AKAP95 regulates splicing through scaffolding RNAs and RNA processing factors

YesAlternative splicing of pre-mRNAs significantly contributes to the complexity of gene expression in higher organisms, but the regulation of the splice site selection remains incompletely understood. We have previously demonstrated that a chromatin-associated protein, AKAP95 (AKAP8), has a remarkable activity in enhancing chromatin transcription. In this study, we have shown that AKAP95 physically interacts with many factors involved in transcription and RNA processing, and functionally regulates pre-mRNA splicing. AKAP95 directly promotes splicing in vitro and the inclusion of a specific exon of an endogenous gene FAM126A. The N-terminal YG-rich domain of AKAP95 is important for its binding to RNA processing factors including selective groups of hnRNP proteins, and its zinc finger domains are critical for pre-mRNA binding. Genome-wide binding assays revealed that AKAP95 bound preferentially to proximal intronic regions on a large number of pre-mRNAs in human transcriptome, and AKAP95 depletion predominantly resulted in reduced inclusion of many exons. AKAP95 also selectively coordinates with hnRNP H/F and U proteins in regulating alternative splicing events. We have further shown that AKAP95 directly interacts with itself. Taken together, our results establish AKAP95 as a novel and mostly positive regulator of premRNA splicing and a possible integrator of transcription and splicing regulation, and support a model that AKAP95 facilitates the splice site communication by looping out introns through both RNA-binding and protein-protein interaction.This work was supported by a UAB start-up fund to H.J

Implementing the chronic care model for frail older adults in the Netherlands: study protocol of ACT (frail older adults: care in transition)

<p>Abstract</p> <p>Background</p> <p>Care for older adults is facing a number of challenges: health problems are not consistently identified at a timely stage, older adults report a lack of autonomy in their care process, and care systems are often confronted with the need for better coordination between health care professionals. We aim to address these challenges by introducing the geriatric care model, based on the chronic care model, and to evaluate its effects on the quality of life of community-dwelling frail older adults.</p> <p>Methods/design</p> <p>In a 2-year stepped-wedge cluster randomised clinical trial with 6-monthly measurements, the chronic care model will be compared with usual care. The trial will be carried out among 35 primary care practices in two regions in the Netherlands. Per region, practices will be randomly allocated to four allocation arms designating the starting point of the intervention. <it>Participants</it>: 1200 community-dwelling older adults aged 65 or over and their primary informal caregivers. Primary care physicians will identify frail individuals based on a composite definition of frailty and a polypharmacy criterion. Final inclusion criterion: scoring 3 or more on a disability case-finding tool. <it>Intervention</it>: Every 6 months patients will receive a geriatric in-home assessment by a practice nurse, followed by a tailored care plan. Expert teams will manage and train practice nurses. Patients with complex care needs will be reviewed in interdisciplinary consultations. <it>Evaluation</it>: We will perform an effect evaluation, an economic evaluation, and a process evaluation. Primary outcome is quality of life as measured with the Short Form-12 questionnaire. Effect analyses will be based on the “intention-to-treat” principle, using multilevel regression analysis. Cost measurements will be administered continually during the study period. A cost-effectiveness analysis and cost-utility analysis will be conducted comparing mean total costs to functional status, care needs and QALYs. We will investigate the level of implementation, barriers and facilitators to successful implementation and the extent to which the intervention manages to achieve the transition necessary to overcome challenges in elderly care.</p> <p>Discussion</p> <p>This is one of the first studies assessing the effectiveness, cost-effectiveness and implementation process of the chronic care model for frail community-dwelling older adults.</p> <p>Trial registration</p> <p>The Netherlands National Trial Register NTR2160.</p

