Pathology environmental & nutritional disease

5,522 views

Published on

0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
5,522
On SlideShare
0
From Embeds
0
Number of Embeds
4
Actions
Shares
0
Downloads
359
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide
  • A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it.
    One of the most common Phase I reaction is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system. These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons.
    In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione (GSH), sulfate, glycine, or glucuronic acid.
    Some sources will add Phase III as the final excretion stage.
  • This is actually not a bad diagram, fairly logical.
  • The threshold is the dose at which toxic effects are noted clinically. Below this dose, no adverse effects are noted (sub threshold). This is a basic Pharm 101 graph.
  • Just in case you need, at parties, to rattle of specific tar chemicals proven to be carcinogens.
  • The asterisk represents one of my favorite rants. The only fucking thing ONE or TWO drinks per day ever led to was THREE or FOUR.
  • Many people living in denial (i.e., alcoholics) are violently opposed to defining alcoholism at >2* drinks per day, so probably the TRUEST definition of alcoholism is subjective but involves impairment and degradation of family and social relationships. Most alcoholics living in denial devote most of their brilliant brain power proving to themselves and the world that they are NOT alcoholic.
    *2 beers, 2 wines, 2 shots
  • At clinically important alcohol concentrations, microsomal and ADH enzymes are saturated and show zero order kinetics, i.e. metabolism proceeds at a constant rate and is independent of alcohol concentration.
  • Note: Robbins states 8 bottles of beer is needed to reach legal limit for intoxication, a dangerous overestimation
    Medical measurements use mg/dl in plasma, whereas legal definitions use percentage (volume/volume) in whole blood
    To estimate the alcohol level in whole blood using the alcohol level in blood plasma, divide by 1.16
    What is “a drink”? Ans: “A drink” is 1.5 oz of 80 proof (i.e. 40%) ethanol, a 12 oz. can of beer, or a 5 oz. glass of wine.
  • Remember this number if you drive.
  • Widmark took all the logical factors contributing to alcohol concentration in the blood and put them into an equation:
    N = the number of drinks consumed
    W = body weight in ounces
    r = volume of distribution (a constant relating the
    distribution of water in the body in L/Kg)
    Ct = the blood alcohol concentration (BAC) in Kg/L
    β = the alcohol elimination rate in Kg/L/hr
    t = time since the first drink in hours
    z = the fluid ounces of alcohol per drink
    0.8 = the density of ethanol (0.8 oz. per fluid ounce)
  • Factors of fatty change.
  • Liver with extensive macrovessicular fat. Nearly all of the hepatocytes in this field are filled with a large clear lipid vacuole. The vacule is clear because the fat has been removed in tissue processing.
    If you estimate that 50% of the histologic cross area of this slide is “clear”, i.e., “fat”, and the liver weighs, say 2000 gm. (normal = 1400-1800), then you can say 1000 gms are fat, right? Ans:YES
  • Point out the microvesicular and macrovescicular fat.
  • Liver with alcoholic hyaline (Mallory bodies), fatty change, and focal hepatocyte necrosis and inflamation.
    They are highly eosinophilic and thus appear pink on H&E stain. The bodies themselves are made up of intermediate keratin filament proteins that have been ubiquinated, or bound by other proteins such as heat shock proteins, or p62.
  • There are nodules of regenerated hepatocytes (R)surrounded by fibrous bands (F). This pattern of regeneration and repair results from a previous episode or episodes of hepatocellular necrosis which destroyed liver heptocytes and their architectural framework. Alternatively there may have been chronic and ongoing necrosis of hepatocytes. Residual hepatocytes eventually regenerate in nodules surrounded by fibrosis.
  • Previous teaching was that estrogen had a cardio-protective effect since it raises high density lipoproteins (HDL, good cholesterol). This is an example of how the use of a surrogate marker can be misleading.
  • Indoor air pollution is increased by current construction methods in which the house is sealed from the outside for energy efficiency
  • Basophilic stippling is RIBOSOMES, gingival “lead” lines are at tooth-gingiva brder, x-ray “lead” lines are the densities at the metaphyses
  • What is pica? ANS: It is NOT a type of typewriter font, NOT a genus of magpie, or a city in Chile or England.
    Pica is a medical disorder characterized by an appetite for substances largely non-nutritive (e.g., clay, coal, soil, feces, chalk, paper, soap,mucus, ash, gum etc.)
  • The cells that “turn over” the most rapidly are generally those most sensitive to radiation, e.g., bone marrow, GI mucosa.
  • Vascular damage and parenchymal atrophy are seen with therapeutic radiation. A whole body exposure sufficient to cause these changes would be lethal before these changes could appear.
  • Injuries can be considered as “exposures” too, to keep in tune with the rest of this chapter.
