Effects Of Tobacco
Effects of Tobacco
It is the most common exogenous cause of
human cancers, being responsible for 90% of
lung cancers
The...
When you inhale smoke, these chemicals
enter your lungs and spread around the rest of
your body
 Tar, not nicotine, is t...
EFFECTS OF SELECTED TOBACCO SMOKE CONSTITUENTS
Substance Effects
Tar Carcinogenesis
Polycyclic aromatic hydrocarbons Carci...
Adverse effects
of smoking:
those that are
more common
are in boldface
Lung Cancer
Genetic and epigenetic changes lead to cancer
through alteration of critical cellular pathways
that foster un...
Lung Cancer
Normal Lung Lung with cancer
How smoking damages your lungs
How smoking causes cancer
Heart Attack and Stroke
Smoking leads to heart attack
and stroke
Smoking is one cause of dangerous plaque
buildup inside your arteries
 Plaque i...
Emphysema
The lung is made up of numerous minute
air sacs called alveoli, each surrounded
by very thin walls. Networks of...
Emphysema
The alveolar walls are vested
with elastic fibers so that they
can stretch with inhalation and
recoil with exha...
Emphysema
Emphysema is a pathological
condition of the lung that results
from breakdown of the elastic fibers.
This ultim...
Normal Alveoli Emphysema
LIVER
• Fatty changes
• Alcoholic hepatitis
• Cirrhosis
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PANCREATITIS
• Characterized by inflammation which may
ultimately lead to scarring
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USE OF ETHANOL DURING
PREGNANCY
• Fetal alcohol syndrome
–Microcephaly
–Growth retardation
–Facial abnormalities in newbor...
Injury by Therapeutic Drugs &
Drugs of Abuse
Injury by Therapeutic Drugs
Adverse drug reactions (ADRs) refer to untoward
effects of drugs that are given in conventiona...
Oral Contraceptives (Ocs)
• Always contain a synthetic estradiol and a
variable amount of a progestin. They act by
inhibit...
Anabolic Steroids
• Anabolic steroids are synthetic versions of
testosterone, and for performance
enhancement they are use...
• Anabolic steroids have multiple adverse
effects including stunted growth in
adolescents, acne, gynecomastia and
testicul...
Acetaminophen
• Acetaminophen is the most commonly used
analgesic in the United States.
• Toxicity begins with nausea, vom...
Aspirin (Acetylsalicylic Acid)
• A source of salicylate poisoning is the
excessive use of ointments containing oil of
wint...
INJURY BY NONTHERAPEUTIC AGENTS
(DRUG ABUSE)
• Drug abuse generally involves the use of mind-
altering substances, beyond ...
Cocaine
• Cocaine is extracted from the leaves of the
coca plant, and is usually prepared as a water-
soluble powder, coca...
Heroin
• Heroin is an addictive opioid derived from the
poppy plant that is closely related to
morphine. Its use is even m...
Methamphetamine
• Also known as speed or meth.
• It acts by releasing dopamine in the brain,
which inhibits presynaptic ne...
MDMA
• MDMA (3,4
methylenedioxymethamphetamine) is
popularly known as ecstasy.
• It is generally taken orally. Its effects...
Marijuana
• Marijuana, or pot, is made from the leaves of
the Cannabis sativa plant, which contain the
psychoactive substa...
EFFECTS OF ALCOHOL
Absorbed UNALTERED
80 mg/dL3
bottles 15 oz 4-5 oz
Figure 9-12 Metabolism of ethanol: oxidation of ethanol to acetaldehyde by three different routes, and the generation of a...
ACETALDEHYDE
• Responsible for some of the
acute affects of alcohol and;
• Development of oral cancers
ACETALDEHYDE
• Efficiency of alcohol metabolism varies
between populations, depending on:
–Expression levels of ADH and AL...
ACETALDEHYDE
• ALDH2*1
– Normal allele
• ALDH2*2
– Inactive variant
– Dominant-negative activity
• One copy of ALDH2*2 red...
ALCOHOL OXIDATION BY ADH
• Causes reduction of NAD to NADH
– Consequent ↓ in NAD and ↑ in NADH
• NAD deficiency is a main ...
METABOLISM OF ETHANOL IN THE
LIVER BY CYP2E1
• Produces ROS
• Causes lipid peroxidation of cell membranes
• Alcohol also c...
ACUTE ALCOHOLISM
• Exerts its effects mainly on the CNS
– But may induce hepatic and gastric changes
• Reversible if alcoh...
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ACUTE ALCOHOLISM
• Gastric changes:
–Acute gastritis
–ulceration
ACUTE ALCOHOLISM
• CNS:
–Depressant
–Consequently, there is stimulation &
disordered cortical, motor & intellectual
behavi...
ACUTE ALCOHOLISM
• CNS:
–At progressively higher blood levels, cortical
neurons & lower medullary centers are
depressed
• ...
CHRONIC ALCOHOLISM
• Affects:
–Liver
–Stomach
–All other tissues and organs
CHRONIC ALCOHOLISM
• Chronic alcoholics suffer significant morbidity
and have a shortened life span, related
principally t...
CHRONIC ALCOHOLISMLIVER
LIVER
• Fatty changes
• Alcoholic hepatitis
• Cirrhosis
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CHRONIC ALCOHOLISM
GASTROINTESTINAL
TRACT
GASTROINTESTINAL TRACT
• Massive bleeding from:
– Gastritis
– Gastric ulcer
– Esophageal varices (associated with cirrhosi...
