CD4+ T cell hyporesponsiveness after repeated exposure to Schistosoma mansoni larvae is dependent upon interleukin-10

The effect that multiple percutaneous exposures to Schistosoma larvae has on the development of early CD4+ lymphocyte reactivity is unclear, yet it is important in the context of humans living in areas where schistosomiasis is endemic. In a murine model of multiple infections, we show that exposure of mice to repeated doses (4×) of Schistosoma mansoni cercariae, compared to a single dose (1×), results in CD4+ T cell hyporesponsiveness within the skin-draining lymph nodes (sdLN), manifested as reduced CD4+ cell proliferation and cytokine production. FoxP3+ CD4+ regulatory T cells were present in similar numbers in the sdLN of 4× and 1× mice and thus are unlikely to have a role in effecting hyporesponsiveness. Moreover, anergy of the CD4+ cell population from 4× mice was slight, as proliferation was only partly circumvented through the in vitro addition of exogenous interleukin-2 (IL-2), and the in vivo blockade of the regulatory molecule PD1 had a minimal effect on restoring responsiveness. In contrast, IL-10 was observed to be critical in mediating hyporesponsiveness, as CD4+ cells from the sdLN of 4× mice deficient for IL-10 were readily able to proliferate, unlike those from 4× wild-type cohorts. CD4+ cells from the sdLN of 4× mice exhibited higher levels of apoptosis and cell death, but in the absence of IL-10, there was significantly less cell death. Combined, our data show that IL-10 is a key factor in the development of CD4+ T cell hyporesponsiveness after repeated parasite exposure involving CD4+ cell apoptosis

A pragmatic multi-centre randomised controlled trial of fluid loading and level of dependency in high-risk surgical patients undergoing major elective surgery : trial protocol

Peer reviewedPublisher PD

Professional Sports Teams: Going Beyond the Core

Purpose - The addition of products to the core of matches by Professional Sports Teams (PSTs) has received much coverage. However, there has been limited work as to how their stadiums are used to stage non-sporting events. This paper investigates how clubs in the English Football League (EFL) use their venues to diversify into other markets. Design/methodology - Secondary sources were used to categorise the teams who played in the EFL by: average division turnover, stadium capacity and stadium age. Semi-structured interviews were held with a member of the commercial teams of 21 clubs. Findings - Clubs use their stadiums to supply a range of products and working with partners is commonplace. These products are targeted at a range of stakeholders, such as supporters, the local community and regionally based organisations. In addition to their own efforts, increased geographical coverage for clubs usually develops in three ways: via internal marketing by local organisations who use the facilities, agents who market the stadium for the club, and the EFL who market the league/clubs holistically. Research limitations/implications - The use of a stadium allows PSTs to diversify by providing new products for new markets. In this instance it has led to the development of capabilities in areas such as conferencing, funerals and weddings. Originality - This is one of the first papers to examine the capabilities developed by PSTs that lie outside the staging of matches

Anterior Talofibular Ligament and Superior Extensor Ankle Retinaculum Thicknesses: Relationship with Balance

Purpose This study determined if anterior talofibular ligament (ATFL)/superior extensor ankle retinaculum (SEAR) thicknesses are related to dynamic balance in individuals with chronic ankle instability (CAI). Materials and Methods The subjects were 14 males and 15 females (age=24.52±3.46 years). Ankle instability was assessed using the Cumberland Ankle Instability Tool (CAIT) with a cut off score of 25 to define two groups. SonoSite MTurbo (Fugifilm Sonosite, Inc.) musculoskeletal ultrasound (MSKUS) unit was used to assess ATFL and SEAR thicknesses. Dynamic balance was measured with the Y Balance Test (YBT) and two NeuroCom balance tests. Results There were no significant differences in the average ATFL thickness between stable and unstable ankles in those subjects with CAI (0.25±0.03 cm and 0.21±0.05 cm, respectively) or in the SEAR thickness (0.09±0.04 cm and 0.10±0.03 cm, respectively). There were also no significant differences in the right and left ATFL thicknesses (0.23±0.07 cm and 0.21±0.04 cm, respectively) or the SEAR thicknesses (0.09±0.01 cm and 0.09±0.01 cm, respectively) in those without CAI. There were no differences between limbs in composite scores on YBT in those with CAI (p=0.35) and those without CAI (p=0.33). There was a moderate correlation between the left SEAR thickness and the large forward/backward perturbations on the NeuroCom (Natus) motor control test (r=0.51, p=0.006 and r=0.54, p=0.003, respectively). Conclusion There were no differences in the ATFL/SEAR thicknesses or balance measures between or within the groups, likely because CAI is multi-factorial and related to mechanisms other than tissue changes alone. More sensitive technology and a better definition of the measurement process may provide more definitive results

Examining the patient and caregiver experience with diazepam nasal spray for seizure clusters: Results from an exit survey of a phase 3, open-label, repeat-dose safety study

