ICM/Genetics 2

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ICM/Genetics 2
2012-04-06 23:08:25
icm genetics

icm, genetics
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  1. Types of interview questions (4)
    • leading
    • yes/no
    • double
    • open-ended (best)
  2. interviewing techniques (4)
    • silence
    • facilitation
    • confrontation (only use when the patient is lying on purpose)
    • direction
  3. Closure - components (5)
    • *allocate time (10 minutes)
    • address important issures
    • assure patient's understanding
    • negotiate further testing/treatment/follow-up
    • be concrete
  4. ID and chief complaint contents
    (name) a (age) year old (race, occupation, and marital status) male/female. A history of (major, pertinent illnesses or surgeries), presents with (patients own words) for the past (time).
  5. History of Present Illness
    • "When was the last time you were perfectly well?"
    • listen first, then direct and facilitate
  6. Dimensions of a symptom
    time, quantity, location, aggravating/alleviating factors, quality, setting, associated symptoms, inconstate dimensions
  7. Past medical history (6)
    • significant illnesses: childhood illnesses, serious infections, anything requiring lifestyle modification or absence from school/work
    • Surgeries: in/outpatient, obstetrical deliveries, significant injuries
    • Hospitalizations:
    • Disease exposures: TB/HIV
    • Medications: prescriptions, OTC, herbs, home remedies
    • Allergies/Sensitivies: describe and date reaction; antibiotics, penicillin, eggs, shellfish, nuts, environment
  8. Social history (6)
    • job
    • marital status/kids
    • education
    • tobacco/alcohol/drug use
    • diet
    • exercise
  9. Spiritual Assessment
    • F - Faith: "Do you consider yourself to be a religious/spiritual person?"
    • I - Influence: "Does your religion influence the way your care for yourself/illness?"
    • C- Church: "Are you a part of a congregation/spiritual community?"
    • A- Address: "How would you like me to address these issures with you?"
  10. Family History - what do you include and record?
    • include: ALL first degree relatives (ideally a 3-generation history --> genogram)
    • record: age/health if alive or age/etiology of death; all major illnesses (CV disease, DM, HTN)
  11. Routine Health Maintenance (5)
    • **appropriate for age and circumstance
    • immunizations
    • PAP smear
    • breast exam/mammogram
    • colon cancer screening
    • special circumstances (ophthalmology, CXR, exercise stress test)
  12. Review of Systems
    cover chief symptoms referable to each system
  13. Focused medical history - what? how?
    • what: cc; age/sex,; HPI; pertinent PMH, HF, SH, ROS
    • determine potential diagnoses and think about organ systems or chronic conditions that accompany the diagnosis
  14. techniques for differential diagnosis determination
    • V: vascular
    • I: infection/inflammatory
    • T: trauma/toxin
    • A: autoimmune
    • M: metabolic
    • I: idiopathic
    • N: neoplastic
    • C: congenital
  15. MSE - appearance and behavior
    • appearance: grooming, hygiene, older/younger than stated age, appropriate wardrobe, disfigurations/scars/tattoos
    • behavior: cooperative, agitated, disinhibited, disinterested, acute distress? eye contact?
  16. MSE - motor
    Abnormal movements (tremors, slow mvmts, lip smacking, tongue protrusions), gait, posturing, pacing, hand wringing, tics, restlessness
  17. MSE - speech (5)
    • fluency
    • amount
    • rate
    • tone
    • volume
  18. MSE - mood
    best used by describing the patient's own words
  19. MSE - affect (definition and discription)
    • expression of mood during interview
    • flat (nothing) --> blunted --> constricted --> full range (normal)
  20. MSE - thought content (5)
    • describes throughs occurring to the patient
    • obsessions
    • paranoia: "Do you ever feel like peopler are out to get you?"
