Exam 2 Tissue Injury & Host Defense

Free Radicles know bold bc red on slides path 2/14

(REACTIVE OXYGEN METABOLITES) - UNSTABLE MOLECULES WITH A SINGLE UNPAIRED ELECTRON IN THE OUTER ORBIT - EXEMPLIFIED BY ACTIVATED PRODUCTS OF OXYGEN REDUCTION : SUPEROXIDE (O2-), & HYDROXYL RADICALS [(OH-), H2O2{HYDROGEN PEROXIDE}]. - Cause cell injury by (free radical injury): -- Lipid peroxidation of membranes- extensive membrane damage. -- Modify proteins-cause misfolding & breakdown -- Damage to DNA- cause single & double-strand breaks -> result in cellular aging -> malignant transformation GENERATION OF FREE RADICALS: - NORMAL METABOLISM - OXYGEN TOXICITY: EX. ALVEOLAR DAMAGE IN ARDS - IONIZING RADIATION - UV LIGHT - REPERFUSION AFTER ISCHEMIC INJURY - DRUGS AND CHEMICALS - TRANSITION METALS [IRON AND COPPER].

AB TOXINS know bold

(how do pathogens cause disease) = Intracellular Targets (inside cells); Problem: how do these toxins access these targets? HOW A-B TOXINS SOLVE THE PROBLEM OF GETTING ACROSS HOST MEMBRANES: 1. A-B TOXIN SECRETED BY BACTERIA: A-SUBUNIT ACTIVITY (ENZYMATIC DOMAIN). 2. B-SUBUNIT: BINDING TO CELL RECEPTOR(S) 3. ENDOCYTOSIS OF TOXIN 4. TRANSLOCATION AND RELEASE OF A-SUBUNIT. AB TOXINS HAVE DIVERSE ACTIVITIES, DESPITE THEIR SIMILAR MODE OF ENTRY: CHOLERA TOXIN vs. TETANUS TOXIN & BOTULINUM TOXIN [recall: cholera enzymatic activity is ADP-ribosyltransferase, and cholera toxin vaccine is in development] [tetanus toxin and bot toxin enzymatic activities are protease, and vaccine is tetanus. - A NUMBER OF DISEASES ARE PRIMARILY TOXIN-MEDIATED, E.G. CHOLERA, C. DIFFICILE-ASSOCIATED DISEASE, TETANUS, BOTULISM... - SITE OF TOXIN ACTION IN BODY DETERMINES THEIR EFFECT ON HOST.

Superantigens know caps

(how do pathogens cause disease) = MEMBRANE-ACTIVE TOXINS (TSST-1) secreted by subset of S. aureus; ACTS EXTRACELLULARLY that cause TOXIC SHOCK SYNDROME. Superantigens cause NON-SPECIFIC (antigen-independent) T CELL ACTIVATION (2-20%) = massive proliferation EXCESSIVE INFLAMMATION causes organ failure (toxic shock) Superantigen: exotoxin that binds T cell receptor and MHC Class II molecules together to induce polyclonal activation of T cells (antigen-independent)

1) How to deal with exogenous antigen? 2) How deal with endogenous antigen? very important. will be on exam

1) Processing of an EXOGENOUS (outside apc) antigen = MHC Class 2 Pathway: Virus Protein in vaccine (e.g.) TAKEN INTO APC CELL (phagocytosis) => goes into ACID VESICLE that turns it into peptides -> Peptides associate w. newly synthesized (golgi) MHC class 2 molecules in that groove -> MHC2+Peptide transported to outside/surface of cell, now ready for presentation to CD4"T Cells. 2) Processing of ENDOGENOUS antigen = MHC Class 1 Pathway: Any protein or Antigen in Cell (infected cell) -> CATABOLIZE ANTIGEN IN CYTOPLASM to peptides -> transport peptides to ER, where they associate with MHC Class 1 (go thru golgi) -> MHC class 1 + Peptide to surface of cell ready for presentation to CD8" T cells.

1) What are the three parts of phagocytosis? 2) What is involved in Neutrophil Phagocytosis? (must know! path 2/15)

1) Recognition and attachment of particle. Engulfment. Killing and Degradation. 2) Membrane receptors bind to material. Neutrophils do not phagocytose material to which they do NOT bind.

What is the IMMEDIATE TRANSIENT RESPONSE in acute inflammation? (must know path 2/15)

1) TRANSIENT VASOCONSTRICTION 2) VASO-DILATION OF ARTERIOLES, CAPILLARIES AND POSTCAPILLARY VENULES. OTHER VASCULAR REACTIONS OF ACUTE INFLAMMATION (is this involved also in the transient response?) = INCREASED PERMEABILITY AT ARTERIOLE, CAPILLARY, AND VENULE LEVEL (results in leakage of proteinaceous fluid).

MEMORIZE ALL THIS - ACUTE INFLAMMATORY MEDIATORS: 1) Vasodilation 2) Increased Permeability 3) Neutrophil Adhesion 4) Neutrophil Chemotaxis 5) Fever 6) Pain 7) Tissue Necrosis

1) VASODILATION = HISTAMINE, PROSTAGLANDIN, NITRIC OXIDE, BRADYKININ, PAF. 2) INC. PERMEABILITY = HISTAMINE, C3A, C5A, BRADYKININ, LEUKOTRINES, PAF, NITRIC OXIDE. 3) NEUTROPHIL ADHESION = IL-1, TNF, PAF, LTB4, C5A, CHEMOKINES. 4) NEUTROPHIL CHEMOTAXIS= C5A, LTB4, BACTERIAL COMPONENTS, CHEMOKINES. 5) FEVER = IL-1, TNF, PROSTAGLANDINS 6) PAIN = PROSTAGLANDINS; BRADYKININ 7) TISSUE NECROSIS = NEUTROPHIL LYSOSOMAL GRANULES; FREE RADICALS FROM NEUTROPHILS.

Definitions (Pathology 2/15) 1) Four aspects of disease process (know, red) 2) Homeostasis (know, red)

1. (a) Etiology-cause that can be acquired or genetic (Why?); (b) Pathogenesis-mechanism for the development of disease (How?); (c) Morphologic changes; (d) Clinical manifestations (signs and symptoms). 2. Homeostasis is Steady state cells normally exist, Equilibrium between cells and environment for adequate function, and if disturbed, can be predisposed for onset of pathology.

1. At what stage of development do self-reactive lymphocytes undergo negative selection? a. Immature B cells and single-positive thymocytes b. Plasma cells and CTLs c. Mature B cells and CD4+ T cells d. Memory B cells and Memory T cells e. Pre-B cells and Pre-T cells

1. A In the bone marrow, an immature B cell (which has only IgM on its membrane) will die (be deleted) if its BCR binds antigen. Similarly, in the thymus, immature T cells (single-positive thymocytes expressing either CD4 and CD8) that bind antigen with high affinity die (are deleted). Thus, both developing B cells and developing T cells are undergo NEGATIVE SELECTION to delete lymphocytes that are self-reactive (auto-reactive).

What are some important causes of EOSINOPHILIA? must know path 2/15

1. Allergies (hay fever, asthma, hives) 2. Parasitic infections 3. Polyarteritis nodosa 4. Hodgkin lymphoma bc Eosinophils are predominant inflammatory cells in ALLERGIC rxns and PARASITIC infections.

Signs of inflammation (must know EVERYTHING, red path 2/15)

1. Calor 2. Rubor 3. Tumor 4. Dolor (sorrow, distress) 5. Loss of Function 6. Additional Clinical Findings - Malaise, Fever, Elevated Heart Rate & Blood Pressure. 7. Plasma Proteins - C-reactive Protein (CRP), Fibrinogen [binds to RBCs and allows for measurement of erythrocyte sedimentation rate (ESR)], Serum Amyloid A (SAA), Lab Values 8. Leukocytosis

5. A dendritic cell at the site of an infection will do all of the following EXCEPT a. receive signals through its pattern recognition receptors b. ingest exogenous antigens and cleave proteins into small peptides c. increase expression of B7 molecules on its surface d. undergo clonal expansion and differentiate into memory dendritic cells e. express MHC class II molecules, some of which are binding pathogen-derived peptides

5. D ONLY B cells and T cells are antigen-specific and undergo clonal expansion and memory cell formation.

6. Which of the following statements regarding MHC molecules is NOT correct? a. All nucleated cells express MHC class I molecules b. MHC class I molecules bind peptides from endogenous proteins c. If a peptide binds to HLA-A, it must also bind to HLA-B d. A single macrophage expresses HLA-DR, HLA-DP, and HLA-DQ molecules e. Dendritic cells express BOTH MHC class I and MHC class II molecules

6. C Each MHC molecule binds a variety of peptides with similar amino acid sequences. The particular peptides that bind vary from one MHC molecule to the next.

7. Which of the following pairs of proteins do NOT interact with each other? a. CD28 and B7 b. CD8 and MHC class II c. IgE and FcgR d. CD40 and CD40L e. IgG and FcgR

7. B MHC class II molecules interact with CD4 molecules on CD4+ T cells.

Which statement concerning CD8 is INCORRECT? a. Following activation, CD8+ T cells develop into CTLs b. CD8 is a coreceptor found on TH1, TH2 cells, but not Treg cells c. CD8+ cells kill target cells by releasing perforin and granzymes d. In the thymus, some immature T cells express CD3, CD4, and CD8 e. CD8 binds to an invariant region of

8. B TH1, TH2, TH17, and Treg cells are subsets of CD4+ T cells and do not express CD8.

CAUSES OF DEFICIENT PHAGOCYTOSIS? know path 2/15

= "LEUKOCYTE FUNCTION DEFECTS" 1) opsonization defects = hypogammaglobulinemia 2) engulfment defects = drugs, morphine. 3) degranulation defects = drugs, steroids; lack of NADPH-oxidase -> failure to kill organisms. 4) Severe Glucose-6-phosphate dehydrogenase deficiency - no peroxide is generated.

Injurious Stimuli

= CAUSES OF CELL INJURY (know this all in red path 2/14) 1. Hypoxia - Lack of oxygen to tissues commonly caused by ischemia (loss of blood supply). 2. Genetic 3. Nutritional 4. Physical: Trauma, Temperature, Shock, Electrical. 5. Chemical: Therapeutic or Non-therapeutic 6. Biological (Infectious agents): Bacterial, viral, fungal. 7. Immunological: Autoimmune or Allergic reactions. 8. Aging

Biochemical events / steps in apoptosis? know this red on slides 2/14 path

(S, E, D, P) Biochemical events - active, gene expression, protein synthesis, energy consumption. - Initiated by diverse injurious stimuli (free radicals, radiation, toxic substances, withdrawal of growth factors or hormones). S- Signaling by molecules (ex. FAS ligand, TNF) and associated proteins E- Release of cytochrome-c and AIF (apoptosis inducing factor) from mitochondria - caspase activation (cytosolic cytotoxic proteases; 'MAJOR EXECUTIONERS') Aspartate-specific cysteine proteases Analogues of interleukin-1β-converting enzyme D - DNA degradation by endonucleases - nucleosomal chromatin fragments - DNA ladder appearance Activation of transglutaminases (cross-link apoptotic cytoplasmic proteins) No inflammatory reaction; apoptotic bodies P - Phagocytosis ; Apoptotic cells submit signal to attract phagocytes

Cholera toxin (enterotoxin) - know bold

(how do pathogens cause disease) 1. B subunit: binds gangliosides & blood group antigens = B SUBUNIT: BINDS INTESTINAL EPITHELIAL CELLS. 2. A subunit: ADP RIBOSYLTRANSFERASE activity; substrate = adenylate cyclase = A SUBUNIT : ADP RIBOSYLTRANSFERASE ACTIVITY DISRUPTS TRANSPORTER FUNCTION LEADING TO MASSIVE SECRETION OF FLUID INTO INTESTINAL LUMEN. 3. Increased cyclic-AMP (cAMP) levels a) Massive efflux of Cl- ions into lumen b) Na+ and Cl- absorption inhibited HOW ORAL REHYDRATION SOLUTIONS CAN TREAT CHOLERA = Oral hydration solutions (Na+ and glucose or amino acids) are still absorbed by the SLC5A1 symporter EVEN in the presence of cholera toxin.

What happens if you give Gram-POSITIVE Streptococcus mutans glucose and SUCROSE?

