Checkpoints are blind to replication restart and recombination intermediates that result in gross chromosomal rearrangements

Replication fork inactivation can be overcome by homologous recombination, but this can cause gross chromosomal rearrangements that subsequently missegregate at mitosis, driving further chromosome instability. It is unclear when the chromosome rearrangements are generated and whether individual replication problems or the resulting recombination intermediates delay the cell cycle. Here we have investigated checkpoint activation during HR-dependent replication restart using a site-specific replication fork-arrest system. Analysis during a single cell cycle shows that HR-dependent replication intermediates arise in S phase, shortly after replication arrest, and are resolved into acentric and dicentric chromosomes in G2. Despite this, cells progress into mitosis without delay. Neither the DNA damage nor the intra-S phase checkpoints are activated in the first cell cycle, demonstrating that these checkpoints are blind to replication and recombination intermediates as well as to rearranged chromosomes. The dicentrics form anaphase bridges that subsequently break, inducing checkpoint activation in the second cell cycle

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

Monitoring the level of government trust, risk perception and intention of the general public to adopt protective measures during the influenza A (H1N1) pandemic in the Netherlands

<p>Abstract</p> <p>Background</p> <p>During the course of an influenza pandemic, governments know relatively little about the possibly changing influence of government trust, risk perception, and receipt of information on the public's intention to adopt protective measures or on the acceptance of vaccination. This study aims to identify and describe possible changes in and factors associated with public's intentions during the 2009 influenza A (H1N1) pandemic in the Netherlands.</p> <p>Methods</p> <p>Sixteen cross-sectional telephone surveys were conducted (N = 8060) between April - November 2009. From these repeated measurements three consecutive periods were categorized based on crucial events during the influenza A (H1N1) pandemic. Time trends in government trust, risk perception, intention to adopt protective measures, and the acceptance of vaccination were analysed. Factors associated with an intention to adopt protective measures or vaccination were identified.</p> <p>Results</p> <p>Trust in the government was high, but decreased over time. During the course of the pandemic, perceived vulnerability and an intention to adopt protective measures increased. Trust and vulnerability were associated with an intention to adopt protective measures in general only during period one. Higher levels of intention to receive vaccination were associated with increased government trust, fear/worry, and perceived vulnerability. In periods two and three receipt of information was positively associated with an intention to adopt protective measures. Most respondents wanted to receive information about infection prevention from municipal health services, health care providers, and the media.</p> <p>Conclusions</p> <p>The Dutch response to the H1N1 virus was relatively muted. Higher levels of trust in the government, fear/worry, and perceived vulnerability were all positively related to an intention to accept vaccination. Only fear/worry was positively linked to an intention to adopt protective measures during the entire pandemic. Risk and crisis communication by the government should focus on building and maintaining trust by providing information about preventing infection in close collaboration with municipal health services, health care providers, and the media.</p

Wealth and sexual behaviour among men in Cameroon

BACKGROUND: The 2004 Demographic and Health Survey (DHS) in Cameroon revealed a higher prevalence of HIV in richest and most educated people than their poorest and least educated compatriots. It is not certain whether the higher prevalence results partly or wholly from wealthier people adopting more unsafe sexual behaviours, surviving longer due to greater access to treatment and care, or being exposed to unsafe injections or other HIV risk factors. As unsafe sex is currently believed to be the main driver of the HIV epidemic in sub-Saharan Africa, we designed this study to examine the association between wealth and sexual behaviour in Cameroon. METHODS: We analysed data from 4409 sexually active men aged 15–59 years who participated in the Cameroon DHS using logistic regression models, and have reported odds ratios (OR) with confidence intervals (CI). RESULTS: When we controlled for the potential confounding effects of marital status, place of residence, religion and age, men in the richest third of the population were less likely to have used a condom in the last sex with a non-spousal non-cohabiting partner (OR 0.43, 95% CI 0.32–0.56) and more likely to have had at least two concurrent sex partners in the last 12 months (OR 1.38, 95% CI 1.12–1.19) and more than five lifetime sex partners (OR 1.97, 95% CI 1.60–2.43). However, there was no difference between the richest and poorest men in the purchase of sexual services. Regarding education, men with secondary or higher education were less likely to have used a condom in the last sex with a non-spousal non-cohabiting partner (OR 0.24, 95% CI 0.16–0.38) and more likely to have started sexual activity at age 17 years or less (OR 2.73, 95% CI 2.10–3.56) and had more than five lifetime sexual partners (OR 2.59, 95% CI 2.02–3.31). There was no significant association between education and multiple concurrent sexual partnerships in the last 12 months or purchase of sexual services. CONCLUSION: Wealthy men in Cameroon are more likely to start sexual activity early and have both multiple concurrent and lifetime sex partners, and are less likely to (consistently) use a condom in sex with a non-spousal non-cohabiting partner. These unsafe sexual behaviours may explain the higher HIV prevalence among wealthier men in the country. While these findings do not suggest a redirection of HIV prevention efforts from the poor to the wealthy, they do call for efforts to ensure that HIV prevention messages get across all strata of society

