Absite killer Plus Basic Science



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ABSITE Killer Plus

Basic Science

General


Null hypothesis = "no difference exists"; Type I Error - reject null hypothesis incorrectly; Type II Error = accept null hypothesis error; Type III Error = conclusions not supported by data

Prospective cohort study = non-random assignment to treatment group

Meta-analysis is review and statistical combining of data from different studies

ANOVA is a t-test for >2 samples of quantitative data (continuous variables)

Non-parametric statistics: for qualitative data analysis.

Qualtitative variables: a) nominal = named (e.g. color) b) ordinal = on a scale (e.g. pain rated 1-10)

Prevalence = # of patients having the disease in the population (is higher in diseases that last a long time)

Incidence = # of newly diagnosed cases in a population in a given time period

Sensitivity = ability to detect disease = # with disease and positive test result / # that have disease (true positive)

Specificity = ability to state no disease is present = # with no disease and negative test result /# without disease (true negative)






DISEASE













+

-







TEST

+

a

b

(a+b)

test positives

-

c

d

(c + d)

test negatives







(a+c)

(b+d)

a+b+c+d










true positive

true negative










Sensitivity = a / (a+b)

Specificity = d / (b+d)



Alveolar macrophages = source of fever in atelectasis

Mitochondria = 2 membranes, TCA cycle in inner matrix

Nucleus has an outer membrane that is continuous with rough ER; ribosomes are made in the nucleolus, which has no membrane

Rough ER makes protein for export, smooth ER for cytoplasmic proteins

Plasma membrane is 60% protein, 40% lipids. Incr cholesterol = incr mobility of proteins

Malignant hyperthermia is due to Ca release from sarcoplasmic reticulum. Fever, tachy, rigid, acidosis. 1st sign is incr in end tidal CO2. Rx = dantrolene, stop operation/anesthetic, supportive care, often is not patient's 1st exposure to anesthetic agent

Diaphragm is 1st muscle to recover from paralytics (neck and face are last)

Lymphatics: no basement membrane. Loose cell to cell jxn. Not present in muscle, bone, tendon, brain.

Rate limiting step in cholesterol formation (in liver, steroid precursor): HMG coA Reductase

Steroid hormones go to nucleus after binding in cytoplasm of target cell

Kreb's cycle -> 38 ATP from 1 glucose (anaerobic glycolysis = 2 ATP and lactate)

Macula densa senses low Na/Cl, produces renin which converts angiotensinogen to angiotensin I, which is converted to angiotensin II in the lung by A.C.E. ATII is a vasoconstrictor and increases aldosterone which keeps Na, loses K/H in urine (Every Year)

Renal osteodystrophy: kidney loses Ca, keeps PO4; decr vit D 1-hydroxylation; all leads to secondary hyper PTH

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Gut Physiology


L vagus n (anterior) gives hepatic branch, R (posterior) gives celiac brance and the 'criminal nerve of Grassi' which if undivided can keep elevated acid levels post vagotomy

Chief cells produce pepsinogen (converted to pepsin) which initiates proteolysis

Parietal cells produce H+ and intrinsic factor which binds B12, and is absorbed in terminal ileum

Acetylcholine (ACh), gastrin and histamine are main stimuli for H+ production

ACh (vagus) and gastrin activate PIP, DAG to incr Ca, activate protein kinase C which incr HCl production

Histamine acts on parietal cells via cAMP (H for Happy cAMPer) to incr HCl production

Gastrin produced by antral G cells (why antrectomy helpful); inhibited by H+ in duodenum. Stimulated by amino acids, Ach

Omeprazole blocks H/K ATPase of parietal cell (Every Year)

Somatostatin inhibits gastrin, insulin, secretin, ACh; decreases pancreatic and biliary output. Stimulated by acid in duodenum

Proximal vagotomy abolishes receptive relaxation which incr liquid emptying; no change for solids

Truncal vagotomy also incr emptying of solids when pyloroplasty done. Decreases basal acid by 80%

Most common symptom post-vagotomy is diarrhea (35%). Dumping syndrom in 10%; early due to hyperosmotic load, fluid shift; late due to increased insulin with decr glucose. Very rare (1%) that dumping is unresponsive to dietary measures (Every Year)

