Y2S1B1

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Genetic Disease

Features

Hereditary diseases

inherited via gametes from parents; all hereditary diseases are familial

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Familial diseases

increased incidence above normal within a family; disease pattern is NOT predictable/Mendelian

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Congenital diseases

onset of symptoms at birth or shortly thereafter; may not be genetic

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Sporadic genetic diseases

mutation arises de novo; not familial, but there may be a familial predisposition to form a de novo mutation; not hereditary, but they are genetic

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De novo mutation

arises in post-fertilization development and may present in gametes of affected individual (later to possess Mendelian patterns); ex: Achondroplasia

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Familial hypercholesteremia

Auto Dom; >50% of gene product is required for normal function

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Marfans and Type II Osteogenesis Imperfecta

Auto dom; protein product from abnormal allele interferes with function of normal protein

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Huntington disease

Auto dom; protein product from abnormal allele is disruptive/toxic to normal protein

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Forme Fruste

a partial, arrested or inapparent form of a disease (ex: Penetrance and Variable expressivity)

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Penetrance (ex: reduced penetrance)

some auto. dom diseases are present in an individual, but manifest no clinical symptoms

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Variable Expressivity

certain auto dom diseases ALWAYS manifest some symptoms (fully penetrant), but there are differences in phenotype

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Autosomal recessive

disease expression may occur if the one mutated allele translates a functional protein or if the body needs the protein gene product (generally <50% production from the normal allele is enough for heterozygotes not to manifest disease symptoms)

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Heterozygous Hemoglobin S

Sickle Cell Trait; a heterozygote can manifest disease symptoms when placed under severe physiological stress d/t hypoxia

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Compound Heterozygote

individual has DIFFERENT mutations in each allele of a gene pair (ex: Sicke Cell Trait - hetero, and Sickle Cell Disease - homo; no normal Hb, and Hemoglobin S-C Disease - one allele has Hb-S other Hb-C)

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X-Linked Recessive - manifestations in females

1. female inherits a defective X chromosome from each parent (homozygote), 2. female undergoes unfavorable Lyonization/X-inactivation resulting in silencing of many normal X chromosmes

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X-Linked Dominant Diseases

symptoms manifest in males and females; less severe in females d/t Lionization/X-inactivation

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Tay-Sachs

Auto recessive; enzyme deficiency

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Cystic Fibrosis

Auto recessive; transport protein deficiency

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Marfan Syndrome

Auto dominant; structural protein deficiency

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Achondroplasia

Auto dominant; developmental gene deficiency

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Familial Hypercholesterolemia

Auto dominant; receptor deficiencies

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Gene polymorphisms

genes can vary in base sequence w/o damaging the function of transcribed proteins; many are benign and can be subclinical or identifiable as diseases

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Most Common Genetic Diseases in Ashkenazi Jews

1. Gaucher Disease, 2. Niemann-Pick Disease, 3. Canavan Disease, 4. Tay-Sachs Disease

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Most Common Genetic Diseases in Blacks

1. Sickle Cell Trait, 2. Sickle Cell Anemia, 3. Glucose-6-DH deficiency

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Most Common Genetic Diseases in Whites

1. Cystic Fibrosis, 2. Hereditary Hemochromatosis

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Most Common Lethal Genetic Diseases

1. Neurodegenerative Diseases, 2. Storage Diseases, 3. Inborn Errors of Metabolism, 4. Inherited Hematologic Diseases

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Trisomy 21

most common chromosomopathy and genetic MR (1 in 40 births to women >39); translocations can occur leading to multiple Downs children in one family; abnormal facies, simian crease, congenital heart disease

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Trisomy 21 clinical course/sequlae

immune deficiency = increased infection and malignancy (leukemias); Alzheimer's; atlantoaxial subluxation; autoimmune thyroiditis/ hypothyroidsm

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Trisomy 21 mosaicism

d/t mitotic error in post-fertilization mitosis; phenotype is proportional to number of trisomic cells

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Hereditary Trisomy 21

d/t parental translocation; phenotype proportional to size of translocation; can occur in serial offspring

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Trisomy 18

Edward's Syndrome; inc incidence w/advanced maternal age

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Trisomy 18 clinical features

severe MR; cong HD (VSD, valve abnormalities); growth/developmental delay; microcephaly; micro-ophthalmia; micrognatia (mandible); microstomia; clenched fists (2nd digit overriding 3rd and 3rd/5th over 4th) d/t camptodactyly; rocker-bottom feet

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Trisomy 18 clinical course/sequelae

<1% survive into 2nd decade w/o social delays; mosaics and hereditary/translocations are possible

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Trisomy 13

Patau Syndrome; MR; poor feeding; developmental delay; holoprosencephaly w/median facial clefting; polydactyly (postaxial); rocker-bottom feet; congenital HD

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Cri du Chat Syndrome

deletion of short arm of paternal 5p15.3-5.2

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Cri du Chat features

MR; microcephaly; abnormal facies; low birth weight; laryngeal hypoplasia-> characteristic cry; simian crease; congenital HD; ok survival w/ok social skills

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Catch 22 Syndrome

C-cardiac defects, A-abnormal facies, T-thymic hypoplasia, C-cleft palate, H-hypocalcemia/hypoparathyroid, 22-microdeleted chromosome 22q11.2

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22q11.2 microdeletion

Catch 22 syndrome, DiGeorge Syndrome, Velocardiofacial syndrome

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Catch 22 features

altered migration of neural crest cells to pharyngeal pouches; defect proportional to size of deletion (can be subclinical)

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Monogenetic Enzyme Defects (enzymopathies)

Rule: substrate/product ratio is 0.10 meaning that only 10% of normal enzyme activity is required for normal functioning...therefore hets are rarely symptomatic

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Pathological consequence of enzymopathies

1. accumulation of substrate (diverted down alternative met path making toxic mebabolite); 2. deficiency of product; 3. combo of both

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Pathophysiologic Categories of Enzymopathies

1. Substrate Accumulation (large - tissue of origin; small - whole body; co-factor - all enzymes requiring it); 2. Deficiency of End Product (associated w/substrate accum); 3. Failure of Function (toxic product causes cellular damage)

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Phenylketonuria

deficiency of hydroxylase; elevated [Phe], deficiency of tyrosine; Phe turns toxic (Phenylalanine, phenylpyruvic acid, phenylacetic acid)

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PKU features

nml at birth; progressive DD --> MR; seizures; incoordination; "musty" odor; light skin and iris (lack of tyr for melanin); Tx: restrict phenylalanine in diet

