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118 Cards in this Set

  • Front
  • Back
Define the four aspects of a disease process?
(i) Etiology - Cause, can be genetic, acquired, or sometimes interaction of genes and acquired.

(ii) The pathogenesis or development of the disease - what happens in the response to the etiology?
(iii) Morphologic changes - they are the appearance of the tissue or cells that are characteristic in a given disease process.
(iv) Functional derangement and clinical significance - the nature of the morphologic changes determine the clinical presentation (symptoms and signs), clinical course, and excepted outcome of the disease process.
Explain the mechanisms by which a cell achieves homeostasis.
The cells achieves homeostasis when it is in balance with its environment. The cell is protected from stress by:
- cell membrane
- phagocytosis
- excretion of exogenous chemicals
- host defenses
- system repair

in excessive stimuli the cell may adopt to the changes (hypertrophy and atrophy.
Define Cell Injury and the sequential changes associated with it.
If limits of adaptive capability of the cell are exceeded, or the protective system is overloaded, the cell becomes injured. The injury may range from mild (and fully reversible) to severe and lethal (cell death).

The three possible non-lethal outcomes of cell injury are:
- Temporary alternation of cell function
- Structural damage to the cell w/ permanent impairment.
- DNA damage w/ mutation and its consequences.
Give five examples of etiology of cell injury.
->Metabolic: oxygen, glucose, vit. def.
->Physical: cold, heat, trauma, dusts (silica), electricity.
->Chemical agents and drugs: Tylenol, alcohol, narcotics, pollutants etc.
->Genetic: Chromosomal, gene-specific, etc.
->Biologic: bacteria, viruses, parasites, etc.,
Explain the sequence of events that occurs during cell injury.
Usually the agent causes injury to the most metabolically active cells.

Most agents cause damage by direct insult to one or more major organelle (The cell membrane, nucleus, mitochondria, endoplasmic ret. and lysosomes.

Toxic Substances affect endoplasmic reticulum (i.e. carbon Tetrachloride which gets converted to trichloromethyl free radical).

When an injurious agent affects the lysosomes, cell degeneration is said to occur. This may produce:
- Increased or incomplete autorophy
- Hereditary absence of an enzyme
- Failure of degradation of phagocytosed material
- Liberation and activation of lysosomal enzymes (residual bodies).

Many drugs, including antibiotics produce these effects because of the lysosomal role in degradation of drugs.
Compare and Contrast reversible vs. irreversible cell injury.
Ischemic Injury = Interruption of blood flow.

Cell can be injured by: Hypoxia, Injury of Free Radicals, Chemical Injury, Viral Injury.

Reversible: changes are known to occur when the duration of the ischemia is shot and in the following sequence: (1) Impaired aerobic respiration, (2) Decreased ATP, (3) Anaerobic Glycolysis, (4) Glycogen Depletion, (4) Accumulation of lactic acid w/ associated nuclear chromatin clumping.

-> swelling of the cell due to inactivity of Na/K pump and increased lactic acid. Detached ribosomes from RER and swollen mitochondria. If oxygen is restored, then the cell goes back to normal.
Describe chemical injury?
Affects the cell in two ways:

-> Directly: affecting of targeting a specific organelle or cellular component (mercuary binds to sulphydryl group of cell membrane and protein).

->Metabolic Activation: within the cell (reactive toxic metabolites which usually are reactive free radicals).

Best Examples: CCL4-induced cell injury. (CCL3 initiates lipid per-oxidation and cellular swelling).
Describe viral injury?
Viruses can have either a cytopathic/cytolytic (cell killing) effect or an oncogenic effect (tumor production).

The cytopathic effect: due to rapid virus replication of the virus within the affected cell, thus interfering with basic cellular functions.

The cytolytic effect of virus is often cell specific (receptors). In addition to lysis, virus can affect cells by interfering with the cellular cytoskeleton (most important on ciliated cells of respiratory epithelium), by producing inclusion bodies in nuclei or cytoplasm.
List the morphological changes of cellular injury at ultrastructural level.
- Cellular Swelling
- Bleb Formation
- Myeline Figures
- Swelling of mitochondria
- Accumulation of dense material in mitochnodria (Ca++, lipoprotein complex)
- Dilatation of endoplasm reticulum
- increase in lysosomes
Reversible cellular injury consists of:
Swelling and Fatty Changs
Define Apoptosis:
Characterized: cell shrinkage, chromatin condensation, and fragmentation into apoptotic bodies. The apoptotic cell is recognized by phagocytes and gets phagocytosed. KEY POINT: NO INFLAMMATORY REACTION OCCURS

Residual bodies are easily recognized under routine microscope as acidophilic bodies.
What is the function of apoptosis ?
a. Embryogenesis
b. hormone-dependent involution
c. in cell deletion in proliferating cells of liable cells.
d. in deletion of auto-reactive T-Cells in the thymus or cell death by cytotoxic T cells.
How does apoptosis occur?
1. Initial trigger (intrinsic or extrinsic) leads to increased intracellular protease activity and/or increased intracellular Ca++ followed by intracellular degradation. The result is the development of apoptotic bodies with ligands for phagocytic cell receptors and eventual phagocytosis.
How do apoptotic cells look morphologically?
- Single or in small clusters
- Bright eosinophilic cytoplasm
- irregular nuclei
Define Necrosis?
- Results from severely disturbed extracellular environment.
- Acute Inflammatory Reaction
- Cell Swelling, and Cell Rupture can occur.
What is Coagulative Necrosis?
-> Most Common
-> The cell is literarily coagulated / clotted.
-> Proteins are denatured, and cell becomes histologically opaque.
-> Usually the nucleus disappears.
-> Occurs in conditions of ischemia
-> Usually such areas of coagulative necrosis are removed by phagocytosis and enzymatic destruction by inflammatory cells.
What is liquefaction necrosis?
-> When powerful hydrolytic enzymes play a predominant role over proteins denaturation. This occurs classically in brain tissue and in some bacterial infections.
What is Fat Necrosis?
->Usually occurs in adipose tissues and is due to release of lipases from dead cells.
-> Lipases acts on triglycerides to generate free fatty acids which combine with Ca++ and produce soaps.
-> Cheesy-Like appearance
-> Have inflammatory cells and phagocytes within the fat.
Define Caseous necrosis?
->Characteristic of tuberculosis.
-> is actually a combination of coagulative and liquefactive necrosis. The necrotic areas macroscopically have cheesy-milky appearance.
Gangrenous necrosis?
is not a distinct type of cell death but a common clinical term in surgical practice. It refers to a combination of ischemic coagulative necrosis ( usually a limb ) with a superimposed infection.
What components can a cell accumulate?
- Normal Cellular Components (i.e. lipids, glycogen, some proteins). because either the metabolism is inadequate or overwhelmed.
- an abnormal substance (because the cell lacks the enzyme required or is unable to transport it).
-> A pigment (unable to digest or transport).
What is lipid accumulation, how is it seen?
Fat vacuoles within the cells other then lipocytes indicated lipid accumulation.

