Chp 1 Cell Pathology -1 antitrypsin gene deficiency (AAT gene) rare vs.

Hereditary hemochromatosis

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only 20% with PiZZ genotype get liver disease (only phenotype that can) all other phenotypes can get emphysema, not associated with any liver disease Diagnosis: -1 band on protein electrophoresis Liver Biopsy: PASD(+) accumulations of partially folded molecules in the endoplasmic reticulum that cant get secreted

vs. particular CFTR mutations impaired dissociation from chaperones can cause some cases of CF Telomerase Activity telomeres set the limit to how many times a given cell lineage can divide. With telomerase you get add on to the limit.

germ cells have highest activity allow them to retain ability to divide throughout life somatic cells have no telomerase. Telomeres progressively shorten like in these cells: o Permanent (G0 dont divide) Neurons, skeletal+cardiac muscle, RBC o Stable (can go G0G1): hepatocytes, lymphocytes o Labile (never in G0): marrow, gut epithelium, skin, hair p53 tumor suppressor involved in cell cycle regulation (prevent G1 S) + DNA repair vs. apoptosis initiation DNA damage p53 to upregulate p21 (cdk inhibitor) and GADD45 (DNA repair) + BAX (apoptotic by competing with bcl-2) o bcl-2 and NF- - anti-apoptotic proteins o Bax/Bak proapoptotic mutation in p53 no cell cycle arrest, repair, or apoptosis cancerous cell Li-Fraumeni germline mutation in p53 + of all cancers esp breast, bone, etc. Reversible Injury: cell swelling + organelle swelling (mitochondria + ER) due to failed ion pumps ATP Plasma membrane alterations blebbing, blunting, loss of microvilli

Polyribosome detachment from ER Fatty changes (heart get tigered effect with mild hypoxia) nuclear changes chromatin clumping Irreversible: Necrosis* Nuclear Changes: pyknosis karyorrhexic karolysis breaking of plasma + organelle membranes (lysosomes + mitochondria) o Mitochondria release cytochrome c (activates capases) + Ca2+ (activates ATPases, phospholipases, proteases, etc) intracytoplasmic myelin figures (whorled phospholipids from damaged membranes)

 eosinophilia denatured proteins + loss of RNA *Dystrophic Calcification basophilic Ca deposits indicating previous necrosis vs. Metastatic Calcification deposits in normal tissue due to hypercalcemia Cellular Growth agenesis no development since dont have embryonal structures (always inherited) Aplasia lack of any embryonic development although have the needed structures hypoplasia poor or subnormal development Dysplasia abnormal growth of the organ/tissue Atrophy reduction in size after it was already full size Uterus Growth During pregnanc 1 mediated by in myometrial smooth muscle hyptertrophy endometrium also increases in size but is only a lining and doesnt contribute much to the change in size Apoptosis Histology single cell is shrunken + converted to dense eosinophillic mass surrounding cells are normal + no inflammation common in GvHD Autophagy + Single Cell Necrosis Autophagy lysosomal degradation of cellular components due to aging, malnutrition, chronic disease (cellular downsizing) lipofuscin granules are residual bodies left over lipid oxidation Can progress to single cell necrosis (vs. apoptosis you actually get cell fragmentation) o Councilman Bodies single cell necrosis (red glassy appearance w/o nuclei) in liver biopsy o commonly seen in acute hepatitis

cancer cells that PTEN can autophagy Brown Atrophy* marked deposition of lipofuscin in myocardium of a small heart turns firm + chocolate brown throughout

has no effect on cellular function and heart shows no evidence of athresclerosis commonly seen in aging Antracotic pigment common in lung and hilar LN when carbon pigment inhaled major source is tar in smoke Fenton Reaction production of free radicals (OH) when free Fe reacts with H2O2 excessive iron ingestion can overwhelm transferrin ability to bind up free Fe excess can produce free radicals and cause oxidative damage* Vitamin C and E important antioxidants that protect against this damage

Hemosiderin storage for of iron excess but doesnt cause cell injury acutely more likely with huge amount in hemochromatosis. Acute Fe ingestion more likely to get damage from Free radicals histone deacetylases remove acetyl groups from histones (making more positive so bind tighter to DNA - transcription) vs. Histone acetyltransferases (transcription) Sirtuins are HDACs that promote transcription of proteins the metabolic activity + free radicals commonly red wines shown to sirtuins only way to live longer is through carlorie restriction. Red wine not the answer but can help through its 2 activities by sirtuins

Sirtuins:

Chapter 2 Acute and Chronic Inflammation Macrophages in Healing of Ischemic Tissue not only involved in phagocytosis/cleanup

