Transcript 30 - International Students Association

Dietary Balances;
Regulation of Feeding;
Obesity and Starvation
Prof. dr. Zoran Valić
Department of Physiology
University of Split School of Medicine
Energy Intake and Output
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used or stored for later use (fat)
appropriate balanced intake (proteins,
carbohydrates, fats, minerals, and vitamins)
1 g carbohydrates – 4.1 Cal (98% – 4(17 kJ)
1 g fats – 9.3 Cal (95% – 9 (38 kJ))
1 g proteins – 4.35 kJ (92% – 4 (17 kJ))
45%, 40%, 15% (average Americans)
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30-50 g of protein per day (20-30 g are
degraded)
partial proteins (inadequate quantities of
certain essential amino acids)
protein of corn has almost no tryptophan
protein-deficiency syndrome – kwashiorkor
carbohydrates and fats – protein sparers
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nitrogen excretion can be used to assess
protein metabolism (16% nitrogen)
90% of nitrogen is excreted in the urine
(urea, uric acid, creatinine), 10% by feces
rate of protein breakdown (g) =
N2(urine) x 1.1 x 6.25 (100/16)
negative or positive nitrogen balance
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“respiratory quotient” – ratio of CO2
production to O2 utilization (1h and more)
fat utilization (0.7), carbohydrates (1.0),
proteins (0.8)
excess hydrogen atoms
right after meal close to 1.0; 8-10 h after
meal about 0.7; in diabetes melitus always
about 0.7
Regulation of Food Intake and
Energy Storage
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only 27% of the energy ingested normally
reaches the functional systems of the cells
food intake, energy expenditure and fat
storage – environmental, cultural and
genetic factors + physiological control
“epidemics” of obesity (64% & 33%)
2000 Cal daily expenditure of energy
(6000-7000 Cal)
Neural Centers Regulate Food
Intake
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sensation of hunger (rhythmical
contractions of stomach and restlessness)
appetite –desire for particular type of food
feeling of satiety
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lateral nuclei of the hypothalamus – feeding
center (hyperphagia, inanition)
operates by exciting the motor drives to
search for food
ventromedial nuclei of the hypothalamus –
satiety center (aphagia, hyperphagia)
other centers also play a major role
(arcuate!), hormonal secretion (thyroid and
adrenal glands, pancreatic islet cells)
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integration of neural signals from the
gastrointestinal tract (stomach filling),
chemical signals from nutrients in the blood,
signals from gastrointestinal hormones,
hormones released by adipose tissue and
signals from the cerebral cortex (sight,
smell, and taste)
feeding behavior
orexigenic and anorexigenic substances and
receptors – therapeutic sites
Neurons and Neurotransmitters in
the Hypothalamus
pro-opiomelanocortin (POMC) neurons
1)
1)
2)
α-MSH (α-melanocyte-stimulating hormone)
CART (cocaine and amphetamine related transcript)
neurons that produce orexigenic substances
2)
1)
2)
NPY (neuropeptide Y)
AGRP (agouti-related protein)
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activation of POMC neurons  decreases
food intake and increases energy
expenditure
activation of NPY-AGRP neurons 
increases food intake and reduces energy
expenditure
major targets for: leptin, insulin,
cholecystokinin (CCK), and ghrelin
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POMC neurons release α-MSH (acts on
melanocortin receptors found especially in
neurons of the paraventricular nuclei)
at least five subtypes of melanocortin
receptors
MCR-3 and MCR-4 are especially
important in regulating food intake and
energy balance
activation of these receptors reduces food
intake while increasing energy expenditure
inhibition has an opposite effect
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MCR activation is mediated by activation of
nucleus tractus solitarius (sympathetics)
defective signaling of the melanocortin
pathway is associated with extreme obesity
mutations of MCR-4 – most common
known monogenic (single-gene) cause of
human obesity (5-6% of early-onset severe
obesity in children)
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AGRP is a natural antagonist of MCR-3 and
MCR-4 receptors
role of AGRP in normal physiologic control
of food intake is unclear
excessive formation of AGRP in mice and
humans, due to gene mutations, is
associated with increased food intake and
obesity
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NPY (arcuate nuclei) – when energy stores
of the body are low – stimulates appetite +
firing of the POMC neurons is reduced =
decreased activity of the melanocortin
pathway and further stimulated appetite
Factors That Regulate Quantity
of Food Intake
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short-term regulation – preventing
overeating at each meal
long-term regulation – maintenance of
normal quantities of energy stores in the
body
Short-Term Regulation
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1)
2)
What turns off the eating?
distending of gastrointestinal tract (stomach
and the duodenum – vagus nerve)
humoral and hormonal factors
1)
2)
3)
cholecystokinin (CCK) – fat
peptide YY from the ileum and colon – fat, ??