Fatty change has little or mild functional effect (except CCL4 poisoning) and is reversible.

In hereditary and acquired hyperlipidemic syndromes, macrophages accumulate intracellular cholesterol. Cholesterol filled microphages are called xanthomas.

Fatty change is also seen in other organs, i.e. the heart, usually 2nd to prolonged hypoxia or in diphteric myocarditis.
Other then fats, what else can accumulate?
- Protein accumulation - less common. For example albumin can accumulate in tubular cells when diseased glomeruli leak excess albumin.

Glycogen Accumulation - it is often seen in kidneys, heart, liver and islet cells of diabetics.
Describe Atrophy:
It is the size and function of a cell:

Causes:
-> Decreased workload
-> Decreased blood supply.
-> Loss of innervation
-> Interruption of trophic singles
-> Aging

If atrophy persists, the cell may die.
Hypertrophy
Increase in the size of a cell accompanied by an augmented function capacity.

Caused by:
-> Increased functional demand
-> Muscle hypertrophy in athletes
-> Physiological hypertrophy
Describe hyperplasia:
Increased in the number of cells in an organ or tissues:
-> increased functional demand
-> Hormonal stimulation
-> Persistent cell injury
What is Metaplasia
Conversion of one differentiated cell type to another.
-> It may be a protective mechanism, but there may be loss of function.
What is dysplasia?
-> Alternation in size, shape and organization of cellular components of a tissue feature:

Features:
-> Variation of shape and size of cells.
-> Enlargement, irregularity and hyperchromatism of the nuclei.
What is the significance of dyplasia:
Dysplasia is a preneoplasmic lesion.
Persistence injury may lead to dysplasia.

i.e.
-> dysplasia in bronchial epithelium
-> dysplasia in cervical epithelium
What is cellular aging?
Senescence is the progressive deterioration of the cell function with age. They have irregularly lobed nuclei, vacuolated mitochondria and other organelle abnormalities.
What are five ways in which our bodies are protected from injury.
->Tears lysozyme
->Ears have cerumen
->Skin is on anatomical barrier with antibacterial secretions.
->Skin is an anatomical barrier with antibacterial secretions.
->The respiratory tract is protected by air flow, mucus, cilia and alveolar microphages.
->The stomach has low pH and the intestine
-> Urine (low pH, lyzosymes)
-> Complex Immune System
Define inflammation and infection?
Inflammation:
-> Reaction of living tissue to injury
-> is a dynamic process that starts with the injury of and culminated with healing and repair.
-> Is a primarily a defense mechanisms but it can be potentially harmful.
-> is a stereotyped process regardless of the nature of the injury.
-> The intensity, duration and outcome is modified by a variety of host factors and factors related to the etiological agent.
-> in order for inflammation to occur, injury must be non-lethal.

Infection:
-> Inflammation due to biological agents. Usually elicit a more intense and prolonged inflammatory reaction.
Define and differentiate Exudation and Transudation:
Exudation (Problems w/ permeability): Outpouring of fluids, proteins and cells from vessels into intersitutium and body cavities. Exudate is extravascular fluid rich in proteins and cells with a specific gravity of >1.020. It implies significant alternation in the normal permeability of small blood vessels in the area of injury.

Transduction: Outpouring of fluid with little protein (albumin) witha specific gravity of < 1.012. Transudate is ultra-filtrate of plasma and it is usually due to hydrostatic imbalance. Permeability is normal.
What are some of the cardinal signs of inflammation.
Cardinal Signs:

1. Rubor - Redness
2. Tumour - Swelling
3. Color - Heat
4. Dolor - Pain
5. Functio - impaired function
What is the difference between acute and chronic inflammation?
Acute: Short Duration, Exudation, PMNs.

Chronic: longer duration, lymphocytes, macrophages, tissue repair.
Explain the series of steps that take place in the capillary bed during an acute inflammatory process?
1. Transient vasoconstriction of arterioles.
2. Vasodilation: first of arterioles, then the remaining microcirculation. Chemically, mediated. Blood flow = heat and redness.
3. Permeability changes with exudation (edema and swelling), (also by chemical mediators) with slowing of the circulation. It cold culminate in stasis. (Increased blood viscosity and RBC packing).
4. As blood flows more slowly and becomes more viscous, cellular events being to take place.
5. Time period from 1 to 4 varies with degree of injury (injury, time).
Define normal and abnormal permeability at the microcirculation during inflammation.
Starling's Hypothesis: The normal fluid balance is maintained by two opposites sets of forces:

FLUID MOVES OUT:
-> Osmatic Pressure of Interstitial Fluid
-> Intravascular hydrostatic pressure

FLUID MOVES IN:
-> Osmotic Pressure plasma protein
-> Tissue hydrostatic pressure

-----------------------------

The balance is such that net movement under normal conditions is quite small and is outward in direction. This excess interstitial fluid drains into the lymphatics and no edema occurs.

