With acute cold exposure in a laboratory setting, Simmons et al. [70–72] studied HKI-272 mouse the effect of hypoxia on cutaneous vascular conductance during cold exposure. Data from these three studies are mixed, suggesting both increased and decreased cutaneous vasoconstriction in the forearm. However, further improvements in CIVD responses from hypoxic exposure may be

possible even in those with presumably some degree of cold acclimatization or self-selection for cold. A subgrouping of peripheral cold adaptation studies has explored responses in alpinists over the course of expeditions at altitude. Daanen and van Ruiten [21] investigated if repeated finger cold water immersions at high altitude (4350 m) improved the ITF2357 cost CIVD response and observed no improvement in seven days. This was in contrast to the same study observing some improvement in mean finger temperature when subjects were acclimatized to high altitude (>5100 m) over 45 days. Therefore, a threshold for acclimatization duration may exist at altitude, as Mathew et al. [53] and Purkayastha et al. [64] reported CIVD enhancement within a time span of three weeks at altitude. Recently, Felicijan et al. [23] tested highly experienced (>20 years) Slovenian alpinists before and following a three-week high-altitude mountaineering

expedition. Compared with a group of Slovenian nonmountaineering controls, CIVD was more pronounced in the toes pre-expedition, and the CIVD response was further enhanced in both the fingers and toes of the alpinists post-expedition. Amon [3] recently confirmed these

observations in a laboratory study in which nine subjects were sleeping high and training low for 28 days without cold exposure; in particular, the number of CIVD waves increased. Overall, it seems that prolonged exposure to altitude may improve CIVD, and that a threshold exposure duration in excess of one week and close to three weeks or longer is required for significant Aspartate adaptation. Longitudinal acclimatization studies, where a subject group is naturally exposed to cold for a prolonged period and tested for CIVD response, have to date presented equivocal results. However, studies in which local extremity cold water immersion was combined with altitude exposure for a prolonged period exceeding a week seem to yield positive results on CIVD. Such acclimatization studies can be logistically difficult to execute, due to the requirement to track subjects over a prolonged period of time and possibly in different geographical settings. Similar to population studies, another inherent problem in research design remains direct quantification of the level of actual cold exposure over the course of the acclimatization protocol, and the partitioning of local versus whole body exposure. Some longitudinal studies also lack a control group, making it difficult to assess the true environmental effect of exposure.