2. 1ST PART
• Environmental Effects on Global Disease Burden
• Health Effects of Climate Change
• Toxicity of Chemical and Physical Agents
• Environmental Pollution
• Occupational Health Risks
3. Environmental Diseases
• Many human diseases are caused or
influenced by environmental factors
• Environment = indoor, outdoor, and
occupational settings in w/c human beings
live and work
• Things which we are exposed to or consume
are major determinants of health in this
setting
• Individual personal behavior > ambient
environment
4. Environmental Diseases
• Refers to conditions caused by exposure to
chemical or physical agents in the ambient,
workplace, and personal environment,
including diseases of nutritional origin
• Examples:
Dramatic
• Dioxin exposure in Italy
• Methyl isocyanate gas leak
in Bhopal, India
• Fukushima nuclear
meltdown
Subtle
• Work related exposure or
accidents
• Nutritional deficiencies:50%
of childhood mortality
worldwide
5. Environmental Effects on
Global Disease Burden
On a worldwide basis:
• dramatic increases in mortality due to HIV/AIDS and
assoc. infxns
Undernutrition
• single leading global cause of health loss (defined as
morbidity and premature death)
Ischemic heart disease and CVD
• remain the leading causes of death in developed countries
In developing countries
• 5 of the 10 leading causes of death are infectious dses
6. Environmental Effects on
Global Disease Burden
• In the postnatal period, about 50% of all
deaths in children younger than 5 years
of age are attributed to only three
conditions, all preventable:
Pneumonia
Diarrheal diseases
Malaria
7.
8. Environmental Effects on
Global Disease Burden
Emerging infectious diseases
• Infectious disorders whose incidence has recently
increased or could reasonably be expected to increase in
the near future
• Change in envt’l and socioeconomic conditions
• Categories:
Diseases caused by
newly evolved strains or
organisms
Diseases caused by
pathogens endemic in
other species that
“jumped” to human
population
Diseases caused by
pathogens that have
been present in humans
but show a recent
increase in incidence
9. Health Effects of Climate
Change
Measurements show that earth has warmed at an
accelerating rate over the past 50 yrs
Since 1960, the global ave. temp. has increased by
≈ 0.6°C, with the greatest increases seen over land
areas bet. 40 degrees north and 70 degrees north
9 of the 10 hottest years in the meteorologic record
have occurred in the 21st century
10. Health Effects of Climate
Change
• glaciers may disappear by the year 2025
• arctic ocean will be completely ice-free in
summer by the year 2040
Rapid loss of
glacial and sea ice
leading to
predictions that:
• particularly carbon dioxide (CO2) released
through the burning of fossil fuels
• as well as ozone (an important air
pollutant, discussed later) and methane
Principal culprit is
the rising
atmospheric level
of greenhouse
gases
11. Health Effects of Climate
Change
• Greenhouse effect = absorption and re-emission
of infrared energy radiated from the earth’s
surface that otherwise would be lost into space
• Atmospheric CO2 in late 2012 (about 391 ppm)
was higher than at any point in ≈ 650,000 yrs
• Expected to increase to between 500 to
1200 ppm by the end of this century
• Increased CO2 production but also from
deforestation and the attendant decrease in
carbon fixation by plants
12. Health Effects of Climate
Change
• also projected to increase the variability
and severity of weather events, such as
floods, droughts, and storms
Increased heat
energy in the oceans
and atmosphere
• is increasing acidity of the oceans, which
may disrupt marine ecosystems and
fisheries
Increased
atmospheric
CO2 conc.
• will raise sea levels by at least 1 to 2 feet
by 2100
Combined w/
thermal expansion
of warming oceans
13. Health Effects of Climate
Change
• Its Extent and rapidity
• Nature and severity of ensuing consequences
• Humankind’s ability to mitigate the damage
Health impacts of
climate change will
depend on:
• Cardiovascular, cerebrovascular,
and respiratory dses
• Gastroenteritis, cholera, and other
foodborne and waterborne infectious dses
• Vector-borne infectious dses
(ex: malaria, dengue)
• Malnutrition
Climate change is
expected to have
serious impact on
health by increasing
incidence of dses
14. Health Effects of Climate
Change
• The resulting displacement of people will disrupt
lives and commerce, creating conditions ripe for
political unrest, war, and poverty, the “vectors” of
malnutrition, sickness, and death
• Both developed and developing countries will
suffer the consequences of climate change
• Burden will be greatest in developing countries
• The urgent challenge is to develop new
renewable energy resources that stem the
production of greenhouse gases
15. Toxicity of Chemical & Physical
Agents
• Distribution
• Effects
• Mechanisms of action of toxic agents
• Effects of physical agents such as radiation
and heat
Toxicology =
the science of poisons
Only a very small proportion has been tested experimentally for
health effects
• Interaction between various pollutants, and
the age, genetic predisposition ≈ tissue
sensitivities of exposed persons
• Variations in individual sensitivity to toxic
agents
Factors
16. Toxicity of Chemical & Physical
Agents
• basically a quantitative concept strictly
dependent on dosagePoisons
“All substances are poisons; the right dosage differentiates a poison from
a remedy”
– Paracelsus
• exogenous chemicals in the environment in air,
water, food, and soil that may be absorbed
into the body through inhalation, ingestion,
and skin contact
Xenobiotics
18. Toxicity of Chemical & Physical
Agents
Chemicals may
be
• excreted in urine
or feces
• eliminated in
expired air
• or may
accumulate in
bone, fat, brain,
or other tissues
Chemicals may
act
• at the site of
entry
• or at other sites
following
transport
through the
blood
Most solvents
and drugs are
lipophilic
• which facilitates
their transport in
the blood by
lipoproteins and
their penetration
through the
plasma
membrane into
cells
Most solvents,
drugs, and
xenobiotics are
• metabolized to
form inactive
water-soluble
products
(detoxification)
• activated to form
toxic metabolites
19. Toxicity of Chemical & Physical
Agents• Reactions that metabolize xenobiotics occur in 2 phases
• Form water-soluble compounds that are readily
excreted
• Drug-metabolizing enzymes = enzymes that catalyze
the biotransformation of xenobiotics and drugs
Phase I reactions
• chemicals undergo
hydrolysis, oxidation or
reduction
Phase II reactions
• include
glucuronidation,
sulfation, methylation,
and conjugation with
glutathione
20.
