Pathology 2 Flashcards
0
Q
What is the job of NK cells, how are they regulated, and what do they secrete?
A
Killers of virus infected and tumor cells.
Activating receptors: activated by viral and stress-induced proteins
Inhibiting receptors: engaged by normal levels of MHC I
Secrete: IFN-y and TNF
1
Q
What does innate immunity consist of?
A
Barrier
Phagocytes - neutrophils and macrophages
NK cells
Plasma proteins - compliment, CRP, mannose-binding lectin
2
Q
What occurs with Tcell activation?
A
Release of cytokines, proliferation, differentiation into effector or memory cells.
3
Q
What is the difference between TH1 and TH2 cells?
A
TH1: Release IL-2 and IFN-gamma. Tcell proliferation, macrophage activation, Ab production
TH2: Release IL-4, 5, 13. eosinophil activation and IgE synthesis
4
Q
What are 2 subclasses of T regulatory cells?
A
Treg: Express CD4, CD25, and FoxP3. Suppress Tcell activity, APCs. Suppress autoreactive Tcells
adaptive regulatory Tcells: Express CD4 and upregulate CD25 in the periphery (MALT). induced by inflammation
Release IL-10 and TGF-B
5
Q
CD8 cell function
A
Interact with MHC I (expressed on most cells). Activated by foreign peptide, self-restricted. Important in response to virus infection.
6
Q
What effect does CD 21 have on Bcell activation?
A
amplifies. Binds complement component (Cdg) that is attached to pathogen surface. Amplifies BCR signal and Bcell response
7
Q
What is the function of Dendritic cells? What is a follicular dendritic cell?
A
Dendritic cells: in epithelium and interstitium. major APC for CD4+ Tcells. Can migrate to lymph organs
Follicular dendritic cells: found in germinal centers of lymph follicles. Present to B cells -> activation
8
Q
What chromosome houses MHC / HLA genes?
A
Chromosome 6
9
Q
What genetec loci encode MHC I variable regions?
A
HLA A, B, C
10
Q
What genetic loci encode MHC II variable regions?
A
Subregions of HLA D:
HLA DP, DQ, DR
11
Q
What types of proteins are presented by MHC I and II?
A
MHC I: cytoplasmic antigens
MHC II: exogenous antigens
12
Q
Type I hypersensitivity
A
Anaphylactic type
IgE mediated, TH2 dependent
Antigen -> dendritic cell -> presentation to Tcell -> TH2 activation, secretion of IL-4 -> Bcell activation -> IgE plasma cell -> IgE attaches to mast cells (first exposure)
Second exposure: allergen cross-links IgE on mast cell -> degranulation
13
Q
What is released with degranulation of mast cells / basophils in the setting of allergic reaction?
A
- Primary response - preformed mediators in granules: biogenic amines (histamine, adenosine), chemotactic factor (eosinophil), enzymes, proteoglycans
- Secondary response - newly synthesized (later): PLP A2 activation -> leukotrienes (LTB4, C4, D4) and prostaglandins (PGD2), PAF
cytokine / chemokine secretion: Interleukins, TNFa, GM-CSF
14
Q
What histopathologic findings are associated with Type I hypersensitivity?
A
Vascular: vasodilation, increased permeability, edema
-histamine, PAF, LTC4 and D4
Bronchial sm. muscle contractoin: biogenic amines, LTC4 and D4, PAF, PGD2
Increased secretion - mucinous metaplasia: histamine, PGD2
Infiltration - eosinophil, chron. inflamm. cels: eosinophil chemotactic factor, LTB4, PAF, TNFa
15
Q
What is type II hypersensitivity?
A
Involves antibody binding to cell surfaces or tissue antigens.
May or may not involve complement
Results in cell destruction or cell/ tissue dysfunction
16
Q
Examples of Type II hypersensitivity, w/ and w/o compliment.
A
Compliment dependent:
Autoimmune rxn to blood cells
Transfusion rxns, hemolytic disease of the newborn
Autoimmune skin-bistering (pemphigous vulgaris)
Goodpasture (Ab to glomerular and pulmonary basement membrane)
Antibody-dependent cell-mediated cytotoxicity (ADCC):
Response to parasite / malignant cells
Antibody mediated tissue dysfunction: no cell death
Myasthenia gravis, Graves
17
Q
What are type III hypersensitivity reactions?
A
Immune complex mediated
Excess antigen -> immune complex formation and deposition in tissue -> complement activation -> acute inflammation / coagulation, tissue injury
Results in vasodilation, edema, necrosis
18
Q
What is an Arthus Reaction?
A
Local immune complex disease
tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin.
Immune complexes precipitate in vessel walls -> fibrinoid necrosis
19
Q
What are 3 phases of Type III hypersensitivity?
A
1) immune complex formation (exogenous or endogenous antigen)
2) immune complex depisition (local or systemic)
3) tissue injury (complement activation (not at native site), acute inflammation, coagulation)
20
Q
Examples of Type III hypersensitivity
A
Acute post-streptococcal glomerulonephritis
SLE
Polyarteritis Nodosa
Rheumatoid Arthritis
21
Q
What type of necrosis is associated with Type III hypersensitivity?
A
fibrinous
Due to compliment activation and MAC -> coagulation -> fibrin deposition
22
Q
What is the key pathologic finding in Type III hypersensitivity?
A
Acute necrotizing vasculitis of small to medium sized blood vessels
23
Q
What is Type IV hypersensitivity?
A
Cell mediated: delayed or cytotoxic
Delayed: TH1 mediated
Cytotoxic: CD8 mediated
24
Examples of Type IV hypersensitivity
Delayed: TB and TB skin test, contact dermatitis (poison ivy), fungal infections
Cytotoxic: viral infection, tumor immunity, acute graft rejection
25
IL-12
Produced by macrophages
| Results in differentiation and activation of TH1 cells
26
Describe the Direct and Indirect pathways of transplant rejection
Direct: recipient Tcells recognize MHC on donor APCs. (Acute rejection)
- -Paradoxical Mimicry
a) MHC-1 -> CD8+ Tcell proliferation and cytotoxic hypersensitivity. Results in apoptotic death of graft cells
b) MHC-II -> CD4+ Tcell proliferation (TH1) -> delayed type hypersensitivity. IL-2, TNF-a, and IFN-y ->Inflammatory response and tissue destruction by mobilized macrophages
Indirect: Usual mode of rejection (Chronic Rejection)
Host APCs present graft antigen on self-MHC II
CD4+ Tcell activation -> delayed type hypersensitivity and transplant rejection
27
What is rejection vasculitis?
Antibody mediated transplant rejection
a) hyperacute: preformed Ab
b) acute: induced Ab
28
What is hyperacute rejection?
Due to preformed antibody -> rejection vasculitis
w/in minutes - hours of transplant
immune complex formation and vascular deposition -> complement activation -> vasodilation, vascular permeability -> inflammatory infiltrate -> necrosis, hemorrhage, thrombosis -> infarction
29
How long after transplantation does acute rejection take place? What usually causes it?
days to weeks after transplant or later due to reduction in immunosuppression
30
What drugs are frequently used to prevent transplant rejection?
Cyclosporine: calcineurin inhibitor - decreases IL-2 expression
Tacrolimus: binds FKPB to inhibit calcineurin (less nephrotoxic)
Corticosteroids: anti-inflammatory and decreases lymphocytes, monoycytes, eosinophils and basophils
Azothioprine: inhibits denovo purine synth. converted to 6-MP
Anti-Tcell receptor Ab
31
GVH disease and tissues affected
Graft vs. Host disease: donor's CD4 and CD8 cells react against host tissue
Skin: maculopapular rash, desquamation
Mucosal surfaces: GI: NVD ; eyes and mouth: dryness and irritation
Liver: jaundice (bile duct injury)
Lymph organs: coumpound recipients immunodeficiency may -> autoimmune disease
32
What are 4 mechanisms of peripheral immunotolerance?
1. Anergy - recognition of self antigen w/o co-stimulatory signal -> negative signal -> eventual inactivation / inability to propogate stimulatory signal.
2. Suppression - regulatory Tcells suppress self-reactive Tcells
3. Deletion - repeated activation of self-recognizing Tcells -> expression of Fas and Fas ligand -> apoptosis
4. Antigen sequestration - antigens "hidden" in tissues not directly exposed to blood and lymph. Ex: brain, testes, eye
33
how can infection lead to autoimmunity?
1) infection -> increased expression of co-stimulatory molecules on APCs -> activation of self-recognizing Tcells
2) tissue damage 2ndary to infection -> release / alteration of self antigens and exposure of previously "hidden" antigen -> reactivity of self-specific lyphocytes.
34
What is the genetic link in SLE?
Disease is multifactorial
Increased frequency in family members of pts. w/ SLE, especially monozygotic twins.
-assoc. between certain HLA alleles and certain SLE antibodies (anti-dsDNA, anti-Smith Ag)
-inherited deficiencies in complement in minority of SLE patients - impaired immune complex clearance
35
What environmental factors are associated w/ SLE?
UV radiation - pyrimidine dimerization -> cell death -> exposure to nuclear Ag
Elevated sex hormones - estrogen - women more affected
Certain meds - hydralazine (HTN)
36
What are the major antibodies seen in SLE (3 groups)?
