Path Exam 2 Flashcards
(525 cards)
1
Q
personalized medicine
A
selection of treatment best suited for a particular individual and not an average representation of a population
2
Q
Analysis of age-standardized death rates shows shows significant success in treatment of ___
A
heart disease
stroke
3
Q
Death rates for ____ increase despite increased health care spending
A
COPD
diabetes
4
Q
how are most existing drugs approved?
A
on basis of performance in a population
5
Q
what is warfarin used for?
A
long-term treatment and prevention of thromboembolic events
6
Q
what are the 2 genes involved in warfarin metabolism?
A
VKORC1
CYP2C9
7
Q
Herceptin
A
Monoclonal antibody that targets breast cancers overexpressing HER2/neu gene
8
Q
how do personalized cancer vaccines work?
A
- Cell therapy product is created using a technique that fuses the patient’s own tumor cells with immune-stimulating dendritic cells
- Fusion product is then injected back into the patient causing a specific immune response against the cancer
9
Q
OncoVax results
A
33% increase in overall survival and a 40% reduction in deaths in colon cancer patients
10
Q
MyVax
A
investigational treatment that combines a protein derived from the patient’s own tumor with an immunologic carrier protein and is administered with an immunologic adjuvant
11
Q
DCVax
A
personalized therapeutic cancer vaccine manufactured from the patient’s own DCs that have been modified to teach the immune system to recognize and kill cancer cells bearing the biomarker of patient’s tumor
12
Q
autologous cell vaccine
A
- cancer cells are treated with a hapten which binds to molecules on the surface of cells and helps trigger immune responses
- combined with an adjuvant to enhance effectiveness
- injected into pt so immune system can better locate and combat cancer cells
13
Q
BIOVAXID
A
cancer vaccine recognizes and eliminates cancerous lymphoma cells, while sparing normal B cells
14
Q
how does BIOVAXID work?
A
specific cancer antigen-bearing tumor cells harvested from a patient’s lymph node are fused to antibody-producing mouse cells and the produced large quantities of the protein antigens are then given back to patients with an immune system booster
15
Q
ChemoFx assay
A
ex vivo assay designed to predict the sensitivity or resistance of a solid tumor to a variety of chemotherapeutic agents
16
Q
main cancer biomarkers
A
estrogen and progesterone R
HER-2
17
Q
what is the reason for identifying HER-2 cancers?
A
Identifying breast cancer patients with metastatic disease who may benefit from Herceptin
18
Q
companion diagnostics
A
Use genetic, proteomic, gene expression or other molecular markers to predict whether a drug will work in someone or not, what dose is optimal and whether there is a risk of adverse effects
19
Q
Verigene warfarin metabolism nucleic acid test
A
FDA approved test that detects variants of CYP2C9 and VKORC1 genes responsible for sensitivity to warfarin
20
Q
HLA-B57
A
Marker for the potentially fatal hypersensitivity reactions in some patients taking the HIV-1 reverse inhibitor, abacavir
21
Q
HLA-B1502
A
Those with this gene have a higher chance of developing adverse drug reactions against carbamazepine
22
Q
Thiopurine methyltransferase
A
NZ involved metab of azathioprine and 6-mercaptopurin
23
Q
Patients with low TPMP are at an ___ risk of myelotoxicity if taking azathioprine or 6-mercaptopurin
A
increased
24
Q
Azathioprine
A
used in renal homotransplantations and for the management of active rheumatoid arthritis
25
6-Mercaptopurin
therapy of acute lymphatic (lymphocytic, lymphoblastic) leukemia
26
Erbitux and panitumumab
Drugs that require testing of patients with colorectal cancer for EGFR receptor before treatment
27
Imatinib
Targeted therapy for leukemia and a test for the bcr/abl translocation determines if a patient benefits from this drug
28
Ivacaftor is effective in treating patients with the ___ mutation in ___
G551D
| cystic fibrosis
29
genetic test for breast cancer
BRCA
30
genetic test of colon cancer
MLH1
| MSH2
31
microarray
Consists of an arrayed series of microscopic spots of probes on a solid surface which bind to the components of the analyzed sample with high specificity
32
what are the probes in microarrays?
oligonucleotides or fragments of cDNA attached to solid surfaces or beads
33
how are microarrays created?
in situ synthesis
| depostion of presynthesized oligonucleotides
34
Affymetrix arrays
oligonucleotide probes are synthesized directly in situ using photolithography techniques adapted from the microelectronics industry
35
how are microarrays made with ink jet printing?
- Nucleotide monomers are printed onto the chip and coupled using phosphoramidite chemistry
- Hybridization is detected by using a confocal laser scanning microscope to image the intensity of fluorescently labeled samples
36
Compared to cDNA arrays, the oligonucleotide arrays offer ________
greater specificity and can distinguish single nucleotide polymorphisms (SNPs) and splice variants
37
4 categories of research with microarrays in humans
Normal tissue taxonomy
Disease diagnosis and classification
Disease prognostication
Dissection of biological mechanisms
38
mammaprint
70 gene signature that identifies which early-stage breast cancer patients are at risk of distant recurrence following surgery, independent of estrogen receptor status and any prior treatment
39
MINDACT
- microarray for node-negative disease may avoid chemotherapy trial
- aims to determine whether this expression signature can be used for making clinical decisions
40
Oncotype assay
- RT-PCR assay based on a 21-gene signature derived from 250 candidate genes selected from the published microarray literature
- used to see if a pt will benefit from chemo
41
Genome-wide studies of gene expression microarrays
- Differentiation of biological states by differences in gene expression
- What pathways are affected by different biological states
42
Locus copy # microarray
Disease specific chromosomal loss and amplification
| Chromosome instability in cancer
43
1st generation DNA sequencing
“Sequencing by synthesis” → uses DNA polymerase
Adds bases to the 3’ end of a primer bound to a DNA template
Incorporates dNTP bases complementary to the template
44
limitations of 1st generation DNA sequencing
only one sequence per lane can be sequenced and a complex and labor-intensive separation of template sequences is needed
45
how did fluorescent ddNTPs change DNA sequencing?
Allows analysis of all 4 reactions in 1 lane
Fluorescent fragments detected by laser excitation
Possibility for automation
46
how did fluorescent capillary electrophoresis change DNA sequencing?
