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What is the Global Burden of Disease project?

standard for reporting health information about environmental diseases. DALY (disability-adjusted life year) used to assess mortality and morbidity of dz.

What is the single leading global cause of health loss?

undernutrition; 1/3 the disease burden in developing countries. Increase risk of infections related to poor general nutrition or deficiencies in specific nutrients.

Two leading causes of death in developed countries

ischemic heart dz and cerebrovascular dz.

In developing countries, what accounts for 5 of the 10 leading causes of death?

Infectious dz: respiratory infx, HIV, diarrheal dz, TB, malaria

About 70% of all child deaths are attributed to what five dz?

pneumonia, diarrheal dz, malaria, measles, and perinatal/neonatal problems (mostly infx)

How has worldwide mortality of under 5 yo children changed since 1980?

about 27% decline. Does not meet UN goal of 67% decline. Under 5 yo-mortality in Central and West Africa has not sig declined.

3 examples of emerging infectious diseases (EIDs)

1. newly evolved strains or organisms (MRSA, XDF TB, chloroquine-resistant malaria)
2. endemic in other species that have recently entered human population (HIV and SARS)
3. present in human populations but show a recent increase in incidence (dengue fever)

4 aspects of health and disease affected by global warming

1. increase in vector-borne diseases (dengue fever, west nile, hantavirus pulmonary syndrome)
2. malnutrition: due to disrupted crops
3. gastroenteritis and infx dz epidemics: due to contamination after natural disasters
4. CV, cerebV, resp dz: heat waves and air pollution

The concept of a poison is dependent on....

dosage

What are xenobiotics?

exogenous chemicals in air, water, food, soil that may be absorbed through inhalation, ingestion, and skin contact

Most solvents and drugs are of what chemical category?

liophilic, facilitating transport in blood by lipoproteins and penetration through PM into cells

What are the two phases of biotransformation of xenobiotics?

Phase 1: P-450 (CYP family) catalyzes hydrolysis, oxidation, or reduction. Concentrated in ER of liver cells. Can either detoxify or activate xenobiotics.
Phase 2: glucuronidation, sulfation, methylation, and conjugation with glutathione

What can be produced in Phase 1 reactions that is harmful to cells?

ROS
e.g. trichloromethyl free radical from CCL4, DNA binding metabolite from benzo[a]pyrene in cig smoke

What are some inducers of CYP?

environmental chemicals, drugs, smoking, EtOH, and hormones.

What can decrease CYP activity?

fasting or starvation

Mechanism of inducers of CYP

1. bind nuclear receptors
2. heterodimerize with retinoic X receptor
3. form transcriptional activation complex in 5'-flanking region of CYP genes

What nuclear receptors participate in CYP induction?

aryl hydrocarbon receptor, peroxisome proliferator-activated receptors, and two orphan nuclear receptors (androstane receptor and pregnane X receptor)

6 pollutants in outdoor air

1. ozone
2. sulfur dioxide
3. nitrogen dioxide
4. carbon monoxide
5. lead
6. particulate matter

Health effects of ozone exposure

damaged mediated by free radicals, injuring respiratory epithelial cells and type 1 alveolar cells with inflammatory mediator.
Decreased lung function, chest discomfort, ozone-induced asthma (airway hyper-reactivity and neutrophilia)

Health effects of sulfur dioxide exposure

converted into sulfuric acid and sulfuric trioxide
burning sensation in nose and throat, dyspnea, asthma attacks

Health effects of particulate matter (aka soot)

fine or ultrafine particles less than 10 um in diameter are most harmful.
Inhaled into alveoli-->inflammatory mediators (macrophage inflammatory protein 1 alpha and endothelin)
irritation to eyes, throat, lungs, induce asthma attacks, promote myocardial ischemia

What gets damaged most markedly in chronic carbon monoxide poisoning?

ischemia in CNS, especially basal ganglia and lenticular nuclei
impaired memory, vision, hearing, and speech.

