Magnitude Of Protection Research Articles

Chemical Management of Spilosoma obliqua Walker in Greengram

Background: Greengram the most important pulse crops in India suffers a lot due to infestation of many lepidopteran caterpillars mainly at its reproductive stage. Spilosoma obliqua Walk. Arctiidae, Lepidoptera commonly called Bihar hairy caterpillar (BHC) is categorized as the most devastating. Methods: Field efficacy of nine new generation popular insecticides were tested in coastal saline zone of West Bengal against BHC in greengram (IPM 2-3) during 2021-2022. Leaf dip bioassay study of those selected insecticides were also conducted to compute the LC50 value against the field collected as well as laboratory reared F2 generation 3rd instar larvae of BHC. Result: All the test insecticides showed lethal effect towards BHC but the magnitude of protection over control was significantly higher in spinosad (70.92%) followed by flubendiamide (70.35%). Pyriproxifen+fenpropathrin (29.92%) was proved to be the least effective treatment followed by pyriproxyfen+bifenthrin (31.91%). As per LC50 value (ppm) flubendiamide showed the highest toxicity against BHC in respect of laboratory reared caterpillar and field collected caterpillar (4.49 and 6.71 respectively), while pyriproxifen+fenpropathrin the lowest (624 and 637 ppm). BHC was recorded as potent defoliator which was reflected in yield, while pod damage is not so pronounced.

Life expectancy and active life expectancy by marital status among older U.S. adults: Results from the U.S. Medicare Health Outcome Survey (HOS).

BackgroundPrevious investigations of the relationship between marital status and life expectancy and healthy life expectancy rely on the assumption that participants will remain in a given marital status until death. This study estimated total life expectancy (TLE) and active life expectancy (ALE) for respondents by their baseline marital status using a large longitudinal sample of the U.S. community-dwelling elderly population.MethodsData were from the Medicare Health Outcomes Survey Cohort 15 (2012 baseline, 2014 follow-up). We included respondents aged ≥65 years (n = 164,597). Multi-state models estimated TLE and ALE by marital status to allow participants’ marital status to change during the remaining lifetime.ResultsBetween 65 and 85 years, married men and women had a longer TLE and ALE than unmarried men and women. For example, at 65 years, TLE for married men was 18.6 years, 2.2 years longer than unmarried men, and ALE for married men was 12.3 years, 2.4 years longer than unmarried men. Similarly, at 65 years, TLE for married women was 21.1 years, 1.5 years longer than unmarried women, and ALE for married women was 13.0 years, 2.0 years longer than unmarried women. Such marriage protection effects decreased with age. In subgroups of unmarried persons, never married persons had the shortest TLE and ALE among men, and never married, divorced, and widowed persons had a similar, and shorter, TLE and ALE among women. The difference in TLE between married and unmarried persons was smaller after adjusting for baseline activity limitation status.ConclusionsThis study provides additional evidence for marriage's protective effect, with the magnitude of protection being greater for younger as compared to older persons. Selection bias was a large contributor to longer life expectancy among married persons.

How long does it take until the effects of endoscopic screening on colorectal cancer mortality are fully disclosed? A Markov Model study

Introduction Colorectal cancer (CRC) is one of the leading causes of cancer morbidity and mortality worldwide. A recent randomized trial has suggested persisting protection from CRC incidence and mortality of a single flexible sigmoidoscopy for up to 17 years and possibly beyond. We performed a simulation study to explore the time course and magnitude of protection provided by screening colonoscopy against CRC death over 25 years. Methods Using data from the German national screening colonoscopy registry, a multi-state Markov model was set up based on the adenoma-carcinoma pathway to estimate the cumulative CRC mortality when different proportions of the population have a single screening colonoscopy at age 55, or two screening colonoscopies at ages 55 and 65. Ratio and difference of the expected cumulative CRC mortalities among screened and unscreened populations were calculated over follow-up to reflect the impact of screening colonoscopy. Results Cumulative CRC mortality continuously increased with age, and in the absence of screening reached 2.6% and 1.7% at age 80 for men and women, respectively. A single colonoscopy at age 55, even with limited uptake, was predicted to lead to much lower cumulative mortality (0.7% and 0.5% for men and women, respectively at age 80 when uptake was 100%). Relative mortality reduction continued to increase over more than 10 years and reached the maximum around 12–13 years after screening. Although relative risk reduction became attenuated for even longer periods of follow-up, absolute risk reduction steadily increased throughout follow-up and more than 70% of the total risk reduction was observed between 13–25 years. A repeat colonoscopy 10 year later further enhanced the effects and the cumulative mortality remained at 0.1% to 0.2% throughout follow-up when uptake was 100%. Conclusions Even a single (once only) screening colonoscopy has the potential to prevent most of CRC mortalities. Protective effects are expected to be long lasting and to become fully manifest after more than two decades from screening.

