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Environmental and Nutritional Diseases (Nutritional Diseases (Obesity: …

- - - - somatic compartment (in skeletal muscles): affected more severely in marasmus
      - visceral compartment (in visceral organs, primarily liver): depleted more severely in kwashiorkor
    - - most severe forms: obvious
      - mild to moderate forms:
        
        u. compare body weight for a given height against standard tables;
        
        other helpful parameters:
        
        fat stores: loss of fat--> measured skinfold thickness (skin + subcutaneous tissue) reduced
        
        muscle mass: somatic pr catabolized--> reflected by reduced circumference of midarm
        
        serum prs: Measurement of serum prs provides a measure of adequacy of visceral pr compartment.
    - - Marasmus: weight <60% of normal for sex, height, and age
        growth retardation + loss of muscle mass bc of catabolism of somatic pr (an adaptive response); visceral compartment (more critical for survival) depleted only marginally (albumin levels either normal or only slightly reduced)
        subcut fat also mobilized + used; Leptin production low--> *hypothalamicpituitary-adrenal axis--> high levels of cortisol--> lipolysis.
        losses of muscle + subcutaneous fat--> extremities are emaciated; head appears too large; Anemia + manifestations of multivitamin deficiencies present; evidence of immune deficiency, partic T cell– mediated--> concurrent infections u. present (impose an additional stress)
      - Kwashiorkor: occurs when pr deprivation> reduction in total calories; weight: 60% to 80% of normal (true loss masked by edema); most common form of PEM seen in African children weaned too early + subsequently fed, almost exclusively, a carbohydrate diet; also high in impoverished countries of Southeast Asia; Less severe forms may occur worldwide in persons w/ chronic diarrheal states (pr not absorbed) or in those w/ chronic pr loss (e.g., pr-losing enteropathies, nephrotic syndrome, or aftermath of extensive burns); Rare cases from fad diets or replacement of milk by rice-based beverages in US.
        severe loss of visceral compartment--> hypoalbuminemia--> generalized or dependent edema
        relative sparing of subcut fat + muscle mass. modest loss of these compartments may also be masked by edema.
        characteristic skin lesions w/ alternating zones of hyperpigmentation, desquamation, and hypopigmentation: “flaky paint” appearance.
        Hair changes: loss of color / alternating bands of pale + darker color, straightening, fine texture, and loss of firm attachment to scalp.
        Other features distinguishing from marasmus: enlarged, fatty liver (reduced synth of carrier prs); development of apathy, listlessness, and loss of appetite.
        As in marasmus: vitamin deficiencies + defects in immunity and secondary infections. In kwashiorkor, inflammation caused by infection--> catabolic state that aggravates malnutrition.
      - Secondary PEM: common in chronically ill / hospitalized
        patients.
        A partic severe form: cachexia, often develops in advanced cancer; often presages death. loss of appetite may partly explain it, but may appear before appetite decrs. “cachectins” such as proteolysis-inducing factor, secreted by tumor cells, + cytokines, partic TNF, part of host response--> directly stimulate degradation of skeletal muscle prs; (cytokines such as TNF also stimulate fat mobilization from lipid stores.)
    - - liver: in kwashiorkor, but not in marasmus, enlarged + fatty; superimposed cirrhosis rare.
      - small bowel: In kwashiorkor (rarely in marasmus): decr in mitotic index in crypts of glands--> mucosal atrophy--> loss of villi + microvilli--> loss of small intestinal Es: most often manifested as disaccharidase deficiency--> lactate intolerant initially + may not respond well to full-strength, milk-based diets; With treatment, the mucosal changes are reversible.
      - bone marrow: may be hypoplastic in both (mainly bc of decr #s of RBC precursors; deficiency of pr, folates + decr synth of transferrin, ceruloplasmin)--> anemia u. present, most often hypochromic, microcytic anemia, but a concurrent deficiency of folates--> mixed microcytic-macrocytic anemia.
      - brain: infants born to malnourished mothers + who suffer from PEM during first 1 or 2 yrs: cerebral atrophy, a reduced # of neurons, impaired myelination of white matter.
      - Many other changes: (1) thymic + lymphoid atrophy (more marked in kwashiorkor) (2) anatomic alterations induced by intercurrent infections, partic w/ endemic helminths and other parasites, and (3) deficiencies of other required nutrients such as iodine and vits)
  - - - effects on endocrine prominent: decr secretion of GRH--> Amenorrhea (so common that its presence is almost a diagnostic feature); decr thyroid hormone release (cold intolerance, bradycardia, constipation, and changes in the skin and hair); dehydration + electrolyte abnormalities frequent; low estrogen levels-->Bone density decr
      - skin: dry, scaly, may be yellow-tinged (excess carotene in blood.) Body hair may be incr but u. is fine + pale (lanugo).
      - anemia, lymphopenia, and hypoalbuminemia (like PEM)
      - major complication: incr susceptibility to cardiac arrhythmia + sudden death, both due to hypokalemia.
    - - menstrual irregularities are common, amenorrhea occurs in <50% of bulimic patients, probably bc weight + gonadotropin levels normal. major medical complications: no specific signs + symptoms for this syndrome, diagnosis must rely on a comprehensive psychologic assessment of the patient.
        
