Molecular Medicine Exam Block 5 Flashcards
1
Q
empiric therapy
A
dont know exact microbe
2
Q
definitive therapy
A
culture returned and organism identified
3
Q
determining which antibiotic to use utilizes
A
pharmokinetics
4
Q
selective toxicity
A
must kill organism without damaging host
5
Q
classification by
A
biochemical pathway and structure
6
Q
prophylaxis
A
treat patients not yet infected
7
Q
preemptive therapy
A
early targeted therapy in high risk patients who are asymptomatic but infected
8
Q
suppressive therapy
A
initial disease controlled, therapy continued at lower dose
9
Q
prokaryotic targets
A
inhibit cell wall synthesis
interfere with cell membrane function
disrupt ribosomal function reversibly (bacteriostatic) or irreversibly (bacteriocidal)
inhibit nucleic acid metabolism
block enzymes
10
Q
minimum inhibitory concentration
A
lowest concentration that prevents visible growth after 18-24 hours
11
Q
bactericidal concentration
A
concentration that kills organism
12
Q
inoculum effect
A
efficacy decreases with increased bacterial density
13
Q
inhibitory receptors (coinhibitors)
A
CTLA4 - recognize B7 1/2 on APC, role in suppressive function of regulatory T cells
PD1 - recognize PD-L 1/2
induced in activated T cells and terminate response
14
Q
activation of CD8 cells
A
by class 1 MHC peptides
requires costimulator and helper T cells
requires cytosolic agent from 1 cell to be crossed with dendritic cell
differentiation into cytotoxic T lymphocytes and memory cells may require concomitant activation of CD4 helper T cells
15
Q
CD4 helper T cells differentiate into 3 subsets of effector cells that produce distinct cytokines
A
TH1 produces IFN gamma
TH2 produces IL4/5/13
TH17 produces IL21
16
Q
antibodies use what to to bind and block harmful effects of microbes and toxins
A
antigen binding Fab region
17
Q
antibodies use what to activate diverse effector mechanisms that eliminate microbes and toxins
A
Fc regions
18
Q
opsonization
A
antibodies coat microbes and promote ingestion by phagocytes
IgG1/3 Fc region binds to receptor (Fc gamme RI or CD64) expressed on neutrophils and macrophages
19
Q
NK cells bind to antibody coated cells and destroy them
A
NK cells express Fc gamma receptor which is a NK cell activating receptor
20
Q
mucosal immunity
A
IgA produced, transported across epithelia, bind and neutralize microbes in lumen of mucosal organs
B1 cell produces IgA in response to nonprotein antigens without T cell help
21
Q
adaptation
A
cell changes to enable it to cope with excess stress
22
Q
injury
A
if cell unable to adapt to stress
reversible - injurous agent removed and cell reverts to normal
irreversible - cell wont revert to normal and death innevitable
23
Q
response to cell injury
A
death - apoptosis/necrosis, end or irreversible inury
atrophy, hypertrophy, hyperplasia, hypoplasia, aplasia, metaplasia, dysplasia
24
Q
atrophy
A
decrease size of organ because decrease size of cells and number of cells
increase protein degradation and decrease protein synthesis
physiologic - embryologic structures, uterus after birth
pathalogic - decreased workload, lass of innervation or blood supply, no nutrition, aging
25
hypertrophy
increase cell size so increase organ size
increase protein production or organelles
26
hyperplasia
increase cell number so increase size of organ
hormonal - increase functional capacity of tissue under hormones
compensatory - increase tissue mass after damage or resection
27
hypoplasia
incomplete development of organ
28
aplasia
lack of development of organ
29
metaplasia
reversiible change in one adult cell type replaced by another (can lead to dysplasia)
30
dysplasia
abnormal increase in immature cells with decrease in number and location of mature cells
loss of uniformity of individual cells and organization
reversible or precedes development of cancer
31
hypoxia
decrease in oxygen delivery to tissue
32
morphological changes in reversible injury
cell swelling, fatty change, membrane blubbing/loss of microvilli, organelle swelling, detached ribosomes from ER, eosinophilia, nuclear chromatin clumping
33
injurous agents and calcium
calcium enters cytosol and denatures proteins
34
free radical induced cell injury
oxygen derived free radicals
35
ischemic/hypoxic injury
reversible - decrease or loss of ATP, increase anaerobic glycolysis, increase lactic acid, decrease pH, decrease enzymes
irreversible - ATP generation permanently lost, membrane function disturbed, loss of phospholipids, loss of intracellular amino acids
36
free radical injury
injurous agents increase production of free radicals, lipid peroxidation of membranes, oxidative modification of proteins, DNA damage
37
chemical injury
direct toxicity, conversion to toxic metabolites
38
necrosis
changes in individual cells, changes in tissues
morphological changes that follow cell death
lysosomal enzymes enter cytoplasm and digest cell
39
necrosis cytoplasmic changes
1. eosinophilia - denatured proteins bind easin
2. hyalinization - cytoplasm glossy and homogenous
3. vacuolization - enzymatic digestion of organelles
4. calcification - deposition of calcium
40
necrosis nuclear changes
1. pyknosis - nucleus shrinks and becomes darker blue
2. karyorrhexis - nucleus undergoes fragmentation
3. karyolysis - nucleus stains pale blue
2 days after necrotic cell death nucleus disappears
41
necrotic tissue
mass of dead cells in same physical area
