DD+LOs+Unit+2

toc =**Preamble**= (from James Rose, the author of these notes) Monday, December 15, 2008

What follows is the original preamble (same as the notes from M2M). A few points on D+D: it’s a lot like M2M, with the unfortunate exception of actually being useful clinical information so you can’t tune it out. The block directors are well-meaning but it’s a sort of a hodgepodge course with a little of everything. Rest assured that by the time you hit ID you will likely remember about 3% of what you’re about to learn with regards to infection. That said, having a basic vocabulary to talk about common pathogens makes you look a little less like an idiot at your preceptor’s. And for the 3 or 4 people who really, desperately want to be dermatologists, the derm section will enable you to suck up to the derm staff with terrifying efficiency. So go to it, try and retain as much important info as you can, don’t kill yourself worrying about remembering pharmacokinetics, and enjoy. Trust me, first year is the time to really enjoy your classes. –jcr

=**Acute Inflammation**=


 * List and describe the 5 clinical signs of acute inflammation and give their clinicopathogenetic basis.
 * **Redness**
 * **Warmth**
 * **Swelling**
 * **Pain**
 * **Loss of Function**
 * Latin, respectively: rubor, calor, tumor, dolor, functio laesa (rhymes pretty good til the end there-- even first century Roman med students needed their mnemonics. Trust a 19th-century German to mess it up.).
 * Redness and warmth are due to increased blood flow secondary to vasodilation of capillaries and arterioles. Note brief initial pallor.
 * Swelling, pain, and loss of function are due to increased vascular permeability, secondary to endothelial alteration to allow exudation of plasma fluid into the extracellular space (pain due to irritation of nerves by exudate) and possibly extravasation of leukocytes. Note that leukocytes can cause additional tissue damage, which can in turn can trigger more inflammation.
 * Ways to allow exudation:
 * Vasodilation (increase circumference of vessel, separating endothelial cells)
 * Certain chemicals (notably **histamine** ) **bind to endothelial cells and actively induce them to separate** apart.
 * Burns or tissue damage, which physically tears or erodes holes in the capillary walls to allow exudation.
 * If the capillary itself is damaged or infected, the neutrophils that show up and release their granules can themselves degrade the walls of the capillary, leading to exudation.
 * Transcytosis: specific chemical mediators can create pores in endothelium that allows leakage of fluid.
 * Describe the 3 major pathogenetic mechanisms of acute inflammation. Summarize the role of the endothelial cell.
 * These are the three already mentioned-- __increased blood flow, increased vascular permeability, and the accumulation of leukocytes__.
 * The endothelial cell is responsible for all three, as it usually has to spread to allow vasodilation and make sufficient space between endothelial cells to permit fluid and leukocytes to leave the bloodstream.
 * The endothelial cell, as discussed below, is also responsible for expressing adhesion proteins to allow neutrophils to adhere and diapedese.
 * Note that the third pathogenetic mechanism mentioned, leukocytic infiltration, is responsible for the __duration__ of the inflammation-- the neutrophils and other leukocytes keep the inflammation going until the offending immunogens are gone. This can be a problem in any situation in which there are a whole lot immunogens (as with rapidly replicating viruses or bacteria, or autoimmune disorders)-- leads to chronic inflammation (see next section).
 * Icing inflamed regions works because it slows down inflammatory processes of the affected cells-- certain processes and enzymes operate optimally at body temperature (around 37 degrees C), so if you can cool them down, you can slow the inflammation.
 * List and describe the sequence of events involving a neutrophilic response in acute inflammation due to a pyogenic microorganism, e.g., Staphylococcus aureus.
 * [__Pyogenic__ means 'pus-producing' (note difference between pyogenic and pyrogenic!).]
 * (0) Innate immunity is activated-- TLRs on cells in damaged tissue recognize bacterial patterns. This initiates a signaling cascade that involves NF-kB (nuclear factor kappa-B), the result being the production of cytokines that cause vasodilation.
 * Notice that mast cells (and their histamine) play a large role in this vasodilation.
 * Notice also that TLRs can recognize other patterns aside from pathogens. Atherosclerosis occurs in part because TLRs are activated by oxidized low-density lipoproteins on endothelial surfaces. Cellular necrosis causes cell contents to leak out and activate TLR-like receptors, which also causes inflammation reactions.
 * (1) **Vasodilation occurs** ; blood flow slows down, exudate begins to leak out of the capillary walls.
 * (2) **Margination** (rolling along edges of endothelium) of leukocytes is induced by reduced blood flow (ordinarily the shearing forces of blood flow preclude margination).
 * (3) This activates **adhesion** proteins in neutrophils, causing adhesion to the region of the endothelial wall that's near the source of the injury (which region is also expressing leukocyte adhesion proteins).
 * (4) **Diapedesis** of neutrophils through endothelial wall to extravascular tissue ensues, followed by the **migration** of neutrophils to the injury site, following chemotactic signals.
 * Chemotactic signals for neutrophils:
 * Cytokines/chemokines
 * Bacteria or bacterial products with particular PAMPs
 * Complement C5a fragments
 * A derivative of arachidonic acid called leukotriene B (see "Chemical mediators of inflammation").
 * (5) Either the neutrophil is able to attach to the foreign body by itself or it needs opsonin help (like IgG or C3b fragments). Once it's attached, it **phagocytoses** the foreign particles (see below for specific notes on this).
 * (6) Eventually you get some **pus** -- viscous fluid made up of dead and live neutrophils and bacteria.
 * Order of leukocyte arrival: Neutrophils arrive first; macrophages later; lymphocytes later still.
 * First thing that happens is edema, fairly rapidly; neutrophils peak about a day after the injury; macrophages peak about a day after that. Macrophages (and dendritic cells, if present) have to activate Th1 cells, which in turn activate Th2 and B cells, and eventually you wind up getting antibodies.
 * Discuss leukocyte and endothelial cell adhesion molecules and cite an example of each.
 * Adhesion molecules on each grab onto the other.
 * Adhesion proteins on leukocytes: integrins like __LFA-1__.
 * Adhesion proteins on endothelia: immunoglobulin-family proteins like __ICAM-1__.
 * Note that these adhesion molecules often need to be activated by other chemical mediators to be expressed on the cell surfaces or to bind correctly.
 * Note that complement component C5a enhances adhesion of leukocyte proteins to endothelial receptors.
 * Note also that cytokines released by activated macrophages, such as IL-1 and tumor necrosis factor, enhance adhesion of endothelial proteins to leukocyte receptors.
 * Define chemotaxis and list the major chemotactic agents for neutrophils.
 * Once they're slowed, adhered, and diapedesed, leukocytes move to the sites of inflammation. Neutrophils actually produce pseudopods to pull themselves along with quasi-muscular proteins-- they crawl between endothelial cells and get out into infected or damaged extravascular regions, then follow chemotactic signals to find the source of the infection.
 * Note that neutrophils can chemotactically follow bacterial chemical peptides-- sort of the cellular equivalent of hunting bacteria by smell.
 * Other chemotactic substances for neutrophils:
 * complement C5a
 * cytokines and chemokines
 * leukotriene B (see "Chemical mediators of inflammation").
 * bacterial peptides
 * The chemotaxis can set off a kind of "feeding frenzy" where neutrophils are swarming and thrashing all around the source of the chemotaxis. Kind of cool to watch, actually.
 * Define opsonin and list the two major types.
 * Opsonin: compounds that bind to foreign bodies to assist in their phagocytosis.
 * Major types:
 * IgG (antibody-mediated, recall that phagocytes attach to activated Fc regions)
 * C3b (complement-mediated).
 * Describe the process by which a neutrophil engulfs and destroys a bacterium.
 * Engulfing: Neutrophil binds to bacterium, mediated by innate receptors on the neutrophil and/or opsonins on the bacteria. The neutrophil invaginates around the bacterium and ingests its own membrane capsule containing the bacterium (called the __phagosome__).
 * Destroying: Can occur one of several ways:
 * Oxygen-dependent: Phagocytosis triggers rapid consumption of oxygen (respiratory burst), which is converted to reactive oxygen species (ROS) inside the phagosome. This creates an environment inside the capsule in which most pathogens die; the ROS are deactivated by catalases, etc, and the neutrophil goes about its business.
 * Alternatively, can also simply merge the phagosome with the neutrophil's intracellular lysosome-- lysosomes, recall, have all kinds of really unpleasant enzymes inside them, which can generally degrade the bacterium.
 * (In his lecture, he seemed to imply that these are actually the same thing- you stick the phagosome inside the lysosome and trigger ROS production. In any case, both concepts are important.)
 * Important note for pus formation: neutrophils can only do this so many times (sometimes just once) before the lysosomal products accumulate in sufficient quantities to kill them. (They only live a matter of hours anyway, so it's not quite as heroic as it sounds.) Dead neutrophil bodies make up a large portion of the pus volume. They are eventually cleared away by macrophages.
 * Define and compare transudate and exudate. List and describe the different types of exudates, citing etiologic agents for each type.
 * Transudate: fluid leaking from capillaries not due to inflammatory processes.
 * Ie: ascites in peritoneum due to increased hydrostatic pressure in capillaries.
 * Exudate: fluid leaking from capillaries due to inflammatory processes.
 * Ie: well, just that. As we've been saying, can be caused by inflammation.
 * Types of exudates:
 * Notice that there's a lot of different types of this, depending on how much vasodilation is going on and whether adhesion proteins for leukocytes are being expressed.
 * __Serous__ exudate: Contains smaller plasma proteins, albumin in particular. Clear yellow fluid with no cells (ie., no neutrophils).
 * Eg.: Burn blister; edema in anaphylactic reaction to penicillin.
 * __Fibrinous__ exudate: Contains larger plasma proteins, fibrin in particular. Often coats surfaces. No cells.
 * Eg.: Fibrinous pericarditis in rheumatic carditis.
 * __Purulent__ exudate: Contains smaller and larger plasma proteins as well as neutrophils. Generally contains a lot of pus.
 * Eg.: Pneumonia or meningitis caused by pyogenic organisms.
 * __Eosinophilic__ exudate: Contains predominantly eosinophils-- occurs in Type I hypersensitivity reactions and parasitic infections.
 * Eg.: Asthma, nematode infections
 * __Hemorrhagic__ exudate: Endothelia are damaged enough to leak whole red cells.
 * Eg.: rocky mountain spotted fever, rickettsia infections
 * __Mucinous__ exudate: Occurs in tissue containing lots of mucus-secreting glands. Not surprisingly, the exudate has a lot of mucus.
 * Eg.: Bronchitis
 * __Pseudomembranous__ exudate: Occurs in tissue that's injured severely enough that it necroses. This causes a membrane to form containing fluid, proteins, neutrophils, RBCs, and necrotic tissue.
 * Two big ones. One is the upper respiratory pseudomembrane that occurs in //Corynebacterium diphtheriae// infection; the other is the pseudomembranous colitis that occurs after //Clostridium difficile// expansion in the colon after antibiotic (especially clindamycin) usage.
 * I found this on the Web and it's too good to pass up repeating:

A __pseudomembrane__ results when the upper portion of a mucosal surface undergoes necrosis, freeing fibrinogen from vessels that then clots along the surface. A pseudomembrane is actually a very large, very shallow ulcer.

Different roles of macrophages and neutrophils? Neutrophils show up first, macrophages later.

Serous exudate: smaller plasma proteins (albumin) (burn blister) Fibrinous exudate: larger plasma proteins (fibrin) (fibrinous pericarditis) Purulent exudate: neutrophils, larger + smaller, pus (pneumonia) Eosinophilic: as expected. (asthma) Hemorrhagic: red cells (rocky mountain spotted fever) Mucinous: mucus (bronchitis) Psuedomembranous: diptheria in upper RTs, clostridium in GI

