Fuel Use during Exercise at Altitude in Women with Glucose–Fructose Ingestion

Purpose: This study compared the co-ingestion of glucose and fructose on exogenous and endogenous substrate oxidation during prolonged exercise at terrestrial high altitude (HA) versus sea level, in women. Method: Five women completed two bouts of cycling at the same relative workload (55% Wmax) for 120 minutes on acute exposure to HA (3375m) and at sea level (~113m). In each trial, participants ingested 1.2 g.min-1 of glucose (enriched with 13C glucose) and 0.6 g.min-1 of fructose (enriched with 13C fructose) before and every 15 minutes during exercise. Indirect calorimetry and isotope ratio mass spectrometry were used to calculate fat oxidation, total and exogenous carbohydrate oxidation, plasma glucose oxidation and endogenous glucose oxidation derived from liver and muscle glycogen. Results: The rates and absolute contribution of exogenous carbohydrate oxidation was significantly lower at HA compared with sea level (ES>0.99, P<0.024), with the relative exogenous carbohydrate contribution approaching significance (32.6±6.1 vs. 36.0±6.1%, ES=0.56, P=0.059) during the second hour of exercise. In comparison, no significant differences were observed between HA and sea level for the relative and absolute contributions of liver glucose (3.2±1.2 vs. 3.1±0.8%, ES=0.09, P=0.635 and 5.1±1.8 vs. 5.4±1.7 grams, ES=0.19, P=0.217), and muscle glycogen (14.4±12.2% vs. 15.8±9.3%, ES=0.11, P=0.934 and 23.1±19.0 vs. 28.7±17.8 grams, ES=0.30, P=0.367). Furthermore, there was no significant difference in total fat oxidation between HA and sea level (66.3±21.4 vs. 59.6±7.7 grams, ES=0.32, P=0.557). Conclusion: In women, acute exposure to HA reduces the reliance on exogenous carbohydrate oxidation during cycling at the same relative exercise intensity

Oral Bisphosphonates and Risk of Atrial Fibrillation and Flutter in Women: A Self-Controlled Case-Series Safety Analysis

Background: A recent trial unexpectedly reported that atrial fibrillation, when defined as serious, occurred more often in participants randomized to an annual infusion of the relatively new parenteral bisphosphonate, zoledronic acid, than among those given placebo, but had limited power. Two subsequent population-based case-control studies of patients receiving a more established oral bisphosphonate, alendronic acid, reported conflicting results, possibly due to uncontrolled confounding factors.Methodology/Principal Findings: We used the United Kingdom General Practice Research Database to assess the risk of atrial fibrillation and flutter in women exposed to the oral bisphosphonates, alendronic acid and risedronate sodium. The self-controlled case-series method was used to minimise the potential for confounding. The age-adjusted incidence rate ratio for atrial fibrillation or flutter in individuals during their exposure to these oral bisphosphonates (n = 2195) was 1.07 (95% CI 0.94 - 1.21). The age-adjusted incidence rate ratio for alendronic acid (n = 1489) and risedronate sodium (n = 649) exposed individuals were 1.09 (95% CI 0.93 - 1.26) and 0.99 (95% CI 0.78 - 1.26) respectively. In post-hoc analyses, an increased risk of incident atrial fibrillation or flutter was detected for patients during their first few months of alendronic acid therapy.Conclusions/Significance: We found no robust evidence of an overall long-term increased risk of atrial fibrillation or flutter associated with continued exposure to the oral bisphosphonates, alendronic acid and risedronate sodium. A possible signal for an increase in risk during the first few months of therapy with alendronic acid needs to be re-assessed in additional studies

Loss of migratory traditions makes the endangered patagonian Huemul deer a year-round refugee in its summer habitat

