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    <h1>Altitude and Mortality</h1>
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<p class="nav"><span class="nav-left">Listed under <a href="/ray-peat.html">Ray Peat</a>.</span><span class="nav-right"><a href="/theme.html">Theme</a></span></p>
<p>From the <a href="https://raypeat.com/articles/aging/altitude-mortality.shtml" target="_blank">original article</a> in 2006. Author: <a href="https://raypeat.com/" target="_blank">Ray Peat</a>.</p>
  <p>   <em>Breathing 
pure oxygen lowers the oxygen content of tissues; breathing rarefied 
air, or air with carbon dioxide, oxygenates and energizes the tissues; 
if this seems upside down, it's because medical physiology has been 
taught upside down.  And respiratory physiology holds the key to 
the special functions of all the organs, and to many of their basic 
pathological changes.</em>  </p>
<p><strong><em>Stress, shock, inflammation, 
aging, and organ failure are, in important ways,  respiratory problems.</em></strong></p>
<p>Definitions:</p>
<ul>
  <li><strong> Haldane  effect:  </strong>Oxygen displaces carbon dioxide from hemoglobin, in proportion to its partial (specific) pressure.<strong> </li>
  <li>Bohr effect:</strong>  Carbon dioxide (or acidity) displaces oxygen from hemoglobin.<strong> </li>
  <li>Lactic acidemia:  </strong>The presence of lactic acid in the blood.<strong> </li>
  <li>Alkalosis:</strong>  A  pH of the blood above 7.4.       <strong></li>
  <li>Acidosis: </strong>A blood pH below 7.4.             <strong></li>
  <li>Lactate paradox:</strong>  The reduced production of lactic acid at 
a given work rate at high altitude.  Muscle work efficiency may 
be 50% greater at high altitude.  ATP wastage is decreased.</li>
</ul>
<p>There 
are some popular medical ideas that obstruct clear thinking about respiration.  
One is that high altitude deprives you of oxygen, and is likely to be 
bad for people with heart disease and cancer.  Another is that 
breathing pure oxygen helps sick people to oxygenate their tissues while 
exerting less effort in breathing.  These are both exactly wrong, 
and the errors have been explored in quite a few publications, but the 
ideas persist in the culture to such a degree that our <strong><em>perceptions 
and intuitions </em></strong>have been misled, making closely related things 
seem to be unrelated.  In this culture, it is hard to see that 
heart disease, cancer, and cataracts all involve a crucial respiratory 
defect, with the production of too much lactic acid and too little carbon 
dioxide, which leads to a “swelling pathology”<strong>:</strong>  A pathological 
retention of water.  The swollen heart beats poorly, the swollen 
lens turns milky, other cells divide rapidly as a result of swelling.</p>
<p>People 
who live at very high altitudes live significantly longer<strong>;</strong> they 
have a lower incidence of cancer (Weinberg, et al., 1987) and heart 
disease (Mortimer, et al., 1977), and other degenerative conditions, 
than people who live near sea level.  As I have written earlier, 
I think the lower energy transfer from cosmic radiation is likely to 
be a factor in their longevity, but several kinds of evidence indicate 
that it is the lower oxygen pressure itself that makes the biggest contribution 
to their longevity.</p>

<p>“Mountain 
sickness” is a potentially deadly condition that develops in some 
people when they ascend too rapidly to a high altitude.  Edema 
of the lungs and brain can develop rapidly, leading to convulsions and 
death.  The standard drug for preventing it is acetazolamide, which 
inhibits carbonic anhydrase and causes carbon dioxide to be retained, 
creating a slight tendency toward acidosis.  This treatment probably 
mimics the retention of carbon dioxide that occurs naturally in altitude 
adapted people.  The reasons for mountain sickness, and the reasons 
for the low incidence of heart disease, cancer, cataracts, etc., at 
high altitude, offer clues to the prevention of death and deterioration 
from many other causes.</p>
<p>When 
the weather in a particular place is cool, sunny and dry (which in itself 
is very good for the health) the atmospheric pressure usually is higher 
than average.  Although sunny dry weather is healthful,<strong> periods 
of higher pressure correspond to an increased incidence of death</strong> 
from heart disease and strokes.</p>
<p>The Haldane-Bohr effect describes the fact 
that oxygen and carbon dioxide destabilize each other’s binding to 
hemoglobin.  When oxygen pressure is high, the blood releases its 
carbon dioxide more easily.  In stormy weather, or at high altitude, 
the lower oxygen pressure allows the body to retain more carbon dioxide.  
Carbon dioxide, produced in the cells, releases oxygen into the tissues, 
relaxes blood vessels, prevents edema, eliminates ammonia, and increases 
the efficiency of oxidative metabolism.</p>
<p>Hyperventilation, 
breathing excessively and causing too much carbon dioxide to be lost, 
is similar to being in the presence of too much oxygen<strong>;</strong> it’s 
similar to being at low altitude with high atmospheric pressure, only 
worse.  Therefore, the physiological events produced by hyperventilation 
can give us an insight into what happens when the atmospheric pressure 
is low, by looking at the events in reverse.  Likewise, breathing 
100% oxygen has known harmful consequences, which are very similar to 
those produced by hyperventilation.</p>

<p>Hyperventilation 
is defined as breathing enough to produce respiratory alkalosis from 
the loss of carbon dioxide.  Lactic acid is produced in response 
to the alkalosis of hyperventilation.</p>
<p>Breathing 
too much oxygen displaces too much carbon dioxide, provoking an increase 
in lactic acid<strong>;</strong> too much lactate displaces both oxygen and carbon 
dioxide.  Lactate itself tends to suppress respiration.</p>
<p>Oxygen 
toxicity and hyperventilation create a systemic deficiency of carbon 
dioxide.  It is this carbon dioxide deficiency that makes breathing 
more difficult in pure oxygen, that impairs the heart’s ability to 
work, and that increases the resistance of blood vessels, impairing 
circulation and oxygen delivery to tissues.  In conditions that 
permit greater carbon dioxide retention, circulation is improved and 
the heart works more effectively.  Carbon dioxide inhibits the 
production of lactic acid, and lactic acid lowers carbon dioxide's concentratrion 
in a variety of ways..</p>
<p>When 
carbon dioxide production is low, because of hypothyroidism, there will 
usually be some lactate entering the blood even at rest, because adrenalin 
and noradrenalin are produced in large amounts to compensate for hypothyroidism, 
and the adrenergic stimulation, besides mobilizing glucose from the 
glycogen stores, stimulates the production of lactate.  The excess 
production of lactate displaces carbon dioxide from the blood, partly 
as a compensation for acidity.  The increased impulse to breath 
(“ventilatory drive”) produced by adrenalin makes the problem worse, 
and lactate can promote the adrenergic response, in a vicious circle..</p>
<p>Since 
the 1920s when A. V. Hill proposed that the prolonged increase in oxygen consumption after a short 
period of intense work, the “oxygen debt,” was equivalent to the 
amount of lactic acid that had entered the circulation from the muscles’ 
anaerobic work, and that it had to be disposed of by oxidative processes, 
physiology textbooks have given the impression that lactic acid accumulation 
was exactly the same as the oxygen debt.  In reality, several things 
are involved, especially the elevation of temperature produced by the 
intense work.  Increased temperature raises oxygen consumption 
independently of lactic acid, and lower temperature decreases oxygen 
consump-tion, even when lactic acid is present.</p>