=**Chronic Inflammation**=


 * Define and compare abscess and cellulitis.
 * **Abscess** : **localized** inflammation characterized by the collection of pus. Pus is a collection of bacteria, neutrophils, and cellular debris (dead cells, clotting factors, etc).
 * Needs to be drained for effective healing process, because it's been surrounded by a fibrin capsule that makes it difficult to clear through normal fluid flow and macrophagic activity.
 * **Cellulitis** : **diffuse** inflammation spread through tissue (contains fluid, bacteria, neutrophils, generally no pus/necrosis).
 * Gives you an appreciation for different bacterial survival strategies//. Strep pyogenes// produces enzymes that break down fibrin to help itself spread more rapidly (cellulitis), but //Staph aureus// actively produces coagulase to help the walling-off process-- it figures that if it helps wall itself off in an abscess effectively enough, the body can't squeeze any leukocytes through its own fibrin barrier.
 * Define chronic inflammation and compare it to acute inflammation. Give examples of etiologic agents which cause chronic inflammation.
 * Chronic inflammation, as far as I can tell, is a slowly accumulating process similar to acute inflammation but in the presence of an antigen that doesn't go away.
 * Examples of those antigens:
 * Some viral and bacterial infections
 * Autoimmune diseases and transplant rejections
 * __Neutrophils__: __acute__ inflammation sign. __Macrophages and lymphocytes__: __chronic__ inflammation sign. This is mainly due to the time it takes for each of them to accumulate at inflammation sites.
 * Remember that macrophages, unlike neutrophils, are professional antigen-presenting cells; they want to engulf, neutralize, and take to lymph nodes to present.
 * Th1 cells activated by those macrophages can in turn release interferon gamma, activating more macrophages, which can activate more T cells, etc, etc. Positive feedback mechanism, limited by the amount of macrophage-stimulating material present.
 * Note that fibrosis often occurs with chronic inflammation, visible to gross inspection. This is due to deposition of fibrous material as the area is repeatedly injured.
 * For example, in acute inflammation in alveoli, see lots of neutrophils but still some functioning alveolar capillaries (have some extant blood flow); in chronic inflammation in the same place, see lots of macrophages and fibrotic tissue. If the acute inflammation clears up, the tissue can heal; however, the chronic inflammation's fibrous damage is likely to be permanent.
 * Note that if you see a lot of eosinophils in an inflammation, you can start to suspect allergic/parasitic reactions as well (recall that eosinophils can mediate basophil/mast cell activation).
 * Indicate the differential diagnosis of granuloma and discuss its pathogenesis.
 * Granuloma: a particular kind of chronic inflammation. It has the appearance, on pathology, of a necrotic center surrounded by leukocytic cells, some of which are 'giant cells' and some of which are 'epithelioid cells,' and having an outer ring of lymphocytes.
 * Giant cells are the multinucleated products of the fusion of activated macrophages.
 * Epithelioid cells are macrophages that resemble epithelial cells. Their purpose seems to be to form a pseudo-epithelial barrier to the spread of whatever infection they're containing.
 * These (**granulomas** ) **seem mainly to arise from type IV immunopathology** ('collateral damage') after hyperactivation of Th1 cells, which produce factors that transform macrophages into giant/epithelioid cells.
 * Differential:
 * Tuberculosis (cause caseous necrosis and 'caseating' granulomas)
 * Atypical mycobacterial infections (mycobacteria infect macrophages)
 * Leprosy, cat scratch disease, brucellosis, lymphogranuloma venereum (STD transmitted by a particular species of //Chylamidia// )
 * Fungal infections
 * Beryliosis (lung disease caused by repeated exposure to berylium)
 * Foreign body (seems pretty vague)
 * Sarcoidosis (see below, but turns out also to be pretty vague)
 * Define and compare ulcer and erosion
 * **Ulcer** : localized loss of continuity of epithelial/mucosal surface __as well as__ of the submucosa or dermis.
 * **Erosion** : localized loss of continuity of epithelial/mucosal surface only.
 * Define and compare fistula and sinus tract.
 * **Fistula** : channel between the lumina of hollow structures (as in dialysis patients, between a vein and an artery.
 * **Sinus tract** : mainly a channel between the skin and some kind of subcutaneous tissue.
 * Describe the pathogenetic, pathologic and clinical features of leukocyte adhesion deficiency, type I; chronic granulomatous disease of infancy; Chediak-Higashi disease.
 * Note all of these occur in children; the first two also occur in infants. They all result in recurrent infections.
 * Chediak-Higashi: autosomal recessive neutropenia (thus recurrent infections); etiology unknown. Look for albinism in the eyes and aberrant granules in neutrophils.
 * Chronic granulatomous disease of infancy: X-linked recessive defect in NADPH oxidase (thus trouble producing a respiratory burst to kill phagocytosed organisms) leads to recurrent infections.
 * Leukocyte adhesion deficiency: inherited defect in leukocyte integrins that leads to a lack of good adhesion of leukocytes with endothelia (thus trouble with extravasation). Recurrent infections ensue, particularly in mucosa and skin.
 * Define and indicate the major features of the systemic inflammatory response syndrome and the acute phase reaction.
 * Not discussed in class or notes.
 * Wiki defines systemic inflammatory response syndrome as an inflammatory state of the whole body (the "system") without a proven source of infection. Essentially it's sepsis without any observed pathogen. As such it's as serious as sepsis and harder to deal with (no obvious cause).
 * Acute phase reaction is a collection of systemic reactions to infection, whether the infection is local or systemic. Fever, drowsiness, systemic vasodilation and central vasoconstriction, etc. It involves certain proteins (acute phase proteins) that increase or decrease in the circulation in response to signals from neutrophils, macrophages, and granulocytes.
 * That's about all I got. There's a little more on the acute phase reaction under "Chemical mediators of inflammation."
 * Describe sarcoidosis:
 * The catch-all term for granulomas of unknown etiology. Manifests in a whole lot of different ways. Associated with cancer but isn't a tumor-- just a site of massive inflammation and fibrosis.
 * Mainly involves hilar lymph nodes and lungs. Seems to involve constant irritation from a "persistent, poorly degraded antigen."
 * However, can show up in virtually any organ in the body.
 * It is about 10% fatal.

Note difference with fibrin. Fibrin is a temporary barrier laid down early to prevent the spread of infection; fibrous material (like collagen) is laid down by stimulated fibroblasts in chronic inflammation. The latter is what is grossly visible.

Differential for granulomas: TB mycobacterial infections leprosy/cat scratch disease/etc fungal infections berylium exposure foreign body

=**Common Viral Pathogens**=

[Note that I left this lecture halfway through. Consequently you may not want to take my completed LO's as the last word on the subject]


 * Explain how to quantify the frequency of a virus infection or disease in a selected population.
 * You test and count them, pretty much. Or you test and count a representative sample.
 * What factors can affect the severity of disease caused by one virus in different populations?
 * Prior exposure is a big one. If there's no antibodies, **not only to that virus but to any virus like it (ie "virgin soil epidemic"** ), then everybody gets it, or as close to everyone as makes no difference.
 * Understand the type of lab tests that are used to determine when a person first became infected with a particular virus.
 * Can use paired serological assays (like ELISA) to look for the trend in IgG levels against a particular antigen. From that, can extrapolate a recent infection, no infection, or an infection in the recent or distant past. See "Immunity and Vaccines" from Dr. Cohen for more details on IgG levels.
 * Explain why some viruses were much more common 100 years ago than they are now, while other viruses that were only recently discovered are highly prevalent.
 * Viruses that only live in humans, have no latency, and/or have few different serotypes are extremely vulnerable to vaccination strategies. Ie: polio, smallpox, measles.
 * Viruses that live in multiple species or have latency (ie have a reservoir), or have lots of different serotypes, are harder to vaccinate against. Due to globalization, once a disease crops up somewhere, it's very difficult to confine to that place-- thus can spread the virus to a large enough 'herd' that it's tough to get rid of it all.
 * Mutations in the surface epitopes on a virus can lead to escape from immune surveillance. Explain how the viruses could change from one season to the next.
 * Recombinant processes in replication is the big mechanism. Flu virus, with its segmented RNA genome and lack of proofreading enzymes, is particularly adept at switching around the sequences of its two major surface proteins (hemoagglutinin and neuroamidase).
 * "Drift": minor changes in antigens.
 * "Shift: major changes in antigens (often due to two types of flu recombining genomes with each other). Often results in a species-hopping variety of flu (ie H5N1, the current avian-to-human strain).
 * Describe the evidence proving that natural infection with measles virus can lead to very long-lasting resistance to measles. What does this indicate about the number of serotypes of measles?
 * The evidence is more or less that one vaccine is effective against measles for the rest of your life. This indicates there's just one serotype of measles-- once you're immunized against it, there's no different variants of it to get you sick.
 * Explain the purposes for surveillance for viral diseases.
 * Why do you think?

=**Chemical mediators of inflammation**=


 * [Once again, his LOs cover pretty much every conceivable subject in this topic. I've tried to narrow them down here to something reasonable, but you may want to go look at his source material yourself.]
 * [Couple notes: Inflammation reactions are similar independent of the type of tissue involved or the level of innervation in the tissue.]
 * [Something I think is important to understand here: the job of the cells and chemicals involved in the inflammation response is not only to induce inflammation but also to end it. Hence you've got both pro- and anti-coagulants, and vasoconstrictors and vasodilators, etc, in the lists below. Inflammation has to be able to be dismantled fairly quickly-- thus it contains within itself the seeds of its own revolution.]
 * A good example of this: alpha-1-antitrypsin is an acute phase protein produced by inflammation. Recall from M2M that a1-AT deficiency leads to chronic tissue destruction in the lungs by elastase-- which is another inflammation protein, this one in neutrophil granules released at the site of inflammation.
 * [Fever is regulated by certain cytokines and other compounds-- the 'set point' in the hypothalamus is elevated to produce a new body temperature the body's metabolism defends. Prostaglandins and IL-1 (latter produced by macrophages and dendritic cells) are the first two pyrogenic compounds that come to mind.]
 * This touches on a larger point-- systemic effects from inflammation. Activated macrophages that are churning out TNF-alpha and IL-1 have a wide variety of systemic effects, generally called the __acute phase reaction__-- not only fever but procoagulant activity, increased proliferation and collagen remodeling of fibroblasts, and increased cytokine release by leukocytes.
 * List the major inflammatory effects of bacterial endotoxin.
 * The endotoxins (such as LPS in Gram-negative bacteria) trigger __TLR-4__, resulting in vasodilation and adhesion/extravasation of neutrophils and macrophages (these also release cytokines - TNF-alpha, IL-1 - which signal more inflammatory cells as well as induce fever).
 * In addition, the __Hageman factor__ (now generally known as __Factor XII__) becomes activated to set off a targeted coagulation (the formation of fibrin around the site of infection).
 * The __complement system__ also becomes activated (probably largely through the alternative and lectin pathways).
 * Note also that bacterial peptides are chemotactic-- the extravasated neutrophils can 'track' the bacterium through the peptides it sheds.
 * List the major plasma-derived inflammatory mediators from the following systems and describe their inflammatory effects:
 * Clotting system:
 * Thrombin- cleaves fibrinogen to form fibrin; enhances leukocyte adhesion.
 * __Factor Xa__- increases vascular permeability, leukocyte migration.
 * __Fibrinopeptides__- chemotactic, increase vascular permeability.
 * Fibrinolytic system:
 * (acts as a kind of negative feedback mechanism on the clotting system to ensure it doesn't get out of hand.)
 * __Plasmin__- cleaves fibrin to form fibrin fragments (which increase vascular permeability) and complement fragments (which are anaphylatoxic).
 * Kinin system:
 * __Bradykinin__- vasodilator, increases vascular permeability, induces pain, and induces contraction in smooth bronchial (not vascular) muscle.
 * Complement system:
 * C3a, C5a: anaphylatoxins (bind mast cells, induce histamine release).
 * C3b: opsonins.
 * C5a: chemotactic for PMNs and macrophages; increases neutrophil adhesion; stimulates synthesis/secretion of arachidonic acid metabolites (see below).
 * List the major lipid mediators and their role in inflammation.
 * [Notice that he mentioned to me in class that he was more interested here in the big picture than the specific chemical agents. But take it with a grain of salt.]
 * __Arachidonic acid metabolites__- derivatives of cell membrane phospholipids; potent inflammatory mediators, inhibited by aspirin and NSAIDs. Act through G-coupled receptors. Main ones are __leukotrienes__ and __prostaglandin H2__.
 * [Just for shits and giggles: arachidonic acid-to-prostaglandin H2 is catalyzed by cyclooxygenases (COXs); COXs are inhibited by aspirin and most NSAIDs.]
 * Prostaglandin H2 (PGH2) has some derivatives of its own:
 * TXA2 (thromboxane-2): vasoconstriction, platelet aggregation.
 * PGI2 (prostacyclin-2): vasodilation, inhibits platelet aggregation.
 * PGD2, PGE2, PGF2a (prostaglandins): vasodilation, promote edema
 * Leukotrienes:
 * LTC4, LTD4, LTE4: vasoconstriction**, bronchoconstriction, increase vascular permeability.**
 * LTB4: chemotactic for neutrophils.
 * These originate largely from macrophages, but note that particular kinds of cells that are activated to produce these compounds can trigger other cells to produce them as well-- a kind of regulated positive feedback mechanism.
 * Note that Cohen said earlier that prostaglandins and leukotrienes are eosinophil attracting factors.
 * [Cool thing: Phospholipase A is responsible for producing arachidonic acid out of cell membranes. Corticosteroids, like prednisone, inhibit this enzyme; they also decrease the number of leukocyte adhesion molecules to reduce neutrophil infiltration.]
 * Describe the pathways (including the enzymes involved) for the production of the inflammatory mediators in objectives #2 and #3.
 * See handout's Powerpoint slides for particulars. General idea:
 * The plasma-derived inflammatory mediators are triggered by Factor XII activation-- this in turn is activated by endotoxin, activated platelets, or contact of plasma with collagen or basolateral membranes in damaged tissue.
 * The arachidonic acid metabolites are (I think) produced initially in macrophages, but notice that arachidonic acid is found in a wide variety of cell membranes and can be activated to form its metabolites by cell-cell interactions.
 * Discuss cytokines and their effects.
 * Cytokines.. yeah. They pretty much do anything. Bring in neutrophils, produce fever, prompt apoptosis, bake cupcakes, you name it. Some important ones he mentions:
 * IL-1 and TNF-alpha: released by activated macrophages to induce the acute phase reaction as well as a variety of local pro-inflammatory events. Notice that they also stimulate suppression of hematopoiesis (may lead to underproduction anemia due to chronic disease/inflammation).
 * Note that IL-1 also activates fibroblasts to start laying down collagen (thus scarring in chronic inflammation).
 * IL-2: released by activated Th1 cells to stimulate activation of nearby Th1, Th2, and killer T cells. Notice that some immunosuppressive drugs (like cyclosporin) target IL-2 (sensible enough since it's the master regulator of the adaptive immune response) and that it's not produced well in some forms of SCID.
 * IFN-gamma: released by activated Th1 cells and NK cells to cause vasodilation and attract/activate macrophages. Since activated macrophages are what secrete IL-1 and TNF-alpha and kick off lipid-soluble mediator synthesis, this is fairly important.
 * IL-8: Chemokine triggered by TLR binding to antigens (can be in any cell with TLRs, which is most of them, but especially in macrophages); chemotactic for neutrophils.
 * Describe the sources and effects of vasoactive amines.
 * Vasoactive amines- a fancy way of saying, primarily, histamine. (also serotonin to a lesser extent.)
 * Made in advance (preformed) in mast cells, basophils, and platelets.
 * Released upon degranulation of those cells; this can be triggered by IgE binding, trauma, heat, C3a/C5a fragments, various cytokines (IL-1, IL-8).
 * Effects are mainly to induce arteriolar dilation as well as vascular permeability (binds to receptors on endothelial cells to induce opening of cellular junctions).
 * Describe the sources, synthesis and effects of nitric oxide.
 * Nitric oxide (NO) is produced pretty much everywhere in the body. The levels at which it is produced, however, depends on a particular enzyme (nitric oxide synthase or NOS), which is upregulated or downregulated in response to various stimuli.
 * Note different effects of NO depending on where it's produced:
 * Type II NOS (type I is involved in CNS blood flow, not general inflammation) is remarkable here particularly for its microbiocidal effects to engulfed pathogens when produced inside macrophages.
 * Type III NOS is expressed by endothelial cells in particular and seems to be at least partly counteractive of certain inflammatory responses. It relaxes smooth muscle, is an anticoagulant (turns off activated platelets), and counteracts leukocyte recruitment. Note that it's also microbiocidal.
 * Discuss the biochemical events involved in stimulus response coupling during neutrophil activation.
 * I'm not really sure what this is, but his notes describe stimulus-response coupling as being mediated by the activation of phospholipase C (leading to the formation of diacylglyceride and inositol triphosphate, second messengers that release calcium from intracellular stores; the calcium potentiates cell movement and adhesion.
 * Describe the neutrophil-derived inflammatory mediators and their effects.
 * Again, I'm not sure what he means. Neutrophils produce a variety of things that can mediate inflammation, most notably reactive oxygen species and proteases in their granules. These are mostly described below.
 * How is the oxidative burst reaction of neutrophils important in inflammation?
 * The intended way: neutrophils use reactive oxygen species (ROS) to destroy engulfed pathogens.
 * The unintended way: the ROS produced by neutrophils, particularly in cases in which there are large numbers of pathogens to be killed, usually winds up killing the neutrophil, and can spill out into the extracellular space where it can damage endogenous cell surfaces and stimulate more inflammation.
 * How is neutrophil degranulation important in inflammation?
 * Again, like the oxidative burst, it seems to be both good (proteases attack pathogens) and bad (the same proteases can attack endogenous cells-- eg. elastase, as mentioned above). It can self-perpetuate its own inflammation by damaging local cells

