Inflammation Squamous cell carcinoma can arise after 3rd degree burns Acute inflammation - neutrophils and IgM

Chronic inflammation - monocytes, macrophages, and IgG Granulomas are type 4 hypersensitivity reaction - macrophage takes Tb around lymph and vessels while it processes it, then presents it via class II MHC to CD4 T cells
CD4 T cells release IFN-gamma and macrophage inhibitory factor
IFN-gamma tells macrophage to kill organism
macrophage inhibitory factor keeps macrophages in situ
macrophage makes IL-12, presenting antigen to Th1 cells to make them into memory T cells
However, Tb stays alive in the granuloma and can reactivate
In TB test, CD1 Langerhans cells with Burbeck granules (tennis racquets) present purified antigen to Th1 memory T cells. The memory T cells release inflammatory cytokines ---> postive test
HIV patient would always be neg b/c no helper T cells. In fact, cant make granulomas so Tb goes all over body. Renal medulla most susceptible to ischemia. Proximal tubule is most active in reabsorption, so that is most susceptible area. Lung repaired by type II pneumocyte Astrocyte repairs brain.
Schwannoma is tumor of Schwann cells. Assoc w/ neurofibromatosis and acoustic neuromas if in auditory canal. ESR - measures agglutination of RBCs by IgM
IgM is a cold-agglutination antibody (explains Raynaud s phenomenon) Oxygen-dependent myeloperoxidase located in lysosomes in neutrophils. Neutrophils do toxic granulation to make more lysosmes and myeloperoxidase.

Fluid and hemodynamics Non pitting edema is either from exudate (inflammatory) or lymphedema
most common lymphedema is after breast mastectomy. can cause lymphangiosarcoma. Pitting edema is transudate
Transudate in pulmonary edema from LH failure. Fluid backup causes increased hydrostatic pressure.
In RH failure, increased hydrostatic pressure in veins causes edema
In cirrhosis, decreased oncotic pressure causes edema Albumin resonsible for oncotic pressure that keeps fluid in vessels
Can see loss in cirrhosis, 3rd degree burn, malabsorption, Kwashiorkor, nephrotic syndrome Histamine is Type 1 hypersensitivity Bee sting, treat with airway management and 1:1000 epinephrine

of ECF is interstitial fluid, is vascular of all fluid is ICF. of is ECF. Na and glucose limited to ECF, urea can move between ICF and ECF Hyponatremia - water moves from ECF to ICF
cerebral edema ---> mental status abnormalities
diliutional hyponatremia from hyperglycemia Hypernatremia - water moves from ICF to ECF
cerebral contraction ---> mental status abnormalities Isotonic Hypertonic Hypotonic

NEOPLASIA Hamartomas - non-malignant overgrowth of tissue (i.e. bronchial hamartoma of cartilage growth and Peutz-Jeghers syndrome) Choristoma - normal tissue in an abnormal location malignant cells usu. longer cell cycle 30 doubling times = clinically detectable tumor metastasis
carcinomas (i.e. breast) - lymphatic first, then hematogenous
sarcoma - hematogenous seeding - tumor throws off pieces of itself (ovarian --> Pouch of Douglas, peripheral lung --> pleura, glioblastoma --> spinal fluid) most common cancers in:
lung - met from breast
bone - met from breast (Batson s plexus)
osteolytic - multiple myeloma (plasma cells make IL1 aka osteoclast activating factor)
osteoblastic - prostate ca. making alkaline phosphatase
liver - met from lung
left superclavicular LN - met from stomach
brain - met from lung
liver - met from lung
adrenal - met from lung stains
desmin - for muscle like embryonal rhabdomyosarcoma
keratin - for carcinomas
S100 - for neural crest tumors (small cells in lung, melanocytes) electron microscopy
neurosecretory granules in neural crest tumor
Burbeck granules in histiocytosis X
actin and myosin in muscle proto-oncogenes
make growth factors that bind to receptors (i.e Erb2 in breast, Ret in MEN, sis)