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also secrete cytokines that promote angiogenesis + fibrosis PDGF, IL-1, TNF- Usually stick around for a while vs PMN that disappear by end of 1st week Serous Inflammation mildest form of acute inflammation. blisters (w/ burns) serous inflammation mostly low protein fluid exudate in subcorneal or subepidermal space protein in the fluid causes fibrin accumulation Leukocyte Rolling and Firm Adhesions Rolling mediated by interaction between selectins (P and E selectins located on endothelial cells) and sialytated Lewis X molecules on PMN o Also have L-selectin on PMN (reversed) that bind GlyCam-1 on endothelium

Firm Adhesion: integrins (LFA-1 + VLA-4) on PMN interacting with ICAM-1 + VCAM-1 on endothelium respectively CGD 2/3 are X-linked and 1/3 are AR infection with catalase (+) bugs (host can still use H2O2 produced from catalase (-) bacteria to kill them)

Ex: S. aureus, enteric GNR, Pseudomonas, Nocardia, Aspergillus onset is early infancy Liquefactive Necrosis: most commonly seen with hypoxia in CNS (unknown MOA) but also can be seen in abscesses elsewhere in the body from bacterial or fungal infections digestion of the dead cells by proteases and lysosomal enzymes released by PMNs aided by release of ROS produces pus (vs. preservation in coagulative necrosis)

similarly purulent exudate empyema Types of Giant Cells: Langerhans Giant cell (horseshoe /periphery arrangement of nuclei) what we see in M. tb granulomas

Foreign Body Giant Cell (nuclei arranged all over) Macrophage Antimicrobial Activity produce NO (that can act as ROS) via iNOS that by itself and reaction with other ROS produce potent antimicrobial activity

endothelium contain eNOS which promotes vasodilation Acute Inflammation + Acute Phase Proteins Acute-phase reactants include C-reactive protein (upregulated by IL-6) and fibrinogen and serum Amyloid A (upregulated by IL-1 and TNF-) proteins rouleaux formation and increase ESR nonspecific indicator of inflammation

Chapter 3: Tissue Renewal and Repair 5/22/2012 7:59:00 AM TGF- fibrogenesis - fibroblast chemotaxis + collagen production Hepatocyte Regeneration viability of the CT framework determines where get complete regeneration vs. scarring

Viral hepatitis vs. liver abcess Glucocorticoids inhibit collagen synthesis - wound healing can use steroids to prevent Keloid formation Re-epithelilization driven by EGF Wound Healing: Day 1: wound filled w/ inflammatory cells + fibrin 2-3: macrophages + granulation tissue 4-5: neovasculariation 14: collagen + inflammation + vessels 30: collagen becoming denser Wound Strength Timeline: Day 7: 5-10% tensile strength, low collagen % Day 70: 30% strength, 100% collagen (Type III>Type I) Day 100: 80% strength, 100% collagen (Type III<Type I) Wound Contraction occurs in healing by 2 intention for larger wounds myofibroblasts contract size of the original wound be a huge % CDK1 + Cyclin B control transition from G2 to M phase o Cyclin transcriptional regulated and proteosome degraded o CDK constitutively expressed o light switches in multiple dark hallways that allow to pass step G1 cdk4/6 and cyclin D Restriction Point cdk2- cyclin E

S cdk2 cyclin A G2 cdk1 and cyclin A and B Basic FGF potent inducer of angiogenesis Stem cells: Embryonic Stem Cells: used for gene targeting/knockouts and then implanted into uterus of surrogate mother. Pleuripotent Stem Cells: dont need embryonic stem cells to get all cell lines. Take 1 cel (fibroblast) and induce it to make all the different cell lines (go backwards)

Chapter 4: Hemodynamic Disorders Response to a small cut that bleeds vasoconstriction takes second platelet aggregation mins Thrombotic Masses

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Vegetation is it occur on a heart valve Mural thrombi if it occurs on surface of the heart or large arteries (usually LA) o can occur in the abdominal aorta too o complication: embolization carried to distal arteries. Wont travel to lung since in the arterial circulation Fat Embolism fractures onset of symptoms occurs 1-3 days after initial injury (up to 1 week after for cerebral symptoms to manifest) Anti-phospholipid Antibody Syndrome: signs: recurrent arterial < venous thrombosis, thrombocytopenia, miscarriages** o Minor: ulcers and cutaneous necrosis present in 40% of lupus patients lupus anticoagulant only in vitro. In vivo its a procoagulant via endothelial injury after binding phospholipid-protein complexes

However not always in SLE patients. vWF Disease: AD inheritance with incomplete penetrance deficiency of vWF defective platelet adhesion Signs: o Mucosal bleeding gingival, nose, GI + petechiae/purpura o frequent nosebleeds + heavy menstruation in young woman since childhood classic signs o *look for Fe deficient anemia as sign of chronic blood loss* Platelet Granules: - fibrinogen, fibronectin, V and VIII, Platelet factor 4, PDGF - ADP, ATP, ionized Ca, histamine, serotonin, Epi Organizing Thrombus small recanalized channels in an other occluded small artery not sufficient enough to produce an infarction (no in enzymes) but can have angina like symptoms if in heart Amniotic Fluid Embolism rarely occurs in vaginal delivery fluid reaches torn uterine veins through ruptured fetal membranes go up to lungs Histo: keratin squames and lanugo hairs (swirls) Complication: DIC

