Path Final

Front 1

What are the 6 fundamental cell changes in cancer?

Back 1

Self sufficient growth signals
 
Insensitive to growth inhibition
 
Evasion of apoptosis
 
Limitless reproductive potential
 
Sustained angiogenesis
 
Ability to invade and metastisize

Front 2

What is the most common oncogene abnormality in human tumors?

Back 2

RAS (signal transducing protein)

Front 3

What gene is the guardian of the genome?

Back 3

TP53

Front 4

What may be inactivated by DNA viruses?

Back 4

RB gene and cell cycle
TP53 gene

Front 5

What is the genetic hypothesis of cancer?

Back 5

Tumor mass results from clonal expansion of single progenitor cell that has genetic damage
--> tumors are monoclonal!

Front 6

What genes are target for damage?

Back 6

Growth promoting protooncogenes
 
Growth inhibiting cancer suppresors (anti-oncogenes)
 
Genes that regulate apoptosis

Front 7

What are mutant protooncogenes?

Back 7

Oncogenes:
Dominant b/c transform despite of presence of one normal allele

Front 8

What must happen for anti-oncogenes to mutate?

Back 8

Both allels must be damaged for transform-->recessive oncogenes

Front 9

What is another type of gene that is important in carcinogenesis?

Back 9

DNA repair genes (indirectly affect survival)

Front 10

How does a tumor progress?

Back 10

At the molecular level!
Accumulate genetic lesions, defects in DNA repair

Front 11

What do oncogenes do?

Back 11

Promote autonomous cell growth

Produce oncoproteins without need of signal

Front 12

How do cancers acquire self-sufficiency from growth signals?

Back 12

By changing the signal transduction cascade or cell cycle regulation

Front 13

Is a growth factor receptor more likely to be mutated or over expressed?

Back 13

Over expressed

ERBB1 receptor-->SCC
 
HER2 (ERBB2)-->breast cancer/adenocarcinoma

Front 14

What is the main function of signal transducing proteins?

Back 14

To couple growth receptors to their nuclear targets

Front 15

Most soluble growth factors work by what action?

Back 15

Paracrine.
(made by one cell, act on neighboring cell to stimulate proliferation)

Front 16

Part of cancer cell acquiring growth self-sufficiency is their ability to synthesize growth factors, what are 2 examples?

Back 16

PDGF
TGF-a

Front 17

What is an autocrine loop?

Back 17

Products of other oncogenes work on growth factor genes and cause over expression!
(Growth factor gene is not altered) –fairly common in many cancers

Front 18

What is overexpressed in 80% of lung SCC?

Back 18

ERBB1
(an Epidermal Growth Factor Receptor)

Front 19

What is amplified in 25-30% of breast, lung, ovary, and SALIVARY GLAND cancers?

Back 19

HER2 (ERBB2)

Front 20

What is a pre-neoplastic peripheral adenoma called, and what does it progress to?

Back 20

atypical adenomatous hyperplasias (AAH)
progress to pre-invasive Bronchioalveolar carcinoma (BAC)

Front 21

What indicates a poor prognosis in breast cancer?

Back 21

High levels of HER2 protein
BUT, maybe useful in txàblock w/antibodies?

Front 22

What are many signal transducing proteins associated with?

Back 22

The inner leaflet of the plasma membrane.

Front 23

What are the 2 types of signal transducing proteins?

Back 23

Those associated with the plasma membrane (RAS)

And, Non-membrane receptor-associated tyrosine kinase (ABL)

Front 24

What is the most common oncogene abnormality in human tumors?

Back 24

Mutated RAS gene
(30% of tumors)
(even higher in colon and pancreatic cancer)

Front 25

What do RAS proteins bind to?

Back 25

Guanosine nucleotides

Front 26

When is normal RAS activated?

Back 26

When the cell is stimulated by GFs and RAS exchanges GDP for GTP

Front 27

So what are inactivated and activated RAS bound to?

Back 27

Inactive RAS-GDP

Active RAS-GTP

Front 28

What is a downstream cascade that RAS activates?

Back 28

RAF-MAP kinase mitogenic cascade
(cues proliferation)

Front 29

What inactivates the RAS protein?

Back 29

GTPase

Front 30

What are the molecular brakes that regulate RAS by amplifying GTPase?

Back 30

GTPase activating proteins (GAPs)

Front 31

What can be used to inhibit RAS action?

Back 31

Drugs that inhibit farnesylation (inhibits anchoring to membrane which is essential to RAS)

Front 32

What and where are common RAS gene mutations?

Back 32

Point mutations, codons 12, 13, 61

Front 33

What do these gene mutations interfere with?

Back 33

GTP-hydrolysis
(RAS remains activated…)

Front 34

What is a common signal transducing protein mutation in chronic myeloid leukemia and certain acute leukemias?

Back 34

ABL gene mutation

Front 35

Where does normal ABL protein localize?

Back 35

Nucleus

Front 36

Where does BCR-ABL localize?

Back 36

It is retained in cytoplasm!

Front 37

What are the 2 ways that a BCR-ABL fusion gene cell are dysregulated?

Back 37

Over tyrosine kinase activity --> growth autonomy
 
Impaired apoptosis

Front 38

What is the gene most commonly involved in nuclear transcription factor mutations in human tumors?

Back 38

MYC gene
(MYC protein induced when cell signaled to divide)

Front 39

What regulates G1-->S?

Back 39

Cyckin D/CDK4, D/CDK6, E/CDK2
 
by phosphorylation of RB protein (pRB)

Front 40

What is active in the S phase?

Back 40

Cyclin A/CDK2

Cyclin A/CDK1

Front 41

What is essential for G2--> M?

Back 41

Cyclin B/CDK1

Front 42

What is the ultimate outcome for all growth-promoting stimuli?

Back 42

Quiescent cells enter the cell cycle

Front 43

What are CDKs?

Back 43

CDKs are activated when they bind cyclins
--> phosphorylate crucial target proteins expressed thru cell cycle
 
**CDKs are the orchestrators of the phases of the cell cycle

Front 44

What is the function of cyclins?

Back 44

Activate CDKs (by binding)
à After bindingàcyclin levels decline rapidly

Front 45

What is the transition from G1àS?

Back 45

Extremely important check point!!
 
Growth promotion signals
àD cyclins INC
à CDK 4 and CDK6 activated

Front 46

What protein guards the G1-->S check point?

Back 46

pRB

(phosphorylation allows G1-->S)

Front 47

What will mutations of cyclins and CDKs cause?

Back 47

Proliferation
(cyclin D and CDK4 are common mishaps)

Front 48

When are Cyclin D genes overexpressed?

Back 48

Breast, esophagus, liver,
some lymphomas

Front 49

When does amplification of CDK4 genes occur?

Back 49

Melanomas
Sarcomas
Glioblastomas

Front 50

What was the 1st prototypic suppressor gene to be discovered?

Back 50

Retinoblastoma gene!
 
13q14

Front 51

In sporadic cases of retinoblastoma, what has to occur?

Back 51

2 somatic mutations
(one on each RB locus)

Front 52

In familial cases of retinoblastoma, what has to occur?

Back 52

1 mutated gene is inherited

1 spontaneous somatic mutation

Front 53

What is the inheritance pattern for familial retinoblastoma?

Back 53

Autosomal dominant

(only req 1 mutation)

Front 54

T/F Both the familial and the sporadic pathways of a retinoblastoma have the same end point.

Back 54

True!

(both RB loci are mutated)

Front 55

Loss of RB gene was 1st discovered in retinoblastomas, but is now known in what other cancers?

Back 55

Breast
 
Small cell cancer of lung
 
Bladder

Front 56

What are patients with retinoblastomas at increased risk for?

Back 56

Osteosarcoma

Some soft tissue sarcomas

Front 57

Tumor suppressor genes encode components of growth-inhibition, what are the 2 complimentary anti-growth mechanism?

Back 57

1) cause dividing cells to enter G0
 
2) cause cell to enter post mitotic differentiated pool and lose replicative potential

Front 58

Where do antigrowth signals exert their effects?

Back 58

G1--> S check point!!

(controlled by RB protein)

Front 59

What is the RB gene product?

Back 59

DNA binding protein
expressed in every cell!
“molecular brake”

Front 60

What is the active form of pRB?

Back 60

Active:
HYPOphosphorylated state

àRB binds E2F (TF) àbind DNA
àinhibits transcription
àstops cells in G1

Front 61

What is the inactive form of pRB?

Back 61

Inactve:
HYPERphosphorylated state

àstim by GF
àRB is INACTIVATED by phosph
à cell goes from G1 to S

Front 62

What phosphorylates pRB?

Back 62

Cycling E/CDK2

Front 63

What is an extremely common target of deletion or mutational inactivation in human tumors related to CDKIs?

Back 63

CDKN2A gene
(aka Inhibitor of kinase 4--INK4A)

Front 64

T/F—Virtually all cancer cells show dysregulation of G1àS due to 1 of 4 mutations.

Back 64

True.
RB*
CDK4*
Cyclin D*
CDKN2A (INK4a; p16)*

Front 65

What is seen in 50% of esophageal cancers?

Back 65

Somatically acquires deletions or inactivations of INK4a, p16

Front 66

In cells that have CDK4, cyclin D, or INK4a, p16 mutations…
What is significant about RB function?

Back 66

Even if it’s not mutated,
It is dysfunctional!

Front 67

What viruses bind to the RB protein, thereby inactivating?

Back 67

SV40 and polyomavirus large T antigens
 
Adenoviruses EIA protein
 
HPV E7 protein

Front 68

What is the best known molecule that transmits antiproliferative signals?

Back 68

TGF-B
POTENT INHIBITION OF PROLIFERATION!!
Present in most normal cells
Regulates cell processes by binding 3 receptor types
(I, II, III)

Front 69

What is TGF-B’s function?

Back 69

arrests cells in G1 by:
Stimulating CDKI p15
Inhibiting transcription of CDK2, CDK4, cyclins A and E

à result in DEC phosphorylation of RB and cell cycle arrest

Front 70

What is commonly affected by mutations in the TGF-B signaling pathway?

Back 70

TYPE II TGF-B receptor

SMAD protein molecs

(serve to transduce antiproliferative signals from receptor to nucleus)

Front 71

At least one component of TGF-B path is mutated in what cancers?

Back 71

100% of pancreatic cancers!!! *
(commonly SMAD4)

83% of colon cancers

Front 72

Which gene is one of the most commonly mutated genes in cancer, but is not easily classified?

Back 72

TP53

Front 73

What does TP53 do?

Back 73

Anti-proliferative effects

REGULATES APOPTOSIS!
 
Central monitor of stress, directs cell towards appropriate response --> cell cycle arrest or apoptosis

Front 74

What stresses can activate TP53?

Back 74

Anoxia
Inappropriate oncogene express (MYC)
Damage to DNA integrity

Front 75

What is significant about TP53’s halflife?

Back 75

Normal TP53 has short half life…20 min
--> due to assoc w/ MDM2
(protein targeted for destruction)
 
BUT, when cell is stressed
àTP53 undergoes post transcriptional modification
à released from MDM2
 à INC half life!!!

Front 76

Once TP53 is activated, it acts as a transcription factor on what 2 types of genes?

Back 76

Genes that cause cell arrest
 
Genes that cause apoptosis

Front 77

What is considered to be the primordial response to DNA damage?

Back 77

TP53 mediated cell cycle arrest
(occurs late in G1)

Caused by TP53-dependent transcription of CDKI CDKN1A p21

Front 78

T/F—TP53 plays no role in activation of DNA repair.

Back 78

False!
(does induce some DNA repair genes)

Front 79

What happens if the DNA cannot be repaired?

Back 79

TP53 signals for apoptosis
(ex—induce BAX gene)

Front 80

What are the 3 leading causes of cancer death?

Back 80

Lung, colon, breast carcinomas

(all have homozygous loss of TP53)

Front 81

What percent of all cancers have TP53 defect?

Back 81

70%

Front 82

What can subvert both the RB gene and the TP53 gene?

Back 82

DNA viruses
(HPV, HBV, EBV)

Front 83

What are some protooncogene products?

Back 83

PDGF, FGF (growth factors)
EGFR
(growth factor receptors)
RAS (signal transducer)
MYC (transcription factor)
Cyclin D, DCK4
(cell cycle regulators)
B-catenin (signal transducer inhibitors)

Front 84

What protein is involved in regulating apoptosis?

Back 84

BCL2 (apoptosis inhib)

Front 85

What are some DNA repair genes?

Back 85

BRCA1
BRCA2
HMSH2

Front 86

What are some cancer suppressor gene?

Back 86

TP53 (cell cycle and apop reg)
CDKI p16 (cell cycle reg)
RB (cell cycle inhib)
APC, NF-1
(signal transducer inhibitor)
Cadherins (adhesion molecule)
TGF-B (GF inhibitor receptors)

Front 87

What role does BCL2 play in cancer cells?

Back 87

Protects tumor cells from apoptosis

Front 88

What characteristic translocation is found in 85% of follicular B-cell lymphomas and Burkitt lymphomas?

Back 88

14 and 18

Causes OVER express of BCL2
(prevent apoptosis)

Front 89

What do BCL2 overexpressing lymphomas arise from?

Back 89

Reduced cell death! à avoid apoptosis
(as opposed to inc proliferation)

Front 90

What is an important pro-apoptotic gene?

Back 90

TP53

Front 91

How do some MALT lymphomas avoid apoptosis?

Back 91

Inactivation of caspases

Front 92

How many times can a normal human cell replicate?

Back 92

60-70 times
(ascribed to shortening of telomeres at ends of chromosomes at every replication)

Front 93

How do tumor cells avoid senescence?

Back 93

By activating Telomerase
àmaintain normal telomere length

Front 94

What cancers involve telomere maintenance?

