A repeated GGA motif is critical for the activity and stability of the riboregulator RsmY of Pseudomonas fluorescens.

The riboregulator RsmY of Pseudomonas fluorescens strain CHA0 is an example of small regulatory RNAs belonging to the global Rsm/Csr regulatory systems controlling diverse cellular processes such as glycogen accumulation, motility, or formation of extracellular products in various bacteria. By binding multiple molecules of the small regulatory protein RsmA, RsmY relieves the negative effect of RsmA on the translation of several target genes involved in the biocontrol properties of strain CHA0. RsmY and functionally related riboregulators have repeated GGA motifs predicted to be exposed in single-stranded regions, notably in the loops of hairpins. The secondary structure of RsmY was corroborated by in vivo cleavage with lead acetate. RsmY mutants lacking three or five (out of six) of the GGA motifs showed reduced ability to derepress the expression of target genes in vivo and failed to bind the RsmA protein efficiently in vitro. The absence of GGA motifs in RsmY mutants resulted in reduced abundance of these transcripts and in a shorter half-life (< or = 6 min as compared with 27 min for wild type RsmY). These results suggest that both the interaction of RsmY with RsmA and the stability of RsmY strongly depend on the GGA repeats and that the ability of RsmY to interact with small regulatory proteins such as RsmA may protect this RNA from degradation.

Current variables, definitions and endpoints of the European cardiovascular magnetic resonance registry.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used in daily clinical practice. However, little is known about its clinical utility such as image quality, safety and impact on patient management. In addition, there is limited information about the potential of CMR to acquire prognostic information. METHODS: The European Cardiovascular Magnetic Resonance Registry (EuroCMR Registry) will consist of two parts: 1) Multicenter registry with consecutive enrolment of patients scanned in all participating European CMR centres using web based online case record forms. 2) Prospective clinical follow up of patients with suspected coronary artery disease (CAD) and hypertrophic cardiomyopathy (HCM) every 12 months after enrolment to assess prognostic data. CONCLUSION: The EuroCMR Registry offers an opportunity to provide information about the clinical utility of routine CMR in a large number of cases and a diverse population. Furthermore it has the potential to gather information about the prognostic value of CMR in specific patient populations.

Constraint and cost of oxidative stress on reproduction: correlative evidence in laboratory mice and review of the literature.

ABSTRACT: BACKGROUND: One central concept in evolutionary ecology is that current and residual reproductive values are negatively linked by the so-called cost of reproduction. Previous studies examining the nature of this cost suggested a possible involvement of oxidative stress resulting from the imbalance between pro- and anti-oxidant processes. Still, data remain conflictory probably because, although oxidative damage increases during reproduction, high systemic levels of oxidative stress might also constrain parental investment in reproduction. Here, we investigated variation in oxidative balance (i.e. oxidative damage and antioxidant defences) over the course of reproduction by comparing female laboratory mice rearing or not pups. RESULTS: A significant increase in oxidative damage over time was only observed in females caring for offspring, whereas antioxidant defences increased over time regardless of reproductive status. Interestingly, oxidative damage measured prior to reproduction was negatively associated with litter size at birth (constraint), whereas damage measured after reproduction was positively related to litter size at weaning (cost). CONCLUSIONS: Globally, our correlative results and the review of literature describing the links between reproduction and oxidative stress underline the importance of timing/dynamics when studying and interpreting oxidative balance in relation to reproduction. Our study highlights the duality (constraint and cost) of oxidative stress in life-history trade-offs, thus supporting the theory that oxidative stress plays a key role in life-history evolution.

Intermittent hemodialysis treatment in cefepime-induced neurotoxicity: Case report, pharmacokinetic modeling, and review of the literature.

Cefepime is a broad-spectrum cephalosporin indicated for in-hospital treatment of severe infections. Acute neurotoxicity, an increasingly recognized adverse effect of this drug in an overdose, predominantly affects patients with reduced renal function. Although dialytic approaches have been advocated to treat this condition, their role in this indication remains unclear. We report the case of an 88-year-old female patient with impaired renal function who developed life-threatening neurologic symptoms during cefepime therapy. She was treated with two intermittent 3-hour high-flux, high-efficiency hemodialysis sessions. Serial pre-, post-, and peridialytic (pre- and postfilter) serum cefepime concentrations were measured. Pharmacokinetic modeling showed that this dialytic strategy allowed for serum cefepime concentrations to return to the estimated nontoxic range 15 hours earlier than would have been the case without an intervention. The patient made a full clinical recovery over the next 48 hours. We conclude that at least 1 session of intermittent hemodialysis may shorten the time to return to the nontoxic range in severe clinically patent intoxication. It should be considered early in its clinical course pending chemical confirmation, even in frail elderly patients. Careful dosage adjustment and a high index of suspicion are essential in this population.