Global trade and trade protection in a globalised world

While the World Trade Organisation and Regional Trade Agreements work for boosting the global trade, trade protection remains prevalent. This contradiction took a new turn during the 2007/2008 global financial and economic crisis. There has been an argument that trade protectionist activities are influenced by diverse factors, including social, economic and institutional factors. This study examines what determines trade protectionist actions, taking into consideration some macro-economic variables. The data were sourced from the Global Trade Alert and World Development Indicators. The authors find that a country's level of economic growth is not a crucial factor for engaging in trade protection. It is also interesting that as a country's institutional quality improves, there might be the less protectionist tendencies. This implies that a country's magnitude of protection is determined by its level of institutional development. The other finding includes that the more a country trades, the higher its tendency to protect.

Systematic review with meta-analysis: breastfeeding and the risk of Crohn's disease and ulcerative colitis.

Breastfeeding is a modifiable factor that may influence development of inflammatory bowel diseases. However, literature on this has been inconsistent and not accounted for heterogeneity in populations and exposure. To conduct a meta-analysis to examine the association between breastfeeding in infancy and risk of Crohn's disease (CD) and ulcerative colitis (UC). A systematic search of Medline/PubMed and Embase was performed for full text, English-language literature through November 2016. Studies were included if they described breastfeeding in infancy in patients with CD or UC, and healthy controls. Data were pooled using a random effects model for analysis. A total of 35 studies were included in the final analysis, comprising 7536 individuals with CD, 7353 with UC and 330222 controls. Ever being breastfed was associated with a lower risk of CD (OR 0.71, 95% CI 0.59-0.85) and UC (OR 0.78, 95% CI 0.67-0.91). While this inverse association was observed in all ethnicity groups, the magnitude of protection was significantly greater among Asians (OR 0.31, 95% CI 0.20-0.48) compared to Caucasians (OR 0.78, 95% CI 0.66-0.93; P=.0001) in CD. Breastfeeding duration showed a dose-dependent association, with strongest decrease in risk when breastfed for at least 12months for CD (OR 0.20, 95% CI 0.08-0.50) and UC (OR 0.21, 95% CI 0.10-0.43) as compared to 3 or 6months. Breastfeeding in infancy protects against the development of CD and ulcerative colitis.

Genetic background impacts vaccine-induced reduction of pneumococcal colonization.

Vaccination has been one of the most successful strategies to reduce morbidity and mortality caused by respiratory infections. Recent evidence suggests that differences in the host genetic background and environmental factors may contribute to heterogeneity in the immune response to vaccination. During pre-clinical testing, vaccines are often evaluated in a single mouse inbred strain, which may not translate well to the heterogeneous human population. Here, we examined the influence of host genetic background on vaccine-induced protection against pneumococcal colonization in two commonly used inbred mouse strains, i.e. C57BL/6 and BALB/cas well as the F1 cross of these two strains. Groups of mice were vaccinated intranasally with a vaccine formulation containing a model pneumococcal antigen, i.e. pneumococcal surface protein A (PspA), adjuvanted with cholera toxin subunit B (CTB). Even in the absence of vaccination, differences in colonization density were observed between mouse strains. Although vaccination significantly reduced pneumococcal density in all mouse strains, differences were observed in the magnitude of protection. We therefore examined immunological parameters known to be involved in vaccine-induced mucosal clearance of S. pneumoniae. We found that PspA-specific IgG levels in nasal tissue differed between mouse strains, but in all cases it correlated significantly with a reduction in colonization. Furthermore, increased mucosal IL17A, but not IFNγ, IL10, or IL4, was found to be mouse strain specific. This suggests that the reduction of bacterial load may be accompanied by a Th17 response in all genetic backgrounds, although the cytokine dynamics may differ. Increased insight into the different immune mechanisms that affect pneumococcal carriage will contribute to development of future vaccines against S. pneumoniae.

Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho

Fibrosis is an exaggerated form of tissue repair that occurs with serious damage or repetitive injury and ultimately leads to organ failure due to the excessive scarring. Increased calcium ion entry through the TRPC6 channel has been associated with the pathogenesis of heart and glomerular diseases, but its role in renal interstitial fibrosis is unknown. We studied this by deletion of Trpc6 in mice and found it decreased unilateral ureteral obstruction-induced interstitial fibrosis and blunted increased mRNA expression of fibrosis-related genes in the ureteral obstructed kidney relative to that in the kidney of wild-type mice. Administration of BTP2, a pyrazol derivative known to inhibit function of several TRPC channels, also ameliorated obstruction-induced renal fibrosis and gene expression in wild-type mice. BTP2 inhibited carbachol-activated TRPC3 and TRPC6 channel activities in HEK293 cells. Ureteral obstruction caused over a 10-fold increase in mRNA expression for TRPC3 as well as TRPC6 in the kidneys of obstructed relative to the sham-operated mice. The magnitude of protection against obstruction-induced fibrosis in Trpc3 and Trpc6 double knockout mice was not different from that in Trpc6 knockout mice. Klotho, a membrane and soluble protein predominantly produced in the kidney, is known to confer protection against renal fibrosis. Administration of soluble klotho significantly reduced obstruction-induced renal fibrosis in wild-type mice, but not in Trpc6 knockout mice, indicating that klotho and TRPC6 inhibition act in the same pathway to protect against obstruction-induced renal fibrosis. Thus klotho and TRPC6 may be pharmacologic targets for treating renal fibrosis.

Intranasal Administration of Chitosan Against Influenza A (H7N9) Virus Infection in a Mouse Model

Influenza virus evolves constantly in an unpredictable fashion, making it necessary to vaccinate people annually for effective prevention and control of influenza. In general, however, during the first wave of an influenza outbreak caused by a newly emerging virus strain, influenza morbidity and mortality have been observed to rise sharply due to the lack of a matching vaccine. This necessitates the exploration of novel intervention approaches, particularly those prophylactic or therapeutic agents that have a broad range of antiviral activities and are also proven to be non-toxic. Here, we reported that stimulation of the innate immune system by intranasal administration of chitosan as a single agent was sufficient to completely protect BALB/c mice from lethal infection by H7N9 virus, a newly emerged viral strain that is highly pathogenic to humans. Remarkably, animals could still be protected against lethal challenge by H7N9 (10×LD50), even ten days after the intranasal chitosan administration. The significantly enhanced infiltration of leukocytes in the bronchoalveolar lavage and elevated levels of proinflammatory cytokines in the bronchia/lung tissues revealed the potent activation of mucosal immune responses by intranasally delivered chitosan. We also observed that chitosan can protect mice from three other virus strains. The marked breadth and magnitude of protection against diverse viral strains makes chitosan an attractive candidate as a universal anti-influenza agent.

