Misc Information 2
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- Antibody component of primary response (first exposure):
- IgD, IgM
- Antibody component of secondary response (subsequent exposures):
- IgG, IgE, IgA
- Th2 cells: other name and function
- Helper T cells. Activate and control B cells.
- Dendritic cells: function
- Presents and costimulates helper naive T cells, which turn into Th1 or Th2.
- Th1 cells: function
- activate macrophages to become more efficient killers and can force the fusion of phagosome and lysosome. Activated macrophages must be controlled by TH1 cells because they can do a lot of damage to normal tissue surrounding the site of infection.
- Compounds that promote naive T cells to go to Th1. Compounds produced by Th1 cells.
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IL-12
IL2, IFN-gamma (proinflammatory, macrophage activation) - Compounds that promote naive T cells to go to Th2. Compounds produced by Th2 cells.
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IL-4
IL4,IL10,IL13 (antiinflammatory, allergic IgE) - Th1 and Th2 regulation:
- Reciprocial. supernatants from DTH (Th1) response (IL-12, IFN-gamma) suppress antibody responses, and Th2 supernatants (IL-4) suppress DTH response.
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Immologically priviledged sites:
location and mechanism -
lens of eye, spermatozoa/testes, brain, ovary, placenta.
Tissue expression of FasL which would induce apoptosis of activated T cells that migrated into tissue. - Positive vs negative selection in thymus/bone.
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Strong self interaction --> clonal deletion (negative selecton)
Intermediate self interaction --> positive selection, saved
No self interaction --> death by neglect... no positive selection. - Anergy:
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A mechanism of periphreal tolerance. Functionally inactivates (no kill!) a cell.
Done by inhibiting costimulatory molecules--> no rx to antigen. - Receptor editing:
- A mechanism of periphreal tolerance. Rearranged immunoglobulin H or L chain gene undergoes secondary rearrangement (under control or RAG-1/RAG-2). Leads to a BCR or TCR with new specificity.
- Deletion:
- A mechanism of periphreal tolerance. Autoreactive T or B cells are eliminated from the repertoire of reactive population. Can occur with cells that bind with extremely high affinity.
- Clonal Ignorance:
- A mechanism of periphreal tolerance. Autoreactive cells are neither anergized, receptor edited, or deleted. They co-exist with antigen in an unactivated state with low affinity for antigen.
- Fas-FasL used to:
-
Control of mature EFFECTOR (not memory) lymphocyte numbers.
Control self-reacting cells. -
Two forms of autoantibody-mediated
tissue damage in kidney -
Smooth -- anti-basement membrane Ab,
vs lumpybumpy -- Immune complex deposition. - Lambert-Eaton Syndrome: hypersensitivity type and pathogenesis.
- Type II. Ab to CaV channels, blockers; presynaptic defect resulting in muscle weakness, vision problems, etc. (associated with small-cell carcinoma of the lung, which expresses CaV)
- Rh factor... what is it exactly?
-
IgM autoantibodies against IgG
~80% positive in RA, ~25% positive in SLE - 3 types of burns, both names:
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Superficial (1st degree)
Partial thickness (2nd degree)
Full thickness (3rd degree) - Superficial burn, characteristics:
-
Reddened skin, blanches with pressure
Painful, short duration
Heals within 24 hours - Partial thickness burn, characteristics:
-
BLISTERS
MOIST UNDER BLISTER
RED WITH BLANCHING
SENSATE
HEALS 7-21 DAYS BY SELF REGENERATION IF PROTECTED - Full thickness burn, characteristics:
-
PALLID, CHARRED, MAY HAVE BLISTER, INSENSATE TO PINPIRCK, NO REGENERATION
HEALS BY CONTRACTION AND SCAR AND EPITHELIAL MIGRATION FROM EDGES >30 DAYS - "4th" degree burn
- DAMAGE DEEP TO SKIN AND APPENDAGES INTO MUSCLE, BONE, OR FASCIA
- Fluid replacement equation... and use what fluid?