        (1) electrolyte imbalances (hypokalemia)--> cardiac arrhythmias;
        
        (2) pulmonary aspiration of gastric contents;
        
        (3) esophageal and stomach rupture;
  - - - • Poverty. often suffer from pr-energy malnutrition (PEM) as well as trace nutrient deficiencies.
      - • Ignorance. about incr nutritional needs + nutritional content of various foods also contributes to malnutrition, as follows:
        
        (1) iron deficiency often in infants fed exclusively artificial milk diets;
        
        (2) polished rice used as mainstay of a diet may lack adequate amounts of thiamine;
        
        (3) iodine often lacking from food + water in regions removed from oceans, unless supplementation.
      - • Chronic alcoholism. sometimes suffer from PEM but more frequently lacking in several vits, esp thiamine, pyridoxine, folate, and vitamin A, as a result of dietary deficiency, defective GI absorption, abnormal nutrient utilization and storage, increased metabolic needs, and an increased rate of loss.(failure to recognize thiamine deficiency in chronic alcoholism may--> irreversible brain damage (e.g., Korsakoff psychosis))
      - • Acute and chronic illnesses. BMR accelerated in many illnesses (in patients w/ extensive burns, may double)--> incr requirements for all nutrients. Failure may delay recovery. PEM often present in patients w/ metastatic cancers
      - • Self-imposed dietary restriction. Anorexia nervosa, bulimia, and less overt eating disorders
      - • Other causes. include GI diseases, acquired and inherited malabsorption syndromes, specific drug therapies (which block uptake or utilization of particular nutrients), and total parenteral nutrition.
  - - - Functions:
        
        • normal vision in reduced light:
        
        visual process involves 4 forms of vit A–containing pigments: rhodopsin (most lightsensitive pigment therefore imp in reduced light, in rod cells) + 3 iodopsins (each for a specific color in bright light, in cone cells)
        
        synth of rhodopsin from retinol: (1) oxidation to all-trans-retinal, (2) isomerization to 11-cis-retinal, and (3) + opsin--> rhodopsin;
        A photon--> 11-cis-retinal to all-trans-retinal + a sequence of configuration changes in rhodopsin--> visual signal-->nerve impulse generated (changes in membr potential)
        Retinoic acid, should be noted, has no effect on vision.
        
        During dark adaptation: some of all-transretinal reconverted, but most reduced to retinol + lost to retina: need for continuous supply of retinol.
        one of the earliest manifestations of deficiency: impaired vision, particularly in reduced light (night blindness).
        
        • differentiation
        
        of specialized epithelial cells, mainly mucus-secreting cells (deficiency: undergoes squamous metaplasia + differ to a keratinizing epith)
        
        upper respiratory passage: Loss of mucociliary epith--> pulmonary infections
        
        urinary tract: desquamation of keratin debris--> renal + bladder stones.
        
        epidermis: Hyperplasia + hyperkeratinization w/ plugging of ducts of adnexal glands--> follicular or papular dermatosis.
        
        most devastating changes: eyes: xerophthalmia (dry eye).
        lachrymal + mucus-secreting epith replaced by keratinized epith--> dryness of conjunctiva (xerosis conjunctivae)--> buildup of keratin debris in small opaque plaques (Bitot spots)--> erosion of roughened corneal surface--> softening + destruction of cornea (keratomalacia) and total blindness; Fig 7-19
        
        of myeloid cells: All-trans–retinoic acid (ATRA) (potent) binds to retinoic acid Rs (RARs): basis for ability of ATRA to induce remission of acute promyelocytic leukemia (APML)
        (APML): t(15 : 17) translocation--> fusion of a truncated RARA gene on chromo 17 w/ PML gene on chromo 15--> fusion gene encodes an abnormal RAR--> blocks expression of genes required for myeloid cell differentiation; Pharmacologic doses of ATRA overcome block--> malignant promyelocytes differ into neutrophils and die. (+ other conventional chemotherapeutic agents or arsenic salts, ATRA therapy is often curative in APML)
        
        • Enhancing immunity (by stimulating it) to infections, partic in children w/ measles
        
        -can reduce morbidity + mortality rates for common infections such as measles (partic malnourished ones, ex eye damage + blindness), pneumonia, and infectious diarrhea (maintenance + restoration of gut epith integrity); In places w/ high prevalence of vit A deficiency, dietary supplements reduce mortality rates for infectious disorders by 20-30%.
        
        -inducing acute phase response--> inhibit RBP synth in liver--> decr in circulating retinol--> decr tissue availability of vit A.
        
        • retinoids, β-carotene, and some related carotenoids: photoprotective + antioxidant. Retinoids have broad biologic effects, (effects on embryonic development, cellular differentiation and proliferation, and lipid metabolism)
      - fatsoluble compounds including retinol (chemical name for vit A; transport form; storage form (as retinol ester)), retinal, and retinoic acid, which have similar biologic activities.
        retinoids: both natural + synthetic chemicals structurally related to vitn A but not necessarily w/ vit A activity.
        recommended dietary allowance for vit A: retinol equivalents
      - Deficiency States.
        in newborn infants absorption is poor
        In children, stores depleted by infections
        In adults, may develop w/ malabsorption syndromes (celiac disease, Crohn disease, and colitis) Bariatric surgery + continuous use of mineral oil laxatives also may lead to deficiency
      - Vitamin A Toxicity.
        
        acute hypervitaminosis A: headache, dizziness, vomiting, stupor, and blurred vision
        
