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ENVIRONMENTAL&NUTRITIONALPATHOLOGY. Environmental and Nutritional Pathology Environment and Disease Environment and Disease Common Exposures Common Exposures.

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Presentation on theme: "ENVIRONMENTAL&NUTRITIONALPATHOLOGY. Environmental and Nutritional Pathology Environment and Disease Environment and Disease Common Exposures Common Exposures."— Presentation transcript:

1 ENVIRONMENTAL&NUTRITIONALPATHOLOGY

2 Environmental and Nutritional Pathology Environment and Disease Environment and Disease Common Exposures Common Exposures Environmental Environmental Occupational Occupational Nutrition and Disease Nutrition and Disease

3 Reported Occupational Diseases DiseaseNumberPercentage Repeated trauma 276,60064 Skin disorders 57,90013 Lung conditions due to toxic exposures 20,3005 Physical injury 16,6004 Poisoning5,1001 Lung disease due to dusts 2,9001 All other illnesses 50,60012 Total430,000100

4 Mechanisms of Toxicity “Threshold” effect “Threshold” effect Absorption at portals of entry Absorption at portals of entry ingestion ingestion inhalation inhalation skin contact skin contact Distribution within the body Distribution within the body Metabolism and Excretion Metabolism and Excretion Toxic effects Toxic effects

5 Xenobiotic Mechanisms Phase I Reactions (Smooth ER), makes them less lipophilic by adding a direct polar group Cytochrome P-450-dependent monooxygenase system Flavin-containing monooxygenase system Peroxidase-dependent cooxidation Phase II Reactions, combines them with other polar substances Glucuronidation Biomethylation Glutathione conjugation

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7 Contents of Toxic Waste Dumps AcetoneDDT, DDE, DDD Aldrin/Dieldrin1,1 and 1,2-Dichloroethane ArsenicLead BariumMercury BenzeneMethylene chloride 2-ButanoneNickel CadmiumPentachlorophenol Carbon tetrachloridePolychlorinated biphenyls ChlordaneTri- and Tetrachloroethylene ChloroformToluene ChromiumVinyl Chloride CyanideZinc

8 Dose-response Curve

9 Common Exposures Personal Personal Medications Medications Outdoor Air Pollution Outdoor Air Pollution Indoor Air Pollution Indoor Air Pollution Industrial Exposures Industrial Exposures Agricultural Hazards Agricultural Hazards Natural Toxins Natural Toxins Radiation Injury Radiation Injury Physical Injury Physical Injury

10 Tobacco 440,000 premature deaths/year in USA 440,000 premature deaths/year in USA cancer cancer cardiovascular disease cardiovascular disease respiratory disease respiratory disease cerebrovascular disease cerebrovascular disease $150 billion in health related costs $150 billion in health related costs By far the most preventable cause of death in the United States By far the most preventable cause of death in the United States

11 Tobacco and Cancer 70% of all lung cancers 30% of all cancers

12 Organ-Specific Carcinogens in Tobacco Smoke OrganCarcinogen Lung, larynxPolycyclic aromatic hydrocarbons 4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none (NNK) Polonium 210 EsophagusN'-Nitrosonornicotine (NNN) PancreasNNK (?) Bladder4-Aminobiphenyl, 2-naphthylamine Oral cavity (smoking)Polycyclic aromatic hydrocarbons, NNK, NNN Oral cavity (snuff)NNK, NNN, polonium 210 Data from Szczesny LB, Holbrook JH: Cigarette smoking. In Rom WH (ed): Environmental and Occupational Medicine, 2nd ed. Boston, Little, Brown, 1992, p. 1211.

