The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population

Background: The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of Pck1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. \ud \ud Methods: We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. \ud \ud Results: Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). \ud \ud Conclusion: This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group. \ud \ud Trial registration: UKADS Trial Registration: ISRCTN38297969

Group interventions to improve health outcomes : a framework for their design and delivery

Peer reviewedPublisher PD

Rehabilitation Enablement in Chronic Heart Failure—a facilitated self-care rehabilitation intervention in patients with heart failure with preserved ejection fraction (REACH-HFpEF) and their caregivers:rationale and protocol for a single-centre pilot randomised controlled trial

This is the final version of the article. Available from the publisher via the DOI in this record.INTRODUCTION: The Rehabilitation EnAblement in CHronic Heart Failure in patients with Heart Failure (HF) with preserved ejection fraction (REACH-HFpEF) pilot trial is part of a research programme designed to develop and evaluate a facilitated, home-based, self-help rehabilitation intervention to improve self-care and quality of life (QoL) in heart failure patients and their caregivers. We will assess the feasibility of a definitive trial of the REACH-HF intervention in patients with HFpEF and their caregivers. The impact of the REACH-HF intervention on echocardiographic outcomes and bloodborne biomarkers will also be assessed. METHODS AND ANALYSIS: A single-centre parallel two-group randomised controlled trial (RCT) with 1:1 individual allocation to the REACH-HF intervention plus usual care (intervention) or usual care alone (control) in 50 HFpEF patients and their caregivers. The REACH-HF intervention comprises a REACH-HF manual with supplementary tools, delivered by trained facilitators over 12 weeks. A mixed methods approach will be used to assess estimation of recruitment and retention rates; fidelity of REACH-HF manual delivery; identification of barriers to participation and adherence to the intervention and study protocol; feasibility of data collection and outcome burden. We will assess the variance in study outcomes to inform a definitive study sample size and assess methods for the collection of resource use and intervention delivery cost data to develop the cost-effectiveness analyses framework for any future trial. Patient outcomes collected at baseline, 4 and 6 months include QoL, psychological well-being, exercise capacity, physical activity and HF-related hospitalisation. Caregiver outcomes will also be assessed, and a substudy will evaluate impact of the REACH-HF manual on resting global cardiovascular function and bloodborne biomarkers in HFpEF patients. ETHICS AND DISSEMINATION: The study is approved by the East of Scotland Research Ethics Service (Ref: 15/ES/0036). Findings will be disseminated via journals and presentations to clinicians, commissioners and service users. TRIAL REGISTRATION NUMBER: ISRCTN78539530; Pre-results .This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-1210-12004). NB, CA, CJG and RST are also supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust; KJ by CLAHRC West Midlands and SS by CLAHRC East-Midlands. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Healt

Monkey Steering Responses Reveal Rapid Visual-Motor Feedback

The neural mechanisms underlying primate locomotion are largely unknown. While behavioral and theoretical work has provided a number of ideas of how navigation is controlled, progress will require direct physiolgical tests of the underlying mechanisms. In turn, this will require development of appropriate animal models. We trained three monkeys to track a moving visual target in a simple virtual environment, using a joystick to control their direction. The monkeys learned to quickly and accurately turn to the target, and their steering behavior was quite stereotyped and reliable. Monkeys typically responded to abrupt steps of target direction with a biphasic steering movement, exhibiting modest but transient overshoot. Response latencies averaged approximately 300 ms, and monkeys were typically back on target after about 1 s. We also exploited the variability of responses about the mean to explore the time-course of correlation between target direction and steering response. This analysis revealed a broad peak of correlation spanning approximately 400 ms in the recent past, during which steering errors provoke a compensatory response. This suggests a continuous, visual-motor loop controls steering behavior, even during the epoch surrounding transient inputs. Many results from the human literature also suggest that steering is controlled by such a closed loop. The similarity of our results to those in humans suggests the monkey is a very good animal model for human visually guided steering

A Functional Architecture of Optic Flow in the Inferior Parietal Lobule of the Behaving Monkey