```
Read length is significantly increased
Adjacent lane spillover is eliminated and lane tracking problems are gone
Higher sensitivity
Less reagents and template
Lower cost, less work
Highly automated and more consistent
```
47
next generation DNA sequencing
“Massively parallel”
Cost-effective and rapid
Production of large numbers of low-cost reads makes the NGS platforms useful for many applications, including clinical applications
48
Chip-Seq
sequencing of DNA associated with active chromatin
49
_% of transcribed RNA are genes
1
50
commensal
normal flora or non-sterile body sites
| symbiotic colonization
51
environmental species
reservoirs are non human
52
obligate pathogens
capable of causing disease in healthy and immunocompromised hosts
53
opportunistic pathogens
typically rely on some kind of immune impairment, local or systemic, in order to cause infection
54
iatrogenic suppression
immunosuppression/therapuetic regimens that increase risk for infection
55
ivermectin treats?
river blindness caused by the filarial worm, transmitted by flies
lymphatic filariasis caused by worms, transmitted by mosquitoes
56
artemisinin
antimalarial drug
57
what kind of pathogen is C diff?
anaerobic bacterium
58
possible treatments for C diff
fecal microbiota transplants
| Monoclonal antibodies block toxin receptors
59
listeria
Can be found in food processing plants
| Survives and proliferates at refrigeration temperatures
60
endemic
steady state of disease in a population
61
examples of endemic diseases
malaria
syphilis
TB
62
outbreak
case numbers exceed usual expectation for a defined community, region, or season
63
epidemic
disease spreads rapidly
64
pandemic
global epidemic
65
examples of epidemics
flu
SARS
ebola
66
examples of pandemics
HIV/AIDS
| flu
67
bioterrorism
use of infectious agents as weapons
68
malaria
Endemic mosquito borne protozoan disease
69
what can lead to new strains of pathogens?
genetic mutations
adaptation
zoonotic transmission
70
selective pressure that drive opportunistic infections
Immunosuppression
| Antimicrobial resistance
71
plague pathogen
Y pestis
72
CDC category A bioterrorism
readily disseminated
pandemic potential
requires public preparedness
73
CDC category B bioterrorism
moderately easy dissemination
morbidity
requires surveillance and diagnostics
74
CDC category C bioterrorism
emerging or engineered
| high morbidity and mortality
75
what allows flu to have persistent genetic mutation
segmented RNA genome
76
antigenic drift
minor mutations in outer viral proteins of the flu
77
antigenic shift
major genetic recombinations that can create a risk for epidemics and pandemics
78
flu reservoirs
birds
| pigs
79
what is the reason that we have to change the flu shot every year?
antigenic drift
80
SARS
respiratory virus
Enveloped single-stranded RNA unsegmented genome
caused a worldwide outbreak
81
MERS
Enveloped single-stranded RNA unsegmented genome
causes upper resp illness
ongoing
82
why was the E Coli outbreak in 2011 more virulent?
novel genetic exchange between a Shiga toxin producing strain and a different strain that manifests strong adherence to intestinal cell epithelium
83
antimicrobials
Drugs that act against bacteria, viruses, fungi or parasites
84
2 major adverse consequences of antimicrobials
Disruption of normal biologic function
| Selection for antimicrobial resistance
85
what is artemisinin resistance due to?
Poor treatment practices
Inadequate patient adherence to regimens
Widespread availability of substandard forms of the drug
86
Carbapenems
broad spectrum beta lactam drugs in the same family as penicillin
87
prion size
<1um
88
what do prions cause?
intracellular propagation of abnormal proteins
89
virus size
<1um
90
what are viruses?
obligate intracellular pathogens
91
the essential nucleic acid core of a virus is surrounded by a ___
capsid
92
herpesviridae
Enveloped viruses with a large complex genome that persist in host cells by establishing latency
93
how is herpes DNA maintained in the host cell?
incorporation into host DNA or as a plasmid-like independent episome, separate from host cell chromosomes by able to interact with DNA
94
how does herpes cause disease after infecting the host cell?
activation of viral replication and release of virus from infected cells causes recurrent symptomatic disease
95
alpha herpes viruses
variable range of tissue tropism including mucocutaneous and neuronal tissue
96
examples of alpha herpes viruses
herpes simplex
| varicella zoster
97
beta herpes viruses
longer reproductive cycle and a different if not more restricted tropism
98
example of beta herpes viruses
cytomegalovirus
99
gamma herpes viruses
predominantly lymphotropic, specific to T or B lymphocytes
100
example of gamma herpes viruses
Epstein-Barr
101
how is HSV transmitted?
close contact with lesions
102
where does HSV establish latency?
neuronal ganglia proximal to the site of initial infection
103
Typical sites of HSV primary and recurrent infection
brain
conjunctiva
orofacial and genital mucocutaneous sites
104
where do shingles outbreak?
in a dermatomal pattern in the areas of the skin innervate by infected ganglia
105
what are the reservoirs for HSV and VSV?
only humans
106
flu transmission
respiratory droplets, contact with contaminated surfaces/hands
107
cytopathic effects
changes that can be seen by light microscopy even if the actual virus can’t be seen
108
what kind of virus is hepatitis B?
DNA
109
what kind of virus is hepatitis C and A?
RNA
110
tropism of hepatitis
liver
111
what kind of cell are bacteria?
prokaryotes
112
bacteria cell wall functions
cell integrity
growth
metabolism
113
gram positive
thick peptidoglycan layer
114
gram negative
thin peptidoglycan layer and lipid bilayer
115
Microbiomes
site-defined complex ecosystems of microbes, genes, and products that contribute to our healthy function
116
Toxigenic C Difficile
Anaerobic spore-forming bacterium with toxin-producing and non-toxigenic strains
117
what kind of cell are fungi?
eukaryotes with a cell wall
118
2 basic kinds of fungi
yeast
| mould
119
difference btwn yeast and mould
yeasts are single celled
| moulds are multicellular
120
hyphae
collections of elongated cells of moulds
121
how do most fungi reproduce?
create environmentally hardy spores that easily disperse
122
what kind of cell are parasites?
