Preliminary definitions for the sonographic features of synovitis in children

Objectives Musculoskeletal ultrasonography (US) has the potential to be an important tool in the assessment of disease activity in childhood arthritides. To assess pathology, clear definitions for synovitis need to be developed first. The aim of this study was to develop and validate these definitions through an international consensus process. Methods The decision on which US techniques to use, the components to be included in the definitions as well as the final wording were developed by 31 ultrasound experts in a consensus process. A Likert scale of 1-5 with 1 indicating complete disagreement and 5 complete agreement was used. A minimum of 80% of the experts scoring 4 or 5 was required for final approval. The definitions were then validated on 120 standardized US images of the wrist, MCP and tibiotalar joints displaying various degrees of synovitis at various ages. Results B-Mode and Doppler should be used for assessing synovitis in children. A US definition of the various components (i.e. synovial hypertrophy, effusion and Doppler signal within the synovium) was developed. The definition was validated on still images with a median of 89% (range 80-100) of participants scoring it as 4 or 5 on a Likert scale. Conclusions US definitions of synovitis and its elementary components covering the entire pediatric age range were successfully developed through a Delphi process and validated in a web-based still images exercise. These results provide the basis for the standardized US assessment of synovitis in clinical practice and research

Structure and dynamics of aqueous 2-propanol: a THz-TDS, NMR and neutron diffraction study.

Aqueous liquid mixtures, in particular, those involving amphiphilic species, play an important role in many physical, chemical and biological processes. Of particular interest are alcohol/water mixtures; however, the structural dynamics of such systems are still not fully understood. Herein, a combination of terahertz time-domain spectroscopy (THz-TDS) and NMR relaxation time analysis has been applied to investigate 2-propanol/water mixtures across the entire composition range; while neutron diffraction studies have been carried out at two specific concentrations. Excellent agreement is seen between the techniques with a maximum in both the relative absorption coefficient and the activation energy to molecular motion occurring at ∼90 mol% H2O. Furthermore, this is the same value at which well-established excess thermodynamic functions exhibit a maximum/minimum. Additionally, both neutron diffraction and THz-TDS have been used to provide estimates of the size of the hydration shell around 2-propanol in solution. Both methods determine that between 4 and 5 H2O molecules per 2-propanol are found in the 2-propanol/water clusters at 90 mol% H2O. Based on the acquired data, a description of the structure of 2-propanol/water across the composition range is presented.The authors would like to acknowledge CASTech (EPSRC grant EP/G011397/1), RCUK Basic Technology Grant (EP/E048811/1), STFC for beamtime allocation (RB910286) and Jon Mitchell (Cambridge) for valuable discussions.This is the final version of the article. It was first available from RSC via http://dx.doi.org/10.1039/C5CP01132

Scoring ultrasound synovitis in Rheumatoid Arthritis: a EULAR-OMERACT Ultrasound Taskforce–Part 1: definition and development of a standardized, consensus-based scoring system

Objectives: To develop a consensus-based ultrasound (US) definition and quantification system for synovitis in rheumatoid arthritis (RA). Methods: A multistep, iterative approach was used to: (1) evaluate the baseline agreement on defining and scoring synovitis according to the usual practice of different sonographers, using both grey-scale (GS) (synovial hypertrophy (SH) and effusion) and power Doppler (PD), by reading static images and scanning patients with RA and (2) evaluate the influence of both the definition and acquisition technique on reliability followed by a Delphi exercise to obtain consensus definitions for synovitis, elementary components and scoring system. Results: Baseline reliability was highly variable but better for static than dynamic images that were directly acquired and immediately scored. Using static images, intrareader and inter-reader reliability for scoring PD were excellent for both binary and semiquantitative (SQ) grading but GS showed greater variability for both scoring systems (κ ranges: −0.05 to 1 and 0.59 to 0.92, respectively). In patient-based exercise, both intraobserver and interobserver reliability were variable and the mean κ coefficients did not reach 0.50 for any of the components. The second step resulted in refinement of the preliminary Outcome Measures in Rheumatology synovitis definition by including the presence of both hypoechoic SH and PD signal and the development of a SQ severity score, depending on both the amount of PD and the volume and appearance of SH. Conclusion: A multistep consensus-based process has produced a standardised US definition and quantification system for RA synovitis including combined and individual SH and PD components. Further evaluation is required to understand its performance before application in clinical trials

Potassium channel dysfunction in human neuronal models of Angelman syndrome

Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases

The impact of early emergency department allied health intervention on admission rates in older people: a non-randomized clinical study

