Gen Path QnA All chapters

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Which would NOT lead to a hypercoaguable state? A. Elevated prothrombin B. Elevated homocysteine C. Deficiency of protein S D. Increased endothelial PGI2 E. Mutated factor V resistance to protein C action

Reference: (A:D) A. Elevated prothrombin would lead to a hypercoaguable state since prothrombin (II) is converted to thrombin (IIa) by the factor Xa-Va complex and thrombin, in turn, is involved in conversion of fibrinogen (I) to fibrin (Ia) B. Hereditarily elevated levels of homocysteine have been found to contribute to arterial and venous thrombosis via inhibitory effects on antithrombin III (inactivates thrombin, factors Xa, IXa) and endothelial thrombomodulin. Thrombomodulin, a thrombin receptor, binds to thrombin converting it from a procoagulant to an anticoagulant capable of activating protein C, which inhibits clotting by proteolytic cleavage of factors Va and VIIIa. Homocysteine is a sulfur-containing amino acid that can serve as an intermediate in cysteine synthesis. C. Deficiency of protein S would lead to a hypercoaguable state since protein S (and protein C) inhibit factors VIIIa and Va D. Increased levels of endothelial-derived eicosanoid PGI2 (prostacyclin), a potent vasodilator and inhibitor of platelets, would NOT lead to a hypercoaguable state E. Mutated factor V resistance to protein C action would lead to a hypercoaguable state since protein C would not inhibit mutated factor V

bid A. Is antiapoptotic and acts by sequestering Apaf-1 and inhibiting release of cytochrome c from mitochondria B. Is associated with microtubules and is central in anoikis C. Combines with and activates caspase 9, forming an "apoptosome" D. Is upregulated by p53 leading to apoptosis E. Is cleaved by caspase 8, providing cross talk between the intrinsic and extrinsic apoptotic pathways

Reference: Am J Pathol 157(5):1415-1430, 2000 (A:E) A. Bcl-2 is antiapoptotic and inhibits apoptosis by inhibition of cytochrome c release and by binding and thus inactivating Apaf-1 (pro-apoptotic protease activating factor) B. Ankyrin family proteins that contain death domain proteins have been implicated in anoikis (i.e., apoptosis induced by depriving cells of integrin-mediated attachments to extracellular matrix) C. Cytochrome c associates with Apaf-1 and caspase-9 to form the so-called "apoptosome" D. p53 has been reported to induce transcription of the death receptor Fas and DR5 in some types of tumor cells, thus linking the extrinsic pathway for apoptosis to genotoxic injury in specific cell contexts. Transcription of the BAX genes is also indirectly regulated by p53, thus providing another connection of this important tumor suppressor to apoptosis pathways. E. In the case of Bid, cleavage by caspase-8 is required, removing the N-terminal 52 amino acids and exposing both the BH3 dimerization domain and the hydrophobic core of the protein, which is believed to be responsible for its insertion into mitochondrial membranes. This caspase-8-mediated activation of Bid represents an important mechanism accounting for cross-talk between the death receptor (extrinsic) and mitochondrial (intrinsic) pathways.

Which statement is true regarding the interaction if IB- and caspase-3? A. Caspase-3 causes phosphorylation of certain residues of IB-, leading to its immediate polyubiqitination. B. Caspase-3 causes degradation of the carboxyl terminus of IB-, allowing its translocation into the nucleus. C. Caspase-3 is upregulated by IB- following IB- activation by TNF-R. D. Caspase-3 cleavage of IB- creates a truncated IB- protein resistant to degradation by the proteasome. E. Caspase-3 and IB- have opposite effects and no direct interaction with one another.

Reference: Am J Pathol 159(2):387-396, 2001 (A:D) Cleave of IB- by caspase-3 has been observed in -radiation-induced apoptosis and NF-B inhibition-induced apoptosis. Cleave of IB- by caspase-3 creates a N-terminal truncated IB- protein that is resistant to degradation by proteasome in response to inducers of NF-B, but is able to bind to and suppress NF-B. Therefore, the role of caspase-3 cleavage on IB- is to ensure that the anti-apoptotic gene is suppressed and apoptotic process is not interrupted once the cells are committed to apoptotic elimination. The nuclear factor (NF)-B family of eukaryotic transcription factors plays an important role in the regulation of immune response, embryo and cell lineage development, cell apoptosis, cell-cycle progression, inflammation, and oncogenesis. A wide range of stimuli, including cytokines, mitogens, environmental particles, toxic metals, and viral or bacterial products, activate NF-B, mostly through IB kinase (IKK)-dependent phosphorylation and subsequent degradation of its inhibitor, the IB family of proteins. Activated NF-B translocates into the nucleus where it modulates the expression of a variety of genes, including those encoding cytokines, growth factors, acute phase response proteins, cell adhesion molecules, other transcription factors, and several cell apoptosis regulators. The signaling pathways of NF-B activation are indicated in the figure on the left. Extracellular inducers, including cytokines, reactive oxygen species (ROS), and viral and bacterial products, activate IKK (a high molecular weight complex that phosphorylates IB- or IB- through upstream kinases directly or indirectly. Activated IKK phosphorylates N-terminal S32 and S36 residues of IB- that is associated with NF-B p50 and p65 heterodimer. The SCF-ß-TrCP complex recognizes phosphorylated IB- and modifies IB- with polyubiquitin chains. This is followed by proteasome-mediated degradation of IB-. After degradation of IB-, the activated NF-B translocates into the nucleus where it binds to the B-sites of gene promoters or enhancers to up-regulate target gene expression. Line arrows and filled arrows denote the NF-B signaling pathways; open arrows denote the connections with the by-standing signaling pathways. Possible targeting point of anti-apoptotic signals from NF-B. Intrinsic (open arrows) and extrinsic (filled arrows) apoptosis pathways. Depending on the use of different initiating caspases, signal-induced apoptosis can be divided into receptor-mediated extrinsic apoptosis and mitochondrial-mediated intrinsic apoptosis. The extrinsic apoptotic pathway is triggered as a consequence of ligand binding to death receptors, including tumor necrosis factor (TNF)-R, CD40 and Fas which contain conserved protein-protein-binding domains termed death domains. These receptors recruit procaspases, mainly caspase-8, via adaptor molecules. The effector caspases, such as caspase-3 and caspase-7, are activated by upstream initiator caspases, caspase-8 and caspase-9. The intrinsic apoptotic pathway is mediated by mitochondria through release of apoptosis promoting factors, including cytochrome c. The initiator caspases themselves are activated by either ligands binding to the death receptor complex or cytochrome c released from damaged mitochondria. Cytochrome c forms a complex with a cytosolic protein named Apaf-1 (pro-apoptotic protease activating factor) to activate caspase 9. Both activated caspase-8 from the extrinsic apoptotic pathway and activated caspase-9 from the intrinsic apoptotic pathway cleave and activate effector caspases, mainly caspase-3 to execute an apoptotic process. An anti-apoptotic effect of NF-B is achieved through its upregulation of IAPs (inhibitors of apoptosis) that inhibits caspases and Bcl-xl that protects mitochondria from further damaging.

