Exam 2 Flashcards
(680 cards)
1
Q
What makes up the epimysium?
A
nerves and blood vessels in CT tissue (investing fascia)
2
Q
What does the perimysium do?
A
separates the muscle into fascicles
3
Q
What does the endomysium do and what is it made of?
A
separates individual muscle fibers, made up of reticular fibers and ECM
4
Q
What is considered the histological functional unit/cell of the muscle?
A
muscle fiber
5
Q
Define myofibrils.
A
parallel cylinders of contractile proteins and organelles
6
Q
Define myofilaments.
A
contractile, structural, and regulatory proteins
7
Q
What is the sarcolemma?
A
the plasma membrane of the muscle cell or fiber
8
Q
What is a syncyctium?
A
multinucleated with nuclei just under the sarcolemma
9
Q
Where can the mitochondria of a skeletal muscle cell be located?
A
nuclear pores and rows between myofibrils
10
Q
Where can the Golgi be found in a skeletal muscle cell?
A
perinuclear region
11
Q
What is the T-tubule system?
A
invagination of sarcolemma, contains voltage sensitive CA2+ channel connected to SR which opens with depolarization
12
Q
What makes up the triad in skeletal muscle cells?
A
the T-tubule and 2 adjoining terminal cisternae, located at the A-I junction (2 per sarcomere)
13
Q
What is the sarcoplasmic reticulum?
A
continuous system of membrane lined canaliculi, longitudinally organized over fiber
14
Q
what are fenestrated cisternae?
A
anastomosis over center of sarcmoere
15
Q
What are terminal cisternae?
A
large transverse channels located next to T tubles, conc CA2+, part of the SR
16
Q
What makes up the protein Actin? What type of muscle protein is it considered?
A
contractile, G actin binds head to tail which makes up f actin, 2 F actin form double helix
17
Q
What prevents the actin in muscles from being degraded?
A
Cap Z at + end where it attaches to the Z line, and tropomodulin on the - end
18
Q
What makes up the protein myosin and what type of muscle protein is it?
A
motor, 2 heavy chains with globular heads and 2 light chains form a helix, fixed together along the M line with globular heads projecting out away from m line and a portion on either side of the line bare of heads
19
Q
What type of muscle protein is tropomyosin and describe it?
A
regulatory, in groove formed by double helix of actin, it inhibits actin myosin interaction, when displaced by troponin it exposes binding site
20
Q
what type of muscle protein is troponin and describe it?
A
regulatory, at intervals along actin and tropomyosin, CA2+ sensitive,
21
Q
What are the three subunits of troponin and their functions?
A
TnT- binds tropomyosin
TnC- binds Ca2+
TnI- inhibits actomyosin Mg2+ ATPase and binding of myosin
22
Q
What proteins can be found in the z-disk matrix?
A
cap Z, filamin, amorphin, a-actin, actin binding protein
23
Q
What type of protein is a-actin in muscles and what does it do?
A
structural, dense amorphous region making up most of the z-disc contains actin binding protein holding actin filaments in a lattice structure
24
Q
What type of protein is Myomesin and what does it do?
A
structural, interconnects 6 myosin filaments and holds them in the center of A band at M line, also called M-protein
25
What does C protein do in muscles?
myosin binding protein in strips parallel to M line
26
What type of muscle protein is Titin and what does it do?
structural, elastic, largest, from z-disk to M-line, associated with myosin, contributes to assembly and resting tension acts as 2 springs in series, also called connectin
27
What type of muscle protein is Nebulin and what does it do?
structural, inextensible filament from z disk along actin to regulate/stabilize length
28
What type of muscle protein are Desmin and Vimentim and what do they do?
Intermediate filaments that link adjacent myofibrils at z-lines
29
What type of muscle protein is Dystrophen and what does it do?
structural, cytoskeletal proteins that binds the ECM protein laminin 2, connects actin to sarcolemma to stabilize and reinforce sarcolemma during contraction
30
Deficiency or lack of Dystrophin results in what condition? How?
Duchenne's muscular dystrophy, tiny ruptures in the sarcolemma occur during contraction leading to cell death
31
What 3 "structures" make up the A band? How are they arranged? What changes during contraction?
M-Line, dark line in center
L Lines, lighter on either side of M line
H band lighter band beyond L lines, changes in length during contraction
32
What structure is in the I band? What changes during contraction?
the Z-line dark line in the center, gets smaller during contraction
33
Explain sliding filament theory fo muscle contraction.
thick and thin filaments maintain length, Actin pulled toward center of A band narrowing and obliterating I band, Z disk drawn toward A band
34
Explain the motor Protein and energy theory of muscle contraction.
myosin "walks" along actin filament in sequence repetitive binding and release, process powered by ATP hydrolysis
35
What is located at the Myoneural junction?
motor end plate= termination of mortor nerve fiber, synaptic vesicles with Ach, receptors for Ach
36
What causes Myasthemia Gravis?
autoimmune disorder, antibodies bind to Ach receptors and block contraction
37
What are muscle spindles? Function?
proprioceptor sensory organs, signal length and rate of contraction
38
What are intrafusal fibers? Function?
specialized muscle fibers, attached to endomyosin, sense contraction
39
What are satellite cells in muscle?
inactive adult stem cells, divide after damage, spindle shaped just below basal lamina
40
Describe Excitation contraction coupling.
AP, release Ach, Muscle AP, T-system transmission, release of Ca2+ from SR, activation of contractile proteins, Ca2+ reaccumulation into SR
41
Name the differences between cardiac and skeletal muscle.
Cardica is uninucleated in center of cell, have branched fibers, myofibrils diverge around nucleus, intercalated discs connect cells end to end, spontaneous rhythmical contraction, fewer larger T-tubules lined with glycoprotein and located at Z line (1/sarcomere), SR smaller & simpler, Termial Cisternae form dyads, larger more numerous mitochondria, many glycogen granules
42
What structures make up the intercalated discs?
maculae adherens, fascia adherens, nexus, and intercellular gap
43
What is the maculae adherens in intercalated discs?
desmosome, thickening of inner layer of plasma membrane, condensation with intermediate filaments
44
What is the fascia adherens?
part of intercalated disc, dense material subadjacent to membrane, termination of I band filaments, corresponds with Z line
45
What is a Nexus in cardiac tissue?
gap junction in intercalated disc, low electrical resistance for spread of imulse
46
What is the intercellular gap in cardiac tissue?
part of intercalated disc, unspecialized region of variable size.
47
Where can smooth muscle be found?
GI tract wall, ducts of glands (GI, Resp, UG), blood vessels and lymph vessels, iris and ciliary body
48
what makes smooth muscles different from skeletal?
long spindle shape, variable size, central elongated nucleus, not striated, staggered arrangement of cells, covered by a basement membrane, surrounded by reticular fibers, capable of active regeneration, dense bodies of a-actin desmin and vimentin inserting into dense bodies, Caveolae, myosin organized into thick filament at activation, actin always arranged
49
What are calveolae?
micropinocytic vesicles act as primitive t-tubule system with a rudimentary SR
50
How do the smooth muscle cells relate cell to cell?
basal lamina with collagen bundles, no desmosomes, mechanical force of contraction transmitted through CT, Nexus-limited areas of narrowed intercellular space-site of low electrical resistance opposing sarcolemma specialized
51
Describe contraction of a smooth muscle cell?
Slow rate, sustained contracted state with little energy expenditure, activation by nerve impulse, Ca2+, calmodulin, cAMP, hormones, local changes and stretching
52
what does Calmodulin do?
Ca2+ binding protein, activates MLCK
53
What does MLCK stand for and what does it do?
myosin light chain kinase, phosphorylates myosin, causes myosin conformational change to expose actin binding site, triggers cross bridge cycling
54
What is signal transduction?
process by which information sent by one cell is chemically converted into a response by another
55
What is contact dependent signaling?
ligand fixed to signaling cell which binds to receptor on target cell, Juxtacrine signaling, very local
56
What is paracrine signaling?
relay system, ligand from signal cell diffuses to local target cell
57
What is synaptic signaling?
also neuronal, very short term, enzymes in synapse hydrolyze ligand rapidly, spike (seconds or less)
58
What is endocrine signaling?
gland, ductless, like beta cell secreting insulin, ligand enters blood stream and acts on target cells through out the body, Wave (minutes to hours)
59
what two signaling methods are important in cancer progression?
autocrine and intracrine
60
What is autocrine signaling?
self signaling release a ligand that acts on cell, signal cell=target cell
61
What is intracrine signaling?
signal never leaves the cell
62
Name the three categories of signaling molecules?
Hormones (steroids, Peptides, amino acid derivatives), Local mediators (paracrine- polypeptides or gas NO), Neurotransmitters (often polypeptides)
63
What is pleiotropy?
signal can cause different effects in a particular target cell or response may be distinct between two different cell types, response is based on target cell not ligand
64
What is integration in cell signaling?
cell specific collection of different receptors leads to modulated response to a particular signal by presence of another, simultaneous signal, ie basal activity, proliferative signal, differentiation, or lack of signal leading to cell death (regional)
65
what signal molecules use direct entry?
Amphipathic- steroid, retinoic acid, vitamin D, and thyroid (gene responses), or Nitric Oxide- dissolved gas from arginine, endothelial cells release NO to stimulate smooth muscle contraction and cause dilation of the vessels.
66
What does NO bind to and describe it effect?
activates enzyme gaunylate cyclase turning GTP to cGMP, the PDE5 (phosphodiesterase) turns cGMP to GMP to make it inactive
67
What are the functions of cell surface repceptors?
transfer signal, transform signal(transduce), amplify signal, distribute signal to parallel paths (pleiotopy), integrate signal in response with other signals
68
What happens in the target cell to respond to signal?
ligand binding, conformational change in receptor, change in activity in cell ->->-> response
69
what two things do different signaling cascades have in common?
G protein as a switch, reversible phosphorylation of proteins controlled by kinases and phosphatases to regulate activity of enzymes
70
What in a signal cascade becomes phosphorylated? What is the result?
enzymes (metabolism up or down)
transcription factors (gene express up or down)
motility factors/cytoskeleton regulators
cell cycle regulators (proliferation/death)
71
Describe the structure of the G Protein coupled receptors (GPCR).
7 pass transmembrane, heterotrimer (alpha, beta, gamma) subunits. Alpha is the speficic to ligand, beta gamma from common pool
72
What is conformation in inactive state of GPCR?
alpha is bound to GDP, beta and gamma in close association
73
What is the conformation in active state of GPCR?
exchange of GTP for GDP, with GTP binding, alpha unit dissociates from beta gamma complex
74
What happens with Cholera toxin?
covalent modification of Gs protein alpha subunit, inhibits GTPase activity and Gs remains in the on state, stimulates transport of NaCl and H2O into the gut, catastrophic diarrhea and dehydration
75
What happens with pertussis toxin?
causes ADP ribosylation of Gi protein that keeps it persistently off. leads to fluid imbalance, severe life threatening congestion of whooping cough
76
What is involved in the G protein switching from binding GDP to GTP?
GEF or guanonucleotide exchange factor
77
What is involved in the G protein switch from binding GTP to GDP?
GAP GTPase Activating Protein, GTPase intrinsic to alpha subunit
78
What two enzymes are the main targets of G-protein in effecting change in the cell? What are their products?
Adenylate cyclase- synthesizes cAMP
Phospholipase C (PLC)- inositol 1,4,5-triphosphate (IP3) and sn-1,2-diacylglycerol (DAG)
Both are second messengers
79
What does the enzyme cAMP phophodiesterase do? Name something that is a common inhibitor.
inactivates cAMP by hydrolysis to AMP, methyl xanthines (ex. caffeine)
80
What protein mediates the effects of cAMP in the cell usually? (i.e. what does it bind to) how does it work?
Protein Kinase A or PKA, active catalytic subunits separate from regulatory units, catalytic units then phosphorylate cellular substrates (Ser or Thr),
81
give an example of a fast response to cAMP and how it works.
glycogen breakdown in skeletal muscles, "fight or flight", active a kinase phosphorylates inactive phosphorylase kinase thus activating it to phosphorylate inactive glycogen phosphorylase thus activating it to change glycogen to glucose-1-phosphate to enter glycolysis
82
Give an example of a slow cAMP response and how it works
gene expression, active A protein phosphorylates CREB activating it to bind to CREB transcription factor then the complex binds to DNA at cAMP response element (CRE) the cis element on DNA. results in transcription
83
How does integration work with G protein?
adenylate cyclase is nexus of integration, stimulator ligand binds receptor and Gs complex passes signal to AC, inhibitory ligand bind receptor and Gi complex passes signal to AC. AC signals via cAMP based on overall info input from Gs and Gi, whole pool of AC involved.
84
Describe the first step in the Inositol phosphate pathway.
Start as inositol-4,5-bisphosphate (PIP2), split by phospholipase C-beta into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3),
85
What does IP3 do?
binds to calcium channels in ER release Ca2+ to cytoplasm
86
What does DAG do?
binds and contributes to activation of protein kinase C (PKC)
87
What three things are required to activate PKC? What does it do when activated?
DAG binding, Ca2+ binding and phosphatidyl serine binding. it phosphorylates cellular substrates to effect changes in enzyme activities and gene expression
88
What are the ten properties that cancer is defined by?
sustain proliferative signaling, evade growth suppressors, resist apoptosis, enable replicative immortality(ignore senescence, ), genomic instability and mutation, activate invasion and metastasis, avoid immune destruction, induce angiogenesis, tumor-promoting inflammation, deregulate energetics
89
What are the key characteristics of dominant somatic mutations?
also called gain of function, create oncogenes, activated, one bad allele=disease
90
What are the key characteristics of recessive somatic mutations?
loss of function mutation delete or inactivate tumor suppressor genes, 2 bad alleles = diesease
91
What is caner susceptibility syndrome?
heterozygous for inactivating mutation of a tumor suppressor gene may have increased susceptibility
92
Describe the pathway for familial colon cancer
first loss of Apc, leads to hyperplastic epithelium, rapid proliferation to early adenoma, activation of K-Ras oncogene leads to intermediate adenoma still rapid proliferation phase, loss of Smad4 and other supressors leads to late adenoma first stage of cancer, then loss of p53 which leads to carcinoma primary cancer, genomic instability leads to invasion and metastasis secondary cancer
93
What leads to genomic instability?
stress cell by shortening cell cycle not allowing time to fix errors
94
What four things can lead to mutations in DNA from endogenous biochemical processes?
spontaneous depurination of guanine to form abasic site, deamination of cytosine to form uracil, deamination of deoxy-5-methyl-cytosine to form deoxythymidine glycol, leakage of ROS reactive oxidative species from the mitochondria into cytoplasm or even nucleus (from metabolism)
95
What does it mean to have fixed changes in the DNA sequence?
a mutation didn't change in the DNA sequence
96
What damage does ionizing radiation cause?
breakage of the phosphodiester backbone, base modifications, abasic sites
97
What damage does ultraviolet radiation cause?
causes cyclobutane structures between neighboring pyrimidines on the same strand, (T=T, C=C, or C=T) and several types of 6-4 photoproducts
98
What does p53 do?
guardian of the genome, pause and check for errors, either repairs damage or if too expensive to repair signals apoptosis
99
What happens if the cell is lacking p53 and undergoes ionizing radiation?
cell cycle doesn't stop, division with damaged chromosome, leads to either tumor regression (massive mitotic failure and cell death) or cancer(continued mutation selection, and tumor evolution)
100
What enzymes are involved with polycyclic aromatic hydrocarbons from incomplete combustion (cigarette smoke)? What is the final product?
after 2 oxidizing steps catalyzed by cytochrome p450, BPDE the ultimate carcinogen is formed which alters Guanine creating an adduct
101
What damage can chemical carcinogens cause?
cause formation of DNA adducts, most common in cancer related mutations is guanyl causing G-T transversion
102
What does aflotoxin B do? How is it potentially ingested?
metabolized by cytochrome p450 then either a gaunyl adduct or metabolized by epoxide hydrase or glutathione s-tranferase resulting in a detoxified product. found in aspergillus flavus which grows on peanuts, causes liver cancer with low exposure
103
Explain how receptor tyrosine kinase works?