messenger systems to nucleus, usu tyrosine kinase (i.e. Ras, Abl)
stimulate transcription of message (i.e. myc) suppressor genes - p53 and Rb keep cells in G1 phase oncogenesis - 1) mutation, 2) replication, 3) specialization
1) mutation
point mutations - Ras and p53
amplification - Erb2
translocation
Abl from 9 --> 22 causes Philadelphia chromosome in CML
Epstein Barr virus translocates myc from 8 --> 14 in Burkitt s lymphoma
virus binding to CD21 to B cells stimulates them to divide into plasma cells --> more errors
t(14:18) in B cell lymphoma
t(15:17) in acute promyelocytic leukemia. cure with vitamin A. causes of cancer - chemical > viral > radiation
cyclophosphamide causes transitional cell carcinoma of bladder
polycyclic hydrocarbons causes squamous and small cell lung cancer
HSV 8 causes Kaposi s sarcoma
EBV causes Burkitt s lymphoma, nasopharyngeal ca
HBV + aflatoxin in rice mold causes hepatic carcinoma
HIV causes primary CNS lymphoma
HPV causes squamous carcinoma of cervix, vagina, or anus
E6 inhibits p53 and E7 inhibits Rb
radiation causes CML, thryoid adenoma, osteogenic sarcoma
UVB light causes basal cell carcinoma by making thymidine dimers
Rb mutation from chromosome 13. see white eyed reflex
helicobacter pylori causes adenocarcinoma and malignant lymphoma
xeroderma pigmentosum - defective DNA repair CD8 cytotoxic T cells recognize altered Class I MHC and stimulate apoptosis cachexia due to TNF-alpha malignancies lead to hypercoaguable state; can observe migratory thrombophlebitis malignancies can elevate platelet count paraneoplastic syndromes
hypercalcemia - tumor makes PTHrp
acanthosis nigricans - assoc w/ gastric adenocarcinoma
clubbing (hypertrophic osteoarthropathy) - assoc w/ primary lung cancer
heliotrope rash + elevated serum CK - dermatomyositis from leukemia
mitral valve vegetations (marantic endocarditis) - assoc w/ colon cancers
hyponatremia or Cushing s - small cell carcinoma of lung (SIADH or ACTH)


hypercalcemia or 2* polycythemia - renal adenocarcinoma (PTHrp or EPO)
hypoglycemia or 2* polycythemia - HCC (insulin or EPO)
hypocalcemia or Cushing s - medullary thyroid carcinoma (calcitonin or ACTH) tumor markers
alpha fetoproten
high - yolk sac tumor, hepatocellular carcinoma, open neural tube defects
low - Down syndrome
Ig-light chain is high in multiple myeloma
CA125 high for ovarian cancer
CEA high for colon cancer, making immune complex and causing nephrosis
beta HCG for hyatidiform mole childhood cancers
cerebellar cystic astrocytoma most common primary brain tumor
medulloblastoma most common brain malignancy
ALL most common malignancy
Ewing s sarcoma, embryonal rhabdomyosarcoma adult cancers
most common in women - breast > lung > colon
most common in men - prostate > lung > colon
most common GYN cancer - endometrial > ovarian > cervical
GYN killers - ovarian > cervical > endometrial
HCC is only cancer preventable with vaccine (HBV)

HEMATOLOGY microcytic anemia (avg MCV < 80) - iron def causing GI bleed (abs in duodenum) thalassemias, sideroblastic anemia, anemia of chronic disease macrocytic anemias (avg MCV > 100) - B12 (ileum) and folate (jejunum) def normocytic anemias
low corrected retic count - aplastic anemia, renal dz
high corrected retic count - hemolytic anemias (spherocytosis, sickle cell, G6PD deficiency, AI) corrected retic count aka reticulocyte production index = retic count (%) x Hct/45
45 is normal Hct
then divide by 2 if there is polychromasia:

3 x Hgb should = Hct every unit of packed RBCs should increase Hgb by 1 and Hct by 3. if not --> GI bleed from iron def Complete blood count
MCV
RDW (red cell distribution width)
WBC count
PLT count spherocytes (too little membrane) target cells (too much membrane) present in alcoholism and hemoglobinopathies hypochromic cells in microcytic anemia b/c not enough hemoglobin B12 or folate deficiency - can t make dNTP or DNA. nucleus can t condense -> megaloblastic anemia

