Arf GTPase interplay with Rho GTPases in regulation of the actin cytoskeleton

The Arf and Rho subfamilies of small GTPases are nucleotide-dependent molecular switches that act as master regulators of vesicular trafficking and the actin cytoskeleton organization. Small GTPases control cell processes with high fidelity by acting through distinct repertoires of binding partners called effectors. While we understand a great deal about how these GTPases act individually, relatively little is known about how they cooperate, especially in the control of effectors. This review highlights how Arf GTPases collaborate with Rac1 to regulate actin cytoskeleton dynamics at the membrane via recruiting and activating the Wave Regulatory Complex (WRC), a Rho effector that underpins lamellipodia formation and macropinocytosis. This provides insight into Arf regulation of the actin cytoskeleton, whilst putting the spotlight on small GTPase cooperation with emerging evidence of its importance in fundamental cell biology and interactions with pathogenic bacteria

Accessing novel fluorinated heterocycles with the hypervalent fluoroiodane reagent by solution and mechanochemical synthesis

A new and efficient strategy for the rapid formation of novel fluorinated tetrahydropyridazines and dihydrooxazines has been developed by fluorocylisation of β,γ-unsaturated hydrazones and oximes with the hypervalent fluoroiodane reagent. Mechanochemical synthesis delivered fluorinated tetrahydropyridazines in similar excellent yields to conventional solution synthesis, whereas fluorinated dihydro-oxazines were prepared in much better yields by ball-milling

Anaesthetic management of endoscopic resection of juvenile nasopharyngeal angiofibroma: our experience and a review of the literature

Background: Juvenile nasopharyngeal angiofibroma (JNA) is a rare, benign, vascular tumour in adolescent males with potential life-threatening complications. Advances in endoscopic surgery, invasive monitoring and hypotensive anaesthesia have made JNAs amenable to endoscopic surgical resection. We present the anaesthetic management of endoscopic resection of 14 JNAs, together with a review.Method: The medical records of patients who underwent endoscopic excision of JNAs within the last seven years were reviewed retrospectively. Information was collected and analysed with regard to demographics, preoperative evaluation, intraoperative management, complications and postoperative course. Fourteen patients were included in the study. If the surgery needed to be converted to open surgery, the patients were excluded from the study.Results: The age of the patients ranged from 10-18 years. Two patients had preoperative embolisation of the feeding vessel. Standard anaesthesia induction technique, together with invasive monitoring, was used. Controlled hypotension (mean arterial pressure of 60 ± 5 mmHg) was achieved with the help of inhalational anaesthetics, vasodilators and beta blockers. Mean duration of surgery was 197.14 ± 77 minutes, and median blood loss was 500 ml (100- 4 300 ml). Seven patients were extubated in the operating room. The other seven patients remained intubated for 24 hours owing to extensive surgery with a risk of postoperative bleeding, and were monitored either in the postoperative care unit (five patients) or the intensive care unit (two patients). There was no significant morbidity or mortality in any of the patients.Conclusion: JNAs remain a challenge for anaesthesiologists because of excessive intraoperative bleeding. Anaesthetists should be aware of recent techniques to reduce tumour vascularity, such as embolisation of the feeding vessel and controlled hypotension. Invasive monitoring, together with multimodal blood conservation strategies, decreases blood loss and provides a clear field of vision for endoscopic surgery.Keywords: anaesthetic management, JNA, endoscopic resection, controlled hypotensio

Disease-modifying therapies alter gut microbial composition in MS.

Objective:To determine the effects of the disease-modifying therapies, glatiramer acetate (GA) and dimethyl fumarate (DMF), on the gut microbiota in patients with MS. Methods:Participants with relapsing MS who were either treatment-naive or treated with GA or DMF were recruited. Peripheral blood mononuclear cells were immunophenotyped. Bacterial DNA was extracted from stool, and amplicons targeting the V4 region of the bacterial/archaeal 16S rRNA gene were sequenced (Illumina MiSeq). Raw reads were clustered into Operational Taxonomic Units using the GreenGenes database. Differential abundance analysis was performed using linear discriminant analysis effect size. Phylogenetic investigation of communities by reconstruction of unobserved states was used to investigate changes to functional pathways resulting from differential taxon abundance. Results:One hundred sixty-eight participants were included (treatment-naive n = 75, DMF n = 33, and GA n = 60). Disease-modifying therapies were associated with changes in the fecal microbiota composition. Both therapies were associated with decreased relative abundance of the Lachnospiraceae and Veillonellaceae families. In addition, DMF was associated with decreased relative abundance of the phyla Firmicutes and Fusobacteria and the order Clostridiales and an increase in the phylum Bacteroidetes. Despite the different changes in bacterial taxa, there was an overlap between functional pathways affected by both therapies. Interpretation:Administration of GA or DMF is associated with differences in gut microbial composition in patients with MS. Because those changes affect critical metabolic pathways, we hypothesize that our findings may highlight mechanisms of pathophysiology and potential therapeutic intervention requiring further investigation

