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MICROBIOLOGY AND PATHOLOGY Green is pre 2002 Yellow is post 2002 USC messed up the following questions: 1981Q61 – wrong – should be ‘(c) fibroblasts & endothelial cells’ 1981Q68 – wrong – should be ‘basophils & mast cells’, not ‘eosinophils & mast cells’ Questions to Find

Which of the following affects the widest organ range? Herpes, rubella, varicella, Moluscam m.

CELLS/ORGANELLES

Cell parts: Mitochondrion – double MB structure responsible for cellular metabolism – powerhouse of the cell Nucleus – controls synthetic activities and stores genetic information Ribosome – site of mRNA attachment and amino acid assembly, protein synthesis Endoplasmic reticulum – functions in intracellular transportation Gogli apparatus/complex – composed of membranous sacs – involved in production of large CHO molecules & lysosomes Lysosome – organelle contains hydrolytic enzymes necessary for intracellular digestion

Membrane bag containing digestive enzymes Cellular food digestion – lysosome MB fuses w/ MB of food vacuole & squirts the enzymes inside

• Digested food diffuses through the vacuole MB to enter the cell to be used for energy or growth Lysosome MB keeps the cell iself from being digested Involved mostly in cells that like to phagocytose Involved in autolytic and digestive processes Formed when the Golgi complex packages up an especially large vesicle of digestive enzyme proteins

Phagosome – vesicle that forms around a particle (bacterial or other) w/in the phagocyte that engulfed it Then separates from the cell MB & fuses w/ lysozome to receive contents This coupling forms phagolysosomes in which digestion of the engulfed particle occurs

Microbodies: Contain catalase Bounded by a single MB Compartments specialized for specific metabolic pathways Similar in function to lysosomes, but are smaller & isolate metabolic reactions involving H2O2 Two general families:

• Peroxisomes: transfer H2 to O2, producing H2O2 – generally not found in plants • Glyoxysomes: common in fat-storing tissues of the germinating seeds of plants

♦ Contain enzymes that convert fats to sugar to make the energy stored in the oils of the seed available Inclusions – transitory, non-living metabolic byproducts found in the cytoplasm of the cell

May appear as fat droplets, CHO accumulations, or engulfed foreign matter. The cell cycle

1) Labile cells (GI tract, blood cells) Described as parenchymal cells that are normally found in the G0 phase that can be stimulated to enter the G1 Undergo continuous replication, and the interval between two consecutive mitoses is designated as the cell cycle After division, the cells enter a gap phase (G1), in which they pursue their own specialized activities

• If they continue in the cycle, after passing the restriction point (R), they are committed to a new round of division • The G1 phase is followed by a period of nuclear DNA synthesis (S) in which all chromosomes are replicated

♦ The S phase is followed by a short gap phase (G2) and then by mitosis ♦ After each cycle, one daughter cell will become committed to differentiation, and the other will continue cycling

2) Stable cells (Hepatocytes, Kidney) After mitosis, the cells take up their specialized functions (G0). They do not re-enter the cycle unless stimulated by the loss of other cells

3) Permanent cells (neurons) Become terminally differentiated after mitosis and cannot re-enter the cell cycle Which cells do not have the ability to differentiate? Cardiac myocytes

Enzymes: Serum lysozyme:

Provides innate & nonspecific immunity

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Lysozyme is a hydrolytic enzyme capable of digesting bacterial cell walls containing peptidoglycan • In the process of cell death, lysosomal NZs fxn mainly to aulolyse necrotic cells (NOT “mediate cell degradation”) • Attacks bacterial cells by breaking the bond between NAG and NAM. • Peptidoglycan – the rigid component of cell walls in most bacteria – not found in archaebacteria or eukaryotic cells • Lysozyme is found in serum, tears, saliva, egg whites & phagocytic cells protecting the host nonspecifically from

microorganisms Superoxide dismutase: catalyzes the destruction of O2 free radicals protecting O2-metabolizing cells against harmful effects Catalase:

catalyzes the decomposition of H2O2 into H2O & O2 Aerobic bacteria and facultative anaerobic w/ catalase are able to resist the effects of H2O2 Anaerobic bacteria w/o catalase are sensitive to H2O2 (Peroxide), like Strep Anaerobic bacteria (obligate anaerobes) lack superoxide dismutase &/or catalase Staph makes catalase, where Strep does not have enough staff to make it!!

Coagulase NOT an NZ, its an adhesin Converts Fibronogen to fibrin

• Coagulase test is the prime criterion for classifying a bug as Staph aureus – from other Staph species • Coagulase is important to the pathogenicity of S. aureus because it helps to establish the typical abscess lesion • Coagulase also coats the surface w/ fibrin upon contact w/ blood, making it harder to phagocytize

♦ NOTE: this is NOT a polysaccharide capsule that forms Cell Functions:

Autolysis: degradative reactions in cells caused by indigenous intracellular enzymes – usually occurs after cell death Irreversible (along with Coagulative necrosis or infarcts) – reversible: fatty degeneration, & hydropic degeneration Autolysin:

• Ab causing cellular lysis in the presence of complement • Autolytic enzymes produced by the organism degrade the cell’s own cell wall structures

In the presence of cephalosporins & penicillins, growing bacterial cells lyse • W/o functional cell wall structures, the bacterial cell bursts

Heterolysis: cellular degradation by enzymes derived from sources extrinsic to the cell (e.g., bacteria) Necrosis: sum of intracellular degradative reactions occurring after individual cell death w/in a living organism

Lymph nodes If a foreign antigen enters through the skin, it will first hit the lymphoid system in the lymph nodes

NOT the MALT, liver, spleen, or thymus Lymphocytes

Motile Immunoglobulin production Produce MIF (Macrophage inhibiting factor)

If a T-lymphocyte from a pt with chronic periodontitis were cultered in vitro with dental plaque antigen, production of MIF would occur • DO NOT PHAGOCYTIZE

When T cells from people with chronic PD are reacted with certain plaque bacterial antigens, they produce: • MIF, OAF, & lymphotoxin (NOT Ab, collagenase, or C3)

B-lymphocytes: Are WBCs that complete maturation in bone marrow then migrate to lymphoid organs Search out, identify, & bind w/ specific Ag/s

Recognize specific antigens by virtue of membrane-bound immunoglobulin Committed to differentiate into Ab-producing plasma cells involved in Ab-mediated immunity When an immature B cell is exposed to a specific Ag (they recognize Ag by MB-bound Ig), the cell is activated It then travels to spleen or lymph nodes, differentiates, and rapidly produces plasma & memory cells Mature B cells have surface IgM & IgD that bind Ag & cause release of immunoglobulins B-cell immunodeficiency can be treated with injections of gamma-globulin

Plasma cells: The predominant cell in synthesis of Abs More common in chronic inflammation than acute inflammation

Cells of Chronic inflammation are Lymphocytes, Plasma cells, and Macrophages T-lymphocytes:

Affected by IL-4??? WBC that complete maturation in thymus & become thymocytes Responsible for initially recognition of antigen

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In pts with chronic PD, when the T cells react with certain plaque bacterial antigens, they produce: IL-2, TNF-alpha, IFN-gamma

• NOT Immunoglobulin – That would be B-cells. Responses to viral infections:

Production of lymphokines Direct cell-mediated cytotoxicity Helper activity to B cells to make Abs

Major classes include helper T-cells, suppressor T-cells, & cytotoxic (killer) T-cells T helper cells:

• CD4+ • NOT antigen-specific • (Antigen-specific cells are):

♦ B cells, Macrophages, Dendritic, and Langerhans (So, reticuloendothelial cells + B-cells). • Two classes of helper T cells→Th1 & Th2 cells

♦ Distinguished by the types of cytokines they secrete ♦ Th1: release IL-2 & IFN-gamma

Stimulate proliferation & cytotoxic responses ♦ Th2: release Il-4, IL-5, IL-6, Il-10

Stimulate B cell maturation, differentiation & class-switching Cytotoxic T-cells

• CD8+ • First activated w/ IL-2, which is secreted by active helper T-cells • Act by recognizing foreign Ag & MHC I molecules w/ their TCR

Natural Killer (NK) cells • Also activated w/ IL-2 • Recognize foreign Ag w/o need for Ag presentation on MHC molecules • NON specific immunity • Activated by cytokines, such as IFN-gamma

Deficiency in T-cells can predispose a person to candidiasis (NOT a deficiency in basophils/eosinophils/plasma cells/MФs) Eosinophils

Release histaminase & aryl sulfatase to help control allergic reactions Basophils

Have receptors for the Fc portion of IgE IgE binding promotes degranulation = release of histamine, etc, which lead to symptoms seen in atopic allergies

Mast Cells IgE has an affinity for the Fc portion of Mast cells

Type I Hypersensitivity Secrete

Histamine Heparin ECF-A (Eosinophil Chemotactic Factor of Anaphylaxis) SRS-A (Slow-Reacting Substances of anaphylaxis (SRS-As)

• Leukotrienes Lymphocytes Function T helper cells (Th) Help or assist other T cells and B cells to express their immune function Cytotoxic T cells (Tc) Kill target cells expressing foreign Ag/s (cells containing obligate intracellular parasistes & tumor cells) T suppressor cells (Ts) Suppress or inhibit the immune function of other lymphocytes T memory cells Long-lived cells that recognize previously encountered T dependent antigens B lymphocytes Differentiate into antibody-producing plasma cells and B memory cells in response to an antigen B memory cells Long lived cells that recognize a previously encounter antigen Natural killer cells (NK) Kill and lyse target cells that express foreign antigens Plasma cells Actively secrete antibody Cells that maintain latent capacity for mitotic division:

Blood (RBCs live for 120 days, WBCs only 2-5 hours), bone marrow, liver, and salivary glands Liver undergoes regeneration: occurs as adaptive mechanism for restoring a tissue or organ

• After removal of 70% of liver, numerous mitoses of hepatocytes occur reaching a peak at 33 hours • By day 12 the mass of liver is totally restored

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• Liver is the least common site for infarcts (than brain, heart, kidney, adrenals) NOTE: Bone cartilage & intestinal mucosa are also able to regenerate

Cells that do not have ability to undergo mitosis: Nerve cells (least ability to regenerate) in the CNS, skeletal, cardiac, & smooth muscle cells, lungs

Striated muscle is harder to regenerate than smooth muscle Heart, brain, & lungs are very vulnerable to hypoxia & anoxia

They die & are unable to regenerate The heart can undergo hypertrophy in response to injury

BACTERIA

A quick note on organisms in general: Commensalism:

Interaction between two populations of different species living together in which one population benefits from the association, while the other is not affected

Symbiosis: An obligatory interactive association between members of two populations

• Produces a stable condition in which the two organisms live together in close physical proximity It may, but does not necessarily, benefit each member

Mutualism: Form of symbiosis – both members live together w/ mutual benefit

Cell types: Eukaryote

Has a true nucleus – surrounded by a nuclear MB & uses a mitotic apparatus in allocating chromosomes Contains organelles & larger (80S) ribosomes Mitotic replication EXs: plants, animals, protozoa, fungi

Prokaryote No nucleus, organelles, or cytoskeleton

• Nuclear material NOT contained w/in a nucleus Naked, single circular molecule of losely organized dsDNA

• Single chromosome • Located in nucleoid (membraneless structure/region containing DNA – little resemblance to eukaryotic nucleus)

Contains no MB-bound organelles & smaller (70S) ribosomes Has a rigid external cell wall containing peptidoglycan (mycoplasmas lack a cell wall) - that’s why they don’t stain. EXs: BACTERIA, mycoplasmas, rickettsia, chlamydia

• Gram-staining ♦ Based on interaction w/ cell wall ♦ Limitations:

Treponema (too thin to be visualized) Use Darkfield for Syphilis Rickettsia (intracellular parasite) Mycobacteria (high-lipid content cell wall) Use acid-fast Mycoplasma (NO cell wall) – M. pneumoniae (walking pneumonia) Legionella Pneumophila (Primarily Intracellular) Use Silver stain Chlamydia (intracellular parasite)

• Acid-fast organisms appear red against blue background (due to lipids/waxes [mycolic acids] in the cell wall) ♦ Staining in tubercle bacilli is due to lipid/waxes mycolic acid ♦ Mycobacteria & Nocardia are acid-fast

True bacteria multiply by binary fission NOTE: viruses are not cells – they are “obligate intracellular parasites”

Either RNA or DNA; no organelles; protein capsid & lipoprotein envelope Classification:

Neutrophiles (pH = 7.0) P. aeruginosa Clostridium sporogenes Proteus species

Acidophiles (pH < 7.0) Thiobacillus thiooxidans Sulfollobus acidocaldaarius Bacillus acidocaldarius

Alkaliphiles (pH > 7.0)

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Nitrobacter species Streptococcus pneumoniae

Bacterial growth 1) Lag phase (Think lagging behind)

Metabolically active, non-dividing 2) Log phase = logarithmic phase (Log Growth)

Exponential growth Most of the cidal Abx work best in this phase

• i.e. Ampicillin Best phase for staining bacterial cultures

• For uniform staining rxn, morphology, and biochemical activity 3) Stationary phase

# of cells are dying = # of cells being produced 4) Death phase/phase of decline

More death than new cell production Logarithmic decrease in cell #

Glucose metabolism (respiration) Oxidative phosphorylation involves the Cell MB in bacterial cells

BUT, ETC in Eukaryotes happens on the inner mitochondrial MB Aerobic respiration

Results in greatest release of energy • The primary result of bacterial carbohydrate metabolism is production of energy (NOT heat, alcohol, or acetone)

Involves a cell MB respiratory chain (electron transport chain = ETC) O2 is the terminal hydrogen acceptor, with final end products of H2O and CO2

Fermentation Substrate phosphorylation Formation of ATP not coupled to electron transfer Occurs when final electron acceptor is an organic compound

• An intermediate glucose product (i.e., pyruvate) is the final hydrogen acceptor Takes place in cytoplasm How Anaerobic bugs get their energy

Aerobic metabolism (obligate aerobes & facultative anaerobes) – They have the Faculty to be Aerobes too Toxic byproducts: H2O2 & free superoxide radicals Final endproducts are H2O and CO2 Cells possess a defense system to destroy these endproducts:

Enzymes include superoxide dismutase & catalase • 1) Superoxide dismutase catalyzes the decomposition of free superoxide radicals into H2O2 & H2O • 2) Catalase then catalyzes H2O2 → H2O + O2

Cytochromes: Respiratory enzymes capable of undergoing alternate reduction & oxidation Contain central iron atom which can be cycled between oxidized ferric state (Fe3+) & reduced ferrous state (Fe2+) Chemically related to hemoglobin Aerobic organotropic (heterotrophic) bacteria which oxidize a substance to CO2 and H2O in the final electron transport, use

NZs containing cytochromes EXs:

Cytochrome oxidase – terminal enzyme in chain of events constituting cellular O2 consumption – found in mitochondria Cytochrome P450 – important in metabolism of many drugs – found in liver microsomes (small particles typically

consisting of fragmented endoplasmic reticulum to which ribosomes are attached) Cytochrome b – cytochrome of respiratory chain Cytochrome b5 – cytochrome of endoplasmic reticulum

Transcription Synthesis of mRNA from DNA by DNA-dependent RNA polymerase Occurs in cytoplasm of prokaryotes (nucleus of eukaryotes) Two strands of DNA are temporarily pulled apart to allow RNA polymerase to access DNA as a template

Translation Process wherein nitrogenous bases are used to determine the aa sequence of a protein

Reverse transcription Formation of DNA from RNA template Retroviruses (HIV, RNA tumor viruses) use this process

RNA genome is used as a template for RNA-dependent DNA polymerase The virion-associated reverse transcriptase makes DNA copies from RNA

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This DNA is then integrated into the host genome • **Retrovirus is an oncogenic RNA virus (papillomavirus is NOT – because it is a DNA virus – don’t get clowned)

3 types of RNA: 1) rRNA – combines w/ proteins to form ribosomes 2) mRNA – dictates sequence of aa assembly 3) tRNA – transports aa’s to ribosomes for protein assembly

Genetic Transfer in Bacteria – 3 processes: 1) DNA TRANSFORMATION

Process in which DNA is released by lysis of one bacterium & taken up by a second, leading to a change in phenotype • Another Q: Transformation is best described as acquisition of an inheritable trait by bacteria mediated by DNA • Transfer of inheritable characteristics among bacteria is dependent upon DNA • Rough pneumoncocci grown in the presence of DNA from smooth pneumococci developed capsules

The most primitive mechanism for gene transfer among bacteria Used in lab to create recombinant DNA & to map gene locations No cell-to-cell contact required Involves the uptake of naked DNA molecules (the other processe of genetic transfer do NOT involve…) The DNA picked up by the recipient cell must be dsDNA

• Intracellular DNAase (endonuclease) degrades one strand, providing energy for uptake of the other ssDNA • Uptake depends on presence of protein called competence factor • The ssDNA inserts into homologous regions of recipient chromosome

2) TRANSDUCTION Transfer of genetic material from one bacterial cell to another by viral infection No cell-to-cell contact required Least susceptible to DNAase Transfer of DNA via a bacteriorphage = phage-mediated

3) CONJUGATION (THINK Conjugal Visit) A form of sexual reproduction in which ssDNA is transferred from one live bacterium to another through direct contact Pili establish the physical contact

• Does NOT require flagella for pair formation • NOTE about pili: The most important function of bacterial pili in causing human infectious disease is by allowing

bacteria to adhere to human cells, and NOT in the transfer of DNA between bacteria – although pili do both This process transfers the greatest amount of genetic information (compared to transformation & transduction)

• Ability to grow in the presence of ABX is passed in vivo from one bacterium to another • The pattern of resistance is transferred to other bacteria via conjugation

F factors • Plasmids transferred from a donor cell (F+ cell) to a recipient cell (F– cell) during conjugation

♦ Integration of the F factor plasmid into the chromosome is essential in order for the F factor to be transferred during conjugation

• An Hfr (high freq of recombination) is a cell w/ an F plasmid incorporated into the chromosome • During conjugation, portions of the Hfr chromosome are transferred from the Hfr bacterium to the F– bacterium

NOTE: all 3 processes contribute to increase in genetic variation w/in a population Cell Parts (inside→out):

Nuclear material Single, double stranded DNA molecule not confined within a nuclear membrane Plasmid

• Contains a variety of genes for ABX resistance, enzymes, and toxins • DNAs

Ribosome Protein Synthesis RNA and protein in 50S and 30S subunits

Cell MB = Cytoplasmic Membrane = Plasma MB Dynamic, selectively permeable MB involved in energy transformations (i.e., oxidative phosphorylation) Regulates movement of substances, including water, into/out of the cell

• Most active cellular structure of bacteria that controls the intake of solutions Encloses the cytoplasm Bordered externally by the cell wall In gram + bacteria, the teichoic acid induces TNF and IL-1 (acute phase)

Periplasm Space between the cytoplasmic membrane and outer membrane in gram – bacteria

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Contains many hydrolytic NZs, including Beta-lactamases Cell Wall – see notes below on G+ & G- cell wall contents

The basic difference between G+ & G- bacteria is the cell wall structure Surrounds plamsa MB Protects cell from changes in osmotic pressure Anchors flagella Maintains cell shape Controls transport of molecules into/out of the cell N-acetylmuramic acid (NAM) is intermediate (also NAG) in cell wall biosynthesis In gram - bacteria, the Lipid A induces TNF and IL-1 (acute phase)

Capsule Gelatinous (polysaccharide) coat often used 1) as an indicator of virulence (Enables them to stick to other cells) & 2) to

determine bacterial pathogenicity • **All are polysaccharide, except for Bacillus anthracis, which is D-glutamate

Surrounds cell wall of certain bacteria Protective against phagocytosis by eukaryotic cells

• Loss of capsule promotes phagocytosis • Prevents opsonization by complement

♦ 1) The capsule is slimy, making it hard for phagocytes to hold onto the bacterial surface ♦ 2) Complement receptors are masked by the capsule, making it difficult/impossible for complement to bind

• Capsule must be first coated w/ specific anticapsular antibodies & complement EXs of bacteria w/ capsules:

• Streptococcus pneumoniae • Hemophilius influenzae • Klebsiella pneumoniae • Cryptococcus neoformans (except this is a yeast)

Pilus/Fimbria Mediates adherence of bacteria to cell surface Sex pilus forms attachment beween 2 bacteria during conjugation Glycoprotein

Flagellum Motility Protein

Spore Provides resistance to dehydratin, heat, and chemicals Keratin-like coat Dipicolinic acid

Glycocalix Mediates adherence to surfaces, especially foreign surfaces (i.e. catheters) Polysaccharide Extracellular

NOTE: Protoplasts – A bacterial cell that is free of a cell wall and a capsule Spherical body produced under appropriate conditions from certain bacilli by the axn of lysozyme or PCN Cells that have their cell walls & capsules removed by enzymatic (lysozyme) or Abx (penicillin) Tx

G+ cell envelope (inside→out): Inner Cell Membrane Cell Wall – components:

Thick murein (peptidoglycan) layer • The backbone biochemical of the bacterial cell wall (makes up ~90% of the cell wall) • Peptidoglycan (murein):

♦ The rigid component of the cell wall in most bacteria – not found in archaebacteria or any eukaryotic cell ♦ Two parts of molecule:

Peptide portion: short, attached, cross-linked peptide chains containing unusual amino acids Glycan portion: alternating units of amino sugars N-acetylglucosamine and N-acetylmuramic acid

The NAG-NAM backbone is attacked by the enzyme lysozyme Lipoteichoic acids Teichoic acids

• Unique to G+ bacteria Polysaccharides that serve as attachment sites for bacteriophages

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No outer membrance Capsule (sometimes)

G- cell envelope (inside→out): Inner Cell Membrane Outer Membrane Cell Wall – components:

More complex than G+ cell wall Thin murein layer (~10% of cell wall) Lipoproteins are an integral part of cell wall Lipopolysaccharide (LPS) layers (= endotoxin)

• Located in the outer MB of G- bacteria ♦ Basic chemical structure consists of:

Somatic O Polysaccharide, Core Polysaccharide, and Lipid A (and Keto-deoxy-octanoate!!!) NOT Teichoic acid (That is only in G+ cell wall !!!)

Lipid A is the most responsible for the endotoxin’s toxic activity Induces TNF alpha and IL-1 Endotoxin is made of Lipid A NOT Protein A, O antigen, or core polysaccharide

• Only released (toxic) after cell dies & outer MB is broken down (i.e., not “secreted”) ♦ Pathogenic effects occur via activation of complement cascade ♦ Has a chemotactic effect on neutrophilic granulocytes – induces phagocytosis

• Host response includes: chills, fever, weakness, aches, shock, death • Accumulates in the gingival crevice in the absence of gingival hygiene

♦ Don’t get clowned by “bacterial metabolites including enzymes” accumulating in the crevice • Shwartzman reaction

♦ In this reaction, endotoxin elicits the response ♦ Rabbit is injected intradermally with a small quantity of lipopolysaccharide (endotoxin) followed by a second

intravenous injection 24 hours later and will develop a hemorrhagic and necrotic lesion at the site of the first injection

Phospholipids Proteins

Other Cell Contents: Granules (inclusion bodies) – storage areas for nutrients

Volutin – reserve of high energy stored in the form of polymerized metaphosphate that can be used in synthesis of ATP • Commonly associated w/ Pseudomonas aeruginosa & Cornybacterium diphtheriae

Sulfur granules PHB (polyhydroxybutyric acid) Metachromatic granules Diphtheria

Plasmids – Extrachromosomal, circular, dsDNA molecules capable of replicating independently of the chromosome

• Molecules of DNA that are separate from the bacterial chromosome Confer conjugal fertility – shooting blanks Carry genetic information between bacteria

• Example: R (resistance) factor Replicate while attached to the bacterial cell membrane Do NOT exist as circular RNA molecues Multiple drug resistance is related most closely to plasmids (NOT viruses, transformation, or cell chromosomes) ABX Resistance

• Most antibiotic resistance in bacteria is caused by genes that are carried on plasmids • Plasma-mediated antibiotic resistance has been observed with all of the following EXCEPT one:

♦ S. aureus, B. pertussis, and H. influenzae, N. gonorrhea, S. pyogenes??? ♦ (Google says they all do!!!)

PCN resistance in N. gonorrhea is explained by its production of a plasmid encoded beta-lactamase Strep pyogenes is resistant to erythromycin (plasma-mediated??), but is sensitive to bacitracin & penicillin

Determine traits not essential for the viability of the organism but that change the organism’s ability to adapt Transposons –

Consists of two insertion sequences flanking an ABX resistance gene Pieces of DNA that move readily from one site to another, either w/in or between the DNAs of bacteria, plasmids, or

bacteriophages

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Genes that often encode proteins necessary for ABX resistance and that can change positions on a chromosome or “jump” from a plasmid to a chromosome

Frequently associated w/ formation of multiple-drug resistance plasmids Encapuslated Bacteria

Polysaccharide capsule is antiphagocytic virulence factor IgG2 necessary for immune response` Capsule serves as antigen in vaccines (Pneumovax, H. influenzae b., Meningococcal vaccines) Quellung Rxn = Caspsular “Swellung” rxn capsule swells when specific anticapsular antisera are added

Streptococcus Pnuemoniae Haemophilus influenzae Neisseria meningitides -BIodome Klebsiella pneumoniae Cryptococcus Neoformans – Inside the Crypt - yeast

Exotoxin Vs. Endotoxin

Property Exotoxin Endotoxin Source Some Gram + and Gram - Cell wall of most Gram – ONLY Secreted Yes (Diffuse out) No (Just a breakdown product) Chemistry Polypeptide Lipopolysaccharide

Most bacterial endotoxins are composed of lipoprotein-polysaccharide complexes

Location of genes Plasmid or bacteriophage Bacterial chromosome Toxicity/Potency High (fatal if dose on the order of

1microg) Low (fatal dose on the order of hundreds of micrograms)

Clinical effects Various Fever, shock Mode of action Various Includes TNF and IL-1 Antigencity Induces high titer antibodies called

antitoxins Poorly antigenic – that’s why no vaccine to this.

Vaccines Toxoids are used No toxoids formed and no vaccine avail. Heat Stability Destroyed rapidly at 60 degrees C (except

Staph enterotoxin) (Heat Labile) Stable at 100 degrees C for 1 hour

Typical Diseases Tetanus, botulism, diphtheria, anthrax Meningococcemia, sepsis by Gram- rods Specificity High Miscellaneous Detoxified by formalin

Highly immunogenic

Different from exotoxins in that they activate complement via the alternate pathway

Play a role in PD because the role endotoxins play in inciting an inflammatory response

Effects of Endotoxin

1. Activates Macrophages Produce IL-1 (acts on T + B cells) Fever Produce TNF Fever, Hemorrhagic tissue necrosis Produce Nitric Oxide Hypotension (shock)

2. Activates Complement (Alternative Pathway) Produce C3a Hypotension, Edema Produce C5a Neutrophil Chemotaxis

3. Activates Hageman Factor (Clotting Factor) Coagulation Cascade DIC (Disseminated Intravascular Coagulation)

Some Protein Toxins (Exotoxins) Produced by Microorganisms That Cause Disease in Humans

Organism Exotoxins Disease Action Gram +

Clostridium botulinum (Gram +)

Several neurotoxins (A,B,E) Botulism Paralysis, blocks neural transmission Blocks release of Ach – just like Lambert Eaton’s Spores found in Canned Food, Honey

Clostridium perfringes a-toxin (a lecinthinase) Gas gangrene Destroys integrity of cell MBs

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(Gram +) K-toxin (a collagenase) Breaks down fibrous tissue Get double zone of hemolysis on blood agar

Clostridium tetany (Gram +)

Neurotoxin (tetanospasmin) Tetanus Spastic paralysis interferes w/ motor neurons Blocks release of inhibitor glycine Causes Lockjaw

Corynebacterium (Gram +)

Diphtheria toxin *a lysogenic phage encodes it

Diphtheria Blocks protein synthesis at level of translation Inactivated E2-F by ADP ribosylation (similar to Exotoxin A of Psuedomonas) Causes Pharyngitits/Psuedomembrane

Streptococcus Pyogenes (Group A Strep) (Gram +)

Various hemolysis Streptolysin O Streptolysin S Erythrogenic

Rheuamtic fever Scarlet fever

Lysis of RBCs Causes symptoms of rheumatic fever Causes rash of scarlet fever

Staphylococcus aureus (Gram +)

Enterotoxin –Very fast food poisoning

Food poisoning Toxic Shock Syndrome

Intestinal inflammation Toxin is a superantigen that binds to MHC II and T cell receptor, inducing IL-1 and IL-2 synthesis in toxic shock syndrome

Bacillus anthracis (Gram +)

Anthrax One toxin in the Tripartite toxin complex is an adenylate cyclase

Gram - Shigella dynsenteriae Neurotoxin Bacterial (bacillary)

dysentery Hemorrhage, paralysis

Escherichia coli Diarrrhea Heat labile toxin stimulates adenylate cyclase by ADP ribosylation of G protein

Vibrio Cholerae Rice-water diarrhea Stimulates adenylate cyclase by ADP ribosylation of G protein, increasing pumping of Cl- and H20 into the gut

Bordetella pertussis Whooping Cough Stimulates adenylate cyclase by ADP ribosylation Inhibits chemokine receptor, causing lymphocytosis

Two other examples: Pyrogenic exotoxin A – similar to the staphylococcal toxic shock syndrome toxin Exotoxin B – a protease that rapidly destroys tissue

NOTE: one Q reads, “tetanus & diphtheria are similar in nature w/ respect to production of exotoxins” Botulism:

Uncommon, life-threatening poisoning (not infection) An intoxication, not an infection – THINK BOTU TOXU

Caused by the toxins produced by the G+ anaerobic bacillus Clostridium botulinum Heat-labile neurotoxin usually from improperly canned food

These exotoxins (neurotoxins) are the most potent poisons known to humans Can severely damage nerves & muscle Bind to presynaptic nerve & block release of ACh from CNS nerve cells Causes flaccid paralysis of skeletal muscle Cause loss of motor function, including respiratory failure = death

Occurs w/ botulism food poisoning, wound botulism, & infant botulism Infant botulism = floppy baby syndrome – leads to failure to thrive

Foods most commonly contaminated – home-canned vegetables, cured pork/ham, smoked/raw fish, & honey or corn syrup Cannot grow in human body – only the toxin causes disease

So another Q reads: It does NOT require the presence of a live organism Mortality from botulism is ~25% – death usually caused by respiratory failure during the 1st week of illness Symptoms appear 8-48 hours after ingestion of toxin:

Initial CN paralysis w/ diplopia (double vision), dysathria (difficulty speaking), & pupil dilation Followed by limb & trunk muscle weakness or paralysis

Antitoxin is given, along w/ respiratory support – Don’t give Abx bc you’ll kill bact and rls more exotoxin.

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Cannot undo damage, but may slow/stop further physical & mental deterioration – body can heal itself over months Diphtheria

ABCDEFG ADP ribosylation Beta-prophage (exotoxin is encoded by) Club Shaped (Coryne means club shaped) Diphtheria Elongation Factor 2 (Exotoxin inhibitrs protein synthesis via ADP ribosylation of EF-2) Granules (Metachromatic Granules)

Causes pseudomembranous pharyngitis Grows on tellurite agar

Bacteria Groupings The following diseases are transmitted by droplets or droplet spray:

Whooping cough Meningitis Diphtheria Pneumonia VSV

• NOT Condylatum acuminatum Gram + (purple/blue)

Rods • Clostridium (tetany, botulism, difficile – psuedomemb. Colitis, Gas gangrene - perfringes) – SPORE FORMING • Corynebacterium (Diphtheria) • Listeria (Fetal Death, cholera, dysentery, meningitis) • Bacillus (Anthrax) – SPORE FORMING

Cocci • Catalase +

Staphylococcus Coagulase +

• S. aureus Coagulase –

• S. epidermidis (Nosocomial with valves/joint replacement) • S. saphrophyticus (UTIs in sexually active women)

• Catalase – ♦ Streptococcus

Hemolysis Alpha

• Capsule (optochin sensitive) ♦ S. Peumoniae (Pneumonia)

• NO Capsule (optochin resistant) ♦ Viridans Streptococci (i.e. S. mutans) (Endocarditis, caries, Brain abscess)

Beta • Group A (Bacitracin Sensitive) -- according to carb found in cell wall

♦ S. Pyogenes • Group B (Bacitracin Resistant)

♦ S. agalactiae (Neonatal meningitis, pneumonia, sepsis) Gamma

♦ Enterococcus (E. Faecalis and Peptostreptococcus) ♦ **Can be either gamma or alpha

Gram - (Pink) Cocci

• Neisseria ♦ Maltose Fermenter

N. meningitidis (Meningitis and Septicemia) ♦ Non-Maltose Fermenter

N. gonorrhoeae “Coccoid” (rods)

• Haemophilus influenzae • Pasteurella (Cat and dog bites Cellulitis)

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• Brucella (Brucellosis fever) • Bordetella pertussis (whooping cough)

Rods ♦ Lactose Fermenter (pink on MacConkey’s)

Fast Fermenter • Klebsiella (Bronchopneumonia and Nosocomial UTIs) • Escherichia coli (UTIs, Diarrhea) • Enterobacter (Diarrhea)

Slow Fermenter • Citrobacter • Serratia (Makes make red pigment) • Others

♦ NON-Lactose Fermenters Oxidase -

• Shigella (Bloody Diarrhea, Paralysis) • Salmonella (Enteric Fever, Typhoid Fever, Bloody Diarrhea, Osteomyelitis in Sickle Cell pts) • Proteus (UTIs)

Oxidase + • Pseudomonas (Pneumonia, Burn wound infection, Osteomyelitis, UTI, Contact lens infection)

MORE on G- aerobic rods and cocci: Pseudomonas family (really just P. aeruginosa):

• G-, straight or curved rods, most are obligate AERobes (PETS -- AIR) • Think PSEUdomonas – Pneumonia (in CF pts), Sepsis (black skin lesion), External Otitis (swimmer’s ear), UTI • Motile by means of polar flagella • Produce characteristic fluorescent pigments (P. aeruginosa), but others do not • Has ability to adapt and thrive in many ecological niches, from water to soil to plants & animals, including humans • Exotoxin A

♦ Inhibits protein synthesis (not DNA synthesis) ♦ Inactivates E2-F

• Important nosocomial infection in immunocompromised & chronically ill patients ♦ People w/ cystic fibrosis, burn victims, individuals w/ cancer & pts requiring extensive care in hospitals ♦ Nosocomial infections often caused by:

Staph, Strep, E. coli, & P. aeruginosa are common bugs in hospital-acquired infections • Once established, produces a number of toxic proteins which cause not only extensive tissue damage, but also interfere

w/ the human immune defense mechanisms ♦ An infection followed a serious skin burn that is characterized by greenish pus and is resistant to ABX is probably

caused by P. aeruginosa (think P. aeru-green-osa) Pyocyanin pigment

• Gentamicin is a broad spectrum aminoglycoside antibiotic effective in treating bacteremias caused by P. aeruginosa • Volutin (aka “metachromatic granule”) is a reserve of high energy stored in the form of polymerized metaphosphate

that can be used in synthesis of ATP ♦ Metachromatic granules are commonly associated w/ Pseudomonas aeruginosa & Corynebacterium diphtheriae

(Remember ABCDEFG) Burn victims

Which of the following will not affect burn victims? • P. aeruginosa, Mycobacterium ulcernus, C. tetany, Staph aureus --- VERIFY

Bordetella Neisseria Brucella Legionella

• Gram – rod • Stains poorly, use Silver stain • Grown on charcoal yeast extract culture with iron and cysteine • Aerosol transmission from water source habitat

♦ Legionella pneumophilia is transmitted via aerosolized organisms in air conditioning cooling towers • French Legionnaire with his Silver Helmet, sitting around a campfire (charcoal) with his iron because he’ no

Cissy (cysteine) and his atypical Pontiac Car parked out front with the A/C on • Young Healthy person exposed to Legionella Pneumophilia, what happens

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♦ Initial symptoms are flu-like, including fever, chills, and dry cough. Advanced stages of the disease cause problems with the gastrointestinal tract and the nervous system and lead to diarrhea and nausea

• Causes Pontiac fever and Legionnaires’ disease and Atypical Pneumonia • Treat w/ erythromycin

Haemophilus Influenzae – The Haemophilus influenza POEM – here it is. • haEMOPhilus causes Pneumonia, Otitis, Epiglottitis, Meningitis, • Large Capsule • Small gram – coccobacillary “coccoid” rod • Aerosol transmission • Most invasive disease is caused by capsular type b

♦ Vaccine contains type b capsular polysaccharide conjugated to diphtheria toxoid or other protein • Tx with Cephalosporin

♦ Think use CEPH because its your brain (MENINGITIS) • Produces IgA protease • Culture on chocolate agar requires Factor V (NAD) and X (hematin) – Go to the FIVE (V) and DIME (X) store to buy

chocolate • Does NOT cause the Flu – that is a VIRUS

Helicobacter pylori • Gram – rod • Causes gastritis and 90% of duodenal ulcers • Risk factor for peptic ulcer and gastric carcinoma – Now officially considered a carcinogen. • Urease positive (cleaves urea to ammonia) – along with Proteus

Bacteria in the mouth use all for nutrients except???? Bicarb or Urea

• Tx with Triple Tx ♦ Bismuth Pepto-bismal (think Stomach) ♦ Metronidazole ♦ Tetracyclin or Amoxicillin

G- anaerobic rods: Bacteroides Fusobacterium Prevotella

Facultative anaerobic, G- rods Highly invasive & can readily become resistant to Abx Enterobacteria

• All have endotoxin • All are found in GI tract (except Y. pestis) • All are motile (except Klebsiella & Shigella) – Kevin Schaffer never liked to go proselyting. • All ferment glucose and are oxidase negative • Think COFFEe

♦ Capsular Related to the virulence ♦ O-antigen, and Oxidase Negative All have Somatic O-antigen (Polysaccharide of Endotoxin) ♦ Flagellar antigen The Flagellar H antigen is found in motile species ♦ Ferment glucose ♦ Enterobacteriaceae

• Escherichia ♦ Short, G-, facultative anaerobic rods ♦ Motile via a peritrichous flagella ♦ Normally present in intestines ♦ Contaminates water supply

DON’T Giardia is NOT in our water supply ♦ Capable of causing mild to severe forms of enterocolitis ♦ The most common cause of UTIs (cystitis) ♦ The most common causative organism in G- sepsis ♦ Etiologic agent of traveler’s diarrhea ♦ Use ELISA assay to detect an enterotoxin produced by E. coli

ELISA can also detect: An enterotoxin produced by Vibrio cholerae (a curved, G- bacillus)

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An enterotoxin produced by S. aureus, which toxin causes acute-onset food poisoning Viral gastroenteritis

• Shigella vs. Salmonella (not usually found in human GI???) ♦ Both cause bloody diarrhea ♦ Both non-lactose fermenters ♦ Both invade intestinal mucosa ♦ salMonella is Motile and can invade heMatogenously

Symptoms of Salmonella can be prolonged if tx with ABX Salmon (animal reservoir)

♦ Oh, Shiii, Shigella is more virulent Shigella is transmitted via food, fingers, feces, and flies

• Klebsiella ♦ Causes severe lobar pneumonia in people w/ underlying conditions like alcoholism, diabetes, COPD

• Yersinia • Enterobacter

Vibrionaceae – Vibrio cholerae Pasteurellas – Haemophilus, Gardnerella, Pasteurella

Gram - and PCN ALL gram - are resistant to PEN-G, but may be susceptible to PCN derivatives, like ampiciliin The gram – outer membrane layer inhibits entry of PEN-G and Vancomycin

SPIROCHETES – Treponema & Borrelia Treponema pallidum

• Found elsewhere in the file – syphilis • Darkfield exam • Dx

♦ FTA-ABS Specific for Treponema, and turns positive earliest in disease Find The Antibody- ABSolutely

♦ VDRL Many false positives Viruses, Drugs, Rheumatic fever, Lupus/Leprosy

Borrelia Burgdorferi – Lyme Disease: • B for Big • Only Borrelia can ve seen using aniline dyes (Wright or Giemsa stain) in light microscopy • Named after Lyme, Connecticut • Most commmon vector-borne disease in the northern hemisphere (from arthropods) • Signs/symptoms: skin rashes, arthritis, & neurological symptoms

♦ Hallmark: erythema chronicum migrans – red macule w/ central clearing – “bullseye” at site of bite • Organism found in tick vectors that have fed on infected deer or mice reservoirs • After hiking through the woods, pts presents with polyarthritis, paresthesias, and a skin rash

RICKETTSIAE & CHLAMYDIAE – Rickettsia, Coxiella, Chlamydia Both rickettsia & chlamydia:

• Can cause human disease • Posess both DNA & RNA – Bacteria have Both. • Growth can be inhibited by antimicrobial drugs • Are inactivated by heat, drying, and chemical agents • NOT “multiply in bacterial cells”

CHLAMYDIA: • C. trachomatis

♦ Lots of info found elsewhere in file • C. psittaci

♦ Transmitted by inhalation of organisms from infected birds & their droppings ♦ Birds + pneumonia = think C. psittaci

RICKETTSIA: • Small G- aerobic coccobacillary bacteria that are obligate intracellular parasites

♦ Rickettsia and viruses have in Common they are both intracellular parasites ♦ The only bacteria that are IPs are Rickettsia and Chlamydia (they stay inside when it’s Really Cold) ♦ This means they only survive by establishing residence inside animal cells and utilizing the host’s ATP ♦ Both Rickettsia and Chlamydia have this ATP/ADP translocator to assist them in “stealing” ATP

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Rickettsia still can oxidize certain molecules and create ATP, whereas Chlamydia does not have a cytochrome system and can not produce ATP

Rickettsia needs CoA and NAD • Results from insect bites – arthropod transmission

♦ Requires an insect vector in the transmission to humans – think Rickettsia = Insectsia • Triad:

♦ Headache, Fever, Vasculitis • Most rickettsial diseases produce severe illness in humans because rickettsiae are destructive for endothelial cells

♦ NOT because they produce potent exotoxins, cause extensive CNS damage, or are destructive to epithelial cells • For Dx and culturing

♦ You can inoculate into living tissues (chicken embryo yolk sac or cell culture) • Target cell: endothelial cell of capillaries and other small blood vessels

♦ Produce severe illness in humans because they attack the endothelial cells • Present as systemic symptoms of headache, myalgias, and fever, followed by rash

♦ Maculopapular rash appears on palms of hands & soles of feet ♦ Rash spreads to the trunk

• Can be dx with certain strains of Proteus vulgaris because they both have certain antigens in common • Rickettsia and Viruses have the following in common:

♦ Growth environment – both require living cells for growth ♦ Small Size ♦ Being obligate intracellular parasites

• NOT in common with virus (in other words…what they have in common with fellow bacteria): ♦ Have BOTH DNA and RNA (viruses only have one or the other) ♦ Synthesize their own proteins (viruses do not) ♦ Are sensitive to ABX (obviously viruses are not) ♦ Reproduce by a complex cycle w/ Binary Fission (Bacteria = Binary Fission; Viruses = synthesis & assembly) ♦ Possess an energy yielding, autonomous enzyme metabolism (Rickettsia only)

• Divided into two groups: ♦ Spotted-Fever Group – Rash is inward (from palms inward)

Rocky mountain spotted fever tick R. rickettsii (which accounts for 95% of rickettsial diseases in U.S.) Endemic in East Coast, that is why it’s a fever only in the Rockies

Queensland tick fever tick Boutonneuse fever, Kenya tick fever tick Siberian tick fever tick Rickettsial pox mite

Is the rickettsia disease that may have oral manifestations (NOT Brill’s disease, or epidemic typhus) Rash that spreads to lips and Buccal mucosa.

♦ Typhus Group – Rash is outward spread Louse-borne typhus (epidemic typhus) louse

R. prowazekii Murine typhus (endemic typhus) flea

R. typhi Scrub typhus mite

R. tsutsu-gamushi Q fever (Queer – has no rash) inhalation

Coxiella burnetii Does NOT cause a skin rash Does NOT require an arthropod vector

• **The Only rickettsia that is xmitted via aerosol (dust) • Tx: tetracycline & chloramphenicol

Mycoplasmas – Mycoplasma, Ureaplasma Lack a cell wall – resistant to beta-lactam ABX

• Has ergosterol in cell membrane Require sterols for growth M. pneumoniae

• Transmitted by respiratory droplets • Frequent in military recruits and prisons • Cause atypical pneumonia “walking pneumonia”= #1 cause of pneumonia in young adults

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• Cold agglutinins used in presumptive dx (IgM) • PCN resistant so tx with Ery or Tetra

G+ cocci – Staphylococcus, Streptococcus, Enterococcus, Peptostreptococcus Endospore forming rods & cocci – Bacillus, Clostridium Regular non-spore forming G+ rods – Lactobacillus Irregular non-spore forming G+ rods – Corynebacterium, Actinomyces Actinomycetes – Streptomyces, Nocardia, Rhodococcus

STAPHYLOCOCCUS G+ coccus that grows in grape-like, usually occur in irregular clusters in culture (NOT in pairs, chains, etc)

Kaplan says they CAN occur in pairs & short chains Facultative

Posess both superoxide dismutase & catalase Bacteria most commonly found on the skin

Most common manifestation of staph infections in humans is cutaneous abscesses One answer option, Scalded skin syndrome, is staph-related, but not the most common manifestation of staph

Resistance to PCN Most frequently develops resistance to PCN Gains resistance to PCN by an having an NZ that attacks PCN

Staph infections are suppurative infections usually caused by S. aureus Abscess formation is characteristic EXs: abscesses, endocarditis, impetigo, osteomyelitis, pneumonia, septicemia, cavernous sinus thrombosis

S. aureus Not part of normal flora Can cause acute-onset food poisoning via enterotoxins Most common cause of suppurative infections involving the skin, joints, & bones

• Osteomyelitis is most commonly caused by S. aureus Causes Acute Bacterial Endocarditis Most commonly causes skin infections (pyoderma) Most often associated with fatalities following influenzal infection Coagulase(+) [other Staphylococci are coagulase(-)]

• Coagulase test is the prime criterion for classifying a bug as Staph aureus – from other Staph species • Coagulase is important to the pathogenicity of S. aureus because it helps to establish the typical abscess lesion –

see 2000 Q56 to discuss w/ Jake • Coagulase also coats the surface w/ fibrin upon contact w/ blood, making it harder to phagocytize

♦ NOTE: this is NOT a polysaccharide capsule that forms Resistant to PCN Tx: methicillin, nafcillin, oxacillin [or for MRSA – vancomycin] Protein A – Know this.

• Binds the Fc receptor of IgG, thereby blocking complement activation by the classical pathway and inhibiting phagocytosis

• (cell wall component) may be responsible for virulence • Antiphagocytic • Elicits Hypersensitivity • Causes Platelet injury

Staphylokinase cleaves plasminogen to plasmin (Streptokinase & Urokinase do, too) – Kind of anti-coagulase Staphylococcal food poisoning:

Food contaminated w/ toxins of certain types of Staph; generally results in diarrhea & vomiting Gastroenteritis is principal feature Incubation period of 2-4 hours (quick) (NOT the case for cholera, botulism, salmonellosis)

STREPTOCOCCUS General Info

Facultative anaerobic G+ cocci that grow in pairs or chains in culture • Does have some aerobics, so:

♦ If you pull human saliva out and let it grow on agar in air for 24 hours, strep will have the most out of the other Facultative Anaerobics (Lactobacillus, Staph, Fusobacterium, and Actinomycetes)

When growing glucose in an unbuffered medium, will cause pH to drop Most numerous group in the oral cavity Most predominant bug in dental plaque Streptococcal pharyngitis infections are preferentially treated w/ Abx affecting cell wall synthesis Lack catalase – although they can live in conditions where O2 is present

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1) α-hemolytic Streptococcus – Know this. Produce a zone of incomplete hemolysis around the colony & adjacent green discoloration Most common organism producting subacute bacterial endocardititis (S. sanguis, under Viridans Streptococci,

below) Most often associated w/ infective endocarditis Most oral Streptococci are alpha-hemolytic streptococcus S. pneumoniae (aka Pneumococcus ) (Optochin sensitive)

♦ Think breathing in through the nose, because its AFRAID of the CHIN) • Most common cause of community acquired bacterial pneumonia in the U.S. • Very well known for its large polysaccharide capsule (so is Cryptococcus neoformans – a yeast.)

♦ Strains of Strep pneumonia are distinquished by their polysaccharide capsules • Host response are chiefly mediated by opsonins • Antigens

♦ Capsular Virulence of pneumococcus is associated with its capsular polysaccharide

♦ C-polysaccharide ♦ F-antigen ♦ M-protein

NOT erythrogenic toxin (that’s strep pyogenes – Scarlet fever/Rheumatic Fever) • Treatment/Prevention:

♦ Vancomycin or erythromycin ♦ PCN resistance on the rise – due to transformation ♦ Vaccine: 23-valent vaccine available

Viridans Streptococcus (optochin resistant) • NOT afraid of the CHIN • Normal flora of the oropharynx and cause dental caries and bacterial endocarditis • S. sanguis – the major cause of subacute endocarditis in those w/ abnormal heart valves

♦ Lots of Blood in heart • S. mutans – causes dental caries • Treat w/ PCN

2) β-hemolytic Streptococcus Produce a clear zone of hemolysis around the colony = complete hemolysis How do you classify Strep? By Hemolysis, BUT if it says How do you classify Beta hemolytic Strep? Lancefield

• Group A, B, C, etc., based on CHO found in the cell wall (C Carbohydrate) (Lancefield groups) 1) Group A β-hemolytic Streptococcus

• Most likely Pathogenic for humans (among Strep bacteria, or what?) ♦ M-protein: -- JUST like S. PneuMoniae

Is closely associated w/ the virulence of the bacteria Specific antigenic subtypes based on the cell wall M-protein Affects the host by inhibiting phagocytosis Antibody to M-protein enhances host defenses against S. pyogenes

• Consists only of S. pyogenes • Streptococcus pyogenes

♦ G+ coccus that occurs in pairs or chains ♦ Frequently part of the endogenous microflora that colonizes the skin & oropharynx

But NOT usually found in plaque ♦ Cause of several acute pyogenic infections in man (Scarlet fever, erysipelas, sore throat [strep throat])

Pyogenic pathogens are associated with acute suppurative inflammation type ♦ Toxins:

Erythrogenic exotoxin (aka pyrogenic exotoxin) – Causes the rash of Scarlet fever A Strep virulence factor that acts like a superantigen, mediating a variety of cytokine-induced

effects that can result in life threatening disease Streptokinase –

Cleaves plasminogen to plasmin Hence has the ability to dissolve a preformed blood clot (same with Stapylokinase and Urokinase)

Streptolysin O – A hemolysin that is inactivated by oxidation (oxygen-labile); antigenic

Streptolysin S –

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a hemolysin that is not inactivated by oxygen (oxygen-stable); not antigenic Hyaluronidase

The spreading factor produced by certain streptococci • NOT involved in Arthus reaction, Shwartzman phenomenon, or localization of staph infections

Streptokinase, Streptodornase, deoxyribonuclease ♦ Diseases of S. pyogenes:

Toxigenic Scarlet Fever Toxic Shock Syndrome

Suppurative Strep throat Erysipelas – acute contagious disease marked by a circumscribed red eruption on the skin + chills/fever Impetigo – localized, intraepidermal skin infection seen in preschool-aged children Cellulitis –

• Results from traumatic inoculation • Diffuse inflammation of soft tissue – painful swelling from purulent exudates that spread along the

facial planes and separate the muscle bundles • Not circumscribed • Not confined to one area

Non-Suppurative (Immunologic) Rheumatic fever (search ‘rheumatic fever’ – more info elsewhere in the file)

• PECCS ♦ Polyarthritis, Eythema marginatum, Chorea, Carditis, Subcutaneous nodules

• Begins w/ sore throat, then progresses to rapid temperature rise, prostration, joint inflammation • The heart is often affected • Can be a sequela of Scarlet Fever • Can result in pathologic changes in the heart valves

Acute poststreptococcal glomerulonephritis • Symptoms: fluid retention, dark tea-colored urine, BP elevation • Occurs primarily in children • Allergic reaction of glomerular and vascular tissue to beta-hemolytic streptococcal products

The two most important post-streptococcal diseases are: 1) Rheumatic fever 2) Glomerulonephritis

Different Q: Which of the following are related to streptococcal cross-antigenicty… Rheumatic fever & acute glomerulonephritis Remember they are from Hemolytic sequelae

2) Group B β-hemolytic Streptococcus • Consists of S. agalactiae • Leading cause of neonatal pneumonia, meningitis, & sepsis

***Although not Streptococci, BOTH Staph aureus and Listeria are ALSO Beta hemolytic 3) γ-hemolytic Streptococcus

Produce no hemolysis Enterococci

• Pen G resistant ♦ Major concern with enterococci in the hospital

• Cause UTI and Subacute endocarditis • Part of normal fecal flora

Lactic Acid bacteria General

Use lactic acid fermentation pathway (pyruvate → lactic acid) Aciduric – can tolerate acid environment Acidogenic – acid-forming

• NOTE: lactic acid is the main cause of enamel decalcification Lactobacillus

Labeled as cariogenic because of ability to produce acid Significant secondary invader of dental caries

• In coronal caries, causes progression of existing caries • Found in deep dental caries and increases in the saliva during periods of caries activity

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Regular, non-sporing, G+ bacteria Most likely to tolerate the lowest pH (lower than even Streptococci) Found in vagina, GI tract, mouth L. acidophilus – added to milk products to aid in digestion of milk products

• Bacterial enzymes convert milk sugars to digestible products Streptococcus

Streptococci are the predominant bacteria found in saliva S. mutans – Know this.

• Smooth surface caries • First stable organism to colonize oral cavity and remains in significant numbers??? LOOK-UP – 2002 Q05 • In the presence of sucrose, produces deposits of a gummy polysaccharide called glucan • Produces Glycosyltransferase from Sucrose

♦ End product of glucose metabolism is lactate Lactic acid forms in large quantities during the degradation of glucose

• Capsule has importance virulence factor that enhances oral accumulation • Can be distinguished from other Streptococci by:

♦ Production of adherent Extracellular polysaccharide ♦ Fermentation of mannitol or sorbitol

(The previous two are the two most important factors for initiation of caries) ♦ Production of intracellular polysaccharide ♦ Colonial morphology on mitis-salivarius agar

NOT gram stain (they’re all G+) Actinomyces – root surface caries

MYCOBACTERIA M. tuberculosis – Often resistant to multiple drugs M. kansasii – Pulmonary like TB symptoms M. scrofulaceum – Cervical lymphadenitis in kids M. avium-intracellulare – Causes disseminated disease in AIDS M. leprae – leprosy (M. leprae = Hansen’s bacillus) Form mycolic acids, which are unusual acids associated w/ the cell wall

Mycolic acids: • Localized in the inner leaflet of the mycobacterial cell wall • Involved in maintaining rigid cell shape • Contribute to resistance to chemical injury • Protect against hydrophobic Abx (isoniazid – inhibits mycolic acid biosynthesis) • NOTE: also present in cell walls of actinomycetes

G+, nonmotile, rod-shaped bacteria Produces neither exotoxins nor endotoxins Acid-fast staining

Important in the early diagnosis of active mycobacterial infections Smear is stained w/ carbol-fuschin stain, decolorized w/ acid alcohol, counterstained w/ methylene blue Acid-fast organisms appear red against blue background (due to lipids/waxes [including mycolic acids] in the cell wall)

• Has highest lipid count in cell wall • Remember Gram + is normally BLUE, but here it is RED

Classic skin test (PPD skin test) May indicate an infection, but not whether the infection is active A PPD (purified protein derivative) from M. tuberculosis is injected subcutaneously Observation of a delayed (Type IV) hypersensitivity reaction indicates a hypersensitivity to tuberculoproteins

M. tuberculosis – TB – Obligate aerobe Cord Factor Glycolipid found in the cell wall of M. Tb and allows them to grow in serpentine cords Slow-growing – 20-60 days before growth can be visualized NO exotoxins or endotoxins Tubercle (Ghon focus) –

• A small, rounded nodule produced by infection w/ M. tuberculosis • Primary lung lesion in the periphery • Usually in lower lobes • Primary lung lesion of pulmonary TB

Primary TB

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• Nonimmune host (usually child) • Ghon Focus Ghon complex (from there it can go to below options)

♦ Heal by fibrosis Immunity and Hypersensitivy Tuberculin positive ♦ Progressive lung disease (HIV) Death (rare) ♦ Severe bacteremia Miliary TB Death ♦ Preallergic lymphatic or hematogenous dissemination Dormant tubercle bacilli in several organs

Reactivation in adulthood Extrapulmonary TB (See below) Secondary TB

• Partially immune hypersensitized host (usually adult) • From either Reinfection or Reactivation tuberculosis in the lungs • Causes fibrocasseous cavitary lesion in upper lobes • Goes to Extrapulmonary TB

♦ CNS (parenchymal TB or meningitis ♦ Vertebral body ♦ Lymphadenitis ♦ Renal ♦ GI

Hypersensitivity (IV) to M. tuberculosis is manifested by necrosis Tuberculosis is produced by an agent that does NOT produce exotoxin NOR endotoxin. Know this M. tuberculosis has the highest lipid content in the cell wall (compared to E. coli, L. casei, S. aureus) Granulomas w/ multinucleate giant cells and caseation necrosis characterize lymph node involvement w/ M.

tuberculosis in the lateral neck M. leprae – leprosy (M. leprae = Hansen’s bacillus)

Also induces delayed-type hypersensitivity in patients Cannot grow in vitro on ay culture medium (same for syphilis) Likes cool temperatures Reservoir in US – Armadillos LEthal

Spore-forming bacteria Spores are specialized resistant cells produced by many microorganisms to enhance the survival potential of the organism Spores are primitive, usually unicellular cells by which bacteria, fungi, green plants reproduce Spores grow into new organisms via asexual reproduction (w/o uniting w/ another reproductive cell) Active spores are thin-walled; dormant spores are thick-walled Spores contain large amounts of Calcium Dipicolinate = calcium + dipicolinic acid

Calcium dipicolinate is thought to be responsible for the heat resistance of the spore Spores are a problem in sterilizing instruments & equipment because they are resistant to physical & chemical agents EX: bacterial endospore – heat-resistant spore

More difficult to destroy than HIV, HBV, TB virus Requires autoclaving at 121°C for 20 min at 15 psi Most important endospore producers: Bacillus & Clostridium genera (perfingens and tetany)

♦ Difference between Clostridium and Bacillus is that Bacillus is aerobic (Nice Pets Must BBBBreath) Clostridium

C. Botulism • Botulism is caused by C. botulinum • From Bad Bottles of food or honey from Bees • Floppy Baby

C. Perfringens • Gas gangrene is caused by C. perfringens • Gas gangrene is produced by a G+, spore-forming anaerobic bacillus • Perforates a gangrenous leg

C. Difficile • Produces a cytotoxin, an exotoxin that kills enterocytes, causing pseudomembranous colitis • Often secondary to ABX use, especially clindamycin or ampicillin • Causes Diarrhea • Tx with Metronidazole

C. tetani • Tetanus is caused by C. tetani • Exotoxin blocks glycine release, which normally is a neurotransmitter inhibitor, so paralysis ensues • Lockjaw

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Bacillus Think B for Breathing!! Anthrax is caused by B. anthracis The antiphagocytic capsule is composed of D-glutamate, NOT polysaccharide Contact via malignant pustule (painless ulcer), but can progress to death

• Black skin lesions vesicular papules covered by black eschar Inhalation can cause life-threatening pneumonia

Septicemia = sepsis Happens when there are too many bacteria in the bloodstream (or their toxins) to be removed easily Symptoms include: fever, weakness, nausea, vomiting, diarrhea, chills Can lead to septic shock Associated w/: S. aureus, E. coli, Klebsiella

The most common causative organism in G- sepsis is E. coli Bacteremia

Refers to the presence of viable bacteria in circulating blood Clinical signs/symptoms usually not present EX: From dental prophy, bugs around teeth enter the blood stream→bacteremia

Viremia A viral infection of the bloodstream Major feature of disseminated infections The infecting virus is most susceptible to circulating antibodies

Some enzymes: Streptodornase (DNAase) – depolymerizes DNA in exudates or necrotic tissue Hyaluronidase – degrades HA, which is the ground substance of subcutaneous tissue

Produced by Streptococcus, Staphylococcus, Clostridium (Think Perfringens) The purposes of Hyaluronidase are

• Avoid the immune system • Cause disease in host • Disseminate

♦ NOT for Nutrition The spreading factor produced by some Strep

Some Extracellular Enzymes Involved in Microbial Virulence

Enzyme Action Example of Bacteria producing enzymes Hyaluronidase Breaks down hyaluronic acid Strep, Staph, and Clostridium Coagulase Converts fibrinogen to fibrin

*coagulase is actually an adhesin, not an enzyme. It results in a clot formation so the bug can establish residence

Staph. Aureus

Lecithinase Destroys RBC and other tissue cells Clostridium Collagenase Breaks down collagen (CT fiber) Clostridium, Bacteroides, Actinobacillus,

AA, and Bacillus (Think PD bugs) Phospholipase Lyses RBC Staph. Aureus Fibrinolysin, staphlokinase, streptokinase Dissolve blood clots (Plasminogen

Plasmin) Staph and Strep

Body site Normal Microbiota Oral cavity (saliva, tongue, plaque) Streptococcuus, Veillonella, Bacteriodes, Fusobacterium,

Peptostreptococcus, and Actinomyces Gastrointestinal tract Lactobacillus, Streptococcus, Clostridium, Veillonella,

Bacteroides, Fusobacterium, Escherichia, Proteus vulgaris (natural to intestinal flora), Klebsiella, and Enterobacter

Upper respiratory tract (nasal cavity and nasopharynx Streptococcus, Staphylococcus, Moraxella, Neisseria, Haemophilus, Bacteroides, and Fusobacterium

Lower respiratory tract None Upper urinary tract (kidney and bladder) None Genitourinary tract (urethra and vaginal tracks) Streptococcus, Lactobacillus, Bacteroides, and Clostridium Predominant subgingival bacteria associated w/ gingival health:

Streptococcus mitis & S. sanguis Actinomyces viscosus & A. naeslundii

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Rothia dentocariosus Staphylococcus epidermidis Small spirochetes

Periodontal disease: IgG is found in the highest concentration in serum samples from pts w/ PD disease Prevotella melaninogenica and Prevotella intermedia (NEW NAMES)

[Bacteroides melaninogenicus = OLD NAME] Anaerobic bug from gingival scrapings Forms a black pigmented colonies on hemin-containinng culture media Found in higher concentrations in the gingival crevice than on the tongue or in plaque

Collagen degradation is observed in chronic periodontal disease, which occurs by collagenase NZs from….Porphyromonas species

Juvenile periodontitis: 1) Generalized

P. intermedia & E. corrodens predominate 12-25 y.o. Prevotella Intermedia (Intermediate, think Juvenile)

• First detectable in the oral cavity in adolescence is a collagenase producing bug associated with PD disease Rapid, severe perio destruction around most teeth Associated w/ DM type 1, Down syndrome, neutropenias, Papillon-Lefevre syndrome, leukemias

2) Localized A. actinomycetemcomitans & Capnocytophaga ochraceus predominate 12-19 y.o. Severe perio destruction around Mx/Mn 1st molars or Mx/Mn Anteriors Relative absence of local factors (plaque) to explain it A.actinomycetemcomitans & C. ochraceus are also associated w/ periodontitis in juvenile diabetes

Adult periodontitis: Porphyromonas gingivalis

High levels of antibodies are seen in adult periodontitis against P. gingivalis (these antibodies are IgG) Known for its collagenase NZs in breaking down collagen in chronic PD G-, so causes inflammation by endotoxin (lipopolysaccharide)

Prevotella intermedia Bacteroides forsythus Campylobacter rectus Fusobacterium nucleatum Spirochetes **When T cells from people with chronic periodontitis react with certain plaque bacterial antigens they produce:

MIF & Lymphotoxin • Lymphotoxin is synonymous with TNF-beta • MIF = (macrophage) migration inhibitory factor

Here’s the story: • T cells produce lymphokines as a result of interaction w/ bacterial antigens • In PD disease, these lymphokines include IL-1, TNF, MAF, MIF & CTX

Refractory periodontitis: (SAME AS ADULT) – Know this. Porphyromonas gingivalis Bacteroides forsythus Campylobacter rectus Prevotella intermedia

Rapidly progressive periodontitis: Features:

Most commonly seen in young adults (20-35 y.o.) Marked inflammation, rapid bone loss, periods of spontaneous remission Most of these pts have depressed neutrophil chemotaxis

Predominant bugs: Porphyromonas gingivalis Eubacterium Prevotella intermedia Fusobacterium nucleatum Campylobacter rectus Eikenella corrodens

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ANUG = acute necrotizing ulcerative gingivitis Principal bacteria: 1) Prevotella intermedia & 2) Spirochetes An anaerobic infection of gingival margins causing ulcerations & ultimately destruction of gingiva & underlying bone

IP areas affected first Spirochetes invade the epithelium & CT

SOME BACTERIAL STDs CHLAMYDIA:

Any of several common, often asymptomatic, STDs Most common cause of STD in the U.S. Caused by C. trachomatis:

An obligate intracellular parasite (NOT a virus) • Along with Rickettsia – Only bacteria to be

Cannot survive on the host extracellularly Also causes ocular trachoma & inclusion conjunctivitis (described elsewhere in file)

Serotypes A,B,C

• Africa, Blindness, Chronic infection D-K

• Everything else L1, L2, L3

• Lymphogranuloma venerum 2 Forms

Elementary Body (small, dense) – Kids get tons of infections in Elementary school • Infectious agent of chlamydia • Enters cell via Endocytosis

Initial or Reticulate Body • Replicates in cell by fission

Young women w/ chlamydia may also acquire salpingitis (inflammation of the fallopian tubes) Most common chlamydial disease in the U.S. is nongonococcal urethritis There is a large number of asymptomatic carriers. Frequent co-infection w/ gonorrhea Most infections of Chlamydia are located on the eyes, genitals, and inside human cells Tx newborns with Ery eye drops as soon as their born Cell wall lacks muramic acid (NAM) – beta-lactam resistant What is not caused by Chlamydia trachomatis? Look up.