Which statements are correct regarding Clostridium perfringens toxin production? a. Type A produces alpha toxin b. Type B produces alpha, beta and epsilon toxins c. Type C produces alpha, and epsilon toxins d. Type D produces alpha and iota toxins e. Type E produces alpha and epsilon toxins A. a, b B. a, b, c C. a, b, c, d D. a, b, c, d, e E. a, b, c, d

Reference: Comp Cont Ed Pract Vet 23(6);577, 2002 & Jubb V2, p. 237 (A:A) Toxin Typ A: a Typ B: a, b, e Typ C: a, b Typ D: a, e Typ E: a, i

Regarding acute respiratory distress syndrome (ARDS), which statement is true? A. The lung is the first organ to fail in the multisystem organ failure syndrome B. Most of the inciting causes of ARDS are noteworthy for their poor neutrophil responses C. Arachidonic acid metabolites have a protective effect on surfactant D. Bronchoalveolar lavage fluid is generally within normal limits in affected animals. E. The hallmark clinical sign is refractory dyspnea in the face of normal PaO2

Reference: Comp Cont Educ Pract Vet 23(8):712, 2001 (A:A) A. The lung is the first organ to fail, with progression to extrapulmonary multisystem organ failure B. Neutrophilic inflammation, driven by IL-8, results in neutrophilic aggregates within vessels resulting in endothelial damage C. Diffuse damage to alveolar capillary walls results in increased capillary permeability, alveolar edema and hyaline membrane formation D. Bronchoalveolar lavage fluid contains fibrin, edema fluid, neutrophils and necrotic epithelial cells E. ARDS is heralded by profound dyspnea and tachypnea due to hypoxemia that may become unresponsive to O2 therapy

. Phosphofructokinase deficiency in which of the following pathways can lead to hemolytic anemia in the dog? A. Embden-Myerhof pathway B. Hexose-monophosphate pathway C. Methemoglobin reductase pathway D. Luebering-Rapoport pathway E. Entner-Doudoroff pathway

Reference: Duncan p.5 (A:A) A. By the Embden-Myerhof pathway glycolysis generates adenosine triphosphate (ATP), which is essential for membrane function and integrity, and NADH, which is used to reduce methemoglobin. Enzyme deficiencies in this pathway can lead to hemolytic anemia (e.g., pyruvate kinase and phosphofructokinase deficiency anemias of dogs). B. Glutathione is maintained in the reduced state by the hexose-monophosphate pathway. Reduced glutathione neutralizes oxidants that can denature hemoglobin. Enzyme deficiency in this pathway (e.g., glucose-6-phophaste dehydrogenase deficiency in the horse) or excess oxidant can cause Heinz body formation and anemia. C. Hemoglobin is maintained in the reduced state (i.e., oxyhemoglobin) necessary for transport of oxygen by the methemoglobin reductase pathway. Enzyme deficiency results in methemoglobin accumulation. Methemoglobin cannot transport oxygen, and cyanosis results. D. The Luebering-Rapoport pathway allows formation of 2,3 diphosphoglycerate (2,3 DPG), which has a regulatory role in oxygen transport. Increased 2,3 DPG favors oxygen release to tissues by lowering oxygen affinity of hemoglobin. Anemic animals usually have increased 2,3 DPG concentrations and deliver more oxygen to tissues with a lesser amount of hemoglobin (a compensatory mechanism). E. The Entner-Doudoroff pathway is a series of enzymatic reactions in bacteria that convert glucose to pyruvate by way of the intermediate 2-keto-3-deoxy-6-phosphogluconate, forming ATP.

Hemophilia B is a result of a deficiency in which of the following factors? A. XI B. IX C. VIII D. VII E. VI

Reference: Duncan p.84 (A:B) Hemophilia B is due to factor IX deficiency (Christmas disease). It is inherited as an X-linked recessive trait (the gene for this coagulation factor is on the X chromosome). As with hemophilia A, activated partial thromboplastin time (APTT) is prolonged and one stage prothrombin time (OSPT) is normal, as is bleeding time. These tests point to an abnormality of the intrinsic coagulation pathway.

. Hemophilia A is a result of a deficiency in which of the following factors? A. XI B. IX C. VIII D. VII E. VI

Reference: Duncan p.84; Robbins p.639; N Engl J Med 344(23):1173-1779, 2001 (A:C) Hemophilia A, deficiency in factor VIII, is inherited as a sex-linked recessive trait that occurs in males (the gene for this coagulation factor is on the X chromosome) and in homozygous females. Patients with hemophilia A typically have normal bleeding time and platelet counts, with prolonged activated partial thromboplastin time (APTT) and normal one stage prothrombin time (OSPT). These tests point to an abnormality of the intrinsic coagulation pathway.

Histologic methods used to assess growth fraction in neoplasms include all of the following EXCEPT: A. Mitotic index B. IHC for Ki-67 protein C. IHC for MIN-antigen D. Staining for argyrophilic nucleolar organizer regions (AgNORs) E. IHC for proliferating cell nuclear antigen (PCNA)

Reference: J Vet Intern Med 15:334-340, 2001; Vet Pathol 35(6):461, 1998; Vet Pathol 34(3):212, 1997 (A:C) A. Large numbers of mitoses reflect the higher proliferative activity of parenchymal cells (Robbins, p. 265) B. Proliferation-associated nuclear antigen is expressed 24-36 H after G1 with maximal level during mitosis C. Not an antigen used to assess growth fraction in neoplasms D. Silver-stained proteins co-localized with rDNA loops are directly related to proliferative cell activity E. Proliferation-associated nuclear antigen is involved in DNA synthesis and repair with S phase expression NB: IHC detection of cyclins and cdks may also be used for measurement of cellular proliferation as well as DNA ploidy measured by flow cytometry, BrdU incorporation 3H-thymidine incorporation and cdk phosphorylation status.

What is the toxic mechanism of grayanotoxins? A. Peroxisomal proliferation B. Inhibition of RNA synthesis C. Increased glomerular capillary hydrostatic pressure D. Increased cell membrane permeability to sodium ions E. Decreased translocation of glucocorticoid-receptor complex

Reference: JAVMA 218(4):573-575, 2001 (A:D) Grayanotoxins are heterocyclic diterpenes found only in plants of the Ericaceae family (i.e. Rhododendron indica; azalea). Grayanotoxins exert toxic effects by binding to sodium channels in cell membranes and increasing the permeability of sodium ions in excitable membranes. Excitable cells such as nerve and muscle are maintained in a state of depolarization. Accumulation of intracellular sodium results in an exchange with extracellular calcium and plays an important role in the control of transmitter release.

Which of the following stimulate bone resorption? a. IL-1 b. IL-2 c. TNF- d. TGF- e. IFN- A. a, b, c B. a, c, d C. b, c, d D. b, d, e E. c, d, e

Reference: Jubb V1, p.5 (A:B) IL-1, TNF- and TGF- all stimulate bone resorption. TNF- also inhibits collagen synthesis by osteoblasts and stimulates production of IL-1 by macrophages. In addition to stimulation of bone resorption via prostaglandin-mediated mechanisms TGF- may also inhibit bone resorption by preventing osteoclast formation and activation.

Aspirin inhibits the activity of cyclooxygenase by which of the following mechanisms? A. Reversibly acetylating a serine residue at position 529 in cyclooxygenase-1 expressed in platelets. B. Reversibly acetylating a serine residue at position 529 in cyclooxygenase-2 expressed in platelets. C. Irreversibly acetylating a serine residue at position 529 in cyclooxygenase-1 expressed in platelets. D. Irreversibly acetylating a serine residue at position 529 in cyclooxygenase-2 expressed in platelets. E. Reversibly acetylating a proline residue at position 529 in cyclooxygenase-1 expressed in platelets.

Reference: N Engl J Med 345(6):433-442, 2001 (A:C) Aspirin inhibits the activity of cyclooxygenase by irreversibly acetylating a serine residue at position 529 in the only form of the enzyme expressed in platelets, cyclooxygenase-1.

. Which of the following are cyclooxygenase inhibitors? 1. Aspirin 2. Dexamethasone 3. Indomethacin 4. Prednisone 5. NSAIDs A. 1, 2, 3 B. 2, 3, 4 C. 2, 3, 5 D. 3, 4, 5 E. 1, 3, 5

Reference: N Engl J Med 345(6):433-442, 2001 (A:E)

Which of the following is not a member of the serpin family of protease inhibitors? A. Alpha1-antitrypsin B. Antiplasmin C. Antithrombin D. Cathepsin D E. C1 inhibitor

Reference: N Engl J Med 346(1):45-53, 2002 (A:D) A. Alpha1-antitrypsin protects connective tissue of the lungs from elastase released by leukocytes (abnormalities associated with emphysema) B. Antiplasmin controls fibrinolysis (abnormalities associated with thrombosis) C. Antithrombin ensures the efficient destruction of released coagulation proteases (abnormalities associated with thrombosis) D. Cathepsin D is a cysteine proteinase important in degradation of extracellular matrix via actions on fibronectin, laminin and proteoglycans E. C1 inhibitor controls complement activation (abnormalities associated with angioedema)

All of the following are true regarding IL-10 EXCEPT? A. Inhibits NK cell function B. Produced mainly by Th2 cells C. Upregulates MHC class II expression D. Acts as a co-stimulator of B cells and mast cells E. Suppresses secretion of IL-1, IL-6 and TNF- by macrophages

Reference: Robbins (A:C) A. True: IL-10 inhibits NK cell function (both IL-10 and TGF- are negative regulators of immune responses) B. True: IL-10 is produced by Th2 cells C. False: IL-10 does not upregulate MHC class II expression; IFN- expression is upregulated by MHC II D. True: IL-10 acts as a co-stimulator of B cells and mast cells (IL-10 also activates macrophages during CMI responses) E. True: IL-10 suppresses secretion of IL-1, IL-6 and TNF- by macrophages

Regarding nitric oxide (NO), all are true EXCEPT? A. NO is cytotoxic to microbes B. NO decreases platelet aggregation C. NO reduces leukocyte recruitment in inflammation D. NO is produced by a variety of cell types including CNS neurons E. iNOS production by macrophages is triggered by intracellular calcium.