Back 94

In virtually all types of cancer.

In 85-95% of cancers this is due to up-reg of telomerase

Front 95

How large can a tumor get without vascularization?

Back 95

1-2mm in diameter
(hypoxia induces TP53à induces apoptosis)

Front 96

What duel effect does vascularization have on a tumor?

Back 96

perfusion = nutrients and O2
 
new endothelial cells stim growth of adjacent tumor cells by secreting:
--insulin like GFs
--PDGF
--GM-CSF (granulocyt-macrophage colony stim fact)
--IL-1

Front 97

With regaurds to angiogenesis, what do tumor cells make and induce?

Back 97

MAKE angiogenenic factors:
VEGF
Basic fibroblastic GF
 
INDUCE anti-angiogenesis molecs:
Angiostatin
Endostatin
vasculostatin

Front 98

With respect to angiogenesis, what does TP53 do?

Back 98

Inhibits angiogenesis be inducing the synth of the anti-angiogenesis factor:
Thrombospondin-1

In cancer, both TP53 alleles may be mutatedà balance favors angiogenesis

Front 99

Because angiogenesis is so crucial for tumor growth, what is being considered?

Back 99

Antiangiogenesis Therapy

Front 100

Whata re the 2 phases of the metastic cascade?

Back 100

1) invasion of ECM
 
2) Vascular dissemination and homing of tumor cells

Front 101

In the metastic cascade, what happens during the invasion of the ECM?

Back 101

INVASION OF ECM:

-Detach of tumor cells from eachother:
(E cadherins act as intercell ular glues-->function lost in almost all epithelial cancers)

 
-Attachment of tumor cells to ECM components:
(laminin and fibronectin; integrin)

 
-Degredation of ECM:
(metalloproteinases [matrix degrading proteolytic enzymes, gelatinases, collagenases]; Cathepsin D- protease)

 
-Migration of tumor cells:
(mediated by tumor cell cytokines
àInsulin like GF I/II; stromal cells also produce paracrine effectors of cell motility)

Front 102

In the metastic cascade, what happens in the vascular dissemination and homing of cancer cells phase?

Back 102

DISSEMINATION and HOMING:

Most tumor cells circulate as single cells.

Some form emboli by aggregating and adhering to circulating leukocytes
Particularly platelets
-->some protection from antitumor host effector cells
 
Organ tropism may be related to:
Express of adhesion molecs by tumor cells w/ligands expressed preferentially on endothelium of target organs
 
Another mechanism of site specific homing--chemokines and receptors:
Blockade of chemokine receptors may limit metastases

Front 103

What is over expressed in many invasive breast cancers?

Back 103

Cathepsin D
àprotease that signals break down of ECM

Front 104

How do most tumor cells circulate?

Back 104

As single cells

Front 105

T/F—Precise location of metastases can be predicted depending on form of cancer.

Back 105

False! Can NOT be predicted.

Front 106

We are surrounded by tons of carcinogens daily, why don’t we all have cancer and die?

Back 106

Normal cells are able to repair DNA

Front 107

What can lead to Xeroderma pigmentosum?

Back 107

Inherited loss of any gene or protein that regulates the nucleotide excision repair system. (DNA repair is defective)

Front 108

What happens in UV exposure of xeroderma pigmentosum patient?

Back 108

UV cuases cross link of pyrimidine
--> prevents normal DNA replication

à INC risk of cancer

Front 109

What does a mutation of the BRCA1 gene increase susceptibility for?

Back 109

Women have much higher risk of epithelium ovarian cancers
 
Men have slightly higher risk of prostate cancer

Front 110

What does a mutation of the BRCA2 gene increase susceptibility for?

Back 110

INC risk of breast cancer in men and women
(also, Cancers of ovary, prostate, pancreas, bile ducts, stomach, melanocytes)

Front 111

What are 3 autosomal recessive disorders that enable malignancy?

Back 111

Bloom syndrome
 
Ataxia-telangiectasia
 
Fanconi anemia

Front 112

What cancer inducers are Bloom syndrome and Ataxia-telangiectasia hypersensitive to?

Back 112

Ionizing radiation

(and DNA-crosslinking agents)

Front 113

What cancer inducer is Fanconi anemia hypersensitive to?

Back 113

Nitrogen mustard

(and DNA-crosslinking agents)

Front 114

What does analysis of every human cancer reveal?

Back 114

Multiple genetic alterations!

Activated oncogenes
 Loss of 2 or more cancer suppressor genes

Front 115

T/F—There are multiple variable pathways of carcinogenesis.

Back 115

True!

Differ chronologically, 1 mutation may be an umbrella mutation including many others (faster), may be stepwise (slower)

Front 116

What increases the rate of carcinogenesis?

Back 116

Loss of TP53

Front 117

What is tumor progression?

Back 117

Over time, tumor may become more aggressive and malignant
(Must be distinguished from and INC in tumor size) 

Also, related to sequential appearance of subpopulations of cells that differ w/ respect to several phenotypes (invasiveness, metastic ability, hormonal responsiveness, etc)

Front 118

How do you differentiate increased malignancy from increased growth?

Back 118

INC malignancy:
Accelerated growth
Invasive
Metastases
(acquired incrementally usually)

Front 119

What is tumor heterogeneity?

Back 119

Despite monoclonal origin, 
By the time cancer tumors are evident the constituent cells are EXTREMELY HETEROGENEOUS
(result of tumor progression)

Front 120

What effect does tumor heterogeneity have on the tumor?

Back 120

Multiple mutations accumulate independently in different cells
à subclones w/different characteristics
Some may be lethal
Others may spur growth by affecting protooncogenes or cancer suppressor genes

Front 121

What are these tumor subclones subjected to?

Back 121

Immune and nonimmune selection pressures:
Highly antigeninc cells are destroyed by host defenses
Cells with reduced GF requirements are positively selected
(more dangerous cells survive)

Front 122

How variable is the rate of subclone formation in various cancers?

Back 122

·         Very!
Osteosarcomas: metastic subclones almost immediately

Mixed salivary gland tumors: aggressive subclones are rare or late

Front 123

What type of karyotipic damage induces carcinogenesis?

Back 123

Subtle (point mutation)
or Large (translocation)

Front 124

In cancer, what is the best example of activation via a point mutation?

Back 124

RAS oncogene

Front 125

Karyotypic abnormalities are often non-random and common in certain cancers, like what?

Back 125

Leukemias

Lymphomas

(Increasingly seen in non-hematopoietic tumors)
`

Front 126

What is the most noted balanced translocation in hematopoietic cancers?

Back 126

Philidelphia (Ph) chromosome

(22 and 9à 22 becomes abbreviated)

Front 127

What cancer is associated with the Ph chromosome?

Back 127

Chronic myelogenous Leukemia (CML)

>90% have thisà MARKER!

Front 128

What translocation occurs in >90% of burkitt’s lymphomas?

Back 128

Translocation of 8 and 14

Front 129

What is the 2nd most common structural abnormality in tumor cells?

Back 129

Chromosomal deletions!
(more common in non-hematopoietic cells)

Front 130

What deletion is associated with retinobastomas?

Back 130

13q14

Front 131

What deletions are associated with colorectal cancers?

Back 131

17p, 15q, 18q
(tumor suppressor genes)

Front 132

What deletion is associated with small cell lung carcinomas?

Back 132

3p

Front 133

What are the 2 karyotypic manifestations of gene amplification?

Back 133

Homogeneously staining regions on single chromosomes
 
Double minutes--small paired fragments of chromatin

Front 134

What are the best studied examples of gene amplification?

Back 134

N-MYC and HER-2 genes

(Neuroblastomas, Breast cancers)

Front 135

What public health measure made the most impact ever in controlling a form of cancer?

Back 135

Danish chimney sweep guild ruled that members must bathe daily
(scrotal skin cancer from coal dust)

Front 136

What are direct acting carcinogens?

Back 136

require NO chemical transformation to induce carcinogenicity

Front 137

What are indirect acting carcinogens?

Back 137

Active only after conversion
(more common!!)

Aka—Procarcinogens
 
Active end productsà Ultimate carcinogens

Some of the most potent carcinogens!

Front 138

What are all direct acting and ultimate carcinogens have?

Back 138

highly reactive electrophiles!!
àe- deficient and react with e- rich:
RNA, Cell proteins, DNA**

Front 139

What is a promoter?

Back 139

Augmenting agents that make low or no carcinogenic agents MORE carcinogenic

Front 140

What are 3 types of cariogenic agents?

Back 140

Chemicals, Viruses, Radiation

Front 141

What are some characteristics of direct carcinogens?

Back 141

Generally = weak carcinogens***

Important because some are cancer chemotherapy drugsà alkylating agents **

Front 142

What are the effects of many cancer chemotherapeutic drugs?

Back 142

Have cured, controlled or delayed recurrence of some cancers
 
BUT, These are direct acting agents, may be weak carcingogens
--> evoke a 2nd form of cancer later (leukemia)

Front 143

What is an example of a chemo drug?

Back 143

Methotrexate

Front 144

What non-cancer conditions are treated w/ chemo?

Back 144

Psoriatic Rheumatoid arthritis
Wegener granulomatosis
(cancer is risk of Txàuse judiciously)

Front 145

What type of carcinogen are polycyclic hydrocarbons?

Back 145

Indirect! à potent!
Ex) Benzo[a]pyrene
(industy, fossil fuels, smoking, charbroil)

Front 146

What is the principle active product of polycyclic hydrocarbons?

Back 146

Epoxides!
(form adducts w/ DNA, RNA, proteins)

Front 147

What are 2 types of direct carcinogens?

Back 147

Alkylating agents
Acylating agents

Front 148

What are some types of indirect carcinogens?

Back 148

Polycyclic and heterocyclic aromatic hydrocarbons
Aromatic amines, amides, azo dyes
Natural plant and microbe products
Nitrosamines, nitrosamides

Front 149

Why are nitrosamines and nitrosamides as indirect carcinogens a great concern?

Back 149

Can be formed endogenously in acidic environment of stomach!
àVarious amines in food may undergo nitrosylation w/nitrites that have been:
Added to food--preservatives
Derived from nitrates by bacterial action

Front 150

What is Aflatoxin B1?

Back 150

Indirect carcinogen
(from Aspergillus flavus and parasiticus)

Improperly stored grains/nuts

Strong correlation w/ hepatocellular carcinoma in Africa and far east**

Front 151

Is there evidence that saccharine and cyclamates are carcinogenic in humans?

Back 151

No.

Front 152

What is a common target for chemical carcinogens?

Back 152

RAS gene

Front 153

What indirect carcinogen has been associated with TP53 mutation?

Back 153

Aflatoxin B1

Front 154

How do tumor promoters contribute to carcinogenesis?

Back 154

They are PLEIOTROPIC!--single gene influences multiple traits
 
Induction of cell proliferation is a sine qua non (indispensable and essential condition)

Front 155

What is the best studied tumor promoter?

Back 155

TPA (Phorbol ester)

-->activates protein kinase C
Crucial part of several signal transduction paths
(inc those activated by GFs)

Front 156

What happens if TPA causes GFs to activate the RAS oncogene?

Back 156

Clonal expansion!
And cells may have reduced GF reqsàless responsive to inhibitors
àproliferationàtumor

Front 157

What is the influence of estrogen on many breast cancers?

Back 157

INC growth
(may relate to prolif effects of estrogen on mammary ductal ep)

Many breast cancers express estrogen receptors
àBenefit from estrogen receptor agonists Tx

Front 158

What is an estrogen receptor agonist that may be used to treat breast cancer?

Back 158

Tamoxifen

Front 159

What is the most important out come of radiation carcinogenesis?

Back 159

dsDNA breaks

Front 160

What does natural UV radiation from the sun often lead to?

Back 160

skin cancers
(melanomas, SCC, basal cell carcinomas )

Front 161

What are melanoma and non-melanoma skin cancers associated with?

Back 161

Non-melanoma skin cancers--associated w/total cumulative exposure to UV radiation
 
Melanomas--associated w/intense intermittent exposure

Front 162

What characteristic mutation does UV light cause?

Back 162

TP53

Front 163

What are the 2 mechanisms by which a retrovirus transforms cells?

Back 163

Acute transforming viruses
-->contain transforming viral oncogene (v-onc)
 
Slow transforming viruses
(ex--mouse mammary tumor virus MMTV**)--> no v-onc, But proviral DNA always inserted near cell oncogene

Front 164

What is a provirus?

Back 164

Viral DNA becomes integrated in host DNA
(usually causes over express of an adjacent oncogene)

Front 165

What is HTLV-1?

Back 165

ONLY known Human retrovirus associated with cancer

Only 1% of infected develop Leukemia after long latent period

Front 166

What are the 4 DNA viruses involved in cancer?

Back 166

HPV
EBV
KSV (HHV8)
HBV

Front 167

What percent of oropharyngeal cancers are associated with HPV?

Back 167

20%

Front 168

What percent of invasive SCC have HPV 16 or 18 DNA?

Back 168

75-100%

Front 169

What type of carcinogen is HPV?

Back 169

Indirect!
(need mutated gene or other environmental factors)

Front 170

What is EBV implicated in?

Back 170

·         Several B-cell tumors:
Burkitt lymphoma
Post-transplant lympho-prolif disease
Primary CNS lymphoma in AIDS
Subset of other AIDS related lymphomas
Subset of hodgkins lymphoma
Nasopharyngeal carcinoma

Front 171

Where is EBV associated Burkitt lymphoma endemic?

Back 171

Africa
(concomitant infection impairs immunityà B-cell proliferation)

Front 172

What is significant about B cells in Burkitt lymphoma?

Back 172

B cells do NOT express cell surface antigens that can be recognized by host T cells
 àRelieved from immunoregulation
àsuch B cells at risk of acquiring mutations 
àactivation of MYC oncogene ***

Front 173

What is a consistent feature of Burkitt lymphoma tumors?

