of the storage form of iron? _____________________________________ 8. What commonly tested disease is associated with high iron deposits in tissues and it is characterized by diabetes, cirrhosis, and dilated (congestive) and/or restricted cardiomyopathy? ____________________________________ 8 months 8 years 16 years 32 years 50 years Mechanism of Hemolytic Anemia Red blood cells are 100% dependent on anaerobic glycolysis for making their ATP. Failure of glycolytic enzymes impedes ATP production. Low ATP reduces Na+/K+-ATPase activity that is required for integrity of RBC’s membrane shape and function. Hence: red cells swell and break apart. Hence: Hemolytic anemia. 9. What is hemosiderin made up of? ____________________________________ 10. What is normal reticulocytic index and when does it increase or decrease? ____________________________________ ____________________________________ 11. What is the term used to describe diabetes as result of hemosiderins deposit in the pancreas? ____________________________________ 40. Northwestern Medical Review, Bare Minimum Review Series, 2012 12. What is the treatment for hemochromatosis? ____________________________________ ____________________________________ 13. Diagnosis of hemochromatosis quite often begins by measuring the serum levels of transferrin and ferritin. What are the two common tests performed on the liver to diagnose hemochromatosis? ____________________________________ ____________________________________ 14. What tissue of the body is most adversely affected by glycolytic enzyme deficiencies? ____________________________________ Regulation of Phosphofructokinase AMP & FR-2,6-BP ATP & CITRATE Parthenogenesis of Hemochromatosis Excessive GI Iron Absorption Iron stimulates collage formation Cirrhosis Iron accumulates as hemosiderin in hepatocytes Iron alters DNA Hepatocellular Carcinoma Phosphofructokinase is the ratelimiting enzyme of glycolysis Iron induces formation of free radicals (due to Fenton reaction.) Fructose 6-P H2O2 and free radicals cause lipid peroxidation of cell membranes Necrosis of Cells Factors Affecting Integrity of Red Blood Cells Increased level of glucose-6-phosphate dehydrogenase (indirect positive effect) Adequate availability of ATP Proper activity of pentose monophosphate shunt Maintenance of glutathione in reduced state G-6-Phosphate: The Gateway to Other Pathways Glucose 6-P Glycogen Pyruvate 6-P Gluconate G1P Phosphofructokinase I Biochemical Control of PFK The purpose of glycolysis is to produce energy High titer of cellular AMP levels (i.e. low energy) will activate the glycolytic enzymes in general and PFK in particular. High levels of intracellular ATP will shut-off the PFK Citrate is the first compound in the Kreb’s cycle, and it is among the few compounds that can exit the mitochondrial membrane and get into the cytoplasm wherein the glycolytic enzymes are located. The titer of citrate increases in the mitochondria whenever there is a high level of ATP production by the Kreb’s cycle. Appearance of the citrate in the cytoplasm will then convey the message of high ATP levels to the PFK. The next potent activator of the PFK is fructose 2,6 bisphosphate (see further below) TCA G6P Glucose Energy Fructose 1,6-P Ribose Glucose 6-phosphate is the substrate of three enzymatic pathways; glycogen synthesis and degradation (the left side pathway in the above diagram), glycolysis (in the center) and hexose mono-phosphate shunt (on the right). 41. Northwestern Medical Review, Bare Minimum Review Series, 2012 Fructose 2, 6-Bisphosphate In the Liver, F2,6-BP is formed from F6-P by PFKII. F2,6-BP activates PFKI It inhibits F1,6-bisphosphatase, that is, the enzyme of the reverse reaction (gluconeogenesis). It is an intra-cellular sensor of glucose level Hepatic levels are decreased with elevated glucagon or during fasting Levels are increased with low glucagon and in the fed state Insulin greatly increases synthesis of PFKII and as a result stimulates the glycolytic pathways. 15. Which hormone stimulates and one inhibits PFK II? ____________________________________ ____________________________________ 16. Which of the two has a higher effect in raising output of insulin from the pancreas; a high carbohydrate diet or IV injection of glucose? ____________________________________ ____________________________________ to hemolytic anemia Increased muscle glycogen causes myopathy, rhabdomyelysis, increased serum CPK, myoglobinemia and myoglobinuria. Substrates before the step increase in muscle. For example, fructose and glucose 6-phosphate increase, whereas, products after the step such as Fr 1,6-diphosphate and 1,3 DPG decrease. 17. List major causes of rhabdomyelysis: ______________________________________ ______________________________________ ______________________________________ ______________________________________ 18. What is the rate-limiting enzyme of glycolysis? _____________________________________ Phosphofructokinase (PFK) Deficiency Glycogen Glucose 1-phosphate Glucose 6-phosphate Fructose 6-phosphate Phosphofructokinase PFK II FR-6-P Fructose 1,6-bisphosphate FR 2,6 BP In phosphofructokinase deficiency glycolysis fails after the F6P step. TCA slows down; ATP and energy levels drop. Substrates before the step; including glycogen, buildup in tissues. PFK I FR 1,6 BP Northwestern Medical Review Fructose 2,6 BP is made in the liver by PFK II and it promotes glycolysis via stimulating Phosphofructokinase I and stops gluconeogenesis. Glycolysis Last Unique Step of Glycolysis 2 Phosphoenolpyruvate Gluconeogenesis Phosphofructokinase (PFK) Deficiency AKA. Type VII Glycogen Storage Disease Inefficient muscle glucose supply causes cramps Glucose is mainly supplied by gluconeogenesis Increased muscle glycogen stores (glucose is shunted toward glycogen production due to improper glycolytic functions). Mild Hypoglycemia. Breakdown of glycogen is slowed down and glycogenesis is enhanced. Rate of ATP formation (by Kreb’s Cycle) decreases. Red cells are deprived of ATP and there is failure of sodium-potassium-ATPase pump. Hence, sodium stays within the red cells and this leads 2 ADP Pyruvate Kinase 2 ATP 2 Pyruvate Sugars make pie! Pyruvate (the pie!) is the end result of carbohydrate metabolism. Pyruvate is also a pirate because it pirates 3 carbon sugars from cytoplasm into the mitochondria. (We will see more on this later!) 