SM01 Mini4 Flashcards Preview

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Flashcards in SM01 Mini4 Deck (252):
1

plasma composition

92% water

7% proteins

remaining: electrolytes, wastes, nutrients, vitamins, hormones, gases

2

functions of albumin

oncotic pressure

transport: fatty acids, bilirubin, etc

drug transport: salicylates, barbituates, sulfonamides, warfarin, PCN

3

alpha1-globulin electrophoresis band proteins

alpha1-antitrypsin

alpha-lipoprotein

4

alpha2-globulin electrophoresis band proteins

haptoglobin

ceruloplasmin

alpha2-macroglobulin

5

beta1-globulin electrophoresis band proteins

transferrin

beta-lipoprotein

6

beta2-globulin electrophoresis band proteins

C3 (complement protein)

fibrinogen (plasma only, NOT serum)

7

gamma-globulin electrophoresis band proteins

immunoglobulins

8

oncotic pressure

aka colloid osmotic pressure

osmotic pressure exerted by proteins in blood vessels, mostly albumin

net oncotic pressure in arteries & veins the same, but net hydrostatic pressure is lower in veins→ pushes water out of blood vessels in arteries & into them in veins 

9

hypoalbuminemia

result: water leaves blood vessels & never returns due to reduced oncotic pressure→ edema

causes: 

  • reduced synthesis: IL-6/stress response
  • altered distribution: increased capillary permeability & decreased lymph clearance
  • increased catabolism: chronic infections & trauma
  • abnormal losses: burns, renal dz, GI loss, hemorrhage
  • inherited: 0 made

 

10

hyperalbuminemia

result: less distribution of fluid to tissue

causes: dehydration & excessive statis (during venepuncture)

11

haptoglobin

binds hemoglobin

binds hemoglobin dimers (not tetramers)→ complex binds CD163 on macrophages→ lysosomal degradation to heme→ breakdown into bilirubin, CO, & ferritin via heme oxygenase-1

12

hemopexin

binds heme

Hb dimer autoxidation→ Heme release→ binds hemopexin→ complex binds LRP-1/CD91 on hepatocyte or macrophage→ degradation to bilirubin, CO, & ferritin via heme oxygenase-1 & 2

13

alpha-fetoprotein

made in fetal liver

enters mother's bloodstream

if levels are high→ neural tube defect

if levels are low→ Down's syndrome

if not pregnant→ hepatocellular cancer

14

ceruloplasmin

binds copper

absence is indicative of Wilson's disease

15

Wilson's disease

absence of ceruloplasmin→ copper deposition

in eyes→ Kayser-Fleisher rings

also in nails, skin, & joints (arthritis)

causes hepatic damage over time

16

beta2-microglobin

subunit of human leukocyte anitgen (HLA)

used in detection of nephrotic syndrome

17

alpha2-macroglobulin

protease inhibitor

used in detection of nephrotic syndrome

18

C-reactive protein

1st protein to rise in acute infection or inflammation

acute phase reactant taht binds extracts of pneumococal cell walls

19

alpha1- antitrypsin

function: antiprotease activity in lungs

low levels seen in pulmonary emphysema

synthesized in liver

20

causes for increased beta-globulins

biliary cirrhosis, iron deficiency anemia, or obstructive jaundice

21

treatment for multiple clotting factor deficiency or liver cirrhosis

fresh frozen plasma

22

cyroprecipitate

treatment for clotting disorders

23

treatment for hemophilia A

factor VIII concentrate

24

treatment for hypovolemic shock

5% albumin

(severe blood & fluid loss)

25

treatment for cerebral edema

25% albumin

26

monoclonal gammopathies

abnormal protein in blood

68% unknown significance= MGUS

band seen beyond gamma region

27

immunofixation electrophoresis for multiple myeloma

IgG band from M-protein band

28

serum electrophoresis during inflammation

decreased albumin band

increased gamma band

others change too, but these are the important 2

29

immunofixation electrophoresis for Waldenstrom's macroglobulinemia

IgM found in M-protein band

30

Waldenstrom's macroglobulinemia

type of non-Hodgkin's lymphoma affecting B cells

increased IgM to point of cryoglobulinemia (too much protein in blood)