Back 173

c-MYC

(transcription factor by MYC gene on chrom 8)

Front 174

What is the common MYC translocation in Burkitts Lymphoma?

Back 174

8 and 14

Front 175

What has been the breakthrough in Dx of Burkitts lymphoma?

Back 175

Identified the gene expression signature àt(8; 14)

Front 176

What do immunocompromised EBV patients experience in Burkitts?

Back 176

Polyclonal expansion of B-cells

àDO express surface antigens
àIf immune status improves, the proliferations can be subdued.

Front 177

Where is nosopharyngeal carcinoma endemic?

Back 177

China (EBV)

Front 178

What cancer is HBC linked to?

Back 178

Hepatocellular carcinoma

àHBV DNA integrated in 90% of pts w/liver cancer who are + for hep surface B antigen *

Front 179

In some HBV patients, what does viral integration seem to cause?

Back 179

Secondary rearrangements:
Multiple deletions that may be unknown tumor suppressor genes*

Front 180

What is also linked to hepatocellular carcinoma?

Back 180

HCV

(but HCV does not have X-protein)

Front 181

What can Heliobacter pylori cause?

Back 181

Peptic ulcers
Gastric carcinoma
Gastric lymphoma
Gastric Lymphoma (Bcell origin)

Front 182

What are Peyer’s patches?

Back 182

Lymphoid follicular tiss in GI tract
àGerminal Center where B cells proliferate à tumors

Front 183

How does H. pylori cause cancer?

Back 183

H. pylori infection à
form H. pylori-reactive T cells à cause polyclonal B cell proliferation
àMonoclonal B cell tumor emerges
(result of accumulated of mutations in growth regulation genes)

Front 184

How was Phenylketonuria discovered?

Back 184

Mentally retarded pts smelled weird
àurine had large amounts of phenylketone (phenylpyruvic acid)

Front 185

What did Dr. Folling recommend to manage Phenylketonuria?

Back 185

Dietary restriction

Front 186

What is the most common form of PKU?

Back 186

Classic PKU
---common in scandinavians
---uncommon in blacks and jews
 
---AUTOSOMAL RECESSIVE

Front 187

What occurs in homozygotes of classic PKU?

Back 187

Svere lack of phenylalanine hydroxylase*
--> Hyperphenylalaninemia
--> PKU

Front 188

What happens if PKU is untreated by age 6 months?

Back 188

< 4% of untreated PKU kids have Iqs over 50-60
1/3 wont walk
2/3 can’t talk
Seizures and other neuro probs
Dec skin/hair pigmentation
eczema

Front 189

How can hyperphenylananinemia and resultant retardation be avoided?

Back 189

Restriction of phenylalanine intake early in life***
 
Phenyl-free dietary protein taken on regular basis--only remedy*

Front 190

What is the Guthrie test?

Back 190

Standard, routine screening test of newborns
detect PKU immediately postnatal

Front 191

What is significant about PKU in pregnant mothers?

Back 191

Have marked hypephenalaninemia
Because Dietary tx discontinued after reaching adulthood
--> teratogenic effects of phenylalanine that crosses placenta and affects development fetus
(INC defects and spontaneous abortions)

MUST control PKU before conception.

Front 192

What characteristics do kids of PKU moms usually have?

Back 192

--Profoundly retarded
--Many congenital anomalies
(even tho infants are heterozygotes)

Front 193

What is the biochemical abnormality in PKU?

Back 193

Can NOT convert phenylalanine into tyrosine
phenylalanine metab is blocked b/c lack of phenylalanine hydroxylase
Minor shunt paths come into play--> intermediates are excreted in large amounts in urine and sweat

Front 194

What does phynylalanine cause?

Back 194

Musty/mousy odor

Front 195

What is lack of tyrosine marked by?

Back 195

light color hair and skin
(it’s a precursor to melanin)

Front 196

What is galactosemia?

Back 196

AUTOSOMAL RECESSIVE
Disorder of galactose metabolism

Front 197

When are humans natural lactose degraders?

Back 197

As babies
(lactase genes turned on to digest mom’s milk)

Front 198

What enzyme is required in converting galactose to glucose?

Back 198

Galactose-1-phosphate uridyltransferse
(GALT

Front 199

What does lack of GALT enzyme lead to?

Back 199

Galactosemia

Front 200

What is the most common mutation of the GALT gene?

Back 200

Single point missense mutation! (70%)
(CAAàCGA)

Front 201

What are the signs and symptoms of galactosemia?

Back 201

From birth--failure to thrive
Vomitting and diarrhea
(w/in few days of milk ingest)
Jaundice and hepatomegaly in 1st week of life
Cataracts in a few weeks**
Mental retard in 6-12months of life

Front 202

How can clinical and morphological changes in galactosemia be prevented?

Back 202

removal of galactose from diet for 1st 2 years of life

Front 203

What can help confirm the Dx of galactosemia?

Back 203

Presence in urine of a reducing sugar other than glucose:
--monosaccharides = fructose, glyceraldehyde, galactose
--disaccharides = lactose, maltose

Front 204

What are lysosomes?

Back 204

Contain variety of hydrolytic enzymes for break down of large molecs into small soluble ones

Front 205

What are some complex molecules broken down by lysosomes?

Back 205

Sphingolipids and Mucopolysaccharides

Front 206

What is a lysosomal storage disease?

Back 206

Inherited lack of one of many enzymes in lysosomes leading to accumulation of partially degredated insoluble metabolites.

AUTOSOMAL RECESSIVE.

Front 207

In what cells are insoluble intermediates often stored?

Back 207

Mononuclear phagocyte cells

Front 208

How do you treat a lysosomal storage diseases?

Back 208

Enzyme replacement therapy

Front 209

What are some lysosomal storage diseases?

Back 209

Glycogenses
Sphindolipidoses
Sulfatidoses
Mucopolysaccharidoses
Glycoproteinoses

Front 210

What is the most common form of Gangliosidoses?

Back 210

Tay-Sachs Diseases

AUTOSOMAL RECESSIVE

Front 211

What is mutated in Tay Sachs?

Back 211

Mutation of hexosaminidase A
ànecessary for degredation of Gm2 ganglioside in lysosmes

Front 212

Where is Gm2 stored?

Back 212

Throughout CNS in:
Neurons
Axon cylinders of nerves
Glial cells
àAffected cells look swollen, possibly foamy

Front 213

What is a diagnostic anatomical change in Tay Sachs?

Back 213

“Cherry red spot” in retina

Front 214

Who is predisposed for Tay Sachs (and othe lipidoses)?

Back 214

Ashkenazi jews!!!

Also,Irish, french canadian, Cajun

Front 215

What does detection of Tay Sachs in fetus possibly indicate?

Back 215

Therapeutic abortion

Front 216

What is Niemann-Pick Diseases?

Back 216

A group of 3 disorders

Type A and B
--> primary deficiency of acid sphingomyelinase------> resultant accumulation of sphingomyelin
 
 
Type C
àNeimann-Pick disease  
à mutation in NPC1 protein**

Front 217

What happens in a sphingomelinase deficiency?

Back 217

break down of shingomyelin into ceramide and phosphorycholine is IMPAIRED
àExcess sphingomyelin accumulation in all phagocytic cells and neurons!
àPhagocytic cells become stuffed w/ complex lipidà fine vacuolation or foaminess to cytoplasm

Front 218

What can estimation of sphingomyelinase activity in leukocytes or cultured fibroblasts be used for?

Back 218

Dx of Niemann-Pick

Detection of carriers

Front 219

What is Gaucher diseases?

Back 219

Mutation in gene encoding glucocerebrosidase
 
3 AUTOSOMAL RECESSIVE variants result from distinct allelic mutations

Deficient activity of glucocerebrosidase
à accumulation of glucocerebrosides in mononuclear phagocytic cells à form "Gaucher cells"

Front 220

What does glucocerebrosidase do?

Back 220

cleaves glucose residue from ceramide

Front 221

What are Gaucher cells?

Back 221

Accumulation of glucocerebrosides in MACROPHAGES

àPhagocytes become enlarge (up to 100um)
àdevelop pathognomonic cytoplasmic appearance:
 
"Wrinkled paper"*

NO DISTINCT VACUOLES!

Front 222

What accounts for 99% of Gaucher Diseases?

Back 222

Type 1—chronic, non-neuropathic

Front 223

What is the current therapy for Type 1 Gauchers?

Back 223

Enzyme replacement by infusion with purified glucocerebrosidase!

(future—gene therapy?)

Front 224

What is Mucopolysaccharidosis?

Back 224

Characterized by defective degredation (and storage) of mucopolysaccs in various tissues

Several enzymes involvedàLack of enzymes à accumulation of mps in lysosomes
 
MPS is classified I to VII

AUTOSOMAL RECESSIVE
(except Hunter—X-linked recessive)

Front 225

What are some Mucopolysaccharides that accumulate in tissue?

Back 225

Dermatan sulfate
Heparan sulfate
Keratan sulfate
Chondroitin sulfate

Front 226

What is Mucopolysaccharidoses most commonly associated with?

Back 226

*INC urination of mps's

(coarse facial features, Clouding of cornea, Joint stiffness, Mental retardation)

Front 227

What form of Mucopolysaccharidoses is NOT autosomal recessive?

Back 227

Hunter Syndrome
(X-linked recessive)

Front 228

What is Glycogenoses?

Back 228

Inherited deficiency of any enzyme involved in:
Glycogen synth
Glycogen deg

Results in accumulation of glycogen or some abnormal form of glycogen in tissues


Most—AUTOSOMAL RECESSIVE


12 forms of glycogenoses

Front 229

What is one type of Glycogenoses?

Back 229

Pompe disease

Front 230

What is Von Gierke disease?

Back 230

Type 1 glycogenosis—hepatic!

àLack of Glucose-6-phosphatase
 
***most important example of hepatic glycogenosis!!**

Front 231

What are myopathic forms of Glycogen Storgae disorders marked by?

Back 231

Muscle cramps after exercise
 
Failure of exercise to induce elevated blood lactate levels
(due to block in glycolysis)

Front 232

What is McArdle Disease?

Back 232

Type V glycogenosis—myopathic
 
Deficiency of muscle phosphorylase

Front 233

What is Pompe Disease?

Back 233

Type II glycogenoses—Misc.
 
Deficiency of lysosomal acid maltase
 
Deposition of glycogen in every organ
àcardiomegaly most prominent*

Front 234

In what percentage of cancers are there mutations affecting tumor suppressor genes in all cell types, including germ cells?

Back 234

~5% of cancers
(indicates hereditary transmission)

Front 235

What are the 2 types of Neurofibromatosis?

Back 235

NF-1 (aka von Recklinghausen disease)
 
NF-2 (aka bilateral acoustic or central NF)

Front 236

Is NF autosomal recessive or dominant?

Back 236

Autosomal Dominant

Front 237

What do the 2 types of neurofibromatosis have in common?

Back 237

Neurogenic tumors are common

Neural crest originà Affects all 3 germ layers
(any organ)

Front 238

How many NF cases are type 1?

Back 238

More than 90%

Front 239

What are the 3 major features of NF-1?

Back 239

-multiple neurofibromas
 
-Café au lait spots
 
-Lisch nodules

Front 240

What is a café au lait spot?

Back 240

Hyperpigmented skin that may overlay a neurofibroma

(sometimes, NF-1 ONLY have these spots)

Front 241

What is not a clinical problem in NF-1 but is a characteristic that can aid in diagnosis?

Back 241

Lisch nodules
(pigmented iris hamartomas)

Front 242

What percent of NF-1 patients experience a transformation of one or more neurofibromas from benign to malignant?

Back 242

~3%
(neurogenic sarcomas)

Front 243

If there is a malignant transformation in NF-1, what is the patient at increased risk for?

Back 243

other tumors,

particularly:
optic gliomas, meningiomas, and
PHEOCHROMOCYTOMAS***
(neuroendocrine tumor of the medulla of the adrenal gland)

Front 244

What is an MPNST?

Back 244

Malignant peripheral nerve sheath tumor

(sarcomas, ~50% of MPNSTs are found in NF-1 patients)

Front 245

30-50% of NF-1 patients experience what type of lesions?

Back 245

Skeletal lesions

Front 246

Where is the NF-1 gene and what protein does it encode?

Back 246

Chromosome 17

Neurofibromin protein
(negative regulator of RAS oncoprotein)

Front 247

What are significant features of NF-2?

Back 247

Café au lait spots (most patients)

Bilateral acoustic schwannomas (VIII) and Multiple meningiomas (defining features!)

NO Lisch nodules

Front 248

What common diseases are underlied by genetic disorders with multifactorial inheritance?

Back 248

Diabetes mellitus
HTN
Gout
Schizophrenia
Biopolar
Some congenital Heart disease
Some skeletal abnormalities

Front 249

How is a multifactorial trait defined?

Back 249

A multifactorial trait is governed by additive effect of 2+ genes of small effect
àconditiond by environment and nongenetic forces

Front 250

What is the threshold effect in relation to polygenetic inheritance?

Back 250

There is a threshold before which there is no change, but
Once threshold is exceeded, severity of disease is directly proportional to # and degree of influence of pathologic genes!

(multifactorial inheritance has a Gaussian distribution)

Front 251

What determines the risk associated with inheriting a disorder of multifactorial inheritance?

Back 251

risk of expressing a multifactorial inheritance disorder is conditioned by the # of mutant genes inherited
--> greater risk in siblings of severe patients

Front 252

What is the rate of recurrence in all 1st degree relatives of an affected multifactorial inherited disorder patient?

Back 252

2-7%
(parents, siblings, offspring)

Front 253

What is the likelihood that both monozygotic twins will have a multifactorial inherited disorder?