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Alkaptonuria

defective homogenistic oxidase enzyme; elevated homogenistic acid; black colored urine/tissues; early arthritis

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Maple Syrup Urine Disease

aka: branched chain ketonuria; onset days/wks after birth; enzyme defect in catabolism of Leu, Iso, Val; accumulation of ketoacids leads to NS damage and progressive neurodegeneration; Auto recessive and common in inbred (Meninites); Tx: branched AAs

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Homocystinuria

deficiency of cystathione synthase elevates [homocysteine]; promotes LDL deposition in blood vessels

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Homocystinuria features

symptoms present over time; Marfanoid habitus; pale skin (melanin); mild MR; decreased lifespan d/t thromboembolic complications, pancreatitis; elevated serum Met/homocysteine; positive urine cyanide-nitroprusside rxn (purple/red)

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Organic Acidurias

defective mitochondrial enzyme in AA synth pathway leads to accumulation of organic-acids and keto-acids...metabolic acidosis; secondary immunodeficiency d/t toxicity to bone marrow

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Urea Cycle Defects

obstruction of nitrogenous waste elimination elevates serum ammonia and low serum urea (BUN); alkalosis; neurological and feeding probs can present in late childhood; Tx: protein restriction/dietary supplementation

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Disorders of Fatty Acid Oxidation

presents early in life; manifests in recurrent symptoms during physiological stress; body normally depends on beta-oxidation of fats for energy when glucose is low (btw meals)

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(MCAD) Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

no b-oxid of FAs; hypoglycemia; hypoketonemia; monocarboxylic FAs and dicarboxylic organic acids (toxic) accumulate; metabolic acidosis; elevated serum ammonia; altered gluconeogeneiss; liver steatosis; presents w/ fasting; seizures/CNS edema; death

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Galactosemia

deficiency of GALT-1; neurotoxicity/hepatotoxicity due to toxins from unconverted galactose; neonatal onset w/milk exposure; Tx: restrict lactose

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Lesch-Nyan Syndrome

X-linked rec; deficiency of HPRT prohibits hypoxanthine from being recycled inot purine synthesis; elevated uric acid levels; onset in infancy; choreoathetosis (writhing of extremities); SELF-MUTILATION; MR; muscle spasm; dec lifespan; Gout; pylonephritis

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Adenosine Deaminase Deficiency

accumulation of deoxyadenosine impairs T and B cells causing SCID (severe combined immunodeficiency)

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Lysosomal Storage Diseases

leads to accumulation of undigested macromolecules and large lysosomes that cause cellular dysfunction and symptomatic disease; classified based on substrate accumulation; hepatosplenomegaly common; neurons are often affected since they are permanent

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Tay-Sachs Disease

Ashkenazi Jews; auto recessive; GM2 ganglioside grp leading to rapid and progressive neurological degeneration; def of hexosaminidase A; ganglioside accumulates in neurons of CNS, myocardial, liver and spleen cells

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Gaucher's Disease

Ashkenazi Jews; auto recessive; defective glucocerebrosidase enzyme; accumulation of glucocerebroside in macrophages, bone marrow, spleen, liver; anemia; thrombocytopenia; nose bleeds; bone pain; SERUM CHITOTRIOSIDASE; arthropathies/fx

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Muscular Dystrophy

X-linked; DYSTROPHIN cytoskeleton/cell membrane component in all muscle and brain (bridges F-actin and basal lamina); rapid degeneration of skeletal myoblasts; progressive weakness (prox-distal); pseudohypertrophy (calves) due to edema

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Duchenne MD

non-functional dystrophin protein; Dx when child starts sitting; "little Hercules" paradoxical muscle hypertrophy; mild MR; elevated CK (muscle damage); death by 20-30 (cardiomyopathy/scoliotic pulmonary effects)

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Becker MD

limited function of dystrophin protein; longer lifespan than Duchenne

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Marfan Syndrome

auto dom; fibrillin mutation (FBN1); tall aortic dilation/rupture/prolapse/valve sclerosis; pectoris excavatum; scoliosis; ligamentous laxity/joint hypermobility

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Ehlers-Danlos Syndrome

familial CT disorders w/dec tensile strength and integrity of skin, joints, soft tissues; poor wound healing; Vascular Type (IV) -- MOST SERIOUS, type III collagen can rupture vessels in pregnancy, aorta or bowel

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Osteogenesis Imperfecta

auto dom; mc=TYPE II COLLAGEN mutation (bone/fibrous tissue); thin trabecular bone w/frequent fx even at birth

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Osteogenesis Imperfecta Type II

example of Dominant Negative Allele affect where the mutated product negatively affects the normal allele

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Familial Hypercholesterolemia

auto dom; LDL receptor gene; liver cannot take up LDL, so serum levels are elevated and hepatocytes continue to produce cholesterol; it accumulates as XANTHOMAS in the skin and arteries; Predisposed to AMI: Heteros by 40/Homos in youth

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Achondroplasia

de novo FGFR3 point mutation; most common cause of dwarfism; decreased endochondral ossification in growth plates; STENOSIS - foramen magnum (hydrocephalous, brainstem compression, ataxia, incontinence, apnea), and spinal canal

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Neurofibromatosis Type I

auto dom disorder of neural crest; mutant NF-1 tumor suppressor gene can't stop ras oncogene from proliferating melanocytes/nerve, schwann cells; CHILDHOOD onset; cafe au lait; scoliosis; ADD, MALIGNANCY --> neurosarcoma

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Neurofibromatosis Type II

auto dom; NF2 mutation allows Schwann cells to proliferate; intracranial neoplasms (acoustic, ependyomas, gliomas, meningiomas) NOT NEUROFIBROMAS; ADULT onet; NO MALIGNANCY, no cafe au lait

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Hereditary Retinoblastoma

mutant RB cell cycle inhibition gene; related to other malignant neoplasms; BILAT RETINOBLASTOMA; inc risk for other malignancy

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Cystic Fibrosis

auto rec; CFTR mutation; altered Cl- transport; alters Na and bicarb ions so secretions are viscous in airways, pancreas and biliary tract; recurrent bronchitis; PSEUDOMONAS - pneumonia and lung abscess; gallstones; infertility

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Common multifactorial diseases

D/T Gen + Environ: atherosclerosis, cancer, cerebrovascular accident, diabetes mellitus, alcohol/drug addiction, suicide, schizophrenia, autism, congenital abnormalities (clefting, congenital heart def, pyloric stenosis), talipes equivarus, hip dysplasia

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Causes of orofacial clefting

genetics, maternal alcoholism or smoking, intrauterine infection; failure of neural crest migration; inc risk if familial

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Cleft lip

6th week; lateral to philtrum on one or both sides; if uncorrected causes speech and social problems

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Cleft palate

8-9th week; soft palate (mucosa) or posteior palatine (secondary) palate; if uncorrected causes sinus infxs, aspiration pneumonia and meningitis

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Fragile X Syndrome

X-linked reduced penetrance FMR1 triplet expansion disease; most common Male and inherited MR; normal pop has up to 50 CGG repeats; full mutation is >200

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Fragile X Syndrome: Inheritance Pattern

expansion occurs in oogenesis of female NOT in spermatogenesis of male; therefore, females can have a normal X turn into a premutation OR a premutation turn into a full mutation; males with premutation will ONLY pass on the premutation; it cannot expand!