TLR-4: inflammation (vasodilation, fluid outflow, neutrophil attraction) Factor XII: fibrin formation Complement activation
 * Endotoxin:

Vasoactive amines- histamines, serotonin. Induce arteriolar dilation and vascular permeability.

Type II nitric oxide synthase (NOS): microbiocidal to engulfed pathogens inside macrophages Type III NOS: anticoagulant, stops leukocyte influx, partly microbiocidal.

=**Vaccines: Basic concepts and novel strategies for vaccine development**=


 * [Again, skipped out on 2 hours of Dra. Holmes. These LOs are from her notes.]**


 * Describe the requirements for an effective vaccine to prevent or treat an infectious disease.
 * Ideally, it contains:
 * Surface antigens of the pathogen in question
 * Any toxins made by the pathogen (or their toxoids, if possible)
 * Any particular peptides that elicit cell-mediated immunity
 * Identify microbial antigens appropriate for immunization
 * Most notably, things like the cold don't work so well-- too many types of surface antigens (serotypes), changing too quickly, to immunize against effectively. Notice that we still make vaccines against the changing varieties of flu, however.
 * Aside from that, live vaccines containing organisms with particularly effective protection against the immune system (ie encapsulated orgs, very very virulent orgs, anti-interferon viruses, etc) are tricky too--concerns about accidental infection.
 * Define the common terms concerning vaccines and immunization
 * Passive immunization: when you inject someone else's antibodies to counter an infection.
 * Active immunization: when you inject some antigen to prompt development of an internal immune response.
 * Efficacy: the degree of protection against a pathogen that is conferred by immunization.
 * Compare the advantages and disadvantages of killed virus vaccine vs. live attenuated vaccine.
 * Killed virus: Safer, but not as efficacious as live (doesn't stimulate MHC type I immune responses).
 * Live attenuated virus: Less safe (are you sure it's attenuated enough not to cause disease?), but provide good all-around, long-lasting immunity due to both MHC types involved and small spread of virus in body of recipient.
 * Describe how early live attenuated vaccines were made to prevent acute systemic diseases
 * Started with yellow fever (isolate a virus and pass it through organisms it's not designed to infect in order to attenuate it), went on to target polio and measles.
 * Describe problems still encountered with developing successful immunization strategies for acute local respiratory or enteric infectious diseases
 * According to the notes, these diseases - because they stay localized outside the epithelia - tend to avoid the circulating IgG and T cells that are ubiquitous inside the body; therefore immunization to produce IgG and T cells doesn't do a whole lot of good.
 * Explain how immunization with recombinant viral proteins, virus-like particles, and DNA vaccination work.
 * Recombinant viral proteins: can insert genes encoding certain viral proteins onto a more innocuous carrier's genome; then can give the carrier to recipient. Should elicit a response against the proteins but not expose the recipient to infection. Notice also that you can give a pretty large dose of carrier to boost immune response without unduly endangering the patient.
 * Virus-like particles: Essentially you take a virus's structural proteins but take out the nucleic acid, then use that as your vaccine.
 * DNA vaccination: insert plasmids into the recipient so that the infected cells create a particular protein (which is a duplicate of a protein expressed by a particular pathogen). This can result in both MHC types of immunity, while avoiding the problem of applying a live pathogen.
 * Explain how some infectious diseases can be prevented or ameliorated by passive immunization with human IgG antibody (or pathogen specific IgG) after exposure to the pathogen or toxin.
 * This is pretty simple. If you've gotten bit on the ass by a rattlesnake and your buddy flatly refuses to suck out the poison, you can take some of his IgG (assuming he's been bitten by a rattlesnake and survived) or some anti-rattlesnake IgG grown in culture, and it'll bind the toxin in your blood so that it can be broken down by complement and phagocytosis.
 * Describe the process for approval and monitoring of new vaccines
 * Several phases of testing:
 * Phase I: small-scale safety testing (does it kill anyone?)
 * Phase II: intermediate-scale safety and dosing testing (does it kill anyone at the optimal dosing?)
 * Phase III: large-scale safety and efficacy testing (does it even work? Oh, and does it kill anyone?)
 * Phase IV: post-marketing safety surveillance (we know we said it's safe, but did it kill anyone anyway?)

=**Influenza- Clinical Correlations**=


 * [Note these are mostly just the LO's Dr. Anderson posted online.]**
 * Know the basic structure of influenza virus:
 * a. Single stranded RNA virus.
 * b. Genome is composed of 8 "negative-strand" RNA segments.
 * c. 2 glycoproteins are important in virulence:
 * i. Hemagglutinin –important in virus __entry__ into cell (binds to sialic acid).
 * ii. Neuraminidase—important in virus __exit__ from cell.
 * iii. Many types of hemagglutinin and neuraminidase-these are designated by numbers.
 * Hemagglutinin type is designated by the letter “H”.
 * Neuraminidase type is designated by the letter “N".
 * Together these designate the virus subtype (example H3N2).
 * Notice that H and N are the main influenza antigens that the immune system recognizes.
 * d. Matrix protein- matrix proteins are proteins that link the viral envelope with the viral core. M2, an antiviral target, is a proton channel protein that triggers release of the genome into the cytoplasm under acidifying conditions in the endosome.
 * [Type A flu: most severe; can cause pandemics/epidemics; infects birds, swine, horses, seals, humans, etc; genome changes very rapidly (which is probably responsible for the other three).]
 * Note that we're mainly concerned with birds, because they're kept together in large numbers under crappy conditions and flu can develop and spread easily, and pigs, because they can be infected with both avian and human flu viruses and could in principle give rise to a mixed-genome flu strain that's particularly nasty.
 * Once again, a good utilitarian medical argument for pushing the decent treatment of animals.
 * [Type B flu: occurs only in humans; less severe.]
 * Understand antigenic drift (point mutation) and antigenic shift (reassortment of genome segments).
 * Drift tends to slightly change the presented H/N antigens (just enough that the immune system doesn't recognize the virus as something it's seen before).
 * Shift radically restructures the viral genome (as when two types of flu virus that have infected the same host cell mix their genomes together by swapping genome segments).
 * By convention, antigenic drift does NOT change the subtype ('named type,' ie. H2N2) of the virus.
 * Understand that antigenic shift causes pandemics.
 * i. Results from 2 different species of influenza virus infecting the same cell.
 * ii. Pigs are a potential mixing vessel (they have receptors for human and avian influenza).
 * iii. If pig cells are co-infected with an avian strain and a human strain, RNA segments could reassort to produce novel virions that can infect humans.
 * iv. Novel virions might be so different than previously circulating strains that humans have no prior immunity to them=pandemic.
 * Understand that the H5N1 avian influenza outbreak is close to evolving into a human epidemic. Understand the stages of a pandemic [new flu subtype, must infect humans and be unpleasant, must pass from human to human] and that sustained human-to–human transmission of an avian influenza virus (such as H5N1) would have to occur to start the pandemic.
 * Basically right now we're waiting for H5N1 or one of its ilk to adapt for efficient human-to-human transmission.
 * [Notice that flu treatment with matrix protein inhibitors are almost universally resisted and no longer much used; currently we use neuramidinase inhibitors instead.]
 * Know basic principles of infl. vaccines:
 * a. Made yearly based on predictions of circulating strains.
 * b. 2 types of vaccines are available:
 * i. Live, attenuated vaccines—administrated intranasally.
 * ii. Killed vaccines—administered intramuscularly.
 * Both are called "__trivalent__"- 2 A types and 1 B type included in every yearly vaccine.
 * c. Know which vaccine can be given to pregnant or immunocompromised persons (killed vaccine) and which vaccine should only be given to those populations if benefit outweighs risk (live vaccine).
 * d. Know that the current influenza vaccines provide no protection for the H5N1 strain
 * Know effective influenza prevention strategies:
 * a. Annual vaccination
 * b. Cover your mouth if you sneeze or cough
 * c. Wash your hands—the most effective strategy
 * Know who is recommended to receive influenza vaccine.
 * "High-risk" group:
 * All children to 5 years
 * All healthy adults over 50
 * People 5-50 with immune problems, diabetes, cancer, pulmonary diseases, etc.
 * Pregnant women
 * Household contacts of high-risk people
 * Health care workers

=**Antiviral agents**=

This lecture will introduce the use of antiviral agents designed to treat patients with: a) Influenza A and B. b) Herpes Simplex and Varicella Zoster Viruses. c) Hepatitis B and C. d) Cytomegalovirus. e) Miscellaneous Viral Infections.

Special emphasis will be placed on learning: 1) The mechanisms of drug action. 2) The mechanisms of drug resistance. 3) The pharmacokinetic properties observed following drug administration. 4) The adverse reactions and toxicities potentially associated with drug administration. 5) The general clinical uses of the drug to treat injections.

Notice that most antivirals target the transcription of the viral genome.


 * Really, aside from the two flu drugs that are still given (both of which inactivate neuramidases), there are two main, general mechanisms of antivirals: they bind to and inactivate the viral DNA polymerase, or they incorporate into the viral DNA and slow or stop it, or both.
 * Exceptions: Docosanol (blocks membrane fusion), Ribavarin (blocks 5' capping and decreases dNTP concentration in Hep C), and Interferon-alpha (triggers endogenous anti-viral state). Honorable mention exception is Entecavir (not only inactivates DNA synthesis but also DNA priming and reverse transcription).
 * That still leaves lots of variation in what gets uptaken by which kinases, pharmacokinetics, adverse reactions, etc. But at least drug action (and thus drug resistance) isn't too complicated, assuming you can remember all the damn names.
 * Notice also that aside from the hepatitis antivirals, the only drugs that are well absorbed orally here are the flu drugs and the prodrugs (Valacyclovir, Valganciclovir, Famciclovir). Of the hepatitis AVs, the only one not available orally is interferon alpha.


 * **Influenza:**
 * Two major types: matrix protein (M2) proton channel inhibitors (not generally used any more due to resistance) and __neuramidase inhibitors__ (zanamivir and oseltamivir).
 * **M2 channel inhibitors:** Amantadine** and **Rimantadine**.
 * Drug action: Binds and inactivates the M2 proton channel in the envelope of influenza A (__A only__) viruses. This prevents acidification of the virion, which in turn inhibits its uncoating and the release of its genome into the cytoplasm.
 * Secondarily, the drug may also negatively affect hemagglutinin production during virion assembly.
 * Drug resistance: Mainly mutations in the M2 protein; prevent drugs binding. Note that these mutations provide resistance to both M2 channel inhibitors.
 * Pharmacokinetics:
 * Good //po// availability.
 * Amantadine is excreted, unchanged, by the kidney.
 * Rimantadine is extensively hepatically metabolized (hydroxylated) and then excreted by the kidney.
 * Adverse reactions: Minor side effects only (minor GI/CNS; more CNS with amantadine due to ability to cross BBB).
 * Clinical uses: Used to treat Influenza A; when taken as a prophylactic, is very effective against type A flu and shortens duration of symptoms by 1-2 days.