Operational benefits and challenges of the use of fingerprint statistical models: a field study

Research projects aimed at proposing fingerprint statistical models based on the likelihood ratio framework have shown that low quality finger impressions left on crime scenes may have significant evidential value. These impressions are currently either not recovered, considered to be of no value when first analyzed by fingerprint examiners, or lead to inconclusive results when compared to control prints. There are growing concerns within the fingerprint community that recovering and examining these low quality impressions will result in a significant increase of the workload of fingerprint units and ultimately of the number of backlogged cases. This study was designed to measure the number of impressions currently not recovered or not considered for examination, and to assess the usefulness of these impressions in terms of the number of additional detections that would result from their examination.

Structure and kinematics of the Jungfrau syncline, Faflertal (Valais, Alps), and its regional significance

The formation and structural evolution of the jungrau syncline is described, based on excellent outcrops occurring in the lotschental, in the central alps of switzerland. the quality of the outcrops allows us to demonstrate that the external massifs of the swiss alps have developed due to internal folding. The jungfrau suncline, which separates the autochtonous gastern dome from the aar massif basement gneiss folds, is composed of slivers of basement rocks with their mesozoic sedimentary cover. in the inner faflertal, a side valley of the lotschental, the 200 m thick syncline cp, roses fpir imots, the gastern massif with a reduced mesozoic sedimentary cover in a normal stratigraphic succession, two units of overturned basement rocks with their mesozoic sedimentary cover, and the overturned lower limn of the tschingelhorn gneiss fold of the aar massif with lenses of its sedimentary cover. stratigraphy shows that the lower units, related to the gastern massis, are condensed and that the upper units, deposited farther away from a gastern paleo-high, form a more complete sequence, linked to the doldenhorn meso-cneozoic basin fill. the integration of these local observations with published regional data leads to the following model. on the northern margin of the doldenhorn hbasin, at the northern fringe of the alpine tethuys, the pre-triassic crystalline basement and its mesozoic sedimentary cover were folded by ductile deformation at temperatures above 300 degrees C and in the presence of high fluid pressures, as the helveti c and penninic nappes were overthrusted towards the northwest during the main alpine deformation phase, the visosity contrast between the basement gneisses and the sediments caused the formation of large basement anticlines and tight sedimentary sunclines (mullion-type structures). The edges of basement blocks bounded buy pre-cursor se-dipping normal faults at the northwestern border of the doldenhorn basin were deformed bu simple shear, creating overturned slices of crystalline rocks with their sedimentary cover in what now forms the hungfrau syncline. the localisation of ductile deformation in the vicinity of pre-existing se-dipping faults is thought to have been helped by the circulation of fluids along the faults; these fluids would have been released from the mesozoic sediments by metamorphic dehydration reactions accompanied by creep and dynamic recrystallisation of quartz at temperatures above 300 degrees C. Quantification of the deformation suggests an strain ellipsoid with a ratio (1 + e(1)/+ e(3)) of approximately 1000. The jungfrau suncline was deformed bu more brittle nw-directed shear creating well-developed shear band cleavages at a late stage, after cooling by uplift and erosion. It is suggested that the external massifs of the apls are basement gneiss folds created at temperatures of 300 degrees C by detachment through ductile deformation of the upper crust of the european plate as it was underthrusted below the adriatic plate.

Exploring the periodicity of cardiovascular events in Switzerland: variation in deaths and hospitalizations across seasons, day of the week and hour of the day.

PURPOSE: The purpose of this study is to explore the periodical patterns of events and deaths related to cardiovascular disease (CVD), acute myocardial infarction (AMI) and stroke in Swiss adults (≥ 18 years). METHODS: Mortality data for period 1969-2007 (N=869,863 CVD events) and hospitalization data for period 1997-2008 (N=959,990 CVD events) were used. The annual, weekly and circadian distribution of CVD-related deaths and events were assessed. Multivariate analysis was conducted using multinomial logistic regression adjusting for age, gender and calendar year and considering deaths from respiratory diseases, accidents or other causes as competitive events. RESULTS: CVD deaths and hospitalizations occurred less frequently in the summer months. Similar patterns were found for AMI and stroke. No significant weekly variation for CVD deaths was found. Stratification by age and gender showed subjects aged <65 years to present a higher probability of dying on Mondays and Saturday, only for men. This finding was confirmed after multivariate adjustment. Finally, a circadian variation in CVD mortality was observed, with a first peak in the morning (8-12 am) and a smaller second peak in the late afternoon (2-6 pm). This pattern persisted after multivariate adjustment and was more pronounced for AMI than for stroke. CONCLUSION: There is a periodicity of hospitalizations and deaths related to CVD, AMI and stroke in Switzerland. This pattern changes slightly according to the age and sex of the subjects. Although the underlying mechanisms are not fully identified, preventive measures should take into account these aspects to develop better strategies of prevention and management of CVD.