- LACTATED-RINGERS 4cc/KG/%BSA BURN IS A REFERENCE ½ IN FIRST 8 HOURS.
- Hemodynamic physiologic response to burn injury:
- TOXINS(CYTOKINES RELEASED FROM BURN TISSUE) PROVOKE CELL MEMBRANE INSTABILITY AND FLUID TRANSLOCATION OCCURS INTO CELLS LED BY SODIUM ION, WATER FOLLOWS LEAVING RBC CONCENTRATED IN THE PLASMA SPACE.
- Metabolic response to burn injury:
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NEUROENDOCRINE ACTIVATION OCCURS MAXIMALLY AS STRESS RESPONSE TO THE BURN RESULTING IN HYPERMETABOLISM WITH A CATABOLIC STATE CONSUMING MUSCLE AND FAT.
CATECHOAMINES, CORTISONE,GLUTAMINE RULE. RME MAY DOUBLE. INSULIN IS SUPPRESSED.
Solution: NG feedings. - Equation for per hour loss of water when burned:
- (25+%BSA) * square meters of BSA = cc/hour
- How long does high rate fluid translocation last in burns:
- TRANSLOCATION ATENUATES AFTER 24 TO 36 HOUR.
- Hyper metabolic response (HMR) leads to:
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Massive lean body weight loss.
In huge burns, 15% of lean body weight lost 4-6 weeks. - Hypermetabolic response (HMR) mechanism:
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Neuroendocrine activation--epinephrine, cortisol, glucagon
Gluconeogenesis, glycogenolysis, proteolysis
Blunted insulin and growth hormone effect - Curreri energy equation:
- (25 x wt kg) + 40 x %TBSA burn)/day
- Harris Benedict energy equation:
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Male:
66 + (13.7 x wt kg) + (5 x ht cm)- (6.8 x age)
= BEE in kcal/kg/day - How to modify energy expenditure in HMR?
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Control pain
Warm environment 32 C. to suit patient
Early enteral feeding
Early excision and graft to close wound
Immune modulation by hormonal and nutrient pharmacologic agents -
Nitrogen needs equation:
(Nitrogen measure of catabolism) -
Nitrogen bal = Nin - (1.25 x UUN + 4)
UUN = 24hr urine urea nitrogen.
Nin = 24hr nitrogen intake -
Allograft
Xenograft
Autograft
Biobrane
Integra -
Human skin graft
Animal skin graft
Same person skin graft
Synthetic biological membrane
2 layer Synthetic skin (dermis matrix for growth, temporary silicon "epidermis".) - Sources and solution to infection in burn care:
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WOUND AND GUT ARE THE PRIMARY SOURCE. BURN WOUND SEPSIS, PNEUMONIA, MULTISYSTEM FAILURE ARE SIGNIFICANT.
EARLY EXCISION OF BURN, GRAFT OR PROVIDE TEMPORARY COVERAGE UNTIL AUTOGRAFT IS AVAILABLE. - Biobrane used on...
- Partial thickness burns. Stays on until burn underneath heals.
- Integra (neodermis) used on...
- Deep wounds (full thickness, 4th degree).
- Homograft is...
- Same as allograft... from one human to another.
- HMR during burns... slow it down or keep up?
-
Easier to keep up with "the fire within" than to modifiy it.
Practical methods (heat lamp, cover etc) to control energy expenditure out-weigh pharmacologic and hormonal methods at present - Intoxication by age
-
<6yo 50%
6-19yo 14%
>19yo 36% - Top 3 substances causing toxic fatality:
-
Analgesics 700
Sedatives/antipsychotics 300
Antidepressants 300 - Total fatalities compared to cases in toxicology:
-
2000 deaths
2million cases! - 2 million cases: breakdown by unintention/intentional...
-
Accidental: <2million
Suicide: 200k
Substance abuse: 40k - Pb toxicology:
- No known biologic functions.
- Pb toxic concentrations ladder:
-
In ug/dL:
5 - placental transfer
9 - Reference range, CNS developmental toxicity.