42. Northwestern Medical Review, Bare Minimum Review Series, 2012 19. A 25-year-old woman with history of heavy menstrual bleeding complains of fatigue and exercise intolerance. Blood analysis is significant for hypochromic microcytic anemia. Which of the following two iron preps would you prescribe for her, ferric or ferrous sulfate? _______________________________________ Formation of Pyruvic Acid Formation of two pyruvic acid molecules from two PEP molecules in the cytoplasm marks the end of glycolysis. But in order for ATP (energy) to become available pyruvate (the pie!) must be further oxidized (eaten!) either under aerobic or anaerobic conditions (see further below for details). The last Step of Glycolysis PEP P AT PK Mnemonic: One of the two Ps of PEP goes to ATP and the other to Pyruvate! Pyruvate Pyruvate kinase is the last key-controlling enzyme of glycolysis. Generalization The purpose of glycolysis is to make energy. As a general rule, accumulation of downstream products and abundance of sources of cellular energy such as ATP and NADH inhibit the glycolytic pathway. Conversely, abundance of uphill substrates (that is, the preceding compounds) promotes the pathway. As we will see later, this principle also holds for the Kreb’s cycle. Regulation of Pyruvate Kinase FR-1,6-BP Phosphoenol Pyruvate ATP & ALANINE Pyruvate Kinase Pyruvate Pyruvate Kinase is the Last Enzyme of Glycolysis Pyruvate Kinase (PK) Deficiency Normal RBC lacks mitochondria, and it is fully dependent on anaerobic glycolysis for ATP. Deficient individuals have a low Pyruvate Kinase level in their red blood cells Hence, the patients have low RBC glycolysis, and low ATP production. Low ATP affects K+/Na+-ATPase pump, and leads to membrane damage, lysis and hemolytic anemia. Consequence is anemia, marked increase in reticulocytic number and mild jaundice. Failure of the last step of glycolysis Abnormal accumulation of glycolytic intermediates before the step High 2,3-DPG production and abnormally low oxygen affinity of Hb (right shift of the Hb-oxygen dissociation curve) Treatment Options: Oxygen therapy, blood transfusion (serious cases), folate or B12 administration and splenectomy. Note: Spleen gets sequestered with and lyses the PK deficient red cells. As such removal of spleen would help to minimize the rate of hemolysis. Furthermore, due to high levels of red cell breakdown these patients are at risk for splenomegaly and rupture of spleen. Hexokinase Contrast of Hexokinase and Pyruvate Kinase Deficiencies. Glycolytic Pathway Pyruvate Kinase Hexokinase stops glycolysis at the inlet and pyruvate kinase at the outlet. Both of them slow down the TCA function and energy-producing machinery. In the case of hexokinase nothing past the step, including 2,3 DPG, is produced. In the case of pyruvate kinase, every thing prior to the step, including 2,3 DPG accumulates in the cell. TCA Pyruvate Kinase and Hexokinase via modulation of the 2,3 DPG levels within the red cells affect oxygenation of hemoglobin. Pyruvate Kinase deficiency causes increased 1,3 DPG levels in the red cells and as such it resembles hypoxemic conditions. Hence, in this deficiency unloading of oxygen to the tissues is enhanced. 20. Where in the cell does the glycolytic pathway take place? _____________________________________ 43. Northwestern Medical Review, Bare Minimum Review Series, 2012 Summary of Glycolysis A 4-year-girl is being evaluated for anemia and jaundice. Lab results are significant for increased reticulocytes, reduced serum haptoglobin, and increased urinary hemosiderins. No sickle cells or spherocytes are identifiable in the child’s blood. She has mild splenomegaly and lacks hepatomegaly. There is no history of any recurrent infections. 22. What is the best descriptive term for explaining above finding? _______________________________________ 23. What are your first impression top differentials? ______________________________________ ______________________________________ ______________________________________ Right shift of hemoglobin (Hb) dissociation curve increases P50 (partial pressure of oxygen that saturates 50% of available Hb sites). That is for any PO2 level saturation of Hb will decrease. Associations of Hemoglobin-Dissociation Curve Left Shift Right Shift Low 2,3 DPG in RBC High hemoglobin oxygen affinity Low unloading of O2 Carbon Monoxide Methemoglobinemia Fetal hemoglobin Hexokinase and phosphofructokinase Deficiencies High 2,3 DPG in RBC Low hemoglobin oxygen affinity High unloading of O2 Increased acidity Increased PCO2 High Temperature Chronic hypoxia High Altitude COPD/Lung Disease Pyruvate Kinase Deficiency 21. Both carbon monoxide poisoning and methemoglobinemia cause left shift of hemoglobin-oxygen dissociation curve and make unloading of oxygen more difficult. Why oxygen therapy is still the mainstay therapy in both conditions? _______________________________________ _______________________________________ 24. What are your second impression top differentials? ______________________________________ ______________________________________ ______________________________________ 25. What makes above enzyme deficiencies similar? ______________________________________ ______________________________________ ______________________________________ 26. Which of the three is the most likely cause of the above findings and also the most commonly tested one on the COMLEX and USMLE exams? ______________________________________ 27. What is by far the most common cause of hemolytic anemia as a result of an enzyme deficiency? ______________________________________ 28. What unique clinical finding will set PFK apart from the other two glycolytic deficiencies? ______________________________________ 29. In which of the aforementioned glycolytic deficiencies the level of 2,3DPG increases in the red cells and the patient assume a right shift of the hemoglobin dissociation curve? ______________________________________ 44. Northwestern Medical Review, Bare Minimum Review Series, 2012 31. Which of the patients in the above three glycolytic enzyme deficiencies will be more benefitted from oxygen therapy? ______________________________________ 30. Why patient with hexokinase deficiency present with the most profound hemolytic anemia among the three glycolytic deficiencies? ______________________________________ Summary of Glycolytic Enzyme Deficiencies HK PFK PK All are major glycolytic enzyme deficiencies All are rare autosomal recessive defects Hemolytic anemia Treatment Options: Blood transfusion, splenectomy, and foliate and vitamin B12 administration Most fatal hemolytic Glycogen storage The most common glycolytic anemia among common disease VII enzyme deficiency glycolytic enzyme Rhabdomyelysis, deficiencies myoglubinemia and high Right shift of Hb-oxygen dissociation curve and Left Shift serum CK difficulty with loading oxygen Treated with blood Left Shift of Hb-oxygen on hemoglobin transfusion dissociation curve 1. 2. 3. 4. Oxygen therapy 32. What is the major source of energy for the red cells during serious starvation? ______________________________________ 33. What is the homeostatic value of maintaining blood glucose levels at about 90 mg/dl? ______________________________________ 34. You are looking at the blood smear of a 6-yearold child with hemolytic anemia due to pyruvate kinase deficiency. What type of anemia based on the size of red cells do you expect to see? ______________________________________ 35. What two clinical conditions are common causes of the same type of anemia based on the size of the red cells? ______________________________________ ______________________________________ 45. Northwestern Medical Review, Bare Minimum Review Series, 2012 ANSWERS 1. Under the influence of insulin, glucokinase traps (sequesters) glucose in the hepatocytes and convert them to glycogen. 2. Autosomal recessive genetic conditions often are diagnosed at early age. Therefore the best answer is [A]. 3. The pump extrudes sodium and returns potassium back into the red cells. In the absence of proper pump function sodium is retained in the red cells and increases osmotic pressure. This leads to swelling and early destruction of the cells. 