Back 253

Should be 100%...but it’s NOT!
(because environmental role)

It is 20-40%.

Front 254

Hypertension is what type of disorder?

Back 254

multifactorial inherited disorder
(many genes of small effect contribute)

Front 255

What is a karyotype?

Back 255

Photographic representation of stained metaphase spread in which chromosomes are arranged in order of decreasing length

Front 256

What is the G-banding technique?

Back 256

Giemsa Stain
 
Each chromosome has distinctive banding of variable widths
 
Use of banding technique allows:
Certain identification of each chromosome
Precise location of structural changes

Front 257

How commonly are newborns born with chromosomal abnormalities?

Back 257

1 of 200 newborns have some chromosomal abnormalities
--> much higher in fetuses that don’t survive

Front 258

What causes about half of all 1st trimester spontaneous abortions?

Back 258

Chromosomal abnormalities

Front 259

How many chromosomes does a human somatic cell have?

Back 259

46 (diploid, n=23)

Front 260

What is euploid?

Back 260

Euploid--any exact multiple of haploid number (n, n=23)

Front 261

What is polyploidy?

Back 261

Polyploid--Chromosome #s such as 3n and 4n (extra sets of chromosomes)

Front 262

What is aneuploidy?

Back 262

Aneuploid--Any number that is not exact multiple of n.
(extra parts of chromosomes)

Front 263

What does polyploidy usually result in?

Back 263

Spontaneous abortion

Front 264

T/F—True polyploidy rarely occurs in humans, but it can occur in some tissues, especially the liver.

Back 264

True.

Front 265

How many chromosomes will human triploidy and tetraploidy cells have?

Back 265

Triploidy--3n
(1.5 x's normal--69) XXX

Tetraploidy--4n
(2 x's normal--92) XXXX


(NOT to be confused w/ 47 XXX or 48 XXXX ANEUPLOIDY)

Front 266

Polyploidy babies rarely make it to or past birth, but if they do, what is the likely explanation?

Back 266

They are probably mixoploidy
(diploid and triploid present)

Front 267

What are the chief causes of aneuploidy?

Back 267

Non-disjunction of homologous pair of chromosomes at:
1st meiotic division
Failure of sister chromatids to separated during 2nd meiotic division
 
May also occur during somatic cell division--> producing 2 aneuploidy cells

Front 268

When non-disjunction occurs in meiosis, what characteristic do the gametes have?

Back 268

--Extra chromosome (n+1)
--One less chromosome (n-1)

Front 269

If an abnormal gamete is fertilized by a normal gamete, what are the 2 resulting zygotes?

Back 269

Trisomic (2n+1) [47]
 
Monosomic (2n-1) [45]

Front 270

T/F--Trisomy of certain autosomes and monosomy of sex chromosomes are NOT compatible with life.

Back 270

FALSE!

Trisomy of certain autosomes and monosomy of sex chroms ARE compatible with life!!

Monosomy of an autosome is NOT compatible with life.

Front 271

What is mosaicism?

Back 271

Mosaicism--2 or more populations of cells in same person
 
Postzygotic mitotic non-disjunction--> trisomic and monosomic daughter cells
--> descendants produce mosaic

Front 272

T/F—Mosaicism commonly affects sex chromosomes and uncommonly affects autosomal chromosomes.

Back 272

True.

Front 273

What do p and q stand for?

Back 273

p (petit)—short arm
q—long arm

Front 274

How do structural chromosomal abnormalities occur?

Back 274

Chromosomal breakage followed by loss or rearrangement.

Front 275

What does 2q33.2 indicate?

Back 275

Chromosome 2

Long arm

Region 3

Band 3.2

Front 276

What are the types of chromosomal rearrangement after breakage?

Back 276

Translocation
(Robertsonian-centric fusion type)
Usually reciprocal
 
Isochromosomes

Deletion
(ring chromosome)
 
Inversion

Front 277

What does 46, XX, t(2;5)(q31;p14) indicate?

Back 277

Reciprocal translocation of:
 
Long arm of 2 at region 3 band 1
 
Short arm of 5 at region 1 band 4

Front 278

T/F—Balanced reciprocal translocations are the most detrimental.

Back 278

False.
Not usually harmful, full genome intact.

Front 279

During gametogenesis, what can result in an abnormal fetus?

Back 279

Unbalanced gametes.

Front 280

What is an acrocentric chromosome?

Back 280

P arm is very small, hard to observe.

Chromosomes 13, 14, 15, 22

Front 281

What is a robertsonian translocation?

Back 281

Robertsonian Translocation (centric fusion type):
Typically breaks close to centromere
Affects short arms of both
Transfer segments, one large and one small
Short fragments are lost, leaves on huge chromosome

àcarrier has 45 chromosomes **

Front 282

In robertsonian translocations, why is the loss of the short arms still compatible with life?

Back 282

All acrocentric short arms have many genes for rRNA.


However, difficulties during gametogenesis may give unbalance gametesàabnormal offspring

Front 283

Where is a common Robertsonian translocation?

Back 283

13 and 14

Front 284

How is an isochromosome formed?

Back 284

Centromere divides horizontally not vertically!!
 
One of chromosome arms then lost, and remaining is duplicated
--> chromosome w/ 2 short arms only or 2 long arms only
 
RARE

Front 285

What do most isochromosomes in live birth involve?

Back 285

Long arm of X and long arm of 21
 
i(Xq) and 1(21q)
 
When fertilized by normal
--> monosomy Xp and 21p
--> Trisomy for Xq and 21q

Front 286

What are 4 types of chromosomal deletion?

Back 286

Single break--> delete terminal segment
 
2 middle breaks w/ reunion

2 middle braks w/ Loss of intermediate segment
results in isolated fragment**
--> lacks centromere and almost never survives, many genes lost

Ring chromosomeà loss of segment at each end, arms unite to form ring

Front 287

What is a chromosomal inversion?

Back 287

2 interstitial breaks
àFragment turns around and reunites

Paracentric (same arm)
 
Pericentric (both arms including centromere)

Front 288

What might structural chromosomal abnormalities be associated with?

Back 288

Absence (deletion, monosomy)
Excess (trisomy)
Translocation rearrangements

Front 289

Which produces more severe defects, loss or gain of chromosomal material?

Back 289

Loss!

Front 290

Which better tolerates imbalances, sex or autosomal chromosomes?

Back 290

Sex chromosomes!

Front 291

What is a common manifestation of sex chromosome imbalances?

Back 291

Infertility
(can’t be Dx until adolescence)

Front 292

Most chromosomal disorders are de novo, meaning Parents are normal and Risk for siblings is low, what is the main exception?

Back 292

Down syndrome translocation!

Front 293

What where the 3 chromosomal abnormalities 1st identified?

Back 293

Three autosomal trisomies:

Trisomy 21--down syndrome
Trisomy 18--Edwards syndrome
Trisomy 13--Patau syndrome

Front 294

What chromosome is affected in cri du chat syndrome?

Back 294

Partial deletion of short arm of 5

Front 295

What 2 autosome abnormalities are very common?

Back 295

Trisomy 21 (Down Syndrome)

22q11 deletion (DiGeorge)

Front 296

What is the most common chromosomal disorder?

Back 296

Down syndrome

95% have trisomy 21

Front 297

What is the most common cause of trisomy and Down syndrome?

Back 297

meiotic non disjunction

Front 298

What has a strong influence on the occurrence of down syndrome?

Back 298

Maternal age!
Occurs in: 
1 in 1550 births over 20yo
1 in 25 live births in women over 45yo!!

Front 299

What does this maternal age correlation suggest?

Back 299

Age correlation suggests that usually meiotic non-disjunction of 21 occurs in the ovum

(95%--maternal origin, but when fathers fault, age hasn't been linked)

Front 300

What type of down syndrome involves extra chromosomal material that is not an extra chromosome but a translocation of the long arm of 21 to 22 or 14?

Back 300

Familial (~4% of patients)
 
Translocated chromosome is inherited from one parent who is most frequently a carrier of a robertsonian translocation.

Even though this should give 1 in 3 chance of giving a down syndrome baby, actual frequency is much lower.

Front 301

What are 1% of Down Syndrome patients?

Back 301

Mosaics--Mix of 46 and 47
 
(From mitotic nondisjunction of 21 in early embryo)
 
Symptoms vary and are milder depending on proportion of abnormal cells.

Front 302

What are the clinical features of Down syndrome?

Back 302

Combo epicanthic folds and flat facial profile!!!

Severe, IQ 25-50
 
Congenital malformations are common and disabling
 
40% have cardiac malformations

INC susceptibility to serious infections
(another important cause of morbidity and mortality) 
 
Sometimes, acute leukemias
(acute megakaryocytic leukemia)

Front 303

What is the leading cause of mental retardation?

Back 303

Down Syndrome

Front 304

What is responsible for most Down Syndrome deaths in early childhood?

Back 304

Cardiac malformations
(40% of patients have)

Front 305

Due to a chromosomal imbalance, what are down syndrome patients also at increased risk for?

Back 305

Acute leukemias
(acute megakaryocytic leukemia)

Front 306

What is the prognosis for down syndrome?

Back 306

Has improved (better control of infections)
 
80% of those w/o congenital heart disease can expect to survive 30 years
(Outlook is less favorable if cardiac malformations)

Front 307

What happens to many down syndrome patients that reach middle age?

Back 307

Develop histologic, metabolic, and neurochemical changes of ALZHEIMERs!!!
 
Many dev frank dementia

Front 308

How many genes is on chromosome 21?

Back 308

225

Front 309

What is the Robertsonian translocation responsible for Down Syndrome?

Back 309

14 and 21

Front 310

What is 22q11 Deletion Syndrome?

Back 310

Encompasses a spectrum of disorders that result from small interstitial deletion of band 11 on the long arm of chromosome 22.

Front 311

What are the clinical symptoms of 22q11 deletion syndrome?

Back 311

Congenital heart disease affecting outflow tracts
 
Abnormalities of palate
 
Facial dysmorphism
 
Developmental delay
 
Thymic hypoplasia w/impaired T cell immunity
 
Parathyroid hypoplasia casuing hypocalcemia


…variations in size and location of deletion are responsible for variability.

Front 312

What are the 2 disorders that 22q11 deletion causes?

Back 312

DiGeorge Syndrome****
 
Velocardiofacial syndrome

Front 313

What are the common clinical manifestations of DiGeorge Syndrome?

Back 313

T cell immunodeficiency
 
Hypocalcemia

Front 314

What 2 things are related to the latitude of deviations in sex chromosomes?

Back 314

Lyonization of X-chromosomes
 
Scant amount of genetic info on Y chromosome

Front 315

What is a Barr body?

Back 315

Aka--sex chromatin
 
Prominent clump of chromatin attached to nuclear membrane in interphase nuclei of all FEMALE somatic cells.
 
(mostly) Deactivated extra X chromosome

Front 316

What is the original Lyon hypothesis of the X chromosome?

Back 316

In females, one X chromosome is inactivated in each cell of the fetus about 16 days after conception.
This may be the mom X or the dad X.
Therefore, females are mosaics.

Front 317

How many X chromosomes does it take to override a Y chromosome?

Back 317

Impossible. Presence of 1 Y dictates male phenotype.

Front 318

Where are the genes for male differentiation located on the Y chromosome?

Back 318

The short arm of the Y

Front 319

What are 2 sex chromosome disorders?

Back 319

Klinefelter syndrome
 
Turner syndrome

Front 320

What is the karyotype of most Klinefelter patients?

Back 320

47, XXY
(extra X may be from mom or dad)

Front 321

What causes the XXY of Klinefelter?

Back 321

nondisjunction of sex chromosomes during meiosis

Front 322

What are probable contributors to meiotic error?

Back 322

Advanced maternal age
 
Hx of irradiation of either parent

Front 323

What do 15% of Klinefelters patients show?

Back 323

Mosaic patterns
(46 XY and 47 XXY
OR 47XXY and 48XXXY)
 
If 46XY is present, usually milder condition

Front 324

T/F--The mildest clinical presentation of Klinefelters is only hypogonadism.

Back 324

True!
(probably a lot of normal cells in the mosaic)

Front 325

What are some characteristics of a Klinefelters patient?

Back 325

Long legs and arms, less body hair, boobs (gynecomastia), small balls, low serum testosterone, high urinary gonadotropin

Front 326

What is the principal clinical effect of Klinefelters?

Back 326

Sterility
(due to impaired spermatogenesis)

Front 327

What is correlated to reduction of intelligence in Klinfelters?

Back 327

# of extra X chromosomes
 
(in most common variant--XXY--intelligence is nearly normal)

Front 328

What is the primary hypogonadism in females?

Back 328

Turner Syndrome (partially or completely missing short arm of X, or missing one X altogether)

Front 329

What percent of Turners patients are missing an entire X?

Back 329

57% (most severe--45, X)

Front 330

What are the clinical symptoms of Turners 45,X?

Back 330

Short
Low neck hairline
Webbed neck
Cubitus Valgus, broud chest, spaced nipples
High arched palate**
Lymphedema of hands and feet
Failure to develop female secondary sex characteristics
Congenital malformations
(horseshoe kidney, bicuspid aortic valve, coarctation of aorta)
primary amenorrhea

Front 331

What is amenorrhea?

Back 331

OVARIES ARE TRANSFORMED into white streaks of fibrous stroma devoid of follicles

Front 332

T/F--Turner syndrome patients are typically severely mentally retarded.

Back 332

False--Usually normal.
 
Though, subtle defects in non verbal, visualspatial info processing have been noted.

Front 333

What causes Hypothyroidism in Turners patients?

Back 333

Autoantibodies
(25-30% of patients)

[Especially in women missing isochromosome Xp]

Front 334

In adults, what should induce suspicion of Turners and how do you Dx?