<p>The 
idea of the “oxygen debt” produced by exercise or stress as being 
equivalent to the accumulation of lactic acid is far from accurate, 
but it’s true that activity increases the need for oxygen, and also 
increases the tendency to accumulate lactic acid, which can then be 
disposed of over an extended time, with the consumption of oxygen.  
This relationship between work and lactic acidemia and oxygen deficit 
led to the term “lactate paradox” to describe the lower production 
of lactic acid during maximal work at high altitude when people are 
adapted to the altiude.  Carbon dioxide, retained through the Haldane 
effect, accounts for the lactate paradox, by inhibiting cellular excitation 
and sustaining oxidative metabolism to consume lactate efficiently.</p>
<p>The 
loss of carbon dioxide from the lungs in the presence of high oxygen 
pressure, the shift toward alkalosis, by the Bohr-Haldane effect increases 
the blood’s affinity for oxygen, and restricts its delivery to the 
tissues, but because of the abundance of oxygen in the lungs, the blood 
is almost competely saturated with oxygen.</p>
<p>At 
high altitude, the slight tendency toward carbon dioxide-retention acidosis 
decreases the blood’s affinity for oxygen, making it more available 
to the tissues.  It happens that lactic acid also affects the blood’s 
oxygen affinity, though not as strongly as carbon dioxide.  <strong>
However, lactic acid doesn’t vaporize as the blood passes through 
the lungs, so its effect on the lungs’ ability to oxygenate the blood 
is the opposite of the easily exchangeable carbon dioxide’s.  </strong>
Besides<strong> </strong>dissociating oxygen from hemoglobin, lactate also displaces 
carbon dioxide from its (carbamino) binding sites on hemoglobin.  
If it does this in hemoglobin, it probably does it in many other places 
in the body.</p>
<p>According 
to Meerson, ascending more than 200 feet per day produces measurable 
stress.  People seldom notice the effects of ascending a few thousand 
feet in a day, but it has been found that a large proportion of people 
have bleeding into the retina when they ascend to 10,000 feet without 
adequate adaptation.  Presumably, similar symptomless bleeding 
occurs in other organs, but the retina can be easily inspected.</p>

<p>If 
hypothyroid people, with increased adrenalin 
and lactate, are hyperventilating even at rest and at sea level, when 
they go to a high altitude where less oxygen is available, and their 
absorption of oxygen is impaired by lactic acidemia, <strong>their “oxygen 
debt,” conceived as circulating lactic acid, is easily increased, 
intensifying their already excessive 
“ventilatory drive,” and in proportion to the lactic acid oxygen 
debt, oxygen absorption is further inhibited.</strong>  </p>
<p>The 
lactic acid has to be disposed of, but their ability to extract oxygen 
is reduced.  The poor oxygenation, and the increased lactic acid 
and free fatty acids cause blood vessels to become leaky, producing 
edema in the lungs and brain.  <strong>This is very similar to the “multiple 
organ failure” that occurs in inflammatory conditions, 
bacteremia, congestive heart failure, cancer, and trauma.</strong></p>
<p><strong>Otto 
Warburg established that lactic acid production even in the presence 
of oxygen is a fundamental property of cancer.</strong>  It is, to a 
great degree, the lactic acid which triggers the defensive reactions 
of the organism, leading to tissue wasting from excessive glucocorticoid 
hormone. The cancer’s production of lactic acid creates the same kind 
of internal imbalance produced by hyperventilation, and if we look at 
the physiology of hyperventilation in the light of Warburg’s description 
of cancer, hyperventilation imitates cancer metabolism, by producing 
lactic acid “even in the presence of oxygen.” Lactate, a supposedly 
benign metabolite of the cancer cells, which appears in all the other 
degenerative conditions, including obesity, diabetes, Alzheimer’s 
disease, multiple sclerosis, is itself a central factor in the degenerative 
process.</p>
<p>Working 
out the mechanisms involved in susceptibility to altitude sickness will 
clarify the issues involved in the things that cause most people to 
die.  At first, all of these changes occur in the regulatory systems, 
and so can be corrected.</p>

<p>The 
vitality of the mitochondria, their capacity for oxidative energy production, 
is influenced by nutrition and hormones.  In healthy people, mitochondria 
work efficiently at almost any altitude, but people with damaged or 
poorly regulated mitochondria are extremely susceptible to stress and 
hyperventilation.  Progesterone, testosterone, and thyroid (T3 
and T2) are protective of normal mitochondrial function, by both local 
and systemic effects.</p>
<p>The 
changes that occur in malnutrition and hypothyroidism affect the mitochondria 
in a multitude of ways, besides the local effects of the thyroid and 
progesterone deficiency.</p>
<p>Increased 
estrogen, nitric oxide, excitatory amino acids, cortisol, lactate, free 
unsaturated fatty acids, prolactin, growth hormone, histamine, serotonin, 
tumor necrosis factor and other pro-inflammatory cytokines and kinins, 
and a variety of prostaglandins 
and eicosanoids, have been identified as anti-mitochondrial, anti-respiratory agents.  Edema 
itself can be counted among these agents.<strong> </strong>
 (Carbon dioxide itself directly reduces tissue edema, as can be seen 
in studies of the cornea.)<strong>  Thyroid, progesterone, magnesium, 
glucose, and saturated fatty acids are among the central protective 
elements.</strong> <br></p>

<p>The 
similarity of the changes occurring under the influence of estrogen 
excess, oxygen deprivation, aging, and ionizing radiation are remarkable.  
People who think that radiation’s biological effects are mainly on 
the DNA, and that estrogen acts through “estrogen receptors,” aren’t 
interested in the parallels, but the idea of a common respiratory defect, 
activating common pathways, suggests that there is something useful 
in the perception that irradiation, hypoxia, and aging have estrogenic 
effects.</p>
<p>Irradiation 
by ultraviolet, gamma, or x-rays, and even by blue light, is damaging 
to mitochondrial respiration.  All of the ionizing radiations produce 
immediate and lingering edema, which continues to damage metabolism 
in a more or less permanent way, apart from any detectable mutagenic 
actions.  The amount of water taken up following irradiation can 
be 20% to 30% of the normal weight, which is similar to the amount of 
swelling that intense work produces in a muscle, and to the weight increase 
under hormonal imbalances.  The energy changes produced by irradiation 
in, for example, the heart, appear to accelerate the changes produced 
by aging.  Since unsaturated fats accumulate in the respiratory 
system with aging, and are targets for radiation damage, the involvement 
of these fats in all sorts of antirespiratory degenerative processes 
deserves more attention.  Darkness, like irradiation, excess lactate, 
and unsaturated fats, has the diabetes-like effect of greatly reducing 
the ability of muscle to absorb sugar, while light stimulates respiration..</p>
<p>When 
the ideas of “stress,” “respiratory defect,” and “hyperventilation” 
are considered together, they seem practically interchangeable.</p>
<p>The 
presence of lactic acid, which indicates stress or defective respiration, 
interferes with energy metabolism in ways that tend to be self-promoting.  
Harry Rubin’s experiments demonstrated that cells become cancerous 
before genetic changes appear.  <strong>The mere presence of lactic 
acid can make cells more susceptible to the transformation into cancer 
cells.  </strong>(Mothersill, et al., 1983.)  The implications 
of this for the increased susceptibility to cancer during stress, and 
for the increased resistance to cancer at high altitude, are obvious.</p>
<p>Blocking 
the production of lactic acid can make cells more resistant (Seymour 
and Mothersill, 1988)<strong>;</strong> 