Anti Nuclear Ab: Type III hypersensitivity rxns
Anti-phospholipid: bind proteins assoc. w/ phospholipids
-in vivo: hypocoagulability (lupus anticoagulant)
-in vitro: hypercoagulability (secondary antiphospholipid antibody syndrome)
-anti B2-glycoprotein Ab binds cardiolipin -> false (+) syphilis
Anti-formed element: type II hypersensitivity (anemia, thrombocytopenia, leukopenia)
37
What are the 5 classes or lupus glomerular nephritis?
I: minimal mesangial: appears normal under LM, but EM reveal mesangial immune complex deposition
II: Mesangial lupus nephritis: visible increase in mesangial cell number and matrix volume
III: Focal proliferative glomerulonephritis: 1/2 of all glomeruli are affected. ***Most severe, most common***
same as III, but more widespread, maybe more necrosis/thrombosis
V: Membranous glomerulonephtiris: Thickening of glom. capillary walls. "wire loop" lesions (may be present in III and IV as well)
38
How can Lupus effect the heart?
1. pericarditis most common - fibrinous inflammation of serous membrane -> chronica inflamm, fibrosis
2. Libman Sacks endocarditis - vegetations present on any surface of any valve
3. Myocarditis
39
How does SLE effect joints?
Results in synovial inflammation w/o articular erosion
40
What pattern of immunoflorescent Anti-Nuclear-Antibody (ANA) testing is most specific for SLE?
Rim pattern - "rim" of flourescence around exposed nuclei is indicative of the presence of Anti-dsDNA Ab in patient's serum.
Other patterns are non-specific or suggest other diagnoses.
41
What are nucleolar and centromere patterns of ANA immunofluorescence suggestive of?
Nucleolar: systemic sclerosis
Centromere: limited systemic sclerosis (CREST)
42
What antibodies are most common in SLE?
Anti-dsDNA and Smith Ag
43
What is a Lupus Erythmatosus (LE) cell or hematoxylin body?
Neutrophil or macrophage that has phagocytosed the nuclei of injured cells.
Seen in SLE
44
What is chronic discoid lupus erythematosis?
Causes scarring skin plaques
| Usually only involves the skin
45
What is subacute cutaneous lupus erythematosis?
Mild form of SLE that typically manifests as a non-scarring photosensitive cutaneous rash. Mild systemic effects.
ANAs are present, especially anti-Ro (SS-A) Ab.
46
What medications can cause lupus like symptoms?
hydralazine, procainamide
Symptoms usually resolve with removal of med.
ANAs (esp. antihistone) may be present w/o symptoms
47
What is Sjorgen Syndrome?
Chronic autoimmune disorder primarily affecting lacrimal and salivary glands.
Mostly women 50-60 y/o
Primary - sicca syndrome
Secondary - associated w/ other disorder (usually RA)
48
What antibodies are most often seen in Sjorgen's?
Anti-ribonucleoproteins
| Anti-Ro (SS-A), Anti-La (SS-B)
49
What serious condition does Sjogren syndrome increase risk for?
B-cell lymphoma - high rate of replication -> increased chance for errors
50
Systemic sclerosis and variants. What causes?
chronic excessive fibrosis. Mostly women 40-50.
1) diffuse: rapidly progressing. start with all skin, progress to visceral organs
2) limited: slowly progressing. limited to skin of face and distal upper extremities - includes CREST
Caused by inappropriate activation of CD4+ Tcells -> secretion of cytokines, growth factors -> fibroblast activation -> excessive collagen production
51
What is CREST?
```
subset of limited systemic sclerosis
Calcinosis
Reynaud's
Esophogeal dysmotility
Sclerodactyly
Telangiectasia
```
52
What antibodies have been found in systemic sclerosis?
Anti-nuclear Ab:
1) anti-Scl 70: against DNA Topoisomerase I. specific for diffuse Systemic sclerosis
2) anti-centromere Ab. mostly CREST
53
What is mixed connective tissue disease?
Has overlapping features of SLE, polymyositis, RA, and systemic sclerosis.
Patients have high titers of anti-U1 RNP
Patients present with minimal renal disease.
Excellent response to corticosteroids
54
What is SCID?
Severe Combined Immunodeficiency Diseases
T and B cell dysfunction
Heterogenous group of diseases
55
What is the most common form of SCID? What causes it?
X-linked recessive SCID
50-60% of all cases
Abnormal IL receptor protein
56
What is the most common cause of autosomal recessive SCID? Others?
Adenosine Deaminase (ADA) deficiency ~50% of AR cases
abnormal metabolism of adenosine / deoxyadenosine -> accumulation of alt. metabolites -> decreased DNA synth and cell toxicity
-especially affects Tcells
-has been treated w/ gene therapy (retrovirus w/ normal ADA gene)
Also:
-MHC II deficiency (bare lymphocyte)
- abnormal receptor or signaling
-PNP deficiency (purine metabolism
57
What are the clinical findings in a patient w/ SCID?
Minimal lymph tissue
Small, non-descended thymus
Severe lymphopenia - decreased mature T and B cells
Deficient cell-mediated immunity: in vitro - no lymphoproliferative response to mitogen or allogeneic substance
in vivo - no delayed-type hypersensitivity or allograft rejection
Deficient humoral immunity: scant IgG, absent M and A
58
What infections are SCID patients susceptible to?
Pyogenic bacteria (PSA, Strep, Staph, H.influenzae
Fungi and protozoa
Viruses
Viable attenuated vaccines -> illness
59
How is SCID treated?
Early allogenic stem cell transplant
| Good chance for take, but high risk for GVH. Donor sample must be depleted of mature Tcells
60
What causes DiGeorge Syndrome?
Defective development of 3rd and 4th pharyngeal pouch.
| Usually due to 22q11deletion
61
What are clinical features of DiGeorge?
Hypoplastic or absent thymus
Low-normal lymphocyte count (Bcells are normal)
Paracortical areas of lymph nodes and PALS in spleen are depleted
Deficient cell-mediated immunity (no delayed hypersensitivity or graft rejection)
**Absent or rudimentary parathyroid glands** hypocalcemia -> tetany in first days of life
congenital defects of heart and great vessels, facial deformity
62
What infections are DiGeorge patients susceptible to?
Viral, Fungal, Mycobacterial
**most bacterial infections are Tcell independent, so immunity is not compromised**
63
How is DiGeorge treated?
Ca++ supplimentation for life
Cardiac surgery
Fetal thymus transplant - often unnecessary. Body has other Tcell maturation zones - often outgrow Tcell deficiency
64
What is the pathogenesis of Bruton's X-linked agammaglobulinemia?
Bruton's Tyrosine Kinase mutation -> inability for Bcells to mature
**X-linked recessive**
65
What infections are XLAG patients particular susceptible to?
```
pyogenic bacteria (Strep, Staph, PSA, Hib)
certain viruses (entero and hepatitis)
Giardia Lamblia (watery diarrhea)
```
66
How is XLAG treated?
periodic gamma-globulin injections
67
What is the most common primary immunodeficiency ?
Isolated IgA deficiency
68
What causes isolated IgA deficiency?
Block in differentiation of IgA Bcells
Other classes are usually normal
May be congenital (variable inh. pattern) or acquired (toxoplasmosis, virus, drugs)
69
What infections are selective IgA deficient patients susceptible to?
Respiratory and GI (sinopulmonary infections and diarrhea: loss of mucosal defense)
Patients may be asymptomatic
70
What is a concern with blood transfusion in selective IgA deficient patients?
~40% of pts. have anti-IgA Ab.
If given blood containing IgA, may have anaphylactic reaction
71
What is common variable immunodeficiency?
Heterogenous group of disorders diagnosed in teens and young adults
Hypogammaglobulinemia (usually all, sometimes only G)
Congenital (variable) or acquired
Bcell deficit - failure to mature to plasma cells
May be defective Tcell regulation: either deficient Thelper or excessive Treg
72
What are features of Common Variable Immunodeficiency?
Normal number of Bcells, but plasma cells lacking
Hyperplastic Bcell areas of lymph tissue in nodes, spleen, GI
Recurrent infections: pyogenic bacteria, intestinal - giardia and C.diff
Non-caseating granulomas (not sure why)
ex. duodenal nodular lymphoid hyperplasia
73
What is Wiscott Aldrich?
Diagnostic triad: 1) cellular and humoral immunodeficiency 2) eczema 3) thrombocytopenia
Recurrent infections, bleeding complications or malignancy -> death around 6-8 yrs
X-linked recessive : defective WASp protein - cytoskeletal actin rearrangement
susceptibility to encapsulated pyogenic bacteria
74
How is Wiscott Aldrich treated?
Stem cell transplant
75
What is the immunoglobin profile seen in Wiscott-Aldrich?
low IgM, normal IgG, elevaged IgA and E
76
What pathogens are Wiscott-Aldrich patients particularly susceptible to?
polysaccharide antigens
77
What is Ataxia-Telangiectasia?
Defect in Ataxia-Telangiectasia Mutant (ATM) gene -> chromosomal instability (compromised DNA repair)
Patients have progressive neurologic dysfunction, cerebellar ataxia, oculocutaneous telangiectasia, X-ray sensitivity, impaired organ development (elevated a-fetoprotein)
Variable immunodeficiency, malignancies
78
What is desmoplasia?
Dense collagenous stroma often induced by malignant neoplasm, especially carcinoma.
Responsible for "hardness" of tumor.
