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521 Cards in this Set

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What receptors are found on macrophages for innate immunity?
Mannose, N-formyl methionine and TLRs
Discuss activation of a cell in innate immunity through a TLR receptor?
LPS binds LBP which attaches to CD14. This complex attaches to TLR4 through MD2. The TLR4 has leucine rich residues on outside and cysteine rich residues near PM. A cytoplasmic adapter protein MyD88 then binds the cytoplasmic domain and phosphorylates IRAK which joins w/ TRAF-6 to activate NFkB.
What cytokines are released when a TLR is activated in innate immunity?
TNF, IL-1, IL-12, nitric oxide and endothelial adhesion molecules.
BIG PICTURE. What do cellular and humoral immunity fight against?
Cellular: intracellular pathogens and viruses
Humoral: extracellular and toxins.
What is the composition of lymphocytes in the blood?
T cells 70% of which 60% are CD4 and 30% are CD8.
B cells 20%
NK cells 10%
Discuss the TCR?
Main portion made up of alpha and beta subunits.
Covalently bonded to the CD3 molecule (delta, gamma, epsilon) and 2 zeta subunits.
How could you tell the difference btw non-neoplastic and neoplastic T cell proliferation?
Non-neoplastic is polyclonal T cell proliferation.
Which molecules propagate the 2 signals of a T cell?
The CD3 and zeta subunits propagate the 1st signal.
The CD28 binding to B7 propagates the 2nd signal.
What is different about γδ T cells? What about an NK T cell?
They don't have TCRs and recognize protein, lipid or soluble molecules on their own.
These recognize glycolipids attached to CD1 (like an MHC).
What main cytokine is produced when a TCR is bound and costimulation is present? What cytokines do TH1 and TH2 cells produce and their function?
TH1 produces IL-2 and IFN-y which stimulate delayed hypersensitivity and activate macrophages.
TH2 produce IL-4, IL-5 and IL-13 which stimulate ab production.
Where are B and T cells found in lymph nodes and spleen respectively?
B cells are found in cortex and white pulp
T cells are found in paracortical areas and periarteriolar sheaths.
Describe the BCR and comolecules?
The BCR is basically an immunoglobulin w/ heavy and light chains.
Costimulatory molecules are the Igα and Igβ and CD21.
What molecule does EBV use to infect B cells?
The CD21 complement receptor which makes up a portion of the BCR complex.
What is essential for B cells to produce IgA, IgG and IgE?
The CD40L-CD40 interaction btw B cell and TH2 cell.
What are the main cells involved in delayed hypersensitivity?
Macrophages and TH1 cells.
What immune and non-immune cytokines activate macrophages and what is the result?
Non-immune: Endotoxin, fibronectin and other chemical mediators.
Immune: T cell produced IFN-y
The result is production of tissue injury through ROS, nitric oxide, AA metabolites and enzymes.
Could also be production of growth factors (TGF-B, FGF and PDGF) for fibrosis.
What allows dendritic cells to home to the same lymphoid area as T cells and what surface molecules help the subsequent interaction?
They have the same adhesion molecules as naive T cells.
They also have MHCII and B7 for the interaction w/ T cells.
What receptors allow follicular dendritic cells to trap Ag?
Fc receptors for IgG and C3b receptors.
What surface markers are used to identify NK cells? Which of these helps w/ ADCC
CD16 and CD56
The CD16 receptor is an Fc receptor for IgG which helps w/ antibody dependent cell-mediated cytotoxicity.
What are the receptors used by NK cells?
Killer Inhibitory Receptors (KIRs) recognize MHC1 and inhibit the cell. NKG2D and other activating receptors recognize stress proteins expressed by virally infected or tumor cells.
What cytokines are associated w/ NK cells?
They release IFN-y, TNF and GM-CSF to stimulate delayed hypersensitivity.
They respond to IL-2, IL-15 by proliferating.
They respond to IL-12 by releasing IFN-y
What cytokines are involved in innate immunity?
IL-1, IL-6, TNF and type I interferons
What are the main functions of the following cytokines: IL2, IL4, IL12, IL15
IL-2 for T cell proliferation
IL-4 for TH2 mediated response
IL-12 for TH1 mediated response
IL-15 for NK proliferation
What chromosome are the HLA molecules found on?
HLA1, HLAII and complement genes are found on chromosome 6.
What is the structure of the MHCI molecule and what does each component do?
MHCI is composed of an α chain and a β chain. The α chain is actually three parts: α1 and α2 bind the Ag fragment and interact w/ the TCR of a CD8. The α3 portion binds to the CD8 molecule itself.
Discuss the specifics of type I hypersensitivity?
IgE mediated release of vasoactive and spasmogenic substances and proinflammatory cytokines from pre-sensitized mast cells.
Describe the immediate type I response and the secondary (or late phase) response?
Immediate is vasodilation, vascular leakage, smooth muscle spasm and glandular secretions which last 5-60mins.
Secondary reaction is infiltrate of basophils, PMNs, macrophages, eosinophils and lymphocytes lasting 2-24 hours.
What cytokines are characteristic of the type I response?
IL-4 release from T cells interacting w/ dendritic cells activates B cells to make IgE.
IL-3, IL-5 and GM-CSF produciton recruit and activate eosinophils.
What are the primary and secondary mediators of mast cells?
Primary: histamine, enzymes (proteases and acid hydrolases) and proteoglycans (chondroitin and heparin sulfate).
Secondary mediators: Leukotrienes C4 and D4, PGD2 and PAF
What are the functions of the mast cell secondary mediators?
Leukotrienes C4 and D4 are vaso and spasmogenic.
Leukotriene B4 is chemotactic for PMNs, eos and monocytes.
PGD2 is bronchospasmic and increases mucus secretion.
PAF activates platelets and is vaso and spasmogenic.
What is atopy?
People that are highly type I hypersensitive.
What is the main idea in type II hypersensitivity? Examples?
Antibody and complement mediated opsonization of cells by monocytes and other cells possessing Fc receptors.
Examples: transfusion reactions, autoimmune hemolytic anemia/thrombocytopenia or agranulocytosis, erythroblastosis fetalis and drugs binding to cell surface.
How is inflammation mediated in type II hypersensitivity? Examples?
Complement deposits on surface of blood vessels and releases C5a which attracts PMNs and monocytes. These use Fc receptors to bind to wall and spew granule contents causing damage.
Examples: some glomerulonephritis and vasculitis
What is antibody mediated cellular dysfunction? Examples?
It is a type II hypersensitivity where there is no cell injury or inflammation but function of the cell is compromised by antibody.
Example: Myasthenia gravis, Graves and pemphigus vulgaris.
Main idea of type III hypersensitivity? Examples?
Ag-ab immune complexes deposit in blood vessels throughout the body.
Example: acute serum sickness where large amounts of drugs are administered.
Which immune complexes cause problems, large or small?
Large immune complexes are cleared easily, this is where there is ab excess.
Small immune complexes can't bind phagocytes as well, this is where there is Ag excess.
What reaction dominates type III hypersensitivity?
Acute necrotizing vasculitis
What is fibrinoid necrosis? What does it look like in the kidney?
Deposition of immune complexes, protein and necrotic tissue during type III hypersensitivity.
In the kidney, it has a granular lumpy appearance w/ proliferation of mesangial cells and infiltration by PMNs and monocytes.
What is the Arthus reaction?
It is type III hypersensitivity when Ag is injected intracutaneously. It causes localized edema, hemorrhage and sometimes ulceration.
What is the difference btw the arthus reaction and type I?
Arthus is type III and usually takes a little longer. There is also hemorrhage, ulceration and localized edema.
What are the morphological changes seen in the PPD and what accounts for this?
It is type IV delayed hypersensitivity. Pre-sensitized CD4 cells stimulate inflammation in the area. This is seen as perivascular cuffing w/ monocytes and TH1 cells. This increases vascular perm which results in protein, fibrin exudation and edema. This causes the induration.
What cytokines are involved in type IV hypersensitivity?
IL-12 from APC during initial sensitization.
IFN-y from TH1 cells to macrophages.
Macrophages respond w/ IL-12 (for TH1 cells), IL-1, TNF, IL-6 and many growth factors for fibrosis.
What hypersensitivity is contact dermatitis?
Type IV delayed hypersensitivity
What is the difference btw direct cell mediated organ rejection and indirect?
In direct, the host T cells recognize Ag presented by donor APCs in either the organ or draining node. The CTLs recognize MHCI molecules and begin to destroy w/ fas and granzyme. The TH1 cells recognize MHCII and secrete cytokines to induce inflammation.
In indirect, the host APCs pick up pieces of donor graft and present to host T cells. No CTLs are activated but TH1 cells are activated through MHCII presentation.
BOTH have increased production of B cells and antibodies.
What is hyperacute rejection?
When the host already has preformed antibody to donor MHCs or cells. It is immediate thrombosis of injured vessels and graft necrosis.
Complement and abs bind to vessel wall and recruit PMNs to destroy.
What is acute rejection?
It can either be cellular or humoral rejection and can take days/months/years.
There is mononuclear cell infiltrate and edema. CD4 and CD8 T cells cause endothelitis and focal tubular necrosis.
What is acute humoral rejection?
This is ab directed at the organ endothelium which results in necrotizing vasculitis, thrombosis, ab/complement and fibrin deposition. Arterioles present w/ thickening of the intima w/ fibroblasts and foamy cell infiltrate.
What is chronic rejection?
Takes months to years and is vascular changes, intimal fibrosis and tubular atrophy. Basically over time, the vasculature has intimal fibrosis which narrows the lumen and results in tubular atrophy and ischemia.
What are the first signs of GVHD? Later?
Generalized rash, jaundice and bloody diarrhea.
This is b/c the skin, liver and GI tract mucosa are the first to be attacked by the donated T cells.
Immunodeficiency will result putting them at risk for CMV infections
How does central tolerance work and what gene can be missing resulting in deficiency?
Central tolerance is T and B cell apoptosis when they recognize self Ag in the thymus and bone marrow, respectively.
The gene AIRE is needed for epithelial reticular cells to present self-Ag to T cells in the thymus.
What are the 3 mechanisms of peripheral tolerance?
Anergy: self-recognizing T cells bind normal cells out in the periphery. These do not have B7 costim molecules so T cell becomes anergic.
Reg T cells: These are T cells spared in negative selection b/c the recognize self Ag but they express CTLA-4 which inhibits other T cells coming into contact w/ self Ag. Reg T cells make IL-10 and TGF-b which inhibits immune activation.
Activation induced: Over activation of T cells in periphery activates Fas-FasL apoptosis.
How would you recognize a reg T cell?
It is CD4 and CD25 positive and expresses the foxP3 tf.
What are the methods that infection can cause autoimmunity?
Infection activates APCs nonspecifically w/ costim molecules. Some of these may be self recognizing.
Molecular mimicry where infections mimic normal tissues.
Antigen release due to tissue damage.
What are signs and symptoms of SLE?
Malar rash, discoid rash, photosensitivity, oral and nasal ulcers, arthritis, serositis, renal dysfunction, neuro disorders, hematologic disorders, immunologic disorders, antinuclear antibodies.
What abs are diagnostic of SLE, Sjogrens, Diffuse and Limited systemic sclerosis?
SLE: Anti-dsDNA, Anti-smith
Sjogrens: Anti-SSA (Ro), Anti-SSB (La).
Diffuse: anti-DNA topoisomerase
Limited: anti-centromere.
What cells initiate SLE?
TH1 mediated B cell production of IgG against self Ag.
What is the main problem in SLE?
Acute necrotizing vessel destruction w/ fibrinoid necrosis.
What are the five classes of lupus nephritis?
Class I: minimal change
Class II: mesangial lupus glomerulonephritis which is small amts of immune complexes in mesangium. Mild hematuria and proteinuria.
Class III: Focal proliferative glomerulonephritis. This is focal deposits, fibrinoid necrosis, mesangial proliferation and PMN infiltrate in parts of < 50% of glomeruli.
Class IV: diffuse proliferative glomerulonephritis. This is endothelial, mesangial and epithelial proliferation. Fibrinoid necrosis, thrombosis and marked hematuria/proteinuria resulting in nephrotic syndrome in 1/2 pts. All glomeruli and all parts of glomeruli are affected.
Class V: membranous glomerulonephritis. Widespread thickening of capillary walls.
What is wire loop glomerulus?
Extensive immune complex deposition in class III and IV SLE nephritis.
What are the main cardiovascular changes seen in SLE?
Libman-Sacks endocarditis which are valvular verrucous nonbacterial deposits.
What is difference btw chronic discoid LE and SLE?
What is subacute cutaneous LE?
What about drug induced LE?
Chronic discoid LE has the skin rash but no systemic findings. The rash is red, swollen and scaly. There are also no anti-dsDNA antibodies.
Subacute, cutaneous LE: Rash is less prominent, diffuse, less scarring and scaliness. Slightly more systemic findings.
Drug induced LE: hydralazine, isoniazid, procainamide and penicillin can cause 80% of pts to get positive ANA but only 1/3 get arthralgias, fever and other symptoms. Anti-histone ab are seen here.
What is CREST syndrome and what is it associated w/?
Raynauds phenomenon
Esophageal dysmotility
Associated w/ the limited form of systemic sclerosis involving face, forearms and hands.
What is the trigger for systemic sclerosis? What cell is implicated?
An abnormal immune response and vasculitis cause fibroblast proliferation and collagen deposition in skin.