Reference: Robbins 12, 75-76, 118, 122 (A:E) A. True: High levels of NO production limit the replication of bacteria, helminthes, protozoa and viruses B. True: NO reduces platelet aggregation and adhesion (NO similar to PGI2 can act as a vasodilator and inhibitor of platelet aggregation) C. True: NO reduces leukocyte recruitment in inflammation D. True: NO is produced by a variety of cell types including CNS neurons (nNOS), endothelial cells (eNOS) and macrophages (iNOS) E. False: iNOS is induced when macrophages are activated by TNF- or IFN-; no intracellular increase in calcium is required Note: Nitric oxide may also act as a free radical and can also be converted to highly reactive peroxynitrite anion (ONOO-) as well as nitrogen dioxide (NO2) and NO3-. It also inhibits several features of mast cell-induced inflammation.

Place the following events in angiogenesis in chronological order from first to last? 1. Proteolysis of the extracellular matrix 2. Increased permeability through gaps and transcytosis 3. Lumen formation, maturation and inhibition of growth 4. Migration and chemotaxis 5. Proliferation A. 1, 2, 3, 4, 5 B. 1, 4, 5, 3, 2 C. 1, 5, 2, 4, 3 D. 5, 1, 3, 4, 2 E. 1, 2, 3, 5, 4

Reference: Robbins p. 104 (A:B) Steps in the development of a new capillary vessel during angiogenesis include: 1. Proteolytic degradation of the basement membrane of the parent vessel to allow formation of a capillary sprout and subsequent cell migration. 2. Migration of endothelial cells toward the angiogenic stimulus. 3. Proliferation of endothelial cells, just behind the leading front of the migrating cells. 4. Maturation of endothelial cells, which includes inhibition of growth and remodeling into capillary tubes. 5. Recruitment of periendothelial cells (i.e. pericytes, vascular smooth muscle cells) to support endothelial tubes and provide maintenance.

Which of the following is NOT true with reference to matrix metalloproteinases? A. Stimulated by PDGF, EGF, IL-1/TNF B. Consist of cathepsin G, kinins, neutrophil elastase and plasmin C. Inhibited by steroids, TGF-, and specific tissue inhibitors of matrix metalloproteinases (TIMP) D. Depend on zinc ions for activity E. Elaborated in the latent form and activated by HOCl

Reference: Robbins p. 107 (A:B) Metalloproteinases are enzymes that degrade extracellular matrix components during tissue remodeling. Degradation of collagen and other ECM proteins is achieved by a family of matrix metalloproteinases, which are dependent on zinc ions for their activity. These should be distinguished from neutrophil elastase, cathepsin G, kinins, plasmin and other important proteolytic enzymes that can also degrade the ECM components but are serine proteinases, not metalloenzymes. Metalloproteinases consist of interstitial collagenases, which cleave the fibrillar collagen types I, II, and III; gelatinases (or type IV collagenases), which degrade amorphous collagen as well as fibronectin; stromeolysins, which act on a variety of ECM components, including proteoglycans, laminin, fibronectin, and amorphous collagens; and the family of membrane-bound matrix metalloproteinases which are cell surface-associated proteases. Matrix metalloproteinases are produced by several cell types (fibroblasts, macrophages, neutrophils, synovial cells and some epithelial cells), and their secretion is induced by growth factors (PDGF, FGF), cytokines (IL-1, TNF-), phagocytosis and physical stress. They are inhibited by TGF- ands steroids. The enzyme is elaborated in a latent (procollagenase) form that requires activation by chemicals such as HOCL. Activated matrix metalloproteinases are inhibited by a family of specific tissue inhibitors of metalloproteinases (TIMP), which are produced by most mesenchymal cells. The four mechanisms of matrix metalloproteinase regulation include: 1) regulation of synthesis by growth factors or cytokines, 2) inhibition of synthesis by corticosteroids or TGF-, 3) regulation of the activation of the secreted by inactive precursors, and 4) blockade of the enzymes by specific tissue inhibitors of metalloproteinases (TIMP).

A chromosomal rearrangement that leads to one abnormally very small and one abnormally very large chromosome is: A. Centric fusion B. Paracentric inversion C. Pericentric inversion D. Isochromosome formation E. Balanced reciprocal translocation

Reference: Robbins p. 120 (A:A) A. Centric fusion (robertsonian translocation) is a translocation between two acrocentric chromosomes. Typically the breaks occur close to the centromeres of each chromosome. Transfer of the segments then leads to one very large chromosome and one extremely small one. Usually the small product is lost, however it carries so little genetic information that this loss is compatible with a normal phenotype. B. Paracentric inversion refers to a rearrangement that involves two breaks within only one arm of a single chromosome with inverted reincorporation of the segment. C. Pericentric inversion refers to a rearrangement that involves breaks on opposite sides of the centromere of a single chromosome with inverted reincorporation of the segment. D. Isochromosome formation results when one arm of a chromosome is lost and the remaining arm is duplicated, resulting in a chromosome consisting of two short arms only or of two long arms. An isochromosome has genetic information that is identical in both arms. E. In translocation, a segment of one chromosome is transferred to another. In one form, called balanced reciprocal translocation there are single breaks in each of two chromosomes, with exchange of material.

The delayed prolonged phenomenon of vascular leakage during acute inflammation occurs in: A. Venules and capillaries B. All levels of the microcirculation C. Only venules 20-60 m diameter D. Only arterioles 20-60 m diameter E. Venules and pulmonary and glomerular capillaries

Reference: Robbins p. 120 (A:A) Delayed prolonged leakage begins after a delay of 2 to 12 hours, lasts for several hours or even days, and involves venules and capillaries. Such leakage is caused, for example, by mild-to-moderate thermal injury, x-radiation or ultraviolet radiation (i.e. sunburn) and certain bacterial toxins. It may result from the direct effect of the injurious agent, leading to delayed cell damage (possibly from apoptosis), or the effect of cytokines causing endothelial retraction.

The protein encoded by the gene hst-1 is a: A. Growth factor B. Transcription factor C. Cell cycle regulator D. Growth factor receptor E. Signal transducing protein

Reference: Robbins p. 120 (A:A) Selected oncogenes, their mode of activation and associated human tumors Growth Factors (his) PDGF- chain Fibroblast growth factor Growth Factor Receptors (ref) EGF-receptor family CSF-1 receptor Proteins Involved in Signal Transduction GTP-binding Nonreceptor tyrosine kinase Nuclear Regulator Proteins Transcriptional activators Cell Cycle Regulators Cyclins Cyclin-dependent kinases

. Which is not a component of platelet -granules? A. PDGF B. TGF- C. Factor V D. Factor VIII E. Platelet factor IV

Reference: Robbins p. 120 (A:D)

Which of the following factors are activated by thrombin? 1. II 2. V 3. VII 4. VIII 5. X A. 1, 3 B. 3, 5 C. 2, 3 D. 2, 4 E. 1, 5

Reference: Robbins p. 121 (A:D)

Which of the following is NOT a characteristic of the Fenton reaction? A. Iron is required for maximal oxidative cell damage B. Superoxide catalyzes the reduction of ferric to ferrous iron C. H2O2 is converted to water via hydroxyl ion formation D. Superoxide catalyzes the reduction of ferrous to ferric iron E. Hydroxyl ion generation is enhanced by the Fenton reaction