The representation of navigational optic flow across the inferior parietal lobule was assessed using optical imaging of intrinsic signals in behaving monkeys. The exposed cortex, corresponding to the dorsal-most portion of areas 7a and dorsal prelunate (DP), was imaged in two hemispheres of two rhesus monkeys. The monkeys actively attended to changes in motion stimuli while fixating. Radial expansion and contraction, and rotation clockwise and counter-clockwise optic flow stimuli were presented concentric to the fixation point at two angles of gaze to assess the interrelationship between the eye position and optic flow signal. The cortical response depended upon the type of flow and was modulated by eye position. The optic flow selectivity was embedded in a patchy architecture within the gain field architecture. All four optic flow stimuli tested were represented in areas 7a and DP. The location of the patches varied across days. However the spatial periodicity of the patches remained constant across days at ∼950 and 1100 µm for the two animals examined. These optical recordings agree with previous electrophysiological studies of area 7a, and provide new evidence for flow selectivity in DP and a fine scale description of its cortical topography. That the functional architectures for optic flow can change over time was unexpected. These and earlier results also from inferior parietal lobule support the inclusion of both static and dynamic functional architectures that define association cortical areas and ultimately support complex cognitive function

Neuronal activity in medial superior temporal area (MST) during memory-based smooth pursuit eye movements in monkeys

We examined recently neuronal substrates for predictive pursuit using a memory-based smooth pursuit task that distinguishes the discharge related to memory of visual motion-direction from that related to movement preparation. We found that the supplementary eye fields (SEF) contain separate signals coding memory and assessment of visual motion-direction, decision not-to-pursue, and preparation for pursuit. Since medial superior temporal area (MST) is essential for visual motion processing and projects to SEF, we examined whether MST carried similar signals. We analyzed the discharge of 108 MSTd neurons responding to visual motion stimuli. The majority (69/108 = 64%) were also modulated during smooth pursuit. However, in nearly all (104/108 = 96%) of the MSTd neurons tested, there was no significant discharge modulation during the delay periods that required memory of visual motion-direction or preparation for smooth pursuit or not-to-pursue. Only 4 neurons of the 108 (4%) exhibited significantly higher discharge rates during the delay periods; however, their responses were non-directional and not instruction specific. Representative signals in the MSTd clearly differed from those in the SEF during memory-based smooth pursuit. MSTd neurons are unlikely to provide signals for memory of visual motion-direction or preparation for smooth pursuit eye movements

A Dual Origin of the Xist Gene from a Protein-Coding Gene and a Set of Transposable Elements

X-chromosome inactivation, which occurs in female eutherian mammals is controlled by a complex X-linked locus termed the X-inactivation center (XIC). Previously it was proposed that genes of the XIC evolved, at least in part, as a result of pseudogenization of protein-coding genes. In this study we show that the key XIC gene Xist, which displays fragmentary homology to a protein-coding gene Lnx3, emerged de novo in early eutherians by integration of mobile elements which gave rise to simple tandem repeats. The Xist gene promoter region and four out of ten exons found in eutherians retain homology to exons of the Lnx3 gene. The remaining six Xist exons including those with simple tandem repeats detectable in their structure have similarity to different transposable elements. Integration of mobile elements into Xist accompanies the overall evolution of the gene and presumably continues in contemporary eutherian species. Additionally we showed that the combination of remnants of protein-coding sequences and mobile elements is not unique to the Xist gene and is found in other XIC genes producing non-coding nuclear RNA

A systematic review and meta-synthesis of the impact of low back pain on people's lives

Copyright @ 2014 Froud et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background - Low back pain (LBP) is a common and costly problem that many interpret within a biopsychosocial model. There is renewed concern that core-sets of outcome measures do not capture what is important. To inform debate about the coverage of back pain outcome measure core-sets, and to suggest areas worthy of exploration within healthcare consultations, we have synthesised the qualitative literature on the impact of low back pain on people’s lives. Methods - Two reviewers searched CINAHL, Embase, PsycINFO, PEDro, and Medline, identifying qualitative studies of people’s experiences of non-specific LBP. Abstracted data were thematic coded and synthesised using a meta-ethnographic, and a meta-narrative approach. Results - We included 49 papers describing 42 studies. Patients are concerned with engagement in meaningful activities; but they also want to be believed and have their experiences and identity, as someone ‘doing battle’ with pain, validated. Patients seek diagnosis, treatment, and cure, but also reassurance of the absence of pathology. Some struggle to meet social expectations and obligations. When these are achieved, the credibility of their pain/disability claims can be jeopardised. Others withdraw, fearful of disapproval, or unable or unwilling to accommodate social demands. Patients generally seek to regain their pre-pain levels of health, and physical and emotional stability. After time, this can be perceived to become unrealistic and some adjust their expectations accordingly. Conclusions - The social component of the biopsychosocial model is not well represented in current core-sets of outcome measures. Clinicians should appreciate that the broader impact of low back pain includes social factors; this may be crucial to improving patients’ experiences of health care. Researchers should consider social factors to help develop a portfolio of more relevant outcome measures.Arthritis Research U