Raynaud's is secondary

31

immunofixation electrophoresis of renal dz serum

decreased albumin

increased alpha2-macroglobulin

increased beta-lipoprotein

32

immunofixation electrophoresis of renal dz urine

increased albumin

increased alpha1-antitrypsin

no alpha2-macroglobulin

33

cholinesterases

catalyses of hydrolytic cleavage of various esters of choline

found in palsma

synthesized in liver

degrades drugs: anesthetics & cocaine

34

causes of decreased plasma cholinesterase levels

  • hepatic dz: decreased synthesis
  • inherited abnormla variant w/low biological activity
  • organophosphate poisoning: irreversible inhibitor of acetylcholinesterase
    • symptoms arise from ACh bind up
    • treated w/atropine sulfate

35

causes of increased plasma cholinesterase levels

  • nephrotic syndrome: excreted in urine normally
  • rapidly growing liver cells

36

Scoline Apnea

condition results from abnormal plasma cholinesterase enzyme protein when given succinylcholine (paralytic for procedures)

37

transaminases

group of enzymes that catalyze transfer of amino group from amino acids to alpha-ketoacids

38

aspartate transaminase

AST

normally found in: cardiac & skeletal muscle, liver, kidney, & erythrocytes

39

causes of high levels of aspartate transaminase

  • moderate
    • hemolysis
    • physiological in neonates
  • very high
    • viral hepatitis
    • myocardial infarction
    • circulatory failure

40

alanine transaminase

ALT

normal high levels in: liver, skeletal & cardiac muscle, and kidney

41

causes of increased plasma alanine transaminase levels

  • moderate
    • circulatory failure
    • acute viral hepatitis
  • very high
    • liver cirrhosis
    • cholestatic jaundice
    • post cardiac sx
    • skeletal muscle dz

42

alkaline & acid phosphatases

group of enzymes w/maximum activity @ pH 5 or 10

attacheed to cell membrane, suggesting a role in membrane transport

43

causes of increased plasma level of alkaline phophatase

  • bone diseases
  • diseases that affect the bile duct
  • normal pregnancy
  • infancy & childhood
  • high fat meals

44

where is acid phosphatase found?

prostate

liver

erythrocytes

platelets

bone

45

what are raised levels of LDH1 & LDH2 an indicator of?

myocardial infarction

46

what is used to detect acute hepatitis?

LDH5

47

What does increased creatine kinase- BB indicate?

possible brain tumor

48

What does increased creatine kinase- MB indicate?

myocardial infarction

released 3hrs after MI

peaks at 10-24 hours after

relatively specific, but not as good as troponin

49

What does increased creatine kinase- MM indicate?

skeletal muscle breakdown

ex. muscular dystrophy

50

Where is gamma-glutamyltransferase found?

**liver & bile duct

kidney

pancreas

other organs

51

causes of raised plasma gamma-glutamyltransferase

  • enzyme induction via drugs (anticonvulsants) & alcohol
  • cholestatic liver dz
  • hepatocellular damage

52

increased plasma enzymes in bile duct disease

alkyline phosphatase & gamma-glutamyltransferase

53

increased plasma enzymes in bile duct disease

alkyline phosphatase & NOT gamma-glutamyltransferase

54

amylase & lipase

produced by pancreas for digestion

55

increased plasma levels of amylase & lipase are indicative of?

acute pancreatitis

renal failure (and excreted)

56

troponin

most sensitive & specific plasma protein indicative of myocardial infarction

peaks 12 hours after incident

initial release 2-4 hours after incident

57

58

what are the basic structures found in protoporphyrin IX?

4 N-facing inward pyrrole rings

mainly hydrophobic side chains

hydrophobic & hydrophilic sides

arranged in single plane

59

what state is iron in when bound to heme?

Fe2+ ferric

60

what stabilizes ferric iron in heme so that it does not oxidize when bound to oxygen?

proximal histidine of nearby alpha helix in protein subunit binding

and distal histidine to oxygen

61

function of myoglobin

store O2 in aerobic muscle

humans have very little

whales have a lot

62

function of hemoglobin

O2 transport from lungs to tissue

63

structure of myoglobin

153 aa

globular

75% alpha helices (8)

heme squeezed between 2 helices

64

how is heme held in myoglobin/hemoglobin?

hydrophobic interactions

65

structure of hemoglobin

2 alpha chains, 2 beta chains

each have a heme group

subunits held together via non-covalent interactions

66

alpha2beta2 hemoglobin

97% adult hemoglobin

67

alpha2delta2 hemoglobin

2% of adult hemoglobin

weaker promoter on delta subunit gene than that of beta gene

68

alpha2gamma2 hemoglobin

fetal hemoglobin

mostly seen in 2nd & 3rd trimesters

takes 4-6 months after birth to replace all with adult type

69

which heme protein displays a hyperbolic binding curve?

myoglobin

70

why does hemoglobin display sigmoidal binding curve?

tense v. relaxed conformations

positive cooperativity among O2 binding sites

71

which hemoglobin conformation is deoxygenated?

tense

72

why does myoglobin display a different curve?

only one unit

73

what percentage of hemoglobin is oxygenated in venous blood?