    • suicidal thoughts/intentions/plans
    • homicidal thoughts
    • delusions: incorrect processing --> fixed ideas not shared by others; can have normal thought processes, but delusional content
  21. Fight of ideas
    • abnormal thought process
    • rapid shifting from one through to another with logical connections
  22. circumstantial thought process
    • abnormal thought process
    • over-inclusion of nonrelavent details, and eventually returning to answer the question
    • listener can follow train of thought
  23. Tangential thought process
    • abnormal thought process
    • irrelevant thoughts, only related in a minor way, never returning to original question
  24. loose thoughts/associations or derailment
    • abnormal thought process
    • impossible to see the connection between the sequential thoughts
    • words make sentences, but they don't make sense
  25. perseveration
    • abnormal thought process
    • repeatedly coming back to the same topic
  26. blocking thought process
    • abnml thought process
    • unable to complete the thought --> stop speaking in the middle of the conversation
    • no recall of events
  27. Neologisms
    • abnormal thought process
    • new words or combinations that are not really words; not easily understood
  28. Word salad
    • abnormal thought process
    • confused language, mixure of words/phrases with not apparent meaning
  29. Clang associations
    • abnml thought process
    • thoughts associated by the sound of words rather than the meaning
  30. Echolalia
    • abnml thought process
    • senseless repetition of a word/phrase
  31. Hallucinations
    • auditory are most predominant in the US, visual are more predominant
    • also tactile, gustatory, and olfactory
  32. Illusions, depersonalization, and derealization
    • illusion: misperception of real external stimuli (hearing tree rustling and thinking someone's called your name)
    • depersonalization: feeling that one is not oneself
    • derealization: feeling that the environment has changed
  33. MSE - orientation to what?
    • name, date, locations, and situation
    • also current events
  34. Tests for attention and concentration
    • calculations
    • "world" backwards
    • 5 things that start with a particular letter
    • seriel 7's or 3's
    • calculations
  35. Memory - types (4)? examples?
    • immediate: digit-span (repeating 6 figures to and from examiner)
    • recall: immediately repeat 3 words, and then 3-5 minutes later
    • recent: past few months or days
    • long term/remote: childhood data
  36. Abstract thinking tests
    • Proverb explanations
    • Similarities/Differences
  37. MSE - Judgment
    • ability to understnad the outcome of behaviors/ capacity to make/act on good decisions
    • test with hypothetical situations
  38. reliable vs valid tests
    • reliability: consistency of exam under different variables
    • validity: how a test measures that which it is intended to measure
  39. major types of psychological testing (4)
    • intelligence/cognitive testing
    • achievement testing
    • neuropsychological testing
    • personality testing
  40. Fluid and crystallized intelligence
    • fluid: capacity for learning and problem solving that is independent of education/experience
    • crystallized: interaction of fluid intelligence and culture; abstract
  41. Verbal Comprehension Index - function? questions?
    • determines verbal knowledge => informal/formal education
    • define words, how are words similar?
  42. Perceptual Reasoning Index - function? questions?
    • ability to form relatively abstract concepts/relationships w/o words (i.e. visuals, manipulation of concepts, relationships)
    • use pictures to fill the last spot (as shown in class)
  43. Working Memory Index - definition and question
    • tests auditory short-term (sequencing skills, attention, and concentration)
    • Remember and repeat these numes and say in ascending order 2-3-1
  44. Processing Speed Index
    Ability to perform simple tasks, maintain focused attention/concentration ~ 2 minutes
  45. Full Scale IQ test - definition and components
    • a composite number to describe intelligence, but doesn't reflect areas of strength and weakenss
    • perceptual reasoning, verbal comprehension, memory, working memory, processing speed
  46. Achievement Testing
    • assesses achievement in academic areas (reading, spelling, writing, arthmetics)
    • expressed as a standard score (IQ) or grade equivalents
  47. Neuropsychological Test
    • determines the degree to which the areas of the brain and neurologically driven areas of skill are intact
    • for localization of disease processes or strength/weakness areas for rehab planning
  48. personality testing - function? types?
