Immunoregulatory functions for murine intraepithelial lymphocytes: gamma/delta T cell receptor-positive (TCR+) T cells abrogate oral tolerance, while alpha/beta TCR+ T cells provide B cell help.

Past work has shown that a subset of effector T cells with unique characteristics could abrogate hapten- or antigen-induced tolerance, and the reconstitution of this immune response has been termed contrasuppression. We have studied contrasuppression in a model of oral tolerance (OT) in which adoptively transferred antigen-specific T contrasuppressor (Tcs) cells reverse OT and result in antibody responses to the eliciting antigen. In the present study, we show that murine intraepithelial lymphocytes (IELs) from mice orally immunized with sheep red blood cells (SRBC) contain T cells that exhibit Tcs cell activity. This effect was mediated by CD3+ gamma/delta T cell receptor-positive (TCR+), but not alpha/beta TCR+ T cells, and gamma/delta TCR+ Tcs cells were associated with both the CD4-,CD8+ and CD4-,CD8- (double-negative) IEL fractions. The CD4-,CD8+ gamma/delta TCR+ IELs were further separated into Vicia villosa-adherent and -nonadherent fractions. Adoptive transfer of V. villosa-adherent gamma/delta TCR+ T cells to mice with OT to SRBC resulted in splenic IgA, IgM, and IgG subclass anti-SRBC responses, while V. villosa-nonadherent gamma/delta TCR+ T cells were without activity. The gamma/delta TCR+ IELs did not support in vitro antibody responses in B cell cultures, while alpha/beta TCR+ IELs were effective T helper cells. Further, cytokine production by the gamma/delta TCR+ IELs was examined, and the gamma/delta TCR+ V. villosa-adherent fraction, which possessed contrasuppressor function, contained low levels of IL-5 mRNA and small numbers of IL-5-producing cells when compared with alpha/beta TCR+ IELs and V. villosa-nonadherent gamma/delta TCR+ IELs. Our results now show that mouse IELs contain two distinct types of T cells that function in the immune response, e.g., alpha/beta TCR+ T cells that produce IL-5 and function as helper cells, and gamma/delta TCR+ T cells that restore antibody responses in mice that had been orally tolerized with antigen

A Phase I Double Blind, Placebo-Controlled, Randomized Study of the Safety and Immunogenicity of Electroporated HIV DNA with or without Interleukin 12 in Prime-Boost Combinations with an Ad35 HIV Vaccine in Healthy HIV-Seronegative African Adults.

Strategies to enhance the immunogenicity of DNA vaccines in humans include i) co-administration of molecular adjuvants, ii) intramuscular administration followed by in vivo electroporation (IM/EP) and/or iii) boosting with a different vaccine. Combining these strategies provided protection of macaques challenged with SIV; this clinical trial was designed to mimic the vaccine regimen in the SIV study.Seventy five healthy, HIV-seronegative adults were enrolled into a phase 1, randomized, double-blind, placebo-controlled trial. Multi-antigenic HIV (HIVMAG) plasmid DNA (pDNA) vaccine alone or co-administered with pDNA encoding human Interleukin 12 (IL-12) (GENEVAX IL-12) given by IM/EP using the TriGrid Delivery System was tested in different prime-boost regimens with recombinant Ad35 HIV vaccine given IM.All local reactions but one were mild or moderate. Systemic reactions and unsolicited adverse events including laboratory abnormalities did not differ between vaccine and placebo recipients. No serious adverse events (SAEs) were reported. T cell and antibody response rates after HIVMAG (x3) prime-Ad35 (x1) boost were independent of IL-12, while the magnitude of interferon gamma (IFN-γ) ELISPOT responses was highest after HIVMAG (x3) without IL-12. The quality and phenotype of T cell responses shown by intracellular cytokine staining (ICS) were similar between groups. Inhibition of HIV replication by autologous T cells was demonstrated after HIVMAG (x3) prime and was boosted after Ad35. HIV specific antibodies were detected only after Ad35 boost, although there was a priming effect with 3 doses of HIVMAG with or without IL-12. No anti-IL-12 antibodies were detected.The vaccines were safe, well tolerated and moderately immunogenic. Repeated administration IM/EP was well accepted. An adjuvant effect of co-administered plasmid IL-12 was not detected.ClinicalTrials.gov NCT01496989