pattern - liquefactive, coagulative, ganguenous, caseous, fat, fibrinoid
42
liquefactive necrosis
cell disappears due to digestion and destruction by hydrolytic enzymes from lysosomes or WBCs
43
coagulative necrosis
outlines of cells preserved , nucleus disappears, denaturation of proteins predominates, cells dont autolyze
hypoxic death outside of CNS
44
gangrenous necrosis
portion of limb or entire limb losses blood supply and dies
starts as coagulative and can become liquefactive
45
caseous necrosis
tissue appears soft and cheesy, necrotic focus of lysed cells and debris surrounded by border of granulomatous inflammation
46
fat necrosis
area of trauma or in peripancreatic fat in pancreatitis, damage and breakdown of fat cells release free fatty acids
47
fibrinoid necrosis
in vasculitis or severe hypertension
vessel walls damaged, fibrin deposited, immune complexes deposited
48
apoptosis
nuclear chromatin condenses and aggregates against nuclear membrane, apoptic bodies bud off, no inflammatory response
mitochondrial path
death receptor
49
pyroptosis
proinflammatory programmed cell death, swelling of cells, loss of plasma membrane integrity, release of inflammatory mediators
50
ferroptosis
iron induced programmed cell death, excess iron produces free radicals, decreased GPX-4 activity leads to lipid peroxidation
neurodegenerative diseases`
51
necroptosis
hybrid
mediated by tumor necrosis factor
triggered by genetically programmed signal transduction, doesnt result in capsase independent programmed cell death
kinases - receptor interacting protein 1 and 3, ligation TNFR1 recruits RIP1 and 3 into multiprotein complexes that contain caspase 8
52
lipid accumulation
fatty changes and steatosis refer to abnormal accumulations of triglycerides in parynchemal cells
53
protein accumulation
round eosinopilic droplets in cytoplasm
54
exogenous pigments
from outside body, most common carbon
55
endogenous pigments
melanin, lipofusion, hemosiderin, bilirubin, contusion
56
pathalogic calcification
dystophic - in damaged and dying tissues, localized
metastatic - calcium deposited in normal tissues, serum levels increased, widespread
57
specific gravity
ratio weight of solution compared to weight of equal colume of water
58
hydrostatic pressure
pressure fluid exerts on walls of its container, drives fluid out of circulatory system
59
plasma oncotic pressure
large proteins cant cross capillary walls, pulls fluid into circulatory system
60
inflammation
reaction of vascularized tissue to injury
2 parts - vascular and cellular`
61
types of leukocytes
neutrophils, lymphocytes, eosinophils, monocytes, basophils
62
acute inflammation
vascular changes - vasodilation, increased permeability, stasis because loss of blood
63
edema
excessive fluid in tissue and body cavity
transudate - filtrate of plasma from increased hydropstatic pressure or decreased oncotic pressure, no increase in permiability
exudate - increase permiability, cell and chemical mediators, high protein content
64
acute inflammatory leukocytes
expected - adhesion and transmigration, chemotaxis, recognition and activation, phagocytosis and killing, termination
undesired - release of products and tissue injury, defect function
65
acute neutrophil arrival and function
margination, rolling, activation, firm adhesion, transmigration, chemotaxis, phagocytosis
66
leukocyte activation
stimulation to produce response
67
phagocytosis
recognition and attachment, engulfment, killing and degradation
68
chemical mediators of inflammation
originate from plasma or cells
those from plasma circulate in precursor form and must be activated
cellular can be preformed and immediately available
most bind specific receptors on target cells
released mediators can bind other mediators
can act on one cell target or variety of types
short lives
most can have harmful effects
69
aarachedonic aci d metabolism
cyclooxygenase path produces prostoglandins which cause pain and fever
lipoxygenase path generates leukotrines and lipoxins
70
cytokines
proteins produced by cells that mediate and regulate immune and imflammatory reactions
71
chemokines
type of cytokine, small proteins that are primarily chemoattractants for leukocytes
72
plasma proteins
factor XII of clotting system activated by contact with injured tissue
kinin cascade produces bradykinin and kallikrein
clotting cascade produces thrombin
complement produces cleavage products
fibrinolytic paths produce plasmin
73
termination
mediators short lived, active mechanisms stop process
74
chronic inflammation
prolonged duration, inflammation by mononuclear cells, tissue destruction, healing by fibrosis, can result in granulomatous inflammation
cells - macrophages, B lymphocytes, plasma cells, eosinophils, mast cells cause granulomas and sometimes necrosis
75
outcomes of inflammation
resolution, abcess formation, healing
76
systemic effects of inflammation
fever, produce acute phase proteins, leukocytes, leukopenia, sepsis
77
hypersensitivity
failure of immune sysstem, reactions unwarranted and harmful to host, immune response responsible for inducction of disease, requires sensitization and antigen specific, classified by Gell and Coombs
78
type 1 hypersensitivity
immediate, IgE
79
type 2 hypersensitivity
cytotoxic, IgG and IgM
80
type 3 hypersensitivity
immune complexes, IgG and IgM
81
type 4 hypersensitivity
delayed, T cells (48 hours)
82