Enterokinase activates trypsinogen to trypsin which then activates other enzymes of digestion

CCK: from intestinal mucosa 1) contract gallbladder 2) relax Sphincter of Oddi 3) incr pancreatic enzyme secretion (Every Year)

Secretin: primary stimulus of pancreatic bicarb secretion. High flow rate = high bicarb, low Cl. Slow flow allows HCO3/Cl exchange so low HCO3, high Cl concentration

Enterglucagon: increased in small bowel mucosal hypertrophy, adaptation after small bowel resection

Peptide YY: released from terminal ileum with mixed meal, inhibits acid secretion "ileal brake"

Bile: 80% bile salts, 15% lecithin, 5% cholesterol. Stones form if incr chol or decr salts or decr lecithin. Gallbladder concentrates bile by active resorptiono of NaCl, H2O then follows. Bile pool 5g, recirculated q4h, lose 0.5g daily (10%) (Every Year)

Primary bile acids: cholic acid, chenodeoxycholic acid
Secondary (formed by intestinal bacteria): deoxycholic acid and lithocholic acid

MMC: interdigestive motility; 90 minute cycles, starts in stomach, goes to TI;


Phase I quiescence
Phase II gallbladder contraction
Phase III peristalsis
Phase IV subsiding electric activity
Motilin is key stimulatory hormone (erythromycin is prokinetic by stimulating motilin receptor)

Jejunum absorbs most Na and H2O (paracellular), more permeable than ileum

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Hemostasis


Intrinsic path (PTT): exposed collagen + XII -> XI, IX -> X which activates thrombin to produce fibrin
Extrinsic path (PT): tissue factor + VII -> activated X -> fibrin
X is common to both pathways
XIII crosslinks fibrin to form 'plug'. PT is best single test to evaluate synthetic function of the liver.

Banked blood is low in 2,3-DPG which increases Hgb affinity for O2 (left shift)


Cryo contains fibrinogen and vWF-VIII; used in vWD, hemophilia A, and DIC if fibrinogen low
Vit K inhibits II, VII, IX, X, protein C and protein S
Protein C degrades active V and VIII. Protein S helps protein C
V and VIII are labile factors, low levels stored in blood
Factor VIII only factor not made in liver (made by reticuloendothelial system)

Von Willebrand's Disease: long PTT, long bleeding time, +ristocetin test. Type I and III have low amounts of vWF, respond to ddAVP; type II is qualitatively poor vWF


Autosomal dominant (only one beside Rosenthal's XI deficiency). Only inherited coagulopathy with long bleeding time.
Rx with VIII, vWF or cryoprecipitate

ddAVP causes release of vWF, useful also in pts on ASA or w/uremic plt

Glanzman's thrombasthenia: plts have IIb/IIIa receptor deficiency. Decr plt aggregation

Bernard Soulier: Ib deficiency, decr adherence to exposed collagen

VII deficiency causes long PT, normal PTT

Hemophilia A = VIII deficiency, sex-linked recessive, replace to 100% levels pre-op


Have long PTT, normal PT. Newborn has VIII from mom, may not bleed at circumcision

Hemophilia B = IX deficiency = Christmas disease, also sex-linked. achieve 50% levels pre-op

Hemophiliac joint = do not aspirate; ice, ROM therapy, give factor VIII

Lupus anticoagulant: antiphospholipid antibodies, not necessarily with Luppus and generally pro-coagulant;


Dx: long Russel viper venom time, long PTT which does not correct by adding normal plasma

Factor XII = Hagemann factor; activated by cardiopulmonary bypass -> need for heparin

Factor V Leyden = resistance to activated protein C = common cause of DVT

Plasmin degrades fibrinogen, is inhibited by alpha-2-plasmin inhibitor

Heparin binds/activates ATIII and inactivates factors 9-12; prolongs PTT; counteract with protamine

epsilon-ACA (epsilon amino caproic acid) inhibits fibrinolysis, is the Rx for overdose of thrombolytics; thrombin is best test to monitor thrombolysis