Neuramidase inhibitors: **Zanamivir** and **Oseltamivir**.
 * Drug action: Bind and inactivate neuramidase proteins on the viral envelope (__both A and B influenza__), causing a loss of ability to dissociate from the host cell.
 * Normally neuramidases bind to and cleave sialic acid residues on the host cell surface; when bound to zanamivir or oseltamivir, can't cleave.
 * Drug resistance: Relatively rare; generally results from mutations in hemagglutinin (not neuramidases) that result in less need for neuramidase-mediated release. Occasionally can result from mutations in neuramidases, but rarer.
 * Pharmacokinetics: Zanamivir: inhaled powder. Oseltamivir: oral administration as a prodrug activated by esterase cleavage.
 * Adverse reactions: Zanamivir well tolerated; oseltamivir can produce nausea and vomiting (mild flu symptoms).
 * Clinical uses: Used to treat influenza A and B; oseltamivir used to treat avian influenza as well.


 * Herpes simplex/varicella zoster:
 * 6 drugs:
 * **Acyclovir** (Acy)
 * **Valacyclovir** (Vala)
 * **Penciclovir** (Pen)
 * **Famciclovir** (Fam)
 * **Vidarabine** (Vid)
 * **Docosanol** (Doc)
 * Drug action: The first 5 inhibit synthesis of viral DNA (generally guanine or adenine analogs); the 6th (docosanol) is a topical over-the-counter drug (saturated fatty alcohol), which seems to prevent viral attachment to/entry into cells.
 * Acyclovir and valacyclovir get monophosphorylated and uptaken into the cell with viral protein kinases, then get a couple more phosphate moieties added by cellular kinases inside the cell. After that, it's integrated into viral DNA but can't be elongated from (no 3' OH), thus terminating viral replication. They also bind irreversibly to the viral DNA polymerase, leading to its inactivation.
 * Penciclovir/Famciclovir: don't function as DNA strand terminators (have 3' OH) but are otherwise similar to acyclovir; primary mechanism of action is to target viral DNA polymerase and inactivate it.
 * Vidarabine: adenine (not guanine) analog. Like Pen/Fam, has a 3' hydroxyl group and thus doesn't terminate DNA strand elongation; also like them, it seems to bind to DNA Poly and inactivate it.
 * Docosanol: inhibits viral envelope's fusion with the host cell membrane.
 * Drug resistance: three main mechanisms.
 * Reduced/lost expression of viral tyrosine kinases (Acy/Vala only)
 * Altered viral tyrosine kinase activity (Acy/Vala only)
 * Altered structure of viral DNA Poly such that it's no longer bound by analogs (Acy/Vala/Pen/Fam/Vid)
 * Pharmacokinetics:
 * Acyclovir = best therapeutic index but poor oral avail; admin. IV/topically.
 * Valacyclovir = esterized prodrug of acyclovir; activated by esterases in GI/liver (allows //po// administration).
 * Penciclovir: poor oral avail; administered IV (assumed)
 * Famciclovir: good oral avail (prodrug of Pen, activated by liver enzymes)
 * Vidarabine: no good //po// ; IV requires too large a concentration; used topically.
 * Docosanol: as mentioned, topical.
 * Adverse reactions:
 * Acyclovir/Valacyclovir: Generally well tolerated; high doses of valacyclovir can cause temporary CNS deficiencies, an effect exacerbated by AZT or cyclosporine.
 * Note trend: prodrugs have more CNS side effects (no surprises there, as they're formulated to get through membranes better).
 * Penciclovir/Famciclovir: similar to Acyclovir.
 * Vidarabine: teratogenic, shouldn't be used during pregnancy.
 * Clinical uses:
 * Acyclovir and valacyclovir are used mainly to treat genital herpes simplex viruses.
 * Penicyclovir and famciclovir used primarily for managing herpes simplex and varicella zoster viruses.
 * Vidarabine is applied solely as a topical, ophthalmic ointment to treat herpes simplex virus keratitis.
 * Docosanol, as mentioned, is a topical cream to treat orolabial herpes.


 * Cytomegalovirus:
 * 4 drugs:**
 * Ganciclovir
 * Valganciclovir
 * Cidofovir
 * Foscarnet


 * Drug action:**
 * Ganciclovir + Valganciclovir: DNA polymerase inhibitors similar in structure to acyclovir, but containing a 3' OH group. Thus they can't function as DNA elongation inhibitors-- but they do slow down, and eventually halt, viral DNA replication. Uptaken and phosphorylated by viral protein kinases that are particular to CMVs, then incorporated into growing DNA. Valganciclovir is the esterized form of ganciclovir (for //po// admin).
 * Cidofovir: cytosine monophosphate analog, comes with an initial phosphate on it; only needs to be phosphorylated twice more. Notice that it's uptaken by cellular, not viral, protein kinases; thus its concentrations are equivalent between virally infected and uninfected cells.
 * Foscarnet: completely different horse from all other viral agents-- it's an inorganic pyrophosphate; requires no cellular activation; binds noncompetitively to DNA/RNA polymerases and inactivates them.
 * Drug resistance:
 * Ganciclovir, Valganciclovir: mutations in CMV protein kinase (UL97) required for uptake.
 * Ganciclovir, Valganciclovir, Cidofovir, Foscarnet: mutations in viral DNA Poly.
 * Pharmacokinetics:
 * Ganciclovir + Valganciclovir: IV and //po// respectively. Excreted unmetabolized by the kidney.
 * Cidofovir: IV; excreted unmetabolized by the kidney.
 * Foscarnet: IV; excreted unmetabolized by the kidney.
 * Adverse reactions:
 * Ganciclovir + Valganciclovir: myelosuppression is the major side effect.
 * Cidofovir: renal toxicity is the major sided effect; it's also a tetratogen (not to be taken during pregnancy)
 * Foscarnet: very severe renal toxicity and hypocalcemia (can be fatal).
 * Clinical uses:
 * Ganciclovir + Valganciclovir: CMV suppression in immunocompromised patients.
 * Cidofovir: Same; used to treat CMV strains resistant to Ganciclovir.
 * Foscarnet: CMV retinitis. Also vs. Ganciclovir-resistant CMV and Acyclovir-resistant herpes/varicella infections.


 * **Hepatitis B and C:**
 * **4 drugs:**
 * Adefovir
 * Entecavir
 * Ribavirin
 * Interferon-alpha

Drug action:
 * Adefovir: Adenosine monophosphate analog, already monophosphorylated; competes for viral DNA polymerases and inactivates them.
 * Entecavir: Guanine analog; uptaken by cellular kinases; competes with cellular dGTP for viral DNA polymerases; inhibits not only DNA synthesis but priming and reverse transcription.
 * Ribavirin: purine analog, uptaken by cellular kinases; inhibits GTP-dependent 5' capping of viral mRNA (decreases transcript stability) and inhibits dGTP production (lowers nucleoside concentrations in cell).
 * Interferon-alpha: mimics of endogenous cytokines (INF beta and gamma aren't used at the moment). Have no enzymatic activity; bind to interferon receptors on cells to induce anti-viral cell states. Anti-viral states inhibit viral mRNA synthesis and translation, alter Golgi function, etc. (see "Host Responses to Viral Infection")
 * Drug resistance:
 * Adefovir: occasionally mutations in DNA polymerase
 * Entecavir: no resistance observed
 * Ribavirin: no resistance observed
 * Interferon-alpha: no resistance observed
 * Pharmacokinetics:
 * Adefovir: IV, or //po// as prodrug (adefovir dipivoxil). Excreted unmetabolized by the kidney.
 * Entecavir: good //po// distribution. Excreted unmetabolized by the kidney.
 * Ribavarin: good //po// distribution. Metabolized by liver, excreted by kidney.
 * Interferon-alpha: IM shots or SC injections. Metabolized by liver and kidney.
 * Adverse reactions:
 * Adefovir: renal toxicity is the main side effect.
 * Entecavir: minor-- headaches, cough, fatigue, minor GI problems.
 * Ribavirin: Main side effect is bone marrow suppression and anemia; it's very teratogenic and shouldn't be used with pregnant women (or pregnant health care workers).
 * Interferon-alpha: myelosuppressive, granulocytopenia, thrombocytopenia, flu-like symptoms that last about a day, some CNS abnormalities.
 * Clinical uses:
 * Adefovir: useful against hepatitis B
 * Entecavir: most useful drug against hepatitis B
 * Ribavirin: combined with interferon-alpha-2 for treatment of hepatitis C.
 * Note can also be used in aerosolized form against pneumonia and respiratory synctial virus.
 * Interferon-alpha: useful against hepatitis B; combined with Ribavirin for hep C.


 * Miscellaneous antivirals:
 * For RSVs (respiratory synctial viruses), as mentioned, can be treated with ribavirin (the anti-hepatitis drug) or **Palivizumab**, a monoclonal antibody vs. RSV (can be therapeutic or prophylactic).
 * For genital warts: a drug he apparently doesn't want us to memorize, Imiquimod, which is a TLR activator.

Amantadine (more CSF) Rimantadine

Zanamivir (inhaled powder) Oseltamivir (oral, ester)

Acyclovir (IM, guanine, stops elong, binds DNA Poly) Valacyclovir (oral, guanine, stops elong, bind DNA Poly) Penciclovir (IM, guanine, binds DNA Poly) Famciclovir (oral, guanine, binds DNA Poly) Vidarabine (topical in eyes, adenine, binds DNA Poly) Docosanol (topical, inhibits viral membrane fusion with host)

All first five get uptaken by viral kinases.

Resistance due to altered viral kinases or altered DNA Poly.

Docosanol used for orolabial herpes, vidarabine for ophthalmic.

Vidarabine is teratogenic-- not for pregnant chicks.

Ganciclovir- similar to acyclovir (G analog) but have 3' OH-- slow down/halt DNA synthesis. Valganciclovir- esterized Ganciclovir Cidofovir (IV) - cytosine analog. Uptaken by cellular kinases, not viral. Same MOA as others. Foscarnet- totally different, inorganic pyrophosphate (IV). Binds and inhibits DNA/RNA Polys.

G+V uptaken by viral kinases; cidofovir by cellular kinases.

Resistance caused by viral protein kinase (G+V only) or DNA Poly.

Cidofovir used to treat G+V-resistant; Foscarnet used for C/G/V-resistant.

Foscarnet = high renal toxicity **and hypocalcemia**. G+V: myelosuppression (tho CMV suppresses it anyway). Cidofovir: renal toxicity and teratogenic.

Adefovir- monophophorylated adenosine analog, binds and inactivates DNA Poly. Entecavir- guanine analog, uptaken by cellular kinases. Inactivates DNA synth, priming, and reverse transcription. Ribavirin- purine analog, uptaken by cellular kinases. Inhibits 5' mRNA capping; reduces levels of dGTP available in cell. Interferon alpha- mimics endogenous compound; not uptaken but acts on surface receptors;

E and R taken up by cellular kinases.

Resistance caused by altered DNA Poly (Adefovir), but mostly none observed.

Adef = B Ente = B IFN-g + Ribavirin = C IFN-g alone: B

Adefovir causes renal toxicity. Ribavirin causes hematosuppression and is teratogenic. INF-a causes some hematosuppression and brief flu-like symptoms.

=**Tissue Repair**=


 * Define repair and compare the concepts of parenchyma and stroma.
 * Repair: the replacement of lost tissue.
 * Two kinds of repair: regeneration and fibrosis.
 * Parenchyma: the "business end" of a tissue (the cells in the tissue that perform its designated function).
 * Stroma: what lets the business ends do their business (the structural and supportive cells in a tissue).
 * Define regeneration, indicate the two requirements and give examples of regeneration.
 * Regeneration: a subset of repair; the replacement of lost tissue by cells identical to the original cells. Requires:
 * (1) viable stem cells what can divide into the type of cells that were lost
 * (2) viable stroma (w/ intact basolateral membrane) what can support, organize, and supply the replacement cells.
 * Examples: regeneration in the parenchyma of the liver (hepatocytes) in acute liver failure, or the parenchyma of the kidney (tubules) in acute tubular necrosis.
 * Define stem, labile, stable, and permanent cells, give examples, and indicate their role in healing and regeneration.
 * Stem cells: by this point, pretty well covered. Recall that they show "asymmetrical replication"-- that is, one daughter cell stays as a stem cell, while the other differentiates into a functional cell.
 * Example: crypt cells in gut epithelia.
 * **Labile cells** : differentiated, mature cells that are __constantly replaced all the time__.
 * Example: surface epithelium of skin and GI tract.

Stable cells:** differentiated, mature cells that are __only slowly replaced__. **
 * Example: hepatocytes, renal tubular epithelial cells, endothelia, smooth muscle.


 * Permanent cells** : differentiated, mature cells that are __never replaced__, though they can sometimes heal or replace damaged parts of themselves.
 * Example: skeletal muscle, cardiac muscle, CNS neurons.