  • 1) Abrasion (Scrape)
    2) Laceration (NOT incision)
    3) Contusion (Blunt Trauma)
  • Look at the amazing black/white differences in HIV and Homicide for USA people <44
    Historically in the USA, young adults do not die from medical diseases, but that is changing, with HIV and cancer.
  • Nothing gives me more pleasure than to show this slide to prove that crime deductions are a very miniscule part of REAL PATHOLOGY, not the majority of it, like most TV heads suspect.
  • First Degree----erythema (redness), epidermal damage only
    Second Degree---(blisters), superficial (papillary) and deep (reticular) dermis involved
    Third Degree----charring, subcutis (hypodermis) involved
    Fourth Degree---- (FULL thickness), tendons, etc., involved.
  • Gut + skin liver kidneys
  • Hypocalcemia is the main trigger of PTH
  • “malacia” in pathology usually mean “softening”
  • Pathology environmental & nutritional disease

    1. 1. ENVIRONMENTALENVIRONMENTAL && NUTRITIONALNUTRITIONAL PATHOLOGYPATHOLOGY
    2. 2. Environmental andEnvironmental and Nutritional PathologyNutritional Pathology  Environment and DiseaseEnvironment and Disease  Common ExposuresCommon Exposures  EnvironmentalEnvironmental  OccupationalOccupational  NutritionNutrition and Diseaseand Disease
    3. 3. Reported Occupational DiseasesReported Occupational Diseases DiseaseDisease NumberNumber PercentagePercentage Repeated traumaRepeated trauma 276,600276,600 6464 Skin disordersSkin disorders 57,90057,900 1313 Lung conditions due toLung conditions due to toxic exposurestoxic exposures 20,30020,300 55 Physical injuryPhysical injury 16,60016,600 44 PoisoningPoisoning 5,1005,100 11 Lung disease due toLung disease due to dustsdusts 2,9002,900 11 All other illnessesAll other illnesses 50,60050,600 1212 TotalTotal 430,000430,000 100100
    4. 4. Mechanisms of ToxicityMechanisms of Toxicity  Threshold effectThreshold effect  Absorption at portals of entryAbsorption at portals of entry  ingestioningestion  inhalationinhalation  skin contactskin contact  Distribution within the bodyDistribution within the body  Metabolism and ExcretionMetabolism and Excretion  Toxic effectsToxic effects
    5. 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
    6. 6. Contents of Toxic Waste Dumps Acetone DDT, DDE, DDD Aldrin/Dieldrin 1,1 and 1,2-Dichloroethane Arsenic Lead Barium Mercury Benzene Methylene chloride 2-Butanone Nickel Cadmium Pentachlorophenol Carbon tetrachloride Polychlorinated biphenyls Chlordane Tri- and Tetrachloroethylene Chloroform Toluene Chromium Vinyl Chloride Cyanide Zinc
    7. 7. Dose-response CurveDose-response Curve
    8. 8. CommonCommon ExposuresExposures  PersonalPersonal  MedicationsMedications  Outdoor Air PollutionOutdoor Air Pollution  Indoor Air PollutionIndoor Air Pollution  Industrial ExposuresIndustrial Exposures  Agricultural HazardsAgricultural Hazards  Natural ToxinsNatural Toxins  Radiation InjuryRadiation Injury  Physical InjuryPhysical Injury
    9. 9. TobaccoTobacco  440,000 premature deaths/year in USA440,000 premature deaths/year in USA  cancercancer  cardiovascular diseasecardiovascular disease  respiratory diseaserespiratory disease  cerebrovascular diseasecerebrovascular disease  $150 billion in health related costs$150 billion in health related costs By farBy far the most preventable causethe most preventable cause of death in the United Statesof death in the United States
    10. 10. Tobacco and Cancer 70% of all lung cancers 30% of all cancers
    11. 11. Organ-Specific Carcinogens in Tobacco Smoke Organ Carcinogen Lung, larynx Polycyclic aromatic hydrocarbons 4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none (NNK) Polonium 210 Esophagus N'-Nitrosonornicotine (NNN) Pancreas NNK (?) Bladder 4-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.
