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1

*3 most commonly described selectins necessary for WBC extravasation during acute inflammation

*E (endothelial)P (platelet)L (leukocyte)WBC extravasation includes1. Margination (selectins)2. Adherence (integrins)3. Diapedesis (interendothelial)

2

*define diapedesis

*Diapedesis = process of WBC migration inbtwn endothelial cells at the site of injury during acute inflammationInvolves both adhesive and proteolytic events

3

*Proinflammatory cytokines

*IL-1, 6TNF alpha (cachectin)PGPDGFTGF Chemokinesleukotriene (LTB4)FIRST SOURCE= resident/sentinel tissue macrophages

4

*2 vasoactive substances involved in acute inflammation

*Histamine---short half life, main source from mast cells, work @ H1 receptorsSerotonin--spp dependentF(x): vasodilation, increase vascular permeability

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*Define cytokines

*Diverse group of small soluble proteins that act as IC messengers during physiologic processes. Can work autocrine, endocrine, paracrine. Redundant, pleiotropism

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*Anti inflammatory cytokines

*IL-10Lipoxins--inhibit neutrophils/chemotaxisSource=cd4+ TH cells, monocytes, B cellsf(x): decr pro inflammatory cytokines, decrease Ag presentationexcess IL-10 can increase susceptibility to microbial infection

7

*Physiologic action of PGE2

*Source= many cellsF(x): hyperalgesia, pyrogenic, vasodilation

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*Physiologic action of PGF2

*Source= endometrial cells F(x): uterine contraction, bronchoconstriction, vasodilation

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*Physiologic action of TxA2 (thromboxane)

*Source : Platelets, macrophagesF(x): Platelet aggregation, Vasoconstriction

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*Hallmarks of an acute phase reaction

*FeverLeukocytosisChange in serum acute phase protein concentration

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Nitric oxide

source:endothelial (primary), neuronal, inducibleF(x): Vasodilator(potent), Decreases platelet aggregation, Decreases white blood cell adhesion (eNO), free rad production to kill microbes (iNO)both inflm and antiinflam

12

C reactive protein

Positive acute phase proteinF(x): Activates complement, decreases PMN, increases macrophages, promotes DIC

13

Complement pathway

ROLE IN OPSONIZATION, PHAGOCYTOSIS, CHEMOTAXIS, CELL LYSIS1. Alternative path (Bacteria)-------->2. Classical path (Ab)--------> Cleave C33. Lectin path (Mannose) -------->C3a---> anaphlatoxinC3b---> phagocytosisC3b + C3convertase---> C5b+ C6789 MAC---> lysis of bacteria

14

reperfusion injury pathophysiology

Prolonged ischemia --> incr hypoxanthineWhen reperfused, add oxygenAllows xanthine oxidase to fx to convert hypoxanthine --> xanthine + h2o2H2o2 destabilizes into free radicles--> oxidize cell membranes--> cell death

15

How are reactive oxygen species counteracted?

1. Antioxidant enzymes (Superoxide dismutase, catalase glutathione peroxidase)2. Antioxidant scavenger molecules (Vitamin A, C, E)

16

Difference btwn Cox1 and cox 2

Both are enzymes in AA pathCOX1 constitutively expressedCOX2 induced by trauma, growth factors, inflm

17

Arachidonic acid pathway

Cell membrane phospholipids-->AA via phospholipase A2AA --> cyclooxygenase path--> PGI2(prostacyclin inhibits platelets), TXA2(thromboxane promotes platelets), PGE2/PGD2 (vasodilation, permeability, pyrogenic)AA-->lipoxygenase path-->lipoxins(inhibit PMN,antiinflm), leukotrienes LTB4(proinflm)

18

Source and MOA on TNF ALPHA

Pro inflm cytokineSource: macrophagesMOA: anti tumor activityRelease inflm mediators and cytokinesIncrease CD8+ cytotoxic T cell immunity and NK cells

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Source and MOA IL 6

Pro inflm cytokineSource: macrophages, epithelial cells, enterocytes, T cellsMOA: incr liver acute phase proteinsIncrease lymphocyte proliferation

20

Purine and pyrimidine bases in DNA

Purine: adenine, guaninePyrimidine: cytosine, thiamineA--TG---C

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Source and MOA IL 6

Pro inflm cytokineSource: macrophages, epithelial cells, enterocytes, T cellsMOA: incr liver acute phase proteinsIncrease lymphocyte proliferation INCREASES WITH DURATION/SEVERITY OF DISEASE (biomarker)

22

Difference btwn DNA & RNA

RNA: uracil, ribose sugar, single strandDNA: thiamine, deoxyribose sugar, double strand

23

Central dogma of molecular biology

Crick 1958Replication(make DNA copy)Transcription(make mRNA)--takes place in nucleusTranslation(make protein)--takes place in ribosome

24

What transcription factor is critical to cartilage formation

SOX9Can be used to restore changes in ECM of osteoarthritic cartilage

25

Insertion of sequences into functional DNA (by way of reverse transcriptases) can result in what canine disease example

Lamellar ichythyosis (epidermal cornification)--JRTCentronuclear myopathy (hereditary Labrador retrievers); muscle weakness;Exercise intolerance

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What is the universal marker of canine malignancy and best described reverse transcriptase

Telomerase expression (adds DNA to the end of chromosomes)Experimental inhibition can inhibit tumor growth

27

Types of genetic mutations

Single nucleotide mutationNonsynonymous mutationMiss sense mutationNonsense mutationSynonymous mutationFrame shift mutationCan be reproductive within the germ line Or nonreproductive (somatic)

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List 4 ways bio markers can be used

1. Diagnostic2. Staging3. Prognostic4. Monitoring clinical response to tx

29

4 steps of acute vascular response of inflammation

1. vasodilation (brief constrict--then dilate)2. permeability3. stasis4. WBC extravasation

30

Alarm signals: pathogen or danger associated molecular patterns recognition and response

body recognizes DAMPs, PAMP through pattern recognition receptors (notably Toll Like Receptors) which then initiate translocation of nuclear factor kappa B into nucleus to act as transcription factor for production of pro inflammatory cytokines.Ex. TLR-4 for recognition of LPS endotoxin of bacteria

31

What are tachykinins

tachykinins are neuropeptides released from peripheral neurons after stimulation/trauma of sensory nervesex. substance P

32

role of substance P

tachykinin released by sensory neurons and inflammatory cells after trauma/stimulationbind G protein receptors (neurokinin-1 receptors) to promote transmission of pain signals and overall proinflammatory (incr vasoperm, neovasc, WBC extravasation, cytokine production)

33

chemical name for serotonin

5-hydroxytryptamine

34

what are chemokines

peak AFTER cytokine (TNFa, IL1,6)chemotactic cytokinesex. IL 8 (is a chemokine of CXC family with ELR moiety--IL-8/CXCL8) attracts neutrophils

35

Most common methods of proteonomics in vet med

IHCWestern BlotELISAMass spectrometry