PATHOLOGY The Very Best for Medical Students

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PATHOLOGY-Part 1

• IMEC INC.
• Quick Learning
• Technique

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PATHOLOGY

• Pathology is literally the study of suffering,
• Pathology actually studies the Etiology or Cause
  of disease.

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Cellular Response to Injury

• Acute Cell Injury
• Reversible Injury
• Cell Death
• Necrosis
• Apoptosis
• Subcellular Alterations and Cell Inclusions
• Intracellular Accumulation
• Pathologic Calcification
• Cellular Adaptations
• Atrophy, hypertrophy, hyperplasia, metaplasia

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Causes of Cell Injury

• Hypoxia
• Physical Agents
• Chemical Agents Drugs
• Infectious Agents
• Immunological Reactions
• Genetic Derangements
• Nutritional Imbalances

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Cell Injury Necrosis

• The molecular mechanism responsible for cell
  injury leading to necrosis are complex
• The morphological changes that take place only
  become apparent after some critical biochemical
  system within the cell has been deranged.
• The type, state, and adaptability of the injured
  cell also determine the consequences of cell
  injury.

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Four Biochemical Schemes

• Oxygen and Oxygen deprived free radical
• Intracellular Calcium and loss calcium
  homeostasis
• ATP Depletion
• Defects in Membrane Permeability

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Ischemic and Hypoxic Change

• Reversible cell injury
• The first point of attack is the cells aerobic
  respiration, that is the oxidative
  phosphorylation by the mitochondria.
• As the oxygen tension decrease, there is a loss
  of oxidative phosphorylation, and the generation
  of ATP slows or ceases
• This can cause a net gain of solute because
  ATPase activity changes, and a iso-osmotic
  swelling of the endoplasmic reticulum, can cause
  detachment of ribosomes

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MITOCHONDRIAL INJURY
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Mechanism of Irreversible injury

• Progressive loss of phospholipids
• Cell Cytoskeletal Abnormalities
• Reactive Oxygen Species
• Lipid Breakdown Products
• Loss of Intracellular amino acids

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Chemical Injury

• Mercuric Chloride
• Binds to sulfhydryl groups
• Cyanide
• Directly poisons mitochondria
• Carbon Tetrachloride
• Highly reactive, converts to CCL3, INITIATING
  LIPID PEROXIFICATION
• Acetaminophen
• Covalently bonds, causing massive liver necrosis
  after about 3-5 days, if taken in large doses

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NECROSIS

• Necrosis is one of two morphological expressions
  of cell death (the 2nd being apoptosis), refers
  to a spectrum of changes that follow in the
  beginning of cell death in living tissue
• Enzymatic digestion of the cell
• Denaturing of proteins

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Types of Necrosis

• Coagulative Necrosis
• Myocardial tissue
• Liquifactive Necrosis
• CNS
• Gangrenous Necrosis
• Bacterial induced
• Caseous Necrosis
• Tuberculosis
• Enzymatic Fat Necrosis
• Pancreatic

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Apoptosis

• Apoptosis is thought to be responsible for
  numerous physiological and pathological events.
  (Essentially Programmed Cell Death)
• The destruction of cell during emryogenesis
• Hormone dependent involution in adults
• Cell death in tumors
• Destruction of immune cells
• Cell injury during viral disease

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Apoptosis Morphology

• Cell Shrinkage
• Chromatin Condensation-
• The most characteristic feature
• Formation of cytoplasmic blebs
• Phagocytosis of apoptotic cell bodies

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General Apoptosis
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Apoptosis
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Apoptosis in Cancer
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Genetic Apoptosis
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Stress (HSP) and Cell Injury

• Heat shock proteins, Hsp70 Hsp60
• ( also called chaperones) are intimately
  involved in intracellular protein folding.
• Another smaller HSP is UBIQUITIN, which is
  involved in protein degradation
• Thus stress can be induced beyond repair of these
  mechanisms, via various insults

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INTRACELLULAR Accumulations

• Fall into 3 categories
• A normal intracellular constituent, I.e water,
  lipids, proteins and carbohydrates
• An abnormal substance, either exogenous, such as
  a mineral, or a product or abnormal metabolism
• A pigment

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Steatosis (Fatty Change)

• The term Steatosis and Fatty Change describes
  abnormal accumulation of triglycerides within the
  parenchymal cells.
• Fatty change is often seem in the liver due to it
  is the major organ involved in fat metabolism
• In industrialized nations, by far the most common
  significant fatty change in liver is alcohol abuse

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Liver Disease Spectrum
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Alcoholic Steatosis
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Cholesterol and its Esters

• Atherosclerosis plaques, accumulate in the intima
  layer of the aorta and large arteries smooth
  muscle cells and macrophages become filled with
  lipid laden foamy cholesterol and lipids
• Xanthomas are an extra-cellular accumulation of
  tryglycerides
• Foamy macrophages are found at sites of cell
  injury. The myelin is the PNS is very susceptible
• Cholesterolosis refers to a focal accumulation in
  the lamina propia of the gall bladder