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Fragile X Syndrome Features

Males - large testes (macroorchidism); MR/DD; abnormally large facial features and stretched out CT (hyperestensibility of joints; flat feet; scoliosis; mitral valve prolapse);

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Fragile X Tremor-Ataxia

occurs in males with premutation

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Female Fragile X Syndrome

premutation can become fully expanded in female; one X is inactivated so her body is a mosaic; if she has UNFAVORABLE LYONIZATION she will have more symptoms//can also occur if both mother and father pass on premutations makinge her homozygous

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Huntington Disease

triplet expan; onset 30-50; altered HD ptn binds abnormally to other ptns; complexes cannot be tagged/degrated by ubiquitin-proteosome system and accumulate as inclusions; prodrome: psychosis/spasmotic movements; die via malnutrition/hypostatic pneumonia

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Defects of Mitochondrial Genome

mothers transmit mitochondrial genome to kids; mutations manifest in brain, heart, liver, kidney and skeletal tissue slowness d/t oxid-phosphorylation and ATP production problems

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Genomic Imprinting

some genes (if from mother) are automatically silenced by methylation process; if the father's gene is normal, there is no problem; if it is mutated, the child lacks a normal allele

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Prader-Willi Syndrome

d/t paternal mutation and genomic imprinting; mutation on long arm of 15q11.2-13

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Angelman's Syndrome

"Happy Puppet" d/t maternal mutation and genomic imprinting; mutation on long arm of 15q11.2-13

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Uniparental Disomy PW Syndrome

no deletion on chromosome 15; after fertilization the reshuffling of chromosomes resulting in 2 maternally derived chromosomes that are imprinted; leaving no functional gene

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Uniparental Disomy AS Syndrome

having 2 imprinted paternal chromosomes and no functional gene

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Klinefelter Syndrome

XXY (presence of barr body); atrophic testes, infertile, gynecomastia, low testosterone - tall, sparse body hair, small penis, high voice; MR inc w/each extra X

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XYY Syndrome

d/t parental meiotic nondisjunction; tall, DD, acne congoblata, aggressive, FERTILE; children are normal

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XO Syndrome

Turner Syndrome; only females; most pts have mosaicism (46, XX, 45, XO) lack barr body; missing either mat/paternal X; some have microdeletion-partial monosomy; ovarian dysgenesis d/t premature apoptosis of oocytes; variable phenotype

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XO Syndrome continued

lymphedema in utero-webbed neck; short, hypogonadism (dec estrogen, inc pit. gonadotropins, amenorrhea, infertility, lack of 1*/2* sex charact.; Congenital heart defect (coarctation); severity relative to mosaicism; IDDM; autoimmune thyroiditis-atrophy

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True Hermaphroditism

46,XX mc; pheno-Male until puberty when breasts develop; ambiguous genitals; usually ovotestis combo

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Pseudohermaphroditism

gonadal sex is discordant with genital sex; Femal pseudos-have ovaries and penis; Male pseudos-have testes and vagina; ALWAYS have normally developed internal singular sex organs BUT ambiguous external genitalia

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Male Pseudohermaphrodite

46, XY; Gonads - testes; Genitals - ambiguously female; d/t testosterone receptor defect causing tissue resistant to testosterone (Testicular Feminization/Androgen Insensitivity Syndrome); X-linked (Xq11-12)...OR mom given female hormones during pregnancy

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Female Pseudohermaphrodite

Androgynism; 46, XX; Gonads - ovaries, Genitals - ambiguously male; d/t Congenital Adrenal Hyperplasia (mc) inc of circulating androgens; OR Androgen-secreting tumor (ovary/adrenal) in mom during pregnancy; OR male hormones administered during pregnancy

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50% of males with hypospadias have a disorder of sexual development

esp. true if cryptorchidism is present; DON'T circumcise a male with hypospadia b/c foreskin can be used to reconstruct penis

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Most common causes of ambiguous genitalia

1. Congenital Adrenal Hyperplasia (majority); 2. Gonadal dysgenesis; 3. pseudohermaphroditism; 4. true hermaphroditism

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Any pt who genetically has a Y chromosome but streak/dysgenic gonads are at risk for:

malignant gonadal tumors (ex: gonadoblastoma)

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Glucose-6-Dehydrogenase Deficiency

(pharmacogenic problem); lack of NADPH leads to reduced-glutathione; no glutathione to inactivate oxidative molecules, severe damage of erythrocytes and rapid hemolysis; Highly oxidative Drugs in these pts can cause hemolysis

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Hepatic Arylamine N-acetyltransferase Deficiency - "Slow Acetylators"

def reduces metabolism/acetylation of drugs; causes higher circulating levels; Conversely, "fast acetylator" drug dose must be increased b/c recommended dose is insufficient to reach therapeutic level; w/carcinogens, acetylation inc carcinogenicity (dec?)