Factors that increase intravascular hydrostatic pressure (vasodilatation) or decrease intravascular osmotic pressure (decreased albumin) will give a net increase in interstitial fluid and edema (transudate)

In INFLAMMATION: leaky endothelium by permeability factors or direct endothelial damage cause loss of high protein fluid (exudate) with reduction of intravascular osmotic pressure and increased interstitial osmotic pressure causing further impairment of return of fluid to blood vessels (venules) producing marked inflammatory edema.
What are three common patterns of increased vascular permeability?
- Endothelial Cell Contraction
-> Mediated by histamine
-> Reversible, Short Lived
-> Venules affected
-> Called an "immediate transient" response.
- Junctional Retraction
-> Structural reorganization of the cytoplasm.
-> Occurs 4-6 hours after infection
-> TNF and IL-1
- Direct Endothelial Injury:
-> Most Important
-> Occurs in more severe injuries.
-> Begins immediately and goes on for hours/days.

Leukocyte Dependent Endothelial Injury:
-> occurs when during inflammation, activated inflammatory cells release toxic Oxygen species and proteolytic enzymes causing endothelial cell detachment. This occurs mostly in venules, pulmonary capillaries. It is usually late in the inflammatory process.

Increased transcytosis: occurs in the presence of vascular endothelial growth factor and other mediators. They increase the venular permeability via a vesiculoacuolar intracellular pathway.
Describe the cellular events of inflammation:
MAIN CELLULAR PHASE OF ACUTE INFLAMMATION: Migration of leukocytes through vessel walls during inflammation into adjacent tissues is the main cellular phase of acute inflammation.

Sequence of Events:
1. Margination: when blood is viscous there is peripheral orientation of WBCs because of sludging of RBCs (ROULEAUX).

WBCs are pushed to periphery of vessels because they are smaller particles (law of physics).

ii. Pavementing & Rolling: Normally up to 50% of PMNs are transiently marginating and sticking. During inflammation, the % increases as well as the absolute numbers of PMNs.
-> Results b/c of interaction of adhesion molecules on leukocytes and endothelial cells. CAMS, they are induced or enchanted by chemical mediators.
-> CAMS: subdivided into those requiring Ca2+ and those that do not.

During ROLLING ADHESION: L-SELECTIN (leukocytes) are present on phagocytes surfaces. On Endothelial sells you have E-SELECTINS (or ELAM-1). Their number increases with cytokines. They interact with the phagocyte adhesion molecules.

ADDHISION and EMIGRATION: Mediated by ICAM-1 (intercellular adhesion molecule) & VCAM (Vascular Cell Adhesion Molecule). Up-regulated during inflammation by various cytokines. ICAM-1 binds to LFA-1 (CD11a/CD18) & Mac1(CD11b/CD18), while VCAM-1 binds to VLA-4. They only adhere to their ligands when the leucocytes are activated by inflammatory chemotactic factors.

When binding occurs the cell diapedisis.

PMNs are the first to appear in the inflammatory reaction. They are later replaced by monocytes or macrophages.

EXCEPTION: in viral infections lymphocytes appear first.

- PMN are short lived, the monocyte migration is sustained longer and chemotactic factors for PMN and monocytes are activated and different times.

Once in tissue:
- These cell stimulate and control subsequent inflammatory response
- Interact with the immune system.
Define chemotaxis, and list three common chemotactic factors.
-> Unidirectional migration of cells towards an attractant or, locomotion oriented along a chemical gradient.
-> Chemokinesis: accelerated random locomotion of cells.
-> All WBCs respond to such stimuli, but PMNs and monocytes are most reactive.
-> Proven experimentally with the micropore filter technique of Boyden
-> Chemotactic factors can be both endogenous and exogenous.

Chemotactic Factors for PMN:
-> Bacterial Products (E. Coli and Staph, aureus best studied).
-> Complement Fractions (C5a)
-> Arachidonic Acid Metabolites (Leukotriene B4).
-> Cytokines (chemokines).
Describe the steps of phagocytosis ?
Phagocytsis Involves:
-> Recognition and Attachment
-> Engulfment
-> Killing and/or degradation.

1. Recognition and attachment
- Organisms have to be opsonized to be recognized (IgG and C3b)
- Opsonins attach to receptors on PMN:
-> Receptor for Fc fragment of IgG
-> A receptor for C3b.

2. Engulfment
-> Psudopods enclose the organisms, combine with lysosome s and creating a phagolysosome.
-> The process of engulfment REQUIRES (Ca++ and Mg++).

3. Killing / Degradation:
-> Two types of bacterial mechanisms:
-> Oxygen Dependent mechanisms:
- increase use of glucose oxidase
- production of active oxygen metabolites
(i) The H2O2-myeloperoxidase-halide system (Cl- is the halide).
(ii) MPO-independent killing (also requires O2).

--> There is also oxygen-independent bacterial mechanisms:
- H+ ions from increase lactate and from action of carbonic anhydrase produces a marked reduction of intravascular pH, which is bactericidal.

Also due to action of substances from leukocytes granules:
-> Following killing, acid hydrolases degrade bacteria within the phagolysosome. Some can destroy their captor (macrophages). Others can survive happily within the phagocyte (i.e. TB) [problem with eradication of the disease].

Remember: Monocytes loose their MPO when transforming into tissue macrophages.
List and explain the three possible mechanisms of release of leukocyte products during inflammation.
Leukocytes release the following:
++ Lysosomal Enzymes
++ Oxygen Derived Metabolites
++ Products of arachidonic acid

The process takes place in 3 ways:
1. Regurgitation during feeding.
2. Reverse endocytosis (frustrated phagocytosis)
3. Cytotoxic Release (following cell death).
Define chemical mediation in inflammation. Explain the mechanisms of action and effects of:

- Vasoactive Amines
Vasoactive Amines: Serotonin and Histamine

Histamine:
-> Present in the granules of mast cells and basophils
-> And in Platelets

Serotonin:
-> Present in platelets only

++ Their effects is: Vasodilation
++ Increased Vascular Permeability (Venules Only).

