Misc Information 1
Terms
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- anasarca
- widespread edema
-
Bleeding into:
external environment
tissue
body cavity -
Exsanguinating
Hematoma
Hemoperitoneum/Hemothorax - Hyperemia
- Increased volume of blood in a particular location, organ, tissue. ACTIVE PROCESS due to increased flow into capillary bed.
- Congestion
- Increased volume of blood in a particular location, organ, tissue. PASSIVE PROCESS due to impaired venous drainage.
- Hemorrhage terminology
-
Petechiae = Minute (1-2mm)
Purpura = Confluent petechiae (>3mm)
Bruise = Ecchymosis (>1-2cm)
Hematoma - Three primary predisposing influences to thrombus formation...
-
Endothelial injury
Abnormal blood flow
Hypercoagulability - 5 fates of a thrombus
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Propagation (enlarge)
Embolization (break off)
Dissolution (lysis)
Organization (incorporation into wall)
Recanalization (new flow) - Lines of Zahn
- Alternating layers of cells and fibrin seen in true "unorganized" premortum thrombus.
- Saddle embolus
- Causes sudden death, blocks pulmonary artery at bifurcation.
- Appearance of infarcted heart tissue
- Pale areas (no blood flow) with periphreal erythema.
- Appearance of cholesterol crystal deposits
- Long slit-like clear areas... may confuse with recanalization... BUT DIFFERENT.
- Appearance of anemic infarct vs hemmorhagic infarct vs septic infarct
- white vs red vs septic
- Possible types of embolii
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marrow
air
atheroma
clots - Describe type I hypersensitivity reactions.
-
Immediate type. IgE mediated. Steps include:
Exposure to allergen
Activation of TH2 cells
Secretion of IgE by B cells
Binding of IgE to Fc receptors on mast cells
Repeat exposure to allergen
Activation of mast cells, degranulation. - Effects of biologic mediators released from mast cells:
-
Biogenic Amines, Lipid mediators --> Vascular leak, broncho constriction, intestinal hypermobility.
Cytokines, Enzymes --> inflammation, tissue damage - Type I hypersensitivity:
-
Immediate hypersensitivity.
Response releases vasoactive and spasmogenic substances that act on vessels and smooth muscle and pro-inflammatory cytokines that recruit inflammatory cells. - Type II hypersensitivity:
-
Antibody mediated hypersensitivity.
Secreted antibodies injure cells by promoting their phagocytosis or lysis and induce tissue damage by inflammation. - Type III hypersensitivity:
-
Immune complex mediated.
Antibodies bind antigens and then induce inflammation directly or by activating complement. Recruited neutrophils and monocytes produce tissue damage by releasing lysosomal enzymes and free radicals. - Type IV hypersensitivity:
-
Sensitized T lymphocytes cause the cellular and tissue injury.
Includes delayed hypersensitivity and contact dermatitis.
Naive CD4+ Tcells are exposed to antigen, differentiate into Th1 cells, which enter circulation. On future exposure to antigen, Th1 cells respond by releaseing IL-12, IFN-gamma, and other cytokines. - High affinity IgE Fc receptor (FcERI)
- Binds IgE-antigen complex, contains signalling chains that fire up intracellular signaling leading to degranulation, protoglandin and leukotriene secretion, and cytokine secretion.
- Drug Intervention for Mediators of Immediate Hypersensitivity
-
Cromolyn to block leukotriene and PAF secretion.
Corticosteroids to block inflammatory cytokine secretion.
Epinephrine or theophylline to block bronchial constriction. - Hyposensitization
- Long term exposure to antigen changes the response from IgE to IgG4, which reduces the inflammatory reaction.
- Antibody mediated cellular dysfunction...
- Antibodies against receptors can either stimulate them in the absence of true ligand or block true ligand for binding and inactivate them.
- Hemolytic Disease of the Newborn
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Rh+ father, Rh- mother.
Mother has a baby that is Rh+, Rh antigens enter the mother, sensitizing her and producing anti-Rh antibodies.
Next baby that is Rh+ has mother's antibodies cross placenta and attack baby's RBCs. - Drug induced cytotoxic reactions...
- Drugs bind to cells, say platelet. This complex induces antibody production against the complex. Antibodies and complement destroy the complex, including the cell (platelet).
- Significant of immune complex deposition.
- Activates complement and attracts inflammatory cells. Enzymes from these cells (neutrophils) destroys local tissue.
- Role of leukotrienes in type I hypersensitivity:
- VERY potent smooth muscle contraction, vasopermeability, broncho constriction.