B12/cobalamin removes methyl from methyltetrahydrofolate and adds it to homocysteine. Homocysteine is now methionine, a 1-carbon donor.
Homocysteine high in folate or B12 def
Homocysteine causes thromboses
B12/Cobalamin also removes 1 C from propionyl coA --> methylmalonyl coA --> succinyl coA


methylmalonate high in B12 deficiency
propioinyl coA block myelin synthesis --> DEMENTIA, dorsal column, and lat CST problems.
treating B12 def with folate cures anemia but NOT neuro Sx
B12 bound by R factor in mouth, cleaved off in duodenum by panc enzymes. Then B12 binds intrisinsic factor in duodenum. Reabs by terminal ileum (where Crohn s hits)
pernicious anemia - AI destroys parietal cells and surrounding area -> atrophic gastritis, achlorhydria, B12 deficiency
B12 deficiency seen in vegans, alcoholics (can t cleave off R factor), bacterial overgrowth (eat B12), Crohn s (hits terminal ileum)
Folate converted to monoglutamate form by intestinal conjugase (phenytoin blocks conjugase). Abs in jejunum. Absorption blocked by OCPs and alcoholism.
Hypersegmented neutrophils in B12 or folate def

Schilling s test localizes B12 def
1. Give radio-B12 orally. None comes out in urine --> not reabsorbing B12
2. Give radio-B12 + IF. If B12 in urine --> pernicious anemia
3. Give 10 days of ABX. Repeat radio-B12. If B12 in urine --> bac overgrowth
4. Give radio-B12 + pancreas factor. If B12 in urine --> pancreatitis Normocytic anemia + corrected retic count < 2% = early iron def, anemia of chronic disease, mild blood loss, aplastic anemia (worry about Hep C causing pancytopenia), only anemia (parvovirus), renal failure (no EPO) Normocytic anemia + corrected retic count > 3%
Intravascular hemolysis - IgM binds, activates complement-mediated killing of RBC. Hemoglobin released in blood ---> hemoglobinuria + dec. haptoglobin
G6PD-def - X-linked recessive. G6PD in PPP makes NADPH and GSH
primaquine and dapsone cause oxidative stress, reducing GSH levels --> hemolytic anemia


infxn causes cells to use NADPH i+ NADPH oxidase in oxygen-dependent MPO system ---> ppt hemolytic anemia
to diagnose during hemolytic episode --> Heinz stain
to diagnose after hemolytic episode --> G6PD assay
microangiopathic anemia - RBCs hit calcified aortic valve or fibrin (in DIC), become fragmented schistocytes
can then cause iron def anemia
Extravascular hemolysis - Mps in spleen or liver destroy IgG or C3b bound RBCs, and altered shape RBCs (shperocytes, Sickle cells). Mp breaks RBC down into unconjugated bilirubin, spits it out into blood, bound by albumin, then carried to liver and conjugated ---> jaundice, but not in urine b/c bilirubin is lipid soluble
spherocytosis - autosomal dom def of spectrin. tx with splenectomy
Sickle cell dz - auto recessive. anemia + vaso-occlusive disease when sickle cells occlude small vessels
spleens die (Howell-Jolly bodies not removed), then Strep. pneumoniae sepsis occurs

b/c no splenic Mps, Salmonella osteomyelitis occurs
hydroxyurea increases HgbF
Most common cause of autoimmune hemolytic anemia
1) lupus - IgG and C3b on RBCs
test with direct Coomb s to test for Ab on RBC
not indirect Coomb s (detects Abs in serum)
2) drugs
penicillin - attaches to RBC and IgG antibody can attack it (Type II)
methyldopa - alters Rh antigens, IgGs can attack Rh antigens (Type II)
hydralazine - causes drug-induced lupus


quinidine - IgM binds drug and makes immune complex (Type III). IgM can then bind RBC and activate complement
decay accelerating factor deficiency - complement deposits on blood cells --> paroxysmal nocturnal hemoglobinuria Infectious mononucleosis - causes activated atypical T cells attacking EBVinfected B cells

