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High altitude retinopathy (HAR) was first described in 1969 as engorgement of retinal veins with occasional papilloedema and vitreous hemorrhage. Since then various studies have attempted to define the incidence, etiology and significance of this phenomenon, usually with small numbers of subjects. Recently studies on relatively large groups of subjects in Nepal, Bolivia and Tibet have confirmed that the retinal vasculature becomes engorged and tortuous in all lowlanders ascending above 2500m. Sometimes this leads to hemorrhages, cotton wool spots and papilloedema, which is the pathological state better known as high altitude retinopathy. These studies have also shown a significant change in both corneal thickness and intraocular pressure at altitude. The retinal blood vessels are the only directly observable vascular system in the human body and also supply some of the most oxygen-demanding tissue, the photoreceptors of the retina. New techniques are being applied in both hypobaric chamber and field expeditions to observe changes in retinal function during conditions of hypobaric hypoxia. This work allows better advice to be given to lowlanders traveling to altitude either if they have pre-existing ocular conditions or if they suffer from visual problems whilst at altitude. This especially applies to the effect of altitude on refractive eye surgery and results of recent studies will be discussed so that physicians can advise their patients using the latest evidence. Retinal hypoxia at sea level accounts for the developed world’s largest cause of blindness, diabetic retinopathy. The investigation of retinal response to hypobaric hypoxia in healthy subjects may open new avenues for treatment of this debilitating disease.

The hypoxic ventilatory response (HVR) is the body’s first line of defense against environmental hypoxia, for example, at high altitude. In acute hypoxia, the HVR ia a reflex increase in ventilation in response to decreased arterial PO, which is rapidly sensed by arterial chemoreceptors primarily in the carotid bodies.With sustained exposure to hypoxia, the HVR changes (8). For example, after 5 to 20 minutes of hypoxia, ventilation “rolls off” relative to the acute hypoxic response and this is called hypoxic ventilatory decline (HVD). With continuous hypoxia, for example during acclimatization to high altitude, ventilation increases above the level of the acute HVR with ventilatory acclimatization to hypoxia (VAH). The different time domains of the HVR raise many questions about the physiological mechanisms of oxygen sensing and the control of breathing. They also raise many issues about experimental methods to measure the HVR and comparing results between laboratories. At the 13th International Hypoxia Symposium, John Severinghaus proposed consensus methods for measuring the HVR in humans, and the discussion continued at the 14th International Hypoxia Symposium in Lake Louise. The goal of this report is to stimulate further discussion and experiments so we can adopt a “Lake Louise Consensus for Measuring the HVR” at the 15th International Hypoxia Symposium in 2007.

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease states in general. Over the past decade, studies involving short-term hypoxic exposure have greatly advanced our knowledge regarding underlying mechanisms and predisposing events of hypoxic pulmonary hypertension. Studies in high altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide (NO) for pulmonary artery pressure homeostasis. More recently, it has been shown that pathological events during the perinatal period (possibly by impairing pulmonary NO synthesis), predispose to exaggerated hypoxic pulmonary hypertension later in life. In an attempt to translate some of this new knowledge to the understanding of underlying mechanisms and predisposing events of chronic hypoxic pulmonary hypertension, we have recently initiated a series of studies among high-risk subpopulations (experiments of nature) of high-altitude dwellers. These studies have allowed to identify novel risk factors and underlying mechanisms that may predispose to sustained hypoxic pulmonary hypertension. The aim of this article is to briefly review this new data, and demonstrate that insufficient NO synthesis/bioavailability, possibly related in part to augmented oxidative stress, may represent an important underlying mechanism predisposing to pulmonary hypertension in high-altitude dwellers.

New technologies in genomics and proteomics are revolutionizing the study of adaptation to environmental stress. These approaches provide a comprehensive overview of the responses of thousands of genes/proteins to stress and enormously expand our view of the molecular and metabolic changes that underlie physiological responses. Several new technologies can help physiological labs to become gene hunters. DNA array screening is particularly effective for two purposes: (1) identifying coordinated responses by functional groups of gene/proteins such as multiple members of a signal transduction cascade or enzymes of a metabolic pathway, and (2) highlighting cell functions that have never before been linked with the stress under consideration. We have shown that heterologous screening of DNA arrays can be a highly effective method of gene hunting for the comparative biochemist provided that it is followed up by species-specific analyses including PCR to quantify transcript levels and Western blotting to analyze protein responses. Recent work in my lab has used cDNA array screening to evaluate responses to low oxygen by multiple hypoxia/anoxia tolerant systems, revealing common gene responses across phylogeny. Analysis of vertebrate facultative anaerobiosis in freshwater turtles reveals an interesting mixture of gene responses, including up-regulation of antioxidant enzymes, protease inhibitors, and proteins of iron metabolism; a few of these are coordinated by the hypoxia inducible factor in other systems but most are not. Array screening is also providing new insights into how exercise stimulates the growth of differentiated muscle cells and studies in our lab are identifying the gene responses associated with “anti-exercise”-gene up-regulation that aids hibernating mammals to maintain their muscle mass despite months of inactivity.