    • diagnosing both enduring personality traits and acute psychiatric conditions
    • objective: checklists/forms --> empirically generates norms; 500 true/false statements (assess depression, schizophrenia, anxiety, ADHD, mania, and personality disorders)
    • projective: patient's response to an ambiguous stimulus, so the pt projects his internal state one the ambiguous stimulus (Roschach Inkblot tests)
  49. Thematic Apperception Test (TAT)
    a type of personality testing allowing the patient to tell a story based on an illustration
  50. Where to break bad news
    face-to-face, quite/private room, leaving lots of time
  51. preparation for breaking bad news
    • determine what the patient knows to prepare them for the possibilities throughout the diagnostic process and their understanding of health and disease
    • recognize that the patient may not want to know all of the information, or designate someone else to communicate on their behalf
  52. "the next step" in breaking bad news (4)
    • do plan the most appropriate next step and offer if to the patient, but remember their right to refuse
    • set a firm date for a follow-up (short interval)
    • ask about the patient's safety in the context of their emotional state
    • discuss potential sources of support
  53. When the family decides they don't want the patient to know - legality, what to do
    • legal obligation to obtain informed consent from the patient
    • honesty with a child --> trust
    • ask the family *why* they don't want the news given (fear? previous experiences? person/cultural/religious context)
    • offer to talk to the patient together
  54. affective, cognitive, and psychophysiologic responses to bad news
    • affective: tears, anger, sadness, love, anxiety, relief
    • cognitive: denial, blame, guilt, disbelief, fear, loss, shame, intellectualization
    • basic psychophysiologic: fight or flight
  55. Physician's response to feelings from breaking bad news
    • listen quietly and attentively
    • encourage descriptions of feelings
  56. Language as a barrier
    • use a skilled translator, but avoid family members
    • consider telephone translation services
    • *speak directly to the patient
  57. Communicating prognosis
    • some patients want a plan and details, others want reassurance
    • avoid precise answers regarding timing
    • *reassure availability*
  58. communication for caregiver
    maintain common chart or log book with goals, treatment choices, emergent situations, likes/dislikes, contact information
  59. Chromosomal banding - function, method?
    • allows identification of individual chromosomes and determination of any structural abnormalities
    • FISH is the most common staining technique
  60. FISH
    • a labeled probe is hybridized to a chromosome to test for missing/additional chromosome material and/or rearrangments
    • multiple probes can be used for multiple colors
  61. chromosome morphology
    • metacentric
    • submetacentric
    • acrocentric
  62. polyploidy vs aneuploidy
    • polyploidy: complete set of extra chromosomes (triploidy or tetraploidy)
    • aneuploidy: cells that are missing/ have extra of a single chromosome (monosomy, trisomy, or tetrasomy), typically => nondisjunction
  63. Mosaicism - origin, aneuploidy rates
    • nondisjunction during a meiotic division (either I or II)--> different chromosome numbers in gametes
    • monosomy is almost always lethal, but some trisomy is compatible with life
  64. Trisomy 21 - occurance, symptoms
    • most common aneuploid condition (90% from mother)
    • --> heart defects, strabismus/eye problems, hypothyroidism, hearing loss, developmental disabilities, SC injuryies in older pts d/t vertebral weakness, GI obstruction
  65. Trisomy 18 Edwards Syndrome - occurance, symptoms
    • 2nd most common autosomal trisomy live births
    • prenatal growth deficiency, VSDs, severe developmental delays, 5% reach 1yr, predisposition to infections and apnea
  66. Trisomy 13 Patau Syndrome - occurance, symptoms
    • least common autosomal trisomy live birth
    • oral-facial clefts, small/malformed eyes, CNS defects, heart defects, renal abnormalities, 5% reach 1st year, *are* able to developmentally progress
  67. Maternal age effects
    • dramatic increase in risk of chromosomal problems after 35 years
    • *check age of mother at due date
  68. Turner Syndrome - genotype, phenotype?
    • 45, XO (70% maternal origin)
    • short stature, sexual infantilism, webbed neck, broad chest, heart/kidney defects
  69. Kleinfelter syndrome - genotype, phenotype?
    • 47, XXY (50% paternal meiosis I)
    • tall/thin, gynecomastia, hypogonadism, no secondary sexual characteristics
  70. pseudoautosomal region of sex-determining chromosomes
    • crossing-over regions between X and Y
    • could possibly include the SRY region (located just centromerically)
  71. reciprocal translocations
    • => two breaks on different chromosomes --> exchange of material
    • carriers have normal phenotypes, but posisbly partial trisomy or monosomy in children
