Adv Exp Med Biol
-
An 8000-m peak bring challenges of extremes of hypoxia and weather as well as the normal hazards of climbing itself. These challenges have taken a severe toll: 604 mountaineers have died on those great peaks since 1950. Little is known about whether mountain height, use of supplemental oxygen, or team size might influence rates of death or of success. ⋯ We present several examples from a research program that is attempting to analyze factors that potentially influence success or death rates on the 8K peaks. (1) Apparent risk of death in the notorious Khumbu Icefall on Mt. Everest has declined dramatically in recent years. This decline could reflect improved route finding and technique, but might also reflect climate warming, which has caused the Khumbu glacier to shrink and slow in recent decades. (2) Risk of death during descent from an 8000-m peak increases with the height of the peak. (3) Risk of death during descent from the summit of Everest or of K2 is elevated for climbers not using supplemental oxygen. (4) We outline some new studies that are exploring how convective heat loss, which influences wind chill, changes with altitude as well as the incidence of storms: both factors will impact the probability success and death of Himalayan mountaineers.
-
Small, muscular pulmonary arteries (PAs) constrict within seconds of the onset of alveolar hypoxia, diverting blood flow to better-ventilated lobes, thereby matching ventilation to perfusion and optimizing systemic PO2. This hypoxic pulmonary vasoconstriction (HPV) is enhanced by endothelial derived vasoconstrictors, such as endothelin, and inhibited by endothelial derived nitric oxide. However, the essence of the response is intrinsic to PA smooth muscle cells in resistance arteries (PASMCs). ⋯ However, inhibition of complex 1 of the mitochondrial electron transport chain mimics hypoxia in that it inhibits IK, reduces the production of activated O2 species and causes vasoconstriction. We hypothesize that a redox O2 sensor, perhaps in the mitochondrion, senses O2 through changes in the accumulation of freely diffusible electron donors. Changes in the ratio of reduced/oxidized redox couples, such as NADH/NAD+ and glutathione (GSH/GSSG) can reduce or oxidize the K+ channels, resulting in alterations of PA tone.
-
Prolactin (PRL), synthesized by the anterior pituitary and to a lesser extent by numerous extrapituitary tissues, affects more physiological processes than all other pituitary hormones combined. This hormone is involved in > 300 separate effects in various vertebrate species where its role has been well documented. The initial step in its action is the binding to a specific membrane receptor which belongs to the superfamily of class 1 cytokine receptors. ⋯ PRL-binding sites have been identified in a number of cells and tissues of adult animals. Disruption of the gene for the PRL receptor has provided a new animal model with which to better understand the actions of PRL on mammary morphogenesis and mammary gland gene expression. The recent availability of genetic mouse models provides new insights into mammary developmental biology and how the action of a hormone at specific stages of development can have effects later in life on processes such as mammary development and breast cancer initiation and progression.
-
Remyelination enables restoration of saltatory conduction and a return of normal function lost during demyelination. Unfortunately, remyelination is often incomplete in the adult human central nervous system (CNS) and this failure of remyelination is one of the main reasons for clinical deficits in demyelinating disease. An understanding of the failure of remyelination in demyelinating diseases such as Multiple Sclerosis depends upon the elucidation of cellular events underlying successful remyelination. ⋯ However, given the increasing recognition that myelin sheaths play a role in protecting axons from degeneration, the success or failure of remyelination has functional consequences for the patient. To understand why remyelination should fail in demyelinating disease and develop strategies to enhance remyelination requires an understanding of the biology of successful remyelination. Firstly, what is the origin of the remyelinating cell population in the adult CNS? Secondly, what are the dynamics of the cellular response of this population during demyelination and remyelination? And thirdly, what are the consequences to the tissue of an episode of demyelination? This review will focus on studies that address these issues, and discuss the implications of the results of these experiments for our understanding of MS and the development of therapeutic interventions aimed at enhancing remyelination.
-
There are conflicting reports in the literature concerning the use of antimalarials in psoriatic patients with arthropathy or coexisting systemic lupus erythematosus. On the basis of a review of 18 publications in English, it was estimated that up to 18% of patients with psoriasis would develop an exacerbation of their disease following antimalarial therapy. In contrast to lithium and beta-blockers, antimalarials do not induce psoriasis de novo, but they only trigger already existing psoriasis, via a pharmacologic mechanism, probably due to an alteration of the activity of enzymes involved in the epidermal proliferation process. ⋯ That antimalarial drugs only trigger latent psoriasis and do not induce psoriasis de novo can be suspected from the fact that psoriasis cleared up completely after withdrawal of the drug in only 30% of patients on antimalarials, as compared with more than 60% of those receiving lithium and nearly 50% of those receiving beta blockers. This is probably also why the incubation period of the cases induced by antimalarial drugs is much shorter than that of lithium and beta blockers. Possibly, in triggered psoriasis (as in antimalarials) the drug only sets off with a chain of pathologic events previously programmed and ready to be set off, whereas in true drug-induced cases (as in some cases of lithium and betablockers) the drug is supposed to cause more profound changes and, therefore, more time is needed for these changes to occur.