Cold-Water Mediates Greater Reductions in Limb Blood Flow than Whole Body Cryotherapy.

PURPOSE: Cold-water immersion (CWI) and whole body cryotherapy (WBC) are widely used recovery methods in an attempt to limit exercise-induced muscle damage, soreness and functional deficits after strenuous exercise. The aim of this study was to compare the effects of ecologically-valid CWI and WBC protocols on post-exercise lower limb thermoregulatory, femoral artery and cutaneous blood flow responses. METHODS: Ten males completed a continuous cycle exercise protocol at 70% maximal oxygen uptake until a rectal temperature of 38°C was attained. Participants were then exposed to lower-body CWI (8°C) for 10 min, or WBC (-110°C) for 2 min, in a randomized cross-over design. Rectal and thigh skin, deep and superficial muscle temperatures, thigh and calf skin blood flow (laser Doppler flowmetry), superficial femoral artery blood flow (duplex ultrasound) and arterial blood pressure were measured prior to, and for 40 min post, cooling interventions. RESULTS: Greater reductions in thigh skin (CWI, -5.9±1.8°C; WBC, 0.2±0.5°C; P < 0.001) and superficial (CWI, -4.4±1.3°C; WBC, -1.8±1.1°C; P < 0.001) and deep (CWI, -2.9±0.8°C; WBC, -1.3±0.6°C; P < 0.001) muscle temperatures occurred immediately after CWI. Decreases in femoral artery conductance were greater after CWI (CWI, -84±11%; WBC, -59±21%, P < 0.02) and thigh (CWI, -80±5%; WBC, -59±14%, P < 0.001) and calf (CWI, -73±13%; WBC, -45±17%, P < 0.001) cutaneous vasoconstriction was greater following CWI. Reductions in rectal temperature were similar between conditions after cooling (CWI, -0.6±0.4°C; WBC, -0.6±0.3°C; P = 0.98). CONCLUSION: Greater reductions in blood flow and tissue temperature were observed after CWI in comparison to WBC. These novel findings have practical and clinical implications for the use of cooling in the recovery from exercise and injury

"I am in other people's hands as regards my health" A sociological critique of health care encounters of people with cirrhosis. A secondary analysis

OBJECTIVES: People with cirrhosis are encouraged to participate in shared decision-making with their doctors, but studies suggest that doctors limit the amount of information that is shared. In this study we explore the presence of medical power in clinical encounters in 2015 from a patient perspective and highlight its effects on healthcare interactions. METHODS: Qualitative semi-structured interviews were conducted with ten people with cirrhosis attending a tertiary liver transplant centre in southern England. We explored their understanding of their disease and prognosis, and their participation in decision-making. Using the lens of medical power as a framework, we analysed findings into thematic sentences to summarise key ideas whilst preserving the complexity of identified concepts. RESULTS: Three key concepts explained patient perspectives of their communication with doctors: (1) portraying a positive image to doctors, (2) avoiding confrontation with doctors, (3) feeling powerless in the face of doctors' medical knowledge. These concepts show deeper dynamic issues of power during healthcare encounters, illustrated by participants' reluctance to voice their concerns and express themselves, challenge decisions, or seek information. CONCLUSION: People with cirrhosis struggle to articulate their concerns or challenge decisions on their care and treatment and may worry about potential consequences. Our findings demonstrate the continuing persistence of issues of power at play in contemporary health care

Scaling Up Towards International Targets for AIDS, Tuberculosis, and Malaria: Contribution of Global Fund-Supported Programs in 2011–2015

OBJECTIVE: The paper projects the contribution to 2011-2015 international targets of three major pandemics by programs in 140 countries funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria, the largest external financier of tuberculosis and malaria programs and a major external funder of HIV programs in low and middle income countries. DESIGN: Estimates, using past trends, for the period 2011-2015 of the number of persons receiving antiretroviral (ARV) treatment, tuberculosis case detection using the internationally approved DOTS strategy, and insecticide-treated nets (ITNs) to be delivered by programs in low and middle income countries supported by the Global Fund compared to international targets established by UNAIDS, Stop TB Partnership, Roll Back Malaria Partnership and the World Health Organisation. RESULTS: Global Fund-supported programs are projected to provide ARV treatment to 5.5-5.8 million people, providing 30%-31% of the 2015 international target. Investments in tuberculosis and malaria control will enable reaching in 2015 60%-63% of the international target for tuberculosis case detection and 30%-35% of the ITN distribution target in sub-Saharan Africa. CONCLUSION: Global Fund investments will substantially contribute to the achievement by 2015 of international targets for HIV, TB and malaria. However, additional large scale international and domestic financing is needed if these targets are to be reached by 2015