Cost-effectiveness and programmatic benefits of maternal vaccination against pertussis in England

Maternal pertussis immunisation was introduced during the pertussis resurgence in England in 2012 as a temporary measure to protect infants too young to be vaccinated. The programme was shown to be safe and highly effective. However, continuation of maternal vaccination as a routine programme requires a cost-effectiveness analysis. The estimated prevented disease burden among mothers and their infants was obtained assuming 89% (95% CI: 19%-99%) vaccine efficacy for mothers and 91% (95% CI: 84%-95%) for infants. Future incidence was projected based on the disease rates in 2010-2012, including the four-year cycle of low and high incidence years. Full probabilistic sensitivity analysis was performed for different scenarios. Assuming a vaccine coverage of 60%, there were 1650 prevented hospitalisations in infants (3.5% discounting, the first 10 years), including 55-60 deaths and ∼20,500 cases among mothers, of which around 1800 would be severe. The annual costs of the programme are £7.3 million assuming a price of £10 per dose and £9.4 million assuming £15 per dose. Using discounting of 3.5%, a 200 year time horizon and a price of £10 per dose (+£7.5 administration costs) only 25% of the iterations were below £30,000 per QALY. Using a 35% higher incidence resulted in 88% of the scenarios below this threshold. Assuming that the incidence remains at the level at the height of 2012, then the programme would be highly cost effective, with an ICER of £16,865 (£12,209-£25,976; price of £10 and 3.5%/3.5% discounting). Maternal vaccination is effective in preventing severe illness and deaths in infants but the cost-effectiveness of the programme is highly dependent on future incidence which is necessarily uncertain. However, the duration and magnitude of protection against transmission afforded by the current acellular vaccines is also uncertain as are the associated effects on future herd immunity. The direct protection offered by the maternal dose provides the only certain way of protecting vulnerable infants from birth.

Acute and sustained isoflurane neuroprotection: The effect of culture age and duration of oxygen and glucose deprivation

Objectives: Organotypic hippocampal slice (OHS) cultures provide the opportunity to dissect factors influencing volatile anaesthetic neuroprotective efficacy. It was hypothesized that three conditions—OHS culture age, oxygen glucose deprivation (OGD) duration and day of evaluation for cell death after OGD—influence isoflurane's ability to provide acute and sustained protection against OGD-induced cell death.Methods: OHS were prepared from PND 9–11 rat pups and maintained in vitro for 0.5, 1, 2 or 3 weeks. The slices were exposed to OGD for 0, 10, 30, 60 or 90 minutes with or without 1.5% isoflurane. Sytox staining was used to determine the amount of cell death on post-OGD days 1, 3 and 7 and was compared to the amount of cell death in culture–age matched controls (no OGD).Results: The duration of OGD necessary to produce cell death was inversely related to culture age. All culture ages showed evidence of both acute and sustained neuroprotection, but the magnitude of protection depended on OHS culture age, duration of OGD and post-OGD day of evaluation. In 1 and 2-week old slices early isoflurane neuroprotection was best observed with 90 minutes OGD and late isoflurane protection was best observed with 10 minutes OGD.Conclusions: In OHS, acute and sustained isoflurane neuroprotection in OGD-induced cell death is dependent on the conditions being studied.

Eimeria species parasites as novel vaccine delivery vectors: Anti-Campylobacter jejuni protective immunity induced by Eimeria tenella-delivered CjaA

Vaccination of poultry against coccidiosis caused by the Eimeria species is almost entirely based upon varied formulations of live parasites. The recent development of a series of protocols that support genetic complementation by transfection in Eimeria now provides an opportunity to utilise live anticoccidial vaccines to deliver additional vaccinal antigens. The capacity of Eimeria tenella to express an exogenous antigen and induce an immune response during in vivo infection which is protective against subsequent bacterial challenge has been tested here using the anti-Campylobacter jejuni vaccine candidate CjaA. Using restriction enzyme mediated integration (REMI) a transgenic E. tenella population expressing CjaA and the fluorescent reporter mCitrine has been developed. Vaccination of specific pathogen free chickens by single or multiple oral inoculation of E. tenella-CjaA oocysts induced 91% and 86% immune protection against C. jejuni challenge compared with unvaccinated and wild-type E. tenella vaccinated controls (p<0.001). Increasing vaccination number had no significant influence on the magnitude of protection. These results support the hypothesis that eimerian parasites can be developed as multivalent vaccine vectors and encourage the extension of these studies.

In-vitro carbofuran induced genotoxicity in human lymphocytes and its mitigation by vitamins C and E.