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Pseudocholinesterase Deficiency

decreased function or complete lack of pseudocholinesterase enzymes (normally in blood and liver); inability to rapidly metabolize muscle relaxant drug succinylcholine; leads to marke prolonged half-life and Respiratory/Skeletal muscle PARALYSIS

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Goals of inflammatory response

1. inactivate/remove injurous agent; 2. remove infected/damaged tissue; 3. initiate tissue regeneration/repair; 4. restore tissues to natural fxn

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Four Cardinal Signs of Acute Inflammation

1. Rubor (redness d/t dilated vessels); 2. Dolor (pain); 3. Calor (heat d/t exotherm rxns of inflam); 4. Tumor (swelling/edema d/t extravascular fluid accum)

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Common causes of acute inflammation

invasion by microorganism; traumatic injury; foreign bodies; immunopathological injury (autoAb, dysfxnl complement activ), malignancy, necrosis, thypothermia, radiation, toxins (chemical/metabolic)

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Vascular dilation

d/t chemical mediators and nerve reflexes; Histamine (mast cells; acts on venules w/H1 receptors); Seratonin; Endothelial-produced NO; Inc blood flow w/in min and erythema/heat

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Increased permeability of venules (vascular leakage)

gaps btw endothelial cells d/t retraction of cytoplasm via intracytoplasmic actin/myosin; allows circulating plasma ptns/Abs to enter extravascular space and increases lymph flow to eliminate pathogen; Histamine/leukotrienes/bradykinin/compl/IL1/TNF/INF

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Chemotaxis mediators

bacterial ptn products, C5a, leukotrienes (arach acid deriv), kallikrein, fibrinogen, fibronectin,

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Leukocyte activation

inc. cytoplasmic Ca; inc exp of adhesion molec/membrane receptors; inc activity of arach acid pathways/lysosomal enzymes; inc secretion of cytokines/inflam factors

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Vascular transmigration (diapedesis)

neutorphils insert pseudopodia into endothelial gaps; facilitated by PECAM-1 (platelet-endothel cell adhesion molec); secrete collagenases to pass basement membrane and enter perivascular ECM

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Movement and accumulation of neutrophils at site of injury

once in ECM, neutrophil cell adhesion molec permit movement thru the ECM

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Acute inflammatory cellular response

#1: neutrophils arrive w/in 6hrs and die off; #2: macrophages arrive at 24hrs

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Viral Invasion Resonse

#1: lymphocytes

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Allergic Invasion Response

#1: eosinophils

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Main functions of neutrophils at site of injury

1. Phagocytosis (microbes, foreign mat, necrotic tissue); 2. Elaboration of proteolytic degradation (microbes/necrotic host tissue); 3. elab of cytokines to maintain inflam response until resolved; 4. source of arach acid for prostoglandin/leukotrienes

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Neutrophils and Bacterial Infections

Greatest neutrophilic chemotractic repsonse!; Infx that attract many neutorphils = PYOGENIC (S.pyogenes, S.aureus, H.influenzae); Accumulation of PUS d/t # of neutrophils/high lysosomal liquifactive necrosis (expands if difficult to erradicate -> abscess)

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Macrophages

can live for days at inflammatory site; phagocytic and intracellular killing properties; elaborate cytokines that help terminate acute infam and initiate regeneration/repair

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Phagocytosis Opsonins

IgG, C3b, fibronectin, fibrinogen, CRP, mannose-binding lectin

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Lysosomal contents

antibacterial ptns (cationic); enzymes producing oxygen free radicals (myeloperoxidase, catalase, superoxide dismutase); lysozyme (muramidase destroys cell wall)

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Oxygen-dependent Microbial Killing

MOST EFFECTIVE method; hexose monophosphate shunt activated by phagocytosis (oxid rxns inc and generate e-s), NADPH oxidase in phagolysosome uses e-s to make free radicals (hydrogen peroxide, free hydorxyl radical)

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Termination of Acute Inflammation

remove injurous agent; short half-life of inflam mediat/enzym; activated/degranulated leukocytes die; inc synth of anti-inflam substances (switch in arach acid path to make anti-inflam lipoxins; inc cortisol; inc macrophage TGF-b ); inhib macrophage-TNF

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Anti-protease ptns

Alpha-1-antitrypsin/Alpha-1-antichymotripsin from liver; inhibit damage done by neutrophil/macrophage lysosomal proteases

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Protein inhibitor: alpha-2-antiplasmin

from liver; helps regulate clotting cascade activated by acute inflam

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Protein inhibitor: C1 esterase inhibitor

from liver; helps regulate/inhibit initiation of complement cascade

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Proteins neutralize reactive oxygen radicals

metal-binding ptns; manganese superoxide dismutase

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Acute inflam response increases pitutitary ACTH

via stimulation from IL-1 and IL-6; ACTH increases production of cortisol; cortisol has inhibitory affect on inflam cytokines; leads to dec levels of cytokines by inhibiting gene expression on inflam cells

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Outcomes of acute inflammation

complete resolution; fibrosis; chronic inflammation

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Classic Acute Inflammtion Histomorphology

manifests in cardinal signs of inflam; usu on skin/mucous membranes

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Suppurative Inflammation Histomorphology

acute inflam w/pus (purulence) d/t predominance of neutrophils (pyogenic bacteria); may or may not form abscess

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Fibrinous Inflammation Histomorphology

acute inflam dominated by formation of fibrin

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Serous inflammation Histopathology

acute inflam dominated by fluid formation

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Necrotizing Inflammation Histomorphology

acute inflam w/areas of necrosis

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Inflammatory fistula

elongated ulcer forms pathologic communication/tract btw two hollow organs or a hollow organ and a surface (ex: colon to peri-anal or abdominal skin (Crohn's); rectosigmoid colon to vagina (traumatic childbirth);

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Histamine

vasodilation, vascular permeability

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Seratonin

vascular permeability

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Phospholipase A2

releases arachidonic acid and PAF from lipid membranes of cells

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Interferon-gamma (INF-gamma)

macrophage activation, esp in relation to granuloma formation

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Nitric Oxide

vasodilation, antimicrobial, anti-inflammatory (inhibits platelet aggregation, cell adhesion and leukocyte chemotaxis)

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Complement system

produced by liver and macrophages; Classic/Alternate/Lectin binding pathways; both alternate and classical converge to activate C3

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Classical Complement Pathway

Initiated by IgM of IgG bound to antigens/epitopes on invader; generates anaphylaxotoxins, kinin system, histamine release, chemotatcis for phagocytes, membrane attack complex (MAC) to punch holes in target cell

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Alternate Complement Pathway

DOESN'T require antibodies; more primitive; C3 directly activated by cell wall components of pathogen (zymosin-yeast; endotoxin-bacteria); Most useful when body is invaded by novel organisms; bypasses early classic complements

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Lectin Binding Complement Pathway

Mannose-binding protein (MBP) binds to mannose of microbial CHOs; complex enzyme is similar to C1 of classic path..initiates complement; ALSO, MBP complex stimulates local macrophages to produce IL-1/IL-6

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Kinins

activated by Factor XII responding to bacteria, damaged collagen or basement memb; Factor XII initiates: Kinin system, complement cascade, hemostasis (coag), fibrinolysis