70%

74

why is oxygen transfered from hemoglobin to myoglobin/fetal hemoglobin?

they bind O2 tighter than adult hemoglobin

75

why is O2 bound tighter to myoglobin than hemoglobin?

must overcome salt bonds between subunits in hemoglobin

76

what does 2,3-bisphosphoglycerate bind to?

1 molecule 2,3-BPG/1 hemoglobin molecule in erythocyte

only binds dexygenated hemoglobin

interacts w/3 + side chains of aa on each beta subunit (6 bonds total): His 2, Lys 82, His 143

77

what is the function of 2,3-BPG in hemoglobin?

stabilizes tense (T) conformation (deoxygenated)

78

Why is 2,3-BPG needed in hemoglobin?

to lower O2 binding affinity below that of myoglobin & fetal hemoglobin

79

Why is 2,3-BPG not present in fetal hemoglobin?

gamma subunits lack one of 2,3-BPG interacting His residues

80

epistasis

aka modifier gene

interaction between non-allelic genes

expression of one gene is dependent on another

ex. O phenotype with AB genotype in someone w/Oh

81

acute hemolytic reaction

40% mortality rate

symptoms: fever, chills, nausea, CP, back pain, pain at site, hypotension, dyspnea, oligurea, & dark urine

cause: inaccurate ABO typing or otehr blood group if prior exposure→ ALWAYS PREVENTABLE

occurs in <24 hrs

82

delayed hemolytic reaction

delayed b/c body needs time to create antibodies

symptoms: low-grade fever, malaise, weakness, mild anemia, sometimes hyperbilirubinemia

occurs w/in 1-2 weeks

cause: other blood groups NEVER ABO

83

hemolytic disease of newborn

anti-Rh+ IgG antibodies cross placenta from mother to child

attack RBC of 2nd Rh+ baby

pre-natal symptoms: anemia, immature RBC in circulation, edema in utero, fetal death

post-natal symptoms: breakdown of RBCs→ hyperbilirubinemia & jaundice→ if untreated, brain damage & death

tx: exhange transfusion

84

febrile nonhemolytic transfusion reaction

fever caused by destruction of transfusion leukocytes

mild reaction

most frequent transfusion problem 

cause: often preformed anitbodies to HLA/MHC on leukocytes

symptoms: mild fever, chills, & rigors

leukocytes are usually removed from blood products for this reason

85

importance of A & B in blood typing

they are antigens

therefore someone w/B blood has antibodies for A

someone w/A blood has antibodies for B

someone w/o blood has antibodies for A & B

someone w/AB blood has no antibodies

***antibodies are pre-formed!!**

caused by variation of glactosyl transferase enzyme

86

function of fucose transferase

addition of L-Fucose to glucoprotein or spingolipid on cell surface

87

what happens when fucose transferase is mutated or absent?

blood type is Oh/Obom

88

A antigen terminal sugar

N-acteylgalatosamine

89

B terminal antigen

D-galactose

90

galactosyl transferase function in each blood type

A & B: attach oligosaccharide antigen

O: inactive due to frameshift mutation

Oh: present, most likely active, but does not recognize substrate w/o L-fucose

91

Secretor phenotype

different fucose transferase initiates production of ABO molecule for secretion

secretion is autosomal dominant

92

What are the side effects of being a non-secreter?

protected against Norwalkd virus (causes gastroenteritis)

more susceptible to: candida albicans, neisseria meningitidis, streptococcus pneumoniae, & haemophilus influenzae

93

Rhesus blood group

Rh- is autosomal recessive

presence or absence of polypeptide D

variants of polypeptide form subgroups

no preformed antibodies

94

Why does hemolytic disease of newborns only occur with 2nd or later pregnancies?