Coagulation Factors synthesized in the liver any liver conditions can production leading to coagulation issues can be corrected if added to normal plasma

Chapter 5 Genetic Disorders Klinefelters: XXY 1:850 common cause of hypogonadism + infertility

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long extremities, bilateral gyncomastia, hypogonadism testosterone = estrogen = FSH/LH Both Seminiferous Tubules + Leydig cells fucked oligospermia males with presence of 1 Barr Body Turners: XO short stature, bicuspid aortic valve, preductal coarctation, streak ovaries (small, elongated, tubular ovaries) webbed neck, broad chest w/ widely spaced nipples most common cause of 1 amenorrhea

estrogen - LH and FSH individuals that reach adulthood may have a mosaic cell line* (45, X/46XX) Mucopolysaccharidoses Hurlers (AR) deficiency of iduronidase o coarse facial features, corneal clouding, hearing loss, joint stiffness, hepatosplenomegaly, MR, subendothelial deposits causing CAD o vacuoles in lysosomes in peripheral leukocytes + macrophages o accumulation of dermatan sulfate + heparan sulfate

Hunters (X-linked) deficiency of iduronate sulftase o milder disease + no corneal clouding o accumulation of same stuff McArdles Syndrome deficiency of muscle glycogen phosphorylase Cramping + fatigue but no lactic acidosis in blood Myoglobin in urine in 50% of cases* - brown color hours after severe exercise Accumulate glycogen in muscle but cant use it Lysosomal glucosidase = acid maltase Gauchers Disease: deficiency in -gluco-cerebrosidase. Glucocerebroside Most common one. Hepatosplenomegaly osteoporesis/aseptic necrosis of femor + bone pain, pancytopenia (recurrent otitis media) o Gaucher Cells dominating marrow forcing everyone out

Gaucher Cells wrinkled paper macrophages in marrow, liver, spleen* Only sphinolipidoses compatible with life. CNS involvement seen in only Type II and III (1% of Gauchers) Niemann Pick deficiency in Sphingomyelinase

Hepatosplenomegaly, neurodegeneration, cherry red spot, foamy macrophages in bone marrow biopsy

vs. Tay Sachs that doesnt have hepatosplenomegaly vs. Gauchers that doesnt have neurodegeneration (99% of time) Tay-Sachs: hexosamindiase A GM2 ganglioside 4 bp insertion that leads to altered reading frame + appearance of stop codon that leads to premature nonfunctional enzyme Neurodegeneration, MW, seizures, cherry red spot + blindness. *No hepatosplenomgaly vs Niemann-Pick Trisomy 21 mosaicism chance that child wont be severly affect likely to survive beyond term and way beyond Edwards Syndrome Trisomy 18 rocker-bottom feet, small face + mouth (micrognathia), low-set ears, Congential HD, clenched hand Pataus Syndrome Trisomy 13 Cleft lip/palate, holoprosencephaly, polydactyly, MR, rocker bottom feet, microcephaly, microphthalmia Hemophilia A usually X-linked recessive mostly seen in boys If present in girls it is likely due to random X inactivation in a carrier o some individuals are out on the tail of Poisson distribution for random events and leads to only few normal alleles o therefore get markedly dimished levels # of trinucleotide repeats only during oogenesis in females o only females can expand the trinucleotide repeats to develop full mutations from premutations o males unable to expand the repeats but can express full mutations. Sperm are unable to pass on full mutations though only pass premutations to sons and daughters to detect in fetus can do PCR analysis on DNA from amniotic fluid or need to do Southern Blot (if the full mutation is too large to be detected by PCR) o Therefore PCR the mom still is dumb because wont detect full mutation o Tests on the dad is dumb because can only pass on premutation

Fragile X:

Signs: size of testes, jaw, ears + autism, MVP Androgen Insensitivity Syndrome / Testicular Feminization syndrome X-linked inheritance defective androgen receptor so doesnt respond to DHT but does respond to estradiol testes are usually present but undescended

Chapter 6 Diseases of Immunity SLE Pathogenesis:

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defective clearance of nuclear apoptotic bodies + loss of self tolerance leads to antiDNA immune complex generation

False (+) syphilis test indicates that have anticardiolipin ab HIV Entry CD4 + chemokine receptor (CXCR4 or CCR5) NOT TCR* Sjogrens SS-A and SS-B (Ro and La) auto ab - to ribonucleoproteins Signs: bilateral corneal scarring, blurred vision, perforated nasal septum, , fissuring of tongue and corners of mouth all due to secretions