characteristics of hypersensitivity
first contact no symptoms, reexposure elicits reaction, reaction highly specific, reexposure increases or decreases severity of reaction
83
type 1 hypersensitivity
all hallmarks of normal immune response, secretion of IgE from plasma cells distinguishes it
IgE binds FcR on mast cells/basophils, coated cells sensitized, future allergen cross link sensitized cells and cause degranulation releasing pharmacologically active mediators, normal 0.1-0.4, severe allergic greater than 1
84
common allergens
small proteins, dried up particles, rehydrated on inhalation and presented by APCs to Th cells, development of Th2 response and increased IgE
85
primary reactions result of increased IgE and degranulation
prestored in granules with immediate short lived effects - histamine, heparin, TNF alpha, proteases, degradative enzymes, inflammatory mediators
86
histamine
binds histamine receptor (H1,2,3)
H1 on endothelial cells and blood vessels (increase permeability, constrict airway, increase mucous secretion)
87
secondary mediators
IL4, platelet activating factor, prostoglandins/leukotrienes, effects after primary and lasts longer
88
mast cell mediators
histatmine - smooth muscle contraction and increased vascular permiability
heparin - anticoagulant
eosinophil chemotactic factor A - chemotactic
prostoglandin D2, E2, F2alpha - increase smooth muscle contraction and vascular permeability
leukotriene C4, D4, E4 (lipooxygenase path) - increase smooth muscle contraction and vasular permiability
leukotriene B4 - chemotactic for neutrophils
89
system anaphylaxis
allergen enters blood and activates mast cells increasing vascular permeability and smooth muscle contraction
90
organ specific anaphylaxis
allergen effects target organ
91
systemic anaphylaxis
allergens - penicillin, insect stings, peanuts and brazil nuts
treatment - rapid administration of epinephrine
92
urticaria and hives
allergen activates mast cells on skin, most common cause insect bites
atopic dermatitis - increase IgE and allergies
93
type 2 hypersensitivity
antibodies binding cells or tissues
IgM
local complement activation, influx of leukocytes
94
type 3 hypersensitivity
immune complex mediated destruction of tissues
high levels of circulating immune complexes (IgG/M), systemic, deposit in tissues and activate complement, neutrophils try to remove causeing degranulation and tissue damage
95
type 4 hypersensitivity
Tcell mediated, takes 24-48 hours, Th1 response develops
can be activated by CD4 T cell cytotoxic production, direct killing of cells by cytotoxic CD8 T cells
celiac disease - Th CD4 T cell cytotokine secretion
poison ivy - CD4 and CD8 T cells because MHC class 1 and 2
96
tolerance
failure to amount an immune response to an antigen
when tolerance fails - autoimmune disease, hypersensitivity reactions, miscarriages
97
immunogens
antigens that induce an immune response
98
tolerogens
antigens that induce tolerance
99
central tolerance
T cells - in thymus, self reacting T cells eliminated by negative selection, strongly recognized antigen in thymus drives negative selection, some differentiate into Treg cells
defect in AIRE gene lead to autoimmune disease
Bcells - in bone marrow, self reactive B cells apoptosis or reedit receptor
100
peripheral tolerance
secondary lymphoid tissue, self reactive T and B cells apoptosis, anergy can render self reactice T/B cells unresponsive to future antigen presentation, Tregs circulate periphery and suppress immune responses
T cells - anergy, suppression, deletion
101
T cell suppression
CTLA4 binds B7 and removes it, PD1 blocks activation and TCR/MHC and B7/CD28
Tregs limit autoreactive cells, express CD25 (IL2 receptor), FoxP3 key transcription factor
102
T cell regulation by IL2 cytokines
stimulate T cell proliferation, inhibit immune response by maintaining functional regulatory T cells
103
Tregs
produce inhibitory cytokines (IL10, TGF beta)
express CTLA4 and consume IL2
104
T cell apoptosis
recognition of MHC/antigen T cell leaks proapoptic proteins (if costimulated and growth factors IL2 present this is countered by prosurvial proteins)
recognition of self antigen may increase death cell receptors and ligands (Fas receptor and FasL ligand)
105
B cell peripheral tolerance
anergy, suppression, deletion
without engagement CD4 T cells the B cells anergy or apoptosis
B cells have inhibitory receptors to inactivate and induce death by FcgammaRIIb, PD1
106
immune privilege
ability to tolerate antigens without eliciting inflammatory immune response
107
autoimmunity
failure of tolerance process
principle factors - genetics, environment triggers, trauma
microchimerism by mother/fetus, blood transfusion, organ transplant, twin to twin utero
environmental influences - infections break tolerance, molecular mimicry, alteration of self antigens, breakdown of antigen sequestration
108
rheumatic fever
complication of strep, production of cress reactive antibodies against protein M, difficult to generate response against it because of molecular mimicry
109
lupus
inflammatory immune disorder, fever/joint pain/rash
110
myasthenia gravis
autoantibodies agains Ach receptors on motor end plates of muscles
visual problems, muscle fatigue and weakness, weakness of neck and limbs
111
multiple sclerosis
autoreactive T cells from inflammatory lesions along myelin sheaths
112
extra cellular matrix