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Proteins

• Excesses of protein sufficient to cause
  morphological changes are less common than lipid
  disorders.
• Examples include
• Reabsorption droplets in Proximal Renal Tubules
• Immunoglobulin in plasma cells
• Alpha-1 Antitrypsin (AAT) in liver cells

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Glycogen

• Excessive intra-cellular deposits of glycogen are
  seen in patients with an abnormality in either
  glucose or glycogen metabolism
• Examples
• Diabetes
• Glycogen Storage Disease

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Hyaline Changes

• The term Hyaline is widely used as a
  Histological marker rather than a specific marker
  for cell injury
• Usually gives a glassy pink appearance in
  histological sections
• Mallory bodies in the liver are considered
  hyaline deposits.
• The protein AMYLOID also has a hyaline
  appearance.

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MALLORY BODIES
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Pigments

• Bilirubin
• The normal pigment found in Bile
• Lipofuscin
• Normal where and tear pigment with age
• Melanin
• Endogenous Brown black pigment associated
  oxidation of tyrosine. And a black pigment with
  alkaptonuria
• Hemosiderin
• This pigment represents the aggregates of IRON
  FERRITIN micelles. Whenever there is an excess
  overload it can be deposited in organs and
  tissues.

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Pathologic Calcification

• Dystrophic Calcification
• This is almost inevitable in atheromas and
  atheroscerosis
• It commonly develops in aging on the damaged
  heart valves
• Metastatic Calcification
• The can happen in many disorders
• It principally effects kidney, interstitial
  tissue in vessels, the lungs, and gastric mucosa

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Cellular Growth and Differentiation
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Repair of Tissue

• This all to control the influences of the cell
  population , whether is be stimulated or
  inhibited
• Repair of tissue involves 2 distinct processes
• Regeneration
• Replacement of connective tissue

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Control of Cell Growth

• Injury, cell death and mechanical deformation of
  tissues all can stimulate the proliferation
  however it is now clear that cell replication is
  controlled largely by the micro-environment,
  which either stimulates or inhibit proliferation.

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Cell Cycle and Types of Cells

• There are mainly three(3) groups on the basis of
  proliferation capacity
• Continuously dividing cells
• Quiescent (stable cells) that show a low level of
  replication
• Non-dividing cells

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Molecular Events and Growth

• Some of these substances only keep the cell cycle
  in tact, whereas others ate actual progression
  molecules
• Ligand Receptor Binding
• Growth Factor Receptor Activation
• Signal Transduction and 2nd Messengers
• Transcription Factors

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Ligand-Receptor Binding

• Cell growth is initiated by the binding of growth
  factors to specific receptors on the cell surface

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Importance of Receptor Ligand
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Growth Factor Receptor

• Most growth factors are equipped with intrinsic
  protein Tyrosine Kinase Activity which is
  activated after ligand binding

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Second Messenger Signals

• PIP2
• IP3
• DAG
• BOTH ACTIVATE PROTEIN KINASES
• GTP Binding Proteins
• Activate MAPK
• Raf 1
• Activates the rest of MAPK

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Signal Transduction
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Transcription Factors

• MAP kinase Cascade
• c-jun
• c-myc
• c-fos
• For protein synthesis between G1-Gs of the cell
  cycle
• Activated ras, in turn, phosphorylates a cascade
  of enzymes that active MAPK (mitogen activated
  protein kinases)

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Cell Cycle Cyclins

• The cycle kinase complexes phosphorylate a number
  of proteins involved in DNA replication,
  formation of the mitotic spindle and other events
  in the cell cycle

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Oncogenes

• Some of the oncogenes such as bcl1, and
  antioncogenes, such as Rb gene and p53, act in
  the cyclin pathway to control cell growth

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Growth Inhibition

• The other side of growth is cellular inhibition.
• The recent discovery that loss of tumor
  suppressor genes occur in certain cancers suggest
  that genes encode components of some cellular
  pathways.
• Polypeptides factors that act as growth
  inhibitors are (TNF) and (TGF-B) transforming
  growth factor -beta

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Growth Factors

• There are many growth factors, examples are
• Epidermal Growth Factor
• Platelet Derived Growth Factor
• Fibroblast Growth Factor
• Insulin Like Growth Factor
• Transforming Growth Factor- Beta
• Cytokines
• Interleukins, Tumor Necrosis Factor, Interferons

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Epidermal Growth Factor

• EGF was first discovered in precocious tooth
  eruption.
• EGF is Mitogenic for a variety of epithelial
  cells and fibroblast cause cell division,
  specifically hepatic.