Basolateral Sorting of Syntaxin 4 Is Dependent on Its N-terminal Domain and the AP1B Clathrin Adaptor, and Required for the Epithelial Cell Polarity

Generation of epithelial cell polarity requires mechanisms to sort plasma membrane proteins to the apical and basolateral domains. Sorting involves incorporation into specific vesicular carriers and subsequent fusion to the correct target membranes mediated by specific SNARE proteins. In polarized epithelial cells, the SNARE protein syntaxin 4 localizes exclusively to the basolateral plasma membrane and plays an important role in basolateral trafficking pathways. However, the mechanism of basolateral targeting of syntaxin 4 itself has remained poorly understood. Here we show that newly synthesized syntaxin 4 is directly targeted to the basolateral plasma membrane in polarized Madin-Darby canine kidney (MDCK) cells. Basolateral targeting depends on a signal that is centered around residues 24–29 in the N-terminal domain of syntaxin 4. Furthermore, basolateral targeting of syntaxin 4 is dependent on the epithelial cell-specific clathrin adaptor AP1B. Disruption of the basolateral targeting signal of syntaxin 4 leads to non-polarized delivery to both the apical and basolateral surface, as well as partial intercellular retention in the trans-Golgi network. Importantly, disruption of the basolateral targeting signal of syntaxin 4 leads to the inability of MDCK cells to establish a polarized morphology which suggests that restriction of syntaxin 4 to the basolateral domain is required for epithelial cell polarity

A step too far? Making health equity interventions in Namibia more sufficient

BACKGROUND: Equality of health status is the health equity goal being pursued in developed countries and advocated by development agencies such as WHO and The Rockefeller Foundation for developing countries also. Other concepts of fair distribution of health such as equity of access to medical care may not be sufficient to equalise health outcomes but, nevertheless, they may be more practical and effective in advancing health equity in developing countries. METHODS: A framework for relating health equity goals to development strategies allowing progressive redistribution of primary health care resources towards the more deprived communities is formulated. The framework is applied to the development of primary health care in post-independence Namibia. RESULTS: In Namibia health equity has been advanced through the progressive application of health equity goals of equal distribution of primary care resources per head, equality of access for equal met need and equality of utilisation for equal need. For practical and efficiency reasons it is unlikely that health equity would have been advanced further or more effectively by attempting to implement the goal of equality of health status. CONCLUSION: The goal of equality of health status may not be appropriate in many developing country situations. A stepwise approach based on progressive redistribution of medical services and resources may be more appropriate. This conclusion challenges the views of health economists who emphasise the need to select a single health equality goal and of development agencies which stress that equality of health status is the most important dimension of health equity

Deletion of the gabra2 gene results in hypersensitivity to the acute effects of ethanol but does not alter ethanol self administration

Human genetic studies have suggested that polymorphisms of the GABRA2 gene encoding the GABA(A) α2-subunit are associated with ethanol dependence. Variations in this gene also convey sensitivity to the subjective effects of ethanol, indicating a role in mediating ethanol-related behaviours. We therefore investigated the consequences of deleting the α2-subunit on the ataxic and rewarding properties of ethanol in mice. Ataxic and sedative effects of ethanol were explored in GABA(A) α2-subunit wildtype (WT) and knockout (KO) mice using a Rotarod apparatus, wire hang and the duration of loss of righting reflex. Following training, KO mice showed shorter latencies to fall than WT littermates under ethanol (2 g/kg i.p.) in both Rotarod and wire hang tests. After administration of ethanol (3.5 g/kg i.p.), KO mice took longer to regain the righting reflex than WT mice. To ensure the acute effects are not due to the gabra2 deletion affecting pharmacokinetics, blood ethanol concentrations were measured at 20 minute intervals after acute administration (2 g/kg i.p.), and did not differ between genotypes. To investigate ethanol's rewarding properties, WT and KO mice were trained to lever press to receive increasing concentrations of ethanol on an FR4 schedule of reinforcement. Both WT and KO mice self-administered ethanol at similar rates, with no differences in the numbers of reinforcers earned. These data indicate a protective role for α2-subunits, against the acute sedative and ataxic effects of ethanol. However, no change was observed in ethanol self administration, suggesting the rewarding effects of ethanol remain unchange