many componenets, form bulk of CT, basal lamina special form, hydration important for density and deformability of matrixf
113
function of ECM
provide structure and support, limits movement and migration, barrier to microorganisms and large molecules, damage leads to movement of things not normally mobile in matrix
114
collagen
in loose CT, bone, tendons, skin, vessels, cornea
triple helix structure
hydroxyproline for H bonds stability in helix, hyroxylysine for cross linking helices together
115
lack of vitamin C
less stability of collage and tissues
116
cross linking reactions for peptide fibril backbone
schiff base crosslinking of 2 allysine residues (generated by lysyl oxidase)
2 allysine residues (generated by lysyl oxidase) react by aldol condensation to lysinonorleucine
117
collagen 4
build mesh (important in basement membranes and basal lamina), globular domains at C termini make dimer, amino termini aggregate creating 7S domain
118
osteogenesis imperfecta
defect in collagen synthesis, blue sclera/brittle bone disease
sometimes collagen itself, maybe mutation at lysine
collagen mutations generally show type of dominant negative effect
processing of amino acid defects due to enzyme deficiencies more likely to be recessive
119
elastin
elastic fibers in smooth muscles, endothelium, near chondrocytes and fibroblasts
allow vessels to deform, lungs to expand
alternating hydrophobic and hydrophilic domains in protein
120
laminin
3 polypeptides in cross configuration
globular domains at N terminal then rigid coils, disulfide bond links cells, only alpha chain has C erminal that binds ECM, various combos of alpha beta gamma
most abundant in basal laminae ofter collagen, binds to ECM molecules and cell integrins, provide stability
defects lead to junctional epidermolysis bullosa
121
proteoglycans
fibrous structural proteins embedded in gels (hyaluronic acid core with branching proteinscovered in glycosaminoglycans
122
glycosaminoglycans
repeating disaccharides with 1 sugar N acetyl glucosamine or glycosamine, other acidic (glucuronic or iduronic acid)
sugars modified with sulfate added from PAPs
123
proteoglycan linkage
GAGs added on serine/threonine residues, trimer of xylose and 2 galactose molecules link GAG to AA, GAG added to linker, repeat units added
addition of normal or modified sugar
modifications made to growing chain
sulfate added to existing chain sugars
124
forming matrix
link proteins bing hyaluronic acid to proteoglycans with noncovalent bonds
negative charges bind positive ions or H bonds to H2O forming a hydrated gel
125
proteoglycans bind fibronectin
fibronectin binds integrins in cell membranes and collagen fibrils, cells attach to matrix components
126
cartilage
high number of negative charges attract cations (high osmotic pressure) water drawn in, tension balances swelling at equilibrium
127
matrix lifecycle
components synthesized and degraded, near cells are less organized, intracellular matrix more organized, synovial fluid has smaller components
128
matrix degradation
components taken up by endocytosis, endosomes from lysosomes, lysosomal hydroxylases break down ECM
129
integrins
transmembrane proteins connect matrix and cytoskeleton, signals pass in either direction, composed of 18 and 10 beta subunits, some cells have inducible integrins
130
matrix metalloproteinases (MMPs)
contain zinc, degrade all ECM proteins
important for migration and remodeling, can release growth factors
synthesized with propeptide containing cysteine blocking active site, removal necessary for activation
highly regulated, one method control of TIMP expression (tissue inhibitors of metalloproteinases)
131
developmental genetics basics
many cell types due to differential gene expression
132
types of genetic mediators
paracrine signaling, DNA transcription factors, ECM proteins
133
paracrine signaling
secreted into intercellular space, diffuse to nearby cells
4 major families - fibroblast growth factor, hedgehog proteins, wingless family, transforming growth factor
need receptors, binding can change gene expression
134
FGFR3 mutations
dwarfism
normally expressed in resting chondrocytes restraining chondrocyte proliferation and differentiation
most common dysplasia is achondroplasia activity inhibiting chondrocyte growth
milder form is hypochondroplasia
135
transcription factors
find DNA and activate or repress gene expression, usually multiple targets
many families - homeobox, high mobility group HMG, T box family
136
SOX family
prototype gene Sry - sex determining region fo Y
sox 9 regulates chondrogenesis, mutations cause comptomelic dysplasia
hirschprung neural crest defect - enteric neurons dont develop properly, sporadic and familial causes, sox 10 is one of several genes causing phenotype
137
ECM mutations
type 1 collagen - osteogenesis imperfecta, bone formation disrupted
fibrillin 1 - marfan syndrome
elastin - supravulvar aortic stenosis
LAMC 2 - junctional epidermolysis bullosa
138
pattern formation
established in developing organisms
139
SHH
important in axis specification, induction of motor neurons, limb patterning
garlin syndrome - nevoid basal cell carcinoma syndrome - defect in tumor suppressor patched
140
gastrulation
day 14-28 embryo becomes trilaminar, cell migration critical
141
axis specification
patterning along AP axis bc HOX genes
142
dorsal ventral axis
established before first cell division in fertilized embryo