2 single pass transmembrane proteins, ligand binds to both, causes cross phosphorylation of the intracellular portion of the proteins, the phosphate becomes a docking site for signaling proteins effectors and adaptors, these proteins send a signal downstream
104
What does Ras do?
it is a small GTPase, activated by Grb2 which binds to tyrosine kinase, Grb2 activates a Ras GEF called SOS this allows the GDP on the inactive membrane bound Ras protein to be exchanges for GTP activating the protein, this activates a kinase cascade
105
How is the signal in a tyrosine kinase receptor shut off?
dephosphorylation by phosphatases
106
Explain the ERK MAP kinase pathway.
active Ras stimulates RAF-1 phosphorylation specifically Ser/Thr, RAF-1 utilizing ATP phosphorylates Mek, then using another ATP Mek phosphorylates ERK, ERK using ATP phosphorylates either a protein to affect its activity or a gene regulatory protein to effect gene expression
107
What does ERK MAP kinase effect?
cell proliferation, gene expression, and protein synthesis
108
What does PI3 kinase/Akt/PKB pathway control?
survival, growth, and proliferation
109
Of the following which is bad and which is good; oncogenes or proto-oncogenes?
oncogenes bad, proto-oncogenes good
110
Tumor viruses can trigger neoplastic transformation in cells they infect how?
in retroviruses the RNA genomes copies then goes back to DNA then inserts itself into host genome
111
What is inserted or mutated in Rous sarcoma virus? What is the result in the cell? What is this virus an example of?
c-src is replaced by v-src, produces a constituitively active tyrosine kinase, example of a tumor retrovirus
112
What cancer is caused by the virus EBV?
Burkitt's lymphoma
113
What cancer is caused by the virus HTLV-1?
non-hodgkins lymphoma
114
What cancer is caused by the virus HHV-8?
Kaposi's sarcoma, body cavity lymphoma
115
What cancer is caused by the virus HBV?
hepatocellular carcinoma
116
What cancer is caused by the virus HCV?
hepatocellular carcinoma
117
What cancer is caused by the virus HPV?
cervical carcinoma
118
What cancer is caused by the virus JCV?
astrocytoma, glioblastoma
119
What are some key cellular regulators of growth and development that proto-oncogenes encode?
growth factor receptors, protein tyrosine kinases (Src, Abl), Signaling molecules (Ras), Transcription factors (Myc, Fos)
120
What is unregulated expression?
insertional mutagenesis, gene amplification, and abberant transcriptional control can cause overexpression of the proto-oncogene at inappropriate phases of the cell cycle
121
what three mechanisms allow proto-oncogenes to be converted or activated to oncogenes?
mutation, unregulated expression, or chromosomal rearrangement
122
What is chromosomal rearrangement?
can alter transcriptional control of the proto-oncogenes or create a fushion protein with altered activity compared with a normal protein
123
What happens if there is a mutation of Ras at codons 12,13, or 61?
encode for amino acid substitutions that makes Ras insensitive to GTPase-activating function of RAS-GAP, GTP cannot be hydrolyzed to GDP so it remains active.
124
ErbB gene is mutated how? What does the gene encode normally?
a critical valine in the membrane bound region is switched with a glutamine causing a polar distortion in NEW causing erbB next to it to be always on, normally encodes form of epidermal growth factor receptor
125
What two methods cause overexpression or unregulated expression of normal growth regulators?
retoviruses that express viral verions of proteins in an unregulated or constitutive manner, transforming capabilities, or amplification by proviral insertional mutagenesis can also lead to unregulated expression of myc in several species, leads to mistiming which leads to cancer
126
What protein inactivates Ras and induces GTP hydrolysis?
RAS-GAP
127
The Philadelphia chromosome is an abnormality that occurs in myeloblastic precursor stem cells of granulocytic lineage leading to what? This is an example of activation by what?
chronic myelogenous leukemia (CML), chromosomal rearrangement
128
What happens in the genetic exchange to cause the Philadelphia chromosome?
between chromosome 9 and 22, the 3' portion of c-ABL gene encoding the cytoplasmic tyrosine kinase was fused with the 5' end of the BCR gene, creating a chimeric Bcr-Abl fusion protein, a constitutively active tyrosine kinase
129
What is Gleevec?
an competitive inhibitor of the Abl kinase activity of the Bcr-Abl oncoprotein, its very effective in treatment of CML
130
How does Gleevec work?
it binds to the ATP binding site of the Bcr-Abl which prevents it from binding to and phosphorylate the substrate protein, stoping the signal for leukemia, not specific for Abl
131
What is retinoblastoma?
a childhood neoplasm, Rb locus maps to chromosome 13
132
Rb is hereditary or familial and is passed how?
heterozygotes have only one good copy of the Rb gene, the normal chromosome is lost or suffers a somatic mutation inactivating the good Rb gene.
133
Explain the pathway that leads to phosphorylation of Rb.
mitogen binds to receptor starting a ERK/Mapk path, gene regulatory protein Fos enters nucleus causing immediate early gene expression, signal passes to Myc which causes delayed-response gene expression by activating cyclins, G1 CDK then phosphorylates active Rb (pocket) bound to inactivated E2F, Rb is now inactivated (lose pocket) and releases E2F which is now active
134
What is the function of the Rb gene? What is it regulated by?
it encodes an inhibitor of the action of several proteins involved in DNA replication, cell cycle dependent phosphorylation mechanism (cell cycle clock)
135
Explain what E2F protein does and the feedback loop on it.
E2F causes s-phase gene transcription, this positively feeds back on itself. S phase transcription leads to G1/S-cyclins which leads to active G1/s-CDK and Active S-CDK, G1/S-CDK feeds back to activation of E2F and forward to activation of S-CDK, S-CDK leads to DNA synthesis
136
What is Li-Fraumeni syndrome?
people who inherit one functional copy of p53, predisposed to cancer, characterized by development of wide variety of tumors in different organs early in adulthood
137
What does p53 do? (function)
homotetrameric transcription factor, controls expression of many geens to arrest cell growth or induce programmed cell death
138
How does p53 induce cell cycle arrest?
after Double strand break, signal sent and p53 is phosphorylated activating it, p53 binds to DNA increasing expression of p21Cip1, creates p21 inhibitor protein which binds to G1/S-CDK and S-CDK inactivating them and blocking cell cycle, also increased expression of 14-3-3sigma which sequesters cell cycle kinase complex cyclin B-Cdc2 in inactive form in cytoplasm, or suppress expression of IGF-1 receptor (critical stimulator of mitogenesis)
139
What are the two pathways for apoptosis signaling and how can they effect each other?
extrinsic and intrinsic, extrinsic can activate the intrinsic path to ensure apoptosis
140
What happens intracellularly after the extracellular signal for apoptosis via receptor?
initiator procaspases (proteolytic enzymes) are activated to caspases, these activate executioner caspases by cleaving them, this mediates the death pathway
141
what two ways can activate the Extrinsic path of apoptosis?
death ligand(many kinds) binding to its death receptor, cytotoxic cell attaching to membrane and releasing granzyme B into the cell
142
Where and how is the intrinsic pathway of apoptosis initiated?
in the mitochondria, cytochrome C or metabolic enzyme leaks out of pores, once in the cytosol they bind to Apaf-1 and caspase 9 (intiator caspase) forming the apoptosome
143
What are some things that lead to activation of the intrinsic pathway of apoptosis?
hypoxia, DNA damage, massive DNA methylation, Nitric oxide stress
144
What is the role of the executioner or effector caspases in apoptosis?
cleave death substrates
145
What happens when there is proteolysis of nuclear lamins? What pathway is this part of and what step?
leads to changes in nucleus like pyknosis (nuclear condensation) and disintegration of the nuclear envelope,cleavage of death substrate in apoptosis
146
What is ICAD? What pathway is part of?
inhibitor of caspase activated DNase, apoptosis, if cleaved it relives inhibition on DNase leading to internucleosomal DNA fragmentation
147
How are vimentin and actin involved in apoptosis?
both are an example of protein complements of the cell surface and cytoskeleton that are altered causing blebbing and increasing the phosphatidyl serine content of the outer leaflet attracting macrophages.
148
How does high levels of p53 block survival signaling? (3 ways)
Upregulation of Fas (death receptor) promoting extrinsic pathway, upregulation of pericellular IGF binding protein 3 (IGFBP-3) sequesters growth/survival factors IGF I and II, and increase expression of BAX the pro-apoptotic pore protein (activates intrinsic pathway)
149
Of the 15k distinct known mutations of p53, what percent are missense mutations?
>90% (amino acid substitution)
150
Most of the missense mutations of p53 are what kind? What does this mean for the cell?
inactivating or recessive, normal cellular p53 activity may be maintained
151
What are the two main types of the Bcl2 family of proteins? What does each do?
pro-apoptotic-stimulate apoptosis, anti-apoptotic- inhibit apoptosis or promote cellular survival
152
What are dominant-negative mutations? What does it mean if it occurs in p53?
poison protein response, bad protein inactivates the good in a complex, interfere with the function of normal p53 in tetramer
153
What is the main anti-apoptotic Bcl2 protein? What functional domains does it have?
Bcl2, BH1, BH2, BH3, and BH4
154
What are the pro-apoptotic Bcl2 proteins? What functional groups does each have?
Bax-BH1, BH2, and BH3
| Bad- BH3
155
How does Bcl2 work?
in absence of death stimulus, Bcl2 binds to BH123 proteins (Bax) on the outer mitochondrial membrane inhibiting their pore-forming activity
156
If apoptotic signal is received what happens to Bcl2 proteins?
Bad (BH3), binds to Bcl2 forming inactive heterodimers, causing Bcl2 to release Bax, Bax proteins cluster together forming pores in mitochondrial membrane beginning the intrinsic path
157
What are IAPs? Which are endogenous to humans?
Inhibitors of apoptosis, endogenous proteins that block cell death by interfering with caspase activity. XIAP(x-linked), cIAP (cellular)
158
What two viruses are known to contain IAPs?
Cytomegalovirus and Epstein Barr virus
159
In cancer cell what happens to IAPs? How is this clinically relevant?
IAPs are upregulated and therefore a drug target,
160
What are some Anti-IAPs? How do they work?
Smac and Diablo, bind to and inhibit certain IAPs which re-activates apoptosis.
161
What are the main proteins involved in the survival signal pathway?
PI-3 kinase, Akt, and PKB
162
In the PI3K/Akt/PKB path, PI-3 kinase phosphorylates what and what does it then become?
PIP2 becomes PIP3 which forms a lipid based docking site on the membrane
163
In the PI3K/Akt/PKB path, what binds to PIP3?
Akt/PKB or PDK1
164
In the PI3K/Akt/PKB path, what activates PDK1?
once bound to PIP3 it is phosphorylated by Akt and mTOR in complex with rictor
165
In the PI3K/Akt/PKB path, what does activated Akt do?
migrates thru cytoplasm phosphorylating substrates (which activates or inactivates them) that mediate cell survival by inhibiting apoptosis and stimulating the cell cycle
166
What are Akt anti-apoptotic substrates? What are they normally? Are they inhibited or activated?
Bad- pro-apoptotic- inhibited
| caspase 9 - pro-apoptotic- inhibited
167
How does Akt activate cellular protein synthesis?
activation of the kinase mTOR in complex with Raptor phosphorylates several regulatory proteins
168
What three examples were given that are phosphorylated by mTOR to increase protein synthesis? How does each effect protein synthesis?
S6kinase ribosome- enhances ribosomal activity, 4E-BP inhibits elF4E
Gene regulatory factors that increase ribosome synthesis
169
Is elimination of p53 enough to cause cancer?
no, need multiple mutations
170
What is needed to maintain tissue viability? What happens to it as we age? Why?
stem cells, decrease in numbers due to a decrease in proliferation
171
What are the four Cellular and molecular events in normal Aging?
reduced signaling thru PI-3K/Akt path, impairment of DNA repair pathways, Elevated levels of cell cycle inhibitors and apoptosis effectors, and decreased mitochondrial activity
172
What is cockayne syndrome?
premature aging disorder, due to mutations of encoding proteins in transcription-coupled DNA repair path
173
What is xeroderma pigmentosum?
inherited disease characterized with extreme sensitivity to UV, cause by mutation of 1 of 8 genes that encode proteins in the NER pathway
174
What is Werner syndrome?
also called adult progeria, due premature aging disorder, due to mutation of WRN which encodes a DNA helicase of BER path
175
What two things lead to cell cycle arrest in normal aging? What state do the cell enter?
rise of cyclin inhibitors p16^Ink4a and p21^Cip1 and chronically elevated p53, replicative cell senescence
176
What happens in the mitochondria during aging?
decrease in effectiveness of ETC, decrease ATP production and increase production of ROS
177
What is the Haflick limit?
number of divisions allowable for normal (non-transformed) cells in culture
178
How does telomerase activity change at differentiation?
high in stem cells and decreases after differentiation, lose 100-200 nucleotides from telomeres everytime the cell divides
179
Erosion of the telomere leads to what?
crisis, increased risk of end to end fushion of sister chromatids while they are paired in G2 by repair enzymes
180
What is the BFB cycle?
fushion of dicentric chromatids due to telomere erosion, breakage then results when sister chromatids separate, imbalance of genetic material and no telomeres, (cycle repeats with a new site on the chromosome effected
181
Cancer cells re-express high levels of what to overcome normal aging? what is the incidence rate of this amongst pre-cancerous cells?
telomerase 85-90% increase in activity, hTERT, avoid mitotic crisis, utilize clonal expansion to do so. this is rare as 99.9% of pre-cancerous cells die
182
What is a Kaplain Meier Survival Curve?
tracks survival rate vs time since diagnosis comparing low TA level or high TA level (Telomerase Activity)
183
What are the phases of mitosis in order?
Prophase, Metaphase, Anaphase, Telophase, and Cytokinesis
184
What are the phases of the cell cycle in order?
G1, S, G2, and M (mitosis)
185
What is the G0 phase of the cell cyle?
resting or non-proliferative stage ( subset of G1), also called quiescence
186
what is karyokinesis?
nuclear division
187
What is cytokinesis?
cytoplasmic division
188
Can karyokinesis occur without subsequent cytokinesis? examples if any.
yes, cardiac and liver cells can be binucleated
189
what are the two types of cell division? What is the resulting cell called.
mitosis = diploid and meiosis = haploid
190
Interphase includes which phases of the cell cycle?
G0, G1, S, and G2
191
what are the features of prophase?
completion of chromosome condensation, tight attachment of sister chromatids to centromere surrounding centrioles, dissolution/disappearance of nuclear envelope and nucleoli, formation of mitotic spindle, appearance of centrosome
192
Explain the assembly and disassembly of the nuclear envelope.
in interphase lamins A,B, and C associate w/ chromatin and inner membrane, at mitosis cyclin B activated Cdc2 phosphorylates lamins creating free lamin dimers A and C, vesicles of the nuclear envelope associate with the B lamins, after division vesicles fuse and free lamins are dephosphorylated and reform the network
193
what are the features of prometaphase?
nuclear envelope breaks into cytoplasmic vesicles, movement of spindle microtubules into nuclear region, maturation of the kinetochore complex on centromere
194
What are the main features of metaphase?
formation of kinetochore (protein DNA complex), attachment of kinetochore to microtubule, formation of polar and astral microtubules
195
What are the key features of Anaphase?
chromosomes move towards the spindle, topoisomerase facilitates separation of sister chromatids, kinetochore microtubules shorten, poles move away from each other, polar microtubules lengthen
196
What are the key features of telophase?
uncoiling of chromosomes, development of nucleoli at nuclear organizer site, spindle disassembly, formation of nuclear envelope, initiation of cytokinesis
197
How is cleavage during cytokinesis achieved?
beltlike bundle of actin and myosin called the contractile ring form in the cell cortex just inside the membrane
198
What are the stages of genetic recombination that occurs during meiosis I and mitosis?
pairing, synapsis, synaptonemal complex, and recombination
199
What are the four stages of meiotic prophase I? What is significant about each?