Reference: Robbins p. 13 (A:D)

Mutation of a single gene that results in multiple end effects is: A. Pleiotropism B. Codominance C. Reduced penetrance D. Variable expressivity E. Genetic heterogeneity

Reference: Robbins p. 144 (A:A) A. Pleiotropism refers to a single mutant gene that may lead to many end effects B. Codominance refers to full expression in the heterozygote of both alleles of a gene pair C. Reduced penetrance refers to a situation in which some individuals inherit the mutant gene but are phenotypically normal D. Variable expressivity refers to a situation in which a trait is seen in all individuals carrying the mutant gene, however it is expressed differently among individuals E. Genetic heterogeneity refers to mutations at several genetic loci that may produce the same trait

Which of the following is NOT a characteristic of autosomal recessive disorders? A. Results when only one allele at a given locus is mutated B. The trait does not usually affect the parents but siblings may show the disease C. Early onset of disease D. Siblings have one chance in four (25%) of being affected E. Complete penetrance is common

Reference: Robbins p. 145 (A:A) Autosomal recessive disorders result only when both alleles at a given gene locus are mutated. The expression of the defect tends to be more uniform than in autosomal dominant disorders. Onset is frequently early in life. New mutations are rarely detected clinically since the individual with a new mutation is an asymptomatic heterozygote, and several generations may pass before the descendants of such an individual mate with other heterozygotes and produce affected offspring. In many cases, enzyme proteins are affected by a loss of function. Autosomal recessive disorders include almost all inborn errors of metabolism (i.e., lysosomal storage diseases, 1-antitrypsin deficiency, glycogen storage diseases and some variants of Ehlers-Danlos syndrome).

. The Intermediate Density Lipoprotein (IDL) molecule has which apoprotein(s) on its surface? 1. ApoA 2. ApoC 3. ApoE 4. B-100 A. 4 B. 2, 3 C. 3, 4 D. 1, 2, 4 E. 2, 3, 4

Reference: Robbins p. 151 (A:C) Very-low-density lipoproteins (VLDL) are secreted by the liver into the bloodstream. VLDL particles are rich in triglycerides. When a VLDL particle reaches the capillaries of adipose tissue or muscle, it is cleaved by lipoprotein lipase, a process that extracts most of the triglycerides. The resulting molecule, called intermediate-density lipoprotein (IDL), is reduced in triglyceride content and enriched in cholesteryl esters, but it retains two of the three apoproteins (B-100 and E) present in the parent VLDL particle. After release from the capillary endothelium, the IDL particles have one of two fates. Approximately 50% of newly formed IDL is rapidly taken up by the liver through a receptor-mediated transport. The receptor responsible for the binding of IDL to liver cell membrane recognizes both apoprotein B-100 and apoprotein E. It is called the LDL receptor. In the liver cells, IDL is recycled to generate VLDL. The IDL particles not taken up by the liver are subjected to further metabolic processing that removes most of the remaining triglycerides and apoprotein E, yielding the cholesterol-rich LDL. It should be emphasized that IDL is the immediate and major source of plasma LDL.

The selective inactivation of the maternal or paternal allele of a given locus is called: A. Linkage B. Mosaicism C. Imprinting D. Anticipation E. Uniparental disomy

Reference: Robbins p. 180 (A:C) A. Linkage analysis refers to indirect DNA diagnosis (i.e. RFLP, microsatellite or minisatellite repeats) B. Mosaicism results from a mutation that occurs postzygotically during early (embryonic) development. If the mutation affects only cells destined to form the gonads, the gametes carry the mutation, but the somatic cells of the individual are completely normal (germ line or gonadal mosaicism). A phenotypically normal parent who has germ line mosaicism can transmit the disease-causing mutation to the offspring through the mutant gamete C. Imprinting selectively inactivates either the maternal or paternal allele. Maternal imprinting refers to transcriptional silencing of the maternal allele, whereas paternal imprinting implies that the paternal allele is inactivated. D. Anticipation refers to the observation that clinical features of fragile X worsen with each successive generation. E. Uniparental disomy refers to inheritance of both chromosomes of a pair from one parent.

Systemic lupus erythematosus is an example of which of the following hypersensitivity disorders? A. Type I B. Type II C. Type III D. Type IV E. Type V

Reference: Robbins p. 196 (A:C)

. All of the following are Type II hypersensitivity reactions EXCEPT? A. Transfusion reactions B. Contact dermatitis C. Pemphigus vulgaris D. Myasthenia gravis E. Autoimmune hemolytic anemia

Reference: Robbins p. 199-202 (A:B) Type II hypersensitivity (cytotoxic type) is mediated by antibodies directed toward antigens present on the surface of cells or other tissue components. The antigenic determinant may be intrinsic to the cell membrane, or they may take the form of an exogenous antigen, such as a drug metabolite, adsorbed to the cell surface and most commonly involves blood cells including RBC, WBC and platelets. Complement-dependent reactions occur by either direct lysis or opsonization and include: a) transfusion reactions (incompatible donor reaction), b) erythroblastosis fetalis (antigenic difference between mother and fetus), c) autoimmune hemolytic anemia, agranulocytosis or thrombocytopenia, d) pemphigus vulgaris, and e) drug reactions. Antibody-dependent cell-mediated cytotoxicity (ADCC) results in cell lysis without phagocytosis. Antibody-mediated cellular dysfunction is a result of antibodies directed against cell surface receptors that impair or dysregulate function without causing cell injury or inflammation (i.e. myasthenia gravis).

Which molecule on the outer membrane of apoptotic cells allows their recognition by macrophages for phagocytosis? A. Sphingosine B. Glycosylamine C. Transglutamine D. Phosphatidylserine E. Acetoamido-glucosamine

Reference: Robbins p. 20 (A:D) Apoptotic cells express phosphatidylserine in the outer layers of their plasma membranes, the phospholipid having "flipped" out from the inner layers. In some types of apoptosis, thrombospondin, an adhesive glycoprotein, is also expressed on the surfaces of apoptotic bodies. These alterations permit the early recognition of dead cells by macrophages and adjacent cells for phagocytosis, without the release of proinflammatory cellular components.

Serum amyloid A (SAA) protein circulates in association with which lipoprotein subclass? A. IDL B. LDL C. VLDL D. HDL2 E. HDL3

Reference: Robbins p. 252 (A:E) The second major class of amyloid fibril protein (AA) does not have structural homology to immunoglobulins. The AA protein is found in those clinical settings described as secondary amyloidosis. AA fibrils are derived from a larger precursor in the serum called SAA (serum amyloid-associated) protein that is synthesized in the liver and circulates in association with the HDL3 subclass of lipoproteins.

The function of GTPase-activating proteins is to: A. Cause activation of the MAP kinase pathway B. Cause termination of intracellular signal transduction C. Enter the nucleus and cause transcription of certain genes D. Allow the cell cycle to progress through the G1 S checkpoint E. Cause persistent dimerization and activation of growth factor receptors

Reference: Robbins p. 281 (A:B) GTPase-activating proteins (GAPs) bind to active ras and augment its GTPase activity by more than 1000-fold, leading to rapid hydrolysis of GTP to GDP and termination of signal transduction. Thus GAPs function as "brakes" that prevent uncontrolled ras activity.

Which of the following is blocked by ras mutation resulting in a pathologic activation of the mitogen-activated protein kinase (MAP kinase) pathway? A. Exchange of GDP for GTP B. Binding of active ras to raf-1 C. Binding of active ras to GTPase activating proteins (GAPs) D. Hydrolysis of GTP to GDP E. Farnesyl membrane anchoring of ras to the cell membrane

Reference: Robbins p. 281 (A:D) When a normal cell is stimulated through a growth factor receptor, inactive (GDP-bound) ras is activated to a GTP-bound state. Activated ras recruits raf-1 and stimulates the MAP-kinase pathway to transmit growth-promoting signals to the nucleus. The mutant ras protein is permanently activated because of inability to hydrolyze GTP, leading to continuous stimulation of cells without any external trigger. The anchoring of ras to the cell membrane by the Farnesyl moiety is essential for its action.