    12. 12. Relative Risks for Current Smokers of CigarettesRelative Risks for Current Smokers of Cigarettes Disease or Condition MalesMales FemalesFemales Coronary heart diseaseCoronary heart disease Age 35–64Age 35–64 2.82.8 3.13.1 Age ≥ 65Age ≥ 65 1.51.5 1.61.6 Cerebrovascular lesionsCerebrovascular lesions Age 35–64Age 35–64 3.33.3 44 Age ≥ 65Age ≥ 65 1.61.6 1.51.5 Aortic aneurysmAortic aneurysm 6.26.2 7.17.1 Chronic airways obstructionChronic airways obstruction 10.610.6 13.113.1 CancerCancer Lip, oral cavity, pharynxLip, oral cavity, pharynx 10.910.9 5.15.1 EsophagusEsophagus 6.86.8 7.87.8 StomachStomach 22 1.41.4 PancreasPancreas 2.32.3 2.32.3 LarynxLarynx 14.614.6 1313 LungLung 23.323.3 12.712.7 CervixCervix 1.61.6 KidneyKidney 2.72.7 1.31.3 Bladder, other urinary organsBladder, other urinary organs 3.33.3 2.22.2
    13. 13. Cigarettes And The WorkplaceCigarettes And The Workplace  Similar to asbestos exposure, cigarette smoke isSimilar to asbestos exposure, cigarette smoke is synergistic with radon decay products in causingsynergistic with radon decay products in causing lung cancerlung cancer  Cigarette smoke exacerbates bronchitis, asthma,Cigarette smoke exacerbates bronchitis, asthma, and pneumoconiosis associated with exposureand pneumoconiosis associated with exposure to silica, coal dust, grain dust, cotton dust, andto silica, coal dust, grain dust, cotton dust, and welding fumeswelding fumes
    14. 14. AlcoholAlcohol  15 to 20 million alcoholics in the USA15 to 20 million alcoholics in the USA  100,000 deaths/year due to alcohol100,000 deaths/year due to alcohol abuseabuse  Economic losses of $100 to $130Economic losses of $100 to $130 billion/yearbillion/year  One to two drinks/day reducesOne to two drinks/day reduces incidence of coronary artery disease*incidence of coronary artery disease* * What kind of person would put this kind of bullet on a powerpoint? A. Drinker? B) Non-Drinker?
    15. 15. Definition of Alcoholism ?
    16. 16. Effects of Blood Alcohol Levels in the Absence of ToleranceEffects of Blood Alcohol Levels in the Absence of Tolerance Blood Level, mg/dLBlood Level, mg/dL Usual EffectUsual Effect 2020 Decreased inhibitions, a slightDecreased inhibitions, a slight feeling of intoxicationfeeling of intoxication 8080 Decrease in complex cognitiveDecrease in complex cognitive functions and motor performancefunctions and motor performance 200200 Obvious slurred speech, motorObvious slurred speech, motor incoordination, irritability, andincoordination, irritability, and poor judgmentpoor judgment 300300 Light coma and depressed vitalLight coma and depressed vital signssigns 400400 DeathDeath Harrison Internal Med, 16th Ed
    17. 17. Metabolism Of EthanolMetabolism Of Ethanol ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase 20% 80%
    18. 18. LEGAL INTOXICATION 0.08%
    19. 19. Widmark EquationWidmark Equation  C = A / (W * r)C = A / (W * r)  C = concentration of EtOH in mg/dlC = concentration of EtOH in mg/dl  A = mass of alcohol ingested in gramsA = mass of alcohol ingested in grams  density of ethanol = 0.8density of ethanol = 0.8  W = body weight in gramsW = body weight in grams  r = Widmark distribution for ethanolr = Widmark distribution for ethanol  0.55 mL/ g body weight for females0.55 mL/ g body weight for females  0.68 mL / g body weight for males0.68 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 kineticszero order kinetics  Medical measurements use mg/dl in plasma, whereasMedical measurements use mg/dl in plasma, whereas legal definitions use percentage (mass/volume) in wholelegal definitions use percentage (mass/volume) in whole bloodblood  to estimate the alcohol level in whole blood using the alcoholto estimate the alcohol level in whole blood using the alcohol level in blood plasma, divide by 1.16level in blood plasma, divide by 1.16
    20. 20. Alcohol and the LiverAlcohol and the Liver  Fatty ChangeFatty Change  present in over 90% of binge and chronic drinkerspresent in over 90% of binge and chronic drinkers  liver is enlarged but patient is asymptomaticliver is enlarged but patient is asymptomatic  changes are reversible with cessation of drinkingchanges are reversible with cessation of drinking  macrosteatosis w/o inflammation or necrosismacrosteatosis w/o inflammation or necrosis  Alcohol hepatitisAlcohol hepatitis  only between 10 - 15% of alcoholics will developonly between 10 - 15% of alcoholics will develop alcoholic hepatitisalcoholic hepatitis  may have systemic symptoms and jaundicemay have systemic symptoms and jaundice  hepatocellular necrosis with Mallory bodies and PMNshepatocellular necrosis with Mallory bodies and PMNs (central hyaline sclerosis)(central hyaline sclerosis)  thought to be a precursor of cirrhosisthought to be a precursor of cirrhosis  Alcoholic cirrhosisAlcoholic cirrhosis  shrunken nodular liver with uniform small nodulesshrunken nodular liver with uniform small nodules (micronodular cirrhosis)(micronodular cirrhosis)