Symptoms of acute CO poisoning

characteristic generalized cherry-red color of the skin and MM
brain edema, punctate hemorrhages, hypoxia-induced neuro changes

8 examples of indoor air pollutants

1. tobacco smoke
2. CO
3. NO2
4. asbestos
5. wood smoke
6. bioaerosols
7. radon
8. formaldehyde

Health effects of bioaerosol exposure

microbes causing Legionnaires' dz, viral pneumonia, cold
allergens from pet danger, dust mites, and fungi/molds -->rhinitis, eye irritation, and asthma

Health effects of radon exposure

lung cancer

Health effects of formaldehyde

0.1 ppm or higher-->dyspnea, burning in eyes and throat, asthma; carcinogen

Four heavy metals most commonly associated with harmful effects in humans

1. lead
2. mercury
3. arsenic
4. cadmium

Health problems associated with subclinical lead poisoning

low intellectual capacity, behavior problems, etc

At about twice the max allowed level of lead, what health problems can develop?

increased nerve conduction velocity, increased level of erythrocyte protoporphyrin, decreased vitamin D metabolism, and decreased calcium homeostasis

At about four times the max allowed level of lead, what health problems can develop?

decreased hemoglobin synthesis

At about ten times the max allowed level of lead, what health problems can develop?

encephalopathy, nephropathy, frank anemia, and colic

Where is most lead absorbed into?

bone and developing teeth

Why are children more susceptible to lead poisoning than adults?

higher intestinal absorption (50% versus <15%) and more permeable blood-brain barrier

Bone consequences of lead poisoning in children

interferes with normal remodeling of cartilage and primary bone trabeculae in epiphyses, causing radiodense "lead lines" of increased bone density, also appears in gums

inhibits healing of fx by increasing chondrogenesis and delaying cartilage mineralization.

Hematopoietic consequences of lead poisoning in children

inhibits delta-aminolevulinic acid dehdyratase and ferrochelatase-->microcytic hypochromic anemia

What is used to dx lead poisoning?

detection of elevated blood levels of lead and free (or zinc-bound) red cell protoporphyrin

Morphological changes in lead poisoning

1.Ringed sideroblasts (iron-laden mitochondria) in marrow
2. Microcytic hypochromic anemia with mild hemolysis
3. punctate basophilic stippling of RBCs

CNS and PNS changes in lead poisoning

CNS: brain edema, demyelination of cortical neurons, diffuse astrocytic proliferation

PNS: peripheral demyelinating neuropathy in motor nerves of most commonly used muscles--wristdrop and footdrop

GI and renal changes in lead poisoning

GI: lead colic
Renal: proximal tubular damage, interstitial fibrosis, renal failure, "saturnine gout"

What is especially susceptible to methyl mercury?

developing CNS due to lipid solubility. Binds with high affinity to thiol groups.

What is the main protective mechanism against mercury-induced CNS and kidney damage?

intracellular glutathione acting as a thiol donor

Arsenic trioxide is used to tx what disease?

relapsing acute promyelocytic leukemia.

Three most toxic forms of arsenic

1. arsenic trioxide
2. sodium arsenite
3. arsenic trichloride

Mechanism of arsenic toxicity

interference with mitochondrial ox phos, since trivalent arsenic can replace the phosphates in ATP

Neurological effects of arsenic toxicity

2-8 weeks after exposure
sensorimotor neuropathy--paresthesias, numbness and pain

Most serious consequence of chronic arsenic exposure

development of CA in almost all tissues, particularly lungs and skin.

Skin changes in arsenic exposure

hyperpigmentation and hyperkeratosis-->basal and squamous cell carcinoma. Appears on palms and soles (unlike skin tumors induced by sunlight)

Mechanism of cadmium toxicity

1. obstructive lung dz, due to necrosis of alveolar macrophages
2. kidney damage, due to tubular damage progressing to ESRD
3. skeletal problems, due to calcium loss (osteoporosis and osteomalacia)
4. elevated risk of lung CA due to ROS causing DNA damage