BACKGROUND: Ideal rescue treatments for acute treatment of seizure clusters should be easy to administer, so it is important to assess user perceptions of these treatments. Diazepam nasal spray is designed to have a rapid, noninvasive, and socially acceptable route of administration. Patient and caregiver (including care partner) responses to surveys from a phase 3 safety study of diazepam nasal spray are reported. METHODS: The study enrolled patients aged 6-65 years with seizure clusters. Surveys distributed to patients and caregivers at study end, completion, or discontinuation collected data on comfort using diazepam nasal spray outside the home, timing of administration and return to their usual selves, and comfort of use compared with rectal diazepam. Safety was assessed. RESULTS: Of 175 patients enrolled at the October 31, 2019, interim cutoff, 158 received diazepam nasal spray. Sixty-seven (42.4%) patients and 84 (53.2%) caregivers responded to the surveys (including 35 matched pairs). Most patients (78.8%, 52/66) responded that they were very comfortable doing activities outside the home with diazepam nasal spray available; 59.4% of patients returned to their usual selves within an hour of administration. Twenty-seven (40.3%) of these patients reported self-administration, 48% doing so at the first sign of a seizure. Administration of diazepam nasal spray was rated extremely or very easy by 93.8% of caregivers. Safety profile was consistent with diazepam rectal gel; no patient discontinued owing to treatment-emergent adverse events. Nasal discomfort was typically mild and transient. Among patients who had used diazepam rectal gel, most were not at all comfortable using it outside the home (86.7%) or at home (64.5%) compared with diazepam nasal spray, whereas caregivers reported that diazepam rectal gel was not at all easy to use compared with diazepam nasal spray. CONCLUSIONS: This survey from the phase 3 safety study of diazepam nasal spray shows that patients and caregivers were satisfied with, and more comfortable using, diazepam nasal spray than rectal diazepam in public. NCT02721069

Distributed System Contract Monitoring

The use of behavioural contracts, to specify, regulate and verify systems, is particularly relevant to runtime monitoring of distributed systems. System distribution poses major challenges to contract monitoring, from monitoring-induced information leaks to computation load balancing, communication overheads and fault-tolerance. We present mDPi, a location-aware process calculus, for reasoning about monitoring of distributed systems. We define a family of Labelled Transition Systems for this calculus, which allow formal reasoning about different monitoring strategies at different levels of abstractions. We also illustrate the expressivity of the calculus by showing how contracts in a simple contract language can be synthesised into different mDPi monitors.Comment: In Proceedings FLACOS 2011, arXiv:1109.239

NKX2-5 regulates vessel remodeling in scleroderma-associated pulmonary arterial hypertension

NKX2-5 is a member of the homeobox-containing transcription factors critical in regulating tissue differentiation in development. Here, we report a role for NKX2-5 in vascular smooth muscle cell phenotypic modulation in vitro and in vascular remodelling in vivo. NKX2-5 is up-regulated in scleroderma (SSc) patients with pulmonary arterial hypertension. Suppression of NKX2-5 expression in smooth muscle cells, halted vascular smooth muscle proliferation and migration, enhanced contractility and blocked the expression of the extracellular matrix genes. Conversely, overexpression of NKX2-5 suppressed the expression of contractile genes (ACTA2, TAGLN, CNN1) and enhanced the expression of matrix genes (COL1) in vascular smooth muscle cells. In vivo, conditional deletion of NKX2-5 attenuated blood vessel remodelling and halted the progression to hypertension in the mouse chronic hypoxia mouse model. This study revealed that signals related to injury such as serum and low confluence, which induce NKX2-5 expression in cultured cells, is potentiated by TGFβ and further enhanced by hypoxia. The effect of TGFβ was sensitive to ERK5 and PI3K inhibition. Our data suggest a pivotal role for NKX2-5 in the phenotypic modulation of smooth muscle cells during pathological vascular remodelling and provide proof of concept for therapeutic targeting of NKX2-5 in vasculopathies

Diazepam nasal spray administration is effective to control seizure clusters irrespective of time of day

IntroductionNeurologic circadian influences, including sleep/wake transitions, processes (e.g., hormonal variation), and behavioral patterns (e.g., consumption of food and oral medications), may affect seizure patterns. Specific circadian patterns of seizures have been reported depending on type, onset location, and severity; however, data on patterns for patients with seizure clusters and effectiveness of rescue therapy by time of day are limited.MethodsWe conducted post hoc analyses using patient diary data from the phase 3 safety study of diazepam nasal spray, which is indicated for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Patients were administered age- and weight-based doses; second doses could be administered if needed to control a seizure cluster. We assessed clock timing of seizure-cluster onset along with second-dose use as a proxy for effectiveness. Treatment-emergent adverse events were recorded.ResultsSeizure-cluster onset was observed to be generally highest during mornings and late evenings and lowest in the early evening and middle of the night. Second-dose use was not consistently associated with a specific time of day. The safety profile was consistent with that expected from previous studies of diazepam nasal spray.ConclusionThese results suggest that diazepam nasal spray can be effectively administered at any time of day

What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: A commonly reported problem with the conduct of multicentre randomised controlled trials (RCTs) is that recruitment is often slower or more difficult than expected, with many trials failing to reach their planned sample size within the timescale and funding originally envisaged. The aim of this study was to explore factors that may have been associated with good and poor recruitment in a cohort of multicentre trials funded by two public bodies: the UK Medical Research Council (MRC) and the Health Technology Assessment (HTA) Programme. METHODS: The cohort of trials was identified from the administrative databases held by the two funding bodies. 114 trials that recruited participants between 1994 and 2002 met the inclusion criteria. The full scientific applications and subsequent trial reports submitted by the trial teams to the funders provided the principal data sources. Associations between trial characteristics and recruitment success were tested using the Chi-squared test, or Fisher's exact test where appropriate. RESULTS: Less than a third (31%) of the trials achieved their original recruitment target and half (53%) were awarded an extension. The proportion achieving targets did not appear to improve over time. The overall start to recruitment was delayed in 47 (41%) trials and early recruitment problems were identified in 77 (63%) trials. The inter-relationship between trial features and recruitment success was complex. A variety of strategies were employed to try to increase recruitment, but their success could not be assessed. CONCLUSION: Recruitment problems are complex and challenging. Many of the trials in the cohort experienced recruitment difficulties. Trials often required extended recruitment periods (sometimes supported by additional funds). While this is of continuing concern, success in addressing the trial question may be more important than recruitment alone.Published versio