    21. 21. Fatty Change BiochemistryFatty Change Biochemistry  Catabolism of fat by peripheral tissues isCatabolism of fat by peripheral tissues is increased, and there is increased delivery ofincreased, and there is increased delivery of free fatty acids to the liverfree fatty acids to the liver  An excess of NADH over NAD stimulatesAn excess of NADH over NAD stimulates lipid biosynthesislipid biosynthesis  Oxidation of fatty acids by mitochondria isOxidation of fatty acids by mitochondria is decreaseddecreased  Acetaldehyde forms adducts with tubulin andAcetaldehyde forms adducts with tubulin and impairs function of microtubules, resulting inimpairs function of microtubules, resulting in decreased transport of lipoproteins from thedecreased transport of lipoproteins from the liverliver
    22. 22. Neurologic Manifestations of AlcoholismNeurologic Manifestations of Alcoholism  Wernicke syndromeWernicke syndrome  confusion, ataxia, and diplopia fromconfusion, ataxia, and diplopia from ophthalmoplegiaophthalmoplegia  damage to mammillary bodies, cerebellum anddamage to mammillary bodies, cerebellum and periaqueductal gray matterperiaqueductal gray matter of the midbrainof the midbrain  due to thiamine deficiencydue to thiamine deficiency  may respond to prompt thiamine replacementmay respond to prompt thiamine replacement  Korsakov syndromeKorsakov syndrome  memory loss and confabulationmemory loss and confabulation  results from thiamine deficiency and directresults from thiamine deficiency and direct toxicitytoxicity
    23. 23. Mechanisms of Disease Caused by Ethanol Abuse Organ System Lesion Mechanism Liver Fatty change Toxicity Acute hepatitis Alcoholic cirrhosis Nervous system Wernicke syndrome Thiamine deficiency Korsakoff syndrome Toxicity and thiamine deficiency Cerebellar degeneration Nutritional deficiency Peripheral neuropathy Thiamine deficiency Cardiovascular system Cardiomyopathy Toxicity Hypertension Vasopressor
    24. 24. Mechanisms of Disease Caused by Ethanol Abuse Organ System Lesion Mechanism Gastrointestinal tract Gastritis Toxicity Pancreatitis Toxicity Skeletal muscle Rhabdomyolysis Toxicity Reproductive system Testicular atrophy ? Spontaneous abortion ? Fetal alcohol syndrome Growth retardation Toxicity Mental retardation Birth defects
    25. 25. Therapeutic DrugsTherapeutic Drugs (Medications)(Medications)  Oral Contraceptives (BCPs)Oral Contraceptives (BCPs)  Hormone Replacement Therapy (HRT)Hormone Replacement Therapy (HRT)  AcetaminophenAcetaminophen  AspirinAspirin
    26. 26. Oral Contraceptives (BCPs)Oral Contraceptives (BCPs)  Breast cancer and other cancersBreast cancer and other cancers  no increase in breast cancerno increase in breast cancer  decrease endometrial and ovarian cancersdecrease endometrial and ovarian cancers  increase in cervical cancer (?lifestyle induced)increase in cervical cancer (?lifestyle induced)  Thromboembolic eventsThromboembolic events  DVT and Pulmonary Embolism increasedDVT 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 diseaseCardiovascular disease  with current low estrogen pills, risk of MI andwith current low estrogen pills, risk of MI and atherosclerosis not increased in non-smoking women < 45 yatherosclerosis not increased in non-smoking women < 45 y  ischemic stroke increased regardless of age or smokingischemic stroke increased regardless of age or smoking  Liver tumorsLiver tumors  benign hepatic adenomasbenign hepatic adenomas  older women with prolonged useolder women with prolonged use  may rupture and cause intra-abdominal bleedingmay rupture and cause intra-abdominal bleeding
    27. 27. Hormone Replacement Therapy (HRT)Hormone Replacement Therapy (HRT)  CancerCancer  in women with a uterus combined estrogen andin women with a uterus combined estrogen and progestin Rx necessary to reduce endometrial cancerprogestin Rx necessary to reduce endometrial cancer  WHI showed increased risk of breast cancer in womenWHI showed increased risk of breast cancer in women who used HRT combined therapy for 5 yearswho used HRT combined therapy for 5 years  Thromboembolic eventsThromboembolic events  elevated approximated twofold in HRT users, especiallyelevated approximated twofold in HRT users, especially within the first 2 yearswithin the first 2 years  Cardiovascular diseaseCardiovascular disease  WHI reported 29% increased risk of myocardialWHI reported 29% increased risk of myocardial infarction, especially during the first year of combinedinfarction, especially during the first year of combined HRT useHRT use
    28. 28. Acetaminophen (Tylenol)Acetaminophen (Tylenol)  Does not affect cyclooxygenase so bleedingDoes not affect cyclooxygenase so bleeding associated with aspirin does not occurassociated with aspirin does not occur  Has analgesic and antipyretic actions but noHas analgesic and antipyretic actions but no anti-inflammatory actionanti-inflammatory action  Large doses may produce hepatic necrosisLarge doses may produce hepatic necrosis  patients should not exceed recommended dosepatients should not exceed recommended dose (4 grams/day)(4 grams/day)  toxic dose in adults is 15 to 25 gmtoxic dose in adults is 15 to 25 gm  dose should be reduced in children with fever ordose should be reduced in children with fever or dehydrationdehydration