21. Toxicity of Chemical & Physical
Agents
• The cytochrome P-450 (CYP) system
catalyzes reactions that either
– detoxify xenobiotics
– or, less commonly, convert
xenobiotics into active compounds
that cause cellular injury
• Both types of reactions may produce,
as a byproduct, reactive oxygen
species (ROS), which can cause cellular
damage
22. Toxicity of Chemical & Physical
Agents
• Great variation in the activity of CYPs among
individuals
• Variation may be a consequence of genetic
polymorphisms in specific CYPs
• More commonly it is due to exposure to drugs
or chemicals that induce or diminish CYP
activity
CYP inducers:
environmental
chemicals, drugs,
smoking, alcohol, and
hormones
Fasting or starvation
can decrease CYP
activity
23. Toxicity of Chemical & Physical
Agents
• Inducers of CYP = binding to nuclear receptors, which then
heterodimerize with the retinoic X receptor (RXR)
• Form a transcriptional activation complex that associates
with promoter elements located in the 5′-flanking region of
CYP genes
• Nuclear receptors forCYP induction:
Aryl hydrocarbon
receptor
Peroxisome
proliferator-
activated
receptors (PPAR)
Nuclear receptors:
androstane receptor
(CAR), and pregnane
X receptor (PXR)
24. Environmental Pollution
• Air pollution
– Air is vital to life, but also contains many causes of disease
– Significant cause of morbidity and mortality worldwide,
particularly among at-risk individuals with preexisting
pulmonary or cardiac disease
Outdoor air pollution
• Ambient air in industrialized nations is contaminated
with mixture of gaseous and particulate pollutants
Indoor air pollution
• “Buttoned up” homes to exclude the environment
25. Environmental Pollution
• Outdoor Air Pollution
• “Smog” – concoction of six pollutants
• Affect mainly the lungs although other organ
systems are also affected
Sulfur dioxide
Carbon
monoxide
Ozone
Nitrogen
dioxide
Lead
Particulate
matter
26. Pollutant Populations at Risk Effects
Ozone
Healthy adults and children
Decreased lung function
Increased airway reactivity
Lung inflammation
Athletes, outdoor workers
Asthmatics
Decreased exercise capacity
Increased hospitalizations
Nitrogen dioxide
Healthy adults Increased airway reactivity
Asthmatics Decreased lung function
Children Increased respiratory infections
Sulfur dioxide
Healthy adults Increased respiratory symptoms
Individuals with chronic lung disease Increased mortality
Asthmatics
Increased hospitalization
Decreased lung function
Acid aerosols
Healthy adults Altered mucociliary clearance
Children Increased respiratory infections
Asthmatics
Decreased lung function
Increased hospitalizations
Particulates
Children Increased respiratory infections
Individuals with chronic lung or heart
disease
Decreased lung function
Asthmatics
Excess mortality
Increased attacks
27. Environmental Pollution
• Good ozone (Stratospheric O3)
– Produced by interaction of ultraviolet (UV)
radiation and oxygen (O2) in the stratosphere
– Protects life on earth by absorbing the most
dangerous UV radiation emitted by the sun
– Ozone layer decreased in both thickness and
extent due to the widespread use of
chlorofluorocarbon gases in air conditioners and
refrigerators and as aerosol propellants
28. Environmental Pollution
• Bad ozone (Ground-level O3)
– Formed by the reaction of nitrogen oxides and
volatile organic compounds in the presence of
sunlight
– Toxicity due to production of free radicals, which
injure epithelial cells along the respiratory tract &
type I alveolar cells
– Cause the release of inflammatory mediators
• Sulfur dioxide
– Produced by power plants burning coal and oil, from
copper smelting, and as a byproduct of paper mills
– Converted into sulfuric acid and sulfuric trioxide
29. Environmental Pollution
• Particulate matter (known as “soot”)
– Particulates are emitted by coal- and oil-fired power plants, by
industrial processes
– Fine or ultrafine particles less than 10 µm in diameter are the
most harmful
• Carbon monoxide
– Systemic asphyxiant that is an important cause of accidental
and suicidal death
– Nonirritating, colorless, tasteless, odorless gas that is produced
during any process that results in the incomplete oxidation of
hydrocarbons
– CO kills in part by inducing central nervous system (CNS)
depression, which appears so insidiously that victims are often
unaware of their plight
– Hemoglobin has 200-fold greater affinity for CO than for
oxygen
30. Environmental Pollution
Chronic CO poisoning
• Ischemic changes in the basal ganglia
and lenticular nuclei
• Residual permanent neurologic
sequelae
Acute CO poisoning
• Characteristic generalized cherry-red
color of the skin and mucous
membranes
• High levels of carboxyhemoglobin
31. Environmental Pollution
• Indoor air pollution
– Wood smoke
• Oxides of nitrogen and carbon particulates,
• Irritant that may predispose to lung infections
• Contain polycyclic hydrocarbons, important carcinogens
– Bioaerosols
• Microbiologic agents capable of causing infectious
diseases
• Pet dander, dust mites, and fungi and molds responsible
for rhinitis, eye irritation, and asthma.
32. Environmental Pollution
• Indoor air pollution
– Radon
• Radioactive gas derived from uranium widely present in soil
and in homes
• Cause lung cancer in uranium miners
– Formaldehyde
• Building materials (e.g., cabinetry, furniture, adhesives)
• Breathing difficulties and a burning sensation in the eyes
and throat
• Carcinogen for humans and animals
– Sick building syndrome
• May be a consequence of exposure to one or more indoor
pollutants, possibly due to poor ventilation
34. Lead
Readily absorbed metal that binds to sulfhydryl groups in proteins
Interferes with calcium metabolism
Lead to hematologic, skeletal, neurologic, gastrointestinal, and renal
toxicities
House paints and gasoline
Low-level lead poisoning include subtle deficits in intellectual capacity,
behavioral problems such as hyperactivity, and poor organizational skills
35.
36.