Various efforts have been made in past in order to predict the underlying mechanism of pesticide-induced toxicity using in vitro and animal models, however, these predictions may or may not be directly correlated with humans. The present study was designed to investigate the carbofuran induced genotoxicity and its amelioration by vitamins C and E by treating human peripheral blood lymphocytes (PBLs) with different concentrations (0, 0.5, 1.25, 2.5, 3.75 and 5.0 μM) of this compound. The treatment of PBLs with carbofuran displayed significant DNA damage in concentration dependent manner. The carbofuran induced genotoxicity could be ameliorated to considerable extent by pretreatment of PBLs with equimolar (10 μM) concentration of each of the vitamins C and E; the magnitude of protection by vitamin E being higher than by vitamin C. Also, it was found that the level of protection by these vitamins was higher when PBLs were treated with lower concentrations of pesticide. The significant DNA damage as observed by H2O2, a positive control in the present study, and its amelioration by natural antioxidants (vitamins C and E) lend an evidence to suggest that carbofuran would have caused genotoxicity via pesticide induced oxidative stress.

In-VitroCarbofuran Induced Genotoxicity in Human Lymphocytes and Its Mitigation by Vitamins C and E

Various efforts have been made in past in order to predict the underlying mechanism of pesticide-induced toxicity usingin vitroand animal models, however, these predictions may or may not be directly correlated with humans. The present study was designed to investigate the carbofuran induced genotoxicity and its amelioration by vitamins C and E by treating human peripheral blood lymphocytes (PBLs) with different concentrations (0, 0.5, 1.25, 2.5, 3.75 and 5.0 μM) of this compound. The treatment of PBLs with carbofuran displayed significant DNA damage in concentration dependent manner. The carbofuran induced genotoxicity could be ameliorated to considerable extent by pretreatment of PBLs with equimolar (10 μM) concentration of each of the vitamins C and E; the magnitude of protection by vitamin E being higher than by vitamin C. Also, it was found that the level of protection by these vitamins was higher when PBLs were treated with lower concentrations of pesticide. The significant DNA damage as observed by H2O2, a positive control in the present study, and its amelioration by natural antioxidants (vitamins C and E) lend an evidence to suggest that carbofuran would have caused genotoxicity via pesticide induced oxidative stress.

Treatment of latent tuberculosis infection in HIV infected persons

Individuals with human immunodeficiency virus (HIV) infection are at an increased risk of developing active tuberculosis (TB). It is known that treatment of latent TB infection (LTBI), also referred to as TB preventive therapy or chemoprophylaxis, helps to prevent progression to active disease in HIV negative populations. However, the extent and magnitude of protection (if any) associated with preventive therapy in those infected with HIV should be quantified. This present study is an update of the original review. To determine the effectiveness of TB preventive therapy in reducing the risk of active tuberculosis and death in HIV-infected persons. This review was updated using the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, AIDSLINE, AIDSTRIALS, AIDSearch, NLM Gateway and AIDSDRUGS (publication date from 01 July 2002 to 04 April 2008). We also scanned reference lists of articles and contacted authors and other researchers in the field in an attempt to identify additional studies that may be eligible for inclusion in this review. We included randomized controlled trials in which HIV positive individuals were randomly allocated to TB preventive therapy or placebo, or to alternative TB preventive therapy regimens. Participants could be tuberculin skin test positive or negative, but without active tuberculosis. Three reviewers independently applied the study selection criteria, assessed study quality and extracted data. Effects were assessed using relative risk for dichotomous data and mean differences for continuous data. 12 trials were included with a total of 8578 randomized participants. TB preventive therapy (any anti-TB drug) versus placebo was associated with a lower incidence of active TB (RR 0.68, 95% CI 0.54 to 0.85). This benefit was more pronounced in individuals with a positive tuberculin skin test (RR 0.38, 95% CI 0.25 to 0.57) than in those who had a negative test (RR 0.89, 95% CI 0.64 to 1.24). Efficacy was similar for all regimens (regardless of drug type, frequency or duration of treatment). However, compared to INH monotherapy, short-course multi-drug regimens were much more likely to require discontinuation of treatment due to adverse effects. Although there was reduction in mortality with INH monotherapy versus placebo among individuals with a positive tuberculin skin test (RR 0.74, 95% CI 0.55 to 1.00) and with INH plus rifampicin versus placebo regardless of tuberculin skin test status (RR 0.69, 95% CI 0.50 to 0.95), overall, there was no evidence that TB preventive therapy versus placebo reduced all-cause mortality (RR 0.94, 95% CI 0.85 to 1.05). Treatment of latent tuberculosis infection reduces the risk of active TB in HIV positive individuals especially in those with a positive tuberculin skin test. The choice of regimen will depend on factors such as availability, cost, adverse effects, adherence and drug resistance. Future studies should assess these aspects. In addition, trials evaluating the long-term effects of anti-tuberculosis chemoprophylaxis, the optimal duration of TB preventive therapy, the influence of level of immunocompromise on effectiveness and combination of anti-tuberculosis chemoprophylaxis with antiretroviral therapy are needed.