Supernovae from rotating stars

The present paper discusses the main physical effects produced by stellar rotation on presupernovae, as well as observations which confirm these effects and their consequences for presupernova models. Rotation critically influences the mass of the exploding cores, the mass and chemical composition of the envelopes and the types of supernovae, as well as the properties of the remnants and the chemical yields. In the formation of gamma-ray bursts, rotation and the properties of rotating stars appear as the key factor. In binaries, the interaction between axial rotation and tidal effects often leads to interesting and unexpected results. Rotation plays a key role in shaping the evolution and nucleosynthesis in massive stars with very low metallicities (metallicity below about the Small Magellanic Cloud metallicity down to Population III stars). At solar and higher metallicities, the effects of rotation compete with those of stellar winds. In close binaries, the synchronisation process can lock the star at a high rotation rate despite strong mass loss and thus both effects, rotation and stellar winds, have a strong impact. In conclusion, rotation is a key physical ingredient of the stellar models and of presupernova stages, and the evolution both of single stars and close binaries. Moreover, important effects are expected along the whole cosmic history.Comment: 36 pages, 15 figures, published in Handbook of Supernovae, A.W. Alsabti and P. Murdin (eds), Springe

The Diabetes Manual trial protocol – a cluster randomized controlled trial of a self-management intervention for type 2 diabetes [ISRCTN06315411]

Background The Diabetes Manual is a type 2 diabetes self-management programme based upon the clinically effective 'Heart Manual'. The 12 week programme is a complex intervention theoretically underpinned by self-efficacy theory. It is a one to one intervention meeting United Kingdom requirements for structured diabetes-education and is delivered within routine primary care. Methods/design In a two-group cluster randomized controlled trial, GP practices are allocated by computer minimisation to an intervention group or a six-month deferred intervention group. We aim to recruit 250 participants from 50 practices across central England. Eligibility criteria are adults able to undertake the programme with type 2 diabetes, not taking insulin, with HbA1c over 8% (first 12 months) and following an agreed protocol change over 7% (months 13 to 18). Following randomisation, intervention nurses receive two-day training and delivered the Diabetes Manual programme to participants. Deferred intervention nurses receive the training following six-month follow-up. Primary outcome is HbA1c with total and HDL cholesterol; blood pressure, body mass index; self-efficacy and quality of life as additional outcomes. Primary analysis is between-group HbA1c differences at 6 months powered to give 80% power to detect a difference in HbA1c of 0.6%. A 12 month cohort analysis will assess maintenance of effect and assess relationship between self-efficacy and outcomes, and a qualitative study is running alongside. Discussion This trial incorporates educational and psychological diabetes interventions into a single programme and assesses both clinical and psychosocial outcomes. The trial will increase our understanding of intervention transferability between conditions, those diabetes related health behaviours that are more or less susceptible to change through efficacy enhancing mechanisms and how this impacts on clinical outcomes

A Wolf-Rayet-like progenitor of SN 2013cu from spectral observations of a stellar wind.

The explosive fate of massive Wolf-Rayet stars (WRSs) is a key open question in stellar physics. An appealing option is that hydrogen-deficient WRSs are the progenitors of some hydrogen-poor supernova explosions of types IIb, Ib and Ic (ref. 2). A blue object, having luminosity and colours consistent with those of some WRSs, has recently been identified in pre-explosion images at the location of a supernova of type Ib (ref. 3), but has not yet been conclusively determined to have been the progenitor. Similar work has so far only resulted in non-detections. Comparison of early photometric observations of type Ic supernovae with theoretical models suggests that the progenitor stars had radii of less than 10(12) centimetres, as expected for some WRSs. The signature of WRSs, their emission line spectra, cannot be probed by such studies. Here we report the detection of strong emission lines in a spectrum of type IIb supernova 2013cu (iPTF13ast) obtained approximately 15.5 hours after explosion (by 'flash spectroscopy', which captures the effects of the supernova explosion shock breakout flash on material surrounding the progenitor star). We identify Wolf-Rayet-like wind signatures, suggesting a progenitor of the WN(h) subclass (those WRSs with winds dominated by helium and nitrogen, with traces of hydrogen). The extent of this dense wind may indicate increased mass loss from the progenitor shortly before its explosion, consistent with recent theoretical predictions

Design effect in multicenter studies: gain or loss of power?