Inclusion conjunctivitis Ocular trachoma LGV Lymphadenopathy ?? Pruritus ??

Chlamydia trachomatis. Which is false? Most women are Sx-atic, More men are Sx-atic than women, causes keratoconjunctivitis

GONORRHEA: (“the clap”) – BIODOME with Rock Climbers get arthritis STD caused by bacterium Neisseria gonorrhea

Species of Neisseria are differentiated by sugar fermentation • MeninGococci ferment Maltose and Glucose • Gonococci ferment Glucose

Most common cause of septic arthritis in adults is caused by Neisseria gonnorrhea Neisseria gonorrhea has affinity for mucous membrane (NOT skin)

• Portal entry of the nasopharynx (in one question, could be other membrane-like questions) One of the most common infectious bacterial diseases 2nd only to chlamydial infections in # of cases ~50% of women w/ gonorrhea have no symptoms Symptoms appear 2–10 days after infection Treated w/ a single injection of ceftriaxone or spectinomycin

REMEMBER POEM (hemophilus) was also tx with CEPH No longer susceptible to PCN:

• Plasmid-mediated beta-lactamase • Chromosomally mediated decrease in affinity of PCN-binding proteins

What makes gonorrhea pathogenic? PCN resistance via Beta-lactamase??

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Often occurs together w/ chlamydia and syphilis Ophthalmia neonatorum

A very serious complication of an infant delivered of mother with gonorrhea Pt who has minimal resistance to a gonococcal infection most probably has:

Deficiency in cell-mediated immunity Women

1st symptoms: • Bleeding associated w/ vaginal intercourse • Painful or burning urination • Yellow or bloody vaginal discharge

More advanced symptoms (may indicate PID): • Cramps and pain • Bleeding between menstrual periods • Vomiting or fever

Men Have symptoms more often than women Pus from the penis Painful, burning urination (may be severe)

SYPHILIS: STD caused by infection w/ Treponema pallidum (a spirochete)

Produces neither endotoxins nor exotoxins (unlike cholera, gonorrhea, brucellosis, and gas gangrene) ♦ SAME WITH M. TB

Congenital infections in neonates & infants can occur Late manifestations include Hutchinson’s triad – abnormal teeth, interstitial keratitis, 8th nerve deafness

Cannot be grown on artificial media (neither can M. leprae) -- armadillos Also disrupts the vasa vasorum of aorta with consequent dilation of aorta and valve ring, often affects the aortic root and

ascending aorta, Associated with tree bark appearance of the aorta, Responsible also for some Aortic anuerysms 3 stages of Syphillis:

PRIMARY: • Non-painful chancre – reddish lesion w/ raised border (appears in 3-6 wks at the site of local contact) • Lips are most common site for chancres to appear in 1° oral syphilis

SECONDARY: • Characterized by:

♦ Cutaneous lesions ♦ Positive VDRL test ♦ Mucous membrane lesions ♦ Presence of Spirochetes in the lesions

NOT Development of a gumma (tertiary) • Highly infectious stage – 6 wks after non-treatment of 1° syphilis • Maculopapular rash

♦ Rash appears on palms of hands & soles of feet – just like in Rocky Mountain spotted fever • Condyloma latum/lata

♦ Flat-topped papules (mucous patches) appearing on moist skin/mucosal surfaces LATENT:

• Develops in 30-40% of infected individuals • Mucocutaneous relapses are most common

TERTIARY: • Occurs in 30% of infected persons many years after non-treatment of 2° syphilis • The gumma (focal nodular mass) typifies this stage. Most commonly occurs on the palate and tongue • Neurologic symptoms are also evident at this stage • Gumma:

♦ Infectious granuloma characteristic of tertiary syphilis ♦ Characterized by a firm, irregular central portion, sometimes partially hyalinized, & consisting of coagulative

necrosis in which “ghosts” of structures may be recognized; a poorly defined middle zone of epithelioid cells, w/ occasional multinucleated giant cells; and a peripheral zone of fibroblasts and numerous capillaries, w/ infiltrated lymphocytes and plasma cells

• Causes irreversible heart failure, dementia, and disability (CNS & cardiac involvement) Good prognosis for early Dx/Tx Parenteral Penicillin G is the drug of choice for treating all stages

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Dx: Darkfield microscope – useful in examining blood for T. pallidum USMLE RANDOM ADD-ONS

Pigment-producing Bacteria Staph aureus Yellow (Gold – Au) Pseudomonas Aeruginosa Blue-green Serratia marcescens Red (Maraschino cherries are red)

IgA Protease Bacteria IgA normally prevents attachment

• Streptococcus pneumoniae • Neisseria meningitidis • Neisseria gonorrhoeae • Haemophilus influenzae

Culture Requirements H. influenzae Chocolate agar with Factors V (NAD) and X (hematin) N. gonorrhoeae Thayer-Martin (VCN) media B. pertussis Bordet-Gengou (potato) agar C. diphtheriae Tellurite agar M. tuberculosis Lowenstein-Jensen agar Lactose fermenting MacConkey’s agar (PINK) Legionella pneumophila Charcoal yeast extract agar buffered with increased iron and cysteine Fungi Sabouraud’s agar

Stains Congo Red Amyloid; apple-green birefringence in polarized light Giemsa’s Borrelia, trypanosomes, Chlamydia PAS (Periodic Acid Schiff) Stains glycogen, mucopolysaccharides, Dx Whipple’s disease Ziehl-Neelson Acid-fast bacteria (military TB) – or Kinyoun’s acid-fast stain – Think German Military India ink Cryptococcus neoformans

Obligate Aerobes Use O2 dependent system to generate ATP

• Nice Pets Must Breathe ♦ Nocardia ♦ Psuedomonas aeruginosa Seen in burn wounds, nosocomial pneumonia, and Cystic Fibrosis pneumonia ♦ Mycobacterium tuberculosis ♦ Bacillus – The spore forming bug that DOES breath

BOTH Nocardia an Psuedomanas Aeruginosa are both surrounded by mycolic acid ♦ Brucella ♦ Bordetella

Obligate Anaerobes Lack catalase and/or superoxide dismutase, and are thus susceptible to oxidative damage Generally the foul smelling, difficult to culture, and produce gas in tissue (CO2 and H2) Normal flora in GI tract, pathogenic elsewhere

• They DON’T know the ABCs of Breathing ♦ Actinomyces -- Sulcus Dwellers ♦ Bacteroides ♦ Clostridium – Spore forming that doesn’t breath

Food Posioning Bugs Staph aureus (Meats, mayonnaise, and custard) THE FASTEST!! Vibrio parahaemolyticus and Vibrio vulnificus (Seafood) Bacillus cereus (Reheated Rice) Clostridium perfringens (Reheated Meat dishes) Clostridium botulism (Canned foods) E. coli (Undercooked meat) Salmonella (Poultry, meat, eggs)

Diarrhea Bugs E. coli Ferments lactose No Fever Watery/Bloody Vibrio cholerae Comma-shaped organism No Fever Watery Salmonella No lactose fermentation, mobile Fever Bloody Shigella No lactose ferm, nonmobile, Fever Bloody Campylobacter jejuni Comma or S shaped organism Fever Bloody Vibrio parahaemolyticus Transmitted by Seafood Fever

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Yersinia enterocolitica From Pet feces (puppies) Fever Bloody Cholera vs. Pertussis

Vibrio cholera • Toxin permanently activates Gs, causing rice water diarrhea • Turns the “on” on

Pertussis • Toxin permanently inactivates Gi, causing whooping cough • Turns the “off” off

Lactose-fermenting enteric bacteria Think pink colonies growing on MacConkey’s agar Think MacKonKEEs

• Klebsiella • E. coli • Enterobacter

Zoonotic Bacteria Think Bugs From Your Pets

• Borrelia burgdorferi Lyme Disease Tick bites (living on deer and mice) • Brucella Brucellosis Fever Dairy products, contact with animals • Francisella tularensis Tularemia Tick bites; rabbits, deer • Yersinia pestis Plaques Flea bite; rodents; especially prairie dogs • Pasteurella multocida Cellulitis Cat, Dog bites

Normal Flora Skin S. epidermidis Nose S. aureus Oropharynx viridans Streptococcoi (S. mutans) Dental Plaque S. mutans Colon B. fragilis, and S. young Vagina Lactobacillus, colonized by E. coli, group B strep, J. Cragun

VIRUSES Virion: the complete infectious viral particle

A viral nucleic acid (genome) is composed of DNA or RNA (NOT both) encased in a protein coat called a capsid Capsid or Protein coat

• Composed of polypeptide units called capsomers • Makes protective vaccines a possibility • The capsid surrounds viral DNA – NOT a nucleocapsid

Cellular tropism of viruses is dependent upon cell surface receptors NOTe: the nucleocapsid = the protein shell + the nucleic acid

Naked or enveloped (an envelope is a lipid bilayer surrounding the capsid) Only naked DNA viruses are Papovaviruses, Adenoviruses, and Parvoviruses (cause gotta be naked for PAP smear).

Almost all are haploid – contain a single copy of their geneome (exception: retrovirus family – diploid) Replicate only in living cells – obligate intracellular parasites

The only bacteria are Rickettsia and Chlamydia (they stay inside when it’s Really Cold) Not sensitive to antibiotics – but are sensitive to interferon, which inhibits their replication Depend on host cells for energy production Cannot be observed w/ a light microscope – they are smaller than cells (duh!) Pass through filters that retain bacteria Peplomers:

Protein spikes (glycoproteinaceous projections) found in the envelope of some viruses The spikes contain hemagglutinin, neuraminidase, OR a fusion protein that causes cell fusion & sometimes hemolysis EXs: orthomyxoviruses & paramyxoviruses

Viriods: Consist solely of a single molecule of circular RNA w/out a protein coat or envelope Cause several plant diseases but are not implicated in any human disease

Prions: Infectious protein particles composed solely of protein (No RNA or DNA)

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Cause certain “slow” diseases such as Creutzfeldt-Jakob disease in humans & scrapie in sheep Mad Cow Disease

Associated with spongiform encephalopathy Harder than spores to get rid of

Host cell: cell w/in which a virus replicates Once inside the host cell, the viral genome achieves control of the cell’s metabolic activities The virus then uses the metabolic capacity of the host cell to reproduce new viruses

Host cell provides the metabolic NZs, and the virus provides the genetic information Often the replication of these new viruses causes death of the host cell Viruses must first adsorb to the cell surface of the host cell

This involves a specific interaction between a viral surface component and a specifice cell receptor on the cell membrane Adsorption does NOT involve insertion of virally specified glycoproteins into the host cell membrane

Cellular tropism by viruses is dependent upon cell surface receptors (they interact with the spikes on the viruses) For a retrovirus, what precedes integration into the host?

Synthesis of complement DNA from RNA NOT synthesis of viral protein, capsid from nuclear membrane, or budding

Identifying viruses: Whether or not antisera neutralize the virus

The most generally accepted laboratory method for dx of most common viral infections Morphology of protein coat Nature of viral nucleic acid (RNA or DNA) The ability of ether or chloroform inactivate the virus

NOT the ability of virus to grow on complex media – Just Like M. leprae and Treponema (syphilis) Viruses cause disease by any of the following:

Lysing many cells of the host Transforming cells to malignant cells Making vital target cells nonfunctional Disrupting the normal defense mechanisms of the host

Viral antigens Viral antigen recognition by CD4+ T-Helper cell from an APC LOOK UP!!! – 2002 Q6

Each of the following is necessary: • Cleavage of viral proteins into small peptides • Internalization of the virus or viral protein by an antigen presenting cell • Transport of viral peptides to a cell surface by MHC II molecule • Binding of the TCR to a MHC II bound viral peptide

♦ Viral replication in host – NOT necessary by T-Helper cell Most viral Ag/s of diagnostic value are proteins

Bacteriophage (aka “phage”) Virus that can only replicate w/in specific host bacterial cells Very delicate bacterial virus which may attach to & destroy bacterial cells under certain conditions Contains a nucleic acid core (DNA or RNA) & a protein coat Some have tail-like structures for injecting the nucleic acid into host cell Phage Conversion

Responsible for conversion of erythrogenic toxin by Strep pyogenes!!!!! Responsible for production of a pyrogenic toxin

Serological & phage typing of pathogenic bacterial species are used to identify bacterial strains in disease outbreaks The best evidence for causal relationship between a nasal carrier of staph and a staph infection in a hospital is the

demonstration that both bugs are of the same phage type – only genetically similar bacteria within a species will be lysed by the same phage.

Bacteriophage follows one of two courses: 1) Lysis: virus multiplies w/in the host cell & destroys it

• The virus is said to be a lytic or virulent phage (lyses & kills host) 2) Lysogeny: virus does not replicate but rather (prophase) integrates into the bacterial chromosome

• The virus is said to be a temperate or lysogenic phage (replicates to incorporate phage genome into host genome) ♦ Temperate phage persists through many cell divisions w/o killing host ♦ Can spontaneously become lytic ♦ Presence of the integrated virus (called a prophage) renders the cell resistant to infection by similar phages

• Lysogenic bacterium ♦ Harbors a temperate bacteriophage ♦ Example is Corynebacterium diphtheriae

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• Lysogenic conversion ♦ Alteration of a bacterium to a virulent strain by the transfer of a DNA temperate bacteriophage ♦ Presence of temperate phage renders C. diphtheriae pathogenic (harmless w/o the phage)

The following may be transmitted by respiratory droplets: Rubeola, Adenoviruses, Influenza virus, Varicella-zoster virus, Diphtheria, Bordetella Pertussis

Arthropods: Transmission by arthropod vectors occurs in:

Malaria Typhus fever – NOT Q fever Dengue Rocky mountain spotted fever (Tick) NOT Diphteria

Viral Replication For RNA viruses:

Transcription occurs in the cytoplasm except for retroviruses and influenza viruses – nucleus Transcription involves an RNA-dependent RNA polymerase except for retrovirus, which has a reverse transcriptase

enzyme (RNA-dependent DNA polymerase) All RNA viruses have Continuous single stranded RNA, except for 4 (BOAR) – which are Segmented

• Bunyaviruses, Orthomyxoviruses (Flu virus), Arenaviruses, Reoviruses ♦ The influenza virus (Orthomyxo) has 8 segments that can reassort a lot, and is the reason for worldwide epidemics

of the flu ♦ Antigenic shift of influenza is caused by Genetic reassortment (then you get new surface receptors)

Polarity: • Positive polarity = RNA w/ same base sequence as the mRNA

♦ Use RNA genome directly as mRNA • Negative polarity = complimentary sequence to mRNA

♦ Must transcribe its own mRNA using the negative strand as template The virus must carry its own RNA-dependent RNA polymerase

♦ EXs – orthomyxoviruses & paramyxoviruses • Only HIV does not function as a positive or negative sense molecule

♦ It acts as a template for the production of viral DNA For DNA viruses:

Transcription occurs in the nucleus except for poxviruses – in a box Transcription involves a host-cell DNA dependent polymerase (to synthesize mRNA) All DNA viruses consist of dsDNA except for the parvoviruses, which have a ssDNA

• (Sean has only made a SINGLE PARhole is whole life) All DNA viruses consist of Linear dsDNA except for Papovavirus and Hepadnavirus, which have circular

Viral Genetics Recombination

Exhchange of genes between 2 chromosomes by crossing over within regions of significant base sequence homology Reassortment

When viruses with segmented genomes (influenza virus) exchange segments High frequency recombination Cause of worldwide pandemics

Complementation When 1 of 2 viruses that infect the cell has a mutation that results in a nonfunctional protein The nonmutaed virus “complements” the mutated one by making a functional protein that serves both viruses

Phenotypic Mixing Genome of virus A can be coated with the surface proteins of virus B Type B protein coat determines the infectivity of the phenotypically mixed virus However, the progeny from this infection has a type A coat and is encoded by its type A genetic material

“Late” proteins synthesized in viral replication: Include viral structural proteins

One-step growth curve: Lysis of bacterial cell release a large number of phages simultaneously

Consequently, the lytic reproduction cycle exhibits a one-step growth curve Growth curve begins w/ an eclipse period:

Period in which there are no complete infective phage particles • Characterized by absence of demonstrable virus particle

Eclipse period is the time between the injection of the viral DNA & formation of the first complete virus w/in host

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Eclipse period is the 1st portion of the latent period, which ends when the 1st assembled virus from the infected cell appears extracellularly

Cytopathic effect (CPE): (old term was cytopathogenic effect, I think) Is characteristic of each virus and can be used for detection of that virus, it is a hallmark of viral infection This change starts w/ alterations of cell morphlogy accompanied by marked derangement of cell function

Culminates in cell lysis The cytopathic reactions include: necrosis, hypertrophy, giant cell formation, hypoplasia, and metaplasia

These changes provide useful evidence for the Dx of the viruses that induce the CPEs seen Not all viruses cause CPE

Slow Growth Viruses In most slow viruses, tissue damage occurs in the brain

Dermatotropic viral diseases: Measles, Smallpox, and Chickenpox

Latency: State of dormancy – may be latent for extended period of time & become active under certain conditions Interval of time between an exposure to a carcinogen and emergence of a neoplasm Existing as a potential, as in TB or HSV infection

HOW TO REMEMBER DNA vs. RNA… Remember the DNA viruses – the rest are RNA Think HHAPPP: (* = exception)

Herpes HepaDNA (* Circular but incomplete DNA) Adeno Papova (* Linear DNA) Parvo (* ssDNA) Pox (* Circular but supercoiled DNA)

(*NOT Icosahedral) (*Replicates in Cyto [Own DNA-dep RNA polymerase])

CAREFUL (picorna & paramyxo are RNA, but start w/ P, clown) PAP = Naked DNA viruses Girls are naked when they get a PAP smear HPH = Enveloped DNA (Think Pox in a Box)

Hepatitis viruses Include DNA & RNA viruses Detailed info is found in the section on the Liver

RNA VIRUSES RNA ENVELOPED VIRUSES

Orthomyxovirus ssRNA Segmented Influenza A, B, C

• Causes influenza, duh! • Composed of unique segmented ssRNA genome, a helical nucleocapsid, and an outer lipoprotein envelope

♦ Envelope is covered w/ two different types of spikes that contain either hemagglutinin or neuraminidase • Causes a fever, runny nose, cough, headache, malaise, muscle ache

♦ Fever distinguishes flu from common cold • Classified as type A, B, or C depending on the nucleocapsid Ag • Passed on via respiratory droplets • Microorganism characteristic of requiring a specific receptor site to infect a host

♦ (incorrect options included anthrax, syphilis, dysentery, gas gangrene) • Influenza A:

♦ Most common flu; causes the most severe disease ♦ Ability to cause epidemics depends on antigenic changes in the hemagglutinin & neuraminidase ♦ Two types of changes:

Antigenic shifts which are major changes based on reassortment of genome pieces

• This leads to new surface molecules (change in envelope) Antigenic drifts

which are minor changes based on random mutations ♦ Amantadine/Rimantadine

Inhibits replication of influenza A virus by interfering w/ viral attachment & uncoating Effective in prophylaxis & Tx of influenza A

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♦ Main mode of prevention is vaccine – consists of killed influenza A & B viruses • Staph aureus is associated with fatalities post influenzal infection • One serious complication associated w/ outbreaks of influenza is the development of Reye’s syndrome, which is an

acute pathological condition affecting the CNS ♦ Seems to be associated w/ outbreak of influenza B virus for unknown reasons ♦ This syndrome is principally associated w/ children who have take aspirin to treat the trivial infection

No cause-and-effect relationship between ASA use & Reye’s syndrome ♦ Reye’s syndrome is characterized by vomiting for one week after infection and either recover in 2 days or go into

coma w/ intracranial pressure Paramyxovirus “Para of Ms”

ssRNA Cause respiratory infections in children Differ from orthomyxoviruses in that the genomes are not segmented, have a larger diameter & different surface spikes Cytopathic effect for paramyxoviruses is syncitia formation (they induce cells to form multinucleated giant cells)

• Multinucleated giant cells of the foreign-body type originate from fusion or division of mononuclear cells Parainfluenza viruses

• Cause croup (acute laryngotracheobronchitis) & pneumonia in children ♦ Characteristic barking cough ♦ Surface spikes include hemagglutinin, neuraminidase, or fusion proteins

• Disease resembles common cold in adults • Transmitted by respiratory droplets & direct contact • Has 4 serotypes • Neither an antiviral therapy nor a vaccine is available

RSV • Disease primarily in infants • Most common cause of pneumonia & bronchiolitis in infants • Only one of the paramyxovirus lacking the glycoproteins hemagglutinin & neuraminidase (surface spikes)

♦ RSV surface spikes are fusion proteins Fusion proteins cause cells to fuse, forming multinucleated giant cells (syncitial, as in RSV)

Multinucleated giant cells of the foreign-body type originate from fusion/division of mononuclear cells • Aerosolized ribavirin is used to treat severely ill, hospitalized infants

Mumps • Transmitted via respiratory droplets • Occurs worldwide – peak incidence in the winter • Most noticeable symptom – painful swelling of the parotid glands PAROTITIS (unilateral or bilateral) • Typically benign & resolves w/in a week • 10 yr old child had case of mumps when she was 5 yrs old Look up

♦ Her specific memory cells are B cells, CD4+ T cells, and CD8+ T cells – maybe only CD8+ T cells, maybe only CD4+ only

• Complications: ♦ Orchitis – (Lumps in my Man Bumps from Mumps)

Chief complication in males Painful swelling of the testicles in postpubertal males, which can result in sterility

♦ Deafness – in children Measles

• Caused by Rubeola virus (RNA paramyxovirus) • Rubeola is characterized by skin rash w/ Koplik’s spots in the oral cavity (BAD cops in Mexico)

♦ Koplik’s spots – small, bluish-white lesions surrounded by a red ring; occur opposite the molars ♦ So, Koplik spot = measles = paramyxovirus ♦ Pt can have:

A cold and red & runny eyes Blotchy reddish rash behind ears and on the face 3 Cs Cough, Coryza, Conjunctivitis

• Transmitted by respiratory droplets • what are features of measles except:

♦ koplik ♦ negri body – this is the answer – seen in Rabies ♦ synctial formation – happens in all Paramyxos

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♦ Rash • measles can affect lots of organs because:

♦ lots of cells are tropic for its receptor Arbovirus

• Colorado tick fever virus • Transmitted by arthropods (mosquitoes, tics) (Also Flavivirus, Bunyavirus, and Togavirus) • Dengue fever • Yellow Fever

Togavirus • Alphaviruses – (Think Alpha Males wearing Red Togas in Germany)

♦ Eastern equine encephalitis ♦ Weatern equine encephalitis

• Rubivirus = rubella ♦ Aka “German measles” - Think kiLLa virus, germans are killers ♦ Caused by rubella virus (RNA virus) ♦ Enveloped virus composed of an icosahedral nucleocapsid and a positive, ssRNA genome ♦ Transmitted by respiratory droplets

The only togavirus not transmitted by an arthropod vector ♦ Initial replication occurs in the nasopharynx & local lymph nodes

From there it spread via the blood to the internal organs & skin ♦ Incubation period of 2-3 wks followed by prodromal period of fever & malaise

This is followed by a characteristic maculopapular rash (appears first on face, then extremities), lasts 2-3 days ♦ Prevention involves immunization w/ live, attenuated vaccine ♦ Posterior auricular lymphadenopathy is characteristic ♦ Milder, shorter disease than measles ♦ A teratogen – causes malformation of an embryo or a fetus (TORCH)

NOT Koplik’s spots That’s Regular measles (Rubeola not Rubella) ♦ Congenital rubella syndrome:

When a nonimmune women is infected during the 1st trimester, especially the 1st month, significant congenital malformations can occur in the fetus

The malformations are widespread & involve primarily: The heart (e.g., patent dutus arteriosus) The eyes (e.g., cataracts) The brain (e.g., deafness & mental retardation)

Flavivirus (Flavi = Yellow) • Yellow fever – a mosquito-borne flavivirus infection

♦ Has a monkey or human reservoir ♦ Symptoms: fever, black vomit, jaundice (yellow) ♦ Councilman bodies (acidophilic inclusions) may be seen in liver

• Dengue fever – also a mosquito-borne illness – characterized by fever, rash, arthralgia, lymphadenopathy • Hepatitis C

♦ Transmitted via blood and resembles Hep B in course and severity ♦ Common cause of IV drug use hepatitis in US ♦ C = Chronic, Cirrhosis, Carcinoma, Carriers

Bunyavirus • California encephalitis virus • Hantavirus

Rhabdovirus Rabies virus

• Has the longest incubation period (up to 3 weeks to months) HBV, HIV????

• Use of vaccines for preventing clinical symptoms after introduction of the virus is most likely to be effective against rabies virus (NOT influenza, poliomyelitis, or herpes zoster)

You can administer vaccine even after inoculation! ♦ Administer Human rabies immunoglobulin (HHIG) immediately in probable cases of rabies

Affects warm-blooded animals reason for human/dog infections More commonly from bat, raccoon, and skunk bites in areas of vaccinated dogs, otherwise worldwide dogs are most

common Bullet-shaped virus transmitted by the bite of a rabid animal

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• Virulence shown is due to?? Envelope (presence of arginine or lysine residue at position 333 in glycoprotein residue)

Negri bodies • Characteristic cytoplamic inclusions in neurons infected by rabies • are pathogenic for the infection • Negri bodies = Rabies = rhabdovirus (Blacks shoot bullets)

Retrovirus Enveloped, linear, positive-polarity ssRNA virus Their genome surrounded by an inner protein envelope & an outer envelope that contains lipid & glycoprotein spikes

• The spikes serve to attach the virus to host cells “Retro” refers to the enzyme reverse transcriptase (an RNA-dependent DNA polymerase)

• RT is packaged w/ the viral RNA genome • RT transcribes RNA to DNA during the process of viral nucleic acid syntheseis

♦ The viral DNA integrates into the host cell genome • Reverse Transcriptase is unique to RNA tumor viruses

The viral genome encodes 3 groups of proteins: • Pol, Env, Gag

Three groups: • 1) Oncovirus group (HTLV): produces leukemias, lymphomas, breast carcinomas, & sarcomas

♦ HTLV III (HIV) is least likely virus to be spread in dental office HTLV III is an obsolete term for HIV

• 2) Lentivirus group: causes AIDS ♦ HIV occurs primarily by sexual contact and by transfer of infected blood ♦ Virus infects/kills helper (CD4) T cells, resulting in the depression of both humoral & cell-mediated immunity ♦ It travels throughout the body, particularly in macrophages ♦ Induces a dinstinctive CPE (cytopathic effect) called giant cell (syncytial) formation

• 3) Spumavirus group: there are no known pathogens HIV

• Only virus with Diploid • Gp41 = Envelope protein • gp120 glycoprotein spike protrudes from the

envelope ♦ This is the ligand for CD4 molecules

• p24 = rectangular nucleocapsid protein (surrounds RNA)

• Black balls = Reverse Transcriptase • Directly affects:

♦ Neurons, Macrophages, CD4 (helper) lymphocytes NOT CD8 (suppressor) lymphocytes

• Transmitted by: ♦ Semen, Serum, Amniotic fluid, Breast milk

NOT Saliva • Initial manifestation of Early, acute HIV infection

♦ Mononucleosis-like syndrome • HIV is responsible for resurgence of

Mycobacterium Tuberculosis • Opportunistic Infections

♦ Bacterial Tuberculosis, M. avium-intracellulare complex

♦ Viral Herpes simplex, Varicella zoster, CMV, Progressive mulitfocal leukoencephalopathy (PML), Hairy

Leukoplakia NOT Adenovirus (conjunctivitis)

♦ Fungal Candidiasis, Cryptococcus (meningitis), Histoplasmosis, Pneumocystic carinii pneumonia (PCP)

Most common cause of pneumonia in HIV pts is from PCP ♦ Protozoan

Toxoplasmosis, Cryptosporidium Enterocolitis

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♦ NOT Adenovirus conjunctivitis • Strains

♦ New strains of HIV are the result of errors in transcription (remember, reverse transcriptase!) In other words, by frequent errors induced by viral reverse transcriptase NOT the result of genomic recombination or errors in translation

• Dx ♦ Made with ELISA High false positive rate, simply a Rule Out test ♦ Positive ELISA are then confirmed with Western blot assay, Rule In test

• HIV is NOT oncogenic AIDS

• Info available elsewhere in file RNA NON-ENVELOPED VIRUSES

NAKED CPR (Calicivirus, Picornavirus, Reovirus) PicoRNAvirus = picornavirus

Very small, non-enveloped; composed of positive stranded, ssRNA genome NOT capable of causing cell transformation (naked DNA)

• Retrovirus, Herpes, Hepatitis B, and Human Papilloma are capable of causing cell transformation Subdivision: Enteroviruses

• Poliovirus ♦ Causes poliomyelitis ♦ RNA is the Only nucleic acid present…duh ♦ Transmitted by the fecal-oral route via consumption of water w/ fecal contaminants ♦ Replicates in the mucosa of the oropharynx and GI tract before entering the blood – Think swimming in

stomach POOL Travels to the spinal cord & infects the anterior horn cells (motor cells) leading to Lower Motor

Neuron destruction ♦ Uncommon in the U.S. due to successful vaccination program initiated in the 1950s ♦ Initial symptoms: headache, vomiting, constipation, and sore throat

Does NOT form a latent infection ♦ Paralysis may follow and is asymmetric & flaccid ♦ Findings include CSF w/ lymphocytic pleocytosis w/ slight elevation of protein ♦ Virus recovered from stool or throat ♦ Two vaccines used currently:

Inactivated polio vaccine -- salk (IPV) vaccine & trivalent oral live virus vaccine (OPV) Polio vaccine uses acquired artificial immunity (and Active) Effective Polio Vaccine forms what kind of antibodies?? Membrane bound IgG??? – I think

This is why SABIN (OPV or live) is better because it ALSO induces sIgA synthesis Vaccine for Polio would be most affective if directed at Intestinal Mucosa These immunize against polio in more than 90% of recipients

• Coxsackie A & B virus ♦ Most commonly isolated virus in the feces

Incorrect options: Hep C, influenza, rubella, herpes simplex NOTE: you can get avian influenza from bird feces…just “food” for thought; Coxsackie is right fo sho

♦ Group A: Causes herpangina and hand-foot-and-mouth disease Summer illness that produces nodular lesions of the uvula, anterior pillars, and posterior pharynx Location of the oral lesions distinguishes these two diseases:

1) Herpangina – • Throat, palate, or tongue, the oral lesions • A viral disease with oral manifestations • 3-yr-old w/ fever, vesicles / ulcers on soft palate, pharynx → herpangina • Herpangina & Coxsackie virus – you can make the connection, right…

2) Hand-foot-and-mouth disease – buccal mucosa and gingiva ♦ Group B:

Causes focal necrosis of skeletal muscle & degeneration in brain & other tissues Pleurodynia (pain in chest), myocardidits, and juvenile diabetes

♦ Cause mild infections in human ♦ Replicates in mucosa of the pharynx & GI tract before entering the blood

• Echovirus

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♦ Echoviruses cause aseptic (viral) meningitis, upper respiratory infections, and severe diarrhea in newborns Subdivision: Rhinoviruses

• Rhinovirus ♦ Main cause of the common cold

There are >100 different serotypes – hence, development of a vaccine is very difficult The common cold also caused by coronaviruses in adults NOT a persistant virus

Hepatitis A • RNA virus • Causes infectious hepatitis • Transmitted via Fecal-oral route – Just Like Hep E • Short incubation (3 weeks) • A for Asymptomatic usually

Reovirus Have a double-shelled icosahedral capsid containing 10 or 11 segments of dsRNA Replicate in cytoplasm Produce minor respiratory tract infections & GI disease Rotavirus

• Segmented (BOAR) • ROTA Right Out of The Anus • Causes infantile diarrhea • Most common cause of viral gastroenteritis in children (2 & under)

♦ A self-limiting disease (aka, “24-hour flu” or “intestinal flu” – not caused by influenza virus) ♦ Sudden onset of GI pain, vomiting, diarrhea ♦ Dehydration is a major concern, especially in infants (can be fatal)

DNA VIRUSES (HHAPPPY) DNA ENVELOPED VIRUSES

Herpesvirus Herpes simplex virus

• General ♦ All are large (120–200 nm diameter) – 2nd only to poxvirus in size ♦ Are medium-sized enveloped viruses w/ an icosahedral nucleocapsid containing linear, dsDNA ♦ Replicate in the nucleus of the host cell and are the only viruses to obtain their envelopes by budding from the

nuclear membrane ♦ Cause acute (primary) infections ♦ Produces a latent virus (ECHO, measles, smallpox, coxsackie all do NOT)

Latency in the ganglion Most common site of latent infection to 1° oral infection by HSV I is in the sensory trigeminal ganglion

♦ Characterized by latency and then clinical symptoms that can follow trauma, fever, and nerve damage ♦ For the majority of individuals, the initial infection results in a subclinical disease ♦ HSV 1&2 and varicella-zoster cause vesicular rash ♦ Often associated with recurrent attacks of dermatitis herpetiformis

NOT aphthous stomatitis or erythema multiforme • HSV Type 1 = primary herpetic gingivostomatitis = recurrent herpes labialis

♦ May involve primary infection (gingivostomatitis) or a recurrent infection (cold sores) First clinical manifestation is usually gingivostomatitis

♦ Affects children under 10 y.o. & 15-25 y.o. ♦ Transmitted by direct contact ♦ Nearly all infections are subclinical (but they range from subclinical to severe systemic infection)

Many children have asymptomatic primary infections ♦ Associated with oral and ocular lesions ♦ Pt may have acute symptoms

Affects the lips, face, skin, & oral mucosa (above the waist) Recurrent herpes most likely found on the labial mucosa Fever; irritability; cervical lymphadenopathy; fiery red gingival tissues; small, yellowish vesicles Most serious potential problem is dehydration due to child not wanting to eat/drink Often reappears later as the familiar “cold sore”, usually at the mucocutaneous junction of the lips

♦ Disease is referred to as recurrent herpes labialis

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Emotional stress, trauma, and excessive exposure to sunlight have been implicated as factors for the appearance of the recurrent herpetic lesions on the lip

♦ May be diagnosed by a Tzanck smear for rapid identification when skin lesions are involved ♦ Enveloped that was acquired by budding through the nuclear membrane – WOW!!!!! ♦ Supportive tx – relieve acute symptoms

Acyclovir 5% ointment (Zovirax) has been successful in reducing the duration and severity of these sores Acyclovir preferentially inhibits viral DNA polymerase when phosphorylated by viral thymidine

kinase (which is far more effective in phosphorylation than cellular thymidine kinase) Clinical use: HSV, VZV, EBV, mucocutaneous & genital herpes lesions

Healing takes 2-3 weeks; non-scarring ♦ Recurrent infection in otherwise healthy people

Occurs in people who have been infected with the herpes virus AND do have Abs against the virus Recurrent infections include: keratoconjunctivitis & encephalitis

♦ Herpes conjunctivitis Specific chemotherapy is used in tx (NOT used to tx measles, hepatitis, herpangina, or infectious mono)

♦ Recurrent Herpes Similar to recurrent apthae in that symptoms are similar, but don’t include apthous stomatitis

• HSV Type 2 = Genital herpes ♦ Spread by sexual contact ♦ Affects the mucosa of the genital and anal regions (below the waist) ♦ HSV-2 becomes latent in the lumbar and sacral ganglion ♦ May have serious consequences in pregnant women

The virus may be transmitted to the infant during vaginal delivery Can cause damage to the infant’s CNS &/or eyes

♦ What causes cervicitis? HSV 2, syphilis, HPV, chlamydia

♦ Has been shown to have relationship to carcinoma of the cervix ♦ Candidate virus for the induction of cervical cancer (carcinoma)

Varicella-zoster virus • Member of the herpes virus group • Causes 2 distinct diseases in different age groups • Very contagious and may be spread by direct contact or respiratory droplets

♦ 90% of cases of chickenpox occur in children under 9 years of age • Chickenpox (varicella)

♦ Local lesions (vesicles) occur in the skin after dissemination of the virus through the body ♦ Lesions become encrusted & fall off in ~1 week

• Shingles (herpes zoster) ♦ Unilateral ♦ Pain along a dermatome (usually 1-3) ♦ Only occurs in an individual having a latent VZV infection ♦ More common in individuals that are Immunocompromised

DOES NOT occur repeatedly in Immunocompromised pts – Look up ♦ Reactiviation of latent varicella-zoster that may have remained w/in the body from previous chickenpox ♦ Reaches the sensory ganglia of the spinal or cranial nerves (most frequently the trigeminal nerve) producing an

inflammatory response ♦ Latent In the sensory ganglia ♦ Characterized by painful vesicles on the skin or mucosal surfaces along the distribution of a sensory nerve ♦ Characterized by individual, blister-like lesions affecting specific dermatomes, usually causing burning pain ♦ Tzanck Test

Smear of an opened skin vesicle to detect multinucleated giant cells Used for HSV-1, HSV-2, and VZV

Epstein-Barr virus • Causes infectious mononucleosis • Infects B lymphocytes & some epithelial cells • Latent EBV is called SBV • Hodkin’s Lymphoma • Associated w/ development of Burkitt’s lymphoma & nasopharyngeal carcinoma • Assocated w/ hairy leukoplakia – a whitish, nonmalignant lesion on the tongue (seen especially in AIDS pts)

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• Has splenomegaly and elevated heterophile titer ♦ Heterophile agglutination test greater than 1:128 ♦ You get a sploner (splenomegaly) when you acquired the kissing disease (IM) from a GIRL (heterophile)

• Associated w/ production of atypical lymphocytes & IgM heterophile antibodies ID’d by the hereophile test ♦ (aka: “mononucleosis spot test” or “monospot test”) ♦ Ab eventually appears in serum of > 80% of pts w/ IM, hence it is highly diagnostic

• Infectious Mononucleosis (IM): ♦ Viral infection causing high temperature, sore throat, & swollen lymph glands, especially in the neck, necrotizing

pharyngititis, and splenomegaly ♦ Typically caused by EBV – can also be cause by CMV ♦ EBV-caused IM is responsible for approximately 85% of IM cases ♦ Often transmitted by saliva ♦ Occurs most often in 15-17 y.o. (may occur in any age) – most often diagnosed between ages 10-35 ♦ Hematologically – a relative lymphocytic leukocytosis w/ atypical lymphocytes & a positive heterophile test

(increased) Heterophile agglutination test greater than 1:128 EBV commonly produces a positive heterophile Ab test After 1 week, many pts develop heterophile Ab/s, which peak at 2-5 wks – may persist for several months to

1 yr Ab eventually appears in 80% of pts – highly diagnostic Serum of the pt will agglutinate sheep red cells

♦ Spontaneous recovery usually occurs in 2-3 weeks ♦ No antiviral therapy necessary for uncomplicated IM; there is no EBV vaccine ♦ NOTE: EBV is associated w/ Burkitt’s lymphoma, nasopharyngeal carcinoma, & hairy leukoplakia

Cytomegalovirus • Congenital abnormalities • CMV is the major viral cause of birth defects in infants in developed countries • C in TORCH

HHV-6 • 6th disease = roseola infection

Virus Usual site of latency Recurrent infection Route of transmission HSV-1 Cranial sensory ganglion (CN V) Herpes labialis, encephalitis, keratitis Via respiratory secretions and saliva HSV-2 Lumbar or sacral sensory Herpes genitalis Sexual contact, perinatal infection Varicella zoster Cranial/thoracic sensory ganglia Zoster Via respiratory secretions Epstein-Barr B lymphocytes None Via respiratory secretions and saliva CMV Uncertain None Intrauterine infection, transfusions,

sexual contact, via secretions (eg saliva and urine)

HepaDNAvirus

Hepatitis B • Blood borne virus

♦ Parenteral, sexual, maternal-fetal • Long incubation period (3 months) • Reverse transcription occurs?????

Poxviruses DNA viruses – the largest & most complex animal viruses Brick shaped particles containing enveloped linear dsDNA genome Multiply in the cytoplasm of host cell & are usually associated w/ skin rashes Smallpox

• Caused by variola virus • An acute, highly infectious, often fatal disease • Characterized by high fever, prostration, & a vesicular, pustular rash • Man is the only reservoir for the virus • Smallpox has been eradicated by global use of the vaccine which contains live, attenuated vaccinia virus • Protection against smallpox afforded by prior injection with cowpox

♦ This represents antigenic cross reactivity Vaccinia virus

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• A related poxvirus used to eradicate smallpox Molluscum contagiosum

• Causes umbilicated wart-like skin lesions DNA NON-ENVELOPED VIRUSES

Papovavirus Pa = Papilloma virus Po = Polyoma virus Va = Vacuolating virus HPV (Human Papilloma Virus)

• Most common cause of VIRAL STD • Cause papillomas (warts) on skin & mucus MBs • A DNA oncogenic virus (NOT RNA oncogenic, that’s retrovirus)

♦ Associated with the induction of cervical carcinoma (16,18) • Condyloma Acuminatum

♦ NOT passed on via respiratory droplets Adenovirus

Naked, medium sized, icosahedral nucleocapsid & linear dsDNA genome Have hemagglutinin spikes Frequently cause subclinical infections Cause upper & lower respiratory infections – “cold” Transmitted via aerosol droplets, fecal-oral route, or direct inoculation

• Can be transmitted via ocular secretions Diseases associated w/ adenoviruses:

• Acute respiratory infections • Acute contagious conjunctivitis (pink eye)

♦ NOT associated with HIV opportunistic infection • Pharyngoconjunctival fever characterized by fever, pharyngitis, & conjunctivitis

Parvovirus (PAR – V – Fifth’s disease) Erythema infectiosum (slapped-cheeks syndrome, 5th disease) Transient aplastic anemia crisis Fetal infections

Virus Disease Vaccine available Treatment

RNA viruses Influenza A Influenza Yes Amantadine/Rimantadine Parainfluenza Croup No None Respiratory synctial Bronchiolitis and pneumonia in

infants No Ribaviron

Rubella Rubella Yes None Measles Measles Yes None Mumps Parotitis, meningitis Yes None Rhinovirus Common cold No None Coronavirus Common cold No None Coxsackie Herpangina, hand foot and mouth No None DNA viruses Herpes simplex type1 Gingivostomatitis No Acyclovir in immunodeficient pt Epstein barr Infection mononucleuosis No None Varicella Chickenpox, shingles No None Adenovirus Pharyngitis, pneumonia No None

Portal of Entry Virus Disease

Respiratory tract Adenovirus Pneumonia Cytomegalovirus Mononucleosis syndrome – most common

pneumonia in bone marrow transplant pt Epstein barr Infection mononucleosis HSV type 1 Herpes labialis Influenza Influenza Measles Measles Mumps Mumps

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Respiratory synctial Bronchiolitis and pneumonia in infants Rhinovirus Common cold Rubella virus Rubella Varicella zoster Chickenpox

Gastrointestinal Hep A Hep A Polio Poliomyelitis Rota Diarrhea

Skin Rabies Rabies HPV Papillomas (warts)

Genital HPV Papillomas (warts) Hep B Hep B HIV AIDS HSV type II Herpes genitalis and neonatal herpes

Blood Hep B Hep B Hep C Hep C HIV AIDS Cytomegalovirus Mononucleosis syndrome or pneumonia

USMLE ADD-ONS Naked/Enveloped Viruses

Naked Most dsDNA (Not Pox) and (+) strand ssRNA viruses are infectious – positively infectious Naked nucleic acids of (-) strand ssRNA and dsRNA are not infectious

Enveloped Usually acquire their envelope from plasma membrane when they exit from the cell

• Except Herpes, which gets it from the nuclear membrane Virus Ploidy

All are Haploid! (one copy of DNA or RNA) Except for Retroviruses, which have 2 identical ssRNA molecules (diploid)

Nosocomial Infections Newborn Nursery CMV, RSV Urinary Catheter **E. Coli, Proteus Respiratory Equipment P. aeruginosa Work in renal dialysis HBV Hyperalimentation Candida Water aerosols Legionella Wound Infection **S. aureus

**2 most common nosocomials If all else Fails

Pus, emphysema, abscess S. aureus Pediatric infection H. influenzae Pneumonia in CF, burn infection P. aeruginosa Branching rods in oral infection Actinomyces israelii Traumatic open wound C. perfringens Surgical wound S. aureus Dog or cat bite Pasteurella multocida Sepsis/meningitis in newborn Group B strep

FUNGI Fungi:

Eukaryotic, all are G+; contain both DNA & RNA Grow in Sabouraud’s agar medium

Cell walls contain chitin, glucans, & protein Cell MB contain sterols (ergosterol) Two types:

Yeasts – grow as single cell that reproduces by asexually budding Molds – grow as long filaments (hyphae) and form a mat or mass which is referred to as mycelium

• Hyphae can be septate or nonseptate

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• All fungi (except for zygomycetes) are septate Dimorphism is characteristic of some fungi

Dimorphism = the fungus forms different structures at different temperatures • Can exist as either filamentous (mold) or yeast (spore) forms • Cold = Mold/Mycelial (soil) Heat = Yeast (tissues) • Characterized by the capability to produce both a yeast & a mycelial phase

Exist as molds in the saprophytic, free-living state at ambient temperatures Exist as yeasts in host tissue at body temperature These fungi include the major pathogens – Blastomyces, Histoplasma, Coccidioides, and Candida

Reproduction Asexual:

• Most fungal spores are asexual • Asexual spores (conidia) form through mitosis • Differentiating conidia help to ID various fungi

Sexual: • They mate & form sexual spores

Mechanism for disease is through type IV hypersensitivity reaction Fungal spores:

Morphological characteristics (e.g., shape, color, & arrangement) of conidia help to ID fungi Conidium is an asexually formed fungal spore Fungal spores cause allergies in some people Most fungal spores are completely killed when heated at 80° for 30 min (unlike bacterial spores)

Examples of asexual spores (conidia) Arthrospores: formed by fragementation of the ends of hyphae; are the mode of transmission of Coccidioides immitis Chlamydospores: thick walled & quite resistant; characteristic of C. albicans Blastospores: formed by budding, as in yeasts; multiple buds are called pseudohyphae (also characteristic of C. albicans) Sporangiospores: formed w/in a sac on a stalk by molds such as Rhizopus and Mucor

Example of sexual spores: Zygospores: single large spores w/ thick walls Ascospores: formed in sacs which are called an ascus Basidiospores: formed externally on the tip of a pedestal called a basidium

Many fungi respond to infection by forming granulomas (as seen in coccidioidomycosis, histoplasmosis, blastomycosis) Nosocomial infections:

Infections acquired during hospitalization, unrelated to the pt’s primary condition Often caused by: C. albicans, Apsergillus, E. coli, Hepatitis viruses, Herpes zoster virus, P. aeruginosa, Strep, & Staph Ability to become resistant to ABX is most important characteristic of enterobacteria in hospitals

CUTANEOUS MYCOSES DERMATOPHYTES:

EXs: Trichophyton, Epidermophyton, and Microsporum Cause superficial skin infections (Trichophyton) – think Tinea…from Dr. Christensen’s Path course Infect only the skin, nails, and hairs

Athlete’s Foot caused by Trichophyton Trichophyton also is involved in ALL types of Tineas

Tx Griseofulvin (You have to be greasy to have these diseases) Responsible for causing dermatophytosis

Common among people who live in communities w/ low standard of sanitation Source – from soil & dust Characterized microscopically by intracytoplasmic microorganisms of Reticuloendothelial system

Epidemiology of Dermatomycoses Disease Causative agent Examples of sources

Tinea capitis (ringworm of scalp) Microsporum, Trichophyton Lesions, combs, toilet articles, headrests Tinea corporis (ringworm of body) Epidermophyton, Microsporum,

Trichophyton Lesions, floors, shower stals, clothing

Tinea pedis (ringworm of feet (athletes foot) Epidermophyton, Trichophyton Lesions, floors, shoes & socks, shower stalls Tinea unguium (ringworm of nails) Trichophyton Lesions Tinea cruris (ringworm of groin [jock itch]) Trichophyton, Epidermophyton Lesions, athletic supports 9 yr old boy has tinea capitis

For tx, he should be given an anti-mycotic agent SUBCUTANEOUS MYCOSES SPOROTRICHOSIS:

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Caused by Sporothrix schenckii Classically associated w/ rose thorns Cigar-shaped budding yeast visible in pus

MYCETOMA: Lesions usually occur on feet or hands Caused by infection w/ several fungi

SYSTEMIC MYCOSES – Can mimic TB granuloma formation – ALL 3 can come from Soil HISTOPLASMOSIS:

Caused by Histoplasma capsulatum – a dimorphic fungus Found in bird & bat droppings Exists 1) as a mold in soil & 2) as a yeast in tissue Endemic in Central and Eastern U.S., especially in the Ohio & Mississippi River valleys

Principal source of endemic form is from soil and dust Infection results from inhaling contaminated air

Infection is usually asymptomatic, but may produce a benign, mild pulmonary illness (primary form of disease) Infection with Histoplasma capsulatum in normal, healthy individuals results in a self-limiting, benign disease “systemic disease, most commonly of the lungs, characterized by production of tuberculate chlamydospores in

culture” Frequently causes pulmonary nodules An oral lesion that may appear as an ulcer, nodule, or vegetative process, and is often mistaken for SCC Uncommon disseminated form of the infection is quite serious Intracellular Parasite of Macrophages --- Have in common with Viruses In infected tissues, yeast cells of Histoplasma capsulatum are found w/in macrophages

Characterized microscopically by intracytoplasmic microorganisms in the RE (reticulo-endothelial or macrophage) system (incorrect options were: intranuclear inclusion bodies, flask-shaped ulcers of the ileum, focal liver abscesses)

Often mistaken for TB in the lungs because it can cause calcifications in the lungs also Resembles TB, causing a granulomatous, tuberculosis-like infection both clinically and pathologically

Produces tuberculate chlamydospores in culture Histoplasmosis and blastomycosis are rarely acquired from another individual (along with Sporotrichosis)

COCCIDIOIDOMYCOSIS: Caused by the inhalation of dust aerosols containing Coccidioides immitis arthrospores (highly infectious)

Fungus that grows as a saprophyte (MOLD) in the soil Endemic in hot, dry regions of the Southwest U.S. & northern Mexico Referred to as “Valley Fever” or “San Joaquin fever” Primary infection or lesion is in the lung It is by and large an inapparent and self limiting infection in endemic areas Amphotericin B is the drug of choice in treatment of fungal infection

Fluconazole & itraconazole are also used to treat various fungal infections BLASTOMYCOSIS: (aka “Gilchrist’s disease” or “North American blastomycosis”)

Caused by Blastomyces dermatidis – a dimorphic fungus that exists 1) as a mold in soil & 2) as a yeast in tissue Causes necrotic skin and bone lesions – Blasted through my Skin to my Bone

Think B for Big, Broad-Based Budding Fungus is endemic in North & Central America Grows in moist soil rich in organic material (poop), forming hyphae w/ small, pear shaped conidia

Inhalation of the conidia cause human infection Rarely, if ever acquire from another individual (Along with Histoplamosis, and Sporotrichosis)

OPPORTUNISTIC MYCOSES CANDIDA:

C. albicans most important species of Candida Characterized by white patches on buccal mucosa, consisting of pseudomycelia & minimal erosion of MBs

• Psuedo cause not in mold Causes thrush, vaginitis, and other diseases An oval yeast w/ a single bud – Not dimorphic

NOT an airborne fungus that causes opportunistic infections in debilitated individuals • Rhizopus, Aspergillus, and Cryptococcus ARE

Overgrowth of C. albicans in those w/ impaired host defenses produces candidiasis Chlamydospores – thick walled & quite resistant; characteristic of C. albicans Genus of fungi most frequently recovered from healthy mucous membranes Prolonged ABX (antibacterials) tx can predispose to infection from indigenous oral microorganism – Candida albicans Pts exposed to chemotherapy for leukemia are particularly prone to widespread oral infection caused by c. albicans Pts with deficiency in T lymphocytes are predisposed

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Pt exposed to long-term corticosteroids are predisposed to candidiasis Candidiasis:

An infection of the oral cavity or vagina, usually by C. albicans Common in patients 1) w/ a T-cell deficiency, 2) receiving chemotherapy & 3) who are immunosuppressed C. albicans causes an inflammatory, pruritic infection characterized by a thick, white discharge

• This yeast-like fungi is a normal inhabitant of the oral cavity & vaginal tract • Normally held in check by indigenous bacteria

Chemotherapy for leukemia predisposes for oral infections by C. albicans Oral Candidiasis:

Acute Pseudomembraneous (“thrush”) – creamy, loose patches of desquamative epithelium containing numerous matted

mycelia over an erythematous mucosa that is easily removed; common in patients with more severe predisposing factors • Pseudomembrane (false MB) = desquamative and necrotic epithelial cells and matted and tangled mycelia • Tx = Ketoconazole or Fluconazole (not Nystatin)

Atrophic (“erythematous”) – the mucosa is thinned, smooth, and bright red with symptoms of burning and increased sensitivity commonly found on the palate under a denture but also on the tongue and other mucosal surfaces • Areas of superficial erosion and petechiae necrosis • Tongue: beefy red appearance due to loss of filiform & fungiform papillae, generalized thinning of the epithelium and

excessive inflammation of the CT Chronic mucocutaneous candidiasis

Chronic Hyperplastic (“candidal leukoplakia”) – white plaques or papules against an erythematous background containing hyphae in the parakeratin layer of the thickened epithelium. • Firmly adherent white plaque to the oral cavity • Differential diagnosis is required: termed “candidal leukoplakia” resembles speckeled leukoplakia or speckled

erythroplasia conditions which are epithelial dysplasia ∴ MUST BIOPSY! • Usually unilateral, don’t rub off like pseudomembranous candidiasis

Oral Lesions Angular Cheilitis (perleche) –

Symptomatic bilateral fissures of the corners of the mouth that are common in patients with C. albicans infection • Intensified with mouth overclosure

Tx = antifungal medication (nystatin ointment) Median Rhomboid Glossitis –

An asymptomatic, elongated, erythematous patch of atrophic mucosa of the middorsal surface of the tongue due to a chronic C. albicans infection • Gradually enlarges • May have on the midline of palate opposite the tongue lesion

Chronic Mucocutaneous Candidiasis – Persistent and refractory candidiasis occuring on mucous MBs, skin & nails of the affected patients Watch out for w/ diabetic pts Tx = topical clotrimazole troches

CRYPTOCOCCUS: Cryptococcus neoformans causes Cryptococcosis Latex agglutination test detects polysaccharide capsular antigen

Antiphagocytic polysaccharide capsules (along with strep pneumoniae – think opsonins) An oval, budding yeast – not dimorphic

Narrow-based, unequal budding Found in soil, pigeon droppings More common than other fungal infections Severe only in people w/ underlying immune system disorders such as AIDS May spread to the meninges, where the resulting disease is cryptococcal meningitis

***Think Cryptococcus for immunocompromised pts and meningeal signs Culture Sabouraud’s agar, Stain with India ink – enCrypted message with India ink

ASPERGILLUS: Species exist only as molds and are not dimorphic Septate hyphae that branch at V-shaped 45 degree angle Aspergillus fumigatus causes an aspergilloma (fungus ball) in the lungs & Aspergillosis

Aspergilliosis is most commonly caused by A. fumigatus, A. niger, or A. flavus Aspergilliosis takes one of three forms:

• Mycetoma (grows in the lung cavities) ♦ Fungus Ball

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• Invasive aspergillosis (begins in lungs, spreads to other organs) • Allergic bronchopulmonary aspergillosis (allergy to spores that produces asthmatic attacks)

♦ One clinical manifestation is eosinophila Cause pulmonary infections in AIDS pts or have undergone organ transplantation Aflatoxin: (A. Flavus)

Coumarin derivatives produced by Aspergillus flavus Causes liver damage & tumors in animals

• Ingestion of food contaminated with Aspergillus is associated with carcinoma of the liver ♦ Think “As” for LIVER problems

Toxin binds to DNA & prevents transcription of genetic information Ingested w/ spoiled grains and peanuts and are metabolized by the liver to epoxide (a potent carcinogen)

ZYGOMYCOSIS (MUCORMYCOSIS): (aka “phycomycosis”) Relatively rare fungal infection caused by saprophytic mold (e.g. Mucor, Rhisopuz, and Absidia) These fungi are not dimorphic – Mold Are morphologically characterized by the lack of septa in their hypha – the ONLY non-septate fungus

Characterized by Hyphae growing in and around vessels Pts w/ diabetic ketoacidosis, burns, or leukemias are particularly susceptible to this fungal infection

Pts w/ uncontrolled DM presents with nasal obstruction, proptosis, & perforation of the palate Results in:

Fungi proliferate in the walls of blood vessels and cause infarction of distal tissue Hemorrhagic infarction and necrosis following fungal infection Massive necrotizing lesions of palate w/ poorly controlled DM Black, dead tissue in the nasal cavity and blocks the blood supply to the brain Leads to neurologic symptoms such as headaches and blindness

NOTE: other infections associated w/ AIDS pts: candidiasis, hairy leukoplakia, and cryptosporidium enterocolitis PNEUMOCYSTIS CARINII

Causes Pneumonia (PCP) Originally classified as protozoan, but it’s a yeast Inhaled Most infections are asymptomatic, but due to AIDS, etc.

