Buddha Basnyat

High altitude illness

High-altitude illness is the collective term for acute mountain sickness (AMS), high-altitude cerebral oedema (HACE), and high-altitude pulmonary oedema (HAPE). The pathophysiology of these syndromes is not completely understood, although studies have substantially contributed to the current understanding of several areas. These areas include the role and potential mechanisms of brain swelling in AMS and HACE, mechanisms accounting for exaggerated pulmonary hypertension in HAPE, and the role of inflammation and alveolar-fluid clearance in HAPE. Only limited information is available about the genetic basis of high-altitude illness, and no clear associations between gene polymorphisms and susceptibility have been discovered. Gradual ascent will always be the best strategy for preventing high-altitude illness, although chemoprophylaxis may be useful in some situations. Despite investigation of other agents, acetazolamide remains the preferred drug for preventing AMS. The next few years are likely to see many advances in the understanding of the causes and management of high-altitude illness.

The Physiologic Basis of High-Altitude Diseases

This review discusses the relationship of altitude to barometric pressure, effects of the hypoxia of high altitude, acclimatization to high altitude, improving working efficiency at high altitude, ...Clinical Principles Three major high-altitude diseases Acute mountain sickness (headache, lightheadedness, fatigue, insomnia, anorexia) High-altitude pulmonary edema (dyspnea, reduced exercise tolerance, cough, tachycardia, crepitations) High-altitude cerebral edema (confusion, ataxia, mood changes, coma, papilledema) Other high-altitude conditions Chronic mountain sickness (severe polycythemia, headache, somnolence, fatigue, depression) Subacute mountain sickness (affects infants and adults; right-heart failure with peripheral edema) Retinal hemorrhage (common at extreme altitude but usually causes no visual impairment) Physiologic Principles Hypoxia of high altitude impairs physical performance, mental performance, and sleep. In acclimatization, hyperventilation is the most important feature. Acclimatization reduces but does not abolish the effects of hypoxia. Extreme altitude causes severe hypoxemia, respiratory alkalosis, and greatly reduced maximal oxygen consumption. The mechanisms of acute mountain sickness and high-altitude cerebral edema are not fully understood, but brain swelling may be a feature. Acetazolamide reduces the incidence of acute mountain sickness. The mechanism of high-altitude pulmonary edema is probably uneven hypoxic pulmonary vasoconstriction that exposes some capillaries to a high pressure, damaging their walls and leading to a high-permeability form of edema. Many physicians are surprised to learn how many people live, work, and play at high altitude. Some 140 million persons reside at altitudes over 2500 m, mainly in North, Central, and South America; Asia; and eastern Africa (1). Increasingly, people are moving to work at high altitude. For example, there are telescopes at altitudes over 5000 m (2) and mines at over 4500 m (3), and the GolmudLhasa railroad being constructed in Tibet will have 30000 to 50000 workers at high altitudes, including many who work at more than 4000 m. Skiers, mountaineers, and trekkers go to altitudes of 3000 m to more than 8000 m for recreation, and sudden ascents to high altitude without the benefits of acclimatization are common. All of these groups are prone to high-altitude diseases that sometimes have fatal consequences. In addition, the physiology of hypoxia, which is at the basis of high-altitude medicine, plays an important role in many lung and heart diseases. Hypoxia of High Altitude Relationship of Altitude to Barometric Pressure Evangelista Torricelli (16081647) was the first person to realize that the atmosphere above us creates a pressure that can, for example, support a column of mercury. In a memorable sentence, he stated, We live submerged at the bottom of an ocean of the element air, which by unquestioned experiments is known to have weight (4). Figure 1 shows the relationship between altitude and barometric pressure in the regions where human exposure to high altitude is common. Table 1 lists some of the barometric pressures and the consequent inspired Po 2. At an altitude of 3000 m, which is commonly encountered in ski resorts, the barometric pressure and inspired Po 2 are only about 70% of the sea level value. At an altitude of 5000 m, the highest at which humans reside, the inspired Po 2 is only about half of the sea level value. On the summit ofMount Everest, at an altitude of 8848 m, the inspired Po 2 is less than 30% of its value at sea level. These numbers emphasize the hypoxic insult of going to high altitude. Figure 1. Relationship among altitude, barometric pressure, and inspired Po 2. o o Table 1. Barometric Pressure and Inspired Po 2 at Various Altitudes Note that the barometric pressures shown here are higher than those found in some textbooks of medicine and physiology, which use the so-called standard atmosphere (5). The aviation industry introduced the standard atmosphere in the 1920s to refer to average conditions in the atmosphere. However, it is now appreciated that most of the high-altitude areas frequented by humans, including the Himalayas and the South American Andes, have a higher barometric pressure than the standard atmosphere indicates. This is because they are relatively near the equator, where the solar radiation causes upwelling of the atmosphere; consequently, the column of air is higher. The difference between the