<p>Abstract</p> <p>Background</p> <p>This study sought to determine whether early allied health intervention by a dedicated Emergency Department (ED) based team, occurring before or in parallel with medical assessment, reduces hospital admission rates amongst older patients presenting with one of ten index problems.</p> <p>Methods</p> <p>A prospective non-randomized trial in patients aged sixty five and over, conducted in two Australian hospital EDs. Intervention group patients, receiving early comprehensive allied health input, were compared to patients that received no allied health assessment. Propensity score matching was used to compare the two groups due to the non-randomized nature of the study. The primary outcome was admission to an inpatient hospital bed from the ED.</p> <p>Results</p> <p>Of five thousand two hundred and sixty five patients in the trial, 3165 were in the intervention group. The admission rate in the intervention group was 72.0% compared to 74.4% in the control group. Using propensity score probabilities of being assigned to either group in a conditional logistic regression model, this difference was of borderline statistical significance (<it>p </it>= 0.046, OR 0.88 (0.76-1.00)). On subgroup analysis the admission rate in patients with musculoskeletal symptoms and angina pectoris was less for those who received allied health intervention versus those who did not. This difference was significant.</p> <p>Conclusions</p> <p>Early allied health intervention in the ED has a significant but modest impact on admission rates in older patients. The effect appears to be limited to a small number of common presenting problems.</p

Genomic and Epigenomic Responses to Chronic Stress Involve miRNA-Mediated Programming

Stress represents a critical influence on motor system function and has been shown to impair movement performance. We hypothesized that stress-induced motor impairments are due to brain-specific changes in miRNA and protein-encoding gene expression. Here we show a causal link between stress-induced motor impairment and associated genetic and epigenetic responses in relevant central motor areas in a rat model. Exposure to two weeks of mild restraint stress altered the expression of 39 genes and nine miRNAs in the cerebellum. In line with persistent behavioural impairments, some changes in gene and miRNA expression were resistant to recovery from stress. Interestingly, stress up-regulated the expression of Adipoq and prolactin receptor mRNAs in the cerebellum. Stress also altered the expression of Prlr, miR-186, and miR-709 in hippocampus and prefrontal cortex. In addition, our findings demonstrate that miR-186 targets the gene Eps15. Furthermore, we found an age-dependent increase in EphrinB3 and GabaA4 receptors. These data show that even mild stress results in substantial genomic and epigenomic changes involving miRNA expression and associated gene targets in the motor system. These findings suggest a central role of miRNA-regulated gene expression in the stress response and in associated neurological function

Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality

<p>Abstract</p> <p>Objective</p> <p>Metformin has had a 'black box' contraindication in diabetic patients with heart failure (HF), but many believe it to be the treatment of choice in this setting. Therefore, we attempted to conduct a pilot study to evaluate the feasibility of undertaking a large randomized controlled trial with clinical endpoints.</p> <p>Study Design</p> <p>The pilot study was a randomized double blinded placebo controlled trial. Patients with HF and type 2 diabetes were screened in hospitals and HF clinics in Edmonton, Alberta, Canada (population ~1 million). Major exclusion criteria included the current use of insulin or high dose metformin, decreased renal function, or a glycosylated hemoglobin <7%. Patients were to be randomized to 1500 mg of metformin daily or matching placebo and followed for 6 months for a variety of functional outcomes, as well as clinical events.</p> <p>Results</p> <p>Fifty-eight patients were screened over a six month period and all were excluded. Because of futility with respect to enrollment, the pilot study was abandoned. The mean age of screened patients was 77 (SD 9) years and 57% were male. The main reasons for exclusion were: use of insulin therapy (n = 23; 40%), glycosylated hemoglobin <7% (n = 17; 29%) and current use of high dose metformin (n = 12; 21%). Overall, contraindicated metformin therapy was the most commonly prescribed oral antihyperglycemic agent (n = 27; 51%). On average, patients were receiving 1,706 mg (SD 488 mg) of metformin daily and 12 (44%) used only metformin.</p> <p>Conclusion</p> <p>Despite uncertainty in the scientific literature, there does not appear to be clinical uncertainty with regards to the safety or effectiveness of metformin in HF making a definitive randomized trial virtually impossible.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: NCT00325910</p

The DISC (Diabetes in Social Context) Study-evaluation of a culturally sensitive social network intervention for diabetic patients in lower socioeconomic groups: a study protocol