Most common cause of pneumonia in HIV pts is PCP Tx when CD4 drop below 200 cells/mL in HIV pts

PARASITES/PROTOZOA

Protozoa Diverse group of eukaryotic, typically unicellular, nonphotosynthetic microorganisms generally lacking a rigid cell wall Infestation = presence of parasites on the body (e.g., ticks, mites, lice) or in the organs (e.g., nematodes or worms)

Balantidium coli: non-pathogenic, nonflagellated protozoan Selective Cytotoxicity

A drug action which affects the parasite more strongly than host cell INTESTINAL/MUCOCUTANEOUS PROTOZOA Cyst = environmental form of a protozoa

Once inside the intestine, the organisms excyst & colonize Trophozoite = motile, feeding, colonizing form found w/in intestine GIARDIASIS:

Infection of the small intestine caused by a flagellated protozoan Giardia lamblia One of the most common parasite infections of the small intestine More common in male homosexuals & people who have traveled to developing countries See in campers & hikers who present w/ diarrhea, bloating, flatulence, etc.

AMEBIASIS: Infection of the large intestine caused by a flagellated protozoan Entamoeba histolytica Acute intestinal amebiasis presents w/ dysentery (bloody, mucous-containing diarrhea) Can also produce liver abscess

TRICHOMONIASIS: STD of the vagina or urethra (men) caused by flagellated protozoan Trichomonas vaginalis

Transmitted sexually Causes vaginitis in women; can lead to urethritis or prostatitis in men

Symptoms are more common in women One of the most common infections worldwide Exists only as a trophozoite Entamoeba and Trichomonas species are found in the oral cavity (appear to be nonpathogenic in the “O.C.”)

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NOT found in O.C.: giordio, plasmodium, leishmania, balantidium CRYPTOSPORIDOSIS:

Caused by Cryptosporidium parvum Main symptom is watery diarrhea accompanied sometimes by abnormal cramps, nausea, & vomiting Most severe in immunocompromised pts – may be fatal in these pts

BLOOD/TISSUE PROTOZOA MALARIA:

An infection of RBC by parasite Plasmodium vivax, ovale, falciparum & malariae Drugs taken for prevention are not 100% effective Symptoms can begin a month after the infecting female mosquito bite, Anopheles Early symptoms are nonspecific & often mistaken for influenza Rapid Dx & early Tx are important, particularly for falciparum malaria, which is fatal in up to 20% of infected people

P. vivax & P. falciparum are more common causes of malaria than P. ovale & P. malariae Often first symptoms are a milde fever, headache, muscle aches, and chills (flu-like symptoms) Enlarged spleen – characteristic of malaria due to congestin of sinusoids w/ RBCs Total WBC count is usually normal – but, hyperplasia of the lymphocytes & macrophages Antimalarial drugs – chloroquine, mefloquine, & pirmaquien

BABESIOSIS: Caused by Babesia microti Common in the Northeast U.S.

LEISHMANIA: Transmitted by the sandfly

TRYPANOSOMIASIS: Cause by the trypanosoma species 1) African sleeping sickness = African trypanosomiasis 2) Chagas’ disease = American trypanosomiasis

TOXOPLASMOSIS: Caused by Toxoplasma gondii Teratogenic (Remember ToRCHeS)

Toxoplasma Rubella CMV HSV, HIV Syphilis

Sexual reproduction by this parasite occurs only in the cells lining the intestine of cats Eggs are shed in the cat’s stool People become infected by eating raw/undercooked meat containing the dormant form (cysts) of the parasite May resemble a mild cold or infectious mononucleosis in adults Treated w/ Sulfadiazine (an ABX)

Nematodes:

Roundworms w/ a cylindrical body & a complete digestive tract Two categories based on primary location of body:

Intestinal nematodes: enterobius (pinworm), trichuris (whipworm), ascaris (giant roundworm) and Necator and Ancylostoma (the two hookworms)

Tissue nematodes: Wuchereria, Onchocerca, and Lao are called “filarial worms” Bx of tongue mass – small, coiled, encysted larvae of nematode worms: Trichinae Infections caused by certain nematodes cause marked eosinophilia (abnormally large numbers of eosiopnils in the blood)

Eosinophils do not ingest the parasites – they attach to the surface of parasites via IgE & secrete cytotoxic enzymes contained w/in their eosinophilic granules

Cestodes Tapeworms

Trematodes Flukes

ANTIMICROBIAL AGENTS

ANTIBIOTICS: Broad-spectrum antibiotics: Tetracycline, Chlormycetin, & Cephalosporins

(NOT isoniazid, PCN, Dihydrostreptomy, or streptomycin) Prolonged use of streptomycin can result in damage to auditory nerve Steptomycin is an ABX which inhibits the process of transcription in prokaryotes

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The indiscriminate use of broad-spectrum ABX is contraindicated because… They interfere with indigenous bacteria (NOT produce dependency rxns – Susan Kinder Haake would be pissed) Possible toxic effects of the antibiotics Allergic reactions induced in patients Development of drug resistance by an infectious agent Secondary effects experienced due to creation of an imbalance in the normal body flora Alteration of the immune response

Mechanisms of Action: Cell wall inhibitors:

***Inhibit terminal step in peptidoglycan formation – NOT cell membrane ***The first 4 in this list are beta-lactams Penicillins Cephalosporins Carbapenems Monobactams Vancomycin Bacitracin Cycloserine

Protein synthesis inhibitors: TAs are usually 30 yrs old

• 30S – Tetracyclines • 30S – Aminoglycosides

♦ 30s – Streptomycin CLEC

• 50S – Chloramphenicol – Protein synthesis inhibition by inhibiting translocation by binding to 50S subunit • 50S – Lincomycin • 50S – Erythromycin – ABX of choice for a dental pt w/ a heart valve abnormality AND a PCN allergy

If you have a bact sensitive to penicillin but pt is allergic what would u use instead Cephalosporin – NO: cross-allergenic Amoxicillin – NO, duh! erythromycin

• clindamycin would have been a better choice??? – except for pseudomembranous colitis – only use when have to.

tetracycline • 50S – Clindamycin

Antimetabolites: Sulfonamides (sulfa drugs) Trimethoprim

Cell MB inhibitors: In G- bacteria: Polymyxin & Colistin In fungi: Amphotericin B, Nystatin, Fluconazole, Clotrimazole, Ketoconazole

Nucleic acid synthesis inhibitors: Fluoroquinolone (e.g., ciprofloxacin)

• Represents a DNA gyrase inhibitor with a broad spectrum of activity • Affects Replication, NOT a metabolic pathway

Quinolones • Blocks DNA topisomerase (which normally helps in the breakage and linkages of phosphodiester linkages) --

Bacteriocidal Rifampin

• Binds to DNA-dependent RNA polymerase and inhibits RNA synthesis PENICILLINS

The ABX of choice for prophylactic dental work Cephalosporins are related both structurally & by mode of action

Penicillin will work only on growing cells that contain peptidoglycan in their cell wall It inhibits the terminal step in the peptidoglycan synthesis (cell wall synthesis) Usually non-toxic to humans because humans lack peptidoglycans

• Greatest bacteriocidal activity against growing G+ bacteria (thick peptiodoglycan layer) Don’t use with Erythromycin – Because Ery stops growth and PCN only works if bacteria is growing

Penicillinase is produced by certain bacteria (e.g., some strains of Staphlococcus) that degrade the β-lactam ring structure Certain penicillins have a structural modification that provides resistance to penicillinase

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• This may also narrow the spectrum of action, limiting the primary use of such Abx to tx of Staph infections Penicillinase-resistant penicillins:

• Used during Log Phase • Methicillin, cloxacillin, dicloxacillin, nafcillin, oxacillin, amoxicillin/clavulonate potassium (Augmentin),

ampicillin/sulbactim (Unasyn), piperacillin/tazobactam (zosyn), ticarcillin/clavulonate potassium (Timentin) Penicillin G:

Used for growing Gram + bacteria Penicillin V: Methicillin:

Prescribed primarily in the treatment of severe penicillinase-producing staphylococcal infections Given IV Not frequently used due to:

• Incidence of interstitial nephritis • Availabitily of equally efficacious alternatives (nafcillin & oxacillin)

Methicillin-resistant Staph aureus (MRSA) • Group of resistant Staph bacteria that can be life threatening • Resistant to all penicillinase-resistant penicillins & cephalosporins • Usually resistant to aminoglycosides, tetracyclines, erythromycins, & clindamycin • In past vancomycin has been used against MRSA but there are some organisms resistant to it (VRE)

Broad-spectrum penicillins: Ampicillin: Amoxicillin

• Amoxicillin Rxn: ♦ Pt becomes hypotensive, itchy, and having difficult breathing ♦ Amox reacts with IgE and activates cytotoxic T cells that release lymphokines

BOTH TYPE I and IV activate cytoxic cells???? CEPHALOSPORINS

Cefactor (Ceclor) is a broad-spectrum antibiotic Bactericidal antibiotics Act like penicillins – affect the bacterial cell wall during cell division, preventing closure Bacteria eventually lyse & die Act against a wide range of G+ & G- There are four generations of cephalosporins

Progression from the first through the fourth is associated w/ a broadening of action against more G- bacteria and a decreased activity against G+

1st – cephalexin, cephradine, cefadroxil, cefazolin 2nd – cefaclor, cefuroxime, cefoxitin 3rd – cefixime, cefoperazone 4th – cefepime

Approx. 10% of individuals w/ a penicillin allergy have cross allergenicity to cephalosporins MONOBACTAMS: CARBAPENEMS: VANCOMYCIN: CLINDAMYCIN:

Binds to 50S ribosomal subunit, blocking bacterial protein synthesis Restricted use due to severe diarrhea, GI upset, & pseudomembranous colitis

Pseudomembranous colitis is a major adverse effect of prolonged therapy with clindamycin • Side effects are caused by overgrowth of Clostridium difficile (95% of Pseudo… cases caused by C. difficile)

Bacteriostatic & active against most G+ & many anaerobic organisms, including Bacteroides fragilis (anaerobic G-) Is alternate antibiotic used in dentistry when:

Amoxicillin cannot be used for bacterial endocarditis prophylaxis Tx of common oral-facial infections caused by aerobic G+ cocci & susceptible anaerobes For prophylaxis for dental patients w/ total joint replacement

Can be given to patients allergic to penicillins since there is no cross allergencitiy AMINOGLYCOSIDES: TETRACYCLINES:

Tetracycline No tetracycline for pregnant women or children under 9 years of age Causes pigmentation of developing teeth

Doxycycline & Minocycline

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MACROLIDES & LINCOSAMIDES: CLEC ***These three bind to 50S ribosomal subunit Erythromycin Clindamycin Chloramphenicol

Prophylaxis – Dental Treatment All are given orally, 1 hour prior to the appointment If no amoxicillin allergy:

Amoxicillin • Adults: 2g • Children: 50 mg/kg

Amoxicillin allergy: Clindamycin

• Adults: 600 mg • Children: 20 mg/kg

Cephalexin • Adults: 2g • Children:: 50 mg/kg

Azithromycin • Adults: 500 mg • Children: 15 mg/kg

Most likely mechanism for the increased occurrence of drug-resistant bugs is R factor transfer of resistance Don’t get clowned by “increased mutation rate”

ANTIMYCOBACTERIAL AGENTS RIPE: For TB

Rifampin Isoniazid Pyrazinamide Ethambutol

ANTIVIRALS For herpesviruses:

Acyclovir Vidarabine Ganciclovir Foscarnet

For respiratory viral infections: Amantadine & Rimantadine – Influenza viruses. Ribavirin

For HIV: Zidovudine (AZT) ddC & ddI 3TC Protease inhibitors

ANTIFUNGALS Antifungal drugs affect cell MB permeability

Cause leakage of cellular constituents, leading to death of affected cells AMPHOTERICIN B:

Given orally or by IV for tx of severe systemic fungal infections caused by fungi such as Candida species, Histo, Crypto, and Coccoidio (NOT Nocardiosis)

Bacitracin, polymyxin-B & neomycin are not anti-fungal agents – they are antibiotics Amphotericin B & Nystatin are polyene Abx which impair ergosterol synthesis

• Ergosterol is the major sterol of fungal MBs Systemic administration is associated w/ a high incidence of kidney toxicity

NYSTATIN & CLOTRIMAZOLE: Two antifungals that are used as “swish & swallow” to treat oral candida infections

Nystatin (Mycostatin) is taken as an oral suspension • NOT For psuedomembranous (Use Diflucan)

Clotrimazole (Mycelex) is taken as a troche (lozenge) They work by binding to sterols in the fungal cell MB

Increase permeability & permit leakage of intracellular contents – leads to cell death

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IMIDAZOLES: Aspergillus is very resistant to imidazoles

Treat aspergillus w/ amphotericin B

Summary of Some Antifungal Agents Topical agent Use Mechanism on fungal cell Form Clotrimazole Oropharyngeal candidiasis Alters cell membrane Troche Nystatin Oral cavity candidiasis Alters cell membrane Oral suspension Topical agents (cream) Amphotericin B Cutaneous & mucocutaneous Cand Alters cell membrane Cream Ketoconazole Cutaneous and muco Cand Alters cell membrane Cream Nystatin Cutaneous and muco Cand Alters cell membrane Ointment Systemic agents Fluconazole Oral, esophageal, oropharyngeal Cand Alters cell membrane Tablets Ketoconazole Oral, esophageal, oropharyngeal Cand Alters cell membrane Tablets Amphotericin Systemic candidiasis Alters cell membrane IV injection

VACCINES

Toxoids Are antigenic and Non-toxic Are most often prepared by treating toxins with formaldehyde Weakened bacterial toxins that are no longer toxic but do induce Ab production

Bacterial vaccines: (3 general classes – Toxoids, Killed Organisms, and Attenuated) Given routinely to children

Diphtheria, pertussis, vaccine (Don’t get clowned by the VIRAL pediatric vaccines – MMR) Capsular polysaccharide vaccines:

Streptococcus pneumonia vaccine – pneumonia Neisseria meningitidis vaccine – meningitis Haemophilus influenzae vaccine – meningitis

• Most common cause of acute purulent meningitis in kids 3 months to 2 years Think EMOP • Antigenic component of Haemophilus influenzae vaccine is from a capsular antigen (polysaccharide capsule)

Inactivated protein exotoxins (toxoids) Corynebacterium diphteriae – diphtheria

• Exhibits pathogenicty through toxemia (NOT via bacteremia or septicemia) Clostridium tetani – tetany

Killed bacteria vaccines: Bordetella pertussis vaccine – whooping cough Salmonella typhi vaccine – fever

• Typhoid Fever ♦ Asymptomatic carriers are a major hazard – “Typhoid Mary”

Vibrio cholerae vaccine – cholera Live attenuated bacterial vaccines:

Mycobacterium bovis vaccine – Tb Francisella tularensis vaccine – tularemia Coxiella burnetii vaccine – Q fever

Active immunity – induced by vaccines prepared from bacteria or their products Passive immunity – provided by the administration of preformed ab in preparations called immune globulins (toxoids)

Provides immediate protection & a vaccine to provide long-term protection Rabies and Clostridium tetani vaccines:

Result in artificially acquired active immunity Can use vaccine after introduction of the virus to stop clinical symptoms Longest incubation period Used to elicit an immune response before the onset of disease symptoms Effectiveness of this type of vaccine depends on:

Slow development of the infecting pathogen prior to the onset of symptoms Ability of the vaccine to initiate Ab production before the active toxins are produced/released

Viral Vaccines Live attenuated

Induce humoral immunity AND cell mediated immunity but have reverted to virulence on rare occasions MMR, Sabin Polio, VZV, Yellow fever (flavaflav)

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Killed Only induce humoral immunity, but are stable Rabies, Influenza, Hepatitis A, SalK (K for Killed) Polio

Recombinant HBV (antigen = recombinant HBsAg)

SOME CURRENT VIRAL VACCINES

Disease Type of Vaccine Smallpox Attenuated live virus Yellow fever (viral hepatitis) Attenuated live virus Hepatitis B Purified HBsAg: recombinants HBsAG Measles Attenuated live virus Mumps Attenuated live virus Rubella Attenuated live virus Polio Attenuated live virus (Sabin)—oral Polio Inactivated virus (Salk vaccine)—injection Influenza Inactivated virus Rabies Inactivated virus Varicella (chickenpox) Attenuated live virus Hepatitis A Inactivated virus

Adjuvants:

Non-specific, mildly irritating substances Purpose: to enhance Ab response Enhance Ag uptake by APCs Added to vaccines to slow down absorption & increase effectiveness Freund’s Adjuvant:

Common experimental adjuvant – consists of killed M. tuberculosis suspended in lanolin & mineral oil Used to elicit stronger T- & B-cell mediated responses when Ag/s alone fail to evoke sufficient response

Human vaccines contain aluminum hydroxide or lipid adjuvants Alum-precipitated Ag/s:

Formed from protein Ag/s mixed w/ aluminum compounds • Serves as a local inflammatory stimulus • A precipitate is formed that is more useful for establishing immunity than are the proteins alone

Released more slowly in the body, enhancing stimulation of the immune response Adjuvants eliminate the need for repeated booster doses of Ag & permits use of smaller Ag doses in the vaccine

Toxoid (aka immune globulins): Inactivated protein exotoxin (bacterial toxin) Induce formation of specific antitoxin Ab/s that serve as the basis for the specific protection from the toxin Used for diphtheria, tetanus, and other diseases Prepared by treating toxins w/ formaldehyde

Not all toxins can be converted to toxoids by treatment w/ formaldehyde But is strong enough to induce formation of antibodies & immunity to the specific disease

Antigenic, non-toxic Antitoxin:

An Ab formed in response to a specific toxin Antitoxins in serum – Tx or prevention of certain bacterial diseases

Can neutralize unbound toxin to prevent the disease from progressing Tetanus antitoxin – Tx or prevention of tetanus

Botulinum antitoxin – Tx of botulism An intoxication rather than an infection

Diphtheria antitoxin – Tx of diphtheria Routine Vaccines

Infants are routinely immunized against: DPT shot - Bordetella pertussis, Corynebacterium diphtheriae, and Clostridum tetani (NOT Brucella abortus or H.

Influenzae) DPT vaccine (diphtheria-pertussis-tetanis): BCG vaccine – avirulent bacteria (TB vaccine), not recom’d in us ‘cuz of low chance of infectivity, ruins PPD test

Unlike DPT, BCG vaccine consist of avirulent bacteria DPT – pertussis is killed whole bact, ∴ in US now suggest DTaP (pertussis Ag/s, not killed bact); diph / tetanus

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Rubeola (measles), pertussis, smallpox, poliomyelitis, mumps & tetanus are all prevented by active immunization

INFECTION CONTROL

The most effective means of preventing disease transmission in a dental office is based on the concept of Universal Precautions ♦ Don’t get clowned by “sterilization”, “asepsis”, or “barrier techniques” – Universal precautions encapsulates all of these

FIND OUT OSHA’s blood borne pathogen protocol is used to protect whom????? ♦ To protect the employees!!!

• OSHA’s Bloodborne Pathogens Standard 29 CFR 1910.1030 recommends the use of a tuberculocidal disinfectant for surfaces/objects that may be contaminated with blood and/or body fluids. (this represents an intermediate level disinfectant)

FIND OUT Dental personnel are most at risk for transmission of TB?? Dental Instruments Or Aerosolization FIND OUT What does OSHA stand for? Occupational Safety and Health Administration Some general notes/definitions:

♦ Concentration & contact time: critical factors that determine effectiveness of an antimicrobial agent • Any/all of the 3 major portions of microbial cells can be affected: cell MB, cytoplasmic contents (particularly enzymes) &

nuclear material ♦ It is not possible, nor necessary to sterilize all environmental surfaces which become contaminated during patient care. In many

instances, because of the relatively low risk of microbial transmission, thorough cleaning of the surfaces is sufficient to break the cycles of cross-contamination and cross-infection

♦ Bactericidal: • Antibacterial solution w/ directly kills bacteria • “Cidal” agents & processes are designed to ensure microbial inactivation • EXs: Glutaraldehyde, betabropiolactone, ethylene oxide, formaldehyde are all bacteriocidal

♦ Bacteristatic: • Inhibit their metabolism and replication • Affected organisms can remain viable but inactive for extended intervals • Not directly kill or inactive microbes

♦ Organism resistance: high→low • Prions→Bacterial spores→Mycobacteria→Parasitic bacteria→Small, non-enveloped viruses→Trophozoites→Non-

sporulating G- bacteria→Fungi→Large non-enveloped viruses→Non-sporulating G+ bacteria→Enveloped viruses STERILIZATION:

♦ The use of physical or chemical procedure to destroy all microbial life, including bacterial endospores ♦ Limiting requirement is removal of spores ♦ Filtration:

• Liquids are generally sterilized by filtration • The most commonly used filter is composed of nitrocellulose and has a pores size of 0.22 µm

This size will retain all bacteria and spores • Filters work by physically trapping particles larger than the spore size • Used for liquids that will be destroyed at temps over 90°C

♦ Pre-cleaning: • The most important step in instrument sterilization • Debris acts as barrier to the sterilant and sterilization process • Ultrasonic instrument cleaning is the safest and most efficacious method of precleaning • 2 purposes of cleaning:

Reduction in concentration/number of pathogens Removal blood, tissue, bioburden, & other debris which can interfere w/ disinfection

♦ Heat sterilization is recognized as the most efficient, reliable, biologically monitorable method of sterilization • All reusable items that come in contact w/ pt must be sterilized

DISINFECTION: ♦ Less lethal than sterilization ♦ Use of chemical agents to destroy virtually all pathogenic microorganisms on inanimate surfaces (headrests, light handles,etc.)

• Does not include destruction of all pathogen or resistant spores Submerging dental instruments for 15 minutes in a cold disinfectant is unacceptable as a sterilizing method because

spores are not killed during that time Immersion of instruments for 30 minutes in cold disinfectant is expected to destroy strep and staph, NOT spores or

Hep B

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Glutaraldehyde is approved as an immersion sterilant, but takes a long time • Not considered safe for use on living tissue

♦ Disinfectant: • Antimicrobial agents that kill (germicide) or prevent growth (microbiostatic) of pathogenic microorganisms • Not safe for living tissues (antiseptics are safe) – applied only to inanimate objects • Chlorine: a powerful oxidizing agent that inactivates bacteria and most viruses by oxidizing free sulfhydryl groups

Active component of hypochlorite (bleach), which is used as a disinfectant • Phenol: original disinfectant used in hospitals, but is rarely used as a disinfectant today because it is too caustic • DNP 2,4-dinitrophenol

P:O = Phosphorylation : Oxygen ratio = amount of ATP produced from ADP + Pi / per nanogram of O2 consumed DNP disrupts coupling in mitochondria DNP decreases the P:O ratio in mitochondria, so NOT allowing it to make energy w/ O2

♦ We want the bugs P:O ratio to do down • Formaldehyde: (37% solution in water = formalin) denatures protein and nucleic acids

♦ A “high level” sterilant (disinfectant) is characterized by what? • Capable of killing all microorganisms and low concentrations of bacterial spores. Used mainly as a sterilant for critical

medical devices; monitored by the FDA • Examples: glutaraldehyde, formaldehyde, peracetic acid, hydrogen peroxide

♦ Intermedial levels agents: • Phenols, iodophors, hypochlorite, certain preparations containing alcohols & others

These are able to penetrate the wax and lipid outer layers surrounding mycobacteria • M. tuberculosis – recognized as a benchmark criterion for disinfectant effectiveness

Morphology/structure of tubercle bacilli make them relatively resistant to penetration by a # of low-level disinfectants • Examples: chlorine compounds, alcohol, phenol compounds, iodophors, quaternary ammonium compound

♦ Low level agents • Effective against most bacteria, some viruses and fungi, but NOT TB or Spores • These disinfectants contain a lower concentration of active ingredients

ANTISEPSIS: ♦ Antiseptics:

• Chemical agents similar to disinfectants but may be applied to living tissue (i.e., handwashing) • Can be applied to external body surfaces or mucous MBs to decrease microbial #s – not to be taken internally

♦ Temporarily lowers the concentration of normal, resident flora ♦ Alcohol

• is the most widely used antiseptic • Used to reduce the # of microorganisms on the skin surface in wound area • Denatures proteins, extracts MB lipids & dehydrates • Dissolves lipids • Inactivates some viruses (only lipophilic viruses) • Disadvantages:

Evaproates too quickly Has diminished activity against viruses in dried blood, saliva & other secretions

♦ So, not regarded as effective surface cleansing agent • Isopropyl alcohol (90-95%) – major form used in hospitals • Isopropyl alcohol 70%

Disinfectants against herpes simplex but NOT rhinovirus • Ethanol (70%) – widely used to clean skin prior to immunization/venipuncture • Iodine – most effective skin antiseptic used in medical practice (oxidizing agent & combines irreversibly w/ proteins)

♦ Handwashing • Primary disease prevention measure in healthcare

Significantly reduces the # of transient & normal microorganisms that colonize host tissue • Soap is only good for removal of bugs from the skin • Handwash agents include: chlorhexidine gluconate & triclosan

Both have been shown to exhibit an antimicrobial effect when used as handwash agents in health care settings They also show substantivity = a residual action on washed tissues for extended periods

• Hand hygiene (not “handwashing”) Isopropyl alcohol – for hand hygiene procedures – products containing 60-80% alcohol DO NOT use water

SANITATION: ♦ Tx of water supplies to reduce microbial levels to safe public health levels

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PASTEURIZATION: ♦ Tx of dairy foods for short intervals w/ heat, to kill certain disease-causing microorganisms ♦ Target of pasteurization is the destruction of M. tuberculosis

Spaulding Classification

♦ Rule of thumb is anything that can be sterilized should be, but for plastics and other, see below ♦ BONE/BLOOD Mucous Skin No contact

Spaulding Inanimate Objects Classification

Category Level Risk Objects

Critical Heat Sterilization Very high Touch bone or penetrate tissue; blood present (scalpels, forceps, scalers, probes, implants)

Semi-Critical Sterilization, High-level disinfection

Moderate Touch mucous membrane but not penetrate; no blood, (mirrors, burnishers, amalgam carriers, etc.)

Non-Critical Intermediate Level Low Unbroken skin contact; no blood; (masks, clothing. b.p. cuffs)

Environmental surfaces: Equipment housekeeping

Low Level disinfection; sanitation

Minimal No direct patient contact, no blood units, knobs, light floors, walls, counters

Saturated steam sterilization (autoclave):

Most practical & economical & most currently effective sporicide Most efficient method for destruction of viral & fungal microorganisms Moist heat destroys bacteria by denaturation of the high protein-containing bacteria via heat under pressure 121°C (250°F) at 15 psi for 20 min

Used for wrapped instruments To positively destroy all living organisms, the minimum required temperature is 121°C So, a case with solder that melts at 175°C is OK

134°C (270°F) at 30 psi for at least 3 minutes (flash cycle) Indicated for unwrapped instruments

Usually only 10 min required to destroy all bacteria Additional time is allowed for penetration when the instruments are wrapped

Spore forming pathogens provide the ultimate test for efficacy of sterilization Resist boiling at 100°C at sea level – they must be exposed to higher temperatures

• Cannot be achieved unless the pressure is increased Kills even the highly heat resistant spores of Clostridium botulinum

• Clostridium and Bacillus anthracis spores used to check effectiveness of autclaving Weekly spore testing of autoclave units is recommended Using calibrated biological indicators remains the main guarantee of sterilization

• Spores from Bacillus stearothermophilus should be used to verify heat in autoclave • These preparations contain bacterial spores – more heat resistant than vegatiative bacteria, viruses & other microbes

Best method of avoid cross-contamination of Hepatitis B is by autoclaving or using dry heat on all instruments used in Tx

Dry heat sterilization: 320°F (160°C) for 2hrs at 15 psi 340°F (171°C) for 1hr – also effective According to Spaulding Classification

Semi-critical items should be reprocessed by heat stabilization if the material is heat stable Items which are usually sterilized by dry heat can be autoclaved

Remove immediately after cycle to diminish possibility of corrosion & dulling sharp points/edges (carbon steel instruments)

Dry heat destroys microorganisms by causing coagulation of proteins Advantages:

Effective & safe for sterilization of metal instruments Does not dull or corrode instruments

Disadvantages: Long cycle

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Poor penetration Ruins heat-sensitive material

Rapid Dry Heat Sterilization Can NOT be WET 12 minutes at 350 °F/177°C for Wrapped 6 minutes at 350 °F/177°C for Unwrapped Internal Air control Provides a very fast cycle time, no dulling of cutting edges, & dry instruments after cycle Forced air, dry heat convection ovens used for sterilization of heat-stable instruments Higher temperature is used; shorter duration

Ethylene Oxide: (Unsaturated chemical vapor) Used extensively in hospitals for sterilization of heat-sensitve (heat-labile) materials such as surgical instruments & plastics Kills by alkylating both proteins & nucleic acids – irreversibly inactivates them

Primarily inactivates cellular DNA!!!!! Most reliable gaseous sterilizing agent available for dental instruments Limited use because:

Fairly toxic to humans and is also flammable – unsafe Slow process (10-16 hours) depending on the material to be sterilized – Kaplan says 8-12 hours

• The method of sterilization that takes the Longest Advantages:

Highly penetrative Does not damage heat sensitive materials (rubber, cotton, plastic) Evaporates w/out leaving a residue Works well for materials that cannot be exposed to moisture

NOTE: instruments must be dry before both ethylene oxide & dry heat sterilization – water interferes w/ sterilization process

Glutaraldehyde 2%: Can be used as a disinfectant or sterilant An alkalizing agent highly lethal to essentially all microorganism

Chemical with broadest antimicrobial spectrum of activity Recommendend for disinfecting dental units & handpieces Requires sufficient contact time (12-15 hours) Requires absence of extraneous organic material

Advantages: Most potent category of chemical germicide Can kill spores (after 10 hours) EPA registered as chemical sterilant

• Approved as an immersion sterilant Can be used on heat sensitive materials

Disadvantages: Long period required for sterilization Allergenic Not an environmental disinfectant Extremely toxic to tissues

In hospitals, glutaraldehydes are used to sterilize respiratory therapy equipment Other Disinfectants:

Alcohols, chlorhexidine, & quaternary ammonium compounds Immersion of dental instruments in cold disinfectants will not destroy spores or the hepatitis viruses (they are resistant

to physical and chemical agents) Quaternary ammonium compounds (e.g., benzalkonium chloride):

Cationic detergents and have the narrowest range of effectiveness Quaternary ammmonium compounds have the narrowest antimicrobial spectrum Used as disinfectants & antiseptics G+ bacteria are most susceptible to destruction These compounds are not sporicidal, tuberculocidal, or viricidal Inactivated by anionic detergents (soaps & iron in hard water) Mechanism of action is against the cytoplasmic membrane

UV Sterilization UV light at germicidal wavelengths (185 -254 nm) causes thymine molecules in the DNA to dimerize and become inactive Bacteria is rendered useless, though it may not die Only used as supplementary sterilization in conjunction with other methods

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Irritation dermatitis: Most common form of adverse epithelial reaction noted for health-care professionals 20–30% of HC workers suffer from occasional or chronic dermatitis on their hands Most common manifestation of the condition is irritation dermatitis, a non-specific immune reaction caused by contact w/ a

substance that physically or chemically damages the skin Aggravated by frequent hand washing, residual glove powder left on hands, & harshness or repeated use of some antiseptic

handwash agents More common in cold climates during winter months

Face masks should be changed between patients and more often if heavy spatter (becomes moist w/in or w/out) is generated Personal protective equipment clinical jackets should be long sleeve, high neck and are required to minimize the potential for

exposed skin to contact, and therefore become contaminated w/ a pt’s blood, saliva, or other potentially infectious material Antigens most responsible for an immediate Type I reaction to natural latex are: Proteins

Only a few of over 250 proteins found in sap from rubber tree Hevea brasiliensis are responsible for Type I immediate IgE mediated reactions to natural rubber latex These are water-soluble macromolecules that can leach out of latex gloves when a person perspires, or be detected on the

surface of other products containing natural rubber latex Vinyl or nitrile gloves are worn to treat individuals who develop Type I immediate allergic reaction to latex

Hypoallergenic latex gloves are still latex w/ a chemical coating • Not an appropriate latex alternative, as allergic manifestation can still develop

Latex allergy risks factors include: person w/ multiple surgeries, atopy (type I), rubber industry workers, persons w/ an allergy to bananas but NOT a person w/ a pollen allergy

Hepatitis and Sterilization HBV is the most infectious target of Standard Blood Precautions

HBV is the most infectious bloodborne pathogen known = greatest occupation health care risk of bloodborne disease Infection control precautions aimed at preventing this viral transmission have also been shown to be effective in preventing

HBV & HCV cross-infection Responsible for infection in 10–30% of exposed, susceptible HC workers Concentration of HBV in chronic carrier ranges between 106 & 109 virions per ml, it is significantly lower for AIDS

• Viral concentration of HCV infected individuals is between HIV & HBV Transmission of Hep B – parenteral, dirty instruments, microabrasions, and blood, feces, saliva

Hepatitis C – transmitted by accidental needle sticks, blood transfusions, drug addicts sharing contaminated syringes Anionic surface acting substances (soaps/detergents):

These substances alter the nature of interfaces to lower surface tension & increase cleaning Their primary value appears to be their ability to remove microorganisms mechanically from the skin surface Include synthetic anionic detergents & soaps Detergents:

Are “surface-active” agents composed of long-chain, lipid-soluble, hydrophobic portion & a polar hydrophilic group which can be a cation, an anion, or a nonionic group

These surfactants interact w/ cell membrane lipids through their hydrophobic chain and w/ the surrounding water through their polar group and thus disrupt the cell MB

Nonionic chemicals do not possess any antimicrobial properties

IMMUNOLOGY Immune system

Main function = to prevent or limit infection by microorganisms such as bacteria, viruses, fungi, and parasites Protection is provided primarily by the cell-mediated & Ab-mediated arms of the immune system The other two major components of the immune system: 1) complement and 2) phagocytes

Opsonization ***Opsonin helps prepare bacteria for phagocytosis (NOT intracellular microorganisms or viruses) Phagocyte locates microorganism via chemotaxis Adherence sometimes facilitated by opsonization:

Opsonization is the coating of the microbial cell w/ plasma proteins This speeds up phagocytosis!!! Opsonins = C3 & the Fc portion of the Ab - These both mark bacteria for phagocytosis. The Fc receptors on macrophages react w/ the Fc region of IgG & hold the microbe close to the phagocytic cell MB, thus

facilitating the engulfment process Pseudopods then encircle/engulf the microbe

The phagocytized microbe, enclosed in a vacuole (phagosome), is killed by lysosomal enzymes & oxidizing agents Remember, the capsule protects bacteria from phagocytosis

Neutralization Ab prevents bacterial adherence

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Example is sIgA in the mouth Complement Activation (more below)

Ab activates complement enhancing opsonization and lysis Phagocytosis

Involves ingestion/digestion of: microorganisms, insoluble particles (like tattoo ink!), damaged/dead host cells, cell debris, activated clotting factors

Mediated by macrophages & PMNs Both will phagocytize bacteria coated w/ Ab & complement

• The C3b fragment of complement binds to bacteria opsonized by Ab • Then the C3b binds to receptors on phagocytic cells & signals them to phagocytize the organism

Stages: Chemotaxis – movement of cells up a gradient of chemotactic factors Adherence – works well for whole bacteria/viruses; less so for proteins or encapsulated bacteria Pseudopodium formation – protrusion of MBs to flow around the “prey” Phagosome formation – fusion of the psuedopodium w/ a MB enclosing the prey Phagolysosome formation – phagosome-lysosome fusion

• Lysosome contains H2O2, free radicals, peroxidase, lysosyme, hydrolytic enzymes Elimination – via exocytosis

Phagocytes: Includes PMNs, Macrophages, Dendrititic cells and Langerhans, and apparently Eosinophils

• Bacteria are ingested by Neutrophilic Lymphocytes Fixed – do not circulate (fixed macrophages & cells of the reticuloendothelial system) Free – circulate in bloodstream (PMNs & macrophages) One Q said: PMNs and Eosinophils (remember granulocytes are not part of RE system)

• Eosinophils CAN phagocytose antigen/antibody complexes Macrophages

Macrophages are activated by lymphokines (mostly IFN-gamma) Chemotactically, C5a and various cytokines are chemoattractants for activated macrophages Macrophages have MHC II molecules that present antigenic peptides to T cells

Macrophages present Ag to antigen-specific T cells (CD4 T helper cells) See discussion below on MHC

Hemosiderin: Insoluble, iron-containing protein derived from ferritin Normally occurs in small amounts w/in macrophages of bone marrow, liver, & spleen Can accumulate in tissues in excess amounts, causing:

• Hemosiderosis: ♦ Occurs when hemosiderin builds up in tissue macrophages ♦ Usually does not cause tissue or organ damage ♦ Often associated w/ thalassemia major (beta) –

Think H for Hb H and tHalassemia for Hemosiderin and Histoplasmosis • Hemochromatosis (aka bronzed disease):

♦ More extensive accumulation of hemosiderin throughout the body ♦ Tissue & organ damage ♦ Increased ferritin and increased transferritin saturation ♦ Most often is hereditary disorder – develops in men >40 y.o. ♦ Classic triad – micronodular cirrhosis, pancreatic fibrosis, & skin pigmentation “bronze diabetes” ♦ Results in CHF & increase risk of hepatocellular carcinoma ♦ Disease may be primary (auto recessive) or secondary to chronic transfusion therapy

Immunologic Tolerance Self vs. Non-self --- How the body knows…why individuals do NOT have an immune response to self proteins

Clonal deletion: • Immature lymphocytes that make self reactive receptors, are deleted before they are released to do their thing

♦ In the medulla of the thymus • 1 of 3 current theories to explain why we don’t attack ourselves – and Kaplan describes it…

Lack of co-stimulatory signals: • Foreign & self peptides are the same, so both are able to bind to MHC molecules (so, not the answer) • In order for an immune response to occur, the APC presents the Ag to the TCR

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♦ It must ALSO have a secondary signal, or costimulator…this is all part of Congitive Recognition, which is the reason Frogs don’t snap at every black particle, it must act like a fly…which is the same thing as why our body’s cells must have dual signals to know when to attack

Humoral vs. Cellular Immunity (i.e. Differentiation of B/T cells) Microorganism activates either: Cell Mediated Immunity

Macrophage via IL-12 Activates Naïve Helper T-cell (Th-0) via IL-12 Activates Th-1 cells ♦ Then Activated Th-1 either

via Gamma Interferon Activates Macrophage via IL-2 Activates Cytotoxic T cell (CD8)

Humoral Immunity (No name cell) via IL-4 Activates Naïve Helper T-cell (Th-0) via IL-4 Activates Th-2 cells

♦ Then Activated Th-2 cell via IL-4 or Il-5 Activates B cell Plasma cell Produces antibodies Summary

Th1 (cell mediated) • Produce IL-2 and gamma interferon, activate macrophages and Tc cells

Th2 (humoral) • Produce IL-4 or IL-5, IL-6, IL-10 and help B cells make Ab

Cellular immunity: Cellular responses involve T-cells, and result in production of helper T cells & cytotoxic T cells Mediated by T-cells either through 1) release of lymphokines or 2) exertion of direct cytotoxicity Immunologic resistance to MOST intracellular pathogens is manifested with Cellular immunity

NOT humoral immunity, wheal & flare reactions, or non-specific serum protection Host defense against M. tuberculosis, viruses, and fungi, Allergy (only poison oak –contact), Graft and tumor rejection, and

regulation of antibody response (Help/Suppression) It comprises delayed-type (type IV) hypersensitivity reactions Specific acquired immunity involving T-cells Acts to resist most intracellular pathogens (bacteria & viruses)

Humoral (Ab-mediated) immunity: Humoral responses are generated against most antigens and require the secretion of Ab by plasma cells (activated B-cells) The primary response is always IgM

IgM is initially produced (after a 3-5 day lag phase – Ig/s undetectable), followed by class switching & a decline in IgM Later, IgG & sIgA become detectable

The secondary response is the result of isotype or class switching, resulting in synthesis of IgG, IgA, &/or IgE An anamnestic response to previously encountered Ag Memory B & T cells are responsible for this phase IgG levels rise more rapidly than in 1° phase (requires less Ag to elicit response) This response explains the efficacy of booster injections of vaccines May produce high levels of IgE

B-cells (like T-cells) have surface receptors which enable them to recognize the appropriate Ag Do not themselves interact to neutralize or destroy the Ag After Ag recognition, B-cells reside in the 2° lymphoid tissue & proliferate to form daughter lymphocytes These B-cells then develop into short-lived plasma cells The plasma cells produce Ab/s & release them into blood at the lymph nodes Some activated B-cells become memory cells instead of plasma cells

• They continue to produce small amounts of Ab long after beating the infection The key to humoral immunity = ability to react specifically w/ Ag/s Accomplishes neutralization and inactivation of bacterial toxins Provides protection against encapsulated bacteria Opsonization may occur as a component of the humoral immune system in response to virulent Strep pneumoniae

(Because you have to opsonize the S. pneumoniae’s antiphagocytic capsule before you can kill it) If B cells were eliminated, how would you achieve humoral immunity???

Injections of gamma (G) globulin (Ig)??? Natural (innate) immunity:

Present at birth Occurs naturally as a result of a person’s genetic constitution or physiology Does not arise from a previous infection or vaccination

Comprised of skin, mucous MBs, secretions such as saliva & tears, phagocytic cells & NK cells Nonspecific An example of innate immunity is the alternative pathway of complement, which is demonstrated by phagocytosis of

microbes by neutrophils and macrophages

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See 2000 Q1 & 2001 Q309 Response does not improve after exposure to the organism Processes have no memory EX: HCl in stomach, fever, phagocytosis by PMN (NOT sIgA in mother’s milk)

Acquired immunity: Develops in response to Ag exposure Comprised of Ab/s (IgG, IgA, etc) and sensitized lymphocytes (T cells & B cells) Specific Improves upon repeated exposure to the organism Long-term memory

May have an anamnestic response – subsequent response is faster & bigger Due to memory T cells & B cells

Active or passive Active immunity

• Host actively produces an immune response consisting of Ab/s & activates helper and cytotoxic T-cells • Main advantage – resistance is long-term (years) • Major disadvantage – slow onset • Rubeola, pertussis, poliomyelitis, and mumps • Toxoid still give active

Passive immunity • Ab/s are preformed in another host • Main advantage – immediate availability of Ab/s • Rapid onset • Major disadvantage – short duration of active immunity (That’s why you need the tetanus shot every 10 years) • Think To Be Healed Rapidly

♦ Tetanus toxin, Botulism toxin, Hbv, Rabies (After exposure, pts are given preformed antibodies) • Antitoxin is Passive

Occurs naturally or artificially Natural Active –

• REGULAR • Person is exposed to an Ag & body produces Ab/s • EX: Recovery from mumps infection confers lifelong immunity

Natural Passive – • EX: Ab/s (IgG) passed across placenta from mother to fetus • EX: IgA passes from mother to newborn during breast-feeding • Resistance of new-born to whooping cough

Artificial Active – vaccination w/ killed, inactivated or attenuated bacteria or toxoid • Administration of tetanus toxoid – which is a watered-down toxin • Injection of a killed viral vaccine

Artificial Passive – injection of immune serum or γ-globulin • If person were given tetanus antitoxin NOTE Toxin = ANTItoxin

NOTE: Hypersensitivity – an exaggerated immunological response upon re-exposure to a specific antigen EX – positive skin test after having a disease See below for more info on the four types of hypersensitivity reactions

Immunogens & Antigens: Antigen = any substance that can be specifically bound by Ab or a TCR

Immunogen = an antigen that induces an immune response Include all proteins (they are the most antigenic), most polysaccharides, nucleoproteins, and lipoproteins

Epitope – ON the AntiGEN the Ab binding site of the Ag for a specific Ab

Antibodies: (See below) Able to bind to epitopes on a wide variety of molecules

T-cell receptors (TCR): CD3 molecules link noncovalently to the TCR

• This causes internal signaling, triggering the T-cell Only able to recognize peptides bound to MHC proteins Cannot recognize Ag alone – only in the context of MHC molecules

Haptens:

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Small molecules that act as an Ab epitope, but will not induce immune responses since they are not recognized as T-cell Ag/s

Have antigenic determinants, but are too small to elicit the formation of Ab/s by themselves Can do so when covalently bound to a carrier protein

Many allergens (e.g., penicillin) are haptens The catechol in the plant oil that causes poison oak is a hapten Usually responsible for contact sensitivity Not immunogenic because they cannot activate helper T cells

Ab production involves activation of 1) B lymphocytes by the hapten & 2) helper T cells by the carrier MHC (major histocompatibility complex):

Glycoprotein A collection of polymorphic genes encoding for proteins that regulate immune responses In humans, the MHC genes are termed HLA (human leukocyte antigens)

MHC is an antigen located where? 6th Human chromosome (I don’t know if this is what they really asked) Fxns Present exogenous antigens to T cells and determine tissue type *Antigen processing = mechanism for internalization & re-expression of Ag on APC MBs by MHC I & II MHC I: (Think whistle blower, broadcasting that the factory is making something they are not supposed to)

Found on the surface of all nucleated cells & platelets • HLA-1 is found on all nucleated cells

Bind peptides processed from protein synthesized in the cell cytosol • Endogenous Ag/s are presented by MHC I molecules to CD8 T cells

HLA Class I = HLA-A, HLA-B, HLA-C • T-lymphocytes (not B) recognize Ag on the surface of APCs in the context of HLA-B

Cytotoxic T cells (CD8) recognize MHC I on infected cells (Product is 8) MHC I Ag loading occurs in rER (viral antigens)

MHC II: (Think Public Health Inspector—Ate something that made them sick, so the APCs, via MHC II to CD4s to B cells to post their Poor Health Grade (Ab) everywhere) Found on some cells, including APCs, B cells, and thymic epithelial cells invovled in T cell maturation Bind peptide epitopes from endocytosed molecules

• Exogenous Ag/s are processed & presented by MHC II molecules to CD4 T cells Are necessary for Ag recognition by helper T cells HLA Class II = HLA-DR, HLA-DQ, HLA-DP CD4 cells recognize viral, bacterial, parasite, or injected proteins in association w/ class II (Product is 8) Are the main determinant of organ rejection MHC II Ag loading occurs in acidified endosome

Short Story for Clarification -- REVIEW 1st – Virus or bug infects the cell 2nd – APC (macrophage, B cell, or Dendritic cell) eats part of the produced virus or protein from the infected cell and grabs a

viral epitope and then displays it on its MHC II in hopes that a Helper CD4 cell will come to the rescue 3rd—CD4 T cell recognizes the viral epitope on the APC with its own TCR and receives costimulation via IL-1 from the APC

to verify the distress signal The Costimulatory signal is given from APC (B7) to the Helper T-cell (CD 28)

4th—With the newly confirmed distress signal, the CD4 cell either: Activates Cellular immunity (Tags a CD8 cell with IL-2 to go find a cell with such and such epitope and kill it) Activates Humoral immunity (Tags a B cell with IL-2,IL-4, IL-5 to start making antibodies against such and such epitope

in the lymph node Interleukins (largest group of cytokines):

Fundamental function appears to be communications between (“inter-”) various populations of WBCs Group of well-characterized cytokines produced by leukocytes & other cell types Have broad spectrum of functional activities that regulate the activities & capabilities of a wide variety of cell types Particularly important as members of cytokine networks that regulate inflammatory & immune responses

Act as messengers between leukocytes involved in the immunologic or inflammatory response Think mmmm, T-Bone stEAk

IL-1: A macrophage-derived factor Stimulates activites of T-cells, B-cells, & macrophages (mmmmm for Macrophage) Stimulates IL-2 secretion Pyrogenic (HOT)

IL-2: Produced by activated T cells (T- in T-bone)

Stimulates antigen-activated T helper & NK cells (as well as cytotoxic T cells) Also stimulates B cells

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IL-3: T-cell product that stimulates the growth & differentiation of various blood cells in bone marrow

(B in T-Bone) Secreted by activated T cells

IL-4: Secreted by activated helper T cells & mast cells

Stimulates B-cells Increases IgG & IgE (E in stEAk)

IL-5: Secreted by activated helper T cells Promotes B cell maturation IL-5 is a B-cell growth & differentiation factor Increases IgA & synthesis of Eosinophils (A in stEAk)

Acute Phase cytokines IL-1, IL-6, and TNF alpha (secreted by macrophage to do a bunch of stuff, like suppress viral replication)

IL-6, 7, 8, 10, 12: see Kaplan, p. 101 for thie summaries Immunoglobulins = Antibodies:

Glycoproteins found in blood serum Synthesized by plasma cells in the spleen & lymph nodes in response to detection of a foreign Ag Two functions:

Bind epitopes on Ag/s – direct attack Stimulate other biologic phenomena such as activating

complement & binding Fc receptors on other lymphoid cells

Mediate anaphylaxis, atopic allergies, serum sickness, and arthus reactions

Structure: Consist of two heavy chains & two light chains Heavy chain contributes to both Fc and Fab fragments Light chain only contributes to Fab Fab (Antibody)

• Contains Antigen binding site • Area from the Hinge region and up • Hypervariable Region • Ag binding to the Fab is noncovalent

Fc (Cell) • The Stem of the “Y” • Binds to the Phagocytes, Mast cells, Basophils,

Eosinophils, etc. • Think C Constant, Carboxy, Complement binding, and Carbohydrate side chains

The variable part • VH and VL (amino terminal side) recognizes the antigens

Constant regions • In IgG and IgM, it fixes complement • Carboxyl terminal side

Disulfide Bonds Between 2 Heavy Chains Between Heavy and Light Chains

Ig Epitopes Allotype (polymorphism)

Ig epitope that differs among members of same species Can be on light or heavy chain

Isotype (IgG, IgA,etc.) Ig epitope common to a single class of Ig (five classes, determined by heavy chain) An immune cell posseses IgM and IgD on its cell surface…which of the following differs between them?

• Heavy Chain Variable - VH Idiotype (specific for an antigen)

Ig epitope determined by antigen-binding site Think “Idio” are unique

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Immunoglobulin functions (condensed): IgG: Opsonization, Placental passage, Complement activation, 2ndary Response IgA: Mucosal (secretory) immunity, prevents attachment, Gets secretory portion from epi cells first IgM: Complement activation, 1ary Response, does NOT cross placenta, Ag receptor on B cells IgE: Basophil & mast cell sensitization, Type I hypersensitivity, Immunity to worms IgD: Antigen triggering of B cells

Ig Isotypes (detailed): IgG:

Most abundant Only Ig that crosses the placenta Activates complement Predominant serum Ig found during a memory response Main defense against various pathogenic organisms As the severity of Periodontal Disease increases, there is an increase in plasma cells that produce IgG Secondary or amanestic response to protein antigen

• Characterized by production of IgG Ab/s with High Titer T1/2 = 1 month Where is it activated????

IgA: 2nd most abundant

• Remember that IgA produces more than all of the others combined, but SHORT half life, that is why IgG is most abundant

Polymeric IgA • Present in body secretions, such as (saliva, tears, breast milk, especially colostrums)

Protects surface tissues Synthesized by plasma cells in mucous MBs of the GI, respiratory & urinary tracts

• Important in these areas – plays a major role in protecting surface tissue against invasion by pathogenic microorganisms

• Provides 1° defense at mucosal surfaces – bronchioles, nasal mucosa, vagina, prostate, & intestine sIgA

• Found in tears, colostrum, saliva, & milk • Producd by plasma cells in lamina propria of Gi & respiratory tracts • A week old baby has sIgA antibodies already, where does the B cell first get exposed to the Antigen?

♦ In spleen of baby ♦ In spleen of mom ♦ In intestine of baby ♦ Intestine of the mom – If it says for the B cell that made the plasma cell that made the IgA ♦ In breast of mom –only if they ask us where the sIgA comes from

• Primary fxn: ♦ To bond w/ surface Ag/s of microorganisms, preventing the adherence and ingress of Ag through the mucosa ♦ Aggregates microorganisms, and prevents colonization ♦ Acts against bacteria in the oral cavity

• Resistant to hydrolysis by microbial proteolytic NZs (IgA, IgE, IgG are NOT) ♦ J chain is for Dimeric IgA ♦ J chain is for pentamic IgM

• Polymeric 2 IgAs joined by a J chain (Think J for Joining) ♦ This happens just below the ductal epithelium (lamina propia) ♦ J chain is added by the Plasma cell (step 10)

J chain also connects up the IgM Pentamer ♦ Then the dimer diffuses to the intraepithelial space and binds to Pig R (polymeric Ig Receptor)

Then that complex is endocytosed, then the Pig R becomes the Secretory Component (SC) ♦ Secretory portion added by the epi cell

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• Enterosalivary Pathway (SEE PIC) ♦ We absorbed antigen in the gut (via

M cell of Peyer’s patch) ♦ Stimulates B cells via CD4+ T-cell

Switch cell ♦ B cells then migrate back to salivary

glands ♦ Gut has inducer site ♦ Salivary gland has effector site

IgD: Makes up < 1% of Ig/s Present in high levels in MBs of many

circulating, mature B-cells Functions in Ag recognition by B cells (but

function is not fully understood) IgM:

Largest Ig First Ab produced in response to infection or

after primary immunization (M for priMary iMmunization) • 3 days ago, a pt received her 3rd

immunization w/ tetanus toxoid, you would expect to see Low IgM and High IgG

If type A blood is transfused into a type B recipient, the immediate hemolytic reaction would be the result of IgM against the A antigen (NOT IgA or IgG)

Efficient activator of complement IgE:

Present only in trace amounts in serum Has reagenic acivity Protects external mucosal surfaces Tightly bound to its receptors on mast cells

and basophils Responsible for Type I hypersensitivity reactions (allergic & anaphylactic)

• IgE is responsible for atopic allergy Complement:

Collective term for a system of ~20 plasma proteins, which are the primary mediators of Ag-Ab reactions Present in normal human serum Plays a role in humoral immuntiy & inflammation Participates in lysis of foreign cells, inflammation, & phagocytosis Acts in a cascade w/ one protein activating another Synthesized mainly by the liver – some are made in macrophages – C1 is made in GI epithelium Chemotactic component of complement attracts PMNs Is not an Ig Is heat labile

Complement system: Functions to destroy forgein substances

Either directly or in conjunction w/ other components of the immune system Components of complement bind to IgG, NOT IgA, IgM, Endotoxins, mast cells– 1999 Q78 Are you sure? Maybe not

IgA What does complement NOT bind to??? (If it says Alternate pathway then Immune complexes is the answer!!)

Consists of ~20 plasma proteins that function as enzymes or binding proteins Activated by C1 (classical) or C3 (alternative) Includes multiple distinct cell surface receptors – specific for physiological fragments of complement proteins

These receptors occur on inflammatory cells & cells of the immune system Two pathways:

Alternate pathway: • Activated by:

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♦ C3 – Think 311 is an alternate band ♦ LPS (endotoxin) ♦ Aggregated IgA, IgG, IgE, IgM ♦ Cobra venom factor

• Example of innate immunity – because you don’t need Ab to work like Classical does ♦ This pathway protects the body in the absence of antibody

• Seems to be of major importance in host defense against bacterial infection ♦ Activated by invading microorganisms ♦ Ab independent

Classical pathway: • Activated by IgG and IgM (Think GM makes classic cars) • Activated by Ab-Ag complexes (immune complexes) • Activated by C1 – binds to a specific part of the Ab

♦ C1 – composed of three proteins (C1q, C1r, & C1s); Ca2+ is required for activation • Ab dependent

NOTE: both pathways lead to cell lysis by terminal components (C8 & C9); initiation differs NOTE: C1 esterase deficiency leads to angioedema (overactive complement)

Membrane attack complex (MAC) End product of the activation Contains C5b, C6, C7, C8, & C9 Makes holes in the MBs of G- bacteria & RBCs, resulting in cytolysis

Biologically important C proteins: C2a, C4a = weak anaphylatoxins C3a, C5a = strong anaphlatoxins (bigger numbers, bigger response) C5a = potent chemotaxin C3b = potent opsonin (think C3b-O, like C3PO, O for opsonin)

Complement fixation: Binding of complement as a result of its interaction w/:

1) Immune complexes (classic pathway) OR 2) Particular surface (alternative pathway)

Used in detecting Ag or Ab (e.g., Wassermann test [for syphilis]) Only IgM and IgG fix complement – meaning activate

Antigen Detection Techniques Immunofluorescence (fluorescent antibody)

Most frequently used diagnostic lab technique for microscopic detection of Ag/s in tissue secretions & cell suspensions Fluorescent dyes (fluorescein & rhodamine) are covalently attached to Ab molecules

• Made visible by ultraviolet light in the fluorescence microscope Labeled antibody can be used to identify bacterial surface Ag/s

Radioimmunoassy (RIA) Used for the quantification of Ag/s or haptens that can be radioactively labeled

Enzyme-linked-immunosorbent assay (ELISA): Used for the quantification of either Ag/s or Ab/s in pt specimens

Precipitation (precipitin): Ag is a solution in this test The Ab cross-links Ag molecules in variable proportions & precipitates form

Agglutination: The antibody that attacks in agglutination is IgM Ag is a particulate in this test (e.g., bacteria & RBCs) Remember agglutination in a mis-matched transfusion would happen on the donor’s RBCs in the pt

• The most common side effect of a blood transfusion is ALLERGIC Rxn, NOT agglutination Because Ab (agglutinin) is divalent or multivalent, it cross-links the multivalent Ag particles & forms a latticework

• Clumping (agglutination) can be seen Hemagglutination – when clumping results from addition of Ab to RBCs (Ag/s must be present on surface of RBCs)

• Is the basis for blood typing & distinguishing the presence of A type Ag or B type Ag on the surface of RBCs • If blood mixed with A antiserum, and Rh Positive antiserum and NO agglutination occurs, then they are TYPE B and

Rh Negative • If blood mixed with A antiserum, B antiserum, and Rh Positive antiserum and NO agglutination occurs, then they are

TYPE O and Rh Negative • If blood mixed with anti-A serum, anti-B serum, and anti-Rh serum, and agglutination DOES occur, this pt has Rh(+)

type AB

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Prozone • Immune systems with high titers of agglutination often fail to agglutinate homologous bacteria in low dilution

How things leave blood vessels: Cellular adherence to vascular endothelium

Upregulation of endothelial adhesion molecules (ICAM-1 and VCAM-1) is in part response to cytokine stimulation ICAM-1 & LFA-1 are specific receptors that make endothelial adherence of leukocytes possible

• T cells use LFA-1 to bind to ICAM-1 of the endothelial cell Margination

Lining up of the leukocytes along the wall of a dilated vessel Transendothelial migration

Active passage of the leukocytes through the capillary wall happens by means of endothelial pores Things that happen inside the blood & things that happen outside the blood:

Extravascular events: Chemotaxis (totally extravascular)

• Movement of cells towards chemicals (positive) or away from chemicals (negative) Intravascular events:

Stasis (Stagnation of the blood or other fluids) Hyperemia (Presence of increased amount of blood in a part or organ Margination (Lining up of the leukocytes along the vessel walls in inflammation) Pavementing – flattening of a cell against the interior wall of the venule

Anaphylatoxins: Family of peptides C3a, C4a, & C5a produced in the serum during complement activation

Probably mediated indirectly via histamine release from mast cells & basophils C5a – most powerful

• 100x more effective than C3a…1000x more effective than C4a • Most important chemotactic factor from the complement pathway • Chemotactic accumulation of inflammatory cells where immune complexes are deposited is most probably due

to the presence of C5a Produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, & act as mediators of the local

inflammatory process Anaphylaxis caused by complement components is less common that caused by Type 1 (IgE mediated) hypersensitivity

Sensitization All of the following require prior sensitization:

Anaphylaxis (TYPE I), Arthus rxn (TYPE III), Erythroblastosis fetalis, and Contact Dermatitis (TYPE IV) Anaphylactoid reactions do not require prior sensitization

Uticaria = Hives Skin reaction characterized by wheals (small, smooth, slightly elevated areas that are redder or paler than surrounding skin) Can be allergic reaction to food, medicine, or other substance 1st symptom is usually itching – quickly followed by wheals

Angioedema: Related to & sometimes coexistant w/ uticaria The swelling covers large areas & extends deep beneath skin Involve part or all of the hands, feet, eyelids, lips, genitals, or even oral mucosa, throat, & airways (makes breathing difficult) Uticaria & angioedema are anaphylactic-type reactions limited to skin & underlying tissues Uticaria & angioedema are of rapid onset & can either be just annoying or life-threatening Therapy – use of epinephrine, antihistamines or steroids Deficiency of C1 esterase inhibition

Angioneurotic edema (Absence of the inhibitor of the C1 component of complement – same as above) Hereditary angioedema:

Absence of C1 esterase inhibitor In other words, absense of the inhibitor of C1 component of complement may result in angioneurotic edema

HYPERSENSITIVITY REACTIONS: Think ACID 1, Anaphylaxis/Atopic 2, Cytotoxic 3, Immune complex 4, Delayed

TYPE I: (Anaphylaxis and Atopic) Think First and Fast Antigens (allergens) combine w/ specific IgE Ab/s bound to MB receptors on tissue mast cells & blood basophils Requires previous exposure that sensitizes mast cells & basophils The Ag-Ab reaction causes rapid release of potent vasoactive & inflammatory mediators

• Mediators are preformed (histamine, tryptase) OR newly generated from MB lipids (leukotrienes & prostaglandins)

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• Leukotrienes & prostaglandins • Anaphlatoxins – C3a & C5a are generated via tryptase action • Bradykinin – generated from kininogen by the action of kallikrein, activated Hageman factor (XIIa) or trypsin

Common allergens – foods, pollen, drugs, insect venom, animal dander, house dust Severe anaphylaxis (anaphylactic shock):

• Physiological shock from anaphylactic hypersensitivity reaction ♦ Occurs suddenly (seconds or minutes) in an allergic individual after Ag exposure ♦ EXs: bee bites or penicillin reaction ♦ PCN rxn is Type I ♦ Anaphylaxis is inducible in a normal host, unlike atopy ♦ Anaphylactic reaction involves degranulation of mast cells

Release of histamine, heparin, platelet-activating factors, SRS-As & serotonin into bloodstream Histamine is responsible for the principle symptoms of anaphylaxis

• 1st symptoms – anxiety, weakness, sweating, SOB, & generalized urticaria • Associated with immediate rxn, passive transfer by serum, participation of Abs, smooth muscle spasm and

capillary damage ♦ NOT associated with delayed rxn

• Constriction of the bronchioli and ↓ BP are the usual causes of death ♦ EX: after an injection of penicillin into a penicillin-sensitized person may lead to death by the above means

• Immediate treatment: ♦ Maintain airway ♦ Inject epinephrine

Drug of choice for shock Opens airways & raises BP by constricting BVs Conscious pt – IM or subcutaneous Unconscious pt – IV Which of the following causes vasoconstriction and vasodilation when administered IV? Epinephrine

• Antihistamines (e.g., diphenhydramine) & corticosteroids (e.g., prednisone) ♦ May be given to further reduce symptoms

Atopic allergies: • Predisposition of an individual to sensitization is characteristic of atopy • Result from a localized expression of Type I hypersensitivity reactions • Interaction of Ag/s (allergens) w/ cell-bound IgE on the mucosal MBs of the upper respiratory tract & conjunctival

tissues initiates a localized type I hypersensitivity reaction • Most allergy sufferers are atopic

♦ Possible to become allergic w/out being atopic • Heredity plays an important role

♦ Allergies can jump a generation ♦ Atopy can only occur in genetically predisposed individuals, unlike anaphylaxis

• Atopic individuals are genetically programmed to produce an abundance of IgE Ab/s ♦ IgE strongly reacts against allergens in the environment (pollen, moulds, household dust, etc)

• Risk for becoming allergic ♦ One parent w/ allergies = 30% risk ♦ Both parents w/ allergies = 60% risk

• Three principal kinds of atopic allergies: (Triad) ♦ Atopic dermatitis (eczema):

Chronic skin disorder categorized by scaly & itching rashes Most common in infants – at least ½ of the cases clear by 3 y.o. In adults – chronic or recurring condition A hypersensitivity reaction occurs in the skin, causing chronic inflammation

Result: skin becomes itchy & scaly ♦ Rhinitis (hay fever & year-around symptoms):

When the allergen interacts w/ sensitized cell of the upper respiratory tract Symptoms – coughing, sneezing, congestion, tearing eyes, & respiratory difficulties Histamine is the 1° mediator – released from sensitized mast cells & basophils

♦ Allergic asthma: Allergic reaction primarily affecting the lower respiratory tract Common in children Characterized by SOB & wheezing

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Specific IgE Ab/s & nonspecific inhaled irritants provoke mast cell degranulation Release of histamine & leukotrienes (SRS-As) cause bronchospasm & bronchial mucus secretions

♦ Allergic desensitization is produced by competitive inhibition Basis for allergy shots FIND OUT What kind of hypersensitivity is it if you take multiple doses of Pen G for syphilis, and then the ABX seeps

into the RBCs?????? – I think Type I TYPE II: (Cytotoxic) – “C” in “ACID”.