13 Relative Risks for Current Smokers of Cigarettes Disease or ConditionMalesFemales Coronary heart disease Age 35–64 2.83.1 Age ≥ 65 1.51.6 Cerebrovascular lesions Age 35–64 3.34 Age ≥ 65 1.61.5 Aortic aneurysm 6.27.1 Chronic airways obstruction 10.613.1 Cancer Lip, oral cavity, pharynx 10.95.1 Esophagus6.87.8 Stomach21.4 Pancreas2.32.3 Larynx14.613 Lung23.312.7 Cervix1.6 Kidney2.71.3 Bladder, other urinary organs 3.32.2

14 Cigarettes And The Workplace Similar to asbestos exposure, cigarette smoke is “ synergistic” with radon decay products in causing lung cancer Similar to asbestos exposure, cigarette smoke is “ synergistic” with radon decay products in causing lung cancer Cigarette smoke exacerbates bronchitis, asthma, and pneumoconiosis associated with exposure to silica, coal dust, grain dust, cotton dust, and welding fumes (DUH) Cigarette smoke exacerbates bronchitis, asthma, and pneumoconiosis associated with exposure to silica, coal dust, grain dust, cotton dust, and welding fumes (DUH)

15 Alcohol 15 to 20 million alcoholics in the USA 15 to 20 million alcoholics in the USA 100,000 deaths/year due to alcohol abuse 100,000 deaths/year due to alcohol abuse Economic losses of $100 to $130 billion/year Economic losses of $100 to $130 billion/year One to two drinks/day reduces incidence of coronary artery disease* One to two drinks/day reduces incidence of coronary artery disease* * What kind of person would put this kind of bullet on a powerpoint? A) Drinker? B) Non-Drinker? C) Alcoholic in Denial?

16 Definition of Alcoholism ?

17 Effects of Blood Alcohol Levels in the Absence of Tolerance Blood Level, mg/dL Usual Effect 20 Decreased inhibitions, a slight feeling of intoxication 80 Decrease in complex cognitive functions and motor performance 200 Obvious slurred speech, motor incoordination, irritability, and poor judgment 300 Light coma and depressed vital signs 400Death Harrison Internal Med, 16 th Ed

18 Metabolism Of Ethanol CTP2E1, a P450 oxidase; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase 20% 80%

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20 LEGAL INTOXICATION 0.08% = BAC = % BY VOLUME

21 Widmark Equation C = A / (W * r) C = A / (W * r) C = concentration of EtOH in mg/dl C = concentration of EtOH in mg/dl A = mass of alcohol ingested in grams A = mass of alcohol ingested in grams density of ethanol = 0.8 density of ethanol = 0.8 W = body weight in grams W = body weight in grams r = Widmark distribution for ethanol r = Widmark distribution for ethanol 0.55 mL/ g body weight for females 0.55 mL/ g body weight for females 0.68 mL / g body weight for males 0.68 mL / g body weight for males Elimination of ethanol = 0.015%/h (15mg/dl/h) Elimination of ethanol = 0.015%/h (15mg/dl/h) zero order kinetics, i.e., is INDEPENDENT of the amount of reactants. zero order kinetics, i.e., is INDEPENDENT of the amount of reactants. Medical measurements use mg/dl in plasma, whereas legal definitions use percentage (mass/volume) in whole blood Medical measurements use mg/dl in plasma, whereas legal definitions use percentage (mass/volume) in whole blood to estimate the alcohol level in whole blood using the alcohol level in blood plasma, divide by 1.16 to estimate the alcohol level in whole blood using the alcohol level in blood plasma, divide by 1.16

22 Alcohol and the Liver Fatty Change Fatty Change present in over 90% of binge and chronic drinkers present in over 90% of binge and chronic drinkers liver is enlarged but patient is asymptomatic liver is enlarged but patient is asymptomatic changes are reversible with cessation of drinking changes are reversible with cessation of drinking macrosteatosis w/o inflammation or necrosis macrosteatosis w/o inflammation or necrosis Alcohol hepatitis Alcohol hepatitis only between 10 - 15% of alcoholics will develop alcoholic hepatitis only between 10 - 15% of alcoholics will develop alcoholic hepatitis may have systemic symptoms and jaundice may have systemic symptoms and jaundice hepatocellular necrosis with Mallory bodies and PMNs (central hyaline sclerosis) hepatocellular necrosis with Mallory bodies and PMNs (central hyaline sclerosis) thought to be a precursor of cirrhosis thought to be a precursor of cirrhosis probably more than HALF will go onto cirrhosis if ETOH is not stopped probably more than HALF will go onto cirrhosis if ETOH is not stopped Alcoholic cirrhosis Alcoholic cirrhosis shrunken nodular liver with uniform small nodules (micronodular cirrhosis) shrunken nodular liver with uniform small nodules (micronodular cirrhosis)