<p>Abstract</p> <p>Background</p> <p>Compared to those in higher socioeconomic groups, diabetic patients in lower socioeconomic groups have less favourable metabolic control and experience more diabetes-related complications. They encounter specific barriers that hinder optimal diabetes self-management, including a lack of social support and other psychosocial mechanisms in their immediate social environments. <it>Powerful Together with Diabetes </it>is a culturally sensitive social network intervention specifically targeted to ethnic Dutch, Moroccan, Turkish, and Surinamese diabetic patients in lower socioeconomic groups. For ten months, patients will participate in peer support groups in which they will share experiences, support each other in maintaining healthy lifestyles, and learn skills to resist social pressure. At the same time, their significant others will also receive an intervention, aimed at maximizing support for and minimizing the negative social influences on diabetes self-management. This study aims to test the effectiveness of <it>Powerful Together with Diabetes</it>.</p> <p>Methods/Design</p> <p>We will use a quasi-experimental design with an intervention group (Group 1) and two comparison groups (Groups 2 and 3), N = 128 in each group. Group 1 will receive <it>Powerful Together with Diabetes</it>. Group 2 will receive <it>Know your Sugar</it>, a six-week group intervention that does not focus on the participants' social environments. Group 3 receives standard care only. Participants in Groups 1 and 2 will be interviewed and physically examined at baseline, 3, 10, and 16 months. We will compare their haemoglobin A1C levels with the haemoglobin A1C levels of Group 3. Main outcome measures are haemoglobin A1C, diabetes-related quality of life, diabetes self-management, health-related, and intermediate outcome measures. We will conduct a process evaluation and a qualitative study to gain more insights into the intervention fidelity, feasibility, and changes in the psychosocial mechanism in the participants' immediate social environments.</p> <p>Discussion</p> <p>With this study, we will assess the feasibility and effectiveness of a culturally sensitive social network intervention for lower socioeconomic groups. Furthermore, we will study how to enable these patients to optimally manage their diabetes. This trial is registered in the Dutch Trial Register: NTR1886</p

Regulation of N-WASP and the Arp2/3 Complex by Abp1 Controls Neuronal Morphology

Polymerization and organization of actin filaments into complex superstructures is indispensable for structure and function of neuronal networks. We here report that knock down of the F-actin-binding protein Abp1, which is important for endocytosis and synaptic organization, results in changes in axon development virtually identical to Arp2/3 complex inhibition, i.e., a selective increase of axon length. Our in vitro and in vivo experiments demonstrate that Abp1 interacts directly with N-WASP, an activator of the Arp2/3 complex, and releases the autoinhibition of N-WASP in cooperation with Cdc42 and thereby promotes N-WASP-triggered Arp2/3 complex-mediated actin polymerization. In line with our mechanistical studies and the colocalization of Abp1, N-WASP and Arp2/3 at sites of actin polymerization in neurons, we reveal an essential role of Abp1 and its cooperativity with Cdc42 in N-WASP-induced rearrangements of the neuronal cytoskeleton. We furthermore show that introduction of N-WASP mutants lacking the ability to bind Abp1 or Cdc42, Arp2/3 complex inhibition, Abp1 knock down, N-WASP knock down and Arp3 knock down, all cause identical neuromorphological phenotypes. Our data thus strongly suggest that these proteins and their complex formation are important for cytoskeletal processes underlying neuronal network formation

Prevalence of lipid abnormalities before and after introduction of lipid modifying therapy among Swedish patients with dyslipidemia (PRIMULA)

<p>Abstract</p> <p>Background</p> <p>Data on the prevalence of dyslipidemia and attainment of goal/normal lipid levels in a Swedish population are scarce. The objective of this study is to estimate the prevalence of dyslipidemia and attainment of goal/normal lipid levels in patients treated with lipid modifying therapy (LMT).</p> <p>Methods</p> <p>This longitudinal retrospective observational study covers time periods before and after treatment. Data were collected from 1994-2007 electronic patient records in public primary healthcare centers in Uppsala County, Sweden. Patients were included if they had been treated with LMT and had at least one lipid abnormality indicating dyslipidemia and if complete lipid profile data were available. Thresholds levels for lipids were defined as per Swedish guidelines.</p> <p>Results</p> <p>Among 5,424 patients included, at baseline, the prevalence of dyslipidemia (≥1 lipid abnormality) was by definition 100%, while this figure was 82% at follow-up. At baseline, 60% had elevated low-density lipoprotein (LDL-C) combined with low high-density lipoprotein (HDL-C) and/or elevated triglycerides (TG s), corresponding figure at follow-up was 36%. Low HDL-C and/or elevated TGs at follow-up remained at 69% for patients with type 2 diabetes mellitus (T2DM), 50% among patients with coronary heart disease (CHD) and 66% among patients with 10 year CHD risk >20%. Of the total sample, 40% attained goal levels of LDL-C and 18% attained goal/normal levels on all three lipid parameters.</p> <p>Conclusions</p> <p>Focusing therapy on LDL-C reduction allows 40% of patients to achieve LDL-C goal and helps reducing triglyceride levels. Almost 60% of patients experience persistent HDL-C and/or triglyceride abnormality independently of LDL-C levels and could be candidates for additional treatments.</p