Endothelial ICAM-1 binds to which leukocyte receptor? A. ESL-2 B. LFA-1 C. PSGL-1 D. 41 integrin E. Sialyl-Lewis X

Reference: Robbins p. 282 (A:B) The immunoglobulin family molecules include two endothelial adhesion molecules: ICAM-1 (intracellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1). Both of these molecules interact with integrins found on leucocytes. Integrins are transmembrane-adhesive heterodimeric glycoproteins, made up of and chains that also function as receptors of the extracellular matrix. The principal integrin receptors for ICAM-1 are the integrins LFA-1 (CD11a/CD18) and MAC-1 (CD11b/CD18), and those for VCAM-1 are the integrins 41 (VLA-4) and 47 (LPAM-1).

What protein types are typically affected in autosomal dominant disorders? 1. Enzymes 2. Structural proteins 3. Regulators of complex metabolic pathways 4. Those susceptible to gain of function mutations A. 1 B. 1, 2 C. 2, 3, 4 D. 3, 4 E. 4

Reference: Robbins p. 282 (A:C) Autosomal dominant disorders are manifested in the heterozygous state, so at least one parent of an index case is usually affected. Most mutations lead to the reduced production of a gene product or give rise to an inactive protein (loss of function mutations) including: a) those involved in regulation of complex metabolic pathways that are subject to feedback inhibition such as regulatory proteins (i.e., membrane receptors such as the LDL receptor), and b) key subunits of multimeric structural proteins (i.e., collagen and cytoskeletal elements of the red cell membrane). Mutations that impair the function of a normal allele are referred to as dominant negative. Less common than loss of function mutations are gain of function mutations (the protein product of the mutant allele acquires properties not normally associated with the wild-type protein and may have toxic properties).

Endothelial VCAM-1 binds to which leukocyte receptor? A. ESL-2 B. LFA-1 C. PSGL-1 D. 41 (VLA4) integrin E. Sialyl-Lewis X

Reference: Robbins p. 282 (A:D)

Which is a transcription factor amino acid motif that allows binding between the transcription factor and DNA? A. Helix-helix B. Offset ring C. Copper-finger D. Heterodomain E. Leucine zipper

Reference: Robbins p. 282 (A:E) Ultimately, all signal transduction pathways enter the nucleus and impact on responder genes that orchestrate the cells' orderly advance through the mitotic cycle. This process is regulated by a family of genes whose products are localized to the nucleus, where they control the transcription of growth-related genes. The transcription factors contain specific amino acid sequences or motifs that allow them to bind to DNA or to dimerize for DNA binding. Examples of such motifs include helix-loop-helix, leucine zipper, zinc-finger, and homeodomains. Many of these proteins bind DNA at specific sites from which they can activate or inhibit transcription of adjacent genes.

. Which of the following is essential for the G2 M transition in the cell cycle? A. Cyclin B/CDK1 B. Cyclin A/CDK1 C. Cyclin E/CDK2 D. Cyclin D/CDK4 E. Cyclin D/CDK6

Reference: Robbins p. 284 (A:A)

Which of the following is utilized for lymphocyte homing to high endothelial vessels? A. GlyCam-1 (CD34) B. VCAM-1 C. ICAM-1 D. E-selectin E. P-selectin

Reference: Robbins p. 284 (A:A)

. Cyclin D/CDK4 regulates the G1 S transition by phosphorylation of which of the following proteins? A. p21 B. p19 C. pRb D. p53 E. p57

Reference: Robbins p. 284 (A:C)

Which of the following is not a common cause of atrophy? A. Decreased workload B. Increased endocrine stimulation C. Loss of innervation D. Inadequate nutrition E. Diminished blood supply

Reference: Robbins p. 35 (A:B) A. Decreased workload results in disuse atrophy and may be accompanied by skeletal muscle fiber decrease and osteoporosis of disuse. B. Loss of endocrine stimulation results in physiologic atrophy of the endometrium, vaginal epithelium and breast. C. Damage to nerves leads to rapid denervation atrophy of muscle fibers supplied by those nerves. D. Inadequate nutrition (protein-calorie malnutrition) is associated with marked muscle wasting. E. Diminished blood supply (ischemia) results in atrophy of tissue due to progressive cell loss NB: Aging (senile atrophy) is also associated with cell loss. Tissue compression can cause pressure atrophy.

Normal defenses against ingested pathogens include all of the following except? A. Acid gastric juices B. A viscous mucous layer that covers the gut C. Antigen specific T cells D. Lytic pancreatic enzymes and bile detergents E. Secreted IgA antibodies

Reference: Robbins p. 354 (A:C)

Which of the following is a phase II reaction enzyme system used in the biotransformation of lipophilic toxicants to hydrophilic metabolites? A. Cytochrome P-450-dependent monooxygenase B. Flavin-containing monooxygenase C. Peroxidase-dependent cooxidation D. Glucoronidation E. Superoxide dismutase

Reference: Robbins p. 406 (A:D)

Which of the following is NOT one of the four principal causes of hypercalcemia in patients with metastatic mineralization? A. Increased secretion of parathyroid hormone B. Release of intracellular calcium ion from areas of soft tissue necrosis C. Destruction of bone tissue D. Vitamin D related disorders E. Renal failure

Reference: Robbins p. 45 (A:B) 1. Increased secretion of parathyroid hormone due to parathyroid tumors or PTH secretion by malignant tumors results in bone resorption, hypercalcemia and metastatic calcification. 2. Release of intracellular calcium ion from areas of soft tissue necrosis is NOT a mechanism involved in metastatic calcification. 3. Destruction of bone tissue occurs with primary tumors of bone marrow (i.e., multiple myeloma) accelerating bone turnover and resulting in hypercalcemia and metastatic calcification. 4. Vitamin D related disorders, including vitamin D toxicity results in hypercalcemia and metastatic calcification. 5. Renal failure causes retention of phosphate, resulting in secondary hyperparathyroidism, hypercalcemia and metastatic calcification.

The correct sequence of vascular changes in acute inflammation is: 1. Arteriolar vasodilation 2. Leukocyte margination 3. Arteriolar vasoconstriction 4. Increased vascular permeability A. 1 2 3 4 B. 1 4 2 3 C. 3 1 4 2 D. 3 4 1 2 E. 4 3 2 1

Reference: Robbins p. 53 (A:C) Changes in vascular flow and caliber begin early after injury and occur in the following order: a) Transient vasoconstriction of arterioles lasting a few seconds b) Vasodilation resulting in increased blood flow, the cause of heat and redness c) Increased permeability of the microvasculature resulting in slowing of the circulation and outpouring of protein-rich fluid into the extravascular tissues, concentration of RBC, increased viscosity of blood and stasis. d) Leukocyte margination

Identify the correct sequence of neutrophilic events in inflammation? 1. Transmigration 2. Rolling 3. Adhesion 4. Activation 5. Chemotaxis A. 2 3 4 5 1 B. 2 4 3 1 5 C. 3 2 4 1 5 D. 3 4 5 2 1 E. 4 2 3 1 5

Reference: Robbins p. 56 (A:B) Sequence of leukocyte events in inflammation. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, then pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Selectins are involved in rolling, chemoattractants activate neutrophils to increase avidity of integrins, ICAM-1 and VCAM-1 are involved in firm adhesion and PECAM-1 is involved in transmigration.

The redistribution of P-selectin containing Weibel-Palade bodies to the cell surface is induced by which of the following? A. Platelet activating factor, IL-1, and TNF B. Platelet activating factor, histamine, and thrombin C. Platelet activating factor, C3a, and NO D. Platelet activating factor, histamine, and serotonin E. Histamine, thrombin, and C3a

Reference: Robbins p. 57 (A:B) Redistribution of adhesion molecules to the cell surface is stimulated by mediators such as histamine, thrombin and platelet activating factor (PAF). P-selectin is normally present in the membrane of intracytoplasmic endothelial granules, Weibel-Palade bodies, and on stimulation by mediators is rapidly redistributed to the cell surface where it can bind the leukocytes. This process occurs within minutes in flowing blood and serves to deliver preformed adhesion molecules in short order to the surface.