Eukaryotes
123
2 basic kinds of parasites
protozoa
| helminths
124
what kind of cell are protozoa
single celled eukaryote
125
helminths
Multicellular parasites with complex life cycles
126
roundworms
nematodes
nonsegmented
collagenous tegument
127
flatworms
cestodes
gutless
head and body segments
128
flukes
trematodes
| primitive, leaf like worms
129
Ectoparasites
Live on skin or elsewhere outside of the host
130
are prions prokaryotes or eukaryotes?
neither- proteins
131
are viruses prokaryotes or eukaryotes?
neither
132
how do candida yeast cause infection?
part of normal gut flora
| changes in flora allow yeast to cause infections
133
what is the first barrier of defense against pathogens?
skin
134
how is hepatitis A acquired?
ingestion of something contaminated, but it is tropic to the liver and causes inflammation of the liver
135
how is hepatitis B and C acquired?
transmitted by blood-borne exposures but also are hepatotropic
136
how do microbes cause disease?
direct cell damage
transformation
cell death
137
tropism
preferential cell or tissue infection
138
HIV tropism
CD4 T cells
139
where does Epstein Barr establish latency?
memory B cell compartment
140
where does BKV establish latency?
renal epithelium
141
where does CMV establish latency?
salivary glands
142
which herpes viruses insert episomal viral genome into the host nucleus?
HSV
| VZV
143
which pathogen incorporates proviral DNA into the host genome?
HIV
144
which viruses control cell apoptosis?
HCV
CMV
EBV
HIV
145
how do microbes avoid clearance by the immune system?
immunosuppressive cytokine
| alteration of MHC expression
146
which pathogen stimulates production of immunosuppressive cytokines like interleukin 10?
hepatitis C
147
which pathogens alter host-cell antigen expression to avoid immune recognition?
HIV
HSV
CMV
148
S pyogenes induced immune complexes cause ___
renal injury
149
TB causes
granulomatous inflammation and necrosis
150
endotoxins
components of the microbe
151
exotoxins
substances released by the microbe
152
pathogens that use binary toxins
diphtheria
| anthrax
153
what are the symptoms of anthrax a result of?
2 Bacillus anthracis exotoxins:
edema factor
lethal factor
154
how do binary toxins works?
the B component binds the host cell R
| A component catalyzes cell signaling mechanisms to produce exotoxin
155
4 basic ways of evading the host immune system
staying inaccessible
antigenic variation
evasion of innate defenses
evasion of adaptive defenses
156
how do pathogens stay inaccessible to host immunity?
become enclosed in a protective structure
camouflage
establish latency
157
how do pathogens use antigenic variation to evade the host immune system?
change or shed surface antigens
| replication errors
158
how do pathogens evade innate defenses?
bind antibodies
degrade antibodies
avoid phagocytosis
block complement
159
how do pathogens evade adaptive defenses?
prevent MHC expression
express fake MHC
degrade MHCII
infect lymphocytes
160
suppurative inflammation
pathogen encourages an influx of neutrophils to the site of infection → pus or abscess
161
Granulomatous inflammation
organism survives inside macrophages, walled off by surrounding fibrous tissue and other inflammatory cells including multicellular macrophages
162
examples of cytopathic agents
herpes
| hepatitis B
163
examples of cytoproliferative agents
HPV
| molluscum contagiosum
164
cytopathic
kill cells as they escape to infect another cell
165
cytoproliferative
induce autonomous growth and produce tumors
166
cytoproliferative pathogens that are potential inducers of neoplasia
EBV
| HPV
167
necrotizing pathogens
cause rapid and severe tissue destruction via potent toxins and enzymes
168
examples of pathogens that cause chronic inflammation and scarring
hepatitis B and C can cause cirrhosis of the liver
169
Increased cell turnover associated with chronic inflammation and scarring can lead to ____
cellular mutations and increased risk for tumor and malignancy
170
autosomal chromosomal disorders
gain or loss of all or part an autosome
171
general phenotype of autosomal chromosomal disorders
```
low birth weight
short stature
failure to thrive
severe mental retardation
multiple organ systems affected
```
172
single gene disorders
Submicroscopic changes to 1 gene, ranging from a single base change to deletion of the whole gene
173
Pleiotropism
a single gene affects a number of phenotypic traits in the same organism
174
Variable expressivity
range of signs and symptoms that can occur in different people with the same genetic condition
175
Incomplete penetrance
If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance
176
advanced paternal age is associated with an increased risk of ____
autosomal dominant disorders
177
what kind of transmission is in the autosomal dominant family tree?
vertical
178
_% of offspring are affected in autosomal dominant disorders
50%
179
are more males or females affected in autosomal dominant disorders?
= #s
180
familial hypercholesterolemia
elevated levels of cholesterol that induce premature atherosclerosis and increased risk of early myocardial infarction due to a mutant LDL R gene
181
LDL receptor mutation class 1
non LDL R protein made
null allele
uncommon
182
LDL receptor mutation class 2
accumulation in the ER
| fairly common
183
LDL receptor mutation class 3
little or no binding of receptor to LDL
184
LDL receptor mutation class 4
poor internalization of LDL+ R
185
LDL receptor mutation class 5
tight LDL R binding
| no recycling
186
where do FH heterozygotes get xanthomas?
tendons
187
where do FH homozygotes get xanthomas?
cutaneous
188
diagnosis of familial hypercholesterolemia
```
Serum LDL > 200
Elevated triglycerides
Plasma cholesterol >300
mg/cc in adults
Xanthomas seen by physical exam
chest pain
obesity
family history
```
189
how do statins works?
suppress cholesterol synthesis and allow greater synthesis of LDL R
190
what kind of disease is Tay Sachs?
autosomal recessive
191
Tay Sachs pathology
No detectable hexosaminidase A
No degradation of GM2 ganglioside in the lysosome
Accumulation of GM2 ganglioside in brain cells
Neurologic changes and eventual death
192
what causes Tay Sachs?
Frameshift mutation in hexosaminidase A gene (15q)
193
what is tested to find out if someone is a Tay Sachs carrier?
levels of Hex A activity
| <50% activity indicates carrier
194
Sandhoff's
mutant in hexosaminidase B gene (chromosome 5)
| Clinically similar to Tay Sachs
195
Variant AB
mutation in HexA/Hax B activator protein (chromosome 5)
| Clinically similar to Tay Sachs
196
what kind of disease is cystic fibrosis?
autosomal recessive
197
what causes CF?
Mutant CFTR gene → Cl channel deficiency
198
diagnosis of CF
symptoms
sibling with CF
sweat test
199
symptoms of CF
```
Meconium ileus in infant
Recurrent respiratory infections
Greasy, foul smelling stools due to pancreatic insufficiency and lack of digestive enzymes
Malnutrition, stunted growth
Male infertility
```
200
how do CF sweat tests works?
