Zebrafish mesonephric renin cells are functionally conserved and comprise of two distinct morphological populations

Zebrafish provide an excellent model in which to assess the role of the renin-angiotensin system in renal development, injury and repair. In contrast to mammals, zebrafish kidney organogenesis terminates with the mesonephros. Despite this, the basic functional structure of the nephron is conserved across vertebrates. The relevance of teleosts for studies relating to the regulation of the renin-angiotensin system was established by assessing the phenotype and functional regulation of renin-expressing cells in zebrafish. Transgenic fluorescent reporters for renin (ren), smooth muscle actin (acta2), and platelet derived growth factor receptor beta (pdgfrb) were studied to determine the phenotype and secretory ultrastructure of perivascular renin-expressing cells. Whole-kidney ren transcription responded to altered salinity, pharmacological renin-angiotensin system inhibition, and renal injury. Mesonephric ren-expressing cells occupied niches at the pre-glomerular arteries and afferent arterioles, forming intermittent epithelioid-like multi-cellular clusters exhibiting a granular secretory ultrastructure. In contrast, renin cells of the efferent arterioles were thin-bodied and lacked secretory granules. Renin cells expressed the perivascular cell markers acta2 and pdgfrb. Transcriptional responses of ren to physiological challenge support the presence of a functional renin-angiotensin system and are consistent with the production of active renin. The reparative capability of the zebrafish kidney was harnessed to demonstrate that ren transcription is a marker for renal injury and repair. Our studies demonstrate substantive conservation of renin regulation across vertebrates and ultrastructural studies of renin cells reveal at least two distinct morphologies of mesonephric perivascular ren-expressing cells

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer's disease

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer's disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures

Internet-based medical education: a realist review of what works, for whom and in what circumstances

http://creativecommons.org/licenses/by/2.0

Compression garments and fabric orthoses for rehabilitation and function: a systematic mapping review.

Background/aims: Compression garments, joint supports and dynamic movement orthoses all use elastic fibres and close-fitting designs and have been researched for their effects on movement. There is little cross-referencing between research into these interventions. This review aimed to improve inter-disciplinary understanding by analysing key characteristics of the published evidence. Methods: Systematic mapping reviews identify gaps in an evidence base and identify questions for more in-depth reviews. This review was conducted in-line with current guidance. MEDLINE, CINAHL and Sports Discuss were searched for primary research investigating compression garments and orthoses for movement and function. The following search terms were used: "elastane", "spandex", "Lycra", "elastomer*", "Theratog*", "compression", "Neoprene", "orthotic", "orthosis", "shorts", "garment*", "splint", "brace", "sock*" and "stockings". Studies were screened against predetermined criteria and key study characteristics extracted. Findings: Three hundred and fifty-one studies were selected and analysed. Compression garment research was most common (236 studies), followed by research into joint supports (64 studies) and dynamic movement orthoses (42 studies). Research largely reflects the purpose for which each intervention was originally designed. Common topics investigated include posture and movement control, proprioception and muscle activity. Pressure beneath compression garments was measured in 30% of studies. Conclusions: The review highlights a need for more robust study designs in patient populations and accurate description of interventions. There is a need for a review on the possible effects of compression and support on movement control which should be used to inform future primary research

Risk factors for moderate and severe persistent pain in patients undergoing total knee and hip arthroplasty : a prospective predictive study

Persistent post-surgical pain (PPSP) is a major clinical problem with significant individual, social and health care costs. The aim of this study was to examine the joint role of demographic, clinical and psychological risk factors in the development of moderate and severe PPSP after Total Knee and Hip Arthroplasty (TKA and THA, respectively). This was a prospective study wherein a consecutive sample of 92 patients were assessed 24 hours before (T1), 48 hours after (T2) and 4-6 months (T3) after surgery. Hierarchical logistic regression analyses were performed to identify predictors of moderate and severe levels of PPSP. Four to six months after TKA and THA, 54 patients (58.7%) reported none or mild pain (Numerical Rating Scale: NRS 3). In the final multivariate hierarchical logistic regression analyses, illness representations concerning the condition leading to surgery (osteoarthritis), such as a chronic timeline perception of the disease, emerged as a significant predictor of PPSP. Additionally, post-surgical anxiety also showed a predictive role in the development of PPSP. Pre-surgical pain was the most significant clinical predictive factor and, as expected, undergoing TKA was associated with greater odds of PPSP development than THA. The findings on PPSP predictors after major joint arthroplasties can guide clinical practice in terms of considering cognitive and emotional factors, together with clinical factors, in planning acute pain management before and after surgery.This work was supported by a Project grant (PTDC/SAU-NEU/108557/2008) and by a PhD grant (SFRH/BD/36368/2007) from the Portuguese Foundation of Science and Technology, COMPETE and FEDER. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Translational models for vascular cognitive impairment: a review including larger species.