Rh- mother does not have preformed antibodies

must be exposed by Rh+ fetus first

95

prevention of hemolytic dz of newborn

injection of anti-Rh+ antibodies into mother prevents her from producing them herself

given 72hrs after birth

often given at week 28 & 34 in low concentrations

96

what is a common cause of neonatal mild jaundice?

hemolytic dz of newborn due to mismatch of ABO type w/mother

mild & usually doesn't require treatment

anti-A & anti-B antibodies are usually IgM that cannot pass placenta

97

role of platelets in blood clotting

  • plug formation
  • release of 

 

98

thromboxane

made in platelets from membrane lipids via arachiconic acid by cyclooxygenase (COX-1 & COX-2)

function: facilitates platelet aggration & vasoconstriction

99

mechanism of ASA

binds & inhibits cyclooxygenase

100

formation of leukotrienes

from platelet membrane lipids via arachidonyl-CoA by 5-lipoxygenase (LOX)

101

function of von Willebrand factor

 

stabilizes factor VIII

102

initiation of clot formation

exposure of basal lamina collagen w/von WIllebrand factor bound to factor VIII

glycoproteins GPIb/IX binds von Willebrand factor

103

how is thrombosis prevented in normal blood vessel?

intact endothelium relase of prostacyclin & NO

both prevent platelet adhesion

104

von Willebrand factor

associated w/sub endothelial connective tissue

serves as bridge between platelet glycoproteins & collagen

105

Protein C

serine protease

activated by thrombomodulin-bound thrombin

function: stop clotting cascade

106

protein S

cofactor of Protein C in anti-coagulation

dependent on vitamin K

107

antithrombin III

most important coagulation inhibitor

aka serpin

controls activites of IIa, IXa, Xa, XIa, & XIIa

108

how is the intrinsic clotting pathway measured?

activated partial thromboplastin time (PTT)

109

how is the extrinsic clotting plathway measured?

prothrombin time (PT)

110

at what step do the intrinsic & extrinsic clotting pathways meet?

activated factor X

111

how is the extrinsic pathway initiated?

via Tissue Factor release by damages tissue to activate factors VII & V

112

TENET

factors of intrinsic pathway in order of activations

  • Twelve
  • eleven
  • nine
  • eight
  • ten

113

prothrombinase complex

forms on phospholipid membrane

activated factor V is cofactor

Factor II (prothrombin)

activated by activates Factor X

114

fibrin formation

thrombin cleaves fibrinogen to make fibrin monomers

dimerization via cross linking

polymerization via transglutaminase rxn by Factor XIIIa

115

Km for plasminogen is likely to decrease in the presence of what substance?

fibrin

116

A patient on warfarin takes aspirin for a headache and later develops signs of bleeding. What is the underlying reason for this?

Aspirin inhibits the formation of Thromboxane A2 whereas warfarin is a vitamin K antagonist

117

The conversion of plasminogen to plasmin can be accomplished by using which one of the following?

streptokinase, urokinase, or tPA

118

A 55-year-old man reports to the physician complaining that his left foot is swollen since he got off the plane after a long flight. Blood tests show that his fibrin-D dimer levels are elevated. The physician decides to administer an anticoagulant. Which of the following would be most suitable for this patient’s immediate treatment?

heparin

119

What protease is responsible for converting fibrinogen to fibrin?

thrombin

120

What is the point where the extrinsic and intrinsic pathways converge?

Factor Xa

121

What factor initiates the extrinsic pathway of the clotting cascade?

factor III

aka tissue factor

122

The degradation of clots is essential. What is responsible for degradation of fibrin clots?

Plasmin

123

Hemophilia A is a classic hemophilia. It is a disease referring to the inability to clot blood. What factor is deficient in this X-linked recessive disorder?

VIII

124

von Willebrand disease is due to an inherited deficiency in von Willebrand factor (vWF). What factors are also affected as a result of deficiency of vWF?

VIII

125

A 7-year-old boy with a history of seizures was found to have a cerebellar tumor. What is likely elevated in his serum?

creatine kinase BB

126

A 51-year-old man is rushed to the ED in a rural area whilst on safari. His wife reports that he has been having severe chest pain for the past 12 hours. The clinical laboratory at the hospital has limited facilities and can only determine his lactate dehydrogenase levels to determine whether he has had a myocardial infarct. What will provide this information?