BOTH consumed at same time (contrast to if given glucose and lactose = glucose-sucrose co-utilization -> glucose consumed first) = sucrose imported into cell by sucrose-specific PTS system (has its own transport protein and is not regulated by glucose and/or CAP-cAMP) , no inducer exclusion, not regulated by CcpA = only one enzyme breaks sucrose down, very EFFICIENT (compared to lactose , here only one extra step): sucrose enzyme II [same locus, same region, but dif. promoters]. - know: Induction of scrBR operon by sucrose in S. mutans = (a) binding of repressor, which auto-represses itself = when sucrose absent. (b) Sucrose present = sucrose-6-P interacts with repressor and INACTIVATES it

Contrasts Between Macrophages and Polymorphs

BOTH: in circulation, are phagocytes. Macrophages: - Long lived - Present in tissues (when mature) - O2-dependent killing not vigorous - Conditions amenable for intracellular growth of pathogens - Pathogen tactics in battle = a) Circumvent respiratory burst b) Break out of phagosome c) Prevent phagolysosome fusion d) Resist granule contents Polymorphs (PMNs) - Short lived - Circulating - Respond to conditions stimulating - Inflammation, leaving circulation - Vigorous respiratory burst during phagocytosis - Exteremely hostile environment for intracellular pathogens. - Pathogen tactics: a) Resist phagocytes b) Kill or be killed

Tetanus toxin causes paralysis through its ability to? A. ADP-ribosylate a protein that alters transporter function. B. ADP-ribosylating a protein that disrupts cell-cell junctions. C. Cleaving proteins requried for membrane fusion and preventing neurotransmission. D. Cleaving a protein that alters transporter function. E. Forming pores in neuronal cells.

C

HYPOXIC CELL INJURY results from?

CELLULAR ANOXIA OR HYPOXIA DUE TO: 1) Ischemia = Obstruction of arterial blood flow = MOST COMMON cause 2) Anemia = Reduction in NUMBER of O2-carrying red blood cells (rbcs) 3) Carbon monoxide poisoning = Diminution in O2-carrying capacity of rbcs by chemical ALTERATION OF HEMOGLOBIN. 4) Decreased perfusion of tissues by O2-carrying blood = Cardiac failure, hypotension, and shock. 5) Poor oxygenation of blood secondary to pulmonary disease

Ubiquitin

Cell stress protein that marks abnormal proteins for degradation (apoptosis) ex. Heat shock proteins induced by stress path 2/15 know

What do corticosteroids block in the arachidonic acid cascade? What do Aspirin and NSAIDs block?

Corticosteroids block phospholipase A2 (conversion of cell membranes / phospholipids into arachidonic acid) = block both "cyclooxyegenase" pathway and "Leukotriens synthesis" pathway and these are potent bronchoconstrictors. Aspirin, NSAIDS block prostaglandin synthetase (cyclooxygenase) that converts Arachidonic Acid to Cyclic Endoperoxides that cause Pain and Vasoconstriction. KEY - Someone with toruble breathing, aspirin and nsaids can make everything worse because they are flowwing everything through the Leukotriens pathway and making more of them (since they block cyclooxygenase pathway).

What are antigen presenting cells (APC)?

Express MHC Class 1 molecules. Present antigens to CD4+T cells. 1) Dendritic Cells (DC) 2) Macrophages (M0) 3) B cells ^ These cells also express MHC Class 2 (unique) bc class 2 is "expressed on ALL nucleated cells"!

What cytokine made by the Th cell influences class (isotype) of the antibody made by the B cell to switch to IgE? must know

IL-4 promotes switching to IgE - for parasite immunity and allergy. - concept that cytokines "direct" switching to particular antibody classes and for the one example of IL-4 promoting switching to IgE

Analgesic actions of NSAIDS are bc they do what?

INHIBITION (reduction) OF PROSTAGLANDIN SYNTHESIS => no sensitization of nerve endings, thus painful actions of bradykinin and histamine are reduced.

Opsonins are involved in what? What are they and what do they do?

Involved in Phagocytosis. Host proteins that coat microbes and target them for phagocytosis (opsonization). Enhance binding to surface antigens. [must know all this path 2/15]

A 60-year old male abruptly develops cough, fever, and pain in the chest that becomes worse with breathing. His breathing is shallow and rapid. An X-ray of his chest shows consolidation in the right lung. A microorganism was grown from his blood culture. The organism was gram-positive coccus that was sensitive to the P disk. What infection is most likely? A. Bacteremia. B. Pneumococcal pneumonia. C. Pneumococcal pneumonia with bacteremia. D. Streptococcal endocarditis E. Streptococcal endocarditis with bacteremia.

breathing issue - think pneumonia (something going on with lungs) C. Pneumococcal pneumonia with bacteremia. This person has lung infection so know its not endocarditis, it is pneumonia. Has microorganism grown on blood culture so know must be with bacteremia.

Chaperones

cell stress protein. Specialized protein required for proper folding and/or assembly of another protein or protein complex.

A 33-year old woman undergoes endodontic treatment of the lower third molar because of caries. After this treatment, she develops fever, tooth pain and swelling of the neck. She is found to have a large, spreading lesion with necrotic tissue. Gram staining and culture of pus from the lesion reveals a beta-hemolytic, Gram-positive coccus. What infection does she probably have? A. Food poisoning B. Necrotizing fasciitis C. Rheumatic fever D. Scarlet fever E. Toxic Shock Syndrome

fix make fc's similar to this case for other infections B. Necrotizing fasciitis (caused by group A strep)

HLA-DR4

is an MHC Class2 allele in HUMANS.

FNR - fix with other fc / mesh

is the key regulator of respiration. Functions anaerobically as both activator and repressor.

What do T cells bind?

they do NOT bind SOLUBLE antigen! T cell receptors (TCR) recognize PEPTIDE ANTIGENS (aka small proteins) that must be PRESENTED to the T-cell on a molecule called MHC {takes proteins, chops them into peptides and presents them to T cells}. - so the peptide antigen must be bound to one of your own molecules which is called MHC. - The original protein must go through: PROCESSING [catabolism of protein antigen to peptides inside host cell: some peptides bind to an MHC molecule] & then PRESENTATION [peptide plus MHC on surface of host cell interacts w. TCR of T cell]. - IMP: Shape of t cell receptor fits both: peptide & MHC molecule. What the TCR is recognizing is a COMBO of the pepdide and the MHC molecule.

Acetaminophin

"The safe Aspirin/NSAID alternative" - For mild pain, pain relief equiv. to aspirin and ibuprofen. - No GI upset (thus, OK for ulcer patients!). - No effects on bleeding (thus, OK in anti-coagulated patients or patients w bleeding disorders!). - Doesn't increased BP! (safe for hypertensive patients). - No allergic reactions! (thus OK in aspirin sensitive patients). - Cheap! like aspirin! - Ok for kids! DOSING: - 325-650 mg (regular strength) q4h, - 500-1000 mg (extra-strength) q6-8h, - Tylenol 8hr/Arthritis: 650mg/pill [dont needa know]. - Analgesic Ceiling (1,000mg) = higher than ibuprofen! = 2 extra-strength pills; 3 regular strength pills = EXAM MATH QUESTION. - Max Dose = 4,000 mg per 24 hour period; 2,000mg/day in patients w liver disease, fasting patients, anorexics. - IV form exists (bypass first pass metabolism). WARNING: alcohol and liver disease - excessive doses can lead to irreversible liver damage. Limit 2,000mg/day in cirrhotic patients. Barbiturates, carbamazepine and ethanol can induce metabolism, increasing the formation of hepatotoxic metabolites. Avoid in patients with G6PD deficiency. Tylenol can kill cats because their liver doesn't metabolize it safetly. NEW RESEARCH: - ACETAMINOPHEN EFFECTIVE FOR 3rd molar extraction pain relief. - Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults (bc one acts on CNS and other is more peripherally; so although both blocking prostaglandin, they are dif. locations).

Cell-derived mediators of inflammation? Role of NSAIDS & COX-2 Inhibitors? must know path 2/15

(A) Cell-Derived: VASOACTIVE AMINES = Histamine & Serotonin! 1) HISTAMINE 2) SEROTONIN = INDUCES VASOCONSTRICTION DURING CLOTTING. (B) Cellular Chemical 1) PROSTAGLANDINS & LEUKOTRINES [ARACHADONIC METABOLITES]- derived thru local synthesis from arachidonic acid; arachidonic acid metabolism pathways = Cyclo-oxygenase and lipoxygenase => COX-1 (CONSTITUTIVELY EXPRESSED, constant amts); COX-2 (SPECIALLY INDUCED IN CELLS FOR INFLAMMATION). - CYCLO-OXYGENASE PRODUCES: Thromboxane A2, Prostacyclin PGI2, Prostaglandins PGD2, PGE2, PGF2. - LIPOXYGENASE PRODUCES: Leukotrienes LTB4 LTC4 LTD4 LTE4, Lipoxins LXA4, LXB4. 2) PLATELET ACTIVATING FACTOR (PAF). 3) CYTOKINES 4) CHEMOKINES (FAMILY OF SMALL RELATED PROTEINS) ACT AS CHEMO-ATTRACTANTS FOR LEUKOCYTES AND CONTROL ANATOMIC ORGANIZATION OF CELLS IN LYMPHOID AND OTHER TISSUES. C) DRUG THERAPY: NSAIDS INHIBITS CYCLO-OXYGENASE PATHWAY; COX-2 INHIBITORS SELECTIVELY INHIBIT ENZYMES PRODUCED BY INFLAMMATORY STIMULI AND MAY INCREASE RISK OF CARDIOVASCULAR OR CEREBROVASCULAR DISEASE.

HEREDITARY NEUTROPHIL DEFECTS (know this path 2/15) : (A) Chronic Granulomatous Disease of Childhood (B) CHEDIAK-HIGASHI SYNDROME

(A)Usu. X-linked, deficient activity of NADPH oxidase. Phagocytic cells ingest but do not kill certain microorganisms: 1) CATALASE-POSITIVE ORGANISMS (e.g. staph aureus) = ingested but NOT killed. 2) CATALASE-NEGATIVE ORGANISMS (e.g. Strep) = injested and KILLED. (B) autosomal recessive. neutropenia, albinism, cranial and peripheral neuropathy, repeated infections; impaired fusion of lysosomes with phagosomes.

Clostridial Neurotoxins Botulinum Neurotoxin (BoNT) - what is it? TETANUS AND BOTULINUM TOXINS HAVE SIMILAR _______, BUT ___________ DIFFER. know caps

(how do pathogens cause disease) Take Home on Clostridial Neurotoxins = BOTULINUM AND TETANUS TOXINS - "A SUBUNIT" = CLEAVES MEMBRANE FUSION COMPONENTS IN NEURONS AND THUS PREVENT NEUROTRANSMISSION. -"B SUBUNIT" = VERY SIMILAR; ~ BINDING SPECIFICITY (NEURONS) FOR BOTH TYPE TOXINS. - DIFFER: B&T TOXINS HAVE "OPPOSITE EFFECTS" [B = FLACCID PARALYSIS; T = SPASTIC PARALYSIS] BC ACT AT DIF. SITES (LOCALLY VS. CENTRAL NERVOUS SYSTEM).- TETANUS TOXIN (inhibit cellular trafficking) BOTULINUM TOXIN {inhibit membrane fusion} BOTULINUM NEUROTOXIN (BoNT) = MUSCLE RELAXANT; BOTULUS = SAUSAGE; note: asoc. w Botox = tx for a tmd, tmj + migranes. NEUROTOXINS PREVENT SYNAPTIC VESICLE FUSION AND THUS PREVENT NEUROTRANSMISSION. * KEY TO KNOW: Botulinum and Tetanus toxin both bind to same substrate. 1. B SUBUNIT OF BoNT & TeNT "BIND" SPECIFICALLY TO NEURONS . 2. NEURONS ENDOCYTOSE TOXINS. 3. ENDOSOME ACIDIFICATION INDUCES TOXIN TRANSLOCATION. 4. THE "S-S BOND"" GETS REDUCED, RELEASING THE 'A SUBUNIT' (ENZYMATIC DOMAIN) INTO THE CYTOSOL. 5. 'A SUBUNIT' CLEAVES SNARE PROTEIN COMPLEX COMPONENTS, PREVENTING NEUROTRANSMISSION.

How do pathogens induce the host to cause damage? know caps

(how do pathogens cause disease) A. Inflammation e.g. chronic inflammation during periodontitis B. Autoimmunity C. Immune complex deposition = MOLECULAR MIMICRY AND IMMUNE COMPLEXES: - Molecular mimicry = Immune reactions against microbial components inadvertently induce auto-antibodies. - e.g. S. PYOGENES strep throat -> RHEUMATIC FEVER, GLOMERULONEPHRITIS (pyogenes = fever). - Binding of auto-antibodies to self-antigen or microbe's antigen leads to deposition of soluble antibody-antigen (Ab-Ag, ("immune complex") on vessels. - When phagocytes try to clear the immune complexes, it induces inflammation impairing vessel function.

Injected Toxins (Molecular Syringes) know caps

(how do pathogens cause disease) DEDICATED SECRETION SYSTEMS CAN DIRECTLY INJECT TOXINS INTO TARGET CELLS

During Leukocyte activation, there is ENHANCEMENT OF? (must know)

1) Phagocytosis 2) Intracellular destruction of microbes and dead cells in phagolysosomes 3) Liberation of enzymes and reactive oxidative species that destroy microbes and necrotic tissue 4) Production of mediators

ACUTE RHEUMATIC FEVER is a consequence of what infection?

- KNOW: follows STREP THROAT caused by GROUP A streptococci (strep. pyogenes). - Characterized by carditis, polyarthritis, neurological disorder (St. Vitus' dance), rash. May be fatal, or cause severe damage to the heart valves. - KNOW: Can be PREVENTED by treating Strep throat with penicillin. Does not RESPOND to penicillin treatment (e.g. after person already has rheumatic fever aka a non-bacterial infection) - Rheumatic fever is thought to be an autoimmune disease, somehow evoked by infection by group A strep.