  72. balanced vs unbalanced rearrangments
    • balanced: no gain or loss of chromosomal material
    • unbalanced: gain/loss of chromosomal material
  73. clastogens
    agents that --> chromosomal breakage during mitosis and meiosis
  74. Robertsonian translocation - definition, phenotype, what does it involve?
    • the p arms of nonhomologous chromosomes are lost and the q (long) arms will fuse together (esp common w/ acrocentric chromosomes)
    • phenotypically normal if the p arms have no genetic material and it's a live birth, but only have 45 chromosomes/cell
    • typically involving chromosomes 14 and 21
    • can --> 3 copies of 21q --> Down's Syndrome
  75. deletions vs microdeletions; definitions and locations/diseases
    • deletions: single chromosomal break --> loss of genetic material (either terminal or interstitial); on 5p --> Cri-du-chat syndrome,
    • microdeletions: < 5Mb deletions, usually determined by FISH, 4p --> Wolf-Hirschhorn; 7q (elastin allele)--> Williams
  76. DiGorge/Celocardiofacial disease - cuase? phenotype?
    • microdeletion on 22q
    • --> tetralogy of Fallot, palatal abnormalities, learning difficulties
  77. Uniparental Disomy - cause? chromosomes at risk?
    • one parent contributes two copies of a chromosome and the other parent contributes none => parental or zygotic nondisjunction
    • deletion on 15q --> Prader-Willi (paternal) or Angelman (maternal)
  78. Duplications - cause? phenotype?
    • unequal crossing over
    • --> less serious consequences than deletions in the same region
  79. Ring chromosomes
    • => deletions of the telomers --> end fusion --> ring
    • possible for 46,X,r(X) --> Turner's syndrome
  80. pericentric vs paracentric inversions - how does it happen? effects? likely chromosome?
    • => two breaks in the chromosomes followed by backwards reinsertion of teh fragment
    • pericentric: involves the centromere
    • paracentric: doesn't involve the centromere
    • can interfere with meiosis --> offspring abnormalities
    • Chromosome 8q --> mental retardation, heart defects, seizures,
  81. Isochromosomes - cause? likely chromosome?
    • => chromosome dividing latitudinaly (perpendicular to normal axis of division)
    • --> i(Xq) w/ Turner Syndrome symptoms
  82. Indications for performing chromosome analysis (8)
    • recognizable chromosome syndrome features
    • unrecognizable pettern of ≥2 malformations
    • ambiguous genitalia
    • ID/developmental delay in children w/ multiple anomalies
    • parents with chromosome abnalities
    • stillborn infants w/ malformations
    • females w/ short stature and primar amenorrhea
    • males w/ small testes or gynecomastia
  83. Metabolic disease inheritance
    usually autosomal recessive, with no morbidity in the carrier state
  84. Galactosemia symptoms - presentation, untreated, chronic
    • most common monogenic disorder of carbohydrate metabolism
    • poor sucking, failure to thrive, jaundice, cataracts (10%)
    • (untreated) --> sepsis, hyperammonemia, shock
    • (chronic) poor growth, mental retardation, ovarian failure
  85. fructose metabolism defects - fructokinase, HFI, hepatic F16BPase deficiency symptoms
    • fructokinase: asymptomatic fru in urine *most common
    • Hereditory fru intolerance: poor feeding, hepatic/renal insufficiency, failure to thrive (FTT), death
    • F16BPase deficiency: impaired gluconeogenesis, hypoglycemia, severe acidemia
  86. glc metabolism defects
    • **most common error of carbohydrate metabolism
    • --> DM1/2 or maturity-onset-diabetes of youth (MODY)
  87. Lactose - prevalence, symptoms?
    • 5-90% depending on the population
    • lactose intolerance is common in tropical/subtropical countries
    • --> nausea, bloating, diarrhea
  88. glycogen metabolism defects
    • impaired synthesis or degradation
    • esp damaging to liver (heaptomegaly) and skeletal muscle (unable to release glu --> hypoglycemia)
  89. AA metabolism disorders - common AA's affected
    • Phe: --> PKU; --> fetal birth defects, growth retardation, microcephayl, and mental retardation if hyperphenylalaninemia during gestation
    • Tyr: --> hereditary tyrosinemia type 1 (HT1) --> neurological, kidney, and liver dysfunction
    • BCAAs: --> Maple Syrup Urine Disease (MSUD), --> ketaoacid accumulation --> neurodegeneration and death