if lactic acid were merely a useful fuel, it’s hard to see how poisoning 
its formation could improve cell survival.  But it happens to be 
an energy-disruptive fuel, interfering with carbon dioxide metabolism, 
among other things.</p>
<p>Hyperventilation 
is present in hypothyroidism, and is driven by adrenalin, lactate, and 
free fatty acids.  Free fatty acids and lactate impair glucose 
use, and promote edema, especially in the lungs.  Edema in the 
lungs limits oxygen absorption.  Swelling of the brain, resulting 
from increased vascular permeability and the entry of free fatty acids, 
reduces its circulation and oxygenation<strong>;</strong> lactic acidemia causes 
swelling of glial cells.  Swelling of the endothelium increases 
vascular resistance by making the channel narrower, eventually affecting 
all organs.  Cells of the immune system release tumor necrosis 
factor and other inflammatory cytokines, and the bowel becomes more 
permeable, allowing endotoxin and even bacteria to enter the blood.  
Endotoxin impairs mitochondria, increases estrogen levels, causes Kupffer 
cells in the liver to produce more tumor necrosis factor, etc..  
Despite its name, tumor necrosis factor stimulates the growth and metastasis 
of some types of cancer.   Dilution of the body fluids, which 
occurs in hypothyroidsim, hyperestrogenism, etc., stimulates tumor growth.</p>
<p>The 
inflammatory factors that can promote cell growth can, with just slight 
variation, deplete cellular energy to the extent that the cells die 
from the energetic cost of the repair process, or mutate from defective 
repairs.  Niacinamide can have an “antiinflammatory” function, 
preventing death from multiple organ failure, by interupting the reactions 
to nitric oxide and peroxynitrile (Cuzzocrea, et al., 1999).  The 
cells’ type, environment, and history determine the different outcomes.</p>
<p>Cataracts, 
cancer, congestive heart failure, seemingly such different degenerative 
problems, have the same sort of metabolic problem, leading to the abnormal 
absorption of water by cells, disrupting their normal functions.</p>
<p>The 
same simple metabolic therapies, 
such as thyroid, progesterone, magnesium, and carbon dioxide, are appropriate 
for a great range of seemingly different diseases.  Other biochemicals, 
such as adenosine and niacinamide, have more specific protective effects, 
farther downstream in the &quot;cascade&quot; effects of stress.</p>

<p>There 
are many little cliches in the medical culture that prevent serious 
thought about integral therapy<strong>:</strong> “Progesterone is the pregnancy 
hormone,” “thyroid makes your heart work too hard,” “thyroid 
uncouples mitochondrial phosphorylation,” “magnesium has nothing 
to do with thyroid or progesterone,” “lactate provides energy,” 
etc.  But many of these minor cliches are held in place by deep 
theoretical errors about the nature of cells and organisms.  Once 
those have been corrected, there should be progress toward more powerful 
integral therapies. <br></p>
<h2>References</h2>
<small>
<p>Cell 
Biol Int Rep 1983 Nov;7(11):971-80.<strong>  Lactate-mediated changes 
in growth morphology and transformation frequency of irradiated 
C3H 10T1/2 cells.</strong> Mothersill C, Seymour CB, Moriarty M. Treatment 
of mammalian cells with lactate or inhibitors of glycolysis alters their 
radiation response, particularly in the low dose region of the dose 
response curve. The occurrence of <strong>both high lactate levels and high 
glycolytic metabolism in tumours</strong> is well known and therefore the 
effect of lactate on a cell line sensitive to radiation induced transformation 
was examined using a single exposure to Cobalt 60 gamma rays as the 
carcinogen challenge. The results indicate that cells treated with <strong>

5mM lactate before irradiation exhibit changes in morphology and growth 
rate and that the transformation frequency is increased by three to 
ten fold following 24 hours lactate treatment just prior to irradiation. </strong>
Examination of radiation survival curves showed a positive correlation 
between transformation frequency and size of the shoulder, but increasing 
transformation frequency was associated with a decrease in Do. A mechanism 
involving altered Redox potential in lactate treated cells is suggested. 
The results are discussed in terms of their possible significance for 
radiotherapy. </p>
<p><strong>Radiat 
Environ Biophys 1988;27(1):49-57.  The effect of 
glycolysis</strong><strong> inhibitors 
on the radiation response of CHO-K1 cells. 
Seymour CB, Mothersill C Saint Luke's Hospital, 
Rathgar, Dublin, Ireland.  Exposure of 
CHO-K1 cells to three different inhibitors of 
glycolysis, prior to treatment with a single dose of 
ionising radiation, reduced their survival. The effects were concentration-dependent 
but occurred under all conditions where cells were exposed to the inhibitors 
prior to irradiation. The results are similar to those obtained by this 
group when glycolysis was altered using analogues of 
D-glucose or by blocking the pyruvate----lactate reaction using added 
lactate or oxamate. They support data from other workers suggesting 
a role for energy metabolism in the final expression of radiation damage. </strong></p>
<p>Crit 
Care Med 1999 Aug;27(8):1517-23. <strong>Protective effect of 
poly(ADP-ribose) synthetase inhibition on multiple organ failure after 
zymosan-induced peritonitis in the rat.</strong> Cuzzocrea S, Zingarelli 
B, Costantino G, Sottile A, Teti D, Caputi AP</p>
<p>Eur 
J Cancer 1975 May;11(5):365-371. <strong>Cancer and altitude. Does intracellular 
pH regulate cell division?</strong> Burton AC.<strong> </strong></p>