Triad: Xerophthalmia, Xerostomia, Arthritis (associated w/ RA) 25% of cases get extraglandular involvement kidney, lung, skin, muscle, etc *risk of B cell lymphoma Tissue Parasites Response ie. Trichinella Spiralis ab mediated phagocytosis is involved too IgE response, eosinophils, PMN also contribute Selective IgA Syndrome mild recurrent URT infection + mild diarrhea throughout life *transfusion rxns can occur due to presence of anti-IgA ab in patients serum Type I Hypersensitivity Early-phase: mediated by degranulation of mast cells Late-phase: o inflammatory infiltrate (PMN, eo, basophils, monocytes, CD4+) o more tissue destruction + more severe o doesnt require reexposure to antigen to occur* Cells that can become infected with HIV CD4+ cells Macrophages and do not get destroyed like CD4+ cells o Macrophages can carry HIV to the brain* - dementia + encephalitis Dendritic cells: (also do not get destroyed o Mucosa: Langerhans cells via Fc receptors capture ab coated HIV virions and transport it to CD4+ cells in the LN how can transmit HIV through sex o Those in the follicles are called follicular dendritic cells and can infect CD4+ cells passing by.

AIDS: development of AIDS takes 8-10 years from contraction of HIV virus NHL and Kaposi sarcoma are the most common neoplasms seen with AIDS Chronic Inflammation + Serum amyloid associated precursor protein

Serum amyloid associated precursor protein (SAA) is an acute phase protein that form major amyloid fibril protein AA

gets deposits all over Brutons Agammaglobinemia X-linked - Defect in BTK tyr kinase block B cell maturation bacterial infections after 6 months (maternal IgG) normal Pro-B and Pre B cells but in mature forms (no CD19(+) cells). o B cell maturation stops after rearrangement of the Heavy chain, and the light chain is subsequently not produced. There are no complete Ig molecules produced as a result.

T cell arm remain intact no viral, fungal, or protozoal infection Treatment: IV IgG and prophylatic antibiotics SCID Types: (Deficient T and B cell immunity) Cytokine receptor mutation (most common X-linked): mutation in chain of many cytokine receptors including IL-2, IL-4, IL-7, and IL-15 all needed for B and T cell development

Adenosine deaminase deficiency (usually AR) Diffuse Scleroderma Clinically: GI malabsorption + villi (90%), hyperplastic arteriosclerosis in kidney causing malignant HTN (66%), difficulty swallowing, synovitis, pulmonary interstitial fibrosis, pericarditis + pericardial effusion, myocarditis, etc.

*unlikely to get perforation or ulceration of GI tract since in fibrosis is pathology can also present with CREST signs too Pathogenesis: CD4+ lymphocytes respond to unknown ag stimulation causing cytokine release activating macrophages + mast cells. PMN have no role GvHD in Skin following SC transplant scaling skin rash: keraitnocyte apoptosis along D-E junction with upper dermal lymphocyte infiltrates

also commonly involves liver + GI epithelium SLE Skin Histology vacuolar degneration of the basal layer of epidermis dermis variable edema and perivascular inflammation IF: Ig and complement deposition at the D-E junction Juvenile RA/ Idiopathetic Arthritis 90% resolve without any joint deformity in there teens + never reoccurs +/- ANA (+) but usually RF (-) tends to involve lower and larger joints that show ROM, swelling, warmth can also have fever Wiskott-Aldrich thrombocytopenia, eczema, IgM, recurrent SP infections

 risk of NHL like with other immunodeficiencies including HIV Amylodosis Type 1 2 Senile Cardiac Type II DM Medullary Thyroid Alzheimers Dialysis associated IL-17 in DTH IL-17 produced by CD4+ cells in DTH rxns and recruits PMN and monocytes to the site causing itching and pain. Protein Amyloid light chain Serum Amyloid associated protein (SAA) Transthyretin Amylin A-Cal -amyloid 2 microglobulin Derived From Ig light chain Acute Phase reactant chronic inflammation Serum T4 and retinol transporter Endocrine Calcitonin Amyloid precursor protein (APP) MHC I proteins

Chapter 7 Neoplasia Hepatocellular Carcinoma from Hep B or C infections

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MOA?: persistent hepatocyte regeneration inadvertently leading to mutations - #1 mechanism for both Hep B and C Other mechanisms: o viral DNA insertion activating host oncogene randomly (no specific site)

o HBx gene (regulatory element encoded by virus) that transcription and growth of host cell Metastasis Localization influenced by the expression of chemokine receptors by metastatic cancer cells and expression of chemokines (lignands) by certain tissues (hone in on target) Ex: breast cancer (with CXCR4 receptor) metastasizing to bilateral lungs

invasion does not dictate where exactly the location of metastasis will be Metastatic Potential: Laminin Receptors in tumor cells: # of laminin receptors than normal cells allow them to attach more readily to basement membranes at distant sites/ metastasize