  90. Smith-Lemli-Opitz Syndrome -cause? symptoms?
    • => defect in cholesterol biosynthesis
    • --> brain/heart/genitle/hand defects at birth (rarely seen with metabolic disorders)
  91. MCAD deficiency - occurance, symptoms, presentation variability
    • most common error of fatty-acid metabolism
    • --> episodic hypoglycemia, comiting, lethargy (esp p minor illness and dec intake), cerebral edema/encephalopathy
    • variability - acute illness, chronic, sudden death, or asymptomatic with mutation
  92. Congenital adrenal hyperplasia - cause? symptoms
    • => cortisol synthesis defect
    • --> masculinization of the genitalia in females, and premature virilization in males
  93. Lysosomal storage diseases - mucopolysaccharidoses and normal
    • => accumulation of substrate from undegraded molecules
    • --> (mucopolysaccharidoses, GAG breakdown defects), hepatosplenomegaly, short stature, hearing/vision loss, C/V dysfunction, andseizures (Hurler Syndrome --> crouched stance, thickened digits, protuberant abdomen)
    • --> (degradation problems) visceromegaly, organ dysfunction, earth death
  94. urea cycle disorders - inheritance patterns, symptoms
    • most types are autosomal recessive, but ornithine transcarbamylase is X-linked recessive
    • --> lethargy, coma,
  95. energy production defect
    • complicated b/c of the varying energy demands for each system
    • --> hypotonia, hepatomegaly, non-ketotic hypoglycemia, and metabolic acidemia
  96. Transport defect phenotypes
    --> cystinosis (Cys is the least soluble AA)--> FTT, renal glomerular damage (p Cys crystals), cystinuria, HTN
  97. Hemochromatosis - inheritance? definition/organs involved? sex differences? penetrance?
    • autosomal recessive disorder of iron accumulation in liver, kidney, heart, joints, and pancreas (associated diseases)
    • earlier penetrance in men b/c women lose iron during menstruation, gestation, and lactation (~40 y/o for men)
  98. Wilson's and Menkes' disease - inheritance and symptoms
    • Wilson's disease (WND): autosomal recessive; accumulation of Cu --> liver disease and neurological abnormalities
    • Menkes' disease (MND): X-linked recessive; lack of Cu, --> kinky hair, mental retardation, seizures, and early death
  99. Zinc deficiency symptoms
    scaly, red rast around mouth, genitals, buttocks, and limbs
  100. Genetic and physical mapping
    • genetic: looking at inheritance patterns in families and establishing the order on the chromosomes
    • physical: tag the chromosomes w/ physical markers to est position/ DNA sequences on the chromosomes
  101. synteny vs linkage
    • synteny: two genes are on the same chromosomes (physical location)
    • linkage: two genes are so close that they are likely to be inherited together *must* be syntenic; cM ≤ 50
  102. centiMorgan units
    • the distance between two loci on a chromosome (probability, not physical distance)
    • 1cM ~ 1% recombination frequency (theta)
  103. Linkage assessment in families and LOD score
    • linkage likelihood/ likelihood of no linkage (theta = 50cM)
    • ratios > 1.0 = favor of linkage
    • ratios < 1.0 = odds against linkage

    LOD: logarithm of linkage ratio, LOD >3.0 = linkage, LOX <-2.0 = not linked
  104. Linkage disequilibrium
    • the nonrandom association of alleles at linked loci, but it will diminish over time as a result of recombination
