Cellular Adaptation, Cell Injury & Cell Death

May-12-10 12:30 PM

Aspects of the Disease Process Etiology: cause Pathogenesis: initial insult --> sequence --> manifestation Morphologic changes: cellular/tissue level of changes Clinical Manifestations: signs vs symptoms Signs: objective, what the doctor sees Symptoms: subjective, what the patient feels Treatment Stressors that cause Cell Injury Oxygen Deprivation Ischemia: lack of blood flow, lack of oxygen & nutrients; more dangerous than hypoxia Hypoxia: lack of oxygen; hypoxemia is low levels of oxygen in the blood Infections Immune Reactions: hypersensitivity, allergic reactions Mechanical trauma: fight, temperature changes, frost bite, accident, atmospheric pressure changes Chemicals, drugs (prescriptions, side effects) Drugs should only be taken for 7-14 days bc liver & kidney work on it and release lots of toxic metabolites & byproducts Nutritional Imbalances (ie: malnutrition, Kwashikor) Metabolic Diseases (ie: diabetes) Radiation Electric Shock

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Some cells are more sensitive to injury than others Neurons are very sensitive to lack of oxygen; it is very difficult to regenerate neurons Skin heals very fast Chemical injuries like to denature enzymes in the ATP production pathway
If a stressor is not removed, you could have 2 scenarios: Adaptation leads to reversible cell injury Irreversible cell injury, which leads to cell death

Mechanisms of Cellular Injury(MITOCHONDRIA IS FIRST ORGAN TO BE DAMAGED) Depletion of ATP & Mitochondrial Damage 1. Hypoxia = decreased ATP synthesis Cell Membrane in Hypoxic Injury Increased Ca in cytoplasm Alterations occur early in injury Inactivation of Na-K ATPase pump Blebbing Increased influx of Na & efflux of K Loss of specialized structures (cilia, microvilli) 2. Cell swells (influx of Na, Ca & water) Abnormal pumps = influx of water & cell swelling 3. Loss of maintenance of mbrn potential Mbrn disruption, loss of lg molecules 4. Anearobic metabolism Decreased glycogen Increased lactic acid = decreased pH (acidosis) Cellular enzymes won't work under very low pH = clumping of chromatin in nucleus ER damage/swelling Reduction in protein synthesis (ribosomes detach) Damage to Ca Pump = Influx of Ca INSIDE cell Loss of Ca homeostasis = damage to mitochondria & lysosome Accumulation of free radicals Defects in membrane permeability
Mitochondrial Damage cont'd Damage to Ca Pump = Influx of Ca INSIDE cell = damage to mitochondria & lysosome Loss of Ca homeostasis = calcification of cells & ACTIVATION of several enzymes (ie: phospholipases & endonucleases) Defects in membrane permeability --> Mitochondrial permeability increases Cytochrome C leaks out - disrupts cellular func'ns Accumulation of free radicals (ie: superoxide & hydroxyl) Eliminated by body via antioxidants (from food)

Cell Injury due to Membrane Damage Causes Irradiation Chemical toxins & drugs (ie: reactive intermediates) Bacterial toxins (ie: phospholipases) Complement system Nutritional
Lipid Peroxidation Initiated by free radicals Metabolism of P450 mixed function oxidases Reactive oxygen species O2, H202, & -OH from inflammatory cells H2O2 = good disinfectant CCl 4 is a byproduct that is harmful to the liver Cellular metabolism Consequences Mbrn dysfunction

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 Mbrn dysfunction Can break DNA strands (ie: too much exposure to UVB from sunlight causes DNA breaks) = DNA damage Protein cleavage & cross linking Enzyme dysfunction Antioxidants = Vit E, A, C, glutathione Try to increase level of transferrin, ferritin, lactoferrin, ceroplasmin, catalase, superoxide dismutases, glutathione peroxidases Whenever a free radical is detected in system, supraoxide dismutase will attack it, breaking it down to H2O2 (can still break down cell mbrn), catalase then jumps in & breaks down H2O2 into water & air; glutathione peroxidase can balance the Oxygen atom ER in Hypoxic Cell Injury Early water influx enters ER = distension & vacuolation Disaggregation & detachment of ribosomes = reduced protein -synthetic capacity Lysosomes in Hypoxic Cell Injury Contain potent hydrolytic enzymes (ie: RNases, DNases, protease, phosphatases, glucosidases, cathepsins) "Suicide bag" Hypothesis: injury to membranes = leakage = cell necrosis

Reactive Oxygen Species & Hypoxic Cell Injury Reperfusion Injury Ex: Patients w/ Atherosclerosis of coronary arteries --> must reperfuse vessels very slowly New damage may generate ROS & further accum of free radicals Ischemic injury w/ inflammation may cause an increase in leukocytes & plasma proteins = activation of complement system = worsens condition Infiltrating leukocytes
Defenses Superoxide dismutase; catalase Antioxidants: Vitamin E, C (ascorbate), glutathione

Reversible vs Irreversible Cell Injury

Reversible Injury Hydropic swelling Plasma mbrn blebs Dissociation of ribosomes Swollen mitochondria Aggregation of nucleolus Irreversible Injury Pathologic changes are permanent and cause cellular death Occurs if ischemia persists

Irreversible Cell Injury Occurs when massive Ca influx worsened when perfusion is re -established Vacuolated mitochondria w/ lg Ca deposits Nuclear changes Lysosomal mbrn injury; release of enzymes Myelin figures Enzymes will be leaked to extracellular space (CK-MB) Cells have the Innate ability to maintain homeostasis Adaptations: physiologic and/or morphologic Processes involved Direct stimulation of cells Activation of cell surface receptors, pthwys New protein synthesis Purpose: preserves cell viability, modulation of function

CELLULAR ADAPTATION Hyperthrophy Increase in size of individual cells Increased structural components Increased size & weight of an organ Not always increased functionality

Hyperplasia Increase in absolute number of cells In response to stimulus or persistent cell injury Increased size & wt of an organ
Atrophy Individual cells decrease in size & may lose function Due to disuse, denervation or interruption of trophic signals (endocrine stimulation), ischemia, or chronic injury, pressure, malnutrition Atrophic cells are NOT dead cells Aging & Alzheimers: aging process may cause loss of cells, esp in heart & brain Renal Artery Stenosis: persistent loss of blood supply will eventually cause the atrophic cells to die Increase in autophagic vacuoles --> digest cellular debris (Residual bodies = lipofuschin granules --> brown atrophy) Metaplasia Adult type cell is replaced by another type Reversible Adaptive mechanism Reprogramming of stem cells or of undifferentiated cells; done by cytokines, GF, ECM components, genes

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Adaptive mechanism Reprogramming of stem cells or of undifferentiated cells; done by cytokines, GF, ECM components, genes Most common: columnar to squamous (ie: Squamous metaplasia of respiratory tract) Most common cause: chronic irritation Other causes: Vitamin A deficiency Persistance of stressor may lead to precancerous conditions Adenocarcinoma (Barret's esophagus): squamous --> columnar

Dysplasia Disordered growth Most commonly seen in squamous epithelial cells following chronic injury Variations in size and shape of the cell Disorderly arrangement within the epithelium Nuclear changes: enlargement, irregular borders, hyperchromasia of individual cell nuclei Pre-malignant Often arises in previously metaplasic epithelium Progress to malignant squamous cell carcinoma, unless treated

Cell Injury: Intracellular Accumulations Fat (triglycerides, cholesterol, phospholipids Glycogen Lipofuschin Melanin Hemosiderosis, hemochromatosis: accumulation of iron Hyaline deposits Exogenous pigments (ie: carbon silica in lungs) = occupational hazard Irreversible Cell Injury = CELL DEATH Permanent (necrosis & apoptosis) Leads to further Ca accumulation Apoptosis: cell dies through the activation of an internal suicide program Membranes are intact, DNA/nucleus is going to dissolve Can occur in a normal way (ie: aging --> remove dying cell to prevent cancerous changes) Eliminate unwanted cells Minimal disruption of surrounding tissue Radiation, Immune system regulation, Viral infections, Cancers, Toxins Embryogenesis Menstruation Necrosis: cell & organelle mbrn removed - contents are all mixed First attacks the cell mbrn & lysosomal mbrn; cellular contents mix with cell & environment Lysosomes secrete enzymes when there is injury Cardiac Injury --> secrete CK-MB & Troponin Liver damage --> secrete AST & ALT Blebs: present in both processes; outpocketing of cell mbrn - way for cell to burst or it can engulf a particular fragment of DNA

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Cell Death Cont'd

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Morphology of Apoptosis Similar or identical to necrosis at light microscopic level EXCEPT: Tends to affect individual cells, against a bg of viable ones Absence of acute inflammatory cells Steps in Apoptosis 1. Pyknosis: condensation of chromatin 2. Fragmentation of DNA by enzymatic digestion 3. Fragmentation of Nucleus & Dissolution of nuclear envelope 4. Loss of junctional complexes & cell shrinkage 5. Fragmentation of Entire cell into mbrn-bound fragments (apoptic bodies) 6. Removal of apoptotic bodies by macrophages & surrounding cells Apoptosis Programmed cell death Normal physiological cell death Initiated by signals --> internal (genes) & external
Apoptosis involves CASPASES Pro-caspase (inactive) becomes activated by limited proteolysis Family of cysteine proteases Work in cascades, digest proteins Initiator caspases: cas 2, 8, 9, 10 Activate Effector Caspases: cas 3, 6, 7 (aka Executioner caspases) 2 Major Pathways of Apoptosis in Cytoplasm

EXTRINSIC (Fas, TNFR)

INTRINSIC (mitochondria-associated)

Mediated by caspase-8 activation --> caspase-3 Independent of cas-8 activation activation, release of cytochrome C by the mitochondria Cytochrome C interacts with cas-9 = activation of cas-3 Caspase-3: degradation of cellular proteins
Necrosis Pathologic death of 1+ cells, or a portion of tissue or organ resulting from irreversible damage 1. Denaturation of proteins 2. Enzymatic digestion of organelles & other cytosolic components Autolysis: cell digestion due to hydrolytic cytosolic components Heterolysis: cell digestion due to enzymes derived from invading inflammatory cells Nuclear Changes Karyolysis: disintegration & dissolution of a cell nucleus when a cell dies; due to DNAse activity Pyknosis: nuclear shrinkage Karyorrhexis: nuclear fragmentation Histologically, look at myelin figures --> accum of pinkish glassy materials = breaking down of cell dur necrosis Cells accumulate a lot of calcium when they become necrotic Renal stenosis: cut off blood supply to kidney = inside of cell will be lysed, but cell mbrn is still intact There is soft tissue, but it won't be liquid, cell mbrn is intact but cell is dead Liquefactive necrosis: if there is liquid in cell death; lots of macrophages & neutrophils; pyogenic (pus-forming) abscesses; common in brain; rate of cell destruction exceeds rate of repair Caseous necrosis: breakdown of cells, hyperactive inflammatory process (ie: tuberculosis of lungs); tissue destroyed around site of inflammation (cheesy-like material) Assoc w/ mycobacterium (mycolic acids w/in their cell mbrn) Coagulative + liquefactive Tuberculosis of lungs: tissue becomes non-functioning (dead) lung tissue Lung function does NOT come back --> very prone to developing secondary infection Tuberculosis in upper lung fields (bacteria are aerotolerant) --> find lesions in upper lung If lesions in lower lung --> put PTB Fat necrosis: adipose tissue; liberated fatty acids become saponified to form calcium soaps Pancreatitis: releases many lipases & proteinases (inactive w/in pancreas itself) Rigidity of back & pain in epigastric region Traumatic fat necrosis in breasts: traumatized breast cells release enzymes, accum fat inside = hardens, felt as a breast mass outside Coagulation Necrosis: most common; denaturation of cytoplasmic proteins; mycocardium, kidney & liver Gangrenous necrosis: interruption of blood supply to lower extremities or bowels Wet --> complicated by liquefactive necrosis Dry --> complicated by coagulative necrosis Fibrinoid necrosis: immune-mediated vascular damage; protein-like material in BV walls Dystrophic calcification: slowly accumulating Ca; patient has tendonitis May occur at any serum Ca level; usually occurs in previously injured tissue Metastatic calcification: calcium deposits in kidney, stomach, lung, brain, eyes, skin, subcutaneous & periarticular tissues, arterial walls Calcinosis: hyperparathyroidism, hypoparathyroidism, renal disease Steatosis: accumulation of fats/TG Lipofuschin: brown pigment granules representing lipid-containing residues of lysosomal digestion Aging or wear-and-tear pigments Commonly seen in liver, kidney, heart muscle, adrenal & ganglion cells Brown atrophy: affected viscus assumes a brownish hue due to intracell accum of lipofuscin Mainly seen in heart, liver & spleen of elderly

AGEING: progressive time-related loss of structural & functional capacity of cells leading to death Senescence, senility, senile changes

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 Intimately related to cellular ageing Factors Affecting Ageing Genetic: genes, fibroblasts Diet: malnutrition, obesity Social conditions Diseases: atherosclerosis, DM Genetic disease (ie: Werner's syndrome, progeria) Theories of Ageing Genetic Theory Ea organism has a genetically programmed finite life span Total cellular lifespan is measured by the number of cell generations, not by chronological time Modified by environmental factors Accumulated somatic damage theory Lipid peroxidation is induced by oxygen free radicals Lipofuscin has products of the peroxidation of FAs (increased in aged cells) - may mean inadeq defenses Summary Hypothesis: Allows for possible alterations in pre-determined genetic aging thru use of anti-oxidants, caloric restriction, exercise Morphologic Changes Accumulation of lipofusin pigment Loss of skin elasticity Easy bruising: fragile capillaries Glycosylation of lens proteins Cellular Ageing Mechanisms Nuclear Reduced synth of nucleic acids Telomere shortening Long stretches of repetitive seq, TTAGGG; shorten with ea cell division Cellular senescence: cells enter irreversible growth arrest Prevents accum of mutations Potent anti-cancer mechanism Telomerase: stabilize telomere length in human stem cells & reproductive cells Adds TTAGGG repeats onto telomeres Activity found in almost all human tumors = long-term proliferation of tumors Activated telomerase = additonal step in oncogenesis "Clock" genes Metabolic Reduced mitochondrial oxidative reactions Reduced protein synth, protein cross -linking Decreased cell receptors, transcrip'n factors Oxidative peroxidation of organelles

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Inflammation
May-17-10 12:30 PM

Case: swollen left foot, probably secondary to insect bite What is Inflammation Reaction to microbes & necrotic cells Vascular response + WBC response + systemic response Functions of Inflammation Protective response May become overstimulated, harmful RA, AS Hypersensitivity reactions Results may be harmful (ie: fibrous bands, scars) Two components of Inflammation Vascular Reaction Cellular reaction (blood cells, proteins, extracellular components) ACUTE INFLAMMATION Increase BV lumen Increase blood flow Increase BV permeability Escape of plasma proteins and WBC into the interstitial tissues Activation of cells in the area of injury Edema Transudate: Fluid that leaves lumen to tissue Increased hydrostatic pressure, decreased colloid osmotic pressure Less proteins in lumen due to inflammation more clear fluid leaves Sp gravity < 1.012; protein <2 g/dL Exudate: more proteins in fluid that leaves lumen Cloudy; Sp gravity > 1.020, protein > 2.9 g/dL Pus: purulent exudate; increased WBC & cell debris, yellowish fluid Edema presents whenever you have transudate or exudate Causes of Acute Inflammation Infections (Bacterial, Viral, maybe parasitic); Fungal organisms = chronic infection Trauma Thermal injury Chemical agents Tissue necrosis Foreign bodies Immune reactions Vascular Changes Changes in vascular flow & caliber Histamine & NO = vasodilation Increased vascular permeability = exudate = edema Immediate transient response on venules for 15 minutes (capillaries, arterioles unaffected) Mediators: histamine, bradykinin, leukotrienes, substance P Binding of Histamine on endoth cells = contraction via myosin cytoskeletal proteins = increase gaps bt endoth cells --> Alb & other cell mediators can escape out Stasis in 15 minutes --> allows WBCs to stay along lumen cell wall WBC margination Sustaining the vascular changes Binding of cytokines causes endoth cells to move away from eo Occurs after 4 hours and lasts for 24 hours Mediators: IL-1, TNF, interferon- Other ways to obtain endothelial permeability 1. Direct injury with necrosis & cell detachment (ie: burns, infections) Affects all vessels & platelets = increased thrombosis 2. Delayed prolonged leakage = direct effect, but causes delayed endoth damage; affects venules & capillaries Lasts for days after injury (mild to moderate thermal injury, UV, bacterial toxins) 3. WBC adhere to venules, pulmonary & renal capillaries Release toxic oxygen species, proteolytic enzymes Increased vessel permeability 4. Increase in # & size of vesicovacuolar organelles Increased transcytosis Fluids loss through channels Mediators: Vascular Endothelial GF (VEGF), histamine, substance P 5. Increased Angiogenesis Young vessels are more permeable Increased # of receptors for histamine & cytokines VEGF has vascular permeability power Principal Cell Effectors 1st 24 hours: NEUTROPHILS (bacterial infections, infarction) Come from bone marrow reserve pool Band neutrophils: less mature cells Cellular Events 1. Stasis of blood 2. Margination 3. Rolling

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Band neutrophils: less mature cells 2nd-3rd day: Monocytes (Macrophages) Eosinophils --> allergic reactions, parasitic infections, Hodgkin lymphoma Mast cells & basophils --> histamine, chronic myelogenous leukemia, myeloproliferative diseases

4. Pavementting 5. Diapedesis 6. Migration

WBC Adhesion Increased adhesion molecules (E-selectin) on vessel walls Histamine moves these molecules from their intracellular location to the cell surface TNF, IL-1 induce expression of these receptors as well Ligands are found on the WBC surface --> complex with selectins Weak bonds = rapid dissociation = rolling TNF & IL-1 produce ligands, VCAM-1 & ICAM-1 on endothelial cells Chemokines move from the injured tissue into the blood lumen & bind to proteoglycans = activate WBCs Increased ligands + activated WBCs = firm bonds Injured tissue releases a chemical concentration gradient WBCs attracted to PECAM-1 or CD3-1 = diapedesis through venules WBCs secrete collagenases --> can break through BM Adherence to injured tissues mediated through -integrins & CD44

Chemotaxis vs Diapedesis Diapedesis: squeezing in through pores Chemotaxis: mov't of WBCs toward injured tissue Most common exogenous chemoattractants: bacterial infection Most common endogenous chemoattractants: C5a, LTB4, ILs, cytokines 1. Chemoattractants bind to 7-TM GPCRs 2. Activation of phospholipases, protein kinases 3. Act on WBC mbrn inositol phospholipids 4. Increase cytosolic Ca 5. Activate GTPases 6. Increased polymerization of actin (myosin may also be involved) 7. Extended filopodia WBC Activation Increase in cytosolic Ca = activation of PK-C, PLA2 Production of Arachidonic acid metabolites Release of lysosomal enzymes = oxidative burst Increased adhesion of WBCs Increased activation of macrophages (interferon-) Opsonization & Opsonins Opsonins: antibodies (IgG), complement proteins, C3 lectins, Mannose-binding Lectins (MBL) Phagocytosis 1. Recognition Macrophages recognize the mannose found in microbial cell walls Macrophage scavenger receptors bind to microbes, LDL 2. Engulfment Pseudopods enclose the particle/organism thru the mov't of actin filaments Formation of phagolysosome complex Degranulation process 3. Oxidative Burst Glycogenolysis Increased glucose oxidation Increased reactive oxygen intermediates (superoxide ion, H 2O2, -OH radical) Intracellular Microbial Killing Oxygen-dependent killing is the MOST important microbial process Phagocytosis activates HMP shunt = oxidative burst --> supplies e- to NADPH oxidase = superoxide anion = H2O2 Killing: H2O2 + Cl --> Hypochlorite Release of acid hydrolases from lysosomes = degrade microbes Oxygen-independent mechanism Due to release of enzymes from WBCs, bacterial permeability increases Lysozyme, Lactoferrin, Major Basic Protein WBC-induced Tissue Injury Mediators: lysosomal enzymes, reactive oxygen intermediates, product of AA metabolism End event: WBCs undergo apoptotic death, ingested by macrophages Cardinal Signs Calor (Heat) --> due to increased blood flow from relaxation of terminal arterioles Rubor (redness) --> " " Tumor (swelling) --> contraction of capillary endoth cells = increased vascular permeability Mildest: extravasation of water, low MW proteins Moderate: & high MW proteins Severe: & blood cells Dolor (pain) Functiolaesa (loss of function) --> may be caused by toxic substances from degranulation

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Acute Inflammation
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Audio recording started: 12:39 PM May-18-10

Chemical Mediators Source: plasma, inactive forms cells; inside intracell vacuoles; synthesized only on demand Stimulus: microbial products, host proteins Lipopolysaccharides in cell wall Mode of Action: mediated by bonds bt receptors & ligands Chain reaction: cause release of other mediators, either amplify or neutralize initial reaction Causes effects on one cell or many cells Short half-life (easily eliminated by the body); reduce long exposure VASOACTIVE AMINES Histamine Most abundant in mast cells, but also in basophils & platelets Stimulus for release Physical injury Immune reactions, AB binding C3a, C5a (anaphylotoxins) proteins from WBC neuropeptides, cytokines (ILs) Anaphylotoxins are so potent that they cause release of Histamine Binds to H1 receptors on endothelium Action: vasodilation, arterioles, increased permeability Allergy: food (ie: seafood, peanuts) contain many antigens 1st exposure: Ab (IgE) attaches to mast cell 2nd exposure: Ab on mast cells binds to Ag = release Histamine = allergic reaction Histamine looks for H1 receptor on endothelial cell wall Vasodilation & vascular permeability (redness) Serotonin (5-HT) Source: platelets, enterochromaffin cells Stimulus: platelets + collagen, thrombin, ADP, Ag-Ab reactions IgE-mediated reactions

Acute Inflammation

PLASMA PROTEINS Complement System Source: plasma 20 compound inactive proteins (active = proteolytic enzymes) Most important step: ACTIVATION OF C3a Classical pathway (FASTEST): IgG-, IgM-activated Alternative pathway (Slower & Weaker): NO ANTIBODIES --> endotoxin, LPS, sugars, venom Lectin pathway: lectin in plasma binds to mannose in microbes Opsonization: enhancement of phagocytosis by coating w/ C3b Inflammation: increase of BV permeability and chemotactic attraction of phagocytes Cytolysis: loss of cellular contents through TM channel formed by MAC End result: Membrane Attack Complex (MAC): C6, 7, 8, 9 When C6,7,8 binds to mast cell, allows C9 to go in Other components are ACTIVE C3a, C5a (anaphylotoxins) activate AA = adhesion, chemotaxis C3b = opsonin Kinin System Source: plasma Most important stimulus: Hageman factor of intrinsic clotting pathway Triggered when collagen is exposed to these proteins (ie: when collagenase breaks down collagen in BM) Hageman factor: recognizes collagen from breakdown by collagenase; reacts w/ prekallikrein --> kallikrein --> kininogen --> kinins --> kininase, ACE (lungs) Produces bradykinin Actions Increase vascular permeability Vasodilation Contraction of sm muscle = Constriction of airways Pain from swelling Bradykinin eventually removed by ACE as it passes through the lungs
Clotting System Intrinsic Pathway Prothrombin --> Thrombin Thrombin helps convert Fibrinogen --> Fibrin = forms fibrin clot Microorganisms can hide inside clots where antibiotics can`t get to them, but clots help prevent spread of infection Extrinsic Pathway --> Tissue Factor (TF) starts process Final Common Pathway: formation of thrombin --> converts fibrinogen to active fibrin Other functions of fibrin Increase P-selectin Produce chemokines Produce endothelial adhesion molecules for WBCs Produce COX-2, PG Produce PAF, NO What Limits the Clot? Activate Hageman factor also induces fibrinolytic system Plasminogen --> Plasminogen activator --> plasmin --> solubilize clot --> increase FSP, also increases C3 Coagulation & inflammation are linked AA Metabolites Autocoids: act locally, short-lived, come from lipid mbrns of activated cells Cycloxygenases --> Thromboxane (TX), Prostaglandin (PG) Thromboxane: causes platelet aggregation & vasoconstriction Prostaglandin: LESS platelet aggregation & vasodilation Lipooxygenases --> Leukotrienes (LT), lipoxins Leukotrienes: vasoconstriction & bronchoconstriction Lipoxins may be regulators of LTs

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Leukotrienes: vasoconstriction & bronchoconstriction Lipoxins may be regulators of LTs Source: neutrophils --> interaction w/ platelet = lipoxins Action: inhibit WBC recruitment, limits inflammation
Platelet Activating Factor Source: IgE sensitized basophils; platelets, mast cells, M&Ms, endothelial cells Action: platelet stimulation, adhesion, chemotaxis, activation, vasoconstriction, bronchoconstriction If you detect very low levels of PAF = vasodilation & increased vasopermeability(opposite effects) Cytokines: Proteins which modulate the function of other cells Source: lymphocytes, macrophages TNF Primes neutrophils Septic shock --> decrease BP, decreased vascular R, increased HR, decreased blood pH Suppresses appetite Mobilizes proteins, lipids cachexia IL-1: has same effects as TNF & is a pyrogen (causes fever) TNF & IL-1 Increase endoth adhesion molecules Enzymes for matrix remodelling Increase thrombus formation of endothelium Systemic acute phase responses Chemokines Increase WBC recruitment to inflammatory sites (chemotaxis) May aid in organogenesis CXCR4 & CCR5 = HIV receptors Nitric Oxide: causes platelets to be less adherent to eo Source: endothelial cells, macrophages, neurons L-arginine --> NO synthase + increases intracell Ca --> NO Paracrine-like action Relaxation of smooth muscles = vasodilation of BVs Decrease platelet aggregation & adhesion Inhibits mast cell-induced inflammation Microbicidal, nitrogen intermediates, reactive oxygen intermediates

Lysosomal Enzymes Acid proteases: degrade bacteria in phagolysosome Neutral proteases: degrade extracell components; enhance C3 & C5a Acid hydrolases (ie: elastases, phospholipases) Neutralized by 1-antitrypsin (antiproteases) Deficiency of 1-antitrypsin = breakdown of lysosomal enzymes are deficient
Substance P Source: PNS, CNS Actions: increase pain signals, regulate BP, increase endoc secr'ns, increase vasc permeability Patterns of Acute Inflammation Serous inflammation:accum of thin fluid Comes from plasma or mesothelium Sites: Peritoneal, pleural, pericardial effusion Burns Fibrinous Inflammation: seen in greater injury --> loss of fibrinogen thru vasc lumen = formation of fibrin Persistence = ingrowth of fibroblast = BV scarring Sites: meninges, pericardium, pleura If can`t remove all the fibrin = scar tissue (common in meninges & heart) Fibrinous pericarditis: heart can`t function as efficiently Suppurative Inflammation Increased amounts of pus Only kind of inflammation in diabetics (have sweet -smelling pus) Abscess: deep seeding of pyogenic bacteria; walled off by fibrotic tissue Ulcers: Sloughing of necrotic tissue Sites: Mouth, stomach, intestines, GUT, lower extremities Outcomes of Acute Inflammation Resolution: restoration of normal tissue Healing by fibrosis: significant destruction, inflamed; tissues can`t regenerate or w/ increased fibrin (common in pyogenic infections) Chronic inflammation

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Chronic Inflammation
May-18-10 1:19 PM

Audio recording started: 1:20 PM May-18-10

Due to persistence of injury Tissue destruction and repair occurs at same time Prolonged, may be asymptomatic Causes: persistent infections --> delayed hypersensitivity; long exposure to toxic agents (ie: silica, AS); autoimmunity

Chronic Inflamma...

Cells of Chronic Inflammation Mononuclear cells --> MACROPHAGES, lymphocytes Angiogenesis is also occurring in chronic inflammation --> endothelial cells & fibroblasts M & M ("monocytes" in blood stream = "macrophages" outside of blood) Recruitment of monocytes from BV Local proliferation of macros Immobilization of macro at site of injury Activated by cytokines, bacterial endotoxins, chemical mediators Increase cell size & number of lysosomes = more tissue destruction (may be more than needed) Activation may lead to tissue destruction Granulomatous Inflammation Very common in TB, sarcodoisis, leprosy, Cat-scratch disease, Berylliosis Focal accumulation of macros in an epitheloid appearance; surrounded by lymphocytes & plasma cells Granuloma surrounded by fibroblasts and endothelial cells (formation of new BVs Immune granuloma: tubercle w/ central caseous necrosis Macros engulf the tubercle bacilli & present to Tcells --> activate other Tcells --> interferon- --> transforms macros into epitheloid cells Foreign body granulomas: foreign body can't be adequately removed Found in the center of granuloma Talc, sutures Suture granuloma: suture doesn't dissolve = keloids Lymphatics in inflammation Lymphagitis Lymphadenitis --> reactive, nodal; hyperplasia of lymphoid follicles Large & irregular-shaped, active appearing germinal centers Very red where lymphatic drainage is, swollen lymph nodes (from hyperplasia)

Systemic Effects of Inflammation Fever due to pyrogens PG (from cyclooxygenase) cause increase cAMP in hypothalamus = reset the temp center to a higher setting Triggered by: LPS, IL-1, TNF May be beneficial because could serve as a defense mechanism since not many bacteria can function at high temperatures Must make sure temperature doesn't become too high so don't dismiss the symptom when examining a patient Fever may also serve as a good indication whether antibiotics are working or not In first 48hrs, if fever doesn't go down after starting treatment - antibiotics are not working (if you had given fever reducer at same time, you would not know if antibiotics are working) Acute phase proteins C-reactive proteins (CRP) --> more released from liver during inflammation Elevated CRP may indicate inflammation, but cannot indicate WHERE the inflammation is May act as opsonins; marker for increased risk of MI Fibrinogen: rouleux formation, increased ESR (erythrocyte sedimentation rate) Rouleux formation: all RBCs stick to eo like stack of coins (heavier = faster sedimentation (higher ESR) = more fibrinogen = more inflammation) C-reactive proteins & ESR may be elevated in inflammation but DO NOT start definitive treatment/therapy based on that Leukocytes (15,000 - 20,000 cells/UI) Accelerated release from BM pool, "Left shift": BM can't wait for WBCs to mature, so it starts spilling out more immature ones (more bands, whereas mature have lobulated nucleus) Must know how to differentiate from leukemia Increased Tumor Necrosis Factor (TNF) causes Disseminated Intravascular Coagulation (DIC) LPS + TNF = increased TF on endoth cells --> coagulation (blood clots all over body) Liver injury due to cytokines = hypoglycemia Increase NO = shock = heart failure Septic shock: DIC + hypoglycemia + CV failure Renal failure (low urine output), Adult Respiratory Distress Syndrome (ARDS) = poor oxygen exchange

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Tissue Renewal & Repair

May-20-10 12:40 PM

Audio recording started: 12:45 PM May -20-10

REGENERATION Regeneration: growth of cells, tissues to replace lost structures Sites: epidermis, bone marrow, liver

Ti s s ue Renewa l ...