23 Fatty Change Biochemistry Catabolism of fat by peripheral tissues is increased, and there is increased delivery of free fatty acids to the liver Catabolism of fat by peripheral tissues is increased, and there is increased delivery of free fatty acids to the liver An excess of NADH over NAD stimulates lipid biosynthesis An excess of NADH over NAD stimulates lipid biosynthesis Oxidation of fatty acids by mitochondria is decreased Oxidation of fatty acids by mitochondria is decreased Acetaldehyde forms adducts with tubulin and impairs function of microtubules, resulting in decreased transport of lipoproteins from the liver Acetaldehyde forms adducts with tubulin and impairs function of microtubules, resulting in decreased transport of lipoproteins from the liver

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28 Neurologic Manifestations of Alcoholism Wernicke syndrome Wernicke syndrome confusion, ataxia, and diplopia from ophthalmoplegia confusion, ataxia, and diplopia from ophthalmoplegia damage to mammillary bodies, cerebellum and periaqueductal gray matter of the midbrain damage to mammillary bodies, cerebellum and periaqueductal gray matter of the midbrain due to thiamine deficiency due to thiamine deficiency may respond to prompt thiamine replacement may respond to prompt thiamine replacement Korsakov syndrome Korsakov syndrome memory loss and confabulation memory loss and confabulation results from thiamine deficiency and direct toxicity results from thiamine deficiency and direct toxicity

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30 Mechanisms of Disease Caused by Ethanol Abuse Organ SystemLesionMechanism LiverFatty changeToxicity Acute hepatitis Alcoholic cirrhosis Nervous systemWernicke syndromeThiamine deficiency Korsakoff syndromeToxicity and thiamine deficiency Cerebellar degenerationNutritional deficiency Peripheral neuropathyThiamine deficiency Cardiovascular system CardiomyopathyToxicity HypertensionVasopressor

31 Mechanisms of Disease Caused by Ethanol Abuse Organ SystemLesionMechanism Gastrointestinal tract GastritisToxicity PancreatitisToxicity Skeletal muscleRhabdomyolysisToxicity Reproductive system Testicular atrophy? Spontaneous abortion ? Fetal alcohol syndrome Growth retardationToxicity Mental retardation Birth defects

32 Therapeutic Drugs (Medications) Oral Contraceptives (BCPs) Oral Contraceptives (BCPs) Hormone Replacement Therapy (HRT) Hormone Replacement Therapy (HRT) Acetaminophen Acetaminophen Aspirin Aspirin

33 Oral Contraceptives (BCPs) Breast cancer and other cancers Breast cancer and other cancers no increase in breast cancer no increase in breast cancer decrease endometrial and ovarian cancers decrease endometrial and ovarian cancers increase in cervical cancer (?lifestyle induced) increase in cervical cancer (?lifestyle induced) Thromboembolic events Thromboembolic events DVT and Pulmonary Embolism increased DVT and Pulmonary Embolism increased adds to other risk factors (e.g. Factor V Leiden) adds to other risk factors (e.g. Factor V Leiden) Cardiovascular disease Cardiovascular disease with current low estrogen pills, risk of MI and atherosclerosis not increased in non-smoking women < 45 y with current low estrogen pills, risk of MI and atherosclerosis not increased in non-smoking women < 45 y ischemic stroke increased regardless of age or smoking ischemic stroke increased regardless of age or smoking Liver tumors Liver tumors benign hepatic adenomas benign hepatic adenomas older women with prolonged use older women with prolonged use may rupture and cause intra-abdominal bleeding may rupture and cause intra-abdominal bleeding

34 Hormone Replacement Therapy (HRT) Cancer Cancer in women with a uterus combined estrogen and progestin Rx necessary to reduce endometrial cancer in women with a uterus combined estrogen and progestin Rx necessary to reduce endometrial cancer WHI showed increased risk of breast cancer in women who used HRT combined therapy for 5 years WHI showed increased risk of breast cancer in women who used HRT combined therapy for 5 years Thromboembolic events Thromboembolic events elevated approximated twofold in HRT users, especially within the first 2 years elevated approximated twofold in HRT users, especially within the first 2 years Cardiovascular disease Cardiovascular disease WHI reported 29% increased risk of myocardial infarction, especially during the first year of combined HRT use WHI reported 29% increased risk of myocardial infarction, especially during the first year of combined HRT use