Lactate dehydrogenase 1 & 2

127

what subunits make up fetal hemoglobin? And where and when is it made?

alpha2gamma2

liver & spleen

W5-birth

 

128

what is HbA2?

alpha2delta2 hemoglobin

2-3% of adult hemoglobin

129

variant

result of an allele

caused by different allele at a gene

ex. hemoglobin w/changed amino acid content

130

what point mutation is seen in sickle cell anemia?

glutamate 6 changed to valine of beta chain

- to 0

mutation has happened independently at least twice

131

when does sickle cell anemia first present in a homozygote? Why?

3-6 months old

b/c alpha2gammaa hemoglobin still active for first 4 months (RBCs live 120 days)

132

how do sickle cell anemia homozygotes present?

  • failure to thrive
  • pale
  • repeated infections→ splenomegaly
  • painful dactylitis (fingers)
  • hemogloblin level: 7-11g/L (normal 12-15g/L)
  • increased reticulocyte count
  • some sickled cell

133

painful episodes of sickle cell

"Crisis" is old nomenclature

  • increased anemia
  • sudden onset of pain:
    • hands & feet in infants/young
    • later: limbs, back, abd, & chest
  • severe 2-3 days→ spontaneously settles
  • fever near end of crisis
  • severe anemia due to RBC sequestration in spleen, liver, or pulmonary circulation→ possible death
  • death due to infection is also common

134

complications seen in chronic sickle cell anemia

  • repeat infarction→ organ malfunction
    • usually seen in kidney, liver, pulmonary, or brain
  • pigment stones in gallbladder
  • increased fetal mortality from homozygote mothers

135

why do RBCs sickle?

deoxygenated HbS polymerizes causing change in cell shape

136

what is the "heterozygote advantage?"

less prone to malaria, but less symptoms of dz state seen in homozygotes

137

what condition is only seen in homozygote HbS?

sickle cell anemia

heterozygotes can onely experience sickle cell dz

138

HbF

fetal hemoglobin or persistent fetal Hb in adults

beneficial in HbSS

139

what is MstII used for?

it's a restriction enzyme used to digest DNA & test for HbS  w/allele specific oligoneucleotide hybridization

140

What is the point mutation seen in HbC?

glutamate 6 to lysine

- to +

141

What populations are HbC found in?

western sub-Saharan Africa

142

what symptoms do HbAC & HbCC display?

none

but HbC carries a lower risk of malarial death

143

what causes beta-thalassaemia?

single base substitutions including frameshifts

144

what is the initial presentation of beta-thalassemia major?

  • severe hemolytic anemia 5% of normal
  • before 2yrs
  • microcytic, hypochromic

145

progression of beta-thalassemia major

  • growth retardation
  • pallor
  • jaundice
  • poor musculature
  • genu valgum
  • hepatosplenomegaly
  • leg ulcers
  • masses of extramedullary hematopoiesis
  • skeletal changes
  • early death <5yrs
  • **increased bone erythropoiesis→ bone marrow expansion & deformities of long bones

146

tx for beta-thalassemia major

possible splenectomy

transfusions to keep blood 9-12g/L

+ chelation to avod hemachromatosis

Zn, VitC, & folate prn

147

what can cure beta-thalassemia major?

bone marrow transplant or gene therapy

148

desferrioxamine

IV chelation treatment for ferritin

given @ 60mg/kg/day

usually takes 8-12 hrs/day

usually needed 5-7days/week

149

what is the life expectancy of beta-thalassemia major pts?

20% mortality by 40 if non-compliant 

otherwise into their 50s

150

deferasirox

oral chelation treatment for ferritin

very expensive

151

cause of beta-thalassemia intermedia

50% production of beta Hb

152

what symptom is more frequent in beta-thalassemia intermedia than major?

gall stones

153

what symptoms are displayed in beta-thalassemia intermedia?

range from asymptomatic to retardation of growth & development

increased risk of osteoporosis

splenomegaly

gall stones

iron overload

154

what causes the iron overload seen in beta-thalassemia intermedia?

body increases iron absorption to try to counteract anemia

155

beta-thalassemia minor

at least 50% of beta Hb production

asymptomatic or mild anemia

156

what is the possible genotype of someone with beta-thalassemia major?

beta0beta0 or beta0beta+

157

what is the possible genotype of someone with beta-thalassemia intermedia?