<p><strong>Monaldi 
Arch Chest Dis 1999 Aug;54(4):365-72.  The 
pathophysiology of hyperventilation syndrome. 
Folgering H.</strong> Dept Pulmonology Dekkerswald, University of Nijmegen, 
Groesbeek, The Netherlands.. <strong>Hyperventilation is defined as breathing 
in excess of the metabolic needs of the body, eliminating more carbon 
dioxide than is produced, and, consequently, resulting in respiratory 
alkalosis and an elevated blood pH.</strong> The traditional definition of 
hyperventilation syndrome describes &quot;a syndrome, characterized 
by a variety of somatic symptoms induced by physiologically inappropriate 
hyperventilation and usually reproduced by voluntary hyperventilation&quot;. 
The spectrum of symptoms ascribed to hyperventilation syndrome is extremely 
broad, aspecific and varying. They stem from virtually every tract, 
and can be caused by physiological mechanisms such as low Pa,CO2, or 
the<strong> increased sympathetic adrenergic tone.</strong> Psychological mechanisms 
also contribute to the symptomatology, or even generate some of the 
symptoms. Taking the traditional definition of hyperventilation syndrome 
as a starting point, there should be three elements to the diagnostic 
criterion: 1) the patient should hyperventilate and have low Pa,CO2, 
2) somatic diseases causing hyperventilation should have been excluded, 
and 3) the patient should have a number of complaints which are, or 
have been, related to the hypocapnia. Recent studies have questioned 
the tight relationship between hypocapnia and complaints. However, the 
latter can be maintained and/or elicited when situations in the absence 
of hypocapnia in which the first hyperventilation and hypocapnia was 
present recur. Thus, the main approach to diagnosis is the detection 
of signs of (possible) dysregulation of breathing leading to hypocapnia. 
The therapeutic approach to hyperventilation syndrome has several stages 
and/or degrees of intervention: psychological counselling, physiotherapy 
and relaxation, and finally drug therapy. Depending on the severity 
of the problem, one or more therapeutic strategies can be chosen.</p>
<p>N 
Engl J Med 1977 Mar 17;296(11):581-585.<strong> Reduction in mortality from 
coronary heart disease in men residing at high altitude.</strong> Mortimer 
EA Jr, Monson RR, MacMahon B In New Mexico, where inhabited areas vary 
from 914 to over 2135 m above sea level, we compared age-adjusted mortality 
rates for arteriosclerotic heart disease for white men and women for 
the years 1957-1970 in five sets of counties, grouped by altitude in 
305-m (1000-foot) increments. The results show a serial decline in mortality 
from the lowest to the highest altitude for males but not for females. 
Mortality rates for males residing in the county groups higher than 
1220 m in order of ascending altitude <strong>were 98, 90, 86 and 72 per 
cent of that for the county group below 1220-m altitude (P less than 
0.0001).</strong> The results do not appear to be explained by artifacts 
in ascertainment, variations in ethnicity or urbanization. A possible 
explanation of the trend is that adjustment to residence at high altitude 
is incomplete and daily activities therefore represent greater exercise 
than when undertaken at lower altitudes. </p>

<p>Br 
Med J 1980 Jan 5;280(6206):5.  Cardiovascular mortality and altitude.</p>
<p>Radiat 
Res 1987 Nov;112(2):381-390.  <strong>Altitude, radiation, and mortality 
from cancer and heart disease.</strong> Weinberg CR, Brown KG, Hoel DG. The 
variation in background radiation levels is an important source of information 
for estimating human risks associated with low-level exposure to ionizing 
radiation. Several studies conducted in the United States, correlating 
mortality rates for cancer with estimated background radiation levels, 
found an unexpected inverse relationship. Such results have been interpreted 
as suggesting that low levels of ionizing radiation may actually confer 
some benefit. An environmental factor strongly correlated with background 
radiation is altitude. Since there are important physiological adaptations 
associated with breathing thinner air, such changes may themselves influence 
risk. We therefore fit models that simultaneously incorporated altitude 
and background radiation as predictors of mortality. The <strong>negative 
correlations with background radiation</strong> seen for <strong>mortality from 
arteriosclerotic heart disease and cancers of the lung, the intestine, 
and the breast</strong> disappeared or became positive once altitude was 
included in the models. <strong>By contrast, the significant negative 
correlations with altitude persisted with adjustment for radiation. 
Interpretation of these results is problematic, but recent evidence 
implicating reactive forms of oxygen in 
carcinogenesis and atherosclerosis may be relevant. We conclude that 
the cancer correlational studies carried out in the United States using 
vital statistics data do not in themselves demonstrate a lack of carcinogenic 
effect of low radiation levels, and that reduced oxygen pressure of 
inspired air may be protective against certain causes of death. </strong></p>
<p>Biull 
Eksp Biol Med 1993 Jun;115(6):576-578.  <strong>[The effect of high-altitude 
ecological and experimental stresses on the 
thrombocyte-vascular wall system].</strong> [Article in Russian]. Bekbolotova 
AK, Lemeshenko VA, Aliev MA. Experiments in animals (rats) and examinations 
of the population of high-altitude shepherds were used to study the 
functional system &quot;Thrombocytes-Vessel Wall&quot; (STVW) for evaluation 
of the organism ecological adaptation to &quot;pure&quot; high-altitude 
stress, with and without combination with experimental-adrenergic cardionecrosogenic 
stress (ACNS, in rats). The adaptive increase of antiaggregation prostacyclin 
activity of the aorta in rats and PGI2 reaction of vessels in human 
population of high-altitude in mountains (2000, 3000-3500 m) were found 
to be a common biologist regularity. The<strong> adaptive increase of coronary 
reserve of the heart and vasodilatator-antiaggregation status in high-altitude 
shepherds correlated with an increase of 
antiaggregation activity of the aorta and decrease of spontaneous aggregation 
of the thrombocytes in rats under conditions of more prolonged adaptation 
to high-altitude ecological stress. </strong></p>

<p>Diabetologia 
1982 Jun;22(6):493. <strong>Measurement of 
glycosylated haemoglobin at high altitudes.</strong> Paisey R, Valles V, 
Arredondo G, Wong B, Lozano-Castaneda O.</p>
<p><strong>[Change 
in the ultrastructure of rat myocardium under the influence of 12-months' 
adaptation to high altitude]</strong>  Zhaparov B; Mirrakhimov MM.  
Biull Eksp Biol Med, 1977 Jul, 84:7, 109-12. The right and left ventricle 
myocardium of rats was studied in the course of a 12-month period of 
adaptation to high altitude (3200 m above the sea level). A long-term 
exposure of the animals to the high altitude led the development of 
ventricular hypertrophy mostly of the right, and partly of the left 
ventricle.<strong> Hyperplasia and hypertrophy of individual 
organellae, particularly mitochondria</strong>, were found in most cardiomyocytes 
of both ventricles. In animals adapted to the high altitude the mitochondrial 
succinic dehydrogenase activity was more pronounced than in control 
ones. The results obtained testified to the enhanced intracellular metabolism 
reflecting myocardial compensatory adaptive responses. </p>
<p><strong>[Morphologic 
characteristics of the hearts of argali continuously dwelling at high 
mountain altitudes]</strong>, Zhaparov B; Kamitov SKh; Mirrakhimov MM, Biull 
Eksp Biol Med, 1980 Apr, 89<strong>:</strong>4, 498-501  The hearts of argali 
[wild sheep] living at 3800-5000 m above the sea level were examined.<strong>  
Macroscopy showed complete absence of fatty tissue under the 
epicardium.</strong>  Increased number of the capillaries surrounding 
cardiomyocytes, intercalated discs in many zones of the myocardium, 
sharp thickening giving pronounced cross lines of myofibrils were revealed 
on semithin and ultrathin sections. The data obtained demonstrate specificity 
of the heart structure of argali and are<strong> discussed from the standpoint 
of increased compensatory-adaptive changes in the test organ, these 
changes being associated with its enhanced function provoked by high 
altitude conditions. </strong></p>