Will ocean acidification affect marine microbes?

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in The ISME Journal 5 (2011): 1-7, doi:10.1038/ismej.2010.79.The pH of the surface ocean is changing as a result of increases in atmospheric carbon dioxide (CO2) and there are concerns about potential impacts of lower pH and associated alterations in seawater carbonate chemistry on the biogeochemical processes in the ocean. However, it is important to place these changes within the context of pH in the present day ocean, which is not constant; it varies systematically with season, depth and along productivity gradients. Yet this natural variability in pH has rarely been considered in assessments of the effect of ocean acidification on marine microbes. Surface pH can change as a consequence of microbial utilisation and production of carbon dioxide, and to a lesser extent other microbiallymediated processes such as nitrification. Useful comparisons can be made with microbes in other aquatic environments that readily accommodate very large and rapid pH change. For example, in many freshwater lakes, pH changes that are orders of magnitude greater than those projected for the 22nd century oceans can occur over periods of hours. Marine and freshwater assemblages have always experienced variable pH conditions. Therefore, an appropriate null hypothesis may be, until evidence is obtained to the contrary, that major biogeochemical processes in the oceans other than calcification will not be fundamentally different under future higher CO2 / lower pH conditions.Funding from the Gordon and Betty Moore Foundation, and logistical support from the Plymouth Marine Laboratory and the Center for Microbial Oceanography: Research and Education (National Science Foundation grant EF-0424599) are gratefully acknowledged

Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity

There are over 6 billion vaccine doses administered each year, most containing aluminium-based adjuvants, yet we still do not have a complete understanding of their mechanisms of action. Recent evidence has identified host DNA and downstream sensing as playing a significant role in aluminium adjuvant (aluminium hydroxide) activity. However, the cellular source of this DNA, how it is sensed by the immune system and the consequences of this for vaccination remains unclear. Here we show that the very early injection site reaction is characterised by inflammatory chemokine production and neutrophil recruitment. Intravital imaging demonstrates that the Alum injection site is a focus of neutrophil swarms and extracellular DNA strands. These strands were confirmed as neutrophil extracellular traps due to their sensitivity to DNAse and absence in mice deficient in peptidylarginine deiminase 4. Further studies in PAD4−/− mice confirmed a significant role for neutrophil extracellular trap formation in the adjuvant activity of Alum. By revealing neutrophils recruited to the site of Alum injection as a source of the DNA that is detected by the immune system this study provides the missing link between Alum injection and the activation of DNA sensors that enhance adjuvant activity, elucidating a key mechanism of action for this important vaccine component

Diurnal changes in seawater carbonate chemistry speciation at increasing atmospheric carbon dioxide

