Of all humans thus far studied, Sherpas are considered by many high-altitude biomedical scientists as most exquisitely adapted for life under continuous hypobaric hypoxia. However, little is known about how the heart is protected in hypoxia. Hypoxia defense mechanisms in the Sherpa heart were explored by in vivo, noninvasive 31p magnetic resonance spectroscopy. Six Sherpas were examined under two experimental conditions [normoxic (21% FiO2) and hypoxic (11% FiO2)] and in two adaptational states-the acclimated state (on arrival at low-altitude study sites) and the deacclimating state (4 weeks of ongoing exposure to low altitude). Four lowland subjects were used for comparison. We found that the concentration ratios of phosphocreatine (PCr)/adenosine triphosphate (ATP) were maintained at steady-state normoxic values (0.96, SEM = 0.22) that were about half those found in normoxic lowlanders (1.76, SEM = 0.03) monitored the same way at the same time. These differences in heart energetic status between Sherpas and lowlanders compared under normoxic conditions remained highly significant (P < 0.02) even after 4 weeks of deacclimation at low altitudes. In Sherpas under acute hypoxia, the heart rate increased by 20 beats per min from resting values of about 70 beats per min, and the percent saturation of hemoglobin decreased to about 75%. However, these perturbations did not alter the PCr/ATP concentration ratios, which remained at about 50% of the values expected in healthy lowlanders. Because the creatine phosphokinase reaction functions close to equilibrium, these steady-state PCr/ATP ratios presumably coincided with about 3-fold higher free adenosine diphosphate (ADP) concentrations. Higher ADP concentrations (i.e., lower [PCr]/ [ATP] ratios) were interpreted to correlate with the Km values for ADP-requiring kinases of glycolysis and to reflect elevated carbohydrate contributions to heart energy needs. This metabolic organization is postulated as advantageous in hypobaria because the ATP yield per 02 molecule is 25-60% higher with glucose than with free fatty acids (the usual fuels utilized in the human heart in postfasting conditions).Heart disease does not develop instantaneously. During early stages in disease development, it therefore is probable that the biochemical responses of the heart are initially "protective" or adaptive, designed to sustain normal organ function in the face of increasingly serious 02 limitation. That certainly is the case in many animal species adapted through phylogenetic time for surviving hypoxic conditions (1-4), and there is no reason to believe that the fundamental processes would not be similar in humans. What then is the nature of such defensive adaptationsThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. in the human species and when do the biochemical responses of the heart stop being adaptive or protective and s...

There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.

Summary: The brain of hypoxia-tolerant vertebrates is known to survive extreme limitations of oxygen in part because of very low rates of energy production and utili zation. To assess if similar adaptations may be involved in humans during hypoxia adaptation over generational time, volunteer Quechua natives, indigenous to the high Andes between about 3,700 and 4,900 m altitude, served as subjects in positron emission tomographic measure ments of brain regional glucose metabolic rates. Two met abolic states were analyzed: (a) the presumed normal (high altitude-adapted) state monitored as soon as possi ble after leaving the Andes and (b) the de acclimated state monitored after 3 weeks at low altitudes. Proton nuclear magnetic resonance spectroscopy studies of the Quechua brain found normal spectra, with no indication of any unusual lactate accumulation; in contrast, in hypoxia-The central nervous system in humans as in most mammals displays surprisingly high mass-specific metabolic rates and is widely considered to be the most hypoxia sensitive organ in the body. For this reason, and because cerebrovascular disease re mains an unacceptably frequent cause of death in modern societies, a very large research interest fo cuses on mechanisms of defense against O2 limita tion in the mammalian brain. Most studies in this area deal with acute (hypoxia or ischemic) exposure and concentrate (a) on mechanism of damage, and 671tolerant species, a relatively large fraction of the glucose taken up by the brain is released as lactate. Positron emis sion tomographic measurements of [18P]2-deoxy-2-fluoro-o-glucose (PDG) uptake rates, quantified in 26 re gions of the brain, indicated systematically lower region by-region glucose metabolic rates in Quechuas than in lowlanders. The metabolic reductions were least pro nounced in primitive brain structures (e.g., cerebellum) and most pronounced in regions classically associated with higher cortical functions (e.g., frontal cortex). These differences between Quechuas with lifetime exposure to hypobaric hypoxia and lowlanders, which seem to be ex pressed to some degree in most brain regions examined, may be the result of a defense adaptation against chronic hypoxia. Key Words: Brain [18P]deoxyglucose-Brain hypoxia adaptation-Brain glucose metabolism.

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The metabolism of glucose in mammalian heart is 25-50% more O2 efficient than the metabolism of free fatty acids. To assess the role of substrate preference in adaptations to chronic hypoxia, positron emission tomographic measurements of heart regional glucose uptake rates after an overnight fast were made in volunteer Quechua subjects and in Sherpa subjects, both indigenous to altitudes of over 3,000 m, and in a group of lowlander volunteers. Highest uptake rates were found in the Quechuas on arrival and in the Sherpas after a 3-wk period at low altitude, intermediate rates in Quechuas after a 3-wk period at low altitude and in the lowlanders, and lowest rates in Sherpas on arrival. These low values were probably related to the stress of travel to the site of the experiments. Measured plasma catecholamines, hormones, and substrates indicated that glucose concentrations correlated best with observed variations in glucose uptake, with a negative correlation for the control subjects and a positive correlation for the Quechuas and Sherpas. Uptake values in Quechuas declined significantly after a 3-wk period at low altitude, but the positive correlation with glucose levels persisted. We conclude that an elevated glucose preference in heart is a true metabolic adaptation in humans adapted over generations to chronic hypoxia.