CHRONIC ALCOHOLISM
THYMINE
DEFICIENCY
THYMINE DEFICIENCY
• Principal lesions:
– Peripheral neuropathies
– Wernicke-Korsakoff syndrome
– Cerebral atrophy
– Cereb...
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CHRONIC ALCOHOLISM
CARDIOVASCULAR
SYSTEM
CARDIOVASCULAR SYSTEM
• Injury to the myocardium may produce dilated
congestive cardiomyopathy (alcoholic
cardiomyopathy)
...
CARDIOVASCULAR SYSTEM
• Moderate amounts of alcohol (20-30 g of
daily intake=250 mL of wine)
–↑ HDL levels
–Inhibit platel...
CARDIOVASCULAR SYSTEM
• Heavy alcohol consumption, with
attendant liver injury,
–results in ↓ HDL levels
• ↑ likelihood of...
CHRONIC ALCOHOLISMPANCREAS
PANCREAS
• Excessive alcohol intake
↑ risk of acute and chronic
pancreatitis
CHRONIC ALCOHOLISM
USE OF ETHANOL
DURING
PREGNANCY
USE OF ETHANOL DURING
PREGNANCY
• Fetal alcohol syndrome
–Microcephaly
–Growth retardation
–Facial abnormalities in newbor...
USE OF ETHANOL DURING
PREGNANCY
• Consumption during the 1st trimester
is particularly harmful
CHRONIC ALCOHOLISMCANCER
CANCER
• Chronic alcohol consumption is associated
with ↑ incidence of cancer of the:
– Oral cavity
– Esophagus
– Liver
– ...
CANCER
• Acetaldehyde is considered to be the
main agent associated with
alcohol-induced laryngeal and
esophageal cancer
RESVERATOL in Red Wine
• Contributes to the protective effect
against CVD in moderate wine
drinkers and possibly provides ...
INJURY PRODUCED BY
IONIZING RADIATION
RADIATION
• Non-ionizing radiation
–Can move atoms in a molecule or cause
them to vibrate, but is NOT sufficient to
displa...
NON-IONIZING RADIATION IONIZING RADIATION
•Alpha particle
•Beta particle
•High-energy neurons
•Gamma rays
X-ray
UV Micro-
...
IONIZING RADIATION
Merits Demerits
•Treatment of cancer
•Diagnostic imaging
•Therapeutic or
diagnostic
radioisotopes
•Fibr...
Main Determinants of the Biologic
Effects of Ionizing Radiation
• Rate of Delivery
–Although the effect of radiant energy ...
Main Determinants of the Biologic
Effects of Ionizing Radiation
• Field size
–The body can sustain relatively high
doses o...
Main Determinants of the Biologic
Effects of Ionizing Radiation
• Cell proliferation
–Because ionizing radiation damages
D...
Main Determinants of the Biologic
Effects of Ionizing Radiation
• Cell proliferation
–Except at extremely high doses that
...
Main Determinants of the Biologic
Effects of Ionizing Radiation
• Cell proliferation
–Dividing cells:
• Mutations and chro...
Main Determinants of the Biologic
Effects of Ionizing Radiation
• Oxygen effects and hypoxia
–The production of ROS from t...
Figure 9-17 Effects of ionizing radiation on DNA and its consequences. The effects on DNA can be direct, or most important...
Main Determinants of the Biologic
Effects of Ionizing Radiation
• Oxygen effects and hypoxia
–Poorly vascularized tissues ...
Main Determinants of the Biologic
Effects of Ionizing Radiation
• Vascular damage
–May cause narrowing or occlusion of
the...
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MORPHOLOGY
• NUCLEUS:
– Swelling
– Membrane breakdown
• CHROMOSOMES:
– Structural changes: deletion, break, translocation
...
MORPHOLOGY
• MITOTIC SPINDLE:
–Becomes disorderly
• CYTOPLASMIC CHANGES:
–Swelling
–Mitochondrial distortion
–Degeneration...
MORPHOLOGY
• Giant cells with pleomorphic or more
than one nucleus may appear and persist
for years after exposure.
• At e...
MORPHOLOGY
• Similarity between radiation injured cells
and cancer cells:
–Cellular pleomorphism
–Giant-cell formation
–Co...
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MORPHOLOGY
• LM:
–Vascular change and interstitial fibrosis
are prominent in irradiated tissue
–Intermediate post-irradiat...
MORPHOLOGY
• LM:
–With higher doses / with time, a variety of
degenerative changes may appear:
• Endothelial cell swelling...
MORPHOLOGY
–Endothelial cell proliferation and
collagenous hyalinization with thickening of
the media
• Resulting in narro...
Total Body Irradiation
• Exposure of large areas of the body to even
very small doses of radiation may have
devastating ef...
Acute Effects on Hematopoietic and
Lymphoid Systems
• High dose levels & large exposure fields:
– Severe lymphopenia may a...
Acute Effects on Hematopoietic and
Lymphoid Systems
• Hematopoietic precursors in BM are also
quite sensitive to radiant e...
Acute Effects on Hematopoietic and
Lymphoid Systems
• Granulocyte ct:
– may first rise but begin to fall toward the end of...