    • helps us map disease genes
  105. Retinitis Pigmentosum - digenic inheritence? symptoms?
    • Digenic inheritance: inherited as AD, AR, XLR or mitochondrial; > 21 different gene mutations w/ 24 additional chromosomal regions that are symptomatic (*locus heterogeneity*)
    • --> rdxn in daytime vision p rod photoreceptor death
  106. linkage vs association in populations
    • linkage: positions of loci on the chromosomes that will be transmitted togehter within families
    • association: statistical relationship between two traits in the population
  107. Ankylosing Spondylitis
    • ossification of discs/joints/ligaments in the spinal column
    • associated with mutation of the HLA gene (for human leukocyte antigen)
    • *association*
  108. Genome-Wide Association Studies (GWAS)
    • GWAS: SNP (single nucleotide polymorph) analysis to test for association or linkage disequilibrium between a disease and a marker by testing thousands of markers across teh genome
    • --> quick identification of candidate disease genes or chromosomal regions of the disease
  109. Candidate gene - definition and analysis approach
    • a gene whose (known) protein produce makes it a likely candidate for the disease in question (collagen genes for Marfan syndrome)
    • analysis = positional candidate approach (much faster)
  110. Innate Immune system (3)
    • recognize general features of invading microorganisms
    • phagocytes: engulf and destroy microorganisms
    • NK cell: specialized lymphocytes that respond to tumor cells and viruses
    • complement system: performate a microbes' membrane and attract phagocytes
  111. Adaptive Immune System (2)
    • T lymphocytes: interact with infected cells to kill them; aid B cell response
    • B lymphocytes: --> antibodies for specific antigens
  112. Humoral Immune System mxn - APCs, costimulatory molecules, plasma cells
    • macrophages and dendritic cells engulf microbes, digest in the phagolysosome, and present peptides on their surface = "antigen-presenting cells"
    • costimulatory molecules: displayed on the surface of the cell encounteriing foreign pathogens that stimulate the T helper cells to secrete cytokines and promote immunoglobulins from B lymphocytes that can bind the invading microbe
    • final step: stimulated B cells --> somatic hypermutations during mitosis --> altering the receptors --> mature plasma cells (secretes 10 million antibodies/hour)
  113. Memory B cells
    • permit a faster/more vigorous response to a second exposure to the same pathogen
    • this is what vaccinations promote
  114. MHC I vs MHC II - function, location, genes?
    • MHC I: present the proteins being made by the cell in questions (viral or cancer proteins); expressed on all cells' encoded by HLA-A, -B, and -C loci on chromosome 6; --> transplant rejection
    • MHC II: present what the cell eats and digests in the phagolysosome; expressed only on APC cells; heterodimers => chromosome 6
  115. Th1 and Th2 cells, also memore and regulatory T cells
    • Th1: T helper cell --> stimulate more cytotoxic T cells to respond to an infection
    • Th2: T helper cell --> stimulate B cells to respond
    • memory T cells: ensure rapid response to a second exposure from the same pathogen
    • regulatory T cells: prevent the immune system from attacking the body's own cells
  116. Interactions between innate, humore, and cellular immune systems
    • innate system: quick reactions
    • humoral system: prevents extracellular pathogens (bacteria and viruses) from taking hold
    • cellular immune system: intracellular infections (parasites and viruses)
    • **overlaping
  117. Genetic basis of structure/diversity of immunoglobulins - heavy and light chains, regions
    • heavy chains: one pair of identical chains - gamma, mu, alpha, delta and epsilon
    • light chains: one pair of identical chains - kappa and lambda
    • both heavy and light chains have Constant, Variable, and Joining regions (with a Diversity region on the heavy chain)
    • **each region on each chain is expressed by the genes and the cell chooses the combination that it want and becomes a constant for that particular B cell!**
  118. Mxns for genetic diversity - both B and T cells (5)
    • multiple germline immunoglobulin genes:
    • Somatic recombination (VDJ regions): deletion of the unwanted sections
    • junctional diversity: the way in which the different regions come together vary