Regeneration requires an intact ECM (like scaffold) Serves as a scaffold for the cells Framework for cell migration Maintains cell polarity Cancerous cells lose their polarity When cells have contact with surrounding cells, they know if there are too many or too little in that space --> in cancerous growth, just keep growing Disrupted ECM --> fibrosis
ECM Collagens & elastins = strength & flexibility Protein-polysaccharide complexes to embed proteoglycans GAGs --> attract water & cations; form the hydrated gelatinous matrix (like sponge) Chondroitin sulfate, keratan sulfate & hyaluronate Hyaluronidase breaks down hyaluronic acid/hyaluronate When bacteria has collagenase, its harmful to us bc allows easy spread throughout body Fibronectins & Laminins: attach cells to matrix = pathway for cell mov't & growth Fibroblasts Macrophages HEALING Restores original structures + Collagen deposition + scar formation Regeneration is a part of healing Incl wounds, inflammatory processes, cell necrosis Tissue Repair: replacement of injured or dead cells is critical to survival; involves 2 processes 1. Regeneration 2. Fibroplasia (replacement by CT) Cell Cycle Labile Cells (ie: bone marrow) Derived from stem cells; constantly turned over Short, finite life span; die via apoptosis & rapidly replaced Myeloid cell line --> RBCs, platelets, macrophage, granulocytes (BEN) Lymphoid cell line --> B-cells (Abs) & T-cells (cytotoxic T-cells) Sites squamous epith of skin, mouth, vagina & cervix Columnar epith of intestinal tract Transitional epith of urinary tract Bone marrow cells Stable Cells (like to stay in G0 phase) Normally replaced very slowly If there is a stimuli (ie: inflammation), jump to G1 and continue thru cycle Capable of rapid renewal after tissue loss Sites Liver hepatocytes Alveolar cells of lung Epithelium of kidney tubules Permanent Cells Can't regenerate (ie: heart) If there is damage to these cells = scar tissue (non-functioning) Like Constrictive Pericarditis Scar tissue occurs after several weeks or months Before scar tissue is formed = very weak tissue that is susceptible to rupture Neurons very prone to damage when lack oxygen After Cerebrovascular Accident --> hard to regain function of limbs Neuroglial cells accum after injury --> useless Possibilities: glial cell prolif'n, skel muscle reanastomosis through satellite cells, scar tissue after MI Stem Cells Retain capacity of self renewal

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 Retain capacity of self renewal Asymmetric renewal: 2 broad populations of cells --> stem cells + differentiated cells Embryonic Stem Cells Devl'p from eggs from IVF (NOT from eggs fertilized in woman's body) Derived from 4-5d stage (32-cell stage) Used as undifferentiated cells or as differentiated cell lineages Adult Stem Cells Niches in adult tissues Specific lineages Outside BM = tissue stem cells; inside BM = hematopoietic stem cells BM Adult Stem Cell --> developmental plasticity = many differentiation options Transdifferentiation: changes from one cell type to another BM --> neurons & liver cells Other options: produce cytokines & GFs; act on existing cells = cell migration & replication Multipotent adult progenitor cells: in muscle, skin & brain (= adult version of ES cells) Differentiate into neurons, hepatocytes Growth Factors Platelet-derived GF (PDGF): platelets, macros, endothelial cells, SMCs Causes migration & proliferation of fibroblasts, PMNs, macrophages, smooth muscle cells Allows fibroblasts to migrate to area of injury = lay down fibrin & begin scar formation Epidermal GF (EGF): platelets, macros, saliva, urine, GIT contents Mitogenic: skin, liver cels, fibroblasts EGFR (ERB): TK receptor; most important --> EGFR1 & ERB 1; may be involved in breast cancer Fibroblast GF(FGF): macrophages, mast cells, lymphocytes, endothelial cells & fibroblasts React with heparan sulfate in ECM Functions: wound repair, angiogenesis, hematopoiesis, wound contracture Important for Angiogenesis (formation of new BVs) & Vasculogenesis (development of those new BVs) Angiogenesis starts the process, Vasculogenesis after Transforming GF- (TGF-): macros, T-lymphocytes, keratinocytes, malignant transformation; same EGFR If body doesn't find a way to lower TGF = cancerous growth Transforming GF- (TGF-): platelets, T-lymphocytes, macros, fibroblasts & SMCs Proliferation of fibroblasts & sm muscle cells Inhibits growth of epithelial cells & leukocytes by blocking cell cycle Cancer = high levels of TGF- & low levels of TGF- Vascular Endothelial GF (VEGF): mesenchymal cells Angiogenesis & vasculogenesis, wound healing, chronic inflammation; angiogenesis in tumors Important in chronic inflammation (has more scarring) Cytokines Hepatocyte Growth Factor: mesenchymal cells, epith cells, hepatocytes, cells of biliary sys in liver, epith of lungs & mammary glands "Scatter Factor" bc causes cell scattering & migration Could enhance cancer growth Direct Extension: cancer spreads to contiguous site Metastasis: cancer spreads to different site

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Tissue Repair & Renewal 2

May-21-10 12:41 PM

Audio recording started: 12:41 PM May-21-10

Audio Recording Case: A 33 year old female came in for scheduled caesarean section for her 3rd pregnancy. She is grossly obese and difficulty was noted in skin closure. Upon discharge from the hospital, she was noncompliant with medications, wound cleaning and hygiene. She was advised followup after 1 week for suture removal, but she did not comply. 2 weeks postop, she came with the complaint of foul-smelling discharge from her suture site: Wound debridement was done daily --> wound was left open and 3rd gen antibiotics given Pack with soaked sterile gauze to avoid anaerobic infection and make sure no space in wound After 2 weeks, significant wound improvement was noted.

Cell Growth Signalling Functions of GFs Stimulate gene transcription Reenter cells into cell cycle ECM ligand + cell receptor Autocrine: cell secretes molecules that act on itself - enhances own growth; liver regeneration, tumor growth Paracrine: molecules that cell releases acts on nearby cells (different from signalling cell); wound healing Juxtacrine: molecules are still attached to signalling cell & receptor att to target cell; 2 cells merge together Endocrine: target cell may be very distant from signalling cells (goes through blood stream) Signal Transduction Pathways Tyrosine Kinase Pathway Ligands: ECF, TGF, HGF, PDGF, VEGF, FGF, Insulin Binding of ligand activates Tyr-K Once Tyr-K is activated = increase intracell Ca = activate PKC = increase TFs If you have hyperactive Tyr-K w/o a feedback mechanism = cancer, diabetes mellitus, artherosclerosis 7-TM GPCRs Ligands: Epi, NE, Vasopressin, 5-HT, Histamine, Calcitonin, Glucagon, PTH, Corticotropin, Rhodopsin, drugs Second Messengers: cAMP & Ca 7 individual proteins embedded in cell mbrn Ligand-binding on one end to receptor which triggers GDP --> GTP Must investigate as deep as possible when diagnosing the root of the problem (ie: hypoparathyroidism could be a result of defective GPCR) Hypoparathyroidism = increased Ca = tetany (GPCR may be root of the cause) Steroid Receptors Receptor is located in the nucleus Steroid has to go through cell mbrn --> cytoplasm --> specific receptor in nucleus Activates transcription Thyroid hormones, Vit D, retinoids Regulation of Cell Cycle Initial step: G0 to G1 phase influenced by TNF, IL-6 Committed step: G1 to S (restriction point); regulated by cyclins & CDKs; HGF & TGF- CDKs: cyclin-dependent kinases --> phosphorylates RB gene & allows cell transcription Errors can occur bt G1 to S which could accumulate later on Checkpoint: occurs bt G1 & S (before replication) and bt G2 & M (after replication) so errors don't accum Collagen Extracellular framework (lysine & proline) Crosslinking = increased tensile strength Vit C = hydroxylation of procollagen Scurvy: Vit C deficiency; bleeding tendencies, teeth fall off & petichae on skin Elastin Allows for stretching & recoil of tissues (esp in BVs) Periphery = Fibrillin (microfibrils); Abundant in uterus, skin & ligaments Marfan's Syndrome = deficiency in Fibrillin 1 Core = Elastin Proteoglycans: consists of GAGs, bind to proteins & FGF Cell growth modulator, cell differentiation Heparan sulfate, chondroitin sulfate, dermatan sulfate Hyaluronic Acid: binds water; viscous gel-like; resists compression; joint cartilage Cell Adhesion Molecules (CAMs): act to integrate the cytoskeleton & ECM Integrins: cell surface receptors that allow fibronectin & laminin to attach to ECM Tissue fibronectin: fibrillin in wound healing Blood fibronectin: forms blood clots Laminins: bind cells to basal lamina Neural-CAMs: plasma mbrn glycoproteins; cell-cell adhesion, recognition Cadherins: require extracell Ca --> act to drive the adhesion of cells of particular tissue type E-cadherin (epithelial), N-cadherin (nervous), P-cadherin (placental)

Angiogenesis Neovascularization Vasculogenesis: BV assembly in the embryo using angioblasts Migrate to sites --> differentiate into arteries, veins, lymphatics, pericytes, smooth muscle cells Angiogenesis from Endothelial Progenitor Cells (EPCs) (from BM) EPCs can differentiate into Hemangioblast --> Hematopoietic Stem Cell (HSC) & Angioblasts Ischemic organs, skin wounds, tumors, vascular implants Tumors cause hyperstimulation of EPCs = tumors may be very vascular because of this which in turn provides more nutrients to the tumor which allows it to keep growing and helps spread of cancer hematogically to other organs Chemotherapy shrinks the tumor and may decrease blood supply = less complications Angiogenesis from preexisting vessels Angiogenic factor binds to endoth cell Rs (endocrine signalling) on existing BVs = activation of endoth cells

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Angiogenic factor binds to endoth cell Rs (endocrine signalling) on existing BVs = activation of endoth cells Try to migrate and proliferate Loop formation necessary bc eventually will have arterial, capillary & venule sites There are many GFs that stimulate Angiogenic factor, but there are also a lot of inhibitors Young BVs --> are very permeable compared to more mature BVs --> lose more fibroblasts --> scar formation
Scar Formation 1. Fibroblast migration & proliferation VEGF allows angiogenesis & increase endothelial permeability Exudation of fibronectin, fibrinogen --> fibroblast stroma TGF- = increased synthesis of collagen, decreased degradation of ECM 2. Amt of collagen formed is going to be balanced with amount degraded Granulation tissue (red bc still has adequate blood supply) changes to scar tissue (very pale or blend-in) Fibroblasts Dense collagen Elastic tissue fragments Minimal BVs 3. Tissue remodelling occurs: balance bt production & degradation of ECM components Matrix metalloproteinases (MMPs) uses Zinc (from macrophages & epithelial cells) Source: fibroblasts, MP, neutrophils, synovial cells, epithelial cells Enhanced by: GFs, cytokines, physical stress Inhibited by: TGF- & steroids (but this can be harmful bc decreases WBCs = decreased immunity) Collagen Regulation Collagenases cut trihelix into unequal fragments Debridement of injured sites Remodel CT Repair defects

Repair by Healing, Scar formation & Fibrosis Can start as early as 24 hrs after injury End result: restore original function Removal of Injury Proliferation of tissues Angiogenesis Granulation tissue formation Tissue remodeling Wound contraction Strengthening

Summary of Wound Healing 0.1 - 3 days --> INFLAMMATION 0.3 - 10 days --> GRANULATION TISSUE 3 days - 30 days --> WOUND CONTRACTION From 3rd day onwards --> collagen accumulation & REMODELLING Steps in Wound Healing 24 hours = increased Neutrophils Deposit ECM; would is starting to close, but very weak closure Day 3 --> macrophages replace neutrophils & granulation tissue & collagen fibersis laid down, but must still keep wound untouched since tissue is still weak Day 5 --> granulation tissue + neovascularization; more formation of BVs, epidermis is almost normal thickness Day 14 --> collagen, fibroblasts, BVs start regressing and scar becomes paler Day 28 --> intact epidermis, no inflammatory cells; loss of dermal appendages (ie: hair follicles) Clinical Surgical Correlates of Wound Healing Primary Union Healing by first intention occurs when surgeons cut along Lines of Langerhans; very neat, closed with stitches or staples Healing by secondary intention - let granulation tissue heal the wound (looks very pink) Lots of fibroblasts --> have actin filaments inside which when contract, fibroblasts bring edges of wound closer and closer together until it becomes small Large wound defects - edges are not approximated Heals with formation of granulation tissue, contraction & eventual spontaneous migration of epith cells Third intention healing (delayed primary) Leave wound open, clean & use occlusive bandage regularly Don't close completely because you don't want anaerobic infection Let heal while open for a few days and then close the wound like in primary healing Wound strength 3rd month after incision: 70-80% tensile strength of the original skin Modifications of collagen cross-linking Wound Dehiscence: deficient scar formation due to increased abd pressure Factors influencing healing Local Persisting infection, foreign material or other stimulus of inflammation Advise patient to use antibiotic ointment, 70% alcohol, iodine or hydrogen peroxide to clean Inadequent blood supply (ie: diabetics have damaged BVs which slow down healing) Excessive mov't Irradiation Locally applied drugs (ie: corticosteroids - too much will harm immunity) Systemic Increased age (ie: older patients heal slower than younger ones) Nutritional deficiencies (ie: Vit C, Zinc & protein) Metabolic diseases (ie: renal failure, diabetes mellitus) Patients with cancer have very accelerated metabolism very high catabolism --> break down most of the proteins they have in their body Systemic drugs (ie: corticosteroids) Complications of Wound Healing Formation of Contracture (esp common in severe burn victims) Exaggeration of wound contraction; common in soles, palms, anterior thorax = ltd mobility of joint Need skin grafting or cosmetic surgery Deficient scar formation Wound dehiscence: caused by increased abdominal pressure (esp common in obese patients) Ulceration: caused by deficient blood supply Excessive formation of collagen Keloids: granulation tissue goes well beyond the border of the incision Inject area with steroids after surgery to avoid keloids Can only be removed by excising Hypertrophic scar: granulation tissue is still within the margin of incision Excessive granulation tissues --> exuberrant granulation - color is very different from surrounding skin Summary & Review of Inflammation & Wound Healing

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Chapter 3 Page 15

Test 1 Answers
May-26-10 1:57 PM

Audio recording started: 2:07 PM May -26-10

Audio Recording ...

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Hemodynamic Disorders, Thrombosis & Shock

May-27-10 2:31 PM
Audio recording started: 2:31 PM May-27-10

Neoplasia

TBW = 42 L (60% body wt) ICF = 2/3 TBW (40% body wt) ECF = 1/3 TBW (20% body wt) ISF = 3/4 ECF (15% body wt) Plasma = 1/4 ECF (4.5% body wt) Transcellular (ie: CSF, aqueous humor) = 0.5 L (1.5% body wt) Basic Principals Free exchange of water, electrolytes & sm molecs bt intravasc & extravasc compartments Fluid exchanges at capillaries & small post-capillary venules Rate of exchange, in either direction, is determined by physical factors: Hydrostatic P (blood flow out of capillary) Oncotic P (blood flow into capillary) Physical nature of the barrier separating the blood & the interstitium of the tissue Whatever isn't absorbed on venule side, goes into lymphatics --> thoracic duct --> IVC Edema Too much fluid left in soft tissue = swelling Expansion of interstitial volume Localized (ie: just in one foot) or generalized Localized --> Hydrothorax, ascites accum of fluid in peritoneal cavity) Generalized --> anasarca (accum of fluid in whole body) Inflammatory or non-inflammatory source Pitting or non-pitting To see if there is edema, find a bony prominence and press - if depression still shows when you remove finger = Pitting edema In X-ray --> water always appears white see straight line bc fluid is being pulled down due to gravity to affected area of lungs Causes High hydrostatic P of veins (ie: Venous obstruction) Ex: If you have tumor in abdominal cavity that is pressing on your IVC, venous drainage can't ascend = stasis of blood = edema in lower extremities DVT causes occlusion Congestive heart failure --> heart is not pumping out from LV to aorta properly, everything backflows on venous side Varicose veins --> defective & incompetent valves = can't propel blood from the lower extremities back up to the heart Low oncotic P Cirrhosis = low Alb Malnutrition (esp protein deficient = low Alb) Nephrotic syndrome (side effect of certain diseases in kidney) --> causes defect in kidneys = lose a lot of protein in urine (protinuria) Minimal change disease --> periorbital edema; self-limited most of the time (ie: can easily treat if find source of infection of kidney) Lymphatic obstruction --> clogs area for fluid to duct... Inflammatory Elephantitis: secondary to infection transmitted by flies --> parasite in bloodstream --> penetrates tissues and lodges in lymphatics where it reproduces --> body tries to form fibrotic capsules around them to limit them = occlusion = chronic lymphatic obstruction = thickening of skin (normally shows up as hydrocele - scrotal area) Neoplastic (ie: cancer --> enlargement of lymph nodes = block) Mastectomy for breast cancer = must remove or dissect lymph nodes in axillary area = fibrosis or damage = blocks drainage from going back to arm Postsurgical (ie: swelling of arm after mastectomy)
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 Postsurgical (ie: swelling of arm after mastectomy) Sodium Retention Excessive salt intake w/ renal failure = increased tubular reabsorp'n of Na Pulmonary edema: alveoli surrounded by fluid --> difficult for gas exchange High altitudes = difficulty breathing, spit blood bc low oxy in atm; if lungs don't have oxygen, they shut down (vasoconstriction) whereas if brain doesn't have oxygen, it undergoes vasodilation) Lungs = vasoconstriction --> Hypoxia = tissue damage, very permeable endothelium --> release a lot of proteins & fluid into surrounding tissue Brain = vasodilation of cerebral arteries = cerebral edema Normal Hemostasis Maintains blood in a fluid, clot-free state in normal vessels Induces rapid formation of a localized hemostatic plug at site of vascular injury Thrombosis Pathological state: Thrombus Inappropriate activation of normal hemostatic process w/in non-interrupted vasc system 4 Steps of Normal Hemostasis 1. Arteriolar Vasoconstriction (transient) Transient; reflex neurogenic mechanisms of endothelin (vasoconstrictor from endoth) Bleeding would resume if there is no activation of platelets or coagulation systems 2. Exposure of subendothelial ECM when there is endothelial injury ECM is highly thrombogenic --> enhances formation of primary platelet plug Platelets adhere & activated --> change shape & release secretory products Aggregation of platelets = hemostatic plug PRIMARY HEMOSTASIS 3. Tissue factor released at site of injury by endoth cells Works w/ secreted platelet factors = Activation of coagulation cascade Activated thrombin & further platelet recruitment & granule release Intrinsic pathway (Inside BVs) Extrinsic pathway (tissue factor, faster) End result: fibrin deposition SECONDARY HEMOSTASIS 4. Formation of Permanent Plug Prevent further hemorrhage Polymerized fibrin & platelet aggregation Can't easily be washed away by flow of blood Counter regulated by tissue plasminogen (t-PA) to prevent excessive clotting Secreted by endothelial cells Endothelial Cells Anti-thrombotic actions Antiplatelet effects Intact, undamaged endothelial cells = barrier to ECM secrete prostacyclin, PGI2 & NO (prevents platelet aggregation - opposite of TxA2) Fibrinolytic properties Tissue-type plasminogen activator (t-PA) Clear fibrin deposits from endothelial surfaces Prothrombotic actions --> Depress fibrinolysis = more fibrin Produce vonWillebrand Factor (vWF) = can allow platelets to start binding to collagen, binds Factor VIII (extrinsic), allows platelets to bind to ea other If have defects in vWF but normal platelet count - can still have bleeding disorder Tissue factor induced by cytokines (TNF, IL-1) --> extrinsic clotting pathway Platelets & the ECM When platelets are just floating in the body, they have a different shape than when activated Activated --> very sticky and adhere to endoth wall = primary plug
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 Activated --> very sticky and adhere to endoth wall = primary plug TXA --> opposite function of prostacyclin General Reactions 1. Adhesion & Shape change mediated by vWF & glycoprotein Ib 2. Secretion (release reaction) ADP: mediator of platelet aggregation Surface expression of phospholipid complex 3. Aggregation ADP & TXA2 = formation of primary hemostatic plug Fused mass of platelets Thrombocytopenia: deficiency of platelets = spontaneous bleeding (ie: from gums when brushing), longer bleeding time (ie: from cut or scrape) To test, make small incisions on side of arm & time how long it bleeds Uremia: end-stage renal disease Aspirin: acts on cyclooxygenase pthwy = inhibition of TXA Aplastic anemia, leukemia Destruction of platelets & RBCs by prosthetic heart valves (ie: when body reacts to valve replacement = lots of fibrin around valves --> RBCs can be destroyed) Main concern: bleeding in CNS (sustained, very slow) = slow development of neurological defects (ie: dull headache that never goes away after mild injury)
Coagulation Cascade Series of conversions of inactive proenzymes to activated enzymes End result: formation of thrombin = fibrinogen --> FIBRIN Extrinsic Pathway tested by prothrombin time; (warfarin) Intrinsic Pathway tested by partial thromboplastin time; (heparin)

I am at war with Control of cascade to prevent clotting elsewhere my ex-girlfriend Antithrombins who is a PT Activated by heparin-like molecules on endothelial cells Heparin minimizes thrombosis Proteins C & S Vitamin K-dependent Inactivate cofactors Va (end common pthwy) & VIIIa (intrinsic) Plasminogen-plasmin system --> breaks down fibrin = inhibits polymerization Detected by levels of fibrin-split products (FSP) high FSP = high Plasmin
4 TESTS for HEMODYNAMICS BLEEDING TIME --> Platelets PROTHROMBIN TIME --> Extrinsic Pathway PARTIAL THROMBOPLASTIN TIME --> Intrinsic Pathway FIBRIN SPLIT PRODUCTS --> Plasmin

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Hemodynamics...
May-28-10 Audio recording started: 1:49 PM May -28-10 1:48 PM

Hemodynam ics...

Hyperemia vs Congestion Increase in blood volume in a particular site Hyperemia --> very oxygenated blood = extremity or tissue is bright red in color Active process Arteriolar dilatation Acute inflammation Release of vasoactive substances Sympathetic stimulation (ie: blushing, fever = vasodilation in periphery = cools core bc blood flows away from center) Muscular exercise, febrile state, blushing Increased redness of affected part of skin When ppl not breathing properly = not enough oxygen = lactic acid build up = cramps Congestion --> less oxygenated blood = Bluish color Passive process Impaired outflow from tissue = venous impairment --> body tries to dilate all BVs Congestive cardiac failure If right side of heart failing and doesn't go to left properly = increased blood in venous side = portal hypertension --> blood from liver doesn't leave freely = chronic congestion = damage parenchyma in liver tissues = scar formation in liver, spleen & lungs Failure in left side = problem in lungs, all blood stagnant in left atrium & can't leave thru aorta = pulmonary hypertension = congestion of lungs --> blood taken out of lungs by macrophages = heart failure cells (FOUND IN LUNGS, SECONDARY TO FAILURE OF LEFT SIDE OF HEART) Hemorrhage Rupture of BVs Trauma, atherosclerosis, inflammation or neoplastic erosion Artherosclerotic plaque activates platelets & macrophages --> eat up endothelial wall = dissecting aneurysms when rupture does not go all the way through wall Hematoma: blood trapped w/in tissues Hemoperitonium: "concealed bleeding" in peritoneal cavity (ie: defect in abd aorta) Hemothorax: injury to lung = blood accumulates in thorax Petechiae: 1-2 mm hemorrhages; thrombocytopenia Dengay fever: tournekey test --> (SP + DP / 2 = mean BP); if have dengay fever, after 5-10 mins will see small petichae on arm (>10-15 = dengay fever) Common manifestation of certain diseases Purpurae: > 3 mm; vasculitis, thrombocytopenia Ecchymosis: large subcutaneous hematoma; 1-2 cm Size depends on what type of artery & vessel is involved & rate of bleeding (body can compensate, unless there is a massive loss & chronic bleeding - peptic ulcers) Can also lead to iron deficiency anemia In eldery, considered to have cancerous nature unless proven otherwise Coagulation disorders Common in alcoholics Causes Parenchymal diseases of the liver Prolonged antibiotic intake (>14 days) --> damage flora Flora = important for digestion; source of nutrients & vitamin K In newborns, supplement Vit K bc GIT is sterile since they have not been eating Vitamin K deficiency (req'd for synth of prothrombin (II) & factors VII, IX, X)
Hereditary Deficiencies (X-linked)
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Hereditary Deficiencies (X-linked) Hemophilia A (30% due to new mutations) Deficiency of Factor VIII Hemarthrosis: bleeding in joints = swollen joints, very red; when you do aspiration of knee-joint space = blood; could just be due to bumping knee on desk Treated with Factor VIII Transfusions (from blood of volunteers) May have a lot of rejection bc components of blood is administered w/ Factor Very prone to have HIV because Factor VIII transfusions may not have been screened for HIV (ie: before 70s & 80s) Hep B & C also common in the US 'safe' factor 8 = cloned gene of Factor VIII Hemophilia B Deficiency of Factor IX Clinically indistinguishable from Hemophilia A vonWillebrand disease vWF deficiency Spontaneous mucous mbrn bleeding, excessive wound bleeding NORMAL bleeding time bc NORMAL PLATELET COUNT

Thrombus & its Composition Platelet aggregates Fibrin Trapped RBCs & leukocytes Bacteria can get trapped in thrombus also --> can't be reached by antibiotics Thrombotic cycle & influences Abnormal blood flow Hypercoagulability Endothelial Injury*** --> once you have exposure of ECM, you will already have start of formation of thrombus Most common in arterial circulation Underlying factors Hypercholesteremia --> Atherosclerotic plaques Cigarette smoke products Radiation Bacterial endotoxins --> mostly from Gram -ve bacteria bc release LPSs Pathology: exposure of subendothelial collagen, adherence of platelets, release of tissue factor & local depletion of prostacyclin

