P2X receptors: epithelial ion channels and regulators of salt and water transport.

When the results from electrophysiological studies of renal epithelial cells are combined with data from in vivo tubule microperfusion experiments and immunohistochemical surveys of the nephron, the accumulated evidence suggests that ATP-gated ion channels, P2X receptors, play a specialized role in the regulation of ion and water movement across the renal tubule and are integral to electrolyte and fluid homeostasis. In this short review, we discuss the concept of P2X receptors as regulators of salt and water salvage pathways, as well as acknowledging their accepted role as ATP-gated ion channels

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

Grading of carotid artery stenosis with multidetector-row CT angiography: visual estimation or caliper measurements?

To assess the optimal method for grading carotid artery stenosis with computed tomographic angiography (CTA), we compared visual estimation to caliper measurements, and determined inter-observer variability and agreement relative to digital subtraction angiography (DSA). We included 46 patients with symptomatic carotid stenosis for whom CTA and DSA of 55 carotids was available. Stenosis quantification by CTA using visual estimation (CTAVE) (method 1) was compared with caliper measurements using subjectively optimized wide window settings (method 2) or predefined contrast-dependent narrow window settings (method 3). Measurements were independently performed by two radiologists and two residents. To determine accuracy and inter-observer variability, we calculated linear weighted kappa, performed a Bland-Altman analysis and calculated mean difference (bias) and standard deviation of differences (SDD). For inter-observer variability, kappa analysis was “very good” (0.85) for expert observers using CTAVE compared with “good” (0.61) for experts using DSA. Compared with DSA, method 1 led to overestimation (bias 5.8–8.0%, SDD 10.6–14.4), method 3 led to underestimation (bias −6.3 to −3.0%, SDD 13.0–18.1). Measurement variability between DSA and visual estimation on CTA (SDD 11.5) is close to the inter-observer variability of repeated measurements on DSA that we found in this study (SDD 11.6). For CTA of carotids, stenosis grading based on visual estimation provides better agreement to grading by DSA compared with stenosis grading based on caliper measurements

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Hypnosis for hot flashes among postmenopausal women study: A study protocol of an ongoing randomized clinical trial

<p>Abstract</p> <p>Background</p> <p>Hot flashes are a highly prevalent problem associated with menopause and breast cancer treatments. The recent findings from the Women's Health Initiative have important implications for the significance of a non-hormonal, mind-body intervention for hot flashes in breast cancer survivors. Women who take hormone therapy long-term may have a 1.2 to 2.0 fold increased risk of developing breast cancer. In addition, it is now known that hormone therapy with estrogen and progestin is associated with increased risk of cardiovascular disease and stroke. Currently there are limited options to hormone replacement therapy as non-hormonal pharmacological agents are associated with only modest activity and many adverse side effects. Because of this there is a need for more alternative, non-hormonal therapies. Hypnosis is a mind-body intervention that has been shown to reduce self-reported hot flashes by up to 68% among breast cancer survivors, however, the use of hypnosis for hot flashes among post-menopausal women has not been adequately explored and the efficacy of hypnosis in reducing physiologically measured hot flashes has not yet been determined.</p> <p>Methods/design</p> <p>A sample of 180 post-menopausal women will be randomly assigned to either a 5-session Hypnosis Intervention or 5-session structured-attention control with 12 week follow-up. The present study will compare hypnosis to a structured-attention control in reducing hot flashes (perceived and physiologically monitored) in post-menopausal women in a randomized clinical trial. Outcomes will be hot flashes (self-report daily diaries; physiological monitoring; Hot Flash Related Daily Interference Scale), anxiety (State-Trait Anxiety Inventory; Hospital Anxiety and Depression Scale (HADS); anxiety visual analog scale (VAS rating); depression (Center for Epidemiologic Studies Depression Scale), sexual functioning (Sexual Activity Questionnaire), sleep quality (Pittsburgh Sleep Quality Index) and cortisol.</p> <p>Discussion</p> <p>This study will be the first full scale test of hypnosis for hot flashes; one of the first studies to examine both perceived impact and physiologically measured impact of a mind-body intervention for hot flashes using state-of-the-art 24 hour ambulatory physiological monitoring; the first study to examine the effect of hypnosis for hot flashes on cortisol; and the first investigation of the role of cognitive expectancies in treatment of hot flashes in comparison to a Structured-Attention Control.</p> <p>Trial Registration</p> <p>This clinical trial has been registered with ClinicalTrials.gov, a service of the U.S. National Institutes of Health, ClinicalTrials.gov Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01293695">NCT01293695</a>.</p

An investigation of the effects of lipid-lowering medications: genome-wide linkage analysis of lipids in the HyperGEN study

BACKGROUND: Use of anti-hyperlipidemic medications compromises genetic analysis because of altered lipid profiles. We propose an empirical method to adjust lipid levels for medication effects so that the adjusted lipid values substitute the unmedicated lipid values in the genetic analysis. RESULTS: Published clinical trials were reviewed for HMG-CoA reductase inhibitors and fibric acid derivatives as mono-drug therapy. HMG-CoA reductase inhibitors showed similar effects in African Americans (AA) and non-African Americans (non-AA) for lowering total cholesterol (TC, -50.7 mg/dl), LDL cholesterol (LDL-C, -48.1 mg/dl), and triglycerides (TG, -19.7 mg/dl). Their effect on increasing HDL cholesterol (HDL-C) in AA (+0.4 mg/dl) was lower than in Non-AA (+2.3 mg/dl). The effects of fibric acid derivatives were estimated as -46.1 mg/dl for TC, -40.1 mg/dl for LDL-C, and +5.9 mg/dl for HDL-C in non-AA. The corresponding effects in AA were less extreme (-20.1 mg/dl, -11.4 mg/dl, and +3.1 mg/dl). Similar effect for TG (59.0 mg/dl) was shown in AA and non-AA. The above estimated effects were applied to a multipoint variance components linkage analysis on the lipid levels in 2,403 Whites and 2,214 AA in the HyperGEN study. The familial effects did vary depending on whether the lipids were adjusted for medication use. For example, the heritabilities increased after medication adjustment for TC and LDL-C, but did not change significantly for HDL-C and TG. CONCLUSION: Ethnicity-specific medication adjustments using our empirical method can be employed in epidemiological and genetic analysis of lipids.National Heart, Lung, and Blood Institute (HL554471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515