<p>Abstract</p> <p>Background</p> <p>In a multicenter trial, responses for subjects belonging to a common center are correlated. Such a clustering is usually assessed through the design effect, defined as a ratio of two variances. The aim of this work was to describe and understand situations where the design effect involves a gain or a loss of power.</p> <p>Methods</p> <p>We developed a design effect formula for a multicenter study aimed at testing the effect of a binary factor (which thus defines two groups) on a continuous outcome, and explored this design effect for several designs (from individually stratified randomized trials to cluster randomized trials, and for other designs such as matched pair designs or observational multicenter studies).</p> <p>Results</p> <p>The design effect depends on the intraclass correlation coefficient (ICC) (which assesses the correlation between data for two subjects from the same center) but also on a statistic <it>S</it>, which quantifies the heterogeneity of the group distributions among centers (thus the level of association between the binary factor and the center) and on the degree of global imbalance (the number of subjects are then different) between the two groups. This design effect may induce either a loss or a gain in power, depending on whether the <it>S </it>statistic is respectively higher or lower than 1.</p> <p>Conclusion</p> <p>We provided a global design effect formula applying for any multicenter study and allowing identifying factors – the ICC and the distribution of the group proportions among centers – that are associated with a gain or a loss of power in such studies.</p

Accessible High-Throughput Virtual Screening Molecular Docking Software for Students and Educators

We survey low cost high-throughput virtual screening (HTVS) computer programs for instructors who wish to demonstrate molecular docking in their courses. Since HTVS programs are a useful adjunct to the time consuming and expensive wet bench experiments necessary to discover new drug therapies, the topic of molecular docking is core to the instruction of biochemistry and molecular biology. The availability of HTVS programs coupled with decreasing costs and advances in computer hardware have made computational approaches to drug discovery possible at institutional and non-profit budgets. This paper focuses on HTVS programs with graphical user interfaces (GUIs) that use either DOCK or AutoDock for the prediction of DockoMatic, PyRx, DockingServer, and MOLA since their utility has been proven by the research community, they are free or affordable, and the programs operate on a range of computer platforms

Right-to-left shunt with hypoxemia in pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>Hypoxemia is common in pulmonary hypertension (PH) and may be partly related to ventilation/perfusion mismatch, low diffusion capacity, low cardiac output, and/or right-to-left (RL) shunting.</p> <p>Methods</p> <p>To determine whether true RL shunting causing hypoxemia is caused by intracardiac shunting, as classically considered, a retrospective single center study was conducted in consecutive patients with precapillary PH, with hypoxemia at rest (PaO₂< 10 kPa), shunt fraction (Qs/Qt) greater than 5%, elevated alveolar-arterial difference of PO₂(AaPO₂), and with transthoracic contrast echocardiography performed within 3 months.</p> <p>Results</p> <p>Among 263 patients with precapillary PH, 34 patients were included: pulmonary arterial hypertension, 21%; PH associated with lung disease, 47% (chronic obstructive pulmonary disease, 23%; interstitial lung disease, 9%; other, 15%); chronic thromboembolic PH, 26%; miscellaneous causes, 6%. Mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance were 45.8 ± 10.8 mmHg, 2.2 ± 0.6 L/min/m², and 469 ± 275 dyn.s.cm^-5, respectively. PaO₂in room air was 6.8 ± 1.3 kPa. Qs/Qt was 10.2 ± 4.2%. AaPO₂under 100% oxygen was 32.5 ± 12.4 kPa. Positive contrast was present at transthoracic contrast echocardiography in 6/34 (18%) of patients, including only 4/34 (12%) with intracardiac RL shunting. Qs/Qt did not correlate with hemodynamic parameters. Patients' characteristics did not differ according to the result of contrast echocardiography.</p> <p>Conclusion</p> <p>When present in patients with precapillary PH, RL shunting is usually not related to reopening of patent <it>foramen ovale</it>, whatever the etiology of PH.</p