DIC: low platelets, prolonged PT/PTT, low fibrinogen, high fibrin split products

HIT: 'white clot syndrom', thrombocytopenia due to anti-platelet antibody causing plt aggregation. Use dextran to anticoagulate. Generally see after 5 days of heparin, less frequent with LMWH

Prostacyclin = PGI2: from endothelium, decr plt aggregation, vasodilatation, bronchial relaxation

Thromboxane: from platelets, opposite effects of above

Best preop test fro pt on NSAIDS/ASA is bleeding time

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Immunology/Infection


IL4 stims B cell to become plasma cell (antibody secreting)
IgG, IgM are opsonins, are able to fix compelment (2 IgGs or IgM needed)
IgM made first, decreased levels after splenectomy
IgA in secretions
IgD a helper, largely unknown
IgG #1 in serum, crosses placenta
IgE allergic reactions, type I hypersensitivity reactions, histamine release (mast cell, basophil), parasites

Variable region of antibody is responsible for antigen recognition

Complement cascade: C3a, C5a are anaphylatoxins; C5-9 = membrane attack complex


Classic path initiated w/antibodies; alternate path by bacteria
Classic and alternate paths converge on C3

MHC I: CD8 activation; on all nucleated cells, single chain


MHC II: CD4 activation; on B cells, dendrites, monocytes, 2 chains

Natural Killer cells: neither T nor B cell. No antigen presentation needed. Recognise cells w/o self-MHC.


Natural Killer is responsible for immunosurveillance against CA
IL-2 converts Natural Killer cell to Lymphokine Activated Killer

Intradermal skin test - best test to evaluate cell-mediated immunity

Basophils - source of histamine in blood

Mast cells - source of histamine in tissue



Endotoxin is lipopolysaccharide A from gram negative bacteria

Hyperglycemia comes 24 hours before overt sepsis


Late sepsis noted by decr O2 extraction so incr in SVO2 and decr A-V O2 difference
SVO2 normal 66-77%, so > 77% = sepsis or cyanide poisoning, <66% = decr CO or decr SA O2

4 intraabdominal abscess locations: sub-diaphragmatic, sub-hepatic, inter-loop, and pelvic

C diff colitis: Rx is oral vancomycin or flagyl

ß-Strep and clostridial infections can present w/in hours postop (Every Year)

Staph aureus is coagulase negative; may produce clear 'slime' with chronic infection (vascular)

Aminoglycosides: bactericidal, irreversible binding to ribosome, resistance due to decr active transport


Clindamycin, tetracycline, erythromycin: bacteriostatic, reversible binding to ribosome

Vancomycin: binds plasma membrane; resistance is due to altered cell wall

MRSA resistance due to change in bacteria binding protein, not due to a ß-lactamase

Sulbactam and clavulanate inhibit ß-lactamase


Amphotericin: binds sterols to alter fungal cell wall. 80% get renal impairment; see anemia, fever
Quinolones (cipro): mechanism is DNA gyrase inhibition. PO and IV routes equivalent

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Medicines


Ketamine: incr cardiac work, O2 use, secretions, BP. No respiratory depressions. Hallucinations.

Methoxyfluorane has renal toxicity.

Halothane is hepatotoxic

Succinylcholine is the only depolarizing agent used; generalized contractions, hyperkalemia in burn patients, fast on/off; risk of aspiration, glaucoma

Clindamycin prolongs neuromuscular blockade

Demerol should be avoided in patients on MAOIs

Octreotide: long-acting somatostatin analog

Reglan = metoclopramide: DA blocker, incr LES tone, incr gastric motility

Omeprazole: mech is blocking Na/H ATPase; assoc w/enterochromaffin hyperplasia in rats. No e/o carcinogenesis in humans

Digoxin: glycoside, inhibits Na-K ATPase to incr Ca in heart. Slows AV conduction. Inotrope but does not incr O2 consumption. Associated with ischemic gut, decr splanchnic flow. Avoid hypokalemia

Amrinone: phosphodiesterase inhibitor, inotrope, incr CO, decr SVR

Metyrapone and Aminoglutethimide: 'medical adrenalectomy'

Leuprolide: 'medical orchiectomy'

Vasopressin: reduces splanchnic blood blow, portal flow ~40%. Useful in GIB, give with ß-blocker to avoid angina.