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Platelet Derived Growth Factor

• Is released in platelet activation.
• It is produced by activated macrophages,
  endothelial cell, and smooth muscle cells.
• PDGF causes both migration and proliferation of
  fibroblasts, and other pro-inflammatory
  properties as well

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Fibroblast Growth Factor

• Basically, FGF, in patricular has the ability to
  create (angiogenesis) blood cell formation

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Insulin Like Growth Factor

• The insulin-like growth factors (IGFs) are
  polypeptides with high sequence similarity to
  insulin.
• IGFs are part of a complex system that cells use
  to communicate with their physiologic
  environment. This complex system (often referred
  to as the IGF "axis") consists of two
  cell-surface receptors (IGF1R and IGF2R), two
  ligands (IGF-I and IGF-II), a family of six
  high-affinity IGF binding proteins (IGFBP 1-6),
  as well as associated IGFBP degrading enzymes,
  referred to collectively as proteases.

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Transforming Growth Factor- Beta

• All of these favor fibrinogenesis

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Cell Matrix Interactions

• Cells grow, move, and differentiate in intimate
  contact with the extra-cellular matrix, and there
  is overwhelming evidence that the matrix
  critically influences these cell functions

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Collagen Matrix
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Laminin Matrix
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Basal Lamina
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Proteoglycans

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Joint Function
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Cellular Adaptation
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Hyperplasia

• Hyperplasia constitutes an increase in the number
  of cells in an organ or tissue, which may have
  increase volume.
• Physiological Hyperplasia is divided
• Hormonal Hyperplasia
• Puberty
• Compensatory
• Liver

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Ductal Hyperplasia
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BPH
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BPH
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Hypertrophy

• Hypertrophy refers to an increase in size of the
  cells, and with it the increased size of an organ
• It is either physiological or pathological.

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Muscle Hypertrophy
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Muscle Hypertrophy
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Cardiac Hypertophy
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Atrophy

• Causes of Atrophy
• Decreased Workload
• Loss of Innervation
• Diminished Blood Supply
• Inadequate Nutrition
• Loss of Endocrine Stimulation
• Aging

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Inflammation Repair
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Inflammation

• Inflammation is fundamentally a protective
  response whose ultimate goal is to rid the
  organism of both the initial cause of cell injury
  (I.e. Microbes, Toxins) and the consequences of
  cell injury

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Inflammation Response

• Inflammation response occurs in vascularized
  connective tissue, including plasma, circulating
  cells, and blood vessels.
• The vascular and cellular response of both acute
  chronic inflammation are mediated by
  chemotactic factors derived from plasma cells,
  and other cells stimulated by histamine,
  leukotrienes, kinins etc.
• The circulating cells include neutrophils,
  eosinophils, lymphocytes, basophils, and
  platelets.

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Signs Symptoms

• Rubor---- Red
• Tumor----Swelling
• Calor----Heat
• Dolar----Pain

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Acute Inflammation
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Keys to Acute Inflammation

1. Alteration in Vascular caliber that leads to an
   increase in blood flow
2. Structural changes in micro-vasculature that
   permit the plasma proteins and leukocytes from
   the micro-circulation
3. Emigration of leukocytes from microcirculation
   and their accumulation and accumulation in focus
   of injury

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Vascular Changes

1. Following a inconstant vasoconstriction of the
   arterioles, lasting a few seconds Vasodilatation
   occurs
2. Slowing of circulation. This is brought on from
   protein rich leakage during the increase in
   micro-vascular membrane permeability
3. Stasis begin in periphery, principally beginning
   with neutrophils, along the vascular epithelium.
4. Leukocyte margination
5. Rolling

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Margination
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Diapedisis

• Diapedesis is the movement of leukocytes across
  the endothelial lining of blood vessels
• Chemo-tactic factors (V-Cams, I-Cams, E-selectin)
  etc alter the expression of regulation of
  adhesion of leukocytes adjacent to site of
  infection.
• This causes leukocytes to slow down and cause
  integrin molecules to switch from low affinity to
  high affinity state.

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Vaso-active amines

• Histamine------ Mast Cells, Platelets
• Serotonin------ Platelets, Mast Cells
• Lysosomal Enzymes------Neutrophils
• Prostaglandins----Leukocytes, platelets
  endothelium
• Leukotrienes-----Leukocytes
• Platelet Activating Factor-----Leukocytes,
  endothelium
• Cytokines-----Macrophages, endothelium
• Nitric Oxide-----Macrophages, endothelium

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Plasma Proteases

• A variety of phenomena in the inflammatory
  response system are mediated by three
  inter-related plasma derived factors The
  Complement, Kinin, and the Clotting System

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Complement System

• The complement system consists 20 component
  proteins which are found in greatest
  concentration in the plasma
• Complement components are present as inactive
  components found in plasma numbers C1 through C9
• They are responsible for
• Vascular phenomena( I.e Histamine Vasodilation)
• Leukocyte adhesion, chemotaxis activation
• Phagocytosis

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Kinin System

• The kinin system is directly triggered by contact
  with surface activation of Hageman Factor (
  factor XII) of the intrinsic clotting pathway
• Bradykinin is ultimately released causing
  vasodilation and INCREASED VASCULAR PERMEABILITY.