Alterations in normal blood flow also lead to thrombus formation Turbulence: slower blood flow; Causes damage to endoth wall Disrupt laminar flow --> brings platelets into contact w/ endothelium More common on arterial side Artherosclerotic plaques Stasis Can create venous thrombi Aneurysms: local stasis Blood isn't moving --> Platelets can settle down to periphery & stick to endoth wall More common on venous side Sickle cell disease: sickle-shape, with sticky nobs on outside; blood flow more sluggish Hypercoagulability increases thrombus formation Genetic: Factor V gene mutations Mutant Factor V is resistant to anticoagulant effect of Protein C = coagulated blood Acquired Obesity --> increased cholesterol lets the blood become sluggish Late Pregnancy & Postpartum --> hormone related or amniotic fluid infusion
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Obesity --> increased cholesterol lets the blood become sluggish Late Pregnancy & Postpartum --> hormone related or amniotic fluid infusion Amniotic fluid infusion: during late pregnancy or deliver, break of sinusoids between maternal & fetal circulation allows amniotic fluid to enter the maternal circulation --> hypercoagulability and immune problems due to rejection Disseminated cancers --> Tumors release procoagulants Advanced age Excessive bed rest Immobilization (ie: DVT) Antiphospholipid Ab syndrome Common in women with SLE & pregnancy (continuous miscarriages) Body has Ab that activate platelets = inactivation of prostacyclin --> platelets aggregate Arterial Thrombi Endothelial injury & turbulence Coronary, cerebral & femoral Grey white, firmly adherent to vessles Lines of Zahn: alternating pale pink bands of platelets with fibrin & red bands of RBCs Venous Thrombi No Lines of Zahn Commonly cause stasis Tail-end is freely mobile; easily fragmented Resemble coagulated blood Most common site: leg veins Usually seen in vessels surr prostate (Periprostatic plexus), uterus & ovaries (Periuterine vessels) Fate of Thrombi Propagation: continues to grow; accumulate more platelets & fibrin & obstruct a critical vessel Embolization: dislodged thrombi transported to other sites in vasculature breaks down (esp near tail) until it finds a vessel where it will block Embolus: pc of blood clot that breaks away Thromboembolism most common --> could be distant from actual thrombus Pulmonary Embolism DEEP LEG VEINS (not varicose veins) --> all the way inside, less muscle to help cause contraction, can break off and cause massive pulmonary embolism --> difficulty breathing, cough up blood, maybe due to immobilization (stasis situations) Venous side --> IVC --> RA --> RV --> Pulmonary vasculature Embolism w/ Pulmonary infarction Saddle embolus: right in the middle of bifurc of arteries --> goes to R & L sides of lung; eventually Undergoes infarction --> tissue dies off slowly Embolism w/o infarction Paradoxical embolus: starts on venous side and jumps to arterial side = coronary embolism Patient probably has septal defect between 2 atria Venous --> IVC --> RA --> LA --> LV --> Aorta Arterial Emboli: common when have aneurysm Usual source: heart or atherosclerotic vessels Aneurysm: dilation of BV, endoth wall balloons out (becomes very weak) - can easily rupture Vegetation in heart or vessels (ie: usually secondary to infection or when have artificial valves) = fibrin forms on valves --> too much mov't causes them to be dislodged --> go into arterial circulation Most commonly affect lower limbs & brain Less common: kidneys, spleen, intestines & upper extremities Fat emboli Usual source: fracture of long bones, burns or soft tissue injury Fat released into blood --> enters BVs if there is a break in the vessels & can lodge Pulmonary insufficiency; neurological symptoms Air emboli: 100 cc of air needed to cause clinical effect
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 Air emboli: 100 cc of air needed to cause clinical effect Usual source: obstetric procedures, chest inuries Trauma to chest (ie: car accident) --> fracture lung --> air escapes Obstretic procedures --> air can enter myometrium (ie: during D & C procedure) Diving --> when ascend too fast, nitrogen that is dissolved in blood changes to air bubbles which lodge in muscles.. = decompression sickness Chronically --> little emboli can accumulate, no decompression chamber; in the long run = Caisson disease Amniotic fluid embolism: important cause of maternal mortality Usual source: amniotic fluid during delivery During labor, there's break in placenta and some fluid enters circulation --> fat from baby = irritates blood stream --> body recognizes it as foreign = Abs Neurological defects Infarction Total occlusion of artery Partial occlusion more often leads to atrophy Red infarct: occurs in organs w/ dual blood supply (ie: lung, liver) - usually enough time for blood to find a way around block bc collateral circulation Pale infarct: in organs w/ end arteries --> no dual supply (ie: kidney) Septic infarct: where bacterial growth is common (ie: necrotic tissue of an infarct becomes seeded w/ bacteria = abscess or embolization of infected cardiac vegetations) Dissolution/Resolution: removed from fibrinolytic activity Organization: induce inflammation, fibrosis OR reopen to allow blood flow Recanalization: form canals so eventually blood flows through Clotting & Biomaterials Artificial valves can form thrombus bc body may recognize them as foreign Artificial surfaces create an imbalance bt activation & inhibition systems Proteins in the complement cascade func'n as inflam mediators Excessive thrombus formation & exaggerated inflammatory response Biomaterials are now coated with a non-thrombogenic surface or add heparin (ie: dialysis tubes or IV canulas) Shock Systemic hypoperfusion Cause: reduction in either cardiac output or effective circulating blood volume Congestive heart failure (low CO), low circulating blood volume (ie: hemorrhage) INITIAL EVENT: Transient VASODILATION Phases of Shock 1. Non-progressive phase: compensated by vasoconstriction (blood goes to vital organs) 2. Progressive stage: hypoperfusion; shift to anaerobic metabolism = ACIDOSIS 3. Irreversible stage: shock keeps progressing Cardiogenic shock: failure of myocardial pump caused by myocardial damage, extrinsic pressure or obstruction to outflow Aortic stenosis: closure of valve bt LV & aorta; flow impeded Cardiac tamponade: pericardial space filled with blood --> all blood pulled to venous side (jugular vein is very dilated), blood can't go out into aorta so it remains in LV, LA, RV, RA Arrhythmia: contraction of heart isn't coordinated --> everything contracts at the same time --> blood isn't moving forward = stagnant in heart Hypovolemic Shock (ie: hemorrhage, diarrhea in children esp, vomitting, burns) Hemorrhage Fluid loss (ie: vomiting & burns) Burns --> blisters filled with fluid or fluid (from ISF & BVs)lost from open areas Dehydration Anaphylactic Shock: IgE Abs = release of Histamin = smooth muscle contraction & capillary dil Capillary dilatation = peripheral blood cooling, all BVs dilated Septic Shock Cause: peripheral vasodilation & pooling of blood; endothelial activation & injury,
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 Cause: peripheral vasodilation & pooling of blood; endothelial activation & injury, activation of cytokine cascades Secondary to Gram -ve bacteria & release of endotoxins LPS causes direct activation of platelets & cytokines LPS also causes inflammation --> TNF & ILs = vasodilation DIC common --> microbial infections, endotoxic shock & fungal sepsis
Disseminated Intravascular Coagulation (DIC) Hemorrhagic syndrome Clots & clot lysis occurs at same time all over body (venules, caps, arterioles) Uncontrolled activation of clotting factors & fibrinolytic enzymes throughout small BVs --> depsoited fibrin Low platelets High fibrin split products Long bleeding time, Long prothrombin time, High PPP Tissue necrosis & bleeding everywhere Causes: septicemia, pregnancy (hypercoagulable state & hormone changes), transfusion (less common now due to extensive screening), trauma, malignancy, acute pancreatitis (release of enzymes), nephrotic syndrome (less Alb) Clinical Presentation --> bleeding everywhere Extensive bruising Bleeding of old venipuncture sites Renal failure --> no urine outpute Gangrene Bleeding in uterus, lungs, CNS Blood culture --> Broken RBCs, Schistocytes (not specific for DIC but are usually deformed), decreased platelets, fibrin degradation products (Fibrin dimers) Extremity infarction Stroke DVT

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Neoplasia
May-31-10 1:34 PM
Audio recording started: 1:36 PM May-31-10

Neoplasia

NEXT TEST: JUNE 11

Neoplasia Neoplasm, new growth --> can be benign or malignant (= cancer) Abnormal tissue mass Uncoordinated growth, exceeds adjacent normal tissue Persists after cessation of the stimuli (ie: hormones, enviro factor) which evoked it Derangement of normal growth ctrl mechanisms Imbalance bt cell division & cell death --> Less cells dying (ie: apoptosis, necrosis) Cancer --> tumor cells have problem with p53 --> mutated cell cont's to divide = growth in which a normal cell can't be found If you can do a biopsy of a certain cancer 1 g of cancer tumor : 30 population doublings in 90 days 1 kg of cancer tumor : 40 population doubling Solid detectable cancer means at least 1 completed cell cycle Growth depends on --> Doubling time, growth fraction, rate of cell loss Growth fraction: portion of cells in proliferative pool (how many cells in mitosis) The bigger the tumor, the faster it grows & spreads, more cells in growth fraction Chemotherapy works better if most cells are M cells Some cells are non-responsive to chemo bc they are in G0/at rest Sometimes, do operation before chemo bc induces cells to undergo mitosis Excessive growth --> Neoplastic (benign, malignant) or non-neoplastic (hyperplasia) Benign Neoplasms Definate border, doesn't invade normal tissue (capsulated) capsule comes from surrounding normal tissue which undergoes atrophy Easy to remove bc has cleavage plane bt actively growing benign tumor & normal tissue Local invasion: spread to nearby locations "oma" + cell of origin Fibroma: fibrous tissue Adenoma: glandular tissue Papilloma: surface epithelium (ie: skin, larynx, tongue) Cystadenoma: adenomatous papillary processes that extend into cystic spaces (ie: ovary) Grow slowly, low mitotic rate Well-differentiated

Malignant Neoplasm Invades surrounding normal tissue (no capsule) Metastasis: spread to distant locations Carcinoma (epithelial) Sarcoma (mesenchymal) Lymphoma (mesenchymal) Melanoma (neural crest) Germ cells (gonadal tissue) Faster growth, high mitotic index Poorly-differentiated

Epithelial Neoplasms (90%) Stratified squamous Squamous cell papilloma (benign) Squamous cell carcinoma (malignant)
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 Squamous cell carcinoma (malignant) Epithelial lining from glands or ducts Adenoma (benign) Adenocarcinoma (malignant) Urinary Epithelium (transitional) Transitional cell papilloma (benign) Transitional cell carcinoma (malignant)

Mesenchymal Neoplasmas Connect Tissue (ie: Bone) Osteoma (benign) Osteosarcoma (malignant) Smooth Muscle Leiomyoma (benign) Leiomyosarcoma (malignant) Striated (skeletal) Muscle Rhabdomyoma (benign) Rhabdomyosarcoma (malignant) Vascular Hemangioma (benign) Angiosarcoma (malignant)
Neoplastic Progression Normal --> Hyperplasia --> Dysplasia --> in situ carcinoma --> invasive carcinoma --> Metastasis May have higher risk of developing cancer w/o treatment Characteristics of Neoplasia Nucleus very large Increased mitoses in nuclei Loss of polarity Tumor giant cells Anaplasia Pleomorphism

Anaplasia Lack of differentiation (reverts to a less mature cell) Don't resemble normal cells Difference in function Difference in morphology Well-differentiated --> more common in benign tumors Patient will have better prognosis bc still have some similarity with normal cells Poorly-differentiated --> more common in malignant tumors Large nuclei, very dark nuclei (hyperchromatic), atypical mitosis Pleomorphism: higher the rate, higher degree = more neoplastic, poorly differentiated Atypical mitosis --> instead of bipolar mitosis, tripolar & quadripolar mitosis Loss of polarity --> very irregular Dysplasia Loss of uniformity of individual cells Similarity to malignancy Pleomorphism Hyperchromatic nuclei (ie: darker staining nuclei) Difference from malignancy Abundant mitotic figures are still normal Does NOT always lead to Cancer --> can be precancerous if stressor is still there Mild to moderate changes may revert to normal if stressor is removed Involvement of entire thickness: CIS
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Mild to moderate changes may revert to normal if stressor is removed Involvement of entire thickness: CIS Carcinoma in situ (CIS): full-thickness dysplasia (BM --> surface of epithelium) Rate of growth Doubling time of tumor cells Fraction of replicating cells Fast growing tumors --> high cell turnover Chemotherapy --> fraction of replicating cells Invasion vs. Metastasis Metastasis: spread of tumor to distant sites Lymphatic/hematogenous routes Seeding of body cavities (ie: pleural, pericardial, subarachnoid & joint space) Reduces cure rate Invasion: growth into the surrounding tissue by direct expansion Benign --> fibrous CT/capsule from native cells Cleavage plane Capsule doesn't prevent tumor growth

Pathways of Spread Seeding of Body Cavities If primary tumor is near cavity, it can easily spread into that area Ovarian cancer --> cells spread into peritoneum --> invades peritoneal lining pseudomyxoma peritonei) Lymphatics Tumor spread is via nearby lymphatics, follows natural routes of drainage Sentinel lymph node: 1st node that receives flow from primary tumor If you can detect enlargement of Left Supraclavicular Node = Virchow's node When there's a block of cancer cells in thoracic duct = node becomes bigger --> sign of possible abdominal cancer Radiolabeling & dyes --> if accum in LSN = indicates growth in that area LN enlargement Growth of cancer cells Reactive hyperplasia, may limit cancer growth TLN classification Hematogenous Pass through veins more easily bc walls are thinner Spread to lungs & liver first Near vertebral column --> paravertebral plexus Thick-walled arteries are less common, but may invade pulmonary capillaries Primary breast cancer will usually show lung involvement (if cancer in lower extremities usually involves liver)
Differentiation Well-differentiated: if normal cell secretes hormones, these cells might secrete hormones at a faster rate so larger amt of hormone in circulation detected Poorly-differentiated: poor resemblance to normal cells Use cell markers AFP can be used as a marker for a malignancy rel to liver/hepatic sys Can produce totally different hormones (ectopic hormones) Ex. Certain types of lung tumors start producing PTH = hyperparathyroidism

Importance of Tumor Differentiation Site of origin in metastatic disease Prognosis well-differentiated often has better prognosis Poorly differentiated have worse prognosis TTx: surgery for well-diff & pallative care for poorly-diff or when surgery not an option
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 TTx: surgery for well-diff & pallative care for poorly-diff or when surgery not an option Epidemiology of Cancer 1/5 Americans die of cancer Men --> most common prostate, lung & colon Women --> most common breast, lung & colon Lung & colon cancer 2nd & 3rd most common

Geographic Factors Age, sex, nationality/country of origin/race can influence diagnosis Stomach cancer is higher in Japanese people (ie: use a lot of preservatives like MSG) Skin cancer more common in New Zealand (bc sun exposure) Environmental Factors Alcohol abuse (liver, oropharynx, larynx, esophagus) Smoking (oropharynx, larynx, esophagus, bronchi, lungs, pancreas, bladder) Asbestos (occupational) --> lung cancer, mesothelioma, GIT Vinyl chloride --> angiosarcoma, liver cancer 2-Napthylamine --> bladder cancer The older you are, the more likely to get cancer Heredity Possible higher risk (esp with autosomal dominant or familal cancers) Inherited cancer syndromes (AUTOSOMAL DOMINANT) Retinoblastoma Breast cancer Defective DNA repair syndromes (AUTOSOMAL RECESSIVE) Xeroderma pigmentosum Familial cancers --> 1st degree and maybe 2nd degree relative will have cancer (doesn't have to be same cancer Must take note of age that relative had cancer (if 20-30yrs very likely that its familial) Multiple tumors (breast, brain, colon)
Other Predisposing Conditions Regeneration, hyperplasia, dysplasia, metaplasia Chronic inflammation Chronic pancreatitis H. pylori gastritis --> bacteria that is a known carcinogen Viral Hepatitis C Ulcerative colitis, Crohn's disease Precancerous conditions (ie: Leukoplakia of oral cavity, penis, vulva)

Grading Tumor Grade: histological estimate of malignancy of tumor Criteria Degree of differentiation Number of mitosis Cellular atypia Invasiveness Low-grade --> well-differentiated High-grade --> poorly differentiated Tumor Stage: clinical estimate of extent of tumor spread (seen at time of surgery); BETTER TNM staging system criteria T: size of primary tumor N: extent of regional lymph node spread (must count how many nodes) M: presence of metastatic disease

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Chapter 7 Page 29

Neoplasia Cont'd
June-01-10 1:39 PM
Audio recording started: 1:44 PM June-01-10

Neoplasia Cont'd

Carcinogenesis is a multistep process Devl't of all human cancers req's the accum of multiple genetic changes Inherited mutations Acquired mutations Occurs outside cell cycle Hybrid BCR-ABL gene produces an abnormal 'fusion' protein that activates cell activities that Increases rate of mitosis Protects cell from apoptosis Inherited mutation ie: translocation bt Chromo 9 & 22 --> BCR close to ABL = Leukemia Mutation leads to cancer bc when you bring sites together = increases rate of mitosis and prevented from undergoing apoptosis Burkitt Lymphoma: t(8:14) --> c-myc protooncogene Chronic Myelogenous Leukemia (CML): t(9:22) --> bcr-abl Acute Lymphocytic Leukemia: t(9:22) --> bcr-abl

Tumors are derived from monoclonal expansion of a mutated cell 1 defected cell --> tumor cells --> all have same defect Normal Regulatory Genes Proto-oncogenes Control normal cell growth & mutation When always switched on = cancer Just 1 defective proto-oncogene can cause cancer Oncogenes Mutated/de-regulated proto-oncogene Inappropriate expression leads to cancer Activation of Growth Promoting Oncogenes Oncogenes are derived from protooncogenes by Change in gene seq = new gene product (oncoprotein) Cause oncoprotein to be produced or over-expression of a normal protein Mechanisms of oncogenes activation Point mutations (RAS) Chromosomal translocations (C-MYC, ABL) Gene amplification (N-MYC, ERB-B2) Insertional mutagenesis: insertion of 1+ bases by viruses; leads to continuous replication
Oncogenes & GFs Increased PDGF --> astrocytoma, osteosarcomas RAS --> increase secr'n of TGF-a --> astrocytoma Autocrine stimulation --> positive fdbk (esp RAS & ) Mycooncogenes --> Burkitt's Lymphoma --> translocation 8:14; cancer of salivary/parotid glands = huge facial deformities Erb-B2 --> breast, lung, ovarian cancers

Inactivation of Tumor Suppressor Genes Regulatory genes (Trans or Cis) --> suppress cell div Need 2 defective genes to inactivate bc recessive Inhibition of signal transduction Adenomatos polyposis coli (APC) --> many polyps in colon --> Adenocarcinoma NF-1 --> Neurofibromatosis --> defects in eyes & brain --> inactivation of NF gene Cytoskeletal stability NF-2 --> Acoustic neuromas & meningioma Tumor suppressor genes
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NF-2 --> Acoustic neuromas & meningioma Tumor suppressor genes Retinoblastoma (Rb) --> Chromo 13q --> retinoblastoma, osteosarcoma BRCA --> breast & ovarian cancer P53 --> Li-fraumeni syndrome = multiple primary cancers Cell cycle & Apoptosis P53 --> activation by DNA damage (ie: carcinogens, hypoxia, or abnormal rel of hormones) Arrests cells in G1 or before it hits mitosis so that cell can try to repair itself Limits growth & prolif of abnormal cells Defective p53 = prolif of abnormal cells & will not undergo apoptosis P21 --> has to be activated by p53 before functions
Regulation of Apoptosis Genes promoting apoptosis --> p53 Most common signals Carcinogen-induced DNA damage Abnormal proliferative signals Hypoxia Loss of cell adhesion Bcl-2defect --> follicular lymphomas C-myc w/ p53 --> promotes apoptosis w/o p53 --> inhibits apoptosis = leukemia & lung cancer

Proapoptotic Bcl-2 Family Members Bax, Bak, BH3 in mitochondrial mbrn & cytoplasm Stimulus (ie: ionizing radiation) activate these proteins Prevent BCL-2 from inhibiting proapoptosis --> apoptosis should occur These proteins have to work alongside Cyt C & caspases = cell destruction Cyclin & Cyclin Kinases Cyclin is a separate protein from CDK CDK has to bind to cyclin to be activated (via phosphorylation) CDK-cyclin 'jumpstarts' cell cycle and then separates Cyclin D-CDK4 complex phosphorylates Rb gene --> promotes cell replication = S Phase Cyclin E-CDK2 complex --> further progression into S Phase --> initiates DNA replication Cyclin A-CDK2 complex --> regulates events in mitotic prophase --> transition from G2 to M phase Cyclin B-CDK1 --> initiates mitosis Inactivation = exit from mitosis --> cells return to G1 or G0 phase
CDK Inhibitors Regulate activity of cyclin-CDK complexes Function as tumor suppressors Cip/Kip --> composed of p21, p27, p57 INK4/ARF --> blocks phosphoryl'n of CDK4 --> blocks phosphorylation of Rb, cells remain in G1 Cell Cycle Checkpoints G1/S phase: check for DNA dmg; if seen --> arrest in cycle to allow repair or apoptosis G2/M phase: monitors completion of DNA rep, checks if mitosis can occur, checks if sister chromatids can separate (important in ionizing radiation); if damaged = cells remain in G2

Growth Factor Receptors There may be defect in receptors = activate tyr-k in cytoplasm w/o binding to GF Multiple Endocrine Neoplasms (parathyroid, adrenal, pancreas) --> all have primary cancers Mutated RET protein --> MEN 2A & 2B Complete loss of RET protein --> Hirschsprung disease Overexpression of Receptors More chances for to att to receptors = cell prolif Overexp of normal forms of c-MET receptor due to gene transc --> Papillary thyroid carcinoma

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 More chances for to att to receptors = cell prolif Overexp of normal forms of c-MET receptor due to gene transc --> Papillary thyroid carcinoma Overexp of normal form of ERB-B1 (EGF receptor gene) Squamous cell carcinoma of lung Glioblastomas, head & neck tumors ERB-B2 --> breast, ovary, lung, salivary gland Summary of Tumor Characteristics Self-sufficiency in growth signals Insensitive to growth inhibitory signals Evade apoptosis Defective DNA repair Limitless replicative potential Sustained angiogenesis --> rapid growth Huge areas of necrosis if growth of tumor is faster than growth of BVs Invade & metastasize (not in benign tumors)

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Neoplasia Cont'd
June-02-10 1:47 PM
Audio recording started: 1:47 PM June-02-10

Neoplasia Cont'd

Questions 1. A 56 yo male presented with chronic left upper quadrant pain & wt loss; lab exams showed point mutation of RAS gene. The most likely primary malignancy is in the GIT: when RAS is mutation = continuous mitosis (mostly in GIT) ***Always associate RAS with GIT*** 2. A 76 yo female w/ CML was given a novel drug, Imatinib mesylate. This drug is highly specific to cancer cells bc it acts BCR-Abl region: 9-22 translocation (Philadelphia chromosome)= abnormality of Tyr K = increased replication Tyr K pthwy is also common in noncancerous cells, but this drug has minimal side effects bc specific to cancer cells (only acts on BCR-Abl region) 3. A 5 yo male diagnosed w/ translocation 8:14 & subsequent abnormality in MYC protein; likely diagnosis is... Burkitt's Lymphoma: common in younger patients; small cell carcinomas of lung secrete a lot of ectopic hormones Mutation of MYC gene = sustained transc'n of other genes which lead to neoplasia - N-MYC --> Neuroblastomas - L-MYC --> small cell cancer of the lung 4. A 4 yo child was noted to have a unilateral white corneal reflex; lab exams showed mutation of 2 alleles of the Rb gene. Mode of inheritance is RECESSIVE Unilateral white corneal reflex = retinoblastoma (bilateral could be congenital cataracts) Mutation of 2 alleles of Rb gene --> Recessive: the first time 1 allele is exposed to genetic mutation = no abnormality, 2nd hit comes from environmental factors = abnormal phenotype --> Knudson's 2 hit hypothesis Rb is inactive in phosphorylated form Active Rb = block cell cycle Retinoblastoma could occur w/ normal Rb gene bc CDK could be defective 5. A 35 yo female diagnosed with Li-Fraumeni syndrome w/ defective p53. Chemotherapy was initiated, but she was unresponsive; resistance to chemotherapy may mean... All cells w/ p53 mutations = unresponsive to chemotherapy; if you have some normal functions of p53 = more responsive Complete lack of p53 function causes damaged cells to persist & chemo may damage the cells further, but no apoptosis Presence of SOME normal function of p53 means that the cells affected by chemo will be cleared via apoptosis 6. A 56 yo male presented w/ adenomatous polyposis coli. Abnormality may be in... APC, B-Catenin, or both APC & B-catenin abnormality may lead to formation of polyps & cancer APC downregulates B-catenin Mutated APC = increase levels of B-Catenin = increased cell proliferation B-catenin decreases E-cadherin = decreases cell adhesiveness Decreased levels of E-cadherin = invasion & metastasis (ie: cancers of esophagus, colon, breast, ovary & prostate) 7. 56 yo male diagnosed w/ Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Genomic instability of cells due to... DNA repair --> APC end up having numerous polyps, but this is non-polyposis (in microsatellite

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sequence) --> can still get cancer (sequence is always constant; defects in microsat seq area becomes very short or very long) --> proto-onco become oncogenes; Mismatch repair genes detect microsatellite instability Microsatellites: tandem repeats of 1-6 nucleotides found throughout the genome Errors lead to expansion & contraction of microsatellites Errors accum in protooncogenes (tumor suppressor genes) Nucleotide excision repair --> Xeroderma pigementosum (UV-B is bad) --> pyrimidine dimers break & no repair by NER = abnormal DNA replication Defective homologous recomb --> ataxia telangiectasia, Bloom syndrome, Fanconi anemia Steps in Invasion Down-regulation of E-cadherin = less adhesion of cells Tumor cells secrete proteolytic enzymes OR stimulate via cytokyines host cells to secrete the enzymes (matrix metalloproteins, MMPs act on Collagen IV) Cleavage products are growth promoting for the tumor & cause chemotactic factors to be released, increased new formation of BVs (angiogenesis); invade BVs & able to attach to platelet Tumor-platelet complex enhances tumor survival & protects tumor from our immune system Tumors get stuck at constrictions in BV in endothelium & try to penetrate through ECM to a favorable site Since liver & lungs take up a lot of venous drainage, tumor will metastasize here Tumor cells may have adhesion molecules which like ligands on target organ endoth cells; may also secrete chemokines Metastasis: tumor invasion at a distant site

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Neoplasia Cont'd
June-03-10 1:38 PM
Audio recording started: 1:39 PM June-03-10

Neoplasia Cont'd

Carcinogenic Agents Chemical --> 2 steps, Initiation & Promotion Radiation Viral/Microbial
Chemical Carcinogenesis Highly reactive electrophiles , form covalent complex bt carcinogen & DNA Most targets = protooncogenes; RAS, p53 Initiator --> irreversible DNA damage to cell, but not enough to cause cancer (no tumor) Direct acting initiators: converted in liver by Cyt P450 Alkylating or acetylating agents; weak initiator activity Indirect initiators (procarcinogens) Breakdown products of pro-carcinogens (inactivation by Cyt P450) are toxic Certain indiv have poorer metabolic activity of Cyt P450 (depends on race, region) = less metabolites = protected from conversion to carcinogens Promoter --> reversible damage (cell could still recover after promoter gone) Acts to augment the damage by initiator Leads to cell prolif directly, or indirectly Proliferation encourages subsequent mutations & malignant transformation Promoter has to always be there in order for malignancy to occur Promotion can only occur if you have initiation first Hormones (ie: supplements & exogenous hormones), phenols, drugs If you just have initiator = no tumor If you have initiator followed by promoter = tumor If you have initiator followed by promoter in constant succession = tumor If you have promoter first and then initiator = no tumor If you have only promoter NO initiator = no tumor If you have initiator first followed by promoter, but there is time for cell to recover bt promoters = no tumors Sometimes cancers can be prevented Initiators Cyclophosphamide, busulfan, chlorambusil = Anti-cancer drugs Cause death to cancer cells and normal cells (ie: hair follicles) Chemotherapeutic drug also acts on GIT(ie: causes vomitting, malabsorption) Chemotherapy may also act on bone marrow = low WBC counts Can cause leukemia & lymphoma Binds to DNA, disrupts cell cycle Weak direct-acting initiator Polycyclic aromatic hydrocarbons from tobacco, smoked fish Very potent procarcinogen Cancer in the region of contact (ie: lung & bladder cancer) Lung cancer, bladder, breast, stomach, esophagus, tongue cancers Smoked meats & fish = many carcinogens esp stomach cancers Aflatoxin B1 from mouldy peanuts Direct initiator --> causes mutation of p53 Higher incidences of hepatocellular carcinoma (in States this is secondary to hepatitis & alcohol) Aromatic amines & azodyes Azo dyes: food coloring, FDA regulated Cytochrome P450: induce hepatocellular carcinoma Beta napthalamine + glucoronic acid --> activated by urinary glucoronidase = breakdown products --> bladder cancer
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breakdown products --> bladder cancer Nitrosamines & Amides (ie: preservatives) Nitrates are procarcinogens; converted to nitrites (carcinogenic) in GIT Gastric cancer, GI cancers Asbestos --> mesotheliomas, lung cancer, GI cancer Vinyl chloride --> liver cancer Chromium & Nickel exposure --> lung cancer Arsenic --> skin cancer
Promoters Irritants (ie: cigarette smoke, viral infections) cause reactive hyperplasia Hormones (ie: Estrogen) --> builds up endometrium, if given w/o progesterone = endometrial hyperplasia = endometrial carcinoma Obese --> more obese = more peripheral fat & peripheral conversion to estrogen Bile acids --> colon cancer, stimulated by dietary fats High fat & low fiber diet can cause colon cancer (low fiber is cancerous bc longer bt bowel mov'ts and carcinogens stay in body longer) Radiation Highly mutagenic, small poriton of malignancies 2 forms --> UV (sun) & Ionizing (ie: X-rays & particulate) UV Radiation UV-B most carcinogenic (UV-C lesser extent) Squamous cell, basal cell, possibly malignant melanoma By acting directly on DNA = break pyrimidine dimers Nucleotide Excision Repair --> helps put broken dimers back together Deficiency of NER = Xeroderma pigmentosum If not deficient, use up all the enzymes to repair = cancer later UV light also causes mutations in p53 and RAS Ionizing Radiation Xrays, gamma-rays, CT scans, Particulate ( particles, particles, protons, neutrons) Hiroshima & Nagasaki Children --> any xray to head & neck increases chances to thyroid cancer Acute & Chronic Myelogenous Leukemia, breast, colon, thyroid & lung cancers Resistant: skin, bone, GIT