79
-oma suffix
refers to benign tumor
80
-carcinoma suffix
epithelial cell malignancy
81
-sarcoma malignancy
mesenchymal cell malignancy - bone, fat, cartilage, epithelial
82
adeno- prefix
glandular epithelium
83
leiomyo- prefix
smooth muscle
84
rhabdomyo- prefix
skeletal muscle
85
what is papillary growth pattern?
multiple finger like projections growing into a cystic space.
86
Polypoid tumor growth
neoplastic cell mass projecting above a mucosal surface.
87
Seminoma
Malignancy of testicular germ cell line
-oma exception
88
Teratoma
Germ cell neoplasm that shows differentiation toward more than one germ cell layer (ecto, meso, or endo - often all 3)
May be benign or malignant
89
Choristoma
Benign tumor - nodules of normal tissue in abnormal places
| "ectopic rest of normal tissue"
90
Hamartoma
Benign mass of normal, mature tissue - disorganized.
| Often found in lung - cartilage, bronchi, vessels
91
what is anaplasia?
Morphologic alterations seen with loss of differentiation.
Anaplasia is a hallmark of malignancy. Reversal of differentiation to a more primitive level.
Associated with pleomorphism, hyperchromatic nuclei, mitoses, loss of polarity, giant tumor cells
92
What atypical functions can be taken on by neoplastic cells?
Aberrant hormone synth: PTH by squamous cell carcinoma of lung; Gastrin by pancreatic islet cell tumor of pancreas
Fetal protein synth: a-fetoprotein by hepatocellular carcinoma; carcinoembryonic antigen produced by colon carcinoma
93
What is dysplasia?
```
Abnormal growth.
Potentially pre-malignant. Confined to epithelial surface. Does not penetrate basement membrane
-Failure of normal maturation
-Loss of polarity
-Cytologic features of anaplasia
```
Full thickness = carcinoma in situ
94
What tends to grow faster: poorly, moderately, or well differentiated malignancy?
Well differentiated tends to grow fastest
95
How do carcinoma and sarcoma spread?
Carcinoma: lymph -> venous -> lung -> arterial circ. and systemic metastasis
Sarcoma: hematogenous spread before lymph
96
What tissues are common sites of venous metastatic spread
Liver - hepatic portal system
Lungs
Vertebral bodies - paravertebral plexus (prostate carcinoma)
97
What are clinical features of metastasis by seeding of body cavities?
Fluid collection (ascites, plural effusion, hydrocephalus)- angiogenesis -> exudative edema
Accumulation of mucinous material: ex. mucus secreting ovarian carcinoma
98
What is malignancy "grade?"
Based on extent of differentiation
| Scale: I-IV (well - poorly differentiated)
99
What is meant by malignancy Stage?
Based on TNM system: Tumor size, lymph Node involvement, hematogenous Metastasis
Scale: 0-IV (T: 0-4, N: 0-3, M: 0-1)
**more valuable than stage for determining prognosis and treatment**
100
What underlies cachexia due to malignancy?
Cytokines produced by macrophages or tumor cells
| TNF, IL-1 -> decreased appetite + increased fat / muscle catabolism -> wasting
101
What tumor type is associated with Cushing's?
Bronchogenic small cell carcinoma
| Ectopic production of ACTH or ACTH-like product -> increased release of corticosteroids
102
What tumor type is associated with SIADH?
Syndrome of inappropriate ADH secretion
Bronchogenic small cell carcinoma
Ectopic ADH production
103
What tumor type is associated with hypercalcemia?
Bronchogenic squamous cell carcinoma
| Ectopic production of PTH
104
What is carcinoid syndrome and what tumor activity causes it?
Characterized by flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea, right sided CV fibrosis.
Caused by ectopic serotonin produced by tumors (ileal)
105
What is polycythemia and what tumor type is it associated with?
Increased RBC mass
Renal cell carcinoma
Ectopic production of erythropoietin
106
What is the name and cause of neuromyopathies seen in association with neoplasm?
Myasthenia Syndrome
| Cross-reactive antibodies
107
What is acanthosis nigricans?
Darkening of the skin, usually in fold areas - axilla, back of neck
Associated with neoplasm
108
What is hypertrophic osteoarthropathy and what tumor type is it associated with?
Periosteal new bone formation of distal long bones and accompanying arthritis and fingertip clubbing
Associated with bronchogenic carcinoma (usually non-small cell)
109
What is Trousseau's Syndrome and what tumor type is it associated with?
Migratory Thrombophlebitis associated with pancreatic adenocarcinoma.
Hypercoagulability -> clot formation, vasculitis and pain in the affected area.
110
What tumors are associated with nonbacterial thrombotic endocarditis?
Mucinic adenocarcinomas
Mucin reacts with platelet selectin -> platelet aggregation and deposition on valve leaflets.
vegetations consist of fibrin and platelets
111
3 hypercoagulation disorders associated with malignancies
```
Migratory Thrombophlebitis (Trousseau's)
Nonbacterial thrombotic endocarditis
Disseminated Intravascular Coagulation
```
Most assoc. w/ mucinous adenocarcinomas (pancreatic)
112
4 most common cancers in men and women
Men: 1) prostate 2) lung 3) colon 4) urinary tract
Women: 1) breast 2) lung 3) colon 4) uterus (endometrium)
*note that all are carcinomas
113
Overall cancer mortality rate and 3 leading cancer mortalities in men and women
Overall mortality 20-25%
Men: lung, prostate, colon
Women: lung, breast, colon
114
What is the key factor underlying the proliferative potential of cancer cells?
Increased telomerase activity
115
What is N/C ratio and what does it say about a cell?
Nucleus / Cytoplasm ratio
Higher ratio = less differentiated cell
Cancer cells tend to have high N/C ratio
116
What is the cause of follicular lymphoma?
Loss of apoptotic capability -> increased survival of lymphocytes
Tumor arises from germinal center Bcells
BCL-2 often hyperactivated
Common translocation: t(14;18)(q32;q21)
117
What kind of receptors are GFR?
Tyrosine Kinase
118
What cancers are HER-1 associated with?
Squamous Cell Carcinoma
Non Small Cell Lung Cancer (NSCLC)
Colon Cancer
119
What cancers are associated with HER-2?
```
Breast
Adenocarcinoma (ovary, lung, stomach, salivary
```
120
What are HER-1 and HER-1?
Both are Human Epidermal Growth Factor Receptors
HER-1 also ERBB1
HER-2 also ERBB2 and NEU
HER family consists of 1-4
121
What is the result of EGFR activation?
Dimerization, auto (cross) phosphorylation, activation of RAS
122
How can an increase in number affect cell proliferation?
More receptors available for ligand -> more likely response or amplified response
More recpetors -> constitutive activity (due to numbers/ proximity -> autophosphorylation)
123
What happens to HER-2 activity that leads to breast cancer?
Ligand independent activation
Gene amplification -> HER-2 overexpression
-> reduced survival
124
What is GIST and what mutation is it associated with?
Gastro Intestinal Stromal Tumor - most common stromal neoplasm
Mutated EGFR c-Kit (TK domain mutation -> constitutive activity) is almost always present.
125
What mutation is associated with lung adenocarcinoma and what group is most at risk?
TK domain mutation of EGFR
| Female, Oriental, Non-smokers
126
What mutation is seen in many glioblastomas?
Deletion of EC domain of EGFR
127
What drugs target EGFRs?
Anti EGFR Ab: Cetuximab
Anti HER-2 Ab: Trastuzumab (Herceptin)
Tyrosine Kinase Inhibitors - target catalytic site
-Iressa (Gefitinib), Erlotinib (Tarceva), Imatinib (Gleevac)
128
What molecule facilitates Ras return to inactive state?
Neurofibromin
129
What is the effect of KRAS mutation and what tumors are associated?
KRAS mutation -> constitutively active RAS signaling
*Tumors are not responsive to anti-EGFR therapy*
Tumors: Pancreas, Colon, Lung, Endometrium, Liver
130
What causes Neurofibromatosis 1?
Autosomal Dominant disorder -> inactivation of Neurofibromin 1
- > increased Ras activity
- proliferation of nerve sheath cells, cafe au lait spots, nodules in iris
- propensity for malignant transformation (neurofibrosarcoma)
131
What colon cancer mutations are associated with ineffectiveness of anti-EGFR therapy?
Ras mutation or downstream Ser/Thr kinase (BRaf) mutation
132
What is an oncogene? Dominant or recessive?
Has cancer promoting ability in heterozygous state
dominant
EGFR, HER-2, Ras
133
What are tumor suppressor genes? Dominant or Recessive?
Genes that inhibit cancer promoting activity (growth / proliferation)
Recessive - homozygous inactivation is needed for cancer formation
Neurofibromin, Rb
134
Steps that follow Ras activation
Ser-Thr kinase activation -> increase of transcription factors -> Cyclin D -> low levels of Rb phosphorylation -> Cyclin E -> hyperphosphorylation of Rb -> S phase
135
How are cyclins degraded?
Ubiquitylation
| ubiquitin added to phosphorylated cyclin, targed for proteosome destruction
136
What is responsible for negative control of cyclin / CDK complexes?
CDKI (CDK inhibitor) - induced by growth inhibitors (TGF-B, p53)
137
What is the result if CDKI inhibition?
malignancy w/ homozygous inactivation of CDKI gene
138
What cyclin facilitates passage through the G1 restriction point?
