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Free STEP1 Exam Braindumps (page: 66)

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A 4-month-old boy presents with painful progressive joint deformity (particularly the ankles, knees, elbows, and wrists), hoarse crying, and granulomatous lesions of the epiglottis and larynx leading to feeding and breathing difficulty. Biopsy of the liver indicates an accumulation of ceramides. The observed symptoms and the results of the liver biopsy are indicative of which disease?

  1. Farber lipogranulomatosis
  2. fucosidosis
  3. Gaucher disease
  4. metachromic leukodystrophy
  5. Sandhoff-Jatzkewitz disease

Answer(s): A

Explanation:

Farber lipogranulomatosis is characterized by painful and progressively deformed joints and progressive hoarseness due to involvement of the larynx. Subcutaneous nodules form near the joints and over pressure points. Granulomatous lesions form in these tissues and there is an accumulation of lipid-laden macrophages. Significant accumulation of ceramide and gangliosides is observed, particularly in the liver. If these compounds accumulate in nervous tissue there may be moderate nervous dysfunction. The illness often leads to death within the first few years of life, although milder forms of the disease have been identified. Fucosidosis (choice B) is characterized by the accumulation and excretion of glycoproteins, glycolipids, and oligosaccharides- containing fucoside moieties. Symptoms of fucosidosis include psychomotor retardation, dystosis multiplex (a term referring to multiple skeletal abnormalities), growth retardation, and coarse facial features. Gaucher disease (choice C) is characterized by an accumulation of glucosylceramide (glucocerebroside). Several forms of the disease have been identified and vary in severity. Typical symptoms include hepatosplenomegaly, bone lesions, and CNS involvement.
Occasionally, the lungs and other organs may be involved. Metachromic leukodystrophy (choice D) is a disorder of myelin metabolism. It is characterized by the accumulation of galactosyl sulfatide (cerebroside sulfate). Symptoms may appear at any age and include mental regression, urinary incontinence, blindness, loss of speech, peripheral neuropathy, and seizures. Sandhoff- Jatzkewitz disease (choice E) is a disorder related to Tay-Sachs disease. It is characterized by a defect in the degradation of GM2 gangliosides with symptoms of severe mental retardation, blindness, and early mortality.



Interference with the action of angiotensinconverting enzyme (ACE) is an effective means at reducing elevations in blood pressure. The circulating concentration of which of the following hormones would be affected as a consequence of the use of ACE inhibitors?

  1. ACTH
  2. aldosterone
  3. corticotrophin-releasing hormone, CRH
  4. estradiol
  5. gonadotropin-releasing hormone, GnRH

Answer(s): B

Explanation:

ACE is responsible for the cleavage of two amino acids from angiotensin I, generating angiotensin II.
Angiotensin II is a peptide hormone of the rennin-angiotensin system responsiblefor regulation of blood pressure. The intra-renal baroreceptor system is a key mechanism for regulating renin secretion. Adrop in pressure results in the release of renin from the juxtaglomerular cells of the kidneys. Renin secretion is also regulated by the rate of and transport across the macula densa. The higher the rate of transport of these ions, the lower is the rate of renin secretion. The only function for renin is to cleave a 10-amino acid peptide from the N-terminal end of angiotensinogen-yielding angiotensin I. ACE action then generates angiotensin II, one of the most potent naturally occurring vasoconstrictors. In addition to the vascular effects, other physiological responses to angiotensin II include induction of adrenal cortex synthesis and secretion of aldosterone. Release of aldosterone leads to further Na+ retention by the kidneys with the consequences being an additional pressive effect on the vasculature. Thus, the use of ACE inhibitors would not only reduce the production of angiotensin II but also aldosterone. Synthesis and secretion of none of the other hormones (choices A, CE) would be affected by ACE inhibitor administration.



AIP is the major autosomal-dominant acute hepatic porphyria. This disease is caused by a deficiency in porphobilinogen (PBG) deaminase, an enzyme of heme biosynthesis. Patients afflicted with this disease would be expected to excrete excess amounts of which of the following?