Think Cy-2-toxic IgG, IgM Cytotoxic reactions resulting when Ab reacts w/ antigenic cell components or tissue elements or w/ antigen or hapten

coupled to a cell or tissue. Ab reacts w/ cell-surface epitopes Complement-mediated lysis or phagocytosis The Ag-Ab reaction may activate certain cytotoxic cells (killer T cells or macrophages) to produce Ab-dependent cell-

mediated cytotoxicity, usually involving complement activation Examples:

• Certain drug allergies • Blood transfusion reactions (red cell lysis) • Hemolytic disease of the newborn

♦ Autoimmune hemolytic anemia • Goodpasture’s syndrome

TYPE III: (Immune complex, Serum Sickess, Lupus, and Arthus Rxn) Immune complex (IC) reactions – result from deposition of excessive soluble circulating Ag-Ab ICs in BVs or tissue

• Think 3 Things stuck together in a complex (Ag –Ab-complement) • Most commonly deposited in kidneys, joints, skin & BVs

♦ Glomerular lesions in the immune complex disease result from IgG The ICs activate complement & thus initiate sequence of events resulting in PMN cell migration & release of lysosomal

proteolytic enzymes & permeability factors in tissues, thereby producing acute inflammation Active mechanism for damage to BVs in an immune complex disorder is phagocytosis of immune complexes by the

RE system (macrophages) • The chemotactic accumulation at the site of the immune complex deposition is a result of complement • Reticuloendothelial system typically clears ICs

NOTE: Histamine does not play a major role in these Type III hypersensitivity reactions Clinical features:

• Urticaria, lymphadenopathy, edema, fever Serum sickness

• The hallmark of Type III hypersensitivity • Results from IC deposition in small vessels • Appears some days after injection of a foreign serum or serum protein • Local & systemic reactions – uticaria, fever, general lymphadenopathy, edema & arthritis • Type of systemic arthus rxn

Arthus rxn: • Is the cutaneous reaction of type III responses • Highly localized, appears w/in 1 hour, resolves w/in 12 hours • Type III hypersentivity – local subacute type III rxn, intradermal injx of ag induces Abs→Ag-Abs complex in

skin • Immediate type of reaction where Histamine does NOT play a major role • EX: When horse serum is injected into a rabbit and again into the skin 2 to 3 weeks later, the necrotizing rxn that

results at site of injection is an Arthus reaction • Serum Sickness is a type of an systemic Arthus rxn, so says an old Q, but Kaplan doesn’t mention it

TYPE IV: (Delayed, cell-mediated) Think 4th and Last (Delayed) Cellular, cell-mediated, delayed, or tuberculin-type reactions caused by sensitive T-cells after contact w/ a specific Ag Circulating Ab/s are neither involved in nor necessary for development of tissue injury Delayed type of hypersensitivity demonstrated by a positive tuberculin skin test

• Hypersensitivity to M. Tuberculosis is manifested by necrosis Delayed type of hypersensitivity can be transferred by sensitized lymphocytes encounter Ag and release

lymphokines – hence the term “cell-mediated” Cellular infiltrate in a fully-developed delayed hypersensitivity reaction consists mainly of macrophages & lymphocytes

• Th1 cells and macrophages

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Contact dermatitis • Usually Latex is Type I (think allergic or atopic contact URTICARIA), but if the questions says it’s a TYPE IV rxn,

which would mean Allergic contact DERMATITIS, then go with the following!!! ♦ Type IV reaction due to latex gloves, consists of Macrophages, Lymphokines, and T lymphocytes

Allograft rejection • When a 1st rejected allograft is followed by a 2nd allograft from the same donor…the 2nd rejection occurs more rapidly

than the 1st ♦ Hence, a reminder that you need presensitization

• Primary tissue transplant, such as allogenic skin, kidney or heart, are most commonly rejected due to ♦ Cell-mediated immune responses to cell-surface autoantigens

Similarities between Type I and IV??? • Complement OR Response after 24 hours???

Thymectomized and nude mice: • Have reduced numbers of T-lymphocytes • Can’t reject allografts • Have reduced Ab production to most antigens – no helper Ts • Have decreased or absent delayed type IV hypersensitivity

Classification of Hypersensitivity Reactions

Type Immunologic Mechanism Example Type I (anaphylactic type): Immediate hypersensitivity

IgE antibody mediated – mast cell activation & degranulation

Hay fever, asthma, anaphylaxis, atopic dermatitis, eczema

Type II (cytotoxic type): Cytotoxic antibodies

Cytotoxic (IgG, IgM) antibodies formed against cell surface antigens. Complement is usually involved

Autoimmune hemolytic anemias, antibody-dependent cellular cytotoxicity (ADCC), Goodpasture’s syndrome

Type III (immune complex type): Immune complex disease

Antibodies (IgG, IgM, IgA) formed against exogenous or endogenous antigens. Complement and leukocytes (neutrophils, macrophages) are often involved

SLE, rheumatoid arthritis, most types of glomerulonephritis, arthus rxn, serum sickness

Type IV (cell mediated type): Delayed type hypersensitivity

Mononuclear cell (T lymphocytes, macrophage) w/ interleukin and lymphokine production *Q answer: sensitized lymphocytes

Granulomatous disease (Tuberculosis, Sarcoidosis, Crohn’s, Fungus), contact dermatitis, graft rejection

Blood Group Ag/s (agglutinogens) on erythrocytes Antibodies (agglutinins) in plasma O (universal donor) *none* Anti A & Anti B A A Anti B B B Anti A AB (universal recipient) A & B (alloantigens – both A & B) *none* Autoantibodies

Anti-nuclear antibodies (ANA) Systemic Lupus Anti-dsDNA, anti-Smith Specific for Systemic Lupus Anti-histone Drug-induced Lupus Anti-IgG Rheumatoid arthritis Anti-neutrophil Vasculitis Anti-centromere Scleroderma (CREST) Anti-Scl-70 Sclerderma (diffuse) Anti-mitochondria 1ary biliary cirrhosis Anti-gliadin Celiac disease Anti-basement membrane Goodpasture’s syndrome Anti-epithelial cell Pemphigus vulgaris Anti-microsomal Hashimoto’s thryoiditis

INFLAMMATION & NECROSIS Inflammation overview:

Exudative component: Involves the movement of fluid, usually containing important proteins like fibrin and immunoglobulins BVs are dilated upstream of an infection (causing redness and heat) and constricted downstream

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Capillary permeability to the affected tissue is increased, resulting in a net loss of blood plasma into the tissue • This gives rise to edema or swelling

The swelling distends the tissues, compresses nerve endings, and thus causes pain Cellular component:

Involves the movement of WBCs from blood vessels into the inflamed tissue The WBCs (leukocytes) take on an important role in inflammation

• They extravasate (filter out) from the capillaries into tissue & act as phagocytes • They may also aid by walling off an infection and preventing its spread

If inflammation persists: Released cytokines IL-1 & TNF will activate endothelial cells to upregulate receptors VCAM-1, ICAM-1, E-selectin,

and L-selectin for various immune cells Receptor upregulation increases extravasation of PMNs, monocytes, activated T-helper and T-cytotoxic cells, as well as

memory T and B cells to the infected site Inflammation can lead to anemia, because shift to making more inflammatory cells rather than RBCs

Cytokines: Soluble mediators that play an important role in immunity Small molecular weight peptides of glycopeptides Many produced by multiple cell types such as lymphocytes, monocytes/macrophages, masts cells, eosinophils, even endothelial

cells lining BVs Each individual cytokine can have multiple functions

Depends upon the cell that produces it & the target cells upon which it acts (pleotropism) Several different cytokines can have the same biologic function (redundancy) Exert their effect:

1) on distant targets through the bloodstream (endocrine) 2) on target cells adjacent to those that produce them (paracrine) 3) on the same cell that produces them (autocrine)

Most important effect of most cytokines is paracrine & autocrine functions Major functions appear to involve host defense or maintenance and repair of blood elements

Four major categories of cytokines: Interferons:

A family of inducible glycoproteins produced by eukaryotic cells in response to viral infections • The fact that eukaryotic cells produce interferon can be used to distinguish viral infections from other microbial

assaults!!!!! Interfere w/ virus replication Act to prevent the replication of a range of viruses by inducing resistance Elaborated by infected host cells that protect non-infected cells from viral infections

• Induce viral resistance in adjacent, non-infected cells Do not block the entry of the virus into a cell, but rather prevent the replication of viral pathogens w/in protected

cells Are not antiviral antibodies

• Have no direct effect on viruses • Antiviral action is mediated by cells in which they induce an antiviral state

Considered a non-specific innate resistance factor (as are lysozyme, complement, etc.) • Interferon proteins do not exhibit specificity toward a particular pathogen

♦ Means interferon produced in response to one virus is also effective in preventing replication of other viruses Alpha and Beta Inhibit viral protein synthesis Gamma Increase MHC I expression and Antigen presentation in all cells

Tumor Necrosis Factors (TNF): Injecting them into animals causes a hemorrhagic necrosis of their tumors Secreted by activated macrophages – Easier to eat dead stuff

Interleukins (largest group of cytokines): Fundamental function appears to be communications between (“inter-”) various populations of WBCs Group of well-characterized cytokines produced by leukocytes & other cell types Have broad spectrum of functional activities that regulate the activities & capabilities of a wide variety of cell types Particularly important as members of cytokine networks that regulate inflammatory & immune responses

• Act as messengers between leukocytes involved in the immunologic or inflammatory response Think mmmm, Hot T-Bone stEAk

IL-1: A macrophage-derived factor (mmmm) Stimulates activites of T-cells, B-cells, & macrophages Stimulates IL-2 secretion

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Pyrogenic (HOT)

IL-2: Produced by activated T cells (T- in T-bone) Stimulates antigen-activated T helper & NK cells (as well as cytotoxic T cells) Also stimulates B cells

IL-3: T-cell product that stimulates the growth & differentiation of various blood cells in bone marrow

(B in T-Bone) Secreted by activated T cells

IL-4: Secreted by activated helper T cells & mast cells

Stimulates B-cells Increases IgG & IgE (E in stEAk)

IL-5: Secreted by activated helper T cells Promotes B cell maturation IL-5 is a B-cell growth & differentiation factor Increases IgA & synthesis of Eosinophils (A in stEAk)

Acute Phase cytokines IL-1, IL-6, and TNF alpha (secreted by macrophage to do a bunch of stuff) IL-6, 7, 8, 10, 12: see Kaplan, p. 101 for thie summaries

Colony Stimulating factors (CSF): They support the growth and differentiation of various elements of the bone marrow

Neutrophils: (aka polymorphonuclear leukocytes or PMNs) Most numerous WBC (50–75%) Increase dramatically in response to infection/inflammation Fxns:

Phagocytosis of bacteria Elaboration of proteolytic NZs 1st cells to infiltrate the inflammation site

PMNs kill by 1) toxic O2 metabolites & 2) digestive enzymes from lysosomal granules Oxygen-dependent killing of bacteria by PMNs involves:

• Superoxide, Myeloperoxidase, Hydrogen Peroxide, NADP Dehydrogenase • NOT collagenase

♦ Remember in Gingivitis you have lots of PMNs, ♦ In order get to PD, you need Collagenase, which comes from Lymphocytes!!!!

Enzymes include myeloperoxidase (azurophilic granules) & lactoferrin (specific granules) Primary constituent of pus Highly mobile cells – attracted to areas of inflammation by chemotaxis

They reach the tissues by diapedisis Identify, attach to & begin engulfing the invading organisms in attempt to contain the infection If infection continues, monocytes arrive (better engulfing ability) NZs responsible for suppuration in an abscess are derived from PMNs

Inflammatory substances: Process of attraction and recruiting cells in which a cell moves toward a higher concentration of a chemical substance The Vasodilators:

Histamine Bradykinin C3 and C5 (via mast cells/Histamine) Prostaglandins

Histamine: Formed from histidine by decarboxylation Released from the coarse cytoplasmic granules of tissue mast cells & basophils In early stages of acute inflammation, histamine mediates the contraction of endothelial cells Histamine is liberated by degranulation triggered by the following stimuli:

• Binding of specific Ag to basophil & mast cell MB-bound IgE ♦ TEST wording: Histamine release requires antibodies (IgE) attached to mast cells and reacting with

antigen • Binding of anaphylatoxins (C3a & C5a) to specific cell-surface receptors on basophils & mast cells

Release causes: increased capillary permeability, bronchial constriction, increased gastric secretion, and a drop in BP

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Responsible for the principal symptoms of anaphylaxis Serotinin has similar actions

Serotonin: Also called 5-hydroxytryptamine

• Synthesized from the aa tryptophan by enteroendocrine cells in the gut & bronchi Plays a role in temperature regulation, in sensory perception, and in the onset of sleep Powerful vasoconstrictor Downstream??? And vasodilator Stimulates platelet aggregation (blood clotting) – rls by platelets. Largest amount is found in cells of the intestinal mucosa

• Smaller amounts in platelets & in CNS In CNS:

• Acts as a neurotransmitter in the brain • Inhibitor of pain pathways in spinal cord • Lysergic acid diethylamide – interferes w/ action of serotonin in the brain

Secreted in tremendous quantities by carcinoid tumors (tumors composed of chromaffin tissue) • Kaplan says, 5-HIAA is secreted, which is a metabolite of serotonin

Bradykinin: Vasoactive kinin – potent vasodilator Mediates vascular permability, arteriolar dilation, & pain

• Pain in inflamed tissue is associated with the Bradykinin mediator Produced by the action of kallikrein (generated by activated Hageman factor, factor XIIa) on an alpha-2 globulin

(kininogen) Chemical mediator of acute inflammation that is generated through the activation of an enzyme precursor (Kallikerin) that

requires activated Hageman factor Hageman factor helps to create Bradykinin May be involved in BP regulation

Arachidonic acid: An unsaturated fatty acid generated by inflammatory cells and injured tissue Major compound from which prostaglandins, prostacyclin thromboxanes, & leukotrienes are derived Part of phospholipids in plasma MBs When a neurotransmitter or hormone stimulates a cell, activating phosholipase A (a plasma MB enzyme)

• PLA splits arachidonic acid from the phospholipids Different metabolic pathways utilize different enzymes that convert arachidonic acid into the different messengers:

• 1) Cyclooxygenase: prostaglandins, prostacyclins, & thromboxanes (NOT leukotrienes) ♦ Prostaglandins – chemical messengers present in every body tissue ♦ Act primarily as local messengers that exert their effect in the tissues that synthesize them ♦ *PGG2 is converted to PGH2, which is ultimately converted to TxA2

• 2) Lipooxygenase: leukotrienes, HETEs, diHETEs Leukotrienes:

A group of compounds derived from unsaturated FAs (arachidonic acid & other polyunsaturated FAs) Extremely potent mediators of immediate hypersensitivity reactions & inflammation Leukotrienes C4, D4, & E4

• Collectively known as slow-reacting substances of anaphylaxis (SRS-As) • Responsible for development of many symptoms associated w/ allergic-type reactions

100-1000x as potent as histamine or prostaglandins in constricting bronchi In asthma, the allergic reaction occurs in the bronchioles of lungs

• The most important products released by mast cells are SRS-As (the 1° mediators of asthma) • SRS-As causes bronchiolar smooth muscle spasms

Anaphylatoxins C3a & C5a – induce physiological response that results in BV dilation, hypotension, ↑ vascular permeability Acute Inflammation:

The initial response of tissue to injury, particularly bacterial infections, involving vascular and cellular responses What is involved in the early phase of wound repair?

Inflammatory bacteria and debris are phagocytosed and removed, factors are released that cause the migration and division of cells involved in proliferative stage • Proliferative and Maturation are more in chronic

Three major phenomena: 1) Increased vascular permeability – tissue exudate forms

• Mean capillary pressure decrease and osmotic pressure decreases in acute inflammation 2) Leukocytic cellular infiltration – mainly PMNs via C5a & C3a 3) Repair – regeneration or replacement

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Chemotactic accumulation of mononuclear cells which occurs at the sites where immune complexes were deposited is probably the result of C3 (only if C5a is not an answer)

Local signs: Redness = rubor, Heat = calor, Swelling = tumor, Pain = dolor, organ dysfunction

Systemic effects: Fever, Tachycardia, Leukocytsosis (esp. PMNs)

Vascular phase: Vasoconstriction (temporary) – seen as blanching of skin

• What happens before Vasodilation in inflammation??? Vasoconstriction • Only transient

Vasodilation – increased blood flow to infected area • Happens immediately after vasoconstriction • Done by Histamine, Bradykinin, and Serotonin • The 1st vascular reaction (following transient vasoconstriction) to injury in the sequence of events in inflammation

Increased permeability – allows diffusible components to enter the site • Congestion in the early stages of inflammation is caused by active hyperemia (NOT ischemia, venous dilitation,

venous constriction, lymphatic obstruction) Cells

• Basophils, Mast cells, Platelets – present in vascular phase – all release histamine Vasodilation and increased permeability lasting for several days in an area of inflammation indicate

• Endothelial cell damage and dysfunction Cellular phase:

Leukocytes (mainly PMNs) are the 1st defense cell to migrate to the injured tissue – chemotaxis Leukocytes engulf particulate matter by phagocytosis Engulfed matter becomes a phagosome – combines w/ lysosomal granules to form a phagolysome for digestion Cells

• PMNs – predominate • Macrophages – appear late & mark transition between acute & chronic inflammation

NOTE: Eosinophils – predominate in allergic reactions & parasitic infections Chronic Inflammation:

Develops at a site of injury that persists longer than several days Cells: Lymphocytes, Macrophages, and Plasma Cells – not PMNs or Mast Cells Necrosis commonly occurs & recurs EXs: chronic hepatitis, pyelonephritis, and autoimmune diseases Granulomatous inflammation:

A subtype of chronic inflammation characterized morphologically by granulomas Proliferative processes dominate (NOT exudation, transudation, and congestion) Characterized by a circumscribed collections of lymphocytes, macrophages, epitheliod cells with a background of

fibroblasts, capillaries, and delicate collagen fibers EXs: TB, sarcoidosis, & silicosis Vasodilation & ↑vasopermeability lasting several days in inflamed area indicate formation of granulation tissue

• Initial vasodilation of inflammation is due to serotonin, histamine, bradykinin SIDENOTE

Chronic Granulomatous Disease Hereditary disease where neutrophil granulocytes are unable to destroy ingested pathogens Neutrophils normally require a set of enzymes to a reactive oxygen species to destroy bacteria after their phagocytosis These NZs are called phagocyte NADPH oxidase complex, which is responsible for initiating the respiratory burst SO in CGD, PMNs ingest baceria but then cannot kill them

• MOST infections are caused by Staph Aureus, or CATALSE + bugs • Hence bugs that destroy the respiratory burst are left behind to cause chronic GD

Inflammatory Infiltrate Fluids, PMNs, and Macrophages

Exudates: Principally water – also contains nutrients, oxygen, Ab/s & WBCs Characterized by being protein-rich, cell-rich, glucose-poor & has a high specific gravity (> 1.020) First role – flush away any foreign material from site of injury

If fluid is cloudy/discolored – strong indication of infection Acts as a carrier to bring fibrin, etc., to the site of injury Acts as a carrier for leukocytes – provides oxygen/nutrients for ingestion of bacteria & debris Nutrients are used by the new tissue to help in the generation of granulation tissue

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Act as a lubricant, speeding up epithelial cell migration across wound surface to complete initial repair Types of imflammatory exudates:

Suppurative Purulent Fibrinous Pseudomembranous Serous

• NOT Fibrous Acute inflammatory exudates

Includes Plasma fluid, plasma proteins and WBCs • NOT Plasma cells

Transudates: Result from ↑ intravascular hydrostatic pressure or from altered osmotic pressure Thin & watery – characterized by few blood cells, low protein content, & low specific gravity (< 1.020)

Differs from Exudate by having a lower protein concentration Present in non-inflammatory conditions, such as cardiac failure

Most common acute inflammatory reactions Contain large # of PMNs Termed suppurative (produce purulent matter)

Suppuration is the result of tissue necrosis, proteolytic enzymes, WBCs, & fluid buildup • NZs responsible for suppuration are found in the PMNs • NOT the result of the presence of lymphocytes

Abscess: Confined collection of pus, which consists of dead WBCs & necrotic tissue Surrounded by a wall of proliferation fibroblasts (produce collagen) – body’s attempt to limit spread of infection

Cyst: Abnormal sac w/in the body containing air or fluid Lined w/ epithelium

Granulation Tissue: Newly formed, highly vascularized CT associated with inflammation Composed of:

Lymphocytes Fibroblasts Macrophages Endothelial cells Newly Formed Collagen Capillary Buds

• NOT Giant cells, Nerve cells, or Epithelioid cells, or Plasma cells – these are Granulomatous Granuloma:

Differentiate!!!! Central necrosis surrounded by macrophages, lymphocytes, plasma cells, and occasional giant cells

Nodular collections of epithelioid cells – specialized macrophages Epithelioid cells are characteristic of granulomas (NOT granulation tissue) Rim of lymphocytes, plasma cells, & fibroblasts surround the nodule of epithelioid cells

Produced by multinucleated giant cells (aka Langerhans giant cells & foreign body giant cells) Multinucleated giant cells of the foreign-body type originate from fusion/division of mononuclear cells

(macrophages) Characteristically associated w/ areas of caseous necrosis – produced by infectious agents, particularly M. tuberculosis Granulomatous inflammation is a subtype of chronic inflammation Etiologic agents associated w/ granulomatous inflammation:

Infectious agents: • Mycobacterial diseases – TB & leprosy

♦ Girl with ulcerated lesion on tongue has Langerhans cells and granulomatosis, what is the disease??? Tuberculosis Granuloma???

• Fungal infections – blastomycosis, histoplasmosis, & coccidiomycosis • Spirochetes: T. pallidum, which causes syphilis • Cat scratch disease – caused by Bartonella henselae

Foreign material – suture or talc Sarcoidosis – unknown etiology, NON-caseating, NON necrotizing (whereas tuberculosis is caseation necrosis)!!!!! Crohn’s disease – NON-caseating, NON-necrosis, granulomatous inflammation of the gut wall

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Healing: The restoration to integrity to an injured tissue After the inflammatory phase, wound healing is accomplished by three mechanisms; contraction, repair, and regeneration. In most instances, all three mechanisms occur simultaneously Healing by 1st intention:

Healing by fibrous adhesion, w/out suppuration or granulation tissue formation Occurs when wound margins are nicely apposed, such as in surgical repair of a surface wound With well-approximated wounds, there is little granulation tissue & the final scar is minimal

Healing by 2nd intention: Large wound defects CT repair occurs when the wound is large & exudative – large amount of necrotic tissue & suppuration formed Site fills in w/ a highly vascular, pinkish tissue known as granulation tissue

• This produces large, irregular scars Uncomplicated healing of a wound by secondary intention, observed microscopically after 3 days is most likely to

show... • Ulceration of the epithelial surface • NOT granulomatous inflammation, lack of acute inflammation, or keloid formation

Healing by 3rd intention: Slow filling of a wound cavity or ulcer by granulations, w/ subsequent cicatrisation (the process of scar formation)

Which hormone establishes the greatest effect on granulation tissue in healing wounds? Cortisone

Glucocorticoids have been shown to have the greatest effect on granulation tissue Tensile strength of healing wound depends upon the formation of collagen fibers Whether a wound heals by 1° or 2° intention is determined by the nature of the wound, rather than by the healing process

Keloids (cheloids): A nodular, firm, movable, nonencapsulated, often linear mass of hyperplastic scar tissue, tender and frequently painful Consist of wide, irregularly distributed bands of collagen fibers Occur in the dermis & adjacent subcutaneous tissue, usually after trauma, surgery, a burn, or severe cutaneous disease such as

cystic acne, and is more common in blacks Tumor:

Growth of tissue that forms an abnormal mass Caused by abnormal regulation of cell division Generally provide no useful function & grow at the expense of healthy tissue

Necrosis: Set of morphologic changes that accompany cell death w/in a living body Differs from autolysis – a process of cell death outside a living body May manifest in different ways, depending on the tissue or organs involved

Coagulative necrosis is the most basic and most common type of necrosis When larger areas of tissues are dead, the tissue is called gangrene

Types Causes Most likely sites involved

Coagulation necrosis Ischemia (loss of blood supply) Heart & kidney (renal & cardiac infarcts) Liquefaction necrosis (infarct to brain) Suppuration, abscesses & ischemic CNS injury Brain or spinal cord Caseous necrosis (Caseation) Granulomatous inflammation (typical of TB)

Calcification and “Soapy” – Think Cheesy TB Lesion

Granulomatous inflammatory sites

Gangrenous necrosis Putrefactive bacteria acting on necrotic bowel or extremity

Lower extremities or bowel

Fibrinoid necrosis Immune-mediated vascular damage Arterial walls (RA, Scleroderma, RF) Fat necrosis Injured pancreas, trauma to adipose tissue Adipose tissue, pancreas Basic Types of Necrosis

Two types of necrosis are recognised and are based on the degree of preservation of the architecture of the cells and tissues. These are as follows:

Coagulative necrosis Coagulative necrosis is characterised by the preservation of cellular and tissue architecture. Microscopically, the nucleus, cytoplasm, and cellular outlines including the arrangements of cells in the necrotic

tissue are still intact. This type of necrosis is often difficult to detect grossly, except probably when the affected area is large where subtle

changes in tissue colour may be recognized. It usually results from acute disease conditions such as acute toxicity (chemical toxicants or biological toxins) and sudden deprivations in blood supply.

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Heart and renal Infarct (MI) Characteristic nuclear changes:

♦ Pyk- = condense ♦ Kary- = nucleus

• Karyolysis – destruction of dissolution of the cell nucleus w/ fading of chromatin ♦ Karyolyis of myocardial cell (& probably any other cell type) is irreversible

• Karyopyknosis = pyknosis – shrinkage of the cell nuclei & condensation of the chromatin ♦ Another Q reads: condensation & shrinking of the cell nucleus w/ chromatin clumping

• Karyorrhexis – fragmentation of the cell nucleus & chromatin ♦ Karyorrhexis follows karyopyknosis during the process of apoptosis

• NOTE: the key point is that these nuclear changes are morphologic hallmarks of irreversible cell injury and necrosis

Liquefactive or Lytic necrosis Rapid enzymatic dissolution of the cell that results in complete destruction is called liquefactive or lytic necrosis (or

colliquative necrosis). It is seen in bacterial infections that lead to pus formation in which proteolytic enzymes are released from leucocytes Pus is the evidence of liquefactive necrosis – Think suppurative, abscesses, and brain injury In a pt who had an infarct in the middle cerebral artery…anticipated type of tissue alteration would be liquefaction necrosis Brain or spinal cord Suppuration

• Acute pyogenic infections are associated with suppuration Strep Pyogenes Causes liquefactive necrosis

Special Forms of Necrosis 1) Fat Necrosis - occur in two forms:

Traumatic Fat Necrosis result from rupture of fat cells because of trauma Enzymic Fat Necrosis occurs following the enzymic splitting of fat into fatty acid and glycerol by action of lipases

(seen in chronic pancreatitis) 2) Zenker Necrosis (Zenker degeneration) - loss of striations in muscles following necrosis (a type of coagulative necrosis in

striated muscles) 3) Caseation Necrosis - the presence of friable, cheesy or pasty, amorphous material in necrotic area, usually reserved but not

limited to those seen in tuberculous lesions 4) Fibrinoid Necrosis - a special form of necrosis associated with the accumulation of fibrinoid (see protein overload) in

connective tissues and blood vessel walls 5) Gangrenous Necrosis (See Below) - necrosis of tissue following deprivation of blood supply, and putrefaction following

invasion by saprophytic bacteria. If it is moist, it is called Wet Gangrene. If moisture is not present, it is called Dry Gangrene 6) Infarct - a form of coagulative necrosis resulting from a sudden deprivation of blood supply (process: infarction, see under

haemodynamic changes) Other Terms Used in Association with Necrosis

1) Malacia - an area of liquefactive necrosis of the nervous tissues. Literally mean "softening" 2) Slough - a piece of necrotic tissue separating from viable tissue. Applied to necrosis of surface epithelia. 3) Ulcer - shallow area of necrosis, applied to epithelial surfaces. 4) Sequestrum - an isolated area of necrosis warded off from viable tissue. Applied to isolated necrosis of bones.

Gas Gangrene: Results from local infection w/ the anaerobic, spore-forming, G+ rod Clostridium perfringens

C. perfringens produces toxins that kill nearby cells Rare infection generally occurs at site of trauma or a recent surgical wound (devitalized tissues)

Results from compromised arterial circulation Onset is sudden & dramatic Inflammation begins at infection site – a pale to brownish-red & extremely painful tissue swelling Gas may feel as a crackly sensation when the swollen area is pressed on Margins of infected area expand rapidly – changes are visible over a few minutes Involved tissue is completely destroyed Gangrene is the death of tissue – usually associated w/ loss of blood supply to the affected area.

A form of necrosis combined w/ putrefaction (decomposition, rotting) Systemic symptoms – sweating, fever & anxiety If untreated, pt develops a shock-like syndrome w/ ↓ BP, renal failure, coma, & death Prevented by proper wound care

Clostridium bacteria: Produce many different toxins (alpha, beta, epsilon, iota)

Most important toxin is alpha toxin (lecithinase) – damages cell MBs, including erythrocyte MBs (hemolysis)

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GASTROINTESTINAL TRACT

ORAL CAVITY Normal healthy mouth:

Consists of mainly obligate & facultative anaerobes, aerobes, and acidogenic bacteria 1979 reads: anaerobic, facultative, & acidogenic (NOT “anaerobic, aerobic & facultative”) 1989 reads: the single most numerous group of microorganisms in the oral cavity is facultative streptococci

Most oral streptococci are alpha-hemolytic Least likely bacteria in the mouth is Mycobacterium

(other options were: Fusobacterium, Prevotella, Actinobacillus, Porphyromonas) Bacteria with limited range of habitats in the oral cavity are:

Treponema and Bacteroides (Streptococcus & Actinomyces do not have a limited range in the O.C.) After two teeth were extracted, a foul smelling, purulent material drains, which bugs are responsible:

Bacteroides and Peptostreptococcal (NOT salmonella, clostridium – these should not normally be in the mouth) Essentially the same bacteria found healthy gingival sulcus become opportunistic & influence the course of PD disease

Obligate anaerobes are found in the oral cavity as part of the normal flora; they are opportunistic ABX, Anticancer therapy, & corticosteroids all would affect the oral microflora Progression from a healthy gingival sulcus to gingivitis is associated with a shift towards more G- anaerobic rods (not cocci) Most dramatic change to the Oral Flora occurs when primary teeth erupt

Gingival sulcus (Periodontal Pocket): Principal oral site for growth of Spirochetes, Fusobacteria, & other G- anaerobes

Endotoxin (LPS) accumulates in the gingival crevice in the absence of gingival hygiene Inhabitants

• Normally G- anaerobic Rods and Fusobacteria • Treponema, Bacteroides, Actinobacillus, and Fusobacterium

♦ NOT Mycobacteria • Actinomyces naeslundii

♦ Branching, filamentous microorganism that is a normal inhabitant of the gingival crevice and tonsilar crypts Crevicular Fluid

Contains: • IgA, IgG, Lymphocytes, PMNs

♦ NOT IgE • Most numerous Leukocyte is the Gingival Crevicular Fluid is the Neutrophil

Area of stagnation & bacterial proliferation; due to: 1) increase in crevicular gingival fluid 2) desquamation of epithelial cells 3) bacterial acid products

Microbial population of the perio pocket is of a low order of intrinsic pathogenicity – means they are opportunistic The fact that oral microorganisms can enter the body by way of gingival sulci and perio pockets is evidenced by….

The transient bacteremias following dental procedures Aerosolizatoin

Dental instrument causing aerosolization of large numbers of bugs is the….ultrasonic scaler The aerosolization produced during dental procedures usually contains gram POSitive bugs Most of the the bugs in the dental operatory come from the pts mouth

Xerostomia Most pronounced effect on reduced salivary flow is a shift toward more acidogenic microflora

Caries: Strep bacteria (G+, facultative anaerobes):

Most numerous group of bacteria in oral cavity • S. mutans – major cariogenic property is ability to produce dextrans & GTF (glucosyltransferase)

• First stable colonizer of the OC • S. sanguis – the most frequently isolated Strep in the oral cavity; produces H2O2; usually 1st to colonize plaque • S. salivarius – found consistently in saliva & oral soft tissue (including under tongue)

♦ Found commonly on the dorsum of the tongue (NOT S. mutans, L. acidophilus, P. melanginogenica) • S. mitis – produces H2O2

Properties necessary for caries formation: • Adhere to tooth surface (colonize) • Produce lactic acid (from degradation of glucose) • Produce a polymeric substance (from CHO metabolism) – causes acid to remain in contact w/ tooth

Produce dextran sucrase (GTF)

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Caries process: GTF catalyzes the formation of extracellular glucans from dietary sucrose Glucan production contributes to the formation of the dental plaque Dental plaque holds lactic acid (produced by Strep bacteria) against the tooth The acid eats through enamel – creating caries

• Acidogenic microorganisms are the most important causative agents of dental caries (Lactobacillus and Streptococcus families)

The ability of certain oral bugs to produce caries appears to be correlated with their capacity to produce an extracellular polysaccharide dextran-like substance involved in the formation of dental plaque

Prerequisites for caries development: Cariogenic bacteria Susceptible host Supply of substrate for lactic acid production

Bacteria that may be etiologically related to dental caries: S. mutans, salivarius, sanguis (not S. mitis, although it is found in dental plaque) A. viscosus, naeslundii, israelii

• A. viscosus & A. naeslundii cause root-surface caries ♦ NOT israeli

L. casei – aciodogenic Bacteria that initiate caries must have ability to produce extracellular insoluble glucans

• Dextrans & mutans – polymers of glucose (Extracellular polysaccharides) ♦ Produced by S. mutans, sanguis, salivarius, & Lactobacillus species

• Levans (fructans) – polymers of fructose ♦ Produced by S. mutans, sanguis, salivarius & L. casei, acidophilus

• Dextrans, mutans & levans are synthesized from dietary sucrose by cariogenic & plaque bacteria ♦ S. mutans acts on sucrose to produce levans and dextrans ♦ In S. mutans, the end-product of glucose metabolism is lactate

Plaque Features:

Key etiologic agent in initiation of gingivitis & PD disease • For a bacterium to be seriously considered in the etiology of dental caries, it must exist regularly in the dental plaque

Accumulation of a mixed bacterial community in a dextran matrix Forms on a cleaned tooth w/in minutes Composed of 80% solids (95% bacteria) & 20% water Two categories: supragingival & subgingival Proportions of varying plaque bacteria (cocci, rods, & filaments) change w/ time, diet & location Direct association between amount of bacterial plaque and amount of gingival inflammation

Stages of plaque formation: Formation of the pellicle (acquired pellicle):

• Surface coating of salivary origin – primarily protein in nature w/ some CHO complexes • Essentially structureless & bacteria free • Forms w/in minutes on a clean tooth surface due to its salivary origin • Also forms on crowns, dentures, & porcelain

Bacterial colonization: • Bacteria attach to pellicle in a somewhat orderly fashion • Cocci (Streptococci) first colonize – in tremendsouly large #s

♦ After a tooth erupts, what increases most rapidly?? aerobic gram + Facultative Gram + (choose this if listed as an option)

• Rods (Bacteroides & Fusobacterium) then colonize tooth surfaces • As plaque matures, shift in morphology to include filamentous types (Actinomyces)

Maturation stage: • Saliva continues to provide agglutinating substances & other proteins to the intercellular matrix

♦ Bacterial intercellular adhesion results • The crystalline structure increases & eventually calcifies

Average time for whole process is 12 days – for calculus Supragingival plaque

Attached or tooth associated Consists primarily of G+ facultative anaerobic cocci Fewer anaerobes than subgingival plaque

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S. sanguis, A. viscosus & A. naeslundii predominate????? With time, Vibrio species, Spirochetes, & G- bacteria predominate

Subgingival plaque: Attached or loosely adherent (epithelium associated) Dominated by G- rods as pockets form More anaerobes than supragingival plaque Actinomyces species, F. nucleatum, Treponema species (spirochetes), and Veillonella (sulcus)

Young plaque: -- REVIEW G+ cocci (40-50%) – Streptococcus G+ rods (10-40%) – Lactobacillus G- rods (10-15%) – Fusobacterium, Actinobacillus (not many until plaque matures) Filaments (≤ 4%) – Actinomyces & Veillonella

As plaque age: 50% G+ 30% G+ # of cocci ↓ # of rods then filaments ↑ # of aerobic bacteria ↓ # of anaerobic bacteria ↑

Calculus: Calcified/mineralized bacterial plaque

Forms by bathing plaque in saliva – high [Ca] & [P] Surface is very rough & is covered by a layer or bacterial plaque Inorganic components –

70-90% of the composition Ca & PO4 w/ small amounts of Mg & CO3 (derived almost entirely from saliva); also hydroxyapatite & F–

Organic components & water – Remainder of composition Includes an abundance of Microorganisms (same as plaque), desquamated epithelial cells, leukocytes, & mucin

Main role in PD disease – serves as a collection site for more bacteria Subgingival calculus is dark due to pigments from blood breakdown

Root Canals Preferred Bacteriologic media for culturing root canals:

Thioglycollate broth Periodontal Disease

Gingivitis Oral bacteria play a role in gingivitis is proven by….a reduction of inflammatory states with ABX OR by reduction in

inflammation after removal of the bacteria Periodontitis

The normal oral microflora causes PD Most likely source of bacteria playing a role in PD is from the Subgingival plaque Bacterial endotoxins play a role in PD due to their role in inciting an inflammatory response As the severity of PD increases, there is an increase in plasma cells that produce IgG In pts with chronic PD, when the T cells react with certain plaque bacterial antigens, they produce:

• IL-2, TNF-alpha, IFN-gamma (looks like here, they want you to know what cytokines are) ♦ NOT Immunoglobulin

Actinobacillus: • G- coccobacillary rods • A. actinomycetemcomitans

♦ Part of normal flora in upper respiratory tract ♦ Rare opportunistic pathogen – causes endocarditis on damaged heart valves & causes sepsis ♦ Most commonly implicated w/ the etiology of:

Localized juvenile periodontitis (LJP) 17 yr old with sparse plaque and periodontitis (A. actinomycetemcomitans)

Periodontitis in juvenile diabetes Acute necrotizing ulcerative gingivitis (ANUG): “Vincent’s infection” or “trench mouth”

• Condition which presents rather pathognomonic (indicative of disease) clinical signs/symptoms ♦ Pathognomonic = “Characteristic of a single disease” ♦ Two most important clinical sings:

1) Interproximal necrosis & pseudomembrane formation on marginal tissues This is why we know its P. intermedia – think Interproximals

2) History of soreness & bleeding gums caused by eating & brushing ♦ Other signs/symptoms – fetor oris (offensive odor), low grade fever, lymphadenopathy, & malaise

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• PMN predominates in inflammatory infiltrate of ANUG ♦ Because it’s a gingivitis

• Occurs most often in adults between 18-30 y.o. • Predisposing factors – Hx of gingivitis, tobacco smoking, gross neglect, fatigue, & stress • Associated bacteria:

♦ Prevotella intermedia ♦ Fusobacterium species ♦ Intermediate-sized Spirochetes ♦ Selenomonas species

Topical Antimicrobials: Chlorhexidine:

Most effective antimicrobial agent for long-term reduction of plaque & gingivitis Leaves greatest residual concentration in mouth after use Rapidly absorbed onto teeth & pellicle – slowly released Characterized by a cumulative antimicrobial effect – substantivity!!! ADA: approved as antimicrobial & antigingivitis agent Peridex & PerioGard

Stannous fluoride: Antimicrobial action related to the tin ion rather F– Available in gel form (e.g., Stop, Gel-Kam) ADA: approved as anticaries but not antiplaque/antigingivitis

SIDE NOTE: Fluoride is most effective and safest as a prophylactic measure when its added to the water supply Phenolic compounds:

ADA: approved as antimicrobial & antigingivitis agent Listerine

Quaternary ammonium coumpounds: Not as effective as others in reducing plaque or gingivitis Best at eliminating halitosis Scope & Cepacol Mechanism of action is against the cytoplasmic membrane

Mandible Infection Soft tissue infection spreading along the mandible and into the floor of the mouth would likely involve:

Eikenella corrodens, Staph aureus, Strep pyogenes, Peptostreptococcus anerobius, and Bacteroides!!!!! Ludwig’s angina:

Aka “submandibular space infection” or “sublingual space infection” Not often seen An extension of infection from the Mn molar teeth into the floor of mouth Characteristics:

First – brawny induration that doesn’t pit on pressure. No fluctuance is present Secondly – three facial spaces are involved bilaterally: submandibular, submental, and sublingual spaces Thirdly – the patient has a typical open-mouthed appearance

It has a rapid onset Dysphagia, dyspnea, and fever are present May swell to block airway = emergency

Goal of emergency Tx is to maintain open airway (intubation or tracheostomy, if needed) Abx (usually penicillin-like drugs) are given via IV to treat until symptoms diminish – then given orally Most cases appear to be mixed infection – Streptococci almost always present

Cervicofacial actinomycosis (Aka “lumpy jaw”): Chronic infection w/ Actinomyces, usually A. israelii

BOTH Actinomyces and Nocardia are gram + rods forming long branching filaments, LIKE FUNGI • SNAP

♦ Sulfa for Nocardia, Actinomyces use PCN Branching, G+, microaerophilic, filamentous

• NOT dimorphic Causes very hard, deep infections with broad swelling and draining fistulas

Slow growing, deep, lumpy pyogenic cutaneous abscesses that extrude a thin, purulent exudate through multiple sinuses A. Israeli causes abscesses

Develops chiefly in the jaws and neck, less frequently in the lungs and alimentary tract Occurs following tissue damage that is contaminated w/ endogenous organism (also found in healthy oral cavities) Can be treated w/ long-term PCN therapy SNAP

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Actinomyces are G+ filamentous bacteria that are normal inhabitants of the oral cavity and GI tract Lesion have characteristic “sulfur granules” – Actually misnomer

These are actually colonies of infecting actinomycotic organism Osteomyelitis is a common occurrence Infection after pulled tooth from Actinomyces “lumpy jaw”

Behcet’s syndrome: Chronic, relapsing inflammatory disease that can produce recurring, painful mouth sores, skin blisters, genital & ocular sores,

& swollen joints Invovles oral, ocular, and genital lesions (incorrect: herpetiform & recurrent aphthous) Formation of a pus-like fluid in the anterior chamber of the eye Pyodermas (pus-producing disease of the skin) are common Often there is CNS involvement in a variety of forms Aphthous-related condition w/ associated genital lesions and a genetic predisposition A multisystem disease of uncertain pathogenesis, consisting of multiple oral, anogenital and ocular apthouslike lesions

Uveitis – inflammation of the uveal tract of the eye, including the iris, ciliary body & choroid Frequently w/ arthralgia (1° ankles and knees), thrombophlebitis, macular and pustular skin lesions and associated CNS

involvement Hypersensitivity to minor scratches or other irritations

Pharyngitis Inflammation of the pharynx Main symptom is a sore throat

Other symptoms Inflammation, exudates, fever, leukocytosis, lymphadenopathy Caused by a variety of viruses (adenoviruses & coxsackie viruses)

ESOPHAGUS Acid reflux:

Backflow of stomach contents upward into the esophagus; most obvious symptom is heartburn Gastroesophageal reflux:

Clinical symptoms related to reflux of the stomach or duodenal contents into esophagus Cause: Inappropriate relaxation of lower esophageal sphincter

Crural diaphragm important anti-reflux function, especially w/ increased pressure. Hiatal hernia interferes w/ crural diaphragm Crural may be damaged by bile and pancreatic secreations Associated w/ smoking, some foods and juices A person with chronic bleeding ulcer in the stomach will most likely present with what?? Esophageal reflux???

• Maybe Hematemesis Heatburn most common sign, also accompanied by dysphagia, regurgitation and bleeding if excessive erosion is present Dx: w/ barium swallow, ambulatory 24 pH monitor, endoscoopy Complications include esophageal ulcers, aspiration, and barrett esophagus that is lined w/ columnar epithelium increasing

incidence of adenocarcinoma. Chronic GERD is associated w/ esophageal carcinoma Tx: lose weight, use antacids, H2 blockers, and surgery

Barrett’s esophagus: BARRett’s = Becomes Adenocarcinoma, Results from Reflux Glandular (columnar epithelila) metaplasia: replacement of nonkeratinized squamous epithelium w/ gastric (columnar)

epithelium in the distal esophagus Achalasia (A-chalasia = absence of relaxation):

Nerve related disorder of unknown cause that can interfere w/ two processes: 1) Rhythmic waves of peristalsis 2) Opening of lower esophageal sphincter [due to the loss of myenteric (Auerbach’s) plexus]

Main symptom: difficulty swallowing both solids & liquids (progressive dyshpagia) Barium swallow shows dilated esophagus w/ an area of distal stenosis Associated w/ increase risk of esophageal carcinoma

Hiatal hernia: Protrusion of a portion of the stomach through the diaphragm Cause is unknown; most people have minor symptoms

Plummer-Vinson syndrome Atrophic glossitis, esophageal webs, dysphagia Associated w/ iron deficiency anemia

Mallory-Weiss syndrome: Mild to massive, usually painless bleeding due to a tear in the mucous MB at junction of esophagus & stomach Also characterized by hematemesis (vomiting of blood) Most common in men > 40, especially alcoholics Tears are usually caused by severe retching & vomiting

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Most common after excessive intake of alcohol DRUNK DUCKS (Mallory (mallard)) Treatment varies w/ severity of bleeding GI bleeding usually stops spontaneously Tear usually heals in ~10 days w/o special Tx – surgery rarely required

Esophageal varices: Found elsewhere in file

Esophageal cancer: Risk factors include ABCDEF: achalasia, Barretts esophagus, Corrosive esophagitis/Cigarettes, Diverticuli (eg., Zenker’s

diverticulum), Esophageal web/EtOH, Familial Most common malignant neoplasm of the esophagus is a squamous cell carcinoma – not adenocarcinoma from Barrett’s

STOMACH Pyloric stenosis:

Associated w/ polyhydramnios, hypertrophy of the pylorus causes obstruction Palpable mass in epigastric region and projectile vomiting at 2 weeks of age. Tx = surgery

Acute Gastritis Alcoholics?? NOT associated with Smoking????

Chronic gastritis: Type A (fundal): (most superior part)

Think 4 A’s Autoimmune disease, Autoantibodies to parietal cells, pernicious Anemia, Achlorhydria Type B (antral): (End part of the stomach)

Think B for Bug Caused by H. pylori infections

Both increase risk of gastric carcinoma Not caused by Cigarette Smoke – (why should it be affected by cigarette smoke…very little smoke gets into stomach.)

Peptic ulcers: (Duodenal) Circumscribed lesions in the mucosal MB from gastric acid & pepsin 80% occur in the duodenum – can also develop in lower esophagus, stomach, pylorus, or jejunum Most commonly occur in men between ages 20-50 Most commonly located in the first part of the duodenum Most common symptom = pain

Temporarily relieved by eating Diet changes don’t help

If erosion is sufficiently severe, stomach wall BVs are damaged, & bleeding occurs into stomach itself Complications:

Duodenal peptic ulcer causes bleeding, stricture, perforation, NOT cancer • This is my good ulcer, pain relieved with eating and NO cancer

Hemorrhage • Most common complication of chronic peptic ulcers • Most likely with duodenal peptic ulcers

Perforation • Most common complication destructive for endothelial cells of peptic ulcers that RESULTS IN DEATH • Perforation with peritonitis • In extreme cases a peptic ulcer can lead to perforation (a hole entirely through the wall of the GI tract

♦ Causes acute peritonitis – can lead to death Stenosis LEAST common complication is malignant degeneration

Esophageal ulcers: Caused by repeated regurgitation of stomach acid (HCl) into lower esophagus

Gastric ulcer: Affect stomach mucosa Most common in middle-aged & elderly men Most are benign but carcinoma must be ruled out Think G Pain Greater w/ meals, which leads to weight loss Caused by H. pylori infection in 70%; NSAIDs is also implicated Due to decrease in mucosal protection against HCL

Duodenal ulcer: (Peptic from above) DO NOT become malignant. Erosion in the duodenum lining Type of peptic disease caused by an imbalance between acid & pepsin secretion and the defenses of the mucosal lining

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Inflammation may be precipitated by aspirin & NSAIDs Commonly associated w/ presence of H. pylori in the stomach Risk factors – aspirin, NSAID use, cigarette smoking, older age Due to increase in gastric acid secretion or decrease in mucosal protection. (gastric ulcers tend to have less acid secretion

than normal). Think D Pain Decreases w/ meals, leading to weight gain Hypertrophy of Brunner’s glands Tend to have clean “punched out” margins unlike the raised/irregular margins of carcinoma Not associated w/ corticosteroids and alcohol 20% aren’t related to H. pylori (other source says that almost 100% are caused by H. pylori), NSAIDs or elevated gastrin &

are idiopathic Tx of H. pylori w/ triple therapy:

• metronidazole, bismuth salicylate, & amoxicillin or tetracycline Zollinger-Ellison syndrome (uncommon):

Gastrin-producing tumor leading to increased HCl & multiple persistant ulcers Usually located in the pancreas May be associated with MEN Type I 50% are malignant

A decubital ulcer is an example of tissue destruction caused by ischemia – (Same thing as bed sores??) A chronic ulcer that appears in pressure areas of skin overlying a bony prominence in debilitated patients confined to bed

or otherwise immobilized, due to a circulatory defect, hence the ischemia. Stomach cancer:

Almost always adenocarcinoma Esophagus is SCC - esoph has no glands so SCC. (Except w/Barrets where epithel has changed to columnar just like

stomach, so now, just like stomach Adenocarcinoma) LUNG is Adenocarcinoma

Early aggressive local spread and node/liver metastasis It is associated w/ dietary nitrosamines, achlorhydra, chronic gastritis Is NOT etiologically associated w/ smoking – smoke doesn’t get into stomach.

BUT…Smoking about doubles the risk of stomach cancer for smokers – American Cancer Society Termed linitis plastica when diffusely infiltrative (thickened, rigid appearance) Associated:

Virchow’s node: involvement of supraclavicular node by metastasis from stomach Krukenberg’s tumor: bilateral metastasis to ovaries. Abundant mucus, signet-ring cells

SMALL INTESTINE Meckel’s diverticulum

A true diverticulum due to persistence of the omphalomesenteric vitelline duct True meaning it has the muscularias propria layer Most are acquired, and False

Atresia – congenital absence of a region of bowel. Atresia = absence Stenosis – narrowing, which may lead to obstruction Diarrhea:

Types: Osmotic: secondary to poorly absorbable solutes, (laxatives), slows w/ fasting Secretory: caused by toxins like enterotoxigenic E. Coli or cholera,large amounts of water, doesn’t slow w/ fasting

• Drinking water is usually checked for E. Coli • You treat Cholera by replacing fluids (Vibrio cholera)

Exudative: secondary to invasive bacteria like shigella, includes inflammatory bowel diseases. Mainly involves colon. • White cells in stool

Motility disorder: irritable bowel syndrome, surgical bypass Tx: treat underlying cause, opiates to slow peristalsis (except in acute infx), replace lost fluids

Bismuth subsalicylate—inhibit colonization of enterotoxins Antibacterial and anitprotozoal

Malabsorption: Impaired intestinal absorption of dietary constituents Can cause deficiencies of nutrients, proteins, fats, vitamins, or minerals Symptoms vary depending on the deficiency Clinical features: diarrhea, steatorrhea, weakness, weight loss

Steatorrhea – results in deficiency of A, D, E, K, and calcium Vitamin B12 malabsorption occurs in pernicious anemia (due to the absence of intrinsic factor) & in Crohn’s disease

Summary of Fat-Soluble Vitamins

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Vitamin Physiologic function Result of deficiency A Helps maintain normal body growth & health of specialized

tissues (esp. retina); production of rhodopsin (photopigment) Promotes differentiation of epithelial cells

Night blindness, skin lesions, xerophthalmia (keratinization & dryness of eye tissues)

D Essential in bone formation Rickets in children; osteomalacia in adults E Antioxidant Possible neurologic dysfunction K Involved blood clotting

*Helps Produce Prothrombin Tendency to hemorrhage

Vitamin Deficiency Leads To Characteristic of Deficiency Symptoms

Vitamin B1 (thiamine)

Wet beriberi, dry beriberi High cardiac output; peripheral neuropathy

Pins and needles sensation, especially in feet

Vitamin B2 (riboflavin)

Cheilosis; glossitis Skin fissures at angle of mouth; inflammation of tongue

Sore tongue and cracks at edge of mouth

Vitamin B3 (niacin)

Pellagra Dementia, dermatitis, & diarrhea

Vitamin B6 (pyridoxine)

Cheilosis; glossitis, anemia Skin fissures at angles of mouth; inflammation of tongue; # of RBCs is below normal

Vitamin B12 (cobalamin)

Megaloblastic anemia (i.e., pernicious anemia) Neurologic dysfunction

Anemia in which there is a predominant # of megaloblasts & few normoblasts

Anemia, pins and needles sensation

Folic acid Megaloblastic anemia Neuroligic dysfunction is not a feature

Anemia w/ a predominant # of megaloblasts (abnormally large nucleated RBCs)

Anemia

Vitamin C (ascorbic acid) Essential in bone formation

Scurvy, defective formation of mesenchymal tissue & osteoid matrix; defective wound healing Impaired collagen formation

Swollen, bleeding gums, muscle, joint, & bone pain, abnormal bleeding

Weakness, bleeding gums

Other nutrient deficiencies Iron – anemia Calcium – bone thinning Vitamin D – Bone thinning (Rickets, Osteomalacia, Rachitic Rosary Vitamin K – Tendency to bruise & bleed Protein – Tissue swelling, usually in legs

Malabsorption syndromes: Develop when nutirents are not absorbed properly into blood Main characteristic finding = steatorrhea – light-colored, soft, bulky, & foul-smelling stool Celiac sprue = celiac disease:

Autoantibodies to gluten (gliadin) in grains leading to steatorrhea Associated with people of North European decent Villus flattening (blunting of villi) and lymphocytic infiltrate, and abnormal D-xylose test

• Think you flattened out the Spruce trees Tends to affect the jejunem, associated w/ dermatitis hepretiformis 10-15% lead to malignancy, often T-cell lymphoma, can be fatal in adults due to development of lymphoma in intestine Some people develop symptoms as children & others as adults The longer a person was breastfed, the later the symptoms appear Other factors – the age at which one began eating gluten-containing foods & how much gluten was eaten

Tropical sprue: Cause is unknown – may be related to an infectious organism (E. coli) since it responds to Ab/s Affects residents of or visitors to the tropics Typical symptoms – steatorrhea, diarrhea, weight loss, & a sore tongue from Vit B deficiency

Disaccharidase deficiency: Most common is lactase deficiency

Whipple’s disease: Rare, causes malabsorption due to intestinal infection Caused by infection w/ Tropheryma whippelii Contains PAS positive macrophages Primarily affects middle-aged white men

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Slow onset of symptoms – skin darkening, inflamed & painful joints, & diarrhea May be fatal w/o Tx

Intestinal lymphangiectasia: Disorder of children & young adults in which lymph vessels supplying the lining of small intestines enlarges Main symptom = massive fluid retention

LARGE INTESTINE Hirschsprung’s disease:

Think you bowels Have SPRUNG out of control (Parasympathetic) Congenital megacolon characterized by lack of enteric nervous plexus in segment (Auerbach’s and Meissner’s plexuses) on

intestinal biopsy Due to failure of neural crest cell migration Presents as chronic constipation early in life. Dilated portion of the colon proximal to the ganglionic segment, resulting in “transition zone”

Diverticular disease: Diverticulum:

Blind pouch leading off the alimentary tract, lined by mucosa, muscularis, and serosa, that communicates w/ the lumen of the gut

Most diverticula (esophagus, stomach, duodenum, colon) are acquired and are termed false in that they lack or have an attenuated muscularis propria • Meckel’s is TRUE

Diverticulosis: The prevalence of diverticulosis (many diverticula) in pt older than 60 approaches 50% Caused by increase intraluminal pressure and focal weakness in the colonic wall Most frequently involve the sigmoid colon Associated w/ low-fiber diets Most often asymptomatic or associated w/ vague discomfort

Diverticulitis: Inflammation of diverticula classically causing lower left quadrant pain (Sigmoid area) May be complicated by perforation, peritonitis, abscess formation, or bowel stenosis

Inflammatory bowel diseases Crohn’s disease & Ulcerative colitis

Crohn’s Disease Ulcerative colitis Possible etiology Infectious Autoimmune Location May involve any portion of the GI tract, usually the

terminal ileum, small intestines, and colon. Skip lesions, rectal sparing

Colitis = colon inflammation. Continuous lesion w/ rectal involvement

Gross morphology Transmural inflammation. Cobblestone mucosa, creeping fat, bowel wall thickening (“string sign” on x ray) linear ulcers, fissures

Mucosal inflammation. Friable mucosal pseudopolyps w/ freely hanging mesentery

Microscopic morphology Noncaseating granulomas Crypt abscesses and ulcers Complications Strictures, fistulas, perianal disease, malabsorption—

nutritional depletion Severe stenosis, toxic megacolon, colorectal carcinoma

Extraintestinal manifestation Migratory polyarthritis, erythema nodosum Pyoderma gangrenosum, sclerosing cholangitis

Crohn’s disease = Granulomatous enteritis Chronic granulomatous inflammation involving any part of the GI tract – ileocolitis most common – usually skip-lesions Characterized by non-necrotizing granulomatous inflammation w/ ulcers, strictures, fistulas Transmural (not limited to mucosa/submucosa) Etiology unknown; no cure Think Fat old Crone skipping down a cobblestone road looking at mural – scratching his anal fissures. Symptoms:

Cobblestone fissuring of buccal mucosa Presence of anal fissures Abdominal pain – often right lower quadrant; diarrhea, weight loss, bleeding is uncommon, rectal abscess and fistula

Complications -intestinal obstruction, fistulas, malabsorption, extra intestinal similar to U.C. Treatment – antibiotics, immunosuppression, anti-TNF antibody, surgical -only w/ complications, since disease may recur,

hyperalimentation if significant absorptive problems are present Ulcerative colitis:

Chronic disease in which the large intestine becomes inflammed & ulcerated Not transmural Leads to episodes of bloody mucous diarrhea, abdominal cramps, & fever

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Increased familial incidence, decreased incidence in Blacks and increased in Jews Onset often occurs after smoking stopped, etiology is unknown Increased incidence of colon cancer w/ pancolitis and duration of more than 10 years Complications include massive hemorrhage, colonic stricture, polyp, greater risk of adenocarcinoma than Crohn’s, toxic

dilation and perforation; extra intestinal pyroderma gangrenosum, and erythema nodusm, arthritis, and kidney stones Pseudomembranous colitis

Clindamycin use allows for proliferation of C. difficile Tx: vancomycin or metronidazole

Hemorrhoids External or internal hemorrhoids

Familial polyposis Familial adenomatous polyposis = familial polyposis coli

Colon becomes covered w/ adenomatous polyps after puberty Progresses to colon cancer unless resected, associated w/ Gardner’s syndrome Deletion on chromosome 5; 5 letters in polyp Polyps appear in 20s, become symptomatic by 30s, and become adenocarcinoma by age 40 (100% of the time)

Gardner’s syndrome: Type of hereditary polyposis Autosomal Dominant Various types of noncancerous tumors occur in intestines & elsewhere in the body Characterized by polyposis of the colon Carries a high risk of colon cancer

Peutz-Jehgers syndrome: (Polyps – Jejunum Syndrome) Condition in which many small lumps (juvenile polyps) appear in a variety of sites in the GI tract

• Most common site = small intestine (esp. jejunum) Hereditary condition affecting males/females equally Characterized by melanin pigmentation of oral mucosa, especially of lips & gums Polyps are hamartomas – not true neoplasms

• They do not increase risk of cancer in intestinal tract • Pts are at increased risk for cancer of pancreas, breast, lung, ovary, & uterus (Wow, that’s tricky!! Intestinal

related dsz that d.n. increase intestinal CA risk, but does increase it for all these other things). Turcots syndrome:

Characterized by polyps along w/ tumors of the CNS Gastrointestinal Cancer:

Most commonly associated with villous adenoma (NOT diverticulosis, Meckel’s diverticulum, or duodenal peptic ulcer) Colon Cancer:

Adenocarcinoma is the most common type of colon cancer Presents w/ rectal bleeding, changed bowel habits, weight loss

Tumors of the L side are more likely to cause symptoms More common in industrialized nations Sigmoidoscopic exam can disclose a majority of tumors Symptoms generally only in late disease Transverse is NOT most common (Sigmoid)

Another Q says: Adenocarcinomas are most common in Rectosigmoid section – hence, then Roto-rooter job NOT etiologically associated with cigarette smoke (Along with STOMACH). Again, smoke d.n. get to these areas.