The leukocyte receptor for the endothelial molecule GlyCam-1 is: A. PSGL-1 B. LPAM-1 C. L-selectin D. CD11/CD18 E. Sialyl-Lewis X

Reference: Robbins p. 57 (A:C)

The transcription factor that induces differentiation of immature cells to mature adipocytes is: A. BMP B. MyoD C. PPAR D. CFA-1 E. CBFA-1

Reference: Robbins p. 57 (A:C) A. Bone morphogenetic proteins (BMP), members of the TGF- superfamily, induce chondrogenic or osteogenic expression in mesenchymal stem cells, while suppressing differentiation into muscle or fat. B. MyoD is a transcription factor that induces differentiation of immature cells into muscle C. PPAR is a transcription factor that induces differentiation of immature cells into adipose tissue D. CFA-1 is a carbohydrate-specific bacterial recognition protein E. CBFA-1 is a transcription factor that induces differentiation of immature cells into osteoblasts

Actin-regulating proteins that help mediate contraction of leukocytes include all EXCEPT: A. Tensin B. Filamin C. Profilin D. Gelsolin E. Calmodulin

Reference: Robbins p. 61 (A:A) During chemotaxis, the leukocyte moves by extending a pseudopod that pulls the remainder of the cell in the direction of extension. The interior of the pseudopod consists of a branching network of filaments composed of actin as wells as the contractile protein myosin. Locomotion involves rapid assembly of actin monomers into linear polymers. These complex events are controlled by the effects of calcium ions and phosphoinositol on a number of actin-regulating proteins such as filamin, gelsolin, profilin, and calmodulin. These components interact with actin and myosin in the pseudopod to produce contractions.

Which of the following initiates the kinin, clotting, fibrinolytic and complement systems involved in the inflammatory response? A. Factor VIIIa B. Factor IXa C. Factor Xa D. Factor XIa E. Factor XIIa

Reference: Robbins p. 68 (A:E)

Which of the following arachadonic acid metabolites does not promote vasodilation? A. PGI2 B. PGD2 C. PGE2 D. Thromboxane A2 E. PGF2

Reference: Robbins p. 71 (A:D)

All are actions of lipoxins EXCEPT? A. Promote vasodilation B. Inhibit neutrophil adhesion C. Promote monocyte adhesion D. Promote neutrophil chemotaxis E. Attenuate vascular effects of LTC4

Reference: Robbins p. 71 (A:D) Lipoxins are the most recent addition to the family of bioactive products generated from arachadonic acid. Platelets alone cannot form lipoxins, but when they interact with leukocytes they can form the metabolites from neutrophil-derived intermediates. Lipoxins A4 and B4 (LXA4, LXB4) are generated by the action of platelet 12-lipoxygenase on neutrophil LTA4. Lipoxins have a number of proinflammatory and anti-inflammatory actions. They inhibit neutrophil chemotaxis and adhesion but stimulate monocyte adhesion. LXA4 stimulates vasodilation and attenuates the actions of LTC4-stimulated vasoconstriction. There is an inverse relationship between the amount of lipoxins and leukotriene formed, suggesting that the lipoxins may be endogenous negative regulators of leukotriene action.

All of the following are found in azurophilic granules of neutrophils EXCEPT? A. Myeloperoxidase B. Lysozymes C. Defensins D. Leukocyte adhesion molecules E. Cathepsin G

Reference: Robbins p. 77 (A:D) specific: Phospholipase A2 Plasminogen activator Lysozyme Lactoferrin Leukocyte adhesion molecules Alkaline phosphatases Type IV collagenase Gelatinase Histaminase azurophilic: Acid hydrolases Bactericidal permeability increasing proteins (BPI) Cathepsin G Cationic proteins Defensins Elastases Lysozymes Myeloperoxidase Non-specific collagenases Phospholipase A2 Proteinase 3

Which of the following signal transduction pathways involves activation of the intracellular kinase Akt? A. PI3 kinase B. MAP-kinase C. IP3 kinase D. cAMP E. JAK/STAT

Reference: Robbins p. 93 (A:A)

Which of the following is NOT true? A. The classic complement pathway is initiated by C1 binding to antigen-antibody complexes B. The alternative complement pathway is initiated by C3b binding to microbial cell walls C. C4b2a is a classical pathway C3 convertase D. C2a3b4b is a classical pathway C5 convertase E. C3bBb3b is an alternative pathway C5 convertase

Reference: Robbins p. 93 (A:D)

Which of the following signal transduction pathways involves binding to seven spanning receptors? 1. PI3 kinase 2. MAP-kinase 3. IP3 kinase 4. cAMP 5. JAK/STAT A. 2 B. 1, 2 C. 2, 3 D. 3, 4 E. 4, 5

Reference: Robbins p. 93 (A:D)

All of the following are pathophysiological categories of edema EXCEPT: A. Increased hydrostatic pressure B. Reduced plasma osmotic pressure (hypoproteinemia) C. Lymphatic obstruction D. Potassium retention E. Inflammation

Reference: Robbins p. 95 (A:D) Sodium and water retention, rather then potassium retention, are contributory factors in several forms of edema.

Which of the following proteins are used in the inositol-lipid (IP3) pathway for cell signaling with seven spanning receptors? A. Ras, Raf, MEK and ERK B. G-protein, phospholipase C, Ras, and MEK C. PIP2, JAK, STAT, and protein kinase C D. G-protein, phospholipase C, PIP2, DAG, and protein kinase C E. G-protein, Akt, PIP2, DAG, JAK, and STAT

Reference: Robbins p. 95 (A:D) The inositol-lipid (IP3) signaling pathway can be coupled to either tyrosine kinase or seven-spanning G-protein-linked receptors causing activation of a G protein. Binding of a ligand to a seven transmembrane receptor activates a G protein, which in turn activates phospholipase C. This enzyme then cleaves phosphatidylinositol 4,5-biphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). DAG activates protein kinase C, which phosphorylates a series of proteins altering cell function. The IP3 diffuses through the cytoplasm and interacts with membrane channels in the endoplasmic reticulum, causing release of calcium ions and cellular responses.

Which of the following types of collagen are the amorphous collagens present in basement membrane and interstitial tissues? 1. Type IV 2. Type V 3. Type II 4. Type I 5. Type VI A. 1, 2, 5 B. 2, 3, 4 C. 3, 4, 5 D. 1, 2, 4 E. 1, 2

Reference: Robbins p. 99 (A:A)

The primary type of collagen in basement membranes is: A. Type I B. Type II C. Type III D. Type IV E. Type V

Reference: Robbins p. 99 (A:D)

. All of the following have antioxidant properties EXCEPT? A. Glutathione peroxidase B. Xanthine oxidase C. Superoxide dismutase D. Ascorbic acid (vitamin C) E. Vitamin E

Reference: Robbins p.13 (A:B) Antioxidants, which either block the initiation of free radical formation or inactivate (i.e. scavenge) free radicals and terminate radical damage include lipid-soluble vitamins E and A as well as ascorbic acid (vitamin C) and glutathione in the cytosol. Enzymes that act as free radical-scavenging systems that break down hydrogen peroxide and superoxide anion include catalase that decomposes H2O2 (2H2O2 O2 + 2H2O), superoxide dismutases that convert superoxide to H2O2 (2O2 + 2H H2O2 + O2), and glutathione peroxidase that catalyzes free radical breakdown (H2O2 + 2 GSH [reduced glutathione] GSSG [glutathione homodimer] + 2H2O, or 2OH + 2 GSH GSSG + 2H2O).

. If a tumor produces a protein that downregulates thrombospondin-1, the likely effect is: A. Pro-apoptotic B. Anti-apoptotic C. Pro-angiogenic D. Anti-angiogenic E. Pro-metastatic

Reference: Robbins p.20, 101, 301 (A:C) Thrombospondins, a family of large multifunctional proteins, inhibit angiogenesis. Antiangiogenesis factors, such as thrombospondin-1, may be produced by the tumor cells themselves. In some types of apoptosis, thrombospondin, an adhesive glycoproteins is expressed on the surfaces of apoptotic bodies (together with phosphatidylserine). These alterations permit the early recognition of dead cells by macrophages.