Acute Effects on Hematopoietic and
Lymphoid Systems
• Platelet ct
– Similar w/ granulocytes but somewhat delayed
• Red cel...
Fibrosis
• Occur weeks or months after irradiation
as a consequence of the replacement of
dead parenchymal cells by connec...
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DNA Damage & Carcinogenesis
• Single-base damage
• Single- & double-stranded breaks
• DNA protein crosslinks
• Double-stra...
DNA Damage & Carcinogenesis
• Repair by NHEJ
– Short deletions or duplications
– Gross chromosomal aberrations
• Transloca...
Cancer Risks from Exposures to
Low-level Radiation
• Any cell capable of division that has
sustained a mutation has the po...
Injury by physical Agents
Divided into the following:
• Mechanical injury
• Thermal injury
• Electrical injury
• Ionizing radiation
MECHANICAL TRAUMA
The type of injury depends on the shape of
the colliding object, the amount of energy
discharged at impa...
Patterns of injury can be divided:
• Abrasions
• contusions
• lacerations
• incised wounds
• puncture wounds
THERMAL INJURY
Causes of thermal injury:
• Thermal Burns
• Hyperthermia
• Hypothermia
Thermal Burns
clinical significance:
• Depth of the burns
• Percentage of body surface involved
• Internal injuries caused...
Classification of burns:
• Superficial burns
• Partial thickness burns
• Full-thickness burns
• Full-thickness burns with ...
• Hyperthermia
Prolonged exposure to
elevated ambient
temperatures can result in
heat cramps, heat
exhaustion, and heat
st...
• ELECTRICAL INJURY
Electrical injuries, which are
often fatal, can arise from
contact with low-voltage
currents (i.e., in...
Injuries are of mechanical injury are two types:
• burns
• ventricular fibrillation or cardiac and
respiratory center fail...
Updates:
EHSI: ‘Skin Gun’ For Burns is Latest Stem
Cell Treatment
The skin gun looks and works similar to an artist’s
airb...
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  • Lung Cancer is the most dangerous disease of tobacco smoking. Death is 100% sure.
  • Heart Attack and stroke are caused by Tar in tobacco causing damage to the blood vessels of the heart
  • SOLICIT EFFECTS OF ALCOHOL--------------MODERATION-- BENEFICIALEXCESS—PHYSICAL & PSYCHOLOGICAL DAMAGE
  • CHRONIC—IRREVERSIBLE
  • Adverse drug reaction. Skin pigmentation caused by minocycline, a long-acting tetracycline derivative. A, Diffuse blue-gray B, Deposition of drug metabolite/iron/melanin pigment particles in the dermis.pigmentation of the forearm;
  • Thromboembolism. Most studies indicate that OC use results in an approximately three-fold increased riskof venous thrombosis and pulmonary thromboembolism. This risk is increased further in carriers of prothrombin and factor V Leiden mutations. The increased thrombotic risk seems to be a consequence he generation of an acute-phase response, with increases in C-reactive protein and coagulation factorsfactors VII, IX, X, XII, and XIII), and reduction in anticoagulants (protein S and anti-thrombin III). Cardiovascular disease. OCs increase the risk of myocardial infarction in smoking women at all ages and in nonsmoking women over age 35. In women over 35 years of age, the effect is more than ten-fold higher in smokers than nonsmokers. Hepatic adenoma. There is a well-defined association between the use of OCs and this hepatic tumor, particularly in older women who have used OCs for prolonged periods of time. The tumor appears as a large, solitary, and well-encapsulated mass.Hepatic adenomas are uncommon benign epithelial liver tumors that develop in an otherwise normal appearing liver. They are seen predominantly in young women (20 to 44 years-old), are frequently located in the right hepatic lobe, and are typically solitary (70 to 80 percent), although multiple adenomas have been described in patients with prolonged contraceptive use, glycogen storage diseases (GSD), and hepatic adenomatosis.
  • They are commonly used by baseball players, track-and-field athletes, and wrestlers to increase performance.
  • Stunted growth is a reduced growth rate in human developmentGynecomastia -enlargement of man's breasts: enlarged breasts on a man caused by hormonal imbalance or hormone therapy.
  • Analgesic nephropathy is injury to the kidney caused by analgesic medications such as aspirin, phenacetin, and paracetamol.
  • fibrosis in the kidney medulla.