<p>J 
Dev Physiol 1990 Sep;14(3):139-46. <strong>Effect of lactate and 
beta-hydroxybutyrate infusions on brain metabolism in the fetal sheep.</strong> 
Harding JE, Charlton VE Department of Pediatrics, University of California, 
San Francisco 94143.  Brain uptake of substrates other than glucose 
has been demonstrated in neonatal but not fetal animals in vivo. This 
study was undertaken to investigate the ability of the fetal sheep brain 
to use potential alternative substrates when they were provided in increased 
amounts. Brain substrate uptake was measured in chronically catheterised 
fetal sheep during 2-h infusions of neutralised lactate (n = 12) or 
beta-hydroxybutyrate (n = 12). <strong>Despite large increases in fetal arterial 
lactate and beta-hydroxybutyrate during the respective infusions, no 
significant uptake of either substrate was demonstrated. However during 
both types of infusion, the brain arterio-venous difference for glucose 
decreased 30% (P less than 0.05). Since the brain 
arterio-venous difference for oxygen was unchanged, and blood flow to 
the cerebral hemispheres (measured in 11 studies) was also unchanged, 
the infusions appeared to cause a true decrease in brain glucose uptake. 
This decrease paralleled the rise in lactate concentration during lactate 
infusions, and the rise in lactate and butyrate</strong> concentrations during 
the butyrate infusions. Both substrates have metabolic actions that 
may inhibit brain glucose uptake. <strong>We speculate that the deleterious 
effects of high lactate and ketone states in the 
perinatal period may in part be due to inhibition of brain glucose uptake.</strong></p>
<p>Hypertens 
1995 Feb;9(2):119-22. <strong> Pressor effect of hyperventilation in healthy 
subjects.</strong> Todd GP, Chadwick IG, Yeo WW, Jackson PR, Ramsay LE University 
Department of Medicine and Pharmacology, Royal Hallamshire Hospital, 
Sheffield, UK Hyperventilation is an important feature of panic disorder, 
and an association has been reported between panic disorder and hypertension. 
We have examined the effect of hyperventilation on the blood pressure 
(BP) of healthy subjects. Twenty six subjects were randomised in a balanced 
two-period cross-over study to compare the effects of hyperventilation 
with that of normal breathing on sitting BP, heart rate and the electrocardiogram. 
Each study phase lasted 40 min, with 15 min of baseline observation, 
5 min of hyperventilation or normal breathing, and 20 min of continued<strong> 

observation. Hyperventilation significantly increased 
SBP by 8.9 mm Hg (95% CI 3.8-13.8, P &lt; 0.01), diastolic blood pressure 
by 8.2 mm Hg (95% CI 1.7-14.7, P &lt; 0.05), mean arterial pressure 
by 10.0 mm Hg (95% CI 3.3-16.7, P &lt; 0.01) and heart rate by 36 beats/min 
(95% CI 31-44, P &lt; 0.01). The changes in diastolic and mean arterial 
pressure correlated significantly with the total</strong> volume of air expired 
during hyperventilation (r = 0.57, p &lt; 0.01 and r = 0.50 P &lt; 0.01, 
Arch Biol Med Exp (Santiago) 1989 Dec;22(4):379-85  Pulmonary response 
to free fatty acid intravenous infusion in the rabbit: role of leukotrienes 
and the effect of prostacyclin. Arenas G, Del Buono R, Oyarzun MJ, Donoso 
P, Quijada D Departamento de Ciencias Preclinicas, Facultad de Medicina, 
Universidad de Chile, Santiago. <strong> Intravenous infusion of free fatty 
acid (FFA) 20 mg.kg-1.min-1 produces pulmonary edema, 
hypoxemia, hyperventilation and increase in the alveolar surfactant 
content in rabbits in less than 15</strong> min. </p>

<p>Respiration 
1986;49(3):187-94. <strong>Role of hypocapnia in the alveolar surfactant 
increase induced by free fatty acid intravenous infusion in the rabbit.</strong> 
Oyarzun MJ, Donoso P, Quijada D<strong>.  Intravenous infusion of free 
fatty acid (FFA) produces an increase in the alveolar surfactant pool 
of the rabbit and pulmonary edema, hyperventilation, 
hypoxemia and hypocapnia. Previous studies suggested that alveolar 
PCO2 would be a regulator of intracellular 
storages of surfactant. In order to</strong> study the role of hypocapnia 
in the increase of lung surfactant in our experiments we administered 
20 mg FFA X kg-1 X min-1 i.v. to rabbits breathing room air (n = 10) 
or 5% CO2, 21% O2, 74% N2 (n = 7). Disaturated phosphatidylcholine (DSPC) 
was determined in bronchial-alveolar lavage fluid as index of alveolar 
surfactant content, 5% CO2 in the inspired air prevented the hypocapnia 
and blocked the increase in DSPC induced by FFA (p less than 0.01). 
Pulmonary edema post-FFA was not changed by 5% CO2 administration. We 
conclude that hypocapnia produced by hyperventilation during FFA infusion 
would be an important factor in the increase of DSPC observed after 
FFA infusion. </p>
<p>Farmakol 
Toksikol 1977. Sep-Oct; 40(5):620-3..<strong>  [Effect of combinations 
of apressin, obsidan, diprazin, adenosine, 
NAD and nicotinamide on the resistance of rats to 
hypoxia and on carbohydrate metabolic indices].</strong> [Article in Russian] 
Abakumov GZ As evidenced from experiments on rats, a combined application 
of apressin with obsidan and diprazine, and also of adenozine with nicotine-amidadenine-dinucleotide 
(NAD), as well as of adeozine with nicotine amide potentiates the protective 
effect of these substances in hypobaric hypoxia, increases the resistance 
of the animals to cerebral ischemia, <strong>brings down the excess lactate 
level and raises the redoz potential of the system 
lactic-acid-pyruvic</strong> acid in the brain of rats exposed to the effects 
of rarefied atmosphere.</p>