4. Mature red cells do not have mitochondria. Therefore they are not capable of performing aerobic respiration. For this reason they cannot use fatty acids and ketone bodies as a source of energy. The only energy producing mechanism available to the red cells is anaerobic glycolysis that yields two ATP molecules for every glucose molecule that they consume. 5. Iron is absorbed in ferrous form (Fe++) 6. Transported by transferrin that is a protein made by the liver in the ferric form (Fe++) 7. The storage form of iron is known as ferritin. It is a protein that combines with iron. 8. Hemochromatosis! The genetic form of the disease is associated with excessive absorption of iron from gut. It is due to mutation in the HFE gene. It is more common among the Caucasians and in particular Irish population. 9. Hemosiderins are made up of iron, protein and polysaccharides. They accumulate in various tissues including heart, pancreas, liver and GI mucosa and often cause death of the tissues. 10. Reticulocytes are immature red cells. Typically about 1% of the red cells are reticulocytes. Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells, reticulocytes do not have a cell nucleus. They are called reticulocytes because of a reticular (mesh-like) network of ribosomal RNA that becomes visible under a microscope with certain stains such as new methylene blue. In hemolytic conditions the reticulocytic index is more than 1. In contrast in bone marrow diseases it may drop to values less than 1. 11. Bronze diabetes 12. Periodic phlebotomy and oral administration of zinc. Zinc competes with iron for absorption from GI. 13. Liver is one the main organs for accumulation of iron deposits. Ferri-Scan is a MRI-based test to noninvasively and accurately measure liver iron concentrations. It identifies iron deposits in the hepatocytes. Currently it is a preferable choice over the widely used liver biopsies (and staining of the tissue with Prussian blue). Note that serum transferrin and transferrin saturation are commonly used as screening for hemochromatosis. Fasting transferrin saturation values in excess of 45% is suggestive of hemochromatosis. Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the HFE gene. Serum ferritin provides another crude estimate of whole body iron stores though many conditions. But it involves a high rate of false positive cases because inflammation, chronic alcoholism, and fatty liver diseases also elevate serum ferritin. Normal serum ferritin values for males are 12–300 ng/ml (and less in females). Serum ferritin in excess of 1000 ng/ml of blood is most likely due to hemochromatosis. 14. Glycolytic enzyme deficiencies most adversely affect the red cells as they can only utilize glucose as the (sole) source of energy. 15. Insulin (fed state) stimulates PFK synthesis whereas glucagon (fasting state) inhibits it. 16. High sugar diet has more profound effect on stimulating the insulin release because in addition to raising sugar levels it activates parasympathetic nervous system. Activation of parasympathetic system greatly activates pancreatic insulin release. 17. Causes of rhabdomyelysis: (1) Muscle Crush (Car accident); (2) Snake Venom; (3) Enzyme Deficiencies: PFK deficiency, McArdle’s disease, Carnitine Acyltransferase and Carnitine deficiency, and MCAD deficiency; (4) Drugs such as Statins, Fibric acid derivatives, Tubocurarine plus halothane, haloperidol, and chlorpromazine; (5) Others: Tetanus, UMN Deficits and grand mal seizures. 18. PFK 19. Ferrous sulfate, because iron is absorbed in ferrous form. 20. In the cytoplasm! 21. Patients who breathe hyperbaric oxygen (pressurized 100% oxygen) show improvement. Although many scholars question the utility of the procedure. It is speculated that by pressurized oxygen we are able to bypass the contributions of the hemoglobin and force feed oxygen into the mitochondria. 46. Northwestern Medical Review, Bare Minimum Review Series, 2012 22. Hemolytic anemia 23. All genetic causes of hemolytic anemia: Hexokinase deficiency, Phosphofructokinase deficiency, Pyruvate kinase deficiency, Glucose 6 phosphate dehydrogenase deficiency, Hereditary Spherocytosis, Sickle Cell disease, Beta-thalassemia (also alphathalassemia, and Hereditary elliptocytosis 24. Hexokinase deficiency, Phosphofructokinase deficiency, and Pyruvate kinase deficiency 25. They are key glycolytic enzyme deficiencies. They all autosomal recessive. All three deficiencies cause hemolytic anemia! 26. Hexokinase deficiency 27. G6PD deficiency 28. Rhabdomyelysis as a result of glycogen build-up in the cytoplasm of striated muscle that leads to myoglobinuria, high serum CK and creatine. 29. PK deficiency. The other two are associated with low 2,3DPG and a left shift 30. Hexokinase is also required for HMP shunt function in the red cells. The shunt makes NADPH that safeguards red cell membrane against oxidizing agents via increasing the level of reduced glutathione. So these patients in addition to osmotic damage of the red cells that is shared among all three are at further risk of oxidizing damages to red cell membrane. Note that the red cells due to 100% reliance on glucose can only use hexose monophosphate shunt and anaerobic glycolysis as the source of energy. 31. Patients with PK deficiency as a result of right shift of the oxygen dissociation curve. 32. Glucose. They cannot utilize any other food source. 33. Even though the brain cells under normal conditions and early starvation rely on glucose, the major contribution of maintain glucose is to nourish red cells and promote respiration that is vital to survival. 34. Normocytic anemia. Hemolytic anemias commonly cause normocytic anemia 35. Kidney diseases due to lack of erythropoietin and hemorrhage cause normocytic anemia. 47. Northwestern Medical Review, Bare Minimum Review Series, 2012 Post-Test Total Items: 50 Allotted Time: 60 Minutes Minimum Passing Score: 33 correct answers * The passing score is calibrated to reflect performance on the Step 1 examination 48. Northwestern Medical Review, Sample Review Book Series, 2012 POST-TEST 1. You are evaluating a 20-year-old female patient with a 4-year history of renal disease for complaint of visual problems. History shows that her disease has begun with an abrupt incidence of hematuria that has gradually progressed to proteinuria of more than 3.5 grams per day. A recent renal biopsy of the patient has been significant for presence of dense homogenous deposition along the glomerular basement membrane and in the mesangium. Which of the following mechanisms will better explain the etiology of this patient’s renal findings? A. B. C. D. E. Activation of classic complement pathway Activation of alternate complement pathway Activation of lectin complement pathway Circulating antistreptolysin O antibodies Circulating HLA-B27 antibodies C. Ankylosing spondylitis is a recessive X-linked condition D. Estrogen in females inhibits expression of the disease E. Genes for the disease are located on Y chromosome 5. Celiac disease is associated with which of the following conditions? A. B. C. D. E. Henoch-Schonlein Purpura Systemic lupus erythematosus Dermatitis herpetiformis Ankylosing spondylitis Rheumatoid arthritis 6. Which of the following immunofluorescence patterns of glomerular deposits is seen in patients with rapidly progressive glomerulonephritis? 