noggin and chordin are dorsalizing signals
Bmp4 ventralizing signal
noggin and chordin bind Bmp4 preventing binding to receptor
143
left right axis
defects random or reversed, most common zinc finger patterning of cerebellum (ZIC3 mutation)
144
limb development
Fgf8 candidate for inductive signal, mediated by Fgf10 expression in mesoderm, Wnt2b and Wat8c maintain Fgf10 expression
145
limb growth signals
proximal/distal stimulated by FGF2/4/8
zone of polarizing activity utilizes SHH to maintain apical epidermal ridge
ZPA signals positional info along proximal/distal axis
146
limb defects
anterior - holt oram syndrome
posterior - ulnar mammary syndrome
147
organs
beta cells require IPF1 to express insulin
148
modes of aquisition for specific immunity
natural - passive is placental transfer, active is recovery from disease
artificial - passive is antiserum for rabies and tetanus, active is immunization
149
passive immunizations
preformed antibodies transferred to recipient
no memory response
immediate protection
150
active immunization
elicit protective immunity and immunologic memory
151
attenuated vaccines
organisms cant cause disease but still grows in host, mimics natural infection
152
inactivated vaccines
kill pathogen, critical to maintain structure of epitopes on surface antigens during inactivation, requires boosters, humoral response predominantly
153
purified macromolecules
capsular polysaccharide, inactivated toxins, recombinant surface antigens
154
polysaccharide vaccines
virulence factor of many organisms is polysaccharide, inability to activate Th
155
conjugated polysaccharide vaccines
polysaccharide conjugated to protein antigen, changes immune system to T cell dependent, increase immunogenicity in infants, antibody booster response to multiple doses
156
toxoid vaccines
exotoxins, entitoxoid antibodies bind toxin and neutralize effects, difficult to make in high quantities
157
recombinant antigen vaccines
gene for immunologic protein isolated and cloned, induces humoral immunity
158
mRNA vaccines
make proteins to trigger immune response
159
live injected vaccines
coverage after first dose, second dose ensures seroconversion
160
inactivated vaccines
not protected by first dose, may not be until second or third, antibody titer wanes over the years
161
adverse reactions
local - common with inactive vaccines
systemic - common with whole cell/live attenuated vaccines
allergic - due to vaccine or vaccine component
162
immunosuppressed
never get live attenuated vaccine
163
cardinal features of inflammation
rubor, tumor, calor, dalor, functo laesa
164
tissue damage
due to inflammatory or non inflammatory process
165
healing
regeneration or scarring
166
repair
synonym for healing or only means scarring
167
regeneration
replacement of injured cells with healthy cells
168
scarring
replacement of injured cells with fibrous connective tissue
169
factors impairing tissue repair
persistent infection, diabetes, malnutrition, corticosteroids, mechanical factors, poor blood flow, foreign bodies
170
cells of body divided into 3 groups
labile, stable, permanent
171
labile cells
short G0, continually dividing
172
stable cells
low level of replication, prolonged G0, reenter cell cycle under certain conditions
173
permanent cells
left cell cycle, cannot undergo mitosis
174
healing by regeneration IF
labile/stable cells, area must contain some surviving cells, CT intact
scarring in tissues unable to regenerate
175
healing by scarring
inflammation, form new blood vessels, migration/proliferation fibroblasts, deposition/agragation of fibrous tissue
176
growth factors
polypeptides, promote or inhibit cell proliferation
177
events for repair by scarring
fibroblasts and vascular endothelial cells proliferate, formation of granulation tissue, remodeling
178
granulation tissues
newly formed small vessels
edematous, synthesize collagen type 3, admixed inflammatory cells, myofibroblast proliferation
179
remodeling
amount of collagen and ECM proteins increase, fibroblasts and vascularity decrease
180
cutaneous wound healing
hemostasis, inflammation, proliferation, collagen accumulates and vascularity decreases, connective tissue formed
181
stem cells
pluripotent, isolated from blastocysts, can be maintained undifferentiated or induced to differentiate
182
adult stem cells
more restricted regeneration, generally lineage specific, located in niches
183
beta lactam mechanism of antibacterial effect
bind beta lactam receptors, proteins have catalytic funtion which is inhibited by binding (bacteriostatic)
beta lactam activates autolysins of bacteria
184
PBPs
transpeptiddases inhibited (catalyzes cross linking of murein) so synthesis of cell wall inhibited
185
susceptibility to beta lactam depends on
constitution of outer layers of cell envelope antibiotic must cross and thickness of proteoglycan layer
186
microbial resistance to beta lactam
acquired resistance - mainly extrachromosomal, mediated by plasmid
cross resistance among beta lactam sensitive penicillins
partial cross resistance among beta lactamase resistant penicillins and cephalosporins
187
mechanisms of beta lactam resistanse
production of beta lactamase enzynes
develop PBPs wiht decreased affinity for antibiotic
decreased eprmeability of cell membrane
develop active efflux pump
188
pharmokinetics of penecillin
absortption parental and oral
distribution - widespread