In humans serotonin has little role, but histamine binds to H-1 receptors. Effect is early but short lived (less then 60 minutes). Agents responsible for release of histamine from mast cells are:
(a) Physical
(b) immunologic
(c) C3a and C5a (anaphylatoxins)
(d) histamine releasing factors from PMN's, monocytes and platelets.
(e) Interleukin-1.

--> Degranulation is mediated by adenyl-cyclase activation and production of cAMP with movement of the granule to the cell surface. Release of histamine and serotonin from platelets is stimulated by their contact with collagen, thrombin AFP and Ag-Ab. Also by the Platelet Activating Factor (produced by basophils and mast cells). Histamine is chemotactic for Eosinophils.
Describe the Complement System:
(i) Complement System:
- has 20 protein
- greatest concentration in plasma
- mediates biological defense mechanisms:
-> Increased Vascular Permeability.
-> Opsonization.
-> Lysis of Organism.

Complement System can be activated by:
-> AG-Ab complex (classical pathways). or by bacterial by-products released by bacteria or by components of other plasma protein system. C1-C5 products produces subunits that enhance inflammation by:
-> opsonizing bacteria (C3b)
-> attracting leukocytes (chemotaxis = C5b, 6, 7, C5a).
-> By acting as mast cell degranulation and histamine release (C3a, C5a).

Components C6-C9 creates pores in the bacterial walls (Membrane Attack Complex).
What are the Plasma Derived Vasoactive Mediators:
Plasma Protease Systems: 3 different but interrelated systems:
(i) Complement System
(ii) Clotting Cascade
(iii) Kinin System

Generally they have a similar mechanisms. A proenzyme gets cleaved producing another proenzyme with a small component which acts as a potent biochemical mediator.
What are some of the Cell Derived Vasoactive Mediators?
(i) Arachodonic Acid metabolites:
-> Prostaglandins - vasodilation and increase permeability.
-> Leukotriens - increase permeability and have chemotactic factors.

(ii) Platelet Derived Factor (PAF):
- Generated by damaged cells (endothelial cells, and damaged tissue cells).
- Vasodilator
- Increases Permeability.
- Stimulation of platelets, inflammatory cells and endothelial cells.
- Best known to aggregate platelets at site of injury.
Describe the Kinin System (Plasma Derived Vasoactive Mediator):
-> Ultimate result is the release of bradykinin (nonapeptide) which is the active kinin. When released, bradykinin increases vascular permeability. It acts in early phases of inflammation only and is derived from plasmic precursor (High Molecular Weight Kininogen - HMWK).
Describe the coagulation (Clotting System) cascade (Plasma Derived Vasoactive mediator)
- forms a meshwork (fibrenous) to trap cells, microorganisms, and foreign bodies at the site of greatest phagocytic activity and forms a clot that stops the bleeding and provides a framework for repair and healing. The main substance of this mesh is FIBRIN, the end product of the coagulation cascade.

Coagulation cascade is activated via intrinsic/extrinsic pathway. The pathways converge at Factor X.

- Two low molecular weigh fibrinopeptides (Fibrin and Fibrinopeptide Monomer) are chemotactic for PMNs and enhance the effects of bradykinin.
What are the most important chemotactic factors?
- C5a (from complement)
- Bacterial and Mitochondrial Products
- Leukotrients
- Cytokines
Clinically what is the difference between chronic and acute inflammation?
Duration. Chronic inflammation lasts 2-4 weeks.
Describe Acute Inflammation:
- Dominated by changes in: vascular and exudative (fluids) therefire also called = exudative inflammation.
- PMNs dominated
Describe Chronic Inflammation:
- Injurious agent persists in the tissues and continues to damage them often for weeks or months.
- There is a great amount of prolifiration of cells and connective tissue, while exudation is less conspicuous (lymph, plasma cells).

Chronic Inflammation:
- May follow acute inflammation
- May be chronic from start
- Acute inflammation becomes chronic when it can't be resolved
- When etiological agent is of low toxcisity, They can be:
-> Persistant Infections (TBC)
-> Exposure to non-degradable material (i.e. dust).
-> Autoimmune reactions (Rheumatoid A).

Chronic Inflammation Cells:
-> Macrophages
-> Lymphocytes, Cell mediated and humoral immunity
-> Plasma Cells, Humoral immunity
-> Eosinophils, when parasitic infestations and allergic reactions.
What are the two forms of Chronic Inflammation:
- Non-Specific Chronic Inflammation:
-> no characteristic pattern of tissue reactions in which the participating cells are mononuclear cells (monocytes, lymphs, and plasma cells) and connective tissue (fibroblasts).

Granumalatous (Chronic) Inflammation:
-> Characterized by a special tissue reaction (see below). The participating cells are reticuloendothelial cells and their derivatives, largely macrophages. It is an attempt to wall-off and isolate the affected site.

This forms a nodule/granuloma ->
- Central Focus (usually)
-> made from necrotic tissue
-> surrounded by microphages
-> surrounded by a rim of lymphocytes and/or plasma cells. Often giant cells (multinuclear, of histocytic or mononuclear origin).
Granulomatous Inflammations are charachtaristic of?
- Tuberculosis
- Syphilis
- Catscrach Disease
- Fungal
- Protozoan

In persistent foreing body granulomotoma:

In Some disease with unknown etiology.
What is a Serious Exudate?
Usually due to mild injuries.
- Only albumin-containing exudate
- Derived from secretions of serosal mesothelial cells. (Peritoneal, Pleural, Pericardial, Synovial).

i.e. Blisters

In tissues: identified with difficulty (abnormally dialted spacesl fine precipitate of protein).
Define Fibrinous Morphologic Patterns in Acute & Chronic Inflammation.
- In more severe inflammations (vessels permitting passage of the large size molecule: fibrinogen).
- Example: Rheumatic Fever ("bread and butter" paracarditis).