35 Acetaminophen (Tylenol) Does not affect cyclooxygenase so bleeding associated with aspirin does not occur Does not affect cyclooxygenase so bleeding associated with aspirin does not occur Has analgesic and antipyretic actions but no anti-inflammatory action Has analgesic and antipyretic actions but no anti-inflammatory action Large doses may produce hepatic necrosis Large doses may produce hepatic necrosis patients should not exceed recommended dose (4 grams/day) patients should not exceed recommended dose (4 grams/day) toxic dose in adults is 15 to 25 gm toxic dose in adults is 15 to 25 gm dose should be reduced in children with fever or dehydration dose should be reduced in children with fever or dehydration

36 Aspirin Overdose Overdose respiratory alkalosis followed by metabolic acidosis that may be fatal respiratory alkalosis followed by metabolic acidosis that may be fatal Chronic aspirin toxicity (salicylism) Chronic aspirin toxicity (salicylism) headache, dizziness, ringing in the ears (tinnitus), mental confusion, drowsiness, nausea, vomiting, and diarrhea headache, dizziness, ringing in the ears (tinnitus), mental confusion, drowsiness, nausea, vomiting, and diarrhea Inhibits cyclooxygenases (COX 1 & 2) Inhibits cyclooxygenases (COX 1 & 2) Erosive gastritis is a major cause of GI bleeding Erosive gastritis is a major cause of GI bleeding May be implicated in Reye syndrome (fatty liver with encephalopathy) in children < 15 years old, especially with influenza and chicken pox May be implicated in Reye syndrome (fatty liver with encephalopathy) in children < 15 years old, especially with influenza and chicken pox

37 Cox-1 and Cox-2 Inhibitors Cyclooxygenase 1 (inhib of COX-1 is BAD) Cyclooxygenase 1 (inhib of COX-1 is BAD) constitutively expressed and active in the normal platelet (thromboxane A2) constitutively expressed and active in the normal platelet (thromboxane A2) involved in synthesis of gastro-protective prostaglandins involved in synthesis of gastro-protective prostaglandins Cyclooxygenase 2 (inhib of COX-2 is GOOD) Cyclooxygenase 2 (inhib of COX-2 is GOOD) induced, especially in inflamed tissue induced, especially in inflamed tissue in vessel wall produces prostacyclin (PGI 2 ) in vessel wall produces prostacyclin (PGI 2 ) Aspirin and other nonselective NSAIDS inhibit both COX-1 and COX-2 Aspirin and other nonselective NSAIDS inhibit both COX-1 and COX-2

38 Figure 2-16 Generation of arachidonic acid metabolites and their roles in inflammation. The molecular targets of action of some anti-inflammatory drugs are indicated by a red X. COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 August 2005 06:35 PM) © 2005 Elsevier

39 Indoor Air Pollution Carbon Monoxide CO Carbon Monoxide CO Nitrogen Dioxide NO 2 ( from acid rain ) Nitrogen Dioxide NO 2 ( from acid rain ) Wood Smoke Wood Smoke Formaldehyde Formaldehyde Radon Radon Manufactured Mineral Fibers Manufactured Mineral Fibers Bioaerosols Bioaerosols

40 Radon Radon is a radioactive gas and a decay product of uranium, naturally occurring Radon is a radioactive gas and a decay product of uranium, naturally occurring It is widely distributed in the soil and is prevalent in homes (especially in basements) It is widely distributed in the soil and is prevalent in homes (especially in basements) Radon decay products are alpha emitters Radon decay products are alpha emitters 10% of US homes have levels associated with an increased risk of lung cancer and an estimated 10,000 lung cancers per year in the United States are due to radon. Smoking elevates risk. 10% of US homes have levels associated with an increased risk of lung cancer and an estimated 10,000 lung cancers per year in the United States are due to radon. Smoking elevates risk. Proper venting reduces the exposure Proper venting reduces the exposure