- Type I hypersensitivity: early and late phase
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Early phase due to degranulation of biogenic amines, enzymes and proteoglycans. (histamine, tryptase, heparin)
Late phase due to lipid mediators and cytokines. (Leukotrienes, Protaglandins, PAF, ILs, etc) - During inflammation P-selectin upregulated by what and binds what?
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Histamine, thrombin upregulates.
Extravasates monocytes, neutrophils. - TNF, IL-1 upregulates what molecules in vessels?
- Endothelial adhesion molecules.
- Virally transformed neoplasms... more common in immunocompromised:
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Kaposi’s - HHV-8
Lymphoma - EBV
Cervix, rectum - HPV - Most opportunistic infections are new or reactivated?
- Reactivation of latent infections.
- Vaccines used in the immunocompromised, names and indications:
-
Hepatitis B Anti-HBc neg
Hepatitis A At risk + neg anti-HAV
S. pneumoniae CD4 > 200
Influenza Annually, Oct – Nov - Vaccines CONTRAINDICATED in the immunocompromised (live):
- Varicella, Yellow Fever, Typhoid live (Ty21a), Measles, Vaccinia
- Most common AIDS opportunistic infection, brief description?
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Pneumocystis carinii (jiroveci)
Pneumonia in profound CMI defects
Commonest AIDS-OI
Treatment- anti-protozoals not antifungals - Toxoplasmosis gondii: host, infection rates, symptom in HIV
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Cats
US- 10-35% infected, Europe. Africa >50%
encephalitis/brain abscess
Disseminated disease less common - Toxoplasmosis gondii: primary prophylaxis in HIV
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Give if toxo IgG+, CD4<100.
TMP/SMX - Cryptosporidiosis: prevention in HIV
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avoid surface water (drink,swim)
...
No effective treatment! - HIV tuberculosis: PPD characteristics,
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Skin test anergy
PPD+ 8% reactivation/yr (5mm induration +) - Common HIV opportunistic infections:
-
Cryptococcal Disease
TB
Cryptosporidiosis
Toxoplasmosis gondii
Pneumocystis carinii pneumonia (PCP)
Histoplasmosis
Coccidioidomycosis
CMV - Pure antagonist acts by...
- Preventing the action of the agonist. AGONIST MUST BE PRESENT.
- 5 types of receptor classes:
-
Integral Membrane Proteins
Transcription Factors
Enzymes
Transport Proteins & Channels
Structural Proteins - Methods of Modification of Receptor Affinity or Number
-
Internalization (sequestration)
Down-regulation (less production)
Inactivation (desensitization, poor coupling) - Methods of receptor inactivation:
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Inactivation of Signaling molecules
Production of Inhibitory molecules -
Equation to determine % effectiveness of a drug at various concentrations:
(E, Emax, [L], Kd) -
E/Emax = [L] / (Kd + [L])
If [L] = Kd, it is ED50, EC50. (Effective dose/concentration to get 50% of max effect). - Efficacy vs. Potency
-
Efficacy - the relative maximal biological response (Emax) achievable
Potency - the relative amount of drug necessary to produce a defined level of effect (ie, ED50) - Competitive antagonists effectively reduce...
- Potency of the agonist.
- Non-competitive antagonists effectively reduce...
- Efficacy of the agonist.
- 5 Basic causes of atrophy:
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Reduced functional demand - (e.g. muscle atrophy)
Inadequate supply of oxygen - (e.g. hypoxia)
Insufficient nutrients - (e.g. vitamin deficiency)
Interruption of trophic signals - (e.g. denervation)
Persistent cell injury – (e.g. radiation) - 5 basic types of necrosis:
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Coagulative
Liquefactive
Fat
Caseous
Gangrenous - Underlying mechanism of hydropic cell swelling:
-
Due to impairment of cellular volume regulation:
Plasma membrane
Plasma membrane Na+ pump
ATP concentration - Ultrastructral changes in hydropic cell swelling:
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Mitochondria - swelling
Plasma Membrane - discontinuities (blebs)
Nucleolus – segregation fibrillar and granular components - Histologic changes in coagulative necrosis:
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Pyknosis (shrunken dark nucleus)
Hypereosinophilia (bright pink cytoplasm)
Karyorrhexis (fragmentation of the nucleus)
Karyolysis (disintegration of the nucleus) - Pathogenesis of coagulative necrosis:
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Irreversible cell injury and death
Loss of the plasma membrane’s ability to maintain ion gradients in the cell
Influx of calcium in the cell
Degradation of cellular RNA’s
Precipitation of cellular proteins in situ - Liquefactive necrosis, definition and characteristics:
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Dissolution of necrotic cells and removal, rather than scar formation
Usually occurs in an abscess secondary to bacterial infection
Inflammatory dissolution of tissue
Also common with cerebral infarctions - Fat necrosis, definition and characteristics:
-
Specific to adipose tissue with triglycerides
With enzymatic destruction (lipases) of fat cells, fatty acids are precipitated as calcium soaps
Grossly- chalky white deposits in the tissue
Microscopically – amorphous, basohilic/purple deposits at the periphery of necrotic adipocytes - Caseous necrosis, definition and characteristics:
- Dead tissue persists indefinitely as amorphous, coarsely granular, eosinophilic debris...Cells do not retain their cellular outline, as they do in coagulative necrosis and do not disappear by lysis, as they do in liquefactive necrosis. Seen in TB.