glucagon-like peptide (GLP) from intestines – enhances
glucose-dependent insulin production and secretion
from the pancreas – suppress appetite
3)
4)
ghrelin – oxyntic cells of the stomach and
intestine, concentrations rise during fasting,
fall rapidly after a meal; administration of
ghrelin increases food intake in
experimental animals; ?
oral receptors (experiment with esophageal
fistula; chewing, salivation, swallowing,
and tasting – shorter duration (20-40 min))
Intermediate and Long-Term
Regulation
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depends on nutritional status of the body
glucostatic, aminostatic and lipostatic
theories of regulation
glucoreceptor ( GUK increases the rate of
firing) and glucosensitive ( GUK
decreases the firing) neurons in the
hypothalamus
Temperature Regulation and
Food Intake
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1)
2)
exposition to cold – increased feeding
interaction within the hypothalamus:
increases metabolic rate
provides increased fat for insulation
Feedback from Adipose Tissue
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1)
2)
3)
4)
5)
hypothalamus senses energy storage
through the actions of leptin, a peptide
hormone released from adipocytes
POMC neurons of the arcuate nuclei and
neurons of the paraventricular nuclei:
 appetite stimulators (NPY i AGRP)
activation of POMC neurons (α-MSH)
 substances that decrease apetite (CRH)
increased sympathetic nerve activity
 insulin secretion by the pancreatic β cells
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in mice or humans with mutations that
render their fat cells unable to produce
leptin or mutations that cause defective
leptin receptors in the hypothalamus –
marked hyperphagia and morbid obesity
in most obese humans – no deficiency of
leptin production
many other mechanisms, questionable
summary
Obesity – excess of body fat
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BMI = mass (kg) / hight2 (m2)
25-30 – overweight, 30 – obese
measurment of total body fat (skin-fold
thickness, bioelectrical impedance, or
underwater weighing; 25% & 35%)
obesity results from greater energy intake
than energy expenditure
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for each 9.3 Cal (38,9 kJ ) of excess energy
– 1 gram of fat is stored
1/3 energy used each day by the average
person goes into muscular activity (2/3)
increase in physical activity!
Psychological factors
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three meals a day and that each meal must
be filling
during or after stressful situations (death of
a parent, a severe illness, or even mental
depression)
eating can be a means of releasing tension
Childhood Overnutrition
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rate of formation of new fat cells
number of fat cells in obese children is
often as three times that in normal children
hyperplastic and hypertrophic obesity
new adipocytes can differentiate from
fibroblast-like preadipocytes at any period
of life
Neurogenic Abnormalities
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lesions in the ventromedial nuclei of the
hypothalamus – tumors
functional organization of the hypothalamic
or other neurogenic feeding centers in obese
individuals may be different
abnormalities of neurotransmitters or
receptor mechanisms
Genetic Factors
obesity definitely runs in families
identical twins mass is usually within 1.5,
or 2.5 kg
20-25% of cases of obesity may be caused
by genetic factors
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1)
2)
3)
mutations of MCR-4
congenital leptin deficiency
mutations of the leptin receptor
Treatment of Obesity
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reducing energy intake or/and increasing
energy expenditure
large quantities of "bulk“ (non-nutritive
cellulose substances, distention)
prevent vitamin deficiencies
amphetamines, sibutramine – dangerous,
overexcite sympathetic nervous system and
raise pressure, addiction
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altering lipid metabolism
orilistat (a lipase inhibitor) – reduces the
intestinal digestion of fat
loss of fat-soluble vitamins in the feces
increase in physical activity
various surgical procedures (gastric bypass
surgery and gastric banding surgery)
Inanition
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lack of food, or
psychological and hypothalamic disorders
anorexia nervosa – reduction in food intake
caused primarily by diminished appetite,
nauseated by food
cachexia – weight loss greater than that
caused by reduced food intake alone
(tumors, AIDS)
Starvation
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tissues preferentially use carbohydrate for
energy
protein depletion: rapid depletion at first,
then greatly slowed depletion, and, finally,
rapid depletion again shortly before death
gluconeogenesis decreases to 1/5
state of ketosis (β- hydroxybutyrate – brain)
Body Temperature
Regulation and Fever
Normal Body Temperatures
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“core” temperature = ± 0,6 ºC (± 1 ºF)
(nude person exposed to air temperatures
10-55 ºC, beautifully designed control
system)
skin temperature rises and falls with the
temperature of the surroundings (ability to
lose heat to the surroundings)
Normal Core Temperature
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range of normal temperatures (36-37,5 ºC)
average normal core temperature 36,5-37
ºC (measured orally; rectally 0,5 ºC higher)
regulatory mechanisms are not perfect:
temperature increases during exercise and
varies with temperature extremes of the
surroundings
balance between heat production and heat
loss
Heat Production
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heat – principal by-product of metabolism
metabolic rate of the body:
1)
2)
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4)
5)
6)
basal rate of metabolism
muscle activity