Sweat absorbed onto filter paper is analyzed for Cl
| [Cl] >60mEq/L → positive
201
CF treatments
Antibiotics
Pancreatic enzyme replacement therapy
Lung inhalation therapies
Lung transplantation
202
what is the current genetic test for CF?
CF86
| tests for the 86 most common mutations
203
Founder effects
mutant allele appeared in a geographically isolated population and was enriched in subsequent generations
204
what kind of transmission are X linked dominant disorders?
vertical
205
are there more females or males affected with x linked dominant disorders?
females
206
what kind of disease is hypophosphatemic rickets
X linked dominant
207
what causes hypophosphatemic rickets?
Mutation in the PHEX gene on chromosome Xp
208
hypophosphatemic rickets symptoms
defective vitamin D metab causes deranged bone growth, skeletal abnormalities and dental problems
209
what characterizes hypophosphatemic rickets?
Failure to thrive
Short stature
Rickets
210
age of onset of hypophosphatemic rickets?
early infancy
| 15 months
211
what kind of disease is hemophilia A?
x linked recessive
212
are there more females or males affected with x linked recessive disorders?
males
213
what causes hemophilia A?
Factor VIIIc gene mutation (x chromosome)
214
severe hemophilia A
<1% normal Factor VIIIc levels
Onset of bleeding in newborn period
Bleeding may be spontaneous
215
moderate hemophilia A
```
1-5% normal Factor VIIIc levels
Onset during infancy
Excessive bruising with ambulation
Some arthrosis
Sometimes spontaneous but usually following mild to moderate trauma
```
216
mild hemophilia A
<6% normal Factor VIIIc
Onset during childhood
Bleeding is not spontaneous but follows moderate to severe trauma, dental work or surgery
217
what causes hemophilia B/Christmas disease?
Mutation in Factor IX gene decreases blood coagulation
218
what do serum studies of hemophilia detect?
Decreased factor VIIIc levels
Prolonged PTT time
Normal → PT, bleeding time, thrombin time, platelet count, Factor VIIvW
219
partial thromboplastin time
seconds for plasma to clot in presence of taolin, cephalin, calcium
prolonged in hemophilias
220
prothrombin time
seconds for plasma to clot in presence of thromboplastin and calcium
normal in hemophilias
221
Von Willebrand disease
Bleeding disorder that is not x-linked
| Mutations in the vWF gene later both platelet function and coagulation pathway
222
what kind of disease is Von Willebrand?
autosomal dominant and recessive
223
quantitative mutations in vWF
change in amount of vWF
224
qualitative mutations in vWF
normal amounts of vWF with abnormal function
225
clinical manifestations of vW disease
spontaneous bleeding from mucous membranes
excessive bleeding from wounds
menorrhagia
prolonged bleeding time but normal platelet count
226
how is vW disease diagnosed?
immunologic tests
| ristocetin aggregation test
227
ristocetin aggregation test
decreased aggregation of platelets in the presence of the antibiotic ristocetin
diagnoses vW disease
228
multifactorial genetic diseases
Caused by multiple factors such as:
Genetic, often multiple genes
Environment
Various genes and environmental interactions
229
threshold model for multifactorial traits
Curves indicate distribution of phenotypes
| Disease occurs in % of cases that are to the right of the threshold
230
what does the threshold represent in the threshold model for multifactorial traits?
measured trait becomes abnormal enough to result in the disease phenotype
231
Characteristics of multifactorial inheritance
- Disorder is familial but with no distinctive pattern of inheritance within a family
- Risk of expressing the disorder is related to the number of mutant genes inherited
- Risk to 1st degree relatives is higher than to 2nd degree relatives but both are higher than the risk in general population
- Recurrence risk is higher when more than 1 family member is affected and when the disease is more severe
232
what is the classic example of multifactorial disease?
diabetes
233
type 1 diabetes susceptibility locus is on ____
chromosome 6
234
type 1 diabetes is linked with the ____
insulin gene allele
235
mtDNA diabetes
a subtype of Type II diabetes, caused by mitochondrial DNA mutations (1% of all cases)
236
PPARγ polymorphism
people with Pro12 allele are more insulin resistant than those with the Ala 12 allele and 1.25x more at risk for diabetes (connection to fatty acid metabolism)
237
Calpain-10 gene polymorphism
increases risk 3-fold (affects -cell function and insulin action in muscle and fat)
238
Impaired glucose tolerance
blood glucose levels intermediate between normal and diabetes, following a glucose load predicts those in the general population with a higher risk of developing diabetes
239
what kind of disease is MODY?
autosomal dominant
240
what is the primary defect in MODY?
beta cell function
241
what causes MODY?
mutation in any of 5 transcription factors responsible for regulating the transcription of insulin and other cell genes or in the glycolytic enzyme glucokinase (one copy of any of these mutant genes will cause MODY)
242
MODY1 mutation
mutation in hepatocyte nuclear factor → HNF-α
243
MODY2 mutation
mutation in glucokinase gene
244
MODY3 mutation
mutation in HNF-1α
245
MODY4 mutation
mutation in insulin promoter factor (IPF-1)
246
MODY5 mutation
mutation in HNF-1β
247
MODY6 mutation
mutation in NeuroD/BETA2 gene
248
arteriosclerosis
hardening of the arteries
249
Monckeberg’s Medial Calcific Sclerosis
Medial calcification of muscular arteries
250
Arteriosclerosis
Thickening of walls of small arteries and arterioles → reduction of luminal diameter of the microvasculature
251
what does arteriosclerosis depend on?
age
252
what accelerates arteriosclerosis?
hypertension
| diabetes mellitus
253
2 froms of arteriosclerosis
hyaline
| hyperplastic
254
Hyaline arteriolosclerosis
Amorphous eosinophilic thickening of the wall of arterioles
255
what influences the development of hyaline arteriolosclerosis?
old age
hypertension
diabetes mellitus
256
what causes hyaline arteriolosclerosis?
leakage of plasma proteins into the blood vessel wall
257
what does hyaline arteriolosclerosis result in?
luminal compromise from small size of involved vessels
258
Hyperplastic arteriolosclerosis
hypertrophy/hyperplasia of medial smooth muscle in small arteries
259
appearance of hyperplastic arteriolosclerosis
"onion skin"
260
where is hyperplastic arteriolosclerosis typically seen?