In tissues: easily identifiable because the pericipated fibrin is deeply acidophilic, in strands and bands, in part fibrillar.

Observed in acute inflammatory but also in active zones of chronic inflammatory process.

Fibrin can be removed (fibrinolysis) or may get replaced by fibrous tissue scar.
What does it mean to be Suppurative or Purulent
A type of liquefactive necrosis caused by pyogens (pus-producing bacteria), the exudate contains large amounts of pus.
What is pus?
a protein-rich fluid containing viable and necrotic neutrophils and tissue debris partially liquefied by proteolytic enzymes. Characteristically seen in pyogenic infections by:
- Staphylococcus, Pneumonococcus, meningococcus, gonococcus, E.Coli, some non-haemolytic streptococcus.
What is pus?
- protein-rich fluid
- contains neutrophils and tissue debris
- seen in pyogenic infections
-> staphylococcus, pneumococcus, meningococcus, gonococcus, E.Coli, some non-hemolytic streptococcus.
Define Sanguinous Exudate:
- Containing large number of RBCs.
- Indicates serious damage to the cells
- almost never "pure" but a mixture of purulent or fibernous or both.

Often seen in TB

Tissues are characteristic by the presence of many RBCs in exudate.

N.B. all exudates are rarely 'pure' in nature; more often they represent a combination of two or even three types and we speak of: serosanguinous, fibrinopurulent, etc, exudate.
Define Abscess:
it is a localized collection of pus caused by suppuration (formation of visible pus) in tissues or organs.

Caused by irritation of great intensity (staphylococcus; turpentine, etc.). that characteristically remains localized leads to outpouring of great numbers or polys; the locally liberated large amounts of TRYPSIN overcome the tryptic inhibitor of the serum (difficulty in permeating solid tissues); the trypsin digests damaged and dead tissues and converts it into a semisolid mass.
Define Paronychia:
Infection extends around the side and base of the fingernail.
Define Felon:
it is a deep-seated infection in the anterior portion of the distal phalanx of the finger (usually secondary to penetrating wound); may cause osteomyelitis.
What is Empyema?
it is a localized collection of pus in the pleural cavity.
What is an Ulcer?
is a local defect or excavation of the surface of an organ covered or lined by an epithelium (mucus membrane; epidermis): produced by sloughing of inflammatory necrotic tissue on or near the surface.
What is a Pseudomembranous Inflammation?
Inflammation produced by a powerful necrotizing toxin (i.e. Diphtheria). Characterized by the formation of a pseudomembrane overlaying the affected area. The false membrane consists of precipitated fibrin, necrotic epithelium and WBCs. It usually occurs on mucosal surfaces such as pharynx, larynx and other respiratory passages as well as the GI tract. This type of inflammation occurs occasionally in the intestine of people receiving oral antibiotics.
What is a Fistula?
It is an abnormal communication (usually but not always the result of inflammation: it may e congenital or produced by tumor invasion) between two hollow organs both lined by an endothelium (arteriovenous) or an epithelium (vesicourterine; vesico-vaginal., etc.)
What is a Sinus?
It is an abnormal tract (communication) between a solid organ (or tissue) to an epithelium covered surface, usually skin (such as may be caused by abscess burrowing from deep tissues); usually caused by an inflammatory process.
Define Bacteriemia?
Micro-organism circulate in blood but the patient does not appear to be ill (has no fever, chills, etc.)
Define Septacemia?
Bacteriemia associated with clinical manifestation of illness: fever, chills. increased sedimentation rate, evidence of secondary seeding of organs (abscesses).
Define amyloid and describe its staining proporties.
- Abnormal extracellular proteinaceous deposits.
- On H&E stain it looks 'glossy' pink.
- Stains blue with iodine (people thought it was starch).

Appearence:
- non-branching fibrils w/ charachtaristic "B-pleated sheet." Configuration.
- The non-fibrally components of amyloid is the P-component, made of alpha-1-glycoportein.
- It is very similar to C-reactive protein.
- All amyloids stain RED with Congo-Red dye. Under polarized light, the deposits show an 'apple-green' birefringence.
Compare and contrast AL amyloid and AA amyloid.
- AL amyloid: amyloid light chains, composed of immunoglobulin light chains, usually of the lambda type. It is usually seen in pateints w/ B-Cell dyscrasias and is produced by immunoglobulin-producing cells.

- AA amyloid: amyloid associated chains, composed of non-immunoglobulin protein. It is derived from a larger circulating protein called serum-amyloid-associated protein.) SAA is seen in inflammatory response and is the amyloid associated with CHRONIC INFLAMMATORY REACTION.
What are additional amyloid to AL/AA?
- Transthyretin (Age Related)
- B2-Amyloid (Alzhimer's Disease)
Describe Systemic Amyloidosis?
- Result of deposition of AL or their fragments in extracellular spaces throughout the body. This is due to existance of abnormal clones of B cells, such as Multiple Myeloma.
- Key is, it is not necesserly caused by a neoplasm, but just a slight increase in light chains (can be due to increase in B-Cells in the Bone Merrow).
- Most common, used to be called "primary amyloidosis".
Describe Reactive Systemic Amyloidosis?
- Deposition of AA protein in exrtracellular spaces of most organs and systems.
- "secondery amyloidosis"
What is amyloidosis of patients on hemodyalisis ?
- Systemic
- Associated w/ deposition of B2-microglobulin.
What is heredofamilial amyloidosis?
- Various mandalian disease
- Deposits could be be AA or transthyretin composition.
What is localized or system amyloidosis?
- Involved the single organ / system.
- Some are AL amyloids
- Can be associated with neoplasms that produce prolypeptide hormones (i.e. Islet of Langharen's, involved in pathogensis of Diabities Mellitus).

- Senile Cerebral Amyloidosis - Alzhimer's , associated with B2-amyloid protein.