BACKGROUND: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. METHODS: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). CONCLUSIONS: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required

Photochemical activation of TRPA1 channels in neurons and animals

Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild type animals. Surprisingly, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in non-transgenic animals, including humans

Dementia education in Higher Education Institutions, now and in the future: the role of the professional regulatory bodies in the UK

Dementia is a global challenge and educating and upskilling the workforce is a policy imperative. A World Health Organisation priority area is the development of dementia knowledge and skills amongst health and social care professionals. The European Parliament has called for European countries to develop action plans and create common guidelines to provide education and training to professionals caring for people with dementia and their family caregivers. The inconsistencies and gaps in dementia education have been repeatedly highlighted internationally as well as in the United Kingdom (UK); this is despite the four home nations having voluntary frameworks and guidelines for dementia education. This perspectives article on dementia education is written by representatives of the Higher Education Dementia Network (HEDN), a well-established group of academics involved in dementia education and research in over 65 Higher Education Institutions across the UK. HEDN works collaboratively with Dementia UK to promote consistent, high quality dementia education and share best practice. At HEDN we believe that reference to the knowledge and skills frameworks of the four nations within Professional Regulatory Body (PRB) requirements would ensure a more rigorous and consistent approach to dementia education across the UK. Reference to the Frameworks would support their adoption as a required and monitored sector minimum standard across professional boundaries. HEDN therefore recommends that application of the knowledge and skills within these frameworks becomes a requirement for (re)validation/approval of relevant health, social and housing professional programmes. In this article we explain the rationale behind the recommendations made by HEDN and the implications for PRBs and Higher Education Institutions

A palmitoyl transferase chemical-genetic system to map ZDHHC-specific S-acylation

The 23 human zinc finger Asp-His-His-Cys motif-containing (ZDHHC) S-acyltransferases catalyze long-chain S-acylation at cysteine residues across an extensive network of hundreds of proteins important for normal physiology or dysregulated in disease. Here we present a technology to directly map the protein substrates of a specific ZDHHC at the whole-proteome level, in intact cells. Structure-guided engineering of paired ZDHHC 'hole' mutants and 'bumped' chemically tagged fatty acid probes enabled probe transfer to specific protein substrates with excellent selectivity over wild-type ZDHHCs. Chemical-genetic systems were exemplified for five human ZDHHCs (3, 7, 11, 15 and 20) and applied to generate de novo ZDHHC substrate profiles, identifying >300 substrates and S-acylation sites for new functionally diverse proteins across multiple cell lines. We expect that this platform will elucidate S-acylation biology for a wide range of models and organisms

Effect of anakinra on arthropathy in CINCA/NOMID syndrome

CINCA/NOMID is an autoinflammatory disorder characterized by the triad of neonatal onset of cutaneous symptoms, chronic meningitis, and recurrent fever and it presents with distinctive osteoarthropathy, synovitis mainly of the large joints and overgrowth of epimetaphyseal cartilage, particularly of the long bones. The cartilage overgrowth eventually causes osseous overgrowth and deformity that persists beyond skeletal maturity and leads to limb length discrepancy, joint contracture, and early degenerative arthropathy. Autoinflammation in CAPS/NOMID has been proven to derive from excessive release of interleukin-1 (IL-1). It has been well documented that the IL-1 receptor antagonist anakinra (Kineret(R)) helps mitigate systemic inflammation in the disorder. However, a general consensus has not been reached on its beneficial effect on osteoarthropathy. The case of a girl with CINCA/NOMID syndrome who showed dramatic improvement of osteoarthropathy after anakinra treatment is reported. A 4-year-old girl suffered at the age of 10 months from a generalized urticarial skin lesion with recurrent episodes of fever and growth disorder. Blood examination revealed persistent massive neutrophilia, anemia and intense acute phase response. She manifested knee joint swelling with limited ROM when she was 20 months old and was diagnosed as being CINCA/NOMID based on characteristic findings of radiograph despite negative CIAS1 mutation. Radiological examination demonstrated metaphyseal fraying and cupping and widening of the growth plate in the distal femur. MR imaging showed mottled gadolinium enhancement at the chondrosseous junction. Neither significant joint effusion nor synovitis was identified. At 2 years and 7 months of age, anakinra, 2 mg/kg/day given by regular daily subcutaneous injections, was started. A few days after the initiation of the treatment, her clinical symptoms and laboratory findings of active inflammation were promptly alleviated. She was not able to walk unaided prior to the treatment, but she walked independently 1 month after the treatment. Follow-up radiographs and MR imaging showed that growth plate widening and gadolinium enhancement at the chondrosseous junction were less conspicuous. Furthermore, longitudinal growth of the femur and tibia was identified during 20 months of observation