(Lung, Esophageal, Oral, Laryngeal and Urinary bladder ARE) BUT…Recent studies have shown that smokers are 30-40% more likely to die of colorectal cancer than nonsmokers –

American Cancer Society Intussusception: telescoping of one bowel segment into distal segment; can compromise blood supply (Like a telescope) Volvulus: twisting of portion of bowel around its mesentery; can lead to obstruction APPENDIX Appendicitis:

Possible sequelae of acute appendicitis: general peritonitis, periappendiceal abscess formation, pylephlebitis, hepatic abscess

Sudden inflammation of the appendix One of the most common causes of emergency abdominal surgery in children More common in males – peak in the teens & early 20s Leukocytosis is a “Sign” of appendicitis Generally follows obstruction of the appendix by feces, a foreign body, or a tumor (rare) 1st symptom is typically crampy or “colicky” pain around the navel. Usually a marked reduction in or total absence of appetite

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Often assocatied w/ nausea and occasionally vomiting & low grade fever As inflammation in increase, pain moves down & to the right – localizes directly above the appendix

Appendix is found at “McBurnery’s point” – 2/3 of the way from the navel to the right superior iliac crest Momentary increase in pain when abdomen is pressed, held momentarily, & then rapidly released

“Rebound tenderness” suggests inflammation has spread to the peritoneum If rupture, pain may disappear briefly & pt may feel suddenly better

However, once peritonitis sets in, pain returns & pt becomes progressively more ill Abdomen may become rigid & extremely tender

Appendectomy performed ASAP after Dx Differntial Dx for acute appendicitis:

Crohn’s (Left) Meckel’s diverticulitis (Duodenum) Pelvic Inflammatory Disease Gastroenteritis with mesenteric adenitis

• NOT Duodenal Peptic Ulcer (heart burn) – relieved pain with eating Carcinoid tumor

The most common neoplasm of the appendix – rarely metastasizes Tumors secrete high levels of 5HT that does not get metabolized by the liver due to the liver metastases Results in recurrent diarrhea, cutaneous flushing, asthmatic wheezing, and right-sided valvular disease

PANCREAS (non-endocrine) Pancreatitis:

Inflammation or infection of the pancreas Often caused by digestion of parts of pancreas by pancreatic enzymes normally carried to small intestine w/ pancreatic ducts Acute hemorrhagic pancreatitis:

Caused by obstruction of normal pathway of secretion of pancreatic juice into intestine Causes

• GET SMASHeD ♦ Gallstones, Ethanol, Trauma, Steriods, Mumps, Autoimmune disease, Scorpion sting, Hyperlipidemia, Drugs

Zymogens of proteolytic enzymes are converted into catalytically active form prematurely inside pancreatic cells Causes painful & serious destruction of the organ – can be fatal Associated w/ alcoholism & biliary disease Manifestations/consequences –

• Enzymatic hemorrhagic fat necrosis w/ calcium soap formation & resultant hypocalcemia • Hemmorrhage • Inlammation • Fat necrosis • Parenchymal necrosis

♦ NOT Fibrosis Outstanding symptom – severe, knife-like, upper abdominal pain Dx – made by noting the type of pain & by detecting elevated serum lipase (mostly) & amylase enzymes in pt’s serum &

urine Chronic pancreatitis:

Strongly associated with alcoholism Presents w/ steatorrhea, diabetes, and abdominal mass (pseudocyst) Dx – elevated amylase and alkaline phosphatase

BRAIN / NERVOUS SYSTEM

Counterparts Thyroid CAUSE:

Hyper (Thyrotoxicosis) Graves’/Plummer’s Hypo (Myxedema/Cretinism) Hashimoto’s

Adrenal Hyper Cushing’s Hypo Addison’s

HEAD / BRAIN PROBLEMS One out-of-place congenital problem:

Neural tube defects: associated w/ high levels of alpha fetoprotein in the amniotic fluid and maternal serum. Their incidenc is decreased

w/ maternal folate ingesting during pregnancy Spina bifida occulta:

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• failure of bony spinal canal to close, but no structural herniation. Usually seen in lower vertebral levels in association w/ tuft of hair (associated with increased levels of AFP)

Meningocele: • meninges herniate through spinal defect

Meningomyelocele: • meninges and spinal cord herniate through spinal canal defect

Anencephaly: no development Concussion:

Transient paralysis of cerebral function immediately after head trauma Manifested by dizziness, cold perspiration, visual disturbance & loss of consciousness Most people recover completely w/in a few hours or days

Contusion: Bruise of the brain parenchyma typically involving the subunit of the gyrus

Brain Tumors Adult

70% above Tentorium (i.e. cerebral hemispheres) Incidence: Metastases > Astrocytoma (including glioblastoma) > Meningioma

Child 70% below Tentorium (i.e. cerebellum) Incidence: Astrocytoma > Medulloblastoma > Ependymoma

Subdural head injury: Traumatic subdural hematomas are among the most lethal of all head injuries, common during abuse cases See in 15% of head traumas Tiny “bridging veins” running between brain surface & its outer covering stretch & tear, allowing blood to collect

These veins rupture due to sudden change in velocity of head during trauma Signs/symptoms – confusion, headaches, disorientation, fluctuating levels of consciousness or coma

Develop gradually over time, occurring several hours or even days after initial injury Intracranial hemorrhage:

Epidural hematoma Rupture of middle meningeal artery, often secondary to fracture of temporal bone Lucid interval; CT shows biconcave disk not crossing suture lines

Subdural hematoma Rupture of bridging veins. Venous bleeding (less pressure) w/ delayed onset of symptoms. Seen in elderly individuals, alcoholics, and blunt trauma. Crescent shaped hemorrhage that crosses suture lines Pt lapses into a coma and fluctuating levels consiousness hours after blunt trauma→dx: subdural hematoma

Subarachnoid hemorrhage Rupture of an aneurysm (usually Berry aneurysm) or AV malformation Patient complains of “worst headache of my life” Bloody or xanthochromic spinal tap Berry aneurysms:

• Aka “saccular aneurysms” • Most common cause of nontraumatic subarachnoid hemorrhage • 90% are in the anterior part of the circle of Willis

♦ MOST common site is the anterior communicating artery (Or branch of the middle cerebral) In the past, middle meningeal

• Rupture, is the most common complication, causes severe headache, and leads to hemorrhagic stroke • Associated with adult polycystic kidney disease, Ehlers-Danlos syndrome, and Marfan’s syndrome • May result in cerebrovascular accident

Parenchymal Hematoma Caused by HTN, amyloid angiopathy, DM, and Tumor

Meningioma: Intracranial tumor arising from arachnoid, usually occurring in adults >30 y.o.

Cerebral infarction (stroke): Infarction of cerebrum due to arterial occlusion by a thrombus or embolus from the heart or carotid artery Common signs/symptoms – sudden paralysis & numbness on one side of body

Encephalitis: An uncommon inflammation of the brain Most commonly caused by VIRAL infection –Like HSV

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Exposure to viruses via: Insect bites, food/drink contamination, inhalation of respiratory droplets, skin contact

• In rural settings – arboviruses carried by mosquitos or ticks or that are accidentally ingested • In urban settings – enteroviruses are most common (Coxsackie virus, poliovirus, & echovirus)

Other causes: HSV, varicella, measles, mumps, rubella, adenovirus, rabies, West Nile virus

Once virus is in blood it can localize in brain tissue causing inflammation WBCs invade to try to fight off infection – brain swells – can cause destruction of nerve cells, bleeding & brain damage Symptoms – fever, headache, vomiting, photophobia, stiff neck/back, confusion (disorientation, drowsiness, clumsiness)

Meningitis: Brain & spinal cord meninges become inflamed May be bacterial OR may be caused by a number of viruses (Echovirus, Coxsackie, Mumps, etc.)

Bacteria are the most common cause of Meningitis – think Neisseria meningitides is BActeria • Don’t get clowned, because Encephalitis is from VIRAL

Viral meningitis rarely results in permanent neural damage CSF Findings in Meningitis

Type Pressure Cell Type Protein Sugar Bacterial Up PMNs Up Up Down Fungal/TB Up Lymphos Up Up Down Viral Normal/Up Lymphos Up Normal Normal

May be transferred by respiratory droplets Most common in adults – Neisseria meningitidis & S. pneumoniae (elderly)

• N. meningitidis: ♦ Transmission via respiratory droplets ♦ Key virulence factor in N. meningitidis is its antiphagocytic capsule, same as S. Pneumoniae ♦ IgA protease also in an important virulence factor ♦ Treat it w/ PEN G

Most common in children < 2 y.o. – H. influenzae Most common in adults – Neisseria meningitidis & S. pneumoniae Most common in the elderly – S. pneumoniae

• NOTE all 3 of the most common have Capules Common Causes of Meningitis

Newborn (0-6 m) Group B Strep, E. coli, Listeria • Listeria Monocytogenes might cause Fetal Death or meningitis (Think the baby goes LISTless)

Don’t confuse with Floppy baby (Botulism) ♦ Also causes Dysentery, Cholera, and Gastroenteritis

Children (6 m – 6y) S. pneumoniae, N. meningitidis, H. influenza B, Enteroviruses Adults (6y – 60y) N. meningitides, Enteroviruses, S. pneumoniae, HSV Adults (60+) S. pneumoniae (#1 in eldely), Gram – rods, Listeria

Infecting organism enters body through nose & throat Signs & symptoms – high fever, severe headache, & neck stiffness

Arnold-chiari Malformation Brain coming through Foramen Magnum Syringomyelia

Softening and cavitation around central canal of spinal cord Crossing fibers of spinothalamic tract are damaged Bilateral loss of pain and temperature sensation in upper extremities with preservation of touch sensation Most common C8-T1 Common in Arnold Chiari malformation

Tabes Dorsalis Degeneration of dorsal columns and dorsal roots due to tertiary syphilis, resulting in impaired proprioception and

locomotor ataxia Associated with Charcot joints, shooting lightening pain, Argyll-Robertson pupils, and absence of deep tendon reflexes

One out-of-place disorder: Fetal alcohol syndrome:

Newborns of moms who consumed significant amounts of alcohol (teratogen) during pregnancy (highest risk at 3-8 wks) Have increased incidence of congenital abnormalities, including pre- & postnatal developmental retardation, microcephaly,

facial abnormalities, limb dislocation, and heart and lung fistulas Mechanism may include inhibition of cell migration The #1 cause of congenital malformations in the U.S.

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NERVOUS SYSTEM Degenerative disease:

Cerebral cortex: Alzheimer’s disease:

• Most common cause of dementia in the elderly ♦ Multi-infarct dementia is the 2nd most common cause

• Associated w/ senile plaques (beta amyloid core) & neurofibrillary tangles (abnormally phospharylated tau protein) • Gross cortical atrophy • Familial form (10%) associated w/ specific genes

Pick’s disease: • Associated w/ Pick bodies (intracytoplasmic inclusion bodies) & is specific for the frontal & temporal lobes

Basal ganglia and brain stem: Huntington’s disease:

• Autosomal dominant inheritance, choréa, dementia • Atrophy of caudate nucleus (loss of GABA neurons)

Parkinson’s disease: • Think TRAP for being trapped in your body Tremor (at rest), Rigidity, Akinesia, Postural Instability • Associated w/ Lewy bodies and depigmentation of the substantia nigra • Due to loss of dopaminergic neurons in the caudate & putamen • Rare cases have been linked to exposure to MPTP, a contaminant in illicit street drugs • Signs/symptoms:

♦ Bradykinesia, rigidity, resting tremor, masked faces, dementia Motor Neuron

Amyotropic Lateral Sclerosis (ALS) (AKA Lou Gehrig’s Disease) • Associated with BOTH lower and upper motor neurons (Think ALLS the motor neurons)

Werdnig-Hoffmann Disease • Present at birth as a “floppy baby” --- Botulism • Tongue fasciculations

Polio • Lower motor neuron signs • Think Can’t play water polio because no lower motor neurons to tread water

Demyelinating Diseases Multiple Sclerosis:

Demyelinating disease Disorder of brain & spinal cord (CNS) caused by progressive damage to myelin Cause is unknown Results in ↓ nerve functioning – leads to a variety of symptoms Spontaneous exacerbations & remissions 90% of pts develop pyramidal tract dysfunction (hyperreflexia, weakness, spasticity) Disease involves repeated episodes of inflammation of nervous tissue in any area of CNS

• Episodes occur when body’s own immune cells attack nervous system • Inflammation destroys myelin sheath in that area, leaving multiple areas of scar tissue (sclerosis) along the

myelin • Results in slower transmission of nerve impulse, leading to symptoms of MS

Affects approximately 1/1000 – women more commonly affected Commonly begins between 20-40 y.o. Characterized by paresthesia, unsteadiness of gait, incontinence, paralysis, and plaques of demyelination

• Plaques are evident in the white matter Large amounts of protein are found in CSF Injectable interferon reduces frequency of MS relapses Periventricular plaques, preservation of axons, loss of oligodendrocytes, reactive astrocytic gliosis Patients present w/ sudden loss of vision Classic triad is: Think SIN Scanning speech, Intention tremor, and Nystagmus Increase incident w/ increased distance from equator

Progressive multifocal leukoencephalopathy: Associated w/ JC virus and seen in 2-4% of AIDS patients (reactivation of latent viral infection)

Postinfectious Encephalomyelitis Metachromatic Leukodystrophy Guillain Barre syndrome: (Guillen can’t lift the Barre)

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Inflammation and demyelination of peripheral nerves & motor fibers of ventral roots (sensory effect less severe than motor)

Causing symmetric ascending muscle weakness beginning in distal lower extremities Facial diplegia in 50% of cases Autonomic function may be severly affected (eg., cardiac irregularities, hypertension) Findings include: elevated CSF protein w/ normal cell count (“albumino-cytologic dissociation) and elevated

proteinpapilledema Associated with C. jejuni or herpesvirus, but non definite link to pathology

Seizures: Causes

Children Genetic, infection, trauma, congenital, metabolic Adults Tumors, trauma, stroke, infection Elderly Stroke, tumor, trauma, metabolic, infection

Partial seizures: 1 area of the brain They can secondarily generalize Simple partial (awareness intact): motor, sensory, autonomic, psychic Complex partial (impaired awareness)

Generalized seizures: Absence: blank stare (petit mal) Myoclonic: quick, repetitive jerks Tonic clonic: alternating stiffening and movements (grand mal) Tonic: stiffening Atonic: “drop” siezures

Aphasia: Broca’s (expressive): nonfluent aphasia w/ intact comprehension: Broca’s area—inferior frontal gyrus

Think Broca for Broken speech Wernicke’s (receptive): fluent aphasia w/ impaired comprehension. Wernicke’s area—superior temporal gyrus

Wernicke’s encephalopathy is characterized by confusion, ocular disturbance & ataxia of gait • Results from vitamin B1 deficiency • Think W for Wordy, but makes no sense

Beriberi peripheral neuropathy: Results from vitamin B1 deficiency An axonal degeneration w/ 2° demyelination Mechanism unknown

Myasthenia Gravis: Neuromuscular disorder characterized by variable weakness of voluntary muscles

Often improves w/ rest & worsens w/ activity Condition is caused by an abnormal immune response

Immune system produces Ab/s that attack ACh receptors that lie on the muscle side of the neuromuscular junction This decreases responsiveness of muscle fibers to ACh released from motor neuron endings

Characterized by: Muscle atrophy Thymic hyperplasia or neoplasm (THYMOMA) Antibody to acetylcholine receptors

• NOT CNS degeneration Pts have higher risk of having other autoimmune disorders (e.g., thyrotoxicosis, RA, & SLE) Affects ~3/10,000 people – most common in young women & older men ~10% of the pts develop a life-threatening weakness of muscles needed for breathing (called myasthenic crisis)

Eaton-Lambert syndrome: Similar to myasthenia gravis in that it’s also an autoimmune disease that causes weakness Caused by inadequate release of ACh rather than by abnormal Ab/s to ACh receptors

(Think they were “Eaton” up all the Ach!!!) • Similar to Clostridium Botulism (FLOPPY BABY) – Inhibits Ach Release

CNS infections with AIDS Toxoplasma Diffuse (intracerebral calcifications) Cryptococcus Periventricular calcifications

LIVER / BILIARY / GALLBLADDER

LIVER Chronic Passive Liver Congestion

“nutmeg” liver, from Right sided failure leads to liver congestion, and widening of sinusoids and central veins

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Portal hypertension: High BP in the portal vein

Portal vein receives blood drained from entire intestines, spleen, pancreas, & gallbladder After entering the liver, the blood divides into tiny channels Blood drains back into the general circulation via central vein hepatic vein

Indicators/Complications of portal HTN: Esophageal varices (first sign) – diluted tortuous veins in the submucosa of the lower esophagus

• Common complications of cirrhosis (varices are NOT a complication of other liver disorders/diseases) ♦ Esophageal varices is the sequelae of fatty nutritional cirrhosis that is the most likely to result in death AND

exsanguination ♦ Obstruction of portal circulation

Most common cause of esophageal varices is Portal HTN ♦ Most common cause of massive hematemesis in alcoholics

Hemorrhoids Testicular atrophy Enlarged veins on the anterior abdominal wall (caput Medusae) Ascities (fluid w/in abdominal cavity) Splenomegaly – single most important sign of portal HTN

Factors increasing BP: Increased blood volume flowing through vessels Increased resistance to blood flow through liver – most common cause of portal HTN

Jaundice (aka “icterus”): Yellow discoloring of skin, mucous MBs & eyes, caused by excessive amount of bilirubin dissolving in subcutaneous fat Bilirubin – waste product resulting from breakdown of heme moiety of hemoglobin molecules (from worn out RBCs)

Ordinarily excreted from body as chief component of bile Conjugated bilirubin – formed by the conjugation of bilirubin w/ glucuronic acid Unconjugated (free) bilirubin – toxic (unlike that bound to albumin or conjugated) High bilirubin levels in blood – can cause kernicterus (deposition of pigments in gray matter - permanent damage to certain

areas of the brain of newborns) • This can cause a characteristic form of crippling – athetoid cerebral palsy

Normally, liver cells conjugate bilirubin and excrete it into bile, where it is converted by bacteria to urobilinogen (some of which is reabsorbed) Some urobilinogen is also formed directly from heme metabolism

Termed unconjugated (indirect) bilirubin before conjugation and conjugated (direct) after. • Conjugated can enter urine and is soluble

Defects in bile excretion produce elevated levels of conjugated or unconjugated bilirubin • BUT Acute biliary obstruction causes a rise in conjugated bilirubin in the serum

Common in newborns in 1st week of life All types (except physiologic jaundice in newborns) indicate:

Overload or damage to the liver Inability to move bilirubin from the liver through the biliary tract to the gut Very common; leading manifestation of liver disease

Common causes: Increased destruction of RBCs w/ rapid release of bilirubin into the blood (unconjugated) Obstruction of bile ducts or damage to liver cells causing inability of bilirubin to be excreted into GI tract (conjugated) Pathogenesis of jaundice in patients with infectious hepatitis is the result from damage to liver cells Gallstones, hemolytic anemia, infection hepatitis, carcinoma of common bile duct, carcinoma of head of the

pancreas Hemolysis of any cause usually results in unconjugated bilirubin predomination

NOT Causes: Aplastic anemia –Don’t have the cells Fibrosis of the liver Vitamin K Deficiency

Obstructive jaundice: Often caused by gallstones blocking the common bile duct

Hepatomegaly: Most common cause of hepatomegaly w/o other signs and symptoms is fatty change (NOT ascites, hepatitis, etc)

Hepatic Failure: These things can be Attributed to hepatic failure:

Tremor (Encephalitis), Gynecomastia, Hypoalbuminemia, Asterixis, and Spider Telangiectasia

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NOT Mallory Bodies • Mallory bodies are large, poorly defined accumulations of eosinophilic material in the cytoplasm of damaged

hepatic cells in certain forms of cirrhosis and marked fatty change especially due to alcoholism ♦ DRUNK DUCKS

Budd-Chiari syndrome: Occlusion of IVC or hepatic veins w/ centrilobular congestion and necrosis, leading to congestive liver disease (heptomegaly,

ascites, abdominal pian, and eventual liver failure) Associated w/ polycythemia vera, pregnancy, hepatocelluar carcinoma

Ascites: Accumulation of free serous fluid in the peritoneal cavity

Almost pure plasma containing tremendous quantities of protein Typically results from liver disease

Disorders that may be associated w/ ascites Cirrhosis, hepatitis, portal vein thrombosis, portal HTN, constrictive pericarditis, CHF, liver cancer, nephritic syndrome,

pancreatitis, Decreased protein production by the liver (no albumin to maintain capillary osmotic pressure) Does NOT develop as a result of esophageal varices

Cirrhosis: Chronic liver disease characterized by generalized disorganization of hepatic architecture w/ scarring & nodule formation

Normal hepatic architecture is destroyed & replaced by bands of fibrous scar tissue Characterized by diffuse destruction & fibrotic regeneration of hepatic cells Most common chronic liver disease 2x more common in men Among people 45-65 y.o., cirrhosis is 3rd most common cause of death (after heart disease & cancer) Signs/Symptoms/Complications:

Ascites Bleeding disorders (coagulopathy, i.e. hemophilia)

• NOTE: PT (not PTT) is used to assess coaguopathy due to liver disease Portal hypertension

♦ Complication of Cirrhosis is obstruction of portal circulation Confusion or change in level of consciousness (hepatic encephalopathy) – TREMORS – asterixis (hand tremor) Splenomegaly

• Indicates portal HTN, which in turn causes esophageal varices Esophageal varices are most common source of massive hematemesis in alcoholics

• Hematemesis Vomiting blood • Hemoptysis (coughing up blood) Lung

Esophageal varices is the sequelae of fatty nutritional cirrhosis that is the most likely to result in death and exsanguination Spider angiomas are common in alcoholics Sudden onset of upper GI bleeding w/ massive hematemesis (vomiting of blood) Jaundice

Causes: Alcohol abuse (most common – 75%), use of certain drugs, and the exposure to certain chemicals Infections (includig Hep B & C) Biliary obstruction Hemochromatosis (iron overload) Congestive heart failure Wilson’s disease

• (A hereditary accumulation of copper in the liver, kidney, brain, and cornea) Other inborn metabolism errors: galactosemia, glycogen storage disease, or alpha1-antitrypsin deficiency

• alpha1-antitrypsin deficiency affects BOTH the Lung and the Liver Associated w/ an increased incidence of hepatocellular carcinoma Is especially prevalent among malnourished persons >50 y.o. w/ chronic alcoholism Mortality is high; many patients die w/in 5 years of onset Nodular Regeneration

Types: • Micronodular: nodules < 3mm, uniform size, due to metabolic insult (e.g., alcohol) • Macronodular: nodules > 3mm, varied sized. Usually due to significant liver injury leading to hepatic necrosis (eg.,

postinfectious or drug induced hepatitis). Has increase risk of developing hepatocellular carcinoma Tx: portacaval shunt between splenic vein and left renal vein may relieve portal hypertension

Fatty Liver Fat is deposited in the hepatocytes (Intracellularly)

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Hepatocellular carcinoma: (hepatoma) Most common primary malignancy in liver of adult Risk factors include: Hep B and C, Wilsons disease, hemochromatosis, alpha-1 antitrypsin deficiency, alcoholic cirrhosis,

and carcinogens (aflatoxin B1) Commonly spread through hematogenous dissemination yielding alpha fetoprotein (AFP)

Reye’s syndrome: Involves brain damage (encephalopathy) & fatty liver changes Most often seen in children 4-12 y.o. (peak = age 6) Associated w/ use of ASA in children to Tx chickenpox or influenza

Typically follows an upper respiratory infection or chickenpox by ~1 week Rapid onset & varying symptoms

Changes in mental status occur including delirium, combative behavior, & coma Frequently begins w/ vomiting – persistent over many hours Vomiting is rapidly followed by irritable & combative behaivior As condition progresses, child may become semi-conscious or stuporous Ultimatley, seizures & coma develop – can quickly lead to death

Is associated w/ the use of aspirin in children to treat chickenpox or influenza Wilson’s disease:

Think Wilson in Castaway He was so hungry he ate copper Aka hepatolenticular degeneration Inherited disorder of copper metabolism

Results in excessive deposits of copper in liver cells Copper fails to enter circulation in form of ceruloplasmin

Characterized by Think ABCsD Asterixis, Basal ganglia degeneration, Ceruloplasmin decrease, Cirrhosis, Corneal Deposits,

Copper Accumulation, Carcinoma, Choreiform movements, Dementia cirrhosis, degeneration of basal ganglia, & deposition of green pigment in the periphery of the cornea

HEPATITIS A: A picoRNAvirus A FOR ASYMPTOMATIC Aka viral, infectious, or short-incubation hepatitis (15-40 days) Least serious, most mild among Hep A, B & C High morbidity, low mortality Highly contagious infectious disease involving liver Usually transmitted by the fecal-oral route

Also transmitted parenterally or sexually May also be transmitted via blood products Usually from ingestion of contaminated food, milk, or water Outbreaks often traced to ingestion of seafood from polluted water Also caused by an RNA enterovirus

Occurs most often in young Adults Does not lead to chronic liver disease, only 0.5% suffer from fatal liver necrosis Symptoms – fever, malaise, abdominal pain, anorexia, jaundice

Appear after incubation period of 3-6 wks Jaundice

• Pathogenesis by Hepatitis A characterized by damage to the liver cells Damage to liver cells results in increased serum levels of enzymes (e.g., transaminases) in liver cells

Detection of increases enzyme levels used to diagnose Hep A Most cases are self-limiting and recovery occurs w/in 4 months Surface Ag (A or B) in pt’s serum indicates the pt is potentially infectious for Hep (carrier state) Hepatitis viruses are very heat resistant (more so than AIDS virus)

Proper autoclaving kills Hep IgM-anti-HAV diagnostic of acute active or recent infection IgG-anti-HAV indicates immunity to Hep A Vaccine is available and should be taken when traveling to endemic areas

A = Asymptomatic (usually), young Adults, Arrives Quickly HEPATITIS B:

Transmitted by a DNA virus Aka “Serum Hepatitis” – Hep B for Blood

HB5 antigen in the plasma is associated with Serum Hepatitis Infectious disease producing liver inflammation & necrosis

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Commonly transmitted by blood-derived products (more so than CMV, Hep A, herpes simplex keratitis) Including perinatal, parenteral of sexual exposure, or mucous or skin openend and exposed to blood, saliva, or feces Not by fecal-oral route

Severity varies from an asymptomatic carrier state to fulminate hepatitis Chronic Hep is common, as are hepatomas Less easily transmitted than Hep A Can be transmitted through blood or by contact w/ human secretions & feces

Common among injection drug users who share needles, as well as between sexual partners Signs/symptoms similar to Hep A (fever, abdominal pain, nausea etc.)

Longer incubation period of 6-8 weeks (one Q says: 1-6 months) Symptoms are slower in developing, but longer in duration

Clinical manifestations: Elevated transaminases, hyperbilirubinemia, elevated alkaline phosphatase

Most patients recover fully Some develop chronic persistent hepatitis or chronic active hepatitis

Markers: A patient recovering from Hep B:

• Detection of the Hep B antigen in serum is indicative of the carrier state • EX: Pt’s lab results show both the HBs and anti-HBs…means pt is a carrier

HBsAg – surface antigen • Indicates active infection with HBV • Earliest marker of virus in serum • Continued presence indicates carrier state (Both HBsAg and anti-HBsAg) • It usually disappears with antibody IgG for the sAg

♦ If IgG comes and takes out HBs-Ag Confers immunity (IgG anti-HBsAg) and affords protection

• If no antibody (IgG) develops: ♦ sAg remains high and the person is a carrier and potentially infectious ♦ Persisting for more than six months indicates chronic hepatitis B

HBsAb • Indicates successful immunization

HBcAg (core antigen) • Is found in the capsid

HBeAg (e-antigen) • Indicates active HBV replication making patient highly infective

IgM-anti-HBc • Indicates acute Hepatitis B

IgG-anti HBc • Indicates previous exposure to hepatitis B (may confer immunity)

How does Hep B cause disease in the liver??? • Type III-- Ag/Ab complexes lead to extrahepatic problems like rash, urticaria, arthritis, vasculitis and

glomerulonephritis Vaccines available and all health care professionals should be vaccinated and children Hepatitis B immune globulin (HBIG) conferes passive immunity

B = Blood borne Non-A and Non-B Hepatitis [HEY: this is actually Hepatitis C]

Type of infection most commonly transmitted via transfusion of properly screened blood HEPATITIS C:

Serum hepatitis that is caused by a virus antigenically different from Hep A or B Most likely results in chronic hepatitis Most often transmitted through blood-transfusions (or via needle stick in a dental office) Death from advanced liver disease caused by hepatitis C infection is primarily due to inhibition of urea synthesis Accounts for 85% of post-transfusion hepatitis but w/ screnning for anti HCV it is reduced Much milder than A or B but is otherwise clinically indistinguishable from them Higher incidence of chronic disease (85%), cirrhosis (20%) Increased risk of Hepatocellular Carcinoma Most common reason for liver transplantation in the U.S. Extrahepatic manifestations: rash, arthritis, glomerulonephris, all mediated by cryoglobulins Anti-HCV and RT-PCR available for dx and genotyping Interferon plus ribavirin used in therapy

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C = Chronic, Cirrhosis, Carcinoma, Carriers HEPATITIS D:

Found in pts w/ acute or chronic episodes of Hepatitis B Makes Hep B infection more severe Drug addicts are at relatively high risk Depends on host having been previoiusly infected with Hep B

Prevention of Hep B also prevents Hep D D = Defective, Dependent on HBV

HEPATITIS E: RNA Calcivirus (NAKED CPR) Transmitted enterically much like Hepatitis A Causes occasional epidemics similar to those of Hepatitis A

Hep E epidemics have only occurred in underdeveloped countries Responsible for most waterborne outbreaks

Self limited illness but can be fulminant (worse) in pregnant women E = Enteric, Expectant, Epidemics

A and E by Fecal-Oral Routes “The vowels hit your bowels”

Alcoholic hepatitis: Swollen and necrotic hepatocytes, neutrophil infiltration Mallory bodies (hyaline), fatty change, and sclerosis around central vein

DRUNK DUCKS – Eosinophils in the liver of drunkies AST is elevated. AST ratio to ALT is > 1.5 Think A Scotch and Tonic

BILIARY Cholelithiasis (Gallstones):

Stone or calculi in gallbladder result from changes in the bile component Virtually all gallstones are formed w/in the gallbladder

Bile: Composed of water, bile salts, lecithin, cholesterol & some other small solutes

• Primary component is Cholesterol Changes in relative concentrations may cause precipitation & formation of a nidus, or nest, around which gallstones form

Risk Factors: Think 4 Fs Female, Fat, Fertile, Forty

Signs: Pt with conjugated hyperbilirubinemia and an absence of urobilinogen

• Urobilinogen is low because the bile can’t get down into the intestine where it is made • (pt does NOT have aplastic anemia, hemolytic anemia, acute hepatitis, or alcoholic cirrhosis)

Types: Cholesterol stones (radiolucent w/ 10-20% opaque due to calicifications):

• Associated w/ obesity, Crohn’s disease, cystic fibrosis, advanced age & Native American origin Mixed stones (radiolucent):

• Have both cholesterol and pigmented components • Most common type

Pigement stones (radiopaque): • Seen in patients w/ chronic RBC hemolysis, alcoholic cirrhosis, advanced age, & biliary infection

Choledocholithiasis – term for gallstones are in bile duct Size – from grain of sand to > 1 inch Color – from yellow to other pigment, depending on what it is made of

GALLBLADDER Cholesterolosis (strawberry gallbladder):

Characterized by small, yellow, cholesterol-containing flecks highlighted against a red background in the gallbladder lining Polyps may form inside gallbladder & require its removal

Diverticulosis of the gallbladder: Small, finger-like out-pouchings of the gallbladder lining – may develop as a person ages May cause inflammation & require gallbladder removal

KIDNEY DISEASE

Renin: Renal hormone associated with HTN (don’t get clowned by angiotensin)

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Does not directly invoke vasodilation Proteolytic enzyme formed in kidney & released into bloodstream where it has an important role in activating angiotensin Produced by & stored in the juxtaglomerular apparatus that surrounds each arteriole as it enters a glomerulus Release is controlled by activity of sympathetic nerves to kidney & renal arterial BP (if ↓ pressure, renin secretion ↑) Acts on angiotensinogen (manufactured by the liver & present in the blood) Converts angiotensinogen to angiotensin I

In turn AT I is converted to AT II by ACE – associated w/ capillary walls, particularly in the lungs AT II stimulates aldosterone release from the zona glomerulosa of the adrenal cortex

• Aldosterone causes Na+ retention by enhancing Na+ reabsorption by distal convoluted tubules & collecting ducts Nephrolithiasis (Kidney Stones)

Presence of renal calculi (kidney stones) w/in renal pelvis or calyces Calcium stones are the most commonly occurring form of nephrolithiasis Most likely the result from Hyperparathyroidism Many stones are asymptomatic until they pass into the ureter – causes renal colic (characterized by severe pain) Complications:

Obstruction of the ureter Acute or chronic pyelonephritis Hydronephrosis

Stone formation w/in urinary tract represents a potential complication of many different diseases 4 types of stones:

Composed of Calcium salts, Uric acid, Cystine , and Ammonium Magnesium Phosphage (struvite) Each has its own group of causes & specific management All are caused by excessive supersaturation of the urine w/ a poorly soluble material

Stones grow upon the surfaces of the papillae, which detach & accompany the urine through the collecting system Many stones are too large to negotiate the narrow circuit – they obstruct flow of urine & can cause severe pain

More common in men; rare in children Exact cause is unknown Predisposing factors: dehydration, infection, changes in urine pH, obstruction of urine flow, immobilization causing bone

reabsorption, metabolic factors (such as hyperparathyroidism [leads to hypercalcemia]), renal acidosis, eleveated uric acid, & defective oxalate metabolism

Painless hematuria as a common early clinical sign in acute diffuse glomerulonephritis, carcinoma of the bladder, focal glomerulonephritis, and renal cell carcinoma – so, if you see urinary disease, think hematuria. BUT NOT Nephrolithiasis (because that mofo just plain hurts)

Hydronephrosis: Abnormal dilation of the renal pelvis & calyces

Caused by an obstruction of urine flow in the genitourinary tract Not a separate disease entity

Rather, a physical manifestation of the disease process that causes impairment of urine drainage “Nephrosis” describes kidney disease usually of the tubules, NOT the glomeruli

Urolithiasis: Urinary calculus, formed in any part of the urinary tract Associated with obstruction of urine flow

Composed of calcium oxalate &/or calcium phosphate Calcium stones account for 80-90% of urinary stones Associated with:

Gout, Hypercalcemia, Renal Infection, and Hyperparathyroidism • NOT systemic HTN

Pyelonephritis: Bacterial infection (usually E. coli) of the renal pelvis & ureters Fever, chills, flank pain, CVA tenderness Acute – active infection of the renal pelvis – the pelvis may become inflamed & filled w/ pus

One feature is costovertebral angle tenderness Chronic – extensive scar tissue forms in the kidney – renal failure becomes a possibility Most often result from UTIs (from urinary refux), particularly in the presence of occasional or persistent backflow or urine

from the bladder into the ureters or kidney pelvis (vesicoureteric reflux); abscesses often develop Cystitis:

UTI Dysuria, Frequency, suprapubic pain Most common causing bugs are E. Coli and Proteus

• Staph saprophyticus is 2nd common cause in young ambulatory women

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Think SSEEK PP Serratia marcescens, Staph saprophyticus, E. coli, Enterobacter, Klebsiella, Proteus, Pseudomonas Aer.

Women have it 10x as much as men (short urethra) NOT associated with blocked urinary flow (Hydronephrosis and Pyelonephritis are!!)

Kidney infections are usually caused by microorganisms ascending from the lower urinary tract Nephrosis generally implies renal disease associated w/ the tubules Tubulointerstitial disease: tubular defects

From a variety of conditions and may be acute or chronic Causes include drugs, obstruction, infections, toxins and vascular problems Urine contains RBC, WBC, and WBC casts but proteinuria is less common w/ low molecular weight proteins Can lead to renal tubular acidosis, aminoaciduria, salt, potassium magnesium wasting, and concentrating defect

Glomerulopathies: Kidney disorders in which inflammation affects mainly the glomeruli

Nephrosis is only Tubules Causes vary – glomerulopathies are similar since glomeruli respond similarly to several types of injury

Four major types of glomerulopathies: 1) NephrOTIC syndrome:

Subtypes: • Membranous glomerulonephritis • Minimal change disease (lipoid nephrosis) • Focal segmental glomerular sclerosis • Diabetic nephropathy • SLE Wire loop appearance

Collection of symptoms caused by many diseases that affect the kidneys Condition characterized by marked prOteinuria, generalized edema, hypOalbuminemia Signs/symptoms: result from increased permeability of glomerular capillareis

• PrOteinuria ♦ Severe loss of protein into the urine (>3.5 grams/day)

• Hypoalbuminemia & decreased levels of other blood proteins • Generalized edema • Hyperlipidemia • Hypercholesterolemia • Retention of excess salt & water • NOT anemia, hematuria, hypertension, or red cell casts in the urine

Not a disease itself – results from a specific glomerular defect & indicates renal damage Caused by:

• Amyloidosis, cancer, diabetes, HIV, glomerulopathies, leukemia, lymphomas, multimple myeloma and SLE • 75% of cases result from primary glomerulonephritis

Can occur at any age • In children it is most common between ages 18 months & 4 years

♦ Affects more boys than girls • In older people the sexes are more eqully affected

Early symptoms: • Loss of appetite, malaise, puffy eyelids, abdominal pain, muscle wasting, tissue swelling (excess salt & water

retention), & frothy urine 2) Acute nephrITIS syndrome

Subtypes: • Acute poststreptococcal glomerulonephririts Glomeruli large and bumpy with hypercellular neutrophils • Rapidly progressive Glomerulonephritis, crescent, moon-shaped • Goodpasture’s syndrome Type II Hypersensitivity, Linear pattern, anti GBM antibodies • Membranoproliferative glomerlonephritis Subendothelial humps, tram track • IgA Nephropathy (Berger’s disease) Mesangial deposits of IgA

Glomerluar inflammation resulting in sudden appearance of hematuria w/ clumps of RBCs (casts) & variable proteinuria Most common in 3-7 y.o. boys Starts suddenly and usually resolves quickly

• Associated with destruction of basement membranes via PMNs (NOT lymphokines, eosinophils, or IgE Ab/s) Elevated antistreptolysin O (ASLO) titers Low serum complement

3) Chronic nephrotic syndrome

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Aka chronic glomerulonephritis Slowly progressive disease characterized by glomerular inflammation resulting in sclerosis, scarring & renal failure Conditions that can lead to chronic GN – SLE, Goodpastures’ syndrome, & acute GN

4) Rapidly progressive glomerulonephritis (RPGN) Aka ‘rapidly progressive nephritic syndrome’ or ‘crescentic GN’ May be idiopathic or associated w/ a proliferative glomerular disease such as acute GN Uncommon disorder in which most of the glomeruli are partly destroyed, resulting in kidney failure Starts suddenly & worsens rapidly Occurs most commonly in 50-60 y.o. people

Glomerular diseases: Damage to glomeruli caused by antibodies directed against glomerular basement membrane or antibody-antigen

complex deposition in which complement helps or hurts condition Hematuria, proteinuria, and renal insufficiency are hallmarks and renal biopsy is needed to establish diagnosis

Renal Insufficiency May produce Parathyroid Hyperplasia

I think it has to do with lacking the Vitamin D formation, so PTH has to work harder to increase serum Ca May have a hemorrhagic tendency

RENAL FAILURE Failure to make urine and excrete nitrogenous waste Consequences Anemia (no erythropoietin), Renal osteodystrophy (No active Vit D), Hyperkalemia (Leads to cardiac

arrhthymias, Metabolic acidosis (due to decreased acid secretion and decreased generation of bicarb), Uremia (increased BUN and creatinine), Sodium and H20 excess, Chronic pyelonephritis, HTN

Acute renal failure: Often due to hypoxia acute reduction in renal excretory capacity causing nitrogenous waste retention Various causes classified according to location:

• Prerenal: intravascular and extracellular volume loss (dehydration, bleeds, burns); decreased intravascular volume but increased extracellular volume (congestive heart failure, cirrhosis); in all cases renal perfusion is diminished

• Renal: diseases of the renal parenchyma (glomerulonephritis, interstitial disease, drug toxicities, vasculities, acute tubular necrosis or renal artery)

• Post renal: might occur in tubules (uric acid nephropathy, or stones or enlarged prostate) Characteristics and dx:

• use of blood urea nitrogen (BUN—normal levels 8 – 20 mg/dL) and creatine (normal levels 0.7 – 1.5 mg/dL) to estimate change in GFR

• RBC, WBC, protein, casts, Na, urea, or urine • Structural evaluation using ultrasound, radionuclides scanning

Chronic renal failure: Often due to HTN and DM GFR decreased by 25% and leads to uremia. It is most likely casued by diabetes mellitus and hypertension and a decrease

in protein intake will slow progression. Uremia: clinical condition from renal failure w/ no underlying chemical basis.

Causes many problems including: fluid and electrolyte imbalance (acidosis, hyperkalemia) metabolic (osteomalacia, hyperuricemia), neuromuscular neuropathys and myopathies, cardiovascular pericarditis and hypertension, pruritis and anemia

Treat w/ hemodialysis and peritoneal dialysis or renal transplant Hematuria:

Blood in urine (more than 5 erythrocytes per high power field) Many causes including infections, stones, malignancies, connective tissue ds, renal disease that originate anywhere in

genitourinal tract Polycystic kidney (PKD):

Inherited kidney disorder in which multiple cysts form on the kidneys Exact mechanism triggering cyst formation is unknown Early stages of disease

Cysts enlarge the kidney & interfere w/ function • Results in chronic high BP, anemia, & kidney infections

Cysts may cause kidneys to increase production of erythropoietin • Results in increased # of RBCs – rather than the expected anemia

Bleeding into a cyst can cause flank pain Increases incidence of kidney stones HTN caused by polycystic kidneys may be difficult to control Slowly progressive – eventually results in end-stage kidney failure

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Also associated w/ liver disease, including infection of liver cysts An autosomal recessive form of PKD exists & appears in infancy or childhood

Tends to be very serious & progresses rapidly Results in end-stage kidney failure & death in infancy or childhood

Medullary cystic disease: Disorder in which kidney failure develops along w/ cysts deep w/in kidneys (in medulla). Uncommon & affects older children

Medullary sponge kidney: Congenital disorder in which urine-containing tubules are dilated, causing the kidney tissue to appear spongy

Malignant HTN: A medical emergency condition where there is a severe rise in BP Cause is unknown – often a prior Hx of HTN, especially HTN resulting from kidney disorders (2° HTN) More common in younger adults, especially African American men Also occurs in women w/ toxemia of pregnancy & people w/ renal or collagen vascular disorders Can cause severe, permanent, life-threatening consequences from pressure damage to brain, eyes, BVs, heart, & kidneys If left untreated usually leads to death in 3-6 months Characterized by:

Marked elevation levels of plasma renin Generally younger pts than benign HTN Corresponding renal lesion is known as Malignant nephrosclerosis May arise as de novo, or appear suddenly in a pt w/ previous mild HTN

• NOT that pts will live a normal lifespan if untreated Benign Essential HTN:

Constriction of arterioles is most likely the cause Hyaline arteriosclerosis (see below: ‘nephrosclerosis’) is the renal lesion most commonly associated w/ benign essential

HTN Chronic HTN:

Leads to reactive changes in the smaller arteries & arterioles throughout the body These changes are collectively referred to as arteriosclerosis

The vascular changes are particularly evident in the kidney They result in a loss of renal parenchyma, refered to as benign nephrosclerosis

Nephrosclerosis: (aka: arteriolonephrosclerosis = hyaline arteriosclerosis) Renal impairment secondary to arteriosclerosis or HTN

Disease most commonly related to benign HTN (incorrect: renal atresia, acute pyelonephritis & chronic pyelonephritis) Benign Nephroscerosis is the most common autopsy find of essential HTN Three types:

1) Arterial – atrophy & scarring of the kidney due to arteriosclerotic thickenings of walls of large branches of renal artery 2) Arteriolar – renal changes associated w/ HTN in which the arterioles thicken & the areas they supply undergo ischemic

atrophy & interstitial fibrosis 3) Malignant – rapid deterioration of renal function caused by inflammation of renal arterioles

• This type accompanies malignant HTN Von Gierke’s disease: Think VON GlyKe’s

Massive accumulation of glycogen in the liver and the kidney The most common of the glycogen storage diseases Genetic disease resulting from deficiency of glucose-6-phosphatase, which helps to make glucose from glycogen

• Deficient in the last NZ of Glyogneolysis Renal Cell Carcinoma

Most common renal malignancy Most common in men 50-70 Increased incidence in smokers Associated with von Hippel-Lindau and gene deletion in chromosome 3 Originates in renal tubule cell polygonal clear cells Signs Hematuria, palpable mass, 2ndary Polycythemia, Flank Pain, and Fever Invades IVC and spreads hematogenously – normally carcinomas spread lymphatically Associated with paraneoplastic syndromes

LUNG DISORDERS

Pulmonary edema: Accumulation of fluid in the extravascular spaces of the lungs Increased pressure in lung veins due to backup from failing left ventricle (CHF)

Increased intravascular hydrostatic pressure

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Fluid is pushed into the air spaces (alveoli) Fluid becomes a barrier to normal O2 exchange resulting in SOB

Physiologically, caused by increase in intracapillary hydrostatic pressure or increase in capillary permeability Early symptoms – dyspnea, orthopnea, and coughing Clinical signs – tachycardia, tachypnea, dependent crackles, & neck vein distension Causes – arteriosclerosis, HTN, cardiomyopathies, valvular heart disease, & left-sided heart failure Treatment – reduce extravascular fluid & improve gas exchange & heart function (oxygen, diuretics, vasopressors, positive

inotropic agents, & antiarrhythmics) Chronic passive congestion of the lungs

Characterized by thickening of the alveolar walls and hemisiderosis Another Q said….by edema of the alveolar walls and “heart failure” cells

Is secondary to atherosclerotic heart disease Productive cough present in:

Chronic lung abscess TB Lobar pneumonia Bronchogenic carcinomas Pulmonary embolism Brochiectasis

Sputum contains mucus, cellular debris, bacteria, & may contain blood or pus Infarcts (Red vs. Pale)

Red RED LILly (Lung, Intestine, Liver) Occur in loose tissues with collaterals, such as lungs, intestine, or following reperfusion (REd for REperfusion) Hemorrhagic (red) infarcts most commonly found in the LUNG (NOT brain, spleen, or kidney) Even if there’s a stoppage, think red is still all around

Pale Occur in solid tissues with single blood supply, such as the brain, heart, kidney, and spleen

Bronchiectasis Irreversible, abnormal dilatation of bronchi/bronchioles caused by destruction of supporting structures by a chronic

necrotizing infection Common in children w/ cystic fibrosis Most common symptom – chronic, productive cough w/ a foul-smelling, purulent sputum Chronic dilation as result of inflammatory disease/chronic obstruction – obstruction, hydothorax, pneumothorax

Atelectasis: Shrunken & airless state of the lung, or portion thereof Due to a failure of expansion or resorption of air from the alveoli Common in premature infants due to a lack of surfactant Collapse of alveoli May be secondary to:

Blockage of bronchus to aspirated foreign body Blockage fo bronchus by mucous Hydrothorax Pneumothorax

PNEUMONIA General info:

Very common lung infection involving the alveoli & the tissues around them Most common fatal infection acquired in hospitals Characterized by chills & fever, productive cough, blood-tinged sputum, & hypoxia w/ SOB Interstitial pulmonary inflammation is most charactistic of viral pneumonia – Think Viruses are IN

(interstilial/intracellular) Clinical signs: crackles are heard when listening to the chest w/ a stethoscope (auscultation) Caused by various organisms: bacteria, viruses, & fungi

Bacterial pneumonia: Tend to be the most serious cause of pneumonia Streptococcus pneumonia (aka Pneumococcus) most common cause in adults

Most common cause of community acquired bacterial pneumonia in the U.S. Well known for its large polysaccharide capsule (so is Cryptococcus neoformans)

• Strains of Strep pneumonia are distinquished by their polysaccharide capsules • Antibodies formed against encapsulated bacteria, like strep pneum., initially fxn as Opsonins

Viral pneumonia: Aka “atypical pneumonia” or “interstitial pneumonia”

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Legionella Most common causes of pneumonia in young children (peak between ages 2-3) Viral pneumonia is most characteristic of interstitial pulmonary inflammation (IN is IN) Diffuse and patchy (>1 lobe) No alveolar exudate Dry hacking cough Elevated cold agglutinins

Bronchopneumonia: Affects infants & elderly Inflammation of the walls of the smaller bronchial tubes Also spread of inflammation into alveoli & alveolar ducts Patchy distribution of lobular inflammation; not just the bronchus itself B for Bacteria

S. aureus, H. flu, Klebsiella, S. Pyogenes Lobar pneumonia:

Diffuse distribution of inflammation Pneumococcus most frequent (Strep pneumoniae) Affects middle-aged people Marked by fever, chest pains, cough & blood-stained sputum

Rusty sputum Inflammation & consolidation of one or more lobes of the lunugs

Chest pain associated w/ lobar pneumonia attributable to coexistent pleurisy (inflammation of pleura) Diplococcus pneumoniae

The essential antigen which determines both its virulence & its specific type is the distinct capsular polysaccharide Common Causes of Pneumonia

Children (6 wk – 18 y) Viruses (RSV), Mycoplasma, Chlamydia pneumoniae, S. pneumoniae Adults (18 y – 40 y) Mycoplasma #1 in Young Adults (THEY WALK a LOT), Chalymdia pneumoniae, S. pneumoniae Adults (41 y – 65 y) S. pneumoniae, H. influenzae, Anaerobes, Viruses, Mycoplasma Elderly (65+) S. pnuemoniae, Viruses, Anaerobes, H. influenzae, Gram – rods

Special Types of Pneumonia Nosocomial Staph, Gram – rods Immunocompromised Staph, Gram – rods, Fungi, Viruses, PCP Aspiration Anaerobes Alcoholic/IV drug user S. pneumoniae, Klebsiella, Staph Postviral Staph, H. influenzae Neonate Group B Strep, E. coli Atypical Mycoplasma, Legionella, Chlamydia

Pneumocystis carinii pneumonia: Originally thought to be a protozoa

But is a YEAST Caused by Pneumocystis carinii in immunocompromised pts (commonly seen in AIDS pts) Causes interstitial pneumonia – often fatal

Type Organism Characteristics Lobar S. pneumoniae (Pneumococcus)

It’s got a big capsule, to go everywhere

Intra-alveolar exudate consolidation, may involve entire lung

Bronchopneumonia S. aureus, H. influenza, Klebsiella, S. Pyogenes

Acute inflammatory infiltrates from bronchioles into adjacent alveoli; patchy distribution involving > 1 lobes

Interstitial (atypical) pneumonia Viruses (RSV, adenoviruses), M. pneumoniae, Legionella, Chlamydia psittaci (Birds)

Diffuse patchy inflammation localized to interstitial areas at alveolar walls; distribution involving primary lobes

Inflammatory exudates in pneumonia

Definitely present in lobar pneumonia, lobular pneumonia & bronchopneumonia Least likely to occur in primary atypical pneumonia (walking pneumonia) – 1999 Q100

Pulmonary Tuberculosis: Contagious bacterial infection caused by M. tuberculosis

NOT from endotoxin or exotoxin (Histoplasmosis is another answer) Lungs are involved, but the infection can spread to other organs Histo:

Granulomas with giant multinucleated cells and caseation necrosis

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Can develop after inhaling droplets from a cough or sneeze by infected person Symptoms – minor cough, mild fever, fatigue, weight loss, hemoptysis, night sweats & a cough w/ phlegm Primary TB:

Immediately follows invasion by tubercle bacilli Characterized by the Ghon focus – 2002 Q8

• Lesion at the pulmonary site of primary TB infection • Usually in middle or lower lung (Micro made simple, Dr. Cragun, and UCSF)

♦ Other sources say subpleural parenchyma (U. of Utah, U. of Delhi) ♦ Kaplan says, “The primary lung infection is usually found subadjacent to the pleura in the lower part of an upper

lobe or in the upper part a lower lobe in one lung” – due to high air flow to these areas • Then the immune system ramps up in 2-4 weeks & now forms a similar caseation granuloma in hilar lymph

nodes ♦ When this happens, it is now called the Ghon Complex

Calcifications in pulmonary parenchyma from earlier TB not to be confused w/ Ranke Complex • Ranke Complex is a lung lesion w/ calcified lymph nodes

Secondary TB: Disease that develops long after the 1° infection – due to reactiviation of the 1° infection Characterized by tubercle formation (caseous granulomas)—[unlike sarcoidosis] & subsequent cavity lesions Lungs are the most common site for secondary TB Miliary TB :

• Results from spread of tubercle bacilli by way of hematogenous spread • Results in the seeding of several organs w/ multiple, small, millet, seed-like lesions

Disseminated TB Treatment of TB:

Generally prolonged & involves daily oral doses of multiple drugs • May include combinations of rifampin, isoniazid, pyrayzinamide, ethambutol = “RIPE”

Possible serious adverse reactions of these drugs Ototoxicity, nephrotoxicity, muscle weakness, & allergic reaction

CHRONIC OBSTRUCTIVE PULMONARY DISEASE General info:

Group of lung diseases characterized by increased airflow resistance Chronic airway obstruction resulting from emphysema, chronic bronchitis, asthma, or a combo of any of these diseases In most cases, bronchitis & emphysema occur together Secondary pulmonary HTN is most often caused by COPD

Chronic Obstructive Pulmonary Disease Disorder Characteristics

Bronchial asthma Dyspnea and wheezing expiration Chronic bronchitis Productive cough characterized by hypersecretion of mucus Emphysema (pulmonary emphysema) Often coexists w/ chronic bronchitis, labored breathing, and an increased

susceptibility to infection Bronchiecstasis Copious purulent sputum, hemoptysis, and recurrent pulmonary

infection Bronchial asthma:

1st definition: disease in which inflammation of the airways causes restriction of airflow 2nd definition: chronic reactive airway disorder that causes episodic airway obstruction Results from bronchospasms, ↑ mucus secretion, airway edema, & ↑ airway resistance

NOT decreased surfactant NOT enlarged air spaces (that’s emphysema) NOT associated with purulent sputum-producing cough (only chronic bronchitis & chronic lung abscess)

Caused by the interaction of Ag & IgE on the surface of mast cells with the release of histamine Here’s what happens:

Prostaglandin D elicits bronchoconstriction & vasodilation Chemotactic factors recruit & activate eosinophils & neutrophils Platelet-activating factor (PAF) aggregates platelets & induces histamine release Leukotrienes C4, D4, & E4 cause prolonged bronchoconstriction & mucin secretion

Found in 3-5% of adults & 7-10% of children ½ of cases develop before age 10; most before age 30 Reversible; symptoms can decrease w/ time Recurring bronchial asthma attacks may predispose pt for future emphysema Two types: 1) allergic asthma (most common) & 2) idiosyncratic asthma

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Common condition – can strike at any age – ½ of all cases first occur < 10 y.o. (2x as often in boys) Findings – cough, characteristic wheezing expiration, dyspnea, tachypnea, hypoxia, & decreased I/E ratio, pulsus paradoxus Symptoms may be triggered by:

Inhaled allergens – pet dander, dust mites, molds, pollens Respiratory infections, exercise, cold air, tobacco smoke, stress, food or drug allergies Aspirin/NSAIDs in some pts

Tx of an acute asthmatic attack – inhalation of a selective β2-agonist (terbutaline, albuterol) Status asthmaticus

Particularly severe episode of asthma Usually requires hospitalization Does not respond adequately to ordinary therapeutic measures

Emphysema: (pink puffer) Form of COPD that involves damage to the air sacs (alveoli) Air sacs are unable to completely deflate (hyperinflation) – unable to fill w/ fresh air to ensure adequate O2 supply to body Characterized by normal or increased lung capacity Lack of elastic recoil in the lungs Generally bilateral More common in males May lead to cardiac failure Is a significant public health problem Does NOT show hemoptysis A tissue change, rather than mucous production (seen in asthma & chronic bronchitis) Cigarette smoker with gradual onset of progressive, labored breathing, with prolonged expiratory effort Labored breathing

Show Pursed Lips Dyspnea, decrease in breathing sounds, tachycardia and decreased I/E ration Increased susceptibility to infection May be fatal, results from degenerative atrophy; and may be secondary to bronchial inflammatory disease Two problems:

1) Lungs are fixed in inspiration 2) Respiratory surfaces of lungs have deteriorated so much that they no longer adequately exchange gases

Complete blood count likely shows polycythemia Recurring attacks of bronchial asthma may predispose to emphysema Most commonly caused by cigarette smoking

Tobacco smoke & other pollutants are thought to cause lungs to release chemicals that damage the walls of alveoli Damage worsens over time, affecting O2 & CO2 exchange in the lungs A naturally occurring substance in the lungs called alpha-1 antitrypsin may protect against this damage

• People w/ alpha-1 antitrypsin deficiency are at increased risk • Alpha-1 antitrypsin deficiency affects both the Lung and Liver

Two important types: Centrilobar – upper lobes of lungs most affected – cigarette smoking is major cause Panlobular – lower lobes of lungs most affected – familiar antiproteinase (caused by alpha-1 antitrypsin deficiency)

Chronic bronchitis: (blue bloater) Common, debilitating respiratory disease, characterized by ↑ mucous production by the glands of trachea & bronchi Characterized by:

Productive cough, often w/ wheezing (universal factor in all cases) Produces purulent sputum for 3+ months in at least 2 consecutive years w/o any other disease that could account for

symptom Dyspnea on exertion Ventilation-perfusion imbalance NOT decreased airway resistance

Strong association w/ smoking Common results of chronic bronchitis:

Cor pulmonale (enlargement of the right ventricle) – from working too hard to push blood through pulmonary system Airway narrowing Obstruction of the bronchial tree along w/ squamous metaplasia

• Squamous metaplasia is most commonly encountered in the bronchial mucosa (NOT stomach, oral mucosa, etc.) Characteristic pathologic change:

Hyperplasia of bronchial submucosal glands & bronchial smooth muscle hypertrophy • Hypertrophy quantified by the Reid index (ratio of glandular layer thickness to bronchial wall thickness) of > 50

Predisposed to bronchogenic carcinoma

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Predisposition is based on bronchitis causing squamous metaplasia of bronchial epithelium Wheezing, crackles, cyanosis

RESTRICTIVE LUNG DISEASE General info:

Restricted lung expansion causes decrease in volumes (decreased Vc and TLC) PFTs FEV1/FVC Ratio = >80%

• In other words, your ratio of blowing volume out at 1 sec vs FVC is greater because the volumes dropped • But in Obstructive, your ratio is less than 80%, because you can’t blow as fast, so less than 80% of the volume is out at

1 second Types:

Poor breathing mechanics (extrapulmonary): poor musclar effort—polio, myasthnia gravis; poor apparatus—scoliosis Interstitial lung disease (pulmonary): adult respiratory distress syndrome, neonatal respiratory distress syndrome,

pneumoconiosis, Sarcoidosis, Goodpasture’s Adult respiratory distress syndrome Pneumoconioses

Lung diseases caused by prolonged inhalation of foreign material Lead to fibrosis of the lungs Main symptoms – chronic dry cough & SOB Coal workers’ pneumoconiosis

Blackened sputum Progressive massive fibrosis Coal dust macules = aggregated macrophages…creates intensly pigmented areas

