Weight Considerations in Pharmacotherapy for Type 2 Diabetes

Obesity has been increasing in prevalence worldwide and the majority of patients with type 2 diabetes are either overweight or obese. Diabetes management in this population has been difficult since a number of antidiabetes agents are associated with weight gain. The effects of various antidiabetes agents and antiobesity agents on glycemic control and body weight will be reviewed. Briefly, sulfonylureas, thiazolidinediones, and insulin are associated with weight gain, whereas metformin and amylin analogs are weight neutral or associated with modest weight loss. Dipeptidyl-peptidase-4 inhibitors are weight neutral, whereas glucagon-like peptide-1 analogs are associated with weight loss. The effect of orlistat and sibutramine in type 2 diabetes is also evaluated. The treatment of diabetes should not only focus on glycemic control as its sole intention, but it should factor in the effect of these various agents on weight, as well, since obesity aggravates insulin resistance, beta cell failure, and cardiovascular risk

Interaction of cyclin-dependent kinase 12/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymerase II

CrkRS (Cdc2-related kinase, Arg/Ser), or cyclin-dependent kinase 12 (CKD12), is a serine/threonine kinase believed to coordinate transcription and RNA splicing. While CDK12/CrkRS complexes were known to phosphorylate the C-terminal domain (CTD) of RNA polymerase II (RNA Pol II), the cyclin regulating this activity was not known. Using immunoprecipitation and mass spectrometry, we identified a 65-kDa isoform of cyclin K (cyclin K1) in endogenous CDK12/CrkRS protein complexes. We show that cyclin K1 complexes isolated from mammalian cells contain CDK12/CrkRS but do not contain CDK9, a presumed partner of cyclin K. Analysis of extensive RNA-Seq data shows that the 65-kDa cyclin K1 isoform is the predominantly expressed form across numerous tissue types. We also demonstrate that CDK12/CrkRS is dependent on cyclin K1 for its kinase activity and that small interfering RNA (siRNA) knockdown of CDK12/CrkRS or cyclin K1 has similar effects on the expression of a luciferase reporter gene. Our data suggest that cyclin K1 is the primary cyclin partner for CDK12/CrkRS and that cyclin K1 is required to activate CDK12/CrkRS to phosphorylate the CTD of RNA Pol II. These properties are consistent with a role of CDK12/CrkRS in regulating gene expression through phosphorylation of RNA Pol II

Designing climate resilient schools: a case study of St Faith’s School, Cambridge

Social and political concerns are frequently reflected in the design of school buildings, often in turn leading to the development of technical innovations. One example is a recurrent concern about the physical health of the nation, which has at several points over the last century prompted new design approaches to natural light and ventilation. The most critical concern of the current era is the global, rather than the indoor, environment. The resultant political focus on mitigating climate change has resulted in new regulations, and in turn considerable technical changes in building design and construction. The vanguard of this movement has again been in school buildings, set the highest targets for reducing operational carbon by the previous Government. The current austerity measures have moved the focus to the refurbishment and retrofit of existing buildings, in order to bring them up to the exacting new standards. Meanwhile there is little doubt that climate change is happening already, and that the impacts will be considerable. Climate scientists have increasing confidence in their predictions for the future; if today’s buildings are to be resilient to these changes, building designers will need to understand and design for the predicted climates in order to continue to provide comfortable and healthy spaces through the lifetimes of the buildings. This paper describes the decision processes, and the planned design measures, for adapting an existing school for future climates. The project is at St Faith’s School in Cambridge, and focuses on three separate buildings: a large Victorian block built as a substantial domestic dwelling in 1885, a smaller single storey 1970s block with a new extension, and an as-yet unbuilt single storey block designed to passivhaus principles and using environmentally friendly materials. The implications of climate change have been considered for the three particular issues of comfort, construction, and water, as set out in the report on Design for Future Climate: opportunities for adaptation in the built environment (Gething, 2010). The adaptation designs aim to ensure each of the three very different buildings remains fit for purpose throughout the 21st century, continuing to provide a healthy environment for the children. A fourth issue, the reduction of carbon and the mitigation of other negative environmental impacts of the construction work, is also a fundamental aim for the school and the project team. Detailed modelling of both the operational and embodied energy and carbon of the design options is therefore being carried out, in order that the whole life carbon costs of the adaptation design options may be minimised