37. Mercury
• Mercury binds to sulfhydryl groups in certain proteins with
high affinity, leading to damage in the CNS and the kidney
• 3 forms of mercury
• Main sources of exposure
Metallic mercury
• also known as
elemental mercury
Inorganic mercury
• mostly mercuric
chloride
Organic mercury
• mostly methyl
mercury
Contaminated fish (methyl mercury)
Mercury vapors released from metallic mercury in
dental amalgams & mercury used in gold mining
38. Mercury
• The developing brain is extremely sensitive to methyl
mercury
• Lipid solubility of methyl mercury and metallic mercury
facilitate their accumulation in the brain, disturbing
neuromotor, cognitive, and behavioral fxns
• There are serious concerns about the effects of chronic
low-level exposure to methyl mercury in food
exposure of the fetus
to high levels of
mercury in utero
Minamata disease
(cerebral palsy,
deafness, and
blindness)
39. Arsenic
• Interfere with several aspects of cellular metabolism,
leading to toxicities most prominent in GI tract,
nervous system, skin, and heart
• Sources:
– Naturally occurring in soils and water & is used in
products such as wood preservers, herbicides and
other agricultural products
– Mines and smelting industries
– Chinese and Indian herbal medicine
• Large concentrations of inorganic arsenic are
present in ground water in countries such as
Bangladesh, Chile, and China
“The poison of kings and the king of
poisons”
40. Arsenic
Most toxic forms of arsenic are the trivalent compounds:
arsenic trioxide, sodium arsenite, and arsenic trichloride
Causes acute GI, cardiovascular, and CNS toxicities that are often fatal
Interference with mitochondrial oxidative phosphorylation
Also has pleiotropic effects on the activity of a number of other enzymes
and ion channels, and these too may contribute to certain toxicities
41. Arsenic
• Usually occur 2 to 8 weeks after exposure
• Paresthesias, numbness, and pain
Neurologic effects
• Hyperpigmentation and hyperkeratosisSkin changes
• The most serious consequence of chronic
exposure
• Particularly of the lungs, bladder and skin
• Arsenic-induced skin tumors - often multiple
and usually appear on the palms and soles
Increased risk for
the development
of cancers
• Chronic exposure to arsenic in drinking water
Non-malignant
respiratory disease
42. Cadmium
• Preferentially toxic to kidneys and lungs through
increased production of reactive oxygen species
• Sources:
Pollutant generated by mining, electroplating,
and production of nickel-cadmium batteries
Can contaminate the soil and plants directly or
through fertilizers and irrigation water
Food is the most important source of cadmium
exposure for the general population
43. Cadmium
• Principal toxic effects of excess cadmium
• caused by necrosis of alveolar epithelial cells
Obstructive lung
disease
• may progress to end-stage renal disease
Renal tubular
damage
• associated with calcium loss
Skeletal
abnormalities
• combination of osteoporosis and osteomalacia
• associated with renal disease
“Itai-itai”
• associated with an elevated risk of lung cancerLung cancer
45. Occupational Health Risks
• Consequence of work-related accidents
and illnesses
• Work-related accidents are the biggest
occupational health problem in developing
countries
• Work-related diseases are more frequent
in industrialized countries
46.
47. Occupational Health Risks
• Organic solvents
– Chloroform and carbon tetrachloride found in degreasing and dry
cleaning agents and paint removers
– Cause dizziness and confusion, leading to CNS depression and
even coma
– Lower levels are toxic for the liver and kidneys
– Exposure of rubber workers to benzene and 1,3-
butadiene increases the risk of leukemia
• Polycyclic hydrocarbons
– Released during the combustion of fossil fuels, particularly
when coal and gas are burned at high temperatures
– In tar and soot
– Among the most potent carcinogens, and industrial exposures
have been implicated in the dev’t of lung and bladder cancer
48. Occupational Health Risks
• Organochlorines
– Synthetic lipophilic products that resist degradation
– Pesticides include DDT
(dichlorodiphenyltrichloroethane), lindane, aldrin,
and dieldrin
– Nonpesticide organochlorines
include polychlorinated biphenyls (pcbs)
and dioxin (tcdd; 2,3,7,8-tetrachlorodibenzo-p-
dioxin)
– Organochlorines disrupt hormonal balance because
of antiestrogenic or antiandrogenic activity
– Dioxins and pcbs - folliculitis and chloracne (acne,
cyst formation, hyperpigmentation, and
hyperkeratosis)
49. Occupational Health Risks
• Mineral dusts
– Chronic, non-neoplastic lung disease = PNEUMOCONIOSIS
– Exposures to coal dust (e.G., Mining of hard coal), silica (e.G.,
Sandblasting, stone cutting), asbestos (e.G., Mining,
fabrication, insulation work), and beryllium (e.G, mining,
fabrication)
• Vinyl chloride
– Synthesis of polyvinyl resins leads to the development of
angiosarcoma of the liver
• Bisphenol A
– Synthesis of polycarbonate food and water containers and of
epoxy resins that line almost all food bottles and cans
– Long been known as a potential endocrine disruptor
51. Effects of Tobacco
Most readily preventable cause of death in humans
Cigarette smoking, “snuff”, “2nd hand smoke”
30% of all smokers worldwide live in China,
10% live in India
Cause 90% of lung cancers
Tobacco contains between 2000 and 4000 substances, more
than 60 of which have been identified as carcinogens
52.
53.
54. Smoking and Lung Cancer
• Direct irritant effect on the tracheobronchial
mucosa
• Inflammation and increased mucus
production (bronchitis)
• Causes the recruitment of leukocytes to the
lung, with increased local elastase production
and subsequent injury to lung tissue, leading
to emphysema
• Polycyclic hydrocarbons and nitrosamines
• Risk of developing lung cancer is related to
the number of pack years or cigarettes
smoked per day
55.