severe hypertension
261
Atherosclerosis
Progressive accumulation of lipids, smooth muscle cells, macrophages and connective tissue, within the intima (atherosclerotic plaque) of large and medium size arteries that results in progressive luminal narrowing with impaired organ perfusion
262
atheroma
Intimal thickening and lipid accumulation leading to a plaque
263
what does an atheroma consist of?
fibrous cap overlying an accumulation of muscle and inflammatory cells with intracellular (foam cells) and extracellular lipid deposits with a necrotic core
264
3 constituents of atheromas
cellular
extracellular matrix
lipid
265
cellular components of atheromas
smooth muscle cells
macrophages
inflammatory cells
266
extracellular matrix cell components of atheromas
collagen
elastin
proteoglycan
267
lipid component of atheromas
cholesterol esters
268
what do atheromas cause as they enlarge?
vascular ingrowth
269
where is atherosclerosis mainly?
abdominal aorta
270
fatty streaks
non-raised accumulations of foam cells and extracellular lipid in the intima
271
where are fatty streaks found?
Universally present
| don't disturb blood flow
272
what is the favored hypothesis of atherosclerosis pathogenesis?
response to injury hypothesis
273
response to injury hypothesis
Proposes that atherosclerosis is a chronic inflammatory response to subtle vascular wall injuries occurring over time
274
what causes endothelial injury?
shear stress
hyperlipidemia
free radicals (from oxidation of LDL)
hyperhomocysteinemia
275
what do endothelial cell injuries lead to?
increased wall permeability
| changes in gene expression that enhance leukocyte adherence
276
which genes are upregulated to enhance leukocyte adherence?
ICAM-1
| VCAM-1
277
lipid insudation
Hyperlipidemia and increased endothelial permeability favor the accumulation of lipoproteins (LDL and VLDL) the arterial intima
278
how are foam cells formed?
Oxidation of LDL by macrophages and endothelial cells or by free radicals generated by the auto-oxidation of homocysteine creates a compound which is preferentially taken up by the scavenger receptor on macrophages
279
what does oxidized LDL promote and attract?
proinflammatory cytokine release
macrophages
monocytes
280
cellular infiltration
Inflammatory cells and T and B lymphocytes are recruited into developing plaques
281
what activates cellular infiltration?
cytokines such as IL-1 and TNF-alpha
| oxidized LDL
282
what induces smooth muscle cell proliferation?
PDGF
FGF
TGF-alpha
283
where does neovascularization of a plaque occur?
periphery
284
effects of hyperlipidemia
endothelial injury/dysfunction
lipid accumulation
oxidized LDL
285
effects of endothelial injury/dysfunction
mononuclear cell recruitment
lipid accumulation
oxidized LDL
fibrosis
286
effects of mononuclear cell recruitment
```
endothelial injury/dysfunction
lipid accumulation
oxidized LDL
myocyte recruitment
fibrosis
```
287
effects of lipid accumulation
endothelial injury/dysfunction
| oxidized LDL
288
effects of oxidized LDL
endothelial injury/dysfunction
mononuclear cell recruitment
myocyte recruitment
fibrosis
289
effects of myocyte recruitment
endothelial injury/dysfunction
mononuclear cell recruitment
fibrosis
290
what disease accounts for the most deaths in the western world?
atherosclerosis
291
major complications of atherosclerosis
ischemic heart disease
MI
stroke
gangrene of extremities
292
major modifiable risk factors of atherosclerosis
hyperlipidemia
hypertension
smoking
diabetes mellitus inflammation
293
major constitutional risk factors of atherosclerosis
age
male gender
family history
genetic abnormalities in LDL-R, ApoB, ApoE
294
minor risk factors of atherosclerosis
```
obesity
stress
factors affecting thrombosis
high CHO intake
homocysteinemia
```
295
complications of atherosclerosis
Acute occlusion → plaque rupture/thrombosis
Thrombosis → sudden arterial occlusion
Chronic narrowing of lumen → chronic ischemia
Aneurysm formation due to weakening of arterial media
Embolism
296
metabolic syndrome risk factors
Central obesity
Low serum HDL and increased triglycerides
Increased BP
Insulin resistance or glucose intolerance
Prothrombotic state
Proinflammatory state
297
what causes a prothrombic state?
increased fibrinogen or plasminogen activator inhibitor
298
what causes a proinflammatory state?
elevated C reactive protein
299
how is metabolic syndrome diagnosed?
must have 3 risk factors
300
aneurysm
arterial dilation with all 3 normal components in its wall
301
aneurysm shape
Saccular, cylindric, or fusiform
302
what is the critical diameter for rupture of an aneurysm?
6cm
303
where is the most common atherosclerotic aneurysm?
abdominal aorta
304
what does the wall of an atherosclerotic aortic aneurysm contain?
atheromatous material
fibroblasts
chronic inflammatory cells
305
complications of atherosclerotic aortic aneurysms
rupture
| blockage of tributary vessels
306
what is the risk of atherosclerotic aortic aneurysm proportional to?
diameter
307
ischemic heart disease
Constellation of disorders in which myocardial ischemia is the common pathophysiologic mechanism
308
what does ischemia usually result from?
obstruction of coronary artery blood flow by atherosclerosis
309
when does coronary atherosclerosis become symptomatic?
luminal cross-sectional area is reduced by more than 75%
310
where do lesions from IHD usually occur?
proximal portions of the LAD and LC arteries and the entire length of the RCA
311
4 clinical syndromes of IHD
Angina pectoris
Myocardial infarction
Chronic ischemic heart disease and congestive heart failure
Sudden cardiac death
312
pathogenesis of IHD
Fixed coronary obstruction
Acute plaque change
Coronary thrombus
vasoconstriction
313
what does acute coronary syndrome include?
Unstable angina
Acute MI which
Sudden Cardiac Death
314
angina pectoris
symptom complex characterized by recurrent attacks of crushing substernal chest pain
315
3 variants of angina pectoris
stable
unstable
prinzmetal (variant)
316
stable/typical angina
precipitated by exertion
relieved by rest or nitroglycerin
due do a fixed coronary lesion
317
significant coronary lesion
>50% reduction in diameter
Takes up 75% cross sectional area
Nutritional demand is met at rest
Symptoms develop with exertion
318
critical coronary lesion
>75% reduction in diameter
Takes up 90% cross sectional area
Chronic IHD
319
unstavle/crescendo angina
pain which occurs more frequently, with progressively less exertion or at rest
Associated with acute plaque change
320
in what kind of atheroma is rupture most likely?