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Hageman Factor
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The Clotting System

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• The Intrinsic Clotting Cascade
• The intrinsic pathway is much less significant to
  hemostasis under normal physiological conditions
  than is the extrinsic pathway. However, abnormal
  physiology such as hyperlipidemic states or
  bacterial infiltration can lead to activation of
  thrombosis via the intrinsic clotting cascade.
• The intrinsic pathway requires the clotting
  factors VIII, IX, X, XI, and XII. Also required
  are the proteins prekallikrein (PK) and
  high-molecular-weight kininogen (HK or HMWK), as
  well as calcium ions and phospholipids secreted
  from platelets. Each of these pathway
  constituents leads to the conversion of factor X
  (inactive) to factor Xa (a signifies active).
  Initiation of the intrinsic pathway occurs when
  prekallikrein, high-molecular-weight kininogen,
  factor XI and factor XII are exposed to a
  negatively charged surface

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• Extrinsic Clotting Cascade
• Activated factor Xa is the site at which the
  intrinsic and extrinsic coagulation cascades
  converge. The extrinsic pathway is initiated at
  the site of injury in response to the release of
  tissue factor (factor III). Tissue factor is a
  cofactor in the factor VIIa-catalyzed activation
  of factor X. Factor VIIa, a gla residue
  containing serine protease, cleaves factor X to
  factor Xa in a manner identical to that of factor
  IXa of the intrinsic pathway. The activation of
  factor VII occurs through the action of thrombin
  or factor Xa. The ability of factor Xa to
  activate factor VII creates a link between the
  intrinsic and extrinsic pathways. An additional
  link between the two pathways exists through the
  ability of tissue factor and factor VIIa to
  activate factor IX. The formation of complex
  between factor VIIa and tissue factor is believed
  to be a principal step in the overall clotting
  cascade. Evidence for this stems from the fact
  that persons with hereditary deficiencies in the
  components of the contact phase of the intrinsic
  pathway do not exhibit clotting problems.

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Arachidonic Acid
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PIP2 IP3, DAG
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CYTOKINE FUNCTION
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Outcomes of Acute
Inflammation

• COMPLETE RESOLUTION
• HEALING BY CONNECTIVE TISSUE REPLACEMENT
• ABSCESS FORMATION
• PRGRESSION TO A CHRONIC INFLAMMATORY STATE

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CHRONIC INFLAMMATION
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Chronic Inflammation

• Persistent Inflammation and tissue destruction
  despite the bodies attempt to heal
• Organisms that cause delayed hypersensitivity
• Prolonged exposure to potentially endogenous or
  exogenous agent
• An auto-immune disorder that can self perpetuate
  a chronic inflammatory state

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Mononuclear Infiltration

• Macrophages are just one part of the mono-nuclear
  inflammatory system, previously referred to as
  the reticular endothelial system Stages are
• Continued recruitment of monocytes from
  circulation, via chemotaxis
• Local Proliferation of Macrophages
• Immobilization of Macrophages

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Reticulo Endothelial System

• Primary (or "central") lymphoid organs - the
  sites where the cells of the RES are produced.
  The cells of the RES are produced in the bone
  marrow.
• The thymus is also included as it is the required
  site for T cell maturation.
• Secondary (or "peripheral") lymphoid organs - the
  sites where the cells of the RES function.
• MALT is further divided into the GALT
  (gut-associated lymphoid tissue) and the BALT
  (bronchus-associated lymphoid tissue).
• The Kupffer cells of the liver act as part of
  this system but are not organized into a tissue
  rather, they are dispersed throughout the liver
  sinusoids

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RES
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Macrophages

• These cells are part of the innate
  response. Unlike T and B cells, they do not
  contain any specific receptors. Macrophages
  continuously phagocytose self-proteins and cells
  in their vicinity, during normal tissue repair
  and aging (e.g. old red blood cells). All of
  these proteins are degraded and presented on
  MHC-II. These self-proteins however, do not
  activate T cells, because in the absence of
  infection, macrophages express low levels of
  MHC-II, and almost no co-stimulator (B7).
  Further, T cells with high affinity receptor for
  self-peptides have been deleted during T cell
  development in the thymus. In the case
  of infection, however, macrophages posses certain
  types of receptors that recognize differential
  carbohydrate patterns on foreign cells. They also
  have receptors for specific bacterial products
  such as lipopolysaccharide (LPS) (endotoxin).
  When these molecules bind their bacterial
  ligands, they stimulate the macrophages to up
  regulate MHC-II and B7, providing these cells
  with strong antigen presentation properties. They
  also start to secrete Cytokines   that aid in
  their functions. (note IL-1, 6, 8, 12 and
  TNF-a). It is at this point that antigen
  presentation by MHC II will activate Th cells.