        Chronic toxicity: weight loss, anorexia, nausea, vomiting, and bone and joint pain. (Retinoic acid stimulates osteoclast production and activity--> incr bone resorption + consequent high risk of fractures) Although synthetic retinoids used for the treatment of acne are not associated with these complications, their use in pregnancy must be avoided because of the well-established teratogenic effect of retinoids.
    - - MORPHOLOGY
        The basic derangement in both rickets and osteomalacia is an excess of unmineralized bone matrix.
        rickets:
        • Overgrowth of epiphyseal cartilage due to inadequate provisional calcification + failure of the cartilage cells to mature and disintegrate
        • Persistence of distorted, irregular masses of cartilage, many of which project into the marrow cavity
        • Deposition of osteoid matrix on inadequately mineralized cartilaginous remnants
        • Disruption of the orderly replacement of cartilage by osteoid matrix, with enlargement and lateral expansion of the osteochondral junction (Fig. 7–21, B)
        • Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone resulting from microfractures and stresses on the inadequately mineralized, weak, poorly formed bone
        • Deformation of the skeleton due to the loss of structural rigidity of the developing bones
        The gross skeletal changes depend on the severity of the rachitic process; its duration; and, in particular, the stresses to which individual bones are subjected. During the nonambulatory stage of infancy, the head and chest sustain the greatest stresses. The softened occipital bones may become flattened, and the parietal bones can be buckled inward by pressure; with the release of the pressure, elastic recoil snaps the bones back into their original positions (craniotabes). An excess of osteoid produces frontal bossing and a squared appearance to the head. Deformation of the chest results from overgrowth of cartilage or osteoid tissue at the costochondral junction, producing the “rachitic rosary.” The weakened metaphyseal areas of the ribs are subject to the pull of the respiratory muscles, causing them to bend inward and creating anterior protrusion of the sternum (pigeon breast deformity). The inward pull at the margin of the diaphragm creates the Harrison groove, girdling the thoracic cavity at the lower margin of the rib cage. The pelvis may become deformed. When an ambulating child develops rickets, deformities are likely to affect the spine, pelvis, and long bones (e.g., tibia), causing, most notably, lumbar lordosis and bowing of the legs (Fig. 7–21, C). In adults, the lack of vitamin D deranges the normal bone
        remodeling that occurs throughout life. The newly formed osteoid matrix laid down by osteoblasts is inadequately mineralized, producing the excess of persistent osteoid that is characteristic of osteomalacia. Although the contours of the bone are not affected, the bone is weak and vulnerable to gross fractures or microfractures, which are most likely to affect vertebral bodies and femoral necks. On histologic examination, the unmineralized osteoid can be visualized as a thickened layer of matrix (which stains pink in hematoxylin and eosin preparations) arranged about the more basophilic, normally mineralized trabeculae
      - Toxicity. Prolonged exposure to normal sunlight does not produce an excess of vitamin D, but megadoses of orally administered vitamin can lead to hypervitaminosis. In children, hypervitaminosis D may take the form of metastatic calcifications of soft tissues such as the kidney; in adults, it causes bone pain and hypercalcemia. As a point of some interest, the toxic potential of this vitamin is so great that in sufficiently large doses it is a potent rodenticide!
    - - antioxidant properties: scavenge free radicals directly + participation in metabolic reactions that regenerate antioxidant form of vit E.
        mild antihistamine action
      - Deficiency States: scurvy
        
        sometimes encountered as a secondary deficiency, partic among elderly persons, ppl who live alone, chronic alcoholics—(erratic + inadequate eating patterns)
        
        Occasionally in those undergoing peritoneal dialysis + hemodialysis + among food faddists.
      - Toxicity: promptly excreted in urine but may cause uricosuria + incr absorption of iron, w/ potential for iron overload.
  - - - ghrelin: produced in stomach; only known gut peptide that incr food intake (by *NPY/AgRP neurons in hypothalamus); normally rises before meals + falls 1-2 hrs afterward, but this drop is attenuated in obese.
      - peptide YY (PYY): secreted from endocrine cells in ileum + colon in response to consumption; *POMC/ CART neurons in hypothalamus-->decr intake.
    - - • insulin resistance + hyperinsulinemia--> retention of Na, expansion of blood v, production of excess norepinephrine, and smooth muscle prolif: hallmarks of hypertension (risk incr proportionately w/ weight)
      - • hyperTG + low HDL cholesterol--> incr risk of coronary artery disease. (relates more to associated diabetes + hypertension than to weight per se.)
      - • incr incidence of certain cancers: underlying mechanisms multiple: One: hyperinsulinemia--> incr Insulin-like GF-1--> growth + survival of many types of cancer cells by *its R.
        
        men: esophagus, thyroid, colon, and kidney; associated w/ 14% of cancer deaths
        
        women: esophagus, endometrium (may be indirect: obesity--> incr estrogen levels--> incr risk of endometrial cancer) (breast cancer: data controversial), gallbladder, and kidney; associated w/ 20% of cancer deaths
      - • Nonalcoholic steatohepatitis (nonalcoholic fatty liver disease) commonly associated w/ obesity + DMII; can progress to fibrosis + cirrhosis
      - • Cholelithiasis (gallstones) 6x more common; incr in total body cholesterol--> incr cholesterol turnover--> augmented biliary excretion of cholesterol in bile
      - • Hypoventilation (pickwickian) syndrome is a constellation of respiratory abnormalities in very obese; Hypersomnolence, both at night + day, is characteristic and is often associated w/ apneic pauses during sleep, polycythemia, and eventual R heart failure.
      - • degenerative joint disease (osteoarthritis): typically appears in older persons, attributed in large part to cumulative effects of wear and tear on joints.
      - • Markers of inflammation (ex CRP) + pro-inflammatory cytokines (ex TNF) often bc: direct pro-inflammatory effect of excess circulating lipids + incr release of cytokines from fat-laden adipocytes; chronic inflammation may contribute to many of complications of obesity (insulin resistance, metabolic abnormalities, thrombosis, cardiovascular disease, and cancer)
    - - output of leptin reg by adequacy of fat stores:
        
        abundant adipose tissue--> *leptin secretion---> in hypoth: decr intake by stimul POMC/CART + inhibiting NPY/AgRP neurons.
        