correlates with the metastatic potential of the malignant neoplasm Invasive Potential: elaboration of enzymes used in ECM degradation metalloproteinases cathepsin D (cysteine proteinase) cleaves fibronectin + laminin HPV Oncogenesis E1 + E2 key for lytic cycle in permissive cells (normally infection) *Oncogenesis: (Subtypes 16 and 18) o integration into the host genome and inactive E1+E2 o E6 + E7 (viral oncogenes) inactivate tumor suppressor genes like p53 and pRb respectively o AIDS, leukemia, immunosuppressed, - risk of oncogenesis Familial Malignant Melanoma: p16 /INK4a mutations (tumor suppressor): product of gene normally inhibit CDKs and regulate cell cyle Neurofibromatosis Type I NF-1 gene (tumor suppressor) encodes a GAP (GTPase activating protein) that normally takes off GTP from Ras

loss of NF-1 leads to always on Ras gene HTLV-1 Disease Manifestations (95% of infected are asymptomatic) Adult T cell Leukemia (ATL) o leukemic T cells (flower cells), immunodeficiency, skin lesions, abnormal LN, hypercalciemia HAM/TSP HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis o demyelinating disease MW, incontinence, spastic paralysis

ERBB2 (HER2) amplificiation seen in 1/3 breast cancers that gradually become more aggressive doesnt indicate any familial mutations or anything *Monoclonality is the hallmark of all malignancies Successful Cancer Screening Test: identifies dysplasia b4 cancer becomes invasive so that can treat early and # of deaths Gastric Cancers Epidemiology occurrence has in developed nations recently Reason: dietary carcinogens + HP eradication? Unknown why Hemangioma: vHL gene small, nontender, raised, smooth mass been there for long time and hasnt changed size red color suggest vascularity* Strawberry Hemangioma in kids grows with age and then spoteneously regresses Cherry Hemangioma in elderly but doesnt regress. Chance with age tumor suppressor that encodes a protein that bind/clear constitutively expressed HIF-1 b4 it goes to nucleus

mutaitons leads to loss of degradation of HIF-1 VEGF + angiogenesis vHL syndrome: hemagioblastomas, renal cell carcinomas, pheos FAP APC gene mutation also APC gene mutations are the earliest mutations seen in the accumulations of mutations in colonic adeno

APC mutations prevents destruction of -catenin that translocates to the nucleus and coactivates transcription of several gene (Functional Activation of the WNT signaling pathway) o Other Wnt-7 produced at apical ectodermal ridge at distal end of limb. Patterns Dorsal-ventral axis TNM system staging TGF-: Tumor Size, LN number, distant mets M1 indicates have distant mets normally inhibits proliferation via activation of growth-inhibiting genes such as CDKIs

all pancreatic cancers and 85% of colon cancers have 1 mutation in TGF- pathway known to act via SMAD4 transcription factor Gene amplification associated with double minutes and homogenously staining regions

double minutes: extrachromosomal DNA in nucleus often seen in tumors carrying oncogenes + drug resistance genes Gene amplification associated with oncogenes activations: o N-myc gene amplification in 40% of neuroblastomas

Chapter 8: Infectious Disease Syphilisis Chancre: lymphocytes + plasma cells infiltrates* - No granulomas

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obliterative endarteritis too which is present in all 3 stages of syphilis treponemes can be visible on the surface of the chancre with the right stain vs. Gummatous inflammation: o necrotic centers with a margin of palisading macrophages + fibroblasts and all surrounded by plasma cells o treponenmes are scarce in gumma Rhinovirus: Babesia most common cause of colds in adults binds to intracellular adhesion molecule-1 (ICAM-1) to gain entry to host cell non-env ss(+) RNA virus of picornavirus family but acid labile

fever + hemolytic anemia predominate in Northeast US Transmission: Ixodes tick (same as Lyme often coinfect) Diagnosis: maltese crosses and ring forms seen in RBC Chlamydia Trichomonas L1-L3 lymphogranuloma venereum 1 = Small painless ulcer that heals 2 = painful lymphadenopathy (groove sign), anorectal syndrome (rectal ulcers), local inflammation due to direct spread o LN biopsy: mixed granulomatous + neutrophillic inflammation = multiple abscess with central necrosis surrounded by palisading histocytes

late = fibrosis + strictures in anogenital tract vs. Granuloma Inguinale (Donovanosis) Klebsiella granulomatis large, painless ulcer with irregular borders and red base pseudobubos abscesses in groin but not true adenopathy Entamoeba histolytica common cause of dysentery in developing countries Extensive mucosal erythema (entire colon) + flask shaped ulcers dysentery, flatulence, cramps trophozoites can be seen engulfing bacteria + RBC (amoeba is so big) and secreting hydrolytic enzymes