Cyclin D1
139
2 CDKIs, their activators and inhibitors
P21 - activated by TGF-B (weakly) and DNA damage via p53
- targets CDKs A,B,E
p15 - activated by TGF-B
- targets CDK D
140
What malignancies are increased levels of CDK 4 associated with?
CDK4: liposarcoma
141
What malignancies are increased levels of Cyclin E associated with?
Breast cancer
| - significantly higher mortality with higher levels of cyclin E
142
Decreased p27 is associated with a worse outcome in what kind of cancer?
breast
143
Rb inactivation is seen in what malignancies?
Small cell carcinoma of the lung
breast ca
glioblastoma
144
Inherited mutations of Rb cause what malignancy?
malignant retinal tumor
145
Leukocoria
Most common presentation of Retinoblastoma
| Eye appears whitish (vs. normal red-eye) under special lighting
146
2 forms of Retinoblastoma
Sporadic: usually unilateral. Age of diagnosis ~24 mos
Familial: Autosomal Dominant. Bilateral disease. Age of diagnosis ~8mos
147
Rosettes
Seen microscopically in Retinoblastoma
| Rings of undifferentiated cells
148
What is Loss of Heterogenosity?
In setting of inherited mutation - one gene affected, other is normal. Normal gene is shut down, usually by methylation.
EX: Rb - dominant pattern of inheritance, but molecularly is recessive - both genes must be deactivated for disease to manifest. Penetrance is near 100% due to high rate of LOH
149
What cancer associated gene type is frequently inactivated by methylation?
Tumor Supressor genes (Rb)
150
What risk is presented by treating familial Rb with radiation treatment?
500x increased risk of 2ndary tumor
151
How does low penetrance Rb differ from usual familial Rb?
Low penetrance mutations result in either decreased expression or expression of a partially functional product vs. deletion as seen in the usual familial mutation.
152
At what rate do mutations occur in normal cells?
1 per 10^-9 or 10^-10 cell divisions
153
What is the effect of inactivation of house keeping genes?
Mutations in other genes
154
What is the key ability of a carcinogen?
Ability to oxidize DNA
155
4 examples of chemical carcinogens and associated turmors.
```
Aromatic Hydrocarbons:lung, bladder, pancreas, sq. of uper aero digestive (cig. smoke)
Asbestos: Malignant Mesothelioma
Chemo drugs: Hematologic Malignancies
-aklylating agents (Busulfan, Melphalan)
Nitrosamines: Gastric
```
156
2 naturally occurring carcinogens and associated tumors
Aflatoxin B1: Hepatocellular carcinoma
| Bile acids: colon cancer
157
What malignancies are ionizing and UV radiations associated with?
Ionizing: hematologic, thyroid
UV: skin
158
3 outcomes of DNA adduct formation
Repair
Cell death
Permanent lesion
159
What is Benzopyrene?
Procarcinogen found in cigarette smoke. Must be metabolized to BPDE for carcinogenic effect.
160
What is BPDE?
benzo(a)pyreinediolepoxide.
| Carcinogenic product of benzopyrene. Inserts into DNA double helix, distorting and facilitating mutation
161
3 substances that ROS react with
Fatty acids
Proteins
DNA
162
Barret's Esophagus
normal squamous epithelium -> goblet cells due to reflux
| May precede dysplasia and invasive esophageal adenocarcinoma
163
Anti-inflamatories and cancer
May reduce risk.
NSAID: adenoma and colorectal in FAP and sporadic settings
-gastric ca. in pts w/ gastritis
Aspirin: post diagnosis of colorectal ca. lowers risk of recurrence, morbidity and mortality (esp. COX2 tumors)
164
What does glutathione reductase do?
Reduces ROS -> OH groups (electron donation)
165
What is GST loss associated with?
GST: glutathione S-transferase (reductase)
Lost in 90% of all prostate cancers
Variants w/ decreased activity -> increased risk
166
What is HNPCC and what mutation is it associated with?
Hereditary Non-Polyposis Colorectal Cancer
Associated with DNA mismatch repair enzyme abnormality
Autosomal Dominant, molecularly recessive
167
What is a loss of MLH-1 associated with?
Sporadic endometrial carcinoma
168
How does carcinogenic inactivation of DNA mismatch repair enzymes occur in HNPCC?
Via mutation of TGF-B receptor -> truncated, inactivated protein
169
Truncation of TGF-B recpetor has what effect?
Inactivation of DNA mismatch repair enzymes -> HNPCC
170
BRCA1 and BRCA 2
BRCA1: 65% LT risk of breast cancer (women only)
40-60% risk of 2nd occurrence
39% LT risk of ovarian
BRCA2: 45% LT risk of breast cancer (women)
6% LT risk of breast cancer (men)
11% LT risk of ovarian cancer
1:40 carrier rate in Ashkenazi Jews
171
What is the function of BRCA genes?
Sensing and responding to DNA damage, sim. to p53
172
Xeroderma Pigmentosum
Caused by defect in Nucleotide Excision Repair Ezymes (any one)
High risk of basal cell ca, squamous cell ca, melanoma
Inability to repair UV damage to DNA
173
NER enzyme
Nucleotide Excision Repair
repairs DNA damage caused by UV
Often involved in Xeroderma Pigmentosum
Polymorphic Variants - involved in esophogeal ca., breast ca., and acute lymphoid leukemia
174
2 things that induce p53
Hypoxia and Mutagens
175
Li Fraumeni Syndrome
Caused by p53 mutation
| Increased risk of many cancers
176
In addition to mutation, what can negatively affect the function of p53?
Interaction w/ other molecules such as HPV protein can -> functional inactivation
177
3 molecules that p53 acts through and what is the effect?
p21 -> G1 arrest
GADD45 -> DNA repair
Bax -> apoptosis
178
What is the most commonly altered tumor suppressor gene?
p53
179
What inheritance pattern does Li Fraumeni follow and what is the penetration?
Autosomal Dominant
Penetration:
Males: 75%
Females: 100%
180
Atypical hyperplasia
Form of dysplasia seen in uterus and breast
181
Compex hyperplasia
Pre-malignancy seen in uterus
182
Barret's esophagus
Metaplasia of esophagus due to reflex
Squamous -> columnar
May preceed dysplasia and invasive columnar adenocarcinoma
183
What is intraepithelial neoplasia?
Term for Dysplasia
184
Pleomorphism
In dysplasia: cells show variation in shape and size
185
How is dysplasia graded?
extent of epithelial occupation by dysplastic cells
4 teir model: mild, moderate, severe, cancer in situ
2 teir model: low and high grade
186
What change takes place in progression from dysplasia to cancer in squamous epithelium?
Breech of basement membrane (epithelium)
Other barriers in other tissues
breast: myoepithelial cells
colon: muscularis mucosae
187
What is Comedo type DCIS?
Type of Ductal Carcinoma in Situ seen in breast
Most likely form to become invasive carcinoma
Has necrotic pus-like center (eosinophilic)
Assoc. w/ HER-2 overexpression
188
What is the relative risk of developing invasive carcinoma for the following conditions:
Nonproliferative fibrocyscic disease
Atypical Ductal Hyperplasia
Ductal Carcinoma in Situ
Nonproliferative fibrocystic disease: RR = 1.0
Atypical Ductal Hyperplasia: RR = 4.0-5.0 (both breasts)
Ductal Carcinoma in Situ: RR = 8.0-10.0 (ipsilateral breast)
189
What is "field effect?"
Cancer often arises from a background of multifocal precursor lesions in an organ or system.
Implies need for systemic rather than local (surgical) treatment.
190
Tamoxifen and use in cancer prevention
Selective Estrogen Receptor Modifier (SERM)
Antagonist in Breast: inhibits cellular prolif
Agonist in Bone (antiresorptive) and Uterus (pro-proliferative)
Reduces risk of contralateral breast cancer in pre-menopausal women.
191
How long does it normally take normal tissue to progress to malignant?
Decades
| 20-40 years
192
What factors are the most important influences in progression of cervical premalignant lesions (cervical intraepithelial neoplasia- CIN)?
Early detection / eradication: PAP, vaccine
Viral serotype: high vs. low risk
p53 polymorphism
Immunocompetence
193
What strains of HPV are high risk?
16,18, 31, 45
194
What is the defining feature of 'high-risk' HPV groups?
Ability to tightly bind p53 and Rb
viral transforming proteins induce cel immortality:
E6: binds p53
E7: binds p53, p21, Rb
195
3 AIDS defining malignancies
Non-Hodgkin's Lymphoma
Kaposi's Sarcoma
Cervical Carcinoma
196
How does pathological stage differ from clinical stage?
Pathological based on complete tissue exam (TNM)
| Clinical stage based on imaging and clinical exam
197
At what cell populations are tumors visible via x-ray, palpable, and likely to cause death?
Visible on x-ray: 10^8 cells
Palpable: 10^9 cells
Likely to cause death: 10^12 cells
198
What is the utility of TNM staging?
Indicate tumor burden, extent of spread.
| Best indicator of prognosis
199
T staging in TNM model
T1-2: contained w/in organ boundaries
ex. kidney: w/in renal capsule
ex. colon: w/in serosa.(T1 penetrates M.mucosa, T2 penetrates M.propria, but not serosa)
T3: escapes boundaries.
ex. kidney: outside renal capsule, still w/in Gerota's fascia
ex. colon: wide infiltration of bowel wall
T4: invasion of neighboring tissue, skin (ex. pectoral muscle or skin ulceration
200
In T staging how does breast tumor size reflect stage?