Living with frailty and haemodialysis: a qualitative study

Background: Frailty is highly prevalent in people receiving haemodialysis (HD) and is associated with poor outcomes. Understanding the lived experiences of this group is essential to inform holistic care delivery. / Methods: Semi-structured interviews with N = 25 prevalent adults receiving HD from 3 HD units in the UK. Eligibility criteria included a Clinical Frailty Scale (CFS) score of 4–7 and a history of at least one fall in the last 6 months. Sampling began guided by maximum variation sampling to ensure diversity in frailty status; subsequently theoretical sampling enabled exploration of preliminary themes. Analysis was informed by constructivist grounded theory; later we drew upon the socioecological model. / Results: Participants had a mean age of 69 ± 10 years, 13 were female, and 13 were White British. 14 participants were vulnerable or mildly frail (CFS 4–5), and 11 moderately or severely frail (CFS 6–7). Participants characterised frailty as weight loss, weakness, exhaustion, pain and sleep disturbance arising from multiple long-term conditions. Participants’ accounts revealed: the consequences of frailty (variable function and psychological ill-health at the individual level; increasing reliance upon family at the interpersonal level; burdensome health and social care interactions at the organisational level; reduced participation at the community level; challenges with financial support at the societal level); coping strategies (avoidance, vigilance, and resignation); and unmet needs (overprotection from family and healthcare professionals, transactional health and social care exchanges). / Conclusions: The implementation of a holistic needs assessment, person-centred health and social care systems, greater family support and enhancing opportunities for community participation may all improve outcomes and experience. An approach which encompasses all these strategies, together with wider public health interventions, may have a greater sustained impact. Trial registration: ISRCTN12840463

Deep Brain Stimulation in Anorexia Nervosa: Hope for the Hopeless or Exploitation of the Vulnerable? The Oxford Neuroethics Gold Standard Framework

Neurosurgical interventions for psychiatric disorders have a long and troubled history (1, 2) but have become much more refined in the last few decades due to the rapid development of neuroimaging and robotic technologies (2). These advances have enabled the design of less invasive techniques, which are more focused, such as deep brain stimulation (DBS) (3). DBS involves electrode insertion into specific neural targets implicated in pathological behavior, which are then repeatedly stimulated at adjustable frequencies. DBS has been used for Parkinson's disease and movement disorders since the 1960s (4-6) and over the last decade has been applied to treatment-refractory psychiatric disorders, with some evidence of benefit in obsessive-compulsive disorder (OCD), major depressive disorder, and addictions (7). Recent consensus guidelines on best practice in psychiatric neurosurgery (8) stress, however, that DBS for psychiatric disorders remains at an experimental and exploratory stage. The ethics of DBS-in particular for psychiatric conditions-is debated (1, 8-10). Much of this discourse surrounds the philosophical implications of competence, authenticity, personality, or identity change following neurosurgical interventions, but there is a paucity of applied guidance on neuroethical best practice in psychiatric DBS, and health-care professionals have expressed that they require more (11). This paper aims to redress this balance by providing a practical, applied neuroethical gold standard framework to guide research ethics committees, researchers, and institutional sponsors. We will describe this as applied to our protocol for a particular research trial of DBS in severe and enduring anorexia nervosa (SE-AN) (https://clinicaltrials.gov/ct2/show/NCT01924598, unique identifier NCT01924598), but believe it may have wider application to DBS in other psychiatric disorders