A Pooled Analysis of the Effect of Condoms in Preventing HSV-2 Acquisition

The degree of effectiveness of condom use in preventing the transmission of herpes simplex virus 2 (HSV-2) is uncertain. To address this issue, we performed a large pooled analysis. We identified prospective studies with individual-level condom use data and laboratory-defined HSV-2 acquisition. Six studies were identified through a review of publications through 2007: 3 candidate HSV-2 vaccine studies, an HSV-2 drug study, an observational sexually transmitted infection (STI) incidence study, and a behavioral STI intervention study. Study investigators provided us individual-level data to perform a pooled analysis. Effect of condom use was modeled using a continuous percentage of sex acts during which a condom was used and, alternatively, using absolute numbers of unprotected sex acts. A total of 5384 HSV-2-negative people at baseline contributed 2 040 894 follow-up days; 415 persons acquired laboratory-documented HSV-2 during follow-up. Consistent condom users (used 100% of the time) had a 30% lower risk of HSV-2 acquisition compared with those who never used condoms (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.40-0.94) (P = .01). Risk for HSV-2 acquisition increased steadily and significantly with each unprotected sex act (HR, 1.16; 95% CI, 1.08-1.25) (P < .001). Condom effectiveness did not vary by gender. To our knowledge, this is the largest analysis using prospective data to assess the effect of condom use in preventing HSV-2 acquisition. Although the magnitude of protection was not as large as has been observed with other STIs, we found that condoms offer moderate protection against HSV-2 acquisition in men and women.

Time to Take Stock in HIV/AIDS Prevention

The first behavioral interventions designed to stem the spread of HIV were tested over 25 years ago, within just a few years of the first reported cases of AIDS. Interventions grounded in sound theories of behavior change have since been demonstrated effective at reducing high-risk injection and sexual practices in nearly every population with known risks for HIV/AIDS. Brief risk reduction counseling, small group skills building workshops, syringe exchange programs, enhanced HIV counseling and testing, interventions aimed at people living with HIV/AIDS, condom social marketing programs, peer influence models and other behavioral HIV prevention approaches have all shown efficacy in carefully controlled clinical and community trials. Meta-analyses repeatedly show that these interventions produce consistent positive behavioral outcomes and several have significantly reduced recurrent sexually transmitted infections. Unfortunately, behavioral interventions have also demanded considerable commitment to implement and resources to sustain. Despite their effectiveness, HIV risk reduction interventions have not provided the quick fix to the AIDS problem that so many policy and decision makers have sought for the past 20 years. In contrast to behavioral interventions, biomedical approaches to HIV prevention offer the promise of immunity, permanent reductions in susceptibility, and diminished infectiousness. By far, the most successful biomedical intervention for HIV prevention remains the use of antiretroviral medications for preventing mother-to-child transmission of HIV. Comprehensive mother-to-child transmission prevention programs have witnessed declines in HIV infected infants to levels approaching zero. For example, in New York there were nearly 100 HIV infected infants in 1997 whereas there were less than 10 in 2006. The number of HIV infected babies has similarly plummeted in Botswana where all pregnant women are tested and treated, whereas neighboring South Africa has been slow to implement mother-to-child prevention of HIV transmission and the country remains burdened by these avoidable and tragic infections. Several important clinical trials that are testing new biomedical HIV prevention interventions were launched in the early part of this decade and their results are now becoming available. Most encouraging has been the definitive findings from three randomized clinical trials of male circumcision for HIV risk reduction (Auvert et al. 2005; Bailey et al. 2007; Gray et al. 2007). These compelling studies all showed as much as a 60% reduction in HIV transmission among men who underwent circumcision, a magnitude of protection that cannot even be expected from most vaccine models. Male circumcision faces implementation challenges due to obvious cultural and religious meanings attached to circumcision, issues that individual communities have to sort out. But the effectiveness of male circumcision for preventing female-to-male HIV transmission is indisputable. The results of several other eagerly awaited biomedical prevention technologies have unfortunately been more disappointing. Based on a clear and convincing model of cervical susceptibility to HIV transmission, Nancy Padian conducted a critical study of the diaphragm for HIV prevention. The findings did not demonstrate added benefit from diaphragm use over and above supplying women with condoms and risk reduction counseling (Padian et al. 2007). In the past year we have also seen two promising vaginal microbicides, cellulose sulfate and Carraguard, fail to demonstrate efficacy. What was another innovative approach to preventing HIV transmission was use of antiviral medication to suppress Herpes Simplex Virus (HSV) S. C. Kalichman (&) University of Connecticut, Storrs, CT, USA e-mail: seth.k@uconn.edu