standard atmosphere and the actual barometric pressures becomes very significant at extreme altitudes, such as at the summit of Mount Everest. If the barometric pressure predicted by the standard atmosphere were correct, the mountain could probably not be climbed without supplementary oxygen (6). Effects of the Hypoxia of High Altitude High altitude affects the human body because of oxygen deprivation. Other factors, such as severe cold, high winds, and intense solar radiation, may be present but can be nullified by appropriate protection. Hypoxia is inevitable unless it is relieved by supplementary oxygen or unless the person is placed in a container at increased pressure, such as a Gamow bag. Oxygen is critical to normal cellular function because it is an essential part of the electron transport chain for energy production in cells. The cellular responses to oxygen deprivation have been clarified by the discovery of the hypoxia-inducible factor-1 complex, which regulates gene transcription. This complex is a heterodimer protein complex that activates transcription through binding to specific hypoxic-responsive sequences present in various genes encoding for glycolytic enzymes, growth factors, and vasoactive peptide (7). The physiologic effects of the hypoxia of high altitude on the human body are legion. The most important in the present context can be considered under 3 headings: physical performance, mental performance, and sleep. Maximal Oxygen Consumption Maximal oxygen consumption is reduced as the inspired Po 2 is lowered. For example, at an altitude of 3000 m, maximal oxygen consumption is reduced to about 85% of the sea level value (8). At 5000 m, it is only about 60% of the value at sea level, and on the summit of Mount Everest, it is only approximately 20%. A coincident feature of the reduced physical performance at high altitude is a great increase in fatigue. The reduced maximal oxygen consumption at high altitude is usually ascribed to the reduction in mitochondrial Po 2, which interferes with the function of the electron transport chain responsible for providing cellular energy. However, some investigators believe that maximal oxygen consumption is reduced by central inhibition from the brain (9). There is little evidence that the pulmonary hypertension of high altitude limits maximal oxygen consumption, and, perhaps surprisingly, myocardial contractility in healthy people is maintained up to extreme altitudes (10); these findings emphasize the difference between the effects of hypoxemia and ischemia on the normal myocardium. Studies of elite mountaineers have suggested that genetic factors have a role in determining maximal oxygen consumption at high altitude, since participants tend to have the insertion rather than the deletion variant of the angiotensin-converting enzyme gene (11). Mental Performance Mental performance is impaired at high altitude, although many people are curiously reluctant to admit this. Neuropsychological testing is difficult because people can perform well in the short-term by concentrating harder than they usually need to during the workday. However, most people working at an altitude of 4000 m experience an increased number of arithmetic errors, reduced attention span, and increased mental fatigue. Visual sensitivity (for example, night vision) is reduced at altitudes as low as 2000 m and has been shown to decrease by about 50% at an altitude of 5000 m, where there are also measurable differences in attention span, short-term memory, arithmetic ability, and decision making (12). The molecular and cellular mechanisms responsible for impaired mental performance during hypoxia are poorly understood. The brain normally accounts for approximately 20% of the bodys total oxygen consumption, and the oxygen is almost entirely used for the oxidation of glucose. Suggested mechanisms for the impairment of nerve cell function during hypoxia include altered ion homeostasis, changes in calcium metabolism, alterations in neurotransmitter metabolism, and impairment of synapse function (13-15). Sleep Sleep is also impaired at high altitude, and many people find this one of the most distressing features of staying there. People at high altitude often wake frequently, have unpleasant dreams, and do not feel refreshed in the morning (16). The periodic breathing that occurs in most people at altitudes above 4000 m is probably an important causative factor (17). Periodic breathing is thought to result from instability in the control system through the hypoxic drive (18) or the response to carbon dioxide (19). The low levels of oxygen in the blood after apneic periods may be responsible for some of the arousals. Experienced trekkers and mountain climbers often recommend climbing high but sleeping low to mitigate these problems. Acclimatization to High Altitude The adaptive changes collectively known as acclimatization greatly improve the tolerance of human beings to high altitude. Physiologists often cite high-altitude acclimatization as one of the best examples of how the body responds to a hostile environment. However, although acclimatization is critically important, several misconceptions have developed. Hyperventilation By far the most important feature of acclimatization is the increase in depth and rate of breathing, which results in an increase in alveolar ventilation. This is brought about by hypoxic stimulation of the peripheral chemoreceptors, mainly the carotid bodies, which sense the low Po 2 in the arterial blood. Hyperventilation reduces the alveolar Pco 2 because there is an inverse relationship between this and the alveolar ventilation for a fixed rate