Viral & Microbial Carcinogenesis H pylori, scystosoma (bladder cancer), parasite that causes carcinoma Viral Oncogenes Carry genes that induce cell replication as part of viral life cycle Viral infection mimics or blocks these normal cellular signals necc for growth regulation RNA virus in cytoplasm DNA viruses replicate in nucleus & can incorporate into our genome Virus DNA forms stable assoc w/ host's DNA Transcribed viral DNA transforms host cell Papilloma viruses, Epstein-Barr (EBV), Hepatitis B (HBV), Kaposi sarcoma herpes virus HPV --> 16 & 18 (high risk); low risk --> 31, 35, 33, 51 E6 & E7 protein secreted & acts directly on p53 & Rb (inactivates) = accel cell growth = cauliflower-like lesions which are found in genitalia Starts as cervical dysplasia Can be treated if go for early screening (ie: Pap smear) Cigarrette smoking, bacterial infections (ie: syphillis), diet, hormones HPV Vaccine (Gardasil) Most effective when given to younger girls (before sexual activity) Men are also exposed to HPV so can also take Gardasil to prevent penile and anal cancer (common in homosexuals & MSM) Epstein-barr (EBV) --> translocation from chromo 8 to 14 = activation of MYC gene Inhibits APCs Down-regulates immune system so that it doesn't know you have a lot of these
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 Down-regulates immune system so that it doesn't know you have a lot of these infected cells = many tumors Inhibit Ag-presenting pathways --> less recognition by cytotoxic T-cells AIDS + EBV = B-cell tumors in lymphoid tissues /CNS Burkitt's lymphoma (Africa) & Nasopharyngeal carcinoma (Asia) Appears in States (esp Texas & California) bc immigrants HTLV-1 RNA retrovirus targets/transforms T-cells Disease: T-cell leukemia/lymphoma Common in Japan, Caribbean, sporadic elsewhere Transmitted via body fluids, blood, sex; affects CD4+ cells TAX gene --> encodes for transforming ability --> genome unstable = increased mutations = increased prolif of defective cells Longer latent period, 20-30 yrs compared to HIV/AIDS (5-10 yrs) H pylori Not all strains cause cancer; High-risk strains --> (+)CagA gene Associated with Peptic ulcer disease Urease breath test Patient asked to drink urea-containing liquid, if do have infection, urea will be broken down and secreted in urine Strain that is positive for CagA gene is the only one that can result in cancer Cag-A gene Buries it self in mucous layer & inserts its genome in host cell Exotoxin --> VacA = Gastrointestinal injury Secretes alkali which reacts with acid = neutralize = stays for long time Chronic gastritis --> Atrophy --> intestinal Metaplasia --> Dysplasia --> Cancer Gut-associated lymphoid tissue (GALT) or MALT --> --> 11:18 translocation Ttx: Proton-pump inhibitors and antibiotics (14 days) Autoinnoculation (ie: don't wash hands properly --> ingest virus) Hepatitis B Virus (HBV) Can be incorp'd into your genome Secretes HBx --> disrupts cell growth --> binds to p53 Aflatoxins + Hep B = more changes of hepatocellular carcinoma Histological Diagnosis of Cancer Complete excision (easier in benign tumors bc have capsule) Biopsy --> just take a portion of tumor --> can be office procedure w/o anesthesia Fine needle aspiration (FNAB) --> common for cystic lesions in breast, can also use syringe Cytology smears (ie: Pap smear) Immunohistochemistry Cheapest, non-invasive May be helpful in confirming tissue of origin of metastatic or poorly diffrnt'd tumors Monoclonal Abs (manuf in labs from hybridoma); when injected, att to target cells Serum tumor markers, actin, CD markers, intermediate filaments Serum tumor markers: usually normal cellular components that are increased in neoplasms; may also be elevated in non-neoplastic conditions AFP = hepatobilliary tract --> Protein Specific Antigen (PSA) = prostatic cancer After treatment, tumor markers should go down but if you see that there is a sudden increase in tumor markers = cancer has returned If tumor marker levels don't change after treatment could mean that all of tumor hasn't been removed or there is a tumor somewhere else Clinically useful markers AFP --> Hepatocellular carcinoma; nonseminomatous testicular germ cell tumors, yolk sac tumor b-HCG --> Hydatidiform moles not cancerous but could = choriocarcinomas Calcitonin --> medullary carcinoma of thyroid (hyperthyroid) Carcinomembryonic Ag (CEA) --> colorectal cancer, carcinomas of lung, pancreas, stomach & breast CA-125 --> Ovarian cancer
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CA-125 --> Ovarian cancer CA19-9 --> Pancreatic cancer Placental alkaline phosphates --> Seminoma Prostatic acid phosphatase & PSA --> Prostate cancer S-100 --> Melanoma, neural tumors, astrocytomas Alkaline phosphatase --> Metastases to bone, obstructive biliary disease, Paget's disease of bone

Paraneoplastic syndromes (PNS): systemic synd caused by remote effects of neoplastic disease Certain symptoms can't be explained by the neoplasia (ie: lung neoplasia & bone pain) Another tumor could be secreting a tumor = other clinical manifestations ACTH --> Small cell carcinoma of lung, pancreatic tumors = Cushing's syndrome SIADH --> small cell carcinoma of lung, intracranial tumors PTH-like peptide --> squamous cell carcinoma of lung, renal cell carcinoma, breast cancer, ovarian cancer; hypercalcemia IGF --> hepatocellular carcinoma, hypoglycemia Serotonin --> pancreatic carcinoma, bronhial adenoma, gastric carcinomas --> carcinoid synd Polycythemia --> renal cell carcinoma, cerebellar hemangioma = EPO secr'n Acanthosis Nigricans: soft thickening of skin (usually around neck & axillary folds) Circumsribed melanosis consiting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae & other body folds Cutaneous manifestations of internal malignancy Common manifestation of internal malignancy (esp GIT; lung cancer) Adenocarcinomas (gastric) Lung --> bronchoalveolar, squamous cell, small cell Melanoma & Sarcomas Tripe palms --> very prominent ridges; intracellular tumor, rough thickening of finger prints; yellowish color; diffuse palmo-planter keratodermia Venous thrombosis Migratory superficial thrombophlebitis (Trousseau's sign) Gastric carcinoma Primary tumor in pancreas (also in prost, lung, liver, bowel, ovary, lymphoma & leuk) Hypercoagulability state Cancer causes occlusion in ankle then upper limb, hip, causes thromboplebitis wherever it occludes Multiple endocrine neoplasia **** MEN-I Pituitary tumors Parathyroid adenomas (benign) Pancreatic tumor MEN-IIa Medullary carcinoma of thyroid Pheochromocytoma Parathyroid adenoma MEN-IIb Medullary carcinoma of thyroid Pheochromocytoma Mucosal neuromas in lips & tongue

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Test 2 Answers
June-08-10 1:55 PM
Audio recording started: 1:56 PM June-08-10

Test 2 Answers

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

Abnormal pap smear w/ HPV+, abnormal cervical cells w/ intact basement membrane --> carcinoma in situ Wt loss for 4 mths, lesions in lumbar spine, high PSA, was treated for cancer before --> metastasis Abnormal cervical cells in upper 1/3 surface of epithelium --> cervical dysplasia (anaplasia accepted) Fixed 4cm mass, poorly defined borders --> invasion (malignant) Leiomyosarcoma of right thigh with lesions in lung, brain & liver --> metastasis Adenocarcinoma of lung --> lymphatic spread Leiomyosarcoma --> hematogenous Squamous cell carcinoma --> lymph Melanoma --> hematogenous .. Recessive gene defect w/ resistance to chemotherapy --> p53 gene Recessive gene defect, unilateral white corneal reflex --> Rb gene 4 cm cancerous mass in lower esophagus, poorly defined border --> E-cadherin Picture = neurofibromatosis --> NF-1 = BRCA gene Many elevated reddish lesions everywhere (allergic reaction) --> Anaphylactic Shock High grade fever, hyper tension, Gram- bacteria after surgery --> Septic Shock Muffled heart sounds, distended neck veins, fluid in pericardium --> Cardiogenic Shock Lose consciousness 1 day after giving delivery (=prolonged effects of epidural) --> Neurogenic Shock Internal bleeding from lacerated spleen --> Hypovolemic Shock Fracture of left femur --> Fat embolism Fetal skin, lenugo in lungs of woman --> Amniotic fluid embolism Atrial septal defect --> Paradoxical embolism Surfacing from deep sea dive --> Air embolism DVT --> Pulmonary thromboembolism Pitting edema, chronic congestive heart failure --> increased hydrostatic P Alcoholic, cirrhotic liver (hypoalbuminemia)--> decreased plasma oncotic P Localized edema after mastectomy --> lymphatic obstruction Enlarged lower extremities, thickening of skin (elephantitis) --> lymphatic obstruction Anasarca (whole body swollen), poor caloric & protein intake --> decreased plasma oncotic P

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Hypersensitivity Reactions
June-10-10 Audio recording started: 1:41 PM June-10-10 1:40 PM

Immune Diseases

Case Impression: hypersensitivity reaction, acute Type I Hypersensitivity Initially localized allergic reaction Portal of entry --> could have localized reaction initially hives or itchiness --> if through skin through eyes --> watery eyes and nose swelling nose, eyes --> conjunctivitis hay fever, asthma Hay fever (pollen levels high in the morning) pollen is very high in the morning when sun comes out and pollen become heavier they settle down to the ground and do not affect so much hypovolemia decreased blood volume Systemic anaphylaxis: severe difficulty breathing, CV responses, hypovolemia (due to severe vasodilation) Pollens --> birch tree & rag weed Drugs --> penicillin Tell nurse to check the drug reactivity by using very small amounts of medicin on skin Loading dose is very high compared to maintenance dose Food --> nuts, eggs, seafood Mast cells & basophils --> granulocytes Blue granules contain a lot of histamine Proteoglycan which can break down Inflammatory reaction Very few basophils compared to neutrophils (neutros high dur infection) Agranular --> lymphocytes & monocytes Granular --> basophils, neutrophils, eosinophils 1st exposure --> SENSITIZATION Ag presented to TH cells via APC = release of Ils (esp IL-13) --> IgE IgE just attaches to mast cells 2nd exposure --> Ag binds to IgE, which is already att to mast cells = increase Ca inside mast cells = leakage through cell membranes of all mediators (vasoactive amines, lipid mediators, cytokines) Vasoactive amines --> hypersensitivity rxn mins after repeat exposure to Ag Cytokins --> late phase rxn --> 2-8 hrs after repeat exposure to Ag Immediate phase Mucous formation & bronchoconstriction = ltd air lumen = trouble breathing Smooth muscle spasm Late phase --> don't need additional exposure; inflam & tissue distruct'n (ie: mucosal epith dmg) Atopic allergy: localized reactions Systemic anaphylaxis Vascular shock Edema Dyspnea Type 1 Mediators Primary: Histamine, proteases, acid hydrolases, heparin Secondary: Histamine (20x more potent) Prostaglandin D2 = most abundant mediator = bronchospasm & increased mucus secr Leukotrienes C2 & D4 = most potent vasoactive & spasmogenic agents; more active than histamine in increasing vascular permeability & causes bronchial sm mus contrc'n Cytokines = important in late phase rxn; IL-4 & 5 amplify TH2 initiated immune rxn
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than histamine in increasing vascular permeability & causes bronchial sm mus contrc'n Cytokines = important in late phase rxn; IL-4 & 5 amplify TH2 initiated immune rxn 50% chance that child will devl'p allergy (atopy) like parent Patch test: use very dilute samples = localized reactions (no system anaphylaxis) Penicillin is sometimes the only drug that can be used, but if patient is allergic to it, you have to DESENSITIZED Inject very dilute amt of allergen under skin = stimulates B-cells to release IgG The next time you are exposed to Ag --> IgG prevents attachment of allergen to IgE Case: 1 yo has yellowing of skin & umbilical stump; no fever, negative for sepsis; blood type A Rh+ Impression: Rh incompatibility
Type II Hypersensitivity Blood transfusions Hemolytic disease of newborn ABO incompatibility Goodpasture's syndrom: hemopurea, hemoptosis Ab mediated Ag on cell-surface (ie: RBCs) + reacting Ab (IgG or IgM) If patient has A Ag on RBCs and is transfused with B blood --> MAC eats up RBCs = release of Hb & you have hemolysis = febrile reactions & rashes NK cells can bind to Ab = direct cell lysis Ag is already att to a cell = fast reaction Rh incompatibility: mother (Rh-), father (Rh+), child could inherit father's blood type 1st pregnancy will be fine, but will devl'p Abs (IgG) bc had no meds If there is a break in placenta, there is mixing of maternal & fetal blood If 2nd baby is also Rh+, IgG crosses placenta = immune reactions When patient had the miscarriage the first time, she should have been given RhoGAM (Abs against Rh+ cells) which agglutinate fetal red cells as they enter the mother's blood, thereby preventing her from forming her own Abs C Ag is on extracell tissues + AB --> complement activation --> C3a, C5a --> monocytes, neutrophils Myestinia gravis: Abs react to cell surface receptors & Ach can't be found in those areas = muscle weakness Grave's disease: hypothyroidism Ag found on cell surface Complement reacts to Ag on cell surface

Case: hematurea, very hypocellular glomeruli & reduction in Bowman's space Impression: poststreptococcal glomerulonephritis, Type 3 Hypersensitivity
Type III Hypersensitivity Exogenous or endogenous Ag Ag is free in plasma (not att to involved organ) Damage via action of neutrophils & platelets in underlying tissue Serum sickness Glomerulonephritis Lungs (aspergillosis) Case: weeping, pruritic, erythematous lesions on her hands (appear after latex gloves) Impression: contact dermatitis, Type IV Hypersensitivity (T-cells)

Type IV Hypersensitivity Delayed type Involves memory cells Stimulates NK cells & T-lymphocytes Completely cellularly mediated (NO Abs) CD8 cells --> viral infection or tumor cells Chronic diseases that end up giving you skin lesions = granulomatous TB (TPP, Mantoux) Test) Leprosy

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TB (TPP, Mantoux) Test) Leprosy Blastomycosis, histoplasmosis Toxoplasmosis Leishmaniasis Mantoux tuberculin skin test (TST) Transplant rejections HLA Polymorphic See slide for HLAs
Host vs Graft T-cell-mediated transplant rejections Direct Pathway Graft has dendritic cells on surface or migrating to the LN --> triggers CD8 --> CTLs CD4 cells of host release cytokines Indirect Pathway APCs of host process the Ags which present to Tcells Hyperacute Rejection (mins to hours) Preformed AB in patients blood react to donor's Ag (cross-reacting Abs) Preivous history of rejection = accelerated secondary rejection Pathogenesis Ag-Ab formation Ig + complement deposits in endoth walls = thrombi formation Obstruction of blood flow = cyanotic, mottle, flacid tissue (blue) Acute Rejections (days to years) After cessation of immunosuppressive drugs Cellular immunitiy Mononuclear cell infiltration, edema, interstitial hemorrhage Hyperactive CD4 & CD8 cells Humoral immunity Rejection vasculitis Chronic Rejection (months to years) Fibrosis sets in & organ atrophies

Graft vs. Host Reaction When you transplant, the Abs from transplant will react with Ags of host Generalized rash initially Jaundice if there is a lot of liver involvement Hyper-pigmented sclerotic plaqes on back Thymus involution = brings down immune defenses bc can't produce cells

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Autoimmune Disorders
June-11-10 1:38 PM
Audio recording started: 1:39 PM June-11-10

Immune Diseases C...

Case A 55 yo woman was admitted for evaluation of a 1 wk history of dyspnea and pleuritic chest pain. She had a mild, nonproductive cough and chills were noted. Over the next several days, she devl'd progressively increasing dyspnea on exertion & bilateral, sharp, anterior chest pain that worsened with inspiration, supine position & mov't.

3 years ago, she would have recurrent episodes of facial rash & arthritis. She was seen by a dermatologist and given continuous prednisone (10-50 mg/d).
The remainder of the past medical history, a miscarriage; family history unremarkable.

Physical Exam: moderate respiratory distress --> BP = 160/90 mmHg, HR = 120 bpm, RR = 30-40, T= 99.1, lung sounds were decreased halfway up on the left & 1/3 way up on the right
Xray: significant amount of haziness on right & left sides, breath sounds when oscultating; right border of heart is large and can't see left border bc haziness ECG: valvular masses (mitral valve) Autopsy: vegetations all over valve leaflets Impression: cardioresp arrest, constrictive pericarditis, bilateral pleural effusions, Systemic Lupus Erythematosus (SLE) Autoimmune Disorders Assoc w/ loss of self tolerance & subsequent reaction against host's own tissue Nervous system: Myasthenia Gravis GIT: Crohn's disease, Ulcerative Colitis, Primary Biliary Cirrhosis BVs: Temporal Arteritis Blood: Autoimmune Hemolytic Anemia Skin: Psoriasis Endocrine glands: Grave's disease, Hashimoto's Thyroiditis Multiple organ systems: Rheumatoid Arthritis, SLE, Scleroderma, Polymyositis, Dermatomyositis, Spondyloarthropaties, Sjogren's Syndrome

Systemic Lupus Erythromatosus (SLE) Type III Hypersensitivity --> has free floating antigens Inflammatory multi-sys disease of unknown etiology
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Type III Hypersensitivity --> has free floating antigens Inflammatory multi-sys disease of unknown etiology More prevalent in black women; reproductive age (up to 35) Genetic link Environmental factors: hydralazine, procainamide, penicillamine; hormones, UV light Pathology Immune complexes form in the microvasculature --> complement activation --> inflam'n Ab-Ag complexes deposit on BM of skin & kidneys; complex = DNA + Ig + complement Damage vasculature/walls = inflammatory reaction Skin, kidneys = renal failure = death IgG-type Antibodies Serum Anti-nuclear Antibodies (ANAs) Antibodies to native dsDNA Fatigue: most common constitutional symptom Active SLE Medications Lifestyle habits (ie: sleeping habits) Fibromyalgia Affective disorders (ie: depression) --> early morning awakenings & like to sleep a lot Head & Neck Manifestations Butterfly rash (Malar rash): first sign in 50% of cases Erythematous maculopapular eruption after sun exposure, oral ulcerations Xerostomia: Discoid lesions/rashes (non-puritic - not itchy); thick, scarring, usually raised or flat, red w/ well-defined borders; sun-exposed surfaces don't itch Proteinuria (0.5g/dL) or cellular casts results from damage to renal vasculature CVS: Pericarditis, Pericardial effusion Libman-sacks endocarditis: sterile vegetations (don't have bacteria), can lodge in BVs = thrombosis = emboli (no infection in area) Respiratory: pleuritis, pleural effusion, chronic interstitial lung disease Blood: thrombocytopenia, autoimmune hemolytic anemia, leukopenia RENAL FAILURE = leading cause of death Most commonly involved visceral organ 50% devl'p clinically evident renal disease All patients have abnormal biopsies (ie: women could have discharge in urine normally) First few years are usually asymptomatic Acute or chronic renal failure --> uremia, fluid overload Acute nephritic disease: hypertension & hematuria Nephrotic syndrome: edema, weight gain, hyperlipidemia Mesangial GN Hypercellular glomerular Deposits of membrane around glomeruli; reduced Bowman's spaces Sclerosing of glomeruli = occlusion Auto-antibodies ANA screening test (other autoimmune diseases could be positive for ANA also) Anti-dsDNA: high specificity; CONFIRMATORY Anti-Sm: most specific Ab for SLE; CONFIRMATORY Anti-SSA (ro) or Anti SSB (La): SLE and Sjogren syndrome Anti-RNP: mixed connective tissue disease and SLE Anticardiolipin: SLE and antiphospholipid Ab syndrome Lupus anticoagulant: multiple tests to screen for inhibitors in clotting cascade; APAS Coombs test: POSITIVE Anti-histone: drug-induced lupus ANA Treatment Try to delay onset of renal failure for as long as possible & improve quality of life Start w/ weak meds first then gradually increase to stronger meds so don't devl'p tolerance NSAIDs = symptomatic relief for arthralgias, fever & mild serositis Antimalarials: mediating subtle immunomodulation w/o overt immunosuppression Lupus skin rashes, arthralgias & arthritis Prevent lupus flares Reduced morbidity & mortality If stronger pain relievers don't work (ie: towards end) Immunosuppressant drugs (ie: methotrexate) IV Immunoglobulin (Passive immunity) --> tries to eliminate foreign Abs in system

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IV Immunoglobulin (Passive immunity) --> tries to eliminate foreign Abs in system Corticosteroids (use carefully, because can accelerate onset of chronic renal failure) Rheumatoid Arthritis Type III Hypersensitivity, autoimmune disease Mostly in females due to hormonal influence Age of onset usually between 25-35 yrs HLADR4 (Chromosome 6) Pathology CD4+ Tcells --> cytokine production --> TNF-a, IL-1 Primary targets of inflammation --> synovial membranes, articular structures Chronic synovial hypertrophy Effusion Synovitis Pannus formation: inflammatory cells, fibrosis, less synovial fluid, cartilage gets eaten up = bone rubbing against bone Articular destruction, capsular stretching, tendon rupture Tendons will be stretched bc decreasing space in joint Extra-articular Devl'p nodules Tendon sheath vasculitis Myopathy & neuropathy Criteria Morning joint stiffness lasting longer than 1 hr before maximal improvement Arthritis involving 3 or more joints (since autoimmune, all joints should be affected) Arthritis of hand: PIP & MCP joints Swan-neck deformity of fingers, ulnar deviation of MCP joints Early symptoms Tendon crepitus: when trying to press down on knee, can hear noise Tiredness, weight loss, malase Myopathy Late Symptoms Joint destruction Pain Deformity instability More prone to devl'p fractures & dislocations Xray Joint space narrowing Peri-articular osteopenia Erosions Cardiac: Carditis, pericarditis Pulmonary: pleuritis, intrapulmonary nodules, interstitial fibrosis Hepatic: hepatitis Ocular: sleritis, episcleritis, dryness of eyes Felty Syndrome RA Neutropenia Splenomegaly --> eventho spleen is enlarged, it doesn't function; very prone to devl'p bacterial infections Higher rates of morbitiy and mortality Diagnosis Elevated ESR (not specific for RA) - in all inflammation cases so most useless test (+) RF (Rheumatoid Factor): 70% of patients (+) ANA: 30% of patients (also seen in SLE, so not best test) Joint-fluid analysis WBC = 2,0000-50,0000/mm3 No crystals No bacteria If negative for bacteria and positive for inflammatory cells, can diagnose w/ RA Gouty arthritis: high uric acid crystals in fluid

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Keratoconjunctivitis sicca & RA Dry eyes 25% of patients w/ RA Ocular discharge Foreign body sensation Episcleritis develops to scleromalacia if untreated Treatment: artificial tears, NSAIDs, steroids & cyclophosphamide (severe) Rest --> salicylates --> NSAIDs, DMARDs
DMARDs Non-biologic DMARDs: Methotrexate, glucocorticoids, sulfasalazine, cyclophosphamide, hydroxychloroquine gold injections, d-penicillamine, minocyclne, azathioprine, cyclosporine Biologic DMARDs: etanercept, adalimubab, infliximab, rituximab Case

56 yo w/ difficulty swallowing dry food , drinks liquids frequently to ease swallowing Eyes always dry up Physical Exam: decrease in lacrimal secr'n & many dental caries There must be problem with salivary & lacrimal glands

Sjogren's Syndrome Slowly progressive, inflammatory autoimmune disease HLA-B8, HLA-DR3, DRW52, DQA1, DQB1 Body produces lymphocytes that act on exocrine glands (esp salivary & lacrimal) Lymphocytic infiltrates replace functional epithelium = decreased exocrine secretions Keratoconjunctivitis sicca Eye complaints: dryness, burning, itching, foreign body sensation Prone to devl'p abrasians in cornea (common in contact lens wearers) Rose Bengal staining: use to check if there are abrasians Dry tongue = difficult to chew & since no saliva in oral cavity = food stuck in gums = dental carries Dryness in mouth could = oral thrush 80% --> Xerostomia Difficulty chewing Dysphagia, taste changes, fissures of tongue & lips Increased dental carries Oral candidiasis Mucosal dryness: skin, vagina, genitalia, lower parts of GIT, upper airways (= chronic bronchitis), renal tubules Diagnosis Characteristic auto-Abs Salivary gland biopsy (more invasive) Labs RF & ANA SS-A/Ro 60% SS-B/La 30% Schirmer test: tests production of tears No. 41 test strip of Whatman filter paper Strip placed near the lower conjunctival sac Get strip of filter paper bend 1 end and let it hang on lower eye lid for 5 mins - test the amount of liquid on filter paper (<5 mm = Sjogrens) Normal: > 15mm of strip wet by tears after 5 mins Positive: < 5mm is wet after 5 mins Treatment: none; mainly symptomatic management (treat whatever patients says is wrong) Lubricants Artificial tears Sugarless gums (stimulate salivary glands if they're still functioning) Pilocarpine has many side effects Cholinergic agents

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Primary Immunodeficiencies
June-14-10 Audio recording started: 1:40 PM June-14-10 1:40 PM

Immune Diseases C...

Primary Immunodeficiencies Immune defects mostly inherited from parents Classified based on site of lesion in the pathway Depending on pathway, you can determine which enzyme will be affected and how severe Ex: ADA deficiency affects both Pro-B & Pro-T cells Earlier in pathway = more serious diseases 10 warning signs 8+ ear infections w/in 1 yr 2+ serious sinus infections w/in 1 yr 2+ months on antibiotics with little effect 2+ pneumonias w/in 1 yr Failure of infant to gain weight or grow normaly Recurrent, deep skin or organ abscesses; image shows spontaneous peritoneal abscesses 2+ deep-seated infections Recurrent, persistant oral thrush after age 1 (image shows candida albicans in mouth) Need for IV antibiotics to clear infections Family history of primary immune diseases

Primary Immunodeficiency Diseases Antibody deficiency disorders Bruton's agammaglobulinemia (X-linked infantile hypogammaglobuilnemia) Most severe B-Cell Immunodeficiency --> decreased or totally absent B-cells Low levels of Ig or totally absent levels (esp. IgG) Defective B-cell TyrK gene (btk gene) --> gets signals from Ag receptors --> B cell When you have class switching, Ag still has to be processed first (need btk gene) Pneumonia presents after baby is ~6mo (takes this long to show bc still has maternal Abs) = fever, chills, shortness of breath, occasional pain when breathing Sinusitis: accum of fluid in sinuses; excessive mucus = clogged sinuses = infection TTx: lifelong IgGs & prophylactic antibiotics IgA deficiency: most common in caucasians Body starts producing autoAbs that kill & neutralize IgA (have normal IgM & IgG) Important in secretions, nostrils, skin (at portals of entry) Can devlp Celiac Disease (malabsorption syndrome due to absence of rugae) & cancer Atopic disorders = scaling in scalp area from allergic reactions Recurrent sinopulmonary infections Neurologic diseases Autoimmunity Malignancy 80% of these patients can be ASYMPTOMATIC TTx: Antibiotics (not prophylactic or lifelong), IgA not recommended Cellular immunodeficiency disorders DiGeorge's syndrome (Congenital Thymic Dysplasia) Pathological Hallmarks Conotruncal abnormalities Absence or hypoplasia of thymus & parathyroid glands Absent, few or Abnormal T-Cells Physical appearance Hypertelorism: eyes are wide apart Micrognathia: small chin Short philtrum Fish mouth: small mouth Antimongoloid slant Low-set ears Cleft palate
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 Cleft palate Xray --> no thymus (just see air) Labs Low PTH = hypocalcemia = tonic convulsions/tetany Flow cytometry measures function of T-cells when Ag is presented to them Estimate number of T-cells in peripheral blood; proliferative responses to mitogens & antigens Best --> KARYOTYPING = defect/deletion in chromosome 22 Catch 22 Syndromes vs VCFS Velo-Cardio-Facial Syndrome (Shprintzen Syndrome) Cleft palate Heart abnormalities Learning disabilities 180+ other clinical findings Catch 22 = one of the most common genetic disorders in humans Cardiac defects Abnormal facies Thymic hypoplasia Cleft palate Hypocalcemia 22q11 deletions Ttx: calcium & Vit D supplements, bone marrow & thymus transplant, surgical correction of cardiac anomalies (ie: septal defects, trilogy of phalo), infection precautions Severe Combined Immunodeficiency (SCID) Defects in both humoral & cellular mediated immunity; occurs in 1:100,000 births Lack of lymphoid cells (ie: thymus, peripheral lymph organs) = small thymus & maybe no LNs LNs important for Ag processing bc a lot of T- & B-cells mixing in periph LNs Children usually die by 1 yo Adenosine Deaminiase (ADA) deficiency ADA & PNP --> remove the toxic metabolites which are formed by T-cells & B-cells Autosomal recessive Severe T & B cell lymphopenia Increased opportunistic infections Deficiency of adenosine deaminase (ADA) or purine nucleotide phosphorylase (PNP) Accum of toxic metabolites in lymphocytes = impaired DNA synthesis Ttx: gene therapy using patient's stem cells X-linked recessive Usually common in baby boys May have normal B-cells, but T-cells will be very low or abnormal Abnormal IL-2 receptors Ttx: Bone marrow transplant, PEG-ADA & Gene therapy ($$) Partial combined immunodeficiency disorders Wiskott-Aldrich syndrome x-linked recessive WASp defective (important in cytoskel of T-cells, phagocytes, dendritic cells for APCs) Key regulator of actin polymerization in hematopoietic cells --> bridge bt signalling & mov't of actin filaments in cytoskeleton T-cells, platelets, phagocytes, dendritic cells = defects in formation of microvilli, filopodia, phagocytic vacuoles Initially normal T-cell numbers, then reduces towards adulthood Low platelets, Low IgM/IgG Initial manifestation --> prolonged bleeding at circumcision or from umbilical stump (ie: days instead of hours); bruising, bloody diarrhea, thrombocytopenic purpura, eczema, recurrent infections Ttx: steroids, antibiotics, immunoglobulins Ataxia-Telangectasia Chronic Granulomatous Disease Defect in NADPH oxidase Inability to produce superoxide ions
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Defect in NADPH oxidase Inability to produce superoxide ions Mutation of CYBB gene on X-chromosome-80% Recurrent infections w/ catalase +ve organisms (ie: staph aureus) Increased catalase+ bacteria (not catalase-ve) bc bacteria do produce their own H2O2, endogenously if they are in aerobic metabolism --> bacteria doesn't realize that they're producing their own H2O2 (apart from WBCs) Increased H2O2 can kill catalase -ve organisms Occurs in first 5 years of life Most common in: skin, lungs, GIT, lymph nodes, liver & spleen, GIT/GUT granuloma Staph aureus = recurrent skin granulomas Granulomas in GIT wall Obstruction = ischemia Intususception mass pushes itself into another part of GIT Common tests: Nitroblue Tetrazolium (colorless) test If have NADH oxidase break down die to Blue formazan = blue granules Patient does not have disease if see blue granules bc have enzyme CGD (-) if there are blue inclusions in phagocytes Treatment: Daily TMP-SMZ (160/800 mg tab BID PO), Itraconazole (200 mg QID PO), Prednisone, stem cell transplant Chediak-Higashi Disease Auto recessive, defect in CHS1 gene Defective melanosomes, lysosomes Defective Neutrophils --> defective MTs, reduced intracell killing, poor chemotactic mov't Affects synthesis/storage of secretory granules in various cells Occulocutaneous albanism Nystagmus (peripheral neuropathy)& very blue eyes (= occular defects) Increased infections (skin) Ttx: bone marrow transplant, microtubule drugs, Acyclovir, Ig

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Immune Diseases Cont'd

June-15-10 NEXT TEST WED JUNE 23 1:32 PM Audio recording started: 1:34 PM June-15-10

Immune Diseases C...