In situ: small
T1: up to 2 cm
T2: 2.1-5 cm
T3: >5cm
201
N staging in breast and lung cancer
extent of lymph node involvement: more = greater mortality
breast: N0: no nodes involved
N1: 1-3 nodes
N2: 4+
Lung: N0: none
N1: ipsi peribronchial or hilar
N2: mediastinal or subcarinal
N3: contralateral involvement
202
TNM staging I-IV generalizations
I: small, superficial - limited to organ
II: large, deep or regional nodes positive
III: contiguous extension to adjacent structure and/or high Nstage
IV: Hematogenous metastasis
203
How are benign / malignant tumors differentiated in a lab?
Pattern recognition
| H&E stain
204
How are tumors classified morphologically?
How much does the tumor resemble a specific tissue type
-Type of differentiation
Light micro, special stains, immunohistochemistry, genetics are used
205
What 2 features are characteristic of squamous cell carcinoma?
Keratinization
| IC bridges
206
Key identifying histological characteristic of lymphoma
No stroma - patternless proliferation of monotonous neoplastic cells
207
Histological characteristic of sarcoma
Spindle shaped cells
208
Histological characteristic of carcinoma
Dense stromal response - heavy collagen deposition - hard tumor
209
How is genetic testing used in cancer treatment (carcinoma vs. sarcoma)
Sarcoma: diagnostic. Translocations are characteristic of certain sarcomas
Carcinoma: guide therapy. treatments targeted tumor specific mutations. ex: EGFR sensitivity to TKi
210
Tumor grades I-IV
I: Low grade: well differentiated
II: Intermediate grade: moderately differentiated
III: High grade: poorly differentiated
IV: Anaplastic: undifferentiated
211
What is quantitative tumor grade useful for?
stratifying prognosis in patients with the same stage cancers
212
How is squamous cell carcinoma graded?
How much keratinization is present
More keratin: well differentiated - lower grade
Less keratin: less differentiated - higher grade
213
What morphological criteria are used in quantitative tumor grading?
Organization (prostate and breast)
Pleomorphism (breast)
Number of mitoses (breast)
214
What is Gleason Grade?
Prostate cancer grading scale
Major and minor growth patterns are scored on 1-5 scale (doubled if only one pattern)
Good predicter of survival / recurrance for organ-confined disease
Predicts survival of prostate cancers
215
What are the criteria used in the Nottingham scale for breast cancer grade?
Tubule formation
Mitotic count
Nuclear pleomorphism
scale 0-9
216
3 consequences of an absent or defective enzyme
1. substrate accumulation
2. diversion of substrate into minor pathways -> alternate end product
3. decreased end product
217
Are most enzyme defects dominant or recessive traits?
Recessive
| Only need a small amt. of enzyme for normal function - single allele is usually sufficient.
218
How are lysosomal storage diseases classified and what are 3 classifications?
Classified by accumulated substrate
- mucopolysaccharide
- sphingolipid
- glycoprotein
219
What is the general synthesis pathway of lysosomal enzymes?
```
Synth in ER
Transport to Golgi
Post-translational modification (addition of Mannose-6-phosphate)
Segregation and release in vessicles
Fusion with lysosome
```
220
Are most lysosomal storage diseases dominant or recessive? Exceptions?
Recessive
Exceptions: Fabry and Hunter are X-linked
221
6 mucopolysaccharides
```
Dermatin Sulfate
Heparan Sulfate
Keratan Sulfate
Chondroitin Sulfate
Hyaluronic Acid
Heparin
```
222
Enzyme defect in muccopolycaccharidosis has what effect?
Tissue accumulation
Urine excretion
of relavent mucopolysaccharide
223
Clinical features of mucopolysaccharaidosis?
```
Chronic, progressive course
Multisystem involvement
Organomegaly
Dysostosis multiplex
Abnormal Facies
```
224
3 methods of diagnosing mucopolysaccharidosis
1. GAGs in urine: age dependent (normal up to 1 yr). small amt. of chondroitin, heparan and dermatin sulfate normal
2. GAGs in amniotic fluid
3. Enzyme assay
-prenatal: cultured cells from amniotic fluid (chorionic villi sampling less desireable - less enzyme activity)
-postnatal: measure enzyme activity in plasma or leukocyte
measure enzyme activity from skin fibroblast
225
Hurler Disease
MPS I
Most common mucopolysaccharidosis
a-L-iduronindase deficiency -> lysosomal accumulation of heparan and dermatan sulfate
Onset: infancy: 6-8 mos, death befor 10 yrs
226
Features of Hurler Disease (MPS I)
Respiratory disease
-restrictive: small ribcage, oar shaped ribs, hepatomegaly
Upper airway obstruction (due to storage)
-enlarged tongue, lymph tissue, airway epithelium, pharyngeal tissue
Joint and Skeletal Disease: joint pain, stiffness and contracture, short stature, deformity
Cardiovascular disease: valvular disease, CAD, CHF
Hepatosplenomegaly
Opthalmic Disease: corneal clouding, retinal disease, glaucoma, blindness
CNS disease: mtard, hydroceph, headache, SC compression, thickened leptomeninges
227
What is the usual cause of death in Hurler Syndrome?
Cardiovascular complication
228
What is Alder-Reilley anomaly?
Dense granulation seen in all leukocytes / PMNs in mucopolysaccharidosis - accumulation of mucopolysaccharides
229
Hunter Disease
MPS II
Deficiency of iduronate sulfatase
X-linked
phenotypically similar to Hurler, but milder. Appears in late infancy, early childhood. No corneal clouding. Slower progression
230
What are sphigolipids and examples
class of membrane lipids
- Sphingomyelin
- Glycosphingolipids
- Cerebrosides
- Sulfatides
- Globosides
- Gangliosides
231
Neimann-Pick Disease
Sphingomyelinase deficiency -> sphingomyelin accumulation
Type I A: severe infantile
-missense mutation -> near complete lack of enzyme
-first weeks of life: hypotonia, failure to thrive
-death by 3 yrs
-Severe neurodegeneration and visceral accumulation
-50% have macular cherry-red spot
Type I B: Chronic Visceral
-splenomegaly and eventually general visceral involvement
232
Neimann-Pick Type C
Most Common Neimann-Pick
Defect in NPC-1 (95%) and NPC-2
Cholesterol accumulation in spleen, liver, bone marrow, and neurons
233
Neimann Pick Type C presentation
Appears in early childhood
variable hepatosplenomegaly
*vertical supranuclear opthalmoplegia* (supranuclear palsy)
progressive ataxia and psychomotor regression
Hydrops fetalis and stillbirth
Fatal neonatal liver disease: giant cell hepatitis
Adult presentation: psychosis and dementia
234
What is Type D Neimann Pick?
Similar to type III, but less severe.
| Mostly limited to Nova Scotia population
235
What disease is associated with neonatal giant cell hepatitis?
Neimann-Pick type III
236
GM1 Gangliosidosis Type I and presentation
Deficiency in B-galactosidase A,B,and C -> ganglioside accumulation in neurons
mucopolysaccharides accumulate in other locations (pseudo-Hurler)
Infantile - 6 mos
Neurodegeneration, ganglioside accumulation in neurons, liver, spleen, renal tubular epithelium, cherry red spot on macula
skeletal deformities
237
GM1 Gangliosidosis Type II and presentation
Juvenile
Absence of A and B isotypes of B-galactosidase
later onset than type I: 1-2 years
slower progression of psychomotor retardation, less visceromegaly
Death 3-10 yrs
238
In a peripheral smear what is a lymphocyte with many small bubbles indcative of?
Gangliosidosis (not unique to this disorder, but may support diagnosis)
239
What are GM2 gangliosidoses?
Tay-Sachs (Hexoseaminidase a subunit)
Sandhoff (Hexoseaminidase B subunit)
GM2 activator deficiency (activator unit of
All result in accumulation of GM2 so similar phenotype
240
features of GM2 gangliosidoses
Accumulation of GM2 in many tiss, esp. CNS and retina
- loss of motor skills at 3-6 mos
- prominent macular cherry red spot
- progressive neurodegeneration w/ death by 2-4 years
- Ashkenazi jews: 1/30 carrier rate
241
Metachromatic Leukodystrophy
Deficiency of Arylsulfatase A -> accumulation of non-degradable cerebroside sulfate in:
- white matter of brain
- peripheral nerves
- liver and kidney
-> demyelination and gliosis (neurodegenerative)
242
3 forms of metachromatic leukodystrophy
Late Infantile: most common- regression of motor skills, mental deterioration, rigidity, convulsions, loss of white matter of CNS on imaging. death by 5 yrs
Juvenile: change in gait, cognitive skills, general regression. death by 6-8 yrs.
Adult onset: psychiatric / cognitive symptoms and later motor symptoms
243
How are sulfatidoses diagnosed?
Urine spot test (acidified cresyl violet) or quantitative analysis
Imaging: loss of white matter
Sural nerve biopsy: demyelination and metachromatic granules
Arylsulfatase A activity levels
**Genetic testing: 22q
244
Gaucher Disease Type I
Glucocerebrosidase deficiency -> glucocerebroside accumulation
Type1: Most common (99%). Chronic non-neuropathic. Children and adults, ashkenazi jews.