  • Cocaine can be snorted or dissolved in water and injected subcutaneously or intravenouslyCocaine produces an intense euphoria and stimulation, making it one of the most addictive drugs. Acute overdose can produce seizures, cardiac arrhythmias, and respiratory arrest.euphoria -extreme happiness: a feeling of great joy, excitement, or well-beingHyperpyrexia- fever: a very high fever ar·rhyth·mi·a- irregular heartbeat: an irregularity in the rhythm of the heartbeat
  • naturally occurring opium-containing substance: any opium-containing substance that is produced naturally in the brainAlong with any contaminating substances, it is usually self-administered intravenously or subcutaneously.Hallucination- false sense perceptionSomnolence - drowsiness, tiredness, lethargySedation - calm, restfulness, drowsiness, peacefulness Abscesse -pus-filled cavity: a pus-filled cavity resulting from inflammation and usually caused by bacterial infectionCellulitis - inflammation of tissues beneath skin
  • , such as inability to judge time, speed, and distance, a frequent cause of automobile accidents.increases the heart rate and sometimes blood pressure, and it may cause angina in a person with coronary artery disease. Chronic marijuana smoking also causes laryngitis, pharyngitis, bronchitis, cough and hoarseness, and asthma-like symptoms. \Hoarseness- sounding rough: sounding rough and grating
  • About 50% of Asians have very low ALDH activity, due to substitution of lysine for glutamine @ residue 487
  • Individuals homozygous for ALDH2*2 are completely unable to oxidize acetaldehyde and cannot tolerate alcohol-nausea, flushing, tachycardia and hyperventilation
  • Nicotinamide adenine dinucleotide-required for FA oxidation in the liver-conversion of lactate -> pyruvate
  • MAIN SITE OF CHRONIC INJURY
  • VITAMIN B1 DEFICIENCYCOMMON IN CHRONIC ALCOHOLICS
  • A wine-loving population with a LOW incidence of obesity and CVD
  • THEREFORE, TISSUES WITH A HIGH RATE OF CELL DIVISION, SUCH ASGONADS, BONE MARROW, LYMPHOID TISSUE AND THE MUCOSA OF THE GIT,ARE EXTREMELY VULNERABLE TO RADIATION AND THE INJURY IS MANIFESTED EARLY AFTER EXPOSURE
  • ALL FORMS OF ABNORMAL NUCLEAR MORPHOLOGY MAY BE SEEN
  • ALL FORMS OF ABNORMAL NUCLEAR MORPHOLOGY MAY BE SEEN
  • HENCE IT IS A PROBLEM THAT PLAGUES THE PATHOLOGIST WHEN EVALUATING POST-IRRADIATION TISSUES FOR THE POSSIBLE PERSISTENCE OF TUMOR CELLS
  • AFFECTED VESSELS MAY RUPTURE OR THROMBOSE
  • LATERRRRRRRRRRRRRRRR….
  • AT HIGHER DOSES INVOLVE THE HEMATOPOIETIC, GASTROINTESTINAL AND CNS
  • The hematopoietic and lymphoid systems are extremely susceptible to radiation injury
  • VERY HIGH DOSES OF RADIATION KILL MAROW STEM CELLS AND PRODUCE PERMANENT APLASIA------------OCCURS IN LOWER DOSES
  • VASCULAR DAMAGE, KILLING OF TISSUE STEM CELLS, AND THE RELEASE OF CYTOKINES AND CHEMOKINES THAT PROMOTE AN INFLAMMATORY RXN & FIBROBLAST ACTIVATION ARE THE MAIN CONTRIBUTORS TO THE DEVELOPMENT OF RADIATION-INDUCED FIBROSIS
  • IONIZING RADIATION CAN CAUSE MULTIPLE TYPES OF DAMAGE IN DNA==================NHEJ ---MOST COMMON REPAIR PATHWAY
  • THESE ABNORMAL CELLS MAY ALSO HAVE A “BYSTANDER EFFECT” --- AND MAY PROMOTE GROWTH OF NON-IRRADIATED SURROUNDING CELLS THROUGH THE PRODUCTION OF GF AND CYTOKINESBYSTANDER EFFECTS ARE REFERRED TO AS NON-TARGET EFFECTS OF RADIATION
  • Thus an ↑ incidence of neoplasms may occur in any organ after exposre to ionizing radiation
  • A, Contusion resulting from blunt trauma. The skin is intact, but there is hemorrhage of subcutaneous vessels, producingextensive discoloration. B, Laceration of the scalp; the bridging strands of fibrous tissues are evident.
  • Superficial burns (formerly known as first-degree burns) are confined to the epidermis.• Partial thickness burns (formerly known as second-degree burns) involve injury to the dermis.• Full-thickness burns (formerly known as third-degree burns) extend to the subcutaneous tissue. Fullthicknessburns may also involve damage to muscle tissue underneath the subcutaneous tissue (these wereknown formerly as fourth-degree burns).
  • Morphology. Grossly, full-thickness burns are white or charred, dry, and anesthetic (because of destruction of nerve endings), whereas, depending on the depth, partial-thickness burns are pink or mottled with blisters and are painful. Histologically, devitalized tissue reveals coagulative necrosis, adjacent to vital tissue that quickly accumulates inflammatory cells and marked exudation
  • Histopathreport

    1. 1. Effects Of Tobacco
    2. 2. Effects of Tobacco It is the most common exogenous cause of human cancers, being responsible for 90% of lung cancers The main culprit is the cigarette smoking but smokeless tobacco (snuff, chewing tobacco, etc.) is also harmful to health and an important cause of oral cancer
    3. 3. When you inhale smoke, these chemicals enter your lungs and spread around the rest of your body  Tar, not nicotine, is the cancer-causing agent in cigarette smoke  The use of tobacco products not only creates personal risks but passive tobacco inhalation from the environment (Secondhand smoker) can cause lung cancer in non-smokers
    4. 4. EFFECTS OF SELECTED TOBACCO SMOKE CONSTITUENTS Substance Effects Tar Carcinogenesis Polycyclic aromatic hydrocarbons Carcinogenesis Nicotine Ganglionic stimulation and depression; tumor production Phenol Tumor production; mucosal irritation Benzopyrene Carcinogenesis Carbon monoxide Impaired oxygen transport and utilization Formaldehyde Toxicity to cilia; mucosal irritation Oxides of nitrogen Toxicity to cilia; mucosal irritation Nitrosamine Carcinogenesis
    5. 5. Adverse effects of smoking: those that are more common are in boldface
    6. 6. Lung Cancer Genetic and epigenetic changes lead to cancer through alteration of critical cellular pathways that foster uncontrolled cell growth and defeat of normal mechanisms to restrain their growth and spread Exposure to cigarette smoke carcinogens leads to DNA damage and subsequent mutations in P53 and K-RAS in lung cancer.