The huemul (Hippocamelus bisulcus) is endangered, with 1500 deer split into >100 subpopulations along 2000 km of the Andes. Currently occupied areas are claimed-erroneously-to be critical prime habitats. We analyzed historical spatiotemporal behavior since current patterns represent only a fraction of pre-Columbian ones. Given the limited knowledge, the first group (n = 6) in Argentina was radio-marked to examine spatial behavior. Historically, huemul resided year-round in winter ranges, while some migrated seasonally, some using grasslands >200 km east of their current presence, reaching the Atlantic. Moreover, huemul anatomy is adapted to open unforested habitats, also corroborated by spotless fawns. Extreme naivety towards humans resulted in early extirpation on many winter ranges—preferentially occupied by humans, resulting in refugee huemul on surrounding mountain summer ranges. Radio-marked huemul remained in small ranges with minimal altitudinal movements, as known from other subpopulations. However, these resident areas documented here are typical summer ranges as evidenced by past migrations, and current usage for livestock. The huemul is the only cervid known to use mountain summer ranges year-round in reaction to anthropogenic activities. Losing migratory traditions is a major threat, and may explain their presently prevalent skeletal diseases, reduced longevity, and lacking recolonizations for most remaining huemul subpopulations.Fil: Fluck, Werner Thomas. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Universidad de Basilea; Suiza. Administración de Parques Nacionales; ArgentinaFil: Smith Flueck, Jo Anne M.. Universidad Nacional del Comahue; Argentina. Parque Protegido Shoonem; Argentina. Deer Lab; ArgentinaFil: Escobar, Miguel E.. Parque Protegido Shoonem; ArgentinaFil: Zuliani, Melina Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Fundación Bariloche; ArgentinaFil: Fuchs, Beat. Deer Lab; ArgentinaFil: Geist, Valerius. University of Calgary; CanadáFil: Heffelfinger, James R.. Arizona Game and Fish Department; Estados UnidosFil: Black de Decima, Patricia Ann. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Gizejewski, Zygmunt. Polish Academy of Sciences; ArgentinaFil: Vidal, Fernando. Univerdidad Santo Tomas; Chile. Centro de Conservacion y Manejo de Vida Silvestre; ChileFil: Barrio, Javier. Centro de Ornitología y Biodiversidad; PerúFil: Molinuevo, María Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Agrarias y Forestales. Departamento de Ciencias Biológicas; ArgentinaFil: Monjeau, Jorge Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Fundación Bariloche; ArgentinaFil: Hoby, Stefan. Berne Animal Park; SuizaFil: Jiménez, Jaime M.. University of North Texas; Estados Unido

PKCα tumor suppression in the intestine is associated with transcriptional and translational inhibition of cyclin D1

Alterations in PKC isozyme expression and aberrant induction of cyclin D1 are early events in intestinal tumorigenesis. Previous studies have identified cyclin D1 as a major target in the antiproliferative effects of PKCα in non-transformed intestinal cells; however, a link between PKC signaling and cyclin D1 in colon cancer remained to be established. The current study further characterized PKC isozyme expression in intestinal neoplasms and explored the consequences of restoring PKCα or PKCδ in a panel of colon carcinoma cell lines. Consistent with patterns of PKC expression in primary tumors, PKCα and δ levels were generally reduced in colon carcinoma cell lines, PKCβII was elevated and PKCε showed variable expression, thus establishing the suitability of these models for analysis of PKC signaling. While colon cancer cells were insensitive to the effects of PKC agonists on cyclin D1 levels, restoration of PKCα downregulated cyclin D1 by two independent mechanisms. PKCα expression consistently (a) reduced steady-state levels of cyclin D1 by a novel transcriptional mechanism not previously seen in non-transformed cells, and (b) re-established the ability of PKC agonists to activate the translational repressor 4E-BP1 and inhibit cyclin D1 translation. In contrast, PKCδ had modest and variable effects on cyclin D1 steady state levels and failed to restore responsiveness to PKC agonists. Notably, PKCα expression blocked anchorage-independent growth in colon cancer cells via a mechanism partially dependent on cyclin D1 deficiency, while PKCδ had only minor effects. Loss of PKCα and effects of its re-expression were independent of the status of the APC/β-catenin signaling pathway or known genetic alterations, indicating that they are a general characteristic of colon tumors. Thus, PKCα is a potent negative regulator of cyclin D1 expression and anchorage-independent cell growth in colon tumor cells, findings that offer important perspectives on the frequent loss of this isozyme during intestinal carcinogenesis