-Accumulation limited to mononuclear phagocytes throughout body. No brain involvement.
-Hepatosplenomegaly
-Bone: avascular necrosis (esp. hip), osteopenia w/ fx
Bone crisis: collections of gaucher cells interfere w/ vascularization causing severe pain
Erlenmeyer flask deformity: new bone formation w/ flat ends of femur.
245
Gaucher Disease Type II
Acute Neuropathic, no Ashkenazi assoc.
Complete lack of glucocerebrosidase
Progressive CNS involvement, death before 2 yrs.
Hepatosplenomegaly, cytopenia secondary to hypersplenism
246
Gaucher Type III
Subacute, intermediate, juvenile form
Reduced glucocerebrosidase
Progressive CNS involvement beginning in teens / twenties
Hepatomegaly, splenomegaly, cytopenias, bone involvement
247
Classic Galactosemia
Galactose-1-phosphate uridyltransferase deficiency
Galactose-1-phosphate accumulation -> minor pathways
Symptoms in infancy a few days after first milk consumption
- vomiting, failure to thrive, diarrhea, liver dysfunction
- renal failure, hepatomegaly, cirrhosis, cataracts, brain damage, increased frequency of E.coli septicemia
Newborn screening
Diet for life
248
Glycogen storage disease
Hepatomegaly, hypoglycemia, growth failure, excessive fat in face and buttocks, mild serum transaminase elevation
Hepatic form type I (Von Gierke)
G6P defect
Hepatomegaly, renomegaly, short stature, xanthomas, hypoglycemia
Distended hepatocytes, uniform distribution of glycogen.
Normal muscle cells
249
McArdle disease
Glycogen Storage type V: Myopathic Form
Deficiency of muscle phosphorylase
Muscle weakness, cramps after exercise (no increase lactate)
Prolonged excercise -> muscle necrosis, myoglobinuria, acute renal failure - potentially fatal
Glycogen accumulation in skeletal muscle
250
Pompe Disease
```
Type II glycogen storage disease
a-1,6-glucosidase (acid maltase) deficiency
Infantile presentation, but very rare
Muscle weakness - profound hypotonia
Heart involvement (progressive HF)
Hepatomegaly
Enlarged tongue
Death in 1-2 years
Glycogen deposits in myocardium, muscle, liver, etc.
```
251
5 glycogen storage disease
```
VPCAM
I. Von Gierke
II. Pompe
III. Cori
IV. Anderson
V. MacArdle
```
252
Anderson disease
Type IV glycogen storage disorder
Brancher enzyme disorder (amylo-1,4,6-transglucosidase)
Generalized
Hepatomegaly, failure to thrive in1st year
Progressive portal fibrosis -> cirrhosis -> death
Cardiomyopathy, muscle atrophy
253
What is deficient in phenylketonuria?
```
Phenylalanine hydroxylase (PAH) - 98%
BH4 synth / recycling abnormality - 2%
```
254
Clinical features of amino acid metabolism disorders
Mtard
fair hair, blue eyes
musty odor
eczema
255
What lab testing is done for PKU?
Urine: minor Phenylalanine metabolism pathway products
phenylpyruvic acid, phenyllactic acid, phenylacetic acid
Serum: phenylalanine levels
256
Describe CFTR function in airway and sweat duct
Airway: Cl- exported from cell to mucus secretion. Keeps Na+ in secretion, thereby keeping water in secretion. In CF, Na+ re-enters cell with water -> very thick secretion
Sweat duct: Cl- pumped into cell -> Na+ re-enters cell. Excessively salty sweat
257
What is the most common mutation seen in cystic fibrosis?
F508 deletion
loss of phenylalanine at position 508
Chromosome 7Q31.2
258
What organs are most affected by CF?
Lungs
Intestines
Pancreas
Vas Deferens
259
What defect is seen in Marfan's syndrome?
Fibrillin defect - microfibrils in ECM
| FBN1 gene on chromosome 15q21
260
What pattern of inheritance does Marfan follow?
Autosomal Dominant
261
What are the clinical features of Marfan?
CV: aortic dilation (ascending), aneurism, dissection (cystic medionecrosis)
Skeletal: tall, abnormal joint flexibility, scoliosis, arachnodactyly
Ocular: ectopia lentis, myopia
262
What gene is affected in Neurofibromatosis and where is it located?
NF-1
| 17q11.2
263
What inheritance pattern does NF-1 follow?
Autosomal Dominant
264
Diagnostic criteria for NF1
CANNOT FAIL 2 B 1ST
```
2 or more of:
CA: 6 cafe au lait spots
NN: 2 neurofibromas or 1 plexiform neurofibroma
OT: OpTic gliomas
FAI: Freckling - Axial or Inguinal
L2: 2 Lisch nodules
B: Bone abnormalities
1st: first degree relative w/ NF-1
```
265
What is the genetic defect seen in Neurofibromatosis II?
NF-2 gene defect - codes for protein merlin
| chromosome 22
266
What are the features of NF-2?
Bilateral acoustic neuroma
multiple meningiomas
ependymomas of spinal cord
267
Most common cause of Trisomy 21
Meiotic non-disjunction
| 95% are 47, XX, +21
268
What cancer are Trisomy 21 patients predisposed to?
Leukemia
269
What is Edward's Syndrome?
Trisomy 18
270
What is seen in Trisomy 18 (Edward's)?
```
Severe Mtard
Congenital heart defects
Renal problems
Apnea
Overlapping fingers / clenched fists
Rocker bottom feet
Micrognathia
```
271
What is trisomy 13?
Patau
272
What are the features of trisomy 13 (Patau)?
```
Midline defects: cleft lip / palate, proboscis, cyclopism, micropthalmia
Mtard
polydactyly
rocker bottom feet
congenital heart defects
renal defects (cysts)
umbilical hernia
```
273
How is 22q11 deletion diagnosed?
FISH
274
What is Kleinfelter Syndrome?
2 or > X + a Y chromosome
| one of most common causes of male hypogonadism
275
What is Turner Syndrome?
one X chromosome
276
What causes fragile X?
Triplet repeat of FMR 1 gene at Xq27.3
| Codes for FXMR
277
What are the two most common causes of mental retardation?
1. Trisomy 21
| 2. Fragile X
278
How many copies of FMR 1 does it take to cause disease?
10-55 = normal
55-200 = transmitting male / carrier female
>200 = full mutation
>230 -> gene methylation and suppression of the gene
279
What is Fragile X Related Tremor / Ataxia?
Occurs in males w/ premutation
late onset cerebellar ataxia and intention tremor.
MRI -> white matter lesions in middle cerebellar peduncles and/ or brain stem
280
What disorder is seen in women w/ FMR 1 premutation?
FMR-1 related premature ovarian failure
20% of women w/ premutation
menopause before 40 yrs
281
What is genomic imprinting and where does it occur?
Selective inactivation of a paternal or maternal gene due to functional difference between maternal / paternal genes.
Occurs in sperm / ovum -> passed to all somatic cells of offspring.
282
Cause of Prader-Willi syndrome
Maternal imprinting of genes at 15q11-13 results in functional allele being provided by father
Deletion of paternal allele -> P-W
Uniparental disomy: both alleles being from mother (thus inactivated) -> P-W
283
Phenotype of Prader-Willi
```
hypotonia at birth
Mtard
Short w/ small hands and feet
Hypogonadism
Obesity
Face: narrow bifrontal diameter, almond eyes, full cheeks
```
284
What is the cause of Angleman's syndrome?
Genes on 15q are imprinted (silenced), functional allele comes from mother.
If maternal allele is missing-> Angelman
285
What are the characteristics of Angelman's Syndrome?
Mtard
Large mouth, prominent chin
Ataxic gait, seizures
Inappropriate laughter (happy puppets)
286
What is the explanation for a phenotypically "normal" parent having 2+ children with an autosomal dominant defect?
Genetic mosaicism
Mutation occurs during early embryonic development and involves cells destined for gonads.
-> set of cells w/ defect that can be transmitted to offspring.
287
2 mitochondrial disorders
MERRF: myoclonal epilepsy and ragged red fiber disease
MELAS: mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes
288
What cancer is bcl-2 [t(14:18)] associated with?
Follicular lymphoma
289
Leading causes of death by age group 0 - 25 yrs.
<1yr: congenital abnormality, prematurity, low birth weight, SIDS
1-4 yrs: accident, congenital abnormality, malignancy
5-14 yrs: accident, malignancy, homicide
15-24 yrs: accident, homicide, suicide
290
What periods is the fetal period divided into?
Fetal previable: 9-20 weeks
Fetal viable: 20-38 weeks
Fetal full-term: 38-42 weeks
291
What is the approximate weight of a fetus at term?
3300 grams
Remember: quadruple numbers in last trimester
292
What are the percentile ranges for AGA, SGA, and LGA?
AGA: 10-90%
SGA: 90%
293
What is intrauterine growth retardation?
Child is SGA in weight, height and head circumference (<10%)
294
What is a very low birth weight infant?
birth weight <1500g
| Usually extreme prematurity. Accounts for 1/2 of all neonatal deaths
295
Type I growth retardation and causes
Symmetric growth retardaion
Fetal in origin, early onset, proportional body and organs
Causes:
chromosomal abnormality
congenital anomoly / malformation syndromes
early intrauterine infections (TORCH)
296
Type II growth retardation and causes
Asymmetric growth retardation
uteroplacental in origin, later onset, disproportional body / organs
*brain relatively spared*
Causes:
maternal: vascular insufficiency, nutrition, toxin/drug, infection
297
What are causes for pathologically large infants?