    29. 29. AspirinAspirin  OverdoseOverdose  respiratory alkalosis followed by metabolic acidosis thatrespiratory alkalosis followed by metabolic acidosis that may be fatalmay be fatal  Chronic aspirin toxicity (salicylism)Chronic aspirin toxicity (salicylism)  headache, dizziness, ringing in the ears (tinnitus),headache, dizziness, ringing in the ears (tinnitus), mental confusion, drowsiness, nausea, vomiting, andmental confusion, drowsiness, nausea, vomiting, and diarrheadiarrhea  Inhibits cyclooxygenase (COX 1 & 2)Inhibits cyclooxygenase (COX 1 & 2)  Erosive gastritis is a major cause of GI bleedingErosive gastritis is a major cause of GI bleeding  May be implicated in Reye syndrome (fatty liverMay be implicated in Reye syndrome (fatty liver with encephalopathy) in children < 15 years old,with encephalopathy) in children < 15 years old, especially with influenza and chicken poxespecially with influenza and chicken pox
    30. 30. Cox-1 and Cox-2 InhibitorsCox-1 and Cox-2 Inhibitors  Cyclooxygenase 1Cyclooxygenase 1  constitutively expressed and active in theconstitutively expressed and active in the normal platelet (thromboxane A2)normal platelet (thromboxane A2)  involved in synthesis of gastro-protectiveinvolved in synthesis of gastro-protective prostaglandinsprostaglandins  Cyclooxygenase 2Cyclooxygenase 2  induced, especially in inflamed tissueinduced, especially in inflamed tissue  in vessel wall produces prostacyclin (PGIin vessel wall produces prostacyclin (PGI22))  Aspirin and other nonselective NSAIDSAspirin and other nonselective NSAIDS inhibit both COX-1 and COX-2inhibit both COX-1 and COX-2
    31. 31. 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
    32. 32. Indoor Air PollutionIndoor Air Pollution  Carbon Monoxide COCarbon Monoxide CO  Nitrogen Dioxide NONitrogen Dioxide NO22  Wood SmokeWood Smoke  FormaldehydeFormaldehyde RadonRadon  Manufactured Mineral FibersManufactured Mineral Fibers  BioaerosolsBioaerosols
    33. 33. RadonRadon  Radon is a radioactive gas and a decayRadon is a radioactive gas and a decay product of uraniumproduct of uranium  It is widely distributed in the soil and isIt is widely distributed in the soil and is prevalent in homes (especially in basements)prevalent in homes (especially in basements)  Radon decay products are alpha emittersRadon decay products are alpha emitters  10% of US homes have levels associated with10% of US homes have levels associated with an increased risk of lung cancer and anan increased risk of lung cancer and an estimated 10,000 lung cancers per year in theestimated 10,000 lung cancers per year in the United States are due to radon. SmokingUnited States are due to radon. Smoking elevates risk.elevates risk.  Proper venting reduces the exposureProper venting reduces the exposure
    34. 34. LeadLead  lead is classified as a heavy metal (otherslead is classified as a heavy metal (others include mercury, arsenic, and cadmium)include mercury, arsenic, and cadmium)  Source of exposureSource of exposure  lead paintlead paint  lead solder in plumbing (older houses)lead solder in plumbing (older houses)  lead-glazed ceramicslead-glazed ceramics  industrial exposureindustrial exposure  Route of exposureRoute of exposure  inhalation with industrial exposureinhalation with industrial exposure  ingestion with household exposureingestion with household exposure
    35. 35. Lead Distribution and ExcretionLead Distribution and Excretion  Lead is a divalent cation that is taken up byLead is a divalent cation that is taken up by bone and developing teeth in children (80%bone and developing teeth in children (80% to 85%)to 85%)  Half-life of lead in bone is 30 yearsHalf-life of lead in bone is 30 years  Blood accumulates 5% to 10% of lead, butBlood accumulates 5% to 10% of lead, but lead is rapidly cleared from the bloodlead is rapidly cleared from the blood  lead in blood indicates recent exposurelead in blood indicates recent exposure  blood level does not allow the determination ofblood level does not allow the determination of total body burdentotal body burden  Remainder is distributed in the soft tissuesRemainder is distributed in the soft tissues  Excretion is via the kidneysExcretion is via the kidneys
    36. 36. Effects of LeadEffects of Lead  High affinity for sulfhydryl groupsHigh affinity for sulfhydryl groups  inhibition of heme biosynthesis with hypochromicinhibition of heme biosynthesis with hypochromic anemia and basophillic stippling of erythrocytesanemia and basophillic stippling of erythrocytes  Competition with calcium ionsCompetition with calcium ions  As a divalent cation, lead competes with calcium and isAs a divalent cation, lead competes with calcium and is stored in bone.stored in bone.  It also interferes with nerve transmission and brainIt also interferes with nerve transmission and brain development.development.  Inhibition of membrane-associated enzymesInhibition of membrane-associated enzymes  Lead inhibits 5'-nucleotidase activity and sodium-Lead inhibits 5'-nucleotidase activity and sodium- potassium ion pumps, leading to decreased survival ofpotassium ion pumps, leading to decreased survival of red blood cells (hemolysis), renal damage, andred blood cells (hemolysis), renal damage, and hypertension.hypertension.