        inadequate stores: Leptin secretion diminished + intake incr.
        
        stable weight: pathways are balanced.
      - incr energy expenditure by stimulating physical activity, energy expenditure, and thermogenesis (efferent hypothalamic signals--> incr release of nor-epi from symp nerve endings in adipose tissue--> β3-adrenergic Rs on fat cells--> FA hydrolysis + uncouple energy production from storage)
      - loss-of-function mutations in leptin pathway--> massive obesity. (fail to sense adequacy of fat stores)
        -mutations of leptin gene (LEP) or R in humans: rare
        -More common: mutations in melanocortin R-4 gene (MC4R) gene (in 4-5% of patients w/ massive obesity)
        -many obese persons have high blood leptin levels, suggesting leptin resistance is prevalent among humans.
    - - • weight in relation to height, ex: BMI= kg/m2
        
        18-25: norm
        
        25-30 overweight
        
        30 obese. (In following discussion obesity is applied to both the overweight and the truly obese)
      - • Skinfold measurements
      - • Various body circumferences, partic waist-to-hip circumference ratio
  - - - • Hypertension reduced by restricting Na
      - • Dietary fiber, or roughage, against diverticulosis of colon.
      - • Caloric restriction incr life span
      - • garlic against heart disease
  - - - vit C and E, β-carotenes, selenium: anticarcinogenic bc of antioxidant properties. (however, no convincing evidence that these act as chemopreventive agents)
      - retinoic acid promotes epithelial differentiation + believed to reverse squamous metaplasia
    - - aflatoxin imp in development of hepatocellular carcinomas in parts of Asia and Africa; exposure--> specific mutation (codon 249) in P53 gene (can be used as a molecular signature for aflatoxin exposure)
      - Some artificial sweeteners (cyclamates + saccharin) implicated in pathogenesis of bladder cancers
    - - High fat intake--> incr level of bile acids in gut--> modifies intestinal flora (favoring growth of microaerophilic bacteria)--> metabolites produced might serve as carcinogens or promoters.
      - high-fiber: (1) incr stool bulk + decr transit time--> decr exposure of mucosa to offenders (2) capacity of certain fibers to bind carcinogens
- - - - Toxicity:
        begins w/ nausea, vomiting, diarrhea, and sometimes shock, followed in a few days by appearance of jaundice.
        
        can be treated in early stages by administration of N-acetylcysteine, which restores GSH.
        
        serious overdoses-->liver failure + centrilobular necrosis may extend to involve entire lobules; patients often require liver transplantation for survival. Some patients also show evidence of concurrent renal damage.
      - toxic doses (15 to 25 g)--> NAPQI accumulates-->(1) covalent binding to hepatic prs + (2) depletion of reduced glutathione (GSH)--> centrilobular hepatic necrosis
        accidental overdoses occur in children + suicide attempts
      - therapeutic doses (u. 0.5 g):
        mostly conjugated in liver w/ glucuronide or sulfate.
        5% or less metabolized to NAPQI (N-acetyl-pbenzoquinoneimine) through hepatic P-450 system.
    - - Chronic aspirin toxicity (salicylism): persons taking 3 gm or more daily (dose used to treat chronic inflammatory conditions);
        
        manifested by headache, dizziness, ringing in ears (tinnitus), difficulty in hearing, mental confusion, drowsiness, nausea, vomiting, and diarrhea; CNS changes may progress to convulsions + coma.
        
        morphologic:
        
        acute erosive gastritis may--> overt or covert GI bleeding--> gastric ulceration;
        
        bleeding tendency (bc aspirin irreversibly inhibits platelet COX + blocks ability to make TxA2, an activator of platelet aggregation) Petechial hemorrhages may appear in skin + internal viscera; bleeding from gastric ulcerations may be exaggerated.
      - Proprietary analgesic mixtures of aspirin and phenacetin or its active metabolite, acetaminophen, when taken over several yrs--> tubulointerstitial nephritis w/ renal papillary necrosis (analgesic nephropathy)
    - - • Hepatic adenoma: well-defined association btw use of OCs + this rare benign hepatic tumor, esp in older women who have used OCs for prolonged periods; tumor appears as a large, solitary, and well-encapsulated mass.
      - • CVD: seems that OCs do not incr risk of coronary artery disease in women <30 yrs or in older women who are nonsmokers, but risk does x2 in women older than 35 yrs who smoke.
      - • Thromboembolism: (including newer low-dose (<50 µg of estrogen) preparations) associated w/ a 3-6x incr risk of venous thrombosis + pulmonary thromboembolism resulting from incr hepatic synthesis of coagulation factors; risk may be even higher w/ newer “3rd-gen” OCs that contain synthetic progestins, partic in women who are carriers of factor V Leiden mutation; (risk of thromboembolism associated w/ OC use is 2-6x lower than risk of thromboembolism associated w/ pregnancy)
      - • Cervical cancer: OCs may incr risk of cervical carcinomas in women infected w/ HPV, although it is unclear whether incr risk results from sexual activity.
      - • Endometrial cancer + ovarian cancers: OCs have a protective effect against these tumors.
      - • Breast carcinoma: do not cause an incr in breast cancer risk.
    - - main adverse effects of HRT:
        
        • HRT w/ estrogen alone--> incr risk of endometrial cancer 3-6x after 5 yrs of use + >10x after 10 yrs; risk is drastically reduced or eliminated when progestins added
        longterm HRT w/ estrogens + progestins: incr risk of breast cancer
        