Global instability in the Ghil--Sellers model

The Ghil--Sellers model, a diffusive one-dimensional energy balance model of Earth's climate, features---for a considerable range of the parameter descriptive of the intensity of the incoming radiation---two stable climate states, where the bistability results from the celebrated ice-albedo feedback. The warm state is qualitatively similar to the present climate, while the cold state corresponds to snowball conditions. Additionally, in the region of bistability, one can find unstable climate states. We find such unstable states by applying for the first time in a geophysical context the so-called edge tracking method, which has been used for studying multiple coexisting states in shear flows. This method has a great potential for studying the global instabilities in multistable systems, and for providing crucial information on the possibility of transitions when forcing is present. We examine robustness, efficiency, and accuracy properties of the edge tracking algorithm. We find that the procedure is the most efficient when taking a single bisection per cycle. Due to the strong diffusivity of the system, the transient dynamics, is approximately confined to the heteroclininc trajectory, connecting the fixed unstable and stable states, after relatively short transient times. Such a constraint dictates a functional relationship between observables. We characterize such a relationship between the global average temperature and a descriptor of nonequilibrium thermodynamics, the large scale temperature gradient between low and high latitudes. We find that a maximum of the temperature gradient is realized at the same value of the average temperature, about 270 K, largely independent of the strength of incoming solar radiation. Due to this maximum, a transient increase and nonmonotonic evolution of the temperature gradient is possible and not untypical. We also examine the structural properties of the system defined by bifurcation diagrams describing the equilibria depending on a system parameter of interest, here the solar strength. We construct new bifurcation diagrams in terms of quantities relevant for describing thermodynamic properties such as the temperature gradient and the material entropy production due to heat transport. We compare our results for the energy balance model to results for the intermediate complexity general circulation model the Planet Simulator and find an interesting qualitative agreement

Basin-Scale Control on the Phytoplankton Biomass in Lake Victoria, Africa

The relative bio-optical variability within Lake Victoria was analyzed through the spatio-temporal decomposition of a 1997–2004 dataset of remotely-sensed reflectance ratios in the visible spectral range. Results show a regular seasonal pattern with a phase shift (around 2 months) between the south and north parts of the lake. Interannual trends suggested a teleconnection between the lake dynamics and El-Niño phenomena. Both seasonal and interannual patterns were associated to conditions of light limitation for phytoplankton growth and basin-scale hydrodynamics on phytoplankton access to light. Phytoplankton blooms developed during the periods of lake surface warming and water column stability. The temporal shift apparent in the bio-optical seasonal cycles was related to the differential cooling of the lake surface by southeastern monsoon winds. North-south differences in the exposure to trade winds are supported by the orography of the Eastern Great Rift Valley. The result is that surface layer warming begins in the northern part of the lake while the formation of cool and dense water continues in the southern part. The resulting buoyancy field is sufficient to induce a lake-wide convective circulation and the tilting of the isotherms along the north-south axis. Once surface warming spreads over the whole lake, the phytoplankton bloom dynamics are subjected to the internal seiche derived from the relaxation of thermocline tilting. In 1997–98, El-Niño phenomenon weakened the monsoon wind flow which led to an increase in water column stability and a higher phytoplankton optical signal throughout the lake. This suggests that phytoplankton response to expected climate scenarios will be opposite to that proposed for nutrient-limited great lakes. The present analysis of remotely-sensed bio-optical properties in combination with environmental data provides a novel basin-scale framework for research and management strategies in Lake Victoria

Propagation of the Madden–Julian Oscillation and scale interaction with the diurnal cycle in a high-resolution GCM

The Madden–Julian Oscillation (MJO) is the chief source of tropical intra-seasonal variability, but is simulated poorly by most state-of-the-art GCMs. Common errors include a lack of eastward propagation at the correct frequency and zonal extent, and too small a ratio of eastward- to westward-propagating variability. Here it is shown that HiGEM, a high-resolution GCM, simulates a very realistic MJO with approximately the correct spatial and temporal scale. Many MJO studies in GCMs are limited to diagnostics which average over a latitude band around the equator, allowing an analysis of the MJO’s structure in time and longitude only. In this study a wider range of diagnostics is applied. It is argued that such an approach is necessary for a comprehensive analysis of a model’s MJO. The standard analysis of Wheeler and Hendon (Mon Wea Rev 132(8):1917–1932, 2004; WH04) is applied to produce composites, which show a realistic spatial structure in the MJO envelopes but for the timing of the peak precipitation in the inter-tropical convergence zone, which bifurcates the MJO signal. Further diagnostics are developed to analyse the MJO’s episodic nature and the “MJO inertia” (the tendency to remain in the same WH04 phase from one day to the next). HiGEM favours phases 2, 3, 6 and 7; has too much MJO inertia; and dies out too frequently in phase 3. Recent research has shown that a key feature of the MJO is its interaction with the diurnal cycle over the Maritime Continent. This interaction is present in HiGEM but is unrealistically weak