Ca2+-Dependent Phosphorylation of RyR2 Can Uncouple Channel Gating from Direct Cytosolic Ca2+ Regulation

Phosphorylation of the cardiac ryanodine receptor (RyR2) is thought to be important not only for normal cardiac excitation-contraction coupling but also in exacerbating abnormalities in Ca2+ homeostasis in heart failure. Linking phosphorylation to specific changes in the single-channel function of RyR2 has proved very difficult, yielding much controversy within the field. We therefore investigated the mechanistic changes that take place at the single-channel level after phosphorylating RyR2 and, in particular, the idea that PKA-dependent phosphorylation increases RyR2 sensitivity to cytosolic Ca2+. We show that hyperphosphorylation by exogenous PKA increases open probability (Po) but, crucially, RyR2 becomes uncoupled from the influence of cytosolic Ca2+; lowering [Ca2+] to subactivating levels no longer closes the channels. Phosphatase (PP1) treatment reverses these gating changes, returning the channels to a Ca2+-sensitive mode of gating. We additionally found that cytosolic incubation with Mg2+/ATP in the absence of exogenously added kinase could phosphorylate RyR2 in approximately 50% of channels, thereby indicating that an endogenous kinase incorporates into the bilayer together with RyR2. Channels activated by the endogenous kinase exhibited identical changes in gating behavior to those activated by exogenous PKA, including uncoupling from the influence of cytosolic Ca2+. We show that the endogenous kinase is both Ca2+-dependent and sensitive to inhibitors of PKC. Moreover, the Ca2+-dependent, endogenous kinase–induced changes in RyR2 gating do not appear to be related to phosphorylation of serine-2809. Further work is required to investigate the identity and physiological role of this Ca2+-dependent endogenous kinase that can uncouple RyR2 gating from direct cytosolic Ca2+ regulation

Childbearing postponement and child well-being: a complex and varied relationship?

Over the past several decades, U.S. fertility has followed a trend toward the postponement of motherhood. The socioeconomic causes and consequences of this trend have been the focus of attention in the demographic literature. Given the socioeconomic advantages of those who postpone having children, some authors have argued that the disadvantage experienced by certain groups would be reduced if they postponed their births. The weathering hypothesis literature, by integrating a biosocial perspective, complicates this argument and posits that the costs and benefits of postponement may vary systematically across population subgroups. In particular, the literature on the weathering hypothesis argues that as a consequence of their unique experiences of racism and disadvantage, African American women may experience a more rapid deterioration of their health, which could offset or eventually reverse any socioeconomic benefit of postponement. But because very few African American women postpone motherhood, efforts to find compelling evidence to support the arguments of this perspective rely on a strategy of comparison that is problematic because a potentially selected group of older black mothers are used to represent the costs of postponement. This might explain why the weathering hypothesis has played a rather limited role in the way demographers conceptualize postponement and its consequences for well-being. In order to explore the potential utility of this perspective, we turn our attention to the UK context. Because first-birth fertility schedules are similar for black and white women, we can observe (rather than assume) whether the meaning and consequences of postponement vary across these population subgroups. The results, obtained using linked UK census and birth record data, reveal evidence consistent with the weathering hypothesis in the United Kingdom and lend support to the arguments that the demographic literature would benefit from integrating insights from this biosocial perspective

Development and validation of a questionnaire to measure moral distress in community pharmacists

The Author(s) 2016. . This article is published with open access at Springerlink.com This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Jayne L. Astbury, and Cathal T. Gallagher, 'Development and validation of a questionnaire to measure moral distress in community pharmacists', International Journal of Clinical Pharmacy (2017) Vol 39(1): 156-164, first published online on 22 December 2016, the version of record is available on line via doi: 10.1007/s11096-016-0413-3 Funding for this work was provided by Pharmacy Research UK (PRUK).Background Pharmacists work within a highly-regulated occupational sphere, and are bound by strict legal frameworks and codes of professional conduct. This regulatory environment creates the potential for moral distress to occur due to the limitations it places on acting in congruence with moral judgements. Very little research regarding this phenomenon has been undertaken in pharmacy: thus, prominent research gaps have arisen for the development of a robust tool to measure and quantify moral distress experienced in the profession. Objective The aim of this study was to develop an instrument to measure moral distress in community pharmacists. Setting Community pharmacies in the United Kingdom. Method This study adopted a three-phase exploratory sequential mixed-method design. Three semi-structured focus groups were then conducted to allow pharmacists to identify and explore scenarios that cause moral distress. Each of the identified scenarios were developed into a statement, which was paired with twin seven-point Likert scales to measure the frequency and intensity of the distress, respectively. Content validity, reliability, and construct validity were all tested, and the questionnaire was refined. Main outcome measure The successful development of the valid instrument for use in the United Kingdom. Results This research has led to the development of a valid and reliable instrument to measure moral distress in community pharmacists in the UK. The questionnaire has already been distributed to a large sample of community pharmacists. Conclusion Results from this distribution will be used to inform the formulation of coping strategies for dealing with moral distress.Peer reviewedFinal Published versio

Ethnic differences in cancer symptom awareness and barriers to seeking medical help in England