DEGRADATIVE ENZYMES IN DISEASE ("for your interest")

- Porphyromonas gingivalis is a keystone pathogen during periodontitis - P. gingivalis produces proteases called gingipains that cleave many substrates and are essential for virulence. [Hemoglobin: releases Fe (essential nutrient); Fibrinogen; MMP9 (indirect): bleeding and bone resorption; Complement: recruits neutrophils but impairs their antimicrobial activity] - Many other factors, e.g. hyaluronidase WHAT ROLE DOES DAMAGE PLAY IN DISEASE? 1. Creates new colonization sites: gingipains 2. Facilitates spread in host or person-to-person: gingipains 3. Generates nutrients: gingipains 4. Antagonizes host defenses: gingipains

Regulation of respiration genes by oxygen in facultative anaerobes 1) Aerobic growth, e- acceptor = oxygen = cytochrome oxidase produces H2O 2) Anaerobic growth, organic e- acceptor = fumarate or nitrate = fumarate reductase produces succinate, nitrate reductase produces ammonia. FNR = is the key regulator of respiration. Functions anaerobically as both activator and repressor MEMORIZE CHART!

.

1) Which of the following statements is TRUE regarding E. COLI lactose metabolism regulation: A. CcpA is used for negative control (repression) B. cAMP-CAP complex is for positive control (activation) C. Phosphorylation of lactose PTS enzyme II by Hpr~P D. Adenylate cyclase activity is regulated by oxidation E. All of the above 2. Which of the following statements is TRUE regarding E. Coli: A. Diauxic bacterial growth is observed when glucose is present with other sugars B. The PTS system is used to import many sugars into the cell C. An effector always interacts with a regulatory protein D. The same regulatory protein can function either as a repressor or an activator for gene expression regulation E. All of the above

1) A. is true for step mutans, but not true in this situation bc its E.Coli B. Is true = answer. C. Not true lactose doesn't come in thru PTS system, ahs its own dedicated permease. D. not true; Adenylate cyclase activity is regulated by phosphorylated enzyme 2 (not by oxidation. FNR is regulated by oxidation. 2. A. not ALWAYS true. when glucose + sucrose, no diauxic! B. False - other transport systems like lac permease exist. C. False - effector will modify function of regulatory protein, can inactivate it or activate it (saw examples of this). D - true. FNR is example of this (she couldve also shown us CAP-cAMP examples)

Neutrophil Granules

1) AZUROPHIL (PRIMARY) - large, dense. 2) SPECIFIC (SECONDARY) - smaller, less dense. fix confused what need to know... came after phagocytosis slides... see picture

Memorize: Regulatory Mechanisms of Lactose Metabolism - What are the "states" of each of these when (a) glucose and lactose are BOTH PRESENT, (b) only lactose is present. 1) Enzyme II for glucose 2) Lac Permease 3) Lac Repressor 4) Adenylate cyclase, cAMP production. 4) CAP-cAMP complex 5) Lac Operon Expression fix - if can, add to the E.Coli two carbon sources fc.

1) Enzyme II for glucose = unphosphorylated (both lactose and glucose present), phosphorylated (only lactose present). 2) Lac Permease = inactive [INDUCER EXCLUSION] (both present), active (only lactose). 3) Lac Repressor = Active [NEGATIVE REGULATION] (both present); Inactive (only lactose). 4) Adenylate Cyclase, cAMP Production = Inactive/low (both present); active/high (only lactose) 5) CAP-cAMP complex = Inactive (both present); active [POSITIVE REGULATION] (only lactose) 6) Lac Operon Expression = Off (both present); On (only lactose). Basically, when both are present, you want to turn off or inactivate stuff so that you can prevent lactose use when glucose is also avaliable!

1. Metastatic calcifications are caused by? 2. Dystrophic calcifications are found where? Caused by what? What is deposited?

1. Caused by hypercalcemia - Most often from hyperparathyroidism - Osteolytic tumors with mobilization of Ca2+ and PO4- (ex. Paget disease of bone) - Vitamin D disorders - Renal failure - Excess calcium intake ( ex. Milk-alkali syndrome - nephrocalcinosis-renal stones caused by milk and antacid self-therapy for peptic ulcer). NOTE: Metastatic calcifications Occurs in normal tissues. 2. Dystrophic Calcifications - Intracellular or extracellular; gritty. - ENCOUNTERED IN AREAS OF NECROSIS ( Occurs in dead or dying tissues). - DEPOSITION OF CALCIUM IN TISSUE ALTERED BY INJURY = Areas of old trauma, Tuberculosis lesions; Affects crucial organs, heart valves, vessels -> Scarred heart valves & Atherosclerosis. - NOT CAUSED BY HYPERCALCEMIA BUT CALCIUM ATTRACTED BY RELEASED MEMBRANE PHOSPHATES, SERUM CALCIUM CONCENTRATION NORMAL. - e.g. pic of CALCIFIC STENOSIS OF AORTIC VALVE - e.g. pic of PERIAPICAL AND PULPAL PATHOSES

Mechanisms for "cellular aging"? (know this path 2/14 red)

1. DNA DAMAGE 2. DECREASED CELLULAR REPLICATION - TELOMERE ATTRITION- LINEAR CHROMOSOMES CAN NOT REPLICATE; BECOME SHORTER AND ENDS APPEAR BROKEN; ACTIVATES CELL CYCLE ARREST AND TUMOR SUPPRESSOR GENES. 3. DEFECTIVE PROTEIN HOMEOSTASIS

Definitions of the types of atrophy: 1. Disuse Atrophy 2. Ischemic atrophy 3. Endocrine atrophy 4. Senile atrophy 5. Denervation atrophy

1. Disuse atrophy - From inactivity of an organ or part (Reversible); ex. Arm in a cast results in loss of muscle due to lack of use 2. Ischemic atrophy - Gradual decrease in blood supply; ex. Bed ulcers (pressure atrophy) 3. Endocrine atrophy - From deprivation of hormonal stimulation; ex. Lactating breast and uterus after menopause. 4. Senile atrophy - Reduced blood supply due to atherosclerosis; ex. Brain and heart affected 5. Denervation atrophy - ex. Damage to axons supply muscle; lack of stimulation

TRUE OR FALSE: 1. Toxins are infectious. 2. Inhibiting toxins can prevent disease. 3. Blocking toxin entry into cells will prevent disease. 4. Blocking A:B toxin entry into cells can prevent disease.

1. False 2. True 3. False 4. True

ADAPTATIONS TO ENVIRONMENTAL STRESS: 1. HYPERTROPHY 2. HYPERPLASIA 3. ATROPHY 4. INVOLUTION 5. METAPLASIA know definitions bc in red on 2/15 path.

1. INC in the SIZE of an organ or tissue due to an INCREASE in the SIZE of cells. (e.g. work hypertrophy of masseter muscle). 2. INC. in the SIZE of an organ or tissue caused by an INC. in the NUMBER of cells (Only occurs in cells that can divide e.g. gums- Neurons and heart muscle not able to divide) 3. DEC. in the SIZE of an organ or tissue resulting from a DECREASE in the MASS of pre-existing cells. (Results from: Disuse, Nutritional or oxygen deprivation, Diminished endocrine stimulation, Aging, Denervation) - Can be generalized or localized, pathologic or physiologic (common during development); Result from decrease protein synthesis and increase protein degradation (Ubiquitin pathway responsible) 4. Physiological DEC. in the NUMBER of cells to their normal NUMBER, ex. Thymus gland involutes during adolescence (childhood-> adult difference), ex. Myometrium involutes during post partum. = Form of atrophy, Involves apoptosis of cells. 5. Replacement of one differentiated cell by another in a hostile environment. Can be reversible. 5a. Squamous metaplasia - ex: Columnar ciliated epithelium to squamous epithelium at the squamocolumnar junction of the cervix - Associated with chronic irritation = ex. Bronchi with long term use of tobacco, Vitamin A deficiency. 5b. Osseous (cartilaginous) metaplasia = Formation of new bone (cartilage) at sites of tissue injury, ex. Ill-fitting dentures 5c. Myeloid metaplasia (Extramedullary hematopoiesis) = Proliferation of hematopoietic tissue in sites other than the bone marrow (liver or spleen), ex. Hepatosplenomegaly due to sickle cell anemia 5d. Examples of metaplasia. - Cervix = Columnar epithelium to squamous epithelium at squamocolumnar junction - Esophagus = Squamous epithelium to mucus-secreting glandular environment, Response to gastric esophageal reflux (GERD).

REVERSIBLE CELLULAR CHANGES AND ACCUMULATIONS know this red in path 2/14

1. Only the cytoplasm is involved, Water accumulates and the cell swells (hydropic degeneration / hydropic change / vacuolar degeneration) - e.g. LEUKOEDEMA fix not sure if that's what pic was references 2. Fatty change (Steatosis, Fatty metamorphosis - fatty liver change) that Results from imbalance among the uptake, utilization, and secretion of fat 3. Hyaline change (Homogeneous, glassy, eosinophilic appearance in H&E stained tissue sections, Caused most often by nonspecific accumulations of proteinaceous material, ex. Glomeruli tufts in diabetic glomerulosclerosis) 4. Argyria (silver poisoning) - note: Can cause permanent gray discoloration of skin and conjunctiva 4. Melanin Pigmentation e.g. LABIAL MELANOTIC MACULE spot on lip (Accumulation of endogenous pigments) is most common endogenous pigment, black or brown in color, formed from tyrosine via tyrosinase, synthesized in melanosomes of melanocytes, located in BM of epidermis and choroid of the eye. Can be present in oral cavity: Generalized pigmentation, Melanotic macule, Melanocytic nevus, Melanoma. 5. Lipofuscin (Lipochrome) = WEAR AND TEAR PIGMENT (commonly accumulates in elderly patients, found most often with hepatocytes, myocardial cells, and brain), BROWN ATROPHY (accumulation of lipofuscin and atropohy of ogans. yellowish to light brown, fat soluble pigment; mixture of lipids/phospholipids and protein; sign of free radical injury - e.g. STRIATED MUSCLE AND LIVER. 6. Bilirubin = Catabolic product of the heme moiety of hemoglobin and myoglobin. - pathological condition (Jauntice) = accumulation in blood, sclera, mucosa, organs. Yellow discoloration. Ex. Hemolytic Jaundice (destruction of RBCs), Obstructive Jaundice (intra/extrahepatic destruction of biliary tract), Hepatocellular Jaundice (parenchymal liver damage). 7. Hemosiderin - Iron-containing pigment; aggregates of ferritin; Appears as golden-brown amorphous aggregates in tissues [PRUSSIAN BLUE DYE - POSITIVE BLUE COLOR STAIN REACTION] ; Exists normally in small amounts as physiologic iron stores within tissue macrophages of bone marrow, liver, and spleen; Excess accumulation can be localized (bruise) or systemic (hemosiderosis, can be caused by: multiple blood transfusions, hemolytic anemia, hemolysis). - picture of HEMOSIDERIN IN LIVER CELLS

How do pathogens cause damage/disease? know this

1. Pathogen (pathogen-derived factors) directly causes damage: a. Growth in tissues [e.g.i. over-growth in normal niche: Candida albicans yeast infection; & e.g.ii. Growth Growth outside normal niche: S. gordonii and dental work] b. Growth inside cells - coopts cell functions or kills cell. Cell death (necrosis) can induce inflammation that exacerbates disease (e.g. cell infected with Chlamydia -> Chlamydia-induced trachomatis of eye). c. TOXINS (know this, other fc) (i) membrane-active (ii) AB toxins (iii) INJECTED TOXINS (MOLECULAR SYRINGES) 2. Pathogen induces HOST to cause damage A. Inflammation e.g. chronic inflammation during periodontitis B. Autoimmunity C. Immune complex deposition

Staphlococcus - types/ dif. species?