Leptotene- condensation of chromosome, telomeres attach to inside of nuclear membrane, Zygotene-homologous pairs formed for synapsis and formation of synaptonemal complex early part of stage resembles bouquet, Pachytene- chromosomes shorter and thicker synaptonemal complex formed, and Diplotene- synaptonemal complex disintegrates and decondense but sisters remain close for recondensation soon
200
In what stage are females eggs stored and how long can it last? What is active in the cell at this time?
diplotene, days to years, active in transcription as they store up materials for the first few embryonic divisions, lampbrush appearance with DNA in center and RNA and proteins are "bristles"
201
Describe the steps of recombination.
between paired homologues not sister chromatids, double strand break initiated by enzyme Spo11p, resection of breaks on the 3' end by exonuclease, next strand invasion of the homologous pair this produces the Holiday Junction where strands cross, DNA synthesis fills in the gap, resolvase cuts at the holiday junction if symmetrical no crossing over, if not there will be crossing over
202
What is diakinesis?
occurs after diplotene in meiosis, homologous chromosomes recondense, and form synaptonemal complex
203
What are the key features of Meiotic metaphase I?
bivalent chromosomes attached to spindle microtubule by kinetochore are lined upon the metaphase plate
204
What are the key features of Meiotic metaphase I?
bivalents move toward opposite poles pulling the homologous chromosomes of each bivalent pair
205
What are the key features of Meiotic telophase I?
movement of chromosomes to opposite poles complete, nuclear envelopes formed and cytoplasm splits to form two daughter cells
206
What are the key features of Meiosis II?
phases similar to mitosis except chromosomes on metaphase plate are half in number
207
What is the significance of meiosis?
preservation of chromosome number and generation of genetic diversity for sexually reproducing organisms
208
What are the major regulation points in the cell cycle? when do they occur?
restriction point in G1, DNA damage checkpoints in G1,S and G2, DNA replication checkpoint (shares components with DNA damage plus stabilizes stalled replication fork and intiates repair), spindle assembly checkpoint during mitosis
209
Cell divisions are controlled by what two things?
external stimuli and nutrient availability
210
When might a cell withdraw from the cell cycle? What type of regulation is this?
if environmental conditions are not suitable, restriction point
211
What are the key factors of the DNA damage checkpoints in cell cycle regulation?
CDKs are master regulators, active only when complexed with cyclin, cyclins are in abundance during cell cycle, CDK partners with different cyclins during different phases to phosphorylate key proteins
212
Explain the process of activation of the CDK complex.
CAK phosphorylates the Thr 167 of CDK1 activating the CDK1/cyclin B, phosphorylation of the Thr 14 and Tyr 15 by Wee family kinases CDK1 complex inactive in G2, at transition into M phase phosphorylation by Wee 1is reversed by Cdc25 family phosphatases resulting in activated complex
213
What are the two ways CDK is inhibited?
CDI (CDK inhibitor) binds to either CDK or CDK cyclin complex or during G2 nuclear export of cyclin B dominates resulting in separation of cyclin B from CDK 1, normally phosphorylation of key residues in cyclin B attenuates its export resulting in nuclear accumulation and accessibility of substrates
214
How is CDK inactivated after mitosis?
proteolysis of cyclin B contributes to it
215
DNA replication checkpoints take advantage of what factors?
replication requires ordered assembly of protein complexes, occurs at origins that may be deined by sequence position or spacing mechanisms, initiation only occurs at origins licensed to regulate, once used they cant be used again until the next cell cycle
216
What drives the release of sister chromatid cohesion?
Ubiquitin-mediated proteolysis by separase
217
How does CDK regulate the activity of separase?
CDK1 phosphorylates APC (anaphase promoting complex) which binds its activator Cdc20. APC and Cdc20 target its substrate securin for proteolysis which normally binds separase
218
What happens with the spindle assembly checkpoint?
if defects in spindle microtubule attachment are found transition from metaphase to anaphase is halted
219
What do proto-oncogenes do in terms of the cell cycle?
encode proteins that drive cells into the cell cycle
220
Tumor suppressor genes do what in terms of the cell cycle?
encode proteins that restrain cell cycle events
221
What is the basic structure of the membrane lipid cardiolipin?
two phospholipids joined by glycerol
222
What are gycosphingolipids?
glycolipids, family based and ceramide and do not contain phosphate
223
Neutral sphingolipids are synthesized via what enzyme primarily? basic structure?
ceramide plus one or many glucose and or galactose
224
What is the basic structure of Acid sphingolipids? What family are most of them?
ceramideplus gal or glu plus N-acetylneuraminic acid (NANA) or a sufoxide group, those containing NANA are the gangliosides
225
What are three main types of lipids found in membranes? What one stiffens the membrane?
phosphoglyceride, sphingolipid and cholesterol-stiffens
226
What are lipid rafts and what is their importance?
clump of phospholipids grouped together, regulate the activity of cell membrane receptors activity of hormone receptors is dependent on their location within the membrane as well as the presence of the ligand
227
What can happen to the body during extensive ketone body production? When does this occur?
ketoacidosis, lower blood pH, starvation, uncontrolled diabetes mellitus
228
Describe the path of ketone body formation.
2 acetyl CoA thiolase kicks off CoA to get acetoacetyl CoA then HMG CoA synthase adds acetyl group to get HMG CoA HMG Coa lyase kicks off Acetyl CoA to get Acetoacetate (first keton body, form here it either spontaneously kicks off a CO2 to become acetate or 3-hydroxybutyrate dehydrogenase makes it 3-hydroxybutyrate
229
How do the peripheral tissues utilize ketone bodies in metabolism?
acetoacetate is converted to Acetyl CoAs and enters TCA
230
what are the three main ketone bodies? Which is not energy yielding?
acetoacetate, acetone and 3-hydroxybutyrate, acetone does not yield energy
231
what two fuels does the brain utilize and when?
glucose in short term and ketone bodies in long term, some amount of ketone bodies are produced in a well fed state
232
What cell in the body requires glucose? Why?
erythrocytes, no mitochondria only utilize glycolysis
233
What portion of cholesterol is from diet and what portion is synthesized?
50/50
234
What is the rate limiting step of Cholesterol biosynthesis? How is this clinically relevant?
HMG-CoA reductase, target of statin drugs
235
what is the pathway of Cholesterol Biosynthesis?
Acetyl CoA to Acetoacetyl CoA to 3-hydroxy-3-methylglutaryl-coA to Mevalonanic acid to isopentanyl pyrophosphate to famesyl pyrophosphate to squalene to lanesterol to cholesterol
236
What can be made from cholesterol?
Bile salts, Vitamin D, Cortisol, Aldosterone, Testosterone, and Estradiol,
237
What percent of bile salts are recycled? How is this clinically significant?
95%, target for cholesterol lowering drugs prevents reuptake so body has to use more cholesterol to make more
238
What supplement is sold to increase testosterone production? Why?
DHEA, becomes Androsterone or Androtenediol which then becomes testosterone
239
What is the general path of synthesis of testosterone?
cholesterol to progesterone to 17-OH-progesterone to Androsterone to Testosterone
240
What is the general path of Estradiol synthesis?
cholesterol to progesterone to 17-OH-progesterone to Androsterone to either testosterone or Estrone then aromatase makes Estradiol
241
What drug is prescribed for prostate cancer and why?
Casodex, its an anti androgen
242
What drugw is often given to post-op women with breast cancer? Why?
tamoxifen or raloxifene, inhibits growth of tumors because most are estrogen receptor positive, it is an estrogen antagonist
243
How do hormones work in the body?
regulate gene expression through hormone receptors in cytoplasm and nucleus
244
What are the four precursors for phsophatidic acid in the acyl glycerol biosynthesis?
Triacylglycerol, Diacylglycerol, Glycerol-3-Phsophate, and DHAP
245
What else is synthesized along the sphingolipid path besides sphingolipids? What is the start? Where does it occur in the cell?
glycolipids, from palmitoyl CoA and Serine, in the lumen of the Golgi (near the cell membrane)
246
What is Tay-Sachs? Characteristics? Cause?
Autosomal recessive neurological disorder, death by 3, first diagnosed by cherry red spot in retina, higher incidence in Ashkenazi Jews, results in accumulation of undigested lipids in lysosomes in nerve cells, Increase in Ganglioside GM2, problem is with B-Hexosaminidase A enzyme in the glycolipid degradation pathway
247
How can carriers of Tay-Sachs be distingiuished?
reduction but not a loss in Hexosaminidase A activity in blood lymphocytes
248
Is genetic screening feasible for Tay-Sachs?
No over 100 types of mutations
249
How are fatty acids broken down?
B-oxidation, two step process releasing acetyl CoA to enter the TCA cycle
250
For fatty acid breakdown to occur what must happen first? Give the pathway that achieves this. What is the rate limiting step?
fatty acids must enter the mitochondria, Acyl CoA Synthetase transport acetyl CoA from FA across the outer membrane, carnitine palmitoyl transferase I puts the Acyl group on carnitine releasing the CoA, Carnitine acylcarnitine translocase on the inner membrane switches a carnitine from inside the mitochondria with the acylcarnitine between the membranes, finally carnitine palmitoyl transferase II puts a CoA back on the Acyl group releasing carnitine to go back between the membranes via Carnitine acylcarnitine translocase, rate limting steps are the Carnitine palmitoyl transferase I and II
251
What are some lipid oxidation disorders? effects and treatment of each?
CPTI and CPT II deficiencies: muscle weakness, hypoketotic hypoglycemia, cardiac malfunction and death, avoid fasting and long chain fatty acids; primary carnitine deficiency: impairment of B-oxidation, dietary supplementation of carnitine; secondary carnitine deficiency: elevated secretion of acylcarnitine derivatives; dietary carnitine helps with effects of depletion
252
List the pathway of B-oxidation.
starts with fatty acyl CoA oxidation via Acyl-CoA dehydrogenase and FAD to trans-Enoyl-CoA which is hydrated by enoyl-CoA hydratase (cronotase) to L-B-hydroxyacyl-CoA which is oxidized by L-hydroxyacyl-CoA dehydrogenase and NAD to B-ketoacyl-CoA which is cleaved by Thiolase and the addition of a new CoA to the remaining shortened fatty acid
253
What happens to the electrons removed by Acyl-CoA dehydrogenase?
enter ETC as reduced coQ yielding 1.5 ATP
254
what are the different enzymes in the Acyl-CoA dehydrogenase family?
SCAD, MCAD, LCAD, and VLCAD for the different length fatty acids short, medium, long and very long
255
How many ATP are yielded by the NADH produced in B-oxidation?
2.5 ATP
256
What differs in the B-oxidation in peroxisomes?
require FAD-dependent acyl-CoA oxidase instead of Acyl-CoA dehydrogenase, the hydrogens attached to FAD are then transferred to O2 producing H2O2 instead of utilizing ETC, fewer ATP
257
What type of fatty acids are oxidized in peroxisomes? How are they brought in and the products out?
VLFA chains, peroxisomal carnitine acyltransferase transports long chain acylcarnitine in, after oxidation acetyl-CoA and octanol-CoA are converted to acetyl-carnitine and octanol-carnitine exported from peroxisome into cytoplasm for entry into the mitochondria, NADH react with pyruvate to form lactate which shuttles electrons to cytoplasm
258
What is the end yield of odd chain fatty acid oxidation? What does the body do with it?
propionyl-CoA, in three reactions it becomes succinyl-CoA and enters TCA cycle
259
How are unsaturated fatty acids oxidized?
an additional enzyme is sometimes needed to rearrange the double bond position so it can continue along the path.
260
What is w-oxidation? When is it important?
oxidation of methyl carbon to carboxyl in ER by cytochrome p450 the dicarboxylic acid product can then be transferred to mitochondria and metabolized by B-oxidation from both ends, normal minor pathway is seen more when there is a disorder in B-oxidation
261
What is lipogenesis? Where does it take place mostly? What is the main source of carbon?
synthesis of fatty acids and their esterification to glycerol to form triglycerides, in the liver, dietary carbohydrate
262
What are the differences between B-oxidation and lipogenesis?
intermediates of synthesis are linked to -SH groups of acyl carrier proteins (compared to the SH groups of CoA), synthesis is in the cytosol oxidation in mitochondria, enzymes of synthesis are one polypeptide fatty acid synthase (multiple rxn sites), biosynthesis uses NADPH/NADP+ breakdown uses NADH/NAD+
263
How does the cytosol get more Acetyl-CoA and NADPH for synthesis?
citrate-malate-pyruvate shuttle
264
How is chain elongation achieved in fatty acid synthesis?
addition of 2 carbon units derived from acetyl CoA, acetate units are activated by formation of malonyl-CoA (use ATP) by acetyl-CoA carboxylase, addition of 2 carbon units is driven by decarboxylation of malonyl-CoA, repeated until 16 carbon length achieved, other enzymes add double bonds and additional carbons
265
What is the first committed step of lipogenesis?
carboxylation of acetyl-CoA by acetyl-CoA carboxylase to malonyl-CoA utilizing ATP, bicarbonate, and biotin, it is irreversible, this is the rate limiting step
266
How is the activity of ACC controlled?
ACC is modulated by phosphorylation, the dephosphorylated form is activated by low citrate and inhibited only by high levels of fatty acyl-CoA, the phosphorylated form is activated by high levels of citrate and inhibited by low fatty acyl-CoA
267
What hormone regulates fatty acid synthesis and break down? How?
glucagon binds to receptor, g protein activates AC which turns ATP to cAMP which activates protein kinase phosphorylating ACC and triacylglycerol Lipase inactivating it. insulin- binds receptor which activates phosphodiesterase turns cAMP to AMP ending glucagon signal
268
How is FA synth. regulated?
malonyl-CoA blocks carnitine acyltransferase and inhibits B-oxidation, citrate activates ACC, fatty acyl-CoA inhibits ACC, hormones regulate ACC: glucagon activates lipases/inhibits ACC and insulin inhibits lipases/activates ACC
269
What is MAT?
malonyl-CoA-acetyl-CoA-ACP transacylase transfers acyl of acetyl CoA to acyl carrier protein(ACP), also transfers malonyl of malonyl-CoA to ACP
270
What two fatty acids are essential? Why? What are they used for in the body?
w-3: cardioprotective, anti-inflammatory, anticarcinogenic precursor of EPA and DHA
w-6: precursor of prostaglandins, thromboxanes, leukotrienes, and arachidonic acid, neither can be synthesized in the body
271
What are the different body fluid compartments?
Intracellular, Extracellular (Interstitial and plasma), and Transcellular
272
Describe the relative level of Na, K, Cl, and Protein in the intracellular compartment.
Na low, K high, Cl low, Protein high
273
Describe the relative level of Na, K, Cl, and Protein in the interstitial compartment.
Na high, K low, Cl high, Protein 0
274
Describe the relative level of Na, K, Cl, and Protein in the Plasma.
Na high, K low, Cl high, Protein low but some present
275
Describe the relative level of Na, K, Cl, and Protein in the transcellular.
all variable, effected by hormones, concentration in the blood
276
Explain Fick's Law of simple diffusion.
net flux (J) is equal to permeability coefficient (P) times the surface area for diffusion times the concentration gradient (delta C)
277
What is the equation for movement of an ion across a cell membrane? the measurements of each.
Current (I, amps) = conductance (g,siemens) x the electrochemical force (membrane potential [Vm] - gradient potential [E], volts)
278
How do electrolytes move across a membrane?
selective ion channels
279
What is the membrane potential?
an electrical field or separation of charges along the cell membrane, it effects the movement of electrolytes across it.
280
What is the chemical potential? how do you convert it to be added to the electrical potential?
if there is a gradient based on the concentrations inside and outside of the cell that is the chemical force driving movement of the chemical E=(60z)mV log(Co/Ci) Co and Ci are concentration inside and out of the cell and z is the valence of the ion
281
What are the three types of carrier mediated transport?
facilitated diffusion, active transport, secondary active transport
282
Carrier mediated facilitated diffusion takes advantage of what? is there a limit?
driven by chemical gradient to transport passively, integral membrane proteins are specific to what they carry, there is a saturation point at Jmax
283
what role does insulin play in facilitated diffusion of glucose?
enhances diffusion of glucose by adding more transporters, GLUT4 to help the GLUT1 transporters when they are overwhelmed
284
What are the characteristics of primary active transport?
break a phosphate bond in ATP to transport against a gradient.
