The Haversian Canal

Before 1906: Patent Medications - anything goes, and all ingredients were secret. Opioids, cocaine, and alcohol were popular ingredients.

1906: Pure Food and Drug Act
1914: Harrison Narcotics Act
1923: US Treasury Department stands up the Narcotics Division, today's DEA.
1924: Heroin Act
1937: The Massengill sells a sulfanilamide elixir diluted with diethylene glycol.
1938: Food, Drug, and Cosmetic Act: drugs must be effective
1951: Durham—Humphrey Amendment, the "prescription drug amendment"
1950s: Thalidomide
1962: Kefauver—Harris Amendment: drugs must be *safe* and effective. Patients in clinical trials must give *informed* consent.
1970: Controlled Substance Act (drug "schedules")
1983: Orphan Drug Act

To do: link these to their Wikipedia entries.

Antipsychotics

• Typical · D₂ receptor antagonists · hyperprolactinemic weight gain (tuberoinfundibular pathway)
• Chlorpromazine · Thorazine
• Haloperidol · Haldol · Severe extrapyramidal symptoms (EPS) with chronic use (nigrostriatial pathway)· used for acute care · prolonged QT · torsade de pointes (α₁) · tardive dyskinesia · orthostatic hypotension · neuroleptic malignant syndrome
• Atypical
• Clozapine · Clozaril · agranulocytosis · 5-HT₂<D₂
• Resperidone · EPS at high doses
• Olanzepine · weight gain at high doses · hypersalivation
• Valproic Acid
• Carbamazepeine

Antidepressants

• Tricyclic Antidepressants · M (xerostomia, constipation, urinary retention, glaucoma) · H₁(sedation) · Na channel (↑QRS) · α₁ (orthostatic hypotension, tachycardia, ED) · P450 2D6
• Amitryptyline
• Imipramine
• SSRIs · Fewer side effects than TCAs, and less risk of lethal overdose · equally effective · P450 2D6 · unmask mania
• Fluoxetine · Prozac · norfluoxetine t_1/2~8d
• Citalopram · Celexa · P450 3A4 & 2C10
• Escitalopram · Lexapro ·
• Sertraline · Zoloft
• Paroxetine · Paxil · teratogenic
• SNRIs · Serotonin & Norepinephrine Reuptake Inhibitors
• Bupropion · Wellbutrin · Zyban · ↓5-HT · NE reuptake · ↓DA reuptake
• Duloxetine (Cymbalta)
• Nefazodone · Serzone · withdrawn due to hepatotoxicity
• Venlafaxine · Effexor · ↓ NE reuptake > ↓ 5-HT · slight ↓DA reuptake
• MAOIs
• Phenelzine
• Selegiline
• Tranylcypromine
• Lithium
• St John's Wort

Anxiolytics, Sedatives, Hypnotics

• Benzodiazepines · αγ · enhances GABA_A Cl^-
• Diazepam · Valium · depresses spinal cord reflexes at relatively low doses · EtOH withdrawal · seizure · anterograde amnesia (date rape drugs)
• Chlordiazepoxide · Librium · mild anxiety · IV for acute EtOH withdrawal
• Alprazolam · Xanax · anxiety & panic disorders
• Flurazepam · Dalmane · for insomnia
• Lorazepam · Ativan · anxiolytic & sedative
• Midazolam · Versed
• Oxazepam · Serax
• Triazolam · Halcion
• Benzodiazepine Antagonist
• Flumazenil
• Benzo-like Drugs
• Zolpidem · Ambien
• Zaleplon · Sonata · not anxiolytic
• Eszopiclone · Lunesta
• Barbiturates · keep GABA_ACl^-channels open longer · directly acts on GABA_A at high doeses
• Pentobarbital
• Secobarbital
• Phenobarbital · Solfoton
• Buspirone · BuSpar
• Ramelteon · Rozerem

Drugs of Abuse

• Stimulants
• Caffeine · methylxanthine · adenosine receptor antagonist leading to increased intracellular cAMP
• Nicotine · nicotinic agonist mainly at locus ceruleus
• Cocaine · blocks monoamine reuptake · blocks I_Kr and Na channels · cocaethylene · TAC, LAT, etc · ABCs, glucose, ice packs, benzos, bicarb · Withdrawal=irritability, dysphoria, and fagiu
• Methylphenidate (Ritalin) · narcolepsy · ADHD · excreted in urine · increases release of monoamines (NE, 5-HT, DA)
• Amphetamine · Dexedrine · Dextrostat · Adderall · Desoxyn · Gradumet
• MDMA (Ecstasy)
• Hallucinogens
• Lysergic acid diethylamine (LSD)
• Phencyclidine · blocks NMDA · glutamate antagonist · psychosis · dissociation · catatonic posturing · Schedule I
• Ketamine · NMDA · sole anesthetic agent for diagnostic & surgical procedures that do not require skeletal muscle relaxation · Schedule III
• Tetrahydrocannabinol · THC · CB₁ & CB₂ · Dronabinol, Marinol

Anatomy

Anterior
Hormone · Releasing Hormones · Feedback loops · Testing · Excess(sx, marker, tx) · Deficiency(sx, tx) · Tumor(sx, tx)
GH
FSH
LH
TSH
ACTH
Prolactin

Posterior
Vasopressin (ADH) · Diabetes Insipidus (DI) · SIADH
Oxytocin

Anatomy
Capsule
Cortex
· Zona glomerulosa
· Zona fasciculata
· Zona reticularis
Medulla
Vessels
Nerves

Steroid synthesis diagram - two branches

Stress response
· ACTH
Renin-angiotensin-aldosterone
· Hypo- & hyperkalemia
· Norepi
· alpha-blockers
Glucocorticoids under control of HPA axis; mineralocorticoids controlled by renin-angiotensin. Primary adrenal failure: both fail. ACTH failure, only glucocorticoids fail.
Adrenal androgens
·
Adrenocortical Diseases
· Glucocorticoid
· · Excess (Cushing syndrome) · moon facies · weight gain · buffalo hump · erythematous · ACTH dependent · ACTH independent · Pseudo-Cushing's · Cushing disease - pituitary · 15% associated non-pituitary tumors · dexamethasone supression test · 24 urine collection · salivary cortisol · find source
· · Deficiency · primary=Addison's disease · skin pigmentation · ACTH stimulation test (measure cortisol at 30 minutes and 60 minutes. Response should be greater than 18).