Natural variability in seawater pH and associated carbonate chemistry parameters is in part driven by biological activities such as photosynthesis and respiration. The amplitude of these variations is expected to increase with increasing seawater carbon dioxide (CO2) concentrations in the future, because of simultaneously decreasing buffer capacity. Here, we address this experimentally during a diurnal cycle in a mesocosm CO2 perturbation study. We show that for about the same amount of dissolved inorganic carbon (DIC) utilized in net community production diel variability in proton (H+) and CO2 concentrations was almost three times higher at CO2 levels of about 675 ± 65 in comparison with levels of 310 ± 30 μatm. With a simple model, adequately simulating our measurements, we visualize carbonate chemistry variability expected for different oceanic regions with relatively low or high net community production. Since enhanced diurnal variability in CO2 and proton concentration may require stronger cellular regulation in phytoplankton to maintain respective gradients, the ability to adjust may differ between communities adapted to low in comparison with high natural variability

Predicting the Lay Preventive Strategies in Response to Avian Influenza from Perceptions of the Threat

Background: The identification of patterns of behaviors that lay people would engage in to protect themselves from the risk of infection in the case of avian influenza outbreak, as well as the lay perceptions of the threat that underlie these risk reduction strategies. Methodology/Principal Findings: A population-based survey (N = 1003) was conducted in 2008 to understand and describe how the French public might respond to a possible outbreak. Factor analyses highlighted three main categories of risk reduction strategies consisting of food quality assurance, food avoidance, and animal avoidance. In combination with the fear of contracting avian influenza, mental representations associated with the manifestation and/or transmission of the disease were found to significantly and systematically shape the behavioral responses to the perceived threat. Conclusions/Significance: This survey provides insight into the nature and predictors of the protective patterns that might be expected from the general public during a novel domestic outbreak of avian influenza

Structural issues affecting mixed methods studies in health research: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Health researchers undertake studies which combine qualitative and quantitative methods. Little attention has been paid to the structural issues affecting this mixed methods approach. We explored the facilitators and barriers to undertaking mixed methods studies in health research.</p> <p>Methods</p> <p>Face-to-face semi-structured interviews with 20 researchers experienced in mixed methods research in health in the United Kingdom.</p> <p>Results</p> <p>Structural facilitators for undertaking mixed methods studies included a perception that funding bodies promoted this approach, and the multidisciplinary constituency of some university departments. Structural barriers to exploiting the potential of these studies included a lack of education and training in mixed methods research, and a lack of templates for reporting mixed methods articles in peer-reviewed journals. The 'hierarchy of evidence' relating to effectiveness studies in health care research, with the randomised controlled trial as the gold standard, appeared to pervade the health research infrastructure. Thus integration of data and findings from qualitative and quantitative components of mixed methods studies, and dissemination of integrated outputs, tended to occur through serendipity and effort, further highlighting the presence of structural constraints. Researchers are agents who may also support current structures - journal reviewers and editors, and directors of postgraduate training courses - and thus have the ability to improve the structural support for exploiting the potential of mixed methods research.</p> <p>Conclusion</p> <p>The environment for health research in the UK appears to be conducive to mixed methods research but not to exploiting the potential of this approach. Structural change, as well as change in researcher behaviour, will be necessary if researchers are to fully exploit the potential of using mixed methods research.</p

How do care-provider and home exercise program characteristics affect patient adherence in chronic neck and back pain: a qualitative study

<p>Abstract</p> <p>Background</p> <p>The aim of this study is to explore perceptions of people with chronic neck or low back pain about how characteristics of home exercise programs and care-provider style during clinical encounters may affect adherence to exercises.</p> <p>Methods</p> <p>This is a qualitative study consisting of seven focus groups, with a total of 34 participants presenting chronic neck or low back pain. The subjects were included if they were receiving physiotherapy treatment and were prescribed home-based exercises.</p> <p>Results</p> <p>Two themes emerged: home-based exercise programme conditions and care provider's style. In the first theme, the participants described their positive and negative experiences regarding time consumption, complexity and effects of prescribed exercises. In the second theme, participants perceived more bonding to prescribed exercises when their care provider presented knowledge about the disease, promoted feedback and motivation during exercise instruction, gave them reminders to exercise, or monitored their results and adherence to exercises.</p> <p>Conclusions</p> <p>Our experiential findings indicate that patient's adherence to home-based exercise is more likely to happen when care providers' style and the content of exercise programme are positively experienced. These findings provide additional information to health care providers, by showing which issues should be considered when delivering health care to patients presenting chronic neck or back pain.</p