2. Which of the following renal diseases is classified as a nephrotic syndrome? A. B. C. D. E. Goodpasture’s syndrome Henoch-Schonlein purpura Membranous glomerulonephritis Membranoproliferative glomerulonephritis Alport’s syndrome 3. Which of the following findings will distinguish membranoproliferative glomerulonephritis (MPGN) type I from type 2? A. B. C. D. E. Red cell casts in urine Activation of complements in the glomeruli Increased number of mesangial cells Mesangial immune deposits Despite therapy may progress to end-stage renal failure 4. Patients with ankylosing spondylitis are often young males that in addition to chronic inflammatory disease of axial skeleton at times are also presented with mesangial immune deposits. Which of the following statements is a better explanation for the fact that ankylosing spondylitis is more common in males? A. Testosterone potentiates effects of the HLAB27 antibodies on the joints and tissues. B. Testosterone potentiates effects of the IgA antibodies on the joints and tissues. 7. You are examining a 3-week female infant who is admitted to the hospital for the complaint of extreme temperature fluctuations, diarrhea, vomiting and apnea of 24-hour duration. On examination the baby is lethargic, bradycardic, hypotensive, and extremely jittery. Head examination is significant for bulging of fontanelles. Based on your clinical suspicion you will order and immediate blood analysis and spinal tap and also start the baby on I.V. ampicillin 100 mg/kg q12hr and gentamicin 2.5 mg/kg q12hr. Results of the spinal tap indicate elevated CSF pressure; leukocytosis with 90% PMNs; glucose, 35 mg/dl; and protein, 400 mg/dl. CSF gram staining is significant for gram-positive bacteria with coccoid morphology. Which of the following laboratory tests would be the most helpful in identifying the cause of the cerebrospinal findings in the patient? 49. Northwestern Medical Review, Sample Review Book Series, 2012 A. B. C. D. E. Coagulase test Catalase test India ink staining Camp test Optochin-sensitivity Use this Case for Questions 8 and 9 A 21-year-old female college student is brought to the emergency department for evaluation of fever, vomiting and severe myalgia that she has had for about 7 hours. On admission she is mildly confused and has high temperature and high pulse rate. She is in her period and uses tampons. Her systolic pressure is 70 and diastolic 30. She has a rash resembling sunburn, particularly on her palms and soles. History is significant for heavy menstrual periods. 8. Assuming an infectious cause for her symptoms, which of the following ionic conditions would have facilitated the pathogenesis of her condition? A. B. C. D. E. Hypocalcemia Hypomagnesemia Hyponatremia Hypochloremia Hypokalemia 9. The patient immediately receives an antibiotic treatment with nafcillin. But her symptoms not only persevere but they get augmented within the next 36 hours. She is then scheduled to receive an alternative IV medication. As part of her therapeutic management her serum creatinine level is monitored quite carefully. Which of the following is the alternative IV medication? A. B. C. D. E. Trimethoprim-sulfamethoxazole Methicillin Vancomycin Dicloxacillin Clindamycin ______________________________ 10. Seven adults are admitted to the emergency room. All of them are nauseating and presented with common symptoms that include vomiting, flushing, abdominal cramps and diarrhea. They all claim that they have been to the same buffet-type restaurant and their symptoms began while they have been still dinning at the restaurant. History shows that all of them have consumed a few hot fish dishes that included anchovy, herring, and mahi-mahi. Assuming that the patients are resented with enterotoxicity, which of the following is the most probable cause of these findings? A. B. C. D. E. Staphylococcus aureus Bacillus cereus Scombroid Vibrio parahaemolyticus Enterotoxigenic E. coli 11. X-ray of the hip of an 8-year-old boy with history of recurrent bone pain is significant for avascular necrosis of the head of femur. If the child has been diagnosed with osteomyelitis on several occasions in the past, which of the following conditions would be the underlining cause of his avascular necrosis? A. B. C. D. E. Sickle cell disease Cystic fibrosis Vascular thrombosis Scalded Skin Syndrome Legg-Calvé-Perthes syndrome 12. You are giving a lecture in microbiology to medical students. The topic of your lecture is food poisoning. A student in the audience is interested to know which of the following food poisonings as a result of preformed toxin is sensitive to heating of the food; what would be your answer? A. B. C. D. E. Staphylococcus aureus Bacillus cereus Scombroid Botulinum Salmonella typhi 13. Which of the following bacteria is the most common cause of necrotizing fasciitis? A. B. C. D. E. Staph auresus Strep pyogenes Pseudomonas aeroginosa Clostridium perfringens Bacillus anthrax 50. Northwestern Medical Review, Sample Review Book Series, 2012 14. In treatment of infections with Staph aureus nafcillin is preferable over methicillin, why? A. Nafcillin in contrast to methicillin is resistant to beta-lactamase B. Nafcillin has more potency for destroying the cell wall of gram-positive bacteria C. Nafcillin is effective against methicillinresistant staph aureus (MRSA) D. Methicillin causes serious nephrotoxicity E. Methicillin causes serious neurotoxicity 15. A 25-year-old man is admitted to the emergency room about 10 days ago for urinary incontinence due to urinary stones, and also for an infected skin wound. He was catheterized with Foley catheter for his incontinence and received topical care for his skin infection. 8 days later he is admitted to the ICU due to sepsis. All of the following listed bacteria might have caused his sepsis as a result of skin infections and/or contamination EXCEPT: A. B. C. D. E. Staph aureus Streptococcus pyogenes Pseudomonas aeroginosa Clostridium tetani Klebsiella pneumoniae 16. A patient with recent history of prosthetic valvuloplasty is presented with sepsis due to vancomycin resistant Staph epidermidis. Which of the following options is a reasonable back-up medication? A. B. C. D. E. Ceftriaxone Aztreonam Trimethoprim-sulfamethoxazole Imipenem Gentamicin 17. A 17-year-old girl is being admitted to the OB/GY clinic for the complaint of amenorrhea. Examination reveals lack of development of secondary sex characteristics. Blood pressure is 180/110; result of funduscopy is normal; she has no lymphadenopathy or hepatosplenomegaly. Blood analysis indicates hypokalemia, hypernatremia, metabolic alkalosis, and suppressed renin. Urinary analysis confirms a high level of urinary gonadotropins. Which of the following deficiencies is the most likely cause of this patient’s problems? (A) (B) (C) (D) (E) 11-hydroxylase 21-hydroxylase 17-hydroxylase Desmolase Hydroxysteroid dehydrogenase 18. Your patient is a 12-year-old male patient with history of precocious puberty and congenital adrenal hyperplasia. On examination he has a blood pressure of 90/60. Which of the following enzyme deficiencies is the most likely cause of his condition? (A) (B) (C) (D) (E) 11-hydroxylase 21-hydroxylase 17-hydroxylase Desmolase Hydroxysteroid dehydrogenase 19. Which of the following conditions is associated with eosinophilia? A. B. C. D. E. Addison’s disease Cushing’s disease Congenital adrenal hyperplasia Candidiasis Paraneoplastic Cushing’s due to oat cell carcinoma 20. A 35-year-old female patient with estrogensensitive