Which of the following are nuclear transcription suppressors? a. c-myc b. myc-max c. max-max d. mad-max A. a, b B. b, c C. c, d D. a, b, c E. b, c, d

Reference: Robbins p.282 (A:C) The c-myc protooncogene is expressed in virtually all eukaryotic cells and belongs to the immediate early growth response genes, which are rapidly induced when quiescent cells receive a signal to divide. After translation, the c-myc protein is rapidly translocated to the nucleus. Either before or after transport to the nucleus, it forms a heterodimer with another protein called max. The myc-max heterodimer binds to specific DNA sequences (termed E-boxes) and is a potent transcriptional activator. mad, another member of the myc superfamily of transcriptional regulators can also bind max to form a dimer. The mad-max heterodimer functions as a transcription repressor. The degree of transcriptional activation by c-myc is regulated not only by the levels of myc protein, but also by the abundance and availability of max and mad proteins. In this network, myc-max favors proliferation, whereas mad-max inhibits cell growth. mad may therefore be considered an antioncogene (or tumor suppressor gene). myc not only controls cell growth, but also it can drive cell death by apoptosis. Thus, when myc activation occurs in the absence of survival signals (growth factors), cells undergo apoptosis.

What is the primary function of the protein GADD45? A. Cell cycle arrest B. DNA repair C. Cell cycle restart D. Apoptosis promotion E. Angiogenesis inhibition

Reference: Robbins p.282; Am J Pathol 159(2):387-397, 2001 (A:B) p53 induces the transcription of GADD45 (Growth Arrest and DNA Damage), a protein involved in DNA repair. GADD45 also assists in G1 arrest by unknown mechanisms (Robbins) and is an inhibitor of the G2/M phase cyclin B/CDC2 complex (Am J Pathol, 2001). Involvement of NF-B in cell-cycle regulation. NF-B may facilitate cell-cycle transition from G1 to S phase by antagonizing the activation or function of p53 and up-regulating cyclin D1 gene expression. NF-B may also promote G2- to M-phase transition by down-regulating the expression of GADD45, a G2/M phase blocker that inhibits CDC2/cyclin B complex.

TGF- A. Inhibits cellular proliferation through upregulation of CDK inhibitors B. Inhibits fibrosis C. Inhibits angiogenesis D. Increases production of collagenases E. Decreases production of plasminogen activator inhibitor type 1

Reference: Robbins p.290 and N Engl J Med 2000 May4;342(18):1350-8 (A:A) A. TGF- is a potent inhibitor of cell proliferation. It arrests the cell cycle in the G1 phase by stimulating production of the cyclin-dependent protein kinase inhibitor p15 and by inhibiting the function of production of essential cell-cycle regulators, especially the cyclin-dependent protein kinases 2 and 4 and cyclins A and E. These changes result in decreased phosphorylation of the retinoblastoma gene product, Rb, which allows it to bind to and sequester members of the E2F family of transcription factors. Sequestered E2F is then unable to stimulate the expression of genes that regulate progression through the cell cycle, such as c-myc and b-myb. B. TGF- favors fibrogenesis by stimulating fibroblast migration to sites of injury with proliferation and increased synthesis of collagen and fibronectin by cells and degradation of ECM by metalloproteinases C. TGF- directly stimulates angiogenesis in vivo and is important for vascular maturation and remodeling via stimulation of vascular endothelial growth factor (VEGF) expression. D. TGF- decreases the production of enzymes that degrade the extracellular matrix, including collagenases, heparinase, and stromelysin, and increases the production of proteins that inhibit enzymes that degrade the extracellular matrix, including plasminogen-activator inhibitor type 1 and tissue inhibitor of metalloprotease. E. TGF- induces synthesis of proteins that inhibit enzymes that degrade the extracellular matrix, including plasminogen-activator inhibitor type 1 and tissue inhibitor of metalloprotease.

Which vascular response in acute inflammation is immediate and prolonged? A. Endothelial contraction B. Increased transcytosis C. Direct endothelial injury D. Leukocyte-mediated endothelial injury E. Cytoskeletal reorganization (endothelial retraction)

Reference: Robbins p.54-55 (A:C) Direct endothelial injury results in endothelial necrosis and detachment. In most instances, leakage starts immediately after injury and is sustained at a high level for several hours until the damaged vessels are thrombosed or repaired. The reaction is known as the immediate sustained response. All levels of the microcirculation are affected including venules, capillaries, and arterioles.

All are key events in leukocyte activation EXCEPT? A. Receptor-ligand binding B. Phospholipase-C activation C. NADPH oxidase activation D. Protein kinase C activation E. Increased intracellular calcium

Reference: Robbins p.60-63 (A:C) Both exogenous chemical mediators (i.e. bacterial products) and endogenous chemical mediators (i.e. C5a, LTB4 and IL-8) can act as chemoattractants. Leukocyte movement is mediated by a branching network of pseudopod filaments composed of actin as well as the contractible protein myosin. These complex events are controlled by the effects of calcium ions and phosphoinositol on a number of actin-regulating proteins such as filamin, gelsolin, profilin and calmodulin, which interact with actin and myosin in the pseudopod to produce contraction.

All of the following are chemotactic EXCEPT? A. C5a B. Annexin II C. Fibrin split products D. HETE E. Leukotriene B

Reference: Robbins p.68, 71, 122 (A:B) A. C5a, a component of the complement system is a powerful chemotactic agent for neutrophils, monocytes, eosinophils and basophils B. Annexin II is a protein that serves as a profibrinolytic coreceptor for both plasminogen and tissue plasminogen activator on the surface of endothelial cells and facilitates the generation of plasmin C. Fibrin split products (fibrinopeptides), which are formed during the conversion of fibrinogen to fibrin, are chemotactic for leukocytes D. 5-HETE, which is converted into leukotrienes, is chemotactic for neutrophils E. Leukotriene B (LTB4), a product of the lipoxygenase pathway, is a potent chemotactic agent and activator of neutrophil functional responses

Thrombin does all of the following EXCEPT? A. Activates protein C B. Activates it receptors through proteolytic cleavage C. Cleaves fibrinogen D. Decreases leukocyte adhesion E. Activates endothelial cells to produce t-PA

Reference: Robbins p.69, 119-123 (A:D) Thrombin receptors are seven transmembrane spanner proteins coupled to G proteins; the amino terminal extracellular end is clipped by the proteolytic activity of thrombin, which generates a tethered peptide, which then binds to the rest of the receptor and causes the conformational change necessary to activate the G protein. Thrombin plays a central role in hemostasis and cellular activation. In addition to generation of fibrin (via cleavage of fibrinogen to fibrin and activation of factor XIII), thrombin also directly induces platelet aggregation and secretion (i.e. of TXA2). Thrombin induces platelet recruitment, platelet contraction and granule release by binding to a platelet surface receptor and along with ADP and TXA2 results in further aggregation (i.e. formation of the secondary hemostatic plug). Inflammatory properties include increasing leukocyte activation, adhesion and fibroblast proliferation. Fibrinopeptides are formed during fibrinogen cleavage, which increase vascular permeability and are chemotactic for leucocytes. Thrombin also activates endothelium to generate leukocyte adhesion molecules and a variety of fibrinolytic (t-PA), vasoactive (NO, PGI2), or cytokine (PDGF) mediators. Endothelial cells modulate both procoagulant and anticoagulant functions. Platelets are inhibited from adhering to uninjured endothelium by endothelial prostacyclin (PGI2) and nitric oxide; both mediators are potent vasodilators and inhibitors of platelet aggregation. Their synthesis is stimulated by ADP, thrombin and cytokines produced during coagulation. Endothelial cells also express adenosine diphosphatase, which degrades ADP and thus inhibits platelet aggregation. Anticoagulants are mediated by membrane-associated heparin-like molecules and thrombomodulin, a specific thrombin receptor. Heparin-like molecules are cofactors allowing antithrombin III to inactivate thrombin. Thrombomodulin binds to thrombin, converting it from a procoagulant to an anticoagulant capable of activating protein C. Activated protein C inhibits clotting by proteolytic cleavage of factors Va and VIIIa. Endothelial cells also synthesize tissue type plasminogen activator (t-PA), which promotes fibrinolysis activity to clear fibrin deposits from endothelial surfaces.