Maternal Diabetes mellitus
| Postmaturity syndrome
298
What is the most common cause of SGA infants?
Maternal : usually low placental blood flow
| -CV, renal, coagulopathy, infection, narcotics, ETOH, smoking
299
Abortion vs. stillbirth
Abortion: termination of pregnancy prior to fetal viability (~22wk)
-may be spontaneous or induced
Stillbirth: death prior to delivery of a potentially viable fetus (>22-23 wk)
- intrauterine: >24 hrs prior to delivery -> macerated stillborn
- intrapartum: fresh stillborn
300
When are most spontaneously aborted fetuses lost?
>60% are lost prior to 12 weeks
| Most are unrecognized pregnancies
301
Progression of maceration - determining time of death
12-24 hours: skin autolysis
color: 1-2 weeks - change from normal -> purple -> yellow/brown -> gray
fluid in body cavities, tissue changes (fibrin deposition, dessication, fibrosis and calcification): after 1 week
302
What trisomy is particularly associated with Intrauterine Growth Retardation (IUGR)?
Trisomy 16
Frequently -> spontaneous abortion
Only mosaic is viable
303
What is hydrops fetalis?
Generalized edema of the fetus
304
What are causes of hydrops fetalis?
Immune:
Rh incompatibility: 90% due to D antigen
ABO incompatibility: principal cause of immune hydrops, usually type A infants - significant disease uncommon
Non-immune:
congenital heart disease, chromosomal abn, twin-twin transfusion, infection, lung / urinary tract malformation, tumor, metabolic disorder
305
What are the possible outcomes of maternal immune reaction against fetal Rh?
ex Rh- mother previously sensitized to Rh+ infant:
Removal and destruction of Rh+ erythrocytes -> anemia: 1) extramedullary hematopoiesis 2) cardiac decompensation and hydrops
Hemoglobin degradation -> increased billirubin -> 1) jaundice 2) kernicterus
306
What is the pathogenesis of non-immune hydrops?
High venous / capillary pressure caused by high output state, vascular obstruction, cardiac failure
Decreased oncotic pressure caused by low albumin production (liver) increased albumin excretion (kidney)
Damaged capillary integrity due to sepsis, drugs, toxins, hypoxia
307
What is the incidence of intrapartum injury?
0.2-0.7/1000 births
308
What is Caput Succedaneum?
Blood or fluid in soft tissues of scalp - common intrapartum injury, but not clinically significant
309
What is cephalhematoma?
Hemorrhage into scalp. Common intrapartum injury - not clinically significant
310
What causes intracranial hemorrhage in an intrapartum setting?
Related to excess molding of the head and sudden sudden pressure changes
Most common important birth injury
311
What is occipital osteodiastasis?
Uncommon intrapartum injury - separation of skull sutures and overlap of bones
312
What is APGAR scoring used for?
Evaluating infants cardiopulmonary and neurologic function at sit intervals (1,5,10 mins) after birth.
Low score -> delivery room intervention, resuscitation, poorer outcomes
313
APGAR scoring
Heart Rate: 0: absent, 1: 100
Respiratory Effort: 0: absent, 1: slow / irreg., 2: good / crying
Muscle Tone: 0: limp, 1: some flexion, 2: active motion
Response to Nasal Cath: 0: non, 1: grimace, 2: cough / sneeze
Color: 0: blue/ pale, 1: pink body, blue extremities, 2: all pink
Score: good is 9 or 10
most are >7
low is 0-3
314
definition of premature birth
spontaneous or induced birth prior to 37 wks GA
315
Birth weight relationship to viability
<500g usually do not survive
500-1000g may survive w/ ICU care, but high risk for morbidity / mortality
1000-2500g usually survive, but elevated morbidity / mortality
316
When do type II pneumocytes begin developing?
appear at ~22 wks gestation, but inadequate surfactant before 36 wks.
317
What test of amniotic fluid is used to estimate fetal lung maturity?
L/S ratio: lecithin/sphingomyelin
>2:1 indicates ability to produce adequate surfactant
--low risk of neonatal respiratory distress syndrome
318
What is the leading cause of neonatal morbidity / mortality?
Neonatal respiratory distress syndrome
| progressive inability to oxygenate blood
319
What happens to alveoli in RDS?
Endothelial / epithelial damage to alvoli -> plasma infiltration and coagulatin -> inflammation, fibrin and necrotic cells -> increased diffusion gradient
320
What is bronchopulmonary dysplasia?
Caused by continued lung development and growth following injury and scarring.
clinical def: seen in neonates under 32 weeks requiring oxygen for >28 days with persistent respiratory difficulty
pathology: fibrous scarring w/ distortion and obliteration of air spaces. Squamous metaplasia, impaired growth.
321
What is the germinal matrix?
Embryonic structure persisting until ~30wks GA.
Highly cellular / vascular area of brain. Cells migrate out. Around ventricles.
Point of spontaneous hemorrhage.
322
Grading of germinal matrix hemorrhages
I: confined to germinal matrix
II: bleed into ventricle
III: blood fills and expands ventricle
IV: grade III + rupture back to brain parenchyma
323
What causes Neonatal Necrotizing Enterocolitis?
Occurs in premature infants recovering from RDS
Usually follows introduction to oral feeding.
Hypoperfusion to intestinal mucosa to provide O2 to vital organs
Ischemic injury -> migration of gut bacteria -> inflammation and necrosis -> perforation, peritonitis, sepsis, shock
324
What complications may occur in survivors of necrotizing enterocolitis?
Short gut syndrome, malabsorption, stricture
325
Legal definition of SIDS
Sudden death, <1 yr. of age, unexplained after complete post-mortem investigation.
326
Medical definition of SIDS
Sudden death, 3wk-8mo age, during sleep and not preceeded by symptoms or signs of lethal disease.
327
Peak age for occurrance of SIDS
2-4 mos.
| 90% of deaths before 6 mos.
328
What are typical findings at SIDS autopsy?
congested lungs
petechiae - pleura, thymus, epicardium
involution of thymus
evidence of URI, but insufficient to account for death
mild gliosis of brainstem and cerebellum
-cardio-respiratory control center
Alteration in serotonin activity in medulla
329
At what point does fetal immune gain function? At what point does it reach adult efficiency?
Cellular elements: monocytes / macrophages 4-5wk GA; T, B, and granulocytes 7-8wk GA
Function begins at about 12wk GA
Adult function at >1yr postnatal
330
4 routes of fetal infection
Transplacental - hematogenous, mom's bloodstream - viral (HIV, HepB, TORCH, listeria
Transcervical - cervical insufficiency
Fetal instrumentation - amniocentesis
Intrapartum
331
TORCH
Microbes pass from mother to fetus, transplacental.
-> hepatosplenomegaly, jaundice, thrombocytopenia, growth retardation
Toxoplasma, Other - syphilis, etc., Rubella, CMV, HSV2
332
What is erythema infectiosum?
Fifth disease - caused by parvovirus B19
-> abortion, stillbirth, hydrops, congenital anemia
Intracellular viral inclusions in infant bone marrow cells
333
What is chorioamnionitis and funisitis?
chorioamnionitis: inflammation of placental membranes
funisitis: inflammation of fetal umbilical cord
334
What is a pathogenic sequence?
Cascade of events secondary to single primary malformation or disruption
335
What is Potter sequence?
Oligohydraminos sequence
Due to oligohydraminos secondary to renal agenesis.
- > pulmonary hypoplasia
- > fetal compression -> altered facies, positioning defects of hands, feet, etc.; breech presentation
336
What are the most common causes of developmental abnormality / malformation ?
```
40-60% unknown
20-25% multifactorial
6-8% maternal disease (DM, endocrinopathy)
2-3% infection (TORCH etc)
10-15% karyotype
2-10% single gene mutation
```
337
4 most common chromosomal syndromes
1. Downs (21)
2. Kleinfelter's (XXY)
3. Turner (X0)
4. Patau (13)
338
What fetal malformations can CMV cause (CMV syndrome)?
Periventricular calcification
| Mtard, Microcephaly, Deafness, Hepatosplenomegaly
339
What is the most dangerous time of fetal development for CMV infection?
2nd trimester
340
What is Rubella syndrome?
Triad: cataracts, congenital heart disease, deafness
| Risk from before conception - 16wks, esp. first 8 wks
341
What period of development is most susceptible to terratogens?
Embryonic period: 3-9 weeks.
0-3 weeks: usually SAB
After 9 weeks: less susceptible. more susceptible to IUGR and injury to formed organs.
342
Cruetzfeldt-Jakob
```
Prion disease
Abnormal PrP (alpha changed to B sheet) -> rapidly deteriorating dementia (4-6 mos)
```
343
What are the underlying causes of Cretuzfeldt-Jakob?
1. spontaneous misfolding - most common -> sporadic cases
2. mutation of PRNP gene
3. direct infection
344
What is the the characteristic inflammatory response seen w/ viral infection?
Perivascular and interstitial lymphocytic infiltrate
345
What kind of virus is mumps virus?
paramyxovirus: enveloped, neg sense ssRNA
346
What is the incubation period for mumps?
2-3 weeks
347
What organs are affected by mumps?