breast cancer will be more effectively treated with which of the following cited medications? A. B. C. D. E. Aminogluthemide Spironolactone Beclomethasone Flutamide Human menopausal gonadotropins 51. Northwestern Medical Review, Sample Review Book Series, 2012 21. Titer of Corticotropin-releasing hormone (CRH) from hypothalamus is increased in which of the following conditions? A. B. C. D. E. Oat cell carcinoma of the lung Cushing’s disease Iatrogenic hypercortisolism Unilateral adrenocortical adenoma Water-house Friderichsen syndrome 22. Sensitivity to a very high dose of dexamethasone suppression is indicative of which of the following conditions? A. B. C. D. E. Adrenal carcinoma-induced hypercortisolism Oat-cell carcinoma-induced hypercortisolism Pituitary adenoma-induced hypercortisolism Drug-induced (iatrogenic) hypercortisolism Adrenal adenoma-induced hypercortisolism 23. A 30 year-old woman complains of gradual weight gain. She has normal menstrual periods. Examination shows that she has a blood pressure of 180/110 mm Hg. Her serum creatinine, sodium, potassium, and chloride are within normal ranges. Further lab findings indicate hypocapnia and hyperglycemia. Which of the following radiological findings would you expect in this patient? A. B. C. D. E. Thyroid mass Ovarian cysts Nodules within one of her lungs Mass in one of her adrenals Pituitary tumors 24. In humans, surgical procedures that involve total hypophysectomy are less fatal than total adrenalectomy without hormone replacement therapy. A reasonable explanation for this striking fatal effect would be which of the following? A. Hypophysectomy does not affect aldosterone release from the adrenal cortex B. After hypophysectomy, the adrenal cortex undergoes total atrophy due to lack of ACTH C. Levels of estrogen and testosterone do not drop after hypophysectomy D. Hypophysectomy does not affect the cortical zones of the adrenals E. The pituitary gland plays only a small role in maintaining the adrenal's integrity 25. A 60 year-old-woman is scheduled for an emergency appendectomy. Her history shows that 18 months ago she was admitted to the hospital as a result of severe headaches, joint pain, tenderness of her temporal areas, and sudden loss of visual acuity in her left eye. Her erythrocytic sedimentation rate (ESR) at the time of admission was elevated at 87 mm/h. At the time, a presumptive diagnosis of giant cell arteritis was made, and she was started on a regimen of prednisone, 60 mg/d, with dramatic improvement in her symptoms. The prednisone dosage was then gradually tapered off as her serum ESR level approached the normal level. Upon admission for appendectomy, she claims that she took her last daily dosage of prednisone 5 days ago. Which of the following medications would you consider giving to this patient prior to her appendectomy? A. B. C. D. E. ACTH Fludrocortisone Indomethacin Vasopressin Prednisone 26. Which of the following findings is the earliest detectable finding associated with the use of inhaled corticosteroids? A. B. C. D. E. Adrenal atrophy Localized Candidiasis Osteoporosis Peptic ulceration Weight gain 27. Your patient is a 65 year-old woman with symptoms of congestive heart failure who has had several episodes of syncope within the past 4 months. She claims that she had no significant cardiovascular problems up until 6 months ago when she started experiencing chest pain during exercise. Auscultation of the carotid pulse indicates that the pulse is weak and late relative to the heart contraction. Which of the following findings would you also expect to see in this patient? A. Discrepancy of pressure between the two brachial arteries B. Split of second sound that disappears with inspiration C. Systolic murmur D. Pulsus paradoxus E. All of the above 52. Northwestern Medical Review, Sample Review Book Series, 2012 28. Which of the following conditions is presented with systolic murmur? A. Aortic insufficiency, mitral stenosis and ventricular septal defect B. Aortic stenosis and aortic insufficiency C. Aortic and pulmonary stenosis, and mitral insufficiency D. Aortic and pulmonary stenosis, and mitral insufficiency E. Aortic and pulmonary stenosis, and mitral insufficiency 29. Which of the following patients may most likely present with paradoxical split of the second heart sound? A. B. C. D. E. A patient with systemic hypertension A patient with pulmonic valve stenosis A patient with Eisenmenger’s syndrome A patient with right bundle branch block A patient who is taking dobutamine 30. Compared to normal heart what will happen to endsystolic ventricular volume in aortic stenosis? A. B. C. D. Increases Decreases It is not affected It increases with inspiration and decreases with expiration E. It increases with expiration and decreases with inspiration 31. A 72-year-old woman who has been diagnosed with aortic stenosis is seen for the complaint of frequent episodes of angina. Which of the following options is the most important cause of angina in the patient? A. Rise of intra-ventricular pressure during systole B. Concentric hypertrophy of the left ventricle C. Low arterial systolic pressure D. Low arterial diastolic pressure E. Increased activity of renin-angiotensin system 32. Why patients who are diagnosed with aortic stenosis at earlier ages are often males? A. Tricuspid valves have a higher tendency for calcification at earlier age B. High titers of estrogen masks the symptoms of aortic stenosis in younger women C. Rheumatic heart disease is more common in males D. Inheritance of bicuspid valves has a sex-linked pattern E. Older women visit their doctors more than the younger women. 33. A 17 year-old boy is seen by the ophthalmologist for evaluation of visual problems. The height of the patient is 8 feet 4 inches. Which of the following visual field defects is most likely exemplified by the patient? A. B. C. D. E. Complete blindness in one eye Binasal heteronymous hemianopia Bitemporal heteronymous hemianopia Bilateral scotoma Homonymous hemianopia 34. Also called “Blue Cell Tumor”, this brain tumor commonly occurs in children. The most common location for it is the midline of cerebellum. It may spread into the CSF. What is this tumor? A. B. C. D. E. Medulloblastoma Neuroblastoma Ganglioneuroma Meningioma Astrocytoma 35. This picture is the left eye report of a 25year-old female patient during her ophthalmologic examination. She is using oral contraceptives. Which of the following conditions is the most likely underlying cause of this finding? A. Thrombosis of left posterior cerebral artery B. Thrombosis of basilar artery at the junction of union of two vertebral arteries C. End-stage glaucoma D. Multiple sclerosis E. A tumor of the occipital lobe 53. Northwestern Medical Review, Sample Review Book Series, 2012 36. This picture is the report of a patient to his ophthalmologist during his eye examination. Which of the following options is the correct diagnosis for this finding? A. Right inferior quadrantanopia and left superior quadrantanopia. B. Right superior quadrantanopia and left inferior quadrantanopia. C. Bitemporal heteronymous quadrantanopia and binasal heteronymous quadrantanopia D. Inferior heteronymous and superior homonymous quadrantanopia E. This type of visual field dysfunctions cannot be demonstrated in humans 37. A patient has been diagnosed with metastatic brain tumors. The tumors have severed his visual pathways as it is shown in the diagram. Which of the following visual field defects are expected in the patient? A. B. C. D. Right homonymous hemianopia Superior homonymous hemianopia Inferior homonymous hemianopia Right inferior quadrantanopia and left superior quadrantanopia E. Bilateral macular sparing 38. Following diagram show severance of projections passing through the temporal lobe. What type of visual field defect is caused by this lesion? 