Large core → >40% of atheroma volume with many macrophages
| Thin fibrous cap with little smooth muscle
321
prinzmetal/variant angina
uncommon, pain occurs at rest
| Due to coronary vasospasm either in a normal coronary artery or close to an atherosclerotic plaque
322
what treatment does prinzmetal/variant angina respond to?
vasodilator therapy- NO, Ca channel blockers
323
myocardial infarction
Ischemic necrosis (coagulation necrosis) in the heart that occurs when myocardial ischemia is prolonged for more than 20 or 40 minutes
324
what is the most common cause of ischemic necrosis
occlusive arterial thrombi
325
what causes myocardial ischemia (cell level)
anaerobic glycolysis
rise in intracellular Na and fall of K
high intracellular Ca
326
what determines extent of MI?
```
Location, severity, rate of occlusion
Size of vascular bed
Duration of ischemic episode
Metabolic demands
Collateral vessels
```
327
where are infarcts from LAD?
antero/apical LV
| anterior 2/3 septum
328
where are infarcts from LCX?
lateral LV
329
where are infarcts from RCA?
posterior/inferior LV
posterior RV
posterior 2/3 septum
330
evolution of an infarct
Necrosis → acute inflammation → chronic inflammation → organization → fibrosis
331
transmural infarct
Entire wall
| Plaque rupture and thrombosis
332
gross appearance of MI 0-4 hours
invisible
333
gross appearance of MI 4-24 hours
dark mottling
334
gross appearance of MI 1-3 days
increasingly pale center
335
gross appearance of MI 3-7 days
sharply outlined with a central pale, yellow region bordered by a hyperemic zone
336
gross appearance of MI 7-10 days
maximally yellow and necrotic with a depressed red margin
337
gross appearance of MI 10-14 days
margin becomes red-gray
338
gross appearance of MI 2-8 weeks
infarcted region progresses to a gray-white scar
339
when is MI scarring complete?
after 8 weeks
340
when does an MI appear to have wavy fiber change?
1-3 hours
341
when does an MI appear to have coagulation necrosis?
4-12 hours
342
when does an MI appear to have nuclear pyknosis?
5 hours
343
when does an MI appear to have karyolysis?
24-48 hours
344
when does an MI appear to have neutrophilic infiltration?
6-8 hours
| peaks at 48 hours
345
when does an MI appear to have macrophage infiltration?
4 days
346
when does an MI appear to have vessel proliferation?
3 days
347
when does an MI appear to have fibroblast proliferation?
4 days
348
when does an MI appear to have collagen deposition?
9 days
349
when does an MI appear to have granulation tissue peak?
2-4 weeks
350
what does tPA do?
promotes hemorrhage in the infarct
351
contraction band necrosis
Accelerated necrosis of irreversible injured myocytes
352
where does contraction band necrosis occur?
margins of infarcts between dead and viable zones
353
hypercontraction
Secondary massive influx of calcium from membrane damage
| Sarcomeres of Z lines produce eosinophilic bands visible by light microscopy
354
Sequelae
a condition that is the consequence of a previous disease or injury
355
what region is most prone to ischemic damage?
subendocardial
356
what is subendocardial infarction related to?
global reduction in coronary blood flow
357
sudden cardiac death
Unexpected death from cardiac causes (lethal arrhythmia) within 1 hour of the onset of symptoms
358
__% of sudden cardiac deaths have IHD
80-90
359
Chronic Ischemic Heart Disease
typically left ventricular hypertrophy with dilatation and focal white scars corresponding to prior acute infarcts are usually present with severe fixed coronary obstructions
360
Hypertensive heart disease
left ventricular hypertrophy in the absence of cardiovascular causes other than hypertension
361
cor pulmonale
Right ventricular failure with hypertrophy and dilatation
362
what is cor pulmonale usually secondary to?
pulmonary hypertension
363
heart failure
A state in which the heart is unable to maintain an output sufficient for metabolic requirements
364
forward heart failure
Decreased output
Decreased myocardial contractility and output
Systolic dysfunction
365
backward heart failure
Increased EDP
Decreased myocardial compliance
diastolic dysfunction, congestion of veins
366
edema
increased fluid in interstitial tissue spaces
367
anasarca
severe generalized edema with subcutaneous tissue swelling
368
hyperemia
active process secondary to dilation of arterioles → increase blood flow
369
Congestion
passive process where blood flows more slowly due to obstruction of the venous system
370
cyanosis
Congested areas are blue and purple due to unsaturated venous blood pooling in the vessels
371
acute liver congestion
Distention of central vein and sinusoids
| Pressure atrophy of centrilobular hepatocytes
372
chronic hepatic congestion
Nutmeg liver
centrilobular necrosis with hemorrhage and hemosiderin-laden macrophages
Fibrosis in severe long-standing cases
373
chronic pulmonary congestion
Alveolar septal fibrosis
| Numerous hemosiderin-laden macrophages within alveolar spaces
374
acute pulmonary congetion
Capillary engorgement
Septal edema
Intra-alveolar hemorrhage
375
hemorrhage
Blood outside of the blood vessel
376
hematoma
hemorrhage which is enclosed within a tissue
377
Petechiae
small 1-2 mm hemorrhages which are typically observed on the skin, mucosal membranes, or serosal surfaces such as the peritoneum or pericardium
378
who is likely to develop petechiae?
Patients with low platelet counts or dysfunctional platelets can develop these
379
what are petechiae associated with?
locally increased intravascular pressure
thrombocytopenia
defective platelet function
clotting factor deficiencies
380
pupura
slightly larger hematomas
| typically >3mm
381
Ecchymoses
large subcutaneous hematomas
1-2 cm
typically observed following traumatic injury
aka a bruise
382
what causes bruise color changes?