TH cells stimulate inflammation and release of cytokines from inflammatory cells.
What cytokines are involved in systemic sclerosis?
IL-1, IL-2, IL-13, PDGF, TNF and TGF-B.
What are the main histologic findings in systemic sclerosis?
Endothelial damage and fibrosis due to cytokine release. This results in microvascular disease and thrombosis.
What abs are found in systemic sclerosis?
Anti-DNA topoisomerase in systemic sclerosis
Anti-centromere ab in limited SS.
What are the skin findings in systemic sclerosis?
Sclerotic atrophy of distal skin and appendages. Dermis becomes infiltrated w/ collagen and fibrosis. Eventually, structure is lost, fingertips begin to taper and face expression becomes mask.
What GI findings do you see in systemic sclerosis?
Mucosa becomes fibrotic and collagenized. Esophagus becomes stiff and inability to swallow prediposes to GERD and Barrett's esophagus.
What renal abnormalities are found in systemic sclerosis?
The interlobular arteries experience intimal thickening. This results in hypertension which worsens the thrombosis and fibrosis of epithelial layers.
What heart and lung findings occur in systemic sclerosis?
Pericardium becomes fibrosed and pericarditis w/ effusion occurs.
Lung manifests w/ pulmonary hypertension and interstitial fibrosis.
Clinical course of systemic sclerosis?
Higher in AA females > 50yrs
Skin thickening, Raynauds
Esophageal motility and GI malabsorption
Pulmonary fibrosis and RHF due to pulmonary hypertension.
Renal failure, cardiac abnormalities and malignant hypertension
Main points about mixed CT disease?
Present w/ symptoms of RA, SS, SLE and polymyositis.
High titers of anti-RNP particle containing U1 RNP.
Main point of Sjogrens syndrome?
Immunologic destruction of salivary and lacrimal glands by TH1 cells and B cell ab. Primary is on it's own but can be secondary to other autoimmune diseases (mainly RA).
What are the markers for Sjogrens syndrome?
Anti-SSA (Ro) and Anti-SSB (La) abs.
Also 75% have rheumatoid factor regardless of underlying RA.
Which has faster onset Anti-SSA (Ro) Sjogrens or Anti-SSB (La)?
Anti-SSA (Ro) is the one where extraglandular manifestations occur and it more rapid progression.
What cells are prominent in glands of Sjogren's syndrome? What histological signs are seen?
Lymphocytes and plasma cells. Germinal centers actually form in the glands.
Ductal hyperplasia of glands causes atrophy and fibrosis of acini.
Clinical signs of Sjogrens?
Dry eyes, keratoconjunctivitis causing blurring of vision, thick secretions.
Nasal drying results in ulceration and epistaxis.
Buccal ulceration results in difficulty swallowing food.
What is diagnosis for Sjogrens?
Lip biopsy b/c a number of diseases can cause glandular enlargement
Main deficiency in agammaglobulinemia?
Called Bruton's agammaglobulinemia b/c bruton's tyrosine kinase is missing required to propagate the IL-7-preBCR signal to mature B cells.
It is X-linked
Pt presents at 6 months w/ respiratory infections, what is it? What other infections do they get?
Bruton's X-linked agammaglobulinemia. Presents at 6 months b/c this is when maternal ab is depleted. Common infections are Hflu, strep pneumo and staph aureus.
They get echovirus, poliovirus and enterovirus infections (common GI viruses).
What vaccines should you not give to pts w/ bruton's agammaglobulinemia?
Live vaccines
Polio vaccine causes poliomyelitis
Echovirus causes fatal encephalitis.
Histologic findings in Bruton's X-linked agammaglobulinemia?
Low peripheral B cells and abs.
Normal CD19 pre-B cells in bone marrow.
Peyer's patches and lymphoid organs are devoid of follicles.
Main point w/ common variable immunodeficiency?
B cell levels are normal but they can't become plasma cells therefore hypogammaglobulinemia. Sometimes all abs are reduced.
Big differences and similarities btw Bruton's agammaglobulinemia and common variable immunodeficiency?
Both present w/ same pyogenic respiratory infxns, giarrdia and enteroviral infxns.
Bruton's however has absent lymphoid follicles b/c B cells are reduced.
Common variable immunodeficiency has hyperplastic follicles b/c B cells are high but plasma cells can't form.
Things to know about isolated IgA deficiency?
Can be familial or acquired (toxo or measles infxns).
Serum and secreted IgA is deficient resulting in recurrent GI, GU and respiratory infxns.
Common in European people.
Main point w/ hyper IgM syndrome?
X-linked (70%) is deficiency of CD40L. AR (30%) is either CD40 deficiency or activation induced deaminase deficiency.
T cells are unable to help B cells isotype switch from IgM when exposed to PROTEIN Ag. B cells can still respond to carb/lipid Ag.
In addition, cell-mediated immunity is deficient.
Pt present w/ pyogenic infxns, pneumonia from PCP, thrombocytopenia, hemolytic anemia and neutropenia, what do they have?
Hyper-IgM syndrome. High levels of Igm cause the blood anemia problems. Lack of other ab causes the infections.
Main point of DiGeorge syndrome?
Failure of pouches 3 and 4 to form thymus and parathyroids. Lack of T cell mediated immunity.
Hypercalcemia, cardiac defects, abnormal facies etc.
Deletion on chromosome 22
Infant presents w/ oral candidiasis, diaper rash, failure to thrive, pseudomonas, PCP and CMV infxns, what is it?
Severe combined immunodeficiency (SCID).
Difference btw X-linked SCID and AR SCID?
X-linked is deficiency of y chain of IL receptor. This prevents B and T cell maturation. (IL-7).
AR is either adenosine deaminase deficiency (increased dATP toxic to lymphocytes), mutation in jak3 kinase or recombinase gene preventing TCR recombination.
What is bare lymphocyte syndrome?
Lack of MHCII molecules prevents CD4 formation. Same presentation as X-linked SCID.
Histologic findings in SCID?
Both T and B cell areas of lymphoid follicles are absent.
Main things in Wiskott-Aldrich syndrome?
Deficiency of WASP protein which links cytoskeleton to surface receptors. Thrombocytopenia and recurrent infxns occur.
Causes of hereditary angioedema?
Deficiency of C1 inhibitor which usually controls C1r and C1s but also factor XII and kallikrein system.
Deficiency results in high bradykinin which causes life threatening edema.
Causes of paroxysmal nocturnal hemoglobinuria?
Lack of CD59 or DAF which control activation of C3 complement on cell surfaces. Complement deposits on RBC surfaces causing break down.
Which abs does the ELISA test for AIDS pick up?
The P24 capsule Ag
Which types of HIV are found in Europe, US and Africa?
HIV1 is found in Europe and US. The substrain is M(B).
Mostly HIV2 in Africa but HIV1 substrain M(C) is found in southern Africa (fast spreading).
Which molecules bind which receptors in HIV infection?
The p120 molecule binds CD4 and either CCR5 or CXCR4. The p41 molecule results in fusion.
What receptors do M-tropic and T-tropic HIV strains use? Which is found in the early stages and which in late stages?
M-tropic uses the CCR5 receptor found in macrophages, T cells and dendritic cells.
T-tropic uses CXCR4 on lymphoid T cells, thymic precursor cells and naive T cells (not peripheral).
Early stages are M-tropic to set up infxn, late stages are T-tropic to progress disease.
What causes HIV to go from latent to active infection?
Who cares?
IL-2 binds to receptor to activate T cell. This activates NFkB to bind to kB sites on DNA. The LTR promoter of HIV is a kB site and thereby activates HIV infxn.
This is why people w/ chronic infxn + HIV progress faster than normal w/ HIV.
What cytokines activate HIV and which inhibit HIV?
IL-2, IFN-y. HIV thrives when macrophages and T cells are activated.
IL-10 inhibits it
List the ways that HIV destroys T cells?
Direct viral replication in both lymphoid organs and precursor cells.
Constant activation of T cells leads to apoptosis.
Gp120 on infected cells causes fusion to noninfected cells forming giant cells.
Soluble gp120 binds to CD4 and causes CTL destruction of T cell.
What do B cell levels look like in HIV infection?
Actually hypergammaglobulinemia occurs b/c either repeat infection w/ EBV or CMV stimulates their proliferation or gp41 stimulates growth. HIV infected cells also release IL-6
Describe acute retroviral syndrome?
It is high viral production, viremia and HIV setting up shop. The symptoms are like mono w/ a sore throat, myalgia, fever and weakness.
Describe middle chronic phase of HIV? How long does it last?
Usually no symptoms b/c virus is only replicating in lymphoid tissue. T cell levels are being sustained and no symptoms except perhaps generalized lymphadenopathy.
It lasts 7-10yrs in normal person, >10yrs in nonprogressor and <3yrs in rapid progressor.
Discuss Ag and ab/cell levels in HIV infection?
Viremia high initially, p24 Ag increases in blood.
CTL response to p24 and abs to both envelope and p24 are made.
Abs trap more HIV on follicular dendritic cells.
During middle phase, CD4's are being knocked down but can regenerate to some extent. Eventually HIV evades immunity and causes opportunistic infxns.
What is a useful surrogate marker of HIV progression?
The initial extent of viremia
Stuff to know about KS? What other tumors do people w/ AIDS get?
Caused by HSV8 virus (KSHV) and is a vascular tumor.
Spindle shaped cells are common which release inflammatory mediators causing angiogenesis (VEGF) and slit formation in existing blood vessels.
non-Hodgkins lymphoma due to polyclonal B cell proliferation.
What would you find if you biopsy a lymph node in someone w/ HIV?
Follicles in all aspects including the medulla due to B cell proliferation. The mantles of the follicles are serrated.
What does amyloid look like stained and unstained?
Stained w/ Congo red, it has an apple green birefringence.
On regular LM, it is amorphous, fibrillar, eosinophilic and hyaline looking.
What are the 3 types of amyloid protein?
AL (amyloid light chain) consist of lamba light chains.
AA (amyloid assoc) is a non-immunoglobulin protein made by the liver. Derived from serum amyloid A protein.
AB (senile amyloid) is found in Alzheimer's pts.
What are the minor amyloid proteins found?
ATTR which is a mutant of the thyroxine and retinal carrier protein transthyretin. Found in senile systemic amyloidosis in the heart and in familial amyloid polyneuropathies.
Aβ2M is amyloid from the β2 microglobulin of MHCI found in pts on hemodialysis.
Prions can form amyloid.
What do you find w/ immunocyte dyscrasia amyloidosis?
The amyloid is AL or light chain amyloid. In 15% of cases this is due to multiple myeloma w/ plasma cells pumping out light chains (Bence Jones proteins).
Most cases of this type of amyloidosis is just due to large amounts of light chains not multiple myeloma.
What is reactive systemic amyloidosis?
Used to be called secondary amyloidosis b/c it is secondary to inflammatory conditions after infections. Used to be associated w/ TB, bronchiectasis and osteomyelitis but now it is RA, IBS and other inflammatory conditions.
What is found in hemodialysis amyloidosis?
Aβ2M amyloid b/c β2 microglobulins can't be filtered.
Main points about heredofamilial amyloidosis?
Mediterranean fever is one of them where inflammation causes high AA.
Familial amyloid polyneuropathies is another where amyloid deposits in peripheral nerves. This amyloid however is ATTR.
What happens w/ endocrine amyloidosis?
Amyloid from either the hormones or mutant protein deposits localized in endocrine glands like pancreas, adrenal etc.
What is found in senile systemic amyloidosis?
TTR amyloid deposits in the heart causing restrictive cardiomyopathy in older people.
What kidney findings do you find in amyloidosis?
Amyloid deposits throughout the mesangium resulting in uneven widening of the basement membrane. Capillary narrowing oocurs and then obliteration of the glomerulus.
Two types of spleen found in amyloidosis?
Sago spleen is when amyloid deposits in follicles forming a tapioca looking appearance.
Lardaceous spleen is when it deposits in the red pulp.
What happens to liver and heart in amyloidosis?
Amyloid deposits in the space of Disse and then around hepatocytes and sinuses which causes compression atrophy.
In the heart (seen in senile amyloidosis) it deposits in the myocardium causing compression atrophy and in the subendocardium causing conduction defects.
Main causes of death in amyloidosis?
Renal failure due to glomerular destruction
Cardiac defects such as restrictive cardiomyopathy and conduction defects.
GI abnormalities w/ macroglossia and malabsorption syndromes.
What antibodies of SLE interfere w/ coagulation and syphilis tests?
The anticardiolipin abs which are against phospholipid-protein complexes.
Pts w/ hyper-IgM are susceptible to a particular infxn, what is it?
PCP pneumonia
What is the most serious complication of Sjogren's syndrome?
Non-Hodgkins lymphoma
What is the difference btw functional cloning and positional cloning?
Functional: You know the biochemically abnormal protein and then you try to localize the gene it comes from. Example: PKU
Positional: You try to map the phenotype to a known region of DNA. Example: CF
What is the difference btw conservative vs. nonconservative missense mutations? Examples?
What about nonsense?
Both are point mutations.
Conservative, the aa sequence is changed but protein function is not.
Nonconservative is replacing the aa and protein function is changed.
Example of nonconservative: mutation in the β chain of sickle cell replacing a glutamic acid w/ valine
Nonsense is when stop codon is created
What do deletion and insertion mutations do? Examples?