Primary hyeraldosteronism · Conn's syndrome · 10% of hypertensives (?!) · adenomas have higher pressure than idiopathic · LVH · damage to renal & cerebral vessels · may cause vascular damage in addition to that caused by HTN · hypokalemia not req'd · CT *after* biochemical dx · NP-59 adrenal scintography to ddx APA & IHA · spirinolactone · amiloride · nefedipine · eplernone

Hypoaldosteronism · Addison's · hypoplasia · hyperplasia · pseudohypoaldosteronism I & II · 21-hydroxylase deficiency · 17alfa-hydroxyprogesterone

Pheochromocytoma · paragangliomas if extra-adrenal · HTN · Triad (headache, palpitations, diaphoresis) · chromaffin cells · NE, Epi, DA · MEN-2 · VHL dx · neurofibromatosis · glomus tumors · measure plasma metanephrins: many sources of interference, consider HPLC · ddx includes renal insufficiency · glucagon & clonidine tests · 98% intrabdominal · imaging *after* biochemical diagnosis - may be hard to id ·

Neuroendocrine tumors · thyroid · adrenal · lung · GI · Brain · Skin · Prostate, bladder, cervix
· NSE+, chrmogranin+, synaptophysin+, CK+

Hyperpituitarism · pituitary adenoma · invasive adenoma · prolactinoma · GH adenoma (markers: GH & IGF-1) · null cell adenoma (non-functioning but many may in fact be secreting gonadotrophs) · rare (gonadotroph, corticotroph, thyrotroph) · may invade bone sella or brain · immunoperoxidase staining · malignant tends to show 'endocrine atypia', larger size, and invasion of large vessels · sheets or rosettes of endocrine cells · salt & pepper chromatin · eccentric nuclei

Hypopituitarism · Empty sella syndrome (sarcoidosis, other) · Sheehan syndrome · tumors · pituitary apoplexy (hemorrhage - CV collapse) · granulomatous inflammation

Hyperparathyroidism · chief cells · oxyphilic cells · clear cell hyperplasia · parathyroid adenoma has less adipose tissue · moth-eaten bone, esp trabeculea, osteoitis fibrosis cystica · multinucleate giant cell osteoclasts will go away

Hypoparathyroidism · radical neck dissection · Chvostek sign · Trousseau sign · long QT

Pancreas · islet cell tumors · insulinoma · gastrinoma (Zollinger-Ellison syndrome) · glucagonoma, somatostatinoma, VIPoma · nesidioblastosis

Iodide trapping · thyroid follicular cells · colloid · Oxidation (Iodide → Iodine) · 2I^· + tyrosine → diiodotyrosine (DIT) · I^· + tyrosine → monoiodotyrosine (MIT) · 2DIT → T₄ (thyroxine) · MIT + DIT → T₃ · therapy is typically T₄

Myxedema coma & myxedema psychosis · hypothyroid emergency · often precipitated by intercurrent illness · mental status changes · hypothermia · hypotension · bradycardia · SIADH · hypoventilation (medullary depression, muscular weakness, weak tongue⇒sleep apnea) · hypoglycemic · pericardial effusion · T₄ & supportive measures · stress doses of steroids

Hyperthyroid · Grave's · 'toxic' adenoma · toxic multinodular goiter · thyroiditis · factitious · hyperemesis gravidarum · weight change (either way) · fatigue · sweating · heat intolerant · pruritus · pretibial myxedema · exophtalmosis · diplopia · lid lag · goiter · lymphadenopathy · palpitations · arrhythmia · CHF · dyspnea, exertional intolerance · thymic enlargement · bowel frequency · altered appetite · vomiting · tremors · weakness · paralysis · dependent edema · menstrual irregularities · miscarriages · gynecomastia · nevousness · irritability · anxiety · depression · psychosis · thionamides · radioiodine · surgical resection of thyroid · PTU · methimazole

Thyroid Storm · hyperthyroid emergency · precipitating event (trauma, surgery, iodine load, poor compliance) · 104-106°F (40-41°C) · psychosis to coma · vomiting & diahrrea · hepatic failure & jaundice · supportive measures · PTU · methimazole · iodine solutions (SSKI, Lugol, NaI) · Sodium ipodate · β-blockers (propranolol, esmolol) · glucocorticoids (dexamethasone, hydrocortisone) · lithium · plasmapheresis

Thyroiditis
· high RAI uptake: Hashitoxicosis
· low RAI uptake: Radiation-, palpation-, drug-induced · subacute granulomatous (de Quervain's) thyroiditis · subacute lymphocytic or postpartum thyroiditis · Hashimoto's thyroiditis (chronic lymphocytic thyroiditis, also potentially postpartum)

Dr Clejan

Pregnancy Testing · hCG (qualitative for yes/no; quantitative for ectopic or failing, peaks around 10 wks) · tumors may produce hCG or β subunit · dilute urine may be - · heterophil antibodies false + · renal failure leads to accumulation of interfering substances · ultrasound to demonstrate gestational sac

Ectopic pregnancies · 1:150 pregnancies · ddx for pelvic pain · abnormal uterine bleeding · low Hb values · hypovolemic shock · 4-6 wks after conception hCG levels off (normal 10 wks), then decline in rater of hCG increase, less than dbling/2d · culdocentesis

Gestational tumors · hydatidiform mole · very high hCG · low human placental lactogen (hPL) · patterns of steroid hormone metabolites in serum vs urnine shows if fetal adrenals are not present · molar pregnancies are follwed by serial measurements of hCG (undetectable 2-3 mo out)

Testing for congenital disease · Alfa feto-protein (AFP) for neural tube defect & Down's · triple marker (hCG, AFP, estriol) · MoM (Multiple of the Median) b/c AFP has normal variation over course: individual results expressed as a multiple of the median rather than [AFP]. Open NTD (Anencephaly, spina bifida) leaks CSF w/ assoc. high AFP · Very high AFP, MoM > 2-2.5 (Normal extends to 2.1 - overlap region requires risk calculation: ~ 1:10) · F/U: repeat AFP to confirm gestation age, ID multiple pregnancies, acetylcholinesterase test

Multiple Markers · AFP, hCG, estriol · 70% of cases with Down's ID'd · correct for gestiational weight, DM, race · good for in vitro · 2x false positive Down's pattern in 2nd trimester of in vitro: correction · Smith-Lemli-Opitz syndrome