Back 334

Short stature and primary amenorrhea combo
 
Dx by karyotyping

Front 335

What percent of Turners patients are Mosaics?

Back 335

43% (one cell type being 45, X)
 
(also have structural abnormalities of X)

Front 336

What is the most common structural abnormality of X in Turners?

Back 336

46, X, i(X)(q10)
 
deletion of the small arm forming an isochromosome of the long arm--> leads to partial monosomy of X

Front 337

T/F--Turner Syndrome has a karyotypic heterogeneity associated with significant variation in phenotype.

Back 337

True!
(mosaics and deletions--> partial monosomy --> varying levels; 45, X--> full monosomy)

Front 338

What is the best case for patients who do not have full monosomy X?

Back 338

Have almost a normal appearance
 
Present w/ only primary amenorrhea

Front 339

What is the modified Lyon hypothesis?

Back 339

Although one X chromosome is inactivated during embryogenesis, it is selectively reactivated in germ cells before 1st meiotic division
 
Certain X chrom genes remain active on both Xs in normal female cells-->2 copies of some X linked genes are essential for normal female development

Front 340

What is an example of a gene that remains activated in both X chromosomes?

Back 340

Short stature homeobox (SHOX) gene ---Xp22.32
--> involved in vertical growth
 
Homologue of SHOX on Y chrom
-->so that Males develop normally

Front 341

What are the 3 groups of diseases from single gene mutations that do not follow mendelian genetics?

Back 341

Diseases caused by triplet repeat mutations
 
Diseases caused by mutations in mitochondrial genes
 
Diseases associated w/ genomic imprinting

Front 342

What is a Triple repeat mutation disease?

Back 342

Mutation characterized by long repeating sequence of 3 nucleotides

Front 343

What are some examples of Triple Repeat Mutation Diseases?

Back 343

Fragile X
Huntingtons
Myotonic Dystrophy

Front 344

What is fragile X syndrome?

Back 344

Mutation of FMR1 gene (Xq27.3)
 
X-linked recessive---> mainly affects Males

Front 345

What is unique about fragile X syndrome in relation to being X-linked recessive?

Back 345

20% of carriers of mutation are normal

Front 346

What is fragile X characterized by?

Back 346

Mental Retardation
(moderate to severe)
 
Abnormality in X (long arm)

Front 347

What is one of most common causes of familial mental retardation?

Back 347

Fragile X

Front 348

What is the characteristic Fragile X phenotype?

Back 348

Long face w/ large mandible
Large everted ears
Large testicles

Front 349

What is the ONLY distinctive physical abnorm in at least 90% of post pubertal male patients?

Back 349

Large testicles (macro-orchidism)

Front 350

What is odd in respect to female carriers of Fragile X?

Back 350

50% are mentally retarded

Front 351

What is the Molecular basis of fragile X?

Back 351

CGG repeats in 5' untranlaated area of FMR1 gene...
 
In disease--expanded CGG repeats are hypermethylated
-->methylation extends upstream to promotor region
--> silences FMR1 gene
à FMRP not produced

Front 352

What is the product of the FMR1 gene?

Back 352

FMR protein
(Common in normal tissues)

High levels in brain and testes

Front 353

What happens in loss of FMRP?

(ie—in Fragile X)

Back 353

Loss of FMRP dysregulates production of critical target proteins involved in normal neuronal function

(mutation=200+ CGG repeats)

Front 354

What do ALL discovered Triple Repeat Mutations have in common?

Back 354

Neurodegenerative changes**
Amplification of codon that disrupts gene function
Unique inheritance

Front 355

What is the mode of mitochondrial DNA inheritance?

Back 355

ONLY maternal

Front 356

What is done to modify specific regions of chromosomes during gametogenesis?

Back 356

They are methylated (silenced)
aka--imprinted

Front 357

T/F--All maternal gametes and All paternal gametes imprint in the same regions.

Back 357

False!
paternal vs maternal imprinting:

all men have same imprinting as all men

all women have same imprinting as all women

But these women do NOT imprint the same genes as men (and vice versa)

Front 358

T/F--Genes that are paternally imprinted are only expressed on the maternal chromosome, and vice versa.

Back 358

True!

Front 359

What is genomic imprinting?

Back 359

Certain genes are inactivated (silenced through methylation) during gametogenesis…
 
Maternal imprinting--silencing of maternal allele
(expressed on paternal)
 
Paternal imprinting--silencing of paternal allele
(expressed on maternal)
 

Imprinting occurs in ovum or sperm--> transmitted to all somatic cells

Front 360

What do all cases of Prader-Willi syndrome involve?

Back 360

Deletion in paternal chromosome 15**
 
50-60% of pts its del(15)(q11;q13)
 
(deletion has been detected in clinically normal patients too)

Front 361

What is Prader-willi syndrome clinically characterized by?

Back 361

Mental retardation
Short
Obese
Small hands and feet
Hypotonia
Hypogonadism

Front 362

What is happy puppet syndrome?

Back 362

Angelman syndrome
 
Deletion in maternal chromsome 15
del(15)(q11;q13)

Front 363

What are characteristics of Angelman Syndrome?

Back 363

Mentally retarded
Ataxic gait
Seizures
Inappropriate laughter

Front 364

How do Prader willi and Angelman Syndromes demonstrate "parent of origin" effects on gene function?

Back 364

If chrom 15 of mom and dad were expressed identically
--> then these diseases should have the same symptoms
 
But they don't...Imprinting can help explain…
 
Maternal 15q12 is imprinted (silenced) Thus, only dad provides genes…
 
If a deletion in paternal chromosome 15
---> Pt develops Prader-Willi syndrome
(because no functioning gene)

Front 365

Normally, Where is the active Angelman gene located?

Back 365

Maternal 15

Front 366

Normally, Where is the active Prader Willi Gene located?

Back 366

Paternal 15

Front 367

What is the leading cause of death in 1-15yo?

Back 367

Injury!

Front 368

Where does the US rank in global infant mortality rates?

Back 368

2nd!! (to slovakia)

Front 369

What percent of neonatal deaths occur in the 1st 24 hrs?

Back 369

50%

Front 370

What percent is of neonatal deaths occur in the 1st week?

Back 370

75%

Front 371

What are the leading causes of infant death in the US?

Back 371

Congenital anomalies (20%)
 
Low birth weight (17%)
 
SIDS (8%)
 
Preggo complications (6%)
 
Injuries (4%)

Front 372

How often do congenital anomalies occur in newborns?

Back 372

3%

Front 373

What percent of congenital anomalies have a known cause?

Back 373

50%
 
(genetic, environmental, multifactorial)

Front 374

What is the most common cause of congenital anomalies in infants?

Back 374

Multifactorial
(genetic + environment)
 
(cleft lip/palate, neural tube defects)

Front 375

What is a malformation congenital anomaly?

Back 375

Primary errors in morphogenesis, usually multifactorial

Ex) congenital heart defects

Front 376

What is a disruption congenital anomaly?

Back 376

Secondary destruction of previously normal tissue
 
Extrinsic, non heritable, no INC risk in siblings
 
Ex) amniotic bands

Front 377

What is a deformation congenital anomaly?

Back 377

2% of all births
 
Extrinsic, usually due to fetal compression
(from multiple fetuses, fibromas, uterine abnormalities)

Front 378

What is a sequence congenital anomaly?

Back 378

Cascade of multiple abnormalities due to single initiating event
 
Ex) Renal agenesis causing oligohydraminos resulting in feta compression

Front 379

What is malformation Syndrome?

Back 379

Usually caused by single factor affecting multiple systems
 
Ex) viral infect, chromosomal abnormality

Front 380

What is the Most common malformation in US?

Back 380

Clubfoot w/o CNS abnormalities (25.7/10K)

Front 381

How common is a cleft palate?

Back 381

1 in 1000 births in white
 
Unilateral is 9x's more likely than bilateral
 
(failure to fuse maxillary and medial nasal processes)

Front 382

How common is a cleft palate?

Back 382

1 in 700 births
 
(palate plates don't fuse, usually also cleft lip)

Front 383

Where are cleft palate and cleft lip most common?

Back 383

Native American and Asians (multifactorial)

Front 384

How is risk for cleft lip and palate reduced?

Back 384

Prenatal folic acid

Front 385

What is the Potter sequence?

Back 385

Renal agenesis--> oligohydramnios (insufficient amniotic fluid)
 
--> fetal compression--> deformation
 
Flattened face
Club foot
Pulmonary hypoplasia (restricted thoracic movement)

Front 386

What are the 2 types of perinatal infections?

Back 386

Ascending (transcervical)
 
Transplacental

Front 387

What is an ascending infection?

Back 387

Bacterial (Strep agalactiae)
Viral (HSV)
Pneumonia, sepsis, meningitis

Front 388

What is a Transplacental infection?

Back 388

TORCH is most important

(toxoplasma, rubella, CMV, HSV, other--syphilis)

Front 389

What is the reservoir for Toxoplasma gondii?

Back 389

Cat

Front 390

How does a prenatal Toxoplasma gondii infection affect the baby?

Back 390

1-5% die before born
 
Serious brain damage
 
Chorioretinitis (blindness)

Front 391

What are the craniofacial anomalies associated w/ Treponema pallidum?

Back 391

Hutchinson's teeth
Mulberry (Moon's) molars
Mucous patches
Perforated palate
Saddle nose

Front 392

What is neonatal herpes encephalitis?

Back 392

From Neo or perinatal HSV
 
Brain is almost liquified
 
High mortality rate
 
Survivors have residual disabilities
(quadriplegia, microcephaly, blind)

Front 393

What is the 2nd leading cause of neonatal and infant mortality in the US?

Back 393

Prematurity! (earlier than 37 wks)

Front 394

What does Organ immaturity predispose?

Back 394

Respiratory Distress syndrome (Hyaline membrane disease)
 
Necrotizing enterocolitis

Front 395

What causes Fetal Growth Retardation?

Back 395

( less than 2500g at term)
 
Maternal factors--MOST COMMON! **
(preeclampsia, HTN, narcotics, alcohol, cigarettes)
 
Fetal factors:
(Chromosomal abnormalities, Infections--TORCH)

Front 396

What is the greatest risk factor for Neonatal Respiratory Distress Syndrome (RDS)?

Back 396

Prematurity!
 
(Aka--hyaline membrane disease--> major cause of neonatal death)

Front 397

What is wrong in neonatal RDS?

Back 397

Insufficient lung surfactant synthesis by immature lung

(type 2 pneumocytes secrete surfactant)

Front 398

How do you increase secretion of lung surfactant in RDS?

Back 398

Steroids, thyroxine, normal delivery process
 
(inhibited by insulin)

Front 399

What is the long term sequelae of neonatal RSD?

Back 399

Bronchopulmonary dysplasia
(fibrosis and honeycombing)

Front 400

What is the Tx for RSD?

Back 400

O2
Mechanical ventilation
Surfactant replacement

Front 401

How do you prevent RSD?

Back 401

Antenatal corticosteroids

(indicated to all preggos of 24-34 weeks at risk of premature delivery w/in 7 days)

Front 402

What are the clinical signs of necrotizing enterocolitis?

Back 402

Bloody stoold, abdominal distention, circulatory collapse

Front 403

What is an important cause of death in infants 1-12months?

Back 403

SIDS

Front 404

What type of factors are likely associated with SIDS?

Back 404

Multifactorial (lots of factors…low SES, black, male)

--> position of sleeping makes more prone

Front 405

What is Hydrops Fetalis?

Back 405

Generalized fetal edema

Front 406

What is the most common cause of hydrops fetalis?

Back 406

Non-Immune!!
Chromosomal (Turner, Down syndromes)
Anemia (a-thalassemia)
Parvovirus B19--causes anemia
CV defects

Front 407

What immune diseases can cause hydrops fetalis?

Back 407

Rh or ABO incompatability
(hemolytic disease of newborn, erythroblastosis fetalis)

Front 408

What is kernicterus?

Back 408

Brain damage caused by release of too much bilirubin
 
If Rh or ABO incompatibiility--> attack/lyse RBC--> release bilirubinà crosses BBB

Front 409

What is a cystic hygroma?

Back 409

In turner syndrome, abnormal lymphatic drainage leads to accumualtion of postnuchal fluid
Hydrops fetalis

Front 410

What is the most common autosomal recessive disease in NW europe?

Back 410

Cystic Fibrosis

Front 411

What causes cystic fibrosis?

Back 411

Mutation in CF gene on Chromosome 7 that encodes CFTR

"cystic fibrosis transmemb conductance regulator" protein

Front 412

What do mutaton in CFTR result in?

Back 412

Abnormal Cl transport across epithelia

Front 413

What is the Primary defect in cystic fibrosis?

Back 413

Abnormal Cl transport across epithelia!!

(CTFR mutation!)

Front 414

What does CTFR do?

Back 414

Allow release of Cl from cell thru Cl channels
 
Inhibits epithelial sodium channel
EXCEPT--sweat glands
 
Overall function--Control of bulk water flow across epithelia!

Front 415

What is the most common mutation of CTFR?

Back 415

(70%) deletion at 508--ATP binding cassette #1

Front 416

What causes salty sweat?

Back 416

Loss of function of CFTR in sweat glands!

(Reabsorb Cl-, Augment Na+ reabsorb via ENaC)

Front 417

What is the result of loss of function of CFTR in the respiratory and intestinal epithelium?

Back 417

Thick and viscous secretions!!
 
(Loss of Cl secretion, INC Na absorption--> INC passive water reabsortion--> lowers water content of mucus--thick and viscous secretions)

Front 418

What are 2 easy clinical sings of Cystic Fibrosis?

Back 418

Salty skin (usually 1st)
Viscous Mucus

Front 419

What are the most important clinical manifestations of CF?