Cause frameshift mutations like O blood group or Tay Sachs disease.
Features of AD disorders?
Heterozygotes present w/ the condition.
Usually at least 1 parent is affected but NEW MUTATIONS are common.
No predisposition for male or female.
Reduced penetrance and variable expressivity are common.
AD disorders are usually a defective _____? Whereas AR are usually defective ______?
Proteins (the functional protein product can perform the function).
What is the dominant negative effect?
It occurs generally w/ AD disorders where the mutated protein product affects the nonmutated one.
Gain of function mutations are always ______? Example?
Inherited in AD fashion
Huntington's disease: trinucleotide repeat.
Features of AR disorders?
Parent is usually not affected.
Each child has 1/4 chance of getting it w/ heterozygous parents.
The onset is uniform (no variable expressivity), complete penetrance is common.
Onset early in life
Usually loss of enzyme.
Features of X-linked disorders?
Almost always X-linked recessive.
Males are affected but don't transmit disease, females are carriers.
Males considered hemizygous.
What are the 3 types of enzyme defects and examples?
Accumulation of substrate due to loss of enzyme: Phenylketonuria or galactosemia.
Lack of end product due to loss of enzyme: albinism due to lack of tyrosinase.
Lack of enzyme to remove damaging substrates: α1-antitrypsin deficiency
Pt presents as very tall, slender fingers, prominent forehead ridges and chest deformity?
What is it?
What else will be wrong?
Marfans syndrome
Pt might have ectopia lentis (dislocated lens) but if so then diagnostic.
Cystic medionecrosis is weakening of tunica media of the aortic root. This results in aortic incompetence and predisposition to aortic dissection.
Mitral valve prolapse is more common but less serious.
Pathogenesis: Defect in extracellular glycoprotein fibrillin found in aorta, ciliary fibers of lens and ligaments. Defective genes are FBN1 (15) and FBN2 (5)
Main problems in pts w/ Ehlers Danlos Syndrome?
Skin, skeleton and ligaments are affected.
Skin is stretchy and prone to damage. Joints are hyperflexible and mobile. Surgery is almost impossible due to wound healing defects.
Pathogenesis of vascular EDS?
Defective type III collagen synthesis (either pro α1 chain defect, or secretion).
Result is large artery and colon rupture due to weak walls.
Autosomal dominant trait due to protein defect.
Pathogenesis of kyphoscoliosis EDS?
Missing lysyl hydroxylase resulting in ability to cross link collagen.
Presents w/ corneal rupture and retinal detachment.
AR disorder due to enzyme defect.
Pathogenesis of arthrochalasia EDS and dermatosparaxis EDS?
Arthrochalasia is defective pro α1 chains which prevent propeptide cleavage from type I collagen. Therefore AD disorder.
Dermatosparaxis however is defective procollagen N-terminal peptidase which is same result but AR disorder.
Pt presents w/ achilles tendon xanthoma and MI by age 20.
What is it?
Familial hypercholesterolemia
AD defect in LDL receptor resulting in 2-3X higher cholesterol in heterozygotes and 5-6X higher in homozygotes.
Discuss cholesterol synthesis and circulation?
Liver produces VLDL w/ Apo-C, Apo-E and B-100 apolipoproteins.
Upon reaching tissues, endothelial lipoprotein lipase removes some TGLs to leave IDL w/ Apo-E and B-100.
Liver uses LDL receptors to take up 50% of IDL and convert into VLDL for recirculation.
Rest of IDL circulates, more TGLs are removed and LDL is formed w/ B-100 apolipoprotein.
LDL is then taken up either by LDL receptor or oxidized LDL scavenger receptor.
Discuss the LDL receptor pathway?
LDL is taken up through clathrin mediated endocytosis.
Apolipoprotein is broken down and aa's recycled.
Cholesterol esters are converted into cholesterol and diffuses out of lysosome.
Receptor it returned to surface.
Cholesterol is then stored in cell.
What are the 3 effects of increased cholesterol in the cell?
Cholesterol inhibits HMG-coA reductase which prevents new cholesterol synthesis.
It activates acyl-CoA:cholesterol acyltransferase which esterifies cholesterol and stores it.
Cholesterol inhibits production of LDL receptors for cell surface.
Name 3 reasons why people w/ familial hyperchosterolemia have high serum LDL?
1) Tissue LDL receptors are deficient so can't take up LDL.
2) Liver LDL receptors are deficient so IDL builds up leading to increased LDL.
3) Tissue synthesis of cholesterol increases (HMG-CoA) b/c LDL intake is not good.
What contributes to xanthoma formation and atherosclerosis in pts w/ familial hypercholesterolemia?
Macrophage and endothelial oxidized LDL scavenger receptors take up excess LDL causing foamy cell deposition.
Discuss the 5 classes of LDL receptor deficiencies?
Class I - defective production in ER.
Class II - defective movement from ER to Golgi
Class III - defective extracellular LDL binding domain.
Class IV - defective cytoplasmic clathrin binding domain
Class V - defective release of LDL from receptor in lysosome.
Treatment for familial hypercholesterolemia?
Statin drugs block HMG-CoA reductase thereby preventing fresh synthesis. Also increase LDL expression through feedback inhibition.
What are examples of lysosomal storage diseases?
Gauchers, Pompe's, Niemann-Pick, Tay-Sachs, Sandhoff
What are the 3 different defects in GM2 gangliosidoses?
Tay-Sachs where the α-subunit of Hexosaminidase A is defective.
Sandhoff where the β subunit of HexA and HexB are deficient
Activator deficiency where the activator of Hex is deficient.
What is a ganglioside?
It is a glycosphingolipid which is ceramide attached to oligosaccharides and sialic acid linkages.
6mo old infant presents w/ blindness, dementia, muscular flaccidity and cherry red spot on macula?
What is it? Pathogenesis?
Histologic appearance?
Tay-SaX disease
Defect in Hexosaminidase A, GM2 accumulates in CNS, retina (cherry red spot), liver, heart and spleen.
Neurons under LM have giant cytoplasmic vacuoles filled w/ gangliosides. Under EM, whorled figures are seen in lysosomes.
4mo old infant presents w/ swollen abdomen, failure to thrive, vomiting, fever and generalized lymphadenopathy?
What is it?
Niemann Pick (type A most common). Infants usually die in 1-2yrs, massive hepatosplenomegaly caused swollen abdomen.
Pathogenesis is defective sphingomyelinase resulting in sphingomyelin accumulation.
Sphingomyelin is normally found in organelle membranes but builds up in lysosomes.
Histology shows foamy looking cells (macrophages) in liver and spleen (and other organs) due to vacuolation of lysosomes w/ storage sphingomyelin. Under EM, lysosomes take on palisaded, parallel, lamellar bodies called Zebra bodies.
Use biochemical assay for sphingomyelinase activity in liver and bone marrow.
Difference btw Type A, B and C Niemann-Pick?
Type A presents early in life w/ swollen abdomen and neurologic defects. Infants usually die early.
Type B only have visceral organ involvement but not CNS. Live into adulthood.
Type C is cholesterol trafficking defect but has neurologic involvement and hepatosplenomegaly.
Adult pt presents w/ splenomegaly, pancytopenia and pathologic fractures.
What is it?
Type I Gaucher's disease (most common lysosomal storage disease). Defect is in glucocerebrosidase which results in accumulation of glucocerebroside.
Type I accumulation is in monocytes, NO CNS involvement, presents as adult.
Type II accumulation is in CNS causing infantile convulsions and progressive mental decline. Results in early death.
Type III is a mixture affecting both spleen, bone marrow and CNS.
Where does glucocerebroside come from?
It is glycolipid membrane breakdown from old RBCs and leukocytes
Histology and diagnosis for Gaucher's disease?
Glucocerebroside accumulates in phagocytic cells throughout the body forming Gauchers cells.
Under LM, Gaucher cells have large vacuoles w/ eccentric nuclei and granular appearance. Under EM, the cell looks like crumpled tissue paper.
Measure glucocerebrosidase activity in peripheral blood or skin fibroblasts.
What are the 3 cells targeted in Tay-Sax, Niemann Pick and Gauchers disease?
Tay-Sachs the GM2 targets neurons
Niemann pick, sphingomyelin accumulates in cells of the monocyte system.
Gauchers (type I), glucocerebroside accumulates in macrophages. Type II is neurons.
What is different about diagnosis for Tay Sax, Niemann Picks and Gauchers?
You can use DNA analysis for Tay-SaX and Niemann Pick but Gauchers has too many mutations.
Why do pts w/ Gaucher's present w/ pathologic fractures and pancytopenia?
B/c bone marrow is destroyed by Gaucher cells (monocytes storing glucocerebroside)
What are the 3 groups of glycogenoses and their main idea?
1) Defects in liver enzymes result in ability to break down glycogen and therefore hepatomegaly and hypoglycemia.
2) Muscle glycogen enzyme defects prevent muscle from using glycogen and therefore present as muscle weakness and low energy.
3) Non-liver or sk muscle enzyme deficiencies. In these either lysosomal glycogen enzymes are missing or lack of branching enzyme. Result is glycogen accumulation in all organs and severe presentation, usually fatal.
Pt presents w/ failure to thrive, stunted growth, hepato and renomegaly and hypoglycemia after fasting? What is it?
It is von Gierke's disease (type I) where liver and kidney lack glucose-6-phosphatase (turning them into muscles). They can't mobilize glycogen so it accumulates and BGL is low.
Adult pt presents w/ painful cramps after strenous exercise and myoglobinuria. Blood lactate levels during exercise are also unable to increase.
What is it?
McArdles disease (type V, muscle phosphorylase) or type VII (muscle phosphofructokinase). Both enzymes prevent muscles from mobilizing glycogen to produce glucose and thereby energy for muscles.
1 yr old presents w/ massive cardiomegaly, muscle hypotonia and cardiorespiratory failure.
What is it?
Pompe's Disease (type II) is lack of acid maltase (α-glucosidase) which results in glycogen accumulation in heart (and other organs).
Histologically, cardiac myocytes are packed w/ glycogen look like lacy cytoplasmic pattern.
What are the 2 other names for Neurofibromatosis 1 and 2?
NFB 1: von Reckinghausen's disease
NFB 2: Acoustic neurofibromatosis
What is a fibroma?
It is a proliferation of nerve, schwann cell and fibroblasts into a tumor.
Differentiate from Schwannomas which are just proliferations of Schwann cells.
Pt presents w/ numerous pigmented lesions all over his body, a number of swollen masses below the skin surface and lesions in the iris.
What is it?
Neurofibromatosis type I b/c of the cafe au lait spots, the numerous neurofibromas and the Lisch nodules (hamartomas of the eye).
You can differentiate from type II b/c type II has no Lisch nodules and multiple tumors like meningiomas, acoustic neuromas and gliomas.
Mutations in NF-1 gene (17) results in production of neurofibromin which is an antagonist of the p21 Ras oncoprotein.
What is a ring chromosome?
When 2 terminal deletions occur and the two ends of the chromosome fuse to form a ring.
Usually expressed 46XY,r(14)
What is the difference btw paracentric and pericentric inversions?
Paracentric is when the piece that is cut out does not involve the centromere.
Pericentric is when the piece cut out and flipped around includes the centromere.
What is a balanced translocation?
Basically like homologous recombination but btw two different chromosomes. Switching a balanced amt of material.
What is the most common chromosomal disorder and the #1 cause of MR?
Trisomy 21
Infant presents w/ oblique palpebral fissues, medial epicanthal folds, MR, single simian crease and severe hypotonia.
What is it?
What is main risk factor?
It is trisomy 21 or Down Syndrome.
Advanced maternal age
Usually nondisjunction of chromosome 21 but parents are normal.
Robertsonian translocation and mosaic down account for few cases.
What cancer are pts w/ Down prone to develop?
10-20X risk for acute leukemia (ALL and AML).
Pt presents w/ microphthalmia, polydactyly, microcephaly and mental retardation, cleft lip and palate, cardiac defects, renal defects, umbilical hernia and rocker bottom feet.
What is it?
Trisomy 13
Pt presents w/ low set ears, short neck, overlapping fingers, renal malformations, micrognathia, prominent occiput, mental retardation and rocker bottom feet.
What is it?
Trisomy 18
Pt presents w/ congenital heart defects, palate abnormalities, facial dysmorphism, developmental delay, T cell immunodeficiency and hypocalcemia.
What is it?
Diagnostic measure?
DiGeorge syndrome (22q11.2)
FISH probe for deletion.
What are 3 big features of sex chromsome disorders?
They are often subtle,
They only present at puberty not birth
More X chromosomes means more MR
Pt is extremely tall w/ abnormally long legs, atrophied testes, small penis and lower IQ.
What is it?
Histology and hormone levels?
Kleinfelters syndrome
Additional X and Y chromosomes usually XXY.
Elevated Fsh but low testosterone. High estrogen leads to feminization effect.
Testicular tubules are atrophied and Leydig overcrowd.
Short female pt presents w/ amenorrhea, lack of pubic hair and secondary female sex characteristics and you notice short stature and webbed neck. Pt also has preductal coarctation of the aorta and a bicuspid aortic valve.
What is it?
Turner syndrome w/ chromosome complement being 45 XO (57%). Some are mosaics and some just have partial abnormalities of X.
What accounts for the short stature in Turner's syndrome?
Deletion of the homeobox Shox gene.
What is female pseudohermaphroditism?
