Differences in the control of breathing between Himalayan and sea-level residents.

We compared the control of breathing of 12 male Himalayan highlanders with that of 21 male sea-level Caucasian lowlanders using isoxic hyperoxic ( = 150 mmHg) and hypoxic ( = 50 mmHg) Duffin's rebreathing tests. Highlanders had lower mean +/- s.e.m. ventilatory sensitivities to CO(2) than lowlanders at both isoxic tensions (hyperoxic: 2.3 +/- 0.3 vs. 4.2 +/- 0.3 l min(1) mmHg(1), P = 0.021; hypoxic: 2.8 +/- 0.3 vs. 7.1 +/- 0.6 l min(1) mmHg(1), P < 0.001), and the usual increase in ventilatory sensitivity to CO(2) induced by hypoxia in lowlanders was absent in highlanders (P = 0.361). Furthermore, the ventilatory recruitment threshold (VRT) CO(2) tensions in highlanders were lower than in lowlanders (hyperoxic: 33.8 +/- 0.9 vs. 48.9 +/- 0.7 mmHg, P < 0.001; hypoxic: 31.2 +/- 1.1 vs. 44.7 +/- 0.7 mmHg, P < 0.001). Both groups had reduced ventilatory recruitment thresholds with hypoxia (P < 0.001) and there were no differences in the sub-threshold ventilations (non-chemoreflex drives to breathe) between lowlanders and highlanders at both isoxic tensions (P = 0.982), with a trend for higher basal ventilation during hypoxia (P = 0.052). We conclude that control of breathing in Himalayan highlanders is distinctly different from that of sea-level lowlanders. Specifically, Himalayan highlanders have decreased central and absent peripheral sensitivities to CO(2). Their response to hypoxia was heterogeneous, with the majority decreasing their VRT indicating either a CO(2)-independent increase in activity of peripheral chemoreceptor or hypoxia-induced increase in [H(+)] at the central chemoreceptor. In some highlanders, the decrease in VRT was accompanied by an increase in sensitivity to CO(2), while in others VRT remained unchanged and their sub-threshold ventilations increased, although these were not statistically significant.

Effect of aging on blood pressure in Leh, Ladakh, a high-altitude (3524 m) community, by comparison with a Japanese town.

The effect of aging on blood pressure (BP) and heart rate (HR) was investigated in a cross-sectional study in the high-altitude community of Leh, Ladakh (altitude: 3524 m) and a Japanese community in U town, Hokkaido (altitude: 25 m). BP and HR were obtained in a sitting position from 332 subjects 13-81 years of age in Ladakh, and from 216 Japanese citizens, 24-79 years of age. Measurements were taken after a 2-min rest, using a semi-automated BP device (UA-767 PC, A and D Co. LTD, Tokyo). High-altitude people showed higher diastolic BP and HR values than lowland people (83.2 vs. 76.9 mmHg and 78.6 vs. 69.2 bpm, P < 0.001), but no difference in systolic BP. Highland people also showed a steeper BP increase with age than the lowland people (systolic BP: 0.7476 vs. 0.3179 mmHg/year, P < 0.0005; diastolic BP: 0.3196 vs. 0.0750 mmHg/year, P < 0.001). This chronoecologic investigation in Ladakh examined the circulation as a physiological system at high-altitude. Our data indicate the need for a more comprehensive cardiovascular assessment for a better diagnosis and a more fruitful treatment. Longitudinal observations of effects of socio-ecologic factors on the cardiovascular system should help prevent strokes and other cardiovascular events, especially at high altitude.

Chronoecological health watch of arterial stiffness and neuro-cardio-pulmonary function in elderly community at high altitude (3524 m), compared with Japanese town.