All of the following are morphologic features of reversible cell injury EXCEPT? A. Membrane blebs B. Myelin figures C. Amorphous mitochondrial densities D. Disassociation of ribosomes from endoplasmic reticulum E. Nuclear chromatin clumping

Reference: Robbins p.8-9 (A:C) A. Membrane bleb formation at the cell surface is a morphologic feature of reversible cell injury B. Myelin figures derived from plasma or organellar membranes seen within the cytoplasm or extracellularly is a reversible cellular feature C. Large, flocculent, amorphous densities develop in the mitochondrial matrix in irreversible cell injury D. Detachment of ribosomes from the granular endoplasmic reticulum and reduction in protein synthesis is a reversible cellular feature E. Nuclear chromatin clumping is a reversible cellular feature

All the following promote mast cell development EXCEPT: A. IgE B. IL-3 C. IFN- D. Stem cell factor E. Nerve growth factor

Reference: Vet Derm 9:146-148, 1998 (A:C)

All of the following regarding chemokines are true EXCEPT? A. Chemokines are a family of cytokines that have the ability to recruit specific populations of leukocytes during inflammation. B. CXC chemokines are specifically chemotactic for activated T-lymphocytes. C. Lymphotactin is the only member of the C family of chemokines and is produced only by activated CD8+ T lymphocytes D. RANTES, MCP-1 and MIP are examples of the CC family of chemokines E. CC chemokines are specifically chemotactic for eosinophils

Reference: Vet Path 37:357-367, 1999 (A:B) B is false; CXC chemokines ( chemokines) are specifically chemotactic for neutrophils.

Cattle with leukocyte adhesion deficiency have an autosomal recessive point mutation in which of the following? A. CD11a B. CD11b C. CD11c D. CD18 E. CD62L

Reference: Vet Pathol 33(6):639-646, 1996 (A:D) CD18 is a subunit for three 2 integrin molecules (Mac-1, p150, 95, LFA-1), which are expressed on the plasma membrane of neutrophils. The 2 integrins mediate stable adherence to endothelial cells and have a role in adherence to the interstitial tissue matrix. Deficiency of 2 integrins has been characterized in cattle with bovine leukocyte adhesion deficiency (BLAD). Cattle have an autosomal recessive point mutation in the subunit, CD18, of the 2 integrin heterodimer. This mutation results in <1% normal expression of all three (Mac-1, p150, 95, LFA-1) 2 integrins. Affected cattle develop a variety of pathologic changes because of impaired transmigration of neutrophils across vascular walls into sites of infection.

Simian Virus 40 (SV40) disrupts the cell cycle by: A. Binding cyclin A B. Binding pp60src C. Acting as an EGF homolog D. Binding and sequestering pRb E. Stimulating increased cyclin D1 expression

Reference: Vet Pathol 35(6):461-478, 1998 (A:D) A. Bovine herpesvirus 1 and Herpes simplex bind cyclin A, thus preventing cell cycle progression B. Mouse polyomavirus binds pp60src resulting in activation of pp60src in all stages of the cell cycle C. Rabbit myxoma virus, malignant rabbit (shope) fibroma virus and vaccinia virus encode homologs of epidermal growth factor D. SV40 large T antigen (LTA), mouse polyomavirus LTA, adenovirus early gene 1A protein and papillomavirus early gene 7 all bind pRb E. SV40 small T antigen stimulates cyclin D1 expression, thus activating cdk4 and cdk6 to phosphorylate pRb, which then releases E2F

. The p16 family proteins: A. Are oncogenes B. Activate G2/S cdk's C. Promote G1 arrest after DNA damage D. Override p53 transcriptional activity E. Are G1 cell cycle inhibitors that inactivate cyclin-cdk complexes

Reference: Vet Pathol 35(6):461-478, 1998 (A:E) The p16 family includes p16, p15, p18 and p19, which inactivate only the G1 cdks, cdk4 and cdk6. These proteins form stable complexes with the cdks before they are bound to cyclins. By binding cdk4 and cdk6, the p16 family members prevent the phosphorylation and inactivation of pRb. Once the G1 cyclin-cdk complexes are inactivated, they can no longer maintain pRb in its hyperphosphorylated, inactive state. Therefore, p16 proteins are indirect activators of pRb, and p16 and p15 could be considered tumor suppressors. Deletions of p16 and p15 result in the loss of the pRb-regulated restriction point. Without the normal cell cycle inhibitory function of p16 family proteins, cdk-cyclin complexes phosphorylate and inactivate pRb. Cyclin D/CDK4, cyclin D/CDK6, and cyclin E/CDK2 regulate the G1 S transition by phosphorylation of the Rb protein (pRb). Cyclin A/CDK2 and cyclin A/CDK1 are active in the S phase. Cyclin B/CDK1 is essential for the G2 M transition. Two families of CDK inhibitors, so called INK4 inhibitors composed of P16, p15, p18 and p19, act on cyclin D/CDK4 and cyclin D/CDK6. The other family of three inhibitors, p21, p27, and p57, can inhibit all CDKs.

CC chemokines ( chemokines) include which of the following? A. Eotaxin, RANTES, MIP, MCP, HCC, MPIF, SLC, I-309, TARC B. IL-8, IP-10, GRO, GCP, ENA, NAP, MIG, I-TAC, SDF, BCL C. Lymphotactin D. Fractalkine E. IFN-, IFN-, IFN-

Reference: Vet Pathol 36(5):357-367, 1999 (A:A)

The process of leukocyte movement and localization to higher concentration of soluble chemokine is known as: A. Chemotaxis B. Haplotaxis C. Prototaxis D. Transmigration E. Diapedesis

Reference: Vet Pathol 36(5):357-367, 1999 (A:A)

Which is the correct sequence of steps following the binding of the chemokine IP-10 to CXCR3? a. Protein kinase C activation b. G-protein-coupled signaling c. Release of intracellular Ca2+ stores d. Cleavage of PIP2 e. Activation of MAPK and phospholipase C A. bedac B. abecd C. dabec D. abcde E. bcdea

Reference: Vet Pathol 36(5):357-367, 1999 (A:A) Chemokine receptor intracellular loops are closely associated with a GTP-binding protein composed of , , and subunits. IP-10 binding to CXCR3, results in G-protein-coupled signaling, including activation of MAPK (family of mitogen activated protein kinases) and phospholipase C (PLC). Upon ligand (chemokine) binding, the receptor is activated, triggering an exchange of GTP for GDP on the G subunit of the GTP-binding protein. Subsequently, G dissociates from G, and the subunits bind and activate phospholipase C1 and C2 (PLC). PLC cleaves PIP2 (phosphatidylinositol 4,5-biphosphate) into two second messengers, DAG (diacylglycerol) and IP3 (inositol triphosphate). IP3 diffuses into the cytosol and causes mobilization of intra- and extracellular calcium. DAG activates PKC (protein kinase C) resulting in the phosphorylation of a variety of down stream intracellular proteins including the mitogen activated protein kinases (MAPKs). MAPK activation may activate transcription factors, phospholipase A2, or other kinases and reorganize cytoskeletal elements. Collectively these events lead to functional responses. Simultaneously, the G-protein subunit binds to GPK (G-protein-activated receptor kinase), which phosphorylates serine and threonine residues on the CXCR3 terminus, resulting in receptor desensitization to future chemokine (MIG) stimulation.

Which mediates both chemotaxis and adhesion of T cells and monocytes? A. Fractalkine B. Lymphotactin C. Thymus expressed chemokine D. Secondary lymphoid tissue chemokine E. Thymus and activation regulated chemokine

Reference: Vet Pathol 36(5):357-367, 1999 (A:A) Fractalkine, a CX3C chemokine can mediate both chemotaxis and adhesion of T cells and monocytes.

CXC chemokines ( chemokines) include which of the following? A. Eotaxin, RANTES, MIP, MCP, HCC, MPIF, SLC, I-309, TARC B. IL-8, IP-10, GRO, GCP, ENA, NAP, MIG, I-TAC, SDF, BCL C. Lymphotactin D. Fractalkine E. IFN-, IFN-, IFN-