Vinyl chloride: associated disease

liver angiosarcoma

Polychlorinated biphenyls, dioxins, and herbicides: associated diseases

folliculitis and acneiform dermatosis

Benzene and 1,3-butadiene: associated disease

leukemia

Chemicals associated with male infertility

lead, phthalate plasticizers, and cadmium

Chemicals associated with female infertility/stillbirths

lead and mercury

Chemicals associated with teratogenesis

mercury, polychlorinated biphenyls

Chemicals associated with urinary system toxicity

mercury, lead, glycol ethers, solvents

Chemicals associated with bladder CA

naphthylamines, 4-aminobiphenyl, benzidine, rubber products

Chemicals associated with peripheral neuropathies

solvents, acrylamide, methyl chloride, mercury, lead, arsenic

Chemical associated with ataxic gait

DDT

Chemicals associated with CNS depression

chlordane, toluene, acrylamide, mercury

Chemicals associated with cataracts

alcohols, ketones, aldehydes, solvents, UV

Chemicals associated with respiratory fibrosis

silica, asbestos, cobalt

Chemicals associated with respiratory irritation

ammonia, sulfur oxides, formaldehyde

Chemicals associated with respiratory hypersensitivity

beryllium, isocyanates

Chemicals associated with COPD

grain dust, coal dust, cadmium

Chemicals associated with lung CA

radon, asbestos, silica, bis(chloromethyly)ether, nickel, arsenic, chromium, mustard gas, uranium

Chemicals associated with nasal CA

isopropyl EtOH, wood dust

Chemicals associated with heart disease

CO, lead, solvents, cobalt, cadmium

How is benzene metabolized?

hepatic CYP2E1 to toxic metabolites that disrupt differentiation of hematopoietic cells in bone marrow-->aplasia and acute myeloid leukemia

Polycyclic hydrocarbons: diseases associated

lung and bladder CA

Examples of organochlorides

DDT, PCBs, dioxin-->pesticides
PBDEs-->flame retardant

Diseases associated with organochlorides

1. endocrinopathies, having anti-estrogen or anti-androgen effects
2. folliculitis and chloracne dermatosis
3. PCBs induce CYPs-->abnormal drug metabolism

Inhalation of mineral dusts cause what disease?

pneumoconioses: chronic, non-neoplastic lung disease

Toxins in tobacco smoke

tar, polycyclic aromatic hydrocarbons, phenol, benzopyrene, nitrosamine (carcinogenesis and tumor promotion)
CO
nicotine
formaldehyde and nitrogen oxides (toxic to cilia)

What two drugs interact in forming laryngeal CA?

tobacco and EtOH

How is ethanol metabolized?

biotransformed into acetaldehyde in liver by alcohol dehydrogenase (mainly), microsomal ethanol-oxidizing system, and catalase.
ADH in cytosol of hepatocytes
Then, acetaldehyde is converted to acetate by acetaldehyde dehydrogenase (ALDH)
MEOS involves CYPs (esp CYP2E1)

What produces a majority of the toxic effects of alcohol consumption?

Acetaldehyde. Responsible for acute effects of EtOH and for developing oral CA

Allelic variation of what enzyme affects 50% of Asians?

ALDH; very low ALDH activity due to base substitution (ALDH2*2) of one allele

People who cannot oxidize acetaldehyde have what abnormal enzyme?

homozygous for ALDH2*2; nausea, flushing, tachycardia, and hyperventilation

What causes hepatic steatosis and lactic acidosis in alcoholics?

Increased NADH/NAD ratio

How do gram-negative bacteria in the intestinal flora respond to alcohol?

release of endotoxin (lipopolysaccharide) to stimulate TNF production and cytokines from macrophages and Kupffer cells-->hepatic injury

Gastric changes in acute alcoholism

gastritis and ulceration

CNS changes in acute alcoholism

depressant, first affecting subcortical structures (high brain stem reticular formation) modulating cerebral cortical activity.
At higher levels, cortical neurons and then lower medullary centers are depressed.

What vitamin deficiency is common in alcoholics?

thiamine (vitamin B1); causing peripheral neuropathies and Wernicke-Korsakoff syndrome

CV effects of alcohol

dilated congestive cardiomyopathy
heavy EtOH causes decreased levels of HDL
HTN

EtOH is most harmful during which trimester of preg?

first

Mechanism of EtOH-induced laryngeal and esophageal CA

acetaldehyde-DNA adducts

People with this allele who drink are at higher risk of developing esophageal CA

one copy of ALDH2*2 allele

What compound in red wine may have protective effects against CV dz?

resveratrol
activates protein deacetylases of the Sir2 family, including histone deacetylases

Estrogen therapy alone is only used in these patients

hysterectomized women
increased risk of uterine CA in other patients

Findings by the WHI in 2002

combined therapy caused a reduction in fx, but increased risk of breast CA and venous thromboembolism; no effect on preventing CV dz in patients over 60. 10 million drop in therapy in 5 years.