    7. 7. Lung Cancer Normal Lung Lung with cancer
    8. 8. How smoking damages your lungs
    9. 9. How smoking causes cancer
    10. 10. Heart Attack and Stroke
    11. 11. Smoking leads to heart attack and stroke Smoking is one cause of dangerous plaque buildup inside your arteries  Plaque is made of cholesterol and scar tissue. It clogs and narrows your arteries. This can trigger chest pain, weakness, heart attack, or stroke. Plaque can rupture and cause clots that block arteries  Completely blocked arteries can cause sudden death
    12. 12. Emphysema The lung is made up of numerous minute air sacs called alveoli, each surrounded by very thin walls. Networks of capillaries run through these walls and exchange of carbon dioxide with oxygen takes place between the blood in those capillaries and the air in the alveoli
    13. 13. Emphysema The alveolar walls are vested with elastic fibers so that they can stretch with inhalation and recoil with exhalation
    14. 14. Emphysema Emphysema is a pathological condition of the lung that results from breakdown of the elastic fibers. This ultimately leads to disruption of the alveolar walls themselves, due to rupture of the alveoli from over inflation
    15. 15. Normal Alveoli Emphysema
    16. 16. LIVER • Fatty changes • Alcoholic hepatitis • Cirrhosis
    17. 17. Downloaded from: StudentConsult (on 23 June 2013 05:17 AM) © 2005 Elsevier
    18. 18. Downloaded from: StudentConsult (on 23 June 2013 05:17 AM) © 2005 Elsevier
    19. 19. Downloaded from: StudentConsult (on 23 June 2013 05:17 AM) © 2005 Elsevier
    20. 20. Downloaded from: StudentConsult (on 23 June 2013 05:55 AM) © 2005 Elsevier
    21. 21. Downloaded from: StudentConsult (on 23 June 2013 05:55 AM) © 2005 Elsevier
    22. 22. PANCREATITIS • Characterized by inflammation which may ultimately lead to scarring
    23. 23. Downloaded from: StudentConsult (on 23 June 2013 05:17 AM) © 2005 Elsevier
    24. 24. Downloaded from: StudentConsult (on 23 June 2013 05:17 AM) © 2005 Elsevier
    25. 25. USE OF ETHANOL DURING PREGNANCY • Fetal alcohol syndrome –Microcephaly –Growth retardation –Facial abnormalities in newborns –Reduction in mental functions as the child grows older
    26. 26. Injury by Therapeutic Drugs & Drugs of Abuse
    27. 27. Injury by Therapeutic Drugs Adverse drug reactions (ADRs) refer to untoward effects of drugs that are given in conventional therapeutic settings. These reactions are extremely common in the practice of medicine and affect almost 10% of patients admitted to a hospital.
    28. 28. Oral Contraceptives (Ocs) • Always contain a synthetic estradiol and a variable amount of a progestin. They act by inhibiting ovulation or preventing implantation. • There is evidence that the use of OCs is associated with thromboembolism, cardiovascular disease, and hepatic adenoma.
    29. 29. Anabolic Steroids • Anabolic steroids are synthetic versions of testosterone, and for performance enhancement they are used at doses that are about 10 to 100 times higher than therapeutic indications.
    30. 30. • Anabolic steroids have multiple adverse effects including stunted growth in adolescents, acne, gynecomastia and testicular atrophy in males, and growth of facial hair and menstrual changes in women. Other effects include psychiatric problems and premature heart attacks.
    31. 31. Acetaminophen • Acetaminophen is the most commonly used analgesic in the United States. • Toxicity begins with nausea, vomiting, diarrhea, and sometimes shock, followed in a few days by evidence of jaundice.
    32. 32. Aspirin (Acetylsalicylic Acid) • A source of salicylate poisoning is the excessive use of ointments containing oil of wintergreen (methyl salicylate). • Proprietary analgesic mixtures of aspirin and phenacetin or its active metabolite, acetaminophen, when taken over several years, can cause analgesic nephropathy.
    33. 33. INJURY BY NONTHERAPEUTIC AGENTS (DRUG ABUSE) • Drug abuse generally involves the use of mind- altering substances, beyond therapeutic or social norms.
    34. 34. Cocaine • Cocaine is extracted from the leaves of the coca plant, and is usually prepared as a water- soluble powder, cocaine hydrochloride. • Sold on the street, it is liberally diluted with talcum powder, lactose, or other look-alikes.
    35. 35. Heroin • Heroin is an addictive opioid derived from the poppy plant that is closely related to morphine. Its use is even more harmful than that of cocaine. • Effects are varied and include euphoria, hallucinations, somnolence, and sedation.
