A ROLE FOR BIOELECTRIC EFFECTS IN THE INDUCTION OF BYSTANDER SIGNALS BY IONIZING RADIATION?

The induction of “bystander effects” i.e. effects in cells which have not received an ionizing radiation track, is now accepted but the mechanisms are not completely clear. Bystander effects following high and low LET radiation exposure are accepted but mechanisms are still not understood. There is some evidence for a physical component to the signal. This paper tests the hypothesis that bioelectric or biomagnetic phenomena are involved. Human immortalized skin keratinocytes and primary explants of mouse bladder and fish skin, were exposed directly to ionizing radiation or treated in a variety of bystander protocols. Exposure of cells was conducted by shielding one group of flasks using lead, to reduce the dose below the threshold of 2mGy 60Cobalt gamma rays established for the bystander effect. The endpoint for the bystander effect in the reporter system used was reduction in cloning efficiency (RCE). The magnitude of the RCE was similar in shielded and unshielded flasks. When cells were placed in a Faraday cage the magnitude of the RCE was less but not eliminated. The results suggest that liquid media or cellcell contact transmission of bystander factors may be only part of the bystander mechanism. Bioelectric or bio magnetic fields may have a role to play. To test this further, cells were placed in a Magnetic Resonance Imaging (MRI) machine for 10min using a typical head scan protocol. This treatment also induced a bystander response. Apart from the obvious clinical relevance, the MRI results further suggest that bystander effects may be produced by non-ionizing exposures. It is concluded that bioelectric or magnetic effects may be involved in producing bystander signaling cascades commonly seen following ionizing radiation exposure

A pragmatic cluster randomised trial evaluating three implementation interventions

Background Implementation research is concerned with bridging the gap between evidence and practice through the study of methods to promote the uptake of research into routine practice. Good quality evidence has been summarised into guideline recommendations to show that peri-operative fasting times could be considerably shorter than patients currently experience. The objective of this trial was to evaluate the effectiveness of three strategies for the implementation of recommendations about peri-operative fasting. Methods A pragmatic cluster randomised trial underpinned by the PARIHS framework was conducted during 2006 to 2009 with a national sample of UK hospitals using time series with mixed methods process evaluation and cost analysis. Hospitals were randomised to one of three interventions: standard dissemination (SD) of a guideline package, SD plus a web-based resource championed by an opinion leader, and SD plus plan-do-study-act (PDSA). The primary outcome was duration of fluid fast prior to induction of anaesthesia. Secondary outcomes included duration of food fast, patients' experiences, and stakeholders' experiences of implementation, including influences. ANOVA was used to test differences over time and interventions. Results Nineteen acute NHS hospitals participated. Across timepoints, 3,505 duration of fasting observations were recorded. No significant effect of the interventions was observed for either fluid or food fasting times. The effect size was 0.33 for the web-based intervention compared to SD alone for the change in fluid fasting and was 0.12 for PDSA compared to SD alone. The process evaluation showed different types of impact, including changes to practices, policies, and attitudes. A rich picture of the implementation challenges emerged, including inter-professional tensions and a lack of clarity for decision-making authority and responsibility. Conclusions This was a large, complex study and one of the first national randomised controlled trials conducted within acute care in implementation research. The evidence base for fasting practice was accepted by those participating in this study and the messages from it simple; however, implementation and practical challenges influenced the interventions' impact. A set of conditions for implementation emerges from the findings of this study, which are presented as theoretically transferable propositions that have international relevance. Trial registration ISRCTN18046709 - Peri-operative Implementation Study Evaluation (POISE

Blood culture status and mortality among patients with suspected community-acquired bacteremia: a population-based cohort study

<p>Abstract</p> <p>Background</p> <p>Comparison of mortality among patients with positive and negative blood cultures may indicate the contribution of bacteremia to mortality. This study (1) compared mortality among patients with community-acquired bacteremia with mortality among patients with negative blood cultures and (2) determined the effects of bacteremia type and comorbidity level on mortality among patients with positive blood cultures.</p> <p>Methods</p> <p>This cohort study included 29,273 adults with blood cultures performed within the first 2 days following hospital admission to an internal medical ward in northern Denmark during 1995-2006. We computed product limit estimates and used Cox regression to compute adjusted mortality rate ratios (MRRs) within 0-2, 3-7, 8-30, and 31-180 days following admission for bacteremia patients compared to culture-negative patients.</p> <p>Results</p> <p>Mortality in 2,648 bacteremic patients and 26,625 culture-negative patients was 4.8% vs. 2.0% 0-2 days after admission, 3.7% vs. 2.7% 3-7 days after admission, 5.6% vs. 5.1% 8-30 days after admission, and 9.7% vs. 8.7% 31-180 days after admission, corresponding to adjusted MRRs of 1.9 (95% confidence interval (CI): 1.6-2.2), 1.1 (95% CI: 0.9-1.5), 0.9 (95% CI: 0.8-1.1), and 1.0 (95% CI: 0.8-1.1), respectively. Mortality was higher among patients with Gram-positive (adjusted 0-2-day MRR 1.9, 95% CI: 1.6-2.2) and polymicrobial bacteremia (adjusted 0-2-day MRR 3.5, 95% CI: 2.2-5.5) than among patients with Gram-negative bacteremia (adjusted 0-2-day MRR 1.5, 95% CI 1.2-2.0). After the first 2 days, patients with Gram-negative bacteremia had the same risk of dying as culture-negative patients (adjusted MRR 0.8, 95% CI: 0.5-1.1). Only patients with polymicrobial bacteremia had increased mortality within 31-180 days following admission (adjusted MRR 1.3, 95% CI: 0.8-2.1) compared to culture-negative patients. The association between blood culture status and mortality did not differ substantially by level of comorbidity.</p> <p>Conclusions</p> <p>Community-acquired bacteremia was associated with an increased risk of mortality in the first week of medical ward admission. Higher mortality among patients with Gram-positive and polymicrobial bacteremia compared with patients with Gram-negative bacteremia and negative cultures emphasizes the prognostic importance of these infections.</p

An experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study

BACKGROUND: Acute exacerbations of COPD are a major cause of morbidity, mortality and hospitalisation. Respiratory viruses are associated with the majority of exacerbations but a causal relationship has not been demonstrated and the mechanisms of virus-induced exacerbations are poorly understood. Development of a human experimental model would provide evidence of causation and would greatly facilitate understanding mechanisms, but no such model exists. METHODS: We aimed to evaluate the feasibility of developing an experimental model of rhinovirus induced COPD exacerbations and to assess safety of rhinovirus infection in COPD patients. We carried out a pilot virus dose escalating study to assess the minimum dose of rhinovirus 16 required to induce experimental rhinovirus infection in subjects with COPD (GOLD stage II). Outcomes were assessed by monitoring of upper and lower respiratory tract symptoms, lung function, and virus replication and inflammatory responses in nasal lavage. RESULTS: All 4 subjects developed symptomatic colds with the lowest dose of virus tested, associated with evidence of viral replication and increased pro-inflammatory cytokines in nasal lavage. These were accompanied by significant increases in lower respiratory tract symptoms and reductions in PEF and FEV(1). There were no severe exacerbations or other adverse events. CONCLUSION: Low dose experimental rhinovirus infection in patients with COPD induces symptoms and lung function changes typical of an acute exacerbation of COPD, appears safe, and provides preliminary evidence of causation

siRNA Off-Target Effects Can Be Reduced at Concentrations That Match Their Individual Potency

Small interfering RNAs (siRNAs) are routinely used to reduce mRNA levels for a specific gene with the goal of studying its function. Several studies have demonstrated that siRNAs are not always specific and can have many off-target effects. The 3′ UTRs of off-target mRNAs are often enriched in sequences that are complementary to the seed-region of the siRNA. We demonstrate that siRNA off-targets can be significantly reduced when cells are treated with a dose of siRNA that is relatively low (e.g. 1 nM), but sufficient to effectively silence the intended target. The reduction in off-targets was demonstrated for both modified and unmodified siRNAs that targeted either STAT3 or hexokinase II. Low concentrations reduced silencing of transcripts with complementarity to the seed region of the siRNA. Similarly, off-targets that were not complementary to the siRNA were reduced at lower doses, including up-regulated genes that are involved in immune response. Importantly, the unintended induction of caspase activity following treatment with a siRNA that targeted hexokinase II was also shown to be a concentration-dependent off-target effect. We conclude that off-targets and their related phenotypic effects can be reduced for certain siRNA that potently silence their intended target at low concentrations

Playwork in prison as a mechanism to support family health and well-being

Objective: The health of the prison population has become an increasing concern, given the disproportionate rates of ill health in this population. Moreover, the challenges faced by prisoners’ families and their children are also becoming more apparent, with prisoners’ children being more likely than other children to experience mental and emotional health problems and more likely to go to prison themselves. Prison visits are an integral part of institutional structures and are a key way by which families stay in contact and mitigate against the negative effects of family separation. This paper focuses particularly on the impact of prison play visits as an alternative to ‘standard’ visiting procedures. Design: Cross-sectional qualitative study. Setting: A male prison in Northern England. Method: Telephone interviews with six prison visitors who had regularly participated in a play visit, plus a focus group with five prisoners. Results: The paper identifies play visits as a useful way to maintain family well-being as they ‘mimic’, albeit temporarily, domestic life. This is reported to be beneficial for future family outcomes and in enabling children to adjust to parental incarceration. Play visits improve levels of intimacy, which is beneficial for the mental and emotional health both of prisoners and their children. Conclusion: The paper argues for a more holistic notion of prisoner health that sees family connections as a key part of supporting health and well-being

The use of gamma-irradiation and ultraviolet-irradiation in the preparation of human melanoma cells for use in autologous whole-cell vaccines

<p>Abstract</p> <p>Background</p> <p>Human cancer vaccines incorporating autologous tumor cells carry a risk of implantation and subsequent metastasis of viable tumor cells into the patient who is being treated. Despite the fact that the melanoma cell preparations used in a recent vaccine trial (Mel37) were gamma-irradiated (200 Gy), approximately 25% of the preparations failed quality control release criteria which required that the irradiated cells incorporate ³H-thymidine at no more than 5% the level seen in the non-irradiated cells. We have, therefore, investigated ultraviolet (UV)-irradiation as a possible adjunct to, or replacement for gamma-irradiation.</p> <p>Methods</p> <p>Melanoma cells were gamma- and/or UV-irradiated. ³H-thymidine uptake was used to assess proliferation of the treated and untreated cells. Caspase-3 activity and DNA fragmentation were measured as indicators of apoptosis. Immunohistochemistry and Western blot analysis was used to assess antigen expression.</p> <p>Results</p> <p>UV-irradiation, either alone or in combination with gamma-irradiation, proved to be extremely effective in controlling the proliferation of melanoma cells. In contrast to gamma-irradiation, UV-irradiation was also capable of inducing significant levels of apoptosis. UV-irradiation, but not gamma-irradiation, was associated with the loss of tyrosinase expression. Neither form of radiation affected the expression of gp100, MART-1/MelanA, or S100.</p> <p>Conclusion</p> <p>These results indicate that UV-irradiation may increase the safety of autologous melanoma vaccines, although it may do so at the expense of altering the antigenic profile of the irradiated tumor cells.</p