- Senile Cardiac Amyloidosis - Associarted with transtherytin.
Describe Macroscopic and Microscopic finding of amyloidosis and correlate it to the possible clinical implications/
Macroscopic: organ may show enlargment or atrophy. Initially the deposits called hypertrophy but later, the occlusion causes ischemia and organ atrophy.

Microscopically: Shows charachtaristic Congo-Red positive deposits in extracellular spaces around parenchymal cells and in blood vessels.

* Review The Organs on page 3*

Kidney - inital site of amyloidosis

The Spleen - Also commonly involved.

The Liver - often massivly enlraged.

The Heart - Can be involved in systemic and localized amyloidosis.
Explain the exogenous pigments such as carbon in the body.
Exogenous pigments - inhaled from the environment.

Carbon / Coal Dust is the most common pollutant in urban centers (from oil).

- Inhaled dust is phagocytosed by alveolar macrophages.
- They are unable to digest it, and they transport it to regional lymph nodes, where they accumulate.
- Tissues containing large amounts of carbon are called "anthracotic". (large city dwellers have anthracotic lungs and lymph nodes).
- Carbon itself does not produce an inflammatory reaction BUT if it is mixed with Silica or other inflammatory particles, then there may be a inflammatory reaction.
Give the role of melanin in the body including: source and function. Give 3 examples of abnormalities of melanin pigmentation in the skin.
- Melanin is an endogenous pigment produced by melanocytes. The pigment is insoluble and is dark-brown/black in colour.

- Stored in melanosomes

- Some people (albinos) can't produce melanin.

- Melanin has a protective barrier, by absorbing potentially harmful UV light.

- Melanin can be accumulated by:
-->basal epithelial cells forming freckles.
-->Nervous Cells (epidermis/dermis).
-->Dermal Macrophages
--> Some tumors also contain melanin.
Define Lipofucsin?
- Wear and Tear pogment is also endogenous. It is the result of free-radical induced break down of intracellular membranes. The pigment is insoluble and is light-brown yellowish in color.
- Becomes present in sufficient amounts to be seen when the tissue age.
- Most visible in liver, cardiac and brain cells.
- Lipofucsin is considered a hallmark of aging.
Define Jaundice. Explain why it occurs in obstructive bile disease.
- During obstruction of the biliary ductal system, bile ducts and bile canaliculi will be seen filled w/ bile.
- Excess billirubin in the circulation accumulated.
- Of particular interest is the skin and the conjunctiva, which becomes yellow (jaundice). Bile is golden in color, it changes color as it becomes stores in the gallbladder (greenish) and metabolized in the intestine (brown).
Compare and contrast hemosideroosis and hemochromatosis.
Hemosiderin - pigment derived from catabolism of haemoglobin. It is visualized by Prussian blue histochemical reaction. It is normally found stored in cells of the spleen, bone marrow and Kupffer cells of the liver. 75% or the body's iron content in erythrocytes while the remaining 25% is in this intracellular storage pool of ferritin and hemosidering.

- HEMOSIDEROSIS is the accumulation of iron in the form of hemosedrin.

- > can occur by excess interstinal iron absorbption.
- > excess breakdown on erythrocytes (haemolysis)
- > Blood transfusion

Iron is then present throught the body.. skin, pancreas, heart, kidney, etc. In most cases this extra pigment is not harmful to the cells.

In extreme increases of body iron, you get iron overload. This is called "Hemochromatosis" --> iron presense in the skin, the patients have Bronze Skin, therefore it is also called Bronze Diabetes. These patients are also at an increased risk of malignant tumors of the liver.

Wilson's Disease --> hereditary disorder of copper metabolism, the excess copper in the liver and brain causes severe chronic disease of those organs and predisposes to liver tumors.
What is gout?
- Describe the pathogenesis.
- disease characterized by recurring attacks of arthritis due o deposition of urate crystals in and around joints. With time, large collections of urates (tophi) are deposited in joints and surrounding soft tissue. (A lot in the ear)

This leads to an intense inflammatory reaction. Cytokine mediated destruction of articular
cartilage leads to chronic gouty arthritis.

Pathogenesis:
- Disorder in purine metabolism
- 90% of cases defect is unknown.
- 20-30 yrs of hyperuricemia is usually required before gout appears.
- There is a genetic pre-desposition as well as an X-linked disorder (hypoxanthineguanin-phosphoribosyl-transferase) [HGRPT].
Describe acute and chronic gout?
Acute gout: Early Gouty Arthritis
- PMNs
- macrophages w/ phagocytized urate crystals.
- Microscopically: collections of urate crystals associated with foreign body type of granulomatous inflammation are the main features.

Acute:
- Gout crystals in neutrophils, needle-shaped urate crystals.

Chronic:
- Macrophage, Lymphocytes
- Deposits in synovium

From text book:
he synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells, forming a pannus that destroys the underlying cartilage, and leading to juxta-articular bone erosions. In severe cases, fibrous or bony ankylosis ensues, resulting in loss of joint function.
What makes gout worse?
- Intake of large amounts of alcohol, large meal, which can increase hyperurecimia. Lymphomas (b/c increase in cell # production).
What is dystrophic and metastatic calcification?
Dystrophic Calcification:
- Macroscopic deposition of Ca2+.
- Predisposing cause is cell/tissue injury.
- Release of Ca++ to the outside
- Ca2+ binds with phosphorous and causes the formation of Ca2+ phosphate crystals.
- Collagen enhances the rate of crystal propagation / growth.
- Often occurs in cardiac tissue / cardiac valves ( i.e. aortic valves coronary arteries, and other aortic branches --> leads to narrowing, causing ischemia).

Metastatic Calficiation:
- occurs in normal tissue, and is associated with hypercalcemia. It is systemic and is caused by any disease that increases serum level of Calcium.
- Ca deposits in alveolar walls of the lungs, gastric mucosa, renal tubules and collecting system and blood vessels.
[Alveolar Walls, Gastric Mucosa, Renal Tubules, Collecting Systems and Blood Vessels]
Define Regeneration and Repair:
Regeneration: Replacement of cells with similar type of cell.