56. Smoking is linked to
many other malignant
and nonmalignant
disorders that affect
numerous organ
systems
Maternal smoking
increases risk of
abortion,
premature birth,
and intrauterine
growth retardation
58. Effects of Alcohol
• Excessive amounts alcohol causes serious
physical and psychological damage
• Alcohol abuse is a far more widespread
hazard and claims many more lives
–Drunken driving and alcohol-related
homicides and suicides
–Consequence of cirrhosis of the liver
59. Alcohol Concentration in the Blood
• 80 mg/dl = legal definition of drunk driving
– After 3 standard drinks, about three (12 ounce)
bottles of beer, 15 ounces of wine, or 4 to 5
ounces of 80 proof distilled spirits
• 200 mg/dl = drowsiness occurs
• 300 mg/dl = stupor
• Higher levels = coma with possible respiratory arrest
• Rate of metabolism affects blood alcohol level
• Chronic alcoholics can tolerate levels of up to
700 mg/dl due to accelerated ethanol metabolism
60. Metabolism of Alcohol
• Absorbed unaltered
• Metabolized by 3 enzyme
systems:
– CYP2E1
– Alcohol Dehydrogenase
(ADH)
– Catalase
• Acetaldehyde – acted upon
by Aldehyde
Dehydrogenase to form
Acetic acid
61. Metabolites of Alcohol
• Acetaldehyde
– Responsible for some of the acute effects of alcohol and for
the development of oral cancers
– ALDH2*2 gene = low ALDH activity
• Cannot tolerate alcohol, experiencing nausea, flushing,
tachycardia, and hyperventilation
• NADH/NAD
– Increased NADH & decreased NAD = fatty liver & lactic
acidosis
• ROS
– Produced by CYP2E1
– Lipid peroxidation of plasma membrane
– Causes release of endotoxin from enteric bacteria =
TNF & other cytokines resulting to hepatic damage
62. Adverse Effects of Alcohol
Acute alcoholism
• Mainly on the CNS, but it may induce hepatic and
gastric changes that are reversible if alcohol
consumption is discontinued
• Fatty change or hepatic steatosis
• Acute gastritis and ulceration
• Disordered cortical, motor, intellectual behavior &
depressed, including those that regulate
respiration. Respiratory arrest
63. Adverse Effects of Alcohol
Chronic alcoholism
• Significant morbidity and have a shortened life span, related
principally to damage to the liver, gastrointestinal tract, CNS,
cardiovascular system, and pancreas
• Cirrhosis
• Thiamine (vitamin B1) deficiency = peripheral neuropathies &
Wernicke-Korsakoff Syndrome
• Alcoholic cardiomyopathy
• Acute and chronic pancreatitis
• Fetal alcohol syndrome
• Increased incidence of cancer of the oral cavity, esophagus, liver
64. Moderate consumption of
Alcohol
• 20-30 gm/day, corresponding to
approximately 250 ml of wine
• ↑ high-density lipoprotein (HDL) levels
• Inhibit platelet aggregation
• ↓ fibrinogen levels
• Light to moderate alcohol consumption =
↑ overall survival as compared to
teetotalers and heavy drinkers
68. Injury by Therapeutic Drugs
(Adverse Drug Reactions)
• Adverse drug reactions = untoward effects of
drugs that are given in conventional
therapeutic settings
• Due to direct actions of the drug or to
immunologically based hypersensitivity
reactions
72. Menopausal Hormone Therapy
• Previously known as HRT (hormone replacement therapy)
• Administration of estrogens together with a progestogen
• Counteract symptoms of menopause, could prevent or
slow the progression of osteoporosis and reduce the
likelihood of myocardial infarction
Increased the risk of breast cancer, stroke, and
venous thromboembolism and had no effect
on the incidence of coronary heart disease
Should not be used long term for chronic
disease prevention
73. Oral Contraceptives
• OCs nearly always contain a synthetic estradiol and a
variable amount of a progestin, but some preparations
contain only progestins
• Inhibiting ovulation or preventing implantation
Increased risk of cervical cancer in HPV infected women
Threefold to sixfold increased risk of venous thrombosis and
pulmonary thromboembolism
Increase in cardiovascular diseases in women (>35 yo) who
smoke
Hepatic adenoma in older women with prolonged use
74. Anabolic Steroids
Synthetic versions of testosterone
Inhibits production and release of luteinizing hormone & follicle-
stimulating hormone by a feedback mechanism
Increases the amount of estrogens
Stunted growth in adolescents, acne, gynecomastia, and testicular atrophy
in males, and growth of facial hair and menstrual changes in women
Psychiatric disturbances
Increased risk of myocardial infarction. Hepatic cholestasis
75. Acetaminophen
• Most commonly used analgesic, toxicity is common
• Detoxification in the liver by phase II enzymes
• Is excreted in the urine as glucuronate or sulfate
conjugates
95% of
acetaminophen
undergoes
detoxification
• NAPQI (n-acetyl-p-benzoquinoneimine) is a
highly reactive metabolite
• When acetaminophen is taken in large doses,
unconjugated NAPQI accumulates and causes
hepatocellular injury
5% or less is
metabolized
through CYPs
(primarily CYP2E)
to NAPQI
76. Acetaminophen
• 50% of cases of acute liver failure, with 30% mortality
• NAPQI mechanism of injury:
• Nausea, vomiting, diarrhea, and sometimes shock,
followed in a few days by evidence of jaundice
• Centrilobular necrosis that may progress to liver failure
1. Covalent binding to
hepatic proteins, which
causes damage to cellular
membranes and
mitochondrial dysfunction
2. Depletion of GSH,
making hepatocytes more
susceptible to reactive
oxygen species-induced
injury
77.
78. Aspirin: Acetylsalicylic acid
• Acute salicylate overdose causes alkalosis
as a consequence of the stimulation of the
respiratory center in the medulla
• Followed by metabolic acidosis and
accumulation of pyruvate and lactate,
caused by uncoupling of oxidative
phosphorylation and inhibition of the
Krebs cycle
• Nausea to coma
81. Injury by Nontherapeutic Agents
(Drug Abuse)
• Illicit substance
• Occasional users of illicit “recreational”
drugs suffer no apparent long-term health
effects
• Acute effects may take a significant toll in
the form of accidents, violence, or even fatal
drug-related complications
• Generally involves the repeated or chronic
use of mind-altering substances, beyond
therapeutic or social norms, and may lead
to drug addiction and overdose, both
serious public health problems
82.
