Michael J. Decker

Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara

Elevated hemoglobin concentrations have been reported for high-altitude sojourners and Andean high-altitude natives since early in the 20th century. Thus, reports that have appeared since the 1970s describing relatively low hemoglobin concentration among Tibetan high-altitude natives were unexpected. These suggested a hypothesis of population differences in hematological response to high-altitude hypoxia. A case of quantitatively different responses to one environmental stress would offer an opportunity to study the broad evolutionary question of the origin of adaptations. However, many factors may confound population comparisons. The present study was designed to test the null hypothesis of no difference in mean hemoglobin concentration of Tibetan and Aymara native residents at 3,800-4,065 meters by using healthy samples that were screened for iron deficiency, abnormal hemoglobins, and thalassemias, recruited and assessed using the same techniques. The hypothesis was rejected, because Tibetan males had a significantly lower mean hemoglobin concentration of 15.6 gm/dl compared with 19.2 gm/dl for Aymara males, and Tibetan females had a mean hemoglobin concentration of 14.2 gm/dl compared with 17.8 gm/dl for Aymara females. The Tibetan hemoglobin distribution closely resembled that from a comparable, sea-level sample from the United States, whereas the Aymara distribution was shifted toward 3-4 gm/dl higher values. Genetic factors accounted for a very high proportion of the phenotypic variance in hemoglobin concentration in both samples (0.86 in the Tibetan sample and 0.87 in the Aymara sample). The presence of significant genetic variance means that there is the potential for natural selection and genetic adaptation of hemoglobin concentration in Tibetan and Aymara high-altitude populations.

An Ethiopian pattern of human adaptation to high-altitude hypoxia

We describe, in Ethiopia, a third successful pattern of human adaptation to high-altitude hypoxia that contrasts with both the Andean “classic” (erythrocytosis with arterial hypoxemia) and the more recently identified Tibetan (normal venous hemoglobin concentration with arterial hypoxemia) patterns. A field survey of 236 Ethiopian native residents at 3,530 m (11,650 feet), 14–86 years of age, without evidence of iron deficiency, hemoglobinopathy, or chronic inflammation, found an average hemoglobin concentration of 15.9 and 15.0 g/dl for males and females, respectively, and an average oxygen saturation of hemoglobin of 95.3%. Thus, Ethiopian highlanders maintain venous hemoglobin concentrations and arterial oxygen saturation within the ranges of sea level populations, despite the unavoidable, universal decrease in the ambient oxygen tension at high altitude.

Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives

Newcomers acclimatizing to high altitude and adult male Tibetan high altitude natives have increased ventilation relative to sea level natives at sea level. However, Andean and Rocky Mountain high altitude natives have an intermediate level of ventilation lower than that of newcomers and Tibetan high altitude natives although generally higher than that of sea level natives at sea level. Because the reason for the relative hypoventilation of some high altitude native populations was unknown, a study was designed to describe ventilation from adolescence through old age in samples of Tibetan and Andean high altitude natives and to estimate the relative genetic and environmental influences. This paper compares resting ventilation and hypoxic ventilatory response (HVR) of 320 Tibetans 9-82 years of age and 542 Bolivian Aymara 13-94 years of age, native residents at 3,800-4,065 m. Tibetan resting ventilation was roughly 1.5 times higher and Tibetan HVR was roughly double that of Aymara. Greater duration of hypoxia (older age) was not an important source of variation in resting ventilation or HVR in either sample. That is, contrary to previous studies, neither sample acquired hypoventilation in the age ranges under study. Within populations, greater severity of hypoxia (lower percent of oxygen saturation of arterial hemoglobin) was associated with slightly higher resting ventilation among Tibetans and lower resting ventilation and HVR among Aymara women, although the associations accounted for just 2-7% of the variation. Between populations, the Tibetan sample was more hypoxic and had higher resting ventilation and HVR. Other systematic environmental contrasts did not appear to elevate Tibetan or depress Aymara ventilation. There was more intrapopulation genetic variation in these traits in the Tibetan than the Aymara sample. Thirty-five percent of the Tibetan, but none of the Aymara, resting ventilation variance was due to genetic differences among individuals. Thirty-one percent of the Tibetan HVR, but just 21% of the Aymara, HVR variance was due to genetic differences among individuals. Thus there is greater potential for evolutionary change in these traits in the Tibetans. Presently, there are two different ventilation phenotypes among high altitude natives as compared with sea level populations at sea level: lifelong sustained high resting ventilation and a moderate HVR among Tibetans in contrast with a slightly elevated resting ventilation and a low HVR among Aymara.

Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: A population-based study☆

UNLABELLED Autonomic nervous system (ANS) dysfunction has been suggested in patients with chronic fatigue syndrome (CFS). In this study, we sought to determine whether increased heart rate (HR) and reduced heart rate variability (HRV) parameters observed in CFS patients during wakefulness persist during sleep. To this end, we compared heart rate (HR) and HRV as indicators of ANS function in CFS subjects and non-fatigued (NF) controls in a population-based, case-control study. Thirty subjects with CFS and 38 NF controls, matched for age-, sex- and body mass index, were eligible for analysis. Main outcome measures included mean RR interval (RRI), HR, and HRV parameters derived from overnight ECG. Plasma aldosterone and norepinephrine levels, medicines with cardiovascular effect, and reported physical activity were examined as covariates. General Linear Models were used to assess significance of associations and adjust for potential confounders. Compared to controls, CFS cases had significantly higher mean HR (71.4 vs 64.8 bpm), with a shorter mean RRI [840.4 (85.3) vs 925.4(97.8) ms] (p<0.0004, each), and reduced low frequency (LF), very low frequency (VLF), and total power (TP) of HRV (p<0.02, all). CFS cases had significantly lower plasma aldosterone (p<0.05), and tended to have higher plasma norepinephrine levels. HR correlated weakly with plasma norepinephrine (r=0.23, p=0.05) and moderately with vitality and fatigue scores (r=-0.49 and 0.46, respectively, p<0.0001). Limitation in moderate physical activity was strongly associated with increased HR and decreased HRV. Nevertheless, among 42 subjects with similar physical activity limitations, CFS cases still had higher HR (71.8 bpm) than respective controls (64.9 bpm), p=0.023, suggesting that reduced physical activity could not fully explain CFS-associated differences in HR and HRV. After adjusting for potential confounders case-control differences in HR and TP remained significant (p<0.05). CONCLUSION the presence of increased HR and reduced HRV in CFS during sleep coupled with higher norepinephrine levels and lower plasma aldosterone suggest a state of sympathetic ANS predominance and neuroendocrine alterations. Future research on the underlying pathophysiologic mechanisms of the association is needed.

The role of muscarinic acetylcholine receptor-mediated activation of extracellular signal-regulated kinase 1/2 in pilocarpine-induced seizures

Pilocarpine‐induced seizures are mediated by the M1 subtype of muscarinic acetylcholine receptor (mAChR), but little is known about the signaling mechanisms linking the receptor to seizures. The extracellular signal‐regulated kinase (ERK) signaling cascade is activated by M1 mAChR and is elevated during status epilepticus. Yet, the role of ERK activation prior to seizure has not been evaluated. Here, we examine the role of pilocarpine‐induced ERK activation in the induction of seizures in mice by pharmacological and behavioral approaches. We show that pilocarpine induces ERK activation prior to the induction of seizures by both western blot and immunocytochemistry with an antibody to phosphorylated ERK. In addition, we show that the ERK pathway inhibitor SL327 effectively blocks the pilocarpine‐induced ERK activation. However, SL327 pretreatment has no effect on the initiation of seizures. In fact, animals treated with SL327 had higher seizure‐related mortality than vehicle‐treated animals, suggesting activated ERK may serve a protective role during seizures. In addition, ERK inhibition had no effect on the development of the long‐term sequelae of status epilepticus (SE), including mossy fiber sprouting, neuronal death and spontaneous recurrent seizures.

Percent of Oxygen Saturation of Arterial Hemoglobin Among Bolivian Aymara at 3,900-4,000 m

A range of variation in percent of oxygen saturation of arterial hemoglobin (SaO2) among healthy individuals at a given high altitude indicates differences in physiological hypoxemia despite uniform ambient hypoxic stress. In populations native to the Tibetan plateau, a significant portion of the variance is attributable to additive genetic factors, and there is a major gene influencing SaO2. To determine whether there is genetic variance in other high-altitude populations, we designed a study to test the hypothesis that additive genetic factors contribute to phenotypic variation in SaO2 among Aymara natives of the Andean plateau, a population geographically distant from the Tibetan plateau and with a long, separate history of high-altitude residence. The average SaO2 of 381 Aymara at 3,900-4,000 m was 92+/-0.15% (SEM) with a range of 84-99%. The average was 2.6% higher than the average SaO2 of a sample of Tibetans at 3,800-4,065 m measured with the same techniques. Quantitative genetic analyses of the Aymara sample detected no significant variance attributable to genetic factors. The presence of genetic variance in SaO2 in the Tibetan sample and its absence in the Aymara sample indicate there is potential for natural selection on this trait in the Tibetan but not the Aymara population.

Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study

BackgroundThe etiology and pathophysiology of chronic fatigue syndrome (CFS) remain inchoate. Attempts to elucidate the pathophysiology must consider sleep physiology, as unrefreshing sleep is the most commonly reported of the 8 case-defining symptoms of CFS. Although published studies have consistently reported inefficient sleep and documented a variable occurrence of previously undiagnosed primary sleep disorders, they have not identified characteristic disturbances in sleep architecture or a distinctive pattern of polysomnographic abnormalities associated with CFS.MethodsThis study recruited CFS cases and non-fatigued controls from a population based study of CFS in Wichita, Kansas. Participants spent two nights in the research unit of a local hospital and underwent overnight polysomnographic and daytime multiple sleep latency testing in order to characterize sleep architecture.ResultsApproximately 18% of persons with CFS and 7% of asymptomatic controls were diagnosed with severe primary sleep disorders and were excluded from further analysis. These rates were not significantly different. Persons with CFS had a significantly higher mean frequency of obstructive apnea per hour (p = .003); however, the difference was not clinically meaningful. Other characteristics of sleep architecture did not differ between persons with CFS and controls.ConclusionAlthough disordered breathing during sleep may be associated with CFS, this study generally did not provide evidence that altered sleep architecture is a critical factor in CFS. Future studies should further scrutinize the relationship between subjective sleep quality relative to objective polysomnographic measures.

Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning

Mesotelencephalic dopamine (DA) pathways are exquisitely vulnerable to ischemic-anoxic insult. These insults are known to produce long-term derangements in DA signaling and have been hypothesized to contribute, at least in part, to pathologic behaviors such as cerebral palsy, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Whether modest intermittent hypoxia, such as that encountered with repetitive apneas in premature infants, contributes to clinically significant impairments in DA signaling, and how these impairments manifest at a systems level, is unknown. To address these voids there is a need to develop animal models emulating features of a common disorder of prematurity, namely, apnea with hypoxia. Behavioral traits exhibited by such models include disturbed sleep-wake architecture, excessive locomotion, and impaired working memory persisting 1 to 2 months post-insult. Western-blot analysis of expression patterns of proteins involved in DA signaling (e.g., DA and vesicular monoamine transporters, tyrosine hydroxylase, and D1 receptors) are consistent with that which might be expected from hyper- or hypodopaminergic functioning in DA-responsive prefrontal cortex and striatal circuits, respectively. These novel observations suggest that intermittent hypoxia occurring during a period of critical brain development disrupts development of those mesotelencephalic pathways modulating the expression of sleep and wakefulness, locomotion, and executive functioning.

Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study

BackgroundComplaints of unrefreshing sleep are a prominent component of chronic fatigue syndrome (CFS); yet, polysomnographic studies have not consistently documented sleep abnormalities in CFS patients. We conducted this study to determine whether alterations in objective sleep characteristics are associated with subjective measures of poor sleep quality in persons with CFS.MethodsWe examined the relationship between perceived sleep quality and polysomnographic measures of nighttime and daytime sleep in 35 people with CFS and 40 non-fatigued control subjects, identified from the general population of Wichita, Kansas and defined by empiric criteria. Perceived sleep quality and daytime sleepiness were assessed using clinical sleep questionnaires. Objective sleep characteristics were assessed by nocturnal polysomnography and daytime multiple sleep latency testing.ResultsParticipants with CFS reported unrefreshing sleep and problems sleeping during the preceding month significantly more often than did non-fatigued controls. Participants with CFS also rated their quality of sleep during the overnight sleep study as significantly worse than did control subjects. Control subjects reported significantly longer sleep onset latency than latency to fall asleep as measured by PSG and MSLT. There were no significant differences in sleep pathology or architecture between subjects with CFS and control subjects.ConclusionPeople with CFS reported sleep problems significantly more often than control subjects. Yet, when measured these parameters and sleep architecture did not differ between the two subject groups. A unique finding requiring further study is that control, but not CFS subjects, significantly over reported sleep latency suggesting CFS subjects may have an increased appreciation of sleep behaviour that may contribute to their perception of sleep problems.

Arterial oxygen saturation in chronic congestive heart failure

Continuous, 24-hour, ambulatory pulse oximetry was used in 10 subjects with New York Heart Association functional class II to III heart failure and in 5 age-matched controls to test the prevailing view that arterial oxygen saturation is preserved during wakefulness in chronic mild to moderate heart failure. Subjects with heart failure were stabilized on digitalis and diuretics at the time of the study. All subjects maintained time-activity logs, with an emphasis on self-reported sleep and wakefulness. A desaturation event was defined as a decrease in arterial oxygen saturation > or = 4% from baseline lasting > 5 seconds. Variables assessed included total desaturation events, decrease in arterial oxygen saturation duration/event, nadir of arterial oxygen saturation/event, and desaturation index ([cumulative desaturation time/total monitoring time] x 100). The ratio of self-reported wakefulness:sleep desaturation time was 47:53% for subjects with heart failure versus 64:36% for controls (p = NS). Mean (+/- SEM) time of arterial oxygen saturation < 90% was 123 +/- 67 minutes for subjects with heart failure versus 22 +/- 25 minutes for controls (p < 0.01). Total desaturations were 220 +/- 63 and 76 +/- 35 (p = NS) for the heart failure and control groups, respectively. The heart failure group had a statistically, significantly greater decrease in arterial oxygen saturation, and a longer duration and deeper nadir of the desaturation event than did the age-matched control group. The desaturation index was 21 +/- 3% and 4 +/- 1% for the heart failure and control groups, respectively (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)