41 Lead Lead is classified as a heavy metal (others include mercury, arsenic, and cadmium) Lead is classified as a heavy metal (others include mercury, arsenic, and cadmium) Source of exposure Source of exposure lead paint lead paint lead solder in plumbing (older houses) lead solder in plumbing (older houses) lead-glazed ceramics lead-glazed ceramics industrial exposure industrial exposure Route of exposure Route of exposure inhalation with industrial exposure inhalation with industrial exposure ingestion with household exposure ingestion with household exposure

42 Lead Distribution and Excretion Lead is a divalent cation that is taken up by bone and developing teeth in children (80% to 85%) Lead is a divalent cation that is taken up by bone and developing teeth in children (80% to 85%) Half-life of lead in bone is 30 years Half-life of lead in bone is 30 years Blood accumulates 5% to 10% of lead, but lead is rapidly cleared from the blood Blood accumulates 5% to 10% of lead, but lead is rapidly cleared from the blood lead in blood indicates recent exposure lead in blood indicates recent exposure blood level does not allow the determination of total body burden blood level does not allow the determination of total body burden Remainder is distributed in the soft tissues Remainder is distributed in the soft tissues Excretion is via the kidneys Excretion is via the kidneys

43 Effects of Lead High affinity for sulfhydryl groups High affinity for sulfhydryl groups inhibition of heme biosynthesis with hypochromic anemia and basophillic stippling of erythrocytes inhibition of heme biosynthesis with hypochromic anemia and basophillic stippling of erythrocytes Competition with calcium ions Competition with calcium ions As a divalent cation, lead competes with calcium and is stored in bone. As a divalent cation, lead competes with calcium and is stored in bone. It also interferes with nerve transmission and brain development. It also interferes with nerve transmission and brain development. Inhibition of membrane-associated enzymes Inhibition of membrane-associated enzymes Lead inhibits 5'-nucleotidase activity and sodium- potassium ion pumps, leading to decreased survival of red blood cells (hemolysis), renal damage, and hypertension. Lead inhibits 5'-nucleotidase activity and sodium- potassium ion pumps, leading to decreased survival of red blood cells (hemolysis), renal damage, and hypertension.

44 Consequences of lead exposure

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47 “RADIATION” T ½ (m)Curie vs. (M)Becqerel IONIZING vs. NON-IONIZING PARTICULATE vs. NON-PARTICULATE (Photons) ENERGY: Kev, Mev (~Wavelength) Linear Energy Transfer (LET), Relative Biologic Effect (RBE) LD50@60d

48 This is the single most RADIOSENSITIVE CELL In your body

49 Radiation Dosimetry Roentgen: unit of charge produced by x-rays or gamma rays that ionize a specific volume of air. Physics unit. Roentgen: unit of charge produced by x-rays or gamma rays that ionize a specific volume of air. Physics unit. RAD (radiation absorbed dose): the dose of radiation that will produce absorption of 100 ergs of energy per gram of tissue; 1 gm of tissue exposed to 1 roentgen of gamma rays is equal to 93 ergs RAD (radiation absorbed dose): the dose of radiation that will produce absorption of 100 ergs of energy per gram of tissue; 1 gm of tissue exposed to 1 roentgen of gamma rays is equal to 93 ergs Gray (Gy): the dose of radiation that will produce absorption of 1 joule of energy per kilogram of tissue; 1 Gy corresponds to 100 rad (SI unit for absorbed dose) Gray (Gy): the dose of radiation that will produce absorption of 1 joule of energy per kilogram of tissue; 1 Gy corresponds to 100 rad (SI unit for absorbed dose) REM (radiation equivalent man): the dose of radiation that causes a biologic effect equivalent to 1 rad of x-rays or gamma rays REM (radiation equivalent man): the dose of radiation that causes a biologic effect equivalent to 1 rad of x-rays or gamma rays Sievert (Sv): the dose of radiation that causes a biologic effect equivalent to 1 Gy of x-rays or gamma rays; 1 Sv corresponds to 100 rem (SI unit) Sievert (Sv): the dose of radiation that causes a biologic effect equivalent to 1 Gy of x-rays or gamma rays; 1 Sv corresponds to 100 rem (SI unit)

