Chp 1 – 1 – Cell Cell Pathology -1 antitrypsin gene deficiency (AAT gene)
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rare vs. Hereditary hemochromatosis 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(+) – PASD(+) – accumulations accumulations of partially folded molecules in the endoplasmic reticulum that cant get secreted
vs. particular CFTR mutations – mutations – impaired 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 – activity – allow allow them to retain ability to divide throughout life somatic cells have no telomerase. Telomeres progressively shorten like in these cells: o
Permanent (G0 – don’t – don’t divide) – Neurons, – Neurons, skeletal+cardiac muscle, RBC
o
Stable (can go G0G1): hepatocytes, lymphocytes
o
Labile (never in G0): marrow, gut epithelium, skin, hair
p53 – p53 – tumor 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 – proapoptotic
mutation in p53 – p53 – no no cell cycle arrest, repair, or apoptosis cancerous cell Li-Fraumeni – Li-Fraumeni – germline germline mutation in p53 + of all cancers esp breast, bone, etc. Reversible Injury:
cell swelling + organelle swelling (mitochondria + ER) – ER) – due due to failed ion pumps ATP Plasma membrane alterations – alterations – blebbing, blebbing, blunting, loss of microvilli Polyribosome detachment from ER Fatty changes (heart get “tigered effect” with mild h ypoxia) nuclear changes – changes – chromatin chromatin clumping Irreversible: Necrosis*
Nuclear Changes: pyknosis karyorrhexic karolysis breaking of plasma + organelle membranes (lysosomes + mitochondria) o
2+
Mitochondria release cytochrome c (activates capases) + Ca
(activates
ATPases, phospholipases, proteases, etc)
intracytoplasmic myelin figures (whorled phospholipids from damaged membranes)
eosinophilia – eosinophilia – denatured denatured proteins + loss of RNA *Dystrophic Calcification – Calcification – basophilic basophilic Ca deposits indicating previous necrosis vs. Metastatic Calcification – Calcification – deposits deposits in normal tissue due to hypercalcemia Cellular Growth
agenesis – agenesis – no no development since don’t have embryonal structures (always inherited) inherited) Aplasia – Aplasia – lack lack of any embryonic development although have the needed structures hypoplasia – hypoplasia – poor poor or subnormal development Dysplasia – Dysplasia – abnormal abnormal growth of the organ/tissue Atrophy – Atrophy – reduction 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 onl y a lining and doesn’t contribute much to the change in size Apoptosis Histology
single cell is shrunken + converted to dense den se eosinophillic mass surrounding cells are normal + no inflammation common in GvHD Autophagy + Single Cell Necrosis
Autophagy – Autophagy – lysosomal lysosomal degradation of cellular components due to aging, malnutrition, chronic disease (“cellular downsizing”)
lipofuscin granules are residual bodies left over – lipid – lipid oxidation Can progress to single cell necrosis – necrosis – (vs. (vs. apoptosis you actually get cell fragmentation) o
Councilman Bodies – Bodies – single 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 – heart – turns 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 H 2O2 excessive iron ingestion can overwhelm transferrin ability to bind up free Fe – Fe – excess excess can produce free radicals and cause oxidative damage*
Vitamin C and E – E – important important antioxidants that protect against this damage
Hemosiderin – storage for of iron excess but doesn’t cause cell injury acutely – more likely with huge amount in hemochromatosis. Acute Fe ingestion more likely to get damage from Free radicals Sirtuins:
histone deacetylases – remove acetyl groups from histones (making more po sitive so bind tighter to DNA - transcription) vs. Histone acetyltransferases ( transcription) Sirtuins are HDAC’s 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
Chapter 2 Acute and Chronic Inflammation Macrophages in Healing of Ischemic Tissue
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not only involved in phagocytosis/cleanup 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 spac e
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 produ ced 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 PMN’s 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 TGF-
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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
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: don’t 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
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vasoconstriction – takes second platelet aggregation – mins Thrombotic Masses
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. Won’t 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 it’s 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
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1:850 – common cause of hypogonadism + infertility long extremities, bilateral gyncomastia, hypogonadism testosterone = estrogen = FSH/LH Both Seminiferous Tubules + Leydig cells fucked – oligospermia males with presence of 1 Barr Body
Turner’s: 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
Hurler’s (AR) – deficiency of iduronidase o
coarse facial features, corneal clouding, hea ring loss, joint stiffness, hepatosplenomegaly, MR, subendothelial deposits causing CAD
o
vacuoles in lysosomes in peripheral leukocytes + macrophag es
o
accumulation of dermatan sulfate + heparan sulfate
Hunter’s (X-linked) – deficiency of iduronate sulftase o
milder disease + no corneal clouding
o
accumulation of same stuff
McArdle’s 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 can’t use it
Lysosomal glucosidase = acid maltase Gaucher’s 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 Gaucher’s) Niemann Pick – deficiency in Sphingomyelinase
Hepatosplenomegaly, neurodegeneration, cherry red spot, foamy macrophages in bone marrow biopsy
vs. Tay Sachs that doesn’t have hepatosplenomegaly vs. Gaucher’s that doesn’t 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 Patau’s 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 ina ctivation 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