Methods of nutrition surveillance in low-income countries

Background In 1974 a joint FAO/UNICEF/WHO Expert Committee met to develop methods for nutrition surveillance. There has been much interest and activity in this topic since then, however there is a lack of guidance for practitioners and confusion exists around the terminology of nutrition surveillance. In this paper we propose a classification of data collection activities, consider the technical issues for each category, and examine the potential applications and challenges related to information and communication technology. Analysis There are three major approaches used to collect primary data for nutrition surveillance: repeated cross-sectional surveys; community-based sentinel monitoring; and the collection of data in schools. There are three major sources of secondary data for surveillance: from feeding centres, health facilities, and community-based data collection, including mass screening for malnutrition in children. Surveillance systems involving repeated surveys are suitable for monitoring and comparing national trends and for planning and policy development. To plan at a local level, surveys at district level or in programme implementation areas are ideal, but given the usually high cost of primary data collection, data obtained from health systems are more appropriate provided they are interpreted with caution and with contextual information. For early warning, data from health systems and sentinel site assessments may be valuable, if consistent in their methods of collection and any systematic bias is deemed to be steady. For evaluation purposes, surveillance systems can only give plausible evidence of whether a programme is effective. However the implementation of programmes can be monitored as long as data are collected on process indicators such as access to, and use of, services. Surveillance systems also have an important role to provide information that can be used for advocacy and for promoting accountability for actions or lack of actions, including service delivery. Conclusion This paper identifies issues that affect the collection of nutrition surveillance data, and proposes definitions of terms to differentiate between diverse sources of data of variable accuracy and validity. Increased interest in nutrition globally has resulted in high level commitments to reduce and prevent undernutrition. This review helps to address the need for accurate and regular data to convert these commitments into practice

Nurse-Led Medicines' Monitoring for Patients with Dementia in Care Homes: A Pragmatic Cohort Stepped Wedge Cluster Randomised Trial

People with dementia are susceptible to adverse drug reactions (ADRs). However, they are not always closely monitored for potential problems relating to their medicines: structured nurse-led ADR Profiles have the potential to address this care gap. We aimed to assess the number and nature of clinical problems identified and addressed and changes in prescribing following introduction of nurse-led medicines' monitoring.Pragmatic cohort stepped-wedge cluster Randomised Controlled Trial (RCT) of structured nurse-led medicines' monitoring versus usual care.Five UK private sector care homes.41 service users, taking at least one antipsychotic, antidepressant or anti-epileptic medicine.Nurses completed the West Wales ADR (WWADR) Profile for Mental Health Medicines with each participant according to trial step.Problems addressed and changes in medicines prescribed.Information was collected from participants' notes before randomisation and after each of five monthly trial steps. The impact of the Profile on problems found, actions taken and reduction in mental health medicines was explored in multivariate analyses, accounting for data collection step and site.Five of 10 sites and 43 of 49 service users approached participated. Profile administration increased the number of problems addressed from a mean of 6.02 [SD 2.92] to 9.86 [4.48], effect size 3.84, 95% CI 2.57-4.11, P <0.001. For example, pain was more likely to be treated (adjusted Odds Ratio [aOR] 3.84, 1.78-8.30), and more patients attended dentists and opticians (aOR 52.76 [11.80-235.90] and 5.12 [1.45-18.03] respectively). Profile use was associated with reduction in mental health medicines (aOR 4.45, 1.15-17.22).The WWADR Profile for Mental Health Medicines can improve the quality and safety of care, and warrants further investigation as a strategy to mitigate the known adverse effects of prescribed medicines.ISRCTN 48133332

Adenosine A2A receptors: localization and function

Adenosine is an endogenous purine nucleoside present in all mammalian tissues, that originates from the breakdown of ATP. By binding to its four receptor subtypes (A1, A2A, A2B, and A3), adenosine regulates several important physiological functions at both the central and peripheral levels. Therefore, ligands for the different adenosine receptors are attracting increasing attention as new potential drugs to be used in the treatment of several diseases. This chapter is aimed at providing an overview of adenosine metabolism, adenosine receptors localization and their signal transduction pathways. Particular attention will be paid to the biochemistry and pharmacology of A2A receptors, since antagonists of these receptors have emerged as promising new drugs for the treatment of Parkinson's disease. The interactions of A2A receptors with other nonadenosinergic receptors, and the effects of the pharmacological manipulation of A2A receptors on different body organs will be discussed, together with the usefulness of A2A receptor antagonists for the treatment of Parkinson's disease and the potential adverse effects of these drugs