50 Acute Effects of Ionizing Radiation Free radical generation Free radical generation Ionizing radiation + H 2 0 → H 3 0 + + OH· Ionizing radiation + H 2 0 → H 3 0 + + OH· DNA Damage DNA Damage double-stranded DNA breaks needed to kill cell (mammalian cells can repair single stranded breaks) double-stranded DNA breaks needed to kill cell (mammalian cells can repair single stranded breaks) cross-linking of DNA strands, cleavage of sugar-phosphate bonds cross-linking of DNA strands, cleavage of sugar-phosphate bonds Tumor-suppressor gene p53 activation Tumor-suppressor gene p53 activation cell cycle arrest in presence of damaged DNA cell cycle arrest in presence of damaged DNA repair of DNA damage or apoptosis repair of DNA damage or apoptosis

51 Acute Whole Body Radiation LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 rad) LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 rad) Hematopoietic Hematopoietic 200–600 REM 200–600 REM Maximum neutrophil and platelet depression in 2 wk Maximum neutrophil and platelet depression in 2 wk Gastrointestinal Gastrointestinal 600–1000 REM 600–1000 REM Nausea, vomiting, diarrhea Nausea, vomiting, diarrhea Hemorrhage and infection in 1–3 wk Hemorrhage and infection in 1–3 wk Central nervous system Central nervous system >1000 REM >1000 REM Intractable nausea and vomiting Intractable nausea and vomiting Confusion, somnolence, convulsions Confusion, somnolence, convulsions death in 14–36 hr death in 14–36 hr

52 Therapeutic Radiation External radiation is delivered to malignant neoplasms at fractionated doses up to 40 to 70 Gy (4000 to 7000 rad), with shielding of adjacent normal tissues External radiation is delivered to malignant neoplasms at fractionated doses up to 40 to 70 Gy (4000 to 7000 rad), with shielding of adjacent normal tissues Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people exposed to alkylating agents Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people exposed to alkylating agents Fatigue, nausea and vomiting frequent Fatigue, nausea and vomiting frequent Bone marrow suppression may occur especially with chest or abdominal radiation Bone marrow suppression may occur especially with chest or abdominal radiation

53 Delayed Radiation Injury Carcinogenesis (atom bomb survivors) Carcinogenesis (atom bomb survivors) myeloid leukemias peak 5 to 7 years after exposure myeloid leukemias peak 5 to 7 years after exposure breast and thyroid cancers may show greater latency breast and thyroid cancers may show greater latency no germline mutations noted in progeny of survivors no germline mutations noted in progeny of survivors Vascular effects Vascular effects endothelial necrosis followed by intimal and medial fibrosis endothelial necrosis followed by intimal and medial fibrosis capillaries may become thrombosed and obliterated or ectatic capillaries may become thrombosed and obliterated or ectatic Parenchymal atrophy and fibrosis Parenchymal atrophy and fibrosis

54 Radiation effects on TISSUE ACUTE (vasculitis, possibly “fibrinoid” necrosis) CHRONIC (fibrosis)

55 Physical Injury Abrasion Abrasion basically a scrape basically a scrape superficial epidermis is torn off by friction or force superficial epidermis is torn off by friction or force regeneration without scarring usually occurs regeneration without scarring usually occurs Laceration vs. Incision Laceration vs. Incision a laceration is an irregular tear in the skin produced by overstretching. The wound margins are frequently hemorrhagic and traumatized a laceration is an irregular tear in the skin produced by overstretching. The wound margins are frequently hemorrhagic and traumatized an incision is made by a sharp cutting object. The margins of the incision are usually relatively clean an incision is made by a sharp cutting object. The margins of the incision are usually relatively clean Contusion Contusion an injury caused by a blunt force that damages small blood vessels and causes interstitial bleeding, usually without disruption of the continuity of the tissue (cf ecchymosis) an injury caused by a blunt force that damages small blood vessels and causes interstitial bleeding, usually without disruption of the continuity of the tissue (cf ecchymosis)

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57 Adult Mortality Rates in the United States, Ages 25 – 44, in 1998 Rate per 100,000 population CauseHispanicBlackWhite Unintentional injuries33.440.131.6 Cancer16.838.025.3 Homicide13.1 36.24.7 Human immunodeficiency virus12.1 43.34.8 Heart disease10.343.518.3 Suicide7.8 — 17.0 Total130.2303.7139.4 Data from CDC Fact Book, 2000/2001, Department of Health and Human Services, Centers for Disease Control and Prevention.