Ultrasound · 1st trimester: "Combined Test" at 10-13 wks · narrow line of nuchal translucency sort of associated with Down's if other markers also favor · culture live cells · FISH · Karyotyping · other Down's syndrome: heart, GI, choriod plexus cysts hydronephrosis · Spina Bifida (scalloping, lemon sign viewing fetal head coronal, increased vetebral separation on coronal of lumbar vertebrae)

Amniocentesis · test AFP · indicated if positive screen for spina bifida or Down's

CVS · chorionic villi sampling · rate of miscarriage is 3x higher than with amniocentesis · placental mosaicism artifact due to cell culturing process · since no fluid is collected, it doesn't test for AFP

PUBS · Pecutaneous Umbilical Blood Sampling · needle draws blood from the umbilical vein · manage Rh isoimmunization (mom Rh - and previous Rh + pregnancy, or Rh + blood transfusion): if baby is suspected anemic, blood sampling is the only way to confirm this Hemolytic Disease of the Newborn (erythroblastosis fetalis)· RhoGam at 28 wks and after delivery of first Rh + delivery (1-2 cc IM, antibodies that would have naturally formed, but binds the fetal blood before mother's immune system mounts response). All Rh-, Rh+naive women should get 1 RhoGam shot at 28 wks. If father is known Rh-, then RhoGam unnecessary.

Fetal & Placental Viability Test · high risk pregnancies ·

Premature delivery testing · Fetal fibronection: negative means less than 1% chance of premature delivery in next two weeks · neonatal respiratory distress syndrome (RDS or hyaline membrane disease) · Pulmonary surfactant lipids · disaturated phophatidyl choline (lecithin), expressed as ratio against sphhingomyelin, a non-pulmonary lipid found at fairly constant levels in amniotic fluid (L/S ratio, by thin layer chromatography) · PG assay

Nodules · 25% neoplastic, 80% adenomas · MEN mutations, family hx of

Papillary carcinoma · 1% of all cancers and 0.2% of cancer deaths · remove whole gland · Hiroshima, Chernobyl · PTC oncogene · Tyrosine kinase receptor rearrangements · Orphan Annie nuclei · powdery chromatin · SAMoma bodies

Follicular carcinoma · usually cold on scan, but may be warm · iodine deficient women in 5th or 6th decade · capsular & vascular invasion · NRAS, KRAS, HRAS in 50% · fusion of PAX8, a paired homeobox gene · PPARγ1 (peroxisome proliferator-activated receptor) in 30% · well-differentiated follicular carcinoma can't be differentiated from follicular adenoma until resected

Hurthle cell tumors · large cells, granular cytoplasm · Hurthle cell tumors tend to be more angioinvasive · 30% of Hurthle cell carcinomas metastasize to lymph nodes

Medullary carcinoma · 5% of thyroid cancers arise from parafollicular C cells · 80% sporadic · RET→MEN · may secrete calcitonin, somatostatin, serotonin, CEA, ACTH, VIP (paraneoplastic syndrome) · amyloid stroma in tumor · C cell hyperplasia in family members · 50% 5 yr survival, better in familial cases

MEN
· IIA (Sipple) · Medullary carcinoma · multifocal, associated C cell hyperplasia · pheo, parathyroid, RET on 10 (germline)
· IIB · non-germline

Anaplastic Carcinoma · <5% of thyroid ca · dead in 6 mo · elderly in endemic goiter area · pressure symptoms · spindle cells, giant cells, small cells · arise in follicular or papillary carcinoma · undifferentiated

Lymphoma · uncommon · arise in background of Hashimoto's · women:men 4:1 · diffuse, non-Hodgkin's ·

Calcium

Parathyroid hormone induces bone resorbtion, recovering calcium & phosphorus, induces kidney to excrete phosphorus, then activates vitamin D, which then goes to the gut to absorb more calcium.

Calcium · most abundant mineral · 1000-1200 mg/d in diet req'd · Hypocalcemia=tetany, muscle spasms, rickets, bone pain · hypercalcemia · adjust albumin. Normal albumin is 4. For every 1 drop in albumin, add 0.8 to your measured calcium · Bone, gut, and kidney

Parathyroid hormone · secreted w/in seconds of ↓ ECF Ca, ↓ 1,25 Vit D, or ↑in P04 · activates 1alpha hydroxylase · maximizes reabsortion of Ca in kidney · Vit D formed by sun in skin · PTH & phosphorus will increase activity of 1 α hydroxylase

1, 25 Vit D acts on gut. Cholecalciferol · 7-dehydrocholesterol → Cholecalciferol→23-chole→Cal→25→1, 25

Calcitonin · not needed for life · reduces blood calcium levels · useful for acute hypercalcemia · used to be used for osteoporosis · allows calcium out renally immediately, also promotes bone deposition

Hypercalcemia · hypercalcemia of malignancy or primary hyperparathyroidism · granulomatous disease (tuberculosis, sarcoidosis, other) · pheochromocytoma · VIPoma · adrenal insufficiency (dehydration may contribute, definitely seen clinically) · medications (lithium, thiazides, thyroid hormone, Vit A, Vit D (toxicity)) · Familial Hypocalciuric Hypercalcemia · Lymphoma · acute or chronic renal disease

Hypercalcemia · does not equal hyperparathyroidism, check PTH · high PTH causes kidney stones even though the Ca/Cr ratio is low, b/c serum Ca is high, therefore kidney filtered load of Ca is high.

FHH · inactivating mutation in the calcium-sensing receptor in the parathyroid glands & kidneys · autosomal dominant (any family history) · Absence of symptoms & signs of hypercalcemia · low urine calcium excretion & Ca/Cr clearance ratio is low

High Ca + low PTH · Hypercalcemia of malignancies (PTH-rp (related protein)) · Granulomatous disease (very high 1,25 Vit D, extra-renal 1 alpha hydroxylase (low PtH, no PTH-rp) · Vit D intoxication (150-200, low PTH, no PTH-rp) · Increased bone resorption (multiple myeloma, thyrotoxicosis, immobilization, Paget's disease, Vit A toxicity) · Markedly increased calcium (Milk alkali syndrome (too many Tums))

Hyperparathyroidism · Primary (parathyroid adenoma or hyperplasia, surgery, observation, calcimimetics, bisphosphonates, estrogen) · Secondary (gland hypertrophy: kidney failure, Vit D deficiency) · Tertiary hyperparathyroidism (long-standing secondary hyperparathyroidism leads to an increased parathyroid mass & autonomous PTH secretion)

Surgical indications · summary statement 2002 NIH Workshop Asymptomatic Primary Hyperparathyroidism Expert Opinion · >1.0 mg/dL above patient's upper limit of normal · hypercalciuria (>400 mg/d) · Cr clearance <30% age-matched controls · osteoporosis @ any site · <50 yo · Px in whom periodic follow-up will be difficult

Hyaline Membrane Disease · 28 wks< gestation < 32 wks · trauma of trying to breath injures pneumocytes → inflammation → protein deposited renders glassy, hyaline, appearance · infants of diabetic mothers have delayed surfactant maturation: may be born term without surfactant.