HRT: risk highest and latency times shorter for developing these CA

lobular carcinomas and ductal-lobular CA

CV protective effect of HRT based on:

younger women: response of estrogen receptors regulating calcium homeostasis in blood vessels

Four types of diseases associated with OCs

1. thromboembolism: due to generation of acute-phase response, with increase in CRP and coagulation factors and reduction in anticoagulants
2. CV disease
3. reduce incidence of endometrial and ovarian CA; small increase in breast CA incidence during first 5 years of use
4. Hepatic adenoma

Disease associated with orally administered anabolic steroids

hepatic cholestasis

Metabolism of acetaminophen

95% by phase 2 enzymes, excreted as glucuronate or sulfate conjugates
5% through CYPs (especially CYP2E) to NAPQI, a reactive metabolite. Conjugated to glutathione.

Consequence of acetaminophen overdose

GSH is depleted, so NAPQI accumulates, causing centrilobular necrosis and liver failure

Tx of acetaminophen overdose

N-acetylcysteine, which restores GSH
may need liver transplant in serious overdoses

Mechanism of disease in aspirin overdose

Salicylate causes alkalosis due to stimulating respiratory center in the medulla-->metabolic acidosis to compensate-->accumulation of pyruvate and lactate-->uncoupling of ox phos and inhibition of Krebs cycle
Also, formation of non-ionized forms of salicylates that can diffuse into brain and produce nausea-->coma

Consequences of chronic aspiring toxicity (salicylism)

1.H/A, dizziness, tinnitus, confusion, hearing impairment, n/v/d, drowsiness-->convulsions and coma.
2. acute erosive gastritis-->GI bleeding and gastric ulceration
3. bleeding tendency, petechial hemorrhages

Proprietary analgesic mixtures of ASA and phenacetin or acetaminophen, when taken over several years, can lead to this disease:

analgesic nephropathy: tubulointerstitial nephritis with renal papillary necrosis

Drugs associated with acute dystonic reactions and parkinsonian syndrome

phenothiazine antipsychotics

Drug-induced lupus

hydralazine and procainamide

Abx associated with hepatic steatosis

tetracycline

Drugs associated with hepatic cholestasis

chlorpromazine, estrogens, contraceptives

Drugs associated with asthma

salicylates

Drug associated with acute pneumonitis

nitrofurantoin

Drugs associated with interstitial fibrosis

busulfan, nitrofurantoin, bleomycin

Drugs associated with acute tubular necrosis

aminoglycoside abx, cyclosporin, amphotericin B

Drug associated with glomerulonephritis

penicillamine

Drugs associated with cardiomyopathy

doxorubicin, daunorubicin

Drugs associated with arrhtyhmias

theophylline, hydantoins, digoxin

Drugs associated with skin changes

antineoplastic agents, sulfonamies, hydantoins, some abx, many others

Drugs associated with granulocytopenia, aplastic anemia, and pancytopenia

antineoplastic agents, immunosuppressives, and chloramphenicol

Drugs associated with hemolytic anemia and thrombocytopenia

penicillin, methyldopa, quinidine, and heparin

CV effects of cocaine

sympathomimetic; blocks dopamine reuptake in CNS and epi/NE at adrenergic nerve endings. Also stimulates release of NE. Can precipitate lethal arrhythmias
Causes coronary artery vasoconstriction and enhances platelet aggregation.
Increases oxygen demand while causing vasoconstriction-->MI

CNS effects of cocaine

hyperpyrexia and seizures
likely due to aberrations of dopaminergic pathways that control body temperature

Cocaine effects on pregnancy

decreased blood flow to placenta--fetal hypoxia and spont AB

Mechanism of sudden death in heroin use

profound respiratory depression, arrhythmia and cardiac arrest, and severe pulmonary edema