Silicosis: Aka Stone Mason’s disease (S for Stone for Serious) Progressive disease characterized by nodular lesions – commonly progress to fibrosis The most common & most serious pneumoconiosis (NOT siderosis, calcinosis, or anthracosis)

• Characterized by massive fibrosis of the lung Production of fibroblast growth factor (FGF) Associated w/ increased susceptibility to TB

Asbestosis: Characterized by diffuse interstial fibrosis caused by inhaled asbestos fibers Can develop up to 15-20 yrs after regular asbestos exposure – long latency Results in marked predisposition to bronchogenic carcinoma & malignant mesothelioma of the pleura & peritoneum Histologically – ferruginous bodies found in lung (asbestos fibers coated w/ hemosiderin) & w/ ivory pleural plaques

Berylliosis: A systemic granulomatous disorder w/ dominant pulmonary manifestations

Anthracosis: Aka Coal Worker’s pneumoconiosis, Black Lung disease NOT known to predispose a pt to cancer Progressive nodular pulmonary disease caused by deposits of coal dust in lungs Ocurrs in two forms:

• 1) Simple – small lung opacities • 2) Complicated – aka “progressive massive fibrosis” – masses of fibrous tissue occasionally develop in pt’s lungs

Goodpasture’s syndrome: Anti-glomerular basement membrane antibodies produce linear staining on immunofluorescence Findings: pulmonary hemorrhage leading to hemoptysis; renal lesions lead glomerulonephritis w/ hematuria This is a type II hypersensitivity Think GP Good Pasture, Glomerular and Pulmonary Most common in men between ages 20-40

Cystic Fibrosis Autonomic recessive disorder – heterozygotes unaffected Generalized dysfunction of the exocrine glands affecting multiple organ systems Inherited disease caused by a defective gene, chromosome 7q

The gene encodes a MB-associated protein called “cystic fibrosis transmembrane regulator (CFTR)” Is thought to regulate Cl– & Na+ across epithelial MBs

Results in defective Cl- channels, leading to very thick mucous secretions Has elevation of Na+ and Cl- secretions

Affects mucus & sweat glands & Na+ channels Causes respiratory & digestive problems

Thick mucus forms in breathing passages of lungs & predisposes pt to chronic lung infections Effects males & females – life expectancy = 28 yrs

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Present usually in 1st year of life w/ steatorrhea Most common fatal genetic disease in white children Dx with Sweat Chloride test (elevated Cl- in sweat) Complications include:

Pulmonary disease, pancreatic insufficiency, & meconium ileus (form of intestinal obstruction in newborns) Lung abscess:

Pus-filled cavity in the lung surrounded by inflamed tissue & caused by infection Most common cause is aspiration – often in the settings of altered consciousness Associated with aspiration of material from caries teeth Alcoholism is the single most common condition predisposing to lung abscess

Also at risk: persons suffering from drug OD, epileptics, & pts w/ neuroloic dysfunction impairing the gag reflex Almost all pts w/ a lung abscess present w/ cough & fever: Characteristic symptoms:

Production of large amounts of foul-smelling sputum Also dyspnea, chest pain, & cyanosis may be present

Common causes: Most common – aspiration of anaerobic bacteria (decayed teeth, vomitus, foreign material) from the oral cavity

• Staphylococcus (most common bacterial cause) – NOT strep which you would think • Inhaled Endo File, you may get a lung abscess • Also Pseudomonas, Klebsiella, & Proteus

Complications of pneumonia or bronchiestasis Septic arterial embolus from a heart valve

Aspiration of Food May cause Pneumonia, Lung abscess, Atelectasis, and Asphyxiation

NOT Pneumothorax Adult respiratory distress syndrome

Might be caused by each of the following: Shock Heroine overdose Viral pneumonia Breathing 100% O2 – Too much O2 causes respiratory depression, same result as heroine – person may go into respiratory

arrest; because person is not breathing, respiratory acidosis occurs = bad news • NOT cigarette smoking – You’re not going to immediately die due to smoking a cig

Neonatal respiratory distress syndrome: Surfactant deficiency leading to increase surface tension, resulting in alveolar collapse Surfactant is made by type II pneumocytes most abundantly after 35 weeks in gestation. The lecithin to sphingomyelin ratio

in the amniotic fluid, a measure of the lung maturity, is usually less than 1.5 in neonatal respiratory distress syndrome. Surfactant = dipalmitoyl phosphatidylcholine Tx with maternal steroids before birth, artificial surfactant for infant

Kartagener’s syndrome: Think Can’t move you grocery KART Immotile cilia due to a dynein arm defect. Results in sterility (sperm also immotile) bronchiectasis, and recurrent sinusitis

Bronchogenic cancers: Lung cancer usually develops in the wall or epithelium of the bronchial tree – such cancer is called bronchogenic

carcinoma Lung cancer that starts in the bronchoepithelium

Tumors that arise centrally: Epidermoid (squamous) carcinoma:

• Most arise in the central portion of the lung • Appears as a hilar mass & frequently undergoes central cavitation. • Clearly linked to cigarette smoking • SCC is also linked to increase in PTH, and endocrine effect of hyperparathyroidism

♦ Pulmonary neoplasm to which the endocrine effect of hyperparathyroidism is attributed!!! Small cell (oat cell) carcinoma:

• Most arise in the central portion of the lungs • Most aggressive & highly malignant • Most commonly affects men (80%), 90% of whom are cigarette smokers • Clearly linked to cigarette smoking • Oat cell that is observed in these carcinomas is a short, bluntly spindle-shaped, anaplastic cell containing a relatively

large hyperchromatic nucleus w/ little or no cytoplasm

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• Associated w/ ectopic hormone production (ADH, ACTH) • May lead to Lambert Eaton syndrome (muscle weakness due to Ag against motor nerve – can’t rls ACh)

Tumors that arise peripherally: Adenocarcinoma:

• Most common bronchogenic cancer • Tends to arise in the periphery, usually in the upper lobes of the lung • Develops on site of prior pulmonary inflammation or injury (old TB, scars, healed infarcts) • Less clearly linked to cigarette smoking

Large cell (anaplastic) carcinoma: • Tends to arise in the periphery • Very poorly differentiated

Bronchioalveolar Carcinoma Only about 14% of patients w/ lung cancer survive 5 years after Dx

The Cancer with the best 5 yr prognosis is Lungs 15%, Stomach 21%, Colon 60%, Pancreas 4%, Esophagus15% Metastases is very common to brain, bone, & liver Pancoast’s tumor:

May result from intrathoracic spread of bronchogenic cancer Carcinoma that occurs in apex of lung and may affect cervical sympathetic plexus, causing Horner’s syndrome:

• Ptosis (slight drooping of eye) • Anhidrosis (absence of sweating) and flushing (rubo of affected side of face) • Miosis (pupil constriction)

3 neuron oclusosympathetic pathway above projects from the hypothalamus to intermediolateral column of the spinal cord, then to the superior cervical (sympathetic ganglion, and finally to the pupil, the smooth muscles of the eyelids, and the sweat glands of the forehead and face

Interruption of these pathways result in Horner’s syndrome

HEART DISORDERS CONGENITAL HEART DEFECTS:

Infective endocardititis The following are predisposers:

• Tetraology of Fallot • Congenital aortic stenosis • Patent ductus arteriosus • Ventricular septal defect

Right-to-left shunts – cyanotic congenital heart disease (“Blue Babies”) Think the 3 T’s Tetralogy, Transposition, Truncus Eisenmenger’s Tetralogy of Fallot (most common cause of early cyanosis) – PROVe:

• 1) Pulmonary stenosis • 2) Right ventricular hypertrophy • 3) Overriding aorta (overrides the ventricular septal defect) • 4) Ventricular septal defect – patient suffers from cyanoic spells • Caused by anterosuperior displacement of infundibular septum

Transposition of great vessels: • Aorta leaves the right ventricle and pulmonary trunk leaves the left ventricle which separates the systemic and the

pulmonary circulations. Pt will die • Due to failure of aorticopulmonary septum to spiral, common in babies to diabetic mothers

Persistent truncus arteriosus: Left-to-right shunts – acyanotic congenital heart disease (“Blue Kids”)

Ventricular septal defect (most common congenital cardiac anomaly) Atrial septal defect: has loud S2; wide, fixed split S2 Patent ductus arteriosus:

• there is a minor vessel that connects the blood from the aortic arch to the pulmonary artery • Lung resistance decreases and shunt becomes left to right w/ subsequent right ventricular hypertrophy and failure • Associated w/ continuous “machine-like” murmur. Patency maintained by PGE synthesis and low O2 tension • Indomethacin is used to close patent ductus arteriosus, and PGE is used to keep it open to sustain life in case of

transposition of greater vessels Eisenmenger’s syndrome:

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Uncorrected ventricular septal defect, arterial septal defect & patent ductus arteriosus leads to progressively pulmonary HTN

As pulmonary resistance increases, the shunt changes from left to right to right to left, which causes late cyanosis (clubbing and polycythemia)

Coarctation of aorta: Infantile type (preductal): aortic stenosis proximal to insertion of ductus arteriousus. Male to female 3:1

INfantile: IN close to the heart (associated w/ Turner syndrome) Adult type (postductal): stenosis distal to ductus arteriosus, associated w/ notching of the ribs, hypertension in upper extremities,

weak pulses in lower extremities aDult: Distal to Ductus

PERICARDITIS: Causes infection, ischemic heart disease, chronic renal failure, CT diseases Effusions are usually serious; hemorrhagic effusion are associated with TB and malignancy Findings Pericardial pain, friction rub, EKG changes, Pulsus paradoxus Can resolve w/o scarring or lead to chronic adhesive or chronic constrictive pericarditis Acute Pericarditis:

Inflammation of pericardium that begins suddenly & is often painful Inflammation causes fluid & blood products (e.g., fibrin, RBCs, & WBCs) to pour into the pericardial space

Constrictive Pericarditis: Post-inflammatory thickening & scarring of the pericardial MB – constricts chambers Can be caused by TB

Serous Pericarditis: Caused by SLE, rheumatoid arthritis, infection, uremia, renal failure

Fibrinous Pericarditis: Caused by uremia, MI, rheumatic fever, renal failure

Hemorrhagic Pericarditis: Caused by TB or malignancy Findings – pericardial pain, friction rub, ECG changes (diffuse ST elevations in all leads), distant heart sounds Can resolve w/out scarring or lead to chronic adhesive or chronic constrictive pericarditis

Cardiac Tamponade: Heart compression caused by blood or fluid accumulation in the space between myocardium & pericardium – leads to ↓

CO Blood cannot flow into the right atrium – pt can die suddenly of decreased CO

Most likely to cause sudden arrest of heart fxn (incorrect answers: cardiac cirrhosis, mitral stenosis, constrictive pericarditis)

Can occur after large myocardial infarction Dead heart musculature of a ventricle can rupture, causing blood loss into the pericardial space

Signs – distended neck veins, hypotension, decreased heart sounds, tachypnea, & weak or absent peripheral pulses The most serious complication of percarditis

Aneurysms Berry aneurysm Atherosclerotic aneurysm Syphilitic aneurysm Microaneurysm Dissecting aneurysm:

Most frequently occur in the aorta Characteristically results in aortic ruptures, most often into the pericardial sac, causing fatal cardiac tamponade

ISCHEMIC HEART DISEASE = Coronary artery disease (CAD): Leading cause of death in U.S. Usually caused by atherosclerosis Condition in which fatty deposits (plaques) accumulate in cells lining coronary artery walls – obstructs blood flow

As coronary artery obstruction worsens, ischemia to heart muscle can develop – damages heart Primary effect is loss of O2 & nutrients to myocardial tissue due to diminished blood flow NOTE: right coronary artery supplies blood from aorta to right side of heart

Characteristic features: Represents an imbalance between myocardial oxygen demand and available blood supply Has a peak incidence in men over 60 years and women over 70 Contributing factors include chronic HTN and high levels of LDLs

• NOT Usually results from complete occlusion of one or more coronary arteries ♦ Doesn’t have to be complete occlusion – that would be a heart attack.

Risk factors – high BP, hyperlipidemia, smoking, being overweight, inactivity

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Dx – based on pt Hx, especially Hx w/ characteristic risk factors Major complications of CAD = 1) angina pectoris & 2) myocardial infarction

1) Angina: • Specific type of chest discomfort caused by inadequate blood flow through BVs of heart • Usually described as burning, squeezing or tight feeling in substernal chest

♦ May radiate to left arm, neck, jaw, or shoulder blade • Most people w/ chronic angina feel pain only during exercise • Occurs when heart load becomes too great relative to coronary blood flow • Relieved by rest or nitrates (myocardial infarction is not)

2) Myocardial Infarction: • Heals by way of organization of collagen • Most frequently characterized by coagulation necrosis (eosinophilic masses w/ nuclei; result protein coagulation) • Most commonly caused by coronary atherosclerosis – interrupts blood supply to heart • The most common autopsy finding in sudden death caused by a M.I. is coronary thrombosis • Very common in males & postmenopausal females • Signs & symptoms – crushing pain in chest area over the heart, pain in left arm and/or jaw, sweating, GI upset, fatigue,

shortness of breath • Prognosis is fairly good if pt reaches hospital – most deaths occur outside hospital – due to arrhythmias • Most acute MIs are caused by coronary artery thrombosis

♦ Coronary artery occlusion LAD (left anterior descending) > RCA > circumflex • Acute MI is the most common cause of death in industrialized nations • Pain from an MI is NOT relieved by vasodilators such as nitroglycerin – only angina is relieved by this. • Thrombolytic agents such as streptokinase often limit the size of infarction • Myocardial necrosis usually begins 20-30 min after coronary artery occlusion • Dx of a MI

♦ First 6 hours, EKG is the gold standard ST elevation (transmural ischemia) Q Waves (transmural infarct)

• There is death of heart muscle tissue causes leakage of enzymes into blood ♦ Elevated enzyme levels following a myocardial infarction:

Cardiac troponin – GOLD STANDARD w/in 1st 4 hours up to 7-10 days, more specific than other protein markers

Serum Glutamate-Pyruvate Transaminase (SGPT) = AST, nonspecific and can be found in cardiac, liver, and skeletal muscle cells

Serum Glutamic-Oxaloacetic Transaminase (SGOT) Serum Lactic Dehydrogenase (LDH) – former test of choice is also elevated from 2-7 days post-MI Creatine Kinase (CK), or CK-MB test – test of choice in 1st 24 hours post- MI

• Evolution of a MI ♦ First Day

Occluded artery Infarct Pallor Coagulative necrosis – w/in the first (20-30min) 24 hours leads to release of contents of necrotic cells into

bloodstream with the beginning of neutrophil emigration ♦ 2 – 4 Days

Pallor Hyperemia Tissue surrounding infarct shows acute inflammation Dilated vessels (hyperemia) Neutrophil emigration Muscle shows extensive coagulative necrosis

♦ 5 – 10 Days Hyperemic border; central yellow-brown softening, maximally yellow and soft by 10 days Outer zone (in growth of granulation tissue) Macrophages, and Neutrophils

♦ 7 weeks Now its Grey-white Contracted scar is complete

♦ Infarcts heal by organization • ECG changes:

♦ ST elevation (transmural infact), ST depression (subendocardial infarct), & Q waves (transmural infarct) • Complications of myocardial infarctions:

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♦ Cardiac arrhythmia (90%), highest rise 2 days postinfarct ♦ LV failure and pulmonary edema (60%) ♦ Thromboembolism—mural thrombus (a thrombus produced as a result of damage to the ventricular

endocardium) Death from MI and Bx reveals thromboembolism From the Right Ventricle

♦ Cardiogenic shock (large infarct—highest risk of mortality) ♦ Rupture of ventricular free wall, interventricular septum, papillary muscle (4 – 10 days post MI), cardiac

tamponade ♦ Fibrinous pericarditis—friction rub (3-5 days post MI) ♦ Dressler syndrome—autoimmune phenomenon resulting in fibrinous pericarditis (several weeks post MI)

3) Sudden cardiac death • Death from cardiac causes within 1 hour of onset of symptoms, most commonly due to lethal arrhythmia

4) Chronic ischemic heart disease • Progressive onset of congestive heart failure over many years due to chronic ischemic myocardial damage

RHEUMATIC FEVER: Acute inflammatory disease w/ systemic manifestations & particular involvement of heart valves Follows an upper respiratory infection w/ a Group A, β-hemolytic streptococcus

Secondary infection from Group A strep, due to autoimmune, not from bacteria Can be a sequelae to Scarlet Fever

Most common in children 5-15 y.o. Onset is usually sudden Occurs 1-5 symptom-free wks following recovery from sore throat or scarlet fever Mild cases may last 3-4 wks, severe cases may last 2-3 months Treatment – penicillin & rest Although RF may follow a streptococcal infection, it is not an infection

It is an inflammatory reaction to an infection Heart is damaged because of a hypersensitivity rxn to group A, Beta Hemolytic streptococci

Clinical Dx – requires 2 major criteria or 1 major + 2 minor (the Jones criteria) Major – carditis, arthritis, chorea, erythema marginatum & subcutaneous nodules Minor – fever, arthralgias (joint pain w/o inflammation), Hx of RF, EKG changes & lab tests

Heart inflammation A pt with rheumatic heart disease would most likely develop congestive heart failure due to valvular insufficiency Disappears gradually, usually w/in 5 months May permanently damage heart valves – resulting in rheumatic heart disease

• Mitral valve (between left atrium & ventricle) is most commonly damaged • Valve may become leaky (mitral valve regurgitation) abnormally narrow (mitral valve stenosis) or both

Classic lesion of rheumatic fever is the Aschoff body – FEVER Causes ASHES An area of focal interstitial myocardial inflammation Characterized by fragmented collagen & fibrinoid material by large unusual cells (Anitschkow cells) & by occasional

multinucleated giant cells (Aschoff myocytes) NOTE: Most common characteristic lesion of rheumatic fever, scleroderma and RA is fibrinoid degeneration Think FEVERSS Fever, Erythema marginatum, Valvular damage, ESR increase, Red-hot joints, Subcutaneous

nodules, St. Vitus’ dance (chorea) VALVULAR HEART DISEASE:

Mitral valve prolase Mitral valve leaflets billow into the left atrium during systole, leading to insufficiency High pitched murmur, & mid-systolic click are characteristic of MVP

Mitral stenosis Due to scarring, calcification, or fusion of the mitral valve Early diastolic opening snap is characteristic of MS

Aortic valve insufficiency Insufficiency = regurgitation Backflow thru aortic valve leads to increased LV volume, raising filling pressure, leading to LV failure

Aortic valve stenosis CONGESTIVE HEART FAILURE (CHF):

Disorder in which heart loses ability to pump blood efficiently Almost always a chronic, long-term condition – it can sometimes develop suddenly May affect the right &/or left side

Left ventricle usually fails first – right-sided failure soon follows Earliest & most common signs:

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Exertional dyspnea Paroxysmal nocturnal dyspnea (pt wakes up up grasping for air)

Other signs: Peripheral edema (ankle edema), cyanosis, high venous pressure, passive congestion of the liver, and orthopnea (sitting or

standing in order to breath comfortably) Left-sided failure:

Common causes: • Coronary heart disease

♦ Leading cause of cardiac death in the U.S. • HTN causes left ventricular hypertrophy • Aortic & mitral valvular disease • Myocardial disease • Rheumatic heart disease – 1988 Q96 • Presence of hemosiderin-laden macrophages (heart failure cells) w/ pulmonary congestion in LV failure

Complications of left-sided failure: • Life-threatening complication = pulmonary edema

♦ Most reliable post mortem indicator is chronic passive congestion of the lungs ♦ Presence of hemosiderin-laden macrophages (“heart failure”) cells

• Orthopnea pooling of blood in lungs in supine position adds volume to congested pulmonary vascular system • Dyspnea Failure of LV output to increase during exercise • Pleural effusion • Bacterial pneumonia • Paroxysmal nocturnal dyspnea

♦ NOT Myocardial hyperplasia (HYPERTROPHY!!) Right-sided failure:

Most common cause = left-sided failure Most common cause of pure RS-CHF = cor pulmonale

• Cor pulmonale – ♦ Enlargement of the right ventricle ♦ Most commonly direct result of pulmonary HTN due to resistance to blood flow thru lungs ♦ Right sided heart failure w/out involvement of the left side of the heart occurs most often w/ cor pulmonale

Most conspicuous sign is systemic venous congestion & peripheral edema Clinical hallmarks of right-sided failure:

• Jugular venous distension • Hepatomegaly Increased venous pressure, leads to increased portal resistance • Splenomegaly • Generalized edema

Affects the kidneys by causing: (All because BP is Down) • Renal hypoxia • Venous congestion • Retention of H2O and NaCl • Decreased GFR

Cells of Heart Failure: Hemosiderin-laden macrophage in alveoli, aka siderophore

• Hemosiderin in the lungs is caused by…Heart Failure! INFECTIOUS ENDOCARDITIS:

Type of inflammation of heart valves Vegetations on the valves usually consist of fused platelets, fibrin, and masses of bacteria

Can affect the heart muscle (myocarditis) or lining of the heart (pericarditis) Mitral valve is most commonly involved, followed by aortic valve Source of infection:

Transient bacteremia (presence of bacteria in the blood) • Common during dental, upper respiratory, urologic, & lower GI diagnostic & surgical procedures

Most common: Streptococcus viridans – α-hemolytic strep causes ~½ of cases • Most common cause from a dental procedure S. viridans

Other common organisms: Staph, Group D Strep Less common organisms: Pseudomonas, Serratia, Candida

Can cause growths on heart valves, lining of heart or lining of the BVs Fused platelets, fibrin, bugs are found in vegetation due to bacterial endocarditis

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Growths may be dislodged & send clots to brain, lungs, kidneys or spleen Health care provider may hear changing murmurs & detect enlarged spleen & mild anemia Murmurs result from changes in valvular blood flow when clumps of bacteria, fibrin & cellular debris collect on valves

Self-infection (esp. by IV drug users) w/ S. aureus causes most severe damage (acute endocarditis) Endocarditis on right side of the heart suggests IV drug abuse

Symptoms: Fever is hallmark – may be present daily for months before other symptoms appear Fatigue, headache, malaise, night sweats Janeway lesions (small red lesions on palm/sole) – Roth’s spots (round white spots on retina surrounded by hemorrhage) Nail bed (splinter) hemorrhages – Osler’s nodes (tender raised lesions on finger or toe pads) Fever – Anemia – Murmur – Emboli

Think JR = NO FAME Janeway Lesions, Roth’s spots, Nail-bed hemorrhage, Osler nodes, Fever, Anemia, Murmur, Emboli

TYPES OF ENDOCARDITIS: Acute bacterial endocarditis: HIGH VIRULENCE

• STAPHylococcus aureus • Large vegetations on previously normal valves, rapid onset

Subacute bacterial endocarditis: LOW VIRULENCE • STREPtococcus viridans

♦ The most common organism producing subacute bacterial endocarditis is alpha-hemolytic streptococcus (S. sanguis, which is a Viridans Streptococcus)

• Smaller vegetations on congenitally abnormal or diseased valves • Sequela of dental procedures • More insidious onset than Acute

Tetralogy of Fallot, Congenital aortic stenosis; Patent ductus arteriosus; & Ventricular septal defect are all at risk of developing secondary endocartitis

MYOCARDITIS = Cardiomyopathy: Disease of myocardium w/ unknown etiology Dilated (congestive) cardiomyopathies: heart dilates and looks like a balloon on chest X ray

Systolic dysfunction ensues most common 90% of casts Think ABCsDs Alcohol, Beriberi, Coxsackie B, Cocaine, Chagas’ disease, Doxorubicin, Diastolic Dysfunction

Hypertrophic cardiomyopathy (formerly IHSS): Diastolic dysfunction ensues often asymmetric and involving the intraventricular septum. 50% of cases are familial and are inheritied as an autosomal-dominant trait Cause of sudden death in young athletes Walls of LV are thickened and chamber becomes banana shaped on echocardiogram

Restrictive/obliterative cardiomyopathy: major causes include sacroidosis, amyloidosis, scleroderma, hemochromatoisis, endcardial fibroelastosis, and

endomyocaridal fibrosis (Loffler’s) Cardiac tumors:

Myxomas are the most common primary tumor in adults. 90% occur in the atria (mostly LA) Myxomas are usually described as a “ball-valve” obstruction in the LA

Rhabdomyomas are the most frequent primary cardiac tumor in children Metastases most common heart tumor

Cardiac muscle: Following injury, restores fxnal capacity via hypertrophy

Creatine phosphokinase: Found in heart, brain & skeletal muscle – NOT found in liver If total CPK level is substantially elevated, usually indicates injury/stress to one or more of these tissue

Heart Murmurs Aortic stenosis Crescendo-decrescendo systoslic ejection murmur, with LV >> aortic pressure during systole Aortic Regurgitation High-pitched “blowing” diastolic murmur. Wide pulse pressure Mitral Stenosis Rumbling late diastolic murmurs. LA >> LV pressure during diastole. Opening snap Mitral Regurgitation High-pitched “blowing” holosystolic murmur Mitral Prolapse Systolic murmur with midsystolic check. Most frequent valvular lesion, especially in young women VSD (Ventricular Septal Defect) Holosystolic murmur PDA (Patent Ductos Arteriosus) Continous machine-like murmur

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Buerger’s Disease Known as smoker’s disease and thromboangitis obliterans Idiopathic, segmental, thrombosing vasculitis of intermediate and small peripheral arteries and veins Findings Intermittent claudication, superficial nodular phlebitis, cold sensitivity, severe pain in affected part, may lead to

gangrene Tx with Cessation of Smoking Don’t smoke in Burger King

VS. Raynaud’s Disease • Symmetric asphyxia (impaired oxygen exchange); idiopathic paroxysmal bilateral cyanosis of the digits due to

arterial and arteriolar contraction • Caused by cold or emotion

Takayasu’s Arteritis “Pulseless Disease” Thickening of aortic arch and/or proximal great vessels, causing weak pulse in upper extremeities and ocular disturbances Associated with elevated ESR Think FAN My Skin Fever, Arthralgia, Night sweats, MYalgia, SKIN nodules

HEMODYNAMIC DYSFUNCTION Edema

Abnormal accumulation of fluid in the interstitial spaces or body cavities Edema due to hemodynamic dysfunction may result in the brain, lung, subcutaneous tissue, peritoneal cavity

NOT the pancreas May result from:

Increased capillary permeability (principal factor) Elevated capillary pressure Increased interstitial fluid colloid osmotic pressure Decreased plasma colloid osmotic pressure Increased sodium retention Increased venule blood pressure Lymphatic obstruction

Types of edema: Anasarca – Can’t see your Sarcs (Muscles because you’re so swollen)

• generalized swelling or massive edema; generalized infiltration of edema fluid into subcutaneous CT • NOT usually associated with CHF

Hydrothorax – excess serous fluid in the pleural cavity • Usually from cardiac failure

Hydropericardium – excess watery fluid in the pericardial cavity Ascities (hydroperitoneum) – excess serous fluid in the peritoneal cavity Transudate – noninflammatory edema fluid resulting from altered intravascular hydrostatic or osmotic pressure Exudate – inflammatory edema fluid from increased vascular permeability

Right sided CHF leads to peripheral edema Most conspicuous clinical sign of right sided heart failure

Left-sided CHF leads to pulmonary edema Edema may described as:

1) Pitting edema – press against swollen area for 5 sec, then quickly remove it – indentation left that fills slowly 2) Nonpitting edema – press against swollen area for 5 sec, then quickly remove it – no indentation left in skin

Thrombus: Solid mass of clotted blood that develops in & is attached to a BV wall Formation enhanced by endothelial injury, alteration in blood flow (turbulence), & hypercoagulability Arterial thrombi show alternating red & white laminations (lines of Zahn) Venous thrombi are more uniformly red w/ distinct lines

Conditions predisposing to venous thrombosis: • Heart failure, extensive tissue damage, bed rest, pregnancy, oral contraceptives, age, obesity, & smoking, Just

had surgery, bound to wheelchair, cirrhosis/Increased Portal HTN ♦ Except COPD

A whole thrombus may detach to form a large embolus or fragments may break off to generate small emboli Different types of Thrombi:

Agonal – forms in heart during the dying process after prolonged heart failure Mural –

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• forms as a result of damage to ventricular endocardium (usually left ventricle, following myocardial infarct) • A major complication is a cerebral embolism • It complicates myocardial infarctions, atrial fibrillation, & atherosclerosis of the aorta

White – composed chiefly of blood platelets Red – rapidly forms by coagulation of stagnating blood – composed of RBCs rather than platelets Fibrin – formed by repeated deposits of fibrin from circulating blood – usually does not completely occlude the vessels

Ten days after hospitalization for a large, incapacitating myocardial infarct, a 50-year-old man suddenly develops paralysis of the right side of his body. The best explanation for his brain damage is…detachment of a mural thrombus from the left ventricle Stoke following MI is caused by arterial thrombi (not venous)

Thrombosis: Formation or presence of a blood clot inside a blood vessel or cavity of the heart

Deep Vein Thrombosis Predisposed by Virchow’s triad

• Stasis, Hypercoagulability, and Endothelial damage Thrombotic occlusion in a coronary artery may result in:

Infarction Fibrosis Conductive changes Nothing

Thrombolysis: Breaking up of a blood clot

Embolus: Blood clot that moves through the bloodstream until it lodges in a narrowed vessel and blocks circulation Mass of solid, liquid, or gas that moves w/in a BV to lodge at a site distant from its origin Most emboli are thromboemboli Can lodge in the vascular beds of vital organs, occluding blood flow & possibly causing infarction Splenic infarcts most commonly result from emboli originating in the left side of the heart 56-yr-old with atrial fibrillation and hx of MI 2 yrs ago, experiences a right flank pain and hematuria, paralysis of the right side

of the body and ischemia to the left foot DUE to arterial emboli (NOT septicemia, venous thrombi or venous emboli)

A pt w/ cardiovascular disease has chronic atrial fibrillation. She is prescribed warfarin (Coumadin) to prevent stroke Think FAT BAT Fat, Air, Thrombus, Bacteria, Amniotic fluid, Tumor Fat embolism

Associated w/ long bone fractures More info found elsewhere in file

Air Pulmonary thromboembolus = pulmonary embolus Very common occurrence Occurs during times of venous stasis (prolonged bed rest or sitting, CHF) Most common source of a pulmonary embolism is thrombophlebitis (a thrombus formed w/in a vein) 95% of pulmonary embolus come from Deep Leg Veins

• In this case, a deep leg vein is the common source for the origination of the thrombus • A thrombotic embolus originating in the femoral vein usually becomes arrested in the pulmonary circulation

Saddle Embolus: • A large embolus that may occlude the bifurcation of the main pulmonary artery • Usually results in sudden death

Symptoms: • Sudden shortness of breath, tachycardia, hyperventilation, cardiognenic shock

May result in: • Atelectasias • Cardiogenic shock • Pulmonary hemorrhage • Pulmonary HTN

♦ NOT absence of symptoms Diagnosis:

• Ventilation/perfusion scan Amniotic Fluid embolus

Can lead to DIC, especially postpartum Atheroslcerotic Brain Infarction

Most likely warning sign of impending brain infarction is transient ischemic attacks

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So, here’s the story on TIAs: TIAs are caused by a temporary disturbance of blood supply to a restricted portion of the brain TIAs are called mini strokes, because their neurological symptoms last < 24 hours TIAs are often called a warning sign for an approaching cerebrovascular accident, or “stroke”

• Strokes last > 24 hours The most common cause of a TIA is an embolus, which most frequently arises from an atherosclerotic plaque OR

from a thrombus Phlebitis:

Inflammation of a vein Pylephlebitis:

Inflammation of portal vein or any branches Congestion:

Accumulation of excessive blood w/in BVs Shock:

Set of hemodynamic changes reducing blood flow below a level providing adequate O2 for metabolic needs of organs/ tissues Requires immediate medical Tx – can worsen very rapidly Clinical signs:

Reduced cardiac output is the main factor in all types of shock Tachycardia, hypotension, pallor, diminished urinary output, & muscular weakness

Anoxia most severly affects brain & heart The body produces excess acid in the advanced stages of shock, when lactic acid is formed through the metabolism of sugar Major classes of shock:

Hypovolemic • Produced by a reduction of blood volume • Causes include hemorrhage, dehydration, vomiting, diarrhea, & fluid loss from burns

Cardiogenic • Due to the sudden reduction of cardiac output • Main cause is myocardial infarction

Septic • Due to severe infection • Most frequently caused by endotoxins from G- bacteria!!!!!

Minor classes of shock: Neurogenic

• Results from injury to the CNS Anaphylactic

• Shock that occurs w/ severe allergic reactions Stages of shock:

1) Non-progressive (early) • Compensatory mechanisms maintain perfusion of vital organs (↑ HR & ↑ peripheral resistance)

2) Progressive • Metabolic acidosis occurs (compensatory mechanisms are no longer adequate)

3) Irreversible • Organ damage – survival not possible

Tx: Epinephrine is the drug of choice

Amoxicillin Rxn Pt becomes hypotensive, itchy, and having difficult breathing

• This means Amox reacts with IgE and activates cytotoxic T cells that release lymphokines

BLOOD DISORDERS Purpura spots:

Purplish discolorations in the skin produced by small bleeding BVs near skin surface Petechiae = small purpura spots, small pinpoint hemorrhages Ecchymoses = large purpura spots

Both ecchymosis & purpura are manifestations of hemorrhage May also occur in the mucous MBs (e.g., lining of mouth) & in internal organs By itself is only a sign of other underlying causes of bleeding May occur w/ either normal platelet counts or decreased platelet counts Kinds of Purpura:

Thrombocytopenic Purpura (Werlhof’s disease):

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• Autoimmune disorder • Bleeding disorder characterized by deficiency in platelet # • Results in multiple bruises, petechiae, & hemorrhage into the tissues

Thrombotic Thrombocytopenic Purpura (TTP): • Severe & frequently fatal form characterized by low blood platelet count • Due to consumption of platelets by thrombosis in terminal arterioles & capillaries of many organs

Melena: Presence of dark, tarry stools, due to the presence of blood altered by the intestinal juices Refers to digested blood in the stool – a manifestation of hemorrhage

BLEEDING/CLOTTING DISRODERS: Laboratory values:

PT = prothrombin time • Measures Factors I, II, V, VII, X

PTT = partial thromboplastin time • Measures Factor XII, prekallikren, kininogen, Factors I, II, V, VII, IX, X, XI

TT = thrombin time • Measures Factor I

Clotting/Clot lysis Process:

• Prothrombin converted to thrombin (in presence of thromboplastin & calcium ions) ♦ Thromboplastin is released by damaged cells, thereby initiating the formation of fibrin ♦ Prothrombin is produced in the liver with help from Vitamin K

• Thrombin in turn converts fibrinogen to fibrin • Fibrin threads then entrap blood cells, platelets, & plasma to form a blood clot

Fibrinogen: • Plasma protein that is essential for the coagulation of blood and is converted to fibrin by thrombin & ionized calcium • NOT in serum

Fibrin: • Stringy, insoluble protein responsible for the semisolid character of blood clot • Serves as a template for fibroblasts to repair tissue & walls of the area to infection • The product of the action of thrombin on fibrinogen in the clotting process

Plasminogen: • Inactive precursor to plasmin that is present in tissues, body fluids, circulating blood, & w/in clots • Converted by Steptokinase, Staphylokinase, and Urokinase

Fibrinolysin = Plasmin: • A proteolytic enzyme derived from plasminogen • Essential in blood clot dissolution • Not a component of the body’s nonspecific disease mechanism

♦ Lysozyme, complement, interferon & properdin ARE components of the body’s nonspecific disease mechanism • The most important fibrinolytic protease

Fibrinolysis: • Restores blood flow in the vessels occluded by a thrombus and facilitates healing after inflammation and injury

Aspirin Marked with normal clotting time and normal platelet count, but prolonged bleeding time It just inactivates them, meaning they are still there, but don’t work

Factors causing delayed blood clotting: **Pt taking Heparin (anticoagulant) – acts as an antithrombin by preventing platelet agglutination

• Heparin is found in the blood **Pt w/ leukemia – often has thrombocytopenia (reduced # of platelets)

• Spontaneous gingival bleeding with leukemia **Pts w/ cirrhosis – have hypoprothrombinemia (abnormally small smounts of prothrombin in circulation)

• In pts w/ liver disorders, it is difficult to curb hemorrhage due to hypoprothrombinemia • Prothrobmin is formed & stored in parenchymal cells of liver • In cirrhosis, these cells are profusely damaged • Pts w/ severe liver disease may have hemorrhages due to a deficiency in prothrombin

**Scurvy **Thrombocytopenia:

• Condition in which there is a reduced number of platelets • Causes bleeding states wherein blood loss occurs through capillaries & other small vessels

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• Most common cause of bleeding disorders • Causes spontaneous bleeding • Most common sign is petechiae and purpura • Platelet count must reach a very low value (15,000 – 20,000/mm) before generalized bleeding occurs • Is the cause of prolonged bleeding time in pts w/ leukemia • Bleeding time increases but neither PT or PTT are affected (bc thrombin and thromboplastin and all the factors they

measure (1,2,5,7,10…) are unaffected) ♦ They don’t change because they measure FACTORS, not platelets

**Von Willebrand’s disease: • Characterized by spontaneous bleeding from mucous MBs & excessive bleeding following trauma • Deficiency of vWf resulting in impaired platelet adhesion (although there’s nothing wrong w/ the platelets) • Autosomal dominant bleeding disorder – equal frequency in both sexes • Prolonged bleeding time; Normal platelet count & PT; Prolonged PTT • Results in a functional Factor VIII deficiency, because vWf serves as a carrier for factor VIII (hence prolonged PTT)

**Long-term ASA (cyclooxygenase inhibitor) Tx • Rsults in impaired thromboxane production (important platelet aggregants)

**Dicumarol: • An anticoagulant that inhibits formation of prothrombin in liver • Interferes w/ metabolism of Vit K (needed for prothrombin synthesis) • Used to delay blood clotting especially in preventing & treating thromboembolic disease • Has largely been replaced by Warfarin

**Bernard-Soulier disease – hereditary platelet adhesion disorder **Glanzmann’s thombasthenia – defect of platelet aggregation

Hemophilia: Hereditary bleeding disorder causing 1) increase in clotting time & 2) abnormal bleeding

• Normal PT (Prothrombin time) but Prolonged PTT (Partial Thromboplastin Time) Hemophilia A & B are inherited as a sex-linked recessive trait

• Males are affected & females are carriers • Majority of people have type A & it presents under age 25

Excessive bleeding form minor cuts, epistaxis, hematomas, & hemarthroses Classifications of hemophilia:

• A – classical type – deficiency of coagulation factor VIII (antihemophilic factor) ♦ 10 yr old boy dies post tooth extraction. He also had bleeding into his joints, especially his knees, maternal uncle

and male cousin had similar experience • B (Christmas disease) – deficiency of factor IX (plasma thromboplastin component) • C (Rosenthal’s syndrome) – not sex-linked, less severe bleeding – deficiency of factor XI (plasma thromboplastin

antecedent) True hemophiliac is characterized by:

• Prolonged partial thromboplastin time (PTT) – because it measures Intrinsic Pathway 12-11-9-10 • Normal prothrombin time (PT) • Normal bleeding time

HYPERTENSION: Usually has no symptoms at all (called the silent killer) – millions of people w/ high BP don’t even know they have it Factors age, obesity, DM, smoking, genetics, race (black > white > asian) Predisposes to Coronary heart disease, CVA, CHF, renal failure, and aortic dissection Pathology Hyaline thickening and atherosclerosis The following may be evident:

Tiredness, confusion, visual changes, nausea, vomiting, anxiety, perspiration, pale skin, or an angina-like pain Hypertensive heart disease is usually associated with left ventricular hypertrophy as an anatomic finding

Organs damaged due to prolonged HTN: Heart – 60% die of complications Kidneys – 25% die to complications Brain – 15% die of complications

Essential HTN: High BP from no identifiable cause Accounts for 90-95% of HTN cases (related to increased CO or increased TPR) If left untreated can lead to retinal changes, left ventricular hypertrophy, & cardiac failure Genetic factors include family Hx of HTN – more common & usually more severe in blacks Benign Nephrosclerosis is the most common autopsy find of essential HTN

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Environmental factors – stress, obesity, cigarette smoking & physical inactivity Secondary HTN:

Kidney failure = most common cause Others causes: Obstructive sleep apnea, Aldosteronism, Renal artery bruits (suggests renal artery stenosis)

• If renal artery is occluded, you get secondary HTN – kidney thinks blood volume is low, so tries to compensate and you get HTN.

Others causes still: Renal parenchymal disease, Excess catecholamines, Coarctation of the aorta, Cushing’s syndrome Even more other causes: Drugs, Diet, Excess erythropoietin, Endocrine disorders

Findings in HTN

Findings Basis of findings Cardiovascular

BP persistently >140/90 Constricted arterioles – cause abnormal resistance to blood flow Angina pain Insufficient blood flow to coronary vasculature Dyspnea on exertion Left-sided heart failure Edema of extremities Right-sided heart failure Intermittent claudication Decrease in blood supply from peripheral vessels to legs

Neurologic Severe occipital headaches w/ nausea & vomiting; drowsiness, giddiness; anxiety; mental impairment

Vessel damage w/in brain, characteristic of severe HTN

Renal Polyuria; nocturin; diminished ability to concentrate urine; protein & RBCs in urine

Arteriolar nephrosclerosis (hardening of arterioles w/in kidney) 25% die of renal failure

Ocular Retinal hemorrhage & exudates Damage to arterioles that supply retina

Preeclampsia (Pregnancy-Induced HTN)

Triad HTN, proteinuria, and Edema When seizures are added, its called Eclampsia Affects 7% of pregnant women from 20 weeks gestation to 6 weeks postpartum Increased incidence in pts with preexisting HTN, DM, Chronic renal disease, and autoimmune disorder Can be associated with HELLP Hemolysis, Elevated LFTs, Low Platelets Clinical features Headache, blurred vision, abdominal pain, edema of face and extremities, altered mentation, hyperreflexia, Tx Deliver fetus ASAP

ANEMIA:

Condition in which # of RBCs is lower than normal Measured by a decrease in hemoglobin Body gets less O2 & therefore less energy than it needs

Symptoms – fatigue, weakness, inability to exercise, & lightheadedness Megaloblastic anemia:

Any anemia usually caused by deficiency of vitamin B12 or folic acid • Deficiency in Folic acid is most common

Characterized by macrocytic erythrocytes (same as below under macrocytic) Includes pernicious anemia & anemias caused by folic acid deficiency (sprue & megaloblastic anemia of pregnancy) Pernicious anemia:

• Caused by lack of intrinsic factor (needed to absorb Vit B12 from GI tract) ♦ Vit B12 is necessary for formation of RBCs ♦ Vit B12 also needed to help by nerve cells function properly ♦ Best Tx with Vit B12

• Causes a wide variety of symptoms – fatigue, SOB, tingling sensation, difficulty walking & diarrhea • Characteristics –

♦ Reduction in acid secretion by the stomach ♦ An increased tendency toward gastric carcinoma ♦ Atrophic glossitis ♦ Myelin degeneration in the spinal cord ♦ Easy fatigability ♦ Peripheral neuropathy

NOT Microcytic or hypochromic

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• A type of megaloblastic anemia • Erythrocytes produced are macrocytic & appear hyperchromic • Atrophic glossitis AND Atrophic gastritis is common

Aplastic anemia: Result of inadequate erythrocyte production – due to inhibition or destruction of red bone marrow

• A stem cell defect, leading to pancytopenia Results from drug-induced bone marrow suppression Can be caused by radiation, various toxins, & certain medications

• In drug-induced aplastic anemias: ♦ RBCs appear normochromic (normal [hemoglobin]) & normocytic (normal size) ♦ Just Few in #

Pancytopenia characterizd by severe anemia, neutropenia, and thrombocytopenia caused by failure or destruction of multipotent myeloid stem cells, w/ inadequate production of differentiated lines

Tx: withdrawal of offending agent, allogenic bone marrow transplant, RBC & platelet transfusion w/ G-CSF & GM-CSF Hemolytic anemias:

Anemias due to shortening of RBC life span (↑ RBC destruction) Problems often result from the subsequent increase in bilirubin levels (breakdown product of hemoglobin)

• Elevated levels of urobilinogen (compound formed in intestine by reduction of bilirubin) • Elevated kernicterus – Jaundice of the KERNAL – your head • Elevated levels of unconjugated bilirubin (water-insoluble bilirubin)

♦ Unconjugated bilirubin normally combines w/ serum albumin in the liver to become water-soluble (conjugated) Conjugated bilirubin is then secreted w/ other bile components into the small intestine Kernicterus = toxic accumulation of unconjugated bilirubin in the brain & spinal cord

EXs of hemolytic anemia: 1) Erythroblastosis fetalis, 2) Sickle cell anemia, 3) Thalassemias, 4) Hereditary spherocytosis • By the way, these are all red cell disorders

1) Erythroblastosis fetalis: • Not an autoimmune Disease • Fetus is Rh-positive because the father passed along the dominant trait • Mother is Rh-negative & responds to the incompatible blood by producing Ab/s against it

♦ High risk = Dad is Rh-positive and Mom is Rh-negative ♦ In a case of Erythrblastosis fetalis, the mother has very high levels of serum complement and anti-Rh IgE

• Antibodies cross placenta into fetus’ circulation, where they attach to & destroy the fetus’ RBC – leads to anemia • Can also result from blood type incompatibilities (i.e., mother may be type O & fetus may be type A or B)

2) Sickle Cell anemia: • Caused by Hemoglobin S – an abnormal type of hemoglobin • Autosomal recessive

♦ Heterozygous get the trait ♦ Homozygous get the disease (You know Homos are bad)

So if pt homozygous, bad • Globin portion of Hb S is abnormal – valine is substituted for glutamic acid in the 6th position of Hb molecule

♦ Valine replacing glutamic acid is a MISSENSE mutation – base substitution leading to different AA • When Hb molecules are exposed to low [O2], they form fibrous precipitates w/ the erythrocytes

♦ This distorts the RBCs into a sickle (crescent) shape ♦ Sickle cells function abnormally & cause microvascular occlusion & hemolysis

The clots give rise to recurrent painful episodes called “sickle cell pain crisis” • Also characteristic – non-healing leg ulcers & recurrent bouts of abnormal chest pain • 4 yr old black kid, long bones, enlarged spleen and liver, Lesion of skull Hair on end • Homozygotes have sickle cell disease

♦ Occurs primarily in blacks • Heterozygotes have sickle cell trait

♦ Relatively malaria resistant (balanced polymorphism) • Becomes life-threatening when:

♦ 1) Damaged RBCs break down (hemolytic crisis) ♦ 2) The spleen enlarges & traps the RBCs (splenic sequestration crisis) ♦ 3) A certain type of infection causes the marrow to stop producing RBCs (aplastic crisis) ♦ **Repeated crises can cause damage to kidneys, lungs, bones, eyes, & CNS

• Blocked BVs & damaged organs can cause acute painful episodes (occur in almost all pts at some point) ♦ Episodes can last hours to days, affecting bones of the back, long bones, & the chest

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• Complications – aplastic crisis due to B19 parvovirus infection, autosplenectomy, increase risk of encapsulated organism infection, Salmonella osteomyelitis, painful crisis (vaso occlusive) & splenic sequestration crisis

3) Thalassemias: • Group of inherited disorders resulting from imbalance in production of 1 of 4 chains of aa/s making up

hemoglobin • Characterized by low levels of erthhyrocytes & abnormal hemoglobin • Common in Mediterranean populations (ThalaSEAmia) • Alpha Thalassemias:

♦ Due to gene deletion ♦ No compensatory increase of any other chain. Some forms result in hydrops fetalis and intrauterine fetal death

• Beta Thalassemias: ♦ Due to defect in mRNA processing ♦ Beta chain is underproduced ♦ In beta thalassemia major (homozygous), the beta chain is absent – results in severe anemia requiring blood

transfusion. Cardiac failure is due to secondary hemochromatosis ♦ In both cases, fetal hemoglobin production is compensatorily increased but is inadequate ♦ HbS/beta thalassemia heterozygotes has mild to moderate disease

4) Hereditary Spherocytosis Macrocytic anemia/Megaloblastic:

Any anemia in which average size of circulating RBCs is greater than normal Frequently caused by deficiency of folic acid & Vit B12 (cyanocobalamin)

• These are associated w/ hypersegmented PMNs • Unlike folate deficiency, Vitamin B12 is associated w/ neurologic problems

♦ Folate deficiency can develop w/in months ♦ Vitamin B12 deficiency takes years to develop

Also caused by drugs that block DNA synthesis (sulfa drugs, AZT) Marked by reticulocytosis

Microcytic anemia: Any anemia in which average size of circulating RBCs is smaller than normal Frequently associated w/ chronic blood loss or nutritional anemia as in iron deficiency anemia Iron deficiency anemia – NO iron, then they’re SMALLER

• Most likely caused by chronic blood loss to a long standing peptic ulcer • Total iron binding capacity increases while ferritin and serum iron decreases • Hypochromic, microcytic, MCV < 80

♦ MCV = mean corpuscular volume • Diagnosis commonly made by demonstrating low serum iron, high TIBC, , & low serum ferritin

Normocytic normochromic anemias: Include: Size is still normal

• Myelophthisic • Acute hemorrhage • Enzyme defects (G6PH, PK deficiency) • RBC membrane defects (eg., hereditary spherocytosis) • Bone marrow disorders (aplastic anemia, leukemia, drug-induced bone marrow suppression) • Hemoglobinopathies (eg., sickle cell disease) • Autoimmune hemolytic anemia • Anemia of chronic disease

Disseminated Intravascular Coagulation (DIC): Activation of coagulation cascade leading to microthrombi & global consumption of platelets, fibrin, & coagulation factors

Splenic embolism most likely stems from DIC Caused by obstetric complications (most common), G- sepsis, transfusion, trauma, malignancy, acute pancreatitis, nephritic

syndrome Increased PT, PTT, fibrin split products (D dimers), low platelets, low fibrinogen Characterized by helmet shaped cells on blood smear Several days after an extraction, pt comes in with malaise and splinter hemorrhages beneath the fingernails

Caused from DIC or ENDOCARDITIS????? – Endocarditis. Arteriosclerosis:

“Hardening of the arteries” – arterial walls become thicker & less elastic (harder) Aorta & coronary arteries most affected

Abdominal aorta is the most common location for an atherosclerotic induced aneurysm

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Atherosclerosis: Is a form of arteriosclerosis Disease of elastic arteries and large and medium sized muscular arteries Most important & common form of arteriosclerosis Fatty material (atherosclerotic plaque) accumulates under inner lining of arterial wall Eventually the fatty tissue erodes arterial wall, diminishing elasticity (stretchiness) & interfere w/ blood flow Plaques can also rupture, causing debris to migrate downstream w/in an artery Signs & symptoms – Angina, claudication, changes in skin color & temperature, headache, dizziness, & memory defects Consequences of atherosclerosis:

• Ischemic heart disease (coronary artery disease) & heart attack (myocardial infarct) • Stroke or aneurysm formation

Described as degenerative changes in the walls of the arteries Microscopically:

• Fibrous cap of smooth muscle cells, collagen, CT matrix, leukocytes • Cellular zone of necrotic cells, lipid-filled foam cells, plasma proteins • Proliferating capillaries in advanced lesions

Location Abdominal aorta > Coronary artery > Popliteal artery > Carotid artery More common in men in all age groups & in post-menopausal women In very advanced cases, atherosclerotic plaques can become calcified & ulcerated Risks – smoking, HTN, heredity, nephrosclerosis, diabetes, & hyperlipidemia – NOT alcoholism

• Glass of wine a day Arteriolosclerosis:

Diffuse thickening of the arterioles & small arteries The kidney is particularly vulnerable to arteriolosclerosis

Carbon monoxide poisoning: Very dangerous, colorless, odorless gas, generally associated w/ fumes from a car or a home heating system Attaches to hemoglobin & blocks their ability to carry O2 Severe CO poisoning can cause a coma or irreversible brain damage because of O2 deprivation Hemoglobin has higher affinity to CO than to O2, even when minute amounts of CO is inhaled (Carboxyhemoglobin) Hemoglobin-CO bone is strong that very little is ever removed from blood Patients w/ acute CO poisoning exhibit cherry-red discoloration of the skin, mucosa, & tissues

Think CO from your Cherry-red Porsche!!! Death is ultimately due to hypoxia Symptoms of low-level CO poisoning are easily mistaken for a common cold, flu or exhaustion – proper Dx can be delayed

Chronic toxicity results in fatty changes in the heart, liver, kidney Other environmental & chemical agents & their manifestations if ingested:

Carbon tetrachloride – hepatocellular damage (also CNS, but think Liver and kidneys) Mercury poisoning

Inactivates enzymes & damages cell MBs Acute toxicity: severe renal tubular necrosis & GI ulceration Chronic toxicity: excessive salivation, gingivitis, gastritis, cerebral & cerebellar atrophy

Cyanide poisoning – prevents cellular oxidation, results in odor of bitter almonds Methyl alcohol – blindness Lead Poisoning

Basophilic stippling of RBCs Anemia, poorly localized abdominal pain (Abdominal colic) Peripheral neuropathy due to myelin degeneration – primarily affects motor neurons Wrist and Foot drop (makes sense – radial nerve is MOST affected) Lead lines in bone

Acetaminophen Acetaminophen toxicity causes severe centrilobular hepatic necrosis Hepatic failure 2-6 days after ingestion

Polyarteritis nodosa: Serious BV disease wherein small & medium-sized arteries become inflamed & damaged when certain immune cells attack Result is reduced blood supply to organs Typically involves renal and visceral vessels Symptoms Fever, weight loss, malaise, abdominal pain, headache, myalgia, HTN Findings Cotton-wool spots, microaneurysms, pericarditis, myocarditis, palpable purpura, Increased ESR, Associated with Hep B in 30% of pts P-ANCA is often present in serum and correlates with disease activity, primarily in small vessel disease Tx Corticosteroids

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Temporal arteritis: Chronic inflammatory disease of large arteries Usually branches of the carotid artery Findings Unilateral headaches, jaw claudication, impaired vision Half of pts have systemic involvement and syndrome of polymyalgia rheumatica Associated with elevated ESR, Responds well to steroids

Raynaud's syndrome: Symmetric asphyxia (impaired oxygen exchange); idiopathic paroxysmal bilateral cyanosis of the digits due to arterial and

arteriolar contraction Caused by cold or emotion Differentiate from Buerger’s caused from smoking

Phlebitis: Inflammation of the veins Most common in the legs Common causes – local irritation (IV line), infection in or near a vein, & blood clots

Thrombophlebitis: Vein inflammation related to a blood clot Most common source of pulmonary embolism Symptoms:

Tenderness over the vein Pain in the affected part of the body Skin redness or inflammation (not always present)

Specific disorders associated w/ thrombophlebitis: Superficial thrombophlebitis – affects veins near skin surface Deep venous thrombosis – affects deeper, larger veins

• 90% of cases occur in the deep veins of the leg Pelvic vein thrombophlebitis

Congestion (hyperemia): Localized increase in the volume of blood in the capillaries & small vessels Active congestion – results from localized arteriolar dilation (e.g., inflammation, blushing) Passive congestion – results from obstructive venous return or increased back pressure from CHF

Occurs secondary to venous obstruction 1) Acute – occurs in shock or right sided heart failure 2) Chronic –

• a) of the lung (mostly caused by left-sided failure) • b) of the liver (mostly caused by right-sided failure) Leads to “Nutmeg Liver”

Myeloproliferative disorders: Conditions in which myeloid stem cells develop & reproduce abnormally Characteristics – peak incidence in middle-aged persons, ↑ in blood basophils, serum uric acid, & prominent splenomegaly

Polycythemia vera: Aka primary polycythemia or erythemia A myeloproliferative syndrome characterized by a marked increase in erythrocyte mass Rare disorder of blood precursors – results in excess of RBCs (opposite of anemia)

Pts may later develop anemia or acute leukemia due to “bone marrow burn out” Folate deficiency may also develop for the same reason

Characteristics – Clubbing and cyanotic digits, erythrocytosis, leukocytsosis, thrombocytosis, & splenomegaly, along w/ ↓

[erythropoietin] 2° polycythemia – an excess of RBCs caused by conditions other than polycythemia vera

EXs: chronic hypoxia associated w/ pulmonary disease, residency at high altitudes (Osker’s disease), & heavy smoking or secretion of erythropoietin associated w/ adult polycystic kidney & tumors

Myelofibrosis: Disorder in which fibrous tissue may replace precursor cells in marrow Results in an ↑ # of immature RBCs & WBCs & abnormally shaped RBCs, anemia & splenomegaly

CML – disease in which a bone marrow cell becomes cancerous & produces a large # of abnormal granulocytes White cell count

Differential Increase in juvenile immature neutrophils or bands (shift to the left) – suggests bacterial infection Increase in mononuclear cells (shift to the right) – suggests viral, occasionally fungal infections Increase in eosinophils – suggests parasitic infections among others

Leukocytosis:

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Abnormally large # of leukocytes Found as a result of a systemic bacterial infection Most often there is a disproportionate increase in PMN # (called Neutrophilic Leukocytosis) Scarlet Fever, Appendicitis, Staphylococcal Septicemia, Tularemia & acute abscesses all cause leukocytosis Present in Acute abscess and Osteomyelitis Not all bacterial infections show this characteristic

EX: typhoid fever & brucellosis actually result in a depression of PMNs Many viral infections result in leukopenia, particularly of PMNs

Leukocyte count: a general indicator of bacterial vs. viral infection Normal range for leukocytes: 5k–10k/mm3 blood

Leukemoid reaction – when circulating levels of leukocytes reach very high levels (up to 100k/mm3) • Sometimes difficult to differentiate from leukemia

Parasitic infections cause an increase in eosinophil # in peripheral blood Pyemia: septicemia due to pyogenic organisms causing multiple abscesses

BONE & JOINT DISORDERS

BONE Long bones

May be affected by Rickets, osteopetrosis, chondrodystrophy, fibrous dysplasia, osteogenesis imperfecta Fracture:

A break in the bone, usually accompanied by injury to surrounding tissues Occurs when force against bone exceeds bone strength Described as:

Complete – bone breaks into two pieces Greenstick – bone cracks on one side only (not all the way through ) Single – bone breaks into 2 pieces Comminuted – bone breaks into 3+ two pieces (or is crushed) Bending – bone bends but doesn’t break (only happens in kids) Open – bone sticks through skin

Three phases of fracture healing: 1) Inflammatory phase – characterized by bloot clot formation 2) Reparative phase: characterized by formation of a callus of cartilage (replaced by a bony callus) 3) Remodeling phase: cortex is revitalized

Reasons for failure of a fracture to heal: Ischemia – navicular bone of wrist, femoral neck, & lower 1/3 of tibia are all poorly vascularized & therefore subject to

coagulation necrosis Inadequate immobilization after fracture – pseudoarthrosis or a pseudojoint may occur Presence of a sequestrum Interposition of soft tissue – between fractured ends Infection – most likely w/ compound fractures

Fat embolism: Most often a sequela of fracture Due to mechanical disruption of bone marrow fat & by alterations in plasma lipids 18 yr old male sustains a fracture to the femur, 24 hours later, after manipulating the fragments to help them heal better, the

pt dies suddenly….Fat embolism Osteomyelitis:

Acute pyogenic bone infection most often caused by Staph. Aureus Sexually active N. gonorrheae Druggies Pseudomonas Aeruginosa Sickle Cell Salmonella Prosthetic Replacement S. aureus and S. epidermidis Vertebral M. tuberculosis The infection causing osteomyelitis is often in another part of body – spreads to bone via blood

Affected bone may have been predisposed to infection due to recent trauma In children – long bones usually affected In adults – vertebrae & pelvis are most commonly affected Infected bone usually produces pus – may causes an abscess

The Abscess deprives bone of blood supply Presents w/ pain, redness, swelling; also fever & malaise Risk factors – recent trauma, diabetes, hemodialysis, IV drug abuse, & people w/ removed spleen Chronic osteomyelitis

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Results when bone tissue dies as a result of lost blood supply Can persist intermittently for years

Osteoporosis: Thinning of bone tinssue & loss of bone density over time Most common type of bone disease Occurs when 1) body fails to form enough new bone, 2) too much old bone is reabsorbed, or 3) both happen Calcium & phosphate – two minerals essential for normal bone formation

With age, minerals may be reabsorbed into body from bones, weakening bone tissue End result in brittle, fragile bones that are subject to pathologic fracture even in absence of trauma Type I Postmenopausal, increased bone resorption due to decreased estrogen levels, Tx with estrogen replacement Type II Senile osteoporosis, affects men and women >70 years Affects whites > blacks > Asians Causes:

Leading cause – • Drop in estrogen in women at time of menopause • Drop in testosterone in men

Corticosteroids Prolonged immobilization Chronic malnutrition Advanced age

• NOT hypervitaminosis D Women, especially > 50 get it more often than men Can result from prolonged corticosteroid administration

Osteomalacia: (in adults) Softening of bones caused by Vit D deficiency or problems w/ Vit D metabolism In children = Rickets

Bones become bowed in rickets because of failure of osteoid tissue to calcify (failure of bone matrix calcification) Conditions leading to osteomalacia:

Inadequate dietary intake of Vit D Inadequate exposure to sunlight (UV radiation) – normally produces Vit D in body Malabsorption of vitamin D by intestines Hereditary or acquired disorders of Vit D metabolism Kidney failure & acidosis Phosphate depletion associated w/ low dietary intake of phosphates Kidney disease or cancer (rare) Side effects of mediations used to treat seizures

Characterized radiographically by diffuse radiolucency – can mimic osteoporosis Bone biospsy is often only way to differentiate between osteoporosis & osteomalacia