285
Where are Na/K pumps usually located?
on the basolateral plasma membrane of all cells
286
Besides Na/K pumps what are some other examples of primary active transport?
H/K/ATPase, H-ATPase, and Ca-ATPase
287
What are the different kinds of secondary active transport? Define them.
symport-the chemical gradient for one is used to transport another chemical the same direction and antiport- the chemical gradient is used to transport something in the opposite direction against its own gradient
288
What are some examples of symport?
Na+-glucose and Na+-amino acid
289
What are some examples of antiport?
Na-H exchanger and Na-Ca exchanger
290
What is osmosis?
the flow or displacement of volume across a barrier due to movements of matter in response to a concentration difference, dependent on random thermal motion, result is abolition of the chemical gradient, difference is that volume is displaced in osmosis
291
what special channel does water use? What are the features of it?
aquaporin, a non-gated channel
292
What is the equation for the movement of water across a membrane barrier?
rate at which water moves (Jv) is equal to hydraulic conductivity of the barrier (Kf) times the driving force in terms of total pressure (deltaPt)
293
What are the two types of pressure on a biological membrane?
Hydrostatic (blood pressure), Osmotic (Interstitial fluid to plasma) Osmotic pressure (delta pi) - hydrostatic pressure (delta p)
294
How do you calculate osmotic pressure?
19.3 mm Hg/mM times the concentration difference of the impermeable solute (delta C)
295
What is the reflection coefficient?
sigma, used to factor the partial permeability of a solute, 1-(Cf/Ci) Cf being concentration final and Ci being concentration initial, zero is impermeable 1 is completely permeable
296
How does cystic fibrosis effect Cl secretion in the lungs?
defect in the Cl channel prevents secretion of fluid which follows Cl into the lungs
297
What is the embryological origin of fibroblasts and chondroblasts?
Mesenchyme
298
What are some key characteristics of cartilage?
avascular so nutrients and waste diffuse to adjacent loos connective tissue, Fibers embedded in a gel provides viscoelastic properties of firmness and resilience, have lacuna with cell in them, classified by the matrix characteristic, contains cells
299
Describe the cells in cartilage. Lineage, differences, etc.
have a well developed rER and Golgi, stem cells give rise to chondroblasts start flat and get round as they migrate inward form perichondrium once in a lacuna and separated from other cells it becomes a chondrocyte.
300
What is the difference between territorial matrix and interterritorial matrix?
Territorial is immediately surrounding a cell and between cells sharing a lacuna darker staining, interterritorial is between lacuna lighter staining
301
What makes up the matrix of cartilage?
Type II collagen, GAGs (hyaluronic acid, chondroitin sulfate, keratin sulfate, aggregan), and Proteoglycans (multiadhesive glycoproteins like fibronectin, chondronectin and anchorin)- 60% water
302
What are the primary characteristics of Hyaline Cartilage? Common sites?
homologous, amorphous matrix, because Type II collagen and GAGs have similar refractive index compressible and flexible but not elastic, covered by perichondrium except where it lines joints, initial skeleton of fetus, synovial joints, large airways, ventral ends of ribs, epiphyseal plate
303
What are the primary characteristics of Elastic Cartilage? Common sites?
matrix with elastic fibers and collagen type II, perichondrium, blends into hyaline, visualized with special staining to make out elastic fibers (resourcin-fuchsin), Ear, auditory tube, epiglottis
304
What are the primary characteristics of Fibrocartilage? Common sites?
Intermediate btwn Dense CT and Hyaline cartilage, no perichondrium, Type I (coarse) and II (opaque) collagen, chondrocytes can occur singularly or aligned in rows btwn bundles of I collagen. Site: Intervertebral disc, pubic symphysis, menisci, tendon attachments
305
What are the two types of growth in cartilage? Define them.
Interstitial-isogenic groups secreting matrix outward for each cell, Appositional-lay down new matrix on the outside heading inward.
306
What is an isogenic group?
cells in a lacuna derived from a single cell
307
what are some characteristics of cartilage growth?
constant remodeling with synthesis and breakdown, breakdown favored with aging, limited regenerative/healing bcuz avascular, nutrients must diffuse through matrix to supply cells, no contact between cells
308
What degenerative changes can occur in cartilage and why? Treatments.
most commonly calcification of matrix- shuts off normal diffusion which leads to cell death and further degeneration, modest repair capacity, Rx: perichondral grafts, cell transplantation, artificial matrices or growth factors
309
What are the different covering of bone? cells or fibers in each?
Periosteum- outer fibrous (fibroblasts) and inner cellular (osteoprogenitor cells/osteoblasts), sharpey's fibers(collagen, penetrate bone at an angle to anchor tissue)
Endosteum- usually single layer (bone lining cells at rest, osteoblasts and osteoclasts can become active)
310
What is a osteoprogenitor cell? function?
stem cell derived from mesenchyme, differentiates into osteoblasts
311
What is an osteoblast? function?
active bone forming cells, prime funct. is synthesis and mineralization of organic matrix (type I collagen, proteoglycans, glycoproteins & non collagenous proteins), formsepithelial like layer on outside of bone
312
what is an osteocyte? function?
terminally differentiated cell derived from osteoblasts when surrounded by matrix, cell body trapped in space btween lamellae in lacunae, cytoplasmic process with cell to cell and cell to BV contact trapped in Canaliculi, maintainence of matrix
313
what is an osteoclast? function?
multinucleated, giant cell, motile, derived from monocyte-macrophage lineage, phagocytic monocytes, secrete acid, collagenase, proteolytic enzymes (bone remodeling)
314
What is a cytoplasmic process? What cell has them?
contact with adjacent osteoblasts via gap junctions, osteoblasts retain when become osteocytes used to pass nutrient and waste through network of cells to get to nearest blood vessel
315
What is a Howship's Lacunae? Components and functions of them?
etched depression in matrix at site of osteoclast attachment, Ruffles border- active border with folds on side facing matrix, Clear zone- area on osteoclast free of organelles on either side of ruffle border creates a tight seal to prevent leakage of enzymes
316
How are osteoclasts regulated?
Parathyroid hormone stimulates synthesis of M-CSF- transforms monocytes into macrophages and differentiation into osteoclasts, increases serum Ca2+, Calcitonin (thyroid gland) inhibits osteoclast activity and stimulates osteoblast activity which decreases serum Ca2+ levels
317
What are the organic components of bone matrix? What percent of bone matrix is organic?
Type I collagen (90%), Proteoglycans (10%)-chondroitin sulfate, keratin sulfate, hyaluronic acid, non collagenous proteins, 35%
318
What are the inorganic components of bone matrix? What percent of bone matrix is inorganic?
calcium, phosphorus, calcium as hydroxyapatite crystals, 65%, high levels of alkaline phosphatase secreted by osteoblasts in to blood during active bone formation
319
What are the different parts of the long bone?
Epiphysis (bulbous end, spongy bone covered by compact), Diaphysis (shaft of compact bone), Metaphysis (tapering transitional junction, ends when marrow cavity begins), and Epiphyseal plate (growth plate in metaphysis)
320
What are the different parts of the long bone?
Epiphysis (bulbous end, spongy bone covered by compact), Diaphysis (shaft of compact bone), Metaphysis (tapering transitional junction, ends when marrow cavity begins), and Epiphyseal plate (growth plate in metaphysis)
321
When can primary bone be seen?
immature, embryonic, or repair
322
Describe the process of intramembranous ossification.
mesenchyme differentiates into osteoblasts and secretes matrix, anastomosing trabeculae form spongy bone, depositing of Ca2+, osteoblasts and vessels trapped in matrix as osteocytes and hematopoiesis tissues, woven converted to lamellar
323
what are the general features of endochondrial ossification?
within hyaline cartilage, bone collar produced by osteoprogenitor cells in perichondrium (periosteum), bone collar prevents diffusion of nutrients, hypertrophic chondrocytes secrete VEGF, calcification of apoptosis of chondrocytes, BV of osteogenic bud enter through openings by osteoclasts, spaces filled with osteoprogenitor cells differentiate into osteoblasts, deposition of matrix (eosinophilic) on calcified cartilage (basophilic). primary ossification center along diaphysis, then a secondary ossification center in epiphysis forms the came way.
324
/how does the epiphyseal plate achieve bone lengthening?
chondrocytes divide and expand (hypertrophy) adding length zones: resting, proliferation, hypertrophy and calcification of matrix then apoptosis; then there is removal of calcified matrix by osteoclasts
325
What are the zones of endochondral ossification?
resting, proliferation (chondrocytes dividing into columns, "run" away from ossification center, hypertrophic (large chondrocytes), Calcification of cartilage begins then cells die, ossification-endochondrial bone appears, blood vessels and osteoprogenitor cells invade chondrocyte spaces
326
What is the functional unit in the bone? How is it made up?
osteon or haversian system, haversian canal in center with BV, nerves, and loose CT, lined with osteoprogenitor cells (osteoblasts)4-20 concentric lamellae surround it, parallel to long axis, canaliculi channels with cellular processes running between cells and connecting to haversian canal, continuous construction and rebuilding, small hole = more mature osteon
327
What are the different lamellae and where can they be found?
Concentric- around single Haversian canal, Circumferential- outer (whole bone) and inner (whole bone) lamellae, Interstitial (intermediate)- btwn Haversian systems left behind during remodeling
328
What is a Volkman's canal?
cross connections between haversian canals, contain BV but no concentric lamellae
329
What type of growth occurs in remodeling?
piezo electricity realigns new bone growth in direction of force, so it will withstand force in a new direction but does not change overall mass
330
Describe the phases of fracture repair.
hematoma formed is converted by granulation tissue by invasion of cells (macrophages) and capillaries, soft callus formation by conversion from the deposited collagen and fibrocartilage, osteoblasts deposit temporary bony collar around fracture to unite broken pieces while ossification occurs, small fragments are removed by osteoclasts with osteoblasts depositing spongy bone and then converting it to compact bone
331
What is a greenstick fracture?
abnormal bending in younger children, incomplete mineralization
332
What is osteoporosis?
loss of bone mass leading to bone fragility and fractures, primarily estrogen deficiency, resorbed bone exceeds amount formed, due to increase in osteoclasts, reversed by estrogen therapy, Calcium, Vit D
333
What is osteomalacia?
progressive softeneing and bending of bones, due to defect in mineralization of osteoid,due to lack of vit D or renal tubulardysfunction
334
What is ricket's?
juvenile osteomalacia, defect in mineralization of growth plate cartilage
335
What is Paget's disease?
uncontrolled osteoclast activity along with increased osteoblast activity in thicker but softer bones
336
What is osteoarthritis?
most common joint disease, degeneration or loss of articular cartilaeg
337
What is Rheumatoid arthritis?
autoimmune dx with damage to synovial memb. and cartilage, inflammation and thickening of synovial membrane, hypertrophy and replaced by CT
338
What is marasmus?
a condtion caused by calorie deprivation, often deprivation of carbs and protein in infants
339
What is kwashiorkor?
a condition resulting from protein deprivation, grossly distended belly, due to edema related to reduction in plasma proteins resulting in inability to maintain fluid distribution between blood and tissues
340
What is the percent breakdown of calories from different sources?
Fat 20-35 (n-6 5-10, n-3 0.6-1.2), Carbohydrate 45-65 (no less than 130g/day and no more than 25% from added sugars, fiber M 38g, Women 25g) Protein 10-35
341
What occurs in the mouth for digestion?
hydration and starch digestion by alpha-amylase, some sugar absorbed
342
What occurs in the stomach for digestion? absorption?
protein denaturation, hydrolysis (pH 2, )proteases pepsin from pepsinogen and some lipase and amylase activity, alcohol and aspirin absorped
343
What occurs in the duodenum for digestion?absorption?
pH 7 activation of trypsinogen to trypsin, contains enteropeptidases, activation of propeptidases, prophospholipases A2, intraluminal hydrolysis of starch, protein, and lipids, all absorbed a little
344
What occurs in the jejunum for digestion? absorption?
surface hydrolysis of oligo- and disaccharides and oligopeptides, all absorbed a little
345
What occurs in the ileum for digestion? absorption?
absorption of monosaccharides, free amino acids, di and tripeptides, free fatty acids, and monoacylglycerols, bile acids, NaCal and Water
346
What occurs in the colon for digestion? absorption?
nothing that is used by body just further digestion and breakdown by bacteria, only absorb H20 and NaCl.
347
Explain concept of lactose intolerance? Prevalence rates?
human milk has highest amount of lactose, need enzyme lactase to breakdown into glucose and galactose, enzyme typically in brushborder in SI, as much as 75% of human population loses this enzyme expression partial or complete resulting in lactose intolerance (gas, diarrhea, abdominal pain, and nausea. 90% of northern Europeans or those of northern European descent are tolerant
348
What are the fat soluble vitamins? why is too much dangerous?
A,D,K, and E, deposit in membranes and are harder to excrete out excess
349
What does vitamin A do?
precursor to visual receptor, retinol, and controls gene expression through interaction with nuclear receptors
350
what condition results from deficiency in thiamine? What are the symptoms and contributing factors to deficiency?
beriberi: neuropathy, muscle weakness and wasting, cardiomegaly, edema, opthalmoplegia; alcholism
351
what condition results from deficiency in Riboflavin? What are the symptoms and contributing factors to deficiency?
magenta tongue, angular stomatitis, seborrhea, cheilosis
352
what condition results from deficiency in niacin? What are the symptoms and contributing factors to deficiency?
pellagra: pigmented rash of sun exposed areas, bright tongue, diarrhea, apathy, memory loss, disorientation; alcoholism, vit B6 deficiency, riboflavin deficiency
353
what condition results from deficiency in B6? What are the symptoms and contributing factors to deficiency?
seborrhea, glossitis convulsions, neuropathy, depression, confusion; alcoholism, isoniazide treatment (TB)
354
what condition results from deficiency in folate? What are the symptoms and contributing factors to deficiency?
megaloblastic anemia, atrophic glossitis, depression, homocysteine, embryonic development of spina bifida or anencephaly; alcoholism, sulfasalazine, pyrimethamine, triamterene
355
what condition results from deficiency in B12? What are the symptoms and contributing factors to deficiency?
megaloblastic anemia, loss of vibratory and position so abnormal gait, dementia, impotence, loss of bladder and bowel control, increase in homocysteine and methylmalonic acid; gastric atrophy (pernicious anemia), terminal ileal disease, strict vegetarian
356
what condition results from deficiency in vitamin C? What are the symptoms and contributing factors to deficiency?
scurvy: petechaie, ecchymosis, coiled hairs, inflamed bleeding gums, joint effusion, poor wound healing; smoking, alcoholism
357
what condition results from deficiency in vitamin A? What are the symptoms and contributing factors to deficiency?
xerophthalmia, night blindness, BitA t spots, follicular hyperkarytosis, impaired embryonic development and dysfunction; fat malabsorption, infection, measles, alcoholism, protein energy malnutrition
358
what condition results from deficiency in vitamin D? What are the symptoms and contributing factors to deficiency?
rickets: skeletal deformities, rachitic rosary, bowed legs, osteomalacia; aging, lack of sunlight exposure, fat malabsorption
359
what condition results from deficiency in vitamin E? What are the symptoms and contributing factors to deficiency?
peripheral neuropathy, spinocerebellar ataxia, skeletal muscular atrophy, retinopathy; fat malabsorption, genetic abnormalities of Vit E metabolism/transport
360
what condition results from deficiency in vitamin K? What are the symptoms and contributing factors to deficiency?
elevated prothrombin time, bleeding; fat malabsorption, liver disease, antibiotic use
361
why does folic acid cause megaloblastic anemia?
involved in reactions in biosynthesis of amino acids, purines and DNA specific pyr, thiamine, impaired nucleotide synthesis is cause
362
How does vitamin cause night blindness? What are some sources?
retinal in in visual pigment rhodopsin, deficiency of that causes night blindness; as retinoic acid in liver, kidney, dairy and egg yolks or cleaved from B-carotene in yellow and dark green veggies and fruit
363
Why is vitamin C needed?
required for collagen hydroxylation, needed for cross-linking of collagen fibrils and in synthesis of carnitine. We lost ability to synthesize.