Enzymatic conversion into hemosiderin
383
hemorrhagic shock
Rapid loss of ~20% of the blood volume
384
what can chronic blood loss cause?
iron deficiency
| anemia
385
2 important functions of normal hemostasis
Maintains flow of blood in a fluid state under normal conditions
Cause a rapid and localized hemostatic plug vascular injury occurs
386
normal hemostasis temporal sequence
arteriolar vasoconstriction
primary hemostasis
secondary hemostasis
anti-thrombotic events
387
Arteriolar vasoconstriction in hemostasis
First event that takes place
| Within seconds due to activation of neurogenic mechanisms and production of local mediators
388
primary hemostasis
Formed within minutes by the deposition and activation of platelets
Occurs on extracellular matrix proteins which have been exposed at the site of injury
389
secondary hemostasis
Platelet plug needs to stabilized and this occurs through activation of coagulation cascade which eventually culminates in local fibrin deposition
390
antithrombotic events in hemostasis
Counter regulatory mechanism occur to keep the hemostasis localized to the site of injury by preventing uncontrolled growth and activation
391
antiplatelet effects of the vascular wall
secrete prostacyclin and NO which are inhibitors of platelet aggregation
392
anticoagulant effects of endothelial cells
membrane associated heparin-like molecules, thrombomodulin, and tissue factor pathway inhibitor
393
fibrinolytic effects of endothelial cells
produce tissue type plasminogen activator (tPA) which enhances breakdown of fibrin deposits
394
von Willebrand factors
Produced by endothelial cells and this serves as a cofactor for platelet binding to collagen
395
tissue factor
Secreted by endothelial cells when they have been stimulated by cytokines
Activates clotting cascade
396
what secretes plasminogen activator inhibitors
endothelial cells
397
3 reactions of platelets when exposed to extracellular matrix proteins
adhesion
secretion
aggregation
398
what is the bridge btwn platelet R and collagen in the ECM?
von willebrand factor
399
what do platelet release during the secretion phase?
calcium
| ADP
400
role of Ca in coagulation cascade
activates cascade
401
role of ADP in coagulation cascade
aggregates platelets
402
role of platelet aggregation
serves to expand the primary hemostatic plug
403
when is the coagulation cascade irreversible?
when the secondary plug is formed
404
coagulation cascade
Series of enzymatic steps in which each factor serves to convert inactive pro-enzymes into active enzymes
405
final product of the coagulation casde
formation of fibrin
406
how is clotting normally regulated?
restricting activation of the cascade to sites of exposed phospholipids (damaged vascular wall)
407
3 types of naturally occurring anticoagulants
antithrombins
proteins S and C
tissue factor pathway inhibitor
408
antithrombins
Block the activity of thrombin and other coagulation factors
409
what activates antithrombins
binding to the heparin-like molecules on endothelial cells or to heparin injected by doctors into patients
410
role of proteins S and C
Inactivate specific coagulation factors
411
Tissue factor pathway inhibitor role
Binds and inactivates specific coagulation factors
412
thrombin role
cleaves fibrinogen to produce fibrin
413
Plasminogen activator inhibitors role
decrease fibrinolysis
414
tissue factor role
activates the clotting cascade
415
Von Willebrand’s factor role
enhances platelet adhesion
416
plasmin
molecule that interferes with fibrin polymerization and breaks down fibrin into fibrin split products which can be measured in the plasma as D-dimer
417
plasminogen
inactivate circulating precursor of plasmin
418
when is tPA most effective?
when attached to fibrin
419
thrombus
formation of an intravascular blood clot in a location where it shouldn’t occur
420
virchow's triad
endothelial injury
abnormal blood flow
hypercoagulability
421
what is the most important determinant of whether a thrombus will form?
endothelial cell injury
422
what kind of blood flow predisposes thrombus formation?
turbulent
| slow
423
how is a hypercoagulable state created?
alteration of the complex coagulation cascade
424
primary hypercoaguble states
due to genetic alterations → mutations or deficiencies of elements of the pathways
425
Factor V Leiden Mutations
Results in factor Va that can’t be cleaved by protein C
426
Prothrombin mutation
Results in increased prothrombin transcription
427
secondary hypercoaguable states
acquired
428
High risk factors of secondary hypercoaguable states
```
Prolonged bed rest/immobilization
MI
Atrial fibrillation
Tissue damage
Cancer
Prosthetic cardiac valves
Disseminated intravascular coagulation
Heparin induced thrombocytopenia
Antiphospholipid antibody syndrome
```
429
low risk factors of secondary hypercoaguable states
```
Cardiomyopathy
Nephrotic syndrome
Hyperestrogenic states → pregnancy
Oral contraceptive use
Sickle cell anemia
Smoking
```
430
arterial thrombi common locations
Coronary arteries
Cerebral arteries
Femoral arteries
Superimposed on atherosclerotic plaque
431
where do arterial thrombi typically arise?
site of endothelial cell injury such as an atherosclerotic plaque
432
what direction do arterial thrombi form?
retrograde
433
lines of Zahn
light colored layers of platelets and fibrin alternating with darker areas of blood cells
434
where are lines of Zahn?
arterial thrombi
435
mural thrombi
large thrombi tightly adhered to the underlying blood vessel wall
436
where are venous thrombi formed?
areas of blood stasis
437
what direction do venous thrombi form?
same direction as blood flow
438
how are post mortem clots differentiated from venous thrombi?
composition:
Soft rubbery white portion → chicken fat
Dark portion → currant jelly
Lack of vascular wall adherence
439
clinical consequences of superficial thrombi
```
localized pain and swelling
varicose veins
eczema
ulcer
rarely embolize
```
440
Trousseau's syndrome
Migratory thrombophlebitis
| pancreatic cancer
441
4 states of a thrombus
propagation
embolization
dissolution
organization and recanalization
442
embolization
thrombus travels to other sites in the vasculature and causes acute occlusion
443
goal of anticoagulant therapy
prevents the thrombus from forming
444
goal of fibrinolytic therapy
attempts to dissolve an already formed thrombus
445
Organization and recanalization
Fibrosis of the thrombus can occur in the process of organization and formation of new vascular channels may recanalize the vessel in the area of the thrombus
446
Disseminated intravascular coagulation
Widespread formation of numerous fibrin thrombi throughout the micro-vasculature
447
causes of DIC
obstetric complications
advanced malignancy
systemic inflammation such as sepsis
448
Embolus
detached intravascular solid, liquid or gaseous mass carried by the blood to a site distant from its point of origin
449
what are the majority of emboli?
thrombi which have dissolved
450
what can large pulmonary emboli cause?
saddle embolus
| sudden death
451
what causes fat embolism?
Fractures of long bones or soft tissue trauma and burns → fat globules enter the bloodstream and embolize
452
what symptoms characterizes fat emoblism?
pulmonary insufficiency
neurologic symptoms
anemia
thrombocytopenia
453
how big does an air embolus need to be to occlude the vasculature?