        • HRT w/ estrogen, w/ or w/o progestins--> incr risk of thromboembolism, including deep vein thrombosis, pulmonary embolism, and stroke, by several-fold; increase is more pronounced during first 2 years of treatment + in association w/ other risk factors (immobilization or factor V or prothrombin mutations)
        
        • Estrogens + progestins incr blood levels of HDL + decr levels of LDL; was thought that HRT would be beneficial in protecting against atherosclerosis + ischemic heart disease; byt studies did not demonstrate a protective effect of HRT against myocardial infarction
      - endogenous hyperestrinism incr risk of endometrial + probably breast carcinoma; Recent data have confirmed adverse effects of HRT on endometrial + breast cancers but do not support protection against ischemic heart disease.
  - - - • Chronic cocaine use may cause
        
        (1) perforation of the nasal septum in snorters
        
        (2) decr in lung diffusing capacity in users who inhale the smoke
        
        (3) the development of dilated cardiomyopathy
      - • Effects on the fetus: may cause decr blood flow to placenta--> fetal hypoxia + spontaneous abortion; Neurologic development may be impaired in fetuses of pregnant women who are chronic drug users.
      - • CNS effects. most common CNS findings: hyperpyrexia (thought to be caused by aberrations of dopaminergic pathways that control body temp) + seizures.
      - • Cardiovascular effects: most serious physical effects; tachycardia, hypertension, and peripheral vasoconstriction; causes coronary artery vasoconstriction + promotes thrombus formation by facilitating platelet aggregation. Cigarette smoking potentiates cocaine-induced coronary vasospasm.
        
        incr myocardial oxygen demand by its sympathomimetic action + reducing coronary blood flow-->often myocardial ischemia(basis multifactorial)--> myocardial infarction.
        
        also can precipitate lethal arrhythmias by enhanced sympathetic activity + disrupting normal ion (K+, Ca2+ , Na+ )
        transport in myocardium.
        
        These toxic effects are not necessarily dose-related, and a fatal event may occur in a first-time user w/ what is a typical mood-altering dose.
    - - can be categorized etiologically according to (1) pharmacologic action of agent, (2) reactions to cutting agents or contaminants, (3) hypersensitivity reactions to drug or its adulterants, and (4) diseases contracted through sharing of needles
      - • Sudden death: u. related to overdose (bc drug purity generally is unknown + may range from 2-90%); sometimes due to loss of tolerance for drug, such as after a period of incarceration; mechanisms of death: profound respiratory depression, arrhythmia and cardiac arrest, and pulmonary edema.
      - • Pulmonary disease: edema, septic embolism, lung abscess, opportunistic infections, and foreign body granulomas from talc and other adulterants. Although granulomas occur principally in lung, also sometimes found in spleen, liver, and lymph nodes that drain the upper extremities. Examination under polarized light often highlights trapped talc crystals, sometimes enclosed within foreign body giant cells
      - • Infections: common; sites most commonly affected: skin + subcutaneous tissue, heart valves, liver, and lungs; ex endocarditis (often takes a distinctive form involving R-sided heart valves, partic tricuspid); Most cases caused by s. aureus, but fungi + others also; Viral hepatitis most common infection among addicts (acquired by sharing dirty needles).
      - • Skin lesions: Cutaneous lesions probably are most frequent telltale sign of heroin addiction. Acute changes include abscesses, cellulitis, and ulcerations due to subcutaneous injections. Scarring at injection sites, hyperpigmentation over commonly used veins, and thrombosed veins are the usual sequelae of repeated IV inoculations.
      - • Renal problems. Kidney disease relatively common; two forms most frequently encountered are amyloidosis (generally secondary to skin infections) + focal glomerulosclerosis; both induce heavy proteinuria and nephrotic syndrome.
    - - untoward anecdotal: allergic/idiosyncratic reactions or possibly related to contaminants in preparations,
      - beneficial: its capacity to decr intraocular P in glaucoma + to combat intractable nausea secondary to cancer chemotherapy.
      - CNS: distort sensory perception + impair motor coordination, but these acute effects generally clear in 4-5 hrs. continued use--> may progress to cognitive + psychomotor impairments (inability to judge time, speed, and distance); Among adolescents, such impairment often leads to automobile accidents.
      - cardiovascular: incr heart rate + sometimes blood P; may cause angina in a person w/ coronary artery disease.
      - lungs: affected by chronic marijuana smoking; laryngitis, pharyngitis, bronchitis, cough, hoarseness, and asthma-like symptoms; along w/ mild but significant airway obstruction.
      - Smoking a marijuana cigarette, compared with a tobacco cigarette, is associated w/ a 3x incr in amount of tar inhaled + retained in lungs, as a consequence of deeper inhalation and longer breath holding.
    - - PCP (1-(1-phenylcyclohexyl) piperidine), or phenylcyclidine, and ketamine (related anesthetic agents);
      - lysergic acid diethylamide (LSD), the most potent hallucinogen known; Acutely, has unpredictable effects on mood, affect, and thought, sometimes leading to bizarre and dangerous behaviors.
      - “ecstasy” (3,4-methylenedioxymethamphetamine [MDMA]); Chronic use may deplete CNS of serotonin, potentially leading to sleep disorders, depression, anxiety, and aggressive behavior.
      - oxycodone (an opiate).
- - - - Sulfur dioxide, particles, and acid aerosols emitted by coal- and oil-fired power plants and industrial processes burning these fuels. Of these, particles appear to be main cause of morbidity and death.
      - Carbon monoxide (CO): nonirritating, colorless, tasteless, odorless gas; low levels: impaired respiratory function but u. not life-threatening; working in confined enviro w/ high exposure to fumes (tunnel + underground garage workers)--> chronic poisoning.
        