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Products released by
Macrophages

• Enzymes
• Elastase
• Collagenases
• Plasma Proteases
• Complement
• Coagulaton factors
• Reactive oxygen species
• Eicosenoids
• Cytokines (IL-1, TNF, IL-8)
• Growth factors
• Nitric oxide

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Connective Tissue Repair

• FIBROSIS HAS (4) COMPONENTS TO THE PROCESS
• FORMATION OF NEW BLOOD VESSELS
• (ANGIOGENESIS)
• MIGRATION AND PROLIFERATION OF FIBROBLASTS
• DEPOSITION OF EXTRACELLUALR MATRIX
• MATURATION AND REMODELING OF TISSUE

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Granulomatous Inflammation

• Bacterial
• Tuberculosis
• Leprosy
• Syphilis
• Cat Scratch Fever
• Parasitic
• Schistosomiasis
• Fungal
• Crypyococcus
• Coccidioidis
• Inorganic Metals
• Unknown

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Lymphatic Inflammation

• Lymphatics are very delicate channels that are
  often very difficult to visualize because they
  readily collapse.
• Lymphadenititis may be caused by a bacteremia of
  ,the vascular system that prevents drainage that
  way.
• The constellation of nodal involvement is usually
  termed reactive or inflammatory because of the
  loose pattern of the infective process.

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Serous Inflammation

• Serous inflammation is marked by an outpouring of
  thin non proteinacious fluid.
• The fluid is a cause of effusions amd skin
  blistering that may be a result of various
  sources to include (viral, osmotic, and other
  non-bacterial sources)

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Fibrinous Inflammation

• With more severe injuries, resulting is greater
  vascular permeability, larger molecules including
  fibrin pass the vascular barrier.
• Histologically, fibrin appears as an eosinopholic
  meshwork of threads.
• Conversion of this fibrinous exudate leads to
  scar tissue organization, and sometimes a
  thickening of the tissue itself.

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Purulent Inflammation

• This type of inflammation is what can cause
  abscesses, pus, or exudate consisting mainly of
  neutrophils and necrotic cells.
• There is usually a necrotic foci of
  staphylococcus or other pyogenic bacteria.

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Ulcers

• An ulcer is a local defect, or excavation of the
  surface of an organ that is produced by continual
  (shedding) sloughing or inflammatory necrotic
  tissue.
• It is common to the GI tract, and during the
  acute phase there is intense polymophonuclear
  infiltration and vascular dilation.
• Chronically fibroblastic proliferation continues

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Systemic effects of
Inflammation

• Release in interleukins, prostaglandins, after an
  initial leukocytosis can cause serum proteins,
  including amyloid, complement and coagulation
  factors to invade surrounding tissue.
• Certain infection increase the risk of such an
  inflammatory state, creating a tissue
  eosinophilia that may briefly impede tissue
  repair until treated.

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Wound Healing

• Within 24 hours, neutrophil appear at margin of
  insult. The cut edges thicken as a result of
  mitotic activity of basal cells
• By day 3, granulation tissue continues to invade
  the area
• By day 5, the area in granulated and
  neo-vascularization begins to develop
• During the second week there is an accumulation
  of collagen, accompanied by a regression of
  vascular channels.
• Hypoxia lead to pain, and prostaglandin release
• By the end of the 1st month, inflammatory tissue
  has ceased and tensile strength element begin to
  develop.

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Wound Healing
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FEVER
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Infectious Disease
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General Principles

• Improved living conditions, help in decreasing
  infection in developed countries, yet in
  undeveloped or developing countries, unsanitary
  living condition (sewage/ water) and malnutrition
  leave the massive burden of infectious disease 10
  million people each year.
• Most of these are children that die from
  complicated respiratory and diarrheal infections
  caused by viruses and bacteria

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Kochs Postulate

• 1 The microganism is regularily found in the
  lesion
• The organism can be isolated as single colonies
  on a solid medium
• Inoculation of the culture organism can cause a
  lesion in experimental animals
• The organism can be recovered from experimental
  animals

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Categories of Infection Agents

• Viruses
• Bacteriophages, plasmids
• Bacteria
• Chlamydia, Rickettsia
• Fungi
• Protozoa
• Helminths
• Ectoparacytes

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Respiratory Viruses

• Adenovirus
• Echovirus
• Cocksackie virus
• Coronavirus
• Inluenza A, B
• Parainfluenza Type 1-4
• RSV

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Digestive Viruses

• Mumps
• Rotavirus
• Norwalk
• Hepatitis A
• Hepatitis B
• Hepatitis C
• Hepatitis D
• Hepatitis E