Symptoms: diffuse bone pain (esp. in hips), muscle weakness, & bone fractures w/ minimal trauma More common in women Softening of bones occurs because bones contain osteoid tissue which has failed to calcify due to lack of Vit D Teeth in child w/ Rickets – delayed eruption, malocclusion, developmental abnormalities of dentin/enamel, & ↑ caries

rate Osteopetrosis = Albers-Schonberg disease = marble bone disease – Think FAT ALBERtS BONE

May be inherited as a dominant OR recessive trait Marked by ↑ bone density, brittle bones, & in some cases skeletal abnormalities Often initially asymptomatic, trivial injuries may cause bone fractures due to bone abnormalities Adult type is milder than the malignant infantile & intermediate types Main features:

Overgrowth & sclerosis of bone Thickening of cortex Narrowing (or obliteration) of medullary cavity

Liver & spleen may become enlarged, blindness & progressive deafness may occur Achondroplasia:

One of the most common causes of dwarfism Autosomal dominant disorder characterized by short limbs w/ normal-sized head & trunk

Due to defect of fibroblast growth factor (FGF) Best known form of dwarfism: Short limbs, large body, frontal bossing, & saddle nose

Osteogenesis imperfecta: Unbreakable Hereditary disorder (aka “brittle bones”) Rare but demonstrates the effect of inadequate osteoid production

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Defect in synthesis of type I collagen Chris Kaman

Results in skeletal fragility, thin skin, poor teeth, thin blue sclera, tendency towards macular bleeding, & joint hypermotility Joint hypermobility = ligamentous laxity

Teeth are poor because of malformation of dentin (dentinogenesis imperfecta) Patients have Hx of multiple fractures

Fibrous dysplasia: Characterized by replacement of normal bone w/ fibrous tissue Three classifications depending on extensiveness of skeletal involvement:

Monostatic = 1 bone involved Polyostic = 2+ bones involved Polyostic associated w/ endocrine disturbances (Albright’s syndrome)

• NOTE: Albright’s syndrome is a disease where two of the following three are present: ♦ Café-au-lait spots ♦ Fibrous dysplasia ♦ Endocrine hyperfunction (includes precocious puberty)

Pathologic fractures are often presenting complaint Paget’s Disease (aka Osteitis deformans):

Metabolic bone disease involving bone destruction & regrowth – resulting in deformity Diffuse, “cotton-wool” opacities Cause is unknown – early viral infections (possibly w/ mumps) & genetic causes have been theorized Characterized by excessive breakdown of bone tissue, followed by abnormal bone formation

Reversal lines with mosaic pattern New bone is structurally enlarged, but weakened & filled w/ new BVs Predisposition for osteosarcoma Irregular resorption of bone with a poorly mineralized osteoid matrix

• NOT decreased serum Ca & elevated serum P May localize or be widespread – frequently in pelvis, femur, tibia, vertebrae, clavicle, or humerus Skull may enlarge the head size & cause hearing loss if cranial nerves are damaged by bone growth Intraorally the teeth are spread Lab findings:

Anemia Markedly increased serum ALP (alkaline phosphatase – NOT acid phosphatase) levels

• ALP is an index of osteoblastic activity & bone formation Elevated 24-hr UHP (urinary hydroxyproline), an index of osteoclastic hyperactivity

Von Recklinghasuen’s disease: Disease of bone (osteitis fibrosa cystica) caused by hyperparathyroidism Characterized by ↓ serum phosphorus & ↑ serum calcium & alkaline phosphatase

Condensing Osteitis (Sclerosing osteitis): Unusual reaction or inflammatory response of dental pulp of the tooth to a low-grade infection

Osteochondroma: Big mushroom-like neoplasm of bone showing peripheral cartilage cap in metaphyseal area of young person Most common benign bone tumor Usually seen in men < 25 y.o. Commonly originates in the long metaphysic Malignant transformation to chondorsarcoma is rare

Osteochondroses: Group of diseases in children & adolescents (years of rapid bone growth) Localized tissue death (necrosis) occurs, usually followed by full regeneration of healthy bone tissue Blood supply to growing ends of bones (epiphyses) may become insufficient resulting in necrotic bone, usually near joints Avascular necrosis is used to described osteochondrosis Necrotic areas are most often self-repaired over period of weeks or months Characterized by degeneration & aseptic necrosis followed by regeneration & reossiffication Affects different parts of body – categorized by one of three locations:

1) Physeal: • Aka Scheuermann’s disease • Occurs in the spine at intervertebral joints (physes), esp. in thoracic region

2) Articular: • Occurs at the joints (articulations) • Legg-Calvé-Perthes disease – occurs at the hip

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• Kohlers disease – foot • Freiberg’s disease – 2nd toe

♦ The only type of osteochondrosis more common in females – all others affect sexes equally • Panner’s disease: elbow

3) Non-articular: • Occurs at any other skeletal location • EX: Osgood-Schlatter disease of the tibia – relatively common

JOINTS Suppurative arthritis:

Usually monoarticular Primarily a hematogenous seeding of joints during bacteremia (mostly Staph, Strep, or Gonococci) Tender, swollen, erythematous joints – requires rapid intervention to prevent permanent damage Cloudy synovial fluid & high PMN count

Rheumatoid arthritis: Chronic inflammatory disease primarily affecting the synovial joints & surrounding tissue – can also affect other organ systems Cause is unknown – there is a genetic predisposition Characterized by the classic microscopic lesion called pannus

What is pannus, you ask? – it is a hanging flap of skin…that sounds a lot like another kind of hanging flap of skin Usually starts in the small joints of hands & feet – usually symmetric involvement Classic presentation: Morning stiffness (gross – think Pannus) improving with use, symmetric AND systemic symptoms!! RA involves an attack on body by its own immune cells (may be an autoimmune disease)

80% have positive rheumatoid factor (anti-IgG Ab) Marked by proliferative inflammation of the synovial MBs leading to deformity, ankylosis, & invalidism

Primarily attacks peripheral joints & surrounding muscles, tendons, ligaments, & BVs Synovia are the sites of the earliest changes in RA

Begins most often between ages 25-55 More common in older people – women are more affected (2.5x) Affects ~1-2% of population – course & severity can vary considerably Still’s disease = type of RA occurring in young people Gradual onset – fatigue, weakness, morning stiffness (lasting >1hr), diffuse muscular aches, loss of appetite Joint pain eventually appears w/ warmth, swelling, tenderness, & stiffness of joint after inactivity NOTE: RA, SLE, polyarteritis nodosa, dermatomyositis & scleroderma are all classified as collagen diseases

All have common inflammatory damage to CTs & BVs w/ deposition of fibrinoid material NOTE: Most common characteristic lesion of rheumatic fever, scleroderma and RA is Fibrinoid degeneration

Osteoarthritis (OA): Chronic inflammation that causes:

1) articular cartilage of affected joint to gradually degenerate 2) development of bony spurs, osteophytes

NOTE: Osteophyte (bony spur) formation is a cardinal feature of osteoarthritis not RA Most common form of arthritis Inflammation is accompanied by pain, swelling, & stiffness Most commonly affects joints constantly exposed to wear & tear Classic presentation: is pain in weight-bearing joints after use, improving with rest, but no systemic symptoms X-rays show loss of joint space Higher incidence in women, most often >50 y.o. Joints most often affected – intervertebral joints, phalangeal joints, knees, & hips Heberden’s nodes: (Heber City is far away -- distal)

Hard nodules/bony swellings which develop around the distal IP joints in patients w/ osteoarthritis Produced by osteophytes of articular cartilage at the base of terminal planges in OA 2nd & 3rd fingers are most often affected More common in females – onset in middle life

Bouchard’s nodes Same as Heberden’s, but… Found in the proximal IP joint

Characteristic morphologic changes in OA (in addition to Heberden’s & Bouchard’s nodes): Eburnation of bone – polished ivory like appearance of bone Osteophyte formation – bony spur formation

• They fracture & float into synovial fluid along w/ fragments of separated cartilage & are called joint mice Gout

Inherited disorder of purine metabolism occurring predominantly in men

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Marked by uric acid deposits in the joints There is hyperuricemia, too

Can be characterized by acute arthritis of big toe Asymmetric

Caused by a metabolic defect resulting in either: 1) Overproduction of uric acid (monosodium urate crystals) OR

• Uric acid – end-product of purine metabolism, specifically xanthine metabolism • Overproduction due to hyperuricemia (caused by Lesch-Nyhan syndrome, decreased uric acid excretion, or G6P

Deficiency) 2) Reduced ability of the kidney to eliminate uric acid

• Almost 25% of all people who have gout develop kidney stones Exact cause of the metabolic defect is unknown May also develop in people w/ diabetes, obesity, sickle cell anemia, & kidney disease, or it may follow drug therapy (Thiazide

Diuretics inhibit the secretion of uric acid) Crystals are needle shaped and negatively birefringent Gout has 4 stages:

1) Asymptomatic 2) Acute

• Causes painful arthritis – especially in joints of feet & legs • Symptoms develop suddenly & usually involve only one or a few joints (asymmetric)

♦ Pain frequently starts at night – described as throbbing, crushing or excruciating ♦ Joint appears infected – signs of warmth, redness, & tenderness ♦ Attacks may subside in several days, but may recur at irregular intervals ♦ Subsequent attacks usually have a longer duration

• Acute attack tends to occur after alchol consumption or large meal • Some pts progress to chronic gouty arthritis – others may have no further attacks • Tophus formation – often on external ear or Achilles tendon

♦ Tophi are pathognomonic of gout 3) Intercritical 4) Chronic

Pseudogout: Disorder characterized by intermittent attacks of painful arthritis caused by deposits of calcium pyrophosphate crystals Usually occurs in older people – affects both sexes equally Forms basophilic, rhomboid crystals (as opposed to the negatively birefringent, needle shaped of gout) Usually affects large joints

Ankylosing spondylitis: CT disease characterized by inflammation of spine & large joints, resulting in stiffness & pain, along w/ aortic regurgitation Associated w/ HLA-B27, gene that codes for HLA-MHC I

Reiter’s syndrome: Inflammation of joints & tendon attachments at the joints, often accompanied by inflammation of conjunctiva & mucous MBs

(mouth, urinary tract, etc.) & by a distinctive rash Males Can’t see (conjunctivitis), can’t pee (urethritis), can’t climb a tree (arthritis) Common in post GI or Chlamydia infections

NEOPLASMS

Changes in Cell Growth Atrophy:

Decrease in organ or tissue size resulting from a pathological decrease in mass of preexisting cells Most often results from disuse, aging, or a disease process Long standing gradual ischemia of an organ or tissue most likely result in atrophy General causes of pathologic atrophy are:

• Disuse • Pressure • Loss of innervation • Lack of nutrition

♦ NOT chemical stimulation or oversstimulation w/ hormones Hypertrophy (reversible):

Increase in organ or tissue size due to an increase in cell size Cardiac muscle

• Following injury, restores functional capacity via hypertrophy

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• Increase in ventricular wall thickness in pt with HTN • Increase in the size of a heart of an athlete

Hyperplasia: An increase in the size of the organ caused by an increase in the number of cells

Hypoplasia: Decrease in cell production less extreme than aplasia Example is the underdevelopment of an organ, NOT an acquired reduction in the size of the organ

Aplasia: Failure of cell production During fetal development, aplasia results in agenesis (the absence of an organ) Abnormal cells lacking differentiation, often equated w/ undifferentiated malignant neoplasms Tumor giant cells may be formed

• NOT a feature of malignancy (Anaplasia is) Anaplasia:

Absence of cellular differentiation (which is a measure of tumor’s resemblance to normal tissue) When malignant cells resemble more primitive undifferentiated cells

Metaplasia: Process whereby one cell type changes to another cell type in response to stress

• Change of a more specialized cell type to a less specialized cell type Generally assists the host to adapt to the stress Does NOT change the number of cells involved only type of cell Examples:

• The most common type of epithelial metaplasia involves replacement of columnar cells by stratified squamous epithelium (respiratory tract – smokers)

• Early bronchial mucosal alteration most likely seen in cigarette smokers • Bone production in scar tissue • Transformation of mucous secreting bronchial epithelium to a squamous epithelium

Dysplasia (reversible): Type of nonmalignant cellular growth – it may precede malignant changes (preneoplastic)

• Epithelial change most predictive of cancer Associated w/ chronic tissue irritation by:

• 1) chemical agents (e.g., cigarette smoke) OR • 2) chronic inflammatory irritation (e.g., chronic cervitis)

Tissue appears somewhat structureless/disorganized & may consist of atypical cells w/o invasion • Abnormal tissue development

Epithelium exhibitis acanthosis (abnormal thickening of the prickle cell layer) Changes in epithelial dysplasia: hyperchromatic nuclei, mitosis near the surface, pleomorphism of cells EX: squamous cells exhibiting acanthosis, disorganization & atypical cells w/o invasion is diagnostic of dysplasia May be reversed if causative factor is removed

Desmoplasia: Excessive fibrous tissue formation in tumor stroma

Neoplasia Clonal proliferation of cells that is uncontrolled and excessive When cells grow out of control and proliferate

Tumor grade vs. stage: Grade: (Think missing Histo by 1 point)

Histologic appearance of tumor Usually graded I – IV based on degree of differentiation & # of mitoses per high power field; character of tumor itself

Stage: Based on site & size of primary lesion, spread to regional lymph nodes, presence of metastases Spread of tumor in a specific pattern Has more prognostic value than grade TNM staging system: T = size of tumor; N = Node involvement; M = Metastases What’s more important???? STAGE

Neoplasm vs. Inflammatory Overgrowth Most characteristic feature of neoplasm as opposed to inflammatory overgrowth is that there is still progressive growth after

removal of causative stimuli (NOT abnormal mitosis, tendency to grow rapidly, or tendency to recur after removal) Oncogenes

Proteins that serve in normal control, but can be mutated or come in contact with a retrovirus and then growth occurs uncontrollably

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C-myc Burkitt’s lymphoma Bcl-2 Follicular and undifferentiated lymphomas (inhibits apoptosis) – Think Blood Cell Lesion -2 Erb-B2 Breast, ovarian, and gastric carcinomas Ras Colon carcinoma – It’s in your Ass

Protooncogene Gene sequences (in human cells) that are homologous to virus genome sequences known to cause cancer in animals

Tumor Suppressor Genes Gene Chromosome Tumor Rb 13q Retinoblastoma, osteosarcoma BRCA-1 and 2 17q, 13q Breast and ovarian cancer P53 17q Most human cancers, Li-Fraumeni syndrome

Genetic Hypothesis of Cancer: Implies that a single progenitor cell is damaged, resulting in a tumor mass of Monoclonal cells

Mutation: Stable, heritable change in nucleotide sequence of DNA Results in an alteration in products coded for by the gene Result from 3 types of molecular change:

1) Base substitutions – one base is inserted in place of another – results in either a missense or nonsense mutation • Missense mutation:

♦ Results in substitution of one aa for another ♦ Example Val to glut in Sickle Cell

• Nonsense mutation: ♦ When base substitution generates a termination codon that prematurely stops protein synthesis ♦ These mutations almost always destroy protein function

• Transverse mutation: ♦ Point mutation involving base substitutions in which the orientation of purine and pyrimidine is reversed

A purine is replaced by a pyrimidine or vice versa • Transition mutation:

♦ Point mutation involving substitution of one base pair for another by replacing one purine by another purine & one pyrimidine by another pyrimidine – no change in the purine-pyrimidine orientation.

♦ Caused by base analogues 2) Frame shift mutation –

• occurs when 1+ base pairs are added or deleted 3) Transposons

• (insertion sequence) or deletions are integrated into DNA Caused by:

Chemicals – nitrous oxide & alkylating agents alter the existing base Ionizing radiation (gamma & x-rays) – produce free radicals that attack DNA bases UV radiation – has lower energy than x-rays, causes cross-linking of adjacent pyrimidine bases to form dimers

• Nucleic acids in bacteria and viruses are most sensitive to UV radiation (versus protein, lipid, CHOs) • Thymine dimers result in inability of the DNA to replicate properly • THINK UV STERILIZATION

Viruses – bacterial virus Mu (mutator bacteriophage) causes either frame-shift mutations or deletions Bacterial mutation leading to the requirement for a single amino acid is due to absence of a single NZ activity

Radiosensitivity High radiosensitivity cells: lymphocytes > blood-forming cells >reproductive cells > epithelial cells of GI tract Low radiosensitivity (radioresistant) – nerve cells, mature bone cells, muscle cells Most to least radiosensitive: spermatogonium > intestinal mucosa > endothelial > skeletal muscle > osteocytes Most closely related to mitotic rate

X-radiation Repeated exposure of low dose x-radiation can cause:

Genetic mutations Carcinogenesis

Basic effect on living tissues is ionization (NOT denaturation, etc) Benign tumor:

Localized, has a fibrous capsule, limited potential for growth, a regular shape, & well differentiated cells Does not invade surrounding tissue or metastasize to distant sites Grow by expansion Causes harm only by:

Pressure, hormone overproduction, or hemorrhage following ulcerations of overlying mucosal surface

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Usually do not recur after surgical excision BENIGN neoplasms:

Adenoma, Fibroma, Hemangioma, Lipoma Malignant tumors spread by local invasion and metastasis

MALIGNANT neoplasms: Hepatoma, Lymphoma, Melanoma, Myeloma, Seminoma Metastasis occurs via bloodstream or lymph system

• Lymphatic – tumor 1st spreads to local & regional lymph nodes – then disseminates via blood • Hematogenous – 2° tumor nodules develop in liver, lung, brain, bone marrow, & sometimes spleen & soft tissue

Benign Malignant

Well-differentiated (neoplastic cells resemble comparable normal cells – meaning blasts are still making it to cytes, etc.)

Less well differentiated (anaplastic: loss of structural difference) **Can be either (Can either be well or poorly differentiated)

Slow growth Rapid growth Encapsulated; well circumscribed Invasion Localized Metastasis – most important distinguishing characteristic Movable Immovable

Host response to a malignancy is best reflected by lymphocytic infiltration at the edge of the tumor

Malignancy differentiated from inflammation in that malignancy will grow after removal of the causative agent Most important characteristic of malignant neoplasms (distinguishing them from benign neoplasms) – ability to invade &

metastasize Seed vs. Soil Metastasis

Soil = Target organ liver, lungs, bone, brain, etc. Seed = Tumor Embolus

Implantation or seeding metastasis Most often seen in stomach, ovary, colon (NOT in tongue, skin)

• These most often send out SEEDS B and L are always Breast and Lung for Pneumonics Metastasis to brain:

Lots of Bad Stuff Kills Glia: Lung, Breast, Skin (melanoma), Kidney (renal cell carcinoma), GI ~50% of brain tumors are from metastasis

Metastasis to liver: Cancer Sometimes Penetrates Benign Liver: Colon>Stomach>Pancreas>Breast>Lung Liver & lung are the most common sites of metastasis after the regional lymph nodes Metastasis to liver are much more common than primary liver tumors

Metastasis to bone: BLT2 w/ Kosher Pickles: Breast, Lung, Thyroid, Testes, Kidney, Prostate

Primary tumor of the tongue is LEAST likely to metastasis to bone Brain tumors also tend NOT to metastasize to bone

Lung = lytic Prostate = blastic Breast = both lytic & blastic Metastases from breast & prostate are most common

Metastisis to jaw: breast > lung (breast & prostate greatest) Most likely to metastasize to jaw Breast

Metastatic bone tumors are far more common than 1° bone tumors MOST common organ receiving metastasis Adrenal Glands (Rich blood supply)

Usually first in medulla and then rest of gland MOST common organ sending metastasis LUNG>Breast>Stomach

Paraneoplastic effects of tumors Neoplasm Effects of tumors Effect

Small cell lung carcinoma (oat cell) ACTH or ACTH-like peptide Cushing’s syndrome Small cell lung carcinoma and intracranial neoplasms

ADH or ANP SIADH

Squamous cell lung carcinoma, renal cell carcinoma, breast carcinoma, multiple myeloma, & bone metastasis (lysed bone)

PTH-related peptide, TGF-alpha, TNF-alpha, IL-2

Hypercalcemia

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Renal cell carcinoma Erythropoietin Polycythemia Thymoma, bronchogenic carcinoma Antiboides against presynaptic Ca

channels at neuromuscular junction Lambert-Eaton syndrome (muscle weakness)

Various neoplasms Hyperuricemia due to excesss nuclei acid turnover (cytotoxic therapy)

Gout

Cell type Benign Malignant

Epithelium Adenoma, papilloma Adenocarcinoma, papillary carcinoma Mesenchyme

Blood cells Leukemia, lymphoma Blood vessels Hemangioma Angiosarcoma Smooth muscle Leiomyoma (uterus) Leiomyosarcoma Skeletal muscle (voluntary m) Rhabdomyoma Rhabdomyosarcoma Bone Osteoma Osteosarcoma Fat Lipoma Liposarcoma >1 cell type Mature teratoma Immature teratoma

Predisposers of cancer:

Abestosis - mesothelioma Hepatitis C – hepatocellular carcinoma Gardner’s syndrome – multiple polyps 100% malignant change Ulcerative colitis – colonic adenocarcinoma.

NOT Anthracosis – Coal miners (black lung) – doesn’t CA Histological features of malignancy:

Anaplasia Absence of differentiation (which is a measure of tumor’s resemblance to normal tissue) When malignant cells resemble more primitive undifferentiated cells

Invasion Hyperchromatism Pleomorphism Abnormal mitosis

Diseases associated w/ neoplasms

Condition Neoplasm Down syndrome Acute lymphoblastic leukemia –ALL We DOWN Xeroderma pigmentosum Squamous cell and basal cell carcinoma of the skin Chronic atrophic gastritis, pernicious anemia Gastric adenocarcinoma Tuberous sclerosis (facial angiofibroma, seizures, mental retardation)

Astrocytoma and cardia rhabdomyoma

Actinic keratosis Squamous cell carcinoma of skin Barrett’s esophagus (chronic GI reflux) Esophageal adenocarcinoma Plummer-Vinson syndrome (atrophic glossitis, esophageal webs, anemia; all due to iron deficiency)

Squamous cell carcinoma of esophagus (most common CA of esophagus – more so than adenocarcinoma)

Cirrhosis (alcoholic, hepatitis B or C) Hepatocellular carcinoma Ulcerative colitis Colonic adenocarcinoma Paget’s disease of bone Secondary osteosarcoma and fibrosarcoma Immunodeficiency states Malignant lymphomas AIDS Aggressive malignant lymphomas (non-Hodgkin’s & Kaposi’s) Autoimmune disease (e.g., Hashimoto’s thyroiditis, myasthenia gravis)

Benign and malignant thymomas

Acanthosis nigricans (hyperpigmentation and epidermal thickening)

Visceral malignancy (stomach, lung, breast, uterus)

Dysplastic nevus Malignant melanoma Tumor markers: should not be used as primary tool for cancer diagnosis. They may be used to confirm diagnosis, to monitor for

tumor recurrence, and to monitor response to therapy: Marker Tumor

PSA (prostate-specific antigen) Prostatic carcinoma Carcinoembryoonic antigen (CEA) Carcinoembryonic antigen. Very nonspecific but produced by

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70% of colorectal and pancreatic cancers; also produced by gastric and breast carcinoma

Alpha fetoprotein (AFP) Normally made by fetus. Hepatocellular carcinomas. Nonseminomatous germ cell tumors of the testis (yolk sac tumor)

Human Chorionic Gonadotropin (Beta hCG) Think HCG Hydatidiform moles, Choriocarcinomas, and Gestational trophoblastic tumor

CA-125 Ovarian, malignant epithelial tumors S-100 Melanoma, neural tumors, astrocytomas Alkaline phosphatase (OSTEOBLASTS) Metastases to bone, obstructive biliary disease, Paget’s

disease Acid phosphatase Prostate tumors extending outside prostate capsule (Stage C or D) Bombesin Neuroblastoma, lung and gastric cancer TRAP Tartate-resistant acid phosphatase. Hairy cell leukemia—a B cell

neoplasm

Oncogenic Virus Associated Cancer HTLV-1 Adult T-cell leukemia HBV, HCV Hepatocellular carcinoma EBV Burkitt’s lymphoma, nasopharyngeal carcinoma HPV Cervical carcinoma (16,18) penile/anal carcinoma HHV-8 (Kaposi’s sarcoma associated herpes virus) Kaposi’s sarcoma, body cavity fluid B cell lymphoma

Chemical Carcinogens Associated Cancer Aflatoxins, vinyl chloride Liver Nitrosamines Esophagus, stomach Asbestos Lung (mesothelioma and bronchogenic carcinoma) Arsenic Skin (squamous cell) CCl4 Liver (centrilobular necrosis, fatty change) Naphthalene (aniline dyes) Bladder (transitional cell carcinoma) Carcinoma in situ:

Pleomorphism Disorderly maturation Hyperchromatic nuclei

BUT Basement membrane remains intact Carcinoma:

Malignant tumor of epithelial origin – think squamous cells carcinoma Usually metastasize via lymphatics Occurs in the following variations:

Squamous cell carcinoma – originates from stratified squamous epithelium; marked by production of keratin Transitional cell carcinoma – arises from transitional cell epithelium of urinary tract Adenocarcinoma – a carcinoma of glandular epithelium

Metastatic Carcinoma Most common malignancy found in bone (NOT osteosarcoma, giant cell tumor, chondrosarcoma, multiple

myeloma) - Most bone CA came from somewhere else. Sarcoma:

Malignant tumor of mesenchymal origin. Think liposarcoma. Usually metastasize via blood EXs: osteosarcoma (bone), leiomyosarcoma (smooth muscle), & liposarcoma (adipose tissue)

Cancer Facts/Figures Men

Most common = Lung > Colorectal > Prostate Highest Mortality = Lung > Colorectal > Prostate

Women Most common = Breast > Lung > Colorectal Highest Mortality = Lung > Breast > Colorectal

IN general Cancer is the second leading cause of death in the US (Heart disease is 1st)

Lung cancer:

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Most common cause of cancer in men Most common cause of cancer death in women and Men Affects males 4x more than females—outdated????

But in the past 30 years, the mortality rate for women has increased Most common types:

Adenocarcinoma – • Most common primary malignancy of the lung

Epidermoid (SCC) ♦ Most forms arise from lining epithelium of the tracheobronchial tree

• SCC of lung associated endocrine effect of hyperparathyroidism; calcitonin Small cell (oat cell) – 25%

• Most commonly associated with Paraneoplastic Syndrome Large cell (anaplastic) – 15%

Most arise from main bronchus & are therefore termed bronchogenic carcinomas Primary malignant neoplasm of the lung, originating from transformed epithelium of bronchial tree walls Main symptom – persistent cough (smoker’s cough)

Other signs & symptoms – hoarseness, wheezing, dyspnea, hemoptysis, & chest pains ½ of the cancers are inoperable by the time pt is first seen in hospital First signs of lung cancer are often related to metastatic spread, particularly to the brain

Other areas include to endocrine glands, skin, liver, & bones Metastasis is through lymphatic channels Metastasis to lungs commonly from breast, colon, prostate, kidney, thyroid, stomach, cervix, rectum, testis, bone, & skin Etiologic agents in causation of lung cancer: cigarette smoking, industrial & air pollutants, familial susceptibility

Other diseases due to smoking: Chronic obstructive pulmonary disease, which includes emphysema, chronic bronchitis Carcinoma of the larynx and oral cavity

Dx for a pt with a hx of smoking, dysphonia, dysphagia, and weight loss Increased incidence of carcinoma of the esophagus, pancreas, kidney, & bladder Peptic ulcer disease Low birth weight infants

NOT – 5 things • STOMACH or COLON CANCER, CHRONIC GASTRITIS (Acute?), or Acute Respiratory Distress Syndrome

- smoking has nothing to do with GI tract beyond the esophagus. Carcinogens

Most potent is Benzopyrene Benzopyrene is a very potent carcinogen found in cigarette smoke

Binds to existing DNA bases & causes frame-shift mutations Breast Cancer:

Most common cancer affecting women # 2 Killer of women ages 35-54 Second to Lung Lifetime risk: 1 out of 11 ¾ Rare before age 25 & increasingly more common w/ age until menopause – incidence then slows down

Almost always an adenocarcinoma Factors increasing risk: from Wikipedia

Age (40+) Nulliparity Family Hx

• Strongest association – family Hx, specifically breast cancer in 1st-degree relatives (mother, sister, daughter) Early menarche Late menopause Fibrocystic disease Previous Hx of breast cancer Obesity (but NOT Estrogen deficiency or silicone implants)

• Younai says silicone implants for sure increased risk!! • Wikipedia begs to differ with Fariba, search ‘silicone implants’ and click on the risks link

Alcohol / Hormones – both are debated More common in left breast than right & more commonly in the outer upper quadrant –Boys are right handed!! Widespread metastasis can occur by way of lymphatic system & bloodstream, through right side of heart & lungs, eventually to

the other breast, chest wall, liver, bone, & brain A women with metastastic carcinoma of the jaws most likely came from Breast cancer

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Characterized by: Painless mass is usually the initial sign or symptom Retraction of skin or nipple Peau d’orange (swollen pitted skin surface) along w/ … Enlargement of axillary lymph nodes may also be present Increased pigmentation of the nipple

• NOT spontaneous acute redness, swelling, and tenderness of the breast Lymph node involvement is most valuable prognostic predictor With adjuvant therapy, 70-75% w/ negative nodes will survive 10+ years; only 20-25% of women w/ positive nodes Growth is influenced by hormones (same as Prostatic carcinoma)

Fibrocystic disease: Most common cause of a clinically palpable breast mass in women (28-44 y.o.) Signs & symptoms – lumpiness throughout both breasts Pain is common, especially prior to menstruation Non-malignant – may lead to increased risk of developing carcinoma

Teratoma: Tumor composed of multiple tissues (may contain elements of all 3 embryonic germ cell layers)

Includes tissues not normally found in the organ in which they arise Occurs most frequently in the ovary – here it is usually benign & forms dermoid cysts Also occurs commonly in testes – here it is usually malignant

Pancreatic Cancer Tumors MORE common in the HEAD (because obstructive) Carcinoma of the tail of the pancreas is the LEAST likely to cause acute pain Pt with this malignancy have the WORST Px of any malignancy Associated w/ ↑ serum concentration of carcinoembryonic antigen (CEA)

Colon & rectal cancer: Malignant neoplasm of colonic or rectal mucosa Almost always an adenocarcinoma 2nd most common cancer-causing death in men; 3rd most common cancer-causing death in women Disease is entirely treatable if caught early

Greatest 5 yr survival Rate @ 60% No single cause, but almost all begin as a polyp

Most colorectal carcinomas arise from Adenomatous polyps (NOT hemorrhoids, diverticula, etc) Associated w/ ↑ serum concentration of carcinoembryonic antigen (CEA) – and Pancreas Predisposing factors – adenomatous polyps, inherited multiple polyposis syndromes, long-standing ulcerative colitis, genetic

factors, & low fiber, high animal fat diet, more common in industrialized nations Rapidly increasing incidence w/ age, starting at age 40 Symptoms – rectal bleeding w/ diarrhea, abdominal pain, & weight loss

Tumors on the left side are more likely to cause symptoms Symptoms usually only occur in advanced states

Sigmoid colon – most common site (NOT TRANSVERSE) Sigmoidoscopy can disclose the majority of the tumors Tumors of descending colon usually cause constipation & are generally dx’d at an earlier stage than tumors ascending colon

Prostate cancer: 3rd most common cause of death from cancer in men of all ages Most common cause of death from cancer in men >75 y.o., common in men > 50 y.o., rarely found in men <40 y.o. Most are adenocarcinomas that arise in peripheral glands (posterior lobe)

Invade throughout prostate Most likely metastasize to Bone & other tissues (e.g., lungs)

• Clinical findings of prostatic cancer are often the mestastasis to the vertebral column (bone) Indication of ↑in serum Acid Phosphatase & PSA (prostate-specific antigen)

Lab findings – elevated levels of acid phosphatase & PSA Most prostate cancers are now found before they cause symptoms – due to PSA testing Prostate cancer – ↑ serum acid phosphatase with prostate cancer that metastisizes to bone

Unknown cause – relationship between high fat intake & increased testosterone levels (may be hormonally dependent – same as breast cancer)

Benign prostatic hyperplasia = Benign prostatic hypertrophy = Nodular hyperplasia of prostate: Very common in men over 50 May be due to an age-related increase in estradiol with possible sensitization of the prostate to the growth promoting effects of

DHT

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Characterized by a nodular enlargement of the periurethral (lateral and middle lobes) of the prostate gland, compressing the urethra into a vertical slit

Often presents with increased frequency of urination, nocturia, difficulty starting and stopping the stream of urine, dysuria May lead to destruction and hypertrophy of the bladder, hydronephrosis, and UTIs **NOTE: hypertrophy is a misnomer in this case, because the increase in size is due to hyperplasia Benign enlargement of prostate gland due to hyperplastic nodules of stroma & glands distorting the prostate Compresses urethra & causes urinary tract obstruction Complications –

Pyelonephritis, hydronephrosis, & painful or difficult urination (dysuria) • Chief complication is urinary obstructions

Not considered to be premalignant (LEAST possible complication) Not malignant or inflammatory – usually progressive & may lead to obstruction of the urethra 65 yr old male who can’t void bladder and has urinary retention

Rhabdomyosarcoma: Malignant neoplasm derived from skeletal (striated) muscle

NOTE: neoplasms of muscles are rare & usually malignant Affects throat, bladder, prostate, or vagina in infants & large muscle groups of arm & leg in the elderly Prognosis is poor

Rhabdomyoma – Benign tumor arising from voluntary muscle Can arise in any skeletal muscle & produce a mass in the affected muscle

Leiomyoma (aka fibroid): Benign tumor derived from smooth muscle Occurs anywhere in body but most frequently in the myometrium of the uterus

Most common tumor of women – 25% of women >30 y.o. (during the reproductive years) Other areas (less frequent) – stomach, esophagus, & small intestine

Prognosis is good Cause of fibroid tumors of uterus is unknown

Suggested that fibroids may enlarge w/ estrogen therapy (such as oral contraceptives) or w/ pregnancy Growth depends on regular estrogen stimulation – rare before age 20 & shrinks after menopause Fibroid will continue to grow as long as women menstruates, but growth is slow

Uterine fibroids – most common pelvic tumor – present in 15-20% of reproductive-age women, 30-40% of women > 30 y.o. Endometrial Carcinoma/Uterine Cancer

Risk factor is Hyperestrogenism Cervical Cancer

Predisposed by Multiple sex partners, Having Sex with Uncircumcized Males, Smoking, HIV, Chlamydia, Oral Contraceptives, Lots of pregnancies, Early age of Intercourse, HPV NOT Early Menarche

• Early Menarche ♦ Risk factor for,

The ones involved in the Menses Process Endometrial (uterine), Ovarian, Uterine Sarcoma, Breast (sensitive during Menses)

Keratoacanthoma: Relatively common low grade malignancy that originates in the pilosebaceous glands Pathologically resembles SCC Characterized by rapid growth over a few wks to months, followed by spontaneous resolution over 4-6 months in most cases Etiologic factors – sunlight, chemical carcinogens, trauma, HPV, genetic factors, immunocompromised status Can (rarely) progress to invasive or metastatic carcinoma

Aggressive surgical Tx is advocated Dermatofibromas:

Benign neoplasms that appear as small, red-to-brown nodules that result from fibroblast accumumlation Acrochordon (aka skin tag):

Extremmly common lesion – most often found on neck, in armpit, or groin Actinic keratosis:

Premalignant epidermal lesion caused by excessive chronic sunlight exposure NOTE: don’t get clowned by verrucus vulgaris (wart) as an option for “What is generally considered precancerous?”

Common in light-skinned elderly people Seborrheic keratosis (aka seborrheic warts):

Extremely common benign neoplasm of older people Flesh-colored, brown, gray, or black growths that can appear anywhere on skin

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Think “gray, scaly, & greasy” (typical appearance) Acanthosis nigricans:

Cutaneous disorder marked by hyperkeratosis & pigmentation of axilla, neck, flexures, & anogenital region More than ½ of these pts have cancer (GI carcinomas, particularly of the stomach)

More skin disorders (while we’re here): Dermatitis:

Group of inflammatory pruritic skin disorders Etiology: allergy (usually type IV hypersensitivity), chemic injury, or infection

Psoriasis: Nonpruritic chronic inflammation of the skin, particularly on the knees and elbows Associated w/ HLA-B27, HLA-13, etc Auspitz sign: seen when removal of scale results in pinpoint areas of bleeding Treat w/ topical steroids & UV irradiation

Bullous pemphigoid: Autoimmune disorder w/ IgG antibody against epidural basement membrane (linear immunofluorescence). Similar to

but less severe than pemphigus vulgaris—affects skin but spares oral mucosa Pemphigus vulgaris:

Potentially fat autoimmune skin disorder. Intrdermal bullae involving the oral mucosa and skin. Findings: acantholysis (breakdown of epithelial cell-to-cell junctions), IgG antibody against epidermal cell surface.

Impetigo: Highly infectious skin infection most common in pre-school aged children during warm weather Results from epidermal invasion by Staph. aureus or Strep. pyogenes Similar to cellulitis, but more superficial Begins as an itchy, red sore that blisters, oozes & finally becomes covered w/ a tightly adherent crust

• Tends to grow & spread • Impetigo sores heal slowly & seldom scar

Impetigo is contagious – infection is carried in the fluid that oozes from the blister Rarely, impetigo may form deep skin ulcers Tx – mild infection typically treated w/ Rx antibacterial cream (Bactroban)

• Oral Abx (erythromycin or dicloxacillin) frequently prescribed – rapid clearing of lesions Cure rate is extremely high but often recurs in young children Acute glomerulonephritis – one of the more common renal diseases in children – an occasional complication of

impetigo Erythema multiforme (EM):

Type of hypersensitivity (allergic) IgM reaction occurring in response to medication, infections, or illness • Medications – sulfonamides, penicillin, barbiturates, & phenytoin • Infections – HSV & mycoplasma

Exact cause is unknown Believed to involve damage to BVs of skin w/ subsequent damage to skin tissues Fairly common, w/ a peak incidence in 2nd & 3rd decades of life May present w/ classic skin lesions over dorsal aspect of hands/forearms w/ or w/o systemic symptoms

• Classic lesion – a central lesion surrounded by concentric rings of pallor & redness (“target”, “bull’s eye” shape) Stevens-Johnson syndrome:

• Severe systemic symptoms & extensive lesions involving multiple body areas (especially mucous MBs) Toxic epidermal necrolysis (TEN syndrome, or Lyell’s syndrome)

• Involves multiple large blisters (bullae) that coalesce, followed by sloughing of all or most of the skin & mucous MBs Lymphadenitis

Inflammation of a lymph node or nodes Lymphadenopathy

Any disease process affecting a lymph node or nodes The Q reads: Enlarged, tender, & inflamed lymph nodes are one form of….Lymphadenitis or Lymphadenopathy??? – 2000 Q86 Hodgkin’s lymphoma = Hodgkin’s disease (Ryan Hodges is nice not as malignant)

Malignancy characterized by painless progressive enlargement of lymphoid tissue 1st sign – often an enlarged lymph node that appears w/o a known cause Can spread to adjacent lymph nodes & later may spread outside lymph nodes - to lungs, liver, bones, or bone marrow Unknown cause BIMODAL (Also Think also HOMOzygous Histo) Affects 2x as many males as females; usually develops between ages 15-35 Splenomegaly is common

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Most important – presence of Reed-Sternberg cells (Ryan Hodges looks like a Reed) – the actual neoplastic cells (Reed S. cells are CD30+ & CD15+)

Heterozygous Histology is NOT characteristic of Hodgkin’s Symptoms – anorexia, weight loss, generalized pruritus, low-grade fever, night sweats, anemia, & leukocytosis

Prognosis – most favorable w/ early Dx & limited involvement & with lymphocytic predominance Believed to start as an inflammatory/infectious process & then become a neoplasm

Some believe it is an immune disorder 50% of cases are associated with EBV

Non-Hodgkin’s lymphomas = “malignant lymphomas” = “lymphosarcomas” Heterogenous group of malignant diseases originating in lymphoid tissue Associated with HIV and immunosuppression Most involve B cells Cause is unknown – some suggest a viral source Occur in all age groups; 2-3x more common in males More common than Hodgkin’s disease Present as solid tumors composed of cells that appear primitive or resemble lymphocytes, plasma cells, histiocytes

Small lymphocytic lymphoma: adult B cells, that clinically presents like CLL, low grade. Follicular lymphoma: (small cleaved cell): Adult B cells with t(14;18) chromosome, bcl-2 expression. It is difficult to

cure; indolent course; bcl-2 is involved in apoptosis Diffuse large cell: usually older adules, but 20% are children w/ 80% B cell and 20% T cells (mature). It is aggressive but

50% are curable Lymphobalstic lymphoma: children most often affected, T cells are immature. Commonly presents w/ ALL and

mediastinal mass; very aggressive T cell lymphoma Burkitt’s lymphoma:

• High-grade B-cell lymphoma (lymph gland tumor) classified as a non-Hodgkin’s type of lymphoma • EBV may be the cause of this lymphoma • The 1st human cancer that has been strongly linked to a virus • Undifferentiated malignant lymphoma that usually begins as:

♦ African form: (ENDEMIC FORM) 95% of cases associated w/ EBV Affects children of middle African regions Usually begins as a large mass in the jaw

♦ American form: Less closely associated w/ EBV Usually begins as an abdominal mass Jaw tumors are rare

♦ Both types are caused by defective B-cells • Children affected most, their B cells: t(18;14) c myc gene moves next to heavy chain Ig gene 14. • Starry sky appearance (sheets of lymphocytes w/ interspersed macrophages, associated w/ EBV; jaw lesions in

endemic form in Africa, pelvis or abdomen in sporadic form Mycoisis fungoides:

• Rare, persistent, slow-growing type of non-Hodgkin’s lymphoma originating from a mature T-cell • Affects the skin; may progress to lymph nodes & internal organs

1st indication – swollen lymph glands (lymphadenopathy), enlarged tonsils & adenoids; painless, rubbery nodes in cervical supraclavicular areas

Pt develops symptoms specific to involved area & systemic complains – fatigue, malaise, weight loss, fever, & night sweats Pathophysiologically similar to Hodgkin’s disease, but:

Reed-Sternberg cells are not present Specific mechanism of lymph node destruction is different

Biopsy differentiates Non-Hodgkin’s from Hodgkin’s

Hodgkin’s Non-Hodgkin’s Presence of Reed-Sternberg cells Non-Hodgkin’s associated w/ HIV and immunosuppression Localized, single group of nodes, extranodal rare; contiguous spread

Multiple, peripheral nodes;extranodal involvement common; noncontinguous spread

Constitutional signs/symptoms—low-grade fever, night sweats, weight loss

Majority involve B cells (except lymphoblastic T cell origin)

Mediastinal lymphadenopathy No hypergammaglobulinemia (cf., multiple myeloma, where excess B cells are in resting stage)

50% of cases associated w/ EB; bimodal distribution: young and Fewer constitutional symptoms

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old; more common in men except nodular sclerosis type Good prognosis = increase lymphocytes, low number of Reed Sternberg cells

Peak incidence 20 -40 years old

Ann Arbor staging of Hodgkin’s: HENCE Extranodal a definite possibility

I: single lymph node or single extralymph organ II: 2 or more sites, on same side of diaphragm III: 2 or more sites; on both sides of diaphragm IV: Disseminated

Which type of Hodkin’s is dx at Stage IV?? A: without constitutional symptoms B: with constitutional symptoms (fever, night sweats, weight loss)

Multiple Myeloma: A cancer of plasma cells arising in bone marrow (a monoclonal plasma cell w/ “fried-egg” appearance) or older aged adults Disease associated with proliferation of plasma cells showing “punched out” lesions Most common bone tumor arising from w/in the bone in adults Characterized by excessive growth & malfunction of plasma cells in bone marrow

Hyperglobulinemia • Produces large amounts of IgG (55%) or IgA (25%)

Growth of these extra plasma cells interferes w/ the production of RBC, WBC, & platelets • Causes anemia & susceptibility to infection

Clinical features: Anemia, pathologic bone fractures, increased susceptibility to infection (most common cause of death), increased

bleeding tendencies, anemia, hypercalcemia, renal failure, & amyloidosis Cancer cells produce osteolytic lesions throughout skeleton (flat bones, vertebrae, skull, pelvis, ribs) Renal failure is frequent complication – caused by excess calcium in blood from bone destruction

This increases the susceptibility of pt to infection & anemia Accounts for 1% of all cancers – mostly found in men >40 y.o. Earliest indication – severe, constant back & rib pain increasing w/ exercise – may be worse at night

The pain arises from pressure created by malignant plasma cells on nerves in the periosteum Radiographs – punched-out appearance & primary amyloidosis Bence Jones protein in urine & hypercalciuria

Result of light-chain dimers in urine Absence does not rule out multiple myeloma

Has monoclonal Ig spike (M-protein, also found in Waldenstrom’s macroglobulinemia) SIDENOTE on Waldenstrom’s:

• Neoplasms of lymphocytoid plasma cells that produce monoclonal IgM • Lacks the lytic bone lesions of multiple myeloma

Blood smear shows RBC stacked like poker chips (rouleaux formation) SKIN CANCER: General info:

Most common malignancy in U.S. Most to least common: Basal cell carcinoma – SCC – Malignant melanoma

Basal cell carcinoma (BCC): Most common skin malignancy in man

75% of all skin cancers – most common of all cancers in U.S. Derived from epidermal basal cells >90% occur on areas of skin regularly exposed to sunglight/UV radiation

Most common site is the upper face Invasive, ulcerative, often indurated, slow-growing & locally destructive – does NOT metastasize

53-yr-old pt with chronic, indurated lesion near the inner canthus Prognosis is good – usually cured by excision; radiosensitive (if necessary)

Px is Better than multiple myeloma, osteosarcoma, carcinoma of breast or esophagus Characterized by clusters of darkly staining cells w/ typical palisade arrangement of cell nuclei at periphery of cell cluster

Also has “pearly papules” in gross pathology Usually occurs in persons > 40 More prevalent in blond, fair-skinned males on skin exposed to regular sunlight/UV radiant Similar to SCC in that BOTH are:

Invasive Exhibit mitotic figures Cured by early excision

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• Incorrect: readily metastasize, commonly occur in the oral cavity LEAST likely to metastasize (among neuroblastoma, chondrosarcoma, epidermoid carcinoma, or mucinous adenocarcinoma)

Squamous Cell Carcinoma (SCC): Involves cancerous changes to keratinocytes – middle portion of epidermal skin layer Usually painless initially – may become painful w/ development of non-healing ulcers May begin on normal skin; skin of a burn, injury, or scar; or site of chronic inflammation

Commonly found on hands & face Most often originates from sun-damaged skin areas, such as actinic keratosis

Actinic keratosis is a precursor to SCC Usually begins > age 50 Usually metastasizes via lymphatics Malignant & more aggressive than basal cell carcinoma, but still may grow slowly Also associated w/ chemical carcinogens (e.g., arsenic) & radiation Most often locally invasive – but SCC can infiltrate underlying tissue or metastasize in lymphatic channels Oral Cancer (squamous cell) most commonly resembles the most common form of cervical cancer in histology &

behavior Adenocarcinoma is the most common primary malignant neoplasm of the lung Histopathologically contains squamous / epithelial / keratin pearls and intercellular bridges

Resemble prickle cells & form keratin pearls Malignant epithelial cells have ↑ # of laminin receptors

Laminin (a glycoprotein) = major component of basement MBs??????? • Has as numerous biological activities including promotion of cell adhesion, migration, growth & differentiation • IS in the ECM, where as tubulin is NOT, remember laminins in the lamina lucida!!

Malignant melanoma: Involves the melanocytes – produce melanin – responsible for skin & hair color Can spread very rapidly Most severe & most deadly skin cancer – leading cause of death from skin disease May appear on normal skin OR may begin at a mole (nevus) or other area that has changed appearance Relevance to prognosis of pt:

Depth of invasion has the GREATEST relevance to Px • Vertical invasion or growth is related to Px of Melanoma

Degree of pigmentation has the LEAST relevance to Px Multiple biopsies Sex of the pt Palpable lymphadenopathy

Some moles that are present at birth may develop into melanomas Development is related to sun exposure, particularly to sunburns during childhood

Most common among people w/ fair skin, blue or green eyes, & red or blonde hair Depth of tumor correlates w/ risk of metastasis Four Types:

Superficial spreading melanoma (most common): • Usually flat & irregular in shape & color, w/ varying shades of black & brown • May occur at any age or site • Most common in Caucasions

Nodular melanoma: • Usually starts as a raised area – dark blackish-blue or bluish-red (although some lack color) • Poorest prognosis

Lentigo maligna melanoma: • Usually occurs in the elderly • Most common in sun-damaged skin on face, neck, & arms • Abnormal skin areas are usually large, flat, & tan w/ intermixed areas of brown • Develops from preexisting lentigo maligna (Hutchinson freckle)

Acral lentiginous melanoma: • Least common form of melanoma. • Usually occurs on palms, soles & under nails • More common in African Americans

Tumor growth patterns w/in skin: Initial radial growth (do not metastasize) – characteristic of spreading types Vertical growth (metastasis may occur) – characteristic of nodular melanoma

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Tumors of the adrenal medulla: 1) Pheochromocytoma:

Chronic chromaffin-cell tumor of the adrenal medulla that secretes an excess of epinephrine & norepinephrine • Results in severe HTN, increasd metabolism, & hyperglycemia • Endocrine effect of HTN

Common between ages 30-60 – most common tumor of adrenal medulla in adults If tumor is derived from extra-adrenal chromaffin cells, it is called a paraganglia (metastasis is more common in this

tumor) Episodic hyperadrenergic symptoms: 5 P’s—Pressure (elevated BP); Pain (headache), Perspiration; Palpitations;

Pallor/diaphoresis Rule of 10s 10% are malignant, bilateral, extraadrenal, calcify, kids, familial Tx with alpha antagonists, especially pheoxybenzamine, a nonselective irreversible alpha blocker May be a part of or associated w/ MEN II and III(multiple endocrine neoplasia), neurofibromatosis (von Recklinghausen’s

disease) or von Hipple-Lindau disease (multiple hemangiomas) 2) Neuroblastoma:

Highly malignant tumor of early childhood – most common malignant tumor of childhood & infancy • Think NEUW and BLASTIC

Usually originates in the adrenal medulla, but it can go anywhere on the sympathetic chain Complications – invasion of abdominal organs by direct spread & metastasis to liver, lung or bones First symptoms in many children – large abdomen, sensation of fullness, & abdominal pain

• These are followed by an abdominal mass ~90% of neuroblastomas produce hormones, such as epinephrine, which can ↑ HR & cause anxiety I think it has highest incidence in Causcasians

NOT schwannoma, Wilms’ tumor, carcinoid tumor Multiple endocrine neoplasm: all have auto dom characteristic, II, and II have ret gene association

Think MEN have large Adam’s apple or THYROID MEN type I (Wermer’s syndrome):

three P organs, pancreas, pituitary, and parathyroid. Presents w/ kidney stones and stomach ulcers. MEN type II (Sipple’s syndrome): -- Sipping get to your thyroid

medullary carcinoma of the thyroid, pheochromacytoma, parathyroid tumor, or adenoma MEN type III (Formerly MEN IIb):

medullary carcinoma of the thyroid, pheochromocytoma, and oral and intestinal ganglioneuromatosis Increased incidence of medullary carcinoma of the thyroid with pts suffereing from MEN type III

Von Hippel-Lindau disease (neurofibromatosis II): Characterized by hemangiomas of the retina, medulla, & the cerebellum Associated w/ cysts of liver, kidney (bilateral renal cell carcinomas), adrenal glands, & pancreas Autosomal dominant associated w/ VHL gene (tumor suppressor on chromosome 3 (3p)

Bone tumors: Most are secondary (caused by seeding from a primary site) – From Stomach, Ovary, and Colon Primary tumors are more common in males, usually children & adolescents – some types occur in persons ages 35-60 They may originate in osseous or nonosseous tissue

Osseous bone tumors arise from bony structure itself Non-osseous tumors arise from hematopoietic, vascular, or neural tissue

Primary malignant bone tumors (aka sarcomas of bone) Rare, constituting less than 1% of all malignant tumors

Metastatic bone tumors Have spread to bone from original site elsewhere in the body Cancers most likely spread to bone – breast, lung, prostate, kidney, & thyroid cancers

In children, the most common types of bone tumors are Osteogenic & Ewings’s sarcomas Most common malignancy in bone is metastatic carcinoma

Bone tumors of osseous origin: Osteogenic sarcoma: (aka Osteosarcoma)

Most common Usually in males ages 10-30 Occurs most often in femur, but also tibia & humerus; occasionally, in fibula, ileum, vertebra, or Mn Tumor arises from bone-forming osteoblasts and bone-digesting osteoclast Most often in metaphysis of long bones Bone lesion w/ radiopaque structures radiating from the periphery Predisposing factors include: Paget’s disease, bone infarcts, radiation, and familial retinoblastoma – think Rb gene

Periosteal osteogenic sarcoma: Usually in females ages 30-40

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Occurs most often in distal femur, may also be in humerus, tibia, & ulna Develops on bone surface (instead of interior) & progresses slowly

Chondrosarcoma: Usually in males ages 30-50 Occurs most often in pelvis, proximal femur, ribs, & shoulder girdle Develops from cartilage & grows slowly Usually painless; locally recurrent & invasive May be from primary origin or from osteochondroma

Malignant giant cell tumor: Usually in females ages 18-50 Arises from benign giant cell tumor Found most often in long bones, more so in knee area (epiphysis) Locally aggressive tumore found around the distal femur, proximal tubial region Characteristic “double bubble” or soap bubble appearance on x-ray; spindle-shaped cells w/ multinucleated giant

cells Bone pain is the most common indication of 1° malignant bone tumors

Bone pain has greater intensity at night, is associated w/ movement & is dull & usually localized Bone tumors of nonosseous origin:

Ewing’s Sarcoma: Malignant tumor that can occur any time during childhood – usually develops during puberty during rapid bone growth

• NOTE: osteogenic sarcoma is another malignant tumor in kids – myeloma is not (Mark’s Dad). Characteristic of kids and Teens??? Ewing’s Sarcoma (I watched Patrick Ewing when I was in my teens) Usually in males ages 10-20 Usually originates in bone marrow & invades diaphyses of long & flat bones Usually affects lower extremeties, most often in femur, innominate bones, ribs, tibia, humerus, vertebra, & fibula Often metastasizes to lungs & other bones

• Metastasis in ~ 1/3 of children at time of Dx From anaplastic small blue cell malignant tumor Extrememly aggressive w/ early metastisis Few symptoms – most common is pain

• Pain is increasingly severe & persistent • Occasionally swelling at tumor site • Fever may also be present • Children may also have a pathologic fracture

Very radiosensitive tumor Also exhibits characteristic onion skin Often difficult to distinguish histologically from a neuroblastoma or reticulum cell sarcoma

Fibrosarcoma: Usually in males ages 30-40 Originates in fibrous tissues of bone Invades long or flat bones – femur, tibia, & Mn Also involves periosteum & overlying muscle

Chordoma: Usually in males ages 50-60 Derived from embryonic remnants of notochord Progresses slowly Usually found at end of spinal column & in spheno-occipital, sacrococcygeal, & vertebral areas Characterized by constipation & visual disturbances

Benign tumors of mesenchymal origin (& where they’re derived from): Leiomyoma – from smooth muscle – includes the uterine leiomyoma or fibroid tumor – most common neoplasm of women Rhabdomyom – skeletal muscle Lipoma – adipose tissue – most common soft tissue tumor Chondroma – cartilage Papilloma – surface epithelium (e.g., squamous epithelium of skin or tongue) Adenoma – glandular epithelium Myxoma – connective tissue Angioma – neoplasm of either blood or lymph vessels

Choristoma: Small, benign mass of normal tissue misplaced w/in another organ, such as liver tissue w/in intestinal wall

Hamartoma: Benign tumor-like overgrowth of cell types; regularly found w/in affected organ, such as a hemangioma

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Glioblastoma Multiforme: Most common type of astrocytoma

FIND OUT Malignant Myoepithelia is associated with cigarettes, asbestos, polyaromatic hydrocarbons?????

LEUKEMIAS Leukemia:

Form of cancer that begins in blood-forming cells of bone marrow Damaged leukocytes remain in immature form:

Become poor infection fighters Multiply excessively & do not die off Increased number of circulating leukocytes in the blood

Leukemic cells accumulate & reduce production of RBCs, platelets & normal leukocytes Prolongation of bleeding time in leukemia is a result of thrombocytopenia (reduced #s of platelets)

If untreated, surplus leukemic cells overwhelm the bone marrow, enter the bloodstream, & invade other parts of the body: Lymph nodes, spleen, liver & CNS

Behavior is different from other cancers, which usually begin in major organs & ultimately spread to bone marrow Classified by the dominant cell type & by the duration from onset to death

Incidence evenly split (50:50) between acute & chronic leukemias Can modify the inflammatory reaction Chemotherapy for leukemia predisposes for oral infections by C. albicans

Risk factors for leukemias:

Familial tendency Congenital disorders (Down syndrome [higher incidence of acute leukemias]; presence of Philadelphia chromosome [CML]) Leukemic pts have high Ab titer to EBV Ionizing radiation & exposure to benzene & cytotoxins (such as alkylating agents), some anti-cancer drugs

Acute leukemias: Rapid onset & progression: (few months) Sudden high fever, weakness, malaise, severe anemia, generalized lymphadenopathy, bone & joint pain Common in children

Most often seen in the under 20-yr-old age group Principal organ involved: bone marrow (along w/ liver & spleen) Characterized by immature, abnormal cells in bone marrow & peripheral blood

Frequently in the liver, spleen, lymph nodes, & other parenchymatous organs Fatal, unless treated quickly Petechiae & ecchymosis on skin & mucous MBs, hemorrhage from various sites; bacterial infections common Clinical picture is marked by:

Effects of severe anemia (fatigue, malaise) & thrombocytopenia

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Absence of functioning granulocytes (prone to infection/inflammation) Spleen & liver usually moderately enlarged Enlarged lymph nodes seen mainly in ALL

Lab findings: leukocytosis 30k-100k/mm3; immature forms (myeloblasts & lymphoblasts) predominate In 75% of cases of ALL, the lymphocytes are neither B- nor T-cells (they are called “null cells”) Untreated pts die w/in 6 months

Wth intensive therapy (chemo, radiation, & bone marrow transplants), remissions may last up to 5 years Death usually due to hemorrhage (brain) or a superimposed bacterial infection

Shorter, more devastating clinical course than chronic leukemias Are characterized by proliferations of lymphoid or hematopeoietic cells that are less mature than those of the chronic leukemias

Chronic leukemias: Slower onset & progression: w/ weakness and weight loss, disease may be detected during examination for some other

condition (e.g., anemia, unexplained hemorrhages, or recurrent intractable infection) Longer, less devastating clinical course than acute leukemias Develop in more mature cells – can perform some duties, but not well More difficult to treat in many cases Characterized by proliferations of lymphoid or hematopoeitic cells (more mature than those of acute leukemias) Organ involvement

Massive splenomegaly is characteristic of CML Lymph node enlargement in CLL

Petechiae & ecchymosis, recurrent hemorrhages, baceterial infections Lymphocytic anemia may be complicated by autoimmune hemolytic anemia Lab findings: leukocytosis >100k/mm3; mature forms (granulocytes and lymphocytes) predominate Philadelphia chromosome & low levels of leukocyte ALP alkaline phosphatase common in CML Median survival time:

CML – 4 years w/ death due to hemorrhage or infection CLL – runs a variable course (older pt may survive years even w/o Tx)

Major Types of Leukemias

Type Progression WBC affected % of Leukemias Age group ALL Rapid Lymphocytes 20 3-5 y.o. AML Rapid Myelocytes 27 Mostly adults CLL Slow Lymphocytes 31 > 60 y.o. CML Slow Myelocytes 22 Any age

Quick Notes on Several Leukemias:

ALL: Children/lymphoblasts Down’s

AML: Myeloblasts Auer rods

CLL: Elderly Very similar to SLL (small lymphocytic lymphoma)

CML: Massive splenomegaly Philadelphia chromosome (9,22)

Acute Lymphoblastic Leukemia (ALL): Most common type in children Peak age – 4 y.o. Characteristics: found in children, is most responsive to therapy and is associated w/ Down syndrome biologically distinct

has a t(15;17) that juxtaposes the RARα gene on chromosome 17 w/ the PML gene on chromosome 15 associated w/ frequent DIC responds to All-trans-retinoic acid

In the monoblastic type of leukemia (FAB M5) leukemic cells often infiltrate: Skin Gums, perianal area CNS

Treatment: Chemotherapy bone marrow transplant

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Allogeneic form causes graft vs. host disease But graft vs. leukemia can be beneficial

Prognosis depends on:

• age of patient • cytogenetic pattern of leukemic cells • previous exposure to radiation, benzene or chemotherapy (worse) • aggressiveness of post remission therapy

Overall about 70% of adults enter complete remission 10 yr old with ALL, has clinical features:

CNS infiltration related to headaches, vomiting, and palsies Bone pain secondary to leukemia infiltration of the marrow and periosteum Symptoms related to bone marrow suppression, including anemia and thrombocytopenia

• NOT multiple, acutely tender lymph nodes due to the central node ischemic necrosis Same pt, white cell count reveals no neutrophils, Why?