    • Somatic hypermutation: the secondary differentiation by B cells have a VERY high mutation rate for antibody diversity (not used for T cells)
    • multiple combinations of heavy/light chains: randome combos are possible
  119. T cell receptors - function, regions
    • only able to respond to MHC presented peptides
    • same regions (Variable (V), Constant (C), Joining (J), and Diversity (D)) as immunoglobulins
  120. Killer Cell Immunoglobin-like Receptors - function
    • MHC I present: --> inhibition of NK cells
    • MHC I absent: --> activation of NK cells
  121. inter-individual and intra-individual immune variations
    • inter-individual variation: KIR and MHC genes (b/c they're part of a gene family)
    • intra-individual variation: immunoglobins and T-cell receptors
  122. Cytomegalovirus
    • --> mononucleosis, hemoytic anemia, etc
    • infected cells destroy cutotoxic T cells by downregulating MHC I molecules and expresses an inactive analog
  123. Pregnancy and the immune system
    fetal MHC I cells would express paternal molecules, but the MHC I cells are downregulated and the cells present HLA-G on the surface -x-> T cell response or NK cells
  124. HIV and CCR5
    • HIV infections send RNA to the nucleus of macrophage and helpter T cells to incorporate into the cell's chromosomes
    • CCR5: the gene for the cytokine receptor through which HIV likes to invade; individuals who are homozygously lacking the receptor are HIV resistant
  125. Maternal-fetal Rh incompatibility
    • Rh negative mother and Rh positive daughter --> mother's antibodies attacking the baby
    • Mother must be given Rh immune globulin (Rhogam) to prevent the reaction
  126. Primary immunodeficiency disease - definition and examples (11)
    • intrinsic defect with B or T cells, MHC, complement system or phagocytes => genetic alterations
    • agammaglobulinemia, SCID, Zap70 kinase deficiency, purine nucleoside phosphorylase deficiency, bare lymphocyte syndrome, DiGeorge, ataxia telangiectasa, Wiskott-Aldrich, Chediak-Higashi, Leukocyte adhesion deficiency, chronic granulomatous disease
  127. rate of congenital birth defects in the US
    • 1 in 30 - 1 in 50
    • 2-3% are recognizable
  128. 3 major embryonic develpment processes
    • axis formation: anterior/posterior, ventral/dorsal, etc
    • pattern formation: spatial location of cells --> differentiation
    • organogenesis: differentiated cells --> organ systems
  129. Paracrine signalling molecule major families (4) and function
    • **regulate development!!
    • Fibroblast Growth Factor (FGF): cartilage/bone formation
    • Hedgehog family: axis specification, motoneuron placement, and limb patterning
    • Wingless (Wnt) family: est polarity; abnormalities --> tumors
    • Transforming Growth Factor beta (TGF-beta): --> homo/heterodimers --> BMPs --> bone, etc
  130. Fibroblast Growth Factor Receptor defects - function of FGFR3, problems with mutations
    • FGFR3: restrains chondrocyte proliferation and differentiation; inactivation --> cartilage proliferation and inc long bone growth, overexpression --> short bones and skeletal defects
    • FGR1, 2, and 3 mutations: --> hypochondro/achondroplasia (depending on the area/domain of mutation), short status, mid-face hypoplasia, hearing loss, skeltal disorders
  131. DNA transcription factors for development - examples, function
    • HOX, PAX, SOX families, etc
    • control the transcription of genes, so a mutation here could have many different effects (pleiotropic effects)
  132. Extracellular Matrix Proteins and development - function
    function: collagens/fibrills/proteoglycans as scaffolds for tissues and organs, also serve to separate adjacent groups of cells during development
  133. Hirschsprung disease (HSCR) - definition, symptoms, what other syndromes include HSCR (2)? what genes are associated (2)?
    • neural crest cells do not migrate --> enteric nervous system --> bowel hypomotility, obstruction, and gross distention
    • Down's Syndrome or Waardenburg --> HSCR
    • => inactivation of RET (rearranged during transfection) gene, EDNRB or -3(endothelin-B or -3),
  134. Induction and Neurulation
    • Induction: cells of one embryonic region influence the differentiation of a second embryonic region
    • Neurulation: initiates organogenesis and induces the neural tube/neural crest cells to form