The reason these divisions are important is that the extent and rate of possible regeneration depends on how rapidly the cells turn over normally. Damage to permanent cells cannot be regenerated (which is why MIs result in permanent cardiac damage). Generally, both labile and stable cells can be well regenerated.
 * **Define fibrosis and describe the three types of situations in which repair occurs by fibrosis rather than by regeneration. Give examples.**
 * Fibrosis** : a subset of repair; the replacement of lost tissue by fibrous connective tissue (generally, after maturation, type I collagen). **
 * Situations that result in fibrosis:
 * Loss of permanent parenchymal cells
 * Example: myocardial infarctions, as mentioned.
 * Loss of stroma
 * Example: acute tubular necrosis or liver damage which progresses past tubules or hepatocytes to impact the stromal cells around them.
 * Continuous loss of parenchyma/stroma
 * Example: alcoholic hepatic cirrhosis- constant damage to parenchyma results in a lack of ability to regenerate.
 * **Define organization and indicate the situations in which it occurs; give examples. Describe a recanalized thrombus.**
 * Organization** : fibrosis leading to scar (mature, type I collagen) formation (some fibroses may break up before this point). Seems, from his notes, to apply mainly to thrombi and exudates.
 * Examples: Pneumonic lung exudate organization can lead to scar formation on the outside of the lung; coronary artery thrombi can become organized into scar tissue as well.


 * A __recanalized__ thrombus is a clot (thrombus) through which new vascular channels have been tunneled, allowing reperfusion of the blocked tissue.**
 * Describe the sequence of events involved in the healing of a skin wound and an infarct.
 * Notice that this sequence describes __fibrosis__ only.
 * (1) Removal of dead tissue, exudate, or blood. This is accomplished by neutrophils and macrophages and is called **debridement**.
 * (2) New angiogenesis and fibrogenesis takes place: new proliferation and ingrowth of blood vessels by VEGF (vascular endothelial growth factor), fibroblast-driven production of the //ground substance// (remember this? extracellular matrix with proteoglycans?) and //Type III (pliable) collagen//.
 * This new tissue produced in healing is called **granulation tissue**.
 * (3) By 10 days to two weeks later, the debridement is complete and the debrided material has been replaced by granulation tissue. Increased amount of mature, strong Type I collagen is being laid down to replace the pliant Type III collagen. Revascularization and restoration of ECM continues.
 * (4) At the end of about 2 months, the area has been wholly converted to Type I collagen - a __scar__ - which can get up to about three-quarters of the original tissue's tensile strength.
 * Define: debridement, granulation tissue, collagens types I and III, tensile strength, scar, and keloid.
 * Most of these have already been described. Tensile strength is what resists when you pull of both sides of something.
 * A **keloid** refers to a scar that exceeds the dimensions of the original tissue, and thus protrudes out of the surface of the surrounding tissue. Particularly seen in African-Americans.
 * Indicate the difference between healing by primary vs. secondary union.
 * **Primary union** : fibrosis within a wound whose edges have been brought together (as in a sutured wound).
 * **Secondary union** : fibrosis within a wound whose edges are unapposed. The wound has to contract in order for healing to occur. Notice, vis-a-vis wound packing, that the surface epithelia of secondary wounds usually heal before the rest of it (which can produce subcutaneous abscesses).
 * Discuss some systemic and local factors which may impede wound healing.
 * Systemic: poor nutrition (incapacity to make more tissue), disease (diabetes- possibly by peripheral nerve and artery deterioration), some drugs (corticosteroids suppress inflammation).
 * Local: retention of dead tissue or foreign body at wound site, infection at wound site, reduced blood supply to wound site.

=**Hemodynamic Basis of Disease**=


 * Discuss the three pathogenetic mechanisms of transudate formation. Describe clinicopathologic examples.
 * Recall that there are no cells found in transudate, as opposed to exudate-- transudate tends to be less concentrated with protein as well.
 * __Increased intravascular hydrostatic pressure__.
 * Example: Left ventricular failure leads to increased left ventricle pressure, which backs up into left atrial pressure, which leads to increased pressure in the pulmonary veins, venules, and capillaries. This leads to transudate forming in the alveolar spaces-- a phenomenon called **pulmonary edema**.
 * __Reduced intravascular oncotic pressure__ (ie not enough of an osmotic gradient to reabsorb water at capillaries).
 * Example: Hypoalbumenia due to malnutrition (not enough albumen concentrated in blood; when water diffuses out through capillary walls, it's not reuptaken due to osmotic gradient).
 * __Increased pressure in lymphatic vessels__.
 * Lymphatic blockage, as in excision of lymph nodes in a chain, results in the accumulation of fluid.
 * Define and compare/contrast: active vs. passive hyperemia.
 * Hyperemia: (hyper + heme = lots of blood) an abnormally large amount of blood at a particular location.
 * __Active hyperemia__: dilation of arterioles/arteries results in increased supply of oxygenated blood in a tissue-- thus it appears red (ie //rubor// in inflammation).
 * __Passive hyperemia__: impaired venous drainage results in stasis of deoxygenated blood at the tissue site-- thus it appears blue.
 * Note that hyperemia is often described as "congestion" of an organ.
 * List some terms used to describe different types of hemorrhage.
 * Terms relating to quantity:
 * //Petechiae// : very small amounts of blood (specks).
 * __Purpura__: spots of blood up to 1 cm (as in Idiopathic Thrombocytopenic Purpura, see "Type II Immunopathology").
 * __Ecchymoses__: larger quantities of blood.
 * Terms relating to location:
 * __Hematoma__: mass of blood infiltrating soft tissue.
 * Hemothorax, -pericardium, -peritoneum: blood in all those places.
 * Describe the features, possible outcomes, predisposing factors and complications of thrombosis
 * Thrombosis is an __intravascular phenomenon only__. Clotting of a hematoma, for example, is not thrombosis.
 * The clots that are formed in thrombosis are made up largely of platelets and fibrin, and are adherent to endothelial surfaces.
 * [Note that clots never form without ionic calcium.]
 * Outcomes:
 * Lysis of thrombus: fibrinolytic agents dissolve the clot.
 * Propagation of thrombus: clot grows and gets bigger.
 * Organization of thrombus: clot transforms into scar tissue (fibrin and platelets replaced by permanent fibrous tissue).
 * Recanalization of thrombus: usually happens during organization; new vessels form through the clot.
 * Define and describe disseminated intravascular coagulation (DIC).
 * **DIC** : clotting factors get extensively, abnormally activated. Often caused by Gram-negative sepsis or extensive tissue necrosis. The blood begins to coagulate and form clots in vessels, leading to ischemia and organ damage. Notice that the available supply of clotting factors is taken up in these clots, leading to intractable bleeding from mucosa, skin, and internal vessels.
 * Define amniotic fluid, air/gas and fat emboli and their clinicopathologic syndromes
 * Note that an __embolus__ (plural, __emboli__) is basically something that's partly or fully obstructing a vessel. Technically, that's probably all thrombi.
 * __Amniotic fluid emboli__ come about due to tearing of umbilical veins and placental membranes during childbirth. Amniotic fluid gets into the mother's circulation and has some manner of chemical effect by which emboli are produced in the mother.
 * __Air/gas emboli__: air introduced into the arterial system (in venous system, generally air is absorbed) during delivery, abortion, thoracic trauma, etc, can form an embolus.
 * __Fat emboli__: Generally, these are bits of adipose bone marrow (fat) that get into the bloodstream and cause emboli after severe bone fracture.
 * Define infarction with regard to total vs partial obstruction. Discuss reversibility, healing and modifying factors.
 * **Infarction** : an area of ischemic (coagulative), irreversible necrosis resulting from obstruction of the corresponding artery by an embolus.
 * Results in fibrosis (scarring) of the affected area.
 * Both total obstruction and partial obstruction of the artery can result in infarction or a lack of infarction (a total obstruction's target tissue can still be supplied by collateral arteries, a partial obstruction can still sufficiently reduce blood flow to a tissue to result in ischemic injury).
 * Define and describe the four types of shock, the key metabolic changes, the three stages and four important target organs and lesions
 * **Shock** : systemic hypoperfusion of tissues. Characterized by tachycardia and hypotension, with increasing metabolic acidosis secondary to lactate accumulation from the shift to anaerobic metabolism.
 * Types of shock:
 * Cardiogenic: reduced cardiac output
 * Hemorrhagic/hypovolemic: reduced blood volume
 * Septic: systemic vasodilation due to TNF-alpha, IL-1, and other cytokines, most often due to extensive exposure to Gram-negative bacteria (LPS).
 * Neurogenic: a defect in autonomic nervous system control, often due to CNS damage, leading to systemic vasoconstriction. Uncommon.
 * Stages of shock:
 * Nonprogressive shock: The body's compensatory mechanisms are holding their own; vital organs are still being perfused adequately.
 * Progressive shock: The body's compensatory mechanisms are being overwhelmed; vital organs are becoming ischemic.
 * Irreversible shock: The body's compensatory mechanisms have more or less given up; vital organs are irreversibly damaged.
 * Important organs in shock:
 * //Brain// (shock can result in hypoxic encephalopathy)
 * //Lungs// (shock can result in acute respiratory distress syndrome)
 * //Kidneys// (shock can result in acute tubular necrosis)
 * //GI tract// (shock can result in hemorrhagic necrosis of the GI mucosa)

=**Introduction to Fungal Pathogens**=


 * Describe the characteristics of fungi with respect to morphology, cell composition, and biochemical functioning. Be able to explain why fungi differ from bacteria, plants, and animals.
 * Contain membrane-bound organelles (including nuclei), as per animal cells.
 * Have rigid cell walls, which (unlike bacterial cell walls) are chitinous.
 * Cell membranes contain a particular sterol compound called ergosterol.
 * Heterophilic (no photosynthesis)
 * Vary widely in size
 * Can be unicellular or multicellular, and can reproduce sexually or asexually
 * Different from bacteria: no peptidoglycan in cell wall, membrane-bound nuclei, etc.
 * Different from animal cells: cell walls
 * Different from plants: no photosynthesis, must consume matter to survive
 * Describe three means (one Linnean, two functional) for categorizing fungi. Understand that the functional categorization schema are used chiefly to discriminate between: a) superficial and deep/systemic mycoses, or b) superficial fungi acquired from soil, animals or other humans.
 * (1) Linneus: fungi are one (Mycota) of the five kingdoms at the top of the phylogenetic classification scheme, as opposed to bacteria (Monera) or protozoa (Protista).
 * (2) Classification between sexually and asexually reproducing fungi.
 * (3) Classification between where acquired:
 * From soil (geophilic)
 * From animals (zoophilic)
 * From humans (anthrophilic)
 * Notice that human-native fungi (anthrophilic) tend to trigger less immune responses than the others-- they can evade the human immune system better.
 * What he means with the whole superficial vs deep thing: a clinical way of classifying fungi is to look at whether they stay on epithelia or get into the bloodstream. Generally the former are more benign, as you would expect.
 * Explain the differences between yeast and hyphal forms of fungi (molds), and understand that some organisms may be dimorphic.
 * __Yeast__: a uninucleated (one nucleus) growth form of fungi where the fungus reproduces asexually by budding (producing blastoconidia) or dividing in half (fission). Colonies are often creamy in texture and appearance.
 * __Molds__: a more filamentous growth form ("hyphal form") of fungi in tubular forms, typically with a bunch of branching. Sometimes there's superficial divisions or walls (septae) between segments. Important distinction: with septae or not, it's still one big, branched cell (though multinucleated). There's no real separation between segments of the hyphae-- cytoplasm and substances can pass back and forth.
 * Note that yeast (uninucleated) can show psuedohyphal forms-- they're a bunch of unicellular organisms lined up in rows (Dr. High: "Like sausage links"), but still distinct segments, unlike true hyphae.
 * Many (__dimorphic__) fungi can go back and forth between these two forms depending on environmental conditions.
 * [**Rhizoids** : little tentacle-looking forms coming off of hyphal fungal forms.]
 * Understand that fungi may reproduce sexually or asexually, and be able to recognize the morphology of the basic forms of asexual spores.
 * Asexual spores:
 * Conidium: can be either macro- (multinucleated) or micro- (uninucleated). Bud off of a thin protrusion from hyphal fungi.
 * Sporangium: Similar to macroconidia, but is a membrane-bound sac containing a lot of small "endospores" (spores within spores)-- bursts to release endospores.
 * Chlamydiaspores: Extremely resistant to adverse environmental conditions. Can form at the end of hyphae (terminal) or in their middle (intercalary).
 * Arthrospores: develop along hyphae; thick-walled, barrel-shaped spores, resemble 'vertebrae' in the hyphal chain.
 * Spherules: Like sporangia, except they don't protrude off a little fungal extension.
 * Blastoconidia: Not really a spore, not sure why it's here. This is how yeast (uninucleated) buds to divide.
 * Note divisions between sexually produced spores aren't useful clinically.
 * Describe four means to diagnose fungal infections (empirical, direct examination, culture, tissue) and have a general understanding that other advanced techniques (serological or PCR) may be used for certain infections or in specific circumstances.
 * Empirical: Peer at the thing. What's it look like?
 * Direct examination: Look at a scraping of the thing under a microscope, stained with KOH (can use DMSO to lyse human material and leave cell walls).
 * Other staining techniques: India ink, chlorazol E stain.
 * Culture: Incubate a scraping on media.
 * Can use special media that are antibiotic (inhibit bacterial contamination) or which turn particular colors if a certain type of fungi are added, etc.
 * Can also use lactophenol blue to stain fungi that have already been cultured.
 * Tissue: Get a slice of the tissue and do histological analysis.
 * Use various agents (most common is PAS/D, others are calcofluor white and methenamine silver) to stain chitinous cell wells, or use mucicarmine to stain mucoid capsule.
 * I hear that other advanced techniques (serological or PCR) may be used for certain infections or in specific circumstances. No foolin'.
 * Understand the mechanism of action and selective inhibition associated with polyenes, azoles/triazoles, allylamines/benzylamines, and antimetabolites/antimitotics and unique antifungals. Be able to give an example of a drug from each of the above listed classes.
 * Note all drugs exploit differences between fungal cells and human cells.
 * Polyenes:
 * Eg. **Amphotericin** : __Fungicidal__. Punches holes in ergosterol-based cell membranes. Moderate to severe side effects: fever, chills.
 * Imidazoles/triazoles:
 * Eg. //Ketaconazole// : __Fungistatic__. Interfere with ergosterol synthesis enzyme. Note also inhibits human cholesterol synthesis very slightly. Some risk of hepatic toxicity if taken orally (inhibits CYP enzymes).
 * Allylamines/Benzylamines:
 * Eg. //Butenafine// : __Fungicidal__. Also block ergosterol synthesis by inhibiting a different enzyme; byproducts begin to accumulate within the fungal cell and are toxic to it. Less risk of hepatic toxicity than imidazoles/triazoles.
 * Echinocandins: No example given (Wiki: //Anidulafungin// ). Fungicidal against some fungi //(Candida// ) //,// fungistatic against others //(Aspergillus// ) //.// Most recent antifungals. Inhibit glycan synthesis in cell wall.
 * Lots of other antifungals: none of them affect ergosterol at all. Inhibit microtubule formation, chelate metals needed for fungal survival, inhibit fungal DNA synthesis.
 * [There's a variety of fungal resistance to various of these.]
 * [Note fungistatics affect only actively dividing fungi; fungicidals affect any fungi.]