biotransformation variable
excretion - kidney
allergic reactions - highest with respiratory penicillins, lowest with oral, 1st and 2nd generations more cross reactivity so use a ceph, use alztreonam or macrolide
189
cephalosporins
given after surgery
absorption - oral variable, parental very good
distribution - throughout body
biotransformation - variable
excretion - by kidney
adverse effects - hypersesitivity, thrombophlebitis, nephrotoxicity,
190
monobactam
aerobic gram negative rods
IM/IV
allergic rections but major toxicity uncommon
191
carbapenems
resistant to most betalactamases, parenteral, seizures and superinfections
192
beta lactamase inhibitors
poor intrinsic antimicrobial activity
increase spectrum for beta lactam antibiotics against organisms producing beta lactamase
193
non beta lactams
vancomycin
daptomycin'fosfomycin
colistin
194
vancomycin
inhibits transglycosylate by binding D alamoyl D alanine of cell wall precursor
195
daptomycin
depolarize cell membrane
pulmonary surfactant innactivates
196
fasfomycin
inhibit bacterial cell wall synthesis, inhibits enolpyruvate transferase (bacteriacidal)
197
colistins
cationic detergent
198
neoplasia
new growth
abnormal, mass of tissue, growth exceeds and is uncoordinated with that of normal tissue, persists after cessation of inciting stimulus
genetic alterations passed down, clonal, excessive unregulated proliferation, altered differentiation of tumor cells, autonomous
199
benign tumors
resemble normal tissues, function preserved, cannot metastasize
200
malignant tumors
can metastasize, less differentiation and anaplastic, may be invasive
201
benign leioyoma vs malignant leiomyosarcoma
benign leioyoma - small, well differentiated, slow growing, noninvasive, nonmetastatic
malignant leiomyosarcoma - large, poorly differentiated, rapidly growing, locally invasive, metastatic
202
nomenclature
benign - end in oma
malignant - end in sarcoma or carcinoma
prefix based on origin
203
acquired conditions predispose cancer
chronic inflammatory disorders, precursor lesions, immunodeficiency
204
grading
varies with differentiation, relationship to growth rate, exact grade based on type of tumor
205
staging denotes extent of diease
T - tumor size
N - nodal envolvement
M - metstases
206
metastasis
genetic influence, stromal factors important
steps - loosening intracellular junctions, adherence to matrix proteins, degradation of matrix, locomotion, entry into circulation, travel to site, enter target organ, angiogenesis
207
effects on host
local, hormonal production, cachexia
208
treatment
depends on type, grade, stage
surgery, chemo, radiation, hormone therapy, immunotherapy
209
fine needle aspiration
aspirating cells and attendant fluid with small bore needle
immunochemistry used to identify metastatic tumor
210
tumor classification
carcinomas - epithelial tissue derived
sarcomas - CT derived
lymphomas - lymphatic tissue derived
gliomas - glial cells from nervous system
leukemias - hemotpoietic cells
211
classes of cancer genes
oncogenes, tumor suppressors, DNA repair
212
inherited cancer
defect in certain classes of genes, mutations can occur in germline, predisposed to cancer, all cells hace mutant gene, most loss of function mutation in tumor suppressor genes
213
knudson two hit model
tumor requires mutations in both chromosomes so 2 mutations necessary
214
identifying oncogenes
study of retroviruses, chromosomal rearrangement
215
genomic instability
aneuploidy, translocations, DNA hypomethylation
216
mapping cancer genes
array CGH, whole genome sequencing, STRs in linkage analysis, exome sequencing, GWAS
217
loss of heterozygosity
missing markers, give probably gene locations
218
refining
mutations in unrelated families examined, narrow the region with linkage studies, look for anomalies in region
219
inherited TP53 mutation
rare Li-Fraumen syndrome
many tissues can show tumors, autosomal dominant, early age
220
familial colon cancer
familial adencematous polyposis coli
hereditary nonpoluposis colon cancer
loss of both APC tumor suppressor genes
1. APC mutation
2. KRaas activation
3. TP53 mutations
4. other genes alteres
221
HNPCC genes
1-5% colorectal cancers, autosomal dominant, causes other cancers
mutations in MSH 2 and 1
222
breast cancer
BRCA 1 and 2
both repair double stranded DNA breaks
223
melanoma
increased risk with affected relative
gain protooncogene CDK4
loss of function tumor suppressor gene CDKN2A
224
many genes contribute to a trait
true for most quantitative traits
may show normal distribution (bell curve)
225
threshold model
some diseases only present or absent, distribution not that of single genes
may be liability distribution - ends of curve effected (pyloric stenosis)
226
recurrent risk
very complex, empirical risk derived
227
specific indications
hard to distinguish from single gene with complicating factors
look for relative recurrent risk
228
complex single gene traits
locus heterogeneity, background effects on major genes, many traits full into multiple categories
229
twin pairs
concordant = both affected
discordant = 1 affected
heritability = 2(MZ-DZ)
adoption studies
230
finding genes
some caused by genes, some caused by phenocopies
use population with affected and unaffected
perform genome scan
compare alleles at each locus with the trait
locate regions correlating with trait
screen region for candidate genes