Diseases of prematurity · Retinopathy of prematurity (high respirator O2 causes proliferation of blood vessels) · Bronchopulmonary dysplasia (granulation tissue of capillaries & fibroblasts scar the lung) · Necrotizing enterocolitis (NEC, lack adequate blood flow to intestine (patent ductus arteriosus, patent foramen ovale), immature lymphoid system) · Intraventricular Hemorrhages (IVH, PFO & PDA allow uniquely high pressure waves to hit cerebral vasculature)

Most common cause of death in children is accidents: poisoning, burns, drowning. Suicide in adolescents.

Otitis · Irish viruses (Rhin O'Virus, Aden O'Virus, Ech O'Virus) · Otitis media (S. pneumo, H. flu, moraxella) · inflammation can dissolve ossicles, break into mastoid air spaces, or involve brain · chronic otitis media can lead to cholesteatoma

Galactosemia · Galactose-1-P-uridyl-transferase (lactose→glucose+galactose→glucose) · Hepatitis · cirrhosis · jaundice · lens → cataract · mental retardation occurs before diagnosis can be made clinically · newborn screening: reducing substances in urine.

SIDS · "crib death" · susceptible infant (maternal smoking 2x incidence · young mother · tends to run in families) · critical time period in development (about 15 minute warning) · external stressor · technically first year, most in first 2-4 mo, 90% by 6 mo · 5% show a fatty acid oxidation (medium chain acyl-CoA (MCACoA) enzyme deficiency) · DDx requires autopsy, dx of exclusion · child abuse: hemorrhage or fibrosis in periosteum, petechial hemorrages (visible in back of eye)

*Small blue cell tumors*
Lymphoma · pre-B cell lymphoma · peaks about 4 yo · success of remission (90%) associated with identifying sanctuary sites (blood brain barrier, blood gonad barrier) · intrathecal chemotherapy · 2/3 of all cases considered cured.

Neuroblastoma · adrenal medulla, peaks about 2 yo · catecholamine breakdown products (VMA, HVA) in urine (also useful for monitoring tx progress) · paraspinal neural ganglia · rosettes of cells around lumen, suspected to be recapitulation of neural tube

Nephroblastoma · Wilm's tumor · 3 yo (rotate cw 3 = W) ·

Mechanisms of Action · increase insulin secretion · increase glucose uptake · delay glucose absorption · decrease hepatic glucose output

Groups · (1) Sulfonylureas (1st & 2nd gen) · meglitinides (repaglinide) · phenlyalanine derivatives (nateglinide) · (w) biguanides (metformin) ·(4) alpha-Glucosidase inhibitors (acarbose, mig...) · (3) thiazolidinediones

Anatomy of an islet: α — glucagon · β—insulin · PP — pancreatic polypeptide · δ—somatostatin

Mechanism of insulin secretion · (Lehninger diagram) · glucose powers mitochondria→ATP allows 4-subunit K_ATP channel to open→depolarization→opens Ca²⁺ channel→Ca²⁺ rushes in→exocytose insulin granules · sulfonylurea receptor blocks K channel action

Insulin secretagogues

Sulfonylureas · Onset longer · duration longer · dosing 1/d · FPG ↓↓ · PPG ↓↓· A1C ↓↓↓ · disadvantages (hypoglycemia, weight gain, caution in patients w/ hepatic & renal dysfunction)

Meglitinides · Repaglinide · same function as sulfonylureas, but doesn't appear to act on sulfonylurea receptor, at least not same site (?) · fast-acting → take just before meal · safer than sulfonylurea · less hypoglycemic risk than sulfonylureas · $$$

D-Phenylalanine derivatives · MoA unknown · nateglinide · may be metabolized to something else · seems to work particularly in type 2, but works on first phase, so effect is small · may be good in combination

Insulin sensitizers

Thiazolidinediones · "glitazones" rosiglitazone · pioglitzaone · decrease FPG 45-55 mg/dL · decrease HbA1C 1.-1.4 % · triglycerides down quite a bit · HDL goes up · LDL goes up · body weight may go up · PPAR-γ (Peroxisome proliferator-activated receptor-γ) · precautions (CHF, pregnancy, 1 other) · side effects (fluid retention, anemia, weight gain) · new · can be used in renal insufficency ·

alpha-glucosidase inhibitors · non-systemic · few contraindications · no weight gain · no hypoglycemia ·

Progressive Therapy for type 2 Diabetes (A1C%) · Diet & exercise (9) · oral monotherapy (8) · oral combination therapy (8) · Bedtime insulin (7.5) · Complex insulin regimens (7)

Sitagliptin · Januvia · DPP-4 (dipeptidyl poptidase-4) inhibitor, which otherwise degrades GLP-1 · approved 17 October 2006

Ms LRP · LRP-5 gene, 11q11-12, wnt signaling pathway · osteoporosis-pseudoglioma syndrome · multiple myeloma px have osteoporosis, bisphosphonates don't prevent lesions: Dickoff protein · Osteopetrosis (marble bone disease described by Albers-Schonberg 1904) · autosomal dominant adult benign · autosomal recessive infantile malignant · failure of osteoclast · reduced marrow space

Hyperparathyroidism · osteitis fibrosa cystica · hypercalcemia · kidney, gut, bone keep, gather, and resorb calcium · hypercalcemia and 1-25(OH)₂ Vit D inhibit parathyroid hormone release · drugs that bind calcium sensor are available for kidney disease, work the same way for bone metabolic disease