+/- hepatic abscess = can invade submucosa and enter venules of portal system o usually colonic lesions long gone by the time hepatic lesions shows up o hepatic abscess can extend to pneumonia, peritonitis, chronic pericarditis, etc Rickettsial diseases small rods do not gram stain (have PG cell wall w/ LPS + outer membrane though) vector-borne vector varies

obligate intracellular parasites Virulence: vasculitis multiply in endothelial cells* + CPE and lysis thrombosis of effective vessels produces the foci of skin necrosis (hemorrhagic rashes) RMSF: (R. rickettsi) o fever, headache, fatigue, chills o rash 2-4 days after = limbs to trunk, include palms+soles, evolves from macular to petechial (vs. epidemic typhus R. prowasekii) o Complications: DIC, encephalitis, thrombocytopenia, renal/cardiac failure (blood volume)

Actinomyces: chronic suppurative disease of CT granulomas +/-abscess 4 Clinical Forms of Actinomycosis: o cervicofacial (most common) usually following dental disease of surgery o abdominal rupture of appendix or cecum o thoracic aspiration or from cervicofacial extension chronic abscessing pneumonia o pelvic associated w/ IUD or PID Cerebral Malaria (usually P. falciparum) esp kids 3-5 yo* headache, impaired consciousness, somnolence, cerebral dysfunction death Infected RBC sequesteration + rossetes o involved specific receptor-lignand interactions o production of knob-like structures (including PfEMP-1 protein) on infected RBC that allow to bind endothelium, placenta, other uninfected RBC o also involved in Rosette Formation (around uninfected RBC) Ischemia/hypoxia, inflammation, and cerebral edema results* Histo: cerebral vein occluded with RBCs Schistosoma haematobium Tetanus severe granulomatous inflammation, fibrosis, calcification of bladder wall (shurken bladder) chronic infection SCC of the bladder + painless hematuria toxin that release of GABA + Gly MOA: tetanus toxin is a protease that cleaves synaptobrevin, a major transmembrane protein of synaptic vesicles of inhibitory neurons (GABA + Gly) o similarly C. botulinum toxin cleaves synaptobrevin in ACh terminals

(release of ACh) Histoplasmosis Capsulatum sputum or biopsy stains - yeasts within macrophage (stacked up) look bubbly Produced granulomatous inflammation (mononuclear cells + macrophages) in sharply demarcated, rounded coin lesion seen on CXR

Poliovirus enterovirus: naked, ss (+) RNA that acid stable transmission: fecal-oral virus 1st infects the oropharynx and URT (mild pharygitis). From there it goes to GI +/- aseptic meningitis or paralytic polio Trypanosoma Cruzi Acute (usually occur in kids): fever, myalgia, fatigue, liver, spleen, LN o Chagoma red + indurate nodule o Romanas Sign unilateral chagoma or the eye (swelling) Chronic: (mostly autoimmune mediated) o hepatosplenomegaly o megacolon + megaesophagus o myocarditis (Rare) + dilated cardiomyopathy heart failure + death* o CNS: granulomas, cysts, menigoencephalitis Rotavirus: MOA: villous destruction with atrophy cause absorption of Na and H2O major cause of diarrhea in infancy Older kids develop sIgA so much more resistant to infection Nocardia Asteroids: soil - inhalation or direct inoculation of skin no person to person* Pathogensis/Clinical o opportunistic pathogen immunocompromised o start as pneumoniae spread to brain, kidney, skin

cross between pyogenic infection (PMNs) and granuloma. NOT true granuloma facultative intracellular pathogen Shigella Histology: mononuclear infiltrate extending to the lamina propria + neutrophillic exudate overlying the ulcerated areas* Schistosoma mansoni or japonicum married in hepatic venules can incite granulomatous inflammation in liver that undergoes fibrosis compress portal veins and lead to pre-sinusoidal portal HTN Pseudomonas Virulence Factors Exotoxin A inhibits protein synthesis by inhibiting EF Exoenzyme S interferes with host cell growth phospholipase C degrades pulmonary surfactant Fe compounds toxic to endothelial Pseudomonas can lead to extensive vasculitis with necrosis especially in neutropenic patient

Dengue Hemorrhagic Feverflavivirus mediated

**does not cause encephalitis, but is transmitted by arthrpod - mosquito* Clinically: +/- asymptomatic or flu-like + pain/myalgias Dengue Hemorrhagic Shock Syndrome: o complication in person previously infect and gets reinfected* - most commonly in endemic areas o platelets, hematocrit, PT and PTT, cardiovascular shock o petechiae and purpura and hemorrhage in brain o pre-existing cross reactive ab facilitates opsonization/phagocytosis of virus by

macrophages = response causing plasma leakage and hemorrhage Congenital Syphillis: stillbirth, hydrops fetalis lung: pale + poorly aerated with interstitial mononuclear infiltrate hepatosplenomegaly periosteitis + osteochondritis of femur + vertebrae diffuse rash with sloughing of skin on palms and soles Saber shins (bending A-P direction), Saddle nose (Loss of bridge), Hutchinsons teeth (small widely spaced teeth with notch), mulberry molars (black dots on em) CN VIII deafness

Chapter 9: Environmental Pathology Vitamin E deficiency neuro manifestaton similar to B12 deficiency have anemia (hemolytic) but its normocytic mediated by free radical damage Regeneration following Severe Burns

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full thickness burns all structures that could facilitate re-epthieliazation are lost including dermal appendages such as sweat glands and hair follicles

partial thickness burns can usually reepithelize Heat Exhaustion: failure of CV system to compensate for hypovolemia due to water depletion. Common in elderly.