    36. 36. Methamphetamine • Also known as speed or meth. • It acts by releasing dopamine in the brain, which inhibits presynaptic neurotransmission at corticostriatal synapses, slowing glutamate release. • Long-term use leads to violent behaviors, confusion, and psychotic features that include paranoia and hallucinations.
    37. 37. MDMA • MDMA (3,4 methylenedioxymethamphetamine) is popularly known as ecstasy. • It is generally taken orally. Its effects, which include euphoria and hallucinogen-like feelings that last for 4 to 6 hours, are mainly due to an increase in serotonin release in the CNS.
    38. 38. Marijuana • Marijuana, or pot, is made from the leaves of the Cannabis sativa plant, which contain the psychoactive substance 9- tetrahydrocannabinol (THC). • Its use distorts sensory perception and impairs motor coordination. With continued use these changes may progress to cognitive and psychomotor impairments
    39. 39. EFFECTS OF ALCOHOL
    40. 40. Absorbed UNALTERED
    41. 41. 80 mg/dL3 bottles 15 oz 4-5 oz
    42. 42. Figure 9-12 Metabolism of ethanol: oxidation of ethanol to acetaldehyde by three different routes, and the generation of acetic acid. Note that oxidation by ADH (alcohol dehydrogenase) takes place in the cytosol; the cytochrome P-450 system and its CYP2E1 isoform are located in the endoplasmic reticulum (microsomes), and catalase is located in peroxisomes. Oxidation of acetaldehyde by ALDH (aldehyde dehydrogenase) oc-curs in mitochondria. ADH oxidation is the most important route; catalase is involved in only 5% of ethanol metabolism. Oxidation through CYPs may also generate reactive oxygen species (not shown). (From Parkinson A: Biotransformation of xenobiotics. In Klassen CD [ed]: Casarett and Doull's Toxicology: The Basic Science of Poisons, 6th ed. New York, McGraw-Hill, 2001, p 133.) Downloaded from: StudentConsult (on 22 June 2013 10:05 AM) © 2005 Elsevier
    43. 43. ACETALDEHYDE • Responsible for some of the acute affects of alcohol and; • Development of oral cancers
    44. 44. ACETALDEHYDE • Efficiency of alcohol metabolism varies between populations, depending on: –Expression levels of ADH and ALDH isoenzymes –Presence of genetic variants that alter enzyme activity
    45. 45. ACETALDEHYDE • ALDH2*1 – Normal allele • ALDH2*2 – Inactive variant – Dominant-negative activity • One copy of ALDH2*2 reduces ALDH activity significantly
    46. 46. ALCOHOL OXIDATION BY ADH • Causes reduction of NAD to NADH – Consequent ↓ in NAD and ↑ in NADH • NAD deficiency is a main cause of fat accumulation in the liver of alcoholics • ↑ NADH/NAD ratio in alcoholics causes lactic acidosis
    47. 47. METABOLISM OF ETHANOL IN THE LIVER BY CYP2E1 • Produces ROS • Causes lipid peroxidation of cell membranes • Alcohol also causes release of endotoxin (lps) from gm— bacteria in the intestinal flora – Stimulates production of TNF and other cytokines from macrophages and Kupffer cells, leading to hepatic injury
    48. 48. ACUTE ALCOHOLISM • Exerts its effects mainly on the CNS – But may induce hepatic and gastric changes • Reversible if alcohol consumption is discontinued • Multiple fat droplets accumulate in the cytoplasm of heptocytes (fatty change or steatosis)
    49. 49. Downloaded from: StudentConsult (on 23 June 2013 05:17 AM) © 2005 Elsevier
    50. 50. ACUTE ALCOHOLISM • Gastric changes: –Acute gastritis –ulceration
    51. 51. ACUTE ALCOHOLISM • CNS: –Depressant –Consequently, there is stimulation & disordered cortical, motor & intellectual behavior
    52. 52. ACUTE ALCOHOLISM • CNS: –At progressively higher blood levels, cortical neurons & lower medullary centers are depressed • including those that regulate respiration RESPIRATORY ARREST
    53. 53. CHRONIC ALCOHOLISM • Affects: –Liver –Stomach –All other tissues and organs
    54. 54. CHRONIC ALCOHOLISM • Chronic alcoholics suffer significant morbidity and have a shortened life span, related principally to damaged… Liver GIT CNS Cardiovascular system pancreas
    55. 55. CHRONIC ALCOHOLISMLIVER
    56. 56. LIVER • Fatty changes • Alcoholic hepatitis • Cirrhosis
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    59. 59. CHRONIC ALCOHOLISM GASTROINTESTINAL TRACT
    60. 60. GASTROINTESTINAL TRACT • Massive bleeding from: – Gastritis – Gastric ulcer – Esophageal varices (associated with cirrhosis)
    61. 61. CHRONIC ALCOHOLISM THYMINE DEFICIENCY
    62. 62. THYMINE DEFICIENCY • Principal lesions: – Peripheral neuropathies – Wernicke-Korsakoff syndrome – Cerebral atrophy – Cerebellar degeneration – Optic neuropathy
    63. 63. Downloaded from: StudentConsult (on 23 June 2013 05:17 AM) © 2005 Elsevier
    64. 64. CHRONIC ALCOHOLISM CARDIOVASCULAR SYSTEM
    65. 65. CARDIOVASCULAR SYSTEM • Injury to the myocardium may produce dilated congestive cardiomyopathy (alcoholic cardiomyopathy) • Chronic alcoholism is associated with ↑ incidence of hypertension
    66. 66. CARDIOVASCULAR SYSTEM • Moderate amounts of alcohol (20-30 g of daily intake=250 mL of wine) –↑ HDL levels –Inhibit platelet aggregation • Thus protecting against coronary heart dse