Back 419

Recurrent and chronic pulmonary infections
pancreatic insufficiency
(mal absorption)
Diabetes

Front 420

More than 90% of CF patients will die of what type of complication?

Back 420

Pulmonary complications!!

Front 421

What are common along with CF pulmonary disease?

Back 421

Severe bronchitis
Bronchiectasis
lung abscesses

Front 422

What organisms are most commonly isolated from CF pulmonary disease?

Back 422

Staph aureus and
Pseudomonas aeruginosa (green)

Front 423

What causes fibrocystic disease of the pancreas?

Back 423

In CF, viscous secretions fill and plug ducts--> become cysts

Front 424

What are 2 types of tumor-like lesions?

Back 424

Heterotopia or Choristoma:
(Normal cells or tiss in abnormal locations!)
 
Hamartoma:
(Excessive focal overgrowth of mature cells of an organ)

Front 425

What are the most common tumors in infancy?

Back 425

Hemangiomas

Front 426

What is characteristic of a hemangioma?

Back 426

Port wine stains

Front 427

What is a lymphangioma?

Back 427

Benign hyperplasia of lymphatic vessels lined w/endothelial cells...Contain lymph

Front 428

What is a Simple (Capillary) Lymphangioma?

Back 428

--mostly head, neck, axilla
--lesions up to 2 cm
--network of lymph channels

Front 429

What is a Cavernous Lymphangioma (Cystic hygroma)?

Back 429

--neck or axilla
(rarely the retroperitoneum)
--Can be ENORMOUS (<15cm)
--massively dilated lymph spaces; lymphoid aggregates
--lesions NOT encapsulated, NO discrete margins

Front 430

What chromosomal disorder is associated with cavernous lymphangiomas
(or cystic hygromas)?

Back 430

Neck lesions common in Turner syndrome

Front 431

What is the most common germ cell tumor of childhood?

Back 431

Sarcococcygeal Teratomas (40% )
 
--75% benign, 12% malignant, 10% congenital abnormality

Front 432

What is the 2nd most common cause of death in kids 4-14yo?

Back 432

Malignant Tumors
 
(Neuroblastoma, Retinoblastoma, Wilms)

Front 433

What causes 15% of childhood cancer deaths?

Back 433

Neuroblastoma

Front 434

What is the mechanism of Neuroblastomas?

Back 434

Mostly sporadic! (recessive)

Some autosomal dominant familial transmissions

Front 435

Where do neuroblastomas originate?

Back 435

The neural crest

Front 436

Where are 75% of neuroblastomas Located?

Back 436

The abdomen (adrenal medulla and paravertebral sympathetic ganglia)

Front 437

What do 90% of neuroblastomas produce?

Back 437

Cateholamines

Front 438

What kind of cells make up a Neuroblastoma?

Back 438

Undifferentiated cells!
 
Homer-Wright rosettes--Tumor cells arranged around central space

Front 439

What is the most common malignant eye tumor of childhood?

Back 439

Retinoblastoma

Front 440

What are the characteristics of Familial retinoblastomas?

Back 440

Multiple bilateral tumors

Front 441

What are the characteristics of a sporadic retinoblastoma?

Back 441

Single, unilateral tumor

Front 442

What causes a retinoblastoma?

Back 442

Loss of function mutation of RB1 gene
(recessive)

Front 443

Where do retinoblastomas usually arise?

Back 443

POSTERIOR to retina
 
--> disseminate thru optic nerve
 
Metastases in CNS, Skull, bones, lymph nodes

Front 444

What is the most common primary tumor of the kidney in children?

Back 444

Wilms tumor

Front 445

What are the 6 pollutants that the Environment Protection Agency (EPA) monitors and sets allowable upper limits for?

Back 445

Lead
Sulfur dioxide
Particulate matter
Ozone
Carbon monoxide
Nitrogen dioxide

Front 446

Collectively, what do these agents produce?

Back 446

Smog

Front 447

What is the most intractable air pollutant and what is its toxicity related to?

Back 447

Ozone. It initiates free radicals.

Front 448

What symptoms are felt after exposure to ozone?

Back 448

Healthy subjects--mild respiratory symptoms
(DEC lung function, pain)
 
Very harmful to people w/ asthma or emphysema

Front 449

What air particles constitute the greatest hazard?

Back 449

Less than 10 um in diameter, no matter what composition

Front 450

What else do these same fine particles (<10um) contribute to?

Back 450

Creation of smog

Front 451

Why are a combination of air pollutants considered a "witch's brew"?

Back 451

Single pollutants may be tolerated and do have capacity to impair lung function
 
But when there is a combo--> amplified effect is much worse

Front 452

What is the most common indoor air pollutant?

Back 452

Tobacco smoke

Front 453

What is radon?

Back 453

Radioactive gas from uranium (Indoor pollutant)
 
Widely present in soil
 
Low levels in homes
(ESP near nuc power plants and waste disposal sites)

Front 454

What has Radon been linked to the etiology of?

Back 454

Lung cancer!

(even low levels over time)

Front 455

What are bioaerosols?

Back 455

Microbiologic agent and Allergens
 
(Less threatening but still distressing)

Front 456

What is the range industrial exposures?

Back 456

Varied!

Irritation of airway mucosa by formaldehyde or ammonia fumes

Lung cancer is secndary to exposure to asbestos, volatized Ni, arsenic, or Cr

Leukemia after prolonged exposure to benzene or uranium

Front 457

Where can organic compound pollutants be commonly found?

Back 457

In degreasing and dry cleaning agents and paint removers
(chloroform and carbon tetrachloride)
 
In combustion of fossil fuels
 
In synthesis of plastics

Front 458

What are symptoms of organic compound exposure?

Back 458

Acute exposure to high levels of vapors:
Dizzy, confused
--> CNS depression, even coma
 
Lower levels:
liver and kidney toxicity

Front 459

What organic compound has been implicated in industrial exposures in production of lung and bladder cancer?

Back 459

Polycyclic hydrocarbons
(potent carcinogen)

Front 460

How are polycyclic hydrocarbons released industrially?

Back 460

Released from combustion of fossil fuels
(High temp burn of coal and gas in steel foundries)

Front 461

Exposure to what organic compound predisposes angiosarcoma of the liver?

Back 461

Vinyl chloride monomers
(synthesis of polyvinyl resins)

Front 462

What have rubber workers using 1,3-butadiene developed?

Back 462

Leukemia

Front 463

To what indoor air pollutants are only children at risk?

Back 463

--N2O
--Wood smoke
 
(INC respiratory infections)

Front 464

T/F--Lead poisoning is restricted to workers in particular industries.

Back 464

False! Potential household danger as well!

Front 465

When metals (like, Arsenic, Ni, Cr) are volatized, what do they predispose?

Back 465

Lung cancer

Front 466

What is the most dangerous sized particle in Pneumoconioses?

Back 466

Particles 1-5 um
(impact on bifurcation of distal airways)

Front 467

What are 3 examples of dust that are more reactive than coal dust and lead to fibrosis at lower concentrations?

Back 467

Silica, asbestos, and beryllium

Front 468

What happens to dust particles that are not removed from the lung by the ciliary elevator?

Back 468

become impacted at alveolar duct bifurcations
--> macrophages accumulate and endocytose particles

More reactive particles trigger macrophages to release products that are toxic to lung -->Inflamm response --> initiates fibroblast prolif and collagen deposition

Front 469

What is the key element in initiation and perpetuation of lung injury and fibrosis?

Back 469

Pulmonary alveolar macrophage

Front 470

What mediators do these macrophages release?

Back 470

Free radicals! (reactive oxygen and nitrogen species)
 
--> induce lipid peroxidation and tissue damage

Front 471

What do chemotactic factors do?

Back 471

recruit and activate inflammatory cells
 
Release damaging oxidants and proteases

Front 472

What are some chemotactic factors?

Back 472

LTB4
IL8
IL6
TNF

Front 473

What worsens the effects of all inhaled mineral dusts?

Back 473

Tobacco smoke
(largest effect on--Asbestos!!)

Front 474

What are the lung findings in coal workers?

Back 474

Wide spectrum
 
Asymptomatic anthracosis
(pigment accumulates, no cell reaction)
 
Simple coal workers' pneumoconiosis (CWP)
(caccumulations of macrophages, little to no pulmonary dysfunction)
 
Complicated CWP or Progressive Massive Fibrosis (PMF)
(confluent fibrosis is extensive and lung function is compromised)

Front 475

What percent of simple CWP progress to PMF?

Back 475

Less than 10%

Front 476

What has been associated with higher risk of CWP?

Back 476

Mining of anthracite coal
(has most carbon)
 
(bituminous has the least)

Front 477

What is the most innocuous coal induced pulmonary lesion in coal miners?

Back 477

Pulmonary anthracosis
 
(inhaled carbon pigment engulfed by macrophages--> accumulate in CT along lymphatics or in organized lymph tissue along bronchi or lung hilus)

Front 478

Where else is pulmonary anthracosis commonly seen?

Back 478

Urban dwellers
and tobacco smokers

Front 479

At autopsy, where can Pulmonary anthracosis be seen?

Back 479

Linear streaks of aggregates of anthracotic pigment
 
(pulmonary lymphatics, pulmonary lymph node)

Front 480

What is simple CWP charaterized by?

Back 480

Coal macule = dust laden macrophages
 
Coal nodule = dust macrophages and delicate network of collagen fibers (larger)

Front 481

What is centrolobular emphysema?

Back 481

Dilation of alveoli that is adjacent to CWP lesions
(near dust accumulation)

Front 482

What is Complicated CWP/PMF characterized by?

Back 482

Intensely blackened scars more than 2-10cm
 
Microscopically--lesions = dense collagen and pigment
 
Center of lesion is often necrotic (most likely due to ischemia)

Front 483

What distinguishes CWP from Silicosis?

Back 483

In CWP--No evidence to show that coal dust increases susceptibility to TB!
(not so in silicosis)

Front 484

What distinguishes CWP from Asbestosis?

Back 484

In CWP--no increased frequency of bronchogenic carcinoma
(not so in asbestosis)

Front 485

What is most commonly implicated in silicosis?

Back 485

Quarts (1um particles are worst!)
 
(crystalline silic = most toxic/fibrogenic form)

Front 486

What is a characteristic sign of acute silicosis?

Back 486

Cyanosis

Front 487

Histologically, what is diagnostic of acute silicosis?

Back 487

Accumulation of proteinaceous fluid rich in surfactants w/alveolar space

Front 488

What is characteristic of Chronic nodular silicosis?

Back 488

fibrotic nodules of silicosis
(upper lung, subpleural spaces)
 
X-ray---well demarcated round opacities

Front 489

What causes acute, chronic, and complicated silicosis, respectively?

Back 489

Acute silicosis--very high levels
 
Chronic silicosis--Exposure over long time
 
Complicated silicosis--Progression from chronic

Front 490

What is characteristic of chronic conglomerate silicosis?

Back 490

expansion and coalescence of individual silicotic nodules
Destruction of lung parynchema (PMF)
Silicotic noduels more
than 2cm!**

Front 491

What pulmonary disease is a silicosis patient increasingly susceptible to?

Back 491

TB

(nodules of silico-TB often have central zone of caseation)

Front 492

T/F--The IARC has concluded that crystalline silica from occupational sources is carcinogenic to humans.

Back 492

True!

(may be related to silica's ability to induce ROS)

Front 493

What is microscopically distinctive for silicosis?

Back 493

"whorled" appearance of collagen fibers

Front 494

What did polarized microscopy of silicosis nodules show?

Back 494

Weakly birefringent silica particles
àPrimarily in center of nodules

Front 495

When do most silicosis patients develop shortness of breath?

Back 495

Late! (after PMF is present)

Front 496

What is asbestos?

Back 496

Asbestos--crystalline hydrated silicates w/fibrous geometry

Front 497

What is occupational asbestos exposure linked to?

Back 497

Parenchymal interstitial fibrosis
 
Bronchogenic carcinoma
 
Pleural effusions
 
Localized fibrous plaqies
 
Diffuse pleaural fibrosis (rare)
 
Malignant pleural and peritoneal mesotheliomas*****
 
Laryngeal carcinomas (possibly)

Front 498

What are the 2 distinct forms of asbestos?

Back 498

Serpentine (curly and flexible fibers)
 
Amphibole (straight, stiff, brittle)

Front 499

What is the most commonly used form of asbestos?

Back 499

Serpentine

Front 500

What is the most pathogenic type of asbestos?

Back 500

Amphibole
(induce malignant mesotheliomas)

Front 501

Why is amphibole asbestos more pathogenic?

Back 501

Straight, stiff---> align in airstream--> delivered deeper in lungs, may penetrate epithelial cells and reach interstitium

Front 502

What are the functions of asbestos?

Back 502

Cellular and fibrotic reactions
 
Tumor initiator and promoter

Front 503

What contributes to the pathogenicity of asbestos fibers?

Back 503

Toxic chemicals can be absorbed into asbestos fibers
Ex) cig smoke toxins

Front 504

T/F--Asbestos causes fibrosis by interacting w/ lung macrophages.

Back 504

True. (causes diffuse interstitial fibrosis)

Front 505

T/F--Diffuse pulmonary interstitial fibrosis caused by asbestos is indistinguishable from other similar causes like idiopathic pulmonary fibrosis--EXCEPT for presence of asbestos bodies.

Back 505

True.

Front 506

What is an asbestos body?

Back 506

Golden brown, fusiform or beaded rods w/translucent center
 
Asbestos fibers coated w/ iron containing proteinaceous material
 
Distingushes diffuse pulmonary interstitial fibrosis caused by asbestos

Front 507

Can asbestos bodies be found in normal lungs?

Back 507

Yes.
(lower concentration, w/o interstitial fibrosis)

Front 508

What makes asbestosis different from CWP or silicosis?