effect of thyroxine, (hGH, testosterone)
effect of sympathetic stimulation
increased chemical activity in the cells
thermogenic effect of food
Heat Loss
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heat is generated in deep organs: liver,
brain, and heart, and in the skeletal muscles
heat is lost to the air via skin
rate at which heat is lost:
1)
2)
how rapidly heat can be conducted from where
it is produced to the skin
how rapidly heat can then be transferred from
the skin to the surroundings
Insulator System of the Body
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skin, subcutaneous tissues (fat) – insulator
conduction of heat through fat = 1/3
conduction through other tissues
insulator properties of female body are
better than male body
Blood Flow to the Skin from the
Body Core
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enables heat to be conducted from the core
of the body to the skin
especially important is a continuous venous
plexus
rate of blood flow into the skin venous
plexus can vary tremendously (0-30% CO)
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skin is an effective controlled "heat
radiator" system
flow of blood to the skin is a most effective
mechanism for heat transfer from the body
core to the skin
vasoconstriction of the arterioles and the
arteriovenous anastomoses that supply
blood to the venous plexus of the skin is
controlled almost entirely by the
sympathetic nervous system
Basic Physics of How Heat Is
Lost from the Skin Surface
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radiation (about 60%, infrared heat rays, a
type of electromagnetic wave (5-20 μm), in
all directions)
conduction (about 3% direct conduction
from to solid objects, about 15% to air –
convection (currents), suspension in water!)
evaporation (evaporation of 1g water – 0.58
Cal (2,5 kJ) heat, insensibly and
evaporation of sweat, necessary cooling
mechanism at very high air temperatures)
Effect of Clothing
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increasing the thickness of the so-called
private zone of air + decreasing air currents
rate of heat loss from the body by
conduction and convection (to 1/2, or 1/6 –
arctic-type clothing)
coating the inside of clothing with a thin
layer of gold – reflects radiant heat back
extreme caution against allowing the
clothing to become wet
Sweating
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starts by stimulation of the anterior
hypothalamus-preoptic area in the brain by
electricity or by excess heat
nerve impulses are transmitted in the
autonomic pathways to the spinal cord and
then through sympathetic outflow to the
skin everywhere in the body
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sweat glands are innervated by cholinergic
nerve fibers (but that run in the sympathetic
nerves along with the adrenergic fibers)
they can also be stimulated by epinephrine
or norepinephrine circulating in the blood
Mechanism of Sweat Secretion
1)
2)
deep subdermal coiled portion – secretes
the sweat (primary or precursor secretion)
duct portion (modify concentrations of
constituents)
Primary secretion
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active secretory product of the epithelial
cells
composition is similar to that of plasma
(Na+ = 142 mmol/L, a Cl- = 104 mmol/L),
does not contain plasma proteins
Reabsorption of ions
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slight stimulation – most of Na+ and Cl- are
reabsorbed (concentration of each falls to as
low as 5 mmol/L)
this reduces the osmotic pressure of the
sweat fluid to such a low level that most of
the water is also reabsorbed, which
concentrates most of the other constituents
(urea, K+, lactic acid)
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strong stimulation – Na+ and Cl- are
reabsorbed to concentrations of 50-60
mmol/L, little of the water is reabsorbed –
significant loss of NaCl
Acclimatization. Role of
Aldosterone
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normal unacclimatized person ~ 1L/h sweat
after 1-6 weeks ~ 2-3 L/h sweat
removing 10x more heat from the body
change in the internal sweat gland cells to
increase their sweating capability
better conservation of body salt – increased
secretion of aldosterone (decreases loses
from 15-30 g/day to 3-5 g/day)
Loss of Heat by Panting
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substitute mechanism due to:
1)
surfaces often covered with fur
2)
skin of most lower animals is not
supplied with sweat glands
panting center is associated with
pneumotaxic respiratory center in the pons
evaporation of saliva from the tongue,
without increase in alveolar ventilation
Role of the Hypothalamus
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experiments with use of a thermode
principal areas in the brain for temperature
control are the preoptic and anterior
hypothalamic nuclei of the hypothalamus
large numbers of heat-sensitive neurons
about one-third as many cold-sensitive
neurons
heating of preoptic area – profuse sweating
and vasodilation in the skin
Detection of Temperature
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temperature receptors in skin and in a few
specific deep tissues (spinal cord,
abdominal viscera, around the great veins)
in the skin: cold receptors (far more) and
warmth receptors
in deep tissues: function differently from
the skin receptors because they are exposed
to the body core temperature, they detect
mainly cold
Integration of the Central and
Peripheral Temperature Signals
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area of the hypothalamus that is located
bilaterally in the posterior hypothalamus
approximately at the level of the
mammillary bodies
combination and integration of signals from
the preoptic area and from elsewhere in the
body
Temperature-Decreasing
Mechanisms
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vasodilation
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sweating