Repair: is a broader term, it includes the process of replacement by similar tissue or different(simpler) tissue.
Define Liable, Stable and Permanent Cells.
Liable: Cells which continue to proliferate throughout life (epithelium, blood cells).

Stable: low normal level of replication but able to divide in response to stimuli. Considered to be on G0 but recruited to G1.

Permanent: Cannot divide in postnatal life (neurons of CNS). Have left the cell cycle.
Define how stable cells (G0) get promoted to (G1) cells.
1. Growth Stimulatory Factors
-> estrogens, progesterone, somatotropin.
-> Many growth factors (polypeptides)
-> Essentially they are all mitogenic.

2. Loss of growth inhibitor which is normally present:
-> Proliferation is controlled by -ve feedback system. Mediated by endogenous hormone-like mitoic inhibitors. The inhibitory factors are called (chalones):
- The three chalone systems are:
-> Epidermal Chalone
-> Granulocyte Chalone
-> Lymphocyte Chalone
3. Cell - Cell Interaction:
-> Cessation of growth can be due to "contact inhibition" also known as "density dependent".

3a. Cell-Matrix Interactions:
- Cells (via transmembrane glycoprotein receptors) can recognize ECM.
- Integrins (receptor on cell) include: Fibronecin Receptor, Platelet Suraface Receptor, Leukocyte Adhesion Molecules.

They recognize a specific AA sequence. Extracellular Matrix Includes:
- Collagens
- Glycosaminoglcans
- Proteoglycans
- Glycoproteins (adhesive)
The most important molecules in healing are considered to be Fibronectins, what are they?
Fibronectins are found in:
- Cell Surface
- Basement Membrane
- Pericellular Matrices

Produced by :
- Fibroblasts
- Endothelial Cells
- Monocytes

In wound healing they:
-> Facilitate migration of new epithelium (glue-like).
-> Chemotactic for monocytes
-> Chemotactic for fibroblasts
-> Stimulate endothelial cells
-> Migration and Organization
-> Releases fibroblast growth factors from monocytes.
Describe the steps involved in repair process?
-> Angiogenesis: formation of new blood vessels by budding from pre-existing blood vessels.
-> Fibrosis: Proliferation of site fibroblasts and deposition of ECM by these cells. Again, process id dependent on various growth factors released by inflammatory cells.
-> Maturation and Organization o the scar (remodelling): collagen and other ECM are degraded by a family of metalloproteinases (ZINC dependant). They cleave fibrillar collegen I, II, and III as well as colalgen IV and Fibronectin. They are produced by inflammatory cells as well as some epithelial cells. They aid in the debridement of injured site and remodeling of connective tissue.
Why is wound strength never the same after an injury? [Stays at around 70-80%]
It is related to the type of collagen laid.

Adult Skin Have: Collagen Type I
Granulation Tissue: Collagen Type III
Cicatrization: Replacement of type III by type I.
Discuss Repair of Skin Wounds:
i. Crust Formation - provides a quick provisional closure to the wound.
- stops further bleeding
- infection barrier
- no crust formation in cornea and uterine mucosa.

ii. Removal of Dead Tissue, Other Debris and Exudate.

iii. Replacement of Lost Cells and Tissues:
- takes place largely by two processes:
-> Cell Migration
-> Cell Division
+The cell swell and reassume embryonal proporties.
+In skin wounds three kind of cells proliferate and migrate:
- Fibroblasts
- Endothelium
- Epithelium

New tissue is formed, replacing the old. It is termed: Granulation Tissue. [tiny pink granules].
Consists of:
- Newly Formed Capillaries
- Fibroblasts
- Many Microphages

Granulation Tissue has the following properties:
- Its bleeds freely
- It is insensitive (to pain)
- It is quite resistant to infection.

Cicatrization: Conversion of granulation tissue to scar ( via gradual closing of small vessels).
List three factors that influence the rate of healing:
- Age
- Size of Wound
- Secondery Infection
- Dietary Statue (Vit. D. Vid C. protein intake).

How May we Influence healing
- Protect the wound
- Prompt irrigation
- Immobilize the injured area.
What are the two Mechanisms involved in Repair?
i. Control of Cell Proliferation
ii. Collagenization and Wound Strength

* Read up on it*
Give three examples of factors in the host which may modify the inflammatory response and repair.
Factors Related to the Host:

1. Adequacy of blood supply
- > Good Vascularization = resistant to infection
- > Bad Vascularization = Relatively inefficient in responding to inflammatory stimuli.

2. Location of Injury
-> Densely compact tissues resist the spread of infection.

3. Presence of Infection
4. Presence of Foreign Bodies
5. Immobilization of wounds.
What do you need to do PCR?
- Template
- Primers
- dNTPs
- Taq Polymerase

PCR - exponential gene amplification.
Describe restriction enzymes
Restriction Nucleases hydrolyze DNA molecules at specific sequences.

DNA from different individuals may show different length due to variation or mutations [Restriction Fragment Length Polymorphism].
In electrophoresis the electric current separates DNA according to?
SIZE
What is Hemochromatosis?

Where is the mutation, what is the frequency?
Mutation in the HFE gene.
Increased IRON in the body.
Specific mutation: C282Y - 90% and H63D - 10%

-Defective function of this gene leads to excessive iron absorption and deposition.

- Causes chronic fatigue, arthritis, heart disease, cirrhosis, diabetes.

- Frequency s 1 in 200 in North America.
Describe Factor V Leiden:
In factor V Leiden, a mutation changes factor V protein making it resistant to inactivation by protein C resulting in thrombophilia.

Prevalence: Northern Europian Decent 5%, highest prevalance in Sweeden and in some Middle Eastern Countries. Virtually absent in African and Asian population.