364
Why is Vitamin E needed?
antioxidant, thought to help prevent lipid peroxidation and other damage caused by oxidative stress
365
What is needed to absorb Vitamin B12? How long can boy go without?
binds in intestine to intrinsic factor, stores well so years
366
Why is vitamin B6 needed?
precursor of pyridoxal phosphate which is coenzyme for number of transamination, deamination, decarboxylation, and condensation reactions
367
Why is niacin needed? What happens if receive a high dose?
precursor of NAD and NADP, at high doses is a treatment for hyperlipidemia because it inhibits lipolysis in adipose tissue
368
Why is vitamin D needed? synthesized? synthesis regulated?
it is a hormone, which binds to intracellular receptors increasing gene expression of Ca2+ binding protein resulting in increase in absorption, body can synthesize UV changes 7-dehydrocholesterol to cholecalciferol, liver changes that to 25-(OH)D3 then the kidney changes that to 1,25(OH)D3 active form (last step effected by low PO4 and PTH
369
Why is vitamin K needed? How can vitamin k mechanism be used clinically?
blood coagulation, promotes gamma-carboxylation of glutamic acid in proteins esp. prothrombin, inhibiting action of K is a clinical treatment for hypercoagulation
370
why is iodine needed? 2 sources?
needed in thyroid to make thyroxine, goiter will result as thyroid enlarges trying to overcome problem, sources: iodine rich soil or supplementation (salt in states)
371
what condition results from Toxicity in Boron?
Developmental defects, male sterility, testicular atrophy
372
what condition results from deficiency in Calcium? Toxicity?
reduced bone mass and osteoporosis; Renal insufficiency (milk-alkalai syndrome), nephrolithiasis, impaired iron absorption
373
what condition results from deficiency in Copper? Toxicity?
Anemia, growth retardation, defective keratinization and pigmentation of hair, hypothermia, degenerative changes in aortic elastin, osteopenia, mental deterioration; Nausea, vomiting, diarrhea, hepatic failure, tremor, mental deterioration, hemolytic anemia, renal dysfunction
374
what condition results from deficiency in Chromium? Toxicity?
Impaired glucose tolerance; Occupational: renal failure, dermatitis, pulmonary cancer
375
what condition results from deficiency in flouride? Toxicity?
increased Dental caries;Dental and skeletal fluorosis, osteoscleroisis
376
what condition results from deficiency in iodine? Toxicity?
Thyroid enlargement, decreased T4; Thyroid dysfunction, acne-like eruptions
377
what condition results from deficiency in iron? Toxicity?
Muscle abnormalities, kilonychia, pica, anemia, work performance, impaired cognitive development, premature labor, perinatal maternal mortality; Gastrointestinal effects (nausea, vomiting, diarrhea, constipation), iron overload with organ damage, acute systemic toxicity
378
what condition results from deficiency in manganese? Toxicity?
Impaired growth and skeletal development, reproduction, lipid and carbohydrate metabolism; upper body rash; General: Neurotoxicity, Parkinson-like symptoms Occupational: Encephalitis-like syndrome, Parkinson-like syndrome, psychosis, pneumoconiosis
379
what condition results from deficiency in molybdenum? Toxicity?
severe neurological abnormalities; reproductive and fetal abnormalities
380
what condition results from deficiency in selenium? Toxicity?
Cardiomyopathy, heart failure, striated muscle degeneration; striated muscle degeneration General: Alopecia, nausea, vomiting, abnormal nails, emotional lability, peripheral neuropathy, lassitude, garlic odor to breath, dermatitis Occupational: Lung and nasal carcinomas, liver necrosis, pulmonary inflammation
381
what condition results from deficiency in phosphorus? Toxicity?
Rickets (osteomalacia), proximal muscle weakness, rhabdomyolysis, paresthesia, ataxia, seizure, confusion, heart failure, hemolysis, acidosis: hyperphosphatemia
382
what condition results from deficiency in zinc? Toxicity?
Growth retardation, taste and smell, alopecia, dermatitis, diarrhea, immune dysfunction, failure to thrive, gonadal atrophy, congenital malformations; General: Reduced copper absorption, gastritis, sweating, fever, nausea, vomiting. Occupational: Respiratory distress, pulmonary fibrosis
383
What are the different types of effects from mutation on protein function?
loss of protein function, gain of function, novel property, ectopic or heterochromic expression
384
Which genes are responsible for HbF?
gamma G and A within the Beta globin gene cluster on chromosome 11
385
What genes are responsible for alpha globin?
Alpha globin gene cluster on chromosome 16
386
What genes are responsible for B-globin?
Beta Globin Gene Cluster Chromosome 11 delta region -> HbA2 and Bets -> HbA
387
what is alpha thalassemia?
lowered production of alpha-globin, resulting form deletions of Alppha globin genes (4), Hb Barts (gamma 4) can remain in infancy to compenasate in adulthood (sometimes infancy if major) have formation of HbH to compensate. if all 4 are deleted = hydrops fetalis and in utero death
388
How can two thal minor parents combine bad genes and get different results?
deletions can be 2 on one chromosome and an intact chromosome can lead to 4 deletions in child (common in Asian ancestry), or one parent can have a deletion on one chromosome each resulting in 3 deletions and thal major
389
What is the cause of most B-thal cases?
single base changes leading to lowered production of B-globin from single B-globin gene on chr 11
390
How genetically can B thal patients differ?
Minor- heterozygote with null and normal or heterozygote with mild and normal
Intermedia: 2 mild, very mild and normal
Major: 2 null or a null and a minor
391
What are hemoglobin structural mutatnts?
point mutations in structural genes are most common (insertion, deletion, gene fusion and chain extension mutations exist), HbVar= hemoglobin variants, a variant can have multiple mutations
392
What is sickle cell anemia?
a HbVar, 1st genetic disease from structural change in protein, Bs gene, autosomal recessive, HbS
393
What is Hb Kempsey?
a:B interface is locked in relaxed oxygenated form, reduced ability to release O2 to tissue
394
What is Hb Kansas?
a:B interface is permanently in taut non-oxygenated form, reduced oxygen affinity leading to cyanosis
395
What is Hb constant spring?
mutation in stop codon of a-globin gene, 30 AA added then stop, result is unstable a-globin results in reduced synthesis of normal.
396
What is significant with the distribution of hemoglobinopathies?
correlate to areas with malaria problems
397
What is osteogenesis imperfect?
OI, disorder in a1 or a2 collagen genes, Type I is mild with bone fractures, Type IImay get progressively worse resultin in a still born, or intermediate with fractures and bonydeformities (type III and IV). Dominant disorder, can be caused by partial loss of a-1 (I) or mutation in coding region of a1 or a2 (I-IV)
398
What is Ehlers-Danlos Syndrome?
vascular defects, stretchy skin, disorder in collagens I, II, III and IV as well as post-translational modification of collagen chains (6 types)
399
What is marfan syndrome?
defect in collagen associated protein fibrillin; tall thin people, often athletes, aortic aneurysms, dislocated lens die to fibrillin gene involvement in attachment of lens to zonular ligaments
400
In mendelian inheritance what does P stand for? F?
parent generation or first generation, filial generation (2nd filial is a cross between filial 1 generation)
401
What of the law of segregation?
during gamete formation each member of allelic pair for a specific genetic trait separates from one another to form the genetic contribution to a gamete
402
What is the law of independent assortment?
segregation of alleles of one allelic pair is independent of the segregation of alleles of another pair
403
What does the frequency of independence tell us?
how far apart two alleles are
404
What is codominance? example?
pattern observed with contributions of both alleles at a locus are expressed equally, A and B in blood types
405
What is incomplete dominance? examples?
pattern that results where the contributions of both alleles are expressed in a phenotype that is between the parent organism, red and white snapdragon= pink
406
What is polygenic inheritance? examples?
2 or more genes contribute to eventual phenotype, more genes = less each individual plays in phenotype, height and hair color, CVD
407
What is pleiotropy? examples?
one gene influences multiple different phenotypic traits, PKU, lack of phenyalanine dehydrogenase causes MR, seizures, and decreased pigment
408
What is epistasis? examples?
effects of one gene are modified by one or several other genes, very common throughout genome, patients with oculocutaneous albinism, inherit genes for skin, hair and eye pigmentation but cant express them
409
what is penetrance?
binary description of whether a particular trait or disease is present or not
410
What is expressivity?
qualitative description of degree or severity of trait or disease
411
What are features of inheritance of autosomal recessive?
both parents must be carriers, most metabolic diseases are autosomal recessive
412
What are features of autosomal dominant disease?
2 types= affected parent usually demonstrate high fitness, or new mutation = low fitness;
413
What is haplosufficiency? example? mutation type?
autosomal dominant,50% reduction in normal gene amount causes disease. Type I OI, stop premature and degrade, nonsense mutation, mild deformity, all ok collagen just 50% less
414
What is dominant negative? examples? mutation type?
autosomal dominant,mutant gene product interferes with function of normal gene product type II, III, and IV OI), missense mutation, nonfunctional incorporated in cause bad collagen formation
415
What is cytotoxicity in term of genetics? example?
autosomal dominant, mutant gene product is toxic to normal tissues, huntingtons, variable expressivity due to length of repeat effects when/ if symptoms manifest
416
What is first hit in genetics? examples?
autosomal dominant, many dominant hereditary cancer syndromes are mutations of oncogenes (RB, LFS) human stand point dominant, phenotype behaves as dominant due to a spontaneous mutation of good
417
Describe the difference in incidence and inheritance in x-linked recessive and dominant. exmples
recessive- higher incidence in male than female, frequently a single copy of working gene is sufficient for normal function, mom is carrier, (hemophilia)
dominant- incidence is much higher in females due to frequent male lethality, muatation in one gene is sufficient to cause disease in female (incontinentia pigmenti)
418
What do you look for in pedigree for autosomal recessive?
parents of affected child typically unaffected, both are obligate heterozygotes, family history may be negative for disease, consanguineous mating should be asked about, no sex preference observed
419
What do you look for in pedigree for autosomal dominant?
one parent affected if child is affected, family history frequently positive, no sex preference, new dominant mutations frequently seen and difficult to separate from AR
420
What do you look for in pedigree for x-linked recessive?
incidence is much higher in men than women, no male to male transmission, look for affected grandfather, unaffected daughter, affected child triangle
421
What do you look for in pedigree for x-linked dominant?
males and females can both be affected, males tend to be more severe phenotype, often look like AD transmission, no male to male transmission, several XLD causes disease in female and death in male
422
What do you look for in pedigree for mitochondrial?
passed directly from mother to child, will not see transmission from male to child, frequently wide variances in severity of disease
423
What is Hardy-Weinberg principle?
allele and genotype frequencies remain constant in a population from generation to generation, useful in risk description
424
What are exceptions to hardy-Weinberg?
non-random mating (inbreeding), small population size, new mutations, open group (migration in or out), selective pressure
425
What are chromosomes crossovers?
necessary for chromosome maintenance and repairs, responsible for generating new haplotypes in each generation and add diversity to individual germ cells, source of CNV detected by DNA microarrays
426
What is the holiday junction?
mobile junction between 4 DNA strands, in prophase of meiosis I duplicated homologous chromosomes pair and align, crossover can occur between aligned chromatids leading to exchange of homologous segments by homologous recombination
427
What is the Lyon law?
in a female one X chromosome will become inactive, it condenses to form a Barr body attached to nuclear membrane, # of barr bodies equals the number of x chromosomes minus 1
428
How is it "decided" which x is inactivated?
random but x with deletion or mutation is preferentially inactivated, occasionally the normal is preferentially inactivated
429
What is skewed x-inactivation?
larger than average proportion of cells with a mutated gene on the active X-chromosome, may result in signs of disorder, "manifesting carrier"
430
what is on the y chromosome?
sex determining region, handful of genes for testicular function and sperm formation, and pseudoautosomal region
431
what is the pseudoautosomal region? How can this be a problem?
contains genes that are inherited like autosomal, males have 2 copies one on Y and one on X, these genes escape X inactivation
432
How can the pseudoautosomal region lead to abnormal passing of fenes?
males can receive a gene that was on their fathers X chromosome, females can receive a gene that was originally on their fathers y chromorome
433
What is somatic mosaicism?
mutations occur after conception, depending on timing can involve many, a few or just a single cell, phenotype depends on number of factors: type of abnormality, level of mosaicism (abnormal vs normal), tissue mosaic state is expressed
434
What is germline mosaicism? example?
person may possess a mutation in gonads that is not necessarily expressed, person would not tend to show any phenotype, any gametes produced from affected gonadal tissue would transmit the mutation, Osteogenesis Imperfecta
435
What is sex limited inheritance?
not x linked, autosomal inheritance but expression only in one sex, gender specific factors required for expression (ovarian cancer, prostatitis)
436
What is sex influenced inheritance? examples
mainly expressed in one gender, alopecia androgenetica mostly men, BCRA2 mostly effects women
437
What is uniparental disomy? Types?
two copies of particular chromosome from the same parent; isodisomy (same chromosome) or heterodisomy (different chromosome)
438
What is monosomy rescue?
results from non-disjunction event in gamete causing nullisomy, duplication of remaining chromosome results in uniparental isodisomy for that chromosome
439
What is trisomy rescue?
results from nondisjunction event in gamete causing disomy for that chromosome, one chromosome is lost restoring numerical balance, 2/3 of time results in normal biparental inheritance, 1/3 results in uniparental heterodisomy
440
What is UPD and neonatal diabetes mellitus an example of in genetic inheritance?
uniparental disomy, and imprinting
441
What is genomic imprinting?
differential expression of paternal versus maternal DNA, monoallelic expression, differential expression of chromosomal deletions, temporary alteration in function, involves only certain genes (locus specific), may occur as early as gamete formation and as late as early embryogenesis, achieved by methylation
442
What are possible reasons for imprinting?
normal regulation of placenta, maintenance of sexual reproduction, flexibility during development, response to environmental factors
443
What is Russel-Silver syndrome? Cause?
intrauterine growth retardation, triangle shape head, above eyes larger than below eyes; hypermethylation at location IC1 on paternal chromosome, causes decreased expression of IGF2 and increase expression of H19
444
What is Beckwith-Wiedemann Syndrome?
macroglossia, macrosomia, omphalocele or umbilical hernia; one cause is hypermethylation at IC1 on maternal chromosome causes increased expression of IGF2 and decreased expression of H19
445
What is Sherman paradox? example?
unusual pattern of inheritance in disorders which show anticipation, Fragile X syndrome, symptoms worsened with each generation
446
How can trinucleotides repeats be normal? How can they be dangerous?
can just be a repeat for polymorphic variation with no clinical significance, a certain threshold of repeats is associated with a tendancy for further expansion without a clinical phenotype=permutation, at a certain point there is effected gene expression and phenotype.
447
What is myotonic Dystrohpy?
muscle weakness, distal leg hand, face and neck, respiratory can be affected; caused by trinucleotide repeats
448
How can trinucleotide repeats cause disease?
LOSS OF FUNCTION: disrupt gene transcription, translation due to hypermethylation (Fragile X)
GAIN OF FUNCTION: excess metabolite inhibit other enzymes and/or regulatory systems (direct toxicity), mechanism of disease in Huntington disease; DOMINANT NEGATIVE EFFECT: abnormal product interfereswith normal physiological function of product (myotonic dystrophy)
449
How is mitochondrial DNA different?
circular, double stranded, no introns, UGA=Trp not stop, AGA and AGG stop rather than arginine, AUA AUU sometimes initiation , codes for 13 oxidative phosphorylation enzyme complex subunits, 2 ribosomal RNA and 22 tRNA
450
What is the difference between mitochondria content in eggs and sperm
eggs- 100,000, sperm 100-1500
451
What is semiautonomous inheritance?
mitochondrial DNA segregates in daughter cells independent of nuclear chromosomes; have to have cell replication for segregation
452
What is maternal inheritance?
mtDNA transmission is exclusively maternal; mtDNA from spermatozoa actively degraded at 2-4 cell stage
453
What is replicative segregation?
homoplasmy: single mtDNA sequence in a given cell; heteroplasmy: more than one mtDNA sequence in a cell; cytokinesis stage of heteroplasmic cells partitions different into daughter cells -> replicative drift
454
What is the bottleneck phenomenom?
restriction and subsequent amplification creates a genetic bottleneck, leads to an overall reduction in diversity
455
What are the characteristics of mitochondrial disease?
since mitochondria are responsible for energy production the organs most effected are those which require more energy; pigmentary retinopathy, ptosis, external ophthalmoplegia, proximal myopathy, diabete mellitus
456
What is MELAS?