Doxorubicin-induced cardiotoxicity: direct correlation of cardiac fibroblast and H9c2 cell survival and aconitase activity with heat shock protein 27

The use of doxorubicin (Dox) and its derivatives as chemotherapeutic drugs to treat patients with cancer causes dilated cardiomyopathy and congestive heart failure due to Dox-induced cardiotoxicity. In this work, using heat shock factor-1 wild-type (HSF-1(+/+)) and HSF-1 knockout (HSF-1(-/-)) mouse fibroblasts and embryonic rat heart-derived cardiac H9c2 cells, we show that the magnitude of protection from Dox-induced toxicity directly correlates with the level of the heat shock protein 27 (HSP27). Western blot analysis of normal and heat-shocked cells showed the maximum expression of HSP27 in heat-shocked cardiac H9c2 cells and no HSP27 in HSF-1(-/-) cells (normal or heat-shocked). Correspondingly, the cell viability, measured [with (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay] after treatment with various concentrations of Dox, was the highest in heat-shocked H9c2 cells and the lowest in HSF-1(-/-) cells. Depleting HSP27 in cardiac H9c2 cells by small interfering (si)RNA also reduced the viability against Dox, confirming that HSP27 does protect cardiac cells against the Dox-induced toxicity. The cells that have lower HSP27 levels such as HSF-1(-/-), were found to be more susceptible for aconitase inactivation. Based on these results we propose a novel mechanism that HSP27 plays an important role in protecting aconitase from Dox-generated O(2)*(-), by increasing SOD activity. Such a protection of aconitase by HSP27 eliminates the catalytic recycling of aconitase released Fe(II) and its deleterious effects in cardiac cells.

The Anti-Apoptotic Protein PEA-15 Is a Tight Binding Inhibitor of ERK1 and ERK2, Which Blocks Docking Interactions at the D-Recruitment Site