Expression of autism spectrum disorder associated genes in non-diseased fetal brain and thymus

Autism spectrum disorder (ASD) is a highly variable neurodevelopmental disorder. The main hallmarks of individuals with ASD are social communication impairments and repetitive sensory-motor behaviors, and they may present with additional comorbidities such as intellectual disability, epilepsy, anxiety, and/or attention-deficit/hyperactivity disorder. The underlying cause of ASD is similarly heterogeneous. More than a thousand associated genetic variants including chromosomal abnormalities and de novo rare genetic variants have been identified to be associated with ASD. However, there is a general lack of understanding of how genetic variants contribute to the fetal development of ASD. One interesting idea between the biological mechanism and ASD centers around immune associations and neurodevelopment. Many studies have found that a subset of genes are connected to immune pathways that converge on associated mechanisms of ASD. This work interrogates this idea by examining single cell expression of highly associated ASD genes in non-diseased human fetal thymus and brain. The high resolution of single cell expression highlights potential associations between specific cell types or pathways to ASD at a time point that is critical for neurodevelopment. Additionally, gene expression analysis has largely been focused on the brain, and this work investigates the thymus, a transient organ responsible for T cell development and a central component of the immune system. By analyzing highly associated ASD genes in non-diseased tissues of the fetal brain and thymus, the finding that a subset of genes are enriched in thymus tissue substantiates the reason for further interrogation of the possible associations of the thymus and ASD. This analysis also offers a baseline to compare to upon similar analyses of affected tissues of fetal brain and thymus from individuals with ASD

An exploration of the prescribing and administration of medicines in a sample of UK care homes

Residents of care homes are some of the most vulnerable members of society and are particularly susceptible to medicines harm. The safe and effective management of medicines helps to maintain or improve the quality of life of residents. However, there have been concerns surrounding poor prescribing and medicines administration practices within the setting. The aim of this thesis was to explore current prescribing and medicines administration practices in a sample of UK care homes, and to understand whether senior carers could administer medicines safely and effectively. Medicines administration data was extracted from a digital medication management system (PCS™) to explore prescribing patterns, and medicines administration by staff in nursing homes. Semi-structured interviews and surveys were used to explore staff perceptions of senior carers administering medicines under the delegation of nurses. Analysis showed that a significant number of residents were prescribed medicines commonly associated with adverse outcomes in older adults. These included anticholinergic drugs (50%), hypnotics and/or anxiolytics (30%), analgesics (49%), and antimicrobials (24%). Although senior carers were at least as competent as nurses in administering medicines (no statistically significant differences in error rates; pvalue> 0.05), 92% of residents were exposed to medication administration errors during the three-month study period. Interviews and surveys explored staff perceptions of medication administration errors in care homes and a number of themes were identified notably the need for medicines training by senior carers. The findings from this thesis have highlighted that the quality of prescribing and medicines administration remains suboptimal in care homes, and the issues identified may ultimately cause resident harm. New models of care, such as senior carers administering medicines in nursing homes may fail if systemic issues which give rise to such issues are not addressed. Therefore, exploring strategies to efficiently safeguard the quality of medicines management in this setting should be prioritised

Tetherin and Its Viral Antagonists

Restriction factors comprise an important layer of host defense to fight against viral infection. Some restriction factors are constitutively expressed whereas the majority is induced by interferon to elicit innate immunity. In addition to a number of well-characterized interferon-inducible antiviral factors such as RNaseL/OAS, ISG15, Mx, PKR, and ADAR, tetherin (BST-2/CD317/HM1.24) was recently discovered to block the release of enveloped viruses from the cell surface, which is regarded as a novel antiviral mechanism induced by interferon. Here, we briefly review the history of tetherin discovery, discuss how tetherin blocks virus production, and highlight the viral countermeasures to evade tetherin restriction