Parotid glands : uni or bilateral - swelling (parotitis)
CNS: frequent, but usually no symptoms
orchitis: frequent - testicular atrophy, but no sterility
pancreatitis: uncommon. may -> hyperglycemia
oophoritis: uncommon
348
What kind of genome does herpesvirus have?
enveloped dsDNA
349
What is a Tzanck smear?
smear taken from the bottom of vessicle to test for herpesvirus (VZV)
Used for quick ID when clinically important. ex. woman in labor deciding to do C-section
350
Microscopic features of CMV
cytomegaly w/ large intranuclear basophilic inclusion surrounded by clear halo
smaller cytoplasmic inclusion
351
What are CMV symptoms? Who is at risk for life-threatening infection?
Usually asymptomatic in healthy adults. Otherwise mild, self-limiting mononucleosis type (fever, sore throat, lymphadenopathy, fatigue)
developing fetus and immunocompromized at risk for life threatening infection.
352
What is the most common TORCH pathogen?
CMV
353
How is fetal CMV acquired and what is the risk of infection?
Primary maternal infection can produce fetal infection
Risk of CNS abnormality
-periventricular calcification, sensorineural hearing loss, microcephaly, chorioretinitis
IUGR, hepatosplenomegaly, thrombocytopenia
354
Microscopic feature of Hep B infection?
Ground glass hepatocytes w/ high viral loads
| -pink cytoplasm pushed to periphery due to high viral load
355
What constitutes HBV chronic carrier state?
Evidence of HBsAg +/- continuing liver disease for >6mos
-more common w/ HBV acquired early in life (esp. infancy) and immunocompromise
356
What kind of virus is HPV?
non-enveloped, ds circular DNA
357
How does HPV replicate?
basal epithelial cells - genome only
| superficial mature keratinocytes - virus particle production
358
What are high-risk HPV strains?
16 and 18
359
What are koilocytes?
wrinkled raisinoid nuclei with perinuclear clearing
| Hallmark of HPV
360
What is Verruca Vulgaris?
Common wart
| caused by hpv
361
What is condyloma acuminatum?
Venereal wart (HPV)
362
What strains of HPV are most frequently associated with genital warts?
strains 6 and 11
| low risk for cancer
363
Pathogenesis of HPV related cancers
infection w/ high-risk HPV -> integration of Viral DNA into genome -> viral E6 and E7 proteins -> inactivation of p53 and Rb, upregulation of telomerase -> increased replication + other factors (smoking, immune status)-> neoplasia
364
Major virulence factors of S.pneumo?
polysaccharide capsule and pneumolysin
365
What bacterial strain produces a double zone of hemolysis on blood agar?
C.perfringens
366
What are the major virulence factors of C.perfringens?
exotoxin, lecithinases (a-toxin), collagenase, hemolysin (B-hemolysis), hyaluronidase
367
What diseases does C.perfringens cause?
Food poisoning - undercooked meat - self limited 6-24 hours
Gas gangrene - usually post-surgical. inocculation into poorly oxygenated tussue
368
What is the microscopic hallmark of syphilis?
dense mononuclear inflammatory infiltrate with many plasma cells -> obliterative endarteritis
369
What is a gumma and what is it associated with?
destructive granulomatous lesion seen w/ tertiary syphilis.
Multiple tissues affected - skin, liver, bone
370
Lifecycle phases of Chlamydia trachomatis
Elementary body - infective
| Reticulate body - replicative
371
Lymphogranuloma venereum
Chlamydia infectoin - more common in Africa and S. America. Starts as small painless genital ulcers and becomes painful inguinal lymphadenopathy
372
What is trachoma?
Occular infection caused by Chlamydia trachomatis
Scarring of conjunctiva and cornea -> blindness
Hygeine is a factor
Spread by flies that feed on human feces
373
Reiter syndrome
Reactive arthritis
may be seen in chlamydia infection - immune mediated
Polyarthritis, urethritis, conjunctivitis, often mucocutaneous lesions
374
Morphology of mycobacterium leprosae
gram pos, acid fast, rod-shaped, slow-growing bacillus
375
Hansen disease
Leprosy
| Affects skin, peripheral nerves, URT, eyes.
376
What drugs are used to treat leprosy?
Dapsone, rifampin, clofazimine
377
Tuberculoid leprosy
Paucibacillary leprosy
Mildest infection - good cellular immune response
Granulomas form, walling off bacteria
378
What causes most disfigurement and loss of extremities in leprosy?
secondary infections
| infection kills nerves, no pain w/ injury -> infection
379
What causes "valley fever"?
Coccioides immitis
380
Symptoms of coccidioides immitis infection
May be subclinical
Pulmonary symptoms, headache, arthralgia, skin manifestations
Similar to TB: cavitary progressive pulmonary and disseminated coccidioides
381
Fungus endemic to soil of Ohio, Missouri and Mississippi River valleys
Histoplasma capsulatum
| especially prevalent in areas inhabited by bats and birds
382
What is a "coin lesion" on x-ray indicative of?
Histoplasma capsulatum - calcified granuloma. previous asymptomatic infection
383
What is a narrow based budding yeast w/ a prominent polysaccharide capusle?
Cryptococcus neoformans
384
What is aspergilloma?
"fungus ball"
localized collection of aspergillus growing in a previously existing cavitation
hemoptysis is common
385
2 zygomycetes
Mucor and Rhizopus sp
386
Who is particularly vulnerable to zygomycete infection?
immunosuppressed individuals w/ diabetes w/ ketoacidosis or neutropenia.
387
rhinocerebral disease
Infection of Zygomycetes (Mucor, Rhizopus)
| Inhalation -> sinus infectoin -> orbital involvement -> necrotizing cellulitis, facial paralysis, CNS involvement
388
What is used to treat Giardia?
metronidazole
389
3 stages of Trypanosoma cruzi
1. epimastigote: replicative. found in insects
2. flagellate trypomastigote: infective
3. amastigote: replicative. found in mammals - intracellular. in cardiomyocytes and sm. muscle cells
390
What is Chagas disease?
caused by Trypanosoma cruzi (central and s. america, esp. brazil)
Results in myocarditis (trypanosomes w/in cardiomyocytes), GI involvement (megaespohagus and megacolon), nervous involvement (meningoencephalitis)
391
3 phases of Chagas disease
Caused by Trypanosoma cruzi
1. acute: often asymptomatic. localized swelling,
2. indeterminate phase: asymptomatic w/ few circulating parasites
3. chronic: occurs in 20-30% and occurs decades after infection
392
What is Lymphatic filariasis?
Elaphantiasis - caused by Wuchereria bancrofti (helminth) and to lesser extent Brugia sp.
Worms inhabit lymph nodes and vessels -> damage
Limb swelling and skin thickening
393
What is the physiological effect of nicotine?
Stimulates the release of catecholamines -> cardiovascular effect (increased BP, and pulse rate)
394
In what ways does tobacco smoking contribute to MI?
decreased O2 supply, increased O2 demand
395
What is the only known risk factor for pancreatic carcinoma
Smoking
396
3 paths of ETOH metabolism
Alcohol dehydrogenase in cytoplasm - main
Microsomal (CYP2E1) oxidation at high blood concentration
Catalase in peroxisomes
397
Where is acetaldehyde dehydrogenase found?
Mitochondria
398
3 ETOH related conditions that can -> upper GI bleed
peptic ulcer disease
gastritis
esophageal varices
399
Dry beri-beri is a result of what?
Thiamine deficiency
| seen in chronic alcohol abuse
400
2 reasons that lead toxicity is more common in children than adults
increased intestinal absorption
| less effective BBB
401
What effect does lead have in bone marrow and peripheral blood?
Inhibits d-aminolevulinic acid (ALA) dehydrogenase and ferrochelatase -> decreased iron incorporated in protoporphyrin -> increased level of protoporphyrin and decreased hemoglobin
Ringed sideroblasts in marrow
Microcytic hypochromic anemia w/ punctate basophilic stippling of erythrocytes
402
How does lead lead to reduced intelligence
Interference with Ca++ channels during nerve conduction
403
Saturine gout
Lead related gout
| tubular injury with hyaline intranuclear lead inclusions -> decreased uric acid excretion
404
Acute As poisoning
Metallic taste, garlic odor, hypersalivation, vomiting, abd pain, bloody diarrhea, hemolytic anemia, hypovolemic shock, seizures, delerium, coma, death
405
Chronic low-level As poisoning
Pigmentation abnormalities (raindrop, Mees lines of nails), hyperkeratosis (palms and soles), sensorimotor peripheral neuropathy, CV, pulmonary, hepatic, renal, bone marrow disorders.
Malignancies (skin, lung, kidney, urinary bladder)
406
Main pathologic effect of Cd poisoning
Kidney dysfunction
glomerular damage and CKD
407
Vinyl chloride
Used in production of PVC
| Hepatic angiosarcoma
408
2-Naphthylamine
Previously used in rubber and dye industries
| Urothelial carcinoma
409
4 risks associated w/ estrogen replacement
1. thromboembolic events
2. breast carcinoma w/ continuous use (also increased breast density -> false pos. mammograms)
3. CV atherosclerotic disease (>60 yoa)
4. gallbladder disease
410
What is the most common cause of acute liver failure?
Acetaminophen toxicity
Toxic threshold is lowered by ETOH (induction of CYP2E1)
-> increase in NAPQ