- Hetrozygous
--> 5 to 7 X RR of normal
- Hetrozygous + Oral Contraceptives
--> 30 to 35 X RR of normal
Homozygous
--> 80X of normal
Homozygous + Oral Contraceptives
--> ??

Treatment: Heprin propholactyc.
Which disease would you do DNA base diagnosis for?
- Hemochromatosis
- Fragile X syndrome
- Cystic Fibrosis
- Sickle Cell Disease
- Hemophilia
- Huntigton's Disease
- Neurofibromatosis
What is an estimated risk for BRCA1 and BRCA2 for breast cancer and ovarian cancer?
Breast Cancer - 56%
Ovarian Cancer - 16%
Describe the tumor susceptibility for:
-RET
-P53
-APC
-BRCA 1
-BRCA 2
RET - MEN Syndrome
P53 - Li Fraumeni Syndrome
APC - Adenomatous Polyposis
-BRCA 1 - Ovarian and Breast Cancer
-BRCA 2 - Breast Cancer
What is Hereditary Non Polyposis Colon Cancer (HNPCC)?
- Younger set of onset, increased risk of developing colorectal cancer
- Tumors, more likely to develop in the right colon
- synchronous and metachronous colon CA
- a high frequency of tumors in
-> endometrium (uterus), ovary, stomach, small bowel, ureter and kidney.
-> HNPCC reated tumors in 1st degree relatives
-> Mutations in DNA mismach repair genes
-> Most common - MSH2 (hMSH2 at 2p22 -> p21), MLH1 (hMLH1, at 3p21.3).

Use immunohistochemistry:
-> is MLH1 and MSH2 are mutated or methylated, their protein products will be absent in the tumor tissue.

-> Immunocytochemistry in the parrafin embedded tissue using specific antibody.
What are MSI? Microsatellite Instability?
Microsattelite -> short repetitive DNA segments scattered throughout the genome predominantly in non-coding DNA

In the coding region of genes regulating cell growth and apaptosis

MSI - change in lenght of microsattelites due to insertion/deletion compared to normal tissue.
-Failure of error correction by mismatch repair (MMR) system during DNA replication >> MSI.

When you have defective mismatch repair --> frameshift mutation in the coding region. --> TGFBII in HNPCC.
Why test for microsattelites/HNPCC?
Because individuals with HNPCC are:
- 80% life time risk for developing colorectal cancer.
- 80% life time risk of developing endometrial cancer.

Surveillance
- Colonoscopy every 1-3 years begining @ 20-25 years.
- Transveginal Ultrasound and endometrial aspiration

Other Options:
- Surgery: Coloctomy
- Consideration of histeroctemy/SO at the time of colectomy.
What is the HER-2 Gene?
Associated with breast cancer. Amplification of the Human Epidermal Growth Factor Receptor (HER2) Gene.

Her2 overexpression correlated wtih:
- aggressive features
- shortened disease-free survivial

Herceptin (antibody against Her2 protein) treatment.
What does brain tumor present as?
Tumor with uniform cells and small nuclei - "fried egg" appearance.
What is an oligodendrogiomas? What is the genetic component of it?
50-80% of oligodendrogilomas has 1p and/or 19q deletions.

Oligodendrogilioma with 1p/19q loss stand a good chance of responding to PCV-treatment (PCV = procarbazine, lomustine (CCNU), Vincristine].

Oligodendroglioma with 1p/19q intact may be steered toward surgery +/- other treatments.
What is K-RAS? And why anti-EGFR treatment.
KRAS encodes one of the proteins in the epidermal growth factor receptor (EGFR) signaling pathway.

Monoclonal Antibodies against EGFR block signaling by the receptor and inhibit downstream events, including effects mediated by KRAS

When KRAS is mutated and permanently switched on, blocking EGFR will probably not affect downstream events.

Therefore, blocking EGFR is more effective in KRAS wild-type tumors.

Read more in the lecture.
What is Scorpian Reaction?
Alternation to PCR.

1. The scorpion is extended on target DNA.

2. The extended primer is heat denatured and the quencher disassociates.

3. As it cools the extended Scorpion undergoes an internal rearrangement and begins to fluoresce in a target specific manner. Unextended primer is quenched. Single is detected if mutation is present.
What is Chronic Myelogenous Leukemia (CML)?
Epidemiology of CML:
- Incidence of CML is 1-2 per 100,000.
- Incidence increases with age.

-> 12%-30% of patients are >60 y/o.
-> Median age 53 y/o
-> Male to Female ratio - 1.3:1

CML is caused by a 9:22 translocation of Philadelphia Chromosome.

The product of this fusion gene is Bcr-Abl tyrosine kinase --> lymphogenic.

Gleevec is an inhibitor of Bcr-Abl kinase

Inhibition of Bcr-Abl kinase (Gleevec) is an effective therapy for CML.

Demonstration of translocation by FISH or PCR is essential.

-> its not exactly selective for Bcr-Abl, but also inhibits c-Kit and PDGF-R. Used in the treatment of Gastrointestinal Stromal Tumors.
What is a major factor (genetics) influencing how we respond to drugs?
1. SNPs play a major role in how we respond to drugs.

Example: 6-Mercaptopurine, need to check if it will be metabolized or not. May cause toxicity if not metabolized.
How can you identify someone's identity?
Using Variable Number Tandem Repeates (VNTRs)

VNTR can contain from 20 - several thousand base pairs.

To determine if a person has a particular VNTR, a southern blot is performed with specific probes - the result is also called DNA fingerprinting.

Multiple probes are usually used.
The Following hyberdizations are used for:

1. Southern Blotting:
2. Northern Blotting:
3. Slot/Dot Blotting:
4. In Situ Hyberdization:
5. FISH
6. Western Blotting:
1. DNA
2. RNA
3. DNA applied Directly on membrane
4. Hyberdization of intact cell/tissue
5. Fluorescent Labeled Probe
6. Protein is Hyberdized to anbibody.