1. Staphylococcus aureus = e.g. MRSA is a form of this. = positive coagulase enzyme (plasma clot) = can do mannitol fermentation - ENCOUNTER: colonizes 20-30% of people 2. Staphylococcus epidermidis = NO coagulase enzyme and cannot do mannitol fermentation. - ENCOUNTER: commonly colonizes humans. 3. BOTH: - ENCOUNTER: Staph colonize the skin, nose and mucous membranes. Staph tolerate high salt and can grow in salt concentrations that inhibit growth of other bacteria (nose and skin are salty where staph can grow) Break down fatty acids found on skin (allow for grow on skin). Spread from person to person by hand contact (HAND SHAKE). - ENTRY, SPREAD, MULTIPLICATION, DAMAGE Enter deep tissues via a wound. The highly vascularized organs [bones, lungs, kidneys] are sites of abscesses in hematogenous (in blood) spread. The area of inflammation usually remains LOCALIZED [deep wounds here localized, vs. w strep they spread!] - DISEASES CAUSED BY STAPH: (Usu. AUREUS species): 1. Localized = Abscesses (BOILS), wound infections, Osteomyelitis (boil in the bone). 2. Generalized = Bacteremia w. metastatic abscesses (bacteria get into blood, then caused localized abscesses at dif locations in body which is the metastatic part), Endocarditis. 3. Caused by Toxins: Scalded skin syndrome--exfoliatin; Toxic shock syndrome; Gastroenteritis. 4. ONE OF THE MAJOR CAUSES OF BACTERIAL INFECTIONS IN THE ORAL CAVITY - INFECTED ROOT CANALS, OSTEOMYELITIS OF THE JAWS, FACIAL CELLULITIS, DENTOALVEOLAR ABSCESSES. VIRULENCE FACTORS OF STAPHYLOCOCCI 1. Capsule, cell wall components (resist phagocytes) 2. Protein A 3. Leukocidin-- kills neutrophils 4. Catalase-- reduces killing by neutrophils (by breaking down H2o2) 5. Coagulase--causes plasma to clot 6. Toxins (made by the bacteria) 6a. Scalded skin syndrome--exfoliatin 6b. Toxic shock syndrome 6c. Food poisoning--enterotoxins

1. CD3 2. CD4 3. CD8 4. CD28 5. B7 6. CD40 7. CD40L

1. TCR Signal Transduction (expressed on all T cells) 2. Binds MHC II 3. Binds MHC I 4. Co-stimulatory molecule on T cell (binds B7). 5. co-stimulatory molecule on APCs (binds CD28) 6. Co-stim molecule on APCs ** 7. Co-stim molecule on T cells ** **IMP FOR B CELL ACTIVATION: making memory B cells, Class Switch Recombination, and Somatic Hypermutation (for Increased Affinity response)** = CD40-CD40L interaction = THIS IS FOR THYMUS-DEPENDENT ANTIGENS. CD40 on B cell; and CD40L on Helper T cell. (helper T cell gives second signal to activate the B cell). Interact => Activates B cell, now can become memory B cells, undergo CLASS SWITCH Recombination. fix add other .c. to this. need to know top sentence from review lecture.

What are the two possible types of Leukocyte Responses when they are killing microbes? Which is more effective?!

2 types of microbial killing: [KNOW PATH 2/15] 1) OXYGEN-DEPENDENT 2) OXYGEN-INDEPENDENT = LESS EFFECTIVE.

2. A child with recurrent infections is shown to have a mutation that results in a defective CD3 molecule. The infections are not surprising since the function of normal CD3 is to a. bind class II MHC molecules b. bind CD4 molecules on Th cells c. provide signal transduction from the TCR d. serve as a pattern recognition receptor for LPS e. cause the degranulation of mast cells and basophils

2. C All T cells have a TCR complex that includes the CD3 molecule. CD3 transmits activation signals to the cell when the TCR binds antigen (peptide plus MHC).

3. Which of the following statements is INCORRECT? a. Most protein antigens are thymus-dependent b. Bacterial capsular polysaccharides are typical thymus-independent antigens c. CD8+ T cells recognize peptides bound to MHC class I. d. T cells only recognize epitopes on proteins. e. Infection with a virus will result in CD4+ T cells specific to only one epitope of the virus.

3. E All microbes have many epitopes and infection results in a polyclonal response. This is true of B cell and T cells.

4. A CD4+ T cell recognizes a particular virus peptide on the surface of a dendritic cell. Of the following, which molecule might be "presenting" this peptide to the CD4+ T cell? a. HLA-A b. HLA-B c. HLA-C d. HLA-DQ e. Beta-2 microglobulin

4. D CD4+ T cells recognize foreign peptides associated with (bound to) MHC class II molecules. In humans, MHC class II molecules are HLA-DP, HLA-DQ, and HLA-DP. What are the names of the three MHC class I molecules in humans?

INFECTIVE ENDOCARDITIS is caused by? HOW CAN U (DENTIST) REDUCE RISK IN UR PATIENT?

= Infection of the inner surfaces of the heart and valves. Subacute endocarditis patients have mild fever, anorexia, weakness, weight loss for several weeks duration. = 60% of infections are caused by VIRIDANS streptococci. - PREDISPOSING FACTORS = Usually affects heart valves whose surfaces have already been damaged; Rheumatic fever; Congenital heart disease/defects; Degenerative disease; Mitral valve prolapse; Prosthetic heart valves; Previous infective endocarditis; Post-transplant valvulopathy. = ALSO CAUSED BY: flossing or dental procedure => blood in mouth => secretions from mouth can enter blood including viridans strep (main in oral) => "BACTEREMIA" aka presence of bacteria in blood, and this along w/ "predisposing factors" => cause infection e.g. endocarditis. - Recommend maintaining GOOD ORAL HEALTH (no bleeding) to reduce risk endocarditis. AHA recommends for patients w cardiac conditions that place them at high risk = "Prophylaxis w. antibiotics" for all dental procedures involving manipulation of gingival tissue or the periapical region of teeth or perforation of oral mucosa".

What happens right BEFORE engulfment (phagocytosis)?

= MANY MECHANISMS OF MICROBICIDAL (KILLING MICRO-ORGANISMS) = 1) Antimicrobial activity begins before the microbe is completely engulfed. Primary mode of killing prior to engulfment is the oxidative burst, in which toxic oxygen free radicals are produced. = key player is NADPH Oxidase, which forms a complex ("NADPH oxidase complex") in RESPONSE to MICROBIAL adhesion -> generation of OXYGEN FREE RADICALS = Reactive Oxygen Species (ROS). 2) Suicide by NADPH oxidase releases antimicrobial "NETS" - DNA histone complexes killing microorganism (traps within) - "histones associated with NETS are antimicrobial" 3) Oxygen-DEPendent mechanisms occur PRIOR to engulfment (see other fc) 4) Antimicrobial PEPTIDES: "Defensins", Cathelicidin

CD3 know all this

= count number of cells with CD3 on surface to figure out how many (#) of T cells you have. = function is to transduce signal to nucleus (signal transduction molecule). = on each T cell receptor; so when T cell recognizes antigen, the signal actually goes through the CD3 molecule. ("All T cells express CD3 as part of the CDR complex"].

Celebrex

= cox-2 inhibitor avaliable for use - tx inflammation, pain, fever (oral pain control). = 2D6 enzyme inhibitor (codeine to morphine), thus reducing the analgesic effect of codeine.

ANTIPYREXIC actions of Nsaids?

= fever reduction . NSAIDS, Aspirin, Acetaminophen inhibits the action of prostaglandins (always starts with this for these drugs!) -> thermoregulatory center resets and body figures out how gonna get heat / temp back to normal in body.

TGF-Beta

= inhibitory cytokine of T cells (e.g. Treg who produces it!) notes: Treg (t-regulatory cells) => TGF-beta & IL-10=> act on: other lymphocytes; inhibits function of other sets of T cells )TH17, TH2, TH1) and non-T cells. [if u have genetic defect or mouse without Treg -> you get autoimmunity, and CANT turn off the immune response].

Changes of Injury - define: 1. Congestion 2. Edema 3. Hemorrhage 4. Thrombosis 5. Embolus 6. Cellular Infiltration 7. Fibrosis

= know all of these & their defintions. 1. CONGESTION - INCREASE BLOOD FLOW WITHIN VESSELS; VESSELS DILATED AND PACKED WITH RED BLOOD CELLS (ERYTHROCYTES). 2. EDEMA - INCREASE INTERSTITIAL FLUID WITH WIDENED SPACE BETWEEN INTERSTITIAL COMPONENTS; CAUSES SWELLING EXCEPT IN BONE 3. HEMORRHAGE - ACCUMULATION OF BLOOD OUTSIDE VESSELS; EXTRAVASATION OF RED BLOOD CELLS INTO TISSUES OR EXTERNAL SURFACE 4. THROMBOSIS - CLOT WITHIN A BLOOD VESSEL FORMED DURING LIFE . 5. EMBOLUS - DETACHED INTRAVASCULAR SOLID, LIQUID OR GASEOUS MASS; CARRIED IN BLOOD TO SITE DISTANT FROM POINT OF ORIGIN - EX. FAT, BUBBLE OF AIR OR N₂, ATHEROSCLEROTIC PLAQUE, TUMOR, BONE MARROW, FOREIGN BODIES, THROMBUS. 6. Cellular infiltration (e.g. from inflammation usually) 7. Fibrosis (keloids)

In bacteria many genes are regulated at the transcriptional level because: A. It is expensive to express genes for unrequired functions so for optimal growth only necessary functions are expressed. B. There are not enough pre-cursors in a cell to make all of the proteins encoded in their genome. C. The lactose repressor of E.coli is only active when lactose is present. D. Cyclic AMP is required for regulation in E. Coli and S. mutans E. Bacteria found at different sites of the human body are always in exponential growth phase.

A

Which of the following disease states is caused by the formation of immune complexes that induce inflammation? A. Glomerulonephritis B. Spastic paralysis C. Flacid paralysis D. Cholera E. Toxic Shock Syndrome

A

Associated with degeneration and loss of function of many cellular systems?

AGING (know this association) path 2/14 - Cumulative environmental exposure to a causative agent - Risk factor for chronic diseases (Cancer, Alzheimer disease, Heart disease)

Naproxen Sodium

ALEVE has longer half life (than ibuprofen) so give LOADING DOSE (2 to start). - similar efficacy to ibuprofen, but longer duration of action (up to 7 hours). - dosing: OTC Alleve 200 mg tab - dose 2 to start (loading dose), then 1 tab every 8-12 hours up to 3 tabs per day. - RX: ANAPROX (275mg tab) or ANAPROX (DS) (550 mg/tab) - dose 550 mg to start, then 275 mg every 6-8 hours or 550 mg every 12 hours, not to exceed 1375 mg in 24 hours.

Which of the following statements is TRUE? A. Diauxic bacterial growth is observed when glucose is present with other sugars. B. An effector always interacts with a regulatory protein. C. An effector always activates a regulatory protein. D. The same regulatory protein can function either as a represor or an activator for gene expression regulation.

A. False - not always. S. mutans in glucose and sucrose. B. True C. False - sometimes but not always: cAMP actiates CAP; Allolactose inactivates Lac repressor; O2 inactivates FNR. D. True - FNR can be an activator or a repressor depending on where it binds in the promotor region.

ibuprofen

ADVIL, MOTRIN, NUPRIN. - Avaliable OTC in 200 mg tablets or caplets, or 600-800 tablets by prescription. - Analgesic ceiling: 400-600m, with higher doses having increased anti-inflammatory effects (as well a the pain relief). - Dosing 200-800mg, every 4-6 hours for at least the first 24 hours, not to exceed 3200 mg (under medical supervision, otherwise OTC limit is 1.2 gr). - IV form = CALDOLOR (know this)

What adaptation to environmental stress is "marked by the presence of AUTOPHAGY?

ATROPHY responds to autophagy (intracytoplasmic vacuoles containing debris) - Cell eats its own contents; - Survival mechanism due to nutrient deprivation; - Prominent in atrophic cells-recycles essential metabolites and clear cellular debris; - Three forms: Chaperone-mediated, Micro, Macro (major form). know this, red (autophagy = atrophy)

A mutation in the gene encoding the cholera toxin prevents the A-subunit from interacting with any host protein. Which of the following statements regarding the resulting mutant toxin is TRUE? A. The toxin can enter cells and cause diarrhea. B. The toxin can enter cells but cannot cause diarrhea. C. The toxin cannot enter cells but can cause diarrhea. D. The toxin cannot enter cells or cause diarrhea. E. None of the statements are correct.

Answer: B

GI EFFECTS OF NSAIDS? Aka a side-effect of prolonged use or if give patient who has GI issues and you give them NSAID?

Aspirin - increases stomach acid by blocking prostaglandin (PG) synthesis; decreases PG maintenance of protective mucous barrier -> increased acid secretion in stomach (stomach acid pH = 2). Gastric Erosion results from: 1. back diffusion of acid causes ulceration. 2. Sequestration of salicylic acid in epithelial lining due to ionization factors.

Anti-Platelet effects of NSAIDs?

Aspirin results in prolonged bleeding time. Irreversible blocking THROMBOXANE A2 {promotes platelet aggregation} in COX1 pathway [note: NSAIDs reversible block of this]. & Reversible blocking PROSTACYCLIN (PGI2) {blocks platelet aggregation} in COX2 pathway. - low dose aspirin used daily for this reason s.t. don't form clots! VIOXX (cox2 specific) blocks Prostacyclin (PGI2) resulting in increased RISK of THROMBOSIS (inc. platelet aggregation).

KETOROLAC (TORADOL)

Avaliable in Oral and IV forms. Limit dosing to 5 days. Indicated for short-term management (up to 5 days) of MODERATE TO SEVERE PAIN, as an NSAID alternative to injectable narcotics. The most problematic in terms of GI ulceration. Avoid in patients w renal insufficiency. Also avaliable Intranasal form (e.g. for patient with pain following third molar impaction surgery) .

Pathogenic bacteria may avoid killing by phagocytes in any of the following ways EXCEPT: A. Disrupting signaling pathways of the phagocyte. B. Increasing phagosome-lysosome fusion. C. Escaping from the phagosome. D. Inhibiting opsonization by possessing a capsule. E. Killing phagocytes using toxins.