Antimicrobial Drug Resistance of Salmonella enterica Serovar Typhi in Asia and Molecular Mechanism of Reduced Susceptibility to the Fluoroquinolones

ABSTRACT This study describes the pattern and extent of drug resistance in 1,774 strains of Salmonella enterica serovar Typhi isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibilities to fluoroquinolones of these strains. For 1,393 serovar Typhi strains collected in southern Vietnam, the proportion of multidrug resistance has remained high since 1993 (50% in 2004) and there was a dramatic increase in nalidixic acid resistance between 1993 (4%) and 2005 (97%). In a cross-sectional sample of 381 serovar Typhi strains from 8 Asian countries, Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, and central Vietnam, collected in 2002 to 2004, various rates of multidrug resistance (16 to 37%) and nalidixic acid resistance (5 to 51%) were found. The eight Asian countries involved in this study are home to approximately 80% of the worlds typhoid fever cases. These results document the scale of drug resistance across Asia. The Ser83→Phe substitution in GyrA was the predominant alteration in serovar Typhi strains from Vietnam (117/127 isolates; 92.1%). No mutations in gyrB, parC, or parE were detected in 55 of these strains. In vitro time-kill experiments showed a reduction in the efficacy of ofloxacin against strains harboring a single-amino-acid substitution at codon 83 or 87 of GyrA; this effect was more marked against a strain with a double substitution. The 8-methoxy fluoroquinolone gatifloxacin showed rapid killing of serovar Typhi harboring both the single- and double-amino-acid substitutions.

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events

The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.

Salmonella enterica Serovar Paratyphi A and S. enterica Serovar Typhi Cause Indistinguishable Clinical Syndromes in Kathmandu, Nepal