  1. delta-aminolevulinic acid (ALA)
  2. coproporphyrinogen III
  3. hydroxymethylbilane
  4. protoporphyrin IX
  5. type III uroporphyrinogen

Answer(s): A

Explanation:

PBG deaminase (also called hydroxymethylbilane synthase) catalyzes the heme biosynthesis reaction involving the head-to-tail condensation of four molecules of PBG to produce the linear tetrapyrrole intermediate, hydroxymethylbilane. Hydroxymethylbilane can nonenzymatically cyclize into uroporphyrinogen I, which is why PBG deaminase is also known as uroporphyrinogen I synthase. ALA is the precursor for PBG, thus a defect in PBG deaminase would lead to excess ALA excretion. The compounds in choices BE all represent products of reactions that are downstream of PBG deaminase in the heme biosynthetic pathway and thus would not be excreted in high amounts in someone with AIP.



In a comparative study of two related cell lines, you find that one responds normally to insulin while the other has an impaired response. You discover that both cell lines bind insulin with equal affinity but that the impaired response is manifest in an inability to recruit the insulin response substrate-1 (IRS-1) protein to the receptor. This would most likely be due to which of the following?

  1. inability of the receptor to phosphorylate the RAS G-protein
  2. loss of activation of phospholipase C-gamma (PLC-g)
  3. mutation in the tyrosine phosphorylation site of IRS
  4. serine phosphorylation of the insulin receptor preventing IRS binding
  5. tyrosine phosphorylation of the insulin receptor leading to the loss of the IRS binding site

Answer(s): C

Explanation:

Many causes of insulin-resistance are due to defects that occur in events of the insulininduced signaling cascade, which takes place after insulin binds to its receptor. All of the postreceptor responses initiated by insulin binding to its receptor are mediated as a consequence of the activation of several signal transduction pathways that require tyrosine phosphorylation of sites in the intracellular portion of the receptor. These include receptor activation of PI3K. Activation of PI3K involves a linkage to receptor activation of insulin receptor substrates (of which there are four: IRS-1, IRS-2, IRS-3, and IRS-4). Activated PI3K phosphorylates membrane phospholipids, the major product being phosphotidylinositol 3, 4, 5- trisphosphate, PIP3. PIP3 in turn activates the enzymes protein kinase B, PKB (also called Akt), PIP3- dependent kinase (PDK), some isoforms of PKC, principally PKC-l, and small ribosomal subunit protein 6 kinase, S6K. The mitogen-activated protein (MAP) kinase pathway is also activated either through receptor activation of the protein tyrosine phosphatase (Shp-2) or growth factor receptor- binding protein-2 (Grb2).
With respect to insulin responses, activation of PKB and PKC-l leads to translocation of GLUT4 molecules to the cell surface. resulting in increased glucose uptake which is significant in skeletal muscle. Activation of PKB also leads to the phosphorylation and activation of GSK3, which is a major regulatory kinase of glycogen homeostasis. In addition, PKB phosphorylates and inhibits the activity of a transcription factor (FKHRL1) that has proapoptotic activity. This results in reduced apoptosis in response to insulin action.
Activation of S6K leads to the phosphorylation of the regulator of translation eIF-4E-binding protein, 4E-BP.
Phosphorylation of 4E-BP prevents it from binding to eIF-4E, the consequences of which would normally lead to a reduction in translation rate. Insulin also has profound effects on the transcription of numerous genes, effects that are primarily mediated by regulated function of sterol-regulated element- binding protein (SREBP). These transcriptional effects include (but are not limited to) increases in glucokinase, PK, LPL, FAS, and ACC and decreases in glucose-6-phosphatase, fructose-1, 6-bisphosphatase, and PEPCK. The insulin receptor does not phosphorylate the RAS gene product (choice A). Loss of activation of PLC-g (choice B) would not prevent IRS proteins from binding to the activated insulin receptor. Serine phosphorylation of the insulin receptor (choice D) is not involved in IRS binding. Tyrosine phosphorylation of the insulin receptor results in the formation of IRS binding sites, not in the loss (choice E) of such binding sites.






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