=**Apoptosis**=


 * Discuss the origin and meaning of the term apoptosis, and relate it to programmed cell death.
 * //apo// : Greek "away from," //ptosis//, Greek "falling"; originally //apoptosis// meant trees losing their leaves. The idea is that it's a natural mechanism of losing parts you don't need any more, to make room for new parts-- which is more or less what its cellular equivalent is.
 * I don't care what Cohen says, if you don't pronounce the "p"s in apoptosis then you're an uneducated git. What, you think you're French, you can just drop consonants whenever you feel like?
 * Describe the characteristic plasma membrane, cytoplasmic, and nuclear events of apoptosis.
 * Nucleus: collapses and condenses as it is __chopped up into small, discrete segments__ (about one or two nucleosomes each), ensuring no further cell division.
 * Cytoplasm: shrinks dramatically in volume.
 * Membrane: "boils," tearing the cell apart into small apoptotic bodies which can be easily consumed by macrophages. Notice that there is __no__ leakage of intracellular contents during this process.
 * Compare and contrast apoptosis and necrosis in terms of morphology, common triggers of the two phenomena, and relative importance in physiological and pathological processes.
 * Necrosis: cells lyse and spill their nasty little guts out into the ECM.
 * Apoptosis: shrunken little membrane-bound dead cell bits.
 * Necrosis is a pathological phenomenon-- it is unplanned cell death. Ideally there is no unplanned cell death in organisms. It results in inflammation and can lead to scarring and tissue damage.
 * Apoptosis is a normal, necessary, physiological process. It does not cause inflammation and is needed to turn over senescent cells and prevent cancer. About a trillion of your cells die every day- they need to do it in a way that doesn't cause trouble for the rest.
 * Note also that necrosis is not a genetically triggered process, whereas apoptosis is activated by transcription factors inside the apoptotic cell itself-- it's a suicide, not a cytocide.
 * Common triggers: you know, for the most part, cellular damage is a common trigger for both. Which outcome (repair, apoptosis, or necrosis) depends on the __extent__ of the damage, not the nature of the damage per se. If you give a little H2O2 to a cell, it will apoptose; if you give twice as much H2O2, it will necrose. The specific cutoffs for repair vs apoptosis vs. necrosis depends on the type of cell (see next LO).
 * Name tissues in which there is most and least apoptosis. Suggest reasons for this difference.
 * Lymphocytes are extremely apt to kill themselves by apoptosis with even a small amount of damage or abnormal environmental change. By contrast, most other cells - fibroblasts are the example he gives in the notes - can repair fairly large discrepancies before they start triggering their own apoptosis.
 * The idea here is that in cells that have the most potential to go bad - like lymphocytes- are the ones in which it's easiest to induce apoptosis. This makes sense if you think about it-- you want to have the most control over the cells that have the potential to do you the most damage. This is called the "better dead than wrong" hypothesis.
 * Note that T cells are particularly susceptible to having their apoptotic pathways activated by glucocorticoid levels, which actually seems to be the mechanism by which unselected T cells are killed in the thymus-- normal fluctuation in glucocorticoid levels induces destruction in any T cell that isn't protected by selection.
 * Note also that fever induces a lot of lymphocyte cell death, which seems counterproductive.
 * Describe the role of proteases in apoptosis, and discuss the role that the mitochondrion may play in the process.
 * The idea, currently, is that proteases are largely responsible for apoptotic signaling. Partly this is because protease activity is by nature largely irreversible-- as most of us know, it's easier to cut something up than to put it back together again.
 * Apoptotic factors trigger release of cytochrome C from the mitochondria, which cleaves and activates inactive caspase 9 (protease) in the cytoplasm. Caspase 9 in turn activates cleaves and activates caspase 3, which is what actually starts to kill the cell by cleaving all kinds of stuff.
 * Notice that viruses inhibit caspases like all get-out by making viral copies of endogenous anti-apoptotic genes.
 * Discuss the essential biological difference between phagocytosis of apoptotic and necrotic cells.
 * Necrotic cells __lyse__ is the important difference-- whereas apoptosis is a nice, orderly transition into a membrane-bound, dead cell.
 * Thus macrophages that clean up necrosis have to deal with all the unpleasant things that used to be inside the necrotic cell, which are __highly pro-inflammatory__- attract leukocytes from all over the body to the site of necrosis.
 * Macrophages that clean up apotosis, by contrast, bind to phosphatidylserines that are expressed only on the surface of apoptotic cells, and can eat the whole dying thing without lysis or spillage of intracellular contents. This also means that there's no inflammation associated with it.
 * Important point about this: Most apoptosis seems to occur __inside macrophages__ after phagocytosis-- the macrophages pick it up while it's in the initial phases of apoptosis, to prevent any possible leakage during the process.
 * Interestingly: almost any cell can eat almost any other apoptotic cell in the body, although it's usually the job of macrophages. This means that in tumors, cancer cells can eat other, apoptotic cancer cells (though why would cancer cells be apoptotic?) without macrophage involvement.
 * Discuss the importance of apoptosis in tumor formation and progression.
 * Remember Dr. Sclafani from M2M-- to form malignant tumors, the idea is that you need one mutation to turn into an tumor cell (turn on oncogene), but you need a __second__ one to turn off apoptosis (the normal safety valve against tumorigenesis). (then you need some more mutations to facilitate cell mobility, metastasis, etc.)
 * Note that this is not, although it sounds similar, related to the Knudson two-hit hypothesis (that's where you inherit one defective copy of a gene and the other one gets knocked out at some point in your life-- we saw it in the context of p53 tumor suppressor genes and Li-Fraumeni syndrome).
 * Cohen's notes also say that if you just turn off normal apoptotic signaling genes, even without oncogene activation, you start to get enormous lymphadenopathy and autoimmune problems-- not producing abnormal numbers of lymphocytes, but can't get rid of the ones you have.
 * Describe the mechanisms by which one cell can induce apoptosis in another cell, and give an example.
 * Killer T cells (CD8+), recall, scan cells for the peptides they're presenting on their MHC type I complexes; if they detect and bind to something in the peptide-presenting cleft, they transduce apoptotic signaling pathways in the other cell.
 * They do this by triggering //Fas// receptors on the target cell.

=**NSAIDs**=


 * Describe the biosynthetic pathways for production of prostaglandins, prostacyclin, thromboxane, and leukotrienes, including the source of the precursor arachidonic acid and the specific enzymes involved.
 * Note that you can't make arachidonic acid; you can only ingest it or ingest its immediate precursor molecules (AA = phospholipid: it's an omega-6 fatty acid).
 * Arachidonic acid is stored as ester; cleaved by esterases to become activated and be processed into descendant molecules.
 * __Prostaglandins__: AA is converted into a cyclic intermediate by **cyclooxygenases** ( **COX-1** and **COX-2** ). This cyclic intermediate is further transformed by endoperoxide isomerases to prostaglandins E2, D2, or F2a.
 * __Thromboxane__: The same cyclic intermediate is transformed to thromboxane.
 * __Prostacyclin__: The same cyclic intermediate is transformed to prostacyclin.
 * __Leukotrienes__: Completely different pathway. AA is converted by **5-lipoxygenase** to leukotriene A4 (LTA4); this is further enzymatically converted to LTB4 and LTC C4/D4/E4 (which are more or less interchangeable for our purposes).
 * Compare and contrast the biochemistry and physiology of cyclooxygenase-1 and cyclooxygenase-2 with regards to expression, tissue locations, physiologic role, inducers, and inhibitors.
 * __COX-1__: Constitutively expressed pretty much everywhere- for the most part perform global, housekeeping functions. This means it has important normophysiological roles:
 * GI tract: Decreases secretion of gastric acid, increases mucosal secretion (protective mechanism), promotes smooth muscle contraction.
 * Platelets: show a pro-aggregation effect.
 * Kidneys: promote increased renal blood flow, diuresis.
 * Vascular smooth muscle:
 * Prostaglandin/prostacyclin: vasodilation.
 * Tromboxane: vasoconstriction.
 * Bone: stimulates formation/resorption.
 * __COX-2__: Induced by inflammatory cytokines (IL-1, IL-2, IFN-gamma; also LPS); it is not expressed (mostly) without induction by those cytokines. The important exception is in the endothelial cells, in which COX-2 is expressed all the time to prevent intravascular clotting.
 * Pain: potentiates bradykinin-mediated nociception (pain).
 * Inflammation: enhances 'leakiness' of vessels (pro-edema and leukocyte infiltration).
 * Fever: Resets 'normal point' of body temperature in hypothalamus- increase heat production and decrease heat loss.
 * Kidneys: Maintain steady renal blood flow.
 * Uterine: During pregnancy, the one place where you absolutely have to have an AA derivative-- live birth is more or less impossible without it. PGE F2a induces uterine contractions.
 * This means that if you give a COX inhibitor to a pregnant woman in the third trimester, you can cause a lot of problems with labor and delivery.
 * Notice that the fetus also uses PGE E2 and PGI to keep the ductus arteriosus open-- with COX inhibitors, can cause the ductus to close (which is not a good outcome for the fetus).
 * List the effects of prostaglandins on vascular smooth muscle, platelets, GI tract smooth muscle and secretory cells, kidney cells, uterus, and inflammatory cells and be able to relate these actions to side effects that occur from use of drugs that block their synthesis.
 * **Prostaglandin effects** :
 * Vascular smooth muscle: PGE2 causes vasodilation.
 * Platelets: No effects noted.
 * GI tract smooth muscle/secretory cells: PGE2/PGI2 inhibit HCl secretion, increase mucous secretion.
 * Kidney cells: PGE2/PGI2 increase renal blood flow.
 * Uterine cells: PGF2a induces contractions
 * Inflammatory cells: PGE2/PGI2 potentiate pain, edema, and fever.

>>> Vascular smooth muscle: intense vasodilation, resulting in edema and promoting leukocyte margination and adhesion.
 * Describe the effects of leukotrienes on inflammatory cell function and pulmonary / vascular smooth muscle.
 * **Leukotriene effects** :
 * Inflammatory cell function: LTB4 is chemoattractive for neutrophil- induces endothelial cells and neutrophils to express adhesion proteins.
 * Pulmonary cells: intense contraction in bronchial smooth muscle. Implicated in asthma.

Note that you can use drugs targeting 5-lipoxygenase receptors to reduce the amount of steroids that need to be given (for example, to kids with asthma) to avert the effects of leukotrienes.
 * **Describe the functional interaction of prostacyclin and thromboxane A2 with relation to physiologic effects on vascular smooth muscle and platelets.**
 * Thromboxane effects** :
 * Vascular smooth muscle: vasoconstriction (mainly in platelets).
 * Platelets: aggregation.


 * Prostacyclin effects** (exactly opposite to thromboxane):
 * Vascular smooth muscle: vasodilation (mainly in endothelial cells).
 * Platelets: disaggregation.


 * Compare and contrast the effects of aspirin, acetaminophen, NSAIDs, and COX-2 selective inhibitors on the cyclooxygenase enzymes 1 and 2 as the relation to therapeutic uses and adverse reactions.


 * Aspirin: __Irreversibly__ inactivates COX-1 and COX-2.**
 * Acetaminophen: is __NOT__ an NSAID. Has no anti-inflammatory effects (anti-pyretic and mild analgesic effects only) since it __does not have a substantial effect__ on COX-1 or COX-2.
 * NSAIDs:
 * Reversibly inhibit COX-1 and COX-2.
 * Side effects:
 * Ulceration and bleeding in the GI tract, nausea. Due to inhibition of protective COX-1 effect.
 * Decrease in tissue clotting (thus increased bleeding time). Due to inhibition of thromboxane production.
 * Can reduce uterine contractions, leading to problematic delivery. Due to inhibition of prostaglandins.
 * COX-2 selective inhibitors: As the name implies, inhibits only COX-2 activity. Indicated for people with GI ulcers or for chronic alcoholics. But note that apparently these are being taken off the market due to increased rates of thrombosis (see next LO).