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD

The meta-crisis of secular capitalism

The current global economic crisis concerns the way in which contemporary capitalism has turned to financialisation as a double cure for both a falling rate of profit and a deficiency of demand. Although this turning is by no means unprecedented, policies of financialisation have depressed demand (in part as a result of the long-term stagnation of average wages) while at the same time not proving adequate to restore profits and growth. This paper argues that the current crisis is less the ‘normal’ one that has to do with a constitutive need to balance growth of abstract wealth with demand for concrete commodities. Rather, it marks a meta-crisis of capitalism that is to do with the difficulties of sustaining abstract growth as such. This meta-crisis is the tendency at once to abstract from the real economy of productive activities and to reduce everything to its bare materiality. By contrast with a market economy that binds material value to symbolic meaning, a capitalist economy tends to separate matter from symbol and reduce materiality to calculable numbers representing ‘wealth’. Such a conception of wealth rests on the aggregation of abstract numbers that cuts out all the relational goods and the ‘commons’ on which shared prosperity depends

Effects of ranolazine on astrocytes and neurons in primary culture

Ranolazine (Rn) is an antianginal agent used for the treatment of chronic angina pectoris when angina is not adequately controlled by other drugs. Rn also acts in the central nervous system and it has been proposed for the treatment of pain and epileptic disorders. Under the hypothesis that ranolazine could act as a neuroprotective drug, we studied its effects on astrocytes and neurons in primary culture. We incubated rat astrocytes and neurons in primary cultures for 24 hours with Rn (10−7, 10−6 and 10−5 M). Cell viability and proliferation were measured using trypan blue exclusion assay, MTT conversion assay and LDH release assay. Apoptosis was determined by Caspase 3 activity assay. The effects of Rn on proinflammatory mediators IL-β and TNF-α was determined by ELISA technique, and protein expression levels of Smac/Diablo, PPAR-γ, Mn-SOD and Cu/Zn-SOD by western blot technique. In cultured astrocytes, Rn significantly increased cell viability and proliferation at any concentration tested, and decreased LDH leakage, Smac/Diablo expression and Caspase 3 activity indicating less cell death. Rn also increased anti-inflammatory PPAR-γ protein expression and reduced pro-inflammatory proteins IL-1 β and TNFα levels. Furthermore, antioxidant proteins Cu/Zn-SOD and Mn-SOD significantly increased after Rn addition in cultured astrocytes. Conversely, Rn did not exert any effect on cultured neurons. In conclusion, Rn could act as a neuroprotective drug in the central nervous system by promoting astrocyte viability, preventing necrosis and apoptosis, inhibiting inflammatory phenomena and inducing anti-inflammatory and antioxidant agents

The utility of clinical decision tools for diagnosing osteoporosis in postmenopausal women with rheumatoid arthritis

BACKGROUND: Patients with rheumatoid arthritis have a higher risk of low bone mineral density than normal age matched populations. There is limited evidence to support cost effectiveness of population screening in rheumatoid arthritis and case finding strategies have been proposed as a means to increase cost effectiveness of diagnostic screening for osteoporosis. This study aimed to assess the performance attributes of generic and rheumatoid arthritis specific clinical decision tools for diagnosing osteoporosis in a postmenopausal population with rheumatoid arthritis who attend ambulatory specialist rheumatology clinics. METHODS: A cross-sectional study of 127 ambulatory post-menopausal women with rheumatoid arthritis was performed. Patients currently receiving or who had previously received bone active therapy were excluded. Eligible women underwent clinical assessment and dual-energy-xray absorptiometry (DXA) bone mineral density assessment. Clinical decision tools, including those specific for rheumatoid arthritis, were compared to seven generic post-menopausal tools to predict osteoporosis (defined as T score < -2.5). Sensitivity, specificity, positive predictive and negative predictive values and area under the curve were assessed. The diagnostic attributes of the clinical decision tools were compared by examination of the area under the receiver-operator-curve. RESULTS: One hundred and twenty seven women participated. The median age was 62 (IQR 56-71) years. Median disease duration was 108 (60-168) months. Seventy two (57%) women had no record of a previous DXA examination. Eighty (63%) women had T scores at femoral neck or lumbar spine less than -1. The area under the ROC curve for clinical decision tool prediction of T score <-2.5 varied between 0.63 and 0.76. The rheumatoid arthritis specific decision tools did not perform better than generic tools, however, the National Osteoporosis Foundation score could potentially reduce the number of unnecessary DXA tests by approximately 45% in this population. CONCLUSION: There was limited utility of clinical decision tools for predicting osteoporosis in this patient population. Fracture prediction tools that include risk factors independent of BMD are needed