It is an XX female w/ normal internal structures but virilized external genitalia.
Often caused by excessive androgens during gestation.
What is male pseudohermaphrotidism?
Normal XY male inside w/ testicles and normal internal male structures. Outside is undervirilized or completely female.
Most commonly caused by a mutation in the androgen receptor making it insensitive to androgens (testicular feminization).
The gene for the androgen receptor is actually on the X chromosome.
What is the 2nd most common cause of MR?
Fragile-X syndrome
Why is it called Fragile X?
B/c when you put the X chromosome in a folate deficient medium, it looks like it has a fragile region.
MR male presents w/ long face, large mandible, large everted ears and large testicles (macro-orchidism).
What is it?
Diagnostic method?
Fragile X syndrome. The only distinct feature found in most fragile X is macro-orchidism.
Trinucleotide repeat disorder on the X chromosome FMR gene. FMR gene protein product regulates translation in neurons.
What is weird about the transmission of Fragile X?
It is X linked but there are male carriers, affected females (50% of carrier females), your position in the pedigree matters (Sherman paradox) and anticipation occurs.
What is the difference btw a fragile X carrier and someone affected?
The carrier has a premutation needing amplification through OOGENESIS to convert into a full mutation.
What is the difference in amplification btw Huntington's and Fragile-X?
Huntington's uses spermatogenesis for amplification.
Fragile-X uses oogenesis.
What is the difference btw where repeats occur in Fragile X vs. Huntington's?
Fragile X and myotonic dystrophy have noncoding region amplifications.
Huntington's has coding region amplifications.
What is heteroplasmy?
This is where there are mutant and normal copies of mitochondrial DNA preventing complete presentation of a condition.
20 yr old pt presents w/ bilateral loss of central vision, cardiac dysfunction defects and minor neurologic defects.
What is it?
Leber Hereditary Optic Neuropathy
Pt presents w/ MR, short stature, hypotonia, obesity, small hands and feet and hypogonadism.
What is it?
It is Prader Willi syndrome caused by the deletion del (15)(q11.2q13) on the paternally derived chromosome. B/c in this case the maternal chromosome is imprinted, you have defects.
Pt presents w/ MR, ataxic gait, seizures and inappropriate laughter.
What is it?
It is Angelman syndrome caused by a deletion del (15)(q11.2q13) on the maternal chromosome. Same deletion as Prader Willi, just maternal not paternal. B/c the paternal chromosome here is imprinted, the pt is deficient in genes.
What is uniparental disomy?
When you receive the same 2 alleles from the same parent.
What are the indications for offering a pt prenatal chromosome analysis?
Advanced maternal age > 34
Pt w/ balanced translocation, robertsonian translocation or inversion
Pt w/ X-linked recessive condition
Pt w/ previous children w/ chromosome abnormalities.
What are local and generalized causes of increased hydrostatic pressure?
Local: impaired venous outflow due to clot or extrinsic pressure on vein (inflammation, tumor).
Generalized: LHF causing pulmonary edema or RHF causing systemic edema. CHF also causes renal hypoperfusion resulting in renin/Ang/aldosterone release and Na retention. This worsens edema w/ increased water retention.
What are causes of reduced oncotic pressure edema?
Reduced albumin synthesis: Malnutrition of protein, diffuse liver disease.
Loss of albumin: Protein losing glomerular disease (nephrotic syndrome, minimal change disease) or protein losing SI disease (celiac sprue or gluten enteropathy).
What is minimal change disease of the kidney?
Podocyte foot processes fuse resulting in leakage of albumin during filtration.
What is anasarca?
Generalized edema
What should you do if you remove fluid from a body cavity?
It is never normal so send for sp gravity, chemical analysis, cell count, cytologic exam to rule out malignant cells and culture for infectious agents.
What is difference btw hyperemia and congestion?
Hyperemia is active process of increased arteriolar dilation (physiologic is exercising sk muscle, pathologic is inflammation). Hyperemia is red due to oxygenated blood.
Congestion is passive process due to impaired venous outflow. Congestion is cyanotic due to venous blood.
What causes nutmeg liver?
Passive congestion resulting in blood backing up into liver and causing dilated central veins.
What would chronic pulmonary congestion look like?
Alveoli filled w/ heart failure cells (hemosiderin laden macrophages) and septa thickened and fibrotic.
What is a hemorrhagic diathesis?
An increased tendency to bleed from insignificant injuries.
Definitions of hematoma, petechiae, purpura, echymosis,hemarthrosis?
Hematoma is blood entrapped in a closed space.
Petechiae are hemorrhages in skin or mucosa 1-3mm.
Purpura are hemorrhages in skin or mucosa 3-10mm.
Echymoses are hemorrhages >10mm.
Hemarthrosis is bleeding into a joint.
What is Henoch-Schoenlein's?
Palpable purpura of buttocks, ankles and legs due to IgE mediated nephropathy.
What is cardiac tamponade?
Sudden hemorrhage of 100-200cc of blood into pericardium compressing the heart.
What should you think of when minor trauma causes a hemarthrosis?
An inherited disorder of clotting like hemophilia
What substance causes vasoconstriction in normal hemostasis? Where does it come from?
Endothelin comes from the endothelium (most potent vasoconstrictor in the body).
What are antiplatelet modulators that endothelium releases?
PGI2, NO to cause vasodilation and prevention of platelet adhesion.
Adenosine diphosphatase which breaks down ADP (normally activates platelets).
What are the anticoagulant effects of the endothelium?
Endothelium expresses heparin like molecules which bind ATIII. The complex breaks down II, X, XI and IX.
Endothelium expresses thrombomodulin which binds thrombin. The complex activates protein C + protein S (1000X more active) and together they degrade factor Va and VIIIa.
What are the fibrinolytic effects of endothelium?
Endothelium releases two types of tPA. Tissue tPA and urokinase tPA which degrade fibrin.
What are the platelet effects, procoagulant effects and antifibrinolytic effects of the endothelium?
Endothelium releases vWF and exposes collagen to allow platelet activation.
Endothelium releases tissue factor III activating the extrinsic pathway.
Endothelium release plasminogen activator inhibitors (PAIs) to inactivate tPA.
What is found in and on the α granules of platelets?
Fibrinogen, vWF, PDGF, TGF-β, fibronectin, factors V and VIII and platelet factor 4. On the surface is P-selectin
What is found in δ granules of platelets?
ADP, ATP, TXA2, Ca2+, histamine, serotonin and epinephrine.
What interaction initiates platelet adhesion? Describe platelet shape change?
vWF from endothelium and exposed collagen bind to Gp1b receptors on platelet surface.
Previous interaction causes Ca2+ influx which removes gelsolin from actin filaments. Water follows Ca2+ causing pseudopod formation. Filamin and fimbrin bundle and secure actin filaments.
What is the difference btw vW disease and Bernard Soulier?
vW disease is an absence of vWF and Bernard Soulier is an absence of the Gp1b vWF platelet receptor.
Up until what point is a platelet plug reversible?
Primary hemostatic plugs are reversible but when thrombin binds PAR receptors and activates fibrin, the platelets contract and a secondary hemostatic plug forms.
Describe the P2Y12 receptor and drugs that block it's action?
This is the ADP receptor on platelets which is a Gi. Binding of ADP to the receptor lowers cAMP through adenylate cyclase inhibition. Lower cAMP causes platelet activation.
Clopidogrel (plavix) blocks this receptor and Dipyridamole blocks the phosphodiesterase that normally breaks down the cAMP. Increased cAMP means platelet inhibition.
Describe the thrombin receptor?
It is the P2Y1 receptor on platelets and both thrombin and ADP bind to it. Binding increases PLC which activates the platelet.
Describe the thromboxane receptor?
It is a Gq receptor that ultimately increases PLC, PKC and activation of the fibrinogen binding GpIIb:IIIa receptor
What is unstable angina and how would you treat it?
It is angina during rest caused by pre-clot formation. Give clopidogrel or dipyridamole.
What is Glanzmann thrombasthenia?
A defect in the GpIIb:IIIa fibrinogen binding receptor.
What accounts for the fact that clotting stays in 1 place rather than all over?
In order for the coagulation cascade to proceed, the factors need to bind to phospholipid complexes.
What 3 natural anticoagulants keep clotting in 1 spot?
Antithrombin III binds endothelial heparin-like molecules. The complex inhibits II, IX, X, XI and XII.
Thrombin binds to thrombomodulin which activates protein C/S which inactivate factor V and VIII.
Tissue factor pathway inhibitor (TFPI) from endothelium binds to VII-III complex and factor X.
Which 3 things activate factor XII?
Collagen, high molecular weight kininogen and prekallikrein.
Describe the PT test?
Add factor III and Ca2+, tests the extrinsic pathway, takes about 11-13secs.
The International Normalized Ratio is designed to account for different types of tissue factor.
Describe the PTT test?
Add phospholipids, Ca2+ and activated XII, tests the intrinsic pathway and takes about 25-35sec.
Discuss ways of activating plasminogen?
Release of urokinase PA from tissues, release of tissue PA from endothelium and Kallikrein activation of plasminogen through Hageman factor.
Discuss ways to inhibit plasmin?
Release of α2-plasmin inhibitor and plasminogen activator inhibitors (PAIs)
Why must you administer clot busters quickly?
B/c older larger clots are more resistant to fibrinolysis.
What are good lab measures for detection of thrombosis and fibrinolysis?
Serum fibrinogen levels
Serum D-dimer levels.
What is Virchows triad?
The factors that predispose to thrombus formation.
Endothelial injury (#1)
Turbulent blood flow
When would you consider inherited hypercoagulable states? Which is most common?
When pts < 50 present w/ thromboemboli.
Factor V Leiden
In which direction do arterial and venous thrombi form? What are lines of Zahn?
Arterial have tails away from the heart. Venous have tails towards the heart, w/ blood flow.
Alternating platelet (white) and RBC (red) laminations characteristic of a thrombus formed while pt is still alive and blood is flowing.
Where are the most common arterial and venous thrombi?
Arterial are coronary, cerebral and then femoral.
Venous are 90% in deep leg veins.
What are the 3 types of endocarditis that we have done?
Bacterial endocarditis is when infection damages the valve and thrombi form vegetations.
People w/ hypercoagulable states form non-bacterial thrombotic endocarditis.
People w/ type III hypersensitivity like SLE have Libman-Sacks endocarditis or non-verrucous endocarditis.
What is a mycotic aneurysm?
When a thrombus forms, organizes and then recanalizes. At this point bacteria can infect this thrombus forming a mycotic aneurysm.
What are we most concerned about w/ venous and arterial thrombi?
Arterial is occlusion and ischemia
Venous is embolization
What is migratory thrombophlebitis or Trousseau syndrome?
When disseminated tumors release procoagulants causing clots all over.
Where are arterial thrombi most likely to embolize?
75% go to lower extremities then brain (20%), kidneys and spleen due to high blood flow.
What is the sequence of events w/ lab tests in DIC?
Fibrin/platelet thrombi form in microcirculation resulting in decreased fibrinogen and platelets.
RBCs fragment on thrombi forming Schistocytes.
Diffuse activation of plasmin resulting in increased D-dimers.
What is a saddle embolus?
What is a paradoxical embolus?
A venous embolus straddling both pulmonary arteries occluding them.
An embolus formed in the venous system that goes through an ASD or VSD to lodge in arterial circulation.
Generally ____ of pulmonary circulation must be occluded for death? (what is this called) If a pt has 1 PE ______?
>60 occlusion results in RHF or Cor Pulmonale
At risk for more PEs
Where do most arterial thrombi come from?
Intracardiac mural thrombi (80%)
Pt presents 3 days post injury w/ tachypnea, dyspnea, tachycardia, irritability, restlessness and diffuse petechial rash.
What is it?
It is a fat embolus which occurs after long bone fracture, soft tissue or burns.
What is the pathogenesis of fat emboli?
The fat embolus occludes the vessel and causes toxic injury due to free fatty acid damage. This activates platelets and promotes inflammation.
When do you see air emboli and how much is needed?
Obstetric procedures, chest wall damage and decompression sickness. >100cc of air is required to produce symptoms.
What is the cause of an amniotic embolism? Histology?
Placental tear releases amniotic fluid and fetal cells into maternal circulation through uterine veins.
Histologic evidence is squamous cells from fetal skin in mom's capillaries.
Following giving birth, mother presents w/ severe dyspnea, cyanosis, hypotension, DIC, seizures and coma.
What is it?
Amniotic fluid embolism.
What is an infarction?
Where are the common sites?
An area of ischemic necrosis due to lack of arterial inflow or obstructed venous outflow (rare)
Myocardial, cerebral, pulmonary and bowel.
Where do you see red vs. white infarcts?
Red are seen in organs w/ multiple blood flow or soft (like lungs).
White are seen in solid organs w/ end arterial flow like kidneys and spleen.
Discuss the morphologic aspects of an infarct?
Wider shaped at periphery of occlusion (wedge shaped).
Borders become more defined due to hyperemia and inflammation over time.
Initially soft and hemorrhagic become firm and fibrotic.
What are the 4 factors that contribute to the severity of an infarct?
Nature of vascular supply (dual or single)
Rate the occlusion develops (slower allows collateral circulation)
Vulnerability of cells to hypoxia (neurons and myocytes screwed).
Blood O2 content (anemia or hypoxemia worse).
What is shock?