Sodium nitroprusside relaxes arteries and veins; has cyanide toxicity

Nitroglycerin primarily relaxes veins

Aspirin irreversibly binds cyclooxygenase, effective for life of platelets (~7 days)

Indomethacin blocks PG production, used to close PDA (effective in ~70%), decr renal blood flow

Misoprostil replaces PGE2 (cytoprotective) for pt on NSAIDS, to reduce PUD

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Fluids, Electrolytes, Nutrition


FeNa < 1, Urine Na < 20, BUN/CR > 30, all indicative of low volume, 'pre-renal'

Saliva has highest K conc (20 meq), then gastric (10 meq), pancreatic/duodenal (5 meq)

Branched chain amino acids are metabolized in muscle (leucine, isoleucine, valine); all essential

Vit D is made in skin, to liver for (25-OH) then to kidney (1-OH) then active


Vit D incr calcium binding protein to incr intestinal absorption of Ca

Vit A systemic or topical reverses adverse effects of steroids on wound healing

TBW: infant highest (80%), then men (60%), then women (50%). 10% less if obese (less H2O in fat)
Water distribution: if TBW is 60%, then 40% is cellular, 15% is intestinal, and 5% in plasma

Carbs have 3.4 kcal/g (Every Year)


Protein has 4 kcal/g (Every Year)
Fat has 9 kcal/g (Every Year)

Basal calorie expenditure = 25 kcal/kg/day (~1g protein/kg/day needed)

Respiratory quotient = ratio of CO2 produced to O2 consumed, 0.7 = fat used, 1.0 = carb used

6.25 g of protein contains 1 g of Nitrogen. N balance = N in - N out = (Protein/6.25) - (24 hr urine N + 4 g)

Short chain fatty acids: preferred fuel of the colon

Glutamine: preferred fuel of the small bowel. #1 amino acid in bloodstream, see decr levels with stress as glutamine goes to kidney to form ammonium to help acidosis. Shown to decr translocation, incr mucosal health with chemo or RT to bowel

Fat digestion: micelles to enterocytes to chylomicrons to lymphatics (to jxn LIJ/SCV) (Every Year)

Only Medium and Short Chain Triglycerides go to portal system with aa's and carbs.

Deficiencies:

Chromium deficiency: hyperglycemia (relative diabetes), neuropathy


Zinc: perioral rash, hair loss, poor healing, change in taste
Phosphate: weakness (respiratory), encephalopathy (needed for ATP)
Copper: anemia, neutropenia
Linoleic acid (essential fatty acids) = dermatitis, hair loss, change in vision
Vit A: can decr vit C stores

Cori cycle: glucose to lactate, to the liver, to glucose

Starvation: brain begins using ketones from fatty acids (normally brain and RBCs are dependent on glutamine)

Late starvation: gluconeogenesis shifts to kidney as liver is depleted of alanine

IVF: normal saline is 154 meq Na and Cl; LR is Na 130, K 4, Ca 2.7, Cl 109, bicarb 28

Alkalosis causes hypokalemia by driving K into cells and into urine (exchange for H+)


Hyperkalemia (peaKed t wave, wide QRS): give Ca to protect hear, Bicarb/insulin/glucose, kayexalate, dialysis if severe: 'C Big K die'

Na deficit = .6(wt in kg)(140-Na); replace no more than 1 meq/hr to avoid CPM

Hyperglycemia lowers Na; for every 100 glucose over 100, add 2 to Na

Hypocalcemia and hypomagnesemia both have hyperexcitability, incr reflexes (Chvostek's), tetany

Anion gap acidosis (MUDPiLES) = methanol, uremia, DKA, paraldehyde, lactic acidosis, ethylene glycol, salicylates. Anion gap = Na - (HCO3 + Cl) Normal < 12.

Low Mg inhibits PTH so replace Mg if difficulty correcting a patient's Ca.

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Oncology


G1: most variable period of cell cycle. Growth factors act here.