Back 508

Asbestosis begins in lower lobe and subpleurally
 
Middle and upper lobes affected as fibrosis progresses

Front 509

What is the most common manifestation of asbestos exposure?

Back 509

Pleural Plaques
 
well circumscribed, collagen
usually anterior and posterolateral parietal pleura, and over domes of diaphragm
No asbestos bodies
Rarely seen w/o asbestos exposure

Front 510

What cancers are predisposed in asbestos workers?

Back 510

Bronchogenic carcinomas (5X's)
 
Malignant mesotheliomas (1000x's)

Front 511

T/F--Mesotheliomas are normally very rare (a few in a million) but asbestos exposure increases likelihood 1000-fold.

Back 511

True.

Front 512

What is significant about asbestos and concomitant cigarette smoking?

Back 512

Greatly INC risk of bronchogenic carcinoma
 
Does NOT inc risk of mesothelioma

Front 513

What is the prognosis of Lung or pleural cancer associated w/ asbestos ?

Back 513

Grim prognosis

Front 514

What does heavy exposure to airborne dusts/fumes of beryllium metal, oxides, aloys, or salts cause?

Back 514

Acute pneumonitis

Front 515

What do longer, low dose exposures to beryllium cause?

Back 515

pulmonary and systemic granulomatous lesions
 àmimic sarcoidosis***

Front 516

Who is at highest risk for beryllium exposure?

Back 516

Workers in nuclear and aerospace industries
(beryllium alloys)

Front 517

How does Beryllium act?

Back 517

As a hapten--Binds proteins and Renders them immunogenic for CD4 helper T cells

Front 518

What gene is associated to susceptibility for berylliosis?

Back 518

MHC II genes

Front 519

What results from the delayed hypersensitivity of beryllium?

Back 519

formation of NON caseating granulomas in lungs and hilar nodes

Front 520

What increases with heavy beryllium exposure?

Back 520

Incidence of cancer

Front 521

How many people die from actively smoking every year in the US?

Back 521

400,000
(1/3 are lung cancer)

Front 522

How does cigaretter smoke lead to edema?

Back 522

Recruits leukocytes to lung --> INC local elastase and subsequent lung injury --> emphysema

Front 523

What are carcinogens of tabacco smoke likely involved in?

Back 523

The origins of cancers in the lung arising from bronchial epithelium
(bronchiogenic carcinoma)

Front 524

What fraction of heart attacks are attributed to cigarette smoking?

Back 524

1/3
(Smoking multiplies HTN and Hypercholesterolemia)

Front 525

What was the birth weight ofinfants born to mothers who stopped smoking before pregnancy?

Back 525

NORMAL!

Front 526

How much does second hand smoke INC risk of lung cancer?

Back 526

1.3x's
(also associated with some other detrimental effects of active smoking)

Front 527

How many deaths every year can be attributed to second hand smoke?

Back 527

30,000-60,000 cardiac deaths a year in US associated w/ 2nd hand smoke! (coronary atherosclerosis and MI)
 
3000 lung cancers deaths each year in nonsmokers over 35 due to second hand smoke

Front 528

What are children living in a house with an adult smoker at an INC risk for?

Back 528

Respiratory illness and asthma

Front 529

What is an example of a chemicals capacity to induce an immune response?

Back 529

Penicillin
in those genetically prone:

May induce type I hypersens
--> IgE mediated anaphylactic response

May induce type II hypersens
--> IgG mediated hemolytic anemia

Front 530

Where are adverse reactions extremely common?

Back 530

Practice of medicine and DENTISTRY!

Front 531

What is an example of hormone replacement therapy (HRT)?

Back 531

Estrogen therapy:
 
Prev. used for menopause, now used in postmenopausal w/ or w/o progesterone:
--Prevent/slow osteoprosis
--DEC chance of heart attack

Front 532

What is a concern with Estrogen HRT?

Back 532

endogenous hyperestrinism INC risk of:
--Endometrial carcinoma
--Breast carcinoma
(Thromboembolism, CV disease)

Front 533

What reduces or eliminates the risk of endometrial carcinoma in Estrogen therapy?

Back 533

Adding progestins!

Front 534

What is the effect of using combo Estrogen and progestin HRT on risk for breast carcinoma?

Back 534

INC risk for breast carcinoma

Front 535

What are 2 of the leading causes of death in postmenopausal women?

Back 535

Myocardial infarction and stroke

Front 536

What effects does estrogen have on cholesterol?

Back 536

Elevates HDL, Lowers LDL--> good! Prevents atherosclerosis.
 
(progestins do the opposite)

Front 537

What is the effect of starting HRT at the beginning of menopause on ischemich heart disease?

Back 537

40-50% DEC in risk of ischemic heart diesease in women that get HRT at beginning of menopause!

Front 538

When is the risk of breast cancer INC by use of combined oral contraceptives?

Back 538

Risk is significantly INC if family Hx of breast cancer or known to carry mutations of BRCA1 or BRCA2

Front 539

What cancer does have an INC risk with ues of oral contraceptives?

Back 539

Cervical cancer
(correlated w/ duration of use and lifestyle)

Front 540

What effects do oral contraceptives exert on ovarian and endometrial cancers?

Back 540

Protective

Front 541

Even with new lower doses, Oral contraceptives have a 3-6x's INC risk of what?

Back 541

--Venous thrombosis
--pulmonary thromboembolism
 
(INC in liver synth coagg factors and DEC activity of protein C)

Front 542

When taken in large doses, what does acetominaphen cause?

Back 542

Hepatic necrosis

Front 543

What are the symptoms of acute lead poisoning in infants and kids?

Back 543

May remain symptomless/
unsuspected until it erupts in catastrophic encephalopathic crisis

Front 544

What is a pathologic feature of lead poisoning relevant to dentistry?

Back 544

Gingiva--lead line
-> hyperpigmentation of gingiva adjacent to teeth

Front 545

What happens to most of absorbed lead (80-85%)?

Back 545

Taken up by bone and developing teeth**
 
(rest in blood and soft tissues)

Front 546

What causes hypochromic anemia?

Back 546

Lead
--> interferes with iron incorporation in heme synthesis

Front 547

What anemia is associated with Lead poisoning?

Back 547

Microcytic, hypochromic--mild hemolytic anemia

Front 548

What 2 things are elevated in blood in Lead poisoning?

Back 548

-- Zn-protoporphyrin
-- Free erythrocyte protopotphyrin
 
(important indicators of lead poisoning)

Front 549

What is the common peripheral neuropathology of Lead poisoning in adults?

Back 549

Demyelination (Typicallly, motor innervation)
 
Extensor muscles of wrist and fingers--1st affected

Front 550

What is a very obvious progression of this demyelination in lead poisoning?

Back 550

wristdrop and footdrop--> paralysis of peroneal muscles

Front 551

What is "saturnine gout"?

Back 551

Lead toxicity--> Chronic renal damage--> interstitial fibrosis, possible renal failure and findings suggestive of gout

Front 552

When does hypoxia appear in CO posioning?

Back 552

when Hb is 20-30% saturated w/CO

Front 553

When does unconciousness and death occur in CO poisoning?

Back 553

Hb is 60-70% saturated w/ CO

Front 554

What can identify CO poisoning in light skinned patients?

Back 554

Acute CO poisoning--"cherry red color of skin and mucous membranes" (From CO-Hb)

Front 555

Why can chronic poisoning occur in CO poisoning?

Back 555

Chronic poisoning may appear b/c CO-Hb is very stable!!
 
(low level persistent exposure, previous exposure)

Front 556

What is Dx of CO poisoning critically dependent on?

Back 556

Identifying significant levels of CO-Hb in blood

Front 557

What is the 4th most comon cause of death between 25-46yo?

Back 557

Alcohol (cirrhosis of liver usually)
 
100,000 deaths in US/yr

Front 558

What is the biotransformation of alcohol?

Back 558

EtOH--(alcohol dehydrogenase)--> Acetaldehyde--> acetic acid

Front 559

What does excess NADH (from oxidation of alcohol) cause?

Back 559

Acidosis

Front 560

What will be the BAC of a 70kg man who drinks 3oz of ethanol in a few hours? (8 beers, 12oz wiine, or 6oz liquor)

Back 560

100 mg/dL

--> legal limit

Front 561

What is the major metabolite of ethanol?

Back 561

Acetaldehyde
àVery reactive

(Mediator of widespread damage?)

Front 562

What is the most common cause of hepatic injury?

Back 562

Alcohol (may lead to cirrhosis)

Front 563

What vitamin deficincy is common in chronic alcoholics?

Back 563

Thiamine--vit B1

Front 564

What have moderate amounts (1/day) of alcohol shown?

Back 564

INC of HDL levels
 
Inhibit platelet aggregation (lower coronary heart disease)

Front 565

What do the most serious physical effects of cocaine relate to?

Back 565

Its acute action on the CV system
(excess epi and norepi--> HTN and tachicardia, MI)

Front 566

T/F--Fatal event may occur in 1st time abuser w/ what is a typical mood altering dose.

Back 566

True.

Front 567

What does cocaines blocking of reuptake do to postsynaptic fibers?

Back 567

Excess stimulation

Front 568

How common is endocarditis in heroin addicts?

Back 568

More than 10%
Staph aureus
Usually right side—tricuspid

Front 569

What is one of the most common infection in addicts?

Back 569

Viral hepatitis

Front 570

What is the most frequent tell tale sign of a heroin addiction?

Back 570

Cutaneous lesions

Front 571

What is the most widely used illegal drug?

Back 571

Marijuana

Front 572

What are 2 beneficial effects of THC?

Back 572

DEC intraocular pressure in glaucoma
 
Counter nausea secondary to chemo

Front 573

What are physical agents that can induce injury?

Back 573

Mechanichal
Thermal
Electrical
Ionizing radiation***

Front 574

What is an abrasion?

Back 574

Wound produced by rubbing or scraping
--> remove superficial layer
 
ONLY epidermal

Front 575

What is a contusion?

Back 575

Bruise--usually produced by blunt object
--> several damaged blood vessels and extravasation of blood into tissues

Front 576

What is a laceration?

Back 576

Tear or disruptive stretching caused by blunt object--> intact bridging blood vessels and jagged, irregular edges

Front 577

What is an incision?

Back 577

Inflicted by sharp instrument--> severed blood vessels

Front 578

What is a puncture wound?

Back 578

Caused by long narrow instrument
--penetrating when pierces tissue
--perforating when traverses tissue and creates exit wound

Front 579

How many deaths from burns a year in the US?

Back 579

5000 deaths/yr
(hospitalizes over 50,000/yr)

Front 580

What is the morphology of a full thickness burn?

Back 580

White or charred
Dry
Anesthetic (nerve ending destruction)

Front 581

What is the morphology of a partial thickness burn?

Back 581

(depends on depth)
Pink or mottled with blisters
Painful

Front 582

What is revealed in devitalized tissue of burns?

Back 582

Coagulative necrosis
(adjacent to vital tissue that quickly starts inflammatory process)

Front 583

What is the prognosis of any burn over more than 50% of body surface (superficial or deep)?

Back 583

Grim and potentially fatal

Front 584

What happens in burns that are more than 20% of the body surface?

Back 584

Rapid shift of body fluid in interstitial compartments
--> can lead to hypovolemic shock

Front 585

What is the leading cause of death in burn patients?

Back 585

Organ system failure from burn sepsis

Front 586

What is the most common bacterial infection in burns?

Back 586

Pseudomonas aeruginosa (opportunist)

Front 587

What are the most common sequelae to bacteremic spread in a burn patient?

Back 587

Pneumonia or septic shock--> Renal failure and/or Acute respiratory distress syndrome

Front 588

What is heat stroke?

Back 588

Hyperthermia
Associated with high ambient temps and humidity
Thermoregulators fail
Sweating stops
Core body temp rises

Front 589

What is hypothermia?

Back 589

Prolonged exposure to low ambient temperature
àLowered body temperature
(hastened by water, moisture)

Front 590

What does the type and severity of electrical injury depend on?

Back 590

Amperage
(and path through body)

Front 591

What does an alternating current induce?

Back 591

Tetanic muscle spasm
 
(electricity in most homes)

Front 592

What is a classic cause of high voltage electrical injury?

Back 592

Lightning

Front 593

What can radiation energy interfere with?

Back 593

Radiation can interfere w/ cardiac pacemakers
(EMF and microwave)

Front 594

What causes secondary malnutrition?

Back 594

Malabsorption
Impaired utilization or storage
Excess nutrient losses
INC need for nutrients

Front 595

What does a polished rice diet create?

Back 595

Thiamine (B1) Deficiency

Front 596

What is lacking in water in regions that are removed oceans and not supplemented?

Back 596

Iodine

Front 597

What are common causes of dietary insufficiency?

Back 597

Ignorance and poverty
Chronic alcoholism
Acute and chronic illness
Self-imposed diet restrictions
Other

Front 598

What deficiencies do chronic alcoholics frequently have?

Back 598

Thiamin (B1)
Pyridoxin (B6)
Folate (B9)
Fat soluble--vit A, D, E

Front 599

What can failure to recognize B1 deficiency in chronic alcoholics lead to?

Back 599

Irreversible brain damage

Front 600

What characterizes PEM?

Back 600

diet inadequate in protein and calories to meet body's needs

Front 601

What are the 2 types of PEM?

Back 601

Marasmus
Kwashiorkor

Front 602

What are the 2 protein compartments of the body?

Back 602

Somatic protein compartment
(skeletal muscle)
Visceral protein compartment
(organs--liver)

Front 603

What protein compartment is affected more severely in marasmus?

Back 603

Somatic

Front 604

What protein compartment is affected more severely in kwashiorkor?

Back 604

Visceral

Front 605

With loss of fat, what happens to skin folds?

Back 605

Reduced thickness

Front 606

What is measurable in Dx of marasmus (somatic)?