Systemic hypoperfusion due to reduced cardiac output or reduced effective blood volume.
5 types of shock?
Cardiogenic is pump failure
Hypovolemic is low blood volume (hemorrhage or burns)
Septic is bacterial infection
Neurogenic is spinal cord injury
Anaphylactic is IgE mediated type I.
Discuss pathogenesis of septic shock?
Most commonly GN organisms have LPS in cell wall. When degraded, LPS binds TLR4, LBP and CD14 on macrophages which release TNF and IL-1.
This results in endothelium releasing IL-6/IL-8/NO and PAF.
Endothelium will also increase adhesion molecules for leukocytes.
What determines outcome of septic shock?
The levels of NO and PAF
At low [], localized inflammation occurs.
At medium [], fever occurs, acute phase reactants are released from liver and leukocytes are released from bone marrow.
At high [], blood vessels dilate, DIC, ARDS and low cardiac output occurs.
Discuss the nonprogressive phase of shock?
Vital organs are maintained w/ vasoconstriction to periphery (cool skin), sympathetic and baroreceptor increase in BP, release of ADH and Ang, renal retention of fluid.
Discuss the progressive phase of shock?
Persistent tissue hypoperfusion result in increased lactic acid production and blunting of vasomotor response which causes blood to pool in periphery and lowering CO.
Discuss irreversible stage of shock?
Tissue hypoperfusion results in multisystem organ failure.
Neoplasms w/ scant ct are ______, whereas those w/ lots are ______?
Soft and fleshy
Scirrhous or hard (desmoplasia - abundant collagenous stroma).
What is an
What is the difference btw a polyp and a polypoid cancer?
Benign epithelial tissue growing like a gland or from glandular tissue
Benign epithelial tissue which grows warty projections
Benign tumor that forms a cystic mass
Polyps are usually benign but polypoid cancer is malignant.
Two types of malignant tumors?
What is a choristoma and hamartoma?
Choristoma is an ectopic rest of normal tissue
Hamartoma is a disorganized mass of cells indigenous to the area.
What is differentiation?
Which are normally more differentiated, benign of malignant?
How much malignant cells resemble normal ones
Benign are usually well differentiated.
Why do malignancies become more aggressive over time?
B/c selective immunologic and survival pressures pick out the best cells apt to survive.
What are the morphologic characteristics of a malignant neoplasm?
Cells are pleiomorphic in size and appearance
Nuclei are dark, N:C ratio is very close and chromatin is granular.
Lots of bizarre mitosing cells
The cells lose polarity and grow in a disorganized mass
Tumor giant cells form
What is the main goal of cancer prevention?
Identifying dysplasia
What is dysplasia? What are the most common forms of dysplasia?
Dysplasia is abnormal growth and refers only to morphology
Barrett's esophagus
Ulcerative colitis
Dysplasia of the cervix
What is a carcinoma in situ?
It is dysplastic cells confined to their region of origin. They have not crossed the bm yet but are precancerous.
Dysplasia is usually ______ and doesn't always lead to ______? Is it usually possible to detect which dysplasias will proceed to cancer?
List 6 general characteristics of benign neoplasias?
Usually well differentiated
Slow growing
Do not invade
Do not metastasize
Do not always behave in a benign fashion
Always encapsulated so they crush surrounding tissues forming ulcers or causing bleeding
What is the best prognostic measure of a tumor?
Stage which is how widely disseminated a tumor is
What is the grade of a tumor? What makes this an imperfect measure for prognosis?
Grade is how well differentiated a tumor is. The levels of grading are I-IV.
It is an imperfect measure b/c it depends on sampling error, tumor progression, disparity btw appearance and behavior and opinion of analyzer.
What are 6 generalizations about malignant neoplasias?
They can invade
They can metastasize (able to spread and kill)
They are undifferentiated
They grow fast
They have no capsule
By the time they are detectable, they have clones that can metastasized.
How many cells is the smallest detectable clinical mass? What is the biggest tumor compatible w/ life?
10 X 9 cells
10 X 12 cells
What are the 3 factors that affect the rate of tumor growth?
The doubling time of cells
The growth fraction
The rate at which cells are lost.
Once a cancer is detected, what portion of cells is in the growth fraction?
Fast growing tumors <20%
Slow growing tumors <10%
What are the 4 stages of the history of malignant neoplasms?
Transformation: one single cell transforms into neoplastic
Growth: this cell multiplies
Local invasion: growth through bm of local tissue
Metastasis: spread to other organs, the ultimate proof of malignancy.
What is the ultimate proof of malignancy?
What are the 3 ways of metastatic spread?
Seeding of cavities when a cancer breaks into a body cavity.
Lymphatic spread: most common for carcinomas but can happen w/ sarcomas.
Hematogenous spread: sarcomas tend to move through the venous system to lung and liver.
What is a pseudomyxoma peritonei?
It is a gelatinous neoplastic mass due to implantation of a mucus secreting carcinoma of ovary or appendix.
Does a swollen lymph node in the vicinity of a primary tumor mean metastasis?
No, it could merely mean a hyperplastic response of tumor immunity.
Where are most sarcoma metastases likely to go?
Sarcoma drains through the venous system to areas of high venous flow like liver and lung.
What are the top 5 incident cancers in men?
Prostate, Lung, Colorectal, Bladder, Lymphoma and Melanoma
What are the top 5 cancer killers in men?
Lung, Prostate, Colorectal, Pancreas, Leukemia
What are the top 5 incident cancers in women?
Breast, Lung, Colorectal, Uterine corpus, Ovary/melanoma/lymphoma
What are the top 5 cancer killers in women?
Lung, Breast, Colorectal, Pancreas, Ovary
What do the statistics look like for leading causes of death?
Heart disease is still number 1 but has declined and will be passed by cancer. Stroke, heart disease and accidental injuries have declined over the years. Cancers and chronic lower respiratory diseases have increased.
What are the most common cancers in childhood < 15yrs?
#1 is acute leukemias
#2 is CNS malignancies
What are the recommendations for breast cancer screening?
At age 40 a mammogram and clinical exam. Then 1 check up every year after that. Normal mammogram does not rule out cancer, especially if the breast mass is palpable.
What are the recommendations for prostate screenings?
PSA and digital rectal exam at age 50 (40 if AA or + family history) and one every year thereafter.
What are the recommendations for colon screening?
1 every 5 years at age 50 or earlier if at risk. Annual fecal occult blood test is optional.
What are the recommendations for cervical screening?
Annual pap smear at age 18 or onset of sexual activity. If 3 consecutive negative pap smears then screen less often.
Autosomal dominant inherited cancers are usually?
Name 2 and discuss?
Single point mutations in 1 allele of tumor suppressor gene. The second allele occurs in somatic cells after birth.
Retinoblastoma - inherited defect in RB suppressor gene. 10,000X risk for retinal neoplasm and osteogenic sarcoma.
Familial adenomatous polyposis - defect in APC tumor suppressor gene (5). >100 colon polyps by age 20 and guaranteed colon cancer by 50. Prophylactic colectomy is done.
Cancers arising from defective DNA repair are ____? Except? Give some examples and discuss?
Autosomal recessive inheritance.
Hereditary non-polyposis colon cancer : AD inheritance. Inactive DNA mismatch repair w/ increased risk of colon cancer at young age.
XP is skin cancers from UV light and nucleotide excision repair defect.
Ataxia-telangiectasia is acute sensitivity to ionizing radiation leading to lymphocyte maturation and lymphoma. Defect is in ATM gene which causes loss of p53 induced delay in cell cycle.
What are characteristics of familial cancers?
Cancers occur at early age
Tumors in 2 or more close relatives
Multiple or bilateral tumors
Risk for siblings 2-4X greater
Name some familial cancers w/ tumor suppressor mutations?
BRCA1 (female breast and ovary)
BRCA2 (male and female breast and ovary)
E-cadherin (gastric carcinoma)
p16 or INK4a (malignant melanoma).
What are examples of acquired preneoplastic disorders?
Endometrial hyperplasia resulting in endometrial carcinoma. Cervical dysplasia resulting in cervical carcinoma. Chronic atrophic gastritis resulting in dysplasia and gastric carcinoma.
How does the RB suppressor protein work?
It normally binds E2F and DP1 on the promoters regions of DNA. It recruits histone deacetylase which clumps chromatin so it can't be transcribed. Activation of cell w/ growth factors increases cyclin D []s which bind to CDK4 and this complex phosphorylates RB. RB can now let go of E2F tf which transcribes genes.
Discuss the activation and controls of RB?
Rb is active when unphosphorylated and is holding E2F tf. Growth factors activate cyclin D/ CDK4 complex which phosphorylates RB. Inhibiting cyclin D/CDK4 is p21 (activated by p53) and p16INK4a
Discuss what activation of E2F does and the connection to RB?
Activating E2F activates many cell cycle genes like cyclin E etc. It also increased production of p14arf and p73. p73 is a brother of p53 so initiates apoptosis. p14arf inhibits MDM2 which is normally the inhibitory control of p53. Inhibiting an inhibitor, activates p53 which does apoptosis and activates many other genes. One other gene it activates is p21 which controls cyclinD/CDK4 thereby providing feedback inhibition.
What is the link btw p16INK4a and p14ARF and what is the difference?
ARF stands for alternate reading frame b/c p14ARF uses an alternate reading frame from the INK4a gene. So they are from the same gene.
However, p14ARF works by preventing p53 degradation and p16INK4a inhibits the cyclinD/CDK4 complex.
What should you look for if you want to id more aggressive breast cancers? What would the treatment be?
Her2 or erbB2 oncogene. It is a mutated EGF receptor found overexpressed on aggressive breast cancers.
The therapy is trastumab which is a mab directed at the EGF receptor.
What is the most common oncogene abnormality found in human tumors?
Most common oncogene is Ras.
Most common mutation in human tumors is p53.
How does Ras work and how do most mutations affect it?
When growth factors bind the cell, Ras binds to GTP which activates it. It then activates the MAP kinase pathway and tfs. Ras has GTPase to remove the GTP to inactivate itself but needs additional GTPase activating proteins (GAPs) to augment the function. Mutations of Ras prevent GAPs from binding Ras thereby making it constitutively active.
What is the best example of a mutated nonreceptor tyrosine kinase? How does the mutation work?
c-ABL is normally a nonreceptor tyrosine kinase which phosphorylates other proteins when gfs bind. Mutations in c-ABL prevent negative control and inhibition.
Best known mutation is translocation of c-ABL (9) to the BCR gene (22) which results in a fusion protein BCR-ABL. This is a constitutive tyrosine kinase and is found in 95% of chronic myelogenous leukemia cases (some ALL too). The fused chromosome is called the Philadelphia chromosome.
Imatinib mesylate
How does the MYC protooncogene work? What antagonizes it?
Myc is a tf that binds to Max and the complex activates transcription.
MAD-Max antagonizes it or represses transcription.
Presence of MYC in the absence of survival signals results in __________? What are the 2 cases the MYC is oncogenic?
N-myc mutation in neuroblastoma
8,14 translocation of myc in Burkitt's lymphoma.
How does the Burkitt's lymphoma translocation work?
It is translocation of myc from chromosome 8 to the IgH locus on chromosome 14.
Which genes are most commonly mutated in B and T cell lymphomas?
Ig locus in B cell
TCR locus in T cell
This is due to the constant rearrangement that these genes are undergoing.
What other cancers are kids w/ retinoblastoma likely to get?
Osteogenic sarcoma and soft tissue sarcomas.
The Rb pathway is mutated in almost all malignancies.
What does a mutation in Rb prevent from happening?
The mutation is usually in the E2F binding pocket of Rb in which case, if you mutate this then the Rb can't bind E2F making it nonfunctional.
How does TGF-β interact w/ Rb?
TGF-β favors the active conformation of Rb thereby preventing cell growth.
What is the most common site of genetic alterations in human tumors?
>50% have a p53 mutation
The p53 protein is composed of __________? The mutation in this protein primarily affects?
4 identical subunits
It's ability to bind DNA. The mutation is usually in the DNA binding domain.
How does MDM2 control p53?
It binds to it's DNA binding domain, it causes p53 degradation and also causes export from the nucleus.
What are stimulators of p53?
DNA damage by radiation, UV light or chemical mutagens.
Stress signals like change in redox potential, hypoxia or senescence
How does p53 sense DNA damage?
DNA-dependent protein kinase and ataxia telangiectasia protein phosphorylate p53 which activates it.
What are the 4 pathways to activate p53?
DNA damage causes p53 phosphorylation
MDM2 inhibition
p14ARF activation
Acetylation or binding of stressor proteins.
What are the 4 proteins that p53 affects to get the job done?
It activates p21 which blocks cyclinD/CDK4.
It activates GADD45 which causes DNA repair.
It activates BAX which binds Bcl-2 causing apoptosis.
It increases MDM2 to inhibit itself.
Other than point mutations in p53, what are other ways to cause mutations in p53 pathway?
Defective MDM2 causes overactivation.
E6 from HPV leads to increased p53 degradation
INK4a/ARF mutation resulting in loss of p14ARF function.
85% of B cell lymphomas are ______?
A 14/18 translocation of the BCL-2 gene to the IgH locus whereby the gene is made constitutively active. This results in reduced apoptosis.
How does p53 initiate apoptosis? What molecules are promoters of cell survival and which ones of cell apoptosis?
It activates BAX found in the cytosol which moves to the mitochondrial membrane.