<p>Schweiz 
Med Wochenschr 1977 Nov 5;107(44):1585-6. <strong>[Protective effect of 
pyridoxilate on the hypoxic myocardium. Experimental studies].</strong> [Article 
in French]  Moret PR, Lutzen U The protective action of piridoxilate 
on hypoxic myocardium has been studied on rats in acute hypoxia (isolated 
heart, perfused with a non-oxygenated solution) and in prolonged hypoxia 
(3 days at high [3454 m] altitude). Piridoxilate maintained a higher 
ATP level with a much lower production of lactate. <strong>The mechanisms 
of action of piridoxilate are probably fairly similar to those of 
Na dichloracetate</strong>.</p>
<p>J. 
Appl Physiol 1991 Apr;70(4):1720-30. .<strong>Metabolic and work efficiencies 
during exercise in Andean natives.</strong> Hochachka PW, Stanley C, Matheson 
GO, McKenzie DC, Allen PS, Parkhouse WS Department of Zoology, University 
of British Columbia, Vancouver, Canada. <strong> Maximum O2 and 
CO2 fluxes during exercise were less perturbed by 
hypoxia in Quechua natives</strong> from the Andes than in lowlanders. In 
exploring how this was achieved, we found that, <strong>for a given work 
rate, Quechua highlanders at 4,200 m accumulated substantially less 
lactate </strong>than lowlanders at sea level normoxia (approximately 5-7 
vs. 10-14 mM) despite hypobaric hypoxia. This phenomenon, known as the 
lactate paradox, was entirely refractory to normoxia-hypoxia transitions. 
In lowlanders, the lactate paradox is an acclimation; however, in Quechuas, 
the lactate paradox is an expression of metabolic organization that 
did not deacclimate, at least over the 6-wk period of our study. Thus 
it was concluded that this metabolic organization is a developmentally 
or genetically fixed characteristic selected because of the <strong>efficiency 
advantage of aerobic metabolism (high ATP yield per 
mol of substrate metabolized) compared with anaerobic 
glycolysis.</strong> Measurements of respiratory quotient indicated preferential 
use of carbohydrate as fuel for muscle work, which is also advantageous 
in hypoxia because it maximizes the yield of ATP per mol of O2 consumed. 
Finally, minimizing the cost of muscle work was also reflected in energetic 
efficiency as classically defined (power output per metabolic power 
input);<strong> this was evident at all work rates but was most pronounced 
at submaximal work rates (efficiency approximately 1.5 times higher 
than in lowlander athletes).</strong> Because plots of power output vs. metabolic 
power input did not extrapolate to the origin, it was concluded 1) that 
exercise in both groups sustained a significant ATP expenditure not 
convertible to mechanical work but 2) that this expenditure was downregulated 
in Andean natives by thus far unexplained mechanisms. </p>

<p>Br 
J Anaesth 1975 Jun;47(6):669-78. <strong>Effect of 
CO2 on myocardial contractility and aortic input impedance during 
anaesthesia.</strong> Foex P, Prys-Roberts C. The haemodynamic responses 
to hypocapnia and hypercapnia have been studied in the dog during intermittent 
positive pressure ventilation under halothane anaesthesia (1% halothane 
in oxygen) and under nitrous oxide anaesthesia (30% oxygen in nitrous 
oxide). In the absence of significant<strong> variations of either myocardial 
contractility or left ventricular end-diastolic pressure, the changes 
of stroke volume and cardiac output (diminution because of 
hypocapnia, augmentation because of 
hypercapnia) were determined by alterations of systemic vascular resistance 
(augmentation because of hypocapnia, diminution because of 
hypercapnia). </strong></p>
<p>J 
Appl Physiol 1991 May;70(5):1963-76.<strong> Skeletal muscle metabolism and 
work capacity: a 31P-NMR study of Andean natives and 
lowlanders.</strong> Matheson GO, Allen PS, Ellinger DC, Hanstock CC, Gheorghiu 
D, McKenzie DC, Stanley C, Parkhouse WS, Hochachka PW Sports Medicine 
Division, University of British Columbia, Vancouver, Canada.  Two 
metabolic features of altitude-adapted humans are the <strong>maximal O2 
consumption (VO2max) paradox (higher work rates following acclimatization 
without increases in VO2max) </strong>and the lactate paradox (progressive 
reductions in muscle and blood lactate with exercise at increasing altitude). 
To</p>

<p>J 
Hum Hypertens 1995 Feb;9(2):119-22.<strong> 
Pressor effect of hyperventilation in healthy 
subjects.</strong>Todd GP, Chadwick IG, Yeo WW, Jackson PR, Ramsay LE.</p>
<p>J 
Infect Dis 1998 May;177(5):1418-21.<strong>The effect of lactic acid on mononuclear 
cell secretion of proinflammatory cytokines in response to group B streptococci.</strong> 
Steele PM, Augustine NH, Hill HR Department of Pathology, University 
of Utah School of Medicine, Salt Lake City 84132, USA.<strong>This study 
found that lactate alone had a stimulatory effect (207.1 +/- 16.3%; 
P = .001) on tumor necrosis factor 
(TNF)-alpha production by human mononuclear cells with the most profound 
secretion being at pathologic concentrations of 4-8 
mM lactate. Furthermore, exposure of these mononuclear cells to group 
B streptococci (GBS, 10(5) cfu) resulted in 
TNF-alpha production of up to 621.1 +/- 42% of control; the combination 
of lactic acid and GBS increased TNF-alpha production up to 1019.3 +/- 
16.1% (P = .001). The combination of 
GBS and lactate also enhanced the secretion of 
interleukin (IL)-1beta and IL-6. Lactate in pathologic concentrations, 
therefore, likely enhances the secretion of these inflammatory mediators 
and contributes to septic shock and meningitis caused by 
GBS. </strong></p>
<p>J 
Appl Physiol 1994 Apr;76(4):1462-7<strong>.</strong> Lactic acidosis as a facilitator 
of oxyhemoglobin dissociation during exercise.  Stringer W, Wasserman 
K, Casaburi R, Porszasz J, Maehara K, French W.</p>

<p><strong>Involvement 
of nitric oxide and N-methyl- D-aspartate in acute hypoxic altitude 
convulsion in mice. </strong>Chen CH; Chen AC; Liu HJ. Aviat Space Environ 
Med, 1997 Apr, 68:4, 296-9. “Altitude convulsion is a rather specific 
form of experimental convulsion which is induced by acute exposure to 
a hypobaric hypoxic condition. Several neurotransmitters have been shown 
to be involved in the mechanisms of altitude convulsions.” “The 
novel neurotransmitter nitric oxide (NO) may be involved in the mechanisms 
of altitude convulsion through its neuronal signalling roles in relation 
to the NMDA receptor.”  <strong>“NO synthesis precursor, L-arginine 
(20, 40, 200, 800 mg/kg), resulted in a dose-dependent decrease in the 
ACT in mice, while the NO synthase (NOS) inhibitor, NG-nitro-L-arginine-methyl 
ester (L-NAME, 1.25, 2.50, 5.00 mg/kg, i.p.) increased the ACT.”</strong> 
“CONCLUSIONS: These findings suggest an important signalling role 
for nitric oxide and NMDA in the development of altitude convulsion 
and further support the hypothesized relationship between NMDA-receptor 
mediated neurotoxicity and nitric oxide.”<strong> </strong></p>
<p><strong>Excitotoxicity 
in the lung: N-methyl-D-aspartate- induced, nitric oxide-dependent, 
pulmonary edema is attenuated by vasoactive intestinal peptide and by 
inhibitors of poly(ADP-ribose) polymerase. </strong>
Said SI; Berisha HI; Pakbaz H.  Proc Natl Acad Sci U S A, 1996 
May 14, 93:10, 4688-92. <strong>“Excitatory amino acid toxicity, resulting 
from overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors, 
is a major mechanism of neuronal cell death in acute and chronic neurological 
diseases. We have investigated whether excitotoxicity may occur in peripheral 
organs, causing tissue injury, and report that NMDA receptor activation 
in perfused, ventilated rat lungs triggered acute injury, marked by 
increased pressures needed to ventilate and perfuse the 
lung, and by high-permeability edema.&quot;</strong> The injury was prevented 
by competitive NMDA receptor antagonists or by channel-blocker MK-801, 
and <strong>was reduced in the presence of Mg2+.</strong> As with NMDA toxicity 
to central neurons, the lung injury was nitric oxide (NO) dependent: 
it <strong>required L-arginine, was associated with increased production 
of NO,</strong> and was attenuated by either of two NO synthase inhibitors. 
The neuropeptide<strong> </strong>vasoactive intestinal peptide and<strong> inhibitors 
of poly(ADP-ribose) polymerase also prevented this injury, but without 
inhibiting NO synthesis, both acting by inhibiting a toxic action of 
NO that is critical to tissue injury.  </strong>