        MORPHOLOGY
        
        Chronic poisoning: develops bc carboxyhemoglobin is remarkably stable--> w/ low-level persistent exposure to CO, may accumulate to a life-threatening [ ]--> slowly developing hypoxia -->insidiously evoke widespread ischemic changes in brain (partic marked in basal ganglia + lenticular nuclei); cessation of exposure to CO--> u. recovers, but there may be permanent neurologic damage; diagnosis of CO poisoning is based on detection of high levels of carboxyhemoglobin in blood
        
        Acute poisoning: In light-skinned people: charac generalized cherry red color of skin + mucous membranes (carboxyhemoglobin);
        
        If death occurs rapidly: morphologic changes may not be present;
        
        longer survival: brain may be slightly edematous + exhibit punctate hemorrhages + hypoxia-induced neuronal changes (not specific; simply imply systemic hypoxia)
        
        survive: complete recovery possible; however, sometimes impairments of memory, vision, hearing, and speech may remain.
        
        a systemic asphyxiant that kills by binding to Hb (200x greater affinity for CO than for O2) -->Hypoxia (Systemic hypoxia appears when Hb is 20-30% saturated w/ CO )--> CNS depression--> unconsciousness + death probable w/ 60-70% saturation.
      - ozone
    - - Wood smoke: contains various oxides of N + C particulates; irritant predisposing to lung infections + may contain carcinogenic polycyclic hydrocarbons.
      - Radon: radioactive gas derived from uranium, widely present in soil + homes. low-level chronic exposures in home don't incr lung cancer risk, at least for nonsmokers.
      - Bioaerosols may contain pathogenic microbiologic agents, (Legionnaires’ disease, viral pneumonia, common cold) as well as allergens derived from pet dander, dust mites, and fungi and molds, which can cause rhinitis, eye irritation, and even asthma
  - - - ingested in large quantities--> acute toxicity manifesting as severe GI, cardiovascular, and CNS disturbances often--> death.
        (bc of interference w/ mitC oxidative phos phorylation)
      - Chronic exposure
        
        --> hyperpigmentation + hyperkeratosis of skin--> basal + squamous cell carcinomas (but not melanomas); Arsenicinduced skin tumors differ from those induced by sunlight by appearing on palms and soles, and by occurring as multiple lesions.
        
        -->incr risk of lung carcinoma
    - - Excessive intake--> obstructive lung disease + renal toxicity (initially tubular damage may-->end-stage disease) + skeletal abnormalities (ca loss)
      - contaminated water used to irrigate rice--> disease in postmenopausal women: “itai-itai” (ouch-ouch): combination of osteoporosis + osteomalacia w/ renal disease.
    - - Inorganic mercury--> organic compounds (methyl mercury) by bacteria--> enters food chain (in carnivorous fish may be a million x higher than in surrounding water)
      - “Minamata disease”: cerebral palsy, deafness, blindness, and major CNS defects in children exposed in utero. (developing brain extremely sensitive to methyl mercury)
    - - diagnosis
        
        suspected: on basis of neurologic changes in children or unexplained anemia w/ basophilic stippling in RBCs.
        
        definitive diagnosis: Elevated blood lead + blood levels of zinc-protoporphyrin or its product, free RBC protoporphyrin (>50 µg/dL); In milder cases, anemia may be only obvious abnormality
      - The major anatomic targets of lead toxicity are the blood, bone marrow, nervous system, GI tract, and kidneys
        young children: sensory, motor, intellectual, and psychologic impairments (reduced IQ, learning disabilities, retarded psychomotor development, and, in more severe cases, blindness, psychoses, seizures, and coma)
        Lead toxicity in mother may be the cause of impairment of prenatal brain development. some defects may be permanent. At more severe end of spectrum: brain edema, demyelination of cerebral and cerebellar white matter, and necrosis of cortical neurons accompanied by diffuse astrocytic proliferation.
  - - - ex chloroform + CCl4;
        
        Acute exposure to high levels of vapors--> dizziness + confusion--> CNS depression + even coma.
        
        Lower levels: toxicity for liver + kidneys.
      - Occupational exposure of rubber workers: 1,3-butadiene + benzene --> (CYP2E1 oxidizes to an epoxide--> disrupt progenitor cell diff in bone marrow--> marrow aplasia + acute myeloid leukemia
    - - used as pesticides: DDT + its metabolites such as lindane, aldrin, and dieldrin; Acute DDT poisoning--> neurologic toxicity.
      - Nonpesticide: PCBs + dioxin TCDD--> skin disorders: folliculitis + acneiform dermatosis known as chloracne (consists of acne, cyst formation, hyperpigmentation, and hyperkeratosis, generally around face and behind ears) can be accompanied by abnormalities in liver and CNS.
        PCBs induce P-450--> may show altered drug metabolism.
- - - - Injury to myocardium may--> dilated congestive cardiomyopathy (alcoholic cardiomyopathy)
      - Moderate amounts of alcohol (one drink/day)--> incr serum levels of HDLs + inhibit platelet aggregation--> protecting against coronary heart disease.
      - heavy consumption, w/ attendant liver injury,--> decr HDL
        incr incidence of hypertension.
- - - - abrasion: a wound produced by scraping/rubbing skin surface, damaging superficial layer. Typical skin abrasions remove only epidermal layer.
      - contusion/bruise: a wound usually produced by a blunt trauma + charac by damage to vessel + extravasation of blood into tissues.
      - laceration: a tear or disruptive stretching of tissue caused by application of force by a blunt object. In contrast w/ an incision, most lacerations have intact bridging blood vessels and jagged, irregular edges.
      - incised wound: one inflicted by a sharp instrument. bridging blood vessels are severed.
      - puncture wound: typically caused by a long, narrow instrument
        