    37. 37. Consequences of lead exposure
    38. 38. “RADIATION” T ½  Curie vs. Becqerel  IONIZING vs. NON-IONIZING  PARTICULATE vs. NON-PARTICULATE (Photons)  ENERGY: Kev, Mev (~Wavelength)  Linear Energy Transfer (LET), Relative Biologic Effect (RBE)  LD50@60d
    39. 39. This is the single most RADIOSENSITIVE CELL In your body
    40. 40. Radiation DosimetryRadiation Dosimetry  Roentgen:Roentgen: unit of charge produced by x-rays or gammaunit of charge produced by x-rays or gamma rays that ionize a specific volume of airrays that ionize a specific volume of air  RADRAD (radiation absorbed dose):(radiation absorbed dose): the dose of radiationthe dose of radiation that will produce absorption of 100 ergs of energy per gramthat will produce absorption of 100 ergs of energy per gram of tissue; 1 gm of tissue exposed to 1 roentgen of gammaof tissue; 1 gm of tissue exposed to 1 roentgen of gamma rays is equal to 93 ergsrays is equal to 93 ergs  GrayGray (Gy): the dose of radiation that will produce(Gy): the dose of radiation that will produce absorption of 1 joule of energy per kilogram of tissue; 1 Gyabsorption of 1 joule of energy per kilogram of tissue; 1 Gy corresponds to 100 rad (SI unit for absorbed dose)corresponds to 100 rad (SI unit for absorbed dose)  REMREM (radiation equivalent man):(radiation equivalent man): the dose of radiation thatthe dose of radiation that causes a biologic effect equivalent to 1 rad of x-rays orcauses a biologic effect equivalent to 1 rad of x-rays or gamma raysgamma rays  SievertSievert (Sv): the dose of radiation that causes a biologic(Sv): the dose of radiation that causes a biologic effect equivalent to 1 Gy of x-rays or gamma rays; 1 Sveffect equivalent to 1 Gy of x-rays or gamma rays; 1 Sv corresponds to 100 rem (SI unit)corresponds to 100 rem (SI unit)
    41. 41. Acute Effects of Ionizing RadiationAcute Effects of Ionizing Radiation  Free radical generationFree radical generation  Ionizing radiation + HIonizing radiation + H220 → H0 → H3300++ + OH·+ OH·  DNA DamageDNA Damage  double-stranded DNA breaks needed to kill celldouble-stranded DNA breaks needed to kill cell (mammalian cells can repair single stranded(mammalian cells can repair single stranded breaks)breaks)  cross-linking of DNA strands, cleavage of sugar-cross-linking of DNA strands, cleavage of sugar- phosphate bondsphosphate bonds  Tumor-suppressor geneTumor-suppressor gene p53p53 activationactivation  cell cycle arrest in presence of damaged DNAcell cycle arrest in presence of damaged DNA  repair of DNA damage or apoptosisrepair of DNA damage or apoptosis
    42. 42. Acute Whole Body RadiationAcute 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)  HematopoieticHematopoietic  200–600 REM200–600 REM  Maximum neutrophil and platelet depression in 2 wkMaximum neutrophil and platelet depression in 2 wk  GastrointestinalGastrointestinal  600–1000 REM600–1000 REM  Nausea, vomiting, diarrheaNausea, vomiting, diarrhea  Hemorrhage and infection in 1–3 wkHemorrhage and infection in 1–3 wk  Central nervous systemCentral nervous system  >1000 REM>1000 REM  Intractable nausea and vomitingIntractable nausea and vomiting  Confusion, somnolence, convulsionsConfusion, somnolence, convulsions  death in 14–36 hrdeath in 14–36 hr
    43. 43. Therapeutic RadiationTherapeutic Radiation  External radiation is delivered to malignantExternal radiation is delivered to malignant neoplasms at fractionated doses up to 40 toneoplasms at fractionated doses up to 40 to 70 Gy (4000 to 7000 rad), with shielding of70 Gy (4000 to 7000 rad), with shielding of adjacent normal tissuesadjacent normal tissues  Therapeutic radiation alone seems to addTherapeutic radiation alone seems to add little risk of AML but can increase the risk inlittle risk of AML but can increase the risk in people exposed to alkylating agentspeople exposed to alkylating agents  Fatigue, nausea and vomiting frequentFatigue, nausea and vomiting frequent  Bone marrow suppression may occurBone marrow suppression may occur especially with chest or abdominal radiationespecially with chest or abdominal radiation