The findings indicate that: (i) NMDA receptors exist in the lung (and 
probably elsewhere outside the central nervous system), (ii) excessive  
activation of these receptors may provoke acute edematous lung injury 
as seen in the &quot;adult respiratory distress syndrome,&quot; and 
(iii) this injury can be modulated by blockade of one of three critical 
steps: NMDA receptor binding, inhibition of NO synthesis, or activation 
of poly(ADP-ribose) polymerase. </p>
<p><strong>Adenosine 
modulates N-methyl-D- aspartate- stimulated hippocampal nitric oxide 
production in vivo. </strong>Bhardwaj A; Northington FJ; Koehler RC; Stiefel 
T; Hanley DF; Traystman RJ. Stroke, 1995 Sep, 26:9, 1627-33.  &quot;Adenosine 
acts presynaptically to inhibit release of excitatory amino acids (EAAs) 
and is thus considered to be neuroprotective. Because EAA-stimulated 
synthesis of nitric oxide (NO) may play an important role in long-term 
potentiation and excitotoxic-mediated injury, we tested the hypotheses 
that adenosine agonists attenuate basal and EAA-induced NO production 
in the hippocampus in vivo and that adenosine A1 receptors mediate this 
response.&quot; &quot;...these data are consistent with in vitro results 
showing that NMDA receptor stimulation enhances NO production. Furthermore, 
we conclude that stimulation of A1 receptors can attenuate the basal 
as well as NMDA-induced production of NO. Because NMDA receptor stimulation 
amplifies glutamate release, our data are consistent with presynaptic 
A1 receptor-mediated inhibition of EAA release and consequent downregulation 
of NO production.&quot; </p>
<p>Anesthesiology 
1993 Jan;78(1):91-9.<strong>  Hypocapnia worsens arterial blood oxygenation 
and increases VA/Q heterogeneity in canine pulmonary edema.</strong> Domino 
KB, Lu Y, Eisenstein BL, Hlastala MP. University of Washington Medical 
School, Seattle. &quot;Hyperventilation frequently is employed to reduce 
carbon dioxide partial pressure in patients in the operating room and 
intensive care unit. However the effect of hypocapnia on oxygenation 
is complex and may result in worsening in patients with preexisting 
intrapulmonary shunt.&quot; &quot;Both hypocapnia and hypercapnia were 
associated with an increased VA/Q inequality. However, PaO2 decreased 
and P[A-a]O2 increased with only hypocapnia. These results suggest that 
hyperventilation to reduce PaCO2 may be detrimental to arterial PO2 
in some patients with lung disease.&quot;</p>

<p><strong>Acta 
Anaesthesiol Scand 1996 Jan;40(1):133-4  
Hyperlactatemia associated with hypocarbic 
hyperventilation. Cheung PY</strong></p>
<p>Am 
J Physiol 1999 May;276(5 Pt 1):E922-9  Hyperlactatemia reduces 
muscle glucose uptake and GLUT-4 mRNA while increasing (E1alpha)PDH 
gene expression in rat. Lombardi AM, Fabris R, Bassetto F, Serra R, 
Leturque A, Federspil G, Girard J, Vettor R Endocrine Metabolic Laboratory, 
Department of Medical and Surgical Sciences, University of Padova, 35100 
Padova, Italy. <strong> An increased basal plasma lactate concentration is 
present in many physiological and pathological conditions, including 
obesity and diabetes. We previously demonstrated that acute lactate 
infusion in rats produced a decrease in overall glucose uptake.</strong> 
The present study was carried out to further investigate the effect 
of lactate on glucose transport and utilization in skeletal muscle. 
In chronically catheterized rats, a 24-h sodium lactate or bicarbonate 
infusion was performed. To study glucose uptake in muscle, a bolus of 
2-deoxy-[3H]glucose was injected in basal condition and during euglycemic-hyperinsulinemic 
clamp. Our results show that hyperlactatemia decreased glucose uptake 
in muscles (i.e., red quadriceps; P &lt; 0.05). Moreover in red muscles, 
both GLUT-4 mRNA (-30% in red quadriceps and -60% in soleus; P &lt; 
0.025) and protein (-40% in red quadriceps; P &lt; 0.05) were decreased, 
whereas the (E1alpha)pyruvate dehydrogenase (PDH) mRNA was increased 
(+40% in red quadriceps; P &lt; 0.001) in lactate-infused animals. PDH 
protein was also increased (4-fold in red gastrocnemius and 2-fold in 
red quadriceps). These results indicate that <strong>chronic 
hyperlactatemia</strong> reduces glucose uptake by affecting the expression 
of genes involved in glucose metabolism in muscle, suggesting a role 
for lactate in t<strong>he development of insulin resistance.</strong></p>

<p>Radiat 
Res 1993 Apr;134(1):79-85 <strong>Effects of in 
vivo heart irradiation on myocardial energy metabolism in rats.</strong> 
Franken NA, Hollaar L, Bosker FJ, van Ravels FJ, van der Laarse A, Wondergem 
J Department of Clinical Oncology, University Hospital, Leiden, The 
Netherlands. To investigate the effect of in vivo heart irradiation 
on myocardial energy metabolism, we measured myocardial adenosine nucleotide 
concentrations and mitochondrial oxygen consumption in left ventricular 
tissue of rats 0-16 months after local heart irradiation (20 Gy). At 
24 h and 2 months no difference in myocardial adenosine nucleotide concentration 
was apparent between irradiated and control hearts. The total myocardial 
adenosine nucleotide concentrations in irradiated hearts compared to 
those of nonirradiated controls tended to be lower from 4 months onward. 
The rate of<strong> oxidative energy production (state 3 respiration) in 
irradiated hearts was significantly reduced 
ompared with that of age-matched controls from 2 months onward. Moreover, 
as a result of aging,  time-dependent decrease in the rate of oxidative 
energy production was observed in both 
rradiated and control hearts </strong>(P &lt; 0.001). The respiratory control 
index (RCI = oxygen consumption n state 3/oxygen consumption in state 
4) in irradiated hearts was not different from the RCI easured in age-matched 
control animals. During the period of study the RCI diminished significantly 
wth age in both groups (P &lt; 0.005). The number of oxygen atoms used 
per molecule of ADP phosphorylated (P/O ratio) was not influenced by 
the irradiation. The P/O ratio for the AD(+)-linked substrates remained 
unchanged at a value of about 3 during the period studied. At 6 months 
after irradiation activities of myocardial enzymes such as lactate dehydrogenase, 
creatine kinase, citrate synthase, and cytochrome c oxidase were reduced. 
The reduction in myocardial energy production and the <strong>changes in 
energy supplies provide a mechanism to explain impaired contractility 
after local heart irradiation. </strong></p>
<p>J 
Radiat Res (Tokyo) 1993 Sep;34(3):195-203.<strong> 