58 GUNSHOT WOUND Entrance Vs. Exit Far range Vs. Close range NOT CLOSE RANGE CLOSE RANGE (POWDER BURNS) EXIT WOUNDS are generally SLOPPIER than ENTRANCE WOUNDS

59 BURNS 1 st, 2 nd, 3 rd, 4 th “Degree” FULL vs. PARTIAL Thickness Survival PERCENT of body using the rule of NINES DEGREE (i.e., Depth) Respiratory Tract Involvement AGE Speed of access to Burn Unit Immune System (Pseudomonas, S. aureus, Candida), infections are usually the lethal delayed cause of death.

60 HYPER -THERMIA HEAT  CRAMPS: Electrolyte loss via sweat EXHAUSTION: Water depletion and lack of cardiovascular compensation “STROKE”: Extensive peripheral vasodilatation, i.e., “shocky”, very serious, T>106º, over 110º have been reported, high mortality. In this case true “SHOCK” would be a better term than “STROKE”

61 HYPO -THERMIA Often in setting of homelessness or alcoholism or both < 90º often fatal, assoc. w. BRADYCARDIA ATRIAL FIBRILLATION

62 LIGHTNING/ELECTRICAL ELECTRIC DISTURBANCES NEURAL (because nerve is such an EXCELLENT conductor of electricity) EKG (like reverse cardioversion) THERMAL INJURY, directly proportional to a particular tissue’s RESISTANCE to electrical flow “LIGHTNING” MARKS

63 ATMOSPHERIC PRESSURE Altitude Illness Blast Injuries Decompression Injuries

64 ALTITUDE ILLNESS Caused by LOW Oxygen Tension HIGH ALTITUDES (>4000 m [12,000 feet]) OBTUNDATION  INCREASED CAPILLARY PERMEABILITY  ACUTE PULMONARY EDEMA (HAPE) Q: What is the name of the base camp at Mt. Everest A: Pulmonary Edema

65 BLAST INJURIES RELATED TO RAPID ATMOSPHERIC PRESSURE CHANGES LUNGS VISCERA, especially GAS filled viscera Rupture, Hemorrhage, etc. IMMERSION BLAST also possible, causing more of a total body compression syndrome

66 DECOMPRESSION Related to GAS SOLUBILITY in divers ascending rapidly, especially the more NON-SOLUBLE gasses, like NITROGEN, and, to a lesser extent, XENON AIR EMBOLISM is the common pathology ACUTE: “BENDS” (peri-articular), acute “CHOKES” (lungs), acute “STAGGERS” (inner ear), acute CHRONIC: ASEPTIC NECROSIS: humeri, femurs

67 NUTRITION & DISEASE Food Safety Food Safety Additives Additives Contaminants Contaminants Nutritional Deficiencies Nutritional Deficiencies Vitamins Vitamins Minerals Minerals Obesity Obesity Diet and Disease Diet and Disease Chemoprevention of Cancer Chemoprevention of Cancer

68 Vitamin Deficiency and Excess Fat soluble vitamins Fat soluble vitamins A, D, E, K A, D, E, K readily stored in body fat readily stored in body fat poorly absorbed in digestive disorders involving malabsorbtion of fat poorly absorbed in digestive disorders involving malabsorbtion of fat Water soluble vitamins Water soluble vitamins remaining vitamins remaining vitamins readily excreted in urine readily excreted in urine Vitamin stores (fat stores longer than water) Vitamin stores (fat stores longer than water) vitamins B-12 and A: stores sufficient for 1 year vitamins B-12 and A: stores sufficient for 1 year folate and thiamine may become depleted within weeks when eating a deficient diet folate and thiamine may become depleted within weeks when eating a deficient diet