Quality Enhancement: Governing Student Learning

This article provides a critique of current debates about what quality enhancement is for and what it does. It outlines a conceptual framework drawing on different understandings of quality assurance and quality enhancement in higher education, which helps to refine the role of quality enhancement in improving student learning. The paper analyses existing debates on emerging trends in quality assurance and enhancement, particularly within European HE systems, with reference to the relationships between research, education, social and economic cohesion, the changing nature of student representation, and learning analytics. A new balance between assurance and enhancement could reconcile ways of thinking generated by higher education, knowledge structures emerging in research communities within the universities, and methods of enhancing learning and teaching which enable a degree of student-led demand

The effectiveness of a multidisciplinary intervention strategy for the treatment of symptomatic joint hypermobility in childhood:A randomised, single Centre parallel group trial (The Bendy Study)

Introduction: Joint hypermobility is common in childhood and can be associated with musculoskeletal pain and dysfunction. Current management is delivered by a multidisciplinary team, but evidence of effectiveness is limited. This clinical trial aimed to determine whether a structured multidisciplinary, multisite intervention resulted in improved clinical outcomes compared with standard care. Method: A prospective randomised, single centre parallel group trial comparing an 8-week individualised multidisciplinary intervention programme (bespoke physiotherapy and occupational therapy in the clinical, home and school environment) with current standard management (advice, information and therapy referral if deemed necessary). The primary endpoint of the study was between group difference in child reported pain from baseline to 12 months as assessed using the Wong Baker faces pain scale. Secondary endpoints were parent reported pain (100 mm visual analogue scale), parent reported function (child health assessment questionnaire), child reported quality of life (child health utility 9-dimensional assessment), coordination (movement assessment battery for children version 2) and grip strength (handheld dynamometer). Results: 119 children aged 5 to 16 years, with symptomatic hypermobility were randomised to receive an individualised multidisciplinary intervention (I) (n = 59) or standard management (S) (n = 60). Of these, 105 completed follow up at 12 months. No additional significant benefit could be shown from the intervention compared to standard management. However, there was a statistically significant improvement in child and parent reported pain, coordination and grip strength in both groups. The response was independent of the degree of hypermobility. Conclusion: This is the first randomised controlled trial to compare a structured multidisciplinary, multisite intervention with standard care in symptomatic childhood hypermobility. For the majority, the provision of education and positive interventions aimed at promoting healthy exercise and self-management was associated with significant benefit without the need for more complex interventions. Trial registration: The trial was registered prospectively with the national database at the Clinical Research Network (UKCRN Portfolio 9366). The trial was registered retrospectively with ISRCTN (ISRCTN86573140)

The identification of QTL controlling ergot sclerotia size in hexaploid wheat implicates a role for the Rht dwarfing alleles

The fungal pathogen Claviceps purpurea infects ovaries of a broad range of temperate grasses and cereals, including hexaploid wheat, causing a disease commonly known as ergot. Sclerotia produced in place of seed carry a cocktail of harmful alkaloid compounds that result in a range of symptoms in humans and animals, causing ergotism. Following a field assessment of C. purpurea infection in winter wheat, two varieties ‘Robigus’ and ‘Solstice’ were selected which consistently produced the largest differential effect on ergot sclerotia weights. They were crossed to produce a doubled haploid mapping population, and a marker map, consisting of 714 genetic loci and a total length of 2895 cM was produced. Four ergot reducing QTL were identified using both sclerotia weight and size as phenotypic parameters; QCp.niab.2A and QCp.niab.4B being detected in the wheat variety ‘Robigus’, and QCp.niab.6A and QCp.niab.4D in the variety ‘Solstice’. The ergot resistance QTL QCp.niab.4B and QCp.niab.4D peaks mapped to the same markers as the known reduced height (Rht) loci on chromosomes 4B and 4D, Rht-B1 and Rht-D1, respectively. In both cases, the reduction in sclerotia weight and size was associated with the semi-dwarfing alleles, Rht-B1b from ‘Robigus’ and Rht-D1b from ‘Solstice’. Two-dimensional, two-QTL scans identified significant additive interactions between QTL QCp.niab.4B and QCp.niab.4D, and between QCp.niab.2A and QCp.niab.4B when looking at sclerotia size, but not between QCp.niab.2A and QCp.niab.4D. The two plant height QTL, QPh.niab.4B and QPh.niab.4D, which mapped to the same locations as QCp.niab.4B and QCp.niab.4D, also displayed significant genetic interactions