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Effects of Bradykinin and Kallidin

relax venular smooth muscle (hypotension); inc vascular permeability; bronchial smooth muscle CONTraction; release of cytokines and eicosanoids (arach acid deriv: prostaglandins, leukotrienes, thromboxanes)

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Coagulation System

intrinsicly initiated by Factor XII; bacteria, damaged collagen or basement membranes;

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Factor XIIa

central component in inflammation; activates all other systems: intrinsic (direct) and extrinsic (indirect) coagulation; Kallikrein-kinin system directly; Plasmin fibrinolysis system directly; Complement system (indirectly via kallikrein/plasmin activ)

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Arachidonic Acid System

complement C5a activates Phospholipase A2 to release arach acid from plasma membrane lipids; they enter either: 1. cyclo-oxygenase or 2. lipoxygenase pathway

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Cyclo-oxygenase pathway

Cox-1 (platelets and stomach mucosa) and Cox-2 (located in many tissues; primarily responsible for thromboxane prostaglandin production in acute inflammation)

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Arachidonic acid is converted by COX enzymes into

1. Thromboxanes - vasoconstriction and thrombogenic (platelet aggreg); 2. Prostaglandins (diff effects on diff tissues; vasodilation, inhib platelet aggreg, stim hypothalamus to inc temp-pyrogen)

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Lipoxygenase pathway

arach acid converted to 5-HPETE then to: 1. leukotrienes (LTB4 - chemotactant for neutrophils-stimulates adhesion); LTC4 - inc vascular permeability; 2. HETE - a powerful chemotactant

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Lipoxins are generated in 2 steps

arach acid pathway in leukocytes generates LEUKOTRIENES; Platelets convert leukotrienes to LIPOXINS; They inhibit many inflammation processes

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Clinical Signs of Acute Inflammation

hyperpyrexia (fever); chills; leukocytosis; inc acute phase reactants; inc ESR; inc gamma globulins; inc CRP; dec complement levels

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Benefits of elevated core temp

denatures foreign ptns; debilitates pathogens; more efficient phagocytosis/killing of bacteria

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Initiators of fever

exogenous (pyrogens - bacterial-related; LPS from G- bacteria); endogenous (cytokines IL-1, IL-6 induce hypothalamus via prostaglandins)

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LPS-induced hyperpyrexia

LPS binds LBP (lipopolysac-bind ptn), which binds CD14 on macrophage; produces IL-1, IL-6, TNF; These cytokines bind to hypothalamus activating arach acid path for PROSTAGLANDIN E2; PGE2 goes to VMPO and PVH to elevate core temp

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Chills (rigors)

systemic response to the difference btw the new core temp set-point and the actual body temp

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Leukocytosis

in most bacterial infx; WBC elevates d/t cytokine accelerated release of leukocytes from bone marrow (left shift)

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Leukopenia

charachteristic of viral and overwhelming bacterial infx (diptheria, salmonella?)

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Toxic Granulation in Peripheral Blood neutrophils

indicative of systemic inflammation from bacterial infx

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Dohle Bodies

basophilic body/super toxic granulation indicative of systemic inflam and inc levels of bone marrow granulopoiesis; cytoplasmic areas of condensed ribosomes

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Elevated levels of acute phase proteins

CRP, complement, fibrinogen, von Willebrand Factor, alpha-1-antitrypsin

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"negative acute phase reactants"

decrease in plasma level as liver makes actue phase reactants (albumin, transferin, etc)

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Elevated ESR

physiological reason why erythrocytes clump together (rouleaux formation) is d/t increased circulating levels of acute phase proteins; especially fibrinogen

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Complement factors

decreased levels of total complement; C3 and C4 b/c they are being used up by inflammatory process

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Circulating Ig

frequently elevated esp if inflam response is d/t microbes; Elevated in Lupus (autoantibodies)

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C-reactive protein

100x increase during acute inflam; functions to: activate classic complement pathway, osponize microbes...these people can be predisposed to atherosclerosis

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Causes of Systemic Inflammatory Response Syndrome (SIRS)

systemic infx/sepsis (septic shock); fulminant hepatic failure; pancreatitis; pneumonia; TSS; anaphylaxis; blood transfusion

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SIRS Pathophysiology

represents a whole organism's immune response to a variety of immune challenges

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Mediators of SIRS

TNF-alpha; IL-1, 5, 6, 8 11, 15

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TNF and SIRS

promotes systemic activation of clotting system leading to systemic microthrombi; multi-organ ischemia and generalized hypoxia

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Features of SIRS

depressed liver fxn-hypoglycemia (no gluconeogenesis b/c of cytokine suppression); leaky capillaries in lungs (acute respiratory distress syndrome); systemic inflammation (general vasodil; hypotens; low blood flow; hypoxia)

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Clinical Syndrome of SIRS

metabolic acidosis, hypotension, hyperpyrexia, tachycardia, tachypnea...many pts progress to Multiple Organ Dysfunction Syndrome

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Causes of Chronic Inflammation

persistent infx; immunopathologic rxn; continual exposure to foreign bodies; autoimmunity; mostly predominated by mononuclear cells (macrophages, lymphocytes, plasma cells)

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Pathophysiology of chronic inflammation - macrophages

continual activation leads to constant secretion of pro-inflammatory substances, degradative enzymes and repair substances (FGF and angiogen factors) leading to combo of injury and repair and fibrosis

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Pathophysiology of chronic inflammaiton - lymphocytes/plasma cells

secrete cytokines and gamma globulins to stimulate neutrophils and macrophages leading to free radical regeneration and further destruction

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Pathophysiology of chronic inflammation - mononuclear cells

secrete chemotactants to recruit more neutrophils and mononuclear cells; further amplifies destruction

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Non-granulomatous chronic inflammation

lymphocytes, plasma cells, macrophages present, mixed with granulation tissue; NO Granulomas; (d/t repetitive trauma, chronic inf disese, autoimmune disease, chronic toxin exposure, allergies, chronic vascular ischemia)

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Chronic Suppurative (pus) Inflammation

usu associated w/immune deficiency; common w/agent (bacteia/foreign body) cannot be eradicated and body switches to a strategy of containment (chronic osteomyelitis, lung or brain abscess)

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Granulomatous Chronic Inflammation

Chronic macrophage activation causes macrophages to swell and take on an epithelioid cell appearance (INF-gamma transforms cells); the epithelioid macrophages can fuse together and form multi-nucleated GIANT CELLS; formation of GRANULOMAS

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Granuloma features/causes

central area of enlarged macrophages w/lots of pale cytoplasm/indistinct membranes/indented nuclei; surrounded by collar of lymphocytes/plasma cells even if fibrous; Due to: #1 TUBERCULOSIS, leprosy, syphilis, fungus, foreign bodies (splinters)

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Granuloma with caseous/central necrosis

high probability of TUBERCULOSIS

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Primary Pulmonary Tuberculosis

most common alveolar infx is at apices/peripheray where O2 is low --> Assmann focus; if area is at periphery other than apices, it is called Ghon focus

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TB-pathognomonic

acute reaction (neutrophils) becomes chronic dominated by macrophages/lymphocytes; granulomas w/central necrosis and Langhans giant cells-called TUBERCLES; organisms spread to enlarge hilar lymph nodes-GHON Complex = TB!