Case 45 yo female complains of recurrent episodes of dysphagia, "food stuck in her throat", for 3 months duration. She also noted frequent color changes of her fingers when she goes out into the cold air. Her finger would turn white, blue, then red. She said that her skin seems to be drier than usual & always feels "tight". Tight, stiff skin Neck, face, lips = "salt-and-pepper" hypopigementation Diffuse hyperpigmentation Skin biopsy --> severe fibrosis, increased # of collagen fibers; superimposed deposition of newly synth delicate collagen bundles interposed bt preexisting collagen bundles Impression: scleroderma, possible CREST syndrome

Scleroderma Increased deposition of collagen Interstitium of small arteries & CT Sclerotic skin changes Multisystem disease Prevalence: 4-12/million/ yr; 3-4:1 F>M, 30-50 yo Prognosis: blacks worse than white, men worse than women Diffuse cutaneous --> worse prognosis Limited cutaneous (CREST) --> more benign, less renal Calcinosis Raynaud's Phenomenon --> color changes in fingers Esophageal Dysfunction Scleroderma Telangectasia Systemic sclerosis in scleroderma: visceral manifestations, no skin changes Kidneys, liver most of vasculature will have a lot of fibrosis Systemic sclerosis in overlap: concomitant w/ SLE, polymyositis, RA General presentation Raynaud's phenomenon Edema of fingers & hands Skin thickening Visceral manifestations --> GIT, lung, ear, kidneys, thyroid GIT = stacked coin appearance when do barium enema Arthralgias & muscle weakness Platelet microthrombi often found in lumen of narrowed vessels = necrosis of digits Tests 95% cases --> ANA + (like SLE) Topoisomerase I Abs (Scl-70): 30% w/ diffuse disease; pulmonary fibrosis Anticentromere Abs: 80-90% of patients w/ ltd disease Anti-PM-Scl: myositis and renal involvement 2D echo Barium swallow & enema recommended if manifestations mostly in lower GIT Radiography Esophagraphy --> esophageal dysmotility; incompetent LES Treatment Skin thickening: D-penicillamine, interferon-, cyclophosphamide, no approved FDA Pruritis: antihistamines, TCAD Raynaud's: Ca channel blockers, prostaglandins, digital sympathectomy cut off some of the sympathetic innervation) Digital ulcers: Bosentan, Sildenafil GIT: proton pump inhibitors, promotility drugs (ie: viagra), antacids Avoid calcium & high doses of Vit C Instruct patient to avoid digital or skin trauma, cold exposure to skin & smoking
Polymyositis
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Polymyositis Group of disorders Proximal muscle weakness --> difficulty lifting arms or standing from sitting Nonsuppurative inflammation of skeletal muscle Prevalence: 5 cases/million/yr; 2:1 F>M, 40-60 yo; pediatrics = 5-15 yrs If All 4 of below symptoms = Definitive Diagnosis Proximal muscle weakness Elevated serum CPK Myopathic changes on EMG Muscle biopsy inflammation 3 of above symptoms = Probable; 2 = Possible
Dermatomyositis Symptoms of Myositis + skin rash Pathogenesis Complement-mediated vascular inflammation (DM) Direct cytotoxic effect of CD8+ lymphocytes on muscle (PM) Cytokines/tumor necrosis factor (TNF) --> another DM theory Treatment for PM/DM PM --> rest, corticosteroids, IVIg, Rituximab (Ab against B-cells) Rituximab doesn't work if there is a problem w/ complement system Skin changes --> avoid sun, broad-spectrum sunscreens, hydroxychloroquine & chloroquine Amyloidosis Whenever a patient has inflammation (local or systemic), sometimes the inflammatory cells are depositing protein which are misfolded = amyloid deposits in local area of inflammation or can precipitate in certain areas of the body Congo red stain will show up as apple green fibrinogens Diseases associated with amyloid deposits Down's syndrome, Alzheimers, diabetes (if localized in pancreas) HIV & AIDS Causative agent of AIDS Retrovirus; lentivirus subfamily HIV-1: distributed world wide; most common HIV-2: mainly endemic in West Africa; less common & less virulent Pneumocystis jiroveci: considered very rare in US population but became more common in homosexuals Kaposi's sarcoma was found primarily in Jewish men & immuno-compromised patients Originally only found in old men of Mediterranean descent Acquired Immune Deficiency Syndrome (AIDS) Presence of 1/25 conditions indicative of severe immunosuppression OR HIV infection in an individual w/ CD4+ cell count of <200 cells/mm3 of blood End point of an infection that is continuous, progressive, pathogenic Both types of HIV originate from primates HIV-1 --> central common chimpanzee, southern Cameroon HIV-2 --> Sooty Mangabey, Guinea Bissae, Gabon, Cameroon Modes of Transmission Most common = sexual contact (MSM is most common) Blood or blood product transfusion (less common due to excessive screening) Transplanted tissue IV drug use w/ shared needles Transplacental or prenatal infection of neonates Pathogenesis HIV can cross epith barrier by transcytosis Picked up by APCs (primarily dendritic cells) Important Components gp120 --> in viral envelope of glycoprotein --> binds to CXCR4 or CCR-5 on CD4 Even if you've been exposed and you have macrophages in that area with receptors, it doesn't necessarily mean you're going to be infected right away with HIV

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with HIV Viral reverse transcriptase = complementary DNA using viral RNA template Provirus: viral DNA is transported into the nucleus & integrated into chromo Decline of CD4+ T-cells Acute infection: 550-800 Viremia: level of viruses found in bloodstream; can be measured by level of p24 antigen (found as cellular component of virus) As levels of Abs go up levels of virus go down (HIV hid inside macrophages) Macrophages allow virus to spread to CNS Chronic lymphadenopathy: 650-200 Sub-clinical immune dysfunction: 200-150 Skin & Mucous mbrn immune defects: 150-0 Systemic Immune deficiency: almost 0 Production of Abs also stops eventually Early stage of infection 1. Punctured Membrane: virus destroys cell as a result of budding 2. All T4 cells disappear Killing of CD4 cells via cytotoxic T-cell mediated lysis Synctium formation --> infected CD4 (gp120 +) fuses with uninfected (gp120-) Excess glycoproteins protrude through mbrn of macrophages Cytotoxic Tcells recognize macrophages as foreign 3. Binding of free gp120 to CD4 Ag = uninfected T4 cells looks like infected cell --> undergoes complement-mediated cell lysis 4 Stages of Infection Stage I: asymptomatic Stage II: minor mucocutaneous manifestations, recurrent URT infections Recurrent oral thrush, always have coughs & colds eventho on antibiotics Stage III: unexplained chronic diarrhea > 1 month, severe bacterial infections Stage IV Toxoplasmosis of brain Candidiasis of esophagus, trachea, bronchi or lungs Kaposi's sarcoma 25 defining illnesses (not specific to AIDS, but may present) Cervical cancer (invasive) Tuberculosis Candidiasis of esophagus, bronchi, trachea, or lungs Coccidioidomycosis (disseminated or extrapulmonary) Crytococcosis (extrapulmonary) Crytopsoridiosis (chronic intestinal for >1 month) Cytomegalovirus disease (other than liver, spleen or LNs) Encephalopathy (HIV-related) Herpes simplex: chronic ulcer(s) for > 1mo; or bronchitis, pneumonitis, or esophagitis Isosporiasis (chronic intestinal for >1 mo) Kaposi's sarcoma Burkitt's lymphoma (immunoblastic or primary brain) Mycobacterium avium complex (more severe than TB) - opportunistic infection with low CD4 count Mycobacterium (disseminated or extrapulmonary) Pneumocystis carinii pneumonia Pneumonia (recurrent) Progressive multifocal leukocephalopathy Salmonella septicemia (recurrent) Toxoplasmosis of brain Wasting syndrome due to HIV When have negative lab results for HIV, diagnosis of AIDS still considered if: Patient hasn't undergone high-dose corticoid therapy, other immunosuppressive/cytotoxic therapy in 3mo before onset of indicator disease Patient hasn't been diagnosed w/ Hodgkin's disease, non-Hodkin's lymphoma, lymphocytic leukemia, multiple myeloma, or any cancer of lymphoreticular or histiocytic tissue or angioimmunoblastic lymphadenopathy Patient doesn't have genetic immunodeficiency syndrome atypical of HIV infection (ie: one involving hypogamma globulinemia)

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(ie: one involving hypogamma globulinemia) Another definition for AIDS: HIV negative AND has Pneumocystis carinii pneumonia OR 1/25 diseases AND CD4 count < 200 cells/microL or CD4+ percentage <14% AIDS-related complex (ARC) can be very non-specific; overlaps in Stage II Fever, Fatigue, Diarrhea, Weight loss, Night sweats, Immunological abnormalities Must confirm diagnosis with lab tests CNS disease (in long-term survivors) --> dementia, spontaneous neoplasms Malignant neoplasms of skin Kaposi's sarcoma: pink - red - purple to brown, anywhere on skin; caused by HHV8 Lymphoma (Hodkin's, non-Hodgkin's, Burkitt's) Invasive cervical cancer Tests Serological tests ELISA --> initial screening; even if its positive you can't start treatment for AIDS, must do confirmatory tests (ie: Western blot) Latex Agglutination --> initial screening Western Blot Analysis --> confirmation test Ab specific for HIV gp120 or gp160 Detectable w/in 4-8 weeks post-exposure Immunofluorescence --> confirmation test Other tests P24 antigen --> early marker of infection (detection of recent infection) Virion RNA RT-PCR --> detection of virus in blood (detection of recent infection) & to confirm treatment efficacy Detect HIV RNA in plasma; first 2-4 wks of infection Lowest limit of detection < 100 RNA copies/mL CD4:CD8 T-cell ratio --> staging the disease & to confirm treatment efficacy CD4+ monitored every 3-6 mths Normal CD4+ levels = 500-1600 <200 = start PCP therapy (TM-SX) <100 = toxoplasmosis (ring-like lesions in brain); cryptococcosis (Pyrimethamine) <75 = MAC (Azithromycin + Ethambutol) Ethambitol causes optic neuritis Normal CD8+ levels = 375-1100 CD4 percentage: total lymphocytes; more reliable indicator of HIV >28% = normal 14-27% = intermediate <14% = clinical AIDS CD4:CD8 ratio Normal = 0.9 - 1.9 In HIV, CD8 appears increased due to decrease of CD4 Isolation & culture of virus --> only available in research labs Highly Active Antiretroviral Therapy (HAART) = improves quality of life Viral load may be low, but not completely gone Results in suppression of viral replication Halts damage to immune system Partially restores immune sys = partial restoration of immune func'n Fewer opportunistic infections & longer life for patients Start of treatment + AIDS-defining illness OR CD4 Tcell count <350 cells/mm3 1-NNRTI (non-nucleotid reverse transcriptase inhibitor) + 2 NRTI or PI + 2NRTI Special cases Antiretroviral therapy should also be initiated in following groups of patients regardless of CD4 T-cell count Pregnant women Zidovudine perinatial transmission = prophylaxis regimen Antepartum: initiation at 14-34 wk gestation cont'd thruout pregnancy ZDV 100 mg 5x daily Intrapartum: ZDV 2 mg/kg intravenously over 1 hr, followed by a cont's infusion of 1 mg/kg/hr intravenously until delivery Post partum: oral admin of ZDV to newborn (ZDV syrup, 2 mg/kg
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 Post partum: oral admin of ZDV to newborn (ZDV syrup, 2 mg/kg every 6 hr) for first 6 wks of life, beginning at 8-12 hrs after birth) HIV-associated nephropathy Patients coinfected w/ HBV PEP for HCP: percutaneous needle exposure; mucous mbrn & nonintact skin exposures 2 or 3 drug regimen (1 month) for confirmed HIV patients No PEP for HIV (-) patients For unknown status patients, consider risk factors Prevention: Why not give PrEP? Pre-exposure prophylaxis 1 antiretroviral pill daily (Tenofovir or Tenofovir plus emtricitabine) 4,000 volunteers in Thailand, US, Botswana Results expected in 4-6 yrs Prevention Male latex condom = reduce sexual transmission if used properly & consistently Avoid oil-based lubricants bc makes latex condom porous Female condom Some studies say circumcision decreases rate of HIV bc excess foreskin in uncircumcized = more trauma during sex = high risk of transmission

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Tuberculin Mantoux Test

June-16-10 1:30 PM
Audio recording started: 1:30 PM June-16-10

Tubercul i n Ma ntoux ...

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Childhood Diseases
June-21-10 1:36 PM
Audio recording started: 1:36 PM June-21-10

Childhood Diseases

Birth Weight Direct links w/ gestational age at which child was born Estimated during pregnancy by measuring fundal height Tape measure from top of symphisis pubis to top of fundus (32cm = 32 wks) Image: Sizes of uterus SGA: small for gestational age Below 10th percentile Low birth weight: wt below a defined limit at any gestational age Fetus < 2500 g (5 lb 8 oz) regardless of gestational age Main cause: intrauterine growth retardation (IUGR) Placental insufficiency Environmental factors Poor nutrition Tobacco smoking Drug addiction Alcoholism Severe anemia can worsen during pregnancy bc baby tries to get what it can (deprives mother of iron stores & nutrients) Thrombophilia Prolonged pregnancy: over 42 wks is dangerous Pre-eclampsia: elevation of BP of mother during pregnancy; Chromosomal abnormalities Damaged or reduced placental tissue due to Chronic renal failure Sickle cell anemia Phenylketonuria Infections Twins & multiple births LGA: large for gestational age Weight is above 90th percentile at gestational age Macrosomia: weight is above a defined limit at any gestational age "big baby syndrome"; fetus > 4000 g Main cause: poorly controlled diabetes Gestational DM Pre-existent DM that doesn't respond to oral hypoglycemic agents & insulin Gestational age >40 wks Male infants > female infants Taller, heavier parents Obese mothers Excessive maternal weight gain When babies fall above or below = abnormalities Factors affecting birth weight Genetics Health of mother (esp during pregnancy) Environmental factors (ie: smoking, alcohol, drugs) Weight gain during pregnancy BMI = weight/height^2 (Normal = 18.5-24.9) Fetal growth restriction due to: Chromosomal abnormalities Congenital abnormalities; infections Uteroplacental insufficiency Vacular abnormalities Placental abnormalities Multiple gestations Maternal diseases Preeclampsia
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 Maternal diseases Preeclampsia Chronic HTN Narcotic abuse Alacohol intake Cigarette smoking malnutrition Categories of Growth Retardation Symmetrical growth retardation Global growth retardation Fetus has devl'pd slowly thru/o pregnancy; affected from a very early age HC is in proportion to rest of body Early intrauterine infections, chromosomal abnormalities, maternal substance abuse Asymmetrical growth retardation: head appears bigger bc abdominal circumference is smaller Maybe devl't was normal at beginning of pregnancy and then infection or something later caused growth retardation Abdomen is small bc liver Normal growth for 1st 2 trimesters then difficult 3rd trimester Pre-eclampsia HC bigger than AC Lack of subcutaneous fat Dry, peeling skin, thin umbilical cord More risk: hypoxia & hypoglycemia Prematurity vs. Preterm Preterm: less than 37 wks Term: 37-42 wks Postterm: >42 wks Postdate: later than expected date Prematurity: physio challenged baby; vital organs are not fully developed for that age of gestation Most premature babies are preterm, but some preterm babies are not premature Risk factors Preterm premature rupture of membranes (PPROM) can occur <37 wks bc lungs not devl'd Smoking Prior preterm delivery Vaginal bleeding during this pregnancy If amniotic sac ruptured, infection from lower genital tract can travel up Intrauterine infection Uterine abnormalities (fibroids) grow dur pregnancy = increase uterine vol = preterm labor Cervical defects (incompetence) Cervix starts opening on its own (ie: in patients who have had prior surgery) Placental abnormalities (previa, abruptio) Multiple gestation Complications of Prematurity Hyaline Membrane Disease (HMD) Necrotizing Enterocolitis (NEC) Sepsis Interventricular Hemorrhage (IVH) --> can lead to mental retardation Apgar score Simple & repeatable method to quickly & summarily assess health of newborns Done at 1 and 5 minutes after birth, may be repeated later if the score is & stays low Interpretation of Apgar Apgar score = 0 Pale or blue HR Absent RR Absent Reflex response Absent Muscle tone Absent Apgar score = 1 Pink body, blue extremities HR < 100 bpm RR slow & irregular Reflex response = grimace or noticeable facial mov't
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 Reflex response = grimace or noticeable facial mov't Muscle tone = some flexion of extremities Apgar score = 2 (normal) Pink body & extremities HR >100 bpm RR: Good breathing w/ crying Reflex response: coughs, sneezes or pulls away Muscle tone: active & spontaneous mov't of limbs Add the scores 7-10 = normal 4-6 = req's some resuscitative measures <3 = immediate resuscitation 0 = baby may be dead

Birth Injuries Clavicular factures: common in big babies (esp when not expecting big baby); heals very well Facial nerve injury Brachial plexus injury Intracranial injury Intracranial hemorrage: excessive molding of head; rupture vessels that are under bone or over bone w/ forceps, precipitate delivery Humeral fractures Lacerations --> in babies that don't have enough hairs on head, sometimes lacerate scalp of baby when trying to pierce amniotic sac
Assisted Deliveries Cephalhematoma Soft tissue mass on head following instrument delivery Subperiosteal hematoma No associated skull fracture Ltd by suture lines Usually in the parietal region May not be visible at birth, but should appear by day 2-3 Caput succedaneum Above suture line; Subcutaneous hemorrhage Occurs after vaginal delivery Requires no intervention Both usually resolve & don't require any intervention

Congenital Anomalies Inherited or sporadic Isolated (just in one baby, or just in particular organ = syndrome) or multiple Apparent or hidden Gross or microscopic Cause nearly half of all deaths in term newborns Down's, Klinefelters, Turner's, Major anomaly is apparent at birth in 3-4% of newborns 7.5% of children manifest a congenital defect by 5 yo Incidence varies w/ type of defect, geographic area, genetic and/or enviro factors Cultural practices increase the risk of genetic abnormalities Increasing age of the mother (less extent of father) may increase risk of chromosomal defects
Causes of Anomalies Karyotype abnormalities Most common in Down syndrome Most karyotype abnormalities die in utero Single gene mutations --> Most common is autosomal dominant or recessive Multifactorial --> Viruses, drugs/chemicals, radiation, maternal diabetes Teratogens & Fetal Devl't All or none effect within 1st 3 wks after fertilization Most sensitive period = 3rd-9th wk --> devl't of germ layers Fetal period --> further growth; less susceptible to teratogens
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 Fetal period --> further growth; less susceptible to teratogens

Teratogenesis Production of non-heritable birth defects Teratogen = drug, chemical or virus Act during critical period of fetal devl't (varies bt organs) Brain --> 15-25 d Eye --> 25-40 d Heart --> 20-40 d Limb --> 24-36 d Drugs as teratogens Hormones (ie: progestogens, diethyl stilbeostrol, male sex hormones) Antipsychotics (ie: Li, haloperidol, thalidomide) Anticonvulsants (ie: sodium valproate, carbamazepine, phenobarbitone) Antimicrobials (ie: tetracycline, chloramphenicol, amphotericin B) Antineoplastics (ie: alkylating agents, folic acid antagonists) Anticoagulants (ie: warfarin) Antithyroid agents (ie: carbimazole, propylthiouracil Toluene, alcohol, marijuana, narcotics Action of teratogens Prevents cell migration Influence cell proliferation and differentiation Affects correct differentiation of tissues Distort cell-matrix associations Influence apoptosis Exert mechanical & hormonal effects Important genes assoc w/ abnormalities HOX genes: patterning of limbs, vertebrae, cranium & face PAX genes: kidney, eye, brain & ear defects Obstetric factors polyhydraminos (CNS or GIT): a lot of amniotic fluid & baby can't swallow oligohydraminos (GUT) Breech --> baby positions it self in opposite way (butt first) Nuchal fold/transluscency: fold of neck is thicker and wider in babies with Down's Synd Congenital Abnormalities Approx 2% of live births; increased in preterm SGA Malformation: disturbance of growth during embryogenesis, intrinsic Disruption: late change in previously normal structure due to intrauterine factors; extrinsic Deformation: extrinsic; abnormal biomechanical forces Potter's syndrome: Potter's sequence or oligohyramnios seq Abnormal ear lobation Micrognathia Flattened nasal tip Pulmonary hypoplasia Talipes equinovarus Amnion nodosa Causes of deformation Usually more common in first time mothers bc uterus hasn't stretched enough

Myomas & Bicornuate Uterus Compression of baby

Anatomical Systems involved --> heart most common

Lithium in pregnancy Causes Epstein's anomaly Tricuspid valve is displaced downward towards apex = Atrialization Everytime cardiac cycle occurs u have regurgitation of blood Discorded contractions Simultaneous atrial-septal defect

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Thalidomide Sedative hypnotic Multiple myeloma Leprosy HIV-related skin desases Autoimmune diseases Antiemetic DES Corpus luteum insufficency to reduce miscarriage in the mid 40s thru early 70s Clear cell adenocarcinoma of vagina in daughters Transgenerational (ie: when grandmothers took DES) Fetal Alcohol Syndrome Metabolites (Ethanol, acetaldehyde) can inhibit DNA & protein synthesis Microbial Agents as Teratogens Rubella Toxoplasmosis Syphilis Cytomegalovirus Coxackie B virus Case

First pregnancy; 17 wks Fever, rash, swollen cervical lymph nodes Baby born with congenital cataracts Ddx: Congenital Rubella Syndrome

Congenital Rubella Syndrome Sequelae Most common = DEAFNESS Eye defects (microopthalmia, cataract) Thrombocytopenic purpura Case

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Childhood Diseases Cont'd

June-22-10 1:37 PM
Audio recording started: 1:37 PM June-22-10

Childhood Diseases C...

Radiation during Pregnancy Prior to 2 wks gestation: 100 mGy Radioactive iodine given to mothers with hypothyroidism (very high mGy so DO NOT give to expectant mothers) If xray is to be done, counsel on No increased risk to fetus No miscarriage No fetal growth restriction No congenital Recommendations from ICRP All medical practices should be justified Missed period: considered pregnancy until proven otherwise Pregnant medical radiation workers: keep fetal dose below 1 mGy during pregnancy If there was significant amount of radiation <100 mGy DO NOT have to terminate pregnancy If 100-500 mGy, decision based on individual circumstances >500 mGy, terminate (but final decision up to mother)

Gestational Diabetes Mellitis Develop glucose intolerence during pregnancy, or had it before but diagnosed dur pregnancy Fetal macrosomia: 4000-5000 g (8-9 lbs) Maternal-fetal glucose metabolism Baby ends up having very high levels of glucose --> high levels of insulin All energy = fat --> depositied into shoulders and back, head same size During delivery, head will be able to pass thru birth canal but stuck at shoulders Increased energy for deposition of fat = use more oxygen = hypoxic Polycythemia bc more EPO = red Birth defects Neural tube defects Caudal regression syndrome --> lower extremities fused together "mermaid baby"
Hyaline Membrane Disease Infant respiratory distress syndrome (IRDS) Neonatal resp distress syndrome One of most common lung disorders in premature infants Components of Surfaction DPPC PG Risk factors Prematurity Diabetes in mother Stress during delivery --> acidosis in newborn at birth Cesarean section --> no compression of chest to expell the fluid in the chest of baby so it is harder for baby to breath bc more fluid in lungs Steps in formation of Hyaline membrane Decreased surfactant --> lungs can collapse easily Increased alveolar surface tension Atelectasis --> uneven perfusion, hypoventilation Acidosis = endothelial damage Pulmonary vasoconstriction . Hyaline membrane = harder for gas exchange = more hypoxia Signs & Symptoms Appear shorthly after birth & becomes progressively more severe Tachypnea
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Tachypnea Intercostal retractions --> depressions bt ribs Shortness of breath Grunting sounds Alar flaring Apneic Xray Diffuse, ground-glass opacification of both lungs Air bronchograms Hypoaeration from loss of lung volume Symmetrical distribution Air is in pleura = rupture in alveoli Diagnostic tests Blood-gas analysis: low oxygen & acidosis Chest xray Lung function studies Sepsis work-up; blood cultures Amniocentesis: allows the measurement of lecithin/sphingomyelin L/S ratio of 2+ --> low risk of IRDS L/S ration <1.5 --> high risk of IRDS RDS Prognosis & Complications Death in 18% Acute complications: Barotrauma may produce Parenchymal pseudocyst Pulmonary interstitial emphysema Pneumomediastinum Retinopathy of prematurity or retrolental fibroplasia Hyperoxic enviro --> endoth cell apoptosis --> resume room air (hypoxic) --> overgrowth of VEGF --> angiogenesis Occurs after you have taken baby off oxygen supplements (hyperoxic) Bronchopulmonary dysplasia Cause: use of high positive-pressure mechanical ventilation & high conc oxygen in neonates w/ RDS HMD --> inflam, mucosal necrosis, fibrosis, sm muscle hypertrophy o fairways, dmg to alveoli Xray --> bubbly appearance; dilated alveoli Necrotizing Enterocolitis Most common & serious gastrointestinal disorder among hospitalized preterm infants 10% of babies weighing <1500 g (3 lbs 5 oz) Tirgger: occurs w/in first 2 wks of life, usually after milk feeding has begun thru NGT Immature bowels; sensitive to changes in blood flow NEC Theory Feedings llows bacteria that are normally found in intestine to invade Signs & symptoms Poor suck (don't want to feed anymore) Vomiting; greenish (bile-colored) vomit Electrolyte imbalances Sepsis; bowel perforation = peritonitis Xray Pneumatosis intestinalis --> air has gone into wall of intestines Pneumoperitonium --> air w/in peritoneal cavity Ttx; remove necrotic portions of bowl,

Erythroblastosis Fetalis Sudden Infant Death Syndrome (SIDS) Crib death

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Crib death Unexplained death in 2-4 mo 12.9x higher risk of death when sleeping on tummy Use firm mattresses, no smoking

Hemangioma Abnormally dense Capillary hemangioma Cavernous hemangioma Main treatment --> leave it alone, usually regresses after 507 yrs

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Test 3 Answers
June-24-10 Audio recording started: 1:37 PM June-24-10 1:37 PM

Test 3

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

NEC --> gas formation in intestinal walls High dose O2 in newborns --> retinopathy of prematurity, alveolar hypoplasia Chronic lung disease --> bronchopulmonary dysplasia Apgar score = 6 Swelling crossing midline of skull --> caput s --> resolves in 1 week Clear cell adenocarcinoma of vagina --> maternal diethylstilbesterol ingestion SIDS --> maternal smoking Hypoglycemia, gestational DM --> polycythemia, increased fatty tissue in shoulders Recurrent cytomegaolvirus --> deafness Missed period in 3 mo --> before xray, do pregnancy test Term baby, preeclampsia in latter half --> asymmetrical growth retardation Amniotic bands affect growth --> disruption HIV, 12% CD4 = 175 --> PCP 14 yo, AIDS, neurological signs & symptoms, ring-like lesions --> Toxoplasmosis Newborn, congenital rubella --> cataracts, neurosensory deafness, microcephaly NOT paralysis Diffuse bilateral infiltrates --> PCP CD4 = 8% --> clinical AIDS CD4 = 55 --> PCP IgG transmitted thru placenta Gestational DM --> clavicular facture Allergic rxn after yellow fever vaccine --> Type I Rh incompatibility --> Type II Poison ivy --> Type IV HIV with 1/25 --> Stage 4 Western blot is confirmatory for HIV HIV+, CD4 = 450, pregnant --> HAART (C) CD4 = 50, invasive cervical cancer --> HAART + opportunistic (D) HIV-, high dose steroids for 4 mo, CD4 = 150 --> infection precautions (B) HIV+, CD4=50 --> HAART + opportunistic (D) HIV-, PCP+ --> HAART + opportunistic (D)

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Hematology
June-28-10 1:41 PM
Audio recording started: 1:43 PM June-28-10

Hematology

Anemia Low Hb content = oxygen capacity reduced = weakness & fatigue Normocytic = 80-100 nm3 Hemorrhage or acute blood loss (ie: GI bleeding) Microcytic < 80 nm3 Thalassemias Anemia of Chronic Disease Iron deficiency Anemia (IDA) Lead poisoning (Sideroblastic Anemia) Macrocytic > 100 nm3 Vit B12, Folate Deficiencies
RBC Indices Hb molecule = tetramer --> HbA (2 & 2) Prosthetic groups contain heme & iron = bind oxygen Reticulocyte count Most effective method of determining if the BM is responding to anemia Normal: 0.5-1.5% Corrected reticulocyte count needed if there is anemia Anemia causes EPO to be released from kidney = incr reticulocyte count Patients Hct/45 x reticulocyte count (normal Hct = 45) >3% --> good response to anemia <2% --> BM abnormality (no effective erythropoiesis) Good Reticulocyte Count Blood loss of > 7 d Hemolytic anemia Iron therapy for Fe-deficiency anemia Folate/B12 therapy for megaloblastic anemia Good erythropoiesis Higher in males bc testosterone = increased Hb EPO released from kidney in response to stimuli Low PaO2 Anemia, 7 gm/dL Left shift in oxygen-dissociation curve bc not enough oxygen Reticulocytes have RNA filaments --> Hgb synthesis Poor Reticulocyte Count Anemia of chronic disease Aplastic anemia --> pancytopenia Untreated iron, folate/B12 anemia Blood loss of < 1 wk Hematocrit (Hct): volume of packed RBC Males: 39-49% Females : 33-43% Hemoglobin Males higher bc effect of testosterone Males: 13.6-17.2 gm/dL Females: 12-15 gm/dL Mean cell volume (MCV): avg volume/size of RBC Hct / RBC Count Normal = 80-100 femtoliters/cell RBC distribution width (RDW) SD of MCV / mean MCV x 100 Coefficient of variation of RBC volume
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 Coefficient of variation of RBC volume Normal = 11-15% Peripheral blood smear Increased RDW in iron deficiency anemia Mean cell hemoglobin (MCH): Avg content of Hb per cell Hgb / RBC Normal = 20 picogram/cell Mean cell hemoglobin concentration (MCHC) = avg conc of Hgb in a given volume of packed RBC Hgb / Hct Normal = 25 gms/dL Classification of Anemia based on MCV Microcytic (MCV < 80) Thalassemia Anemia of chronic disease Iron deficiency anemia (IDA) Lead poisoning (Sideroblastic anemia) Macrocytic (MCV > 100) Folate deficiency B12 deficiency Normocytic (MCV = 80-100) Corrected reticulocyte count (<2%) Acute blood loss Early Fe deficiency Aplastic anemia ACD Renal disease Corrected retic count (>3%) Intrinsic RBC defect Membrane defects (spherocytosis, PNH) Abnormal Hgb (Sickle cell) Deficient enzymes (G6PD) Extrinsic RBC defect Autoimmune hemolytic anemia Microangiopathic anemia (ie: DIC) Blood loss of > 1wk Iron Studies Ferritin: storage form of iron in all tissues; hepatocytes and macrophages Decreased in Fe deficiency anemia Increased in anemia of chronic disease Transferrin: transfer form TIBC: total iron-binding capacity iron bound to transferrin(usually 1/3 occupied) ferritin = liver synth of transferin = TIBC ferritin = liver synth of transferrin = TIBC

Iron Deficiency Anemia Most common cause: GI bleeding Newborn: bleeding Meckel's diverticulum 6mo - 2yrs: nutrition Pregnancy/lactation: avg 500 mg loss Females < 50 yrs: menorrhagia (80 ml/period) Males/females > 50 yrs: PUD Plummer Vinsson Disease Esophageal webs Atrophic glossitis
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Esophageal webs Atrophic glossitis IDA Hypochromic, microcytic anemia Decreased Hgb synthesis Decreased iron stores; decreased ferritin Increased transferrin, increased TIBC BM: disappearance of stainable iron from mononuclear phagocytic cells Therapy Ferrous sulfate Ferrous gluconate Daily iron req't: 7-10 (males), 7-20 (females) 10% absorbed To prevent IDA, 1 mg iron must be absorbed

Anemia of Chronic Disease Most common cause: malignancy Chronic inflammation Rheumatoid arthritis Decreased production & impaired iron utilization Decreased Hgb Difference from IDA: increased iron stores, increased ferritin Decreased liver synth of transferrin, decreased TIBC Ttx: treat underlying disease Thalassemias Hgb A: 2 alpha + 2 beta Hgb A2: 2 alpha + 2 delta Hgb F: 2 alpha + 2 gamma Autosomal recessive Decreased Hb synthesis Alpha thalassemia: asians, afro-americans Chromosome 16 Defect with alpha chain Decrease HgbA, Hgb A2 & HgbF 4 gene deletions involved 1 --> silent carrier 2 --> slight anemia; alpha thalassemia trait (minor); no physical signs 3 --> Hemoglobin H disease 4 b-globin chains; common in asians High affinity for oxygen = tissue hypoxia Prone to oxidation, intracell inclusions Increased splenic removal Moderately severe anemia, compatible to life 4 --> Hemoglobin Bart's disease (fatal to neonate) 4 gamma chains Higher affinity for oxygen = complete tissue hypoxia IUFD: severe pallor, generalized edema, massive HSM Increased incidence of chorioCA Hydrops fetalis

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RBC Pathology Cont'd

June-29-10 1:40 PM
Audio recording started: 1:40 PM June-29-10

RBC Pathology ...