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Systemic and Skin Viruses

• Measles
• Rubella
• Parvavirus
• Vacinnia
• Varicella-zoster
• HSV I
• HSV II

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Systemic and Blood Viruses

• Cytomegalovirus (CMV)
• Epstein-barr virus (Mono)
• HTLV I virus
• HTLV II virus
• HIV I II virus

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Arbor and Hemmorrhagic Viruses

• Denguevirus 1-4
• Yellow fver
• Colorado Tick
• Regional Hemmorhagic (Hanta, Marburg, Ebola )

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Warty Growth Virus

• Papillomavirus (HPV)
• Molluscum Virus

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CNS Viruses

• Polivirus
• Rhabdovirus
• JC virus
• Arboviral encphalitis virus

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Bacteria
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Pyogenic Cocci Bacteria

• Staphylococcus aurues
• Streptococcus pyogenes
• Streptococcus Pneumoniae
• Neisseria Menegitidis
• Neisseria Gonorrhoeae

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Common Gram Negative Infections

• Escherichia Coli
• Klebsiella Pneumonae
• Enterobacter Aerogenes
• Proteus spp.
• Pseudomonas sp.
• Legionella spp.

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Rare Gram Negative
Infections

• Calymmatatobacterium donavons
• Heamophilis ducreyi
• Klebseilla rhinoschleromatis
• Bartonella bacilliforms

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Contagious Childhood Bacteria

• Hemophilus influenze
• Hemophilus pertusis
• Cornyobacterium diptheria

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Enteropathic Infections

• Enterpathogenic E-coli
• Shigella Sp
• Vibrio cholera
• Campylobacter jejuni
• Yersinia enterocolitica
• Salmonella spp (1000 strains)

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K, H, O Antigens
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Mycobacterium Tuberculosis

• Tuberculosis (TB) survives in the United States
  and has been infecting people for more than 3,000
  years.  It is truly a global menace with
  remarkable staying power.  TB remains one of the
  worlds leading killers, responsible for nearly 2
  million deaths every year.  Today, this bacterium
  infects some one-third of all human beings
  worldwide.  It was estimated that in 2005 alone,
  9 million people will be diagnosed with the
  infection and more than 2 million will die. 
  During this same year, about 40 million, most
  unknowingly, will quietly become infected. 
  Mycobacterium tuberculosis, which is the name of
  the bacterium that causes most cases of
  tuberculosis, often times will lie latent
  (dormant), awaiting a future time and place to
  awaken.  This disease is capable of lingering
  undetected in the body for years in its latent
  form, with potentially devastating consequences
  if it becomes active

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Vibrio Chorela

• Annually 5-7 million cases, 100,000 deaths
  worldwide. Cholera gravis, the most severe form
  of the disease, has a 10 death rate.
• Cholera is actually hard to catch. Normal levels
  of stomach acidity make it necessary to ingest
  great volumes of the pathogen--enough to make the
  water cloudy. Water filtration and waste
  treatment are an important part of controlling
  the spread of cholera.

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Malaria

• Humans infected with malaria parasites can
  develop a wide range of symptoms. These vary from
  asymptomatic infections (no apparent illness), to
  the classic symptoms of malaria (fever, chills,
  sweating, headaches, muscle pains), to severe
  complications (cerebral malaria, anemia, kidney
  failure) that can result in death. The severity
  of the symptoms depends on several factors, such
  as the species (type) of infecting parasite and
  the human's acquired immunity and genetic
  background.

153
Malaria Transmission

• Malaria is transmitted among humans by female
  mosquitoes of the genus Anopheles. Female
  mosquitoes take blood meals to carry out egg
  production, and such blood meals are the link
  between the human and the mosquito hosts in the
  parasite life cycle. Of the approximately 430
  known species of Anopheles, only 30-50 transmit
  malaria in nature. The successful development of
  the malaria parasite in the mosquito (from the
  "gametocyte" stage to the "sporozoite" stage)
  depends on several factors. The most important is
  ambient temperature and humidity (higher
  temperatures accelerate the parasite growth in
  the mosquito) and whether the Anopheles survives
  long enough to allow the parasite to complete its
  cycle in the mosquito host ("sporogonic" or
  "extrinsic" cycle, duration 10 to 18 days).
  Differently from the human host, the mosquito
  host does not suffer noticeably from the presence
  of the parasites.

154
Zoonotic Bacteria Infections

• Bacillus Anthracis
• Listeria monocytogenes
• Yersinia pestis
• Franciella tuleremia
• Brucella sp
• Lerptospira sp (many groups)
• Borrelia burgodorferi

155
Various Adhesin Factors
156
Helminths

• Refer to Helminths chapter it is very inclusive
  as to life cycles and treatment of Helminths

157
Ectoparasites

• Ectoparasites are arthropods (lice, ticks,
  bedbugs, fleas) that attach and can burrow into
  skin.
• An example of this is
• LYME Disease (Borrellia Borgedorferi, which is
  transmitted by ticks) it causes an erthymatous
  plaque skin lesion

158
Fungi

• Pathogenic fungi is describes inclusively in the
  Mycology section of IMECs Series

159
Chlamydia

• Is a common sexually transmitted disease (STD)
  caused by the bacterium, Chlamydia trachomatis,
  which can damage a woman's reproductive organs.
  Even though symptoms of chlamydia are usually
  mild or absent, serious complications that cause
  irreversible damage, including infertility, can
  occur "silently" before a woman ever recognizes a
  problem. Chlamydia also can cause discharge from
  the penis of an infected man.