Osteoclastoma of the jaw · PTH · brown tumors

Osteomalacia · Rickets · In adults: Ca²⁺, phosphorus and Vit D deficiency · some Vit D in food, most from UV · Dietary Ca² deficiency occurs in tropical locations an is usually associated with high oxalate and phytate · Phosphate deficiencies tend to be hereditary · Any defect in the pathway to calcitriol · Vit D deficiency in iguanas kept as pets · bowing, varus, valgus, bone pain, delay in tooth resorption · tetracycline gives kids brown teeth, but useful for determining rate of bone deposition ·

hypophosphatemic vit d resistant Rickets (phosphorus low, Ca normal, not hyperparathyroid, normal BMD (bone mineral density)) · X-linked hypophosphatemia (PHEX gene, a membrane bound peroxidase, Fibroblast Growth Factor 23 is a hyperphosphaturic factor, ADHR abnomrality in FGF-23 abnormality, so that it cannot be cleaved, elevating the FGF-23 · autosomal dominant trait (ADHR) · Oncogenic osteomalacia or tumor induces osteomalacia

Oncogenic osteomalacia · low serum phosphorus · inappropriately low calcitriol · mesenchymal, slow growing tumors, osteoblast-like tumors, ossifying fibrous-like, non-ossifying

Paget's Disease · osteoclast-initiated bone resorption · osteoblasts form to compensate · 30% familial · 5q35, NFκB associated · Viral hypothesis: measles, paramyxovirus · NTX, CTX, DPD · alkaline phosphatase · bone markers suggest extent of disease · men and women · pelvis, skull, bending of tibia, back pain, spinal stenosis, skull enlargement of head, trauma fx, Osteosarcomas, fibrosarcomas, and chondrosarcomas · Decreased bone turnover (Bisphosphonate: etidronate, Tilurdronate, etc, see slides) · Paget's bone is disarrayed.

Osteogenesis imperfecta (not in the slides) · Marie Aczema Aucoin family in New Orleans goes back to 1850s, 250 people in the kindred · Sillence classification: type I: quantitative defect of COL1A1, type II letal, type III · variable clinical picture, blue sclera, fractures as children, premature hearing loss, narrow feet, fractures after menopause · most severely affected members of the family in those whose unaffected parent is petite · bisphosphonates · orthopedic intervention: rodding, fixing · rehab · stapes surgery · Type I collagen, glycine repeats

Osteoporosis · free-estradiol level is most correlated in women and men (testosterone is converted to estrogen) · glucocorticoid-induced · osteoporosis<-2.5 T score · Osteopenia -1.0 to 2.5 T score · 40% of white women >50yo get fragility fracture · femoral neck BMD declines 58% in women; 39% in men · falls, age, BMD · increased morbidity & mortality · Colle's fracture predictive of vertebral fracture. Determinants of peak bone mass: genetics (50-85%), COLA1 & Vit D receptor · osteoprotegerin vs RANKL & RANK · IL-1, -6, -11 · TNF-α, Vit D, PGE2, others

Bone strength · can't measure microarchitecture yet, but strength is much, Impact of modeling on strength is more significant that of remodeling

Other: Craniotabes
Rachitic rosary · Harrison's Groove
Pigeon breast
Pyogenic osteomyelitis · Brodie's abscess · Pott's disease
Brown tumor
Renal osteodystrophy
Chalkstick fracture
Mosaic cement lines

Drug list · tridothyronine · iodide · propylthiouracil · methimazaole · levothyroxine

Thyroid function · Iodide transported in · acted on by peroxidase to produce a radical · iodides and thioamides inhibit conversion of I- to thyroglobulin · proteolysis of thyroglobulin is also inhibited by iodides. T4 in the blood is converted to T3; this can be blocked by Ipodate, β-blockers, and corticosteroids.

HPA axis · T3 & T4 autoregulate thyroid · T3 & T4 downregulate TSH in the thyrotrophs in the anterior pituitiary (TSH acts on thyroid by cAMP mechanism to upregulate thyroxine release) · T3 & T4 also feed back on hypothalamus. Hypothalamus also responds to Cold (↑), seizure, psychosis. See figure in Katzung.

T3 & T4 in the cell · protein-bound in blood · PB · T3 & T4 act in nucleus like steroids

Hypothyroidism · congenital disorders · Hashimoto's (↓BMR, ↓CO, fatigue, myxedema. Must titrate b/c physiologic compensation may not tolerate normal dose) · Levothyroxine sodium (T4) aka L-T4 · given once a day do to long half life · Goal: keep TSH normal · steady state in 6-8 wks · T4→T3 by deiodinases · desicated thyroid is available and cheap, good shelf-life but bioavailability is not reliable · PBI=protein-bound iodine (↑estrogen=↑TBG=↑PBI=↓T4/T3) Adrogens, aspriin, phyenytoin, phenylbutazone decrease PBI

Grave's Disease · more common in women· toxic adenoma · goiter · thyroiditis · partial thyroidectomy · thioamides, aka thionamides · methimazole, carbimazole, propylthiouracil

Thyroid storm · β-blocker (propranolol) can blunt sympathetic stimulation · potassium iodide inhibits thyroid hormone release · large doses of propylthiuracil (PTU works peripherally) · adverse effects: metallic taste

Radioactive Iodide · t_1/2 ~ 5 d · for imaging scans and tx of multinodular hyperparathyroidism.

Pituitary hyperfunction disorders · vast majority due to benign tumors that no longer respond to negative feedback control. Exception: prolactinomas and pituitary adenomas that secrete ACTH (pit. Cushing) are only partially autonomous.

Pituitary hypofunction disorders · Hypopituitarism · pituitary adenomas (micro & macro, MEN, pituitary apoplexy) · Sheehan's syndrome—empty-sella syndrome · Infiltrative diseases

Prolactinoma · prolactin ∝ tumor size · ↓FSH, LH · ↓estradrol, testosterone ·

Labs for hypopituitarism (very useful for your test now . . . I give you hint (slides 24-27) · Gonadotropins (FSH and LH) · cortisol is gluconeogenic ·

Sheehan syndrome · postpartum necrosis · relative anoxia of pregnancy exacerbated by hemorrhage, shock, or other event precipitated by pregnancy, can lead to acute necrosis of anterior pituitary

Go through all the stimulation and suppression tests on pages 12—14 of slides.