Syntaxin 16 is a master recruitment factor for cytokinesis

Recently it was shown that both recycling endosome and endosomal sorting complex required for transport (ESCRT) components are required for cytokinesis, in which they are believed to act in a sequential manner to bring about secondary ingression and abscission, respectively. However, it is not clear how either of these complexes is targeted to the midbody and whether their delivery is coordinated. The trafficking of membrane vesicles between different intracellular organelles involves the formation of soluble N-ethylmalei­mide–sensitive factor attachment protein receptor (SNARE) complexes. Although membrane traffic is known to play an important role in cytokinesis, the contribution and identity of intracellular SNAREs to cytokinesis remain unclear. Here we demonstrate that syntaxin 16 is a key regulator of cytokinesis, as it is required for recruitment of both recycling endosome–associated Exocyst and ESCRT machinery during late telophase, and therefore that these two distinct facets of cytokinesis are inextricably linked

Interleukin-1β sequesters hypoxia inducible factor 2α to the primary cilium.

BACKGROUND: The primary cilium coordinates signalling in development, health and disease. Previously we have shown that the cilium is essential for the anabolic response to loading and the inflammatory response to interleukin-1β (IL-1β). We have also shown the primary cilium elongates in response to IL-1β exposure. Both anabolic phenotype and inflammatory pathology are proposed to be dependent on hypoxia-inducible factor 2 alpha (HIF-2α). The present study tests the hypothesis that an association exists between the primary cilium and HIFs in inflammatory signalling. RESULTS: Here we show, in articular chondrocytes, that IL-1β-induces primary cilia elongation with alterations to cilia trafficking of arl13b. This elongation is associated with a transient increase in HIF-2α expression and accumulation in the primary cilium. Prolyl hydroxylase inhibition results in primary cilia elongation also associated with accumulation of HIF-2α in the ciliary base and axoneme. This recruitment and the associated cilia elongation is not inhibited by blockade of HIFα transcription activity or rescue of basal HIF-2α expression. Hypomorphic mutation to intraflagellar transport protein IFT88 results in limited ciliogenesis. This is associated with increased HIF-2α expression and inhibited response to prolyl hydroxylase inhibition. CONCLUSIONS: These findings suggest that ciliary sequestration of HIF-2α provides negative regulation of HIF-2α expression and potentially activity. This study indicates, for the first time, that the primary cilium regulates HIF signalling during inflammation

RNA secondary structure prediction from multi-aligned sequences

It has been well accepted that the RNA secondary structures of most functional non-coding RNAs (ncRNAs) are closely related to their functions and are conserved during evolution. Hence, prediction of conserved secondary structures from evolutionarily related sequences is one important task in RNA bioinformatics; the methods are useful not only to further functional analyses of ncRNAs but also to improve the accuracy of secondary structure predictions and to find novel functional RNAs from the genome. In this review, I focus on common secondary structure prediction from a given aligned RNA sequence, in which one secondary structure whose length is equal to that of the input alignment is predicted. I systematically review and classify existing tools and algorithms for the problem, by utilizing the information employed in the tools and by adopting a unified viewpoint based on maximum expected gain (MEG) estimators. I believe that this classification will allow a deeper understanding of each tool and provide users with useful information for selecting tools for common secondary structure predictions.Comment: A preprint of an invited review manuscript that will be published in a chapter of the book `Methods in Molecular Biology'. Note that this version of the manuscript may differ from the published versio

Early Gas Stripping as the Origin of the Darkest Galaxies in the Universe

The known galaxies most dominated by dark matter (Draco, Ursa Minor and Andromeda IX) are satellites of the Milky Way and the Andromeda galaxies. They are members of a class of faint galaxies, devoid of gas, known as dwarf spheroidals, and have by far the highest ratio of dark to luminous matter. None of the models proposed to unravel their origin can simultaneously explain their exceptional dark matter content and their proximity to a much larger galaxy. Here we report simulations showing that the progenitors of these galaxies were probably gas-dominated dwarf galaxies that became satellites of a larger galaxy earlier than the other dwarf spheroidals. We find that a combination of tidal shocks and ram pressure swept away the entire gas content of such progenitors about ten billion years ago because heating by the cosmic ultraviolet background kept the gas loosely bound: a tiny stellar component embedded in a relatively massive dark halo survived until today. All luminous galaxies should be surrounded by a few extremely dark-matter-dominated dwarf spheroidal satellites, and these should have the shortest orbital periods among dwarf spheroidals because they were accreted early.Comment: Published in Nature (15 February 2007), 28 pages, 8 figures, Supplementary Information include