Effects of high altitude on arterial stiffness and neuro-cardio-pulmonary function were studied. Blood pressure (BP) and heart rate (HR) were measured in a sitting position on resting Ladakhis, living at an altitude of 3250-4647 m (Phey village, 3250 m: 17 men and 55 women; Chumathang village, 4193 m: 29 men and 47 women; Sumdo village, 4540 m: 38 men and 57 women; and Korzok village, 4647 m: 84 men and 70 women). The neuro-cardio-pulmonary function, including the Kohs block design test, the Up and Go, the Functional Reach and the Button tests, was examined in 40 elderly subjects (19 men and 21 women, mean age: 74.7 +/- 3.3 years) in Leh, Ladakh (altitude: 3524 m), for comparison with 324 elderly citizens (97 men and 227 women, mean age: 80.7 +/- 4.7 years) of Tosa, Japan (altitude: 250 m). Cardio-Ankle Vascular Index (CAVI) was measured as the heart-ankle pulse wave velocity (PWV) in these subjects using a VaSera CAVI instrument (Fukuda Denshi, Tokyo). SpO(2) decreased while Hb and diastolic BP increased with increasing altitude. At higher altitude, residents were younger and leaner. Women in Leh vs. Tosa had a poorer cognitive function, estimated by the Kohs block design test (3.7 +/- 3.6 vs. 16.4 +/- 9.6 points, P < 0.0001) and poorer ADL functions (Functional Reach: 13.7 +/- 7.0 cm vs. 25.3 +/- 8.7 cm, P < 0.0001; Button test: 22.5 +/- 4.8 vs. 14.8 +/- 5.7 s, P < 0.0001). Time estimation was shorter at high altitude (60-s estimation with counting: 41.1% shorter in men and 23.0% shorter in women). A higher voltage of the QRS complex was observed in the ECG of Leh residents, but two times measurement of CAVI showed no statistically significant differences between Leh and Tosa (two times of CAVI measures; 9.49 vs. 10.01 m/s and 9.41 vs. 10.05 m/s, respectively), suggesting that most residents succeed to adapt sufficiently to the high-altitude environment. However, correlation of CAVI with age shows several cases who show an extreme increase in CAVI. Thus, for the prevention of stroke and other adverse cardiovascular outcomes, including dementia, CAVI may be very useful, especially at high altitude. In conclusion, elderly people living at high altitude have a higher risk of cardiovascular disease than low-latitude peers. To determine how these indices are associated with maintained cognitive function deserves further study by the longitudinal follow-up of these communities in terms of longevity and aging in relation to their neuro-cardio-pulmonary function.

Simultaneous selection of the wild-type genotypes of the G894T and 4B/ 4A polymorphisms of NOS3 associate with high-altitude adaptation.

The routine performance of high-altitude (HA) natives in the hypoxic environment of HA exemplifies the process of adaptation mainly through natural selection. The recent therapeutic application of nitric oxide (NO) in HA disorders, for the improvement of oxygenation and vasodilation, ushered us to investigate the endothelial nitric oxide synthase gene (NOS3) with respect to HA adaptation. The study subjects, 131 HA monks (HAM), 136 HA controls (HAC), and 170 lowlanders (LLs) were screened for NOS3 G894T (Glu298Asp) and 4B/4A polymorphisms. The NO levels were estimated, for a correlation with the polymorphisms. The three groups were in Hardy-Weinberg equilibrium for the polymorphisms. The overall genotype distributions for the G894T and 4B/4A polymorphisms were significant (P = 0.01 and 0.02, respectively) in the three groups. Wild-type alleles G and 4B were significantly over-represented in the HA groups as compared to the LLs (P = 0.006 and P = 0.02, respectively). The NO levels were in the order of HAM>HAC>LLs (P < 0.0001). Furthermore, combinations of the GG and BB genotypes were distributed significantly more frequently in the HAM (P < 0.0001) and HAC (P = 0.0005) than in LLs. The NO levels contributed by the wild-type genotype combination GG, BB were significantly elevated when compared with the remaining eight genotype combinations together in the HAM, HAC and LLs (P = 0.003, P = 0.0006 and P < 0.0001, respectively). To conclude, the genotype combination of NOS3 wild-type homozygotes (GG, BB) was found significantly more frequently in HA groups than in LLs, by contributing to higher NO levels associated with HA adaptation.