usually beta+beta+ but also could be beta0beta+

158

what is the possible genotype of someone with beta-thalassemia minor?

heterozygotes of different types

betaNbeta0 or betaNbeta+

159

which Hb subunits can form homotetramers and which cannot?

can: beta & gamma

can't: alpha

160

what decreases the time until symptoms appear or delays diagnosis in beta-thalassemia?

shortened RBC lifespan in circulation

161

mechanism of dz in beta-thalassemia

precipitation of alpha Hb in cells→ oxidative damage of membrane proteins & lipids

162

what populations carry alleles A & B responsible for alpha-thalassemia?

africa & south-east asia

163

which beta-thalassemia allele is only found in people of asian decent?

allele B

164

what is the difference between allele A & B in alpha-thalassemia?

A has one copy of alpha Hb

B: both copies of alpha Hb are deleted

165

hemoglobin Barth's disease

aka hydrops fetalis

2 B alleles for alpha Hb→ no alpha Hb made

 mostly Hb-gamma4 (aka Hb-Bart's protein) & 10% Hb-Portland

normally fatal in utero

166

what is hemoglobin H?

Hb-beta4 protein

167

what is the distinguishing characteristic of alpha-thalassemias over beta or sickle cell?

symptoms start at birth

168

how does hemoglobin H dz present?

like beta-thalassemia intermedia except @ birth

severe hemolytic anemia

intraerthrocytic inclusion bodies from precipitating Hb, but less than is seen in beta-thalassemia due to tetramerization of beta units

169

what happens when Fe is free (w/o a carrier protein) in the body?

oxidative damage

Fe2+ oxidized to Fe3+

 

170

How much dietary Fe is required/day & why?

1-3mg

b/c it is lost in sloughing off of GI cells (or menstration in females)

171

what protein stores Fe intracellularly?

ferritin & hemosiderin

172

what protein carries Fe in blood?

transferrin

173

normal functions of Fe

  • O2 carrier in myo/hemoglobin
  • Redox rxns in cytochromes a, b, & c for electron transport chain AND into cytochrome P450s for detoxification AND in lysosomes & peroxisomes
  • Fe3+ in iron-sulfer complex enzymes like aconitase

174

what are Iron Response Elements (IREs) & their function?

polynucleotides in transferrin receptor & ferritin-related mRNA transcripts

sense Fe content of cell to adjust amt of cellular uptake

175

order of Fe presence in body from most to least

hemoglobin

myoglobin

ferritin & hemosiderin (storage)

transferrin

176

what is the main site for Fe uptake?

duodenum

177

what vitamin facilitates Fe absorption?

Vitamin C (ascorbic acid)

178

what compounds inhibit Fe uptake?

phytates, phosphates, tannins, & antacids

179

what is the function of ferriportin?

controls amt of Fe delivered to transferrin

regulated by bodily Fe needs

180

why is hepcidin considered the master iron regulator?

controls ferroportin activity

Fe may be rate-limiting to growth of blood pathogens

restricts Fe availability in cancer & inflammation for this reason

mechanism: hepcidin plugs ferroportin channel

181

why does APA recommend breast feeding?

human breast milk provides infants w/bioavailable Fe & cows milk does not

182

what is the daily allowence for Fe? What does that mean?

men: 10mg/day & women: 15mg/day (when menstrating)

intake more than these values puts at risk for Fe toxicity

183

what is hemochromatosis and its mechanism of dz?

primary Fe overload disorder

gene: HFE

upregulation of DMT1 Fe-transport protien in brush border of GI tract→ accumulation of hemosiderin

184

presentation of inherited hemochromatosis

progressive Fe loading of liver & cardiac tissue

10x more likely men than women

aged 40-60 for clinical symptoms

185

what causes inhertied hemochromatosis?

autosomal recessive

point mutation C282Y (or compound heterozygotes C282Y & H63D)

more common in european populations

186

2º causes of Fe overload

iron loading anemias: thalassemia & sideroblastic anemia

OR 

chronic liver dz: HepC & alcoholic cirrhosis

187

symptoms of Fe overload

arthopathy, hepatomegaly, elevated transaminases, skin hyperpigmentation, splenomegaly, liver cirrhosis, hypogonadism, & diabetes

188

what are B12 & folate necessary for?

1C metabolism

189

what is another name for vitamin B12?

cobalamine

190

What functions require B12?

