Gene expression profiles in the rat streptococcal cell wall-induced arthritis model identified using microarray analysis

Experimental arthritis models are considered valuable tools for delineating mechanisms of inflammation and autoimmune phenomena. Use of microarray-based methods represents a new and challenging approach that allows molecular dissection of complex autoimmune diseases such as arthritis. In order to characterize the temporal gene expression profile in joints from the reactivation model of streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats, total RNA was extracted from ankle joints from naïve, SCW injected, or phosphate buffered saline injected animals (time course study) and gene expression was analyzed using Affymetrix oligonucleotide microarray technology (RAE230A). After normalization and statistical analysis of data, 631 differentially expressed genes were sorted into clusters based on their levels and kinetics of expression using Spotfire(® )profile search and K-mean cluster analysis. Microarray-based data for a subset of genes were validated using real-time PCR TaqMan(® )analysis. Analysis of the microarray data identified 631 genes (441 upregulated and 190 downregulated) that were differentially expressed (Delta > 1.8, P < 0.01), showing specific levels and patterns of gene expression. The genes exhibiting the highest fold increase in expression on days -13.8, -13, or 3 were involved in chemotaxis, inflammatory response, cell adhesion and extracellular matrix remodelling. Transcriptome analysis identified 10 upregulated genes (Delta > 5), which have not previously been associated with arthritis pathology and are located in genomic regions associated with autoimmune disease. The majority of the downregulated genes were associated with metabolism, transport and regulation of muscle development. In conclusion, the present study describes the temporal expression of multiple disease-associated genes with potential pathophysiological roles in the reactivation model of SCW-induced arthritis in Lewis (LEW/N) rat. These findings improve our understanding of the molecular events that underlie the pathology in this animal model, which is potentially a valuable comparator to human rheumatoid arthritis (RA)

Mapping the matrix: using compendium as a tool for recording the analytic group

This paper describes the application of Compendium, a knowledge cartography software tool, for the recording of group process. As a hypertext tool, it enables analysts to visualise connections between people, ideas and information, establishing an evidence base within and across contexts (such as group sessions). After customising its visual language, templates and keyword system, it has been piloted as a research tool for the measurement of group process. This would appear to hold the promise of providing a “digital substrate” for recording, discussing and analysing long term group dynamics in new ways. While the project is in its early stages, early indications are that it is a useful tool which can highlight group process and record change over time. In the longer term, it seems plausible that group processes such as multiple mirroring and identification, and such complex structures as the matrix, could be made visible and researchable through this methodology

Comprehensive Observations of the Bright and Energetic Type Iax SN 2012Z: Interpretation as a Chandrasekhar Mass White Dwarf Explosion

We present UV through NIR broad-band photometry, and optical and NIR spectroscopy of Type Iax supernova 2012Z. The data set consists of both early and late-time observations, including the first late phase NIR spectrum obtained for a spectroscopically classified SN Iax. Simple model calculations of its bolometric light curve suggest SN 2012Z produced ~0.3 M_sun of (56)Ni, ejected about a Chandrasekhar mass of material, and had an explosion energy of ~10^51 erg, making it one of the brightest and most energetic SN Iax yet observed. The late phase NIR spectrum of SN 2012Z is found to broadly resemble similar epoch spectra of normal SNe Ia; however, like other SNe Iax, corresponding visual-wavelength spectra differ substantially compared to all supernova types. Constraints from the distribution of IMEs, e.g. silicon and magnesium, indicate that the outer ejecta did not experience significant mixing during or after burning, and the late phase NIR line profiles suggests most of the (56)Ni is produced during high density burning. The various observational properties of SN 2012Z are found to be consistent with the theoretical expectations of a Chandrasekhar mass white dwarf progenitor that experiences a pulsational delayed detonation, which produced several tenths of a solar mass of (56)Ni during the deflagration burning phase and little (or no) (56)Ni during the detonation phase. Within this scenario only a moderate amount of Rayleigh-Taylor mixing occurs both during the deflagration and fallback phase of the pulsation, and the layered structure of the IMEs is a product of the subsequent denotation phase. The fact that the SNe Iax population does not follow a tight brightness-decline relation similar to SNe Ia can then be understood in the framework of variable amounts of mixing during pulsational rebound and variable amounts of (56)Ni production during the early subsonic phase of expansion.Comment: Submitted to A&A, manuscript includes response to referee's comments. 39 pages, including 16 figures, 9 table

Ongoing initiatives within the Scottish National Health Service to affect the prescribing of selective serotonin reuptake inhibitors and their influence