 * Describe the mechanism whereby low-dose, but not high-dose, aspirin is able to exert an anti-thrombotic / cardioprotective effect. Relate this effect to potential cardiovascular toxicity associated with use of COX-2 selective agents.
 * Ok. The active form of aspirin (ASA) tends to concentrate in the hepatic portal vein (inactivated in the liver). What this means is that you have a concentration differential of aspirin between the endothelial surfaces and the platelets in the bloodstream; the larger concentration in the bloodstream means that COX-1 on the platelets (pro-thrombotic) is preferentially inactivated relative to the COX-2 (anti-thrombotic) on the endothelial cells. This results in a net anti-thrombotic effect.
 * Also, recall that aspirin irreversibly inactivates the COXs-- and platelets, unlike endothelial cells, can't make new enzymes (no nucleus).
 * At higher doses, the concentrations are more or less equal between the bloodstream and the endothelial surfaces-- thus antithrombotic effects are negated.
 * COX-2 selective agents: In endothelia, COX-2 (anti-clotting) is constitutively expressed to prevent intravascular clotting; by blocking COX-2 action there, the unopposed pro-aggregation effects of COX-1 in the endothelium leads to increased thrombus formation.
 * For the following specific agents [aspirin, acetaminophen, ibuprofen / naproxen / ketorolac, celicoxib] describe similarities and distinctions in their: 1) Therapeutic uses 2) Metabolism and excretion 3) Common side effects at therapeutic doses 4) Overdose toxicities and their treatment 5) Contraindications to use 6) Drug-drug interactions.
 * Aspirin:
 * Therapeutic uses: Result from __irreversible inhibition__ of COX-1 and COX-2. Low dose aspirin given to inhibit thrombus formation.
 * Metabolism and excretion: Recall that aspirin, beyond low-dose, is a zero-order kinetic drug. This means that adding more aspirin past a certain (easily reached) point has no effect on COXs-- but it can certainly cause toxic side effects. Doesn't, as such, have a half-life. Rapidly metabolized by esterases in blood and tissues.
 * Side effects: increased bleeding time, GI pain and nausea. Sometimes people can have aspirin hypersensitivities (as well as to other NSAIDs).
 * Overdose: Causes tinnitis (ringing in the ears) at high concentrations. At very high concentrations, get uncoupling of oxidative phosphorylation-- metabolic acidosis, respiratory alkalosis.
 * Contraindications: No one with gastric ulcers, no chronic alcoholics. Notice that aspirin (not other NSAIDs) shouldn't be used in infants with viral infections (liver damage-**Reyes syndrome** ). Avoid use in pregnant patients.
 * Drug-drug interactions: Low-dose aspirin has no effect if it's taken after taking ibuprofen. Ibuprofen preferentially binds to the COXs, making aspirin incapable of binding it. If you take aspirin first, and wait three or four hours, you can take ibuprofen again with pretty close to full effect (the COXs that aspirin are going to target have been targeted).
 * Acetaminophen:
 * Therapeutic uses: mild-moderate analgesic, antipyretic. No significant anti-inflammatory effects. Considered safe at all stages of pregnancy for short-term use; weak to no effect on clotting; no GU upset; safe to give virally infected infants.
 * Metabolism and excretion: See 'overdose,' below.
 * Side effects: mild CNS effects; mild hepatic enzyme inducer.
 * Overdose: recall that acetaminophen is metabolized by conjugation through easily overloaded mechanisms. It has an unconjugated, reactive intermediate form that builds up quickly in overdose situations and is extremely toxic (will destroy liver and kidney tubules). Rapid infusion of intermediate-binding molecules are needed to prevent organ failure and death. Note alcohol induces the enzyme that forms the toxic intermediate (if you've been drinking all night, don't take a bunch of Tylenol to ward off the headache you're going to have the next day).
 * Contraindications: as above.
 * Drug-drug interactions: none noted.
 * NSAIDs (Ibuprofen/Naproxen/Ketorolac):
 * Therapeutic uses: Anti-inflammatory, antipyretic, analgesic. Sometimes used for arthritis. Some transient anti-clotting activity.
 * Metabolism and excretion: rapid, complete absorption; excreted by kidney. Ketorolac is taken IV/IM; the rest can be taken //po//.
 * Side effects: Less GI irritation than aspirin. Ibuprofen is the least-GI-irritating NSAID.
 * Overdose: none noted.
 * Contraindications: Not for use in pregnant women (safety not established-- seriously, after this long?).
 * Drug-drug interactions: None noted.
 * Celicoxib:
 * Therapeutic uses: Marketed as a COX-2 specific inhibitor. Anti-inflammatory, antipyretic, analgesic. Used for arthritis, menstrual pains, acute pain. No anticlotting effect per se.
 * Metabolism and excretion: //po// admin. Metabolized by the liver, excreted by the kidney.
 * Side effects: Some renal side effects; increased risk of adverse cardiovascular events (mainly emboli), as noted above.
 * Overdose: No notes.
 * Contraindications: Not to be used in pregnant women (blocks uterine contractions). Note that celecoxib is a sulfonamide (sulfa drug) so watch out for allergic reactions.
 * Drug-drug interactions: When taken with warfarin, potential for increased bleeding.

=**Steroidal Anti-Inflammatory Drugs**=


 * For the agents listed below (Hydrocortisone, Prednisone, Methylprednisolone, Triamcinolone, Dexamethasone, Aldosterone, Fludrocortisone), describe their:
 * Mechanisms of anti-inflammatory actions
 * Clinical uses
 * Dosing considerations / pharmacokinetics
 * Toxicities (distinguish acute vs. chronic vs. chronic cumulative)
 * Compare and contrast their relative salt-retaining vs. anti-inflammatory activities vs. ACTH suppression and their routes of administration.

__Under physiological stress__: Hypothalamus releases cortisol releasing factor = CRF (targets pituitary) Pituitary releases adrenal corticotrophic hormone = **ACTH** (targets adrenal glands) Adrenal glands release glucocorticoid (= **cortisol** ): maintains glucose supply to tissues, particularly brain. More details on this below. Negative feedback mechanisms: Glucocorticoids (cortisol and the steroidal anti-inflammatory drugs, which mimic cortisol) inhibit mainly the release of ACTH from the pituitary; to some extent, they also inhibit CRF release from the hypothalamus.
 * [Note that these LO's are mostly commentary about the class of steroidal drugs with a few notes about specific agents.]
 * [Note also that I occasionally call there here by their logical acronyms (SAIDs). I don't think this is a commonly used term, possibly because it's a typo away from NSAIDs. It's just easier than writing it all out. Occasionally I also use "steroids"-- this should be taken to imply catabolic steroids (which all of these are) instead of anabolic steroids (bodybuilder stuff).]
 * Here's the thing. All these do essentially the same thing (activate glucocorticoid receptors). Most of the MAOs and clinical uses are, therefore, similar, with a few exceptions as noted.
 * [Background notes on glucocorticoids:]


 * Glucocorticoids: glucose-controlling corticosteroid
 * Aldosterone: mineral-controlling (sodium) corticosteroid
 * Aldosterone is less under the control of the CRF system and more under the control of the renin-angiotensin-aldosterone axis; the reason it's mentioned here is because some drugs have side effects on the mineralocorticosteroid system.
 * Aldosterone: increases sodium retention.
 * This leads to edema (fluid retention), hypertension, hypokalemia.


 * Therefore when French talks about salt-retaining, he's talking mineralocorticoid, and when he's talking about anti-inflammatory and immunosuppressive, he's talking glucocorticoid.


 * Many drugs that target glucocorticoid pathways also have side effects in the mineralic corticoid system.
 * Note that levels of cortisol fluctuate naturally during the day.


 * Cortisol is an **alcohol** ; the inactive (but better absorbed //po// ) form of drugs that mimic cortisol is a **ketone** (reduced in the liver to a metabolically active alcohol).
 * Nomenclature:
 * Drugs that end in "__one__" = inactive form (ketone).
 * These are usually taken orally (need to be activated by the liver).
 * Drugs that end in "__olone__" = already active (alcohol).
 * Ie: Prednisone = inactive form (taken //po//, activated by metabolism in liver)


 * All of these drugs have a MOA that targets glucocortoicoid receptors in the body.
 * All of these diffuse across membranes, get into cellular cytoplasm, and go to nuclei, where they regulate gene expression-- including, but not limited to, __inhibition of cyclooxygenase__(the COX family, recall, are the pro-inflammatory agents inhibited by NSAIDs).
 * Dr. French: "These are probably the most effective anti-inflammatory drugs we have… but they also come along with the worst package of side effects."
 * **More or less intentional effects of glucocorticoids** :
 * On blood vessels: __vasoconstriction__.
 * On immune cells: __decreases accumulation and activation of leukocytes__ at their sites of activation, partly due to the lowered levels of cytokine production.
 * This is what gives rise to one of the major side effects of SAIDs: a diminished immune response, leading to a greater risk of infections.
 * On arachidonic acid derivative production: decreases supply of phospholipase A2 (leading to decreased production of arachidonic acid, which leads to less prostaglandins, prostacyclins, thromboxanes, __and__ leukotrienes). Also block transcription of cyclooxygenase-2.
 * Note the difference: SAIDs block both the cyclooxygenase and 5-lipoxygenase pathways due to decreased substrate (AA) for both. NSAIDs block cyclooxygenase only (no effect on 5-lipoxygenase and subsequent leukotriene production).
 * This mechanism is why SAIDs are such effective anti-inflammatory agents-- they cut off the source (AA) of a lot of the body's pro-inflammatory processes. Sort of a "trunk not branches" approach.
 * Note that NSAIDs, by contrast, can cause problems in asthmatic patients: NSAIDs block cyclooxygenases only, which can shunt more arachidonic acid along the leukotriene synthase pathway (which can evidently worsen asthma).

Side effects of glucocorticoids** : **
 * These mainly have to do with glucose metabolism.
 * Recall that cortisol's main purpose is to increase and keep glucose supply in the brain. Since all these drugs trigger glucocorticoid receptors, their side effects are generally the same effects as normal cortisol binding.
 * They __increase gluconeogenesis__.
 * They __increase the rate of protein breakdown__ to increase amino acid supply.
 * Note difference: anabolic steroids anabolize (assemble little protein pieces to make protein); catabolic steroids (like these) catabolize (disassemble proteins to make little protein pieces).
 * The rise in glucose causes pancreas to __increase the level of insulin released__.
 * Lipolysis and lipogenesis:
 * The glucocorticoids increase the rate of lipolysis to raise free fatty acid levels.
 * However, the rise in insulin levels triggers central lipogenesis, effectively shifting fat from the periphery to the torso.
 * This causes some of the more obvious and classic side effects: the puffy face and 'buffalo hump' from stored fat in the face and upper back.
 * The side effects are definitely time-sensitive. Over a short period of time (5 days or so) the only usual side effect is the rise in blood glucose.
 * Note that over long periods of dosing, (> 2 weeks) more serious side effects:
 * A form of diabetes
 * Atrophy of skin structures (breakdown of collagen/proteins)
 * Osteoporosis (breakdown of osteoblast proteins)
 * "Centripetal" obesity (fat stored in central region)
 * Impaired wound healing (protein breakdown)
 * In children, can see cataracts and some growth-reducing effects, though notice that there's no permanent effects on height.
 * Increased susceptibility to disease (suppressed immune system)
 * Possibly some effects in CNS (mild euphoria, insomnia, mood changes) and GI (decreased calcium uptake, leading to a rise in parathyroid hormone, which also leads to osteoporosis).


 * Notice that it takes a few hours for most of the effects of SAIDs to kick in. The exception is the vasoconstrictive effects, which start up right away.
 * Note that patient usually will want to take steroids with food to avoid an upset stomach.
 * Dosing considerations: remember mineralocorticosteroid side effects (depends on the individual drug). Sometimes can avoid immunosuppressive effects if you give every-other-day therapy. You always want to taper off administration if SAIDs have been taken for more than a week to avoid 'rebound' effects (disease resurgence, adrenal insufficiency).
 * Note that you can develop a drug that separates glucocorticoid effects from mineralic corticosteroid effects-- but you can't separate the glucocorticoid effects from anti-inflammatory effects.
 * That is: you can get anti-inflammation, anti-immune system, glucose effects, and sodium retention all together, or you can get anti-inflammation, anti-immune system, and glucose effects without the sodium retention, but you can't get the anti-inflammation and anti-immune system effects without the glucose effects (high blood glucose, hypertension, protein catabolism, etc).
 * Dosage forms: oral most common. Seems to be no real advantage to giving in IV form (steroids take a while to work anyway).
 * Clinical uses: Best if used to suppress a host response that's the primary etiologic agent of the disease. Ie: Rheumatoid arthritis, allergic disorders, cerebral edema, lupus, asthma, etc.
 * Side effects: as noted, crossover into the mineralocorticoid system causes sodium retention (hypertension, hypokalemia, etc). Notice that this can be particularly ugly combined with the vasoconstriction caused by glucocorticoids. Glucocorticoids have side effects as noted.


 * Specifics about which drugs trigger mineralocorticoid receptors (MCR) or glucocorticoid receptors (GCR), and about their relative anti-inflammatory properties (AIP):
 * Hydrocortisone: moderate GCR, MCR, AIP. Oral or parenteral.
 * Prednisone: low GCR, moderate MCR, high AIP. Mainly oral, can be IV.
 * Methylprednisolone: very high GCR, minimal MCR, high AIP. Oral or IV.
 * Triamcinoline: moderate GCR, no MCR, high AIP. Mainly oral, also depot forms.
 * Dexamethasone: high GCR, minimal MCR, extremely high AIP. Oral and parenteral.
 * Aldosterone: low GCR, sky-high MCR (this is the compound that's supposed to trigger it, after all), no AIP.
 * Fludrocortisone: moderate to high GCR, extremely high MCR, extremely high AIP.