    44. 44. Delayed Radiation InjuryDelayed Radiation Injury  Carcinogenesis (atom bomb survivors)Carcinogenesis (atom bomb survivors)  myeloid leukemias peak 5 to 7 years after exposuremyeloid leukemias peak 5 to 7 years after exposure  breast and thyroid cancers may show greater latencybreast and thyroid cancers may show greater latency  no germline mutations noted in progeny of survivorsno germline mutations noted in progeny of survivors  Vascular effectsVascular effects  endothelial necrosis followed by intimal and medialendothelial necrosis followed by intimal and medial fibrosisfibrosis  capillaries may become thrombosed and obliterated orcapillaries may become thrombosed and obliterated or ectaticectatic  Parenchymal atrophy and fibrosisParenchymal atrophy and fibrosis
    45. 45. Radiation effects on TISSUE  ACUTE (vasculitis, possibly “fibrinoid” necrosis)  CHRONIC (fibrosis)
    46. 46. Physical InjuryPhysical Injury  AbrasionAbrasion  basically a scrapebasically a scrape  superficial epidermis is torn off by friction or forcesuperficial epidermis is torn off by friction or force  regeneration without scarring usually occursregeneration without scarring usually occurs  Laceration vs. IncisionLaceration vs. Incision  a laceration is an irregular tear in the skin produced bya laceration is an irregular tear in the skin produced by overstretching. The wound margins are frequently hemorrhagicoverstretching. The wound margins are frequently hemorrhagic and traumatizedand traumatized  an incision is made by a sharp cutting object. The margins ofan incision is made by a sharp cutting object. The margins of the incision are usually relatively cleanthe incision are usually relatively clean  ContusionContusion  an injury caused by a blunt force that damages small bloodan injury caused by a blunt force that damages small blood vessels and causes interstitial bleeding, usually withoutvessels and causes interstitial bleeding, usually without disruption of the continuity of the tissue (disruption of the continuity of the tissue (cfcf ecchymosis)ecchymosis)
    47. 47. Adult Mortality Rates in the United States, Ages 25–44, in 1998 Rate per 100,000 population Cause Hispanic Black White Unintentional injuries 33.4 40.1 31.6 Cancer 16.8 38.0 25.3 Homicide 13.1 36.2 4.7 Human immunodeficiency virus 12.1 43.3 4.8 Heart disease 10.3 43.5 18.3 Suicide 7.8 — 17.0 Total 130.2 303.7 139.4 Data from CDC Fact Book, 2000/2001, Department of Health and Human Services, Centers for Disease Control and Prevention.
    48. 48. GUNSHOT WOUND  Entrance Vs. Exit  Far range Vs. Close range
    49. 49. BURNS 1st , 2nd , 3rd , 4th “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)
    50. 50. 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.
    51. 51. HYPO-THERMIA Often in setting of homelessness or alcoholism or both < 90º often fatal, assoc. w.  BRADYCARDIA  ATRIAL FIBRILLATION
    52. 52. LIGHTNING/ELECTRICAL  ELECTRIC DISTURBANCES  NEURAL  EKG  THERMAL INJURY, depends upon a particular tissue’s RESISTANCE to electrical flow  “LIGHTNING” MARKS
    53. 53. ATMOSPHERIC PRESSURE Altitude Illness Blast Injuries Decompression Injuries
    54. 54. ALTITUDE ILLNESS  Caused by LOW Oxygen Tension  HIGH ALTITUDES (>4000 m)  OBTUNDATION  INCREASED CAPILLARY PERMEABILITY  ACUTE PULMONARY EDEMA (HAPE) Q: What is the name of the base camp at Mt. Everest A: Pulmonary Edema
    55. 55. 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
    56. 56. 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
    57. 57. NUTRITIONNUTRITION & DISEASE& DISEASE  Food SafetyFood Safety  AdditivesAdditives  ContaminantsContaminants  Nutritional DeficienciesNutritional Deficiencies  VitaminsVitamins  MineralsMinerals  ObesityObesity  Diet and DiseaseDiet and Disease  Chemoprevention of CancerChemoprevention of Cancer
    58. 58. Vitamin Deficiency and ExcessVitamin Deficiency and Excess  Fat soluble vitaminsFat soluble vitamins  A, D, E, KA, D, E, K  readily stored in body fatreadily stored in body fat  poorly absorbed in digestive disorders involvingpoorly absorbed in digestive disorders involving malabsorbtion of fatmalabsorbtion of fat  Water soluble vitaminsWater soluble vitamins  remaining vitaminsremaining vitamins  readily excreted in urinereadily excreted in urine  Vitamin storesVitamin stores  vitamins B-12 and A: stores sufficient for 1 yearvitamins B-12 and A: stores sufficient for 1 year  folate and thiamine may become depletedfolate and thiamine may become depleted within weeks when eating a deficient dietwithin weeks when eating a deficient diet