Patient may collapse + feel light headed but usually doesnt loss consciousness. Treat: fluids Heat Stroke: organ damage when body temperatures are greater than 36C Heat cramps: vigorous exercise with electrolyte loss produce muscle cramping Vitamin A Deficiency: dry skin + Follicular hyperkeratosis = goose bumps squamous metaplasia of upper respiratory tract (bronchitis, pneumonia, even cancer) + urinary tract (desquamation debris can be nidus for kidney stone formation) Xerophthalmia (common in 0.5-3 year old children o nyctalopia (night blindness), Bitots spot (keratinized spot on eye that can be rubbed off), Corenal xerosis (drying), ulcers, and Keratomalacia (necrosis and collagenases activation)

retinopathy increased risk of infections = especially measles Cocaine: potent vasoconstrictor ischemic injury, arrhytmias, hypertensive arteriosclerosis Coronary atherosclerosis esp in small branches also marked* Zinc Protoporphyrin in chronic Pb poisoining, anemia of chronic disease, and iron deficiency anemia Zn incorporated into heme instead of Fe* Vitamin C: (ascorbic acid) Functions: o hydroxylation in collagen synthesis o Fe absorption by keeping in Ferrous state (Fe2+) o Antioxidant activity o dopamine hydroxylase (dopamine NE) Deficiency: Scurvy swollen gums, bruising, hemarthrosis + subperiosteal hematoma, anemia, poor wound healing, diffuse hyperkeratotic skin rash

o most common in elderly o need constant supply of Vitamin C in diet Marasmus: body weight is less than 60% of normal with muscle wasting simply cant be explained by single vitamin/mineral deficiency o no muscle wasting in Pb poisoning no hypoalbuminemia + edema like in Kwashiorkors Refeed slowly carbs will deplete Pi too fast and cause heart failure/death o vs. Kwashiorkors aggressive refeeding Summary of Hormones that are Peripheral Signals to Brain Signals Ghrelin CCK GLP-1 Leptin Hunger Satiation Satiation Satiation Time Short-term Short Short Long-term Location made Stomach/small intestine Small intestine Small intestine Adipose tissue

Leptin product of OB gene MC4R mutations found in 5-8% of obsese adults. Abundant fat stores and plenty of leptin but still have energy consumption leading to weight gain Fat Malabsorption: think chronic cholestatic liver disease, biliary tract disease, and pancreatic disease need those bile acids to form micelles Radiation Acute: edema, mucosal erosion, tissue atrophy delayed: fibrosis + cancers esp of thyroid, brain, bone marrow Levels of Dose: o subclinical (<200) N+V and some bone marrow toxicity but recover o hematopoietic (200-600) - bone marrow o GI (600-1000) ischemia + shock death in 14 days o CNS (>1000) coma and death in <36 hours! Pulmonary Edema from fires Cocaine: vasoconstrictive effect Placenta: blood flow causing fetal hypoxia + spontaneous abortion, abruptio placentae, and fetal hemorrhages Cancer + Obesity inhalation of hot, toxic gases from fires in enclosed spaces can lead to death from pulmonary edema even if there is no injury from flames

esp esophagus and kidney in subjects with BMI >25 insulin IGF-1 IGF-1 promotes cell growth and estrogen+ androgen production favors neoplastic transformation in cells

Chapter 10 Diseases of Infancy + Childhood Sudden Infant Death Syndrome

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occurs between 1 month- 1 yo (Age is the most important risk factor)

incidence in males, blacks, low socioeconomic background of parents lack of any anatomic abnormality on autopsy MOA: abnormalities in medullary centers that regulate hypoxia, hypercarbia, and thermal stress can lead to absence of reflexive response that normally maintain homeostasis. o 5-HT is an implicated neurotransmitter in SIDS pathogenesis Premature Membrane rupture infection is the most common cause release of collagenases + elastase the promote membrane rupture AND PGs that induce smooth muscle contraction/labor

antibiotics prolongs latency to delivery. Also prevent with progesterone (maintain pregnancy) Neuroblastomas amplification of n-myc + chromosome 1p deletions = bad prognosis hyperdiploidy, absense of 1p del, and high levels of nerve GF receptor Trk A = good Type II pneumocytes differentiate after 26th week of gestation: starts DPPC after 26th week gradually progression of lung architecture to saccular alveolar configuration

lecithin to sphingomyelin ratio >2.0 means mature fetal lung* - usually achieved by 35 weeks Multifactoral Inheritance cleft lip has a reoccurrence rate of 2-7% there if some risk of reoccurrence. polygenetic + environmental contribution to multifactoral diseases most common cause of congenital malformation in fetuses that make it to live birth. Chromosomal abnormalities most commonly cause early fetal loss Gestational Diabetes or Regular DM in Mother insulin in fetus of diabetic mother will pulmonary surfactant production risk of RDS in neonates