83. Cocaine
• Extracted from the leaves of the coca plant, and is
usually prepared as a water-soluble powder,
cocaine hydrochloride
• Can be snorted or dissolved in water and injected
subcutaneously or intravenously
• “Crack” form is far more potent
• Intense euphoria and stimulation, making it one
of the most addictive drugs
– Physical dependence generally does not occur
– Psychologic withdrawal is profound
& extremely difficult to treat
84. Cocaine
• Acute and chronic effects
– Tachycardia, hypertension, and peripheral
vasoconstriction, may also induce myocardial
ischemia
– Precipitate lethal arrhythmias
– Hyperpyrexia (thought to be caused by
aberrations of the dopaminergic pathways
that control body temperature) and seizures
– Acute decreases in blood flow to the placenta,
resulting in fetal hypoxia and spontaneous
abortion
– Perforation of the nasal septum in snorters
– Decreased lung diffusing capacity in
those who inhale the smoke
– Dilated cardiomyopathy
85. Opiates
• Opiate drugs of abuse include synthetic
prescription opiates such as oxycodone
(oxycontin) and “street drugs,” most
notably heroin
• An addictive opioid derived from the
poppy plant that is closely related to
morphine
• Even more harmful than that of cocaine
• Effects on the CNS are varied and
include euphoria, hallucinations,
somnolence, and sedation
86. Heroin
• Adverse effects
• Profound respiratory depression, arrhythmia and cardiac
arrest, and severe pulmonary edemaSudden death
• Severe edema, septic embolism, granulomasPulmonary injury
• S. Aureus, but fungi and a multitude of other organisms
have also been implicatedInfections
• Abscesses, cellulitis, and ulcerations due to subcutaneous
injections, hyperpigmentation over commonly used veinsSkin
• Amyloidosis, focal and segmental glomerulosclerosis;
both induce proteinuria and the nephrotic syndromeKidneys
87. Amphetamines and Related
Drugs
Methamphetamine
• “speed” or “meth”
• stronger effects in the CNS
• 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
MDMA
• 3,4 methylenedioxymethamphetamine =
“Ecstasy”
• taken orally
• effects, which include euphoria and
hallucinogen-like feelings that last 4 to 6
hours
• partly attributable to an increase in
serotonin release in the CNS
• reduces the number of serotonergic axon
terminals in the striatum and the cortex,
and it may increase the peripheral
effects of dopamine and adrenergic
agents
88. Marijuana
• Most widely used illicit drug globally
• “Pot”, “weed”
• Leaves of the cannabis sativa plant,
which contain the psychoactive
substance δ9-tetrahydrocannabinol
(THC)
• Untoward anecdotal effects allergic or
idiosyncratic reactions or possibly
related to contaminants in the
preparations rather than to the
pharmacologic effects of marijuana
89. Marijuana
• Beneficial effects of marijuana
– treat nausea secondary to cancer chemotherapy
and as an agent capable of decreasing pain in
some chronic conditions
• Distorts sensory perception and impairs motor
coordination
– acute effects clear in 4 to 5 hours
• With continued use cognitive and psychomotor
impairments occur a potential cause of
automobile accidents
• Increases the heart rate and blood pressure,
and it may cause angina in a person with
coronary artery disease
90. Marijuana
• Chronic marijuana smoking
– laryngitis, pharyngitis, bronchitis, cough
and hoarseness, and asthma-like
symptoms have all been described,
along with mild but significant airway
obstruction
• Large number of carcinogens that are also
present in tobacco
• Smoking a marijuana cigarette, compared
with a tobacco cigarette, is associated w/
threefold increase in amount of tar inhaled
91. Other Drugs
PCP (phencyclidine, an
anesthetic agent) = “OOBE”
Vicodin, and ketamine, an
anesthetic agent
Spray paints, paint thinners,
and some glues that contain
TOLUENE
• Mild to severe dementia
• Bizarre and often aggressive behavior
that leads to violence or depressed
mood and suicidal ideation
“Bath salts”
• Contain 4-methyl-meth-cathinone and
methylenedioxypyrovalerone
• Amphetamine-like effects when
snorted or eaten
• Agitation, psychosis, myocardial
infarction, and suicide
93. Mechanical trauma
• 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
• Mechanical forces, and the patterns of
injury can be divided into abrasions,
contusions, lacerations, incised wounds,
and puncture wounds
• Forensic pathology
94. Thermal Injury
• Excessive heat and excessive cold are
important causes of injury
– Thermal burns
– Hyperthermia
– Hypothermia
95. Thermal Burns
• Caused by fire or by scalding
• Consequence of injuries caused by fire and smoke inhalation
• Clinical significance of a burn injury:
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
96. Thermal Burns
• According to the depth of the injury
Superficial burns
• Formerly known as
first-degree burns
• 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
• Formerly known as
fourth-degree burns:
involve damage to
muscle tissue
underneath the
subcutaneous tissue
97. Thermal Burns
• Greatest threats to life
Shock,
sepsis, and respiratory
insufficiency
• Systemic inflammatory response syndrome = shock
• Hypermetabolic state = increased need for
nutritional support
Burns of more than 20% of
the body surface
• Pseudomonas aeruginosa
• Methicillin-resistant S. Aureus
• Candida species
Infection
• Early excision and grafting of the burn wound
Organ system failure
resulting from burn sepsis
• Inhalation of heated air and noxious gases in the
smoke
Injury to the airways and
lungs
98. Hyperthermia
• Prolonged exposure to elevated ambient
temperatures
• Heat cramps
– Loss of electrolytes via sweating
– Cramping of voluntary muscles, in association with
vigorous exercise, is the hallmark
– Heat-dissipating mechanisms are able to maintain
normal core body temperature
• Heat exhaustion
– Most common: hyperthermic syndrome
– Prostration and collapse, and it results from a failure
of the cardiovascular system to compensate for
hypovolemia caused by dehydration
– After a period of collapse, which is usually brief,
equilibrium is spontaneously re-established if the
victim is able to rehydrate
99. Hyperthermia
• Heat stroke
– Associated with high ambient temperatures,
high humidity, and exertion
– Thermoregulatory mechanisms fail, sweating
ceases, and the core body temperature rises
to more than 40°C, leading to multiorgan
dysfunction that can be rapidly fatal
– Generalized vasodilation, with peripheral
pooling of blood and a decreased effective
circulating blood volume
– Hyperkalemia, tachycardia, arrhythmias, and