Insulin
Rapid-acting · altered peptides don't form hexamers ⇒ dissolve quickly ⇒ good prandial mimic
· insulin lispro
· insulin aspart
· insulin glulisine
Short acting · emergencies · subcutaneous as part of maintenance
· regular insulin (crystalline zinc insulin)
Intermediate · subcutaneous · preciptates ⇒ can't give IV · "twice daily" basal insulins
· isophane insulin (neutral protamine Hagedorn, NPH insulin)
· insulin zinc (lente insulin)
· NPH preferred over lente if mixing b/c lente can retard onset of action for regular insulin
Long-acting
· neutral protamine lispro (insulin lispro protamine, NPL)
· Protamine crystalline (crystal aspart)
· insulin zinc extended (ultralente insulin)
Ultra-long-acting · glargine insulin · microprecipitate in subcutaneous fat delivers constant dose over 20-24 hrs

Insulin stacking: 70% NPH on a 7 hour cycle and 30% regular on a 7 hour cycle leading the NPH by two hours would predictably result in high insulin and hypoglycemia on the second cycle while first NPH is still tapering, the second 30% has been given, and then the next 70% is given.

Impaired glucose tolerance: pre-diabetic · β-cell function is between 80% and 50% · consider insulin if HbA1c approaches 8%
· insulin glargine
· insulin detemir
Insulin analogs ·

Laboratory Thyroid Profile · Free T4 · Resin T3 Uptake · Free T3 · T4 binding ratio (T4BR) · FT4 or FT4 index (FT-I) · Total T4

Thyroiditis
· Acute bacterial thyroiditis · S aureus, S pneumo, S. pyogenes
· Dequervain's Thyroiditis
· Subacute painless thyroiditis
· Reidel's thyroiditis (image)
· Hashimoto's thyroiditis (image)

Hyperthyroid
· Grave's disease · TSI (thyroid stimulating immunoglobulin), a defect in suppressor T-cells, B-cells, synthesize this antibody against the TSH receptor · associated with viral illness · T₄, T₃, RTU, Ft₄, ¹³¹I uptake is high with ↓↓↓TSH (<0.3μU/ml)

Non-toxic goiter · hemorrhages · cysts · varied size of thyroid nodules

Thyroid disease of pregnancy · US Endocrine Society recommends testing thyroid function · NACB guideline 2.3 (TSH & T₄to assess thyroid status and monitor L-T4 therapy) · Serum thyroglobulin

Thyroid disease in neonate

Thyroid testing in Hospitalized patients · NACB Guideline 2.4

Serum thyroglobulin (Tg) · Management of DTC

Interpreting TSH · outline the flowchart

Hypoparathyroidism
Pseudohypoparathyroidism
Primary Hyperparathyroidism · parathyroid adenoma (images) · primary hyperplasia (images) · parathyroid carcinoma (rare)

Other · pretibial myxedema · Plummer's syndrome (Grave's w/o eye signs = Plummer ≠ Plummer-Vinson = webs and iron deficiency) · Chvostek's sign · Trousseau's sign

Pediatrics

Babies have lower renal clearance relative to body weight, thus lower dosing may be required. Gentamicin.

Bilirubinχ · free bili transfers into the liver · ceftriaxone wil compete for bili binding site on albumin. Kernicterus.

Similiarly for liver. Chloramphenicol, which is conjugated to glucuronic acid in the liver and excreted in the bile. Lipid soluble; heyday was 30 years ago when it was used for meningitis. Newborns have physiologic deficiency of hepatic glycuronyl transferase. Grey baby syndrome due to over dosing.

Tetracyclines stain developing teeth, bone. Ciprofloxacin may be used if necessray.

Transplacental passage of medications to the fetus. Can be good (zidovudine for HIV) or bad (others)

Drugs in breast milk: phenobarbitol.

G6PD infant risk: alidixc acid, nitrfurantoin, sulfonamides

♀

Digoxin may increase mortality in women

ACE inhibitors produce more cough in ♀

Elderly

Neisseria · Gonococcus & Meningococcus · Gram− ·

N. gonococci · secondary ascending complications: ♀ PID, ♂ epididymitis · phase & antigenic variation · septic arthritis · less of a capsule · diplococci

N. meningitidis · septicemia & meningitis · capsule · hemolysin · DIC · phagocytes & blood proteins · vaccination works except for Group B · diplococci

Neisseria generally · several species · Gram− · Kidney-bean shaped diplococci · several normal flora species · closely resemles Moraxella & Acinotobacter · All Neisseria are oxidase positive (as are other bugs); if oxidase − then not Neisseria ·

Discriminating Neisseria species · N. meningitidis & N. gonorrhoeae + Modified Thayer-Martin growth media (chocolate agar with antibiotics) · blood agar · nutrient agar · N. gonorrhoeae makes acid from glucose; N meningitidis doesn't.

N. gonorrhoeae · silver drops in eyes · type 4 pili bind CD46, bundle-forming pili · outer surface porin proteins PorA & PorB · Opa protein · piliated organisms bind non-ciliated cells · cross epithelial cells, exiting through basement membrane into lamina propria and invade phagocyte, induces pro-inflammatory cytokines · infectious exudate · polys migrate out to cell surface and the polys are vessels of infection

Evading host defenses · hypervariability of pilin genes (PilE, PilA, PilB, PilS, phase switching between Pil+ & Pil-, antigenic variation) · LOS-lipo-oligosaccharide (sialyation) · induces host to make blocking antibodies against surface proteins which then mask epitopes · Iron acquisition from host
· Hypervariability of pilin genes · multiple copies on the genome, only one expressed at a time b/c only one is upstream of promoter at any given time
· Phase variation · Pil± switching · slipping-strand mispairing produces frameshift mutation in pilC · homologous recombination between pilE and pilS yields large form
· Antigenic variation · changes in DNA sequence of pilE resulting from recombination of different versions of pilE and pilS

Neisseria meningitidis · bacterial meningitis is very severe compared to aseptic meningitis · Binds to and invade ipithelial cells · serum-resistant · mechanisms of iron sequestraton · capsule (A, B, C, Y, ?) · blebs off lipopolysaccharide · 50-75 cases per year · penicillin & cephalosporins (***resistance***)· vaccine is based on capsular polysaccharide · problem with type B is that the antigen would be for sialic acid, which is on host cells

Chlamydiae trachomatis · everyone treated for gonorrhoeae gets treated for chlamydiae · obligate intracellular pathogens⇒can't grow on media (can be grown by other means) · little known about adhesins · EB, elementary body, taken up into endosome · chlamydiae prevents endosome-phagosome fusion, instead endosomes fuse with each other and they form reticulate bodies · smaller than bacteria

Other germs of endearment · papillomavirus · HIV · candida · treponema palidum (syphilis) · Hep B · Herpes ·