  135. Gastrulation - definition and what they turn into
    • formation of the three germ layers
    • endoderm --> digestive/respiratory tract lining, visceral organs and lungs
    • mesoderm --> skeleton, UG system, limbs
    • ecoderm --> neural tube/ CNS, epidermis, and neural crest cells
  136. Primitive Streak - function? gene?
    • determines the anterior/posterior axis
    • HOX gene
  137. Laterality defects - human symmetry? genes (2 + TFs) , situs inversus/ambiguous
    • unpaired structures develop in the midline and lateralize (heart), or the partner may regress (blood vessels),
    • genes: Sonic hedgehog (Shh) and zinc-finer protein of the cerebellum (ZIC3), d adn eHAND TFs,
    • situs inversus: a L/R reversal of organ position
    • situs ambiguous: L/R randomization
  138. Craniofacial Development - what is it derived from? gene for regular development? genes for mutations?
    • => neural crest cells
    • HOX genes determine fate of ncc's
    • mutations in FGFR and GLI3 --> defects
  139. Limb development - mesoderm that it's derived from? names of cell collections (3)? TBX gene mutuations?
    • => lateral plate and somatic mesoderm
    • apical ectodermal ridge, progress zone, and zone of polarizing activity
    • TBX gene mutations --> Ulnar-Mammary and Holt-Oram Syndromes w/ hypoplasia of limbs
  140. Organogenesis - how? mediators?
    • *coordination of multiple processes* esp between the epithelium and mesenchym
    • mediated by multiple signaling molecules, conduct signals, and TFs
  141. nature of mutations
    • 5-10% are inherited (germline mutations)
    • 100% of cancers are acquired changes (somatic mutations)
  142. carcinogens
    environmental facors --> mutation in somatic cells (so not passed on)
  143. Knudson's two-hit hypothesis - definition and example
    • one copy of a mutant gene is inherited, which paves the way for a second, environomental mutation to happen --> tumor
    • e.g. retinoblastoma
  144. proto-oncogenes and oncogenes
    • encode products controlling cell growth
    • mutated proto-oncogene --> oncogene (dominant gain-of-function mutation) --> de-regulation of vell cycle control
    • can be inserted by retroviruses
  145. genomic instability
    • => defects in DNA repeair
    • --> widespread mutations, chromosome breaks, and aneuploidy
  146. telomeres and cancer
    • telomeres shorten after 50-70 divisions
    • tumors activate telomerase to help the cells escape cellular senescence
  147. TP53 gene - function and mutation effects
    • --> TF that induces apoptosis p damaged DNA
    • somatic TP53 mutation is found in most tumors
  148. Familial Adenomatous Polyposis (FAP) or Adenomatous Polyposis Coli (APC) - inheritance pattern, symptoms of mutation, occurance of colon cancer
    • autosomal dominant, germline mutation
    • --> numerous, large polyps develop in 20's,
    • 1/20 Americans are diagnosed with colon cancer,
  149. APC gene - normal function, step-wise path to tumor, and mutations
    • normally a tumor supressor
    • mutations --> hyperproliferative colon epithlium (DNA hypomethylation *epigenetic*) --> activation of KRAS, and loss of SMAD4 and TP53 genes --> tumors
    • assoc w/ majority of colon cancer cases, also one of the earliest alteraions
  150. Hereditary Nonpolyposis Colon Cancer - definition, cause
    • inherited mutations on any 6 genes w/ DNA mismatch repair
    • microsatellite instability
  151. BRCA1/2 mutations - association? mutated product? gene type?
    • inherited breast cancer (esp early onset)
    • mutations --> truncated protein and loss of function
    • *BRCA = suppressor genes*
  152. Hereditary Cancer Syndromes - inheritance pattern, characteristics
    • autosomal dominant; highly penetrant, variably expressive
    • characteristics: early onset, multiple affected family members, *bilaterality*, multiple tumors, rare cancers
    • **take a complete family history with each visit and pay attention to any changes
  153. Types and examples of cancer genes
    • Tumor suppressor genes: BRCA1/2, APC, RB
    • Proto-oncogenes/oncogenes: RET
    • DNA mismatch repair genes: MSH2, MLH1
  154. Classification of cancer in families
    • sporadic: 75-85%, different sides of the family
    • familial: 10-15%, same side of the family, but not very common
    • hereditary: 5-10%, autosomal dominant transfer
  155. Diseases => loss or tumor suppressor and DNA repair genes (12)
    Retinoblastoma, FAP, Neurofibromatosis, Li-Fraumeni, Con-Hippel Lindau disease, Wilms tumor, melanoma, breast/ovarian cancer, Cowden, Ataxia telangiectasia, Gorlin, HNPCC