Treatment: corticosteroids will risk = promote lung maturation Bronchopulmonary Dysplasia: complication of therapy for RDS: high dose O2 and CPAP causes injury to immature lungs mostly inflammation + scarring

Histo: bronchial squamous metaplasia, interstitial fibrosis, dilation of airspaces CXR: hyperinflation, atelectasis, cystic changes Classic Galactosemia (AR): galactose-1-P uridyltransferase (Uses UDP to convert to glucose-1-P) also galactitol infantile cataracts

Other Signs: FTT, cirrhosis/hepatomegaly, jaundice, MR* o *susceptibility to E.coli septicemia that can lead to death early* Neonatal Jaundice: Physiologic Jaundice o Green flags if: peaks at 3-5 days and def <day 12, returns to normal by day 14, cord bilirubin is less than 5 mg/dL, and bilirubin is almost all unconjugated o Causes: 1. Breast milk jaundice 95% 2. ABO incompatilibilites 4% o Other risks: race, diabetic mother, Hx in previous pregnancy o Results in complete recovery Erythroblastosis fetalis/ Hemolytic Disease of the Newborn (Rh disease) o anemia causes CHF (usually cause of death) and hydrops (accumulation in >2 fetal compartments pleural, pericardial, perotineal, etc)

o reticulocytes = erythroblastosis o *BRN level total BRN >20 and cord BRN >10 Fetal Alcohol Syndrome: any amount of alcohol is potentially bad Signs: microcephaly, frontal bossing, jaw hypoplasia, narrow palpebral fissures, saddle nose, thin long philtrum, thin vermilion of upper lip Eyes: Microphthalmia, corneal clouding, etc heart: VSD,etc scoliosis

fatty change and LFT Acute Inflammation of Placenta During Pregnancy Listeria acute choorioamnionitis most commonly due to ascending infection leads to stillbirths Group B Strep since most moms vagina colonized is common agent miscarriage is the most common result if congenital infection o mom may only experience a mild diarrheal illness o mini-epidemics in a community can be linked to a contaminated food Other Neonatal Infections o Early Onset disease in neonate (in utero): granulomatosis infantiseptica o Late onset in neonate (infected After 2 weeks) meningitis, septicemia, pneumonia meningitis treat with ampicillin

facultative intracellular gram (+) non-spore forming rod like cold temps grows at 4C refrigeration growth in these food sources Diagnosis: culture: beta hemolytic, catalase (+), **tumbling end-over-end motility Parvo B19 non-env ssDNA

Complication: fetal loss in infected sero (-) woman (its one of the other infections in TORCHS)

causes profound fetal anemia w/ cardiac failure + hydrops fetalis Histo: erythroid precursors with large, pink, intranuclear inclusions Fetal Losses: Early Pregnancy Spontanous Abortion (very common) o Fetal: chromosomal abnormalities* multiple early fetal losses you should think about balanced translocations in otherwise normal parents. o Maternal inflammation uterine abnormalities (septum, Leiomyoma), trauma (rare cause)

Late Pregnancy: o retroplacental hemorrhage + blood flow knots, compression o ascending infections o uteroplacental insufficiency messed up placenta from beginning Vitamin A/ Retinoic Acid Terratogen Signs: Spontaneous abortions, cleft palate + limb defects, neuro, + cardiac (branchial arch development)

retinoids TGF- signaling pathway that affects homeobox genes (HOX) expression (segmental organization of embryo in craniocaudal direction) Oligohydraminos + Lung hypoplasia lung hypoplasia is a deformation not a disruption caused by the oligohydraminos sequence (1 malformation)

Deformation physical/mechanical force Disruption = destructive intrinsic process that messes up otherwise normal process elsewhere Placental Mosaicism cytogenic abnormality just in the trophoblast so only placenta is effected NOT fetus most cases result in normal live births: all depends on the severity of mosaicism and the exact chromosomal abnormality that present. (range from asymptomatic IUGR stillbirth)

linked to uteroplacental insufficiency: fetal growth restriction the spares the head Potters sequence (oligohydraminos): flattened facies + low set ears, positional abnormalities of hands + feet hypoplastic lungs, amnion nodusum Necrotizing Enterocolitis (NEC) signs: feeding, bile in gastric aspirate, abdominal distention, bloody stools, shock, DIC intestine can perforate pneumatosis intestinalis: free air bubbles in the wall of the intestine (not lumen) o when seen in imaging its specific for NEC

Maternal smoking during pregnancy Smoking preterm labor, placental problems, IUGR, ADHD Most commonly see infant theat small for gestational age without any specific problems pre-or post partum