Mechanism of pulmonary injury in heroin use

edema, septic embolism from endocarditis, lung abscess, opportunistic infections, and FB granulomas from talc and other adulterants

Sites of infections due to heroin use

skin and subQ tissue, heart valves, liver, and lungs
endocarditis: right heart valves (esp tricuspid due to S. aureus)
Viral hepatitis due to shared needles, HIV

Skin changes in heroin use

abscesses, cellulitis, and ulcerations--.scarring, hyperpigmentation and thrombosed veins

Renal changes in heroin use

amyloidosis secondary to skin infections
focal glomerulosclerosis
Heavy proteinuria and the nephrotic syndrome are induced.

How do meth and MDMA work?

meth: releases dopamine in the brain, which slows glutamate release
MDMA: increased serotonin release

How does THC work?

endogenous cannabinoid receptors CB1 and CB2 and endocannabinoids regulate the hypothalamic-pituitary-adrenal axis to modulate control of appetite, food intake, and energy balance, fertility and sexual behavior

Factors influencing mechanical trauma

shape of colliding object, amount of NRG discharged at impact, and tissues/organs bearing the impact

Abrasion

wound produced by scraping or subbin-->removal of superficial layer (e.g. skin abrasions removed only the epidermal layer)

Contusion

bruise, blunt object-->damage to vessels and extravastion of blood into tissues

Laceration

tear or disruptive stretching of tissue due to application of force by a blunt object; intact bridging blood vessels and jagged, irregular edges

Incised wound

inflicted by a sharp instrument with severing of bridging vessels

Puncture wound

long, narrow instrument. Can be penetrating (when it pierces the tissue) or perforating (when traversing a tissue to also create an exit wound)

Factors determining clinical significance of a burn injury

depth of burns, % of body surface involved, internal injuries caused by inhalation of hot and toxic fumes, and promptness/efficacy of therapy

Classification of burns

1. superficial burns (first-degree): confined to epidermis
2. partial thickness burns (second-degree): injury to dermis
3. full-thickness burns (third-degree): extend to subQ or even muscle tissue (fourth-degree)

Greatest threats to life in burn patients

hypovolemic shock, sepsis, and respiratory insufficiency

What develops in heat burns, associated with excess heat loss and an increased need for nutritional support?

hypermetabolic state

Most common opportunistic pathogen during burns

Pseudomonas aeruginosa; also S. aureus and Candida

What has improved mortality from burns?

techniques for early excision and grafting of the burn wound

Long-term consequences of burns

hypertrophic scars and itching

Morphology of burns

grossly, full-thickness burns are white or charred, dry, and anesthetic
Partial-thickness burns are pink or mottled with blisters and painful
Coagulative necrosis, adjacent to vital tissue that accumulates inflammatory cells and marked exudation

What are heat cramps?

loss of electrolytes from sweating

What is heat exhaustion?

sudden onset prostration and collapse, due to hypovolemia from water loss

What is heat stroke?

associated with high temps, high humidity, and exertion.
thermoregulation fails, internal temperature rises above 40 degrees C
Marked vasodilation-->decreased effective circulating blood volume-->hyperkalemia, tachy, arrhythmias, and others.

People with this genetic variation are at increased risk of heat stroke

RYR1-->malignant hyperthermia
ryanodine receptor type 1 in skeletal muscle; SR regulating Ca entry into cytoplasm.

Consequence associated with RYR1 in heat stroke

necrosis of the muscles (rhabdomyolysis) and myocardium due to nitroslyation of the RYR1

What exacerbates hypothermia?

high humidity, wet clothing, and dilation of vessels due to EtOH.

Direct effects of hypothermia

mediated by physical disruptions within cells by high salt concentrations due to crystallization of intra- and extracellular water

Indirect effects of hypothermia

slowly developing chilling--vasoconstriction and increased permeability-->edema and hypoxia
sudden, persistent chilling: ischemic injury and degenerative changes in peripheral nerves; gangrene.

Two types of electrical injuries

burns and V fib or cardiac and respiratory center failure

Factors affecting type and severity of electric burns

1. strength (amps)
2. duration
3. path of current throughout the body

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