Increasing understanding of the relationship between geographic access and gendered decision-making power for treatment-seeking for febrile children in the Chikwawa district of Malawi

Background: This study used qualitative methods to investigate the relationship between geographic access and gendered intra-household hierarchies and how these influence treatment-seeking decision-making for childhood fever within the Chikwawa district of Malawi. Previous cross-sectional survey findings in the district indicated that distance from facility and associated costs are important determinants of health facility attendance in the district. This paper uses qualitative data to add depth of understanding to these findings by exploring the relationship between distance from services, anticipated costs and cultural norms of intra-household decision-making, and to identify potential intervention opportunities to reduce challenges experienced by those in remote locations. Qualitative data collection included 12 focus group discussions and 22 critical incident interviews conducted in the local language, with primary caregivers of children who had recently experienced a febrile episode. Results: Low geographic accessibility to facilities inhibited care-seeking, sometimes by extending the ‘assessment period’ for a child’s illness episode, and led to delays in seeking formal treatment, particularly when the illness occurred at night. Although carers attempted to avoid incurring costs, cash was often needed for transport and food. Whilst in all communities fathers were normatively responsible for treatment costs, mothers generally had greater access to and control over resources and autonomy in decision-making in the matrilineal and matrilocal communities in the central part of the district, which were also closer to formal facilities. Conclusions: This study illustrates the complex interplay between geographic access and gender dynamics in shaping decisions on whether and when formal treatment is sought for febrile children in Chikwawa District. Geographic marginality and cultural norms intersect in remote areas both to increase the logistical and anticipated financial barriers to utilising services and to reduce caretakers’ autonomy to act quickly once they recognize the need for formal care. Health education campaigns should be based within communities, engaging all involved in treatment-seeking decision-making, including men and grandmothers, and should aim to promote the ability of junior women to influence the treatment-seeking process. Both mothers’ financial autonomy and fathers financial contributions are important to enable timely access to effective healthcare for children with malaria

The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro

The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro. Abou El Hassan MA, Verheul HM, Jorna AS, Schalkwijk C, van Bezu J, van der Vijgh WJ, Bast A. Department of Medical Oncology, Free University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. [email protected] Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against doxorubicin-induced cardiotoxicity in vivo. It is not known yet whether monoHER can also protect against doxorubicin-induced inflammatory effects. The aim of the present study was (1) to illustrate the inflammatory effects of doxorubicin in vitro and (2) to evaluate a possibly protective effect of monoHER. In order to demonstrate the inflammatory effects of doxorubicin and the possible protection of monoHER, proliferating human umbilical cord vascular endothelial cells (HUVECs) were incubated with different concentrations of doxorubicin ranging from 12.5 to 600 nM with(out) 200 micro M monoHER. Resting (confluent) HUVECs were incubated with (0.5-25 micro M) doxorubicin with(out) monoHER (0.2-1.2 mM) and the viability of endothelial cells and their propensity to adhere to neutrophils were measured 24 h after treatment. The localisation of adhered neutrophils was determined with immunofluorescence microscopy. To further characterise the mechanism of doxorubicin-induced neutrophil adhesion, the expression of the HUVECs surface adhesion molecules was determined after doxorubicin treatment. Doxorubicin decreased the viability and proliferation capacity of HUVECs in a concentration-dependent manner. The proliferating HUVECs were much more sensitive to doxorubicin (IC(50)=60.0+/-20.8 nM) than resting cells (LC(50)=4.0+/-0.3 micro M). Doxorubicin also increased the adhesion of neutrophils reaching a plateau value at a doxorubicin concentration of > or =0.4 micro M (P=0.0113). The induced neutrophil adhesion was accompanied by overexpression of VCAM and E-selectin but not ICAM. Although monoHER did not reverse the effect of doxorubicin on the proliferation of endothelial cells, it significantly protected resting HUVECs against the cytotoxic effect of doxorubicin (< or =25 micro M, P<0.0015). In addition, monoHER completely protected against the stimulatory effect of doxorubicin on neutrophil adhesion, and inhibited the doxorubin-induced expression of VCAM and E-selectin on the surface of treated HUVECs. This study illustrates that monoHER, which protects against doxorubicin's cardiotoxic effect, can also protect against doxorubicin-induced inflammatory effects. These data prompt further investigation about the possible link between doxorubicin-induced inflammatory effects and its cardiotoxicity in viv