other systemic effects
100. Hyperthermia
• Malignant hyperthermia
– Characterized by a “heat-stroke–like” rise in core
body temperature and muscle contractures
following exposure to common anesthetics due to
inherited mutations in RYR1
– Ryanodine receptor 1 (RYR1), which is located in
the sarcoplasmic reticulum of skeletal muscle
• RYR1 regulates the release of calcium from the
sarcoplasm
• Heat stroke deranges RYR1 function →calcium
to leak into the cytoplasm→muscle contraction
and heat production
101. Hypothermia
• Prolonged exposure to low ambient
temperature
• High humidity, wet clothing, and dilation
of superficial blood vessels resulting from
the ingestion of alcohol hasten the
lowering of body temperature
• Body temperature of about 90°F (32.2°C):
loss of consciousness occurs, followed by
bradycardia and atrial fibrillation at lower
core temperatures
102. Hypothermia
• Hypothermic injury:
• Slow chilling may induce vasoconstriction and
increase vascular permeability, leading to edema
and hypoxia = “trench foot”
• Sudden, persistent chilling, the vasoconstriction and
increased viscosity of the blood in the local area
may cause ischemic injury and degenerative
changes in peripheral nerves
Direct effects
• Mediated by physical disruptions
within cells by high salt
concentrations caused by the
crystallization of intra- and
extracellular water
Indirect effects
• Circulatory changes, which vary
depending on the rate and duration
of the temperature drop
103. Electrical Injury
• Contact with low-voltage currents (i.e., at home
and workplace) or high-voltage currents carried
by high-power lines or produced by lightning
• Two types of injuries:
1. Burns
2. Ventricular fibrillation OR cardiac &
respiratory center failure
• Depend on the strength (amperage), duration,
and path of the electric current within the
body
104. Electrical Injury
• Voltage in the household and workplace (120 or 220 V)
is high enough that with low resistance at the site of
contact , sufficient current can pass through the body
to cause serious injury, including ventricular fibrillation
• Alternating current (AC)
– Type supplied to most homes
– Induces tetanic muscle spasm, so that when a live
wire or switch is grasped, irreversible clutching is
likely to occur, prolonging the period of current flow
– Extensive electrical burns and spasm of the chest
wall muscles, producing death from asphyxia
105. Electrical Injury
Currents generated from high-voltage sources
• Cause similar damage
The large current flows generated are more likely to
produce paralysis of medullary centers and extensive burns
• Lightning
Magnetic fields and microwave radiation
• Produce burns, usually of the skin and subjacent
connective tissue when sufficiently intense
106. Ionizing Radiation Injury
• Energy that travels in the form of waves or high-speed
particlesRadiation
• Ex: UV and infrared light, microwave, and sound waves
• Can move atoms in a molecule or cause them to vibrate,
but is not sufficient to displace bound electrons from
atoms
Nonionizing
Radiation
• Has sufficient energy to remove tightly bound electrons
• X-rays and gamma rays, high-energy neutrons, alpha
particles and beta particles
Ionizing
Radiation
• Fibrosis, mutagenesis, carcinogenesis, and teratogenesisCauses:
107. Ionizing Radiation Injury
• Units of radiation
Curie (Ci)
an expression of
the amount of
radiation
emitted by a
source
Gray (Gy)
is a unit that
expresses the
energy
absorbed by the
target tissue per
unit mass
Sievert (Sv)
is a unit of
equivalent dose
that depends on
the biologic
rather than the
physical effects
of radiation
108. Ionizing Radiation Injury
• Biologic effects of Radiation determinants
• Cumulative effect = fractioned dosesRate of delivery
• Body area of exposure = higher doses tolerated if
limited area is exposedField size
• rapidly dividing cells are more vulnerable to injury
than are quiescent cellsCell proliferation
• production of reactive oxygen species
Oxygen effects and
hypoxia
• Damage to endothelial cells = narrowing or
occlusion of blood vesselsVascular damage
114. Malnutrition
• Consequence of inadequate intake of
proteins and calories, or deficiencies in
the digestion or absorption of proteins
• Loss of fat and muscle tissue, weight
loss, lethargy, and generalized weakness
• Developing nations
– malnutrition, starvation, obesity
115. Dietary insufficiency
• Appropriate diet:
• Primary malnutrition – one or all of these
components are missing from the diet
• Secondary malnutrition – malnutrition results from
malabsorption, impaired utilization or storage, excess
loss, or increased need for nutrients
sufficient energy
amino acids and fatty acids
• to be used as building blocks
for synthesis of proteins and
lipids
vitamins and minerals
• function as coenzymes or
hormones in vital metabolic
pathways
• or, as in the case of calcium
and phosphate, as important
structural components
116. Conditions that lead to malnutrition
Poverty Infections
Acute and
chronic illnesses
Chronic
alcoholism
Ignorance and
failure of diet
supplementation
Self-imposed
dietary
restriction
Other causes
117. Protein Energy Malnutrition
(PEM)• Determined by body mass index
– Weight in kilograms divided by height in meters squared
– Normal range 18.5 to 25 kg/m2
• Thickness of skin folds – fat stores
• Circumference of mid-arm – muscle mass
• Serum proteins – visceral protein
• 2 spectrums of PEM syndromes:
Marasmus
• somatic compartment,
represented by proteins in
skeletal muscles
Kwashiorkor
• visceral compartment,
represented by protein stores in
the visceral organs, primarily
the liver
118. Marasmus
• Weight falls to 60% of normal for
sex, height, and age
• Growth retardation and loss of
muscle
• Visceral protein compartment
minimally depleted
• Serum albumin levels are either
normal or only slightly reduced
• Extremities are emaciated
• Anemia & immune deficiency
119. Kwashiorkor
• Protein deprivation is relatively more
severe than the deficit in total calories
• Severe depletion of the visceral
protein compartment
• Hypoalbuminemia =
generalized or dependent edema
• Skin lesions = flaky paint
• Hair changes = flag sign
• Fatty liver, apathy, listlessness, and
loss of appetite
• Defects in immunity and secondary
infections
120. Cachexia
• PEM in AIDS or advanced cancers
• Extreme weight loss, fatigue, muscle atrophy,
anemia, anorexia, and edema
• Mediators secreted by tumors and during
chronic inflammatory reactions
Proteolysis-
inducing factor
• glycosylated
polypeptide
Lipid-mobilizing
factor
• TNF and IL-6
121.