BACKGROUND Enteric fever is a major global problem. Emergence of antibacterial resistance threatens to render current treatments ineffective. There is little research or public health effort directed toward Salmonella enterica serovar Paratyphi A, because it is assumed to cause less severe enteric fever than does S. enterica serovar Typhi. There are few data on which to base this assumption, little is known of the serovars antibacterial susceptibilities, and there is no readily available tolerable vaccination. METHODS A prospective study was conducted of 609 consecutive cases of enteric fever (confirmed by blood culture) to compare the clinical phenotypes and antibacterial susceptibilities in S. Typhi and S. Paratyphi A infections. Variables independently associated with either infection were identified to develop a diagnostic rule to distinguish the infections. All isolates were tested for susceptibility to antibacterials. RESULTS Six hundred nine patients (409 with S. Typhi infection and 200 with S. Paratyphi A infection) presented during the study period. The infections were clinically indistinguishable and had equal severity. Nalidixic acid resistance, which predicts a poor response to fluoroquinolone treatment, was extremely common (75.25% of S. Paratyphi A isolates and 50.5% of S. Typhi isolates; P < .001). S. Paratyphi A was more likely to be resistant to ofloxacin (3.6% vs. 0.5%; P = .007) or to have intermediate susceptibility to ofloxacin (28.7% vs. 1.8%; P < .001) or ciprofloxacin (39.4% vs. 8.2%; P < .001). MICs for S. Paratyphi A were higher than for S. Typhi (MIC of ciprofloxacin, 0.75 vs. 0.38 microg/mL [P < .001]; MIC of ofloxacin, 2.0 vs. 0.75 microg/mL [P < .001]). CONCLUSIONS The importance of S. Paratyphi A has been underestimated. Infection is common, the agent causes disease as severe as that caused by S. Typhi and is highly likely to be drug resistant. Drug resistance and lack of effective vaccination suggest that S. Paratyphi A infection may become a major world health problem.

Efficacy of Low-dose Acetazolamide (125 mg BID) for the Prophylaxis of Acute Mountain Sickness: A Prospective, Double-blind, Randomized, Placebo-controlled Trial

The objective of this study was to determine the efficacy of low-dose acetazolamide (125 mg twice daily) for the prevention of acute mountain sickness (AMS). The design was a prospective, double-blind, randomized, placebo-controlled trial in the Mt. Everest region of Nepal between Pheriche (4243 m), the study enrollment site, and Lobuje (4937 m), the study endpoint. The participants were 197 healthy male and female trekkers of diverse background, and they were evaluated with the Lake Louise Acute Mountain Sickness Scoring System and pulse oximetry. The main outcome measures were incidence and severity of AMS as judged by the Lake Louise Questionnaire score at Lobuje. Of the 197 participants enrolled, 155 returned their data sheets at Lobuje. In the treatment group there was a statistically significant reduction in incidence of AMS (placebo group, 24.7%, 20 out of 81 subjects; acetazolamide group, 12.2%, 9 out of 74 subjects). Prophylaxis with acetazolamide conferred a 50.6% relative risk reduction, and the number needed to treat in order to prevent one instance of AMS was 8. Of those with AMS, 30% in the placebo group (6 of 20) versus 0% in the acetazolamide group (0 of 9) experienced a more severe degree of AMS as defined by a Lake Louise Questionnaire score of 5 or greater (p = 0.14). Secondary outcome measures associated with statistically significant findings favoring the treatment group included decrease in headache and a greater increase in final oxygen saturation at Lobuje. We concluded that acetazolamide 125 mg twice daily was effective in decreasing the incidence of AMS in this Himalayan trekking population.

Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT)

Abstract Objective To evaluate the efficacy of ginkgo biloba, acetazolamide, and their combination as prophylaxis against acute mountain sickness. Design Prospective, double blind, randomised, placebo controlled trial. Setting Approach to Mount Everest base camp in the Nepal Himalayas at 4280 m or 4358 m and study end point at 4928 m during October and November 2002. Participants 614 healthy western trekkers (487 completed the trial) assigned to receive ginkgo, acetazolamide, combined acetazolamide and ginkgo, or placebo, initially taking at least three or four doses before continued ascent. Main outcome measures Incidence measured by Lake Louise acute mountain sickness score ≥ 3 with headache and one other symptom. Secondary outcome measures included blood oxygen content, severity of syndrome (Lake Louise scores ≥ 5), incidence of headache, and severity of headache. Results Ginkgo was not significantly different from placebo for any outcome; however participants in the acetazolamide group showed significant levels of protection. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide (odds ratio 3.76, 95% confidence interval 1.91 to 7.39, number needed to treat 4), 35% for ginkgo (0.95, 0.56 to 1.62), and 14% for combined ginkgo and acetazolamide (3.04, 1.62 to 5.69). The proportion of patients with increased severity of acute mountain sickness was 18% for placebo, 3% for acetazoalmide (6.46, 2.15 to 19.40, number needed to treat 7), 18% for ginkgo (1, 0.52 to 1.90), and 7% for combined ginkgo and acetazolamide (2.95, 1.30 to 6.70). Conclusions When compared with placebo, ginkgo is not effective at preventing acute mountain sickness. Acetazolamide 250 mg twice daily afforded robust protection against symptoms of acute mountain sickness.