Mitochondrial Encephalopathy Lactic Acidosis Stroke-like-episodes; ragged red fibers on muscle biopsy, may have most but not all, early unexplained stroke
457
What is MERRF
Myoclonic Epilepsy Ragged Red Fibers, hearing loss, short stature, optic atrophy, cardiomyopathy with WPW, some will have Pigmentary Retinopathy (mitochondrial)
458
What is leigh syndrome?
progressive neurologic disease with motor and cognitive delay, can have lactic acidosis or increased lactate in CSF, may be maternal milder history
459
What is kearns-sayre syndrome?
classic triad, onset before age 20, pigmentary retinopathy, progressive external ophthalmoplegia; atleast one of the following: cardiac conduction block, elevated CSF protein, cerebellar ataxia
460
What is hereditary hemochromatosis?
two mutations in HFE1 are causative, C282Y more severe, majority caused by C282Y homozygotes but compound heterozygotes can be affected, carrier rate 19% in US and 53% in Ireland
461
Alpha-1-antitrypsin deficiency causes what commonly?
COPD and Liver disease
462
What is familial hypercholesterolemia?
one of most common monogenetic diseases, mutations in LDL receptor, heterozygotes total cholesterol between 275-500, homozygotes above 500mg/dl severe atherosclerosis by childhood or young adulthood
463
What creates susceptibility to disease?
each gene can have small changes that subtly alter function and interaction with other genes,
464
What is MODY? Causes?
Maturity Onset Diabetes of the Young, Type II DM Variant- no ketoacidosis problem, HNF1A mutation, GCK mutations
465
What causes neonatal diabetes mellitus?
KNJ11 gene or UPD 6 mutation, responds well to sulfonylureas=increases the amount of insulin release in Beta islet cells
466
What is GWAS? What was discovered or suggested?
comparison of genomes or exomes of patients w/ certain disease or trait; numerous SNPs are associated with an increase risk of type II DM, related to insulin production, growth factors for Beta islet cells and reduced glucose-stimulated insulin secretion; also found obesity-associated loci associated with obesity and insulin resistance, neurologic development plausible due to hypothalamic control
467
What is high resolution karyotyping?
G-banding involves a trypsin treatment and staining, AT rich regions stain darkly, GC rich regions stain lightly, analyze under a microscope
468
What are the clinical features of triploidy?
miscarriage, large placenta and late loss if paternal, small placenta and early loss if maternal, etiologies: dispermy, retention of polar body, diploid egg or sperm
469
What is turner syndrome? cause?
primary amenorrhea/infertility, short stature, congenital lymphedema, webbing of the neck, cardiac/renal anomalies; paternal non-disjunction, 18% miscarriage rate
470
What is Klinefelter syndrome? Cause?
XXY, tall thin male with long legs, underdeveloped secondary sex characteristics, small testicles, gynecomastia(50%), infertility in all (30-40% only have infertility) caused by non-disjunction
471
What is XYY? features?
extra Y, tall stature, speech delays, behavioral or learning problems maybe, occasionally: large teeth, glabella, long arms/legs, bad acne;
472
What is down syndrome?
flat facial profile, small nose, epicanthal folds, single palmar crease, sandal gap, brushfield spots, short fingers, hypotonicity, intellectual disability, non-disjunction 95%, translocation 4-5%, risk increases with maternal age
473
What is Williams syndrome? cause?
elfin faces, short stature, suprvalvular aortic stenosis, outgoing personality, developmental delay, hoarse voice, hypercalcemia, deletion on 7q11.23
474
What is CGH microarray?
comparative genomic hybridization, imbalance between patient and control DNA is either control signal deletion or patient duplication, not a sequence, detects subtle deletions and duplications but no rearrangements
475
What is SNP microarray?
similar to oligonucleotide micro-arrays, difficulty in hybridizing unique SNP so lots of built in redundancy
476
What is RFLP?
early and simple method of SNP analysis, restriction endonuclease digestion on genomic sample creates fragments of a certain length which can be ascertained on gel electrophoresis
477
What is PCR?
primers complementary to DNA region of interest are added to target DNA with heat stable polymerase, thermal cycler used to heat and cool repeatedly, allows replicated DNA to serve as templates for successive cycles, end result larger amount of DNA of target region
478
What is Sanger sequencing?
aka chain terminator sequencing, oligonucleotide primers complimentary to a template are used with each of four nucleotides, dna polymerase is used to extend sequence, chain terminating nucleotides are placed in low concentration as well (usually dideoxybase with fluorescent tag)
479
What is next generation sequencing?
a group of high throughput sequencing techniques: reversible dye terminator, parallel pyrosequencing, ligation-based sequencing, ion semiconductor sequencing, and others
480
What is exome sequencing? why is it important
sequencing of all coding regions of all genes, estimated that 85% of all mutations will be in exome
481
What was the first human experiment with gene therapy?
1970 in Germany, shope rabit virus caused decreased arginine levels, gave it to two girls who had a defect in arginase enzyme which cause a build up of arginine, nothing happened
482
When was recombinant DNA via bacterium first possible?
mid1970
483
When was the first experiment of gene therapy using recombinant DNA?
1980, Dr. Cline, 2 patients, trying to treat beta thalassemia, not approved trial, no harm to patients but sanctioned and lost grants
484
What was the first success in gene therapy?
1990s after animal trials and switching from marrow to WBC target for ADA deficiency treatment, still needed enzyme replacement but less after gene therapy
485
What happened with the Gelsinger gene therapy that was notable?
given adenovirus with functional OTC gene to treat metabolic condition, reacted badly to virus and died, later discovered that lead researcher had a financial stake in adenovirus vector, and she did not meet research criteria, language in informed consent had been removed about animal death and illness, didn't report two prior severe reactions, changed order of patients without asking (not random)
486
What are the barriers to gene therapy?
half-life (many therapeutic targets are rapidly dividing cells, therapy must be administered frequently), Immunogenecity (viral vectors/ replacement protein can trigger immune response), unintended viral consequences (inflammation, incorrect targeting of virus to other tissues, causation of initial viral disease or malignancy), and poor efficacy (frequently even if targeted correctly not enough gene product is integrated)
487
What are the challenges to gene therapy in OI?
Type ! is haplosufficiency so replacement of collagen should be curative; Type II, III, and IV are dominant negative effect so need to silence mutant allele to impact disease
488
What is the limitation in stem cell therapy in OI?
poor engraftment (generally expression in below 5% and often below 1%) bone marrow transplant (assumption that myeloablative conditioning would be needed to prevent rejecton of graft, at best means trading one disorder for another
489
How effective is gene therapy in OI?
tried a viral vector with healthy COL1A1 in vitro to disrupt mutant version but cause normal collagen production dominant neg went to haplosufficiency but still not able to work, also have tried overexpression of COL1A1 but not effective enough to outweigh risk
490
How have stem cells been used to treat OI?
mesenchymal cells from patients with OI collected, mutant genes inactivated by adenovirus, induced pluripotent stem cells were derived, mesenchymal cells were then derived, stem cells differentiated into osteoblasts, normal type I collagen made, mineralized bone made, proliferated more than bone-derived multipotent cells
491
What are some problems still present with stem cell treatment of OI?
poor efficiency- only 1% needs to be 10-20%, unclear how to target iPSC into bone to grow (interosseus injection or bone marrow lavage?)
492
What is the future of gene therapy look like?
silica based vector (nanites), polymer and lipid complex as vector, gene transfer to brain following stroke, microRNA to influence expression
493
What are the lymphoid cells? What is the pathway of their development?
NK cell, T cell, B cell; Hematopoietic stem cell to common lymphoid progenitor to pre B cell or pre T cell or pre NK cell, to B cell or T cell or NK cell respectively these are released to blood, B cell can further differentiate into a plasma cell in connective tissue
494
What are the WB cells? What is the pathway of their development? Which one has an exception?
dendritic cell, Neutrophil, Mast cell, Eosinophil, Macrophage, Monocyte, and basophil; hematopoietic stem cell to common myeloid progenitor to granulocyte monocyte progenitor to prodendritic cell or neutrophil progenitor or basophil/mast cell progenitor or eosinophil progenitor cell or monocyte progenitor, then to dendritic cell(CT) or neutrophil (blood) or basophil (blood) or mast cell progenitor (CT) or eosinophil (blood), or monocyte (blood) respectively, mast cell progenitor becomes a mast cell in the CT and a monocyte can become a macrophage in the CT; exception is that a dendritic cell can come from the lymphoid path into the pro-dendritic cell level
495
What is the pathway of development of RBCs?
hematopoietic stem cell, to common myeloid to megakaryocyte/erythrocyte progenitor, to erythrocyte progenitor to proerythroblast to orthochromatophillic erythroblast to erythroblast
496
What Is the pathway of development of platelets?
hematopoietic stem cell to common myeloid to megakaryocyte/erythrocyte progenitor to megakaryocyte progenitor to megakaryoblast to megakaryocyte then cell apoptosis and release of platelets
497
Where and at what age does hematopoiesis occur? Which hemoglobin types are made at each?
yolk sac 4-10wks gestation HbE, fetal liver 6 weeks to term HbF, spleen 10 weeks to 7 months gestation HbF, bone marrow 4 months gestation to death HbA (HbA2) eventually HbB
498
What is the source, target and primary effect of Flt3-ligand?
ubiquitous; stem cells and progenitor cells; synergistic for proliferation of early stem cells
499
What is the source, target and primary effect of Stem cell factor?
BM stroma; stem cells and early myeloid progenitors; proliferation of early stem cells in synergy with other cytokines
500
What is the source, target and primary effect of IL-1?
macrophages and keratinocytes; myeloid stem cells and thymocytes and endothelium; induces early and committed stem cells to enter cycle, induces GM-CSF, G & M CSF and IL-3 production, releases neutrophils from BM
501
What is the source, target and primary effect of IL-3?
t-cells and macrophages; stem cells and immature progenitors; proliferation of early and committed stem cells
502
What is the source, target and primary effect of IL-6?
t-cells, macrophages, endothelium and fibroblasts; stem cells and early myeloid progenitors; induces early stem cell proliferation and induces megakaryoblast proliferation
503
What is the source, target and primary effect of GM-CSF?
t-cells, macrophages, endothelium and fibroblasts; myeloid progenitors; induces proliferation of myeloid stem cells, proliferation and activation of macrophage and granulocyte progenitors
504
What is the source, target and primary effect of M-CSF?
macrophages, endothelium and fibroblasts; committed macrophage progenitors; proliferation and activation of monocyte precursors
505
What is the source, target and primary effect of G-CSF?
macrophages, endothelium and fibroblasts; committed neutrophil progenitors; proliferation and activation of neutrophil precursors
506
What is the source, target and primary effect of IL-5?
t-cells; eosinophil progenitors; proliferation and activation of eosinophil precursors
507
What is the source, target and primary effect of IL-4?
t-cells; basophil progenitors; proliferation and activation of basophil precursors
508
What is the source, target and primary effect of erythropoietin?
kidney, liver connective tissue cells; immature erythroid and megakaryocyte progenitors; proliferation of erythroid and megakaryocyte progenitors
509
What is the source, target and primary effect of thrombopoietin?
liver; committed megakaryocytes; proliferation of megakaryocyte progenitors
510
What is the source, target and primary effect of IL-11?
none listed; committed megakaryocytes progenitors; proliferation of megakaryocyte progenitors
511
What is the normal frequencies of WBC in the blood? Which ones are classified as granulocytes?
Neutrophils: 55-65%, Eosinophils: 3-5%, Basophils: 0-1.5%, Lymphocytes: 25-40%, and Monocytes 3-8%; Neutrophils, Eosinophils, and Basophils
512
What tests make up a CBC? Define each one.
total WBC, RBC- mass concentration, shape and agglutination; hematocrit: space occupied by packed RBCs closely parallels with hemoglobin and RBC; hemoglobin, and MCV-mean corpuscular volume represents average volume of RBC in femtoliters (macrocytic and microcytic); sedimentation rate- distance RBCs fall in one hour; Plasma proteins: fibrinogen, alpha globins and others
513
What are some identifying features of Neutrophils? Function?
multilobed nucleus, primary graunles lysosomes, secondary granules, tertiary granules; phagocytosis mostly bacteria viaH2O2, HOCl, MPO, O2 and PLA2 (respond to acute chemotaxis
514
What are some identifying features of eosinophils? function?
bilobed nucleus, primary granules, secondary eosinophil specific membrane bound to granules with crystalline inclusions; migrate to site of allergic reaction, inflammatory reponse or parasitic worms, eosinophil derived neurotoxin damages nervous system of parasites
515
What enzyme is missing in children that effects the function of their neutrophils leading to their susceptibility to repeated bacterial infectons?
deficiency in NADPH oxidase so neutrophils cant generate superoxide H2O2 during phagocytosis
516
Elevation of corticosteroid levels in the blood does what to which WBC?
suppress the number of eosinophils in circulation
517
What are some identifying features of basophils? function?
bi-lobed or tri-lobed nucleus, specific membrane bound basophilic granules; heparin anticoagulant, histamine-vasoactive, heparin sulfate-vasoactive, leukotrienes-trigger prolonged sustained constriction of smooth muscle cells in pulmonary airways, receptor for IgE-binds to IgE releasing histamine and other vasoactive mediators resulting in hypersensitivity reaction (Anaphylactic shock), becomes mast cell in CT
518
What are some identifying features of lymphocytes? function?
no prominent granules, nucleus takes up most of cell, macrophages are more indented in the nucleus than lymphocytes; t-lymphocytes major role in cell mediated immune response, B lymphocyte, NK cells kill tumor cells and virally infected cells
519
What are some identifying features of monocytes? function?
largest, more indented nucleus because they become macrophages- antigen presenting cells in immune system
520
What are key features of platelets and what is their function?
biconvex until activated, life span of <10 days, granules that store serotonin, microtubule bundles and dense tubular system; cellular phase- platelet adherence and then thrombus=hemostatic plug, enzymatic phase-enzymes and phospholipids released by platelets and injured tissues=fibrin clot, contraction phase-platelets contract platelet derived substances constrict injured vessels
521
What changes cellularly as the cell progresses from pluripotent stem cell to red blood cell?
decrease in size cell and nucleus, increasing heterochromatin, decreasing cytoplasmic basophillia increasing acidophilia (purple to pink), decreasing polyribosomes: increasing Hb, polychromatic cells are the last mitotic stage, regulation by erythropoietin (EPO)-produced by the kidney
522
What changes in the cell in the formation of platelets?
increase of cell size and ploidy, increasing granularity and formation of platelet demarcation zones, gradual complete loss of cytoplasm to platelet production
523
What changes in the cell in the formation of granulopoiesis?
initial increase then decrease in size, increase in heterochromatin, lobulation of the nucleus, myelocytes are the last mitotic stage, acquisition of primary lysosomal granule then specific granules
524
What changes in the cell in the formation of monocytes and macrophages?
relatively small morphological changes with maturation, most monocytes/macrophages retain their ability to divide
525
How does the thymus function in the immune system?
primary lymphoid organ, antigen independent proliferation, multipotent stem cells from bone marrow enter into the epithelial which develops into the thymus, the thymic cortes or parenchyma contains developing T lymphocytes (stains purple),
526
What are the 6 types of cells in the thymus and where are they located?