BCL-2, Bcl-x is pro survival and BAX is pro apoptosis
How do c-myc and bcl-2 work together?
c-myc stimulates proliferation
Bcl-2 prevents apoptosis
The 2 together sequester p53 in the cytosol
What is the main defect in HNPCC? What genes are most commonly involved?
A defect in mismatch repair which results in replication error phenotype.
Defects in hMSH2 and hMLH1
What is replication error phenotype? What does it result in? What disease is it assoc w/?
When mutations in DNA repair result in replication error accumulations. It results in microsatellite instability.
What are some general characteristics about HNPCC?
Colon cancer develops at a young age <50
They are poorly differentiated and invade early.
They are resistant to standard chemo.
They usually occur in the proximal colon.
Some have better prognosis b/c so many mutations occur that they die.
What other cancers are people w/ HNPCC predisposed to?
Endometrial carcinoma.
15% of sporadic colon cancers have ________?
Mutations in mismatch repair genes.
What conditions are associated w/ increased risk for ionizing radiation?
Ataxia telangiectasia and Bloom syndrome.
Discuss ataxia telangiectasia? Symptoms?
Deficiency is in ATM kinase which phosphorylates p53 when DNA double strand breaks occur (caused by ionizing radiation).
Basically neurologic symptoms from degeneration of Purkinje cells of the cerebellum.
There are also immunodeficiencies and lymphoid malignancies
What is the main defect in Bloom syndrome?
BLM helicase, an enzyme involved in DNA repair by homologous recombination.
What are the 3 effects of tumor neovascularization?
Provide nutrients and oxygen for growing cells
Endothelial cells secrete growth factors like PDGF and insulin like gfs.
Promotes metastasis via lymphatics and blood vessels.
What correlates strongly w/ metastasis?
The microvessel density in a neoplasm.
What growth factors are associated w/ tumor vasculogenesis? What cells produce these?
Either tumor cells or macrophages
What anti-angiogenesis factors do tumors produce? Pharmacologic application?
Thrombospondin 1
Angiostatin from plasminogen
Endostatin, tumstatin from collagens.
Endostatin and mabs against VEGF for cancer treatment
What are the steps involved in ECM invasion of a tumor?
Loosening of intercellular junctions: downregulation of E-cadherin and catenins.
Attachment to ECM: tumor cells express receptors for fibronectin and laminin all over their surface
Degradation of ECM: tumor and stromal cells use serine, cysteine and matrix metalloproteinases to degrade. MMP2 and MMP9 are used to degrade through type IV collagen.
Migration into stroma: cleavage products of collagen and proteoglycans have growth promoting/angiogenic and chemotactic effects. The tumor cells develop receptors for ECM and growth factors that they release autocrine which increases motility and migration.
What happens once metastatic cells are into the circulation?
An adaptive and humoral response is directed against them.
They aggregate together and adhere to platelets to protect themselves.
Use integrins and chemokine receptors to home to tissues of tropism.
What is tumor progression? What accounts for it?
A tumor's acquisition of increasing malignant potential
Sequential appearance of heterogeneic subpopulations of cells which have different growth rates, invasion or metastasis ability, response to hormones and susceptibility to drug therapy.
What are the 2 classifications of carcinogens?
Experimental: agents that cause cancer in vitro or animal models
Epidemiologic: agents assoc w/ development of neoplasms
Difference btw direct and indirect acting carcinogens?
Direct are electrophiles that directly bind DNA and alter it (either alkylate or acetylate).
Indirect acting require an enzyme for metabolism.
What promoter substance example did Koles use?
Promoter TPA used in experiments which activates protein kinase C resulting in phosphorylation of signal transduction pathways.
4 regions developing cancer associated w/ alcohol?
Larynx, esophagus and oropharynx in combination w/ smoking
Liver w/ alcohol induced cirrhosis developing into hepatocellular carcinoma.
The single most important environmental contributing to premature death is _________?
Generalizations about radiant carcinogenesis?
What is the hierarchy for tumors in this case?
It is cumulative and latent
Particulate radiation (gamma rays) cause greater damage.
Carcinogenesis is due to formation of thymine dimers.
1) Hematopoietic (Lymphomas and leukemias)
2) Thyroid
3) Breasts, lungs, salivary glands
What strains of HPV are associated w/ which cancers?
5,8,14 skin carcinoma
16,18 (31,33,35,51) squamous dysplasia and carcinoma of uterine cervix.
30,40 squamous cell carcinoma of larynx.
Discuss how E6 and E7 proteins of HPV affect cell cycle?
E6 binds to p53 and increases degradation
E7 binds p53, p21 and RB/E2F
What normally controls EBV B cell proliferation?
CD8 T cells
Where is the incidence of hepatocellular carcinoma highest?
Where HBV is endemic like Africa and Far East. Taiwan has 200X the risk.
What are the 2 classes of RNA retroviruses? What is the only RNA virus implicated in human cancer?
Acute transforming: possess oncogenes to directly cause neoplasia (animals mainly)
Slow transforming: don't possess oncogenes but cause insertional mutagenesis.
Human T cell leukemia virus 1
Discuss HTLV-1 induced cancers? What population is most affected?
Tropic for CD4 T lymphocytes
Transmitted through fluids like blood.
Only 3-5 of people infected get leukemia after a latent period of 40-60yrs
People in japan and caribbean islands
What 2 cancers is H pylori associated w/? Pathogenesis?
Gastric adenocarcinomas
Low-grade B cell lymphomas or MALTomas.
Both are from chronic inflammation. In the MALTomas, chronic inflammation stimulates local B cells to proliferate. In the gastric adenocarcinomas, the surface is eroded through chronic inflammation.
What are the 4 types of proteins presented by tumors to CTLs?
Mutated tumor suppressor or oncogenic proteins
Mutated normal self proteins
Overexpressed self protein
Oncogenic viral Ag from HPV or EBV
What tumor Ag is expressed in 30% of breast cancers? How is it treated?
c-erbB2 is an EGF receptor overexpressed in some breast cancers. It is treated w/ trastuzumab, a mab against the receptor.
What are the 2 well known oncofetal proteins?
Alpha fetoprotein: assoc. hepatocellular carcinoma and germ cell neoplasms
Carcinoembryonic Ag: found in many cancers but used to monitor colon cancer therapy.
What are cell-type specific differentiated Ags? Examples?
Differentiated antigens normally found on tissues of origin of the cancer.
CD10 (CALLA) found on B cell leukemia or lymphoma.
Prostate specific Ag (PSA) found in prostate cancer.
What is adoptive immunotherapy?
When you remove tumor specific CD8 T cells from a pt, mature them in vitro and then replace them
What are 5 ways that tumors evade host immunity?
Decreased expression of MHCI
Subclones of tumor cells evade through natural selection
Tumors express Fas ligand which kills CD8 T cells.
Tumors lack costimulatory molecules causing T cell anergy.
Tumors secrete TGF-B and IL-10 to inhibit the immune system.
What are 4 good examples of biologic response modifiers?
Interferon to treat hematologic and renal cell carcinoma
IL-2 useful in renal cell carcinoma and melanoma
Trastuzumab: mab against erb-B2 (EGF receptor)
Bevacizumab: mab against VEGF
What is cancer cachexia? What is the apparent cause?
Malaise, Anorexia, Weakness and Wasting.
It is attributed to the effects of TNF, IL-1 and IFN-γ. Other postulations are peripheral resistance to insulin, increased glucose usage by tumor, increased BMR, malabsorption and depression
What are paraneoplastic syndromes? Why are they important?
Syndromes where the symptoms cannot be readily explained by local or distant spread of tumor. (Strange side effects of tumors).
They may be the earliest sign of occult neoplasm. 10% of malignancies have them. They may mimic metastatic disease and so confound treatment.
What is a carcinoid tumor and what is a good example?
Neuroendocrine cell tumors making serotonin, histamine, bradykinin etc.
Good example is GI tract carcinoid tumor producing flushing/cyanosis (vasomotor problems), diarrhea/cramps/vomiting (intestinal hypermotility), bronchoconstrictive attacks and systemic fibrosis such as tricuspid valve.
What can be measured in urine to detect carcinoid tumor releasing serotonin?
5-hydroxy indole acetic acid.
What is the example that Koles used for paraneoplastic syndromes?
Cushings due to ACTH elaboration from small cell undifferentiated carcinoma of the lung.
What is found in over 50% of internal malignancies? What causes it?
Acanthosis nigricans
Hyperpigmentation of skin proposed to be from EGF.
What is the grade of a tumor?
What is the stage of a tumor?
Comparing the level of anaplasia compared to normal tissue. The more anaplasia, the higher the grade
The extent of dissemination and affect on regional lymph nodes.
If I want to diagnose a readily palpable mass of breast, thyroid or lymph nodes, what method would I use?
Fine needle aspiration
If I want to detect cervical carcinoma, endometrial carcinoma, bronchogenic carcinoma, bladder and prostate tumors, gastric carcinoma, abdominal spaces, pleura, joints and CSF, what method would I use?
Cytologic pap smears
What is the main mechanism of drug resistance in tumor cells?
Over expression of ATP dependent multi-drug exporter or P-glycoprotein.
Why are anti-neoplastic drugs given over several days w/ rest in btw?
Some drugs are cell cycle specific, you have to allow them to work in the right part.
Drugs don't treat Go so higher growth fraction is better treated.
Toxicities limit the number of days that you can use the drugs continuously.
What part of cell cycle do inhibitors of DNA synthesis, inhibitors of microtubules and DNA damaging agents work in?
Inhibitors of microtubules: M phase
Antimetabolites and folate pathways: S phase
Alkylating agents: cell cycle nonspecific
What is selective toxicity advantage when it comes to chemotherapy?
Normal stem cells repair cell and DNA damage w/o apoptosis better than cancer cells. Non-proliferating cells are much less sensitive
What is wrong w/ the poorly perfused center of a necrotic solid tumor?
It doesn't get chemo drugs
It breeds apoptosis resistant cells
It invites infections and blood clots.
What are the 3 anatomic barriers to passage of tumor drugs?
Tumor outgrows vascularization, no perfusion, no drug
Large tumors have high interstitial pressure which exceeds intra-vascular perfusion pressure
Blood brain barrier permits pharmacologic sanctuary for leukemias and lymphomas
What are the 3 points of DNA synthesis that chemo drugs can work on?
They can work on enzymes involved in producing ribonucleotide precursors.
They can block ribonucleotide reductase to prevent ribonucleotides being converted into deoxyribos
They can bind thymidylate synthase which converts dUMP to dTMP.
What 2 reactions is folate involved in? What form of folate is involved?
PRPP conversion to IMP (purines)
dUMP methylation to dTMP by thymidylate synthase (pyrimidine)
THF formed from DHF and DHFR
What are some general toxicities of anti-neoplastic drugs?
Immune and bm suppression w/ infection and bleeding
GI ulceration, loss of barrier to bacterial uptake
Low TI so easily toxic
Alopecia, sterility, psychologic considerations, teratogenic and mutagenic.
Iatrogenic 2ndary cancers
What are the specific toxicities to know for the following drugs:
Hemorrhagic cystitis
Pulmonary fibrosis
Acute tubular necrosis
Peripheral neuropathy and ataxia
Hepatic cirrhosis or fibrosis
What is the likelihood of having allergies if both parents have allergies? What about 1 parent?
What type of receptor is the histamine receptor?
H1 is a Gq which increases IP3 and DAG.
What is rhinitus medicamentosa?
Overuse of nasal sprays causes rebound effect
What are the differences btw allergic and non allergic (intrinsic) asthma?
Allergic is frequent in family, freq allergic rhinitus/conjunctivitis, negative for hypersensitivity to analgesics, serum is IgE positive, positive skin allergen test, disease begins as a child.
Non-allergic is the opposite of these w/ freq episodes w/ analgesics and disease predominating in adulthood.
Difference btw mild and severe forms of asthma? Is it harder to exhale or inhale?
Mild asthma has asymptomatic periods whereas severe, the bronchioles are always constricted to some degree.
What are the 2 signals responsible for increased mucus production in asthma?
IL-13 and EGF binding to EGFR
What is weird about Albuterol?
~90% of it is actually swallowed and absorbed through GI tract
What are some causes of anaphylactoid reactions?
Exercise, cold air, emotional stress or highly charged compounds (dyes used in contrast media)
What are the symptoms of anaphylaxis?
Generalized itching and erythema, vomiting, abdominal cramps and diarrhea.
Shortness of breath, hypersecretion of mucus and nasal fluids
What is the pathophysiology of anaphylaxis?
Histamine (mast and basophils) binds H1 receptors in lung causing bronchospasm.
Histamine binds H2 receptors on vascular smooth muscle resulting in vasodilation and hypovolemic shock
Smooth muscle of GI tract has H1 receptors which activate contraction causing GI spasm and abdominal cramping.
What allergens cause anaphylaxis?
Bee stings, food (shellfish and nuts), drugs (PCN, streptomycin, cephalosporins) and latex. They are different from allergens that cause allergies or asthma.
What is the treatment for anaphylaxis?
CV - inject Epi IV
Cutaneous/GI - antihistamines like Diphenhydramine
Bronchioles - Albuterol
What are the 2 treatments for contact dermatitis?
Diproline (betamethasone) - topical application
What are routes of lead administration? What is the key target of lead poisoning? Where does lead distribute?