Radiosensitization of human lung fibroblasts by chemical that decrease 
ATP levels. </strong>Kumar A, Kimura H, Aoyama T.<strong> 
&quot;Radiosensitization by lactate, 
pyruvate, nalidixic acid and novobiocin was studied in exponentially 
growing SH-18L human lung fibroblasts. All the chemicals had a slight 
radiosensitizing effect at a low concentration and a definite effect 
at a higher one.&quot; &quot;Fibroblasts incubated with the low concentration 
of each chemical for 24 hrs after X irradiation showed no reduction 
in intracellular ATP content, whereas, the higher concentration produced 
a significant decrease. </strong>These observations suggest that the decrease 
in the ATP content may be involved in the radiosensitization of human 
fibroblasts at high concentrations of these chemicals.<strong> In contrast, 
radiosensitization at a low concentration is not explained by a relationship 
to ATP content. Different mechanisms may be involved in 
radiosensitization at low and high concentrations of these chemicals.&quot;</strong></p>
<p>J 
Exp Med 1993 May 1;177(5):1391-8.  <strong>Enhancement of experimental 
metastasis by tumor necrosis factor.</strong> Orosz P, Echtenacher B, Falk 
W, Ruschoff J, Weber D, Mannel D.N. Institute for Immunology and Genetics, 
German Cancer Research Center, Heidelberg. &quot;The influence of endogenous 
and exogenous tumor necrosis factor (TNF) on metastasis was investigated 
in an experimental fibrosarcoma metastasis model.&quot; &quot;This effect 
was time dependent, as administration of rmTNF 5 h before or 1 h but 
not 24 h after tumor cell inoculation caused an increase of tumor cell 
colony formation on the lung surface, suggesting an influence of TNF 
on the vascular adhesion and diapedesis of tumor cells. Since tumor-bearing 
mice showed an enhanced ability to produce TNF after endotoxin injection 
compared to control mice, tumor-bearing mice were treated with anti-mTNF 
antibodies. Neutralization of endogenous tumor-induced TNF led to a 
significant decrease of the number of pulmonary metastases.  Histological 
analysis of micrometastases in the lung on day 5 by silver staining 
of proteins associated with nucleolar organizer regions revealed <strong>

more metastatic foci and augmented 
proliferative activity of the tumor cells after </strong><strong>rmTNF 
pretreatment of mice.</strong> However, no direct effect of rmTNF on the 
proliferation rate of tumor cells was seen in vitro.&quot;</p>
<p>Nippon 
Geka Gakkai Zasshi 1996 Sep;97(9):726-32.<strong> [Energy substrate metabolism 
during stress]. </strong> Sugimoto H. Department of Traumatology and Critical 
Care Medicine, Osaka University School of Medicine, Suita, Japan.<strong>  
&quot;Energy substrate metabolism during stress is characterized by 
increased REE (resting energy expenditure), hyperglycemia, 
hyperlactatemia and protein catabolism. This stress-induced 
hypermetabolic responses are closely related to increased secretion 
of neurohormonal and cytokine mediators. The insulin resistance hyperglycemia 
has been called &quot;stress diabetes&quot; or 'surgical diabetes.' 
Glucose disposal has been thought to be impaired in this condition.&quot; 

&quot;This hyperglycemia in stress diabetes results from a 
postreceptor mechanism. Stress hyperlactatemia is thought to be caused 
by decreased pyruvate dehydrogenase activity rather than tissue 
hypoperfusion.&quot;</strong></p>
<p><em>Clin 
Physiol 1995 Nov;15(6):581-95. </em>
<strong><em>Effects of lactate infusion on hepatic 
gluconeogenesis and glycogenolysis.</em></strong><em> 
Haesler E, Schneiter P, Temler E, Jequier E, 
Tappy L.</em></p>
<p><em>Cancer 
Res 1993 Apr. 15;53(8):1939-44.. </em><strong><em>Tumor 
necrosis factor alpha as an autocrine and 
paracrine growth factor for ovarian cancer: 
monokine induction of tumor cell proliferation and tumor necrosis factor 
alpha expression.</em></strong><em> Wu S, 
Boyer CM, Whitaker RS, Berchuck A, Wiener 
JR, Weinberg JB, Bast RC Jr.</em></p>
<p>Klin 
Med (Mosk) 1989 May;67(5):38-41<strong>. [&quot;Dry&quot; carbon dioxide 
baths in treating patients with myocardial infarction at the 
sanatorium stage of rehabilitation]. </strong>

[Article in Russian] Barashkova NL, Kartamysheva NL, Krasnova VP, Kriuchkova 
LN, Miasoedova E.S. A group of 75 patients with a history of myocardial 
infarction and repeated myocardial infarction were subjected to treatment 
involving dry carbon dioxide baths. Its results demonstrated normalization 
of IHD manifestations, such as coronary and heart failure, functional 
state of the cardiovascular system, its reserve potentialities and adaptation 
to physical effort. Under the influence of a course treatment with dry 
carbon dioxide baths hemodynamic parameters of cardiac output (cardiac 
and stroke volume) underwent favourable changes, rhythm slowed down, 
diastole became longer and systolic and diastolic arterial pressure 
decreased. The data obtained substantiate application of dry carbon 
dioxide baths in the recovery period to I-III functional classes patients 
with a history of myocardial infarction. </p>
<p>J 
Dev Physiol 1989 Nov;12(5):283-6. <strong>Haemodynamic effects of respiratory 
alkalosis independent of changes in airway pressure in anaesthetized 
newborn dogs.</strong> Reuter JH, Donovan EF, Kotagal U.R. <strong>&quot;We have 
recently reported a decrease in cardiac output in newborn dogs during 
respiratory alkalosis which is independent of changes in airway pressure.&quot;</strong></p>
<p>Undersea 
Hyperb Med 1994 Jun;21(2):169-83. <strong>Influence of 
hyperbaric oxygen on left ventricular contractility, total coronary 
blood flow, and myocardial oxygen consumption in the conscious dog. </strong>
Savitt MA, Rankin JS, Elberry JR, Owen CH, Camporesi E.M. <strong>&quot;It 
is known that hyperbaric oxygenation (HBO) decreases total coronary 
blood flow (TCBF) and cardiac output (CO).&quot;</strong></p>
<p><strong><em>Heart 
rhythm disturbances in the inhabitants of mountainous regions.</em></strong><em>  
Mirrakhimov MM; Meimanaliev TS  
Cor Vasa, 1981, 23:5, 359-65. </em><strong><em>&quot;During exercise heart 
arrhythmias</em></strong><strong><em> 

appeared conspicuously less frequently in the high mountain than in 
the low altitude inhabitants.&quot; </em></strong> 
</p>
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