- Gangrenous necrosis, definition and characteristics:
- Cell death involving an entire region (rather than an organ), resulting from loss of blood supply (coagulative necrosis) combined with infection (liquefactive necrosis).
- Stages of cellular changes in MI:
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4-12 hours – cell swelling, edema, hemorrhage
12-24 hours – pyknosis, contraction bands
hypereosinophilia
24-72 hours – karyolysis, neutrophils
3-7 days – early macrophages, dissolution of cells
7-10 days – granulation, prominent macrophages
10-14 days – prominent granulation, early collagen
2-8 weeks – progressive collagen, scar
>2 months – dense collagen scar, hypocellular - 2 Mechanisms behind cytopathic viruses:
-
Direct cytopathic viruses insert their proteins into the plasma membranes, disrupting the cells permeability
Indirect cytopathic viruses insert their proteins into the plasma membrane, creating an antigenic target for cytotoxic T lymphocytes, which disrupt the membrane
Membrane damage is the final common pathway to necrosis - Characteristics of apoptosis:
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Caspase activation and digestion of cytoskeleton.
Internal and external pathways.
Phagocytosis by resident tissue macrophages
No inflammatory reaction!!! - Extrinsic pathway of apoptosis:
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Initiated by “death receptor†of TNF receptor family which binds Fas at the Fas-Associated Death Domain (FADD).
Inhibited by FLIP (which can be produced by some normal cells and by certain viruses) - Intrinsic mitochondrial pathway of apoptosis:
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Initiated by increased mitochondrial permeability.
Bcl-2 anti-apoptotic
Bak, Bax pro-apoptotic
Balance between pro- and anti-apoptotic signals. - DNA ladder in apoptosis:
- Results from internucleosomal fragmentation. Necrosis results in random DNA fragmentation in multiples of 180-200 bp.
- Morphologic result of apoptosis:
-
Single cells affected
Chromatin condensation with peripheral aggregation
Cytoplasmic buds
Apoptotic bodies
Karyorrhexis (nuclear fragmentation) - Most common form of metaplasia and example:
- Replacement of a glandular epithelium by a squamous epithelium. (Example: respiratory epithelium in the lung from smoking, or replacement of squamous epithelium by glandular mucosa in esophagus )
- Characteristics of dysplasia:
-
Anisocytosis.
Enlargement, irregularity, and hyperchromasia of the nuclei.
Disorderly arrangement of the cells within the epithelium . - Anthracotic pigment
- Pigment from pollution stored in macrophages, usually black.
- Prussian blue stain shows...
- Iron deposition as blue.
- 3 major theories of cellular aging:
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Progressive cell injury (example - oxygen stress) lipofuscin, advanced lycosylation end-products
Somatic and mitochondrial mutations
Intrinsic cellular clocks (telomerase, clk genes) - MS/MS screening detects what compounds?
- amino acids and acylcarnitines
- Marker for medium chain acyl-CoA deficency?
- C8.
- Hb spectrum in normal baby vs trait vs hemoglobinopathy:
-
Most babies have 70% Hb F (fetal Hb) and 30% Hb A (adult Hb). The fetal Hb fades away by age six months.
Babies with abnormal traits have Hb F, A, and something else (S, C, D, E, etc.).
Babies with hemoglobinopathies have Hb F, no (or very little) Hb A, and Hb S,C,D,E, etc. - Definition of shock:
- Inability of the circulatory system to deliver suffcient oxygen and other vital nutrients to meet the normal or increased metabolic demands of the patient/tissues!
- Definition of hypotensive in terms of systolic and mean arterial pressure:
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SBP<90 or 40 mmHg less than normal
MAP<60-65
MAP = (SBP + 2DBP)/3 - Normal O2 Sat of blood entering lungs, blood leaving lungs.