Bone marrow has been replaced by leukemic cells Acute Myeloid Leukemia (AML): Think AMbuLance labs (It’s the Worst)

Most malignant type Characteristics include: 9 FAB subtypes along myelocytic, monocytic, erythrocytic and megakaryocytic lines

Among the most aggressive malignancies of humans • If left untx’d can → death w/in 40 to 100 days from time of Dx

Most common acute leukemia in adults Etiological factors (possible) include: ionizing radiation, chemicals such as benzene and chemotherapeutic agents Symptoms & Signs: Petechiae, sternal tenderness, sometimes adenopathy, splenomegaly and hepatomegaly may be found,

testicular, cutaneous, and meningeal involvement as well Chronic Lymphoid Leukemia (CLL):

Least malignant type – L for Least and NODES Older adults (average age = 60 y.o.) Characterized by abnormal small lymphocytes in lymphoid tissue Affects men 2-3x more than women Presents w/ lymphadenopathy, hepatospenomegaly and few symptoms Takes an indolent course Increase in smudge cells in peripheral blood smear Warm Ab autoimmune hemolytic anemia Very similar to SLL (small lymphocytic lymphoma)

Q reads: On the basis of histo and transitions observed clinically, there appears to be a relationship between lymphocytic lymphoma and….. Lymphocytic Leukemia

Chronic Myeloid Leukemia (CML): Think M for Massive Spleen, cMl, and Ph chroMMMMosome Invariably fatal Most common in young & middle-aged adults (slightly more common in men); rare in children 90% of pt have Philadelphia, or Ph1 chromosome – the long arm of chromosome 22 is translocated, usually to chromosome

9 Induced by radiation, carcinogenic chemicals

Characterized by abnormal overgrowth of granulocytic precursors (myeloblasts & promyelocytes) in bone marrow, peripheral blood & body tissues Characterized by massive splenomegaly

Low-to-absent leukocyte alkaline phosphatase Cells resemble nearly normal granulocytes Two distinct phases of clinical course:

1) Insidious chronic phase – anemia & bleeding disorders 2) Blastic crisis or acute phase – rapid proliferation of myeloblasts, the most primitive granulocyte precursors

ENDOCRINE PATHOLOGY

HYPOTHALAMUS/PITUITARY Gigantism:

Oversecretion of GH in childhood before fusion of growth plates – leads to bone growth & abnormal height Acromegaly:

Chronic metabolic disorder caused by excessive amounts growth hormone (GH) Endocrine etiology

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Occurs after closure of the growth plates Cause of ↑ GH secretion – usually a benign tumor of pituitary gland “Somatotroph adenoma” of the pituitary gland in 30 yr old pt results in acromegaly

• Think GH = somatotropin Results in gradual enlargement of the body tissues – bones of face, jaw, hands, feet, & skull Usually begins between ages 35-55 Growth plates have closed, so bone becomes deformed rather than elongated Common findings:

Gradual marked enlargement of the head, face, hands, feet, & chest Excessive perspiration & offensive body odor Prognathism Enlarged tongue Deep voice

Dwarfism (pituitary dwarfs): Characterized by arrested growth Frequently pts have improperly formed or proportioned limbs & features Caused by undersecretion of GH

Diabetes insipidus (central): Rare condition caused by damage to hypothalamus (specifically, the supraoptic nuclei) or pituitary gland (posterior)

Due to lack of ADH (vasopressin) – produced in supraoptic nuclei (produced in the hypothalamus) & secreted by posterior pituitary

Damage may be related to surgery, infection, inflammation, tumor, or head injury Very rarely caused by a genetic defect

Body fluid volumes remain pretty close to normal so long as the pt drinks enough water to make up for increased clearance Polyuria, Polydipsia Large volumes of dilute urine High serum osmolarity Hypernatremia – Remeber ADH just allows water to leave and doesn’t mess with Na/K pump so relatively more Na left Marked by extreme thirst & excessive urine output caused by ADH deficiency normally limit amount of urine made Responds to exogenous ADH therapy

Nephrogenic diabetes insipidus: Rare disorder characterized by passage of large volumes of urine due to a defect of kidney tubules Specific kidney defect usually a partial or complete failure of receptors on kidney tubules that respond to ADH Excessive amounts of water are excreted w/ the urine, producing a large quantity of very dilute urine May be present at birth as a result of a sex-linked defect (congenital nephrogenic DI) Usually affects men (women can pass on the gene)

SIADH (Syndrome of Inappropriate ADH) Excessive water secretion Hyponatremia Serum hypo-osmolarity with urine osmolarity>serum osmolarity Causes Ectopic ADH (small cell lung cancer), CNS disorder/head trauma, Pulmonary disease, Drugs

ADRENAL GLANDS Addison’s disease:

Adrenal insufficiency Chronic adrenal disorder characterized by anorexia, hypoglycemia, hypotension, and hypovolemia, and skin

hyperpigmentation (increased MSH) Primary deficiency of aldosterone and cortisol due to adrenal atrophy Hormone deficiency caused by damage to the adrenal cortex Aka ‘primary adrenal hypofunction’ or ‘adrenal insufficiency’ Life-threatening condition caused by partial or complete failure of adrenocortical function May be the result of autimmune processes, infection, neoplasm, or hemorrhage in the gland > 90% of cortex must be destroyed before obvious symptoms occur, but it does involve all 3 cortical divisions (GFR) Characterized by

Nausea, vomiting, hypotension, and asthenia – feeling of being weak, but not really Insidious onset of weakness, fatigue, depression hypotension & bronzing of the entire skin

Oral signs: Consist of diffuse pigmentation of the gingiva, tongue, hard palate, & buccal mucosa = melanosis

• The most common oral manifestation of Addison’s is melanosis Pigmentation of oral tissues tends to persist – cutaneous pigmentation most likely disappears following therapy

Lab tests – low BP, low cortisol level, low serum Na+ & perhaps high serum K+

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What disease is associated with Na+ secretion in the urine? Addison’s - bc aldosterone can’t do it’s job. ACTH test: (aka corticotropin test)

• Measures pituitary gland function • *Pituitary releases ACTH which stimulates outer layer of adrenal cortex • *ACTH causes release of hydrocortisone, aldosterone, & androgen. – cortisol is most important • Used to determine if too much cortisol (Cushing’s syndrome) or not enough (Addison’s) is being produced • ACTH levels are high in Addison’s disease

Tx – cortisol administration Distinguished by secondary insufficiency, which has no skin hyperpigmentation

Waterhouse-Friderichsen syndrome: Catastrophic adrenal insufficiency & vascular collapse due to hemorrhagic necrosis of the adrenal cortex Rapidly progressing infection caused by N. meningitidis

Most often found in association w/ meningococcal meningitis Characterized by coagulopathy, hypotension, adrenal cortical necrosis, and sepsis (usually fatal) Produces severe diarrhea, vomiting, seizures

Cushing’s disease: Hyperfunction of the adrenal cortex Excess ACTH production (Also High IN addison’s, trying to compensate)

From pituitary adenomas, higher CNS stimulation CRH Or from tumors like small cell carcinoma of lung

Excess due to pituitary gland hyperplasa, adenoma, or carcinoma Unknown cause, Iatrogenic excess, is most common

From Cushing disease (primary pituitary adenoma); increased ACTH Primary adrenal hyperplasia/neoplasm; decreased ACTH Ectopic ACTH production (small cell lung cancer); increase ACTH

• Pulmonary neoplasm most likely to produce ACTH Iatrogenic; decrease ACTH

Signs: Think IRENE

• Typical habitus, moon faces, buffalo hump, truncal obesity, striae, and osteoporosis Increased body weight, edema, hypertension, osteoporosis and pathologic fractures, fatigabiliy, weakness, hirsutism,

amenorrhea, ecchymosis, personality change, hyperglycemia (from insulin resistance), hyopkalemia Dx: test urinary free Cortisol of suppression test w/ dexamethasone Tx: aims at source – if from pituitary—surgery, radiation (gamma knife), drugs, iatrogenic—taper carefully

Hyperaldosteronism: Primary (Conn’s syndrome):

Caused by an aldosterone-secreting tumor, resulting in HTN, hypokalemia, metabolic alkalosis, & low plasma renin Secondary:

Due to renal artery stenosis, chronic renal failure, CHF, cirrhosis, and nephritic syndrome. Kidney perception of low intravascular volume results in an overactive renin-angiotensin system. Therefore it is associated w/ high plasma renin

THYROID Thyroid Gland:

Secretion of T3 (triiodothyronin) & T4 (thyroxin) – controlled by pituitary gland & hypothalamus Thyroid disorders may result from defects in thyroid gland itself, & also from abnormalities of the pituitary or hypothalamus

Hyperthyroidism (thyrotoxicosis): -- Jared Corbridge Imbalance of metabolism caused by overproduction of thyroid hormone Characterized by exophthalmos, tachycardia, heat intolerance, and fine tremor, warm moist skin, and fine hair Caused by excessive production of T4 (thyroxin)

Thyroxin stimulates cellular metabolism, growth, & differentiation of all tissues Excess leads to high basal metabolism, fatigue, weight loss, excitability, ↑ temperature, & generalized osteoporosis

Premature eruption of teeth & loss of deciduous dentition Findings Increased TSH if primary, increased total T4, increased T4, and increased T3 uptake Graves’ disease (most common form):

Hyperthyroidism with thyroid-stimulating/TSH receptor antibodies Autoimmune disease occuring most frequently in women between ages 20-40 Arises following an infection or physical/emotional stress Symptoms:

• Diffuse Goiter • Range from anxiety & restlessness to insomnia & weight loss • Eyeballs may begin to protrude (exophthalmos) causing irritation & tearing

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Plummer’s disease (toxic nodular goiter): Arises from long-standing simple/Nodular goiter & occurs most often in the elderly Symptoms same as Graves’ disease BUT no protruded eyeballs Risk factors: female > 60 y.o. Never seen in children

Hypothyroidism: Characterized by weight gain, cold intolerance, lowered pitch of voice, mental/physical slowness, constipation, dry skin, coarse

hair, edema, positive nitrogen balance???—Hypothyroid pts are bigger so they keep it in, decrease in plasma bound iodine, decrease in iodine uptake by thyroid, and increased blood cholesterol NOT Increased oxygen consumption Another Q: Congenital hypothyroidism most likely causes delayed eruption of teeth – BUT Jared’s kid has HYPO

Underactivity of the thyroid gland May cause a variety of symptoms and may affect all body functions Normal rate of functioning slows down – causes mental & physical sluggishness Considerably more common in women Extreme hypothyroidism in adults = Myxedema Symptoms – fatigue, slowed speech, cold intolerance, dry skin, coarse, brittle hair, puffy face

Characterized by puffiness of face & eyelids, and swelling of tongue & larynx Skin becomes dry & rough, and hair becomes sparse Affected individuals also have poor muscle tone, low strength, & get tired very easily

Findings Increased TSH (sensitive test for Primary Hypothyroidism, decresed Total T4, Decreased T4, Decreased T3 uptake

Alleviated by administering thyroid hormones Risk factors – age >50, female, obesity, thyroid surgery, & exposure of the neck to x-ray or radiation Tx Hashimoto’s Disease:

Most common cause of hypothyroidism Caused by an autoimmune reaction against the thyroid gland (Thyroiditis) Common thyroid gland disorder Production of Ab/s in response to thyroid Ag/s & the replacement of normal thyroid structures w/ lymphocytes & lymphoid

germinal centers Onset is slow – may take months or years for condition to be detected Most common in middle-aged women & individuals w/ family Hx of thyroid disease Estimated to affect 0.1-5% of all adults in Western countries

Less common cause – failure of pituitary gland to secrete TSH (secondary hypothyroidism) Severe hypothyroidism in children leads to Cretinism:

Endemic cretinism occurs wherever endemic goiter is prevalent (lack of dietary iodine) • (Don’t get confused with the goiters of Grave’s and Plummers)

Sporadic cretinism is caused by defect in T4 foramtion or developmental faiulure in thyroid formation Retardation of growth & abnormal bone development due to lack of thyroid hormone Mental retardation is caused by improper development of the CNS If recognized early, it can be markedly improved by use of thyroid hormones Findings Pot-bellied, puffy faced child with protruding umbilicus and protuberant tongue Dental findings in child – underdeveloped Mn w/ an overdeveloped Mx, delayed eruption & retained deciduous teeth Mental retardation, delayed growth, and delayed tooth eruption – NOT caused by lack of GH (don’t get clowned)

PARATHYROID GLANDS 1° Hyperparathyroidism

Common; major cause is an adenoma (benign tumor of glandular epithelium) Lab findings – hypercalcemia, ↓ serum phosphate (because of diuresis), & ↑ serum ALP & serum PTH Clinical characteristics – cystic bone lesions (osteitis fibrosa cystica or von Recklinghausen’s bone disease), nephrocalcinosis,

kidney stone & peptic duodenal ulcers 43-year-old with radiolucencies (not associated with apices), and radiolucencies in humerus. Lab tests indicate elevated calcium,

but serum phosphorus and alkaline phosphatase are normal. She also has giant cells in her bone lesion Dx: hyperparathyroidism – Paget’s doesn’t have Giant Cell lesions

Signs/Symptoms Urolithiasis/Nephrolithiasis Elevated serum Calcium Central Giant-cell bone lesions Loss of lamina dura surrounding multiple teeth

• NOT tetany NOTE: Osteoporosis, giant cell granulomas, & metastatic calcification are manifestations of hyperparathyroidism 2° Hyperparathyroidism

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Caused by hypocalcemia of chronic renal disease Excessive urinary Ca2+ loss stimulates PT glands to undergo hyperplasia – due to feedback mechanism

Low calcium, high phosphate Resulting metabolic effects are identical to those w/ 1° Hyperparathyroidism REMBER PTH-related Peptide

3° Hyperparathyroidism Hyperparathyroidism that persists after definitive therapy for secondary

Hypoparathyroidism Most commonly caused by accidental surgery excision during thyroidectomy May result in tetany (from low Ca)

Pseudoparathyroidism Defective end-organ responsiveness to PTH

***SIDENOTE on Tetany:*** Clinical neurological syndrome characterized by muscle twitches, cramps & carpopedal spasm When severe, larygnospasm & seizures develop Usually associated w/ Ca2+ deficiency, Vit D deficiency or alkalosis Associated with Parathyroid Hypofunction Kills patient before other effects can develop Normally occurs when blood [Ca2+] reaches approximately 6 mg% (normal is ~10 mg%) – lethal at 4 mg% Chvostek’s sign: tapped with Chop stick

Tap the facial neve above mandibular angle, adjacent to earloble Facial muscle spasm causing upper lip to twitch confirms tetany

Trousseau’s sign: swordfighter Apply a BP cuff to the pt’s arm A carpopedal spasm causing thumb adduction & phalangeal extension confirms tetany

PANCREAS Diabetes Mellitus:

Recessive Inheritance Metabolic disease involving mostly CHOs & lipids Most common pancreatic endocrine disorder Caused by absolute insulin deficiency (type 1) or resistance to insulin action in peripheral tissues (type 2) Causes decrease in liver glycogen, hyperglycemia, glucosuria, and polyuria Classic traid of symptoms = Polydipsia, Polyuria, & Polyphagia

Usually leads to Dehydration or Acidosis Coma, death Only ½ of pts are ever diagnosed More common in blacks, especially females; American Indians Characterized by:

Hyperglycemia, glycosuria, Hyperlipemia, and Ketonuria Increased susceptibility to infection, increased fatigability, recessive inheritance, and polyuria

Signs & symptoms: Non-specific—fatigue, weakness, polydipsia, polyuria, skin lesions-including fungal infections of skin & mucous MBs

Chronic Manifestations • Small vessel disease thickening of BM, retinopathy, nephropathy • Large vessel atherosclerosis, coronary artery disease, peripheral vascular occlusive disease, gangrene, CV disease • Neuropathy • Cataracts, glaucoma

Susceptibility to infections, neuropathies, impotence, ketoacidosis, lipid metabolism abnormalities including atherosclerosis

Long term complications of poorly controlled type I diabetes: Hyaline arteriosclerosis, Proliferative retinopathy, Nodular glomerulosclerosis, peripheral symmetry neuropathy

• NOT Pancreatic Carcinoma Hyperglycemia increase intercellular sorbitol, which is in turn associated with depletion of intracellular myoinositol levels Diabetics are a high-risk group for the following infections:

Klebsiella pneumonia Sinus mucormycosis Malignant otitis externa (P. aeruginosa) Chronic osteomyelitis

Sudden onset of a seizure in a non-compliant type I diabetic would be most likely due to hypoglycemia also from hypocalcemia – NOT from ketoacidosis

Pt takes insulin in the am, goes jogging, then comes into the dental office with symptoms of anxiety and is just not his usual self Pt is Hypoglycemic He forgot to eat.

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Hb A1c – plays role in long-term glucose control Dx:

Fasting serum glucose, glucose tolerance, HbA1c impaired fasting glucose is over 100 after 8 hrs of fasting and oral glucose load is over 200 after 2 hours

Tx: diet, oral hypoglycemics, insulin, weigth loss, transplantation, and vigilance for complications Type 1 DM:

Usually diagnosed in childhood Diminished beta-cell mass Body makes little to no insulin Daily injections of insulin are required to sustain life Three etiologic mechanisms:

• Viral infection, genetic predisposition, autoimmune response Type 1 vs. Type 2 Diabetes Mellitus

Characteristic Type 1 Diabetes Type 2 Diabetes Level of insulin secretion None or almost none May be normal or exceed normal Typical age of onset Childhood <30 Adulthood >40 Percentage of diabetics 10–20% 80–90% Basic defect Destruction of B-cells Reduced sensitivity of insulin’s target cells Associated w/ obesisty No Usually Speed of development of symptoms Rapid Slow Development of ketosis Common if untreated Rare Treatment Insulin injections, dietary management Dietary control & weight reduction;

occasionally oral hypoglycemic drugs Concordance in identical twins 50% 100% Genetic predisposition Weak, polygenic Strong, polygenic Association with HLA system Yes (HLA DR 3 and 4) No Beta cell numbers in islets Reduced Variable Classic symptoms of 3 Polys Common Sometimes Diabetic Ketoacidosis

One of the most complications of DM Type I Usually due to an increase in insulin requirements from an increase in stress (i.e. infection) Excess fat breakdown and increased ketogenesis from the increase in free FAs, which are then made into ketone bodies Signs

Kussmaul Respirations (Rapid/deep breathing), hyperthermia, nausea/vomiting, abdominal pain, psychosis/dementia, dehydration, Fuity breath odor

Labs Hyperglycemia, Increased H+, Decreased HCO3-, Increased blood ketone levels, leukocytosis

Complications Life-threatening mucormycosis, Rhizopus infection, cerebral edema, cardiac arrhythmias, heart failure

Tx Fluids, insulin, and potassium, glucose is necessary to prevent hypoglycemia

EYES Ocular trachoma:

Eye infection caused by Chlamydia trachomatis Incubation period of 5-12 days – begins slowly as conjunctivitis (pink eye)

If untreated, may become chronic & lead to scarring If eyelids are severly irritated, eyelashes may turn in & rub against cornea

This can cause eye ulcers, further scarring, visual loss, & even blindness Occurs worldwide – primarily in rural settings in developing countries (rare in U.S.)

Leading cause of blindness in developing countries Frequently affects children, although the consequences of scarring may not be evident until later in life

Inclusion conjunctivitis: Conjunctivitis caused by Chlamydia trachomatis Often affecting newborns – also contracted by adults in swimming pools or during sexual contact

I wonder what happens if someone has sexual contact in a swimming pool…? Characterized by enlarged papilla on inner eyelids & a purulent discharge Chronic inflammation/hypertrophy of conjuctiva – forms grayish, yellowish translucent granules

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Pinkeye: Aka “acute contagious conjunctivitis” Acute, contagious form of conjunctivitis caused by Hemophilius aegyptius Characterized by inflammation of eyelids & eyeballs w/ a mucopurulent discharge

Keratoconjunctivitis Sicca: Long-standing dryness of both eyes, leading to dehydration of conjunctiva & cornea NOTE: dry eyes may be a symptom RA, SLE or Sjogren’s syndrome

Herpes conjunctivitis Specific chemotherapy is used to tx it (NOT used to tx measles, smallpox, hepatitis, IM)

IMMUNO DISEASES

Sarcoidosis: Characterized by immune-mediated, widespread noncaseating, non-necrotizing granulomas where TB is Caseating and

elevated serum ACE levels TB–Caseating, Necrotizing Crohn’s disease – NON-caseating, NON-necrosis, granulomatous inflammation of the gut wall

Common in black females GRAIN: gammaglobulinemia, rheumatoid arthritis, ACE increase, Interstitial fibrosis, Noncaseating granuloma Associated w/ restrictive lung disease, bilateral hilar lymphadenopathy, erythema nodosum, Bell’s palsy, etc

IMMUNODEFICIENCIES (as outlined in Kaplan) PRIMARY IMMUNODEFICIENCY DISEASES

Selective IgA deficiency: The most common immunodeficient state Low levels of IgA

Common variable (B lymphocyte hypogammaglobulinemia: B cells normal, but fail to differentiate into plasma cells Low circulating Ab levels

X-linked (Bruton’s) agammaglobulinemia: Rare, sex-linked, & results in decreased production of Ab/s Tx involves repeated administration of IgG to maintain adequate Ab levels in blood IgM, IgG, IgA, IgD, IgE, & circulating B-cells are absent or deficient (T-cells are intact) Almost exclusively affects males Causes severe, recurrent bacterial infections during infancy (mostly pyogengic bacteria) Results from failure of B-cells to mature & differentiate into plasma cells (which produce Ab/s)

• Think B for Bruton’s, B-cell deficient, and Bacteria infections • Pre-B cells are normal – B cells are absent • Failure to mature is caused by a mutation in the B-cell protein tyrosine kinase

Tx with Giving Gamma Globulins Normal cell-mediated immunity

• Adequate host defense mechanisms exist for resistance to…virus infections (NOT bacterial or fungal) ♦ Remember viruses are in the cell, so usually T-cell mediated ♦ Viruses enter, start production, then MHC I is made in rER!!!!!!

MHC II, deals more with cells eating Bad bugs of bacteria • ***The pt is just missing gamma globulins

DiGeorge Syndrome: T-- George Think T for Thymic aplasia, T-cell deficiency, Tetany due to hypocalcemia – You need Vitamin D-George!!!! Thymic hypoplasia or aplasia Remember you’re BORN with it Rare immunodeficiency disorder characterized by various congenital abnormalities arising late in fetal development

• The causative defects occur in areas known as the 3rd & 4th pharyngeal pouches • These pouches develop into the thymus & parathyroid glands (which may be missing or underdeveloped) • Development abnormalities may also occur in the 4th branchial arch

Primary problem is the repeated occurrence of various infections due to a diminished immune system • Prone to viral & fungal infections – T cell GUYS!!!

Absence of thymus results in T-cell deficiency • These children have normal B-cells & form antibodies • They have decreased or absent delayed-type hypersensitivity

Absence of parathyroids causes hypocalcemia – leads to development of tetany Severe Combined Immunodeficiency Disease (SCID):

Most dangerous type of congenital (inherited) immunodefieicency Defects in lymphoid stem cells (results from failure of stem cells to differentiate properly)

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• Pts have neither B-cells nor T-cells • Pts are incapable of any immunological response • Children usually die before 2 y.o.

ACQUIRED IMMUNODEFICIENCY DISEASES AIDS = acquired immunodeficiency syndrome

See HIV in virus section for more info Caused by HIV (a lentivirus)

• The viral MB contains a transMB protein, gp160 • gp160 is usually detected by Western blot analysis as 2 fragments – gp41 & gp120

Characterized by a profound loss of CD4+ T cells • The virus can also infect CD4+ cells (macrophages & astrocytes)

Cellular consequences: • T cells: loss of CD4+ T cells AND decrease in response of T cells to Ag AND impaired cytokine production • B cells: steadily lose ability to mount an effective Ab response to new Ag/s

Diagnosis: • ELISA – detects Ab/s to HIV • Western blot – confirmatory tests

Associated with: • Loss of cellular immunity defenses • Alteration of Helper T/Suppressor T ratio • Increased susceptibility to opportunistic infections

Results in Opportunistic infections, i.e.: • Pneumocystis carinii

♦ Most common cause of pneumonia in AIDS pts • Mycobacterium avium intracellulari • Malignant neoplasms:

♦ Kaposi’s sarcoma ♦ Non-Hodgkin’s lymphoma

NOT Bronchogenic or Testicular Carcinomas, Neuroblastoma, Rhabdomyosarcoma, or Mycosis fungoides PHAGOCYTIC CELL DISORDERS

Neutropenias Cyclic, Hereditary, or Acquired

Opsonic defects Chemotactic defects

AUTOIMMUNE DISEASES Autoimmune disorders

Mechanism or cause of autoimmune diseases is not fully known Arise by way of:

Release of sequestered antigen Cross rxn between exogenous and self-antigens Loss of T-suppressor activity against autoreactive (forbidden) clones

• NOT from persistant depression of the immune system Systemic Lupus Erythematosus (SLE):

Chronic, inflammatory autoimmune disorder that may affect many organ systems (skin, joints, kidneys, heart, blood, & CNS) Results in episodes of inflammation in joints, tendons, & other CT & organs Appears most often between ages 10-50

90% of SLE cases are in women in late teens to 30s May be caused by certain drugs (drug-induced lupus erythematosus) – usually reversible when medication is stopped Disease course varies from mild episodic illness to a severe fatal disease Symptoms vary widely in a particular pt over time:

Fever, fatigue, weight loss, arthritis, malar rash, photosensitivity, pleuritis, pericarditis, or non-bacterial endocarditis, Raynaud’s, Wire LUP (loop) lesions in kidney with immune complex deposition • NOT clubbing or cyanotic digits (Polycythemia, congenital heart disease, congestive heart failure, chronic pulmonary

disease DO) – Remember Raynaud’s is just from Cold, emotion SLE causes LSE (Libman-Sacks Endocarditis) Valvular vegetations found on both sides of mitral valve, No

embolizations Characterized by periods of remission & exacerbation At onset, perhaps only one organ system involved Renal failure commonly occurs & is the usual cause of death Severe CNS involvement may appear

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Acrocyanosis (Raynaud’s phenomenon) – often associated w/ SLE Immunosuppressive therapy and corticosteroids medication allow prolonged survival Characteristic auto-antibodies:

Positive ANA Anti-dsDNA & Anti-Sm Ab/s appear to be specific for SLE

Butterfly rash over cheeks & bridge of nose affects ~ ½ of pts w/ SLE – rash worsenes w/ sunlight A more difuse rash may appear on other body parts exposed to sunlight

False positives on syphilis tests (RPR/VDRL) Scleroderma (progressive systemic sclerosis-PSS)

Excessive fibrosis & collagen deposition throughout the body Damage is done to small BVs

75% female Commonly sclerosis of skin but also of cardiovascular and GI systems & kidney NOTE: Most common characteristic lesion of rheumatic fever, scleroderma and RA is Fibrinoid degeneration 2 categories:

Diffuse scleroderma: • Associated with anti-Scl-70 antibody • Widespread skin involvement, rapid progression, early visceral invovlement

CREST: (Remember the Teradactyl) • Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia • Limited skin involvement, confined to fingers and face. • More benign clinical course • Assoicated w/ anticentromere Ab/s – pathognomonic for CREST

Sjogren’s syndrome: 2nd most common autoimmune rheumatic disorder after RA Occurs mainly in women (90% of patients) – mean age is 50 Characterized by diminished lacrimal & salivary gland secretion (sicca complex)

These glands have chronic inflammation caused by WBC infiltration Usually progresses to fibrosis & atrophy of these glands

Triad of findings: 1) Associated CT disorders (e.g., rheumatoid arthritis)

• Chronic arthritis 2) Xerostomia (dry mouth)

• May cause rampant caries reminiscent of radiation caries (due to shift toward more acidogenic microflora) • Parotid enlargement

3) Keratoconjunctivitis Sicca (dry eyes) All three rarely occur in one patient Definite Dx made only when at least two symptoms are present

Occasionally the lymphocytic infiltration is massive, causing enlargement of the glands (called Mikulicz’s syndrome) Increased risk for B-cell lymphoma

Sicca syndrome: dry eyes, dry mouth, nasal and vaginal dryness, chronic bronchitis, reflex esophagus AMYLOIDOSIS Amyloidosis:

Rare, chronic condition related to abnormal production of Ig by plasma cells Characterized by deposition of amyloid protein in the extracellular space of various organs & tissues Results in accumulation of an abnormal fibrillar scleroprotein (amyloid) which infiltrates body organs and soft tissues

In the tongue • Amyloid deposits are primarily in the stromal CT

Usually affects adults – middle-aged & older Renal disease is often the 1st manifestation Displays “apple-green” birefringence under polarized light w/ Congo red stain Forms:

Primary: • Cause unknown • Associated w/ abnormalities of plasma cells (as is multiple myeloma, which may be associated w/ amyloidosis) • Typical sites of amyloid buildup – heart, lungs, skin, tongue, thyroid gland, intestines, liver, kidney, & BVs

Secondary: • Amyloidosis is secondary to another disease such as TB, RA, or familial Mediterranean fever • Amyloid buildup – spleen, liver, kidneys, adrenal glands, & lymph nodes (heart rarely involved)

Hereditary:

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• Affects nerves & certain organs; has been noted in people form Portugal, Sweden, & Japan NOTE: Alzheimer’s disease, Type 2 DM, & Familial Mediterranean fever are amyloid associated conditions

Amyloid deposits characterize all of them (EX – Type 2 DM: amyloid deposits in islet cells) TRANSPLANTATION & TUMOR IMMUNOLOGY Graft types –

Autograft: Surgical transplantation of any tissue from one location to another in the same individual Type of maxillofacial bone graft with best success Aka – autogenic graft, autologous graft, autoplastic graft or auto transplant

Isograft: Composed of tissues taken from an individual of the same species who is genetically identical (e.g., identical twins)

Allograft: Tissue taken from a genetically unrelated individual of the same species Aka allogenic graft, homologous graft, or homoplastic graft

Xenograft: Tissue from another species used as a temporary graft in certain cases, as in treating a severely burned patient

• Quickly rejected but provides a cover for the burn for the first few days In skin graft rejection, the major host response is a cell-mediated immune response (delayed type IV

hypersensitivity) Reaction Types

Hyperacute rejection Antibody mediated due to the presence of preformed anti-donor antibodies in the transplant recipient Occurs within minutes after transplantation

Acute rejection Cell mediated due to cytotoxic T lymphos reacting against foreign MHCs Occurs week after implantation Reversible with immunosuppressants such as cyclosporine and OKT3 Primary tissue transplants, such as allogenic skin, kidney or heart, are most commonly rejected due to:

• Cell-mediated immune responses to cell-surface autoantigens Chronic rejection

Antibody-mediated vascular damage (fibrinoid necrosis) Occurs months to years after transplantation Irreversible

Graft vs. Host Disease Grafted immunocompetent T cells proliferate in the irradiated immunocomprmised host and reject cells with “foreign”

proteins, resulting in severe organ dysfunction Major symptoms include a maculopapular rash, jaundice, hepatosplenomegaly, and diarrhea Most feared consequence of graft therapy in immunodeficient pts is graft vs. host reaction

♦ Usually occurs when graft contains its own viable lymphoid cells Cyclosporin A has been used to control these adverse transplant events (T cell suppressor) When a graft is rejected once & a graft from the same donor is tried, it will be rejected more rapidly the 2nd time

CONGENITAL PATHOLOGY / GENETIC DISORDERS

Penetrance: The frequency, expressed as a fraction or percentage, of individuals who are phenotypically affected, among persons of

an appropriate genotype (i.e., homozygous or hemizygous for recessives, heterozygotes or homozygotes for dominants); factors affecting expression may be environmental, or due to purely random variation; contrasted with hypostasis where the condition has a genetic origin and therefore tends to cause correlation in relatives.

Example: Autosomal dominant trait showing 50% penetance, will be phenotypically present in what percent of the offspring? 25%, because if (Aa x aa) gives 50% Aa & 50% aa, then 50% of the offspring have the right allele; but, with 50%

penetrance, only 25% of all the offspring will phenotypically express the gene Codominance

Phenotypic expression of BOTH alleles in a gene pair Pink flower instead of white and red

Teratogens: Teratology is the study of developmental anomalies Chemical, physical, & biological agents that cause developmental anomalies Susceptibility to teratogens is variable Susceptibility to teratogens is specific for each development state Mechanism is specific for each teratogen

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Teratogens are dose dependent Produce growth retardation, malformation, functional impairment, or death Teratogenic agents:

Misc – Ach inhibitors, cocaine, DES, Iodide, Thalidomide Physical agents – radiation, hypoxia, excessive CO2, & mechanical trauma Maternal infection (‘TORCH’): Toxoplasmosis, Other agents, Rubella, CMV, and HSV

• Rubella and Toxoplasmosis – Both are teratogenic • Rubella

♦ Greatest incidence of rubella associated w/ cardiac anomalies occurs during 1st trimester • CMV

♦ The major viral cause of birth defects in infants in developing countries Hormones – sex hormones & corticosteroids Vitamin deficiencies – riboflavin, niacin, folic acid, and vitamin E Chemotherapy – used for treating malignancies Antibiotics – mitomycin, dactinomycin, puromycin (used as chemotherapy agents)

AUTOSOMAL-DOMINANT DISEASES: Familial hypercholesterolemia:

Genetic defect characterized by abnormalities of LDL receptors Elevated LDL owing to defective or absent LDL receptors. Heterozygotes have cholesterol = 300 mg/dL Homozygotes, very rare, have cholesterol of 700 mg/dL Severe atherosclerotic disease early in life, and tendon xanthomas (classically in the Achilles tendon), myocardial infarcts

may develop before age 20 Marfan’s syndrome:

Fibrillin gene mutation leading to a CT disorder: Uncommon hereditary CT disorder resulting in abnormalities of the eyes, bones, heart, & BV Pts are tall & thin w/ abnormally long legs & arms & spider-like fingers Skeletal abnormalities: tall w/ long extremities, hyperextensive joints, and long tapering fingers and toes Cardiovascular: cystic medial necrosis or aorta leading to aortic incompetence and dissecting aortic aneyrysms. Floppy

mitral valve NOT Mental Retardation Ocular: subluxation of lenses

Familial adenomatous polyposis = familial polyposis coli Think FAP Familal Adenomatous Polyposis, chromosome 5, Autosomal dom, Positively will get colon cancer Adenomatous Polyps predispose for Colon Cancer Info found in GI tract section

Adult polycystic kidney disease: Always bilateral, massive enlargement of kidneys due to multiple large cysts Patients present w/ pain, hematuria, hypertension, progressive renal failure 90% of cases are due to mutation in APKD1 Associated w/ polycystic liver disease, berry aneurysms, mitral valve prolapse Adult form is Autosomal Dominant (renal adenoma, glomerulonephritis, and 2° amyloidosis are NOT)

• Juvenile form is recessive Huntington’s disease:

Progressive neurologic disorder Depression, progressive dementia, choreiform movments, caudate atrophy, & decreased levels of GABA & Ach in brain Symptoms manifest affected individuals between the ages of 30 and 50…death follow 15-20 years later Gene located on chromosome 4, (Hunting 4 Sexy Triplets), triplet repeat disorder

Wilms’ tumor = nephroblastoma Embryonal tumor Most common renal malignancy of childhood

• Don’t Get Clowned Neuroblastoma is most common PLAIN malignancy in children and infants Involves one or both kidneys Often reaches enormous size – palpable abdominal mass Can be part of WAGR complex Wilms’ tumor, Aniridia, Genitourinary malformation, mental-motor Retardation

Retinoblastoma Associated with Rb gene Embryonal tumor affecting one or both eyes

• Osteosarcoma is associated w/ familial forms Neurofibromatosis I: (von Recklinghausen’s disease)

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Characterized by multiple pigmented macules of the skin • TOO reckless with you Coffee and Punch Holes in the Walls (Bone)

Has café au lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas) Also marked by skeletal disorders (dg. Scoliosis) and increased tumor susceptibility On long arm of chromosome 17, 17 letters in von Recklinghausen

Heriditary spherocytosis: Intrinsic, extravascular hemolysis due to spectrin or ankyrin defect RBCs are small and round w/ no central pallor→less MB leading to increase MCHC Osmotic fragility test used to confirm Associated w/ gallstones, splenomegaly, anemia, and jaundice Distinguish from warm antibody hemolysis by direct Coombs test. Hereditary spherocytosis is Coombs negative Spheroid erythrocytes; hemolytic anemia, increased MCHC. Splenectomy is curative

AUTOSOMAL RECESSIVE DISEASES: Cystic fibrosis:

Autosomal recessive defect in CFTR gene on chromosome 7 Defective Cl- channels leads to secretion of abnormally thick mucus that plugs lungs, pancreas, and liver which leads to

recurrent pulmonary infections (Pseduomonas species and S. aureus) Chronic bronchitis, bronchiectasis, pancreatic insufficiency (malabsorption & steatorrhea), meconium ileus in

newborns Increased concentration of Na+ and Cl- ion in sweat test diagnostic Infertile in males due to absent vas deferens Fat soluble vitamin deficiencies (ADEK) Can present as failure to thrive in infancy Most common lethal genetic disease in Caucasions Treatment: N-acetylcystein to loosen mucous plugs

Glycogen storage diseases Type I→Type VI, including von Gierke’s disease (found elsewhere in file)

Lysosomal storage diseases Mucopolysaccaridoses

• NOTE: Hunter’s is not an autosomal recessive disease • Hurler syndrome –Can’t stop GAGGING, so you HURL

♦ Caused by a deficiency of the enzyme alpha L-iduronidase, which results in the accumulation of the mucopolysaccharides, heparin sulfate and dermatan sulfate in the heart, brain, liver, and other organs

♦ It is characterized by dwarfism and mental retardation ♦ Death occurs by age 10 ♦ NOTE: mucopolysaccharide is an old term for glycosaminoglycan (GAG) ♦ Hurler syndrome is an example of the mucopolysaccharidoses, a group of inherited metabolic diseases caused by

the lack of certain enzymes necessary to break down GAGs Mucopolysaccharidoses are hereditary disorders characterized by the accumulation of GAGs in various

tissues due to deficiency of one of the lysosomal hydrolytic enzymes Sphingolipidoses = Lipid storage diseases:

• ***AN APPROPRIATE SIDENOTE (you’ll see)*** • Reticuloendothelial system (mononuclear phagocyte system):

♦ Composed of monocytes & macrophages located in reticular conntect tissue (e.g., spleen) ♦ Functional, rather than an anatomical system involved in defense against infection & disposal of breakdown

products ♦ Constitutes all phagocytic cells of body (except granulocytes) including the cells present in bone marrow, spleen,

& liver ♦ EXs:

Microglia = macrophages of the CNS Kupffer cells = phagocytic cells found within the sinusoids of the liver Alvoelar macrophage (dust cells) = macrophages fixed in alveolar lining of lungs (aka: reticulum cells of the

lungs) Histiocytes = fixed macrophages in CT

♦ Disorders of the Reticuloendothelial system: ALSO LIPID STORAGE DISEASES Gaucher’s disease – caused by deficiency of glucocerebrosidase Niemann Pick disease – caused by a deficiency of sphingomyelinase (die w/in a few years) Tay-Sachs disease – caused by deficiency of hexosaminidase A (rapidly fatal) All are considered Lipid Storage Diseases

Liposes

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Diseases (lipid storage disease) caused by abnormalities in the enzymes that break down (metabolize fats) They result in a toxic accumulation of fat-by-products in tissues:

• Series of disorders due to inborn errors in lipid metabolism – result in abnormal accumulation of lipids • The 4 diseases discussed here are most common in people of Eastern European Jewish (Ashkenazi) ancestory • Tay-Sachs disease:

♦ Tay SaX lacks heXosamididase A (YOU HAVE SACHs of GANGLIOSIDES) ♦ Deficiency of hexosaminidase A leads to accumulation of gangliosides in brain & nerve tissue

This abnormality of fat metabolism in nerve cells causes CNS degeneration ♦ Is an Autosomal recessive hereditary disorder in which the deficiency of the enzyme hexosaminidase A results in

the accumulation of gangliosides especially in neurons ♦ Is associated with an inborn error of metabolism involving a specific enzyme which normally degrades

gangliosides in the gray matter ♦ Characterized by progressive mental retardation, blindness, convulsions, & ultimately death by age 4

• Niemann-Pick disease: ♦ No MAN PICKs his nose with his SPHINGer ♦ Caused by a genetic defect in sphingomyelinase

Deficiency leads to accumulation of sphingomyelin in brain, spleen, & liver ♦ Also causes mental retardation & early death – by age two

• Fabry’s disease: ♦ The only sphingolipidosis that is not autosomal recessive (No, I don’t know which category it fall under) ♦ Very rare, inherited & extremely painful systemic disorder related to deficiency of α-galactosidase ♦ Characterized by glycolipid accumulation in body tissues

• Gaucher’s disease: ♦ Rare, inherited, potentially fatal disorder ♦ Deficiency of glucocerebrosidase leading to accumulation of glucosylceramide in lysosomes of certain cells

Others: Albinism, alpha-1-antitrypsin deficiency, phenylketonuria (PKU), thalassemias, sickle cell anemias, infant polycystic kidney disease, hemochromatosis PKU

• Occurs because pt cannot convert Phenylalanine to Tyrosine • (Due to deficiency of Phenylalanine Hydroxylase)

X LINKED RECESSIVE: Female carriers of X-linked recessive disorders rarely affected due to random inactivation of X chromosomes in each cell Type of disease inherited through the mom while she is not affected X linked recessive Fragile X syndrome:

X linked defect affecting the methylation and expression of the FMR1 2nd most common cause of genetic mental retardation (most common is Down syndrome) associated w/ macro-orchidism (enlarged testis), long face w/ a large jaw, large everted ears, and autism

Duchenne’s muscular dystrophy: Frame shift mutation causes deletion of dystrophin gene and accelerated muscle breakdown Onset occurs before 5 years of age Dystrophin protein is absent (Think D for Duchenne’s, Deleted Dystrophin, and muscle Decrease)

• Usually presesnt in muscle cell MBs (but it’s coded for on the X chromosome) Weakness begins in pelvic girdle muscles and progresses superiorly Pseudohypertophy of calf muscles due to fibrofatty replacement of muscle; cardiac muscle Use of Gowers’ maneuver, requiring assistance of the upper extremities to stand up, is characteristic (indicates proximal

lower limb weakness) Others: Hemophilia A & B, Fabry’s, G6PD deficiency, Hunter’s, Ocular albinism, Lesch Nyhan (Gout – hyperuricemia),

Bruton’s agammaglobulineia, Wiskott-Aldrick syndrome DISORDERS OF CHROMOSOME NUMBER OR STRUCTURE:

Down syndrome (Trisomy 21): Most common chromosomal disorder and cause of congenital mental retardation. Flat facial profile, simian crease, congential heart disease, prominent epicanthal fold, Duodenal atresia, Alzheimer’s

disease for people > than 35, increase risk for acute lymphoid leukemia (we ALL go DOWN) Think D for Drinking age (21) and Down’s, and Decreased AFP – DOWN’s Causes:

• 95% due to meiotic nondisjunction of homologous chromosomes, associated w/ advanced maternal age (from 1:1500 in women < than 20 to 1:25 in women > than 45)

• 4% due to rebersonina translocation • 1% due to down mosaicism (no maternal association)

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Edwards’ syndrome: (Trisomy 18) Mental retardation, rocker bottom feet, low-set ears, micrognathia, congenital heart disease, clenched hands (flexion of

fingers), prominent occiput Death usually occurs w/in 1st year Think E for Election age (18)

Patau’s syndrome: (Trisomy 13) Severe mental retardation, microphthalmia, microcephaly, cleft lip/palate, abnormal forebrain structures, polydactyly,

congenital heart disease Death occurs w/in 1 year Think P for Puberty age (13)

Cri-du-chat syndrome: congenital deletion of short arm of 5 (46, XX or XY, 5p–) Microcephaly, severe mental retardation, high pitched crying/mewing, cardiac abnormalities

• Think Cry of the Chat (high pitched crying) DiGeorge’s syndrome

More info elsewhere in file Results from a deletion of chromosome 22q11

TRISOMY DISORDERS Disorder Incidence Abnormality Description Prognosis

Trisomy 21 Down syndrome

1/700 births Extra chromosome 21 Delayed physical & mental development; many physical abnormatlties. Small head w/ broad & flat face, slanting eyes & a short nose. Enlarged tongue, small & low-set ears. Heart defects are common

Affected people generally live until their 30s or 40s

Trisomy 18 Edward’s syndrome

1/3000 births Extra chromosome 18 Facial abnormalities combine to give the face a pinched appearance. Small head & malformed, low-set ears

Survival > a few months is rare; severe mental retardation

Trisomy 13 Patau’s syndrome

1/5000 births Extra chromosome 13 Severe brain & eye defects are common > 20% survive beyond 1 year; severe mental retardation

Think Johnny DEP D – Trisomy 21 (21 Jump Street) E – Trisomy 18 (Edward Scissorhands) P – Patau Pan (Finding Neverland) – uh…Trisomy 13…

DISORDERS OF SEX CHROMOSOMES: Sex-linked Dominance

Male with x-linked dominant condition has daughters with an unaffected partner, what percentage of the daughters will be affected = 100%

Klinefelter’s syndrome (male XXY): Infant appears normal at birth – the defect usually becomes apparent in puberty when 2° sex characteristic fail to develop Hypogonadism, eunuchoid body shape, tall, long extremities, gynecomastia, female pubic hair distribution

• Common cause of hypogonadism seen in infertility workups Boys tend to be tall w/ long legs Disorder is associated w/ advanced maternal & paternal age Person frequently has mild retardation Diagnosed by presence of inactivated X chromosome (Barr body)

• Normal Females and Klinefelter Males Have 1 Turner syndrome (female XO):

Birth defect caused by the absence or defect of an X chromosome (sex chromosome) • Chromosome just looks like 45,X, and NOT 45.Y

Short stature, webbing of neck skin, absent or retarded development of 2° sex characteristics at puberty, absence of menstruation, coarctation of the aorta, and bone & eye abnormalities

Inhibits sexual development & usually causes infertility • Most common cause of amenorrhea

No Barr body (XO) Think Hugs and Kisses XO from Tina Turner The embryo develops into a female, because to become a male, a Y chromosome is necessary

• A condition of just a Y with no X would be incompatible with life Diagnosed

• Either at birth (due to associated anomalies) or puberty (absent or delayed menses & delayed sexual development) • With Karyotyping

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Double Y male (male XYY) Phenotypical normal, very tall, severe acne, antisocial behavior Seen in 1-2% of XYY males Observed in higher frequency among inmates of penal institutions

Pseudohermaphroditism: disagreement between the phenotypic (external genitalia) and gonaldal (testes vs. ovaries) sex Female (XX): ovaries present, but external genitalia are virilized or ambiguous

• Due to excessive and inappropriate exposure to androgenic steroids during early gestation Male (XY): testes present, but external genitalia are female or ambiguous

• Most common form is testicular feminization which results from maturation in androgen receptor gene, blind end vagina

True hermaphrodite: 46 XX, 47 XXY: both ovary and testicular tissue present; ambiguous genitalia

5-alpha deficiency: unable to convert testosterone to DHT. Ambigous genitalia until puberty, when increased testosterone causes masculinzation of genitalia. Testosterone/estrogen levels are normal; LH is normal or increase

RANDOM STUFF

Infection terminology:

Contagious – highly communicable Subclinical – unapparent; only detected by demonstrating a rise in Ab titer (rising is the most reliable finding) or isolating the

organism Latent state – absence of symptoms until a reactivation occurs Chronic carrier – organisms continue to grow w/ or w/out producing symptoms in the host Pandemic – worldwide distribution Endemic – constantly present at low levels in a specific population and with low incidence of infection Epidemic – occurs much more frequently than usual

Swelling

In an autopsy, cellular swelling (a commonly observed tissue change, is of little practical diagnostic imporance Cloudy swelling:

Early degenerative change characterized by increase cytoplamsic granularity & increased size Swelling of cells due to injury to MBs affecting ionic transfer; causes an accumulation of intracellular water

Shy-drager syndrome (multiple system atrophy)

Rare degenerative condition w/ symptoms similar to Parkinson’s – pt may move slowly, be tremulous, & have shuffling gait Wiskott-Aldrich syndrome (aka immunodeficiency w/ eczema & thrombocytopenia):

Affects only boys Characterized by defective B-cell & T-cell functions, Just like SCID mouse Clinical features – thrombocytopenia w/ severe bleeding, eczema, recurrent infection, & increased risk of lymphoid cancers

Ataxia-telangiectasia: Inherited disorder that affects many tissues & body systems Multiple symptoms – telangiectasis (dilation of capillaries), ataxic (uncoordinated) gait, infection prone, defective humoral &

cellular immunity, & increased risk of malignancies Most obvious symptoms – multiple easily visible telangiectases in the sclera & skin areas such as ear & nose, graying of the

hair, & irregular pigmentation of areas exposed to sunlight Decreased coordination of movement (ataxia) in late childhood

Hyper-IgE syndrome (Job syndrome): -- JOB even got ALLERGIES Immunodeficiency disorder characterized by very high levels of IgE Ab/s & repeated infections (commonly w/ S. aureus) Tx – continual administration of Abx

Calcification abnormalities:

Metastatic calcification: Calcification occurring in nonosseous, viable tissue – stomach, lungs, & kidneys Cells of these organs secrete acid materials & under certain conditions in instances of hypercalcemia, the alteration in pH

seems to cause precipitation of calcium salts at these sites Occurs particularly in hypercalcemia, hyperparathyroidism & hypervitaminosis D, NOT hypoparathyroidism

Pathologic calcification: Calcification occurring in excretory or secretory passages as calculi (in tissues other than bone & teeth)

Eggshell calcification: Thin layer of calcification around an intrathoracic lymph node, usually silicosis, seen on a chest radiograph

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Dystrophic calcification: Deposition of calcium in dying or dead tissues Occurs in degenerated or necrotic tissue, as in hyalinized scars, degenerated foci in leiomyomas, & caseous nodules Secondary to disease of affected tissue NOT associated w/ high blood calcium levels

• Unlike Metastatic Calcification Calcinosis:

Presence of calcification in or under skin – often associated w/ scleroderma & sometimes dermatomyositis Staghorn stones:

Occupy renal pelvis & calyces – big stones! Hematuria:

Blood in urine – should never be ignored!! Usually caused by kidney & urinary tract disease Exceptions:

Women – blood may appear to be in urine when it is actually from the va-jay-jay Men – blood mistaken for urinary bleeding is sometimes a bloody ejaculation due to prostate problems Children – coagulation disorders (e.g., hemophilia) or other hematologic problems (e.g., sickle cell disease, renal vein

thrombosis, or thrombocytopenias) can be underlying reasons for newly discovered blood in urine Kidney disease following strep throat is a classic cause of hematuria

Hematemesis: Vomiting of bright red blood – indication rapid upper GI bleeding Commonly associated w/ esophageal varices (common in alcoholics) or peptic ulcers

Hemoptysis: Coughing up blood from respiratory tract Blood-streaked sputum often occurs in minor upper respiratory infections or in bronchitis Can also be seen in pts suffering from tuberculosis, lobar pneumonia (Diffuse, rusty sputum, S. pneumoniae), or

bronchogenic carcinoma (NOT emphysema) Also can be seen in pts w/ a pulmonary embolism Hemoptysis is the main symptom of idiopathic pulmonary hemosiderosis (iron in the lungs)

Glucosuria: Presence of glucose in urine – common in diabetes

Ketonuria: Presence of ketones in urine – produced by starvation, uncontrolled diabetes, usually Type I, & occasionally alcohol

intoxication Proteinuria:

Presence of protein in urine – usually a sign of kidney disease Accumulation of endogenous pigments:

Bilirubin Hemosiderin

Iron containing protein derived from ferritin, which is an iron storage protein Melanin – formed from tyrosine, synthesized in melanocytes

Increased melanin pigmentation – seen in Addison’s disease Decrease melanin pigmentation – seen in albinism & vitiligo, and PKU

Histiocytosis X (aka Langerhans Cell Histiocytosis & Differntiated Histiocytosis)

FIXED macrophages Group of disorders in which histiocytes (scavenger cells) proliferate, esp. in bones & lung, often causing scars to form Characterized by abnormal increase in # of histiocytes – includes monocytes, macrophages, & dendritic cells Eosinophilic granuloma:

Most benign form More common in males ~20 y.o. May be totally asymptomatic – there may be local pain or swelling In the mouth, Mn is most likely affected – loose teeth on affected side w/ signs of gingivitis

Letterer-Siwe disease: Affects infants (< 2 y.o.) – fatal Child develops a skin rash w/ persistent fever & malaise Anemia, hemorrhage, splenomegaly, lymphadenopathy, & localized tumefaction over bones are usually present Oral lesions are uncommon

Hand-Schuller-Christian disease: Occurs early in life, usually before 5 y.o. – more common in boys

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Triad of symptoms – 1) exophthalmos, 1) diabetes insipidus, 3) bone destruction (skull & jaws are affected) Oral signs – bad breath, sore mouth, & loose teeth Treatment – radiation & chemotherapy (poor prognosis)

Habermann’s disease: Is not an example of Histiocytosis X Sudden onset of a polymorphous skin eruption of macules, papules, & occasionally vesicles w/ hemorrhage

Polymyalgia rheumatica: Condition causing severe pain & stiffness in muscles of neck, shoulders, & hips

Hydatidiform Mole A pathologic ovum (“empty egg” – ovum with no DNA) resulting in cystic swelling of chorionic villi and proliferation of

chorionic epithelium (trophoblasts) Most common precursor of choriocarcinoma High beta HCG “Honeycombed uterus, cluster of grapes appearance Genotype of a complete mole is 46, XX and is purely paternal in origin (no maternal chromosomes); no associated fetus Partial mole is commonly triploid or tetraploid.

Uterine Pathology Endometriosis

Non-neoplastic endometrial glands/stroma in abnormal locations outside the uterus Characterized by cyclic bleeding from ectopic endometrial tissue resulting in blood-filled, chocolate cysts Ovary is most common site Clinically is manifest by severe menstrual related pain Often results in infertility

Endometrial Hyperplasia Abnormal endometrial gland proliferation usually caused by excess estrogen stimulation Increased risk for endometrial carcinoma Most commonly manifest clinically by vaginal bleeding

Endometrial Carcinoma Most common gynecologic malignancy Peak age is 55-65 Clinically presents with vaginal bleeding Typically preceded by endometrial hyperplasia Risk factors prolonged estrogen use, obesity, DM, and HTN

Polycystic Ovarian syndrome Increased LH due to peripheral estrogen production leads to anovulation Manifest clinically by amenorrhea, infertility, obesity, and hirsutism Tx with weight loss, OCPs, gonadotropin analogs, or surgery

Leiomyoma (See “Neoplasm’ section) Leiomyosarcoma (See “Neoplasm’ section)

Breast Disease Fibrocystic Disease

Presents with diffuse breast pain and multiple lesions, often bilateral Bx shows fibrocystic elements Usually does not indicate increased risk for CA, although it is a risk factor Histological types

• Cystic – fluid filled • Epithelial Hyperplasia – Increase in number of epithlelial cell layers in terminal duct lobule, Increase risk for CA • Fibrosis – Hyperplasia of breast stroma • Sclerosing – Increased acini and intralobular fibrosis

Benign Tumors Cystosarcoma phyllodes – large, bulky mass of CT and cysts, breast surface has “leaflike” appearance (“I love Fall”) Fibroadenoma – most common tumor <25 yrs, small, mobile, firm mass with sharp edges, increases with pregnancy

Malignant Tumors Comon Postmenopause Arise from mammary duct epithelium or lobular glands

• Histologic types ♦ Comedocarcinoma – Cheesy consistency of tumor tissue due to central necrosis ♦ Infiltrating ductal – most common carcinoma, Firm, fibrous mass ♦ Inflammatory – lymphatic involvement, poor Px ♦ Paget’s disease – Eczematous patches on nipple

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Risk Factors Gender, age, early menarche, delayed first pregnancy, late menopause, family history of 1st-degree relative with breast cancer at a young age, but NOT fibroadenoma or nonhypplastic cysts

Wegener’s Granulomatosis Characterized by focal necrotizing vasculitis and necrotizing granulomas in the lung and upper airway and by necrotizing

glomerulonephritis Symptoms Perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis, cough, dyspnea, hemoptysis Findings C-ANCA is strong marker of disease, CXR may reveal large nodular densities, hematuria and red cell casts Tx corticosteroids nad methotrexate

Alcoholism Physiologic tolerance and dependence with symptoms of withdrawal (tremor, tachycardia, HTN, malaise, nausea, delirium

tremens) when intake is interrupted Continued drinking despite medical and social contraindications and life disruptions Ethanol via Alcohol Dehydrogenase and MEOS Acetaldehyde Acetate Acetyl-CoA Increased FAs Fat

Liver • Alcohol Dehydrogenase

♦ Increases NADH/NAD+ ratio, which in turn: Basically tricks your body into thinking you have energy Increases Lactate/pyruvate Inhibitis gluconeogenesis Inhibits FA Oxidation Inhibits Glycerophosphate dehydrogenase, leading to elevated glycerophosphate

Complications of Alcoholism Alcoholic Cirrhosis

• Long term alcohol use leads to micronodular cirrhosis with accompanying symptoms of jaundice, hypoalbuminemia, coagulation factor deficiencies, and portal hypertension, leading to peripheral edema, ascites, encephalopathy, and neurologic manifestations

Wernicke-Korsakoff Syndrome • Caused by Vitamin B1 (thiamine) deficiency in alcoholics • Classically may present with triad of psychosis, ophthalmoplegia, and ataxia • May progress to memory loss, confabulation, confusion (Irreversible) • Associated with periventricular hemorrhage/necrosis, especially in mamillary bodies • Tx with IV Vitamin B1

Mallory-Weiss Syndrome • DRUNK DUCKS • Longitudinal lacerations at the gastroesophageal junction caused by excessive vomiting with failure of LES

relaxation that could lead to fatal hematemesis A Quick Review on Pathology Findings

Argyll-Robertson Pupils Constricts with accommodation but is not reactive to light, pathognomonic for Tertiary syphilis Think ARP Argyll-Robertson Pupil, Accommodation Response Present

Amyloidosis Primary seen with multiple myeloma or Wadenstrom’s macroglobulinemia Secondary can cause nephrotic syndrome in kidney, Apple-green birefringement on Congo Red stain Alzheimer’s disease associated with Beta-amyloid deposition in the cerebral cortex Islet cell amyloid deposition characterisitic of DM Type II

Aschoff Body = Granuloma with Giant cells are also found with Anitschkow’s cells (activated histiocytes) in Rheumatic Heart Disease

• Think 2 RHussians Rheumatic Auer bodies

Cytoplasmic inclusions in granulocytes and myeloblasts Primarily seen in Acute Myelocytic Leukemia -- Ambulance

Casts (in Urine) RBC glomerular inflammation, ischemia, or malignant HTN, Bladder Cancer WBC casts inflammation in renal interstitium, tubules and glomeruli, Acute cystitis Hyaline casts often seen in normal urine Waxy casts Seen in chronic renal failure

ESR (Sed Rate) Nonspecific test that measures acute-phase reactants Dramatically increased with infection, malignancy, CT disease, with pregnancy, inflammatory disease, anemia Decreased with Sickle cell anemia, polycythemia, CHF

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Hyperlipidemia signs Atheromata Plaques in blood vessel walls Xantheloma Plaques or Nodules composed of lipid-laden histiocytes in the skin, especially the eyelids Tendinous Xanthoma Lipid deposit in the tendon, especially Achilles,

Familial Hypercholesterolemia Corneal arcus Lipid deposit in cornea, nonspecific (arcus senilis)

Psammoma bodies Laminated, concentric, calcific spherules seen in

• Think PSaMMoma Papillary adenocarcinoma of thyroid, Serous papillary cystadenocarcinoma of ovary, Meningioma, Malignant Mesothelioma

RBC Forms Biconcave Normal Spherocytes Hereditary Spherocytosis, Autoimmune hemolysis Elliptocyte Hereditary Elliptocytosis Macro-ovalocyte Megaloblastic anemia, marrow failure Helmet cell, Schistocyte DIC, traumatic hemolysis Sickle cell Sickle cell anemia Teardrop cell Myeloid metaplasia with myelofibrosis Acanthocyte Spiny appearance in abetalipopreteinemia Target cell Thalassemia, liver disease, HbC Poikilocytes Nonuniform shapes in TTP/HUS, microvascular damage, DIC Burr cell TTP/HUS

HLA-B27 Think PAIR Psoriasis, Ankylosing spondylitis, Inflammatory bowel disease, Reiter’s syndrome

Virschow’s (sentinel) node Firm Supraclavicular lymph node, often on left side, easily palpable, also known as jugular gland Presumptive evidence of malignant visceral neoplasm (usually stomach)

Random Qs All of the following should be HIGHLIGHTED YELLOW

Bacteria surviving in CO2 Capnophiles or Anaerobics -- think????

Tran has another Q stating Anaerobics need CO2 to grow Retrovirus causes what in infants????

Pneumonia, T-cell leukemia???? Mushroom Toxins

The recent answer was some Alpha-amanitin Toxin Ehler-Danlos Syndrome

a group of inherited generalized connective tissue diseases characterized by overelasticity and friability of the skin, hypermobility of the joints, and fragility of the cutaneous blood vessels and sometimes large arteries, due to deficient quality or quantity of collagen;

the most common is inherited as an autosomal dominant trait; some recessive cases have hydroxylysine-deficient collagen due to deficiency of collagen lysyl hydroxylase, and two tentatively ascribed to X-linked inheritance. • Also associated with Berry Aneurysms

What does CD stand for?? Not compact disc, but Cluster of Differentiation

They are surface molecules that are recognized by specific types of antibodies CD 4 and CD 8--- Ring a bell?

Respiratory Burst The rapid release of SUPEROXIDE anion when PMNs come in contact with bacteria

Throat Cancer Most are squamous cell carcinomas – Just like Skin and Esophagus

Oral Cancer Occurs on the side of the tongue

Tracheomalacia Trachea collapsing

Noma Gangrenous disese of the mouth and cheeks