122. Anorexia Nervosa and Bulimia
Anorexia nervosa
• Highest death rate of any
psychiatric disorder
• Altered serotonin metabolism
• Similar to those in severe PEM
• Amenorrhea
• Decreased thyroid hormone
release
• Bone density is decreased
• Cardiac arrhythmia & sudden
death
Bulimia
• Large amounts of food,
principally carbohydrates, are
ingested, only to be followed by
induced vomiting
• Menstrual irregularities
• Frequent vomiting and the
chronic use of laxatives and
diuretics
• Electrolyte imbalances
• Pulmonary aspiration
• Esophageal and gastric
rupture
• Cardiac arrhythmia & sudden
death
123. Vitamin Deficiencies
• Thirteen vitamins are necessary for health
– Fat soluble and water soluble
• Vitamins A, D, E, and K are fat-soluble
• Fat-soluble vitamins are more readily stored
in the body
• Endogenous synthesis of vitamins: D, K &
niacin
• Deficiencies:
– Primary = dietary insufficiency
– Secondary = disturbances in absorption,
transport, storage or metabolism
124. Vitamin A
• Retinol (alcohol), retinal
(aldehyde), and retinoic acid (acid)
• Fat soluble
• Functions:
Maintenance
of normal
vision
Cell growth
and
differentiation
Host
resistance to
infections
Adipogenesis
and fatty acid
metabolism
125. Vitamin A
Deficiency
• Occurs due to:
undernutrition or
malabsorption of fats
• Night blindness
• Epithelial metaplasia and
keratinization
– Xerophthalmia
– Bitot’s spots
– Keratomalacia
– Squamous metaplasia
Toxicity
• Liver = polar bear,
whales, sharks and tuna
• Acute
– Headache, dizziness,
vomiting, stupor, and
blurred vision,
pseudotumor cerebri
• Increased osteoclast
activity
• Teratogenic effect of
retinoids
126. Vitamin D
• Endogenously synthesized
fat soluble vitamin; deep-sea
fish, plants, and grains are
dietary sources
• Cholecalciferol (vitamin D3)
• Maintenance plasma levels
of calcium and phosphorus
– Metabolic functions
– Bone mineralization
– Neuromuscular
transmission
Functions:
Stimulation of intestinal
calcium absorption
Stimulation of calcium
reabsorption in the kidney
Interaction with PTH in the
regulation of blood calcium
Mineralization of bone –
osteocalcin
127. Vitamin D
Deficiency – insufficient diet
and limited sun exposure
– Rickets
• Craniotabes
• Frontal bossing
• Rachitic rosary
• Pigeon breast deformity
• Bowing of the legs
– Osteomalacia
• Gross fractures or
microfractures
– Hypocalcemic tetany
– Osteoporosis (vitamin D
insufficiency)
Vit D supplements –
increased lymphocyte count,
enhanced clearance of MTB
in sputum
Toxicity
– Megadoses of oral vitamins
– Not from prolonged
exposure to sunlight
– Metastatic calcifications
– Bone pain
– Hypercalcemia
128. Vitamin C
• Water soluble vitamin
• Ascorbic acid
• Entirely dependent on
the diet for this nutrient
• Milk and some animal
products (liver, fish) and
is abundant in a variety
of fruits and vegetables
• Functions:
Activation of prolyl and lysyl
hydroxylases
Hydroxylation of procollagen
Promotes secretion of
procollagen
Antioxidant properties – direct
and indirect
129. Vitamin C
• Vitamin excess
– Mild antihistamine action =Tx for common colds
– Toxicities are rare
• Iron overload due to increased absorption
• Hemolytic anemia in G6PD deficiency patients
• Calcium oxalate stones
131. Obesity
• An accumulation of adipose tissue that is of
sufficient magnitude to impair health
• ↑ Incidence type 2 diabetes, dyslipidemias,
cardiovascular disease, hypertension, and cancer
• BMI measurements
18.5 to 25 kg/m2
Normal BMI
range
25 to 30 kg/m2Overweight
> 30 kg/m2Obese
132. Obesity
• Distribution of the stored fat
– Central, or visceral, obesity
– Subcutaneous obesity
• Refined sugars, sweetened beverages, and
vegetable oils
• Disease of caloric imbalance
– Intake of calories ≥ calorie consumption
– Genetic influences play an important role
in weight control
– But the interaction between multiple
factors
133. Obesity
• Neurohumoral control of energy balance
– Peripheral or afferent system – generates signals
Leptin PeptideYY
Adiponectin Insulin
Ghrelin
– Arcuate nucleus in hypothalamus - processes and
integrates neurohumoral signals
• POMC (pro-opiomelanocortin) and CART (cocaine and
amphetamine-regulated transcripts) neurons
• NPY (neuropeptideY) and AgRP (Agouti-Related Peptide)
neurons
– Efferent system
• Anabolic – control food intake
• Catabolic – control energy expenditure
134.
135.
136. Components of the Afferent System
• Regulates appetite and satiety
• Leptin
– Product of the ob gene
– 16-kd hormone synthesized by fat cells
– Signal for energy sufficiency = leptin secretion is stimulated when
fat stores are abundant
– Stimulates POMC/CART neurons that produce anorexigenic
neuropeptides
– Stimulates physical activity, heat production, and energy
expenditure
• Adiponectin (guardian angel against obesity)
– Hormone is produced mainly by adipocytes
– Directs fatty acids to muscle for their oxidation
– Decreases the influx of fatty acids to the liver &
decreases glucose production
– Increase in insulin sensitivity
– Inactivates acetyl coa carboxylase
thru binding with adipor1 and R2
137. Components of the Afferent System
• Gut hormones
• Ghrelin
– Produced in the stomach and arcuate nucleus of the
hypothalamus
– The only known gut hormone that is orexigenic effect
– Likely to stimulate NPY/AgRP neurons
– Post-prandial level attenuation = overeating
• PYY
– Secreted by endocrine cells in the ileum & colon
– Reduces energy intake
– Stimulates POMC/CART neurons
• Amylin
– Peptide secreted with insulin by β cells
– Reduces food intake and weight gain
– Stimulates POMC/CART neurons
140. Obesity and Cancer
• ↑ risk for cancers of the esophagus, pancreas,
colon and rectum, breast, endometrium,
kidney, thyroid, and gallbladder
• Possibly due to the following:
Elevated
insulin levels
Effects on
steroid
hormone
Low
adiponectin
levels
= Elevated
insulin
Pro-
inflammatory
state
141. Diet and Cancer
• Incidence of cancer varies
with geographic areas
• Environmental factors
clearly play a role including
diet
• There are few mechanisms
that link diets and specific
types of cancer
• Aspects of diet concerned
with Carcinogenesis
– Content of exogenous
carcinogens
– Endogenous synthesis of
carcinogens from dietary
components
– Lack of protective factors
• Exogenous carcinogens
– Aflatoxin = liver CA
– Food additives, pesticides,
artificial sweeteners
• Endogenous carcinogens
– Gastric CA
– Nitrosamines
– Nitrosamides
• High animal fat and low
fiber
– Colon CA
– Breast CA
• Low vitamins
– Vitamin C, β carotene,
selenium,Vitamin D
142. Diet and Atherosclerosis
• Association of dietary cholesterol and
saturated animal fats with development of
atherosclerosis
• Role that caloric restriction and special
diets may play in the control of body
weight and prevention of cardiovascular
disease
• Activation of sirtuins and on lowering of
insulin and IGF-1 levels
143. Diet and Atherosclerosis
• Focus on eating an enjoyable and
healthy diet
Rich in fish Vegetables Whole grains Fruits
Olive and
peanut oils
Complex
carbohydrates
Low salt
Limiting the value of establishing rigid “safe levels” for entire populations.