39. A three-year-old child has an autosomal recessive disease that causes hemolysis of his red blood cells. It is determined that his disease is due to an enzymatic deficiency that affects his hexose monophosphate shunt in addition to his glycolytic pathways. Which of the following diseases has a blood smear and red blood cell distribution width (RDW) finding that is most closely similar to this patient? A. B. C. D. E. 40. Which of the following cited conditions decreases the affinity of hemoglobin for oxygen? A. Methemoglobinemia B. Increased 2,3 diphosphoglycerate in the red cells C. Carbon monoxide poisoning D. Phosphofructokinase deficiency E. Hexokinase deficiency 41. Which of the following enzymatic deficiencies is by far the most common cause of red cell hemolysis? A. B. C. D. Hexokinase deficiency Phosphofructokinase deficiency Pyruvate kinase deficiency Glucose 6 phosphate dehydrogenase deficiency E. Phosphoglucomutase deficiency 42. Which of the following conditions is most likely associated with high titer of fructose 2, 6 bisphosphate levels in the hepatocytes? A. B. C. D. E. A. B. C. D. E. Kidney disease Liver disease Orotic aciduria Thalassemia Anemia of chronic disease Hexokinase deficiency Increased parasympathetic tone Uncontrolled type I diabetes Pheochromocytoma Glucagonoma Right inferior quadrantanopia Left inferior quadrantanopia Right superior quadrantanopia Left superior quadrantanopia Right heteronymous hemianopia 54. Northwestern Medical Review, Sample Review Book Series, 2012 Use this Case for Question 43-45 A 12-year-old boy is seen for the complaint of muscle pain and exercise intolerance. History shows that he better tolerates aerobic exercises such as walking and cycling, especially after approximately the first 10 to 15 minutes of exercise. Prior clinical studies have shown that the patient’s cramps were electrically silent and his venous lactate levels failed to increase upon ischemic exercises. Urinalysis of the patient is significant for myoglobinuria. Further history indicates that his older sister has also been presented with similar findings during her early childhood. 43. Assuming that the patient also has hemolytic anemia, which of the following options will be the most likely cause of these findings? A. B. C. D. E. McArdle’s Disease Pompe’s disease Phosphofructokinase deficiency Pyruvate dehydrogenase deficiency Carnitine-acyltransferase deficiency 44. If the patient does not have red blood cell hemolysis but the muscle biopsy shows increased concentrations of glycogen, which of the following options will be the most likely cause of these findings? A. B. C. D. E. McArdle’s Disease Pompe’s disease Phosphofructokinase deficiency Pyruvate dehydrogenase deficiency Carnitine-acyltransferase deficiency 45. If the patient does not have red blood cell hemolysis but the muscle biopsy shows increased concentrations of glycogen, which of the following options is the most adverse long-term effect of this patient’s disease? A. Paralysis of extremity muscles B. Heart failure C. Pancreatic failure D. Liver failure E. Renal failure ___________________________________________ 46. In glycolysis, the only substrate level phosphorylation occurs in a reaction catalyzed by the enzyme: A. B. C. D. E. glucose-6-phosphatase pyruvate dehydrogenase pyruvate kinase succinate thiolase citrate lyase c 47. Which of the following enzymes is a gluconeogenic enzyme that reverses the last glycolytic step? A. B. C. D. E. Phosphoenolpyruvate carboxylases Pyruvate dehydrogenase Pyruvate kinase Glucose 6 phosphatase Glucose 6 phosphate dehydrogenase 48. Which of the following hemolytic conditions is an autosomal dominant condition? A. Sickle cell disease B. Beta-thalassemia C. Glucose 6 phosphate dehydrogenase deficiency D. Hereditary spherocytosis E. Glucose 6 phosphate dehydrogenase deficiency 49. A patient is presented with dyspnea, fatigue and exercise intolerance. He has normal heart and lung functions and a hematocrit of 25%. Which of the following tests is the most informative next step in the diagnosis of his condition? A. B. C. D. E. Coomb’s test Red cell enzyme studies Mean corpuscular volume evaluation Electrophoresis of hemoglobin Measurement of the level 2,3 diphosphoglycerate in the red cells 50. What is the most fatal consequence of serious and untreated anemia? A. B. C. D. E. Myocardial infarction Liver failure Respiratory failure Stroke Kidney failure 55. Northwestern Medical Review, Sample Review Book Series, 2012 Answers 1. [B]. The patient has type II MPGN. The etiology of the disease is most likely due to uncontrolled activation of the alternate complete system. 2. [C]. Membranous glomerulonephritis is a nephrotic syndrome. It should not be mistaken with membranoproliferative glomerulonephritis (MPGN) that has a nephritic pattern. 3. [D]. Only MPGN type I is presented with mesangial and/or sub-endothelial deposits. All other cited options are shared between Type I and II. 4. [A]. Ankylosing spondylitis can affect both men and women. It is postulated that high testosterone levels in young adult males may have positive correlations with damaging expression of HLA-B27 deposits in the axial joints and nephrons. 5. [C]. Dermatitis herpetiformis has a strong association with celiac disease. Note that all the cited conditions are associated with IgA nephropathy and mesangial IgA deposits. 6. [E]. Rapidly progressive glomerulonephritis is also known as crescentic nephritis. Typical glomerular pattern quite often presents with crescents of fibrin deposits within the Bowmen’s capsule. 7. [B]. The baby has symptoms of sepsis and meningitis. The top three causes of meningitis in neonates are Streptococcus agalactiae, Listeria and E. coli. Only streptococcus and listeria are gram-positive. Listeria is catalase-positive and Streptococcus, negative. Note that listeria has coccobacillary morphology and as such its light microscopic distinction from Streptococcus agalactiae is somehow difficult. Note that due lack of full immunologic potency the neonates may not present with classic symptoms of meningitis like nuchal rigidity. As such early signs are for most part nonspecific and subtle and do not differentiate between fungi, bacteria or viruses. The most common symptoms in neonates are diminished spontaneous activity, weak sucking, apnea, bradycardia, and temperature instability. Also note that coagulase test would be helpful to distinguish staph aureus (coagulase positive) from Staph epidermidis and saprophyticus that are coagulase negative. India ink stating is important in identifying Cryptococcus neoformans. Positive Camp test identifies Streptococcus agalactiae, and Optochin-sensitivity is specific for Streptococcus pneumoniae. 