B

Which of the following statements about phagocytosis is FALSE? A. Release of DNA by neutrophils is anti-microbial. B. After binding bacteria, neutrophils are resistant to being killed by oxygen free radicals. C. One step in phagocytosis is engulfment of a particle. D. Phagocytosis results in formation of membrane-bound compartment. E. Phagocytosis is receptor driven.

B

The most common cause of subacute bacterial endocarditis is? A. Staph. Aureus B. alpha-hemolytic Strep (viridans strep) C. beta-hemolytic strep (strep. pyogenes) D. Escherichia coli E. Pneumococcus (strep. pneumoniae)

B.

A mutation in the gene encoding the cholera toxin prevents the B-subunit from interacting with ANY host protein. Which of the following statements regarding the resulting mutant toxin is TRUE? A. The toxin can enter cels and cause diarrhea. B. The toxin can enter cells but cannot cause diarrhea. C. The toxin cannot enter cells but can cause diarrhea. D. The toxin cannot enter cells or cause diarrhea. E. None of the statements are correct.

D

Phagocytes are defined by which property? A. Ability to be found in tissues B. Ability to present secrete cytokines. C. Ability to leave the circulation. D. Ability to phagocytose particles. E. Ability to bind oxygen.

D

Which of the following diseases is caused by a toxin that is NOT taken up by target cells? A. Cholera B. Botulism C. Tetanus D. Toxic Shock Syndrome E. None of the Above

D

NECROSIS - important difference from apoptosis? Most common type of necrosis? Other types and what's going on (the path)?

DEGRADATIVE/INFLAMMATORY REACTION AFTER INJURIOUS TISSUE DEATH - HYPOXIA, TOXIC CHEMICALS MARKED INFLAMMATORY RESPONSE: - LYSOSOMAL ENZYMES - DIGEST CELL MEMBRANES, DISRUPT CELLS - MACROPHAGES AFTER RELEASE OF CHEMOTACTIC FACTORS - DEBRIS REMOVAL BY PHAGOCYTIC MACROPHAGES General and Cellular Characteristcs: 1. HETEROLYSIS - Cellular degradation by enzymes EXTRINSIC to cell (ex. bacteria, leukocytes) - increased pink cytoplasm 2. Nuclear changes - light microscopy Progressive nuclear condensation with eventual disappearance of stainable nuclei. know these nuclear changes see pic. 2a. PYKNOSIS - "SHRINKAGE" OF NUCLEUS INTO SMALL, DEEPLY BASOPHILIC/BLACK CLUMPS OF CHROMATIN 2b. KARYORRHEXIS - "FRAGMENTATION" NUCLEUS INTO MULTIPLE SMALL BLACK DOTS/PIECES 2c. KARYOLYSIS - "FADING" OF NUCLEUS; LESS AND LESS BASOPHILIC UNTIL DISAPPEARS. TYPES: 1) COAGULATIVE NECROSIS [[e.g. acute myocardial infarction; chemical burn (aspirin)] = MOST COMMON TYPE = SUDDEN LOSS OF BLOOD SUPPLY TO ORGAN (ISCHEMIA): HEART AND KIDNEY (ARTERIES WITH LIMITED COLLATERAL CIRCULATION), ADRENAL GLANDS, NOT SEEN IN THE BRAIN = DENATURATION OF PROTEINS = EARLY STAGES W. PRESERVATION OF TISSUE ARCHITECTURE = HISTOLOGY w. GENERAL ARCHITECTURE WELL PRESERVED, Progressive nuclear condensation with eventual disappearance of stainable nuclei Increased pink cytoplasm ('eosinophilic'; 'glassy') "Ghost-like" structures. 2) LIQUEFACTIVE NECROSIS = DIGESTION OF TISSUE; GROSS = LIQUID; HISTOLOGY: SOFTENING AND LIQUEFACTION OF TISSUE; USUALLY ISCHEMIC INJURY TO THE CNS; USUALLY BACTERIAL INFECTION; ALSO SUPPURATIVE INFECTIONS (PUS FORMATION)(ACUTE INFLAMMATION) W. LIQUEFIED TISSUE DEBRIS AND INTENSE INFLAMMATORY RESPONSE OF NEUTROPHILS = ABSCESS (focal collection of neutrophils). 3) CASEOUS NECROSIS = MOST OFTEN SEEN IN TUBERCULOSIS = CHEESE-LIKE CONSISTENCY = HISTOLOGY: ARCHITECTURE NOT PRESERVED; AMORPHOUS PINK, GRANULAR; FEW NUCLEI (NO GHOST-LIKE APPEARANCE) = COMBINES FEATURES OF COAGULATIVE AND LIQUEFACTIVE NECROSIS = OCCURS AS PART OF GRANULOMATOUS INFLAMMATION (GRANULOMA) = COMPONENTS OF GRANULOMA: EPITHELIOID HISTIOCYTES, LYMPHOCYTES, & MULTI-NUCLEATED GIANT CELLS. e.g. at lung - pic. 4) GANGRENOUS NECROSIS = EXTENSIVE = INTERRUPTION OF BLOOD SUPPLY TO LOWER EXTREMITIES OR BOWEL (SECONDARY TO VASCULAR OCCLUSION) = MOST OFTEN BACTERIAL INFECTIONS = EITHER: (A) "WET" GANGRENE W. HETEROLYSIS AND LIQUEFACTIVE NECROSIS AND BACTERIA, OR (B) "DRY" GANGRENE W. COAGULATIVE NECROSIS WITHOUT LIQUEFACTION. (KNOW DIFFERENCE BETWEEN WET AND DRY!) - e.g. pic of NOMA. 5) FIBRINOID NECROSIS = SEEN ONLY BY MICROSCOPIC EXAMINATION = OFTEN ASSOCIATED WITH IMMUNE-MEDIATED VASCULITIS = CONNECTIVE TISSUE AND MUSCLE REPLACED BY HOMOGENOUS PINK MATERIAL RESEMBLING FIBRIN = EX. DEPOSITION OF FIBRIN-LIKE MATERIAL IN THE ARTERIAL WALLS 6) FAT NECROSIS = TYPES: KNOW TRAUMATIC TYPE IS SEVERE INJURY TO HIGH FAT CONTENT (EX. BREAST); other types = ENZYMATIC TYPE - ex. Acute pancreatitis (Complication of acute hemorrhagic pancreatitis; Proteolytic & lipolytic enzymes diffuse into inflamed tissue of pancreatic parenchyma; Attract calcium - fatty acids form calcium salts (saponification - soap formation) Histology: Necrotic fat cells, acute inflammation, hemorrhage & Calcium soap formation & Lipid-laden macrophages (enzymatic type)

What is damage? What role does it play in disease? Why do pathogens cause damage?

Damage = Physical harm that impairs normal function = Localized, distant, or systemic. What is damage good for?(Why do pathogens cause disease?) = 1. Creates new colonization sites, 2. Facilitates spread in host or person-to-person 3. Generates nutrients 4. Antagonizes host defenses. [e.g.: Streptococcus pneumoniae secretes enzymes to penetrate the nasopharynx epithelial barrier. Also secretes factors that inhibit phagocytosis (e.g. pneumolysin) and antibody function. Streptococcus pneumoniae = Normal constituent of the nasopharynx, Disease caused by spread to distal sites. e.g. Strep pneumonae meningitis - induced brain infarction (from nasopharynx to brain)] - PATHOGENS CAUSE DAMAGE TO THEIR HOSTS IN ORDER TO PROMOTE GROWTH (AVOID IMMUNE SYSTEM, CREATE NEW COLONIZATION SITES, GENERATE NUTRIENTS, FACILITATE SPREAD). - PATHOGENS CAUSE DAMAGE EITHER DIRECTLY (E.G. TOXINS) OR INDIRECTLY, BY INDUCING THE HOST TO CAUSE DAMAGE (E.G. INFLAMMATION, AUTOIMMUNITY) TOXINS ARE SECRETED *PROTEINS* THAT DISRUPT NORMAL CELLULAR FUNCTIONS AND THUS CAUSE DAMAGE. - DIVERSE ACTIVITIES AND MODES OF ACTION TOXINS WITH INTRACELLULAR TARGETS HAVE DIFFERENT MECHANISMS FOR CROSSING THE MEMBRANES - MECHANISM OF ACTION OF CHOLERA TOXIN, CLOSTRIDIAL NEUROTOXINS, SUPERANTIGENS

Glossary of Terms (lecture on ID damage): Define... 1) Damage 2) Endotoxin 3) Exotoxin 4) Enterotoxin 5) Neurotoxin 6) Molecular Mimicry 7) Immune Complex

Damage: physical harm so as to impair normal function Endotoxin: lipid-sugar component of Gram-negative bacteria cell envelope that can be very immunostimulatory Exotoxin: a toxin that is secreted into the extracellular milieu (vs. secretion system-injected toxin) e.g. AB toxins, degradative enzymes Enterotoxin: toxin that acts in the GI tract e.g. cholera toxin Neurotoxin: toxin that acts in the neural system e.g. tetanus and botulinum toxin Molecular Mimicry: antigenic similarity between antigens made by pathogens and host (self-)antigens. Antibodies or T cells induced to recognize the pathogen-specific antigen cross-react with self-antigen (autoimmunity). Immune Complex: complex made by antibody binding to soluble antigens. Large immune complexes are cleared away by phagocytosis, but small, soluble immune complexes become deposited on small blood vessels, where they can activate complement and induce damage.

Reactions of cells to REVERSIBLE injury?

Degeneration - Cell functions impaired but cell can recover. (path 2/15 know) Contrast to: Irreversible injury -> Cessation of all cell functions with cellular death, Apoptosis (Programmed cell death) or Necrosis (Tissue death with inflammatory reaction).

Diauxic growth curve in Gram-pos. Streptococcus MUTANS with glucose and lactose

Diauxic growth curve with a two different carbon sources (e.g. Glucose & lactose) in Gram-positive Streptococcus mutans = looks same as that of E.coli (gram negative) aka it also uses glucose first, BUT has different mechanisms of how it uses glucose first: - No CAP-cAMP control - When glucose is present, inducer exclusion occurs and inactives Lac permease (through Hpr instead of Enz II) - CcpA (KNOW) is a REPRESSOR of the lac operon in S. mutans - Fructose-1,6-P2 (from glycolysis) activates CcpA (indirectly).

Killing mechanisms of CD8"T cell?

HAPPENS AFTER U'VE turned on CD8"T cell (activated / effective/ killer / cytotoxic T cell CD*) 1) Perforin channels (made by CD8) placed into target cell; allowing Granzymes enter target cell and induce apoptosis of target cell. 2) Activated CD8+T cell will express Fas L, interaction with Fas (death receptor) on Infected cell, results in apoptosis [note: many of cells already have fas death trigger there, and the cell that can activate that trigger is the CD8"T cell w fas ligand).

Which statement about bacteremia is TRUE? A. Bacteremia can never occur after dental procedures. B. Normal oral flora rarely contains Staphlococci. C. The presence of non-pathogenic bacteria in the blood is normal. D. The term sepsis refers to the presence of bacteria in the blood. E. Viridans Streptococci can spread from the oral cavity into the bloodstream.

E. Viridans Streptococci can spread from the oral cavity into the bloodstream. Bacteremia frequently occur after dental procedures if gums start bleeding; something can get into blood from mouth. Normal oral flora usually contains Staphlococci. Blood is normally sterile (non-pathogenic bacteria in blood is abnormal). Bacteremia = presence of bacteria in blood. Sepsis = bacteria in tissues.

Allolactose, cAMP, and Fructose-1,6-BP are examples of what?

EFFECTORS. They convert active regulatory proteins into inactive regulatory proteins. 1. Active Lac Repressor <--allolactose--> inactive "". 2. Active CAP activator <----cAMP---> inactive. 3. Active CcpA repressor <---Fructose-1,6-BP----> inactive. notes: We talked about lac operon I in E. coli, and in S. mutans To be a transcriptional regulator -there must be a way to control it's activity other they would always be in one confirmation. Effector are necessary to toggle the switch. We talked about allolactose CcpA Turns in to aREPRESSOR only in the presence of F16bP

HYPOXIC CELL INJURY Early Stage? Late stage signs of damage include formation of?

