101,949 research outputs found
A revision of maximal oxygen consumption and exercise capacity at altitude 70 years after the first climb of Mount Everest
No full textOn the 70th anniversary of the first climb of Mount Everest by Edmund Hillary and Tensing Norgay, we discuss the physiological bases of climbing Everest with or without supplementary oxygen. After summarizing the data of the 1953 expedition and the effects of oxygen administration, we analyse the reasons why Reinhold Messner and Peter Habeler succeeded without supplementary oxygen in 1978. The consequences of this climb for physiology are briefly discussed. An overall analysis of maximal oxygen consumption (VO2max) at altitude follows. In this section, we discuss the reasons for the non-linear fall of VO2max at altitude, we support the statement that it is a mirror image of the oxygen equilibrium curve, and we propose an analogue of Hill's model of the oxygen equilibrium curve to analyse the VO2max fall. In the following section, we discuss the role of the ventilatory and pulmonary resistances to oxygen flow in limiting VO2max, which becomes progressively greater while moving toward higher altitudes. On top of Everest, these resistances provide most of the VO2max limitation, and the oxygen equilibrium curve and the respiratory system provide linear responses. This phenomenon is more accentuated in athletes with elevated VO2max, due to exercise-induced arterial hypoxaemia. The large differences in VO2max that we observe at sea level disappear at altitude. There is no need for a very high VO2max at sea level to climb the highest peaks on Earth. imageAbstract figure legend Maximal oxygen consumption (VO2max) shows a non-linear fall with altitude that is a mirror image of the oxygen equilibrium curve. Di Prampero and Ferretti were the first to associate the non-linear behaviour of the respiratory system to the oxygen equilibrium curve. On the other hand, Wagner constructed his convective curve accounting for the effects of the oxygen equilibrium curve. The decrease is more accentuated in athletic subjects with elevated VO2max compared to those who are non-athletic, so that the large differences in VO2max that are observed at sea level disappear at altitude. Such consequences are due to the effect of ventilatory and pulmonary resistances to oxygen flow in limiting VO2max, which becomes progressively greater while moving toward higher altitudes compared to that of the cardiovascular resistance. On top of Everest, the pulmonary resistances provide most of the VO2max limitation and the respiratory system provides linear responses. imag
Should Travelers with Hypertension Adjust Their Medications When Traveling to High Altitude?
No full textProgetto vincitore del concorso internazionale per il restauro dell'Orto Botanico di Padova
No full textAcute mountain sickness in a subject with metabolic syndrome at high altitude
No full textVisitors at high altitude are increasing in age and comorbidities, which can lead
to a failure in acclimatization. We describe the development of acute mountain
sickness (AMS) in a 44-year-old man with metabolic syndrome and the time- and
altitude-dependent correlation between the development of AMS and blood pressure
and heart rate changes. Our observations support a dominant role of endothelial
dysfunction in the pathogenesis of AMS and suggest new behavioral indications
Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus
No full textA combined computational and experimental approach to human osteocalcin and GPCR Family C Group 6 Member A
No full textINTRODUCTION. The use of mouse genetics recently highlighted coordination by endocrine regulation between bone, energy metabolism, and endogenous sex hormones. Osteocalcin, a bone matrix protein that regulates hydroxyapatite size and shape through its vitamin‑K-dependent γ‑carboxylated form, unraveled endocrinological functions in its circulating forms, that are not only simple markers of bone formation. Undercarboxylated osteocalcin administration regulates gene and protein expression in adipocytes, in pancreatic β cells, and in Leydig cells by a G protein-coupled receptor, GPRC6A receptor, with a potential gender selectivity. Total serum osteocalcin concentrations in humans are inversely associated with measures of glucose metabolism and cardiovascular risk factors; however, human data are inconclusive with regard to the role of uncarboxylated osteocalcin because most studies do not account for the influence of vitamin K or differentiate between the different γ‑carboxylated forms of osteocalcin. Intriguingly GPRC6A receptor mediates also the non-genomic effects of androgens and, although the information about SHBG-receptor structure is not conclusive, evidence seems to suggest that a G protein-coupled receptor is involved.
AIM of the STUDY. Starting from clinical observations, we investigated the protein-protein interaction computational predictors of osteocalcin and SHBG with GPRC6A receptor, and we validated experimentally in vitro in a two-step approach.
MATHERIAL and METHODS. Clinical and biochemical characteristics were studied in a cohort of 91 obese patients and healthy controls in a cross-sectional study. 3-D protein structure alignment analysis and protein docking analysis were resolved with a four (i.e. TM-align, FATCAT, TriangleMatch, TopMatch) and three (i.e. GRAMM-X, ZDOCK, PatchDock) different algorithms approach, respectively. ClickMD-min script was used as a molecular dynamic platform for computational analysis of the conformational structure of osteocalcin in presence or absence of Ca2+, developed with MOE software. Steered molecular dynamics simulations related to the carboxylation state were performed, and the data compared with the spectroscopic techniques results. Gene and protein expression analysis and cell-surface receptor binding assays (i.e. immunofluorescence and flow cytometry analysis) on HEK-293T cells experimentally validated the former results in vitro.
RESULTS. Our study shows for the first time the existence of the competition for a specific binding site between osteocalcin and SHBG on human cells expressing GPRC6A receptor. The results are supported by a computational prediction analysis, describing amino acid residues of SHBG from Gly145 to Leu161 as a highly predicted interface. Our experiments describe the structure of human osteocalcin in its carboxylated and undercarboxylated forms for the first time. The influence of the binding of calcium on osteocalcin structure seems to be stronger than the presence of γ-carboxylated glutamic acid residues. Our clinical data show an imbalance between the γ‑carboxylated forms of osteocalcin in a cohort of hypogonadic obese an overweight patients, with decreased levels of SHBG and altered levels of the other sex hormones.
CONCLUSIONS. The current two-step approach offers a target approach of investigation directly in humans, that has the potential to identify novel pathophysiological pathways as well as novel therapeutic possibilities. The computational basis of the possible binding of SHBG and osteocalcin has been experimentally validated and can directly lead to the synthesis of a peptide, whose physiological and therapeutic implications represent a feasible perspective for future research in an area of paramount importance, such as the cross-talk between bone, energy metabolism, and endogenous sex hormones
Comment on: Acute kidney injury and rhabdomyolysis: a role for the regulator of G-protein signaling (RGS)-2
No full text
- …