alternate - affected sibling pair method, GWAS
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common multifactorial disorders
heart disease - coronary artery disease, athlerosclerosis
familial hypercholesterolemia - approximately doubles serum cholesterol, xanthomas, increases athlerosclerosis, autosomal dominant
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LDL receptor
binds LDL, LDL endocytosed, LDL delivered to lysosome where broken down
mutations -
1. no protein found
2. cannot leave ER, degraded
3. cannot bind LDL
4. do not migrate to coated pits
5. cannot dissociate from LDL, not recycled to cell surface
therapies - decrease intake of cholesterol or falts, bile acid binding resins, statins block cholesterol synthesis
233
diabetes
type 1 - early onset, immune destruction of islet cells, no insulin, HLA DR314 mutation
type 2 - late onset (obesity), peripheral insulin resistance, TCF7L2, KCNJ11, PPAR gamma
MODY - intermediate onset, autosomal dominant, no obesity, glucokinase mutations or HNF 1 alpha/beta, HNF4 alpha, IPF 1 NEUROD2
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alzheimers
risk doubles if affected 1st degree relative
presenilin 1/2 and APP approximately 1/2 early onset cases
ApoE variations can increase risk
235
clindamycin
not macrolide
236
macrolides and tetracyclines good for
gram positive, nonvirulent gra negative, atypicals
237
linezolid
potential serotonergic activity
2nd line for vancomycin
238
2/3rd line drugs
linezolid, quinupristin/daflopristin, chloramphenizol, tigecycline
239
MOA's
50S ribosome - macrolides, clindamycin, linezolid, quinupristine/dalfopristin
30S ribosome - aminoglycosides, tetracyclines
all bacteriastatic except aminoglycides
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aminoglycosides
block initiation of translation and cause misreading of mRNA
streptomycin, gentamycin, tobramycin, neomycin, amikacin
241
tetracyclines
block attachment of tRNA to ribosome
tetracycline, minocycline, doxycycline
242
streptogramins
each interfere with distinct step of protein synthesis
quinupristin/dalfopristin
243
macrolides
prevent continuation of protein synthesis
erythromycin, clarithromycin, azithromycin, telithromycin
244
chloramphenicol
prevent peptide bonds from being formed
245
lincosamides
prevent continuation of protein synthesis
clindamycin
246
oxazolidinones
interfere with initiation of protein synthesis
247
MOA aminoglycosides
penetration through cell envelope (passive diffusion via porin channels, active transport across inner membrane requires oxygen and alkaline), irreverisbly bind 30S and alter protein synthesis (interferes with initiation complex, block translation, misread mRNA)
248
aminoglycosides
bactericidal, concentration dependent, post antibiotic effect
natural resistance - cell wall impermiable, anaerobic bacteria, lack receptor, plasmid production of transferase enzymes inactivated by adenylation/acetylation/phosphorylation
serious gram negative infections, synergistic with beta lactam (2nd line of defense)
IM/IV, kidney excretion
ototoxicity, nephrotoxicity, neuromuscular blockade
249
spectromycin
like aminoglycosides but doesnt cause misreading of mRNA, bacteriastatic, IM only, for neisseria gonorrheam discontinued in US in 2001
250
MOA macrolides, ketolides, lincosamides
antibacterial effect - bind 50S ribosome subunit, blockade of translocation, blockade of transpeptidation, bacteriostatic
resistance - plasmid encoded, increased activity of multidrug efflex pump
251
macrolides
biliary excretion, some kidney
against gram positive and some nonvirulent gram negative
nausea, vomiting, diarrhea, acute cholestatic hepatitis, skin eruptions, fever
contraindications - QT prolongation
252
clindamycin
50S ribosome, inhibits bacterial protein synthesis
diarrhea and colitis bc c difficile, nausea, vomiting
strep, staph, MRSA, good against anaerobes/bacteriodes
253
tetracyclines/glycylcyclins
antibacterial effect - passive diffusion/active transport, bind 30S subunit and prevent tRNA binding
resistance - multidrug efflex pump
254
tetracycline
absorption imparied by calcium cations, dairy products and antacids, excretion by kidney and bile, used against gram negative and positive and atypicals
effects - on microflora, bone/teeth growth inhibition or deformity, photosensitivity
255
tigecycline
gram positive and negative
highly lipophilic, binds 30S and inhibits protein synthesis (bacteriostatic)
2/3rd line of defense
256
chloramphenicol
reversibly bind 50S subunit inhibiting peptide formation (bacteriostatic)
used for bacterial meningitis and rickettsial disease
oral bioavailability, metabolized by liver
dose dependent toxicity, suppression of bone marrow, gray baby syndrome, aplastic anemia
257
quinupristin/dalfopristin
50S blockade of translocation or conformation change (bactericidal)
hyper bilirubinemia, phlebitis
serious infections, not first line
258
linezoid
bind 23S RNA of 50S subunit
myelosuppression
weak inhibition of MOA
259
sulfonamides or trimethoprim alone
bacteriostatic
260
sulfonamides and trimethoprim together
bactericidal
261
sulfa drugs inhibit
dihydropteroate synthase
262
trimethoprim inhibits
dihydrofolate reductase
263
microbial resistance to sulfonamides
strep/steph/ecoli
increased production PABA, diminished sensitivity of dihydopteroate synthase, decrease permeability of cell wall to drug
264
microbial resistance to trimethoprim