Early Stage: - Mitochondria - decreased oxidative phosphorylation and ATP synthesis; Decreased ATP availability consequences -> FAILURE OF CELL MEMBRANE PUMP [Increased intracellular Na+ and water and decreased intracellular K+, cellular and organelles swelling] & CELLULAR SWELLING (HYDROPIC CHANGE) - LARGE VACUOLES IN CYTOPLASM [Swelling of ER (EARLY reversible EM change); Swelling of the mitochondria (LATE irreversible EM change) that progresses from reversible to irreversible . LATE STAGE: Signs of damage include formation of: - MYELIN FIGURES (WHORL-LIKE STRUCTURES PROBABLY ORIGINATING FROM DAMAGED MEMBRANES) - CELL BLEBS (CELL SURFACE DEFORMITY MOST LIKELY CAUSED BY DISORDERLY FUNCTION OF THE CELLULAR CYTOSKELETON) -

Why do we say that MHC is polymorphic? (think abotu vaccines to dif people)

Flu vaccine -> same protein in arm to both of us, but because MHC is polymorphic: my MHC will select one distinct goru of peptide and yours will select a distinct dif group (some overlapping) of peptides from the antigenic proteins in that vaccine. POLYMORPHIC = many different alleles at each HLA locus; and MHC is the most polymorphic system in biology. MHC I = HLA-A, B, C (expressed in ALL nucleated CELLS - so every person has 6 dif HLA molecules from MHC1 locus [bc 3 of these from mom + 3 from dad]) MHCII = DP, DQ, DR. - different forms of HLA bind different peptides. e.g. HLA-A each form will bind a different type of peptide (they are not antigen specific, but there is a certain residue in the peptide that it'll bind) for instance HLA-DR4 [mhc class 2 is DR] will bind (processed) peptides 35-48, but then HLA-DP2 [also class 2 mhc] will bind (processed) peptides 110-122. - WHY NOT BIND SAME MHC? Then we would all bind to the same proteins/peptides. A virus would very quickly mutate every peptide it could to try to make it different so that the MHC couldn't see it. The fact that there are SO many of these (polymorphic), a virus just cannot do that (wouldn't get that selection) - will go over this again next time.

Superantigens - know for boards and exam

Food poisening, other microbes, can cause massive release of cytokines. BIND TO BOTH MHC CLASS 2 AND T-CELL RECEPTOR, NON-SPECIFICALLY. - Superantigens (abnormal molecules have evolved to trigger/) activate huge numbers of T cells resulting in massive production of cytokines by CD4+ T cells - often referred to as a "cytokine storm" Examples = Staphylococcal enterotoxins (SEs) cause food poisoning; *& Toxic shock syndrome toxin-1 (TSST-1) from Staph. aureus

Streptococcus - types (encounter, entry, spread)? hemolytic?

Gram positive Coccus 1. Streptococcus pyogenes = Group A streptococci - β-hemolytic {completely translucent when bact. colony on plate -> greater ability hemolysis of RBCs}. - Strep throat - Rheumatic fever - CLIN STREP SWAB: pos. for Group A streptococci: Classified into "Lancefield groups" based on carbohydrate antigens called C-carbohydrate β-hemolytic. - ENCOUNTER: Group A streptococci colonize the skin and mucous membranes. Are spread by infected droplets from person-to-person, often asymptomatically. - ENTRY: The bacteria adhere to epithelial surfaces, e.g. in the throat. Lipoteichoic acid, a constituent of the Gram positive cell surface, is an ADHESIN which makes the organism sticky. - SPREAD (depends on how the infection was acquired): (a) Skin and mucous membrane infections usually localized E.g. in the throat, infection usually remains localized. (b) Wound infections in deeper tissue (e.g. surgical wounds, battle wounds) may spread rapidly. - Streptococci secrete a number of digestive enzymes including proteases, hyaluronidase and DNAase. - Pus is usually thin and runny. MULTIPLICATION: M protein and hyaluronic acid capsule help streptococci resist phagocytosis. M protein binds host molecules that prevent complement deposition on the bacterial surface. Interferes with opsonization. Hyaluronic acid capsule interferes with attachment of phagocytes. - DAMAGE: Damage may be caused by intense inflammatory response.Streptococci also produce many toxins, such as streptococcal pyrogenic exotoxins [SPEs] (associated with scarlet fever and shock-inducing infections). SPEs act by influencing host responses. - DISEASES: Strep throat (culture growing for strep pyogenes, tx to prevent RF), tonsillitis; Scarlet fever (strep throat w. diffused rash); Pyoderma = these remain localized, persons life is not at risk. - INVASIVE DISEASES: Cellulitis (strep infection of subcutaneous tissue), Necrotizing fasciitis (flesh-eating bacteria) = serious infections bc spread rapidly (hard to get antibiotics in there before spread serious, may result in need for amputation). - CONSEQUENCES OF INFECTION W STREP (w.o tx) = Nonsuppurative (non-pus) sequelae: Rheumatic fever, Glomerulonephritis. 2. Viridans streptococci - α-hemolytic {partially translucent when bact. colony on plate -> less ability hemolysis RBCs} = α-hemolytic, not sensitive to P disk (pyogenes are) 30-60% of the normal oral flora E.g. Streptococcus mutans - CARIES (plaque) - Endocarditis - Most common cause of subacute bacterial endocarditis. 3. Streptococcus pneumoniae = (Pneumococcus) - α-hemolytic - Pneumonia - Meningitis - Otitis

Mast cells and basophils are sources of? must know path 2/15

HISTAMINE (pre-formed and stored in mast cells, basophils). Acute Inflammation. IgE binds to Fc-epsilon-Receptor on Mast Cell => Triggers Histamine release. [can also be triggered innately, example given is adaptive response]. - know this immuno review.

Bacteria using two different carbon sources - type of growth curve? If Lactose & Glucose, which is used up first and why? DEFINE OPERON

KNOW: why glucose is used first, why production of lactose metabolism enzymes depends on the presence of lactose, (3) what mechanism prevents lactose utilization when glucose is avaliable, why is there a lag btwn utilization of glucose and that of lactose. 1) Growth Curve will be different: Lag phase -> exponential -> stationary -> EXPONENTIAL AGAIN (versus if just gave single carbon source e.g. glucose, after stationary would see the bacterial growth curve go down bc runs out of nutrient... which is normal). - Lag Phase = btwn utilization of glucose & "" of lactose, bc proteins that need to digest the lactose need to be "transcribed"/created. - PLATEAU in lactose because it takes some time for the lactose to be brought in and induction of enzymes 2) Glucose will be used up first (as source), then lactose ("E.coli has evolved to do this" - glucose is used up FIRST bc "ECONOMICS of SUGAR METABOLILSM" less steps for metabolizing glucose via glycolysis (to pyruvate), versus to metabolize lactose u need extra steps + genes are REGULATED/NOT EXPRESSED ALL THE TIME. -- "Lac Operon" in E.coli has both LacY gene encodes Lac Permease (need to get lactose into cell via this) and Lac Z gene encodes beta-galactosidase (once inside cell, need this to convert lactose into allolactose* (lactose present) or galactose (or glucose) [...and then extra time need glucose outside cell to go into glycolysis]. REPRESSORS: - Lac I, when lactose ABSENT, codes for Lac REPRESSOR, which binds to operator region (downstream of promotor) and prevents RNA polymerase from binding promotor (and doing transcription of the lactose metabolizing enzymes...bc dont have lactose to break down duh). Lac repressor is OPERON-SPECIFIC. - In presence of lactose, ALLOLACTOSE binds to the repressor and prevents the repressor from binding to the operator. So, now RNA polymerase can bind promoter and initiate transcription = bc u have lactose and wanna metabolize it.

MEDIATORS OF APOPTOSIS? know this red on slides 2/14 path

MEDIATED BY A NUMBER OF GENES AND THEIR PRODUCTS - BCL-2, BCL-XL = Gene product inhibits apoptosis (prevent leakage of cytochrome-c). - and others including (not red on slide): Bax/Bak, and p53.

MHC Class 1 vs. MHC Class 2 - where are each expressed? What are the genes and proteins associated with the MHC molecules? Human MHCs? know this! don't need to know structure except that class 2 differs.

MHC Class 1 = ALL NUCLEATED CELLS = HLA-A, B, C (3 from mom, 3 from dad... so each cell has two HLA-A one from mom and one from dad) are the Human Class 1. = process ENDOGENOUS ANTIGEN (in a virally infected cell). MHC CLASS 2 = APC'S (DENDRITIC CELLS, MACROPHAGES, B CELLS) = HLA-DP, DQ, DR (3 from mom, 3 from dad) are the Human Class 2 = processing of EXOogenous antigen (outisde the cell, floating around) = = have a PEPTIDE BINDING GROOVE (can bind peptide and mhc all together). IMP - APC'S ARE NUCLEATED CELLS -> HAVE BOTH MHC1 AND MHC2 (BOTH HUMAN CLASSES ALSO!). MHCs = are NOT antigen specific = Major Histocompatibility Complex = MHC COMPLEX (located all together has genes for both classes!) is what encodes both class 1 and class 2. - located on 6th chromosome in humans = the most POLYMORPHIC system in biology: many different alleles at each HLA locus. (Recall: e.g. flu vaccine puts same protein in arm to both of us, but bc MHC is polymorphic, my MHC will select a distinct dif group (some overlapping) of peptides from the antigenic proteins in that vaccine, than yours)= imp for TRANSPLANTS - [Haplotype = From your parents, there are 4 "possible combinations" you can get (bc dad has 2 strings MHC, and mom has 2 strings MHC).] Consider 4 sibings and the 4 diferent possibilitees of MHC that you get. So if you need a kidney and you want it to be HLA identical to u bc you don't wanna reject it, and you have a sibling, you have a ¼ chance of getting a perfect match. If oyu have an identical twin, your chance would be 100% though.

LYMPHOCYTOSIS is most often caused by? (know this path 2/15)

MOST OFTEN CAUSED BY VIRAL INFECTIONS (e.g. influenza, mumps, rubella, infectious mononucleosis). and it is an increased number of lymphocytes in the peripheral blood.

Post-Treatment Oral Analgesics used in dentistry for "Mild to Moderate Pain" and "Moderate to Severe Pain"?

Mild to Moderate Pain drugs = have limitation to efficacy = Acetaminophen (Tylenol), NSAIDS (Ibuprofen aka motrin or advil; Aspirin), Tylenol #3. = inhibit prostaglandin synthesis (peripherally and centrally), most have good anti-inflammatory action, all have analgesic ceiling, more favorable side effect profile than opioids (below), many avaliable OTC. Moderate to Severe Pain drugs = can give dose and get high efficacy = (1) NSAIDS (max dose), (2) Combinations containing: hydrocodone, oxycodone or tramadol... w/... acetaminophen or ibuprofen = ex: VICODIN, (3) Single OPIOID agents (Demerol) = act on CNS pain mechanisms, lack anti-inflammatory effects, no ceiling dose, more problematic side effects that limit use, subject to the Controlled Substances Act limitations on prescribing. "Patients often want something stronger than OTC drug!"

What is required for lymphocyte activation? (2) Two methods of activating CD*T cells? fix see pic

NEED TWO SIGNALS. fix notes below DC's have PRR's. DC's recognize that there is an infection. Phagocytic Cells (DC's, Macrophages) sense infection (microbial agent), and get activated to do innate immune response, making TNF, IL1 IL6 (inflammatory cytokines that make immune response in the BEGINNING). Recall: Acute Inflammation - is basically correspond to innate Immunity bc fast, basophils/eosinophils/CRPs/early cytokines; fast responses. Immature DC = all around ur body Mature DC = once taken up antigen; go to lymph node (where B and T cells are) ; express B7 co-stimulatory molecule; have Class 2 along with the "bacterial" (or viral fungal) peptide. => Turns on CD4+ T cell bc the T cell that recognizes that peptide on that MHCII - but recquires TWO SIGNALS to become fully activated [all lymphocytes require 2 ignals to become activated] - first signal through either BCR or TCR (signal 1); second signal recquired in order to turn on = CD28 on B cell, reacting with B7 on activated/mature DC. Cannot turn on T cell unless DC makes B7 (only makes B7 if infectoin is there known by PRR recognizing the antigen). CD4+T cells have a number of subsets: KNOW SIGNATURE CYTOKINES FOR THESE 4 CELLS. TH1 (T-helper cells) = IFNgamma, IL-2 => act on: macrophages, NK cells, CD8+T cells; B cells switch to IgG3 = function for responding to intracellular pathogens e.g. Tuberculosis [killing of virus-or bacterially-infected host cells], and CMI. TH2 = > IL-4, IL-5, IL-13 => Act on: Eosinophils, B cells switch to IgE (MEMORIZE THIS; class switch to IgE signaled by IL-4 and IL-5, following worm infection resulting in u to make TH2 cells), IgG4 = responses to worms and allergents. TH17 => IL-17, IL-22 => act on (recruit): NEUTROPHILS, epithelial cells = pro-inflammatory responses to fungi and extracellular bacteria (e.g. if u have extracellular bacteria, u want lots of neutrophils, and TH17 is really good at having neutrophils to come). Treg (t-regulatory cells) => TGF-beta & IL-10=> act on: other lymphocytes; inhibits function of other sets of T cells )TH17, TH2, TH1) and non-T cells. [if u have genetic defect or mouse without Treg -> you get autoimmunity, and CANT turn off the immune response]. Cells of the innate immune system will make cytokines, which cause CD4 cells when their activated bc recognized by antigen, to then differentiate into the CD4 subsets, which make signature cytokines. TAKE HOME: Innate immune system bc of their PRR, not only do they know there's an infection, they also know what it is. Cytokines made by the innate immune system (IL1, IL6, TNFa) are based on what the infection is, and those cytokines will inform or instruct the CD4+ cell coming out of the thymus what it should become. Undesrtand TH2 functions.