>100ml
454
amniotic fluid embolus
Amniotic fluid or fetal tissue may enter the maternal circulation following a tear in the fetal membranes or rupture of the uterine veins
455
infarct
area of ischemic necrosis secondary to occlusion of the vasculature
456
what is ischemic necrosis secondary to?
loss of blood flow
457
what characterizes infarctions?
coagulative necrosis
458
coagulative necrosis
retains the normal appearance of the tissue but there is loss of nuclei and decreased cytoplasmic staining
459
where do red infarcts usually occur?
areas of overlapping vascular supplies
460
where do white/anemic infarcts usually occur?
end of an arteriole in a solid organ
461
infectious endocarditis
Embolization of bacterial valvular vegetation
462
Shock
Clinical state where there is systemic hypoperfusion
463
how to determine if someone is in shock
measure bp
464
cardiogenic shock
myocardial failure results in poor ability to maintain blood pressure
465
hypovolemic shock
loss of blood or other fluids also results in dangerously decreased blood pressure
466
septic shock
due to overwheling bacterial infections
467
macule
fat
468
papule
elevated <5mm
469
nodule
elevated >5mm
470
vesicle
fluid filled <5mm
471
bulla
fluid filled >5mm
472
acanthosis
diffuse epidermal hyperplasia
473
hyperkaeratosis
hyperplasia of stratum corneum
474
letinginous
linear melanocyte proliferation along the epidermal basal layer
475
spongiosis
intercellular edema of the epidermis
476
eczema appearance
Red, elevated lesions that are often oozing and crusty
| small <5mm
477
clinical subtypes of eczema
```
allergic contact
atopic
drug related
light
primary irritant
```
478
pathogenesis of eczema
After initial irritant, some of the patient’s inherent proteins get modified
Processed by langerhans cells in the epidermis and the self proteins are transported to the regional lymph nodes
Processing of antigens in the lymph nodes creates an immunologic memory
On re-exposure a cascade of events initiates the development of eczematous lesions
479
what mediated eczema
sensitized T cells
480
contact dermatitis
patterned erythema and scale stems from a nickel-induced contact dermatitis
481
microscopic appearance of contact dermatitis
fluid accumulation (spongiosis) between epidermal cells that can progress to small vesicles if intercellular connections are stretched until broken
482
psoriasis
Common chronic inflammatory dermatitis
483
pathogenesis of psoriasis
Sensitized populations of T cells move to the dermis
| Secrete cytokines and growth factors that induce keratinocyte hyperproliferation → lesions
484
typical psoriasis lesion
well demarcated pink/salmon colored plaque covered by loosely adherent silver white scale
485
impetigo
superficial skin infection
486
what usually causes impetigo
staphylococcus aureus
487
Verruca vulgaris
Lesion seen in children and adolescents
| Caused by HPV
488
how does verruca vulgaris work?
Interferes with cell cycle regulation → epithelial cell proliferations
489
how is verruca vulgaris trnsmitted?
direct contact
490
Pemphigus vulgaris
Most common blistering skin disorder
491
Pemphigus vulgaris lesions
superficial flaccid vesicles and bullae that rupture easily
| Leaves deep and extensive erosions covered with serum crust
492
what causes pemphigus vulgaris?
antibody-mediated (type II) hypersensitivity
493
Seborrheic keratosis
Common benign epidermal tumor
494
appearance of Seborrheic keratosis
dark brown coin like plaques
495
Seborrheic keratosis usually is found in which patients?
middle aged and older patients in the trunk
496
Actinic keratosis
Squamous cell carcinoma can be preceded by a series of dysplastic changes as a result of chronic exposure to sunlight
497
actinic keratosis lesion
Many lesions regress, but some become malignant
498
actinic keratosis microscopic appearance
lower portions of epidermis show cytologic atypia
499
Squamous cell carcinoma
Common tumor occuring on sun exposed areas of older patients
500
Squamous cell carcinoma appearance
red scaling plaques
501
Basal cell carcinoma involves dysregulation of ___
sonic hedgehog pathway
502
basal cell carcinoma presntation
Present as pearly papules
| With dilated blood vessels on surface
503
rodent ulcer
basal cell carcinoma ulcerates and invades adjacent skin, bone, other structures
504
Dysplastic nevi
nevi that demonstrate atypical features that can transform into melanoma
505
Malignant melanoma
deadly disease that often develops in sun exposed skin
506
malignant melanoma mutations
Germline mutation in CDKN2A gene
Somatic mutations of the proto-oncogene BRAF or NRAS
Loss of function of the tumor suppressor PTEN gene
507
2 patterns of growth of malignant melanomas
radial
| vertical
508
ABC's of melanoma
```
A → asymmetry
B → border
Irregular
C → color changes
D → diameter changes
E → evolution
```
509
osteoporosis
Acquired condition characterized by reduced bone mass → bone fragility and susceptibility to fractures
510
Postmenopausal osteoporosis
Trabecular bone loss is often severe → compression fractures and collapse of vertebral bodies
511
Senile osteoporosis
Cortical bone loss is prominent
| Predisposes to fractures in weight bearing bones
512
most common bone tumor
osteosarcoma
513
Osteoma
benign bone tumor that appears during teenage years
514
Osteoarthritis
Most common disorder affecting joints in older adults
| Degeneration of joint cartilage
515
pathogenesis of osteoarthritis
alteration in articular cartilage due to wear and tear and mechanical stress
516
Rheumatoid arthritis
Autoimmune disease involving complex interactions of genetic risk factors, environment, and the immune system
517
what causes the pathologic changes in RA?
cytokine mediated inflammation from CD4 T cells
518
rheumatoid factor
antibodies to citrullinated fibrinogen, type II collagen, α-enolase, and vimentin are the most important and may form immune complexes that deposit in the joints
519
what are Tenosynovial giant cell tumor associated with?
acquired translocation
520
lipomas
benign tumors of fat
521
Liposarcomas
malignant neoplasms with adipocyte differentiation
522
Fibromatosis
Tumor with an infiltrative pattern of growth
Prone to recur locally
Don’t metastasize
523
Fibrosarcoma
Malignant tumors of the fibroblasts
524
what is the pattern of growth of fibrosarcomas?
herringbone pattern of growth
525
Rhabdomyosarcoma
Malignant tumors of skeletal muscle