Anemia: decreased oxygen transport bc problem w/ heme synthesis or globin chain synthesis Anemias based on MCV values Microcytic < 80 Hydrochromic TAILS Normocytic 80-100 Normochromic Acute blood loss Macrocytic >100 Megaloblastic Vit B12, Folate Deficiencies Defective DNA synthesis = increase susceptibility to injury Thalassemias Alpha-thalassemia (less severe than beta) Shortness of breath, mallaise, loss of appetite Severity of disease increases with number of gene deletions Hb H disease --> 3 gene deletions Bart's disease --> 4 gene deletions (fatal) Hydrops fetalis Inclusion bodies throughout give indication of anemia Compensatory mechanism of Anemia Erythropoeisis by kidney Corrected Reticulocyte count --> indicates if anemia is being corrected appropriately >3% = anemia is being corrected Beta-thalassemia Chromosome 11; deficiency of beta chains Increased amount of alpha chains = aggregates (inclusion bodies w/in cell) --> cause hemolysis = hemolytic anemia Increased erythropoiesis at extra-medullary sites (liver, spleen, LNs) Increased dietary absorption & blood transfusion = iron overload Oxygen transport difficulty Most common: Splicing mutations B+ = producing a little bit of B gene Bo = not producing beta at all B = normal B+/B+, B+/Bo = thalassemia major (severe) Shows up by 6-8 mo of age Overactive BM; skeletal deformities bc erythropoiesis in different areas supplies all those areas Splenomegaly: enlarged spleen Hemosiderosis Hemochromatosis = deposition of Fe in heart, liver, pancreas RBC count normal or increased Microcytic, hypochromic AND hemolytic anemia B/Bo = thalassemia minor Mild, asymptomatic Target Cells Normal RBC = central pallor, biconcave Target cell = bull's eye appearance Erosion of bone (ie: in skull) = hair-on-end appearance on xray
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RBC Indices Hb Hct MCH MCHC MCV Reticulocyte count Corrected reticulocyte count

 Erosion of bone (ie: in skull) = hair-on-end appearance on xray Sideroblastic Anemia Lead exposure, poisoning, toxicity Lead denatures ferrochelatase = decreased binding of Fe to protophorphyrin Basophilic stippling --> ribosomal inclusions w/in cell bc ALA dehydrase is denatured --> ribosomes not degraded Decreased liver synthesis of transferrin Increased ferritin = decreases amount of iron to bind = dec TIBC Lead colic Peripheral neuropathy Cerebral edema MR Kidney failure Causes Alcoholism B6 deficiency Isoniazid use Damage to mitochondria Iron overload Ringed sideroblasts Megaloblastic Anemias Lack of DNA synthesis = defective cell maturation & division Large macrocytic cells due to deficiences (Vit B12, Folate) Treat deficiency Diagnose w/ peripheral blood smears Increased MCV Bone marrow hyperplasia bc defective maturation --> depresses all other cell lines = pancytopenia Peripheral destruction of RBCs Hypersegmented neutrophils (>5 lobes) Pernicious Anemia Lack of intrinsic factor (IF) Autoimmune diseases causing defect --> Abs attack IF Atrophic gastritis with IF deficiency = defective B12 absorption = Vit B12 deficiency Vit B12 Deficiency Vegetarians Chronic pancreatitis Fish tapeworm Bacterial overgrowth Crohn's disease (inflammatory bowel disease) Schilling's Test Stage 1 Give Vit B12 in form of radio isotope (oral) + regular amount (IM injection) IM --> liver receptors Radioisotope should show up in urine if no defect Transcobalamine = transport protein for Vit B12 If >5% radioactive in urine = normal If < 5% in urine = problem (maybe no IF) bc not absorbed = pernicious anemia Stage 2 Give IF + B12 + radioactive B12 If this fixes the problem, then you know its pernicious anemia Stage 3 Give antibiotics + B12 + radioactive B12 If this fixes the problem, then you know it was due to bacterial overgrowth

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to bacterial overgrowth Folate Deficiency Alcoholism Poor diet Pregnancy Lactation Disseminated Carcinoma Phenytoin OCP(oral contraceptive pills) Methotrexate Cases Signs & Symptoms Macrocytic anemia Glossitis Diarrhea Differential Diagnosis Vit B12 Deficiency Posterior column degeneration Lateral corticospinal tract: UMN dementia Pernicious Anemia Achlorhydia --> lack of HCl production Chronic atrophic gastritis --> lack of IF Gastric adenocarcinoma Positive Schilling's test Lab Exams for Vit B12 & Folate Megaloblastic cells Pancytopenia Hypersegmented neturophils (>5 lobes) Decreased conversion of homocysteine to methionine Folate deficiency only Decreased RBC folate Increased forminoglutaminic acid (FIGlu) B12 deficiency only Decreased B12 Increased urine methylmalonic acid

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Case Study
June-30-10 1:43 PM
Audio recording started: 1:44 PM June-30-10

Case Study

59 yo woman complains of fatigue & numbness o fher arms & legs for 1 mo. She has a history of hypothyroidism & takes thyroid replacement therapy. A complete blood count (CBC) shows WBC 4000 Hb = 9, Hct=27%, mean corpuscular volume (MCV)=120 fL, platelets = 150,000. A peripheral blood smear is shown in the next slide.

What is most likely diagnosis What is most likely underlying mechanism causing the anemia What additional lab tests should be done for further evaluation Megaloblastic Anemia - Vitamin B12 deficiency

Case Study
Audio recording started: 2:15 PM June-30-10

Hashimoto's disease Pernicious Anemia Vit B12, Folate Deficiency

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Hematology Cont'd
July-01-10 1:44 PM
Audio recording started: 1:45 PM July-01-10

Hematology Cont'd

Normocytic Anemia Central palor --> normal biconcave cell shape Abnormal BM Ac/chronic blood loss --> GIT bleeding, duodenal ulcer, splenic rupture Positive tilt test LUQ tenderness; rib tenderness Pelvic fractures Exacerbation of angina BM Failure Aplastic Anemia Can be due to toxins, drugs, radiation, virus (ie: Hep C) No cell production = lact of RBC formation Stem cell disease Benzene TTx: chloramphenicol, NANB/HCV, radiation, parvovirus S/Sx: fever, bleeding, fatigue Hypocellular BM Pancytopenia: reduction in ALL cell lines Granulocytopenia --> lack of granules (BEN) Lack of neutrophils = fever, chills... Thrombocytopenia --> decreased platelets Bleeding = petechae, bruising... Anemia Fatigue Renal disease Decreased EPO Burr cells (aka echinocytes) are specific to Uremia Crenated RBC Most common cause: DM Ttx: EPO Intrinsic RBC defect Congenital spherocytosis (autosomal dominant); common in northern European descent Defect in spectrin, ankyrin Instead of biconcave shape, cells look spherical (no central pallor) Shape makes it hard to pass through spleen = splenomegaly Triad = anemia, splenomegaly, jaundice Unconjugated hyperbilirubinemia Calcium bilirubinate stones Osmotic fragility test Increased fragility when immersed in 0.65% saline (lyse easily) Normal BM Paroxysmal Nocturnal Hemoglobinuria (PNH) Deficiency in decay accelerating factor (DAF) which normally blocks formation of MAC Increased intravascular hemolysis PIGA mutation = activates complement cascade = hemolysis Nocturnal: when sleeping there is more CO2 retention = acidosis = more hemolysis First void when wake up in the morning = bloody urine Vessel thrombosis (platelets also affected) Hepatic vein thrombosis (Budd-Chiari Syndrome) Treatment is symptomatic Sugar water test: enhances att of complement = causes lysis to occur (screening test) Acidified Serum Test (Ham's test): lysis occurs in acid sol'n Confirmatory Low haptoglobin bc gets broken down & removed by spleen
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Confirmatory Low haptoglobin bc gets broken down & removed by spleen Haptoglobin binds free Hb released from RBC Hp + Hb complex removed by spleen to prevent renal damage Urine hemosiderin due to excessive Hb breakdown Sickle cell disease Defective Hb --> point mutation at 6th position of beta-globin chain Valine substituted for Glutamic acid Homozygotes: completely Hgb S = a lot of sickling & anemia Heterozygotes: 40% HgbS Hgb S exposed to decreased O2= crystalization/polymerization of cells = viscous gel Can be reversible if give pt oxygen Ca channel defects = less intracellular water Repeated deoxygenation = sticky cells --> att to endoth mbrn Accumulate in microvasculature = ischemia, necrosis Manifests at 6 months Chronic hemolytic anemia Vasoocclusive damage Dactylitis (swollen digits) Acute chest syndrome w/in pulmonary system (ie: lungs) Splenomegaly Autosplenoectomy --> over yrs of exposure, spleen becomes fibrotic Bone infarcts: aseptic necrosis of femoral head Osteomyelitis (salmonella) Priapism = erectile dysfunction Microhematuria = blood in urine Prone to Strept Pneumoniae & encapsulated bacteria Manifests at 6 months of life Screening test --> Sodium bisulfite test Reduces oxygen tension = induces sickling Confirmatory tests (Gold standard test) --> Hgb electrophoresis HbS travels faster than HbA bc has more positive charge Howell-Jolly bodies: DNA inclusions = splenic dysfunction Glucose-6P Deficiency (G6PD) x-linked recessive; common in Afro-Americans, sever --> mediterranean descent If glutathione is absent = oxygen free radicals accum = extensive mbrn damage Stresses RBCs = lysis Defect in HMP shunt or glutathione metabolism Inability of RBC to survive oxidative injuries Infections --> Primaquine, Sulfonamides, Nitrofurantoins, Acetanilid, Dapsone, Fava beans S/Sx: self-limited, anemia, hemoglobenemia, hemoglobinuria, reticulocytosis Heinz bodies: clumps of denatured Hgb Bite cells: macrophage removal of membrane Malaria G6PD may provide protection against malaria Hgb S may protect infants against malaria

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Bleeding Disorders
July-05-10 1:45 PM
Audio recording started: 1:45 PM July-05-10

Bleed Disorders

Terms BT: Bleeding Time (normal bt 2-9 mins) --> determines platelet functioning PT: Prothrombin Time (extrinsic) --> Factors 5, 7, 10 PTT: Partial Thromboplastin Time (intrinsic)--> Factors 8, 9, 10, 11, 12 Platelet count (150-450,000) Plasmin &Prot C help dissolve clot
Vessel Instability & Platelet Problems Most common: epistaxis (nose bleeds) Bleeding from superficial scratches Easy bruising Petechiae Ecchymoses Mucosal bleeding

Vessel Wall Abnormalities Infections --> Meningococcemia Drug reactions --> vasculitis Scurvy (Vit C Deficiency) Ehler-Danlos syndrome (Collagen defects) Henoch-Schonlein purpura Hereditary hemorrhagic telangectasia Amyloid infiltration of BV Damage to vessel wall causes platelet activation Thrombotic Thrombocytopenic Purpura (TTP) Thrombocytopenia: low platelet count Small vessel damage w/ platelet consumption Causes Infection consumes platelets = injury to endothelium --> platelets --> coagulation cascade Systemic sclerosis Drugs --> OCPs, APAs Preeclampsia Labs Normal coagulation factors Low platelets Biopsy --> edothelial damage Increased endothelin Decreased NO, Prostacyclin Hemophilia A X-linked recessive S/Sx Spontaneous hemorrhages Since PT & PTT are missing = massive bleeding into spaces Hemarthroses Massive bleeding after surgery, trauma NO PETECHIAE bc PLATELETS ARE NORMAL Labs: INTRINSIC PATHWAY AFFECTED Prolonged PTT Normal PT Low Factor 8
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 Low Factor 8 Low protein C Normal platelets Tx: Vasopressin (DDAVP); increases Factor 8 or recombinant factor 8

Hemophilia B (Christmas disease) Factor 9 deficiency X-linked recessive Tx: Recombinant Factor 9 Von Willebrand Disease Autosomal dominant Reduction/defects of circulating vWF vWF stabilizes Factor 8 --> if this association doesn't occur = decrease in Factor 8 Labs Prolonged BT Normal platelets Low Factor 8 Low ristocetin cofactor activity If vWF doesn't bind with ristocetin = low vWF

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Iron Studies
July-07-10 1:40 PM
Audio recording started: 1:41 PM July-07-10

Iron Studies

Transferrin --> transfers iron; synthesized by Liver Ferritin --> stores iron (bone marrow) Hepsodin --> allows Fe to be released from ferritin --> transferrin TIBC --> Total Iron-Binding Capacity; reflective of transferrin Microcytic Thalassemia Alpha-globi Beta-globin Anemia of Chronic Disease (ACD) Decreased serum Fe Increased serum Ferritin bc Fe doesn't leave BM (affects hepsodin) Decreased TIBC Iron Deficiency Anemia (IDA) Decreased serum Fe Decreased serum Ferritin Increased TIBC Lead Poisoning/ Sideroblastic Anemia
Normocytic Anemia Normal BM, Extrinsic RBC defect Autoimmune Hemolytic Anemia (AIHA) Immune rxn following drug ingestion IgG/C3 coats RBC --> removal by macros --> hemolytic anemia S/Sx: fever, jaundice, HSM, lymphadenopathy Warm Antibodies (most common) Active at 37 C; IgG Drug ingestion --> penicillin, methyldopa Type II hypersensitivity Ttx: steroids, D/C drug Cold Antibodies Active at 0-4 C; dissociate at 30 C; IgM Infections --> mycoplasma, IM CLL Quinidine, isoniazid Type III hypersensitivity Ttx: alkylating agents Direct Coombs Test: detects IgG, C3 on RBC surface Create Abs against Ab = agglutination = + Coomb's test Indirect Coombs Test: detects antibodies in serum Microangiopathic Hemolytic Anemia Most common cause: aortic stenosis Prosthetic heart valves DIC TTP HUS Runner's anemia HELLP Labs Low haptoglobin Increased urine hemosiderin Normochromic, normocytic (N/N) anemia

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Disseminated Intravascular Coagulation (DIC) Hemorrhagic syndrome Uncontrolled activation of clotting factors & fibrinolytic enzymes throughout small BVs --> Fibrin is deposited Dissolution with Plasmin occurs at same time of clot formation Platelets consumed --> low platelets; TTP reflective of bleeding time Clotting factors consumed --> low clotting factors Fibrin degradation products inhibit fibrin polymerization Increased FDPs Tissue necrosis & bleeding Causes Septicemia Pregnancy (ie: retained placenta = infection) Transfusion Trauma Malignancy Acute pancreatitis Nephrotic syndrome S/Sx Extensive bruising Bleeding of old venipuncture sites Renal failure Gangrene Bleeding anywhere (uterus, lungs & CNS) PBS: broken RBCs, Schistocytes, decreased platelets, FDPs

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Tumors of the Heart & WBC Diseases

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Audio recording started: 1:44 PM July-08-10

Diseases of WBCs

Tumors of the Heart Atrial Myxoma Sessile or pedunculated 'wrecking ball' effect on valves 'ball-valve' obstruction Embolization Elaborate IL-6 --> fever, malaise Ttx: surgery Rhabdomyomas Most common primary tumor in children Hamartomas Assoc w/ tuberous sclerosis Leukopenia Total # of leukocytes in circulating blood is < 4000/mm 3 (Normal = 4000-11000) Neutropenia, lymphopenia Can be caused due to infections, autoimmune disorders, malnutrition, cytotoxic drugs Neutropenia Decreased production (aplastic anemia, tumors, chloramphenicol, busulfan, benzene) Ineffective production (megaloblastic anemia, myelodysplastic syndromes) Increased destruction (SLE, splenic sequestration & Rickettsiae infections) NANB/HCV, typhoid fever, gram negative infections, Candida Lymphopenia (HIV, cytotoxic drugs, malnutrition) Decreased production Increased destruction Loss of cells Granulocytes: neutrophils, eosinobils, basophils Agranulocytosis Acute condition < 500 granulocytes/mm3 Great reduction in number of polymorphonuclear leukocytes

Leukocytosis Abnormally lg number of leukocytes >7000 cells/uL Left shift w/ >10% band neutrophils Toxic granulations/azurophilic granules Most common cause: acute infections Stress, Myeloproliferative disease, Corticosteroid use, lithium, epinephrine, pheochromocytoma, Cushing's syndrome, smoking
Granulocytosis Neutrophilia: (IL-1, TNF) acute bacterial infections, inflammation, hemorrhage, drugs; tissue necrosis, hereditary Eosinophilia: (IL-5) allergy, skin diseases, parasites, malignancy Basophilia: myeloproliferative disorders Monocytosis: chronic infections Lymphocytosis: viral & chronic infections Leukemoid Reaction Resembles leukemia; 30-50,000 leukocytes/uL
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Resembles leukemia; 30-50,000 leukocytes/uL Presence of immature cells in blood (NO BLASTS) Cause: acute infection, metastatic neoplasm, allergies, drug rxn High leukocyte alkaline phosphatase (LAP): marker of mature neutrophil

WBC Neoplasms Lymphoid neoplasms: tumors of B & T-cells Leukemia: BM involved; presence of lg # of tumor cells in peripheral blood Acute: accum of blasts in marrow Acute Lymphoblastic Leukemia (ALL) --> lymphoblasts Acute Myelogenous Leukemia (AML) --> myeloblasts Blast predominate Child or elderly Short, drastic course Chronic Chronic Lymphoblastic Leukemia (CLL) --> lymphocytes Chronic Myelogenous Leukemia (CML) --> myeloid stem cells More mature cells Middle age Longer course Lymphomas: proliferations of tissue masses (lymph nodes, spleen) Myeloid neoplasms: originate from transformed hemopoietic stem cells Histiocytoses: histiocytes
Acute Lymphoblastic Leukemia (ALL) Most common in children <15 yo; avg age = 4 yo Neoplastic transformation of lymphoid clonal stem cells Progressive accum of lymphoblasts in BM Suppression of normal hemopoiesis 80% B-cell subtype 20% T-cell subtype Early pre-B subtype: CALLA+, TdT+ WBC = 10-100,000 cells/uL Thrombocytopenia S/Sx: fever, bone pain, epistaxis/ecchymosis (decreased platelets), HSM, generalized lymphadenopathy, testicular/CNS involvement Pathogenesis Etiology: unknown Genetic predisposition: Down syndrome Karyotypic abnormalities: majority translocations --> t(4:11), t(12:21), t(9:22) Classficiation Morphologic (FAB): L1, L2, L3 Immunologic Precursor B - ALL: CD19, Cd10 Precursor T - ALL: peak in adult males, presents mostly w/ mediastinal mass, high WBC, CD1, CD2, CD5, CD7 Prognosis Favorable (age: 3-7, female) Pre-B WBC <10,000/uL Minimal organ involvement Hyperploidy t(12:21) CALLA+ Unfavorable (age: <1, >10, male) T or mature B WBC > 50,000/uL
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WBC > 50,000/uL Prominent organ involvement Structural chromosomal abnormality t(9:22)

Therapy Induction/Remission: Prednisone, Vincristine, Asparaginase Consolidation: same drugs in short courses Maintenance: -mercaptopurine, methotrexate CNS: intrathecal methotrexate for residual blasts BMT Acute Myelogenous Leukemia (AML) Most common bt 15-60 yo Myeloblasts Very progressive malignancy S/Sx: bleeding, thrombocytopenia, fever, infection, bone pain Auer rods: azurophilic granular material in cytoplasm of blasts; fused lysosomes, elongated needles FAB Classification Mo --> no Auer rods M1 --> undifferentiated blast cells; rare Auer rods M2 --> myeloblastic; most common type; Auer rods, t(8:21) M3 --> promyelocytic; many Auer rods; DIC; abnormal RA metabolism Swollen, bruised hands M4 --> myelomonocytic; uncommon Auer rods M5 --> monocytic; gum infiltration M6 --> erythroleukemia; PAS + M7 --> Megakaryoblastic leukemia; myelobfibrosis Pathogenesis Environmental factors High-dose radiation exposure Myelotoxic agents (benzene, alkylating agents) Genetic abnormalities Down syndrome Fanconi anemia Ataxia telangiectasia Immunodeficency diseases Course Rapidly fatal if untreated, <2 mo Median survival: 3 yrs after chemotherapy Adverse prognostic factors Age > 60; t(9:21), previous chemo, leukocytosis > 100,000/uL Therapy Remission/Induction: Daunorubicin, Cytarabine BMT Vitamin A Death: Gram -ve infections and/or hemorrhage Chronic Lymphocytic Leukemia (CLL) Most common overall leukemia Most common leukemia >60 yo & most common cause of lymphadenopathy Clonal proliferation of small, CD5+ B lymphocytes B-cells are long-lived, but don't differentiate into plasma cells Genetic factors Chromosomal abnormalities; 1/2 of cases, trisomy 12 Pathology Blood Lymphocytosis 15-200,000 cells/uL
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 Lymphocytosis 15-200,000 cells/uL Coombs test +, normocytic anemia Hypogammaglobulinemia (50-70%); monoclonal IgM spike rare Thrombocytopenia, neutropenia Bone marrow Nodular/interstitial infiltrates Diffuse obliteration of normal hematopoiesis Lymphadenopathy, hepatosplenomegaly (50-60%) Smudge cells (basket cells): leukocytes that have been damaged during preparation of peripheral blood smear Increased fragility of the cell Therapy & Prognosis Conversion to prolymphocytic leukemia Richter syndrome: aggressive lymphoma; fever, loss of weight & muscle mass Death due to infecitons Chemotherapy: Prednisone + Chlarmbucil Chronic Myelogenous Leukemia (CML) 15-20% of all leukemias; age 25-60 Mainly uncontrolled prolif of myeloid cells Males more than females Massive splenomegaly Philadelphia chromosome t(9:22) Cont's tyrosine kinase activity Bcr-abl fusion: 100% specific for CML Absence means worse prognosis Pathogenesis Clonal disorder of pluripotent stem cell --> predominant granulocytic hyperplasia --> marked granulocytosis w/ immaturity --> high propensity to evolve into acute leukemia S/Sx Non-specific Related to hypermetabolism (high cell turnover) Splenomegaly Chloromas: soft tissue collections of leukemic cells Course Chronic phase (mean survival, 3-4 yrs) Accelerated phase Blast crisis/myeloid or lymphoid (survival, <1 yr) Lab Normochromic, normocytic leukemia Both mature & immature WBCs Myelocytes are most abundant 50-200,000 cells/uL Only leukemia w/ potential for thrombocytosis Hypercellular bone marrow Low LAP Therapy Busulfan or hydroxyurea BMT Alpha-interferon

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Diseases of WBCs Cont'd

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Heart Diseases ...