Mini review of high altitude health problems in Ladakh.

Ladakh is a sparsely populated area of Indian Himalaya lying at 3-4500 m altitude mainly consisting of arid desert. This paper will discuss high altitude health problems in Ladakh under the following headings. 1. Acute altitude illness: acute mountain sickness (AMS), high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). 2. Effects of prolonged and permanent exposure to high altitude: (subacute and chronic mountain sickness). 3. Environmental dust and domestic fire pollution resulting in non-occupational pneumoconiosis and high prevalence of respiratory morbidity.

Association of high-altitude systemic hypertension with the deletion allele-of the angiotensin-converting enzyme (ACE) gene.

People who visit high-altitude areas are exposed to a stressful environment and a good percentage of them suffer from high-altitude-induced diseases, including systemic hypertension. Identification of genetic markers for high-altitude-induced diseases would help to reduce the rate of morbidity/mortality from such diseases. The development of systemic hypertension on exposure to high altitude (3,500 m) for 30 days in otherwise normotensive natives of low-altitudes was investigated. The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genotypes and renin-angiotensin-aldosterone system were simultaneously studied. In the hypertensives during their stay at high altitude, the ACE D allele frequency was significantly higher than in the normotensives (0.67 versus 0.32 chi(2)(1) = 10.6, P < 0.05). In the normotensives during their stay at high altitude, there was no significant increase in plasma aldosterone levels despite increased plasma renin activity. Results of the present study suggest that environmental changes and pre-existing genetic factors, namely the ACE D allele, might be two of the factors predisposing natives of low altitudes to systemic hypertension, a polygenic disease, at high altitude.

Angiotensin converting enzyme insertion allele in relation to high altitude adaptation.

Angiotensin converting enzyme (ACE) gene I/D polymorphism has been associated with high altitude (HA) disorders as well as physical performance. We, however, envisage that the polymorphism may be associated with adaptation to the hypobaric hypoxia of altitude, thus facilitating physical performance. For this purpose, three unrelated adult male groups, namely (1) the Ladakhis (HLs), who reside at and above a height of 3600 m, (2) lowlanders, who migrated to Ladakh (MLLs), and (3) resident lowlanders (LLs), have been investigated. The HLs had significantly (p & 0.001) greater numbers of the II homozygotes and the ID heterozygotes than the DD homozygotes, the genotype distribution being 0.46, 0.43 and 0.11 for II, ID and DD genotypes respectively. The MLLs comprised 60% II homozygotes, which was higher (p & 0.001) than the HLs (46%). In the LLs, the heterozygotes were greater (p & 0.001) in number than the II and DD homozygotes. The I allele frequency was 0.72 in the MLLs, 0.67 in the HLs and 0.55 in the LLs. Polymorphism study suggested that the II genotype could be associated with altitude adaptation, which might influence physical efficiency.

Gallstones in a community free of obesity but prone to slow intestinal transit.

OBJECTIVES: To verify anecdotal reports that gallstones were frequent in a remote community where obesity is rare and to look for possible explanations of their occurrence, including slow intestinal transit. DESIGN: Population survey of gallbladder status and stool form. SETTING: Two villages in Ladakh, a mountainous region of northern India; for comparison, a stratified random sample from general practitioners' lists in East Bristol. SUBJECTS: Women aged 25-59 years, 437 in Ladakh and 974 in Bristol. MAIN OUTCOME MEASURES: Presence of gallstones on ultrasonography and response to questionnaires about parity, the intake of dried legume seeds (pulses) and bowel function including the form or appearance of the stools on a seven-point, transit-sensitive scale. Weight, height and waist circumference were also recorded. RESULTS: Gallstone disease was at least as frequent in Ladakh as in Bristol although Ladakhi women were uniformly slim and their weight, waist size and body mass index failed to rise with age. After adjustment for age, gallstone disease was associated with higher body mass index and waist size in Bristol but not in Ladakh. It was associated with increased parity in Bristol, but not significantly so after adjusting for age and not at all in Ladakh. Gallstone disease was not directly associated with bowel function but Ladakhis often reported their stools to be lumpy (42.4 vs. 26.5% of Bristol women) and seldom as soft or loose (6.4 vs. 42.5%), implying that their intestinal transit tends to be slow. CONCLUSION: Gallstones can be common in a population free of obesity but prone to intestinal stasis.