Type I, II, III epithelioreticular cells in the cortex, Type Iv, V, and VI epithelioreticular cells in the medulla
527
What makes up the blood epithelial barrier and what is its purpose?
endothelium is highly permeable to macromolecules in the perivascular connective tissue, macrophages in phagocytosing antigenic molecules that escape from capillary lumen, Type I epithelioreticular cells contain occluding junctions to protect developing T lymphocytes, it protects developing T-cells
528
What are the two types of T-cell education and basic principle of each?
positive selection: selection for thymocytes that recognize self MHC molecules expressed on cortical epithelium
negative selection: selection against thymocytes that recognize self antigen in context of self MHC
529
How is positive selection achieved?
entrance of lymphoid stem cells into thymic medulla via post capillary venule, expression of CD2, CD7, CD1 followed by TCRs CD3 and CD4 and CD8, presentation of developing T cells with self by type II and type III cells, if lymphocyte recognizes self MHC and self-antigen, it will survive the positive selection if not death of unselected cell
530
How is negative selection achieved?
cells directed to self antigen displayed by self MHC are eliminated by negative selection, cells that survive that selection become either cytotoxic CD8+ T lymphocytes or Helper CD4 + T lymphocytes, these are immunocompetent cells leave thymus and enter blood circulation, regulatory cytokines secreted by type VI cells promote this process
531
What are the thymic or Hassal's corpuscles and what are they for?
derived from Type VI cells, concentrically arranged exhibiting flattened nuclei, contain keratohyalin granules which are bundles of intermediate filaments and lipid droplets, produce interleukins such as IL-4 and IL-7 that function in thymic differentiation and education of T-lymphocytes
532
What is necessary for B cell differentiation and maturation?
need intimate contact with stromal cell for signaling by GF (Cytokines of interleukins), starts along the endosteal surface and moves inward to let B cells entering circulation
533
What is the lymph nodes function?
filters lymph, main site which T and B lymphocytes undergo antigen-dependent proliferation and differentiation into effector cells and memory cells
534
What is located in the medulla of the lymph node?
medullary cords and sinuses
535
What is located in the cortex of the lymph node? What occurs here?
lymph nodules (aggregates of lymphocytes), in active lymph this is the site of B cell proliferation and differentiation in response to an antigen, contain lighter area known as germinal center
536
What is the area between the medulla and the cortex? What can be found here?
deep cortex contains high endothelial venules made of cuboidal cells, has a dense population of lymphocytes especially T cells
537
What is the flow of lymph through a lymph node?
vessels empty into subcapsular sinus, wall of sinuses allow lymph to freely percolate into superficial and deep cortex allowing lymphocytes to engage in immune surveillance, after entering tissue lymphocytes migrate back to sinuses and leave to medullary sinus then efferent lymph vessel
538
What is the function of reticular cells in the lymph node?
synthesize and secrete type III collagen, and associated ground matrix, provide support, express molecules and produce substance that attracts T and B cells and dendritic cells
539
What is the function of dendritic cells?
involved in antigen presentation, class MHCI and II
540
What is the function of macrophages?
phagocytic and antigen presenting cells expressing MHC I and II and costimulatory molecules but less than a dendritic cell (antigen)
541
What do we know about follicular dendritic cells?
interdigitate between B lymphocytes in germinal centers, not APC (antigen presenting cell) because they lack MHCII
542
What is the function of high endothelial venules?
90% of lymphocytes enter here, signal lymphocyte to leave circulation and migrate into lymph nodes via receptor for antigen primed lymphocytes, T cell remain in deep cortex and B cells migrate to nodular cortex (regulated by HEV)
543
What occurs in germinal centers?
clonal proliferation, Ig class-switching, somatic hyper mutation and selection by antigen
544
What does the spleen do?
major repository for mononuclear phagocytic cells (25%) and 1/3 of platelets, spleen filters blood with morphologic and immunologic filtering functions and reacts immunologically to blood borne antigens
545
What are characteristics of the white pulp? function?
rich in lymphocytes form periarteriolar lymphatic sheath (PALS) around branches of artery that penetrate pulp, PALS predominantly contain T lymphocytes and lymphoid nodules contain B lymphocytes
546
What are characteristics of the red pulp? function?
splenic sinuses surrounded by splenic cords, large number of RBC due to filters and degrading= trapped by macrophage and breakdown RBC and hemoglobin and retrieve and store iron from heme for reutilization in formation of RBC in marrow, non-functional platelets also degraded
547
How does blood enter the red pulp for filtration?
open system, penicillar arterioles empty directly into reticular meshwork, blood percolates in through the cords and is exposed to macrophages there
548
what are the immune functions and hematopoietic functions of the spleen?
immune: antigen presentation, initiation of immune response, activation and proliferation of B and T cells, production of antibodies, and removal of macromolecular antigens from the blood; Hematopoietic functions: removal and destruction of senescent or damaged RBC and platelet, retrieval of iron from hemoglobin, formation of RBC during fetal life, storage of blood and RBC in some species
549
What are characteristics of the tonsil and its function?
dips of epithelium into CT called crypts, lymphatic nodules in crypts, plasma cells differentiate from here and secrete IgA antibodies
550
What is a peyer's patch?
multiple lymphatic nodules with visible germinal centers typically found in ileum,
551
What are the steps in synthesis of purines coming off the denovo path?
IMP to AMP and GMP phosphorylated to ADP, ATP, GDP and GTP, ADP and GDP are reduced by ribonucleotide reductase to dADP and dGDP they can then be phosphorylated to dATP and dGTP or dephosphorylated to dAMP and dGMP
552
What are the ribonucleotides made in denovo synthesis of purines?
IMP, AMP, XMP, GMP, ADP, GDP, ATP and GTP
553
How does the body get rid of extra ribonucleotides?
XMP to xanthosine to xanthine to uric acid or IMP to Inosine to hypoxanthine to xanthine to uric acid or GMP to gaunosine to guanine to xanthine to uric acid
554
What are to carbon donators in denovo synthesis of purines?
aspartate, glutamine, glycine, CO2, and fromyl tetrahydrofolate
555
What is the key intermediate for denovo synthesis of purines?
PRPP, 5-phopshoribosyl pyrophosphate, ribose source
556
What is the pathway for denovo synthesis of purines?
ribose-5-phopshate takes two phosphates from ATP via PRPP Synthetase to make PRPP, amine group added via glutamine and H2O via PRPP amidotransferase giving of PPi and glutamate resulting in Phosphoribosylamine utilizing and ATP glycine adds CO, CH2 and NH3 then formy-THF adds CHO then glutamine adds amine and takes O from first carboxylic carbon lose a water to close the ring, CO2 added to ring then aspartate donates its side chain give off fumerate, formyl-THF donates CHO lose H20 and close ring for IMP
557
What are the main points of regulation in purine synthesis?
formation of IMP, AMP and GMP
558
At what steps and how is IMP synthesis regulated?
1st step formation of PRPP is inhibited by AMP and GMP, 2nd PRPP to phosphoribosylamine via PRPP amidotransferase is feedback inhibited by adenine and guanine and stimulated by PRPP
559
What is Gout? Causes?
build up of uric acid in the body, urate crystals are not soluble and will collect in joints esp big toe, excess synthesis of purines, (overactive PRPP amidotransferase or mutation making it less sensitive to feedback or elevated levels of PRPP synthetase) inadequate salvage of purines (deficiency in HGPRT), or impaired uric acid excretion in kidneys
560
How is synthesis of AMP and GMP regulated?
feedback inhibition by themselves, stimulation of GMP via ATP and AMP via GTP
561
Nucleotide salvage pathway is best defined as converting ____ & ____ to ______. Not What?
nucleobase, nucleoside, nucleotide, not further modification (addition of phosphate groups) of nucleotide
562
What is the source of nucleosides and nucleobases in salvage path?
intracellular degradation of RNA and DNA only a very small amount comes from diet (not absorped
563
What is the most important enzyme in the purine salvage pathway? What disease is caused by its deficiency?
HGPRT or hypoxanthine-guanine phosphoribosyl transferase, partial loss leads to gout complete deficiency causes Lesch-Nyhan syndrome
564
What drug can be used for gout treatment how does it work?
allopurinol inhibits xanthine oxidase thus reducing amount of uric acid made, or probenecid which increases renal secretion of uric acid, colchicine relieves gout pain and is an anti-inflammatory
565
What is Lesch-Nyhan syndrome how is it passed? Characteristics?
complete absence of HGPRT enzyme, x-linked recessive, affects males; self mutilation, mental retardation and gouty arthritis, CNS involved because low capacity for denovo path so complete absence of salvage damages brain by depriving it of purine nucleotides
566
What is combined immunodeficiency?
aka adenosine deaminase deficiency resulting in excess dATP, high levels inhibit ribonucleotide reductase activity which is needed for DNA synthesis, impossible for WBC rapid proliferation for immune response, dATP is toxic in cells but cannot cross membrane due to negative charge, not toxic outside cell
567
How does acyclovir work in treating herpes? Side effects?
acyclovir is purine analog, viral thymidine kinase (but not the hosts) converts acyclovir into a nucleotide, acyclovir has no 3'hydroxyl group, elongation of DNA stops once incorporated, Acute renal failure (poor solubility), nausea, vomiting, abdominal pain, diarrhea, and neurotoxicity
568
In the prymidine pathway what does ribonucleotide reductase do?
UDP to dUDP and CDP to dCDP
569
How is CTP made from UMP
UMP to UDP to UTP to CTP
570
In the pyrimidine pathway what does thymidylate synthase do?
dUMP to dTMP
571
What does thymidine kinase do?
thymidine to dTMP
572
What does uridine kinase do?
uridine to UMP
573
In pyrimidine salvage what is salvaged at a higher frequency?
nucleosides more than pyrimidine bases
574
What are the two products of pyrimidine degradation?
beta-aminoisobutyric acid and beta-alanine
575
What are the molecules contributing to the denovo synthesis of pyrimidines?
aspartate, ribose-5-phosphate, glutamine and CO2
576
Describe the steps for denovo synthesis of pyrimidines.
NH3 and CO2 with ATP form carbamoyl phosphate, aspartate donates CONH2 to make carbamoyl aspartate, lose water to form ring dihydroorotate rearrange to orotate (orotic acid), add PRPP lose PPi and form orotidine monophosphate (OMP), lose CO2 to make Uridine monophosphate (UMP)
577
At what points and by what molecule is denovo synthesis of pyrimidines regulated? difference in mamals and bacteria?
bacteria formation of carbamoyl aspartate (2nd step) stimulated by ATP and inhibited by CTP, mammals same step but activated by PRPP and inhibited byUTP, conversion of UTP to CTP is stimulated by GTP and inhibited by CTP
578
What is orotic aciduria? Cause?
rare genetically inherited disease, 2 enzymes are deficient causing build up of Orotic acid, but problem is lack of nucleotides, onset early infancy, failure to thrive, megaloblastic anemia, orotic acid crystals in urine, regarded physical and mental development, weakness and fatigue, treat with Uridine which Uridine kinase changes to UMP
579
Describe the detailed mechanism of thymidylate synthase.
takes methylene tetrahydrofolate and dUMP and produces dTMP and then regenerates the hydrogens lost on folate by dihydrofolate reductase and NADPH as donor then serine donates the lost methyl group and becomes glycine resulting in another methylene tetrahydrofolate
580
What enzyme involved in dUMP to dTMP is a drug target? give an example and purpose.
dihydrofolate reductase, methotrexate, inhibits dTMP so DNA synthesis is blocked, important in treating cancer
581
What does 5-Fluorouracil do? When is it used?
inhibits thymidylate synthase, breast and colon cancer it is an inactive precursor for FdUMP
582
What is hydroxyurea?
a drug used fo treating leukemia, inhibits ribonucleotide reductase
583
What regulates and where the synthesis of deoxyribonucleotides?
excess dATP caused by adenosine deaminase deficiency inhibits ribonucleotide reductase (immunodeficiency)
584
What is the baseline/background risk for congenital anomaly?
3%, general population risk, cant make it go away
585
What is a teratogen?
any environment agent such as drug, chemical, infection, or pollutant which potentially harms the developing fetus
586
What is karnofsky's law?
anything at the right time of pregnancy and the right does in the right species can be teratogenic
587
What are Wilson's principles of teratology?
4 basic manifestations of abnormal development= loss, malformations, growth retardation, and functional deficits; susceptibility dependent on genotype, nature of damage depends on timing and exposure, rate and severity are dose dependent, syndrome of outcomes is specific to insult, plausible biological explanation for the mechanism of action of the teratogen
588
How important is paternal exposure?
not well studied but little evidence it causes birth defects
589
What are some examples of teratogens and matching outcomes that have a genetic component causing increased susceptibility?
Alcohol-FAS, Smoking-Oral clefts, Retinoic Acid-Embryopathy
590
What is the outcome to teratogenic exposure at each point in gestation? 0-15 days, 15-60 days, 60-80 days, 2nd and 3rd trimester?
0-15: miscarriage, fetal death; 15-60: fetal death, major malformations, growth retardation and impaired IQ; 60-80: fetal death, vascular disruption by hypoxia, hemorrhage, and tissue loss; 2nd and 3rd Tri: stillbirth, growth retardation, impaired IQ
591
What are some results of exposure to alcohol during pregnancy and breastfeeding?
loss, FAS: growth retardation, CNS dysfunction (retardation or hyperactivity), characteristic facial features (microcephaly, flat maxillary area, flat philtrum, thin upper lip), malformations, breastfeeding mom BAL= concentration in milk, >1 a day=drowsiness and delays
592
When is a higher dose of folic acid recommended?
on anticonvulsant, diabetes, inflammatory bowel disease, have had previous child with spina bifida, CL/CP or a heart defect
593
What are the effects of chemotherapeutic agents during pregnancy? When and what dose is appropriate if any?
high dose: malformations 1st tri, IUGR, Pancytopenia, CNS damage, cardiomyopathy, pregnancy loss or prematurity, low dose for autoimmune disorders after 7 weeks significantly lower risk
594
What effects does Accutane have in pregnancy? What is being done?
2x risk miscarriage, 25% chance of major birth defect, possible long term effects on development; iPledge program
595
What is the recommendation on vaccinatons during pregnancy?
caution with live organism (Varicella or MMR during breastfeeding and pregnancy), attenuated usually ok, some even encouraged, Influenza shot not mist, Tdap (20 wks)- pass immunity to baby who will not be able to receive immunization; no evidence any leads to autism
596
What is the purpose and key characteristics of innate immunity?
first line, slow growth of infectious agents until adaptive immunity kicks in, a means of directing adaptive immunity via inflammatory response, activation of dendritic cells, production of cytokines that specialize response, fast, non-specific, and no memory
597
What are the different components of innate immunity?
mechanical barrier (skin, mucous membranes, and normal flora), humoral component (lysozymes, interferons and complements) and cellular components (macrophages, neutrophils, monocytes and nature killer cells)
598
What are the types of phagocytic pattern recognition receptors and what do they bind?
mannose and glucan receptors= bacterial carbs on cell surface, scavenger receptor= negatively charged ligands like on gram + bacteria, CD14= lipopolysaccharide (gram -)
599
What are the different phagocytic opsonin receptors and what do they bind? what does it do?
Fc= bacteria with IgG antibody on surface have Fc region exposed;
complement= C3b(part of complement);
enhances phagocytosis
600
What is the function of toll like receptors?
class of 10 different receptors, recognize distinct set of molecular patterns characteristic of pathogenic microbs, ligation of TLR activates transcription factor NFkB and induction of proinflammatory cytokines and chemokines, some on cell membrane (extracellular infection)and some on nuclear envelope facing in (intracellular infection)
601
How does the complement system work?
20 diff serum proteins, several are proteases that become activated by presence of pathogen, opsonize pathogen for engulfment by phagocytes, chemoattractants to recruit phagocytes, kill bacteria by creating pores in bacterial membrane
602
Which cells are phagocytes in innate response?
macrophage and neutrophil
603
What mechanisms are used to destroy cell in phagocyte? Where are they found? Enzymes?