1C metabolism

ex. cell growth & division, esp. blood cells; contol of fatty acid synthesis, esp. myelin sheaths

191

What does B12 absorption require?

intrinsic factor secreted from gastric parietal cells

192

where does B12 absorption occur?

ileum

193

What 2 rxn require cobalamine?

  1. cobalamine-dependent methylmalonyl CoA mutase
    • deficiency results in methyl-malonyl acidemia
  2. methylcobalamin-dependent methionine synthase
    • deficiency reults in megaloblastic anemia

194

where is folate absorbed?

brush border enterocytes

195

what drugs inhibit folate absorption?

phenytoin

alcohol

oral contraceptives

196

what is folate's most important funciton?

for DNA synthesis: via methionine, purine, & thmidylate synthesis

197

what other functions require folate?

glycine biosynthesis & histidine catabolism

198

does megaloblastic anemia display B12 or folate deficiency?

both are deficient

199

what conditions display B12 deficiency, but not folate deficiency?

neurologic complications & elevated serum methylmalonic acid

200

why is megaloblastic anemia hard to cure?

very complex etiology so it is hard to figure out what is causing it

201

what cofactors are needed for heme biosynthesis?

vitamin B6, Fe, & glycine

202

what are porphyrias?

disorders caused by impaired biosynthesis of heme

have cutaneous and/or neurologic manifestations

203

what substance inhibits ferrochelatase and ALA dehyratase reactions?

Pb

204

what causes jaundice?

interruption of bilirubin clearance

can be caused by liver disease or hemolytic disorder

205

what are the first locations to display signs of jaundice?

sclera & underside of tongue

206

what is the most common cause of jaundice in neonates?

undeveloped liver

207

what is kernicterus & what causes it?

brian dysfunction 

caused by bilirubin build up in gray matter

208

what is the function of heme oxygenase?

heme catabolism

required O2 & NADPH

releases Fe & CO

209

what functions required NADPH?

  1. reduction of nucleotide triphosphates to deoxy-NTPs by reibonucleotide reductase
  2. fatty acid & steroid biosynthesis
  3. oxidant control in erythrocytesby glutathione reductase

210

whate are the products of the pentose phosphate pathway?

2 NADPH, CO2, & ribose

211

what is the 12/23 rule?

recombination of V, D, & J regions obey this rule

 if one recombination signal sequence (RSS) has a 12bp spacer, it must match with an RSS with a 23bp spacer

212

what are the recomination rules?

  1. rearrangements only occur between segments on the same chromosome
  2. heptamer must pair w/complementary heptamer; nonamer must parir w/complementary nonamer
  3. 12/23 rule

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what enzymes are responsible for junctional diversity?

terminal deoxynucleotidyl transferase (TdT)

& exonuclease

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what is the function of RAG proteins in joining together of various gene segments?

RAG 1 & RAG 2 bind the 12 bp & 23bp spacer recombination signal sequences

bring VDJ sequences close together

cleave near immunoglobulin gene segments so they can be boudn together

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How is allelic exclusion accomplished?

turning off RAG genes after a productive heavy chain is formed & again after a productive light chain has been achieved

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what is the purpose of somatic hypermutations?

increase antibody specificity for antigen after initial antigen activation

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what dz occurs in RAG deficiency?

SCID

severe combined immune deficiency

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what dz occurs in AID deficiency?

AID= activation induced cytidine deaminase

autosomal recessive hyper-IgM syndrome (type 2)

intrinsic B cell effect (b/c there is no class switching in T cells)

displays elevated IgM & lack of IgG & IgA

lack of somatic hypermutation

symptomatic display: recurrent bacterial infections

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what dz occurs in CD40 deficiency?

Hyper-IgM syndrome type 3

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what dz occurs in CD40L deficiency?

X-linked hyper-IgM (type 1)

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what events happen occur after B cell meets antigen?

somatic hypermutation

affinity maturation (positive selection)

isotype switching (immunoglobulin class)

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what events occur before B cell meets antigen?

V, D, & J rearrangement of heavy chain

negative selection w/surrogate light chain

V & J rearrangement of light chains

negative selection

survival= naive, mature BCR

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what are the two BCR light chain loci and what chromosomes are they found on?

lambda on chromosome 22

kappa on chromosome 2

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what is combinational diversity?

diversity of achieved via recombination events of V, D, J, & C alone

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what determines the Ig isotype switch?

the cytokines the B cell is exposed to

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what is the end result of signal transduction of IL-4 & CD40 activation?

acitivation induced cytidine deaminase (AID) transcription

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what is the function of AID?

acitvation-induced cytidine deaminase replaces NH2 w/O

converting cytosine to uracil in variable regions of light & heavy chains

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what biochemical differences are seen in cancer cells?