        penetrating when instrument pierces tissue
        
        perforating when it traverses a tissue to also create an exit wound
        
        Gunshot wounds: special forms of puncture wounds; a wound from a bullet fired at close range leaves powder burns, whereas one fired from >4 or 5 feet away does not.
      - Injuries typically sustained in vehicular accident
        
        result from (1) hitting a part of interior of vehicle or being hit by objects that enter passenger compartment during crash, such as engine parts; (2) being thrown from vehicle; or (3) being trapped in a burning vehicle.
        
        pattern of injury relates to whether one or all three of these mechanisms are operative.
        ex: in a head-on collision, a common pattern of injury sustained by a driver who is not wearing a seat belt: trauma to head (windshield impact), chest (steering column impact), knees (dashboard impact). Common chest injuries: sternal + rib fractures, heart contusions, aortic lacerations, and (less commonly) lacerations of spleen and liver. Thus, in caring for an automobile injury victim, it is essential to recognize that internal wounds often accompany superficial abrasions, contusions, and lacerations. Indeed, in many cases, external evidence of serious internal damage is completely absent.
  - - - gross
        
        full-thickness burns are white or charred, dry, and anesthetic (as a result of destruction of nerve endings),
        
        partial-thickness burns, depending on depth, are pink or mottled, blistered and painful.
      - Histologic: coagulative necrosis adj to vital tissue, which quickly accumulates inflam cells + marked exudation.
      - extent of burns
        
        50% of total body surface, superficial or deep,: grave + potentially fatal.
        
        20% of body surface--> rapid shift of body fluids into interstitial compartments, both at burn site + systemically --> hypovolemic shock; bc pr from blood is lost into interstitial tissue, generalized edema, including pulmonary edema, may become severe.
      - Inhalation injury frequent in persons trapped in burning buildings;
        cause:
        
        direct effect of heat on mouth, nose, upper airways
        
        inhalation of heated air + gases in smoke;
        
        Water-soluble gases (chlorine, sulfur oxides, and ammonia) may react w/ water to form acids or alkalis, partic in upper airways--> inflam + swelling--> partial or complete airway obstruction.
        
        Lipid-soluble gases (nitrous oxide + products of burning plastics) more likely to reach deeper airways-->pneumonitis.
        Unlike in shock, which develops within hrs, pulmonary manifestations may not develop for 24-48 hrs.
      - Organ system failure resulting from sepsis: leading cause of death in burned patients.
        
        burn site is ideal for growth of microorganisms
        
        serum + debris: nutrients,
        
        compromised blood flow: blocks effective inflam responses.
        
        most common offender: opportunist Pseudomonas aeruginosa, but antibiotic-resistant strains of other common hospital-acquired bacteria (S. aureus) + fungi (partic Candida spp.) also may be involved.
        
        cellular + humoral defenses against infections compromised; both lymphocyte + phagocyte functions impaired.
        
        Direct bacteremic spread + release of toxic substances (endotoxin) from local site have dire consequences. Pneumonia or septic shock accompanied by renal failure and/or (ARDS): most common serious sequelae.
      - development of a hypermetabolic state, w/ excess heat loss + incr need for nutritional support; when >40% of body surface burned, resting metabolic rate may approach 2x normal.
    - - • Heat cramps
        
        cause: loss of electrolytes through sweating.
        
        hallmark sign: Cramping of voluntary muscles, u. in association w/ vigorous exercise
        
        Heat-dissipating mechanisms are able to maintain normal core body temp
      - • Heat exhaustion: most common hyperthermic syndrome
        
        cause: failure of cardiovascular system to compensate for
        hypovolemia, secondary to water depletion.
        
        sign: onset sudden, w/ prostration + collapse
        
        After a period of collapse, which is usually brief, equilibrium is spontaneously reestablished.
      - • Heat stroke: associated w/ high ambient temps + high humidity.
        
        cause: Thermoregulatory mechanisms fail, sweating ceases, and core body temperature rises--> marked generalized peripheral vasodilation w/ peripheral pooling of blood + decr effective circulating blood v-->Necrosis of muscles + myocardium may occur. Arrhythmias, DIC, and other systemic effects common.
        
        sign: In clinical setting, a rectal temp>=106°F: a grave prognostic sign + mortality rate for such patients >50%.
        
        Elderly people, persons w/ CVD, and otherwise healthy people undergoing physical stress (such as young athletes and military recruits): prime candidates
      - • Malignant hyperthermia: not caused by exposure to high temp; a genetic condition resulting from mutations in genes such as RYR1 that control Ca levels in skeletal muscle cells.
        exposure to certain anesthetics--> rapid rise in Ca levels in skeletal muscle--> muscle rigidity + incr heat production; resulting hyperthermia mortality rate: 80% if untreated, <5% if muscle relaxants given promptly.
    - - • Depth
        
        full-thickness: total destruction of epidermis + dermis, including dermal appendages that harbor cells needed for epithelial regeneration. Both third- + fourth-degree burns are in this category.
        
        partial-thickness: at least deeper portions of dermal appendages spared.
        
        first-degree burns (epithelial involvement only)
        
        second-degree burns (involving both epidermis + superficial dermis).
      - • % of body surface involved
      - • Whether internal injuries from inhalation of hot and toxic fumes are present
      - • Promptness + efficacy of therapy, esp fluid + electrolyte management + prevention/control of wound infections
    - - Chilling/freezing of cells + tissues causes injury by:
        