General Features of Inflammation you need to know

NON-SPECIFIC RESPONSE TO INFECTION AND/OR NECROTIC TISSUE; INCLUDES VASCULAR REACTION & CELLULAR RESPONSE; OUTCOMES INCLUDE ELIMINATION OF STIMULUS OR CHRONIC INFLAMMATION.

In dentistry, what analgesics would you give before the procedure? During procedure? and then Post-procedure?

NSAIDS (400mg ibuprofen 1 hour before). During Procedure = local Anesthetics (long-lasting), Opioids, Steroid Anti-inflammatories. Immediate Post-procedure = NSAIDs otherwise can be given here. Post Procedure = NSAIDS, combination meds, Opioids.

Based on the conclusions drawn from the Oxford League Table, what are the most effective drugs for acute dental pain?

NSAIDs are most effective drugs for acute dental pain. Acetaminophen is less efficacious than NSAIDS. This is because NSAIDs have good Anti-Inflammatory activity, and Acetaminophen has it also but weaker. Opioids used alone are less efficacious than NSAIDs for dental pain and should be used only when NSAIDs are contra-indicated. (in dentistry, opioids most common used in combination with acetaminophen or ibuprofen... that's why we have VIcoden e.g.).

Understand oxygen-dependent and oxygen-INdependent antimicrobial mechanisms

OXYGEN-DEPENDENT MECHANISMS = "PRIOR to ENGULFMENT" = e.g. H202 Production, peroxidase mediated (iodination, aldehyde formation, peptide cleavage), peroxidase independent (interaction w ascorbate, lipid peroxidation); Oxygen-free radicals (superoxide anion, singlet oxygen, hydroxyl radical) OXYGEN-INdependent = AFTER ENGULFMENT = e.g. CATIONIC PROTEINS, lysozyme, Lactoferrine, hydrolytic enzymes, Permeability factor, Complement Components.

PRECATIONS/ CONTRAINDICATIONS TO NSAID USE?

PATIENTS WITH... Ulcers (consider use of PPI or Misoprostil), Inflammatory Bowel Disease, CHF, Pregnancy (esp. last 3 months); W. bleeding disorders or taking anti-coagulants (Coumadin) or anti-platelet agents (Plavix, Aspirin); Severe Renal or Liver Disease; Elderly - more susceptible to GI, renal, and CNS effects; Aspirin intolerant, hypersensitive, or allergic patients (must avoid use of NSAIDS). "FDA Strengthens heart attack, stroke warnings for non-aspirin NSAIDs - FDA Drug Safety and Avaliability" "The risk of heart attack or stroke can occur as early as the first week with NSAID use" "POTENTIAL INTERACTION BTWN NSAIDs and DAILY ASPIRIN" = nsaids taken before aspirin blocks access to binding site on enzyme, decreasing aspirins anti-platelet effect. Advise patient taking aspirin to protect against MI to take the ibuprofen at least 8 hrs before teh aspirin, or 30 min-2hr after immediate release low dose aspirin. For Naproxen, take aspirin 2 hours before or 36-48 hours after. ADVERSE DRUG INTERACTIONS W NSAIDS: - Alcohol: increased GI bleeding. - Anticoagulants: inc. GI bleeding, additive anticoagulant effects. - Antihypertensives (ACEIs, ARBS, Diuretics, Beta Blockers): Nsaid use BEYOND 4-5 days may decreased antihypertensive action, may raise BP by 5mm Hg. Avoid in elderly, severe CHF, or low renin patients (African-American and elderly). NSAIDS + LITHIUM (taken for bipolar disorder) - NSAIDS DEC. RENAL EXCRETION OF THIS DRUG leading to elevated plasma levels (into toxic range) => lightheadedness, fatigue, tremors, nausea. INTERACTIONS W. HERBAL MEDICATIONS or multi-vitamin: resulting in increased bleeding (platelet function) during procedure. SSRIs (anti-depresent drugs like prozac) and NSAIDS = 4th interaction = INCREASED UPPER GI BLEEDING.

Diclofenac (Voltaren)

PRESCRIPTION ONLY. - Dosing for pain: Oral, 50 mg tid, up to max daily dose of 150 mg/day - 6-8 hr duration. - SEEMS TO BE OK IN PATIENTS TAKING CARDIOPROTECTIVE DOSE OF ASPIRIN. - IV FORM IN USE (OUTSIDE USA).

What happens with the T cells in the THYMUS?

PRIMARY LYMPHOID ORGAN - T CELL DEVELOPMENT: T CELLS UNDERGO: 1. V(D)J RECOMBINATION = T-Cell Receptors (TCR) made by V(D)J recombination, which is RANDOM => many are AUTO-REACTIVE so chance of them recognizing self-peptide is high => need to remove these cells via APOPTOSIS to get rid of those self-reactive ones you're making (recall: apoptosis is natural way to die, suicide, that is NON-INFLAMMATORY). 2. POSITIVE & NEGATIVE SELECTION [learn to use UR MHC and rid of self-reactive ones] = two independent selection processes = OF THE DOUBLE POSITIVE CELLS (have CD4 and CD8 on surfaces, are not mature, are developing). 2a. Pos. Selection (for those that'll work with you): only thymocytes whose TCRs can recognize antigens presented by self-MHC can survive and mature. (only give positive signals for survival for T cells that'll fit one of your MHC's) = > Makes single-positive T cell (either CD4 or CD8 on surface) 2b. Neg. Selection (follows after, any of those that bind with self peptide that is in there): self-reactive (autoreactive) thymocytes are deleted (by apoptosis) - THSI WILL BE ASKED IN EXAM, POS. SELECTION WONT. 3. CD4" and CD8" (single positive) T cells leave Thymus. . - KEY **** YOU MUST UNDERGO NEGATIVE SELECTION OF T CELLS IN THE THYMUS *BEFORE* YOU LET THEM OUT AS CD4+ AND CD8+ T CELLS. *** - EACH TCR IS SPECIFIC FOR SPCFC FOREIGN PEPTIDE (IN GROOVE) IN A PARTICULAR MHC ALLELE (E.G. particular influenza peptide stuck in an HLA-DR4 allele, then there will be a T cell specific for this exact peptide in DR4... its that specific for both the particular MHC and the peptide.. .so what you have to do in the thymus is have the T cells selected for only those T cells that have a TCR that will work with only your DQ, DP, DR, and only your class 2 e.g MHC). Notes: Differences Between TCR and BCR: (1) T Cell ReceptoR: Two Chains (α and β) One Ag binding site Recognizes protein Ags as peptides. Ag must be bound by MHC. Not secreted. No somatic hypermutation No Class Switch (2) B Cell Receptor: Four chains (2 H and 2L) Two Ag binding sites Can recognize protein, carbohydrates, lipids Recognizes free Ag Secreted as Ab by plasma cells Somatic hypermutation Class Switch (to IgG, IgA, IgE)

Understand the significance of opsonization - what leads to opsonization?

Phagocytic Receptors What leads up to ("causes") opsonization? EITHER: (1) Alternative Pathway allows pathogens (surface) to be recognized in absence of antibody => complement activation => recruitment of inflammatory cells + opsonization of pathogens + killing of pathogens. - The Alternative Pathway begins opsonization by cleaving and depositing C3 fragment on pathogen surface: opsonin -> C3b opsonization is amplified by an enzyme. (2) Opsonization by complement component: Complement Components (recognized by complement receptors, a type of phagocytic receptor) have three roles = (a) Bacteria Lysis, (b) Phagocyte Chemotaxis, (c) Bacteria Opsonization. - ADVANTAGES OF COMPLEMENT = Does not need antibody & Can recognize largE variety of pathogens. Opsonization = recognition by specific receptors, in absence of acquired immunity. Binding of an opsonin, e.g., antibody, to an epitope on an antigen.After opsonin binds to the membrane, phagocytes are attracted to the pathogen. The Fab portion of the antibody binds to the antigen, whereas the Fc portion of the antibody binds to an Fc receptor on the phagocyte, facilitating phagocytosis

Understand the Definition of Phagocytosis and Phagocytes

Phagocytosis = immune adhesion event; receptors on surface of cell are able to recognize ligands that are on surface of microorganism -> adhesion leads to circumferential binding of phagocyte around microorganism. Ligand is key. Then organism eventually engulfed. Phagocyte = defined by its function aka ingesting particles [Zipper -like fashion] = structure has a bunch of receptors on surface of them, and it has internal organelles. Kinds of Phagocytic Cells: 1. Neutrophils (polymorphonuclear leukocytes; PMNs) 2. Macrophage/monocytes 3. Eosinophils 4. Basophils 5. Dendritic cells 6. Microglial cells 7. Osteoclasts (periodontitis: unregulated activity of osteoclasts -> they start to degrade bone when they go crazy )

Why do we consider preoperative dose?

Preooperative dose for NSAIdS bc advantage of giving patient pill so less inflammatory while ur doing the procedure. e.g. take ibuprofen before dental procedure.

Irreversible injury - how do cells react? know bold (red from slides) 2/4 path

Recall: Reversible injury (degeneration) - Cell functions impaired but cell can recover IRREVERSIBLE INJURY = CESSATION OF ALL CELL FUNCTIONS WITH CELLULAR DEATH 1) APOPTOSIS - PROGRAMMED PHYSIOLOGICAL CELL DEATH; REMOVES UNWANTED CELLS. = CHANGES BUT NO INFLAMMATORY CELL RESPONSE INCLUDE: CELL SHRINKAGE, NUCLEAR CHANGES-CHROMATIN CONDENSATION (NUCLEAR FRAGMENTATION), APOPTOTIC (CIVATTE) BODIES FORMED, & PHAGOCYTOSIS. 1a) INTRINSIC apoptosis = MAJOR MECHANISM OF MAMMALIAN CELLS; INVOLVES MITOCHONDRIA ; RELEASE PRO-APOPTOTIC MOLECULES- CYTOCHROME C INTO CYTOPLASM (CELL NOT HEALTHY); REGULATED BY BCL-2 FAMILY; CASPASE-9 CRITICAL INITIATOR OF PATHWAY. 1b) Extrinsic = Plasma membrane death receptors on cells; Members of TNF receptor family (Fas & TNFR1); Activate caspase-8 2) NECROSIS- CELL DEATH ASSOCIATED WITH AN INFLAMMATORY CELL RESPONSE

Understand the basis of transendothelial migration

Receptors on neutrophils and receptors on integrins => rolling of polymorph until slows down => adhesion => phagocytic cell transmigration through endothelial cell and into the cell. know: receptors is what allows the cell to get into these tissue sites.

FREE RADICAL DEGRADATION (SCAVENGERS) know bold (red from slides) 2/4 path

Removal of free radicals: (1) INTRACELLULAR ENZYMES: GLUTATHIONE PEROXIDASE, CATALASE, SUPEROXIDE DISMUTASE, (2) EXOGENOUS AND ENDOGENOUS ANTIOXIDANTS: VITAMIN A, VITAMIN C, VITAMIN E, CYSTEINE, GLUTATHIONE, SELENIUM, CERULOPLASMIN, TRANSFERRIN.

A persistent ________ injury can cause cell injury.

SUBLETHAL (bolded on slides but not in red) (pathology 2/15)

Pyogenic Cocci bacteria?

Streptococcus (species) & Staphylococcus (species) = PUS {of dead neutrophils, bacteria, inflammatory exudate and tissue debris. It occurs because there is a BATTLE btwn NEUTROPHILS and BACTERIA} FORMING aka pyogenic: 1. Bacterial substances recruit neutrophils. 2. THESE BACTERIA RESIST PHAGOCYTOSIS (by the neutrophil). 3. Bacteria are not killed by neutrophils. 4. Bacteria instead kill neutrophils, which die and release lysosomal enzymes. Enzymes damage Surrounding tissues.

Know that phagocytes share specific structures and receptors

Structure of phagocyte = has a bunch of receptors on surface of them, & internal organelles. Receptor Types involved in phagocytosis: 1) PHAGOCYTIC RECEPTORS define what phagocyte cell is 1a) "COMPLEMENT RECEPTORS" that recognize serum COMPLEMENT COMPONENT positive proteins on surface of pathogens. - 3 ROLES FOR COMPLEMENT COMPONENTS = Bacteria Lysis, Phagocyte Chemotaxis, Bacteria Opsonization [important for this class] 1b) Fc Receptors - on phagocytes, binds constant region of antibody. 1c) Lectins = direct recognition of specific carbohydrates. a specific receptor. ADV: acquired immunity and activation of complement cascade is not required, but.. DISADV: Bug needs to have correct carbohydrate on surface. DECTINS are the major class of phagocyte lectins, is involved in recognition of fungal pathogens. Have dual use: involved in innate, immune signaling too. 2) ADHESION RECEPTORS: mobilize in tissue when moving from circulation to inflammation site; or also move .... 3) ACTIVATION RECEPTORS: change the nature of the phagocytic cell (make them more able to kill microorganisms = Toll like receptors, Il-1 receptor, TNF receptor, iFN gamma receptor = 3a) Early-"M1 macrophages" = "CLASSICAL ACTIVATION (red) = (1) inflammation, (2) bacterial and viral diseases. [CLASSICAL ACTIVATION -> DENTAL PROFESSIONAL]. - Properties of Classically Activated Phagocyte (know these): 1. Enhanced rate of phagocytosis 2. Enhanced production of toxic reactive oxygen intermediates (antimicrobial) 3. Enhanced production of NO (nitric oxide; antimicrobial) 4. Enhanced phagosome-lysosome fusion. 5. Increased number of MHC class II molecules 6. Secretion of IL-12: differentiation of CD4 T cells. 3b) Later - "M2 Macrophages" = "ALTERNATIVE ACTIVATION (red)" = (1) Noninflammatory, (2) clears tissue damage, (3) Often less restrictive of pathogens. 4) MHC Class 1 and 2 - pathogen. all phagocytes have MHC Class 1, most have MHC class 2 but particular is that dendritic cells have about 100x more of MHC2 which is why dendritic cells key role in presentation.