  • increased glycolysis
  • decreased oxidative phosphorylation
  • non-oxdiative pentose phosphate pathway favored over oxidative
  • glutamine "addicted"
  • de novo fatty acid synthesis
  • de novo nucleotide synthesis
  • up-regulation of antioxidative enzymes

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types of proteins that participate in controlling cell growth/can mutate in cancer

  1. growth factors
  2. growth factor receptors
  3. signal-transduction proteins
  4. transcription factors
  5. pro/anti-apoptotic proteins
  6. cell cycle control proteins
  7. DNA repair proteins

1-5: oncogenes; 6: mainly tumor suppressors; 7: increase probability of mutations in others

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proto-oncogene

accelerator

normal protein that moved cell forward in cell cycle

1 hit (mutation) to become oncogene

gain of fuction

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mechanisms to convert proto-oncogene to oncogene

  1. point mutation→ constitutively active protein product
  2. localized duplicaiton (gene amplification)→ over expression
  3. chromosomal translocation under control of different promoter→ inappropriate expression

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tumor-suppressor genes

normally inhibit cell proliferation

"brakes"

loss of one or more→ loss of function

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How can a virus cause cancer?

viral proteins that activate growth factor receptors

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classes of tumor suppressors

  1. cell cycle regulators, ex. p16 (cyclin-kinase inhibitor) & p21
  2. receptors for secreted hormone, ex. TGF-beta
  3. checkpoint control proteins, ex. p53
  4. pro-apoptotic proteins
  5. DNA repair proteins

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What is the one misexpressed growth factor that causes caner? And what is its mechanism?

sis gene

encodes a type of platelet derived growth factor

abberrantly sutostimulates prolieration of cells that express PDGF receptor

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what causes erythroleukemia? under what mechanism?

spleen focus-forming virus

viral gp55 & overexpression of EPO receptor

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2 examples of GFR overexpression & their mechanisms

Her2 (V [aliphatic] to Q [non-charged, polar])→ dimerization w/o ligand binding

EGF losss of extracellular domain→ constitutively acitve

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How is the Trk receptor tyrosine kinase constitutively turned on after chromosomal translocation?

extracellular domain is replaced by tropomysin

tropomysin dimerizes

2 connected Trk receptor tyrosine kinases phosphorylate each other

**also now found in cytosol instead of plasma membrane

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what mutation causes Ras to become oncogenic? why?

any amino acid substitution for Gly-12

reduces Ras GTPase activity→ Ras is turned on longer than it should be

**seen in many cancer types**

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How does the Rous sarcoma virus cause cancer?

c-src normally inactivated by phosphorylation @Tyr527

virus causes 18aa deletion at C terminal end including tyr527

results in v-Src constitutively active

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myc is elevated in many cancers. What two methods allow this to happen?

localized duplication in many cancer types

translocation in Burkitt's lymphoma→ to site near heavy chain antibody genes

*reminder: myc & fos stimulate genes for promotion thru G1 to S transition of cell cycle

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what causes follicular lymphoma?

translocation of Bcl2 to a location on chromosome 14 fusing it with a transcriptional enhancer

blocking induction of apoptosis

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why is TGF-beta considered a tumor suppressor?

it normally induces expression of p15→ arrest in G1

loss of Smad4 (TGF-betaR)→ unconrolled proliferation

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what happens to glycolysis when p53 is mutated?

amount of NADPH produced by PPP decreased

PPP follows non-oxidative path in cancer

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what enzyme is responsible for increase flux thru non-oxidative PPP in tumors?

pyruvate kinse M2

246

what molecule "fills up" the TCA cycle w/carbon compounds so that it can keep working?

glutamine

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what enzyme do tumor cells use to generate enough NADPH to keep fatty acid & nucleotide synthesis going?

ME

malic enzyme

248

what is secreted by tumors?

lactate, alanine, & NH4+

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250

warfarin inhibits the formation of which clotting factors?

II, VII, IX, & X

251

what inactivates the heparin-antithrombin III complex?

serine protease binding

252