Pituitary sends go signal to gonad
Gonad makes germ cells and signals
Gonad sends stop signal to pituitary
Gonad sends go signals to breast, uterus, bone, skin, etc

GnRH · inhibin · FSH receptors (granulosa cells of ovary & sertoli cells in testes) · LH/CG are in overy and leydig cells

Human chorionic gonadotropin for pregnancy test;
GnRH predominantly LH active, spermatogenesis, medically assist undescended testes

Gonadal steroids
· Estrogens · estrogen replacement therapy and contraception · estrogen response element · phytoestrogens (genistein (derived from soy), coumestrol(derived from alfalfa)) · estrogens in many organs (brain, bone, breast, heart, liver) · α & β estrogen receptors (hERα & hERβ) · α is an on effect; β tends to retard the system · phytoestrogens more potent at β than α · ovarian estrogens (estradiol, estrone, estriol) · DES (Diethylstilbestrol - has been used for prostate cancer and estrogen replacement) · premarin · environmental contaminents w/ weak effects (DDT, PCB) · DES associated with clear cell adenocarcinoma of cervix and vagina; risk of effects passing to grandchildren · 17B-estradiol · formed from androstenedione or testosterone · produced primarily in ovaries and placenta · fat cells via aromatase · circulates in plasma bound to α2-globulin (sex-hormone-binding globulin) · neuvaring · 17B-estradiol available as dermal patches, micronized tablets, vaginal creams ("bio-identical" estrogens) · Ethinyl estradiol-synthetic estrogen with ethyne grou at c-17 (orally active) · conjugated estrogens

Patch +: bypasses liver and gut, continuous does, dose can be 1/10thh oral dose, does not raise level of C-reactive protein · binds to nuclear receptor · uses: hypogonadism, w/ progestin to prevent endo metrial carcinoma · sinile atrophic vagnitis · dysmenorrhea · chemical castration · morning after pill · hirsutism · Adverse effects (GI upset, endometrial hyperplasia, vaginal bleeding, breast engorgement, retention of salt & water, cholestatic jaundice & increased gall stone incidence, migraine headaches)

Antiestrogens · clomiphene · tamoxifen (reduces estrogen action in breast, increases estrogen action in uterus · BRCA-1

SERMs · raloxifene, a 1st generation Selective Estrogen Receptor Modulator) change the shape of the estrogen receptor

Progestins

Androgens
Testosterone · Leydig & interstitial cells make it · testosterone→5α-dihydrotestosterone (5α reductase) · testosterone→Estradiol (aromatase, inhibitors function as antitestosterones) · esters are much less polar · muscle mass · anemia · carcinoma of breast · side effects: virilization, hepatic dysfunction, dilation of biliary ducts

Antiandrogens · decrease libido in sex offenders · pattern baldness · finasteride (5α-reductase inhibitor for benign prostate hyperplasia) · SERMs, Selective Progesterone Receptor Modulator(SPRM), Selective Androgen Receptor Modulator (SARM)

Papillomaviruses · polyomaviruses · vacuolating virus (simian vacuolating virus 40 - used in the lab)

Papvaviridae · circular dsDNA · 5-8 kb, 5-10 genes · icosahedral capsid · non-enveloped · 45-55 nm · SV40 is well studied · 3 reading frames · E1-E7 (early) · L1, L2 (late - capsid - target of the new vaccine) · E6 & E7 are involved in transformation of host cells

Polyomavirus family · SV40 · JC · BK · Narrow host range · replicates in nucleus · early gene expression: T antigen · DNA replicatoin · Late gene expression · capsid proteins · Cell lysis · restricted replication in on-permissive cells · like polio, they kill the cells they infect · permissive or non-permissive infection
· permissive cell → productive cycle
· non-permissive → transforming cycle
· original polio vaccines were produced in monkey kidney cells; which introduced many viruses into humans. Probably not HIV, but likely SV40, which appears to be associated with some human tumors (brain tumors, mesotheliomas, osteosarcomas, non-Hodgkin's lymphomas) · LTAg; interacts with RB & p35

BK virus · JC virus (progressive leukoencephalopathy)

Human papillomaviruses · polyomaviruses are similar · ~100 DNA subtypes · induce tumors in the natural host · strict tissue tropism for squamous epithelial cells

Lesions · verrucae vulgarais, plantaris (pedis), planae, butcher's warts, oral focal hyperplasia, kertinization · periunguinal warts · laryngeal papilloma (recurrent respiratory papillomatosis - RRP) · adult and juvenile onset · acetic acid (vinegar) turns the wart white: allows dermatologist to ID otherwise inconspicuous lesions

Virus is very stable in the environment: some cases of warts on hands may be associated with the digging and general unprotected use of hands that drives virus in through microabrasions (wear gloves in the garden)

At least 50% of sexually active people will get HPV at some time · incidence ~6.2 million/yr in US

HPV vaccine is against 6, 11, 16, and 18. 16 & 18 may progress to cancer · Koutsky et al. 2002 NEJM 347:1645 · ♀ 9-26 yo · retail $120/injection, $160/injection under Tulane student health plan · 3 shots over 6 months.

Cures for Warts (maybe) · salicylic acid · duct tape · freeze them off · have to kill the tissue all the way down to the tissue where the virus is replicating, the basal or suprabasal layer. Topical vitamin A · Take a vitamin A capsule, pop it open, spread it into the lesion, frequently. Don't consume capsules orally (risk of overdose). Twice a day, as often as you can think of it (proposed mechanism: Vitamin A speeds up differentiation process so the skin essentially outgrows the virus. The seed bed of virally infected cells gets grown to the top.

Cervical cancer · 10,000 US ♀/yr · 4,000 died in 2006 · mitotic figures in suprabasal layer · Henrietta Lacks had cervical cancer · HeLa cells contain HPV18 · Peitsaro et al 2002

George Papanicolaou · Koliocytosis (rings around the nuclei - keratin?)

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Overview · Insulin resistance · hyperinsulinemia · low HDL · high triglycerides · hyperglycemia & complication · atherosclerosis · hypertension · retinopathy · nephropathy · neuropathy · blindness · renal failure · leg amputation · coronary disease

Fasting glucose for a young healthy person might be 70 or 80. At and over 126, blindess and other complications jump (inflection point is at 125) · hyperglycemia caused by both excess glucose tolerance & impaired glucose clearance (kidney & insulin tolerance)
· glycation of proteins · accumulation of sorbitol & fructose · activation of protein kinase C (eg on vascular cells)
· tissue responses

Microvascular complications are the only complications *specific* to diabetes.