Cut-offs are useful for comparative studies of the effects of harmful agents between specific populations, and for estimating risk of disease in heavily exposed individuals
Xenobiotic metabolism. A, Xenobiotics can be metabolized to nontoxic metabolites and eliminated from the body (detoxification). B, Xenobiotic metabolism may also result in the formation of a reactive metabolite that is toxic to cellular components. If repair is not effective, short- and long-term effects develop.
more heavily in cities and in proximity to heavy industry
such as legionnaires disease, viral pneumonia, and the common cold
Effects of lead poisoning in children related to blood levels.
Pathologic features of lead poisoning in adults.
microcytic hypochromic anemia stemming from the suppression of hemoglobin synthesis.
δ-aminolevulinic acid dehydratase and ferrochelatase inhibition
To protect against potential fetal brain damage, the CDC has recommended that pregnant women avoid consumption of fish known to contain high levels of mercury.
The effects of smoking on survival. The study compared age-specific death rates for current cigarette smokers with that of individuals who never smoked regularly (British Doctors Study). Measured at age 75, the difference in survival between smokers and nonsmokers is 7.5 years.
The risk of lung cancer is determined by the number of cigarettes smoked
Summary of the adverse effects of smoking: those that are more common are in boldface.
caused by a fivefold to 10-fold induction of liver CYPs (discussed later). The effects of alcohol also vary by age, sex, and body fat.
providing a possible basis for protective effects against coronary heart disease
Adverse drug reaction. Skin pigmentation caused by minocycline, a long-acting tetracycline derivative. A, Diffuse blue-gray pigmentation of the forearm; B, Deposition of drug metabolite/iron/melanin pigment particles in the dermis.
may develop in persons who take 3 gm or more daily for long periods of time for treatment of chronic pain or inflammatory conditions
Cracks = Crystallization of the pure alkaloid yields nuggets
(1) the pharmacologic action of the agent, (2) reactions to the cutting agents or contaminants, (3) hypersensitivity reactions to the drug or its adulterants (quinine itself has neurologic, renal, and auditory toxicity), and (4) diseases contracted incident to the use of contaminated needles
such as inability to judge time, speed, and distance,
(as when the skin is wet)
Collision of electrons with other molecules releases electrons in a reaction cascade, referred to as ionization
Effects of ionizing radiation on DNA and its consequences. The effects on DNA can be direct, or most importantly, indirect, through free radical formation.
Radiation-induced chronic vascular injury with subintimal fibrosis occluding the lumen.
, in the form of carbohydrates, fats, and proteins, for the body’s daily metabolic needs;
Homeless persons, aged individuals, and children of the poor often suffer from PEM as well as trace nutrient deficiencies. In poor countries, poverty, crop failures, livestock deaths, and drought, often in times of war and political upheaval, create the setting for the malnourishment of children and adults.
PEM increases susceptibility to many common infectious diseases. Conversely, infections have a negative effect on nutrition, thus establishing a vicious cycle.
The basal metabolic rate becomes accelerated in many illnesses resulting in increased daily requirements for all nutrients. Failure to recognize these nutritional needs may delay recovery. PEM is often present in patients with wasting diseases, such as advanced cancers and AIDS (discussed later).
Alcoholic persons may sometimes suffer PEM but more frequently have deficiencies of vitamins, especially thiamine, pyridoxine, folate, and vitamin A, as a result of poor diet, defective gastrointestinal absorption, abnormal nutrient utilization and storage, increased metabolic needs, and an increased rate of loss. A failure to recognize the likelihood of thiamine deficiency in persons with chronic alcoholism may result in irreversible brain damage (e.g., Wernicke encephalopathy andKorsakoff psychosis, discussed in Chapter 28).
Even the affluent may fail to recognize that infants, adolescents, and pregnant women have increased nutritional needs. Ignorance about the nutritional content of various foods is also a contributing factor. Some examples are: iron deficiency in infants fed exclusively artificial milk diets; polished rice used as the mainstay of a diet may lack adequate amounts of thiamine; lack of iodine from food and water in regions removed from the oceans, unless supplementation is provided.
Anorexia nervosa, bulimia, and less overt eating disorders affect many individuals who are concerned about body image and are obsessed with body weight (anorexia and bulimia are discussed later).
include gastrointestinal diseases and malabsorption syndromes, genetic diseases, specific drug therapies (which block uptake or utilization of particular nutrients), and inadequate total parenteral nutrition.
high in impoverished countries of Southeast Asia
protein-losing enteropathies, the nephrotic syndrome, or after extensive burns; fad diets or replacement of milk by rice-based beverages
relative sparing of subcutaneous fat and muscle mass
Excess adiposity (obesity) and excess body weight
in which fat accumulates in the trunk and in the abdominal cavity (in the mesentery and around viscera), is associated with a much higher risk for several diseases
Diffuse distribution of fat
Excess adiposity (obesity) and excess body weight
in which fat accumulates in the trunk and in the abdominal cavity (in the mesentery and around viscera), is associated with a much higher risk for several diseases
Diffuse distribution of fat
Regulation of energy balance.
Adipose tissues generate afferent signals that influence the activity of the hypothalamus, which is the central regulator of appetite and satiety. These signals decrease food intake by inhibiting anabolic circuits, and enhance energy expenditure through the activation of catabolic circuits. PYY, Peptide YY.
Neurohumoral circuits in the hypothalamus that regulate energy balance. Shown are POMC/CART anorexigenic neurons and NPY/AgRP orexigenic neurons in the arcuate nucleus of the hypothalamus, and their pathways
Obesity, metabolic syndrome, and cancer. Obesity and excessive weight are precursors of the metabolic syndrome, which is associated with insulin resistance, type 2 diabetes, and hormonal changes. Increases in insulin and IGF-1 (insulin-like growth factor-1) stimulate cell proliferation and inhibit apoptosis and may contribute to tumor development. IGF, Insulin-like growth factor; IGFBP, insulin-like growth factor-binding protein; SHBG, sex hormone-binding globulin.
Calorie-restricted animals = less age-related decline in immunologic functions, less oxidative damage, & greater resistance to carcinogenesis