Effectiveness and cost-effectiveness of a group-based pain self-management intervention for patients undergoing total hip replacement: Feasibility study for a randomized controlled trial

Background: Total hip replacement (THR) is a common elective surgical procedure and can be effective for reducing chronic pain. However, waiting times can be considerable. A pain self-management intervention may provide patients with skills to more effectively manage their pain and its impact during their wait for surgery. This study aimed to evaluate the feasibility of conducting a randomized controlled trial to assess the effectiveness and cost-effectiveness of a group-based pain self-management course for patients undergoing THR.Methods: Patients listed for a THR at one orthopedic center were posted a study invitation pack. Participants were randomized to attend a pain self-management course plus standard care or standard care only. The lay-led course was delivered by Arthritis Care and consisted of two half-day sessions prior to surgery and one full-day session after surgery. Participants provided outcome and resource-use data using a diary and postal questionnaires prior to surgery and one month, three months and six months after surgery. Brief telephone interviews were conducted with non-participants to explore barriers to participation.Results: Invitations were sent to 385 eligible patients and 88 patients (23%) consented to participate. Interviews with 57 non-participants revealed the most common reasons for non-participation were views about the course and transport difficulties. Of the 43 patients randomized to the intervention group, 28 attended the pre-operative pain self-management sessions and 11 attended the post-operative sessions. Participant satisfaction with the course was high, and feedback highlighted that patients enjoyed the group format. Retention of participants was acceptable (83% of recruited patients completed follow-up) and questionnaire return rates were high (72% to 93%), with the exception of the pre-operative resource-use diary (35% return rate). Resource-use completion rates allowed for an economic evaluation from the health and social care payer perspective.Conclusions: This study highlights the importance of feasibility work prior to a randomized controlled trial to assess recruitment methods and rates, barriers to participation, logistics of scheduling group-based interventions, acceptability of the intervention and piloting resource use questionnaires to improve data available for economic evaluations. This information is of value to researchers and funders in the design and commissioning of future research.Trial registration: Current Controlled Trials ISRCTN52305381. © 2014 Wylde et al.; licensee BioMed Central Ltd

HALT (Hernia Active Living Trial): protocol for a feasibility study of a randomised controlled trial of a physical activity intervention to improve quality of life in people with bowel stoma with a bulge/parastomal hernia

Background Parastomal hernia (PSH) can be repaired surgically, but results to date have been disappointing, with reported recurrence rates of 30 to 76%. Other types of intervention are therefore needed to improve the quality of life of people with PSH. One potential intervention is physical activity. We hypothesise that the intervention will increase core activation and control across the abdominal wall at a site of potential weakness and thus reduce the risk of PSH progression. Increases in physical activity will improve body image and quality of life (QoL). Methods Subjects and sample There were approximately 20 adults with a bowel stoma and PSH. People with previous PSH repair will be excluded as well as people who already do core training. Study design This is a feasibility study of a randomised controlled trial with 2 months follow-up, in 2 sites using mixed methods. Stage 1 involves intervention development and in stage 2, intervention and trial parameters will be assessed. Intervention A theoretically informed physical activity intervention was done, targeting people with PSH. Main outcome of feasibility study The main outcome is the decision by an independent Study Steering Committee whether to proceed to a full randomised controlled trial of the intervention. Other outcomes We will evaluate 4 intervention parameters—fidelity, adherence, acceptability and safety and 3 trial parameters (eligible patients’ consent rate, acceptability of study design and data availability rates for following endpoints): I. Diagnosis and classification of PSH II. Muscle activation III. Body composition (BMI, waist circumference) IV. Patient reported outcomes: QoL, body image and physical functioning V. Physical activity; VI. Psychological determinants of physical activity Other data Included are other data such as interviews with all participants about the intervention and trial procedures. Data analysis and statistical power As this is a feasibility study, the quantitative data will be analysed using descriptive statistics. Audio-recorded qualitative data from interviews will be transcribed verbatim and analysed thematically. Discussion The feasibility and acceptability of key intervention and trial parameters will be used to decide whether to proceed to a full trial of the intervention, which aims to improve body image, quality of life and PSH progression. Trial registration ISRCTN1520759