GI tract
Respiratory tract
Dermal absorption
Children CNS (children 5X more likely to absorb lead)
Soft tissues for a few months, bone for years
What key enzymes does lead inhibit? What substrates build up as a result?
ALA dehydratase and ferrochelatase
δ-aminolevulinic acid and coproporphyrinogen III respectively
What are key symptoms of lead poisoning?
Inactivation of BBB results in protein leakage and brain edema. Children develop neurocognitive defects. Adults develop peripheral neuropathy w/ wrist drop
Impaired heme synthesis, abdominal pain (lead colic), kidney damage
How do you diagnose lead poisoning and decide on chelation therapy?
15ug/dl in children requires supportive therapy
70ug/dl is assoc w/ encephalopathy
Chelation therapy in kids at 45ug/dl whereas adults it is 50-60ug/dl
Adults have headache, irritability at 30ug/dl and encephalopathy at 100ug/dl.
What would a peripheral blood smear of lead poisoning reveal?
hemolysis, hypochromic microcytic cells, basophilic stippling of cells (aggregated free ribosomes)
What is the treatment for lead poisoning?
IM injection of Dimercaprol
Oral chelator Succimer
What is the pathophysiology of Arsenic poisoning?
As3+ inhibits pyruvate dehydrogenase by binding SH groups.
As5+ replaces inorganic phosphate in all glycolytic reactions resulting in uncoupled phosphorylation. Also blocks GSH production.
Inorganic (As5+) more toxic than organic
Symptoms of acute Arsenic poisoning?
Nausea, vomiting, diarrhea, congestive cardiomyopathy, pulmonary edema, delirium and months after exposure develop WHITE STRIAE in nails (Aldrich-Mees lines)
Symptoms of chronic Arsenic poisoning?
Skin changes most noticeable: Rain drop pattern of hyperpigmentation and hyperkeratosis of palms and soles.
Other symptoms: fatigue, malaise, weight loss, weakness and cancers.
Signs of Arsenic gas poisoning?
Malaise, headache, dyspnea, weakness, abdominal pain.
MASSIVE INTRAVASCULAR HEMOLYSIS: hemoglobinuria where urine looks red-violet due to Hb blocking renal tubules. Results in renal failure.
What is treatment for Arsenic gas poisoning?
You can't chelate it
Intensive support, blood transfusions, alkaline diuresis and hemodialysis.
Diagnosis of Arsenic poisoning? Treatment?
Blood [] > 50ug/gl and basophilic stippling.
Supportive care, chelation w/ dimercaprol
Signs and symptoms of acute mercury toxicity?
Inhalation causes pneumonitis, pulmonary edema and acute gingivostomatitis
Main things to know: Mercury chloride hemorrhagic gastroenteritis and renal failure.
Signs and symptoms of chronic mercury poisoning?
Inhalation mercury results in MEMORY LOSS, fatigue, insomnia, anorexia and depression.
Methylmercury results in hearing impairment and MR.
Diagnosis of mercury poisoning?
Occupational exposure resulting in <15ug/dl in blood.
Treatment of mercury poisoning?
Acute exposure: dimercaprol, succimer and parenteral DMPS.
Chronic: succimer, D-pencillamine and DMPS.
What is the main idea w/ chelation therapy?
Chemical antagonism
Indications for Dimercaprol? Used to be called? Administration?
Arsenic, lead and mercury.
British antilewisite b/c lewisite is an arsenic warfare agent.
Indications for Succimer? Administration?
Basically the water soluble analog of Dimercaprol therefore oral.
Treatment of lead poisoning in children
Indications for EDTA-Ca2+? Administration? Side effects?
Chelator for lead mainly.
Chelates extracellular metal ions, can't enter cells.
Coadminister Ca2+
Administration is parenteral
Toxicity: kidney injury and Zn/Ca loss
Indications for pencillamine? Main side effect?
Treatment of Wilson's disease (Cu), sometimes RA.
Indications for Trientine? Why is it special?
Treatment of Wilson's disease (Cu poisoning).
Marked as an orphan drug as second line treatment for people allergic to penicillamine.
Indications for Deferoxamine?
Treatment of iron and aluminum poisoning
What are the top 4 causes of death in US children < 1yr? What is the top cause of children deaths > 2yrs?
#1 Congenital malformations, deformations, chromosome anomalies.
#2 Short gestation and birth weight.
#4 Sequelae of maternal complications of pregnancy.
What is the difference btw a a malformation, disruption and deformation?
Intrinsic or primary abnormal development is a malformation like polydactyly. Usually multifactorial.
Disruption is distruction of previously normal organ (amniotic sac strangulates leg)
Deformation is extrinsic disturbance w/ local or generalized pressure from mechanical forces
What is the difference btw a sequence and a syndrome?
Sequence is a cascade of anomalies caused by an initial single localized defect in 1 organ.
Syndrome is a group of congenital anomalies that cannot be explained by a single localized initiating defect.
What percentage of congenital anomalies do we actually know the cause? Of that percentage, what is the breakdown of causes?
25% (50% are unknown, 25% are multifactorial).
15% are genetic causes like single gene mutations or chromosomal aberrations (trisomies). 10% are environmental like maternal infections, diabetes or chemicals
What percentage of chromosomal aberrations die in utero?
80-90% of chromosomal aneuploid die in utero
What is the effect of maternal diabetes on the fetus?
Maternal hyperglycemia stimulates fetal pancreas to release insulin and store excess glucose. Fetal macrosomia occurs w/ variable cardiac and CNS anomalies
What is the most common preventable cause of MR? Pathogenesis?
Fetal alcohol syndrome
Acetaldehyde crosses placenta damaging fetal brain.
Child presents w/ MR, growth retardation, microcephaly, micro-ophthalmia w/ short palpebral fissures, ASDs, facial deformities and maxillary hypoplasia. What is it?
Fetal alcohol syndrome.
What are the top 5 congenital malformations in the US?
#1 Clubfoot w/o CNS anomalies
#2 patent ductus
#3 VSD
#4 Cleft lip/palate
#5 Spina bifida w/o anencephaly
What periods are most sensitive to teratogens during development?
First 3 weeks usually not sensitive b/c teratogen either causes so much damage that spontaneous abortion occurs or defects can be recovered from.
3-9weeks VERY SENSITIVE b/c multiple organs are developing
Rest of development, the organs will merely experience growth retardation.
Discuss 2 classes of genes involved in development?
Homeobox genes produce regulators of transcription affecting patterns of limbs, vertebrae and craniofacial structures.
PAX genes which encode transcription factors that act singly (meaning formation of 1 side or structure).
What is considered term, preterm and post-term gestation? What is AGA, SGA and LGA?
Term 37-42 weeks
Preterm <37 weeks
Post term > 42weeks
AGA is appropriate for gestational age (birth weight btw 10-90% for gestational age). SGA is small <10% and LGA is large > 90%.
Which is worse, being preterm or SGA but term?
Preterm is worse, SGA can make up weight.
Preterm is the 2nd leading cause of neonatal mortality.
What are the risk factors for premature birth?
Rupture of membranes before labor
Intrauterine infection
Uterine, cervical or placental structural abnormalities
Multiple babies (twins etc).
How does intrauterine infection cause premature birth?
Inflammatory cells release collagenases and elastases that rupture membranes. Prostaglandins induce smooth muscle contractions
What is good evidence of an intrauterine infection?
What are factors known to cause SGA or fetal growth restriction?
Maternal causes are most common from things like chronic hypertension, preeclampsia, drugs, smoking and alcohol. This all results in decreased placental blood flow.
Fetal causes are any chromosomal or congenital anomalies and infections. These result in symmetric growth restriction.
Placental anomalies resulting in reduced supply. Results in asymmetric growth restriction sparing the brain.
Btw 26-32weeks gestation, what is wrong w/ fetal lungs? What other parts are underdeveloped?
Lining of alveoli is still too thick (cuboidal) and capillaries are too far from lining. Few type II pneumocytes
Brain is not myelinated and homeostatic control is not developed.
Kidneys have incomplete maturation of glomeruli
Liver has inadequate conjugation of bilirubin.
What are the 5 aspects of the APGAR score? If APGAR score is 0-1, what is the predicted outcome?
Heart rate, respiratory effort, muscle tone, response to nasal catheter and color.
50% perinatal mortality (death w/in 1 mo)
What are LGA infants at risk for?
Skeletal and peripheral nerve injury during birth.
What is the most important common birth injury? What are causes?
Intracranial hemorrhage due to excessive head molding, porceps delivery, prolonged labor, hypoxia, hemorrhagic disorders and vascular anomalies.
What is caput succedeneum and cephalhematoma?
Increased interstitial fluid in soft tissues of scalp.
Hemorrhage into scalp.
What are the 3 causes of perinatal infections?
Ascending (transcervical) infections
Hematologic (transplacental) infections
Discuss ascending (transcervical) infections?
Mostly bacterial, herpes simplex 2.
Fetus either inhales amniotic fluid causing pneumonia, sepsis and meningitis or acquires it through the birth canal.
Discuss transplacental infections?
Organisms like viruses, parasites, listeria enter the fetal blood through placenta.
Organisms like HIV or Hep B can pass at delivery through maternal-fetal transfusion.
Discuss perinatal sepsis?
First 7 days, group B strep is most common cause of neonatal bacterial sepsis and meningitis
8d-3mos is Listeria and Candida
What are the risk factors for neonatal RDS?
60% of infants <28wks
20% of infants 32-36 wks
Males, maternal DM and c-section
Natural history of neonatal RDS?
Resuscitation at birth, dyspnea w/in 1 hr, cyanosis w/in a few.
Chest X-ray (diffuse reticulogranular densities) ground glass infiltrates
Severe hypoxemia requiring O2 and risk death in 1st 4 days.
What is the sequence of pathologic events in neonatal RDS?
Decreased surfactant leads to atelectasis which results in uneven perfusion and hypoventilation. This results in acidosis which reduces surfactant production but also pulmonary vascular constriction. The hypoperfusion causes epithelial and endothelial damage resulting in plasma leakage and fibrosis. It is the fibrosis that allows it to be called hyaline membrane disease.
Discuss synthesis of surfactant?
SP-B and SP-C are made by type II alveolar cells and stored as lamellar bodies. They are released and interact w/ SP-A and tubular myelin to form surfactant. The remnants are reused by type II cells.
What are the microscopic features of neonatal RDS?
Eosinophilic hyaline membranes line the alveoli etc. The hyaline is composed of necrotic pneumocytes and fibrin. THERE IS NO SIGNIFICANT INFLAMMATION
What are the complications of neonatal RDS? What causes this? Pathology? Prevention?
Bronchopulmonary dysplasia
Neonates < 32wks who require O2 for > 28 days.
Prolonged exposure to high O2 and mechanical ventilation leads to inflammatory cytokines causing fibrosis.
Antenatal steroid and postnatal surfactant therapy
What are the specific treatments and preventions of neonatal RDS?
Analysis of phospholipid synthesis by amniocentesis.
Antenatal steroids given to mother threatened by prem labor.
Suppression of preterm labor until > 34wks
Surfactant therapy for <28wks or for those w/ symptoms of RDS.
O2 therapy given w/ mechanical ventilation using low [] and short duration.
What are the sequelae of newborn necrotizing enterocolitis? Pathogenesis? Most frequently in?
Pneumotosis intestinalis, intestinal necrosis, perforation and peritonitis. Post-inflammatory strictures resulting from fibrosis.
Pathogenesis: intestinal ischemia followed by postnatal insult (feeding) allows bacterial migration into wall. Inflammation occurs allowing more bacteria, sepsis and shock.
Ileum and right colon
What is fetal hydrops? What are the types? What are the causes? Treatment?
Generalized accumulation of edema fluid in fetus during intrauterine growth.
Localized edema in soft tissues like pleura or neck.
The immune form is EF followed by heart and liver damage resulting in increased hydrostatic pressure and hypoproteinemia (EDEMA).
Non-immune is things like Turners, cardiac malformation etc.
Treatment: Immune more common so Rhogam
What does the internal organ pathology of fetal hydrops look like?
Fetal anemia, hyperplasia of bm, reactivation of liver and spleen hematopoiesis. Excessive hemolysis results in kernicterus due to unconjugated bilirubin.
Child presents w/ MR, seizures, musty odor to urine, decreased pigmentation of hair and skin. What is it? Treatment?
Classic type I PKU lack of phe hydroxlase.
Restrict phe containing foods.
Pt presents w/ failure to thrive, vomiting and diarrhea after milk ingestion, jaundice, hepatomegaly, cataracts of lens and MR. What is it? Organ pathology? Diagnostic method? Antenatal diagnosis? Treatment?
Most common GALT (galactose-1-phosphate uridyl transferase). Less common is galactokinase deficiency
Path: liver fatty change/fibrosis, corneal opacities, brain edema and gliosis.
Diagnosis: GALT enzyme deficiency in RBCs and WBCs, aminoaciduria (due to renal tubular G-1-P buildup) and galactose reducing sugar in urine.
Test GALT activity in amniotic fluid.
Treatment: dietary restriction of galactose.
Common CF misconception? Etiology?
It is all epithelial transport deficiency, not just NaCl.
Primary Caucasians
Structure of CFTR channel and mechanism?
2 transmembrane domains, 2 nucleotide binding domains (ATP binding) and 1 regulatory domain.
Agonist binds, increases cAMP, activated PKA phosphorylates R domain, opens Cl channel w/ help of NBD domains binding ATP.