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in the skin (inhibition of the sympathetic
centers in the posterior hypothalamus), 8x 
rate of heat transfer to the skin
rise above 37 ºC (critical level), 1 ºC 10x 
removal of heat by evaporation
decrease in heat production
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inhibition of shivering and chemical
thermogenesis
Temperature-Increasing
Mechanisms
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vasoconstriction
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piloerection
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in the skin (stimulation of the posterior
hypothalamic sympathetic centers)
hairs "standing on end", not important in
humans, thick layer of "insulator air"
increase in thermogenesis
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promoting shivering, sympathetic excitation of
heat production, and thyroxine secretion
Hypothalamic Stimulation of
Shivering
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primary motor center for shivering located
in the dorsomedial portion of the posterior
hypothalamus near wall of the 3rd ventricle
normally inhibited by signals from the heat
center in anterior preoptic area
cold signals from the skin and spinal cord
body heat production can rise 4-5x normal
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transmits signals to anterior motor neurons
signals are nonrhythmical and do not cause
the actual muscle shaking
they increase the tone of the skeletal
muscles throughout the body
when the tone rises above a certain critical
level, shivering begins
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results from feedback oscillation of the
muscle spindle stretch reflex mechanism
Sympathetic "Chemical"
Excitation
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ability of norepinephrine and epinephrine to
uncouple oxidative phosphorylation
foodstuffs are oxidized but do not cause
ATP to be formed – release of heat
directly proportional to the amount of
brown fat (acclimatization)
adults do not have brown fat ( rate of heat
production 10-15%, in infants 100%)
Increased Thyroxine Output
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cooling preoptic area – increases production
of TRH  TSH  tiroksina 
activates uncoupling protein
yet another mechanism of chemical
thermogenesis
requires several weeks' exposure to cold
humans seldom allow themselves to be
exposed to the same degree of cold
Concept of a "Set-Point"
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critical body core temperature 37,1 °C
called the "set-point" of the temperature
control mechanism
feedback gain of the temperature control
system = (ratio of the change in
environmental temperature to the change in
body core temperature) - 1
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changes about 1°C for each 25° to 30°C
change in environmental temperature (~ 27)
extremely high gain (baroreceptor feedback
gain < 2)
Skin Temperature Can Slightly
Alter the Set-Point
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decrease in skin temperature – increase in
set-point for sweating
decrease in skin temperature – increase in
set-point for shivering
Behavioral Control
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even more potent
person makes appropriate environmental
adjustments to re-establish comfort
there are local skin temperature reflexes
after cutting the spinal cord in the neck
above the sympathetic outflow from the
cord regulation becomes extremely poor
Fever
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body temperature above the usual range of
normal
1)
abnormalities in the brain itself
2)
toxic substances that affect the
temperature-regulating centers
Resetting the Hypothalamic
Temperature-Regulating Center
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many proteins, breakdown products of
proteins, lipopolysaccharide toxins released
from bacterial cell membranes – pyrogens
some pyrogens act directly and immediately
other pyrogens function indirectly and may
require several hours of latency (endotoxins
from gram-negative bacteria)
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phagocytizion of bacteria – release of
interleukin-1 (IL1, leukocyte or endogenous
pyrogen)
IL1 in 8-10 min significantly increases
temperature (in nanograms)
IL1 inducing formation of prostaglandin E2
drugs that impedes the formation of
prostaglandins from arachidonic acid –
antipyretics (aspirin)
Fever Caused by Brain Lesions
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almost always after surgery in the region of
the hypothalamus
compression of the hypothalamus by a brain
tumor
Characteristics of Febrile
Conditions
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chills – extremely cold feeling,
vasoconstriction in the skin, shivers
crisis or “flush” – after factor is removed,
intense sweating and the hot skin
heatstroke body temperature rises beyond a
critical temperature – 40-42 °C (105° to
108°F, dizziness, abdominal distress,
vomiting, delirium, loss of consciousness)
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local hemorrhages and parenchymatous
degeneration of cells
especially in the brain, but also liver and
kidneys
acclimatization
Exposure of the Body to Extreme
Cold
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person exposed to ice water for 20 to 30
minutes ordinarily dies because of heart
standstill or heart fibrillation
once the body temperature has fallen below
about 85°F (30 °C), the ability of the
hypothalamus to regulate temperature is
lost
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sleepiness, coma – depresses the activity of
the central nervous system
frostbites (lobes of the ears and in the digits
of the hands and feet) – formation of ice
crystals – permanent damage – gangrene
artificial hypothermia (heart surgery)