        • Direct effects: physical disruptions within cells + high [salt] (crystallization of IC + EC water)
        
        • Indirect effects: result of circulatory changes (vary depending on rate + duration of temp drop)
        
        Slowly developing, prolonged chilling--> vasoconstriction + incr permeability--> edema (typical of “trench foot”); Atrophy + fibrosis may follow.
        
        sudden sharp drops in temp--> vasoconstriction + incr viscosity of blood in local area--> ischemic injury + degenerative changes in peripheral nerves (vascular injury + incr permeability w/ exudation only become evident w/ rewarming); If ischemia is prolonged, hypoxic changes + infarction of affected tissues (e.g., gangrene of toes or feet) may result.
  - - - light microscopic level: vascular changes + interstitial fibrosis prominent
        problematic similarity btw radiation injured + cancer cells
        
        immediate post-irradiation: vessels may show only dilation.
        
        Later / w higher doses: Endothelial cell swelling + vacuolation, dissolution w/ total necrosis of walls of small vessels (capillaries, venules)--> may rupture/undergo thrombosis.
        
        Still later: endothelial cell prolif + collagenous hyalinization w/ thickening of media layer--> marked narrowing or even obliteration of lumina; incr in interstitial coll--> scarring + contractions, u. becomes evident
      - chromosomes
        
        structural changes (deletions, breaks, translocations, and fragmentation)
        
        numeral: mitotic spindle often becomes disorderly--<polyploidy + aneuploidy
      - nuclear morphology:
        
        Nuclear swelling + condensation + clumping of chromatin; breaks in nuclear membr; Apoptosis;
        
        Cells w/ abnormal nuclear morphology may persist for yrs (ex giant cells w/ pleomorphic nuclei or >1 nucleus.
        
        extremely high dose: features foretelling cell death (nuclear pyknosis)
      - cytoplasmic changes: cytoplasmic swelling, mitC distortion, degeneration of ER.
      - Plasma membrane: breaks; focal defects;
    - - Occupational exposure and cancer development.
        uranium decay-->radon--> 2 carcinogenic radon decay byproducts (polonium-214 and -218, or “radon daughters”): emit alpha particles + have a short halflife--> deposited in lung: chronic exposure in uranium miners--> lung carcinomas.
      - • Environmental exposure and cancer development: in any organ
        acute or prolonged exposures that result in doses of 100 mSv cause serious consequences, including cancer. (ex leukemias + tumors (such as thyroid, breast, and lung) Hiroshima + Nagasaki; thyroid cancers in Chernobyl accident; frequent occurrence of “second cancers” (partic children) treated w/ radiotherapy for neoplastic disease)
      - • Hematopoietic + lymphoid systems:
        
        high dose levels + large exposure fields--> severe lymphopenia within hrs of irradiation + shrinkage of lymph nodes and spleen.
        lymphocytes: directly destroys lymphocytes (circulating + in tissues); sublethal doses: regeneration prompt--> restoration of a normal lymphocyte count in blood within ws to mths.
        
        granulocytes: circulating count may first rise but begins to fall toward end of 1st w. Levels near zero may be reached during 2nd w. If patient survives, recovery of normal count may require 2-3 mths.
        
        Platelets: nadir of count occurring somewhat later than that for granulocytes; recovery is similarly delayed.
        
        Hematopoietic cells: RBCs are radioresistant, but their progenitors are not--> anemia appears after 2-3 ws + may persist for mths.
    - - • Rate of delivery: fractional doses of radiant energy have a cumulative effect only to the extent that repair during the intervals is incomplete. Radiotherapy of tumors exploits capability of normal cells to repair themselves + recover more rapidly than tumor cells.
      - • Field size: body can sustain relatively high doses when delivered to small, carefully shielded fields
      - • Cell prolif: rapidly dividing cells more vulnerable (bc DNA damage); DNA damage compatible w/ survival in nondividing cells (except at extremely high doses that impair transcription); tissues w/ a high rate of cell turnover (gonads, bone marrow, lymphoid tissue, and mucosa of GI tract): extremely vulnerable + injury manifested early after exposure.
      - • Hypoxia: radiolysis of water-->ROS: most imp mechanism of DNA damage; Tissue hypoxia may thus reduce extent of damage + effectiveness of radiotherapy directed against tumors.
      - • Vascular damage: endothelial cell damage (moderately sensitive)--> narrowing/occlusion--> impaired healing, fibrosis, and chronic ischemic atrophy: may appear mths/yrs after exposure; Despite low sensitivity of brain cells: vascular damage after irradiation can lead to late manifestations of radiation injury in this tissue.
    - - • Curie (Ci): disintegrations per second of a radioisotope. One Ci is equal to 3.7 × 10 to the power of 10 disintegrations/s
      - • Gray (Gy): energy absorbed by a target tissue; corresponds to absorption of 10000 ergs/gr of tissue. A centigray (cGy): equivalent to exposure of tissue to 100 rads (R) (“radiation absorbed dose”)
      - • Sievert (Sv): unit of equivalent dose that depends on biologic rather than physical effects of radiation; corresponds to absorbed dose (expressed in grays) x relative biologic effectiveness of radiation.
        The relative biologic effectiveness depends on: type of radiation, type + volume of exposed tissue, duration of exposure, as well as other biologic factors (discussed next).
        The effective dose of x-rays, computed tomography (CT), and other imaging and nuclear medicine procedures are commonly expressed in millisieverts (mSv).