Non-occupational pneumoconiosis at high altitude villages in central Ladakh.

An epidemiological survey was carried out to investigate the occurrence of non-occupational pneumoconiosis in Ladakh, where there are no mines or industries. The clinicoradiological investigations of 449 randomly selected subjects from three villages showed typical cases of pneumoconiosis associated with progressive massive fibrosis and egg shell calcification of hilar glands. The prevalence of pneumoconiosis in these three villages was 2.0%, 20.1% and 45.3% and it corresponded with the severity of dust storms and the use of chimneys in the kitchens. The dust concentrations in the kitchens with no provision for a chimney were very high. The free silica content of the storms was between 60 and 70%. Exposure to free silica from dust storms and soot from domestic fuels are suggested as causes of these cases of pneumoconiosis.

Domestic pollution and respiratory illness in a Himalayan village.

Summer and winter surveys of a village in Ladakh have been used to study respiratory illness and domestic pollution from fires in an arid high altitude region of northern India. The prevalence of chronic cough with chronic phlegm rose steeply with age, and was greater among women than men. The percentage of villagers with a forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio of less than 65% also rose with age, to include 24% of men and 32% of women over 50 years in the summer survey. Lung function was significantly worse in those reporting chronic cough, independently of age and sex (p less than 0.001). Carbon monoxide (CO) measurements were used to assess domestic pollution from fires. Amongst the small minority of smokers (all men) CO in exhaled air was higher than in non-smoking men. In non-smoking men and the women, levels of exhaled CO were very significantly higher in winter than in summer, as were the levels of CO measured in the houses. There was a fall in FEV1 (but not FVC) between summer and winter (p less than 0.0001), and an association was found between individual change from summer to winter in exhaled air CO and the individual change in FEV1 (p less than 0.01). A significant negative association was found between the winter value of CO in exhaled air and FEV1/FVC ratio in women (p less than 0.05), although a similar association in men was non-significant. No significant associations were found between winter pollution levels and the presence of chronic symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Silicosis in a Himalayan village population: role of environmental dust.

The Himalayan villages of Chuchot Shamma and Stok were surveyed because silicosis had been suspected from the radiographs of some of the inhabitants. The villages are agricultural, and Chuchot is exposed to frequent dust storms. Chest radiographs of villagers aged 50-62 were assessed blind by two independent observers using ILO criteria. In Chuchot five of seven men and all of the nine women examined showed varying grades of silicosis, compared with three of 13 men and seven of 11 women in Stok, which lies 300 metres higher and is exposed to fewer dust storms. The difference in prevalence of silicosis between the two villages was significant, as was the differences between men and women. Three patients from the village adjoining Chuchot were later found to have radiological evidence of progressive massive fibrosis. A necropsy on a man in a neighbouring village in the Indus valley showed classical silicosis in a hilar lymph node. Chemical analysis of the inorganic dust in the lung showed that 54.4% was elemental silicon [corrected]. This was similar to the silicon [corrected] content of dust samples collected from houses in Chuchot, which included particles of respirable size. X-ray microanalysis showed that quartz formed 16-21% of the inorganic lung dust. This study suggests that silicosis is common among the older inhabitants of these Himalayan villages. The dust exposure is clearly environmental and not industrial. Further studies are needed to define the extent and severity of silicosis in this community and to examine possible preventive measures.

Seasonal koilonychia in Ladakh.

During a health survey for chest disease in Ladakh, it was noted that women and a few men had marked koilonychia. It caused disfigurement, discomfort and sometimes disturbance of function. It occurred mainly in spring and summer and usually disappeared in winter. It is thought to be due to exposure to cold wet mud while repairing walls and irrigation canals. There was no evidence of iron deficiency.