160
Trichomoniasis

• Trichomoniasis is caused by the single-celled
  protozoan parasite, Trichomonas vaginalis. The
  vagina is the most common site of infection in
  women, and the urethra (urine canal) is the most
  common site of infection in men. The parasite is
  sexually transmitted through penis-to-vagina
  intercourse or vulva-to-vulva (the genital area
  outside the vagina) contact with an infected
  partner. Women can acquire the disease from
  infected men or women, but men usually contract
  it only from infected women.
• Trichomoniasis is the most common curable STD in
  young, sexually active women. An estimated 7.4
  million new cases occur each year in women and
  men.

161
Legionaires Disease

• Legionnaires disease (LEE-juh-nares) is caused
  by a type of bacteria called Legionella. The
  bacteria got its name in 1976, when many people
  who went to a Philadelphia convention of the
  American Legion suffered from an outbreak of this
  disease, a type of pneumonia (lung infection).
  Although this type of bacteria was around
  before1976, more illness from Legionnaires
  disease is being detected now. This is because we
  are now looking for this disease whenever a
  patient has pneumonia
• PONTIAC FEVER !!!

162
Environmental Disease
163
Factors

• Air pollution
• Cigarette smoking
• Ultra-violet light
• Chemical Injury
• Drugs injury
• Physical injuries
• Nutritional disease

164
Air Pollution

• Daily we inhale and exhale 10-20 thousand liters
  of air, that has a myriad of pollutants from
  bacteria, gases, fibers, particles .
• Some pollutants are restricted to specific
  industries and are carefully monitored in the US,
  and in general creat less of a health problem.

165
Environmental Considerations

• All disease are not purely genetic in nature,
  many are aquired through environmental exposure.
  Consideration are almost limitless, but they can
  divided into
• The magnitude of the environmental problem
• The adverse affects associated
• Injuries induced by exposure
• Overall health consequences of nutritional
  adjustments needed

166
Air Pollutants

1. Tobacco Smoke
2. Wood coal Stoves
3. Gas Ranges ( NO, CO2, NO2 )
4. Dust Mites
5. Formaldehyde
6. Radon
7. Solvents Cleaning
8. Pesticides and herbicides
9. ASBESTOS

167
Lung Diseases

• Acute/Chronic inflammation
• Emphysema
• Asthma
• Hypersensitivity pneumonitis
• Pneumococcal Infections
• Neoplasma

168
Ultra-violet light

• Increased ultra-violet exposure may have serious
  threats with increasing global warming and
  depletion of the ozone.
• The direct injury can lead to basal cell
  carcinoma and melanoma.
• Not to mention that the depletion of
  phytoplankton can cause a disruption in the CO2
  and changes in the food change.

169
Chemical Injury

• All chemicals are capable of injury.
• In the United States , OSHA is supposed to
  regulate all of these.
• Yet recently, a dramatic industrial exposure in
  (BHOPAL, India) in 2000 released gaseous cyanide.
• It must be expected that at any time similar
  incidences could happen again.
• LEAD, SILICON, MERCURY

170
Drug Injuries

• Blood dyscrasias
• Agranulocytosis, aplastic anemia, hemolytic
  anemia
• Cutaneous
• Uticaria
• Cardiac
• Arrhythmia
• Renal
• Glomerulonephritis
• Hepatic
• Fatty Changes
• Pulmonary
• Systemic
• CNS

171
Common Drug Injuries

• Tricyclic antidepressants
• Dopamine, serotonin terminals
• Acetominophen
• Toxic metabolite binds to gluthathione
• Aspirin
• Respiratory depression, gastritis
• Oral Contraceptives
• Endometrial defects, cardio, venous thrombus
• Osteoporosis
• Halothane
• Hepatic necrosis, hypersensitivity reaction
• Ethanol
• To many to list

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Major Environmental Carcinogens

• Arsenic ----- Skin, Lung, liver CA
• Asbestos ---Bronchogenic CA
• Benzene----mylogenous leukemia
• Beta-naphylamine ---- bladder
• Cadmium---- Prostate
• Nickel---- Stomach Carcinoma
• Vinyl Chloride-----angio-sarcoma

174
Major Environmental Toxins

• Mercury---Neuronal changes
• Cyanidecytochome oxidase inhibitor
• Mushrooms blocks RNA polymerase
• Insectides Neuronal changes
• MethanolForladehyde and formic acid