Fragile X:
# 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 b e 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
Signs: size of testes, jaw, ears + autism, MVP Androgen Insensitivity Syndrome / Testicular Feminization syndrome
X-linked inheritance defective androgen receptor so doesn’t 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* Sjogren’s
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 patient’s serum Type I Hypersensitivity
Early-phase: mediated by degranulation of mast ce lls Late-phase: o
inflammatory infiltrate (PMN, eo, basophils, monocytes, CD4+)
o
more tissue destruction + more severe
o
doesn’t require reexposure to antigen to occu r*
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 ce lls 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 Bruton’s 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 Heav y 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 unk nown ag stimulation causing cytokine release activating macrophages + mast ce lls. 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
Protein
Derived From
1’
Amyloid light chain
Ig light chain
2’
Serum Amyloid
Acute Phase reactant – chronic
associated protein (SAA)
inflammation
Senile Cardiac
Transthyretin
Serum T4 and retinol transporter
Type II DM
Amylin
Endocrine
Medullary Thyroid
A-Cal
Calcitonin
Alzheimer’s
-amyloid 2 microglobulin
Amyloid precursor protein (APP)
Dialysis associated
MHC I proteins
IL-17 in DTH
IL-17 produced by CD4+ cells in DTH rxns and recruits PMN and monoc ytes to the site causing itching and pain.
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 rand omly (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 CDK’s 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 doesn’t 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:
small, nontender, raised, smooth mass been there for long time and hasn’t changed size red color – suggest vascularity* Strawberry Hemangioma – in kids grows with age and then spoteneously regresses Cherry Hemangioma – in elderly but doesn’t regress. Chance with age
vHL gene
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, pheo’s 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
Tumor Size, LN number, distant mets M1 – indicates have distant mets TGF-:
normally inhibits proliferation via activation of growth-inhibiting genes such as CDKI’s
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:
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lymphocytes + plasma cells infiltrates* - No granulomas obliterative endarteritis too which is present in all 3 stages of s yphilis 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:
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 Babesia
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 ne crosis (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 o
involved specific receptor-lignand interactions 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 RBC’s Schistosoma haematobium
severe granulomatous inflammation, fibrosis, calcification of bladder wall (shurken bladder)
chronic infection SCC of the bladder + painless hematuria Tetanus
toxin that release of GABA + Gly MOA: tetanus toxin is a protease that cleaves s ynaptobrevin, 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
Romana’s 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 (PMN’s) and granuloma. NOT true granuloma facultative intracellular pathogen Shigella Histology:
mononuclear infiltrate extending to the lamina propria + n eutrophillic 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 Fever – flavivirus 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), Hutch inson’s teeth (small widely spaced teeth with notch), mulberry molars (black dots on em)
CN VIII deafness
Chapter 9: Environmental Pathology Vitamin E deficiency
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neuro manifestaton similar to B12 deficiency have anemia (hemolytic) but its normocytic mediated by free radical damage Regeneration following Severe Burns
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 doesn’t loss consciousness. Treat: fluids
Heat Stroke: organ damage when body temperatures are greater than 36’C 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, ev en 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), Bitot’s 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 Kwashiorkor’s Refeed slowly – carbs will deplete Pi too fast and cause heart failure/death o
vs. Kwashiorkor’s – aggressive refeeding Summary of Hormones that are Peripheral Signals to Brain
Ghrelin
Signals
Time
Location made
Hunger
Short-term
Stomach/small intestine
CCK
Satiation
Short
Small intestine
GLP-1
Satiation
Short
Small intestine
Leptin
Satiation
Long-term
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 pan creatic 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
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 Cocaine:
vasoconstrictive effect Placenta: blood flow causing fetal hypoxia + spontaneous abortion, abruptio placentae, and fetal hemorrhages Cancer + Obesity
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
5/22/2012 7:59:00 AM
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, h ypercarbia, 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 me mbrane rupture AND PG’s 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* *susceptibility to E.coli septicemia that can lead to death early* o Neonatal Jaundice:
Physiologic Jaundice o
Green flags if: peaks at 3-5 days and def
o
Causes: 1. Breast milk jaundice – 95% 2. ABO incompatilibilites – 4%
o
Other risks: race, diabetic mother, Hx in previous pregnanc y
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 o
reticulocytes = “erythroblastosis” *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
acute choorioamnionitis most commonly due to ascending infection – leads to stillbirths
Group B Strep since most moms vagina colonized is common agent Listeria
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 4’C – 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) ex pression (“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 Potter ’s 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