altered dihydrofolate reductase
265
sulfonamides
acetylated in liver, excreted by kidney
266
trimethoprim
100% oral absorption, distribute throughout body, biotransformation by liver about 35%, excreted by kidney
267
adverse effects of sulfonamides
dose dependent toxicity, crystalluria, hemolytic/aplastic anemia, increased risk of kernicterus in newborns, allergic reactions, skin eruptions
268
adverse effects trimethoprim
epigastric rash/nausea and vomiting, megoblastic anemia, rash/itching
269
sulfonamide interactions
oral anticoagulants, sulfonylureas, phenyotoin, methotrexate, cyclosporine
270
fluoroquinones
newer agents developed in 1990s
block topoisomerase 2 (DNA gyrase) and topisomerase 4
bacericidal, concentration dependent
microbial resistance - change in target enzyme, mutation decreases permiability of bacterium to drug
oral absorption impaired by cations, distributes throughout body, biotransformation by liver, excretion by kidney
gram positive and negative
adverse effects - cardiac arythmias, headache/dizziness/confusion/hallucinations
BBW - tendinitis, tendon rupture, photosensitivity
271
metronidazole
form labile intermediates which inhibit DNA synthesis and damage DNA
anaerobic bacteria and protozoa
neurotoxicity, disulfiram like effects
272
anaerobes
clindamycin used for those above the diaphram, metronidazole used for those below the diaphram
273
fidaxomicin
inhibit RNA polymerase inhibiting protein synthesis (bactericidal), cofirst line for c diff, abdomineal pain/GI bleeding
274
rifampin
antituberculosis
275
nitrofurantoin
uncomplicated UTI
276
cell growth and differentiation
growth factors and receptors, signal transduction pathways, transcription factors
277
stages of cancer
start as single mutated cells, proliferate in situ, accumulates more mutations, inclusion of nearby tissue/blood vessels/lymphatics, small clusters and single cells migrate and metastasis
278
cause of cancer
genetic aspects and environmental aspects
279
chemical initiation
damage to DNA can change genes, mutations can be inherited at mitosis
280
classes of cancer genes
oncogenes - enhance cell proliferation
tumor suppressor genes - normally control cell cycle and proliferation
DNA repari genes - help maintain integritiy of genome
281
protoconcogenes
normally regulate cell cycle, modified or expressed inappropriately, stimulate cell division at inappropriate times
points - growth factor may be overexpressed or another molecule may bind receptor, receptor may signal without ligand, proteins may act without signal, G proteins may be active without GTP or lose GTPase, kinases active by themselves, TF active/overexpressed
282
Ras path
monomeric G protein, activates Raf when GTP bound, Raf is MAP3K and activates MEP which activates MAP kinase which activates transcription factors
283
cyclins in cell cycle
stimulate change from 1 stage to another, only made at certain stages, stimulate cyclin dependent kinases that are always present
284
cyclin dependent kinases
only active when proper cyclin bound and have proper phosphorylation, inactivated by cyclin dependent kinase inhibitor proteins
285
cell cycle checkpoint
Ras/Raf induce cyclin D which binds Cdk4/6, phosphorylates Rb and release E2F which enters nucleus and induces expression of genes for cell cycle progression
286
RP53 gene
codes p53 protein, 50 tumor typers have mutations, loss of 17p in colon tumor cells, small deletions loclize to TP53 region, most mutations missense in DNA binding domain
287
p53 function
CKI, inhibit cell cycle, DNA damage sensing, direct damaged cells undergo apoptosis, interacts with PTEN and BAX, specific carcinogens cause characteristic mutations in gene
288
DNA damage and p53
p53 increases in response to mutagens, acts as TF for genes that repair damaged DNA, successful repair down regulates p53, stimulates Bax and IGF BP3 which blocks signaling
289
tumor suppressors and Ras
Ras in hormon and growth factor signaling paths, GTPase activating proteins interefere with this, NF1 has loss of Ras
290
combinations
tumor suppressors and oncogenes work together normally, patched is tumor suppressor and smoothened is protooncogene
tumor when patched looses function and smoothened gains function
291
cadherins
mediate calcium dependent cell to cell adhesion, anchored by cadherins to actin incytoskeleton, loss of E cadherin can allow metastasis of tumor cells
292
catenins dual function
affect gene transcription, beta catenin can enter nucleus as TF, degraded by complex including APC
293
telomerase
maintain length and prevent senescence
294
apoptosis
removes damaged cells
295
caspases
cysteine proteases, cleave near aspartates, activates from zymogens by proteolysis, some are initiators which activate protecaspases (execution caspases)
296
Bcl-2
apoptic and atiapoptic signals in cells, have Bcl-2 homology domains
3 types - anitapoptic, channel forming, proapoptic
297
death receptor path
subset of TNF 1 receptors, trimer binds ligand, 2 procaspase molecules bind (initiators 8/10), autocatalytically cleave each other and become active, cleave procaspases 3,6,7 to activate execution ccaspases
298
mitochondrial integrity path
induced by growth factor withdrawal/cell injury, cytochrome c released, bind Apaf 1 which binds/activates procaspase 9 forms apoptosome which cleaves procaspase 3/6/7 activating execution caspases
299
cancer cells
resistant to apoptosis