-
Entering: 70-75% (SVO2)
Leaving: 98-100% (SAO2) - CO, SVR, CVP, SVO2 in HYPOVOLEMIC shock:
- low, high, low, low
- CO, SVR, CVP, SVO2 in CARDIOGENIC shock:
- low, high, high, low
- CO, SVR, CVP, SVO2 in DISTRIBUTIVE or VASODILATORY shock:
- high, low, high OR low, high
- Transcapillary refill:
- Pre and post capillary bed vessel contraction increases flow through capillaries... this reduces pressure resulting in fluid influx, restoring volume.
- Mechanism behind microcirculation dysfunction:
- Pre capillary bed vessels relax due to vasodilator metabolites. Post capillary bed vessels do not relax, leading to build up of pressure and endothelial damage in the capillaries.
- Mechanism behind capillary leak:
- Damaged endothelium leaks protein rich fluid into the interstitium = edema. Lymphatics are overwhelmed. Blood viscocity goes up and clotting occurs. As a result some tissues get huge perfusion but others get none!
- 3 stages of shock
- Compensated, progressive, irreversible.
- Mechanisms fighting to compensate: neural and humoral
-
Neural: baroreceptors, volume receptors, chemoreceptors, cerebral ischemic response
Humoral: Adrenal medulla, hypothalamopituitary, RAAS - Compensitory redistribution of cardiac output and blood volume during shock
-
More to brain, heart... other tissues vasoconstrict to conserve brain and heart.
Venoconstriction to increase venous return and preload of heart. - 4 Classes of Hemorrhagic shock:
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Class 1 (0-15% loss): few signs
Class 2 (15-30%): tachycardia, low PP, tachypnea
Class 3 (30-40%): the above + low systoli BP, oliguria
Class 4 (>40%): above + life threatening, mental changes. - 6 Mechanisms of DEcompenstation in hemmorhagic shock:
-
Cardiac impairment
Sympathetic escape
Cerebral ischemia
Metabolic acidosis
Microcirculatory dysfunction (coagulation)
Systemic inflammatory response syndrome (cytokines, leak, free radicals etc) - When do you use vasopressors in shock?
- AFTER aggressive fluid resuscitation.
- Cystic fibrosis newborn screen:
- Trypsinogen assay: its release into the circulation appears to be enhanced by abnormal pancreatic duct secretions. Follow up with further gene or sweat testing.
- Restriction endonuclease is...
- An enzyme that can recognize a specific sequence of DNA and cut the DNA within the recognition site or a designated nearby site
- PCR: (polymerase chain reaction)
- very common procedure in molecular genetic testing and may be used to: 1) generate a sufficient quantity of DNA to perform a test (e.g., sequencing, mutation scanning), or 2) may be a test in and of itself (e.g., allele-specific amplification, trinucleotide repeat quantification).
- Linkage Analyses is...
- Testing DNA sequence polymorphisms (normal variants) that are near or within a gene of interest to track within a family the inheritance of a disease-causing mutation in a given gene.
- In pedigrees, squares are what and circles are what?
-
Square = male
circle = female - Accuracy of linkage analysis depends on:
-
The accuracy of the clinical diagnosis in affected family member(s).
The distance between the disease-causing mutation and the markers.
The informativeness of genetic markers in the patient's family. - Mutation scanning is used when:
- mutations are distributed throughout a gene and most families have different mutations.
- 3 Types of mutation scanning:
-
SSCP (single-stranded conformational polymorphism): PCR, compare DNA distance on gel.
CSGE (conformation-sensitive gel electrophoresis): denature, recombine, look for mismatches.
DHPLC (Denaturing High Performance Liquid Chromatography) - In genetic testing, if an alteration is found, it can be of 5 different types:
-
Known pathogenic.
Predicted pathogenic
Unknown and unpredicted.
Known benign.
Predicted benign. - Direct DNA sequencing:
- Analysis of the entire coding region, ie get nucleotide sequence.
- Targeted mutation analysis:
- Testing for the presence of a specific type of mutation (e.g., a trinucleotide repeat expansion) or set of mutations (e.g., a panel of mutations for Cystic Fibrosis disease), as opposed to complete gene sequencing or mutation scanning, which detect most mutations in the tested region
- Allele-Specific Oligonucleotide testing (ASO):
- The detection of a specific mutation using a synthetic segment of DNA approximately 20 base pairs in length (an oligonucleotide) that binds (hybridizes) to and hence identifies the complementary sequence in a DNA sample
- Trinucleotide Repeat testing:
-
Quantification of a trinucleotide repeat may involve two methods of mutation analysis:
PCR Amplification (<100) or Southern Blot Analyses (>100) - Southern blot:
- Seperate DNA fragments by gel electrophoresis. Then add a fluroescent DNA probe complementory to the sequence we are looking for.