PEA-15 is a small anti-apoptotic protein that is enriched in astrocytes, but expressed in a broad range of tissues. It sequesters the protein kinases ERK1 and 2 in the cytoplasm, thereby limiting their proximity to nuclear substrates. Using a fluorescence anisotropy approach, PEA-15 is shown to be a high-affinity ligand for both ERK1 and 2, exhibiting a dissociation constant in the range of Kd = 0.2-0.4 microM, regardless of their activation states. Neither the phosphorylation of PEA-15 (phospho Ser-104 and/or phospho Ser-116) nor the phosphorylation of ERK1/2 (by MKK1) significantly affects the stability of the ERK/PEA-15 interaction, and therefore it does not directly regulate the release of ERK2 to the nucleus. The extreme C-terminus of PEA-15 was previously shown by mutagenesis to be important for ERK2 binding; however, the site of binding was not established. Here it is demonstrated that the D-recruitment site (DRS) of ERK2 binds PEA-15, probably at the C-terminus, and renders PEA-15 an inhibitor of ERK2 docking interactions. Using fluorescence anisotropy competition assays it is shown that PEA-15 competes for binding to ERK1/2 with a peptide derived from the D-site of Elk-1, which binds the DRS of ERK1/2. Using modified ERK2 proteins containing single cysteine residues, PEA-15 was shown to protect single cysteines situated within the DRS from alkylation. The pattern and magnitude of protection were very similar to those induced by the binding of the peptide derived from the D-site of Elk-1. These and published data support the notion that PEA-15 binds two sites on ERK1/2 in a bidentate manner: the DRS and a site that includes the MAP kinase insert. Previous reports have suggested that PEA-15 is not an inhibitor of ERK2; however, it is shown here to potently inhibit the ability of ERK2 to phosphorylate two transcription factors, Elk-1 and Ets-1, which contain docking sites for the DRS of ERK2. Therefore, in addition to sequestering ERK1/2 in the cytoplasm, PEA-15 has the potential to modulate the activity of ERK2 in cells by competing directly with proteins that contain D-sites.

Evidence of a contralateral repeated bout effect after maximal eccentric contractions

The aim of this investigation was firstly, to examine whether a contralateral repeated bout effect is manifested after a single bout of maximal eccentric muscle actions and secondly, to compare the magnitude of any such protection to an ipsilateral control. Sixteen male subjects undertook 45 repetitions of maximal eccentric contractions of the elbow flexors. The ipsilateral group (IL, N=8) repeated the exercise using the same arm and the contralateral group (CL, N=8) repeated the exercise using the contralateral arm 14 days later. Serum creatine kinase (CK), muscle soreness, maximal voluntary contraction (MVC) and range of motion (ROM) were significantly attenuated in the repeated bout for IL. CL also showed a significant reduction in the repeated bout for CK, muscle soreness and MVC. Despite the significant attenuation of dependent variables in both groups the magnitude of change was less in CL compared to IL for CK, soreness, MVC and ROM. The findings demonstrate a repeated bout effect in the contralateral limb after a single bout of maximal eccentric exercise; however, the magnitude of protection in the contralateral limb is less than that manifested in the ipsilateral limb. The apparent contralateral repeated bout effect observed in this investigation is thought to be predominantly mediated by neural mechanisms, although further research is required to elucidate this possibility.

Causal Vaccine Effects on Binary Postinfection Outcomes

The effects of vaccine on postinfection outcomes, such as disease, death, and secondary transmission to others, are important scientific and public health aspects of prophylactic vaccination. As a result, evaluation of many vaccine effects condition on being infected. Conditioning on an event that occurs posttreatment (in our case, infection subsequent to assignment to vaccine or control) can result in selection bias. Moreover, because the set of individuals who would become infected if vaccinated is likely not identical to the set of those who would become infected if given control, comparisons that condition on infection do not have a causal interpretation. In this article we consider identifiability and estimation of causal vaccine effects on binary postinfection outcomes. Using the principal stratification framework, we define a postinfection causal vaccine efficacy estimand in individuals who would be infected regardless of treatment assignment. The estimand is shown to be not identifiable under the standard assumptions of the stable unit treatment value, monotonicity, and independence of treatment assignment. Thus selection models are proposed that identify the causal estimand. Closed-form maximum likelihood estimators (MLEs) are then derived under these models, including those assuming maximum possible levels of positive and negative selection bias. These results show the relations between the MLE of the causal estimand and two commonly used estimators for vaccine effects on postinfection outcomes. For example, the usual intent-to-treat estimator is shown to be an upper bound on the postinfection causal vaccine effect provided that the magnitude of protection against infection is not too large. The methods are used to evaluate postinfection vaccine effects in a clinical trial of a rotavirus vaccine candidate and in a field study of a pertussis vaccine. Our results show that pertussis vaccination has a significant causal effect in reducing disease severity.