=**Parasites: Protozoa and Helminths**=


 * Define "parasite".
 * An organism that grows either in or on another organism and derives a benefit from that relationship, while its host derives some harm.
 * Explain the importance of parasitic diseases for human health from a global perspective. Explain why the life cycles of parasites are important for the geographic distribution, diagnosis, and control of parasitic diseases.
 * Important due to extent (most of the planet gets infected every year with something or other) and, in some cases, severity (eg. malaria kills 1-2 million, mainly children, per year). Note also that outcomes in US are often worse than elsewhere due to unfamiliarity with the parasites-- a good patient history, including travel, is very important in diagnosis.
 * Life cycles: Important because many different parasites' life cycles are spread throughout a variety of species or a variety of phases, all of which can provide points at which it is possible to prevent their contraction. For example, since malarial parasites have to go back and forth between humans and a certain species of mosquitos, by eradicating mosquitos it is possible to eliminate malaria.
 * Most helminths go through a developmental cycle in the human host but do not reproduce there. This means the number of worms found in an infected human body - which is usually related to the severity of the disease manifestation - has less to do with time since infection and more to do with the extent of the original exposure.
 * Describe the taxonomic groups in which the major protozoan and metazoan parasites of humans are found.
 * Worms (helminths):
 * Roundworms
 * Flatworms (eg. schistosomiasis parasites)
 * Tapeworms
 * Protozoa:
 * Amoebas
 * Flagellates
 * Ciliates
 * Sporozoa (eg. malaria parasites)
 * Microsporidia
 * **Explain the pathogenesis of schistosomiasis and malaria as paradigms of important diseases caused by metazoan and protozoan parasites.**
 * **__Schistosomiasis__ (prototype of helminth infection):**
 * One of the most prevalent, severe flatworm infections in the world: endemic throughout sub-Saharan Africa.
 * **Eggs laid in the liver cause** hepatic scarring** (portal hypertension, esophageal varices, etc) and severe ascites. **
 * After irreversible liver damage has occurred, eradication of the worms does not resolve the problems.
 * The eggs are deposited in human urine or feces; they hatch into larvae which are picked up by certain species of freshwater snails; they mature further and are released into the water.
 * If the infected water is exposed to skin or ingested, the organism can burrow into the tissues and get into the mesenteric venules; they live in the venous system for many years, sexually reproducing and producing eggs which flow through the bloodstream into the portal system and the liver, where they trigger the inflammatory response responsible for much of the damage caused in the disease. Some eggs are shed into the feces, where the infectious cycle resumes.
 * One species migrates to venules near the bladder instead and shed eggs into the bladder (causing bladder inflammation and scarring and infectious urine as opposed to feces.
 * These are fairly large- several centimeters. Notice that the eggs can't mature in the human body-- thus the number of adult worms in the body depends on the extent of exposure, not time since infection.
 * Eggs in stool or urine detect the presence of schistosomiasis. Morphology, as is usually the case in parasitic infections, is often the best tool for specific diagnosis.
 * The histopathology of the inflamed tissue shows enormous numbers of eosinophils (which, as we know, is a marker for parasite infection).
 * Schistosomiasis control strategies are largely to avoid contact with infected water, mass treatment of population with anti-schistosomal drugs, use of snail-killing agents (which seems unfortunate for the hapless snails).
 * **__Malaria__ (prototype of protozoan infection):**
 * As known, endemic more or less throughout tropical world.
 * **Parasite's immature forms in mosquito's salivary glands travel down and into the human blood, which travel to and infect the** hepatocytes ** (primary infection). **
 * **These replicate in hepatocytes until the cells are lysed; they then move to** erythrocytes ** and repeat the process of invasion, replication and lysis (secondary infection). Notice that synchronous lysis of lots of erythrocytes at once causes fever, chills, and shaking. **
 * Notice that different species of malaria have individual preferences for infecting different ages of red cells- either young red cells, older red cells, or pretty much all red cells (the last is the most dangerous, since all of the red cells in a person can potentially be infected in a single round of lysing).
 * Some progeny (gametocytes) are produced sexually inside red cells; when these are taken up in red cells by a mosquito that draws blood from an infected person, the gametocytes mature further and travel to mosquito salivary glands to begin the cycle again.
 * Infected persons develop splenomegaly (a hallmark of this infection; estimates of prevalence of malaria can be made by looking at the extent of splenomegaly in a population).
 * Also anemia-- the developing malarial parasite consumes hemoglobin. Infected red cells can also be destroyed in the spleen or by lysis, also causing anemia. Can also get hemoglobin release into the bloodstream (and thus urine)-- called blackwater fever. Can also get type III immunopathology with antigen-antibody complexes.
 * Infected red cells in a particular species of malaria (//falciparum// ) also are more adhesive than normal red cells, which can block capillaries and lead to decreased microcirculation-- particularly a problem in cerebral malaria or in major organs (hypoxic injury).
 * Histopathologically, can see infecting agents inside red cells.
 * Immunity: acquired immunity (in high-exposure areas) in older children and adults prevents high-level disease but doesn't eradicate infection (nor being infectious to others through mosquitos). Notice that this immunity is lost if the individuals leave malaria-endemic areas for a few years.
 * Vaccines are being developed but nothing concrete yet. Mosquito eradication seems promising (bed nets + insecticides). Treatment drugs are improving. A medicinal adaptation of a certain Chinese herb also seems to contain anti-malarial properties.
 * As mentioned, sickle-cell, G6PD, and thalassemia seem to partially protect against malaria.
 * Describe some of the major current challenges to treatment and prevention of parasitic diseases.
 * Many parasites have developed elaborate immune-evasion mechanisms (eg. developing surface coat that resembles human proteins).
 * For many parasites there are no vaccines available; most control measures deal with environmental (exposure) control or treatment, but not immunization.
 * The drugs used against parasites tend to be different from antibacterial or antivirals-- targeting nonhuman eukaryotic systems (maybe more similar to antifungals?), not prokaryotic or viral.

=**Review session for exam II**=

Drug review


 * Cell trauma leads to release of phospholipids.
 * Phospholipid PLA2 gives rise to arachidonic acid.
 * Cyclooxygenases give rise to prostaglandins, prostacyclins, and thromboxane, or 5-lipoxygenases give rise to leukotriene A4.
 * Leukotriene A4 differentiates into LTB4, LTC4, LTD4, and LTE4.
 * LTB4: chemotaxis of neutrophils.
 * LTD4/LTE4: bronchospasm.
 * Both of these cause asthmatic complications, good to block them for that purpose.
 * Remember you don't want to prescribe NSAIDs in asthmatics without caution-- shunts more arachidonic acid down the leukotriene synthesis pathway.
 * Prostaglandins, prostacyclins, and thromboxanes: mediate pain, inflammation, and fever. Also clotting but in this context only relevant to celecoxib and aspirin.
 * All of the above are caused by COX-2.
 * Can treat all three (aspirin and traditional NSAIDs) or can just treat pain and fever (acetaminophen).
 * Interesting point: dose to treat inflammation is three or four times higher than that used to treat fever and pain.

__COX-1 and -2 normal effects and side effects of their inhibition__:
 * Normal effects:
 * 1) GI protection (COX-1)
 * 2) Platelet aggregation (COX-1, in platelets)
 * 3) Platelet disaggregation (COX-2, in endothelia)
 * 4) Increased renal blood flow during stress (COX-1 and COX-2)
 * 5) Uterine contraction (COX-2)
 * Side effects of inhibition:
 * 1) GI upset/bleeding (COX-1)
 * 2) Increased bleeding potential (COX-1, in platelets)
 * 3) Increase in thrombotic disorders (COX-2, in endothelia)
 * 4) Decreased renal compensation (COX-1 and COX-2)
 * 5) Delayed labor (COX-2)


 * NSAIDs: aspirin, traditional NSAIDs, acetaminophen, celecoxib.
 * Aspirin: low-dose aspirin is COX-1 selective (recall the active form, ASA, pools in the portal system and thus affects mainly platelets, which preferentially express COX-1; irreversible binding + lack of nucleus in platelets = inhibition of COX-1 for the life of the platelet).
 * Thus protective against clotting (anti- the pro-thrombotic effects of COX-1).
 * However has the most GI upset.
 * Also has the most bleeding effects.
 * Some renal dysfunction effects.
 * Potential to delay labor.
 * No thrombotic disorders.
 * traditional NSAIDs: Both COX-1 and COX-2, reversible.
 * Some GI upset.
 * Ibuprofen: least GI upset.
 * Some bleeding effects.
 * A lot of renal problems due to blood flow effects.
 * Potential to delay labor.
 * No thrombotic disorders.
 * Acetaminophen: Doesn't impact COX system as far as we can tell. Seems to have more effect in the central system than the periphery.
 * Not much GI upset.
 * No bleeding effects.
 * No renal problems due to blood flow effects (though recall toxicity in liver).
 * No potential to delay labor.
 * No thrombotic disorders.
 * Celecoxib: COX-2 only, reversible.
 * Not much GI upset (the point of making COX-2 inhibitors was to provide anti-inflammatory effects without getting GI upset).
 * No bleeding upsets.
 * No renal problems due to blood flow effects.
 * Potential to delay labor.
 * Big potential for thrombotic disorders.


 * Aspirin toxicity: Respiratory alkalosis, followed by metabolic acidosis.
 * Traditional NSAIDs tend to be safer in overdose situations (until the blood flow to the kidneys gives out).
 * Note don't need to know half-lives of NSAIDs.


 * SAIDs (glucocorticoids/steroids): more powerful anti-inflammatories because they block the synthesis of arachidonic acid (thus no PGEs, PGIs, TXAs, LTs). On the other hand they take longer to act.
 * (Because they block leukotriene formation, can be used to treat inflammation in asthmatics without worrying about bronchospasm.)
 * These decrease cytokine synthesis and accumulation/activation of many of the inflammatory cell types (decreased immunologic disease/normal immune function)
 * [Mainly adrenal corticosteroids (from adrenal cortex, vs epinephrine and norepinephrine, which come from the adrenal medulla).]
 * Side effects:
 * Can get away with 2-3 week application with minimal side effects.
 * Glucocorticoids:
 * Raise glucose levels
 * Increase protein catabolism
 * Increase centripetal obesity
 * Long-term application of steroids can suppress normal stress responses from hypothalamus-pituitary-adrenal (HPA) axis-- if a patient on steroids is suddenly subjected to a lot of additional stress, the HPA axis is atrophied and unable to respond well.
 * Mineralocorticoids:
 * Raise sodium retention and H2O content in blood
 * Leads to higher blood pressure and edema
 * Different agents differ in glucocortical stimulation-to-mineralocortical stimulation ratio:
 * Cortisol-- 1:1
 * Prednisone-- 5:1
 * Methylprednisone-- minimal MC
 * Dexamethasone-- minimal MC
 * Betamethasone-- minimal MC


 * Antivirals:
 * Know a lot about acyclovir (commonly prescribed drug).
 * MOAs: identify target and mechanism of activation, which should imply the resistance and selective toxicity information.
 * Note that evidently my LOs were wrong about uptake of various nucleoside analogs-- the difference is in the phosphorylation in, not the uptake into, cells.
 * Pharmacokinetics: keep in mind the intracellular half-life (multiply-phosphorylated form, can't cross membrane and get out of cell again).
 * Excretion: most are excreted by kidney. Know bioavailability info from prodrugs to non-prodrugs.
 * Spectrum/uses: know what's in bold.
 * Adverse reactions: know what's in bold.

Mechanisms of Viral Pathogenesis review


 * LO 1 (characteristics of viral disease determined by):
 * Tropism: what cells does it infect?
 * Virulence: straightforward.
 * Host responses: (1) secretion of cytokines/chemokines (innate immune response), (2) adaptive immune response
 * ie local infections (like flu) can have systemic effects from cytokine effects.
 * LO 2:
 * Acute local viruses: infection and release both from apical surface. Acute systemic: infect apical surface, release basolateral surface.
 * Local: short infection time, good IgA response, but frequently many serotypes-- thus a lot of re-infection potential.
 * Chronic: longer infection time, good IgA/G/T cell response; less (?) re-infection potential.
 * LO 3:
 * Viruses that cross placental borders can become persistent in fetus due to the fetus's lack of ability to produce T cells.
 * Viruses that are highly mutagenic can become persistent.
 * Recall measles only has one serotype, thus can be eradicated with one vaccine.
 * T cell suppression can lead to persistent infections, as can viruses that immunosuppress.
 * LO 4:
 * Latent viruses: no, or few, viral genes expressed-- the minimum to avoid immune response and allow viral chromosome to replicate during the host cell's mitosis phase.
 * Reactivation comes out of immune compromise.
 * Persistent viruses: regular ol' viruses regular ol' gene expression that can't be well cleared (generally due to an acute or chronic immunosuppressed state).
 * LO 5:
 * Symptoms are longer, period of viral shedding is longer, more virus is shed in immune compromised person. Viruses may also alter their tropism to infect different kinds of tissue than they would ordinarily infect.
 * LO 6:
 * "Novel host" means a new __type__ of host or a new species. If the novel hosts is closely related to the old hosts the virus tends to do comparatively better. Note most viruses that 'jump hosts' fare poorly.