Random plasma glucose · fasting plasma glucose · oral glucose tolerance test (2 hr after 75 g load) · postprandial plasma glucose · Hemoglobin A1C (mean glucose over 2-3 mo) · Fructoseamin/glycated serum protein (mean glucose over 1-2 wks)

Glucose tolerance categories -- Diabetes care. 2004; 27(suppl 1):S5-S10

Gestational diabetes: more of a challenge in susceptible women: many go on to develop Type 2 DM later in life.

Course of Type I diabetes (β cell mass): virus (?) · cellular autoimmunity · circulationg autoantibodies · loss of first-phase insulin response · glucose intolerance (OGTT)

Late onset Type 1 · screen for ICA and GAD antibodies

Type 2 diabetes · review: insulin causes liver to halt glucose production; causes muscles and fat to take up glucose · Almost all obese people are insulin resistant; 80% don't get DM, perhaps b/c they make more insulin · Pima Indians 40% · Africans 10% ·

β-cell mechanism + target cell GLUT4 tranporter

Circulating FFAs, as seen in obese peole, seem to be associated with DM. Fat infusions seems to both increase blood glucose and blood FFAs. Waist circumference is a very good indicator insulin resistance, vascular disease, and mortality.

Eye · retinopathy · glaucoma ·

Kidney ·

Intensive therapy with goal of keeping HbA1c near normal shows 76% delay in complications.

Carbs
· monosaccharides · glucose · fructose (fruit, juices, honey) · galactose (derived from hydrolysis of fructose)
· disaccharides · sucrose (glucose + fructose) · lactose (glucose + galactose) · maltose (glucose + glucose)

Fats · N-3 polyunsaturated fat (fish, canola) · N-6 polyunsaturated fat (safflower, soy, corn)

Protein · 9 essential amino acids · valine · leucine · isoleucine · threonine · lysine · phenylalanine · methionine · tryptophan · histidine · 4 kcal/g · Kwashiorkor (edema, dry, brittle hair and nails, diarrhea, risk of infection, hypoalbuminemia, wasted with abdominal edema) · Marasmus (protein calorie deficiency)

Fat soluble vitamins
· Vit A (retinol stored in liver; orange plants) · vision · reproduction · deficiency (night blindess, xeropthalmia w/ corneal xerosis & keratomalacia, hyperkeratosis, impaired enamel, fat malabsorption) · Toxicity (high ICP, skin peeling, diarrhea, anorexia, bone pain) · β-Carotene (orange plants, converted to retinol in intestine · body can modulate how much is converted to Vit A)
· Vit D · bone development · Vit D3 formed in skin exposed to sun · 200-600 IU/d (5-15μg/d) · 400-1000 IU/d to stabilize bone loss · Rickets · Osteomalacia · Womens Health Initiative (85% deficient)
· Vit E · vegetable oils, milk, eggs, meat, fish
· Vit K · coagulation · Vit K-dependent bone proteins · no toxicity state exists · green leafy vegetables, eggs, liver

Water soluble vitamins
· Vit B1 (thiamin) · rapidly absorbed in duodenum · wet beriberi (cardial enlargement, dsypnea) · dry beriberi (muscle weakness, peripheral neuropathy, ataxia) · Wernicke's Encephalopathy (acoholics get banana bag before hanging glucose, confabultion, nystagmus, opthalmoplegia, not reversible)
· Vit B2 (Riboflavin) · cracked lips, cheilosis, glossitis (magenta tongue) · milk, liver, grains & vegetables
· Niacin
· Vit B6 (Pyridoxine)
· Folic acid
· Vit B12 (Cobalamin) · animal products · ileum · intrinsic factor · megaloblastic anemia · neuropathy
· Vit C (Ascorbic acid) · Scurvy · petechia · non-traumatic bruising
· Calcium · increased absorption w/ Vit D toxicity or hyperparathyroid ·
· Phosphorus
· Magnesium
· Potassium · tomato, melon, ctirus, potatoes, yogurt
· Iron · required for hemoglobin synthesis & redox rxs ·
· Sodium
·
· Iodine
· zinc
·

Metropolitan Life Insurance Company tables based on insurance claims (not used by NIH)
BMI=weight÷height² (kg/m²)

Relative Risk of Disease

Papillomavirus · Condyloma Accuminatum (vulva, rectum—papillary) or Planum (cervix) · 20 sided dsDNA circular virus (envelope?) · 16-25 · incubation 4-6 wks · CIN

Cervical cancer & HPV · 90% of cervical cancers contain oncogenic HPV · Same HPVs are detected in malignancies around world

Pathogenesis · virus integrates at E1/E2 open reading frame (ORF) · E2 disruption removes E6 & E7 repression · E6 degrades p53 via ubiquitin · E7 binds RB, up regulating cyclin & P16NK4 · apoptosis fails; cells inappropriately survive (koilocytes)

Vaccine · NEJM, 2002; 374:1703-05

condyloma → dysplasia → Cervical intraepithelial neoplasia (CIN) → squamous intraepithelial lesion (SIL)

Etiology · HPV, HSV-2 (not causitive, but may facilitate), Immune supression, smoking

HSV-2 · encapsulated dsDNA virus · encodes 30 proteins · neurotropic (HSV-1, -2, varicella-zoster)· lymphotropic (CMV, HHV 6, HHV 7) · gamma group (EBM, HHV8)
· HSV-2 · genital herpes · perinatal infections · disseminated infection · incubation 4-7 days · dysuria, urinary retention, prodromal includes tingling, pain, vesicles, pustules, ulcers · mulitnucleated giant cells w/ ground glass nucei & inclusions (cowdry A - molded nuclei, like seeds of pomegranate) · acyclovir · immunoperoxidase with HSV-specific antibodies · tissue culture
Herpes Neonatorum · Active HSV-2 near term⇒C-section · encephalitis, pneumonia, hepatic necrosis, adrenalitis · lethal
Moluscum contagiosum
CMV · transmitted by every conceivable route · 95% asymptomatic · cytomegalic inclusion disease · intrauterine growth retardation · hepatosplenomegaly, microcephaly, hearing loss, neurologic impairment
HIV · pneumocystis pneumonia · kaposi's sarcoma · on-Hodgkin's lymphoma · squamous cell carcinoma of cervix