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Prolonged TB

chronic inflam, scarification and calcification leads to resolution of infection, BUT the m. tuberculosis remains latent "walled off" in fibrosed lung and lymph nodes; this can reactivate if pt becomes immune compromised (old, malnourished, AIDS, CCstroid

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Other mycobacterial infections

all form granulomatous inflammatory reactions, but others usually confined to skin or primary lymphadenitis

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Defects/deficiency in Inflammation

recurrent infections; intractable infections; infections by opportunistic organisms; poor wound healing

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Deficiencies in humoral immunity

lead to recurrent pyogenic bacterial infections

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Deficiencies in cell-mediated immunity

lead to recurrent infections d/t viruses, fungi, mycobacteria, and parasites (toxoplasmosis)

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Primary immune deficient pts are predisposed to:

autoimmune disease, malignant neoplasia (esp hematopoeitic); graft-versus-host disease; and usually accompanied by poor wound healing

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Old Age - acquired immune deficiency

pathogenesis is multifactorial d/t dec function in many systems

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Chronic liver disease - acquired immune deficiency

liver is major player in ptn metabolism; building blocks for Ig and other inflam-related molecules; synthesizes complement

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Diabetes Mellitus - acquired immune deficiency

pts w/poorly controled DM can have many immune deficits

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Chronic CCsteroid use - acquired immune deficiency

leukocyte adherance to endothelial cells is greatly reduced; CCsteroids inhibit activation and function of arachidonic acid system

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Immunosuppressive drugs - acquried immune deficiency

post-transplant pts; chemotherapy for malignancy

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other acquired immune deficiencies

generalized atherosclerosis, drug-induced neutropenia, HIV, malnutrition, chronic anemia, chronic alcoholism

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Primary Diseases of Excessive Inflammation - aka: Immunopathologic Rxns

Autoimmune diseases; more common in women - SLE and RA

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Hypoxic/Anoxic-Sensitive Tissues

1. CNS 2-5min (Purkinje cells of cerebellum, neurons of hippocampus, pyramidal cells of neocortex); 2. Myocardium - 15-20min; 3. Renotubular epithelium

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Tissues that are relatively insensitive to hypoxia/ischemia

1. Skeletal muscle (up to 1hr); 2. Skin; 3. Fibrous tissue (can be viable up to 24hrs after death)

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Pathophysiology of Hypoxia

Inhibition of oxphos; reduction in ATP and ATP-dependent processes (ie: selective permeability and function of cell membrane)

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Disruption of Na-K pump

influx of Na swells intracellular organelles and entire cell

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Influx of calcium

disrupts cellular processes by binding enzymes; b/c it's no longer sequestered in ER; uncontrolled Ca levels in cytoplasm lead to necrosis; disrupts oxphos and activation of lysosomal enzymes

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Increase in anaerobic glycolysis

less ATP and more lactic acid produced; systemic metabolic acidosis

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Disaggregation of ribosomes

decreased protein synthesis; pancellular metabolic dysfunction

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Reactive oxygen radicals

disruption of normal anti-oxidant metabolic processes causes intracellular damage; peroxidation of lipid membrane, oxid inact of enzymes, mitoch membrane damage, DNA fragmentation, depletion of NADPH (required for ATP)

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Structural cellular changes related to hypoxic injury

1st sign - edema (d/t cell swelling); chromatin clumping; cellular shrinkage/distortion (d/t cytoskeletal damage); ==>necrosis

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Clinical Course of Hypoxia/Anoxia

1. Mild/short time: deprived tissues adapt by undergoing apoptosis leading to hypoplasia/atrophy; altered cytoplasmic environment = misfolded ptns and premature apoptosis; 2. Sudden/severe: tissue cannot adapt; it dies; necrosis

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Reperfusion Injury

restoring O2/blood to hypoxic tissue; the quieted anti-oxidant defenses are not prepared for a rapid inc in free radicals (hydrogen peroxide, hydroxyl ion, superoxide); pancellular damage (ex:xanthine oxidase converts accumulated xanthine to radicals

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Time frame for visual changes in damaged cells

Ultrastructural (electron microscope) - minutes to hrs; light microscopy - hrs to days; gross pathology - hours to days

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Cellular swelling

(aka: hydropic change, vacuolar degeneration, oncosis, cloudy swelling); d/t hypoxia/ischemia, poisonings, vitamin deficiencies; reversible cell injury

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Gross pathology of cellular swelling

inc organ weight, tissue consistency, and tissue/organ pallor

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Fatty change

steoaosis; d/t disruption of normal metabolism...slower progression than swelling; occurs in FA-dependent organs (liver, myocardium, kidney) accumulation of TGs and other lipids

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Free fatty acids

normally metab in liver from cholesterol to phospholipids, TGs; in liver and heart via b-oxid to ATP; chronic alcoholics have inc conversion of free FAs to TGs, but cannot leave liver d/t deficient hepatic synth/export of VLDL

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Common causes of FA accumulation

chronic alcoholism, non-alcoholic fatty liver disease (diabetes, obesity, malnutrition); Grossly the liver has a yellow tint in the red/brown parenchyma

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Abnormal protein accumulation - Nephrotic syndrome

hyaline granules, renotubular epithelium

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Abormal protein accumulation - Multiple myeloma

russel bodies, plasma cells (neoplastic)

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Abnormal protein accumulation - Alcoholic liver disease

mallory bodies in hepatocytes

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Abnormal protein accumulation - Alzheimer's disease

neurofibrillary tangles

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Abnormal protein accumulation - Alpha-1-antitrypsin deficiency

inability of hepatocytes to secrete the enzyme leads to toxic acummulation, cell injury and death (cirrhosis)

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Urate accumulation

urate crystals cause severe inflammatory reaction as phagocytes try to break down the crystals in their lysosomes; chronic gout leads to permanent damage to joints and kidney