Heterophile antibodies in serum specific for mono Causes of eosinophilia: Type I hypersenstivity, neoplasia, asthma, collagen vascular dz, invasive helminths Polycythemia - increased RBC count (not mass), Hgb and Hct y Relative decreased plasma volume concentrates RBCs inc RBC count y Absolute - actual increase in RBC number y Approriate compensating for tissue hypoxia from altitude, lung dz, or COPD y Inappropriate not compensating; o polycythemia rubrovera are neoplastic stem cells. Four Hs  hyperviscosity increased TPR and thromboses (cause of death)  hypervolemia only myelodyspastic syndrome with hypervolemia  histaminemia from increased mast cells. Manifests as generalized itching.  Hyperuricemia increased cell turnover produces more purines more uric acid o ectopic EPO synthesis from kidney tumor Leukemia tumor of HSCs. Hepatosplenomegaly. Blasts in blood. Always anemia b/c HSCs crowd out normal RBCs. If blasts <30% of bone marrow chronic. If blasts > 30% of bone marrow acute y 0-14 yrs = ALL (CD10+ B cell leukemias) y 15-39 yrs = AML (myeloblast with Auer rod)

y y

40-59 yrs = AML and CML o CML has Philadelphia chromosome - t(9:22) making Bcr-abl gene 60 + = CLL (most common cause of generalized lymphadenopathy in 60+ patient) o B cell leukemia, so no plasma cells (hypogammaglobulinemia) o Die of infxn Hairy cell leukemia dx with tartrate resistant acid phosphatase

Acute progranulocytic leukemia A LOT of Auer rods, even outside of cell:

o Always have DIC o T(15:17) o Treat with retinoic acid, which forces blasts to mature

Extramedullary hematopoesis in agnogenic myeloid metaplasia hematopoesis shifts to spleen. Meanwhile, Mp cause fibrosis in bone marrow. o Tear drop cells are RBCs that travel through fibrosed bone marrow on way to blood:

Lymphadenopathy o Brutons agammaglobulinemia no germinal follicles o DiGeorge syndrome no paracortex o Follicular B cell lymphoma monotonous cells in lymph node; t(14:18). Most common primary cancer of LN. Most common cancer is metastasis.

o Burkitt s lymphoma t(8:14) of c-myc oncogene o Histiocytosis X gen LAD, HSM. Langerhans cell shows Burbeck granules on EM:

o Hodgkin s disease MC form is nodular sclerosing o Typically woman with mediastinal LN + 1 more above diaphragm o Reed-Sternberg cell is malignant cell:

y y

Polyclonal gammopathy IgG is antibody assoc w/ chronic inflammation. Made by benign plasma cells. Monoclonal gammopathy 1 malignant IgG plasma clone suppresses other plasma cells. See an M-spike . Multiple myeloma. Cells make IL-1 (osteoclast-activating factor) lytic lesions. Plasma cells with bright blue cytoplasm and eccentric nuclei.

y y

Amyloidosis Trisomy 21 pts make more beta amyloid (toxic senile placques to neurons), getting Alzheimer s ~ 40 y/o. Gaucher s disease Mp lysosomes fill with glucocerebroside because deficient in glucocerebrosidase. Cytoplasm looks wrinkly.

Niemann Pick disease pt with severe MR and sphingolipid in lysosomes. Mp looks bubbly :

y y

Why don t we form clots? o Glysoaminoglycans (i.e. heparin) enhance anti-thrombin 3  Anti-thrombin 3 inactivates serine proteases o PGI2 is vasodilator made by endothelial cells o Protein C and S Vit K dependent, inactivate V and VIII o Tissue plasminogen activator activates plasmin Estrogen antagonizes anti-thrombin 3 thrombi! How do we stop bleeding? o Bleeding time test measures platelet function y 1. Cut skin activates tissue thromboplastin, exposes collagen (activates XII) and Von Willebrand s factor in endothelial cell. Platelets adhere to VWF. y 2. Platelets release ADP after sticking y 3. Platelets then make thromboxane A2, which: o vasoconstricts o bronchoconstricts o aggregates platelets and fibrinogen, completing platelet plug. y Abnl bleeding time thrombocytopenia, von Willebrand s dz, aspirin (irreversibly) and NSAIDs (reversible)