15 - Decr nerve conduction
30 - Decr Vitamin D
40 - Decr Hb synthesis, need chelation.
50-100 Anemia, encephalopathy, nepropathy
>100 death - Pb, absorption and excretion:
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Abs in lung, gut.
Found first in soft tissues, then hair/bone/teeth.
Blood halflife months, bone 30 years.
Eliminated in urine. - Molecular effects of Pb:
- Inhibits Heme synthesis.
- Pb: screening for toxicity
- Direct blood Pb.
- Hg: has affinity for?
- Biologic and chemical SH groups.
- Thimerosal
- Organomercury used as preservative in old vaccines, thought to cause autism.
- PB chelation molecule, side effects:
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IV Calcium disodium EDTA.
Proximal tubule toxicity. - Dimercaprol
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Metal antagonists with two SH groups that form useful complexes with Hg, As, Pb and other metal ions.
Many side effects, ion complexes unstable in acidic urine. - Succimer
- Useful to lower soft tissue Pb... does not effect Cu, Fe, Zn. Causes an increase hepatic enzymes.
- Penicillamine
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Useful against Wilson’s disease.
Contraindicated in pregnancy, previous aplastic anemia and poor renal function. - Deferoxamine
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Used vs iron overload of thalassemia but not primary hemochromatosis.
Many adverse effects are known so that the drug is used only when clearly indicated - CO
-
Competes with oxygen to bind to Hb and other heme proteins -- CO has much higher affinity!!
Breathing 0.1% CO in air will result in 50% COHb. - %COHb levels and symptoms:
-
0-10: none
10-20: headache
20-30: throbbing headache
30-40: weakness, nausea, dimvision
40-50: collapse, tachycardia
50-60: Coma, cheyne-stokes
>70: Resp failure, death - CO poisoning: treatment
-
Treatment with oxygen is started before COHb is returned.
The half-life of COHb decreases markedly as oxygen level is increased. - Anti-ChE biological attack: symptoms
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DUMBELS (diarrhea, urination, miosis, bronchospasm, emesis, lacrimation and salivation) includes muscarinic effects.
Nicotinic (neuromuscular junction) effects include: faciculations and paralysis.
CNS effects include: confusion, convulsions, coma and central respiratory paralysis. - Anti-ChE biological attack: treatment
- Treatment includes heroic doses of atropine (competitive antagonist of the muscarinic acetylcholine receptors) and mechanical support of respiration if need.
- Chronic toxicity of organophosphates: symptoms
- A delayed polyneuropathy (ataxia, weakness, slow tendon reflexes, paralysis) with slow, incomplete recovery has been described.
- Histologic signs of inflammation in the airways (asthma):
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Inflammation with leukocyte infiltrate.
Mucus plugs.
Subepithelial fibrosis.
Myocyte hypertrophy/plasia.
Neovascularization - Function and mechanism of APC cells in Th2 differentiation:
- Present antigen to Th0 cells via Class II MHCs. Costimulation by CD4 surface molecules. Together with IL-4 induces Th0 --> Th2.
- Th2 chemotaxis and functions:
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Expresses CCR3 receptor, follows Eotaxin to get to site.
Th2s produce cytokines IL-4,IL-5,& IL-13! - B cell sections and activation:
- Activated by IL-4 from Th2 to produce IgE which in turn activates MC, mast cells, in the presence of the allergen.
- Eosinophils: express what? activated by what? Secrete what?
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express CCR3 --> migrate to Th2 site. Activated by IL-5 from Th2.
Cytotoxic: MBP-major basic protein, ECP eosinophil cation protein.
Cytokines: IL4, IL13
Chemokines: Eotaxin, RANTES
PDGF
NO - Mast cells: express what? activated by what? Secrete what?
-
CCR3 -- chemotaxis.
Activated by IgE, allergen.
Acutely release: histamine, leukotrienes,tryptase & chymase
Chronically: IL-4,IL-5,IL-13, MMP-9, TGF-B, transforming growth factor – stimulates fibroblastic matrix formation - RANTES:
- Chemotaxic cytokine. Attracts T cells, eosinophils and basophils.