What is the most common mutation in CF?
Triplet deletion at F508 position resulting in phe at that position. This prevents folding and CFTR is stuck in ER.
Discuss pancreatic pathology of CF?
Mucus blocks ducts resulting in atrophy of acini, replaced by fibrosis. Insufficient pancreas results in malabsorption and growth inhibition.
Early onset disease has CFTR which affects bicarb transport.
Common infecting organisms in CF?
Staph, Hflu and Pseudomonas.
Other than lungs and pancreas, what organs are affected in CF?
Liver: bile canaliculi blocked by mucus - focal or diffuse cirrhosis.
Salivary glands: ductal obstruction and acinar atrophy.
Gonads: obstruction in vas deferens - infertility
Intestines: meconium ileus and SI obstruction.
What is the main point of diagnosis for CF?
You need a clinical finding (history of CF in sibling or one or more phenotypic features) and a biochemical finding (id of mutant CFTR gene or sweat chloride test on 2 or more occasions)
How would you diagnose SIDS?
It is diagnosis of exclusion. After <1yr old infant dies, do an autopsy, examine the death scene and review the clinical history. If no other cause of death can be found then SIDS. Death usually while infant sleeps
90% of SIDS occurs _________?
While infant of 0-6mos is sleeping. Mostly btw 2-4mos.
Few die from sudden apnea and cyanosis while awake.
What is the triple risk model for SIDS? Where is the proposed deficiency?
Pathogenesis involves a vulnerable infant, a critical homeostatic developmental period and an exogenous stressor.
The arcuate nucleus of the brainstem
What neoplasms are most common in kids? What other lesions are most common?
Benign neoplasms of soft tissue (epithelial neoplasms more common in adults).
Choristoma (heterotopia) and hamartomas are also common (non-neoplastic lesions).
What is the leading cause of death in infants after 1st month before 1yr?
SIDS (although it is third to congenital malformations and prematurity before 1 month)
Number 1 cancer in infancy?
Hemangioma (benign neoplasm). If you were thinking acute leukemias, that is children of all ages.
What syndrome may hemangiomas in children be a part of?
Hereditary disorders affecting CNS like von Hippel Lindau
Sacrococcygeal teratomas are more common in? Are they usually benign or malignant?
Females than males
75% are benign (meaning well differentiated w/ cysts)
What is a neuroblastic tumor? What do you see in the urine?
A neoplasm derived from neural crest cells of sympathetic ganglia and adrenal medulla.
Elevated catecholamines like VMA and HVA.
What malignancy accounts for 50% of infant tumors? What makes prognosis better?
Neuroblastoma (if you were thinking leukemia, that is for all children ages).
Prognosis better: <1yr, stage 1/2, N-myc not amplified and low mitotic rate.
What are the top malignancies in children age 0-9?
Wilms tumor
Hepatic cancers
Soft tissue sarcomas
CNS tumors
What is WAGR syndrome?
It is a chromosomal basis risk for Wilm's tumor
Wilm's tumor, Aniridia, Genital anomalies, mental Retardation.
Deletion is on chromosome 11 w/ WT1 gene.
What 2 syndromes other than WAGR are associated w/ Wilm's tumors?
Denys-Drash (Wilm's tumor + gonadal dysgenesis + early onset nephropathy) and Beckwith-Wiedemann (multiple neoplasias, enlargement of body organs, macroglossia related to IGF-2 overexpression).
What factors influence exposure of a fetus to drugs?
Properties of drug
Rate of delivery to placenta
Duration of exposure
Distribution to fetal tissues (albumin levels)
Stage of development
Multiple drugs used in combo
What happens to maternal albumin levels during pregnancy and why does it matter?
They decrease which causes high free drug [] to cross placenta. At same time, the fetal albumin levels increase
What are sites of drug metabolism affecting fetus? Drug examples?
Some drugs inactivated by placental enzymes (pentobarbital).
Some are activated (ethanol)
Most enter fetal liver before systemic circulation and are metabolized.
Why should you ask pregnant mom if she is using addictive drugs?
B/c baby can be addicted and when they are born you have to give that drug to prevent withdrawal.
What is neonatal drug disposition like? Why? When does it change?
Not good b/c of immature hepatic and renal function. At ~4wks, the infant can begin to metabolize.
What does gastric acid secretion look like after birth? What about gastric emptying and motility? What about SI absorption?
A few hours after birth, pH ~1-3 but achlorhydria occurs for ~10days. Any drugs that need acid to be absorbed will have reduced absorption
Motility and emptying are decreased meaning increased absorption time.
SI absorption is reduced b/c of biliary and pancreatic lack of secretion - poor lipid soluble drug absorption
How does neonatal IM and skin absorption compare?
IM is unpredictable due to muscle mass and blood flow differences.
Skin absorption is higher due to thinner corneum and higher hydration.
Compare preterm, full term and normal adult body water weight?
Preterm is highest (85%) w/ c-sections being higher than vaginal.
Full-term is ~75% and adult is ~55%.
Neonates of DM mothers are low ~70%
Compare ECF and ICF water components of neonates to adult?
ECF is higher in neonates and ICF is lower. Huge diuresis occurs during 1st 2 days which increases [] of water soluble drugs at receptor sites.
Compare body fat of neonate to adult? Effect?
Neonate has much less (15%) than adult (~20%). Affects distribution of lipid soluble drugs.
Compare drug binding ability of neonates to adults? Talk about bilirubin effects?
Neonates have albumin which has low affinity for drugs (meaning more free drug). As you age, drugs bind albumin better.
Bilirubin can be displaced from albumin in neonates if you give certain drugs. This can cause kernicterus.
Drugs can also be displaced by bilirubin causing higher tox.
Compare renal excretion of neonate to adult?
GFR/RBF - 30%
Renal tubular secretion - 20%
60% of normal by 3wks old
How would you keep a patent ductus arteriosus open? What about closing it? Any side effects?
PGE1 to keep it open for tetralogy of fallot. Side effects: hyperplasia of gastric antrum leading to obstruction of outlet.
Indomethacin to close PDA
Why would adolescents have lower drug disposition than children?
Hormones compete w/ drugs for metabolism in liver, leading to decreased metabolism of drug and extended half life.
Why is geriatric pharmacology difficult? Which is more important, frailty or age?
It is hard to separate disease effects from drug side effects. They are also being treated w/ multiple drugs causing many interaction possibilities.
Frailty is more important than age for drug disposition.
What pharmacokinetic changes occur w/ aging?
Intestinal motility and muscle blood flow decreases. Gastric absorption and emptying however are fine.
Serum albumin [] decreases in pts w/ chronic disease or frailty.
Increased body fat and decreased body water (Vd of highly lipophilic drugs increases).
What is the main factor contributing to elderly pharmacokinetic changes?
Alterations in homeostatic mechanisms contributes more than decreased metabolism.
Effects of highly lipophilic drugs in elderly?
Higher body fat [] means plasma levels of drug will drop rapidly below MEC.
Discuss liver changes in metabolism in elderly?
Liver volume decreases ~30%, flow decreases ~30%.
Ratio of liver to body weight increases due to decreased muscle mass - this results in increased clearance of drugs w/ high extraction ratio (aka blood flow to liver = clearance).
The intrinsic capacity of the liver to metabolize however is decreased - this results in decreased clearance of low capacity drugs.
Discuss renal excretion in elderly?
GFR/RBF/tubular secretion decreases.
CCr decreases 1% every year after 20.
The deterioration might be due to accumulation of toxic injury
What pharmacodynamic changes occur in elderly people?
Decreased receptors on CV and CNS.
B1 response reduced due to lower receptors (not less sympathetic drive). Max HR decreases.
Decreased binding affinity for B2 and reduced cAMP response.
Reduced baro-receptor sensitivity (ACE inhibitors can lower BP more, decreased sensitivity to hypotensive effects of B antagonists).
Increased adverse drug reaction susceptibility, decreased vasodilation of histamine, increased sedative effect of benzos, lower doses of narcotics and sedatives needed for efficacy.
What are the effects of cardiac disease on drug disposition?
Decreased hepatic blood flow will cause lower clearance. Decreased shunting of blood causes poor enteral and parenteral drug absorption. Decreased intestinal mobility. Renal Na retention and edema resulting in abnormal clearance.
What effects does uremia have on drug disposition?
Normal oxidation/conjugation
Reduced acetylation/reduction
Altered volume of distribution
Decreased binding of acidic drugs to plasma proteins.
Normal binding of basic proteins.
How does pulmonary disease affect drug disposition?
Stress from chronic hypoxia or hypercapnia results in induction of microsomal enzymes.
What is reductionism?
The idea that a herbal supplement has 1 single magical ingredient and we can purify it.
What can you use Echinacea for? Side effects? Contraindications? Myths? Recommendations?
Enhances immune function (colds and URIs).
Just tastes bad
Anyone w/ immune suppression, autoimmune disorders or TB
It can be used prophylactically for colds.
Reasonable to encourage
What can you use Garlic for? Side effects? Contraindications? Recommendations?
Reduce cholesterol, general health (you must eat fresh, crushed garlic. No use in supplements)
Bad breath, nausea
Anticlotting medications
Give it a try
What can you use Ginseng for? Side effects? Contraindications? Recommendations?
Cure all, mind enhancing, gives energy.
CNS stimulant at high doses (insomnia, nervousness), weakly estrogenic
Pts taking psychotropic, estrogenic, hypoglycemic or anticoagulants
Not too bad
What can you use Ginkgo biloba for? Side effects? Contraindications? Recommendations?
Memory (cerebral insuff), peripheral vascular disease, dementia.
X-allergy w/ poison ivy, anything other than leaves is toxic.
Anticoagulants or seizure disorders
Not too bad
What can you use Goldenseal (berberine) for? Side effects? Contraindications? Recommendations?
Supposed to do everything
Displaces bilirubin, abortifacient, peripheral vasoconstriction, hypertension, increased CO and fatalities.
Infants <1mo
Not a good idea
What can you use Ma Huang for? Side effects? Contraindications? Recommendations?
Weight loss
20-30deaths reported, anxiety, restlessness, insomnia, palpitations, possibly stroke.
Hypertension, ischemic heart disease, DM and glaucoma.
Do not recommend
What can you use Psyllium for? Side effects? Contraindications? Recommendations?
Basically fiber so use for constipation, diarrhea and lower cholesterol.
Obstruction if you don't drink enough fluids
Useful if taken w/ fluids
What can you use Saw Palmetto for? Side effects? Contraindications? Recommendations?
Symptomatic relief of BPH
Decreased libido, abdominal pain and impotence
Pregnant women :)
Try for a couple months but then see urologist
What can you use Cascara sagrada for? Side effects? Contraindications? Recommendations?
GI tract spasm, K depletion
Intestinal obstruction, Crohn's, ulcerative colitis, appendicitis and pts on meds dependent on K levels
Give it a try
What can you use St. John's Wort for? Side effects? Contraindications? Recommendations?
Photosensitivity, hypomania, mania, dry mouth, fatigue.
Avoid in pts already on SSRIs, HIV pts on protease inhibitors.
Meh, not great but can try
What can you use Kava kava for? Side effects? Contraindications? Recommendations?
Anti-anxiety (natural benzo)
Low doses: tingling mouth, GI upset, skin rash, constipation.
High doses: euphoria, ataxia, auditory changes, muscle weakness. Possible rare severe liver disease
Pregnancy, pts on CNS depressants (benzo, alcohol), meds metabolized by liver.
What can you use Feverfew for? Side effects? Contraindications? Recommendations?
Migraine headache prophylaxis
Mouth ulcers, Gi upset, contact dermatitis
Pregnancy, abortifacient, anticoagulants. X-sensitivity w/ chamomile and ragweed.
Not sure
What can you use Ginger for? Side effects? Contraindications? Recommendations?
Prevent motion sickness
Pregnancy, anticoagulants
What can you use DHEA for? Side effects? Contraindications? Recommendations?
Prevention of cancers, decreased risk, life extension, sexual stimulation. Lots of shit
Side effects assoc w/ conversion to testosterone and estrogen.
What can you use Melatonin for? Side effects? Contraindications? Recommendations?
Jet lag, insomnia
Next day drowsiness, vivid dreams, confusion.
Works well but caution b/c it is a hormone
What can you use Andro for? Side effects? Contraindications? Recommendations?
Increased muscle mass, strength
Concern w/ elevated hormone levels.
What can you use Creatine for? Side effects? Contraindications? Recommendations?
Improve activity of short bursts, increase muscle mass
Muscle cramps, dehydration, electrolyte imbalances.
What can you use the following for?
Glucosamine, Chondroitin
Black cohosh/phytoestrogens/red clover
Cortisol blockers
Like NSAIDS, anti-inflammatory
Menopausal hot flashes
Weight loss
Weight loss
Type 2 DM and LDL reduction
Things to know about Vit E?
Antioxidant, assoc w/ reduced prostate cancer in smokers. Apparently good for coronary artery disease. Increased risk of dying.
Food sources: mayonaisse, margarine, nuts
Mild antiplatelet effect, stop before surgery
Things to know about Vit A?
Increased hip fractures in women not on HRT. Stops Vit D ability to absorb Ca2+.
Lung cancer in smokers is contraindicated.
Things to know about Vit K?
Relationship to mineral density and hip fracture rates in elderly women.
Things to know about Carotenoids?
Increased lung cancer in smokers.