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Hemosiderosis accumulation

Fe d/t cellular injury in alcoholics, chronic hemolytic anemias, mult blood transfusions, excessive Fe intake...but no real organ damage

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Primary homochromatosis

Hereditary hemochromatosis is a genetic defect in HFE gene; leads to excessive Fe uptake and multisystem free radical damage, esp in liver, heart and pancreas; (HFE is a glycoprotein that interacts w/transferrin receptors to regulate ferritin uptake)

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Calcium accumulation

d/t necrotic tissue injury or hypercalcemia; 3 types of abnormal calcification: 1. Dystrophic, Metastatic, Pathologic ossification (ectopic ossification)

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Dystrophic calcification

always preceded by cellular injury; calcific aortic valve disease, atherosclerosis; infarction/inflammation/scarification/fibrosis; neoplasm-related Psamomma Bodies - foci

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Metastatic Calcification

occurs in nml tissues w/o injury/necrosis; elev. serum phosphate/Ca: chronic renal failure, hyperparathyroidism, sarcoidosis, paraneoplastic syndromes, multuple myeloma, excessive Ca intake, hypervitaminosis D, metaststic osteolytic malig-breast/prostate

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Metastatic calcification - continued

preferred sites of calcification: gastric mucosa, kidneys, interalveolar septi of lung, joint synovium; Reversible if underlying disease is ameliorated

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Pathologic Ossification

aka: heterotropic bone formation; may occur at sites of old injury or metastatic calcification; can arise spontaneously in lung

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Molecular "Cell Stress Response"

HSP - "heat shock proteins;" small molec weight HSPs protect ptns from denaturation; Ubiquitin binds and removes damaged ptns (ex: mallor bodies in liver or lewy bodies in CNS)

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Necrosis Characteristics

d/t pathological injury; NEVER occurs spontaneously; does NOT need cellular energy; cellular autosysis elicits an inflammatory response

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Serum findings in necrosis

1. Pancreatic: amylase/lipase; 2. Hepatocellular - aminotransferases (AST/ALT); 3. Myocardial cells - creatine phosphpokinase (CK/CPK, troponin)

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Coagulative Necrosis

FAST cellular death; denaturation d/t hypoxia/ischemia/intoxications; Visual changes in tissue seen as: Pus (6-8hrs) disintegration "ghost outline" (24hrs)

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Liquifactive Necrosis

SLOW cell death; enzymatic disintegration/degradation; CNS (encephalomalacia), abscess central liquifaction; "wet" gangrene d/t bacteria; Tissues are soft/liquified and eventually dissolve, leaving a cystic space

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Caseous Necrosis

combo of coagulative and liquifactive necrosis; "Dry cream cheese;" necrosis d/t cytokines/phagocytes/cytotoxic Tcells; repair is inhibited d/t inhibition of angiogenesis; d/t TB (other mycobacterial infx) or fungal infx

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Gangrenous Necrosis - can only be detected at gross level

limbs/bowels; "wet" gangrene - ischemic injury/invasion by anaerobic bacteria (mostly liquefactive necrosis); "Dry" gangrene - mostly coagulative necrosis; inflam cell infiltrates that block bacteria (dessication/mumification);

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The Viscious Cycle Effect

when systems are interdependent, pathological processes often generate other injurious causes; ie: Pneumonia - lungs invade by bug reduces O2 in blood = tissue hypoxia, tubular necrosis in kidney = oliguria = renal failure = fluid retention = pulm edema

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Viscious Cycle of Myocardial Infarction

thrombosis in vessel of heart = immediate ischemia/hypoxia of that area of perfusion = dec cardiac output d/t left ventricular wall dysfxn = reduced CO = reduced circulation to coronary aa = exacerbation of ischemia to myocardium

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Myocardial ischemia

pale to naked eye; dec ATP d/t anaerobic glycolysis; drop in intracellular ATP/creatinine-P; cardiac cells hydropically change; ejection fraction dec; electric instability (dysrrhythmias); contraction band necrosis; Serum inc LDH, CK-MB, and troponins

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Acute Respiratory Distress Syndrome

d/t systemic hypotension/hypoxia, inflammatory response (accum of neutrophils in lung), or free radical endothelial damage; Loss of endothelial integrity = edema and serum ptn in alveolar space; Damage initiates diffuse inflamm response and more damage

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Fatty Change in Liver

non-specific general indicator of liver cell injury and dysfxn (alcoholic liver dx, DM, viral hepatitis); damaged hepatocytes can't make lipoproteins and lipids accumulate in cytoplasm = steatosis lipid droplets; liver turns yellow color

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Apoptosis

no inflammation!! internal contents of cell does not leak out

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Biological Functions of Apoptosis

1. embryogenesis; 2. eliminate cells w/irreparable DNA damage; 3. removal of cells after dec trophic (ie: prostate after castration); 4. Selective destruction of "self-reactive" lymphocytes; 6. cytotoxic Tcell-induced (viral/neoplastic cells)

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Neoplasia

defect in normal fxn of apoptosis allows damaged cells to live; unregulated growth forms tumors;

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Apoptosis ptns involved in tumorgenesis

bcl-2, p53

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Autoimmune disease

lymphocytes synthesizing antibodies against "self-antigens" are NOT being promptly eliminated d/t defect in apoptosis

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Neurodegenerative Diseases

apoptosis is accelerated leading to premature neuronal death

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Functional Deficits of Ageing

1. reduced mitochondrial fxn and oxphos; 2. reduction in ptn synthesis (dec enzyme levels and receptors); 3. reduced nutrient uptake; 4. reduced ability to break down/recycle ptns leading to accumulation of indigestible ptn fragments (lipofuscin)

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Disease of Premature Ageing - Werner Syndrome

aka: Adult Progeria; auto recessive; defect in DNA helicase; cannot repair damaged DNA; most common type; scleroderma-like disease; short, normal development until teens; death by 40s; inc malignancy

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Disease of Premature Ageing - Cockayne Syndrome

aka: Pediatric Progeria; onset as young child of generalized premature ageing; defect in any of several DNA repair genes, including DNA helicase

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Neoplasm

new growth; can be benign OR malignant (these can metastasize); uncontrolled proliferation; ignores negative growth regulation; induces angiogenesis; evades apoptosis

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Dysplasia

abnormal growth and maturation not to extent of malignancy; reversible; developmenta (dysplastic kindneys); cervical dysplasia (disorderly growth, but no obvious malignancy)