Five-year review of an international clinical research-training program

The exponential increase in clinical research has profoundly changed medical sciences. Evidence that has accumulated in the past three decades from clinical trials has led to the proposal that clinical care should not be based solely on clinical expertise and patient values, and should integrate robust data from systematic research. As a consequence, clinical research has become more complex and methods have become more rigorous, and evidence is usually not easily translated into clinical practice. Therefore, the instruction of clinical research methods for scientists and clinicians must adapt to this new reality. To address this challenge, a global distance-learning clinical research-training program was developed, based on collaborative learning, the pedagogical goal of which was to develop critical thinking skills in clinical research. We describe and analyze the challenges and possible solutions of this course after 5 years of experience (2008-2012) with this program. Through evaluation by students and faculty, we identified and reviewed the following challenges of our program: 1) student engagement and motivation, 2) impact of heterogeneous audience on learning, 3) learning in large groups, 4) enhancing group learning, 5) enhancing social presence, 6) dropouts, 7) quality control, and 8) course management. We discuss these issues and potential alternatives with regard to our research and background

Changes in ponderal index and body mass index across childhood and their associations with fat mass and cardiovascular risk factors at age 15

Background: Little is known about whether associations between childhood adiposity and later adverse cardiovascular health outcomes are driven by tracking of overweight from childhood to adulthood and/or by vascular and metabolic changes from childhood overweight that persist into adulthood. Our objective is to characterise associations between trajectories of adiposity across childhood and a wide range of cardiovascular risk factors measured in adolescence, and explore the extent to which these are mediated by fat mass at age 15. Methods and Findings: Using data from the Avon Longitudinal Study of Parents and Children, we estimated individual trajectories of ponderal index (PI) from 0-2 years and BMI from 2-10 years using random-effects linear spline models (N = 4601). We explored associations between PI/BMI trajectories and DXA-determined total-body fat-mass and cardiovascular risk factors at 15 years (systolic and diastolic blood pressure, fasting LDL-and HDL-cholesterol, triglycerides, C-reactive protein, glucose, insulin) with and without adjustment for confounders. Changes in PI/BMI during all periods of infancy and childhood were associated with greater DXA-determined fat-mass at age 15. BMI changes in childhood, but not PI changes from 0-2 years, were associated with most cardiovascular risk factors in adolescence; associations tended to be strongest for BMI changes in later childhood (ages 8.5-10), and were largely mediated by fat mass at age 15. Conclusion: Changes in PI/BMI from 0-10 years were associated with greater fat-mass at age 15. Greater increases in BMI from age 8.5-10 years are most strongly associated with cardiovascular risk factors at age 15, with much of these associations mediated by fat-mass at this age. We found little evidence supporting previous reports that rapid PI changes in infancy are associated with future cardiovascular risk. This study suggests that associations between early overweight and subsequent adverse cardiovascular health are largely due to overweight children tending to remain overweight

The process evaluation of it\u27s your move!, an Australian adolescent community-based obesity prevention project

BackgroundEvidence on interventions for preventing unhealthy weight gain in adolescents is urgently needed. The aim of this paper is to describe the process evaluation for a three-year (2005-2008) project conducted in five secondary schools in the East Geelong/Bellarine region of Victoria, Australia. The project, \u27It\u27s Your Move!\u27 aimed to reduce unhealthy weight gain by promoting healthy eating patterns, regular physical activity, healthy body weight, and body size perception amongst youth; and improve the capacity of families, schools, and community organisations to sustain the promotion of healthy eating and physical activity in the region.MethodsThe project was supported by Deakin University (training and evaluation), a Reference Committee (strategic direction, budgetary approval and monitoring) and a Project Management Committee (project delivery). A workshop of students, teachers and other stakeholders formulated a 10-point action plan, which was then translated into strategies and initiatives specific to each school by the School Project Officers (staff members released from teaching duties one day per week) and trained Student Ambassadors. Baseline surveys informed intervention development. Process data were collected on all intervention activities and these were collated and enumerated, where possible, into a set of mutually exclusive tables to demonstrate the types of strategies and the dose, frequency and reach of intervention activities.ResultsThe action plan included three guiding objectives, four on nutrition, two on physical activity and one on body image. The process evaluation data showed that a mix of intervention strategies were implemented, including social marketing, one-off events, lunch time and curriculum programs, improvements in infrastructure, and healthy school food policies. The majority of the interventions were implemented in schools and focused on capacity building and healthy eating strategies as physical activity practices were seen by the teachers as already meeting students\u27 needs.ConclusionsWhile substantial health-promoting activities were conducted (especially related to healthy eating), there remain further opportunities for secondary schools to use a whole-of-school approach through the school curriculum, environment, policies and ethos to improve healthy eating, physical activity and healthy body perceptions in youth. To achieve this, significant, sustained leadership will be required within the education sector generally and within schools specifically.<br /