Radiation therapy: M phase most sensitive; most effective w/high O2 levels, higher energy = less skin damage; path: obliterative enarteritis; decr healing due to impaired fibroblasts

Extremity Sarcoma biopsy: excisional if < 4cm, otherwise longitudinal incision, incisional bioposy (less lymphatic disruption, easier to excise scar if biopsy positive). (Every Year)
Postop RT if high grade sarcoma, close margins or tumor > 5 cm

Li Fraumeni syndrome: p53 mutation. Sarcomas, breast CA, brain tumors, leukemia

Sarcomas generally spread hematogenously, not to lymphatics. Staging based on grade, not size/nodes

Colon CA associated w/loss of APC gene, p53, DCC (deleted in colon CA), k-ras activation

Breast CA associated w/p53, bcl-2, c-myc, c-myb, her 2 neu

c-myc associated w/small cell lung CA, neuroblastoma, Burkitt's lymphoma

Bcl-2 gene regulates Apoptosis; p53 and c-myc also associated with apoptosis

sis oncogene is homologous to PDGF

erb B codes for epidermal growth factor receptor. Assocaited with decr survival in breast CA

K ras proto oncogene encodes for GTP protein; 90% of pancreatic CA, 50%of colon CA, also in lung CA

Ret proto-oncogene diagnostic for Medullary Thyroid Cancer. Patient with family history of MEN who has Ret proto-oncogene should have total thyroidectomy

Tamoxifen (binds Estrogen Receptor) shown to decr breast CA in high risk; risk DVT endometrial CA

Bleomycin and Busulfan both have pulmonary fibrosis as complication

Vincristine, cisplatin both cause neurotoxicity

Levamisole mechanism: immunostimulant; is an antihelminthic agent

Wound Healing, Cytokines


Myofibroblasts (smooth muscle/fibroblast) provide wound contraction. Contract from center of wound. Responsible for healing by secondary intention.

Collagen Type I: most abundant throughout. Principal collagen in scar (late); III: in healing wound. Low in Ehler-Danlos; IV: in basement membranes; XI (and II): in cartilage

Collagen is glycine x3. alpha-ketoglutarate, vit C, O2, and iron needed for prolyl hydroxylase, crosslinking

Collagen production begins day 3, max at day 21 then constant amount but more crosslinking, strength

Type III becomes type I with maturation ~ week 3

Tensile strength never equal to pre-wound

Opening a 5 day or older wound results in quicker healing the 2nd time (cells, products already in place)

Giving Vitamin A reduces deleterious effects of steroids on wound healing

Cells to wound (in order): platelets, PMN's, macrophages, fibroblasts (dominant by day 5). Macrophages essential

TGF-ß stimulates fibroblasts; too much/too long -> fibrosis (e.g. cirrhosis, pulmonary fibrosis); also chemotactic for neutrophils. Speeds healing

PDGF attracts fibroblasts and incr smooth muscle (active agent in Regranex) to speed matrix deposition and collagen formation

GmCSF is used in chemotherapy patients to incr neutrophil and macrophage activity

TxA2 from platelets; plt aggregation, vasoconstriction

PGI2 (prostacyclin): plt inhibition, vasodilation and bronchodilation

Initial cytokine response to injury/infection dependent on TNF/IL1 (synergistic), CXC, IL6

TNF: main source is Macrophage/Monocyte. Endotoxin (LPS a) is most potent sstimulus for production


Overall has pro-coagulant effect
Responsible for wasting, cachexia in cancer patients, by lipolysis, glycolysis, anorexia
Recruits, activates neutrophils -> more cytokines, free radicals. Exaggerated response -> MOSF

IL-1 also from macs/monos; potentiates TNF; responsible for fever; Acts to incr IL-6 (acute phase response), incr endothelium adherence via selectins, ICAM, VCAM

Acute phase response: incr fever, catabolism
Incr C-reactive protein (CRP, an opsonin), amyloid, fibrinogen, haptoglobin, cerulopasmin, and alpha-1 antitrypsin; Decr levels of albumin, transferrin, and fibronectin

CXC chemokines: chemotactic, important in angiogenesis, wound helaing. C stands for Cysteine

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