Aim: Increasing use of selective serotonin-reuptake inhibitors (SSRIs) in Scotland, coupled with safety concerns with some SSRIs, and the increasing availability of generic SSRIs, have resulted in multiple initiatives to improve the quality and efficiency of their prescribing in Scotland. Our aim is to assess their influence to provide future direction. Materials & methods: The prescription costs analysis database was used to document utilization and expenditure on SSRIs between 2001 and 2017 alongside documenting the initiatives. Results: Multiple interventions over the years increased international nonproprietary name prescribing up to 99.9% lowering overall costs. This, coupled with initiatives to limit escitalopram prescribing due to concerns with its value, resulted in a 73.7% reduction in SSRI expenditure between 2001 and 2017 despite a 2.34-fold increase in utilization. Safety warnings resulted in a significant reduction in the prescribing of paroxetine, citalopram and escitalopram alongside a significant increase in sertraline Conclusion: Multiple initiatives have increased the quality and efficiency of SSRI prescribing in Scotland providing direction to others

Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease.

Anti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn's disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, humanised and engineered for intestinal protease resistance, V900, was combined with a previously-described TNFα-specific domain antibody, V565. V56B2 contains a central protease-labile linker to create a single molecule for oral administration. Incubation of V56B2 with trypsin or human faecal supernatant resulted in a complete separation of the V565 and V900 monomers without loss of neutralising potency. Following oral administration of V900 and V565 in mice, high levels of each domain antibody were detected in the faeces, demonstrating stability in the intestinal milieu. In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies

Activities to optimize quality and efficiency of medicines in Scotland

Introduction: The growing prevalence of non-communicable diseases, combined with greater recognition of the effectiveness of lipid lowering agents (LLAs), has fueled their increasing use in recent years. Similarly, increasing recognition of mental health and, arguably, societal expectations and pressures has driven appreciable growth in antidepressant prescribing in recent years. Concurrent with this, growing resource pressures enhanced by the continual launch of new premium priced medicines necessitates reforms and initiatives within finite budgets. Scotland has introduced multiple measures in recent years to improve both the quality and efficiency of prescribing. There is a need to document these initiatives and outcomes to provide future direction. Method: Assessment of the utilization (items dispensed) and expenditure of key LLAs (mainly statins) and SSRIs between 2001 and 2017 in Scotland alongside initiatives. Results: Multiple interventions have increased international non-proprietary name (INN) prescribing (99% for statins and up to 99.9% for SSRIs). They have also increased preferential prescribing of generic versus patented statins with low costs for generics, reduced inappropriate prescribing of ezetimibe due to effectiveness concerns, and increased the prescribing of higher dose statins (71% in 2015). These measures have resulted in a 50% reduction in LLA expenditure between 2001 and 2015 despite a 412% increase in utilization. Initiatives to reduce the prescribing of escitalopram as lack of evidence demonstrating cost-benefits over generic citalopram, along with high INN prescribing, achieved a 73.7% reduction in SSRI expenditure between 2001 and 2017 despite a 2.34-fold increase in utilisation. Concerns with paroxetine, and more recently citalopram and escitalopram following safety warnings, resulted in a considerable reduction in their use alongside a significant increase in sertraline. Conclusion: Generic availability coupled with multiple measures has resulted in appreciable shifts in statin and SSRI prescribing behavior and reduced ezetimibe prescribing, resulting in improvements in both the quality and efficiency of prescribing to provide future direction

Rehabilitation aimed at improving outdoor mobility for people after stroke: a multicentre randomised controlled study (the Getting out of the House Study)