8. [B]. The patient most likely has toxic shock syndrome. The rash on her palms and soles are most likely scarlatiniform. Low magnesium ion concentration most likely has caused heavy growth of toxic shock syndrome toxin-producing staph aureus. Note that it is postulated that tampons absorb various ions, in particular magnesium. Low magnesium promotes heavy growth of Staph aureus. 9. [C]. The patient most likely has toxic shock syndrome as a result of infection with MRSA. The number one choice of treatment of MRSA is Vancomycin. The common side effects of Vancomycin are flushing, shock, ototoxicity and nephrotoxicity. Trimethoprimsulfamethoxazole is the second choice after Vancomycin for the treatment of MRSA. Note that MRSA infections are mostly acquired in nosocomial settings. As such the community-acquired form of the infection has a low incidence, but it is always a possibility. 10. [C]. Scombroid poisoning has rapid onset, anywhere from 10 minutes to an hour and typically occurs in people who eat certain fish that have been inadequately preserved. Scombroid is preformed histamine-like toxin produced by certain bacteria that grow on fish and it is resistant to cooking. Fish that are susceptible to the growth of the bacteria mainly include anchovy, Australian salmon, bluefish, herring, mackerel, mahimahi, sardine, and tuna. Note that bacillus cereus (mostly acquired from reheated rice) and Staphylococcus aureus have incubation of 3-8 hours and they are also acquired from pre-formed and heat resistant toxins. Also note that Vibrio parahaemolyticus toxicity is acquired from eating raw fish. It is responsible for about 50% of foodpoisoning incidents in Japan. This poisoning is somehow similar to mild forms of cholera and it has an incubation period of about 15 hours. 11. [A]. Sickle cell disease, cystic fibrosis, vascular thrombosis and Legg-Calvé-Perthes syndrome are causes of AVN. Etiology of avascular necrosis of bone is often aseptic. But frequent infections (osteomyelitis) and resultant chronic inflammation would also predispose to avascular necrosis. More commonly, however, avascular necrosis of the bone is a complication of corticosteroid use, trauma, systemic lupus erythematosus, pancreatitis, alcoholism, gout, and sickle cell disease. The two organisms that commonly cause osteomyelitis are salmonella and staph aureus. Children with sickle cell disease are more prone to recurrent osteomyelitis due to salmonella because of splenectomy. Note that a common cause of AVN in children at the femoral head is Legg-Calvé-Perthes syndrome (AKA. Perthes disease) which is an idiopathic degenerative and ischemic disease related to reduction of blood flow to the femur head and hip joint most likely as a result of low flow through the ligamentum teres femoris artery. 56. Northwestern Medical Review, Sample Review Book Series, 2012 Gradual loss of bone mass causes collapse of the hip joint and deformity of the head of the femur. 12. [D]. Botulinum toxin is produced after germination of the spores of clostridium botulinum is anaerobic canned food and it is heat labile. Note that Staphylococcus aureus, Bacillus cereus and scombroid food poisonings are acquired from preformed toxins but they are all heat stable within the household heating ranges. Salmonella typhi does not cause food poisoning; it causes enteric fever. Salmonella enteritidis; the so called salmonella food poisoning, is not due to preformed toxin but the bug is heat-labile (heatsensitive). 13. [B]. Strep pyogenes is the most common cause of necrotizing fasciitis 14. [D]. Methicillin causes serious nephrotoxicity. Note that neither of the two medications is effective against MRSA and both of them are resistant to beta-lactamases. 15. [D]. All of the cited options may causes sepsis as a result of skin infection and/or contamination EXCEPT Clostridium tetani. Note that Klebsiella is quite often acquired via Foley catheterization. 16. [C]. Next DOC for vancomycin-resistant Staph organisms is trimethoprim-sulfamethoxazole. Other choices include Linezolid and Daptomycin. 17. [C]. She has 17-hydrpxylase deficiency. In these patients conversion of progesterone to subsequent sex hormones and glucocorticoids is affected. Pathways are shunted towards mineralocorticoid production and as a result they are presented with hypokalemia, hypernatremia and hypertension. 18. [B]. 21-hydroxylase deficiency causes precocious puberty in males and it is associated with lack of mineralocorticoids and hypotension. It is contracted with 11-hydroxylase deficiency that causes precocious puberty and hypertension due to high levels of deoxycorticosterone. 19. [A]. Addison’s disease is associated with eosinophilia. In contrast Cushing’s is associated with eosinopenia. 20. [A]. Aminogluthemide inhibits P-450 and in turn inhibits desmolase activity, and as a result it reduces steroid output. Additionally it reduces the activity of aromatase enzyme that converts androgens to estrogens. As such this drug is quite effective in the management of estrogen-sensitive breast cancers. 21. [E]. In all cited options with the exception of Waterhouse Friderichsen syndrome the titer of cortisol rises and inhibits hypothalamic output of corticotropinreleasing hormone (CRH). Water-house Friderichsen syndrome that is associated with Neisseria meningitidis bacteremia causes coagulative damages to the adrenal cortex and acute drop of the adrenocortical hormones. As a result of decreased cortisol levels and removal of inhibition over the hypothalmus, CRH is expected to increase. Note that Cushing’s disease refers to hypercortisolism due to adenoma of the anterior pituitary gland. 22. [C]. The dexamethasone suppression test is for diagnosis of Cushing's disease. In practice, the test helps to differentiate the two causes of hypercortisolism that are both associated with high titers of ACTH and cortisol. These two causes are ectopic hypercortisolism (e.g. oat-cell carcinoma of the lung) and pituitary adenoma. A very high dose of ACTH cannot suppress the ACTH of ectopic adenomas, but it will suppress the ACTH output of pituitary adenoma (i.e. Cushing's disease). 23. [D]. Given her gender, hypertension, and hyperglycemia, one would expect unilateral adenoma of the adrenal cortex or adrenal Cushing's as the most probable cause of this patient's ailment. Note that adrenal adenomas are often unilateral. 24. [A]. Aldosterone, a product of the zona glomerulosa, is not controlled by ACTH. After hypophysectomy, all zones of the adrenals will undergo hypotrophy except the zona glomerulosa. Aldosterone and mineralocorticoids are vital hormones for maintaining osmotic pressure of the blood within the normal range. 25. [E]. The patient's adrenals are most likely suppressed as a result of iatrogenic hypercortisolism. Note that fludrocortisone may also be helpful, but primarily has mineralocorticoid effects and fewer glucocorticoid effects compared to prednisone. 26. [B]. Even though all the cited options are related to the use of corticosteroids, localized candidiasis is among the earlier findings in this type of situation. 27. [C]. The patient has aortic stenosis (AS) that is causing a systolic murmur. A common finding in AS is pulsus tardus et parvus; that is, palpation of the pulse is late (tardus) relative to contraction of the heart, and also weak/small (parvus). Almost all AS patients exhibit systolic murmur. Classic symptoms of aortic stenosis are angina, syncope, and congestive heart failure. Note that high pressure in the arm and low in the leg is characteristic of coarctation of the aorta. Discrepancy of pressure between the two brachial arteries is characteristic of Takayasu arteritis. 