- Macrophages: early vs late stage
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Early stage INHIBITED phagocytosis by IL-13.
Late stage STIMULATED phagocytosis by MCP-1 (released by damaged cells) - Smooth muscle, role in asthma pathogenesis:
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early response to agonists – contraction.
Late response to IL-13, is secretion of chemokines, cytokines, & MMP’s, hyperplasia & hypertrophy - Goblet cells: role in asthma pathogenesis
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Both early and late: secretion of mucus under the influence of cytokines, e.g. IL-13.
PS: IL-13 BIG cause of changes in airway. - Endothelial cells: role in asthma
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Early: histamine prompts fluid extravasation
Late response to VEGF, vascular endothelial growth factor, formation of new blood vessels - Myofibroblast: Role in asthma
- late response to TGF-, transforming growth factor-B, leading to airway fibrosis.
- Amplification: example of mast cell and smooth muscle interactions
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MC secreted products cause SmM to secrete Eotaxin.
Eotaxin attracts MCTC via the CCR3 receptor.
Embedded MCTC release IL-4 & IL-13 which in turn cause SmM to secrete more Eotaxin. - Molecules involved in smooth muscle contraction modulation:
-
Agonist receptors -- GP linked, amplifies contraction.
IL-13 -- acts via TyrKin receptors, amplifies contraction by MAPK --> gene transcription. - Smooth muscle relaxers:
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selective receptor antagonists – antihistamines and cholinergics
B-adrenergic receptor agonists
Phosphodiesterase inhibitors
Corticosteroids - Cortcosteroids in asthma: action, problem
-
inhibit gene transcription via activation of Histone deacetylase (HDAC)
Systemic side effects, frequent airway infections, HDAC is often reduced in cells associated with airway inflammation - SmM relaxants: action, problem
-
Usually work vs acute airway constriction.
Symptomatic, limited effectiveness, B-receptors can down regulate. - Asthma vs COPD
-
Asthma: high Th2/Th1 ratio -- Mast cells, B-cells, Eosinophils -- steroids/beta agonists work
COPD: Low Th2/Th1 ratio -- neutrophils, macrophages, CD8 Tcells -- steroids/beta agaonists weak - Final list of current drug classes for asthma
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B2-adrenergic agonists
Leukotriene antag.
Phosphodiesterase 4 inhibitors
Antihistiminics
Anticholinergics - NO produced in macrophages/endothelial cells does what during inflammation?
-
Reduces platelet adhesion.
Reduces leukocyte adhesion.
Causes vacular smooth muscle relaxation and vasodilation. - Effector function of C3b
- Opsonization --> Phagocytosis
- Effector function of C5a, C3a
- Recruitment and activation of leukocytes.
- Effector function of MAC
- Lysis
- Factor XII: name, actions
-
Hageman factor-- activated by exposure to collagen/basement membrane.
Triggers kinin cascade, clotting cascade, fibrinolytic system, complement cascade. - Mediators causing vasodilation
- PGs, NO, Histamines
- Mediators causing increased vascular permeability
- C3a, C5a, Bradykinin
- Mediators causing chemotaxis, leukocyte activation
- C5a, LTB4, IL-1, TNF
- Mediators causing fever
- IL2, TNF, PGs
- Mediators causing tissue damage
- NO, lysosomal enzymes
- Events in resolution of acute inflammation:
-
Return to normal vascular permeability
Drainage of edema fluid and proteins into lymphatics
Pinocytosis into macrophages
Phagocytosis of apoptotic neutrophils
Phagocytosis of necrotic debris
Disposal of macrophages - Chronic inflammation: macrophage released products leading to tissue injury
-
Toxic oxygen metabolites
Proteases
Neutrophil chemotactic factors
Coag factors
AA metabolites`
NO - Chronic inflammation: macrophage released products leading to fibrosis
-
Growth factors (PDGF, TGF-B, FGF) -- fibroblast growth.
Fibrogenic cytokines
Angiogenesis factors
"Remodelling" collagenases