Background: One-third of stroke patients are dependent on others to get outside their homes. This can cause people to become housebound, leading to increased immobility, poor health, isolation and misery. There is some evidence that outdoor mobility rehabilitation can reduce these limitations. Objective: To test the clinical effectiveness and cost-effectiveness of an outdoor mobility rehabilitation intervention for stroke patients. Design: Multicentre, parallel-group randomised controlled trial, with two groups allocated at a 1 : 1 ratio plus qualitative participant interviews. Setting: Fifteen UK NHS stroke services throughout England, Scotland and Wales. Participants: A total of 568 stroke patients who wished to get out of the house more often, mean age of 71 years: 508 reached the 6-month follow-up and 10 were interviewed. Intervention: Control was delivered prior to randomisation to all participants, and consisted of verbal advice and transport and outdoor mobility leaflets. Intervention was a targeted outdoor mobility rehabilitation programme delivered by 29 NHS therapists to 287 randomly chosen participants for up to 12 sessions over 4 months. Main outcome measures: Primary outcome was participant health-related quality of life, measured by the Short Form questionnaire-36 items, version 2 (Social Function domain), 6 months after baseline. Secondary outcomes were functional ability, mobility, number of journeys (from monthly travel diaries), satisfaction with outdoor mobility (SWOM), psychological well-being and resource use [health care and Personal Social Services (PSS)] 6 months after baseline. Carer well-being was recorded. All outcome measures were collected by post and repeated 12 months after baseline. Outcomes for the groups were compared using statistical significance testing and adjusted for multiple membership to account for the effect of multiple therapists at different sites. Interviews were analysed using interpretive phenomenology to explore confidence. Results: A median of seven intervention sessions [interquartile range (IQR) 3–7 sessions], median duration of 369 minutes (IQR 170–691.5 minutes) per participant was delivered. There was no significant difference between the groups on health-related quality of life (social function). There were no significant differences between groups in functional ability, psychological well-being or SWOM at 6- or 12-month follow-ups. There was a significant difference observed for travel journeys with the intervention group being 42% more likely to make a journey compared with the control group [rate ratio 1.42, 95% confidence interval (95% CI) 1.14 to 1.67] at 6 months and 76% more likely (rate ratio 1.76, 95% CI 1.36 to 1.95) at 12 months. The number of journeys was affected by the therapist effect. The mean incremental cost (total NHS and PSS cost) of the intervention was £3413.75 (95% CI –£448.43 to £7121.00), with an incremental quality-adjusted life-year gain of –0.027 (95% CI –0.060 to 0.007) according to the European Quality of Life-5 Dimensions and –0.003 (95% CI –0.016 to 0.006) according to the Short Form questionnaire-6 Dimensions. At baseline, 259 out of 281 (92.2%) participants in the control group were dissatisfied with outdoor mobility but at the 6-month assessment this had reduced to 77.7% (181/233), a 15% reduction. The corresponding reduction in the intervention group was slightly greater (21%) than 268 out of 287 (93.4%) participants dissatisfied with outdoor mobility at baseline to 189 out of 261 (72.4%) at 6 months. Participants described losing confidence after stroke as being detrimental to outdoor mobility. Recruitment and retention rates were high. The intervention was deliverable by the NHS but had a neutral effect in all areas apart from potentially increasing the number of journeys. This was dependent on the therapist effect, meaning that some therapists were more successful than others. The control appeared to affect change. Conclusions: The outdoor mobility intervention provided in this study to these stroke patients was not clinically effective or cost-effective. However, the provision of personalised information and monthly diaries should be considered for all people who wish to get out more

Association between footwear use and neglected tropical diseases: a systematic review and meta-analysis

BACKGROUND The control of neglected tropical diseases (NTDs) has primarily focused on preventive chemotherapy and case management. Less attention has been placed on the role of ensuring access to adequate water, sanitation, and hygiene and personal preventive measures in reducing exposure to infection. Our aim was to assess whether footwear use was associated with a lower risk of selected NTDs. METHODOLOGY We conducted a systematic review and meta-analysis to assess the association between footwear use and infection or disease for those NTDs for which the route of transmission or occurrence may be through the feet. We included Buruli ulcer, cutaneous larva migrans (CLM), leptospirosis, mycetoma, myiasis, podoconiosis, snakebite, tungiasis, and soil-transmitted helminth (STH) infections, particularly hookworm infection and strongyloidiasis. We searched Medline, Embase, Cochrane, Web of Science, CINAHL Plus, and Popline databases, contacted experts, and hand-searched reference lists for eligible studies. The search was conducted in English without language, publication status, or date restrictions up to January 2014. Studies were eligible for inclusion if they reported a measure of the association between footwear use and the risk of each NTD. Publication bias was assessed using funnel plots. Descriptive study characteristics and methodological quality of the included studies were summarized. For each study outcome, both outcome and exposure data were abstracted and crude and adjusted effect estimates presented. Individual and summary odds ratio (OR) estimates and corresponding 95% confidence intervals (CIs) were calculated as a measure of intervention effect, using random effects meta-analyses. PRINCIPAL FINDINGS Among the 427 studies screened, 53 met our inclusion criteria. Footwear use was significantly associated with a lower odds of infection of Buruli ulcer (OR=0.15; 95% CI: 0.08-0.29), CLM (OR=0.24; 95% CI: 0.06-0.96), tungiasis (OR=0.42; 95% CI: 0.26-0.70), hookworm infection (OR=0.48; 95% CI: 0.37-0.61), any STH infection (OR=0.57; 95% CI: 0.39-0.84), strongyloidiasis (OR=0.56; 95% CI: 0.38-0.83), and leptospirosis (OR=0.59; 95% CI: 0.37-0.94). No significant association between footwear use and podoconiosis (OR=0.63; 95% CI: 0.38-1.05) was found and no data were available for mycetoma, myiasis, and snakebite. The main limitations were evidence of heterogeneity and poor study quality inherent to the observational studies included. CONCLUSIONS/SIGNIFICANCE Our results show that footwear use was associated with a lower odds of several different NTDs. Access to footwear should be prioritized alongside existing NTD interventions to ensure a lasting reduction of multiple NTDs and to accelerate their control and elimination. PROTOCOL REGISTRATION PROSPERO International prospective register of systematic reviews CRD42012003338