Back 606

Results in reduction of muscle mass--> reflected by circumference of mid-arm

Front 607

What is measurable in Dx of kwashiorkor (visceral)?

Back 607

Evaluation of serum proteins
(albumin, transferrin, etc)

Front 608

Who are the most common victims of PEM worldwide?

Back 608

Children
(weight under 80% of normal)

Front 609

What is diagnosed when weight is 60% under normal?

Back 609

Marasmus
(child can suffer growth retardation)

Front 610

In PEM, how depleted is the visceral protein compartment?

Back 610

Only marginally
(more precious, critical for survival)
(normal or slightly low serum albumin)

Front 611

Where is Kwashiorkor PEM most commonly seen?

Back 611

African kids who are weaned too early
--> subsequently fed exclusively carb diet

Front 612

Which is more severe malnutrition, Kwashiorkor or Marasmus?

Back 612

Kwashiorkor
(lose visceral protein--> hypoalbuminemia --> edema (distended bellies)

Front 613

T/F--Marasmus and Kwshiorkor are almost the exact same disease.

Back 613

False--they are opposite ends of the spectrum.
(overlap does exist though)

Front 614

What is cachexia?

Back 614

A severe form of secondary PEM seen in advanced cancer.
(May be due to loss of apetite or INC metabolism by tumor.)

Front 615

What are the central anatomic changes in PEM?

Back 615

Growth failure
Peripheral edema (kwash)
Loss of body fat and atrophy of muscle (marasmus)

Front 616

What exists in Kwashiorkor but not marasmus?

Back 616

Enlarged fatty liver

Front 617

What is in Kwashiorkr and rarelyin marasmus?

Back 617

DEC mitotic index of crypts in small intestine
(mucosal atrophy, loss of villi)

Front 618

What causes a disaccharidas deficiency in PEM?

Back 618

(mainly in Kwashiorkor)
DEC mitotic index of crypts in small intestine
-->mucosal atrophy, loss of villi
--> loss of enzymes

Front 619

What is the anemia most common in PEM?

Back 619

Hypochromic microcytic anemia

Front 620

What is so common in anorexia that it is diagnostic of it?

Back 620

Amenorrhea

Front 621

What is languo?

Back 621

INC body hair in anorexia (fine and pale)

Front 622

Why is amenorrhea less common in bulimia?

Back 622

amenorrhea in less than 50%--> weight and gonadotropins are near normal

Front 623

What vitamins can be synthesized endogenously?

Back 623

VitD (steroids)
Vit K and biotin (microflora)
Niacin (from Tryptophan)

Front 624

What are 2 cases of vitamin deficiencies?

Back 624

Primary deficiency
Secondary deficiency
(absorption, transport, storage, metab)

Front 625

T/F--Deficiencies of a single vitamin are uncommon.

Back 625

True! (combos, PEM)

Front 626

What is the most important form of Vitamin A?

Back 626

Retinol
(Retinol=transport form
Retinol ester = storage form)

Front 627

What form of vitamin A is used n visual pigment?

Back 627

Aldehyde retinal (oxidized)

Front 628

What are carotenoids?

Back 628

In yellow and leafy green vegetables
(carrots, squash, spinach)
 
Provitamins that can be activated into VitA

Front 629

What is the most important Carotene?

Back 629

B-carotene

Front 630

Where is 90% of body's vitA stored?

Back 630

Liver--perisinusoidal stellate cells

Front 631

What is retinoic acid active in?

Back 631

Active in epithelial differentiation and growth
 
NOT active in maintenance of vision**

Front 632

What vitA containing pigment is located in rods?

Back 632

Rhodopsin--rods
(most light sensitive--> important in reduced light)

Front 633

What role does VitA play in epithelium?

Back 633

Role in orderly differentiation of mucus-secreting epithelium

Front 634

During a Vit A deficiency, what happens to epithelium?

Back 634

Epithelium undergoes squamous metaplasia
--> differentiation to keratinizing epitheluim

Front 635

What is one of the earliest manifestations of vitA deficiency?

Back 635

Impaired vision
(esp in dark light--> night blindness)

Front 636

What are ocular changes called collectively?

Back 636

Xerophthalmia
(results from vitA deficiency)

(xerosis conjunctivae, Bitot spots, keratomalacia)

Front 637

What is xerosis conjunctivae?

Back 637

Dryness of eye as mucus secreting epithelium changes to keratinized epithelium

Front 638

What are Bitot spots?

Back 638

Build up of keratin debris in small opaque plaques

Front 639

What is keratomalacia?

Back 639

Eventually erosion of roughened corneal surface w/ softening and destruction of cornea---> total blindness

Front 640

Does vitA offer any protection from lung cancer?

Back 640

NO.

Front 641

What are clinical consequences of Vit A toxicity?

Back 641

Headache
Vomiting
Stupor
Papilledema
Symptoms suggestive of brain tumor

Front 642

What is use of synthetic retinoids to treat acne in pregnant moms associated with?

Back 642

INC congenital malformations

Front 643

What is the major function of fat soluble Vit D?

Back 643

Maintain normal plasma levels of Ca and P

Front 644

Vitamin D is required for prevention of what diseases?

Back 644

Bone diseases!
(Rickets in kids, osteomalacia in adults)

Front 645

What else does vit D prevent?

Back 645

Hypocalcemic tetany

Front 646

What is hypocalcemic tetany?

Back 646

Insufficient Ca2+ in ECM --> continuous excitement of muscle!
 
(Dx with Chevostek's sign)

Front 647

What are the major sources of
vit D?

Back 647

Endogenous (90%)
Via sunlight energy

Front 648

What is ergosterol?

Back 648

Precursor to vit D found in plants
(converted to vit D in body)

Front 649

What is the mechanism of vit D synthesis?

Back 649

Vit D absorbed in gut (w/fats) or synth from precursosr in skin
 
--> binds D-binding protein--> transported to liver--> converted --> taken to kidney--> converted to CALCITROL!

Front 650

What is the most active form of Vit D?

Back 650

Calcitrol
(converted in kidney, steroid hormone)

Front 651

What is the mechanism of Vit D deficiency?

Back 651

--> deficiency of calcitrol
--> deficient absorb of Ca and P in gut
--> low serum Ca and P levels
-->hypocalcemia activated parathyroid
--> Ca and P pulled out of bone
--> PTH cues excrete P and retain Ca
--> serum Ca is normal but P is low
--> MINERALIZATION is IMPAIRED

Front 652

What 3 things regulate calcitol production by kidney?

Back 652

Feedback loop
 
Hypocalcemia
 
Hypophosphatemia

Front 653

What does calcitrol do?

Back 653

Stim intestinal absorption of Ca and P
 
Collaborates with PTH to pull Ca and P from bone
 
Stimulates PTH dependent reabsorption of Ca in distal renal tubules

Front 654

What does vit D activate in osteoblasts?

Back 654

Synthesis of Ca-binding protein--osteocalcin
 
(involved in deposit of Ca in osteoid matrix--> contributes to bone mineralization)

Front 655

What is necessary in renal reabsorption of Ca?

Back 655

PTH and vit D

Front 656

What are the more important causes of vit D deficiencies?

Back 656

Limited exposure to sun:
 
--Heavily veiled women
--Children born to vit D def moms
--Northerners (scant sun)

Front 657

What does vit D deficiency lead to?

Back 657

Hypocalcemia

Front 658

After hypocalcemia, what are the Ca and P serum levels?

Back 658

Ca is normal
P is low (mineralization is impaired)

Front 659

What is the basic derangement in Rickets and Osteomalacia?

Back 659

Excess of unmineralized matrix
 
Rickets--> inadequate provisional Ca of growth plates

Front 660

What is Rachitic rosary?

Back 660

Deformation of chest from overgrowth of cartilage or osteoid at costochondrial junction

Front 661

What is a Pigeon breast deformity?

Back 661

Weakend metaphyseal areas of ribs are pulled by resp muscles
--> bend in --> andterior protrusion of sternum

Front 662

What is characteristic of Osteomalacia?

Back 662

Inadequately mineralized osetoid matrix--> excess persistent osteoid

Front 663

What is osteopenia?

Back 663

Persistent failure of mineralitation in adults--> loss of skeletal mass
 
Ex) osteoporosis

Front 664

How does osteoporosis differ from osteomalacia?

Back 664

Osteoporosis--Result of reduced product of osteoid
 
Osteomalacia--Results from reduced mineralization of the osteoid

Front 665

Does a prolonged exposure to sunlight produce an excess of vitamin D?

Back 665

No. Only oral administration has that potential. (very potent)

Front 666

What may excess Vit D lead to?

Back 666

Metastic calcifications (elevated Ca levels)

Front 667

What causes scurvy?

Back 667

Deficency in vit C
(aka--ascorbic acid)

Front 668

What characterizes scurvy?

Back 668

Bone disease in growing kids
 
Hemorrhages and healing defects in adults

Front 669

Who is scurvy usually encountered in?

Back 669

People with erratic and inadequate eating patterns
(elderly, person who lives alone, alcoholic)

Front 670

What is the most clearly established function of vitamin C?

Back 670

Activation of prolyl and lysyl hydroxylases from inactive precursors
 
--> hydroxylation of procollagen

Front 671

What accounts for hemorrhages in scurvy?

Back 671

Callagen malformation (lack strength, more vulnerable)
 
Particularly in blood vessels
 
Defects in collagen synth--> inadeuate support of capillary walls

Front 672

What is the relationship between Vit C and E?

Back 672

Synergistic

Front 673

What is among the striking features of scurvy?

Back 673

Hemorrhages
(purpura/ecchymoses in skin and gingiva)

Front 674

How does Vit C deficiency skeletal effects differ from Rickets?

Back 674

Problem in the formation of the osteoid matrix
(not mineralization)

Front 675

What are common oral manifestations of Vit C deficiency?

Back 675

Gingival swelling
 
Gingival hemorrhages
 
Secondary bacterial perio inection

Front 676

What type of rash often appears in Vit C deficiency?

Back 676

Distinctive perifollicular, hyperkeratotic, papular rash
(may be ringed by hemorrhage)

Front 677

What are the major consequences of Vit C deficiency?

Back 677

Poor vessel support--> bleeding
(gums, skin, joints/periosteum)

Inadequate osteoid synth
 
Impaired wound healing

Front 678

What happens to excess Vit C?

Back 678

Excreted in urine
 
(may cause uricosuria, INC iron absorption)

Front 679

How is obesity defined?

Back 679

State of INC body weight
 
Due to adipose tissue accumulation
--> sufficient magnitude to produce adverse health effects

Front 680

What is considered a normal BMI?

Back 680

25 kg/m^2
 
(27+=oberweight, health risk)
( > 20=underweight health risk)

Front 681

What is associated with a much higher risk for several diseases?

Back 681

Central (visceral) obesity--> fat in abdominal cavity
 
(fat in subcutaneous tissue--> not as harmful)

Front 682

What is a Key player in energy homeostasis?

Back 682

Ob gene and its product--leptin
 
(regulates E equation)

Front 683

How are leptins initiated?

Back 683

Binding to specific receptors on 2 classes of neurons in the hypothalamus
 
(Orexigenic neuropeptides, Norexigenic peptides)

Front 684

What are Orexigenic neuropep?

Back 684

Leptin sensitive neuron
 
Induce feeding

Front 685

What are Norexigenic peptides?

Back 685

Leptin receptor bearing neuron
 
a-MSH, CART
 
Reduce food intake

Front 686

What does abundance of leptin increase?

Back 686

INC physical activity, production of heat, energy expenditure

Front 687

What is a common mutation that gives rise to obesity in humans?

Back 687

Mutations of MC4R gene
(4-5% of massively obese)

Front 688

T/F--Obesity is merely a genetic disease.

Back 688

False!
Complex--genetic and environmental

Front 689

What is obesity associated with in relation to type 2 Diabetes ?

Back 689

Insulin resistance
Hyperinsulinema

Front 690

How is hypertension correlated with weight?

Back 690

Proportional! (heavier---> HTN)

Front 691

Is there a straight forward link between obesity and heart disease?

Back 691

No. (may relate more to diabetes and HTN than weight)

Front 692

What is pickwickian syndrome?

Back 692

"hypoventilation syndrome"
 
Constellation of respiratory abnormalities in VERY obese

Front 693

What is hypersomnolence?

Back 693

Obesity causes Night and day
 
Apneic pauses during sleep
 
Polycythemia
 
--> Eventually right sided heart failure! **

Front 694

T/F--Obese patients who are not HTN, are not at risk for stroke.

Back 694

True.

Front 695

What are obese women at higher risk for?

Back 695

Endometrial cancer
 
May be indirect:
Obesity raises estrogen levels-->High estrogen--> INC endometrial cancer

Front 696

What are good sources of cholesterol lowering polyunsaturated fatty acids?

Back 696

Vegetable oils (corn, safflower) and fish oil!

Front 697

What is the best fatty acid source?

Back 697

Fish oil --> omega 3
 
(have more db's than omega-6 in vegetable oil)

Front 698

What does restricting sodium intake do?

Back 698

Lower HTN

Front 699

What does dietary fiber intake do?

Back 699

INC fecal bulk
(prevent diverticulosis?)

Front 700

What are 3 aspects of the diet are of concern w/ respect to carcingogenesis?

Back 700

Exogenous carcinogen content
 
Endogenously synth carcinogens from diet components
 
Possible lack of protective factors

Front 701

Are Aflatoxins carcinogenic?

Back 701

Yes.

Front 702

What has been shown to clearly induce gastric cancer in animals?

Back 702

Nitrosamines and nitrosamides

Front 703

What dietary components are anticarcinogenic?

Back 703

Vit C and E, B-carotenes, and selenium

Front 704

T/F--There is no proof that diet can cause or protect againstcancer.

Back 704

True.