CD4+T cells have a number of subsets: KNOW SIGNATURE CYTOKINES FOR THESE 4 CELLS. fix - when are these produced/activated?

TH1 (T-helper cells) = IFNgamma, IL-2 => act on: macrophages, NK cells, CD8+T cells; B cells switch to IgG3 = function for responding to intracellular pathogens e.g. Tuberculosis [killing of virus-or bacterially-infected host cells], and CMI. - - TH1 cells are mediators of? CMI - this process is depicted see pic then fix. Killing of infected cells. Clinical applications discussed later in course. TH2 = > IL-4, IL-5, IL-13 => Act on: Eosinophils, B cells switch to IgE (MEMORIZE THIS; class switch to IgE signaled by IL-4 and IL-5, following worm infection resulting in u to make TH2 cells), IgG4 = responses to worms and allergents. - KNOW: In response to worms (usu. Less developed countries) and allergens: CD4 cells become TH2 cells -> IL5 activates eosinophiles; il4 and il13 cause b cells to switch to IgE. TH17 => IL-17, IL-22 => act on (recruit): NEUTROPHILS, epithelial cells = pro-inflammatory responses to fungi and extracellular bacteria (e.g. if u have extracellular bacteria, u want lots of neutrophils, and TH17 is really good at having neutrophils to come). Treg (t-regulatory cells) => TGF-beta => act on: other lymphocytes; inhibits function of other sets of T cells )TH17, TH2, TH1) and non-T cells. [if u have genetic defect or mouse without Treg -> you get autoimmunity, and CANT turn off the immune response]. Signal 1 always between MHCII+Peptide (DP, DQ, DR) on APC (D.C., Mphage, Bcell) with TCR+CD3 on CD4" T cell. Signal 2 can either be: between B7 (APC) and CD28 (CD4+-T cell); or btwn CD40 (Bcell, an APC) w CD40L (on CD4" T cell) ACTIVATING CD8" T CELL: 2 signals also. 1 from MHCI+ Peptide (on infected cell) w. TCR+CDR on CD8"Tcell. Signal 2 either: Btwn B7 (APC) w. CD28 (T cell), OR via activation of CD4+T cells (TH1 type) that produce IL-2 cytokines that act on the CD8+ T cell.

CD40 - CD40L Interaction on this exam

THIS IS FOR THYMUS-DEPENDENT ANTIGENS. CD40 on B cell; and CD40L on Helper T cell. (helper T cell gives second signal to activate the B cell). Interact => Activates B cell, now can become memory B cells, undergo CLASS SWITCH Recombination. fix delete

Plasma-Derived Mediators of Inflammation (must know path 2/15)

THREE INTERRELATED SYSTEMS: COMPLEMENT , KININ, COAGULATION. - know C3a for complement pathway. note: it does histamine release from mast cells/platelets, vascular permeability). - know: ACTIVATED HAGEMAN FACTOR INITIATES 4 SYSTEMS: KININ SYSTEM, CLOTTING SYSTEM, FIBRINOLYTIC SYSTEM, COMPLEMENT SYSTEM. - know: BRADYKININ is principal kinin for kinin system. - COMPLEMENT PROTEINS RESPONSIBLE FOR CHEMOTAXIS, OPSONIZATION, AND PHAGOCYTOSIS. - COAGULATION PROTEINS: ACTIVATED FACTOR XII TRIGGERS CLOTTING, KININ, AND COMPLEMENT CASCADES. - KININS: MEDIATES VASCULAR REACTION AND PAIN.

Know mechanisms by which different bacteria avoid phagocytosis

Tactics Used by Pathogens to Avoid Killing by Phagocytes 1) Kill or be killed (Cytotoxicity)! Streptococcus Streptolysin O Bordetella pertussis Adenylate Cyclase 2) Inhibit opsonization or inactivate phagocytosis 1. Capsule: S. pneumoniae 2. M protein: S. pyogenes 3. Disrupt signaling: RhoGAP proteins " E.g. Phagocyte unable to ingest Streptococcus pnuemoniae bearing a capsule" 3) Survive intracellular killing 1. Inhibit phagosome-lysosome fusion: M. tb. 2. Escape from phagosome: Rickettsia 3. Survive lysosomal enzymes: Salmonella

Two major types of T cells? What do each bind/where? Mech. of Action/function of each?

They come out of the Thymus as either CD4 or CD8 positive. note: both of these have CD3 with their receptor since all T cells do! CD4+ T cells = express on membrane a molecule called CD4 = ONLY RECOGNIZE foreign peptides presented by MHC Class 2 EXPRESSED on APC [CD4 binds to MHC class 2 (expressed on APC)] - action: MHC class 2 plus peptide expressed on APC (dendritic cells, macrophages, and B cells - note: these also express MHC class 1...) interacts with CD4+ T cells => CYTOKINE SYNTHESIS. - know what gives rise to cytokine synthesis. CD8+ T cells = have CD8 on their membrane = only recognize foreign peptides presented by MHC Class 1 EXPRESSED ON on ALL nucleated cells. [CD8 binds MHC class 1 (expressed on all nucleated cells]. - action: MHC Class 1 plus peptide expressed on any nucleated cell interacts with CD8+T cell => results in KILLING of HOST cell. "understand: WHEN A VIRUS INFECTS THE CELL, WHAT THE IMMUNE SYSTEM HAS TO DO IS KILL THAT CELL (YOU CAN'T CURE IT, THE CELL HAS TO DIE). "

Thymus-independent (TI) antigens

Thymus-independent (TI) antigens SOME antigens, such as LPS and most polysaccharides from bacterial capsules, do NOT require T cell help to activate B cells to produce antibodies. Since TI antigen activation does not provide T cell help, there is no class switching and IgM is the predominant antibody produced and NO memory cells are produced. KEY TO UNDERSTAND - most antigens are proteins and thymus=dependent, but the antigens that don't have proteins are thymus-independent and thus they r t-cell independent so dont get t cell help and dont get class switch etc.

What are toxins and how do they cause disease? What types of activities do toxins have? How do toxins enter cells? know in caps

Toxin: a protein that kills cells or alters the cell's functions = "pathogen/derived factors directly causes damage (how do pathogens cause damage/disease) = SECRETED PROTEIN THAT KILLS OR ALTERS THE FUNCTION OF HOST CELLS = can be CYTOTOXIC (KILLS CELLS) or CYTOPATHIC (disrupts cell functions) or BOTH DEPENDING ON DOSE. THREE TYPES OF TOXINS: (1) membrane-active (extracellular) = SUPERANTIGENS; pore-forming toxins. (1a) those that interfere with cell signaling: SUPERANTIGENS =: TCR (T CELL) SIGNALING. & CHOLERA TOXIN = cAMP signaling. (1b) CLOSTRIDIAL NEUROTOXINS = TETANUS TOXIN (inhibit cellular trafficking) BOTULINUM TOXIN {inhibit membrane fusion} (2) Intracellular targets (inside cells) = AB TOXINS; injected toxins. (3) Acellular targets (degradative enzymes).

Instead of giving one carbon source like glucose, you give E.COLI gram-negative BACTERIA TWO carbon sources e.g. glucose and lactose, what happens?

Two Mechs to prevent lactose utilization when glucose is available aka glucose "repression" of lactose utilization: - relevant notes: how glucose gets into cell (phosphorylate it!) = many sugars incl. glucose imported by phosphotransferase systems (PTS) in bacteria where PEP converted to pyruvate in cytoplasm (also seen in glycolysis last step) via enzyme 1 conversion to enzyme-1-p phosphorylated. Then, Phosphorylated enzyme-1-p phosphorylates protein HPr -> HPr-P. This phosphate is given to Enzyme II -> Enzyme II-P, which is specific for certain sugars e.g. EnzymeII-P-Glucose, so it does Glucose-> glucose-P, and the phosphorylated glucose is now able to enter the cell. E.Coli use Glucose first, then lactose (when both are present): 1) When glucose is present, lactose transport into cell is inhibited! ENZYME II (for glucose) is UNPHOSPHORYLATED. Lac Permease is NONfunctional 2) When glucose is present, transcription of "lactose metabolizing enzymes" is "repressed"! Enzyme II (for glucose) unphosphorylated. NO Allolactose (cant be induced into cell - "Inducer Exclusion"), so "Lac repressor" remains on operator and NO transcription of lactose metabolizing enzymes. [normally, when lactose is present, allolactose will bind to Repressor (Lac I gene)/displace it, so that RNA can get to where it was and do transcription of lactose metabolising genes]. 3) When glucose is present, Positive Regulation (activation of transcription) by CAP of "lac operon" is INACTIVATED! (inactivation of positive regulator)! Enzyme II (for glucose) unphosphorylated. cannot interact and activate Adenylate cyclase -> no cyclic-AMP production -> no CAP-cAMP complex = CAP protein NOT ACTIVE and CANNOT bind (positive regulators bind upstream of promotor to many genes/places) to the DNA to transcriptionally activate the lac operon. [note: CAP must be with cyclic amp in order to bind to the DNA, cannot do it alone; and cAMP is made from ATP (know this) via adenylate cyclase enzyme found in membrane]. VERSUS - Only Lactose Present - Enzyme II for glucose in phosphorylated state, and opposites of above happen s.t. lactose can get into the cell, transcription of lactose metabolizing enzymes is not repressed bc allolactose displaces the repressor, and CAP-cAMP can positively regulate transcription of the lac operon.

DISORDERS CHARACTERIZED BY ABNORMAL PROTEIN FOLDING - what are the two known pathogenic mechanisms?

Two known pathogenic mechanisms (1) Abnormal protein aggregation ex. Amyloidosis in Neurodegenerative diseases (Alzheimer, Huntington disease, Parkinson, prion disease) (2) Abnormal protein transport and secretion ex. Cystic fibrosis w. α 1-antitrypsin deficiency

Variable region of antibody is made by....

V(D)J recombination "The varibale regions of both TCR and BCR (antibody) are "created" during lymphocyte development by a unique genetic mechanism that involves the "rearrangement" of gene sqequences. This mechanism is called V(D)J recombination. Most T cells have a TCR consisting of an alpha chain and beta chain (alpha-beta T cells). All T cells discussed in this course will be the major set of alpha-beta T cells."

SPECIFIC COX-2 INHIBITORS? Which drugs block both pathways in the "arachidonic acid cascade?"

Vioxx and Celebrex -> blocking inflammation, pain, fever (from prostaglandins). Contrast this with "Aspirin, NSAIDS = block both" and by blocking COX-1 pathway also, are blocking beneficial functions that come from that path including Homeostatic Functions, GI tract cytoprotection, renal tract, platelet fxn, macrophage diffrentiation -> get SIDE-EFFECTS bc blocking good things.

Is hypoxic cell injury reversible? FIX CONFUSED BUT WAS IN RED PATHOLOGY 2/14

Vulnerability of cells to hypoxic injury varies with the tissue or cell type IRREVERSIBILITY: 3-5 minutes - Neurons 1-2 hours - Myocardial cells and hepatocytes Many hours - Skeletal muscle cells e.g. Localized Infarct - Necrotizing Sialometaplasia

Mechanisms for avoiding phagocytosis? for strep vs. staph

[key element in PUS-FORMING aka pyogenic mech] Streptococcus: 1. M protein is the most important factor (in bact. surface) 2. Hyaluronic acid capsule - Interferes w. opsonization (the one that's due to) / complement deposition, bc cause bacteria to be coated with fibrinogen and fibrin. (thus, bacteria are not recognized for phagocytosis). Staphylococcus: 1. Protein A 2. Cell wall components 3. Leukocidin - Opsonized bacterium - Protein A on bacteria binds to antibodies' constant regions (Antibodies are backwards - bc normally bacteria binds variable region, then constant region is avaliaible to bind to Fc of phagocyte) so constant regions not avlble to bind Fc receptors of phagocytes. Note - SUMMARY: - Two types of organisms, Streptococci and Staphylococci. - Both COLONIZE PEOPLE. - Both SPREAD PERSON-TO-PERSON. - Both produce PYOGENIC INFECTIONS. because they have mechanisms that allow them to RESIST PHAGOCYTOSIS. - DIFFERENCE: Staph: localized infections (vs) Strep: spreading