175
Physical Injuries

• Abrasions
• Lacerations
• Incisions
• Contusions
• Gunshot wounds
• Burns
• Electrical Injuries
• Radiological Injuries

176
Nutritional Disorders

• Protein/Calorie- under-nutrition
• Fat Soluble Vitamin Deficiency
• Water Soluble Vitamin Deficiency

177
Protein/Calorie Under-nutrition

• Decreased Intake
• Poor Teeth
• Dysphagia
• Anorexia
• Systemic disease
• Mal-absorption
• Biliary/Pancreatic Diseases
• Enteric and Vit B12 Malabsorption
• Increase Requirements
• Trauma
• Burns
• Excessive protein loss

178
Protein/Calorie Under-nutrition

• Kwashiorkor is characterized by apathy,
  peripheral edema, sub Q fat, moon face, enlarged
  fatty liver and low serum albumin
• Marismus is muscle wasting , no edema or hepatic
  enlargement

179
Kwashiorkor
180
Fat Soluble Vitamin Deficiency

• Vitamin A------ Night Blindness
• Vitamin D------ Rickets, Osteomalacia
• Vitamin E------ Spinocerebellar effects
• Vitamin K------ Bleeding diathesis

181
Severe Vitamin A defect
182
Water Soluble Vitamin
Deficiency

• Vitamin B1 (Thiamine)---Beriberi
• Vitamin B2 (Riboflavin)---Stomatitis
• Niacin--- Pellegra (demtentia, dermatitis,
  diarrhea)
• Vitamin B6 --- (Peripheral neuropathy)
• Vitamin B12---Megaloblatsic/perniscious anemia
• Vitamin C--Scurvy
• Folate----Megaloblastic anemia

183
Obesity

• Few problems in America have been talked about
  more, yet one quarter of americans are
  overweight, and 1/8th would be considered obese
• Body Mass Index ( BMI ) in whatever form must be
  evaluated to patients morphology
• Obesity in itself can be due to eating habit, as
  well as lower metabolic rates
• Consequences include Heart Disease, Hypertension,
  Diabetes Mellitus, and other coronary artery
  insults

184
Diet and Systemic Disorder

• There is significant studies that show variable
  ratios of HDL, LDL, and VLDL effect coronary
  heart disease
• Hypertension although not entirely clear is
  related to sodium channels, and sodium
  restriction would be the first line of therapy

185
Diet and Cancer

• There is great concern that aromatic compound can
  effect cancer
• Cyclymates, and saccharin although now regulated
  enhance cancinogenic influences
• High fat diet and less bulk grains attribute to
  colon cancer
• Anti-oxidants, such as Vitamins A, E, C, are
  essential as free radical scavengers

186
Vascular Disease
187
Arteries Veins

• Arteries and veins have been distinctively
  structures.
• Artery walls are generally thicker than venous
  counterparts.
• Vein have an overall larger diameter, a larger
  lumen and a more narrow wall.

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Arterial and Venous Lumen

• Under normal situations the Intima layer of
  arteries is less exaggerated than veins
• Whereas under most situations in elastic arteries
  the Media layer is much more prominent than
  corresponding veins
• Arterioles, the smallest branches of the
  arteries, is normally responsible for blood
  pressure regulation

191
Intima Cells
192
Endothelial Cell Activation
193
Endothelial Cell Adhesion
194
Endothelial Cell Properties

• Maintenance of permeability barrier
• Extra cellular Matrix (collagen, procollagen)
• Elaboration of anticoagulant /anti-thrombotic
  molecules
• Prostacyclin
• Plasminogen Activator
• Heparin like molecules
• Elaboration of pro-thrombotic molecules
• Von Willebrand factors (Factor VIIIa)
• Tissue Factor
• Plasminogen Activator Inhibitors

195
Endothelial Cell Properties

• Modulation of Blood Blow Factors
• Vasoconstrictors ACE, endothelin
• Vasodilators NO/EDRF, prostacyclin
• Regulation of Inflammation Factors
• IL-1, IL-6, IL-8
• Adhesion Molecules
• Histocompatibility Antigens
• Regulation of Cell Growth
• Growth Stimulators PDGF, CSF, FGF
• Growth Inhibitors Heperin, TGF-B
• Oxidation of LDL

196
LDL Oxidative Stress
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Endothelial Dysfunction

• In all realization, the term endothelial
  dysfunction refers to potentially reversible
  changes in the state of the endothelial cell that
  occurs in response to environmental stimuli

200
Intimal Thickening

• Healing and damage of blood vessels comprise SMC
  proliferation in the migration from the media to
  the intima, and subsequent multiplication and
  modification of intimal cells.
• An extensive or chronic injury induces a very
  complex and repair sequence. Which include
  proliferation activities of promoters and
  inhibitors.

201
Intimal Thickening