28. [C]. Semilunar (aortic and pulmonary) stenotic murmurs and murmurs of atrioventricular valvular (Mitral and tricuspid) insufficiencies are audible during systole. 29. [A]. The top three causes of paradoxical split are systemic hypertension, aortic stenosis and left bundle branch block. 30. [A]. End-systolic ventricular volume increases in AS due to the fact that less blood is extruded from the left ventricle. 57. Northwestern Medical Review, Sample Review Book Series, 2012 31. [B]. Among all cited options concentric hypertrophy of the left ventricle in response to high afterload seems to have the most drastic effect in increasing the oxygen demand and leading to ischemia. Orotic Aciduria causes pyrimidine deficiency and as a result macrocytic anemia. Liver disease causes lipidemia. Excess lipids adhere to the membrane of red cells and as result they appear bigger and macrocytic. 32. [D]. Bicuspid valves have a recessive sex-linked pattern of inheritance. In females due to presence of a normal allele on the alternate x-chromosome the phenotype of bicuspid valves will not be expressed. Additionally, the bicuspid valves have more tendencies for calcification at an earlier age. In contrast, in females calcification of the tricuspid valves as a result of aging predisposes to aortic stenosis at a very old age. 40. [B]. High levels of 2,3 DPG causes a right shift in the hemoglobin dissociation curve of oxygen and makes unloading of oxygen easier at the tissue sides of the body, and loading of oxygen more difficult in the lungs. In other words it decreases the affinity of hemoglobin for oxygen. All other cited conditions will increase the affinity of hemoglobin for oxygen and make loading easier and unloading more difficult. 33. [C]. The patient has gigantism, most likely due to adenoma of the anterior pituitary gland. Tumors of this nature often press on the optic chiasm and cause bitemporal heteronymous hemianopia. 41. [D]. Glucose 6 phosphate dehydrogenase deficiency is by far the most common genetic cause of red blood cell hemolysis. 34. [A] “Blue Cell” brain tumor of children is medulloblastoma. It is a highly invasive brain tumor that arises in the cerebellum. It is the most common malignant pediatric brain tumor. Histopathologically, this disease is characterized by sheets of small round blue cells that are punctuated by frequent mitoses, apoptosis, and regions of divergent differentiation. 35. [D]. This visual field finding is called central scotoma and it is not uncommon in patients with multiple sclerosis. Note that oral contraceptives predispose to thromboembolism and if a patient presents with occlusion of both posterior cerebral circulation s/he may present with bilateral version of this condition. Also note that occlusion of basilar artery may also theoretically cause bilateral scotoma, but even if the patients do not die as a result of occlusion, they may become comatose and cannot report anything to their doctors. 36. [B]. Right superior quadrantanopia and left inferior quadrantanopia 37. [E]. Bilateral lesions of parietal and temporal lobe radiations cause bilateral macular sparing (AKA. bilateral homonymous macular sparing). 38. [D]. Left superior quadrantanopia ( Pie in the sky!) 39. [A]. The patient has hexokinase deficiency. This enzyme is a key enzyme of several pathways including glycolysis, hexose mono-phosphate shunt and glycogen synthesis. As a result of glycolytic defect, this patient has hemolytic anemia. Hemolytic conditions cause normocytic anemias. Kidney diseases also cause normocytic anemia due to erythropoietin deficiency. On the other had Thalassemia causes microcytic anemia. 42. [B]. Among the cited options increased parasympathetic tone is the only condition that raises the titer of insulin and a result synthesis of PFK II. The latter leads to a higher production of fructose 2,6 bisphosphate. Glucagonoma increases the output of glucagon and drops the glycolytic activities in general, and the level of fructose 2,6 bisphosphate, in particular. Pheochromocytoma increases adrenergic effects and facilitates release of glucagon. Hexokinase deficiency drops the levels of fructose 6 phosphate and as a result formation of both fructose 2,6 bisphosphate and fructose 1,6 bisphosphate. 43. [C]. Phosphofructokinase deficiency is associated with muscles cramps, red blood cell hemolysis, and myoglobinuria. The other cited conditions all cause muscle fatigue and myoglobinuria but they do not present with hemolysis. 44. [A]. McArdle’s or type V glycogen storage disease is associated with all of the cited findings in the case scenario. In this metabolic autosomal recessive disease muscle glycogen phosphorylase fails to degrade glycogen. The patient’s cramps are often described as “electrically silent” cramps because the venous lactate levels fail to increase upon ischemic exercises. They often exhibit the so called “second wind” phenomenon that is characterized by the patient’s better tolerance for aerobic exercises such as walking or cycling after about 10 minutes of muscular efforts. This is due to a combination of increased blood flow to muscle and the ability of the muscle to use alternative sources of aerobic energy such as fatty acids and proteins. Note that anaerobic exercise that is accompanied by high levels of lactate heavily relies on glucose utilization that is derived from muscle glycogen, especially during the early phases of exercise. 45. [E]. Chronic myoglobinuria due to any cause may lead to renal failure. Rhabdomyolysis-induced renal failure represents up to 15% of all cases of acute renal failure. Accumulation of myoglobin in the kidney causes either due to Fenton reaction as a result of presence of free 58. Northwestern Medical Review, Sample Review Book Series, 2012 iron or oxidant injury that damages the cell membrane of glomerular tissues. Additionally, it is show that presence of oxidizing agents can also cause renal vasoconstriction. 46. [C]. Pyruvate kinase accomplishes substrate level phosphorylation, or in other words the synthesis of ATP with the conversion into pyruvate of the high energy compound PEP. 47. [A]. To move pyruvate back from mitochondria to phosphoenolpyruvate in the cytoplasm during gluconeogenesis we require two enzymes; pyruvate carboxylases and phosphoenolpyruvate carboxylases. Pyruvate carboxylase is a mitochondrial enzyme whereas phosphoenolpyruvate carboxylase is a cytoplasmic enzyme. 48. [D]. Hereditary spherocytosis (HS) is an autosomal dominant condition that is more common in Caucasians. Likewise most other dominant conditions it is due to defects in structural proteins. The defective protein in HS is spectrin that maintains the structural integrity of the red cell membranes. 49. [B]. The patient has anemia. Among the given options measurement of mean corpuscular volume (MCV) is the first step in the diagnosis of the patient as it discerns among the major three categories of macrocytic, microcytic and normocytic anemias. 50. [A]. The most dreaded consequence of untreated anemia is myocardial infarction as a result of failure of oxygen delivery to the heart muscles. 59. Northwestern Medical Review, Sample Review Book Series, 2012