Admixture facilitates genetic adaptations to high altitude in Tibet

Admixture is recognized as a widespread feature of human populations, renewing interest in the possibility that genetic exchange can facilitate adaptations to new environments. Studies of Tibetans revealed candidates for high-altitude adaptations in the EGLN1 and EPAS1 genes, associated with lower haemoglobin concentration. However, the history of these variants or that of Tibetans remains poorly understood. Here we analyse genotype data for the Nepalese Sherpa, and find that Tibetans are a mixture of ancestral populations related to the Sherpa and Han Chinese. EGLN1 and EPAS1 genes show a striking enrichment of high-altitude ancestry in the Tibetan genome, indicating that migrants from low altitude acquired adaptive alleles from the highlanders. Accordingly, the Sherpa and Tibetans share adaptive haemoglobin traits. This admixture-mediated adaptation shares important features with adaptive introgression. Therefore, we identify a novel mechanism, beyond selection on new mutations or on standing variation, through which populations can adapt to local environments.

Enteric (Typhoid) Fever in Travelers

The incidence of enteric (typhoid) fever in travelers is estimated to be approximately 3-30 cases per 100,000 travelers to developing countries. Recently, it is become clear that travelers who are visiting friends and relatives, especially travelers to the Indian subcontinent, seem to be the most vulnerable to enteric fever and require special attention for prevention. Recent concerns are the increasing incidence of paratyphoid fever in Asia, which is not covered by available typhoid vaccines, and the emergence of infections caused by antibiotic-resistant strains (including strains resistant to fluoroquinolones). Typhoid vaccination is recommended for most travelers to moderate- to high-risk countries. Because of the nonspecific clinical presentation of enteric fever, a high index of suspicion is important in febrile travelers who have traveled to areas of endemicity.

Disoriented and ataxic pilgrims: an epidemiological study of acute mountain sickness and high-altitude cerebral edema at a sacred lake at 4300 m in the Nepal Himalayas

OBJECTIVE To determine the incidence of high-altitude cerebral edema (HACE), acute mountain sickness (AMS), and high-altitude pulmonary edema (HAPE) in pilgrims. Although it is well known that western trekkers suffer from acute mountain sickness (AMS) in the Himalayas, not much is documented about the incidence of AMS in the local population of Nepal that go to high altitude. METHODS The design was a randomized study set at a sacred high-altitude lake at 4300 m at Gosainkund in the Nepal Himalayas. There was a control study at 1300 m at Pashupatinath in Kathmandu, Nepal. The subjects were pilgrims of different ethnic Nepali backgrounds. The Lake Louise consensus for AMS, HACE, and HAPE was used, and oxygen saturation with a pulse oximeter was performed on HACE subjects. RESULTS Out of 5000 pilgrims, 228 were randomly chosen. Sixty-eight percent had AMS, 31% had HACE, and 5% had HAPE. The mean oxygen saturation of HACE subjects at that altitude was 77%, 87% being normal for 4300 m altitude. Seventy-three percent of the study population were men, yet women had a significantly higher rate of AMS (odds ratio, 4.34; 95% confidence interval, 1.83-10.68), HACE (odds ratio 3.15, confidence interval 1.62-6.12), and HAPE (odds ratio, 5.2; 95% confidence interval, 1.24-24.73). CONCLUSIONS Such a high incidence of HACE in an epidemiological study using the Lake Louise criteria has, to our knowledge, not been reported before. High-altitude pilgrims, especially women pilgrims in this study, seem to be a very susceptible group. Preventive measures in these pilgrims need to be adopted to avoid AMS, specifically life-threatening HACE and HAPE.