    67. 67. CARDIOVASCULAR SYSTEM • Heavy alcohol consumption, with attendant liver injury, –results in ↓ HDL levels • ↑ likelihood of CHD
    68. 68. CHRONIC ALCOHOLISMPANCREAS
    69. 69. PANCREAS • Excessive alcohol intake ↑ risk of acute and chronic pancreatitis
    70. 70. CHRONIC ALCOHOLISM USE OF ETHANOL DURING PREGNANCY
    71. 71. USE OF ETHANOL DURING PREGNANCY • Fetal alcohol syndrome –Microcephaly –Growth retardation –Facial abnormalities in newborns –Reduction in mental functions as the child grows older
    72. 72. USE OF ETHANOL DURING PREGNANCY • Consumption during the 1st trimester is particularly harmful
    73. 73. CHRONIC ALCOHOLISMCANCER
    74. 74. CANCER • Chronic alcohol consumption is associated with ↑ incidence of cancer of the: – Oral cavity – Esophagus – Liver – Breast
    75. 75. CANCER • Acetaldehyde is considered to be the main agent associated with alcohol-induced laryngeal and esophageal cancer
    76. 76. RESVERATOL in Red Wine • Contributes to the protective effect against CVD in moderate wine drinkers and possibly provides the clue to the “French paradox”
    77. 77. INJURY PRODUCED BY IONIZING RADIATION
    78. 78. RADIATION • Non-ionizing radiation –Can move atoms in a molecule or cause them to vibrate, but is NOT sufficient to displace bound electrons from atoms • Ionizing radiation –Has sufficient energy to remove tightly bound electrons
    79. 79. NON-IONIZING RADIATION IONIZING RADIATION •Alpha particle •Beta particle •High-energy neurons •Gamma rays X-ray UV Micro- wave infrared Micro- wave Sound/radio wave
    80. 80. IONIZING RADIATION Merits Demerits •Treatment of cancer •Diagnostic imaging •Therapeutic or diagnostic radioisotopes •Fibrosis •Mutagenesis •Carcinogenesis •Teratogenesis
    81. 81. Main Determinants of the Biologic Effects of Ionizing Radiation • Rate of Delivery –Although the effect of radiant energy is cumulative, divided doses may allow cells to repair some of the damage between exposures –In fractionated doses of radiant energy, repair during “recovery” intervals is incomplete • Radiation therapy of tumors exploits the general capability of normal cells to repair themselves and recover more rapidly than tumor cells, and thus not sustain as much cumulative radiation damage
    82. 82. Main Determinants of the Biologic Effects of Ionizing Radiation • Field size –The body can sustain relatively high doses of radiation when delivered to small, carefully shielded fields, whereas smaller doses delivered to large fields may be lethal
    83. 83. Main Determinants of the Biologic Effects of Ionizing Radiation • Cell proliferation –Because ionizing radiation damages DNA, rapidly dividing cells are more vulnerable to injury than quiescent cells.
    84. 84. Main Determinants of the Biologic Effects of Ionizing Radiation • Cell proliferation –Except at extremely high doses that impair DNA transcription, DNA damage is compatible with survival in nondividing cells, such brain & myocardium.
    85. 85. Main Determinants of the Biologic Effects of Ionizing Radiation • Cell proliferation –Dividing cells: • Mutations and chromosomal abnormalities are recognized by cell cycle checkpoints, which initiate events that lead to growth arrest and apoptosis
    86. 86. Main Determinants of the Biologic Effects of Ionizing Radiation • Oxygen effects and hypoxia –The production of ROS from the radiolysis of water is the most important mechanism of DNA damage by ionizing radiation
    87. 87. Figure 9-17 Effects of ionizing radiation on DNA and its consequences. The effects on DNA can be direct, or most importantly, indirect, through free radical formation. Downloaded from: StudentConsult (on 22 June 2013 10:05 AM) © 2005 Elsevier
    88. 88. Main Determinants of the Biologic Effects of Ionizing Radiation • Oxygen effects and hypoxia –Poorly vascularized tissues with low oxygenation, such as the center of rapidly growing tumors, are generally less sensitive to radiation therapy than nonhypoxic tissues
    89. 89. Main Determinants of the Biologic Effects of Ionizing Radiation • Vascular damage –May cause narrowing or occlusion of the blood vessel leading to impaired healing, fibrosis, and chronic ischemic atrophy
    90. 90. Downloaded from: StudentConsult (on 22 June 2013 10:05 AM) © 2005 Elsevier
    91. 91. MORPHOLOGY • NUCLEUS: – Swelling – Membrane breakdown • CHROMOSOMES: – Structural changes: deletion, break, translocation & fragmentation – Condensation & clumping of chromatin – Polyploidy & aneuploidy
    92. 92. MORPHOLOGY • MITOTIC SPINDLE: –Becomes disorderly • CYTOPLASMIC CHANGES: –Swelling –Mitochondrial distortion –Degeneration of ER
    93. 93. MORPHOLOGY • Giant cells with pleomorphic or more than one nucleus may appear and persist for years after exposure. • At extremely high doses, markers of cell death—pyknosis and lysis, appear quickly
    94. 94. MORPHOLOGY • Similarity between radiation injured cells and cancer cells: –Cellular pleomorphism –Giant-cell formation –Conformational changes in nuclei –Abnormal mitotic figures