Primary grannules: NADPH oxidase=toxic oxygen products, inducible nitric oxide synthase: toxic nitrogen products, and Myeloperoxidase: acidification; Secondary grannules: antimicrobial peptides, lysozymes, and defensin (increase permeability of bacterial membrane), lysosomes= digestive enzymes
604
How do natural killer cells work?
recognize transformed cells (infected) by low MHC1 expression, activity of NK has activating and inhibiting receptors, MHC1 binds inhibitory receptor and blocks activation, when activated relase cytotoxic grannules containing granzymes and perforin, perforin creates pore in membrane and granzymes initiate apoptosis
605
What causes the inflammatory response?
invasion of WBC, swelling= increase vascular permeability and migration of leukocytes, redness= increased blood volume, heat increased blood volume and endogenous pyrogens
606
What is the function of the inflammatory response?
local inflammation restricts damage to site of infection, microbes activate macrophages and dendritic cells via PR receptors, activated macrophages produce proinflammatory cytokines and chemokines, dendritic cells migrate to lymph nodes and initiate adaptive immune response
607
What are the two components of acquired immunity?
antibody mediated humoral immunity and T cell medicated immunity
608
What are the components and types of T cell receptors? Where are they found? What are they found in complex with?
2 polypeptide chains: alpha and beta or gamma sigma, 95% peripheral t cells are alpha beta and gamma sigma are abundant in epithelial and mucosal surfaces, CD3 complex (sigma, gamma, epsilon and s chain both together contain ITAM (immunoreceptor tyrosine activation motif)
609
What is MHC? characteristics?
major histocompatibility complex, aka HLA, cell surface molecule responsible for antigen presentation and lymphocyte recognition, polygenic and polymorphic (diff genes and varieties), major reason for transplant rejection, are promiscuous and bind many peptides but not all (diff set for diff peptides)
610
Characteristics of MHC 1 class?
alpha chain big and has 3 domains, beta chain small, expressed on most cell types, presents to CD8+ cytotoxic T cells, peptides presented are sampling of intracellular environment
611
Characteristics of MHC 2 class?
alpha and beta equal, only on antigen presenting cells mostly dendritic but also B cells and macrophages, presents to CD4+ T helper cells, peptides presented are sampling of extracellular environment
612
What is antigen processing? What are the two pathways? cells and receptors involved?
metabolic process of degrading proteins into peptides 8-10 AA that are capable of binding MHC and being presented; exogenous=MHC II and CD4+, endogenous=MHCI and CD8+
613
What is the general pathway of T cell delopment?
progenitor T cells-> CD4-CD8 Double negative (1,2,3,4)-> Cd4+CD8+ double positive thymocytes--> Cd4+ or CD8+ single positive cells--> exit thymus
614
How does positive selection work?
DP T cells which recognize self-MHC receive a survival signal from specialized APCs in thymus and are positively selected, occurs in cortex, if fail they are eliminated via apoptosis
615
What is negative selection?
T cells which demonstrate too high an affinity for self MHC molecules are deleted in medulla, ensures self tolerance
616
What are the three signals naïve T cells need to become fully activated?
1) antigen specific signal from specific peptide:MHC complex with T receptor 2) co-stimulatory signals derived by B7 and CD28 3) signal directing T cell differentiation into different subsets of effector CD4+ T helper cells
617
What are the 4 accessory signaling molecules in T cell activation and their function?
CD4 and CD8 stabilize TCR and MHC interaction/ signal transduction; CD28 a homodimer on T cells function to interact with B7 on APC; and B7 expressed on APC and function to interact with CD28
618
What does activation of TCR do?
triggers signal cascade leading to induction of IL-2 which is critical for T cell proliferation and differentiation
619
What are the subsets of cells that CD4+ differentiates into after signal 3? function of each?
Th1= secrete IFNgamma and activate macrophage, antibody class switch; Th2 secrete IL4 and IL5, activate B cells and antibody response; Th17= secrete IL17 and trigger inflammation; T regulatory cells= secrete TGF-beta and IL10 and inhibit dendritic and T cell activation (important for immune tolerance maintanence
620
CD8+ T cells are not fully active upon leaving thymus, what must they do to differentiate?
binds to APC and receives signal to proliferate and differentiate and are now active to kill virus infected cells
621
How do CD8+ active cells (CTL) kill cells (induce apoptosis)?
contain perforin and granzymes- perforin makes hole in membrane and granzymes enter to initiate caspase cascade and activate nucleases
622
What are the 5 different heavy chain constant regions or classes of antigens?
A (alpha), D (delta), E (epsilon), G (gamma), M (mu)
623
What are the two different areas of antibodies and their function?
Fab- antigen binding has a variable end to allow binding of different antigens to bind; Fc- effector function- IgE binds mast cells and basophils, IgG crosses placenta, IgA is in mucosal immunity
624
What are the roles antibodies play in humoral immunity?
B-cell activation by antigen and T cell results in antibody secretion by plasma cells-> neutralization (prevent bacterial adherence), opsonization (promotes phagocytosis), complement activation (activates complement which enhances opsonization and lyses some bacteria
625
describe the changes in antibody formation occurring in the developing B cell.
pro B- heavy chain rearrangement, pre-B light chain rearrangement, immature B stage formation of b cell receptor (BCR) on cell surface IgM and induction of central tolerance to get rid of autoreactive B cells, mature B cells express both IgM and IgD on cell surface
626
What are the steps to B cell activation?
antigen cross linking IgM activates tyrosine kinase (Blk, Fyn, or Lyn) which phosphorylates B cell receptor cytoplasmic domains, Syk tyrosine kinase binds to phosphorylated Igbeta and becomes activated and phosphorylates CD19, BLNK, phospholipase C, GEFs and Tec kinase, PLC cleaves PIP2 to yield DAG and IP3, Dag and Ca2+ activate PKC which activates transcription factor NFkB, small G proteins activate MAPK which induces and activates Fos a component of AP1 transcription factor, IP3 increases intracellular Ca2+ activating phosphatase calcineurin which activates transcription factor NFAT; NFAT, NFkB and AP-1 act to induce specific gene transcription->prolif and diff.
627
What occurs in a germinal center? What is needed to form one?
intense B cell proliferation, differentiation, somatic hypermutation (point mutations induced in V region genes for higher affinity to antibody), class switching (allows antibody with single antigenic specificity to associate w/ variety of C region chains and have different effector functions), plasma cell generation (antibody producing) and memory B cell generation; requires helper T cells (B and T cells recognize same antigen)
628
What class of antibody is involved in primary and secondary immune response?
primary= IgM, secondary=IgG
629
What is clonal selection?
each lymphocyte has a single type of receptor w/ unique specificity, interaction with foreign molecule and receptor with high affinity= activation, differentiated effector cells from activated lymphocyte have identical specificity to parent, lymphocytes with receptors for self molecules are deleted early and are absent from mature lymphocytes; theory behind adaptive immunity
630
What are the 4 types of medical genetics? define each
biochemical- metabolic disorders including enzymes and protein; clinical cytogentics- aberrations in chromosome number and structure =microscopic; molecular- mutations in single genes or group of genes, expression and function; and clinical genetics- clinical care including diagnosis counseling and management
631
What is dysmorphology?
study of abnormal form= abnormal morphogenesis, physical development, congenital anomalies
632
What is epigenetics and what are some change?
study of heritable changes in gene expression that occur without change in DNA sequence; chromatin folding, packaging of DNA, histone modification, DNA methylation, imprinting
633
What can DNA methylation effect?
imprinting, x chromosome inactivation, transcriptional silencing, protecting genome from transposition, tissue specific gene expression
634
What is IUGR, causes, and what impact can it have?
Intrauterine Growth Retardation; smoking, placental insufficiency, alcohol, maternal nutrition, and stress; increase type 2 diabetes, obesity, CAD, and hypertension susceptibility
635
Reasons for pediatric genetic consultation
1 or more major organ malformation, abnormal growth, Mental retardation or delay, Blind/Deaf, presence or suspected genetic disorder/ chromosomal abnormality, abnormal newborn screening, family hx
636
Reasons for prenatal or preconception genetic consultation
mom >35, abnormal screens, personal or fam hx, known or suspected teratogen, 2+ losses, consanguous mating, ethnic predisposition, maternal medical condition effecting fetal growth
637
Reasons for adult or adolescent genetic consultation.
MR, personal or family hx, blind/deaf, development of degenerative disease, risk assessment for pregnancy, hereditary cancer hx
638
What are all the etiologies for abnormal development?
chromosomal, single gene- autosomal dominant or recessive or x linked, multifactorial, or environmental
639
If onset is prenatal and it is a single anomaly, what is are potential classifications for the anomaly?
malformation, deformation or disruption
640
If onset is prenatal and multiple anomalies, what is are potential classifications for the anomaly? etiologies?
syndrome, sequence, or association; chromosomal, single gene, multifactorial, teratogenic or unknown
641
If onset of abnormality is postanatal what are the etiologies?
genetic, environmental or unknown
642
What is a malformation? Examples.
abnormal formation of tissue, genetically coded to happen; dysmorphic features, congenital heart malformations
643
What is a deformation? Examples. Causes?
unusual forces on normal tissue; cranial molding, mandibular asymmetry, external ear, tibial torsion, club foot, crowded toes, facial nerve palsy or erb's palsy; large or multiple fetuses, oligohydraminos, small uterine or mom, fibroids
644
What is a disruption? Examples
breakdown of normal tissues; vascular disruption or ischemia, gastroschesis, early amniotic bands or rupture missing limbs or digits, facial clefts
645
What is a syndrome? examples.
primary developmental anomaly of two or more systems due to common etiology; Noonan syndrome or DiGeorge syndrome
646
what is association? examples.
non-random recurring pattern of malformations with no defined etiology; VACTERL: Vertebral, Anal atresia, Cardiac, TracheoEsophageal fistula, Renal malformations, and Limb anomalies
647
What is a sequence? examples.
pattern of malformations due to a cascading effect from a single minor alteration early in morphogenesis; Peirre Robin sequence because small chin can be part of other syndromes, Potter sequence: low fluid inutero, deformation from constraint, abdominal wall cant close
648
What is functional genomics?
study of functional elements of an organisms genome
649
what is transcriptomics?
study of all of the expressed RNA elements of genome
650
what is Proteomics?
study of structure and function of proteins expressed in a cell, tissue, organism
651
what was important in 1990 in genetics?
1st bacterial whole genome sequenced and identified BRCA1
652
what was important in 2005 in genetics?
Phase 1 HapMap, chmp and Dog, 1st GWAS published
653
what was important in 2008 in genetics?
Genetic information Nondiscrimination Act passed
654
what was important in 2013 in genetics?
exome sequencing available and obtainable for patients with rare disease
655
What is gene localization? Advantages?
finding chromosomal region that contains the gene; establish that a trait is genetic, genetic heterogeneity (diff genes and same presentation of disease) genetic counseling and presymptomatic diagnosis, 1st step in ID
656
What is gene identification? Advantages?
finding the gene and determining its sequence; precise diagnosis and counseling, understand pathogenesis, discovery of related genes, treatment
657
what is RFLP?
restriction fragment length polymorphism, variation in sequence which affects presence or absence of a restriction site
658
What is VNTR?
variable number of tandem repeats; variation in number of repeated bases btwn restriction sites
659
What is STRP?
short tandem repeat polymorphisms; Di, tri and tetranucletide repeats
660
What is SNP?
single nucleotide repeat polymorphism, microarray, sequencing
661
What is a LOD score?
ratio of probability that two genes are linked to probability they are not linked expressed as a log, score of 3+ means linked
662
What is recombination frequency?
symbol theta, if 0 genes are highly linked if 0.5 genes are independently assorted, between 0 and 0.5 there is linkage
663
What is a CNV?
copy number variant, microarray or comparative genomic hybridization (deletion or duplication), important if gene is dose sensitive, expose variation on other allele if deletion or disruptive duplication
664
What is NGS?
next generation sequencing, high throughput sequencing technology, allows sequence thousands or millions of short sequences simultaneously in single run, correspond to many genes, increase in genetic info, decrease in cost and time, reversible terminator based method with fluorescence
665
What is Sjorgen-Larrson Syndrome?
autosomal recessive, ichthyosis, mental retardation, spastic diplegia or tetraplegia, deficient fatty aldehyde dehydrogenase
666
What is sialidoses type II?
neurominadase deficiency; developmental delay with neurodegenerative course, bone abnormalities, hepatomegaly, macular cherry red spots, myoclonic seizures, coarse facial features, abnormal glycopeptide,
667
What is gaucher disease?
defect in glucocerebrosidase enzyme so build up of glucosylceramide which can't be broken down, all have hepatosplenomegaly, bone marrow depression and pulmonary infiltration; Type 1: non-neuronopathic effects kids and adults, Type 2: acute neuronopathic effects infants and is fatal, Type 3: sub acute neuronopathic effects children and is fatal
668
How is enzyme replacement feasible in lysosomal storage diseases? Which ones use it?
during normal function the enzyme is secreted from the cell and reabsorbed via endocytosis; gaucher, hurler, hunter, Pompe, and Fabry; not effective on neuropathic forms as it cant cross blood brain barrier
669
What is Acute intermittent Porphyria?
autosomal dominant, most carriers have no symptoms, increased ALA and PBG precursors to heme no feedback inhibition and no heme either, onset after puberty, acute attacks precipitated by drugs, diet, or stress, abdominal pain, nausea, vomiting, neuropathy, psychiatric disturbances, and tachycardia, treat with heme
670
What is peroxisome biogenesis disorders?
defective peroxisome assembly, symtpoms appear at birth or early infancy; hypotonia, seizures, psychomotor retardation, liver disease, dysmorphic facial features , ex. PTS1 receptor problem, not recognized by docking protein, deficiency in numerous enzymes carried by PTS1
671
What is nephropathic cystinosis?
genetic defect in lysosomal membrane protein necessary for efflux of cysteine out of lysosome, intralysosomal cysteine storage in tissues results in renal damage, hypothyroidism, photophobia, bony abnormalities, (hexagonal crytals taking up whole lyososome), cysteamine therapy- binds cysteines and utilize lysine transporter out
672
What methods are used to process newborn screens?
enzyme assays, immunoassays, electrophoresis, tandem mass spectroscopy
673
What is PKU?
phenylketonuria, cant break phenylalanine down; mental retardation, microcephaly, fair complexion and hair, seizure disorder in 15%, hypomyelination, tooth enamel hypoplasia, in brain Phl competitively inhibits Try and Trp which are needed for dopamine and serotonin, few false positives on newborn screen, therapy diet, increase in outcome for earlier detection
674
What is galactosemia?
decresed activity of transferase, cant transport galactose into cell; vomiting, diarrhea, hepatomegaly, liver dysfunction, cataracts, ovarian failure susceptibility to gram negative sepsis, lactose restriction; therapy can reverse liver and renal, cataracts disappear, but ovarian cant be reversed (prenatal damage)
675
What is biotinidase deficiency cause?
failure to thrive, alopecia, scaling dermatitis, vomiting, metabolic acidosis, seizures, hypotonia, ataxia, MR, hearing loss
676
What are mitochondrial fatty acid oxidation disorders?
13 known, different enzymes involved, most asymptomatic initially, episodic metabolic decompensation- fasting hypoglycemia, metabolic acidosis, muscle weakness, cardiomyopathy, rhabdomyolysis, neurological sequel or death
677
What is medium-chain acyl-CoA dehydrogenase deficiency?
most common FAO defect, variable onset with episodic symptoms, accumulation of fatty acid oxidation metabolites, acidosis, liver dysfunction, therapy is preventative only, strict avoidance of fasting
678
What is HELLP syndrome of pregnancy?
hemolysis, elevated liver enzymes and low platelets, associated with mothers carrying fetus with fatty acid oxidation defect, accumulation of baby's substrates goes into mom's circulation, acute fatty liver of preganacy, pre-eclampsia
679
What is Homocystinuria?
mental retardation, dislocated optic lenses, thromboembolic events, thinning and lengthening of long bones, cystathionine deficiency; 50$ respond to high dose of enzyme cofactor, or can use betaine to turn homocysteine to methionine
680
What is the purpose of dendritic receptor binding and costimulation of T cell by dendritic cells?
proliferation and differentiation of T cell to acquire effector function