Hodgkin's Lymphoma Chronic enlargement of lymph nodes Localized at onset & later generalized Enlargement of spleen & liver Reed-Sternberg cells (or variants of RS cells) in affected tissues Bilobed; Owl-eye appearance Mirror-image nuclei S/Sx Enlarged painless nodes in neck & axilla (can spread) Hepatosplenomegaly (HSM) Fever, wt loss, pruritus, night sweats Pel-Ebstein Fever: fever alternating w/ long periods (15-28 days) Anemia = malaise Classification Lymphocyte predominant Mostly males, isolated enlarged cervical or supraclavicular LN Rare RS cells; BEST PROGNOSIS Nodular Sclerosing Mostly females, cervical, supraclavicular, mediastinal mass Collagen fibers; may have RS variants Mixed cellularity Mostly males; RS cells easy to ID; older aged 50% 5-yr survival rate Lymphocyte depleted Mostly males > 40 yo, WORST PROGNOSIS Staging of Hodgkin's Lymphoma Stage I: 1 lymph node involvement Stage II: >1 LN region; same side of diaphragm Stage III: involvement on both sides of diaphragm Stage IV: extra-nodal sites A: absence of B symptoms B: weight loss, night sweats, fevers Non-Hodgkin's Lymphoma All lymphoma's without RS cells Mostly B-cell proliferations; Often asymptomatic Lymphadenopathy, wt loss Extra-nodal spread --> skin, bone, gut, CNS, lung Pancytopenia; infections Fatigue, unexplained fever, sweats Enlarged tonsils --> adenoids Follicular Lymphomas Most common in US Derived from B lymphocytes CD19, CD20, CD10, BCL2 t (14:18) Affects middle age; Mean survival 7-10 yrs Rarely transform into aggressive type of lymphomas
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 Rarely transform into aggressive type of lymphomas Burkitt's Lymphoma Lymphoblastic lymphoma Mainly in African children; associated w/ EBV High incidence in AIDS Facial bones, ovaries & abdominal lymph nodes t(8:14) C-myc oncogene Isolated histiocytes on bg of abnormal lymphoblasts ('Starry Sky appearance') Hairy Cell Leukemia (HCL) Chronic B-cell leukemia; unknown etiology Hair-like cytoplasmic projections on lymphocytes, use TRAP (tartrate resistant acid phosphatase) stain Middle-aged/elderly man Insidiuos onset, indolent course Splenomegaly --> infiltration of red pulp = functional hypersplenism Bone marrow --> patchy or diffuse infiltration, fibrosis = marrow failure Pancytopenia Liver & lymph nodes also affected

Hodgkin's Lymphoma

Non-Hodgkin's Lymphoma (NHL)

Reed-Sternberg cells Non-contiguous spread Bi-lobed (owl's eye appearance) Involvement of B-cells Contiguous spread Extra-nodal involvement Myelodysplastic Syndrome Idiopathic/primary: age > 60 Therapy-related: 2-8 yrs after exposure Chromosomal abnormalities: Chromosome 5, 7, 8 Progression to AML in 10-40% of paitents Limited therapy Multiple Myeloma (Plasma cell neoplasm) Most common primary tumor in bone of adults 20% --> Bence-Jones proteins (light chains, filtered into urine) Bone marrow: increased # of plasma cells (>20%) Peripheral blood smear: rouleux (stacked-coin appearance) Deletion of 13Q Increased serum protein --> M spike (M-protein, para protein) IgG most common Punched out lesions Destructive bone lesions Hypercalcemia Renal insufficiency Increased susceptibility to infection Anemia Waldenstrom's Macroglobulinemia (WM) Lymphoplasmacytic lymphoma M spike (IgM) like in multiple myeloma Infiltration of many organs, lymph nodes, spleen & bone marrow No lytic bone lesions Normal serum calcium levels Hyperviscosity syndrome
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Hyperviscosity syndrome Vascular dilatations & hemorrhages in retina, nose bleeds Headaches & confusion Raynaud's phenomenon: abnormal globulins

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Quiz Topics
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Quiz Topics for Monday

Quiz Topics for Monday Pyruvate Kinase Deficiency RBC glycolytic enzyme deficiency --> Hemolytic Anemia Hemochromatosis: excessive accum of iron in body Secondary w/ ineffective erythropoiesis w/ incr erythroid activity Echinocytes (Burr cells): deformed RBCs Polycythemia Abnormally high conc of RBCs = increased Hb level Relative Polycythemia: hemoconcentration due to decreased plasma Cause: dehydration (ie: water deprivation, vomiting, diarrhea..) Absolute Polycytemia: increase in total mass of RBCs Primary: results from intrinsic abnormality of myeloid stem cells Polycythemia vera --> from myeloid stem cells Congenital --> Mutations in EPO-R = hyperresponsiveness Secondary: RBC progenitors are responding to increased EPO Appropriate: lung disease, high altitude living, cyanotic heart disease Inappropriate: EPO-secreting tumors (ie: renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma) Myeloid Metaplasia w/ myelofibrosis Presence of nucleated RBCs & immature granulocytes in blood Extramedullary hetaopoiesis in spleen & liver Myelophthisic anemia: marrow failure due to space-occupying lesions Pancytopenia in all cell lines due to inability of bone marrow to generate new blood cells Hepatosplenomegaly: production of RBCs outside BM Essential thrombocythemia Chronic blood disorder Over production of platelets by megakaryocytes in BM Platelets don't function properly = bleeding & thrombosis Mutation in JAK2 kinase Adult t-cell leukemia (ATL) Non-hodgkin's lymphoma May be caused by HTLV-1 Hypercalcemia, lytic bone lesions, skin lesions, death w/in 1 yr Reactive lymphadenitis Enlarged lymph nodes as a result of acute or chronic infections Bubonic plague: 1+ lymph nodes bulge out of skin & become necrotic IM: enlgm't of cervical lymph nodes Cutaneous anthrax, measles, toxoplasmosis Follicular hyperplasia: infections, autoimmune disorders, nonspecific rxns Paracortical hyperplasia: viral infections, skin disease & nonspecific rxns Sinus histiocytosis: lymph nodes that drain limbs, inflam lesions & malignancies Diffuse Large B-Cell Lymphoma (DLBCL) Non-Hodgkin's Lymphoma (high-grade) Enlarged lymph nodes in neck, armpit and/or groin which may spread to other organs (ie: liver, lungs, bones) Loss of appetite & tiredness, night sweats, high temps, wt loss Ttx: chemo, high-dose chemo w/ stem cell infusions, radiotherapy,
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Ttx: chemo, high-dose chemo w/ stem cell infusions, radiotherapy, steroid therapy, monoclonal Ab therapy Mantle cell lymphoma (MCL); rare Over express cyclin D1 due to t(11:14) Cells divide to early and do not die so they accum in lymph & spleen More males affected than females Ttx: chemo, immunotherapy, targeted therapy Infectious mononucleosis Acute viral infection (EBV) transmitted orally Flu-like symptoms Fever, fatigue, wt loss, malaise, pharyngeal inflammation, petechiae, enlarged lymph nodes, splenomegaly, hemolysis Self-limiting Bernard soulier syndrome Autosomal recessive bleeding disorder due to deficiency of Gp1b Gp1b = receptor for vWF Giant platelets Prolonged bleeding time bc platelets can't bind/aggregate at injury thrombocytopenia Glanzmann's thrombasthemia Platelets lack Gp2b, Gb3a = prolonged bleeding time Platelets can't bind fibrinogen = can't adhere to eo & damaged BVs Autosomal recessive or acquired as autoimmune disorder Monoclonalgammopathy of unknown significance (MGUS) Paraprotein found in blood like multiple myeloma, but has lower levels of Abs & plasma cells with no symptoms; but later may develop into multiple myeloma No evidence of bone lesions, anemia, hypercalcemia or renal insufficiency related to paraprotein

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Infectious Diseases
July-24-10 12:28 AM

QUIZ: JULY 26TH, 2010

Uncomplicated measles Cough, coryza, conjunctivitis Fever >101 (38.3) replicates in upper/lower resp tract lymph tissues viremia & growth epithelium & muc mbrns MOT: aerosol route, very contagious IP: 1-2 wks Kopliks spots: ulcerated mucosal spots near areas of Stensons duct Rash: mononuclear infiltrate of BVs Warthin-Finkeldey cells Complications of measles Viral/bacterial pneumonia Giant cell pneumonia immunocompromized pts; rare but often fatal Otitis media Subacute Sclerosing Panencephalitis (SSPE) o Devlps 1-10 yrs after initial infection (7/1,000,000 cases) o Behavioral changes, loss of motor ctrl & coordn; myoclonic seizures o Impaired speech, swallowing, vision Mumps Nonpurulent inflamn of salivary glands (esp parotid) o Most characteristic: edematous, painful enlargement of 1 or both parotid glands Most common complication = transient high frequency deafness MOT: direct & close person-to-person contact, airborne IP: 18-21 days local multiplication of virus in epith cells; viremia for 2-3 d Infectious: begins about 6d before onset of symptoms & conts for another 5d Viral shedding o Parotitis & Pancreatitis inflam rxns in salivary glands Histo section shows edema, macros, lymphocytes & plasma cells o Testes swelling, interstitial hemorrhage tight tunical = focal infarcts o Oophoritis: devlps in 5% of infected postpubertal women Pancreas abnormal endo & exo funcns, diabetes-like; incr serum amylase; may = juvenile IDDM Late-onset (postinfectious) type of mumps encephalitis o Autoimmune rxns, demyelination, perivascular cuffing Ddx: PE, IgM (acute) & IgG (later), serum amylase & lipase, lumbar puncture Ttx: supportive Picornavirus Cause of poliomyelitis (+)sense ssRNA Viral capsid resistant to low pH of stomach; inactivated by pasteurization, boiling, formalin & chlorine MOT: fecal-oral o Alimentary tracts of humans & animals o Salivary & resp droplects o Conjunctival secrns & exudates from skin lesions o Nerve & muscle cells Host Defenses o IgA & interferon @ entry point inhibits spread of virus to susceptible epith cells; reduces oral & fecal shedding o IgM first to appear & lasts for 2 wks; IgG lasts for years

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Polio Alimentary phase: primary replication in oropharyngeal & intestinal mucosa Lymphatic phase: tonsils, peyers patches, deep cervical & mesenteric nodes Viremic phase: blood stream, internal organs, regional LN Neurologic phase (RARE): spinal cord and/or brain stem Syndromes o Aseptic meningitis: meningeal signs, no paralysis o Paralytic Poliomyelitis Anterior horn cells of spinal cord, motor cortex, motor nuclei of medulla Lesions neuronal necrosis, necrophagia, loss of nerve cells Scattered nerve cells destroyed No visible sign of muscle weakness, OR More concd damage flaccid paralysis of muscles Spinal poliomyelitis motor neurons in spinal cord Bulbar poliomyelitis CN nuclei or medullary centers; swallowing dysfuncn, cardiac or resp failure Paralysis is IRREVERSIBLE Interfere w/ func of other muscles = skeletal deformities; tightening of joints, movt disability Growth of affected leg is slowed while other leg grows normally Scoliosis: deformities of the spine o Postpoliomyelitis Syndrome Recurrences of weakness or fatigue Usually involve groups of muscles that were initially affected May devlp 20-40 yrs after infection w/ polio virus Viral Hemorrhagic Fever Dengue fever: acute febrile illness of 2-7d plus 2+ of following Severe headache, retroorbital pain, severe myalgias, arthralgia, characteristic rash, hemorrhagic manifestations, leukopenia o MOT: bite of Aedes aegypti & albopictus (Great Lakes) o Pathology: vasc permeability, endoth dysfuncn, thrombocytopenia, severe platelet dysfuncn o (+) tourniquet test petechiae, ecchymoses or purpura o Hematemesis or melena Bleeding from mucosa, GIT, injection sites or other sites o Thrombocytopenia (<100,000 cells/uL) o Plasma leakage >20% rise in avg Hct level >20% drop in Hct level following volume replacement Pleural effusion, ascites, hypoproteinemia o Dengue shock syndrome: all of DF criteria plus evidence of circulatory failure (ie: rapid, weak pulse; narrow pulse P <20 mmHg; hypotension; cool, clammy skin; altered mental status) o TTx: antipyretics, daily platelet count Ringers lactate solution Boluses of 10-20 mL/kg given over 20 mins and may repeat Platelet & fresh frozen plasma transfusions
Herpes Simplex Virus HSV-1: oral lesions HSV-2: genital lesions Inhibit MHC-I, complement, immunoglobulins Pathology: intracell edema, balloon degen of epidermal cells, vesicular lesions MOT: intimate contact inoculation onto skin or mucous mbrn IP: 4-6 days Replicates in epith cells cell lysis & local inflamn vesicles Viremia = visceral dissemination In all hosts, virus ascends the peripheral sensory nerves to reach the dorsal root ganglia Replication w/in neural tissue
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o Replication w/in neural tissue o Retrograde axonal spread mucosal & skin surfaces via peripheral sensory nerves Mucocutaneous infections = most common clinical manifestions o Gingivostomatitis Fever, sore throat, pharyngeal edema & erythematosis Vesicular or ulcerative lesions Oral & pharyngeal mucosa o Herpes simplex labialis Cold sores recurrent infections of oropharynx Herpetic Keratitis: most common cause of blindness in US (HSV-1) o Conjunctivitis, dendritic ulcers best detected by fluorescein staining, deep stromal involvement Herpes Simplex Encephalitis: most common cause of focal, sporadic encephalitis in US (mostly HSV-1) o Hemorrhagic necrosis of inferiomedial portion of temporal lobe o High mortality & morbidity o 70% of cases = significant neurologic sequelae Eczema herpeticum: underlying dermatitis & may be localized Herpetic whitlow: occurs on fingers at or near the cuticle o HSV-1in health care workers or children due to saliva exposure o HSV-2related to digital-genital exposure Genital Herpes (HSV-2) o Vesicles rupture = very tender ulcers o Fever, malaise, anorexia, bilateral inguinal adenopathy o Common in women; new lesions can occur during the course of the illness o Usually forming in 4-10 days o Median duration of viral shedding = 12 days Neonatal HSV o High mortality o Long-term morbidity Encephalitis or disseminated disease Seizures, psychomotor retardation, spasticity, blindness or learning disabilities Ttx: antiviral therapy; delivery via C-section Ddx: Papnicolaou smear stain will show multinucleate giant cells doesnt distinguish bt HSV-1, HSV-2 or varicella-zoster virus Cowdry Type A Cells: pink, purple intranuclear inclusions w/ virions; multinucleated syncytia Varicella-Zoster Virus (VZV) MOT: droplet spread; direct person-to-person contact w/ lesions, transplacentally spread to fetus IP: 1-3 wks enters thru resp system LNs primary viremia RE cells in spleen, liver secondary viremia viscera & skin typical skin lesions Risk factors for severe varicella o Neonatal Period 1st month of life (esp if mother is seronegative) Delivery before 28 weeks gestation o Adolescence & adulthood Steroid therapy, malignancy, immunocompromized state, defects of cellular immunodeficiency, pregnancy Prodrome: low-grade fever, abdominal pain, rash on head & trunk extremities; headache, malaise, anorexia; cough, coryza, sore throat Rash appears in crops; 10 to 250-500 lesions (max 1500) o Red macule papule vesicle pustule crust o Hallmark: simultaneous presence of different stages of the rash o New lesions continue to erupt for 3-5 days; usually crust by 6 days; completely heal by 16 days Congenital Varicella Syndrome o 2% of children born to women who develop varicella o 1st or 2nd trimester IUGR, micropthalmia, cataracts, chorioretinitis, cutaneous scarring Unrelated to severity of disease in mother
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o Unrelated to severity of disease in mother o Microcephaly, cortical atrophy, limb hypoplasia Infantile Zoster o Maternal infection after 20 weeks AOG o Manifests w/in 1st year of life o Thoracic dermatomes Neonatal Varicella o Maternal varicella 5 days before or 2 days after delivery Maternal viremia Absent maternal Ab Severe & disemminated Primary causes of death severe pneumonia, fulminant hepatitis o Maternal varicella >5 days antepartum babies have mild varicella o DDx: immunohistochemical staining of skin lesion scrapings; serologic tests Tzanck smear: multinucleated giant cells Children CXR, CSF Shingles & VZV o Severe radicular pain o Chicken pox-like lesions in dermatome o Trigeminal nerve uveitis, keratitis, conjunctivitis, ophthalmoplegia, iritis o Usually heal in about 2 wks o AIDS multi-dermatomal o Ramsay-Hunt Syndrome (Herpes Zoster Oticus): CN VII & VIII o Reactivated Shingles Post-herpetic neuralgia reactivation; chronic burning or itching pain; hyperesthesia Smallpox (Variola) Highly infectious (contagious until last scab falls off) MOT: droplet spread; prolonged face-to-face contact w/ infected person, 3-6 ft; direct contact w/ infected bodily fluids or contaminated objects Acute onset of fever >101 F (38.3 C) Rash firm, deep seated vesicles or pustules Macules first on whole face proximal extremities & trunk distal extremities Process takes 24-36 hours (no new lesions after) Macules raised papule opaque & turbid w/in 24-48 hrs False pustules Cytomegalovirus (CMV) MOT: transplacental, perinatal, saliva (preschool), venereal disease (15 yo), iatrogenic Pathology: infects WBC gigantism of cell & nucleus = nuclear inclusion (owls eyes) Epstein-Barr Virus (EBV) Trophic for B-lymphocytes transformation Parotid gland, lymph tissues MOT: exchange of saliva; blood Lymphoproliferative disease in highly immunocompromized individuals Common in heart & bone marrow transplant recipients o Main cause of malignant B-cell lymphoma in organ transplants o Post-transplant lymphoproliferative disorder (PTLD) Pathology 1. Lysis of cells infects other cells 2. Latent infection stimulate Ab; anti-sheep heterophile Ab; no effect on EBV o Cytotoxic T-cells; NK cells S/Sx of IM o Latency associated genes EBNA1 & LMP1 EBV-assoc B-cell lymphomas o t(8:14) Infectious Mononucleosis (IM) o MOT: exchange of saliva o IP: 1-2 months Primary infection subclinical in most cases; + serology, shed infectious virus for many yrs
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o Primary infection subclinical in most cases; + serology, shed infectious virus for many yrs o S/Sx: malaise, lymphadenopathy, tonsillitis, enlarged spleen & liver, fever > 1wk Most common complaint = FATIGUE Most specific finding: uvular edema Highly suggestive: posterior bilateral cervical adenopathy Most common cause of mortality: splenic rupture Myalgia, pharyngitis, atypical lymphocytosis Burkitts Lymphoma: tumor of jaw & face in children; t(8:14) o Endemic in equatorial Africa o Resistant to malaria appear to be susceptible to progression to lymphoma o Downey cells starry sky pattern on histo section Nasopharyngeal cancer: tumor of epithelium of upper resp tract o Endemic in south China, Alaska, Tunisia, east Africa o Genetic predisposition + environmental cofactor Oral hairy leukoplakia: lesions in mouth; opportunistic; occurs in HIV+ patients Ddx: Downey cells (atypical lymphocytes) o Presence of heterophile Abs react to Ags from animal RBCs o Paul-Burnell test: sheep RBCs + heterophile Abs o Monospot test: horse RBCs agglutinate + heterophile Abs o If results are initially negative, test weekly for 6 weeks o IgM (+), IgG (+) acute infection o IgM (-), IgG (+) past infection

Human Papillomavirus (HPV) Induce tumors in natural hosts (humans, rabbits, cows, dogs, papillomatous lesions of skin & squamous mucosa) E6 protein binds to p53 tumor suppressor gene product accelerates destruction E7 protein binds to pRb inhibits its tumor suppressive function Koilocyte: large, polygonal squamous cells w/ wrinkled nucleus & lg perinuclear cavity MOT: direct contact with another infected person; minute abrasions by autoinoculations (scratching), indirect contact (ie: showers, spa); genital warts (sexually transmitted) Most common clinical changes in both males & females condylomata acuminate (anogenital warts) o Women Cervix, vagina & vulvar region; Cervical intraepithelial neoplasia o Men anal condylomas & penile warts Laryngeal papillomas (Types 6 & 11) in children o Infected during passage thru birth canal of mothers w/ genital condylomas 1/3 regress in 2 mo; 2/3 regress in 1 yr; complete cure = 5 yrs Squamocolumnar Junction: site where cervical carcinoma & CIN are most commonly found o Active area of metaplasia o Vulnerable to HPV-induced cellular transformation Cervical Intraepithelial Neoplasia (CIN) o CIN 1,2 or 3 based on thickness of epith showing abn cells, degree of mitotic & nuc activity Cervical Cancer o 15 yrs slow progression from CIN 3 to invasive carcinoma o Inhibition of p53 & pRb increased cell proliferation rate o Infected cell acquires more & more DNA damage cant be repaired = oncogenic transformn Fecal-Borne Hepatitis Serious inflam disease of liver; common in under-devlpd countries (poor sanitation) Hepatitis A (HAV): ssRNA, picornavirus (enterovirus 72) = 55% of acute hepatitis o Virus shedding bile & stools o HAV-infected liver lymph infil, Kupffer cell prolif, necrosis of parench cells, Ab-Ag complexes o Most infections are subclinical; self-limited o Induction of IgM and IgG long-lasting immunity; NO carrier state IP: 14-45 days
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IP: 14-45 days Children 84-94% asymptomatic Adults 5-25% asymptomatic; 66% have jaundice Cholestasis dark urine, clay-colored stools, jaundice Increased blood levels of AST, ALT, Bilirubin ALT > AST for 5-20 wks o Anti-HAV IgM acute phase; up to 6 mo o Anti-HAV IgG life long o UTZ & liver biopsy NOT required o TTx: supportive therapy & rest sick leave 10d after jaundice onset HAV low mortality (0.1-0.2%) Hepatitis E (HEV): ssRNA, unenveloped virus o Mortality rate is 10x HAV (1-2%) MOT: ingestion of fecal-contaminated water or food; sporadic outbreaks (shellfish) Pathogenesis o Portal: fecal-oral; withstands harsh conditions in stomach & intestines o Viremia: replicates in oropharynx & epith lining of intestines; viremia liver o Replication: primarily w/in liver parenchymal cells; gastric & SI mucosa, kidney & bones Blood-Borne Hepatitis HBV: dsDNA virus, enveloped, hepadnavirus o HbsAg (Australia Ag) envelope protein; elicits neutralizing Abs o HBcAg HBV core Ag o HBeAg HBV soluble Ag; related to infectivity o Dane particle: infectious HBV virion o MOT: Sexual Transmission High conc blood, serum, wound exudates Moderate semen, vaginal fluid, saliva Low/undetectable urine, feces, sweat, tears, breast milk Percutaneous routes needle sharing, acupuncture, ear piercing, tattooing, transfusions, receiving blood products Very close personal contact involving exchange of blood or secretions Perinatal/horizontal transmission also possible o Pathogenesis: bloodstream acquisition Replicates in liver cells w/in 3 days HBV genomes integrate into host chromos during replication Release of HBsAg Cellular swelling & necrosis of the liver Parenchyma degeneration Immune complexes formed by HBsAg & specific Ab hypersensitivity reactions Arthritis, rash, liver dmg, vasculitis, athralgia, renal failure Immune sys tries to clear HBV destroys infected hepatocytes Increased liver enzymes Resolution of infection = regeneration of liver parenchyma o IP: 7-160 days o 65% Anicteric infections o Acute infection less severe in children; early symptoms, fatigue, anorexia, nausea, pain & fullness in upper RUQ, fever (loss of fever = recovery) o Later symptoms arthritis & rash, cholestasis; more severe symptoms than HAV o HBV Sequelae Chronic HB infection: presence of Hepatitis S Ag (HBsAg) in blood for at least 6 mo Chronic infection more common with HCV 25% children will devlp primary liver cancer or cirrhosis as adults Ttx: sustained suppression of HBV & end to active liver disease Coinfection w/ delta agent Fulminant hepatitis occurs in 1% of acutely infected indiv (more likely if HBV + HDV) More severe symptoms can be fatal
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o o o o o

More severe symptoms can be fatal Severe liver damage ascites & bleeding Liver shrinkage Ttx: liver transplant Liver cirrhosis consequence of repeated immune system attacks Cant be cured, but progress can be stopped if cause is treated Cessation of enzymatic processes in liver Ascites, jaundice, internal bleeding, hepatic encephalopathy Candidates for liver transplantation Primary Hepatocellular Carcinoma follows HBV infection after 9-35 yrs Can also result from chronic HCV infection o Serological Tests HBsAg marker of current infection Chronic if in serum for >6 months HBeAg marker of active infection Infectious if HBeAg is present HBsAb marker of recovery or immunity Convalescence sign if increase HBsAb HBV DNA measures virus activity HBeAb marker of inactive virus (generally) Convalescence sign if increase HBeAb HBcAb marker of present or past infection Window period o Ttx: interferon-alpha Dose: 5 million U/d or 10 million U 3x/wk SQ for 16 wks MOA: immunostimulatory activity; antiviral activity Result: HBV DNA levels & HBeAg become undetectable in 30-40% of patients Babies born to HBV+ mothers HBIG + Hep B vaccine at birth Remaining doses of vaccine given at 1 and 6 mo o Diet: no restrictions for acute & chronic hepatitis Decompensated cirrhosis low sodium, high protein, fluid restriction (1.5 L/d) o Prevention: Active immunization Most commonly used vaccine Energix-B or Recombivax HB Doses: 0-2 mo, 1-4 mo, 6-18 mo Passive Immunization Prepared from plasma w/ high titer of HBsAb, no detectable HBsAg Used in combo w/ vaccination for infants born to HBV+ mothers & people who were accidentally exposed to HBV HCV: ssRNA, enveloped, flavivirus o Leading infectious indication for liver transplantation o 75-85% chronic infection o MOT: injecting drug use (60%) sex (15%) unprotected w/ multiple partners, early coitarche, infected sexual partner, history of other STDs, experience sex w/ trauma Managing Chronic HBV or HCV o Stop drinking alcohol o IDUs should stop injecting drugs substance abuse treatment o Everyone w/ chronic liver disease should be immunized against Hep A o People w/ chronic HCV that are at risk for HBV should also be immunized against Hep B HDV: ssRNA, assoc w/ HBV; a virioid o Delta agent must be coated w/ HBsAg in order to be infective o Usually due to percutaneous exposures (mostly found in IV drug users) o Less efficient MOT sex, perinatal/horizontal & vertical transmission o HBV + HDV more severe acute disease; higher risk of fulminant hepatitis (2%-20%) NANBHV: non-A, non-B hepatitis viruses; multiple types o Infections mainly assoc w/ blood transfusion, hemodialysis, renal transplantation Hepatitis F sporadic, enterically transmitted Hepatitis G RNA virus; may coexist with other hep viruses (mostly HCV) Hepatitis H 10-15% of chronic hepatitis patients that dont fit other categories

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Syphilis Treponema pallidum MOT: direct contact w/ infectious lesions, generally via sexual contact Pathogenesis: plasma cell infiltrates, macrophages, lymphocytes o Endarteritis: endothelial hyperplasia fibrosis (common in all stages) Primary Syphilis o IP: 3 wks (10-80 days) o Hard chancre painless, highly infectious, heals in 3-6 weeks o Lymphadenopathy firm, nonsuppurative, persist for months Secondary Syphilis begin 6-8 wks after chancre; may overlap o Rashes Macular, popular, pustular & nodular type on palms & soles o Patchy alopecia o Condyloma lata o Systemic S/Sx Latent Syphilis positive serological test in absence of any clinical disease symptoms o Duration: highly variable o 25% relapse of secondary o 40% progress to tertiary Tertiary/Late Syphilis noncontagious, but highly destructive o Late benign/gummatous syphilis 15% of untreated cases w/in 1-10 yrs Gummas: nodular granulomatous inflammation o Cardiovascular syphilis aortitis: thickening & hardening of vasa vasorum Necrosis, aortic regurgitation, aneurysm, coronary artery obstruction o Neurosyphilis 8% of untreated cases w/in 5-35 yrs after infection Acute meningitis Chronic meningovascular endarteritis & perivascular infiltration w/ lymphocytes (perivascular cuffing) blocking of BVs necrosis of nerve tissue Gradual intellectual & emotional deterioration hemiparesis CN III, IV & VI are most affected o General Paresis 20+ yrs after untreated infection Personality changes neurosis, euphoria, depression, over activity, paranoia Affect all-out type of reaction Hyperactive reflexes Argyll-Robertson Pupils: constricts during accom (near vision), but unresponsive to light Sensorium delusions, illusions, hallucinations, paranoid ideas Intellect reduction in mental capacity, orientation, retention & recall, calculations, judgment & insight Speech slurred speech, tremors of lips & tongue, mask-like o Tabes dorsalis 5-20 yrs after primary & secondary stages Preataxic: shooting leg pains; loss of position sense & passive motion; poor control of extremities Ataxic Paralytic Congenital Syphilis o 4th month of gestation o Stillborn or rhinitis (snuffles), osteochondritis, HSM & lymphadenopathy, glomerulonephritis o Death in first 2 yrs pulmonary hemorrhage, secondary bacterial infection or hepatitis o Late congenital syphilis (after 2 yo) Cluttons joints: painless, symmetrical hydrarthrosis of knee joint deafness Rhagades: fissures, cracks or fine linear scars in skin esp around mouth Hutchinsons teeth: mulberry molars Saddle nose, saber chins Nontreponemal tests: measure anti-treponemal Ab using cardiolipin as Ag o Venereal Disease Research Labs (VDRL) slide test o Rapid Plasma Reagin (RPR) Treponemal Tests: rely upon Ags derived directly from T pallidum FTA-ABS (fluorescent treponemal Ab-absorption test)
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o FTA-ABS (fluorescent treponemal Ab-absorption test) o MHATP (T. pallidum hemagglutination test) Jarisch-Herxheimer reaction o Transient fever, malaise, chills, headache & myalgias o Existing lesions may intensify temporarily o Devlps w/in several hrs after beginning antibiotic treatment o Usually clears w/in 24 hrs Lyme Disease Borrelia burgdorferi MOT: bite of blacklegged ticks (Ixodes ricinus) S/Sx: fever, headache, fatigue o Erythema chronicum migrans: expanding annular skin rash Carriers white-footed mice, white-tailed deers, dogs & birds Bulls-eye rash Pathology o Skin lesions edema + lymphocytic infiltrates o Early Lyme disease arthritis similar to RA, lymphocytes, plasma cells, synovial hyperplasia o Late Lyme disease erosion of cartilage o Arteritis: onion-skinning Sexually Transmitted Genital & Rectal Infections C. trachomatis Men nongonococcal urethritis, epididymits & proctitis Young women acute salpingitis & cervicitis Superinfection with gonorrhea Lymphogranuloma venereum (LGV): usually occurs in men o Inguinal lymphadenopathy; initial lesions vesicles Histo section regional lymph nodes = stellate abscesses o Irregularly-shaped foci of necrosis + neutrophilic infiltrates fibrosis strictures, obstruction Trachoma: infection of conjunctival epithelial cells o Subepithelial infiltration of lymphocytes devlt of follicles o Eyelids become scarred & malformed trichiasis o Pannus formation fibroblasts & BVs invade infected area = corneal opacification & blindness Rocky Mountain Spotted Fever MOT: R rickettsiae; transmitted by tick bites Pathogenesis: infect vascular endothelium, skin, brain, lungs, heart, kidneys, liver, GIT o Cytokines & inflammatory mediators o Loss of intravascular fluid into tissue spaces (edema) resultant low blood volume = reduced perfusion of organs Disordered funcn of tissues w/ damaged BVs encephalitis, pneumonitis, hemorrhagic rash Major cause of death non-cardiogenic pulmonary edema ARDS
Malaria P falciparum: malignant tertian malaria o Not limited to RBCs of a particular age o Highest level of parasitemia o Infected RBC proteinaceous knobs, bind to endoth cells & adhere to walls = vascular obstrucn o Cerebral malaria most common cause of death in malaria patients coma, altered mental status or multiple seizures o Hemoglobinuria (blackwater fever) passage of dark-colored urine, secondary to hemolysis P malariae: benign quartan malaria o Remain asymptomatic for a much longer amount of time Recrudescence is common often assoc w/ a nephritic syndrome
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o Recrudescence is common often assoc w/ a nephritic syndrome P vivax: benign tertian malaria (Latin America, India & Pakistan) o Lasts for 2-3 mo w/ diminishing frequency & intensity of paroxysms o Untreated 50% relapse in a few weeks to 5 yrs P ovale: benign tertian malaria (Africa) o Similar to P vivax, but less severe o Often resolves w/o treatment Vector Anopheles mosquito (females bite) Cold Stage (1 hour) o Chills, chattering teeth o Peripheral vasoconstriction cyanotic lips & nails Febrile Stage (39-41 C) o Severe headache, nausea, vomiting, convulsions, euphoria o Profuse perspiration o Temperature begins to drop Asymptomatic Phase exhausted, but symptom-less HIV