Background: Ethnic differences in cancer symptom awareness and barriers to seeking medical help in the English population are not fully understood. We aimed to quantify these differences, to help develop more effective health campaigns, tailored to the needs of different ethnic groups. Methods: Using a large national data set (n=38492) of cross-sectional surveys that used the Cancer Research UK Cancer Awareness Measure, we examined how cancer symptom awareness and barriers varied by ethnicity, controlling for socio-economic position, age and gender. Data were analysed using multivariable logistic regression. Results: Awareness of cancer symptoms was lower in minority ethnic groups than White participants, with the lowest awareness observed among Bangladeshis and Black Africans. Ethnic minorities were more likely than White British to report barriers to helpseeking. South Asians reported the highest emotional barriers, such as lack of confidence to talk to the doctor, and practical barriers, such as worry about many other things. The Irish were more likely than the White British to report practical barriers, such as being too busy to visit a doctor. White British participants were more likely than any other ethnic group to report that they would feel worried about wasting the doctor’s time. Overall, Black Africans had the lowest barriers. All differences were statistically significant (P<0.01 level), after controlling for confounders. Conclusions: Our findings suggest the need for culturally sensitive and targeted health campaigns, focused on improving recognition of cancer symptoms among ethnic minorities. Campaigns should tackle the specific barriers prevalent in each ethnic group

Theoretical framework and methodological development of common subjective health outcome measures in osteoarthritis: a critical review

Subjective measures involving clinician ratings or patient self-assessments have become recognised as an important tool for the assessment of health outcome. The value of a health outcome measure is usually assessed by a psychometric evaluation of its reliability, validity and responsiveness. However, psychometric testing involves an accumulation of evidence and has recognised limitations. It has been suggested that an evaluation of how well a measure has been developed would be a useful additional criteria in assessing the value of a measure. This paper explored the theoretical background and methodological development of subjective health status measures commonly used in osteoarthritis research. Fourteen subjective health outcome measures commonly used in osteoarthritis research were examined. Each measure was explored on the basis of their i) theoretical framework (was there a definition of what was being assessed and was it part of a theoretical model?) and ii) methodological development (what was the scaling strategy, how were the items generated and reduced, what was the response format and what was the scoring method?). Only the AIMS, SF-36 and WHOQOL defined what they were assessing (i.e. the construct of interest) and no measure assessed was part of a theoretical model. None of the clinician report measures appeared to have implemented a scaling procedure or described the rationale for the items selected or scoring system. Of the patient self-report measures, the AIMS, MPQ, OXFORD, SF-36, WHOQOL and WOMAC appeared to follow a standard psychometric scaling method. The DRP and EuroQol used alternative scaling methods. The review highlighted the general lack of theoretical framework for both clinician report and patient self-report measures. This review also drew attention to the wide variation in the methodological development of commonly used measures in OA. While, in general the patient self-report measures had good methodological development, the clinician report measures appeared less well developed. It would be of value if new measures defined the construct of interest and, that the construct, be part of theoretical model. By ensuring measures are both theoretically and empirically valid then improvements in subjective health outcome measures should be possible

TBK1: a new player in ALS linking autophagy and neuroinflammation.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder affecting motor neurons, resulting in progressive muscle weakness and death by respiratory failure. Protein and RNA aggregates are a hallmark of ALS pathology and are thought to contribute to ALS by impairing axonal transport. Mutations in several genes known to contribute to ALS result in deposition of their protein products as aggregates; these include TARDBP, C9ORF72, and SOD1. In motor neurons, this can disrupt transport of mitochondria to areas of metabolic need, resulting in damage to cells and can elicit a neuroinflammatory response leading to further neuronal damage. Recently, eight independent human genetics studies have uncovered a link between TANK-binding kinase 1 (TBK1) mutations and ALS. TBK1 belongs to the IKK-kinase family of kinases that are involved in innate immunity signaling pathways; specifically, TBK1 is an inducer of type-1 interferons. TBK1 also has a major role in autophagy and mitophagy, chiefly the phosphorylation of autophagy adaptors. Several other ALS genes are also involved in autophagy, including p62 and OPTN. TBK1 is required for efficient cargo recruitment in autophagy; mutations in TBK1 may result in impaired autophagy and contribute to the accumulation of protein aggregates and ALS pathology. In this review, we focus on the role of TBK1 in autophagy and the contributions of this process to the pathophysiology of ALS

The Ontario Mother and Infant Study (TOMIS) III: A multi-site cohort study of the impact of delivery method on health, service use, and costs of care in the first postpartum year

Abstract Background The caesarean section rate continues to rise globally. A caesarean section is inarguably the preferred method of delivery when there is good evidence that a vaginal delivery may unduly risk the health of a woman or her infant. Any decisions about delivery method in the absence of clear medical indication should be based on knowledge of outcomes associated with different childbirth methods. However, there is lack of sold evidence of the short-term and long-term risks and benefits of a planned caesarean delivery compared to a planned vaginal delivery. It also is important to consider the economic aspects of caesarean sections, but very little attention has been given to health care system costs that take into account services used by women for themselves and their infants following hospital discharge. Methods and design The Ontario Mother and Infant Study III is a prospective cohort study to examine relationships between method of delivery and maternal and infant health, service utilization, and cost of care at three time points during the year following postpartum hospital discharge. Over 2500 women were recruited from 11 hospitals across the province of Ontario, Canada, with data collection occurring between April 2006 and October 2008. Participants completed a self-report questionnaire in hospital and structured telephone interviews at 6 weeks, 6 months, and 12 months after discharge. Data will be analyzed using generalized estimating equation, a special generalized linear models technique. A qualitative descriptive component supplements the survey approach, with the goal of assisting in interpretation of data and providing explanations for trends in the findings. Discussion The findings can be incorporated into patient counselling and discussions about the advantages and disadvantages of different delivery methods, potentially leading to changes in preferences and practices. In addition, the findings will be useful to hospital- and community-based postpartum care providers, managers, and administrators in guiding risk assessment and early intervention strategies. Finally, the research findings can provide the basis for policy modification and implementation strategies to improve outcomes and reduce costs of care