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    96. 96. MORPHOLOGY • LM: –Vascular change and interstitial fibrosis are prominent in irradiated tissue –Intermediate post-irradiation period: • Vessels may only show dilation
    97. 97. MORPHOLOGY • LM: –With higher doses / with time, a variety of degenerative changes may appear: • Endothelial cell swelling & vacuolation • Dissolution with total necrosis of the walls of the small vessels
    98. 98. MORPHOLOGY –Endothelial cell proliferation and collagenous hyalinization with thickening of the media • Resulting in narrowing or even obliteration of the vascular lumens • At this time an ↑ in interstitial collagen in the irradiated field usually becomes evident  Scarring and contractions
    99. 99. Total Body Irradiation • Exposure of large areas of the body to even very small doses of radiation may have devastating effects • <1 Sv – Minimal or no symptoms • Higher levels –Acute radiation symptoms
    100. 100. Acute Effects on Hematopoietic and Lymphoid Systems • High dose levels & large exposure fields: – Severe lymphopenia may appear w/in hours – Shrinkage of lymph nodes & spleen • Radiation directly destroys lymphocytes • Sublethal doses: – Regeneration from viable precursors is prompt, leading to restoration of normal lymphocyte ct w/in weeks to months
    101. 101. Acute Effects on Hematopoietic and Lymphoid Systems • Hematopoietic precursors in BM are also quite sensitive to radiant energy, which produces a dose-dependent marrow aplasia • APLASTIC ANEMIA • Transient aplasia
    102. 102. Acute Effects on Hematopoietic and Lymphoid Systems • Granulocyte ct: – may first rise but begin to fall toward the end of the first week – Near zero levels during the second week – Recovery of normal granulocyte ct may require 2- 3 months
    103. 103. Acute Effects on Hematopoietic and Lymphoid Systems • Platelet ct – Similar w/ granulocytes but somewhat delayed • Red cell ct – Falls – Anemia appears after 2-3 weeks and may persist for months
    104. 104. Fibrosis • Occur weeks or months after irradiation as a consequence of the replacement of dead parenchymal cells by connective tissue, leading to the formation of scars and adhesions
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    107. 107. DNA Damage & Carcinogenesis • Single-base damage • Single- & double-stranded breaks • DNA protein crosslinks • Double-stranded breaks – Repaired by: • Homologous recombination • Nonhomologous end joining (NHEJ)
    108. 108. DNA Damage & Carcinogenesis • Repair by NHEJ – Short deletions or duplications – Gross chromosomal aberrations • Translocations • Inversions • If replication of cells containing DSBs is not stopped, this may initiate carcinogenesis
    109. 109. Cancer Risks from Exposures to Low-level Radiation • Any cell capable of division that has sustained a mutation has the potential to become cancerous
    110. 110. Injury by physical Agents
    111. 111. Divided into the following: • Mechanical injury • Thermal injury • Electrical injury • Ionizing radiation
    112. 112. MECHANICAL TRAUMA The type of injury depends on the shape of the colliding object, the amount of energy discharged at impact, and the tissues or organs that bear the impact.
    113. 113. Patterns of injury can be divided: • Abrasions • contusions • lacerations • incised wounds • puncture wounds
    114. 114. THERMAL INJURY Causes of thermal injury: • Thermal Burns • Hyperthermia • Hypothermia
    115. 115. Thermal Burns clinical significance: • Depth of the burns • Percentage of body surface involved • Internal injuries caused by the inhalation of hot and toxic fumes • Promptness and efficacy of therapy, especially fluid and electrolyte management and prevention or control of wound infections
    116. 116. Classification of burns: • Superficial burns • Partial thickness burns • Full-thickness burns • Full-thickness burns with damage to muscle tissue
    117. 117. • Hyperthermia Prolonged exposure to elevated ambient temperatures can result in heat cramps, heat exhaustion, and heat stroke. • Hypothermia Prolonged exposure to low ambient temperature leads
    118. 118. • ELECTRICAL INJURY Electrical injuries, which are often fatal, can arise from contact with low-voltage currents (i.e., in the home and workplace) or high- voltage currents carried by high-power lines or lightning.
    119. 119. Injuries are of mechanical injury are two types: • burns • ventricular fibrillation or cardiac and respiratory center failure, resulting from disruption of normal electrical impulses.
    120. 120. Updates: EHSI: ‘Skin Gun’ For Burns is Latest Stem Cell Treatment The skin gun looks and works similar to an artist’s airbrush, and sprays a solution of the patient's adult stem cells in water. The clinical trials prove that skin gun could represent an incredible breakthrough in burn treatment, helping to shape the future of stem cell therapy and regenerative medicine February 03, 2011 09:01 AM Eastern Daylight Time http://www.businesswire.com/news/ home/20110203005414/en/EHSI- %E2%80%98Skin-Gun%E2%80%99-Burns- Latest-Potential-Stem
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