Pneumocystis carinii & jiroveci Gp120: found in viral envelope glycoprotein; binds to CXCR4 or CCR-5 Viral reverse transcriptase: produces cDNA using viral RNA template Provirus: viral DNA is transported into nucleus & integrated into chromosome Spike in p24 antigen and gradual increase in gp120 (anti-HIV antibody) Cytotoxic T-cell mediated lysis = killing of CD4 T-cells o Syncytium formation: uninfected (gp120 ve) CD4 cells fuses with infected CD4 (gp120 +) o Complement-mediated lysis binding of free gp120 to CD4 antigen makes uninfected cell look like an infected one Induction of apoptosis of CD8 cell binding of gp120 to CXCR4 = expression of TNF-a on surphace Macrophages = reservoir for HIV outside blood o Can carry virus to diff organs (ie: brain) & sustain HIV production for long time w/o being killed Stage I: asymptomatic Stage II: minor mucocutaneous manifestations, recurrent upper resp tract infections Stage III: unexplained chronic diarrhea > 1 mo; severe bacterial infections Stage IV: toxoplasmosis of brain, candidiasis of esoph, trachea, bronchi or lungs; Kaposis sarc; 25 illness o 25 AIDS-defining diseases Cervical cancer (invasive) Tuberculosis Candidasis of bronchi, trachea or lungs; esophageal Coccidioidomycosis disseminated or extrapulmonary Extrapulmonary cryptococcosis Chronic intestinal cryptosporidiosis for > 1mo CMV disease (other than liver, spleen or LNs) HIV-related encephalopathy Herpes simplex: chronic ulcer(s) for >1 mo; bronchitis, pneumonitis or esophagitis Disseminated or extrapulmonary histoplasmosis Chronic intestinal isosporiasis for > 1mo Kaposis sarcoma Immunoblastic or primary brain Burkitts lymphoma Mycobacterium avium complex Disseminated or extrapulmonary other mycobacterium Pneumocystis carinii pneumonia (PCP) Recurrent pneumonia Progressive multifocal leukoencephalopathy Recurrent salmonella septicemia Toxoplasmosis of the brain

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Toxoplasmosis of the brain Wasting syndrome due to HIV HIV (-) but AIDS still possible if o No high-dose corticoid therapy or other immunosupp/cytotoxic therapy in 3 mo before onset o Not diagnosed w/ Hodkins disease, nHL, lymphocytic leukemia, multiple myeloma, or any cancer of lymphoreticular or histiocytic tissue or angioimmunoblastic lymphadenopathy o Doesnt have a genetic immunodeficiency syndrome atypical of HIV infection (ie: one involving hypogammaglobulinemia) o AND Patient has had PCP OR 1/25 defining illnesses AND CD4+ <200 cells/uL or CD4 <14% Classification in Children o Category N: asymptomatic; have only 1 condition listed in Category A o Category A: mildly symptomatic; 2+ of below conditions Lymphadenopathy Hepatomegaly Splenomegaly Dermatitis Parotitis Recurrent or persistent upper resp infection, sinusitis or otitis media o Category B: moderately symptomatic Anemia, neutropenia or thrombocytopenia Bacterial meningitis, pneumonia or sepsis Oropharyngeal candidiasis (thrush) CMV infection Recurrent or chronic diarrhea Persistent fever (> 1 month) Toxoplasmosis o Category C: severely symptomatic AIDS-related complex (ARC) 24-65 months (end of Stage 1 through Stage 2) o Fever, fatigue, diarrhea, wt loss, night sweats, immunological abnormalities Malignant neoplasms of the skin o Kaposis sarcoma: pink-red-purple-brown; anywhere on skin; HHV8 o Lymphomas (ie: Hodgkins, non-Hodgkins, Burkitts) o Invasive cervical cancer Screening Tests: ELISA, Latex agglutination Confirmatory Tests: Western blot, immunoflurescence o Western blot is definitive; specific for HIV gp120 or gp160 w/in 4-8 wks after exposure Other tests o P24 antigen early marker of recent infection (*detection in neonates of HIV+ mothers) o Virion RNA, RT-PCR detects virus in blood & confirms treatment efficacy First 2-4 wks when patients are seronegative but still infective Useful in neonates also o CD4:CD8 Tcell ratio staging & confirms treatment efficacy Normal CD4/CD8 ratio = 0.9-1.9 CD8 appears increased in HIV due to decrease in CD4 Normal CD4 = 500-1600; >28% (intermediate = 14-27%; AIDS < 14%) <200 start PCP therapy <100 toxoplasmosis; cryptococcosis <75 MAC Normal CD8 = 375-1100 o Isolation & culture of virus Highly Active Anti-Retroviral Therapy (HAART) o Suppression of viral replication & halts damage to immune system o Partially restores immune function = fewer opportunistic infections & longer life o Start treatment if (+) AIDS-defining illness OR CD4 < 350 cells/mm3 o Current recommended treatment = 1-NNRTI + 2 NRTI or PI + 2NRTI o Opportunistic Infections PCP: TM-SX Cryptococcosis: Amphotericin B Toxoplasmosis: Pyrimethamine
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 Toxoplasmosis: Pyrimethamine TB: RIPE regimen MAC: Azithromycin + Ethambutol o Start HAART regardless of CD4 count if: Pregnant woman HIV-associated nephropathy Patients coinfected w/ HBV PEP for health care practitioners o 2 or 3 drug regimen for confirmed HIV patients o No PEP for HIV (-) patients o Consider risk factors for patients of unknown status o Given in case of percut needle exposure, mucous mbrn exposures & non-intact skin exposures

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Blood Vessels
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Blood Vessels

Arteriovenous Fistulas Abnormal communications May be congenital Short circuit --> more blood returns to heart = high output cardiac failure Complication: rupture, hemorrhage Arteriosclerosis Thickening of arteries Monckeberg medial calcific sclerosis Calcification in muscular arteries Mostly occurs in media >50 yo Palpable Patent lumen Atherosclerosis Non-modifiable risk factors Middle age, Males, Family/genetics Obesity, Sedentary, Type A, Postmenopausal estrogen. High carb diet Modifiable risk factors High cholesterol, LDL, BP >165/95 mmHg, Cigarette smoking, Diabetes Alcohol, Lipoproteins, Trans fat intake, Chlamydia pneumonia Theories of Atherosclerosis Endothelial dysfunction Turbulent flow Bacterial/viral antigens = inflammation LDL in foam cells Platelets, MP, endoth cells --> release PDGF, FGF & TGF --> sm muscle cell migration Sequence of events 1. Isolated MP foam cells 2. Fatty streak 3. Fatty streak + extracellular lipid pools 4. Atheroma 5. Fibroatheroma 6. Surface defect, hematoma-hemorrhage, thrombus Occurs in medium & large elastic arteries (ie: Aorta, Carotid, Iliac, Coronary, Popliteal As) Complications MI, sudden cardiac death, chromic ischemic heart disease CVA Aortic aneurysms Peripheral vascular disease Mesenteric occlusion Ischemic encephalopathy
Hypertension BP: cardiac output & peripheral resistence Sustained systolic P > 140, diastolic > 90 mmHg 95% idiopathic Benign hypertension Malignant/accelerated hypertension 200/120 mmHg
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 200/120 mmHg Within 1 year Pathogenesis Whole body sodium homeostasis --> blood volume --> CO Neural & hormonal factors --> peripheral vascular resistance Autoregulation in response to increased blood flow NO & PGs from kidney Reduced renal sodium excretion = essential hypertension

Hyaline Arteriosclerosis Hyaline deposition in walls = narrow lumen Nonspecific for hypertension Benign Nephrosclerosis: impaired renal blood flow = loss of nephrons = contraction of kidneys Hyperplastic Arteriolosclerosis Characteristic of malignant hypertension Diastolic > 120 mmHg Onion skin thickening of the walls Necrotizing arteriolitis: fibrinoid & acute necrosis of the vessel walls Aneurysms Abnormal dilatation of BV wall/heart wall True aneurysms: bounded by arterial wall components False aneurysms: breach in the arterial wall, communicates w/ vascular lumen (pulsating hematoma) Abdominal Aorta Aneurysm (AAA) --> most common Mural thrombi --> emboli to lower legs & kidneys Pressure/expanding thrombi: close off ostia of renal, mesenteric arteries (+) lymphocytes/plasma cells --> inflammatory AAA Salmonella gastroenteritis: Mycotic AAA Causes Major cause --> Atherosclerosis most likely in men >50 yo Marfans Increased MMP (matric metalloproteinases) Growth = 0.2-0.3 cm/year LaPlace Law: wall tension is proportional to diameter & internal pressure Complications: rupture, obstruc'n, embolism, impingement, abdom mass Syphilitic (Leutic) Aneurysms Tertiary syphilis Vasa vasorum of thoracic aorta Dilatation of aortic annulus Obliterative endarteritis w/ a rim of lymphocytes Ischemia of aortic media --> loss of medial elastic fibers, muscle cells --> loss of elastic recoil "tree barking" = contraction of the intima Complications Rupture Affect mediastinal structures Impinge on airways/lungs Press on esophagus Presses on recurrent laryngeal nerve Pain, bone erosion Aortic valve dilatation Aortic Dissection Dissecting hematoma
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Dissecting hematoma Presence of blood in laminar planes of vessel wall (media) Rupture & massive hemorrhage Double-barrel lumen Causes: Most commonly occurs in men >40 yo with Hx of hypertension If <40 yo, consider history of collagen diseases Iatrogenic: cannulation, cardiopulmonary bypass Hx of pregnancy Most common location: w/in 10cm of aortic valve Type A --> ascending, descending aorta Type B --> distal lesions (ie: subclavian artery) Dissecting Aneurysm Most common cause of death = rupture Pericardial, pleural or peritoneal

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Blood Vessels Cont'd

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Blood Vessels Cont'd

Vasculitis Inflammation of BV (arteries, veins, lymphatics, capillaries) walls "Angiitis", male > female Fibrinoid necrosis --> if untreated = death Non-infectious Immune complexes: type III/ drug hypersensitivity/viral Anti-endothelial cell antibodies Antineutrophil cytoplasmic antibodies: autoantibodies against neutrophil, monocytes & endothelial cell enzymes (disease markers) c-ANCA --> proteinase p-ANCA --> MPO Direct infection: Bacterial, Rickettsial, Spirochetial, Fungal, Viral Unknown: Giant cell arteritis, Takayasu arteritis, Polyarteritis nodosa Large Vessel Vasculitis Giant cell (temporal) arteritis: granulomatous inflam of cerebral arteries; >50 yo Takayasu's arteritis: granulomatous inflam of aorta & lg branches; <50 yo Medium-sized Vessel Vasculitis Polyarteritis nodosa (PAN) Kawasaki disease: usually children; coronary artery involvement Small Vessel Vasculitis Wegener's granulomatosis: lungs & kidneys; c-ANCA Churg-Strauss syndrome: small artery vasculitis, asthma; blood eosinophilia Leukocytoclastic Vasculitis: Hypersensitivity Vasculitis; palpable purpura Henoch Schonlein purpura: IgA dominant immune complex w/ deposition in skin, gut & kidney
Case 1 A 55 yo woman, complaining of frequent headaches, mainly in temporal area with on & off fever & pain on chewing food. She also noticed double-vision & sudden vision loss in the left eye. On PE, node-like masses could be felt in the area of the temporal lobe. Giant cell arteritis/Temporal arteritis Chronic vascular disease of unknown origin occurring in women >50 yo Inflammation is due to CD4 & CD8 cells Affects extracranial arteries (90% of cases --> temporal arteries) Worst complication: blindness, ophthalmic artery; significant clinical overlap w/ polymyalgia rheumatica Temporal arteries --> tender, dilated, inflamed, thickened or cord-like Skipped lesions Pulsatile Bruits Ulceration may develop Ischemic optic neuropathy ESR > 70 mm/hr Elevated CRP Case 2 35 yo Japanese female, c/o frequent numbness of her right hand & arm, accompanied by intolerance to cold air. She has been a known hypertensive & is maintained to Nifedipine. BP --> left arm: 150/110 mmHg, right arm: 110/90 mmHg

Takayasu's arteritis Pulseless disease

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Takayasu's arteritis Pulseless disease Chronic vasculitis; occurs in women 20-40 yo of Asian descent HLA A24, B52, DR2 Narrowing of the carotid, inominate & subclavian arteries, aorta Must have 3/6 criteria Age <40 yrs at disease onset Claudication of extremities Decreased brachial artery pulse BP difference > 10mmHg between arms Bruit over subclavian arteries or aorta Arteriogram abnormality --> occlusion or narrowing in aorta or main branches Other S/Sx: ischemia due to arterial stenosis & thrombosis Pulmonary hypertension Visual disturbances, retinal detachment Low BP in upper limbs & high BP in lower limbs High ESR Ttx: steroids

Case 3 A 45 yo female, caucasian, increase in BP seen on insurance checkup. She also complained of weight loss of 10 lbs in 4 weeks, and constant fatigue. She was diagnosed w/ Hepatitis B about 6 mo ago, but was given interferon. BP: 140/100 mmHg Increased creatinine Increased BUN Polyarteritis nodosa (PAN) Recurrent necrotizing vasculitis Medium & small muscular arteries GI, hepatobiliary, renal, pancreas & skeletal muscles Deposition of immune complexes in the arterial wall HBsAg is detected in 20-40% of paitients w/ PAN Transmural inflammation Type III Hypersensitivity Fever, abdominal pain, weight loss, bowel ischemia Renal failure = common cause of death Churg-Strauss Syndrome: variant of PAN Granulomatous inflammation of the respiratory tract Necrotizing vasculitis affecting small & medium-sized vessels Blood eosinophilia & high IgE levels Asthma & allergic rhinitis p-ANCA +ve Responds well with corticosteroids Kawasaki disease Febrile systemic vasculitis; occurs in <5 yo Highest incidence in Japan Similar to PAN, less fibrinoid necrosis "Mucocutaneous lymph node syndrome" S/Sx: fever, conjunctivitis, red & dry lips, oral mucosa erythema, truncal rash desquamation of the fingers & toes, cervical LN Hemorrhagic edema of conjunctivae, lips, oral mucosa (red eyes, dry cracked lips, red tongue) Complication --> coronary arteritis, aneurysm formation
Case 4 40 yo male caucasian w/ fever & congested sinuses of 2 wks duration, accompanied by cough, non productive. Urine was minimal in amount, reddish in color; PE showed tender sinuses
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sinuses Cresentic glomerulonephritis Elevated BUN, creatinine c-ANCA +ve

Wegener granulomatosis Males >40 yo Triad 1. Necrotizing granulomatous vasculitis, small & medium vessels 2. Necrotizing granulomas of respiratory tract 3. Cresentic glomerulonephritis kidney 4. Antineutrophil cytoplasmic antibody (c-ANCA) Symptoms Nasal symptoms (saddle nose deformity) Crusting, epistaxis, rhinnorrhea, erosion of septal cartilage, saddle deformity, recurrent sinusitis Treatment: cyclophosphamide 2 mg/kg & prednisone 1 mg/kg

Goodpasture's disease Anti-basement mbrn capillaries antibodies Glomerulonephritis + pneumonitis Type I cresentic glomerulonephritis Pulmonary hemorrhage Case 5 A 4yo male child, caucasian, with rashes & fever of 2 wks duration. History shows that 2 wks ago, he had an epiglotitis secondary to H. influenzae. The patient also complains of intermittent abdominal pain. Palpable purpura Henoch-Schonlein purpura Immune complex-associated vasculitides 75% of male children 4-8 yo Capillaries, venules, arterioles IgA-dominant immune deposits Skin, gut & glomeruli Systemic Hypersensitivity Type III Associated w/ athralgia or arthritis Palpable Purpuric Rash: lower extremities, extensor areas over buttocks Late nephritis: IgA Nephropathy & Renal failure Mesangial deposits of IgA Cellular and/or matrix proliferation
Case 6 35 yo male with complaints of frequent cramps in the lower legs when walking. He also has numerous ulcers on his toes, which started about 2 months ago & were unresponsive to topical antibiotics Patient is non-diabetic, normotensive Smokes 1 pack of cigarettes/day, 10 years Acute inflammation of arteries w/ thrombosis & obliteration of lumen; segmental, microabscesses Thromboangiitis Obliterans Buerger's disease Occlusive, inflam disease ofmedium-sized & small arteries in distal arms & legs Strongly associated w/ smoking Age of onset: <30 (+2)/30-40 (+1) yo Foot intermittent claudication: Present (+2), by history (+1) Upper extremity: symptomatic (+2), asymptomatic (+1)
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Upper extremity: symptomatic (+2), asymptomatic (+1) Migrating superficial vein thrombosis: present (+2), history only (+1) Raynaud: Present (+2), history only (+1) Angiography; biopsy: if typical both (+2), either (+1) Diagnosis 0-1 points --> diagnosis excluded 2-3 points --> suspected, low probability 4-5 points --> probable, medium probability 6+ points --> definite, high probability

Varicose Veins Enlarged & tortuous BVs Occurs most commonly in the legs Risk factors: age > 50, female sex, heredity, posture, obesity Dilation & elongation of veins, incompetence of venous valves Varicose veins of legs (most common) Hemorrhoids Esophageal varices Varicocele

Deep Venous Thrombosis Associated w/ prolonged bed-rest, blood stasis & reduced cardiac output Thrombophlebitis: inflammation, commonly from a bacterial infection w/ secondary thrombosis of deep leg veins Phlebothrombosis: thrombosis of deep leg veins w/o initial inflammation Risk for pulmonary embolism Benign Blood Vessel Tumors Hemiangiomas Capillary Hemiangioma Cavernous Hemiangioma Truly benign Multiple Hemangiomatous Syndromes: angiomatous lesions in 2+ tissues Von Hippel-Lindau Syndrome: hemangiomas in brain & retina Sturge-Weber syndrome: vascular lesions in brain & skin

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Blood Vessels Cont'd

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Congenital Aneurysm Berry Aneurysm Cerebral arteries, small saccular aneurysm (looks like a berry) Congenital defect in arterial wall Associated w/ polycystic kidney disease (PKD or PCKD) Rupture = "worst headache", subarachoid or intracerebral hemorrhage
Benign Tumors Pyogenic Granuloma (lobular capillary hemangioma) Polypoid form of capillary hemangioma Rapidly growing exophytic red nodule attached by a stalk Skin & gingival or oral mucosa Friable, ulcerated Granuloma gravidarum --> in pregnancy, may be estrogen related Glomus Tumor (Glomangioma) Painful, nodular elevated tumor derived from glomus body Glomus body: sensitive to temp & regulates arterial flow Smooth muscle cells Below nail bed Small, reddish blue spots Distal fingers & toes Branching vascular channels; nests of glomus cells Lymphatics Lymphangitis: acute inflam, usually of bacterial origin, purulent contents Lymphedema: occlusion of lymphatics = accum of ISF Invasion of lymphatic & LNs by malignant cells Post-inflammatory scarring Lymphedema-associated Angiosarcoma: devl't of angiosarcoma in lymphedematous arm after axillary LN dissection for breast cancer Stewart-Treves syndrome

Tumors & Tumor-like conditions of BVs Vascular Ectasia Spider telangiectasias --> minute, focal, sc dilated arterioles Pulsatile; arranged radially around central core; mostly above waist Seen in cirrhosis & pregnancy Nevus flammeus: birthmark; port-wine stain of face & neck; thic skin = dilation of vessels in dermis Persists & grows as child grows Struge-Weber Syndrome Vascular lesions in brain --> MR, seizures, hemiplegia Skin --> port-wine stains in distribution of trigeminal N Osler-Weber-Rendu Syndrome (congenital) Hereditary hemorrhagic telangiectasia Dilated capillaries & veins Oral cavity, lips, respiratory, GIT, urinary tracts Complications --> rupture Bacillary Angiomatosis Organism: Bartonella henselae Vascular prliferation/tumors in brain, skin, bone Occurs in patients w/ HIV & AIDS; some features of Kaposi's Responds to antibiotics Protuberant epitheloid endothelial cells --> nuclear atypia &
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Protuberant epitheloid endothelial cells --> nuclear atypia & abnormal mitosis Hemangioendothelioma Vascular tumor of medium & large vessels in soft tissues Well-defined vascular channels Elderly --> may become malignant; if so, excized Children --> mostly benign Angiosarcoma Malignant neoplasm = masses of endothelial cells Hepatic angiosarcomas: Arsenic, thorotrast (radio-opaque contrast medium), polyvinyl chloride (PVC) Skin, soft tissues, breast & liver Prognosis is variable, can be very aggressive Irregular vascular spaces lined by malignant-appearing endoth cells w/ hyper chromatic nuclei Hemangiopericytoma --> tumor of pericytes Lower extremities or in retroperitoneum Composed of round & spindle cells; surround endoth-lined vessels Kaposi's sarcoma = low-grade malignancy, HHV-8 Spindle epithelial cells, slit-like vascular spaces Mostly skin & internal organs involved Red purple patches, plaques, nodules Classic/European KS chronic in eastern european descent (ie: Ashkenazi Jews); not assoc w/ HIV; remissions & relapses African or Endemic KS: lymphadenopathic common in S Africa very aggressive --> can't rule out HIV infection Transplant-associated/Immunosuppression KS months or yrs after organ transplant AIDS-associated endemic type: HHV-8, male homosexuals Mortality due to opportunistic infections

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CVS
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Congenital Heart Disease Devl'p in early pregnancy (3-8 wks); occurs in 1% of all live births) Symptoms appear at birth, infancy & adulthood Causes: genetic (chr 22), chromo anomalies (ie: Down's, Turner's), Rubella, TORCH, alcohol, IV drug abuse (ie: ecstasy) Left-to-Right Shunt CHD Ventricular Septal Defect (VSD) --> most common Isolated or part of Tetralogy of Fallot Small defects close spontaneously, whereas large defects are surgically closed by 1 yo. Most common forms Posterior muscular portion of the septum Apically Anteriorly Perimembranous Below aortic & pul valves (rare, common in asians) Harsh pansystolic murmer at left sternal edge Enlarged left & right ventricles, increased blood flow to lungs Complications: AR, infundibular stenosis, Infective endocarditis, Pulmonary HTN, Eisenmenger complex Eisenmenger Syndrome: shunt reversal of L-->R shunt caused by Pulmonary HTN = cyanosis, maybe heart failure, respiratory infections Atrial Septal Defect (ASD) Ostium secundum involves oval fossa Heart failure & dyspnea in late adulthood Ostium primum --> adjacent to AV valves Heart failure & dyspnea in early adulthood Sinus venosus defect Patent foramen ovale Enlarged Right Ventricle, increased blood flow to the lungs Ssx: Pulmonary HTN, Cyanosis, Arrhythmia, Chest Pain, Hemoptysis, wide fixed split S2, Pulmonary Ejection systolic murmur Complications: Eisenmenger Syndrome Patent Ductus Arteriosus (PDA) --> between pulm trunk & aorta Fetal ductus has medial sm muscle relaxed by circulating PGE 2 Postnatal --> pO2 increases = PGE2 decreases = constric`n of DA Less responsive closure in preterm infants Oxygenated blood: LV --> Aorta --> lungs Excess blood in lungs = volume overload = CHF Machinery-type murmur Ttx: indomethacin, surgical ligation Atrio-ventricular Septal Defect (AVSD) Right-to-Left Shunt CHD Tetralogy of Fallot Pulmonary stenosis: thickened, narrow pulm outflow tract Thickened R ventricle wall VSD Aorta overrides septal defect Pathophysiology dependent on severity of RVOT obstruction Dyspnea on exertion --> common Squatting = unique characteristic in exercising child Cyanosis & clubbing --> variable
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 Cyanosis & clubbing --> variable Systolic ejection murmur Hypoxic Tet Spell: bluish skin dur episodes of crying or feeding Hyper cyanotic epidsodes Paroxysms of hyperpnea, prolonged crying Intense cyanosis & decreased intensity of murmur of pulmonic stenosis May result in syncope, seizure, stroke or death Boot-shaped Heart: uplifted apex, absence of pulm artery segment; diminished pulmonary vascular markings, prominent left-sided aortic arch, indentation in left of trachea Transposition of great vessels (no shunt) Aorta from RV & Pulm A from LV Other anomalies = increase mixing of oxy & deoxy blood Progressive cyanosis --> hypoxia --> acidosis CHF Tacypnea Poor feeding = failure to grow Transposition D-type (most common, cyanotic) Aorticopulmonary septum doesn`t take spiralling course Fatal w/o PDA, ASD & VSD; initially corrected w/ PG Balloon atrial septostomy --> improve systemic saturat`n Atrial Switch Mustard procedure to repair Aortic Coarctation: constriction of aorta distal to L Subclavian Typically near ductus arteriosus (lig. Arteriosum) Preductal --> infantile Postductal --> adult Rib notching caused by dilated intercostal As Aortic knob Post-stenotic dilation of descending aorta Ssx: LV hypertrophy, CVA secondary to HTN in upper extremities; BP differences of 20 mmHg bt upper & lower, full brachial & radial pulses, weak femoral pulses, exercise intolerance Tricuspid atresia: complete occlusion of tricuspid valve Underdevelopment of RV = cyanosis from birth ASD, Patent forament ovale, VSD Truncus arteriosus (PTA): aorta & pulmonary trunk not fully divided DiGeorge syndrome Hypoparathyroidism Hypoplastic thymus Conotruncal heart defects (ie: Tetralogy of Fallot, interrupted aortic arch, ventricular septal defects, vascular rings) Cleft lip and/or palate Total Anomalous Pulmonary Venous Connections Pulmonary veins don`t join LA --> drain into coronary sinus Hypertrophy of right heart ASD/patent foramen ovale Cyanosis Congestive Heart Failure Common complication of AMI; men > women Heart can`t pump enough blood to meet metabolic req`ts Malfunction of contractile properties Low CO Cardiac Output (CO) = HR x SV Factors Affecting HR
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 Factors Affecting HR Autonomic innervation Sympathetic stimulus = increase HR Parasympathetic = decrease HR Hormones Epinephrine = increase HR Tachycardia = resting HR > 100 bpm Bradycardia = resting HR < 60 bpm Factors Affecting SV Preload: stretch on ventricles before contraction increase EDV = increase preload = increase SV Increase venous return = increase preload = increase SV Contractility: force of ventricular contraction SNS, Epi, Ca = Increase contractility = increase SV If HR, Preload & Afterload all remain constant, than increased SV is solely due to increased contractility Governed by amount of Ca available Afterload: pressure w/in BV connected to ventricle = threshold before ventricular ejection High BP = decrease SV Volume of blood in arterial circulation Pressure in aorta at onset of ejection Compliance of aorta Size of outflow orifice Inertial component of ejecting blood column Aortic stenosis Myocardial Hypertrophy: c.s. area of muscle increases when repeatedly exposed to elevated workload Increased preload, afterload or HR = increased wall tension Increase force of contraction to overcome the resistance against increased afterload Compensatory Mechanisms Adrenergic Mechanism Cardiac failure increases sympathetic activity = stimulate release of catecholamines = periph vasoc`n = shunting of blood away from nonvital organs = preferential flow to heart & brain Increased venous return = increased preload Renal Mechanism Acivation of RAAS Renal arteriolar constric`n --> increased reabsorp`n --> fluid retention = increase blood volume = increased venous return = increase preload Failure of Compensatory Mechanisms Increased retention of Na & water = ventricular distension = decr contraction = inc hypertrophy = inc HR Inc HR = inc myocardial oxy demand & dec diastolic filling time = myocardial ischemia & dec CO2 Ventricular Hypertrophy: caused by increased ventricular wall thickness via cardiac failure 1. Eccentric hypertrophy: volume overload = fiber elongation & chamber enlargement 2. Concentric hypertrophy: increases in systolic wall stress = sarcomere replication = increase ventricular wall thickness Right-Sided Cardiac Failure: ineffective right ventricular contraction Acute --> pulm embolus &/or RV infarct = total failure of right side Chronic --> corpulmonale
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Chronic --> corpulmonale Most commonly caused by left CHF Left-Sided Cardiac Failure: LV can`t produce adequate SV = decreased CO LV infract, HTN, mitral valve disease Increased LV EDP, LAP, Pul capillary P = pulmonary congestion Forward Cardiac Failure: both ventricles can`t pump blood into circulation Increased afterload = dec CO = hypoperfusion of vital organs Causes: aortic stenosis &/or systemic hypertension Na & water retention Backward Cardiac Failure: ventricles can`t empty blood into arterial circ Accum of fluid & inc P in heart & venous sys behind ventricles Myocardial infarct & cardiomyopathy: dec systolic ejection LV failure Pulmonary venous HTN: tachycardia, fatigue on exertion, dyspnea on mild exercise, orthopnea Paroxysmal nocturnal dyspnea: nocturnal cough w/ pink or brownish sputum, bronchospasm & wheezing; heart failure cells Chronic LV failure Diffuse & laterally displaced apical impulse Palpable & audible ventricular S3 Atrial gallops (S4) Inspiratory basilar rales Acute LV failure Acute pulmonary edema: life-threatening, sudden onset of pul venous hypertension Extreme dyspnea, deep cyanosis, hyperpnea, restlessness & anxiety, sense of suffocation RV failure Fatigue, awareness of fullness in neck & abdomen, occasional tenderness in RUQ; hepatosplenomegaly, ankle swelling, ascites (abdominal swelling) Congestion of kidneys --> Na & water retention Hypoxic encephalopathy Pleural effusion Anasarca

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