    59. 59. Vitamin D MetabolismVitamin D Metabolism  Absorption of vitamin D in the gut orAbsorption of vitamin D in the gut or synthesis from precursors in the skinsynthesis from precursors in the skin  Binding to a plasma α1 -globulin (D-Binding to a plasma α1 -globulin (D- binding protein) and transport to liverbinding protein) and transport to liver  Conversion to 25-hydroxyvitamin D,Conversion to 25-hydroxyvitamin D, 25(OH)D (calcidol) by 25-hydroxylase in25(OH)D (calcidol) by 25-hydroxylase in the liverthe liver  Conversion of 25(OH)D to 1,25(OH)Conversion of 25(OH)D to 1,25(OH)22 DD (calcitrol, Vitamin D3) by α1-hydroxylase(calcitrol, Vitamin D3) by α1-hydroxylase in the kidney;in the kidney; biologically this is the mostbiologically this is the most active form of vitamin Dactive form of vitamin D..
    60. 60. Functions of Vitamin DFunctions of Vitamin D  Stimulates intestinal absorption of calciumStimulates intestinal absorption of calcium and phosphorusand phosphorus  Collaborates with PTH in the mobilizationCollaborates with PTH in the mobilization of calcium from boneof calcium from bone  Stimulates the PTH-dependent reabsorptionStimulates the PTH-dependent reabsorption of calcium in the distal renal tubulesof calcium in the distal renal tubules  1,25(OH)1,25(OH)22 D, the biologically active form ofD, the biologically active form of vitamin D, is best regarded as a steroidvitamin D, is best regarded as a steroid hormone which acts by binding to a high-hormone which acts by binding to a high- affinity receptoraffinity receptor
    61. 61. Vitamin D DeficiencyVitamin D Deficiency  Holick et al (2005) reported the results of aHolick et al (2005) reported the results of a large North American study that assessedlarge North American study that assessed the vitamin D status of postmenopausalthe vitamin D status of postmenopausal women receiving therapy to treat or preventwomen receiving therapy to treat or prevent osteoporosisosteoporosis  52% of 1536 women had inadequate52% of 1536 women had inadequate [25(OH)D] levels (<30 ng/mL)[25(OH)D] levels (<30 ng/mL)  36% and 18% had levels less than 25 and 2036% and 18% had levels less than 25 and 20 ng/mL, respectively.ng/mL, respectively. Holick MF et al: J Clin Endocrinol Metab 90:3215, 2005
    62. 62. Vitamin D DeficiencyVitamin D Deficiency  Childhood: RicketsChildhood: Rickets  epiphyses are openepiphyses are open  cartilage overgrowthcartilage overgrowth  Adults:Adults: osteomalaciaosteomalacia  bone matrix is not calcifiedbone 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
    63. 63. Vitamin KVitamin K  Clotting factors VII, IX, and X andClotting factors VII, IX, and X and prothrombin (II) all require carboxylation ofprothrombin (II) all require carboxylation of glutamate residues for functional activityglutamate residues for functional activity  anticoagulant coumadin is a Vitamin Kanticoagulant coumadin is a Vitamin K antagonistantagonist  Activation of anticoagulant proteins C and SActivation of anticoagulant proteins C and S also requires glutamate carboxylationalso requires glutamate carboxylation  SourcesSources  endogenous intestinal bacterial floraendogenous intestinal bacterial flora  dietdiet
    64. 64. Vitamin K DeficiencyVitamin K Deficiency  CausesCauses  fat malabsorptionfat malabsorption  reduced gut bacterial florareduced gut bacterial flora  administration of wide specturm antibioticsadministration of wide specturm antibiotics  neonatal period before gut is colonizedneonatal period before gut is colonized  liver disease with reduced recycling of vitamin Kliver disease with reduced recycling of vitamin K  Effects of vitamin K deficiencyEffects of vitamin K deficiency  bleeding diathesisbleeding diathesis  estimated 3% prevalence of vitamin K-estimated 3% prevalence of vitamin K- dependent bleeding diathesis among neonatesdependent bleeding diathesis among neonates warrants routine prophylactic vitamin K therapywarrants routine prophylactic vitamin K therapy for all newbornsfor all newborns

    ×