69 Vitamin D Metabolism Absorption of vitamin D in the gut or synthesis from precursors in the skin Absorption of vitamin D in the gut or synthesis from precursors in the skin Binding to a plasma α1-globulin (D- binding protein) and transport to liver Binding to a plasma α1-globulin (D- binding protein) and transport to liver Conversion to 25-hydroxyvitamin D, 25(OH)D (calcidol) by 25-hydroxylase in the liver Conversion to 25-hydroxyvitamin D, 25(OH)D (calcidol) by 25-hydroxylase in the liver Conversion of 25(OH)D to 1,25(OH) 2 D (calcitrol, Vitamin D3) by α1-hydroxylase in the kidney; biologically this is the most active form of vitamin D. Conversion of 25(OH)D to 1,25(OH) 2 D (calcitrol, Vitamin D3) by α1-hydroxylase in the kidney; biologically this is the most active form of vitamin D.

70 Functions of Vitamin D Stimulates intestinal absorption of calcium and phosphorus Stimulates intestinal absorption of calcium and phosphorus Collaborates with PTH in the mobilization of calcium from bone Collaborates with PTH in the mobilization of calcium from bone Stimulates the PTH-dependent reabsorption of calcium in the distal renal tubules Stimulates the PTH-dependent reabsorption of calcium in the distal renal tubules 1,25(OH) 2 D, the biologically active form of vitamin D, is best regarded as a steroid hormone which acts by binding to a high- affinity receptor 1,25(OH) 2 D, the biologically active form of vitamin D, is best regarded as a steroid hormone which acts by binding to a high- affinity receptor

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72 Vitamin D Deficiency Holick et al (2005) reported the results of a large North American study that assessed the vitamin D status of postmenopausal women receiving therapy to treat or prevent osteoporosis Holick et al (2005) reported the results of a large North American study that assessed the vitamin D status of postmenopausal women receiving therapy to treat or prevent osteoporosis 52% of 1536 women had inadequate [25(OH)D] levels (<30 ng/mL) 52% of 1536 women had inadequate [25(OH)D] levels (<30 ng/mL) 36% and 18% had levels less than 25 and 20 ng/mL, respectively. 36% and 18% had levels less than 25 and 20 ng/mL, respectively. Holick MF et al: J Clin Endocrinol Metab 90:3215, 2005

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74 Vitamin D Deficiency Childhood: Rickets Childhood: Rickets epiphyses are open epiphyses are open cartilage overgrowth cartilage overgrowth Adults: osteomalacia Adults: osteomalacia bone matrix is not calcified bone matrix is not calcified vs osteoporosis (matrix reduced) vs osteoporosis (matrix reduced) ADULTS   CHILDREN (RICKETS) OSTEOMALACIA 1) Bone fractures that happen with very little injury 2) Muscle weakness 3) Widespread bone pain, especially in the hips

75 Vitamin K Clotting factors VII, IX, and X and prothrombin (II) all require carboxylation of glutamate residues for functional activity Clotting factors VII, IX, and X and prothrombin (II) all require carboxylation of glutamate residues for functional activity anticoagulant coumadin is a Vitamin K antagonist anticoagulant coumadin is a Vitamin K antagonist Activation of anticoagulant proteins C and S also requires glutamate carboxylation Activation of anticoagulant proteins C and S also requires glutamate carboxylation Sources Sources endogenous intestinal bacterial flora endogenous intestinal bacterial flora diet diet

76 Vitamin K Deficiency Causes Causes fat malabsorption fat malabsorption reduced gut bacterial flora reduced gut bacterial flora administration of wide specturm antibiotics administration of wide specturm antibiotics neonatal period before gut is colonized neonatal period before gut is colonized liver disease with reduced recycling of vitamin K liver disease with reduced recycling of vitamin K Effects of vitamin K deficiency Effects of vitamin K deficiency bleeding diathesis bleeding diathesis estimated 3% prevalence of vitamin K- dependent bleeding diathesis among neonates warrants routine prophylactic vitamin K therapy for all newborns estimated 3% prevalence of vitamin K- dependent bleeding diathesis among neonates warrants routine prophylactic vitamin K therapy for all newborns


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