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Differentiation

the extent of parenchyma which resembles normal mature cells regarding morphology and function; well differentiated = very similar to normal tissue; moderately differentiated; Poorly Differentiated/anaplastic = unidentifiable cells/tissue

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Metaplasia

a change in cell type usually d/t a stimulus (like smoking); often epithelial cells; may be reversible once stimulus stops; not all are neoplastic since they are replacing normal cells (ex: GERD)

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Hamartoma

small bit of tissue in an organ that normally has that tissue (ex: nevus or foci of cartilage/mature bronchial epithelium in lung); angioma

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Choristoma

ectopic; normal cells in abnormal locations

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Epithelial cells

1. Membranes; ext surface and lining of internal surface; sits on basement membrane separated from CT; 2. Glands - down growth and ingrowth to underlying CT

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Mesenchymal cells

everything besides membranes and glands; CT (fibroblasts, adipoytes, osteocytes, etc)

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Benign Epithelial Neoplasms - Adenoma

forms glands or is formed from a gland

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Benign Epidermal Neoplasms - Papilloma

fingerlike projections from the surface

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Benign Epidermal Neoplasms - Polyp

projection of mucosal surface; "sessile" - broad base of attachment or "pedunculated" stalk of attachment

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Benign Mesenchymal Neoplasms

depends on cell of reference: fibroma; lipoma; leiomyoma (smooth muscle); rhabdomyoma (striated muscle; most common in peds)

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Carcinoma

MALIGNANT tumor of epithelial origin

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Sarcoma

MALIGNANT tumor of connective tissue/mesenchymal origin

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Benign: ademoma, papillary cystadenoma, fibroma, lipoma, leiomyoma, rhabdomyoma

Malignant: adenocarcinoma, papillary cystadenocarcinoma, fibrosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma

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Malignant tumors

clumped chromatin, poorly differentiated, invasive, not encapsulated, destroys tissue, invades vessels, metastasizes, significant effects on host, necrosis/hemorrhage, paraneoplastic syndromes

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Teratomas

formed from all 3 germ layers; may be benign or malignant; teeth, hair, etc

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Tumors of blood cells and lymphatics

ALL are MALIGNANT; lymphoma, leukemias, multiple myeloma, hodgkin's disease

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Tumors of neural and glial cells

neuroblastoma, gliomas, meningiomas (cause probs d/t intracranial pressure)

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Germ cell tumors

seminoma (malignant testicular cancer), teratoma (benign in F, malignant in M), teratocarcinoma, choriocarcinoma

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Hodgkin's Disease

malignant lymphoma

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Ewing Sarcoma

malignant bone tumor in kids

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Wilms Tumor

malignant kidney tumor in kids (nephrobalstoma)

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Kaposi Sarcoma

blood vessel tumor of skin and internal organs

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Burkitt Lymphoma

malignant lymphoma

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"-oma" exceptions...actually malignant tumors

seminoma, glioma, lymphoma, hepatoma, melanoma, insulinoma, gastrinoma, somatostatinoma, glucanoma

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Metastasis via blood vessels

sarcomas (mesenchymal, CT); except synovial sarcoma

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Metastasis via lymphatics

carcinomas (epithelial); except RCC and HCC

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Why does metastasis occur?

neoangiogenesis, dec cell adhesion, inc migration, lytic enzymes, local invasion, penetration of blood vessels

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Preferred sites of metastasis

breast to bone, prostate to bone, bone to lung; lymph nodes, liver, lung, brian, adrenal, bone

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rare sites of metastasis

spleen, kidney, heart, muscle

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Cancer epidemiology

#1/#2: prostate/breast and lung/bronchus...reverse order for cancer death

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Genetic predisposition

1. Autosomal dominant point mutation and 2nd hit ; 2. defective DNA repair; auto recessive; 3. familial cancers - no clearly defined pattern

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Non-hereditary predisposing conditions for cancer

regenerative, hyperplastic, dysplastic proliferations (ex: endometrial hyperplasia, cervical dysplasia, bronchial metaplasia/dysplasia in smokers, cirrhotic livers)

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Chronic inflammation

known association with occurance of canceer (ex: ulcerative colitis, Crohn's disease, H.pylori gastritis, viral hep, chronic pancreasitis)

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Pre-cancerous conditions

chronic atrophic gastritis of pernicious anemia, solar keratosis, leukoplakia, villous adenoma

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Principles of Carcinogenesis

Monoclonal: clonal expansion from single precursor cell; tumor progression w/excessive growth, invasion, metastasis

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Targets for Damage

Genes for: growth factors, apoptosis regulation, tumor suppression, DNA repair enzymes

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Protooncogenes

non-mutated form; the protein product of these are important for cellular growth and proliferation

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Oncogenes

mutated genes that are responsible for the development of cancer

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How protos become oncos

point mutation, gene amplification, chromosomal rearrangement, insertional mutagenesis

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Growth Factor - SIS

encodes for PDGF; viral oncogene v-cis overproduces a PDGF-like molecule that binds to receptors to stimulate cell cycle

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Growth Factor - RET

medullary thyroid carcinoma, adrenal and parathyroid tumors

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Signal Transducing Protein - RAS family

encodes GTP binding proteins; v-ras binds and doesn't let go; causes uncontrolled proliferation

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Translocations - Philadelphia Chromosome

chromosome 22; chronic milogenous leukemia

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Tumor Suppressor Genes

RB - 2-hit theory (genetic and sporadic); p53 - 50% of human tumors contain p53 mutations

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Li-Fraumeni syndrome

inheritance of one mutated p53 allele; 25x greater chance of developing cancer by age 50 than general population

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Tumor adverse effects

based on location due to obstruction and mass effect; cachexia, hormone production, bleeding, secondary infections

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Paraneoplastic Syndromes

grp of symptoms in cancer pts that cannot be explained by local spread of tumor OR elaboration of hormones d/t tissue from which tumor arose; present in 10% of cancer pts

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Cushings

inc ACTH, 50% have small cell carcinoma of lung

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Hypercalcemia

Most common paraneoplastic syndrome!! synth of PTHrP; squamous cell carcinoma of lung

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Acanthosis Nigrans

verrucous hyperkeratosis of skin; often preceeds discovery of cancer

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Hypertrophic osteoarthropathy

seen in up to 10% of lung cancers; new bone on distal ends; arthritis; clubbing of fingers

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Lab diagnosis

morphologic, biochemical, immunohistochemistry, molecular, flow cytometry

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Grading and Staging

Staging is more clinically appicable - size of primary lesion; extent of spread to lymph nodes, and presence of metastasis (T, N, M)

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