Using STD occurence to monitor AIDS prevention : final report of the Working Group on STD Surveillance.

The overall aim of the project has been to assess the extent to which data on the frequency of occurence of STDs [Sexually transmitted diseases] might be useful in the monitoring and evaluation of AIDS prevention programmes. The objectives have been to answer the following questions: (a) Can measures of STD occurence be used as an outcome measure of AIDS/HIV preventive efforts ? In particular: -> which diseases might be useful ? -> in what ways could they be used ? (b) If measures of STD occurence can be used in this way, is existing surveillance data in Western Europe adequate for the purpose ? If not why not ? (c) What do data from existing STD surveillance systems tell us about the success or failure of AIDS prevention to date ? (d) What needs to be done in order taht STD surveillance data in the countries of Western Europe could be used for this purpose ? [Authors, p. 4]

Liberties and constraints of the normative approach to evaluation and decision in forensic science: a discussion towards overcoming some common misconceptions

At a time when disciplined inference and decision making under uncertainty represent common aims to participants in legal proceedings, the scientific community is remarkably heterogenous in its attitudes as to how these goals ought to be achieved. Probability and decision theory exert a considerable influence, and we think by all reason rightly do so, but they go against a mainstream of thinking that does not embrace-or is not aware of-the 'normative' character of this body of theory. It is normative, in the sense understood in this article, in that it prescribes particular properties, typically (logical) coherence, to which reasoning and decision making ought to conform. Disregarding these properties can result in diverging views which are occasionally used as an argument against the theory, or as a pretext for not following it. Typical examples are objections according to which people, both in everyday life but also individuals involved at various levels in the judicial process, find the theory difficult to understand and to apply. A further objection is that the theory does not reflect how people actually behave. This article aims to point out in what sense these examples misinterpret the analytical framework in its normative perspective. Through examples borrowed mostly from forensic science contexts, it is argued that so-called intuitive scientific attitudes are particularly liable to such misconceptions. These attitudes are contrasted with a statement of the actual liberties and constraints of probability and decision theory and the view according to which this theory is normative.

A Candidate HIV/AIDS Vaccine (MVA-B) that Enhances the Magnitude and Polyfunctionality of Memory HIV-1-Specific T-Cell Responses

Background: The poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (MVA-B) is currently used as a HIV/AIDS vaccine candidate. A general strategy to try to improve the immunogenicity of poxvirus HIV-1 vaccine candidates is the deletion of known or suggested immunomodulatory vaccinia virus (VACV) genes.Methods: We have generated and characterized the innate immune sensing and the immunogenicity profile of a new HIV-1 vaccine candidate, which contains a deletion in a VACV gene.Results: We show that this VACV protein is expressed early during virus infection and localizes to the cytoplasm of infected cells. Deletion of this VACV gene from the MVA-B had no effect on virus growth kinetics; therefore this VACV protein is not essential for virus replication. The innate immune signals elicited by the MVA-B deletion mutant in human macrophages and monocyte-derived dendritic cells were characterized. In a DNA prime/MVA boost immunization protocol in mice, flow cytometry analysis revealed that the MVA-B deletion mutant enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4 + and CD8 + T-cell memory immune responses, with most of the HIV-1 responses mediated by the CD8 + T-cell compartment with an effector phenotype. Significantly, while MVA-B induced preferentially Env- and Gag-specific CD8 + T-cell responses, the MVA-B deletion mutant induced more GPN-specific CD8 + T-cell responses. Furthermore, the MVA-B deletion mutant enhanced the levels of antibodies against Env in comparison with MVA-B.Conclusion: These findings revealed that this new VACV protein can be considered as an immunomodulator and that deleting this gene in MVA-B confers an immunological benefit by inducing innate immune responses and increasing the magnitude and quality of the T-cell memory immune responses to HIV-1 antigens. Our observations are relevant for the improvement of MVA vectors as HIV-1 vaccines.

Lon protease negatively affects GacA protein stability and expression of the Gac/Rsm signal transduction pathway in Pseudomonas protegens.

In Pseudomonas protegens CHA0 and other fluorescent pseudomonads, the Gac/Rsm signal transduction pathway controls secondary metabolism and suppression of fungal root pathogens via the expression of regulatory small RNAs (sRNAs). Because of its high cost, this pathway needs to be protected from overexpression and to be turned off in response to environmental stress such as the lack of nutrients. However, little is known about its underlying molecular mechanisms. In this study, we demonstrated that Lon protease, a member of the ATP-dependent protease family, negatively regulated the Gac/Rsm cascade. In a lon mutant, the steady-state levels and the stability of the GacA protein were significantly elevated at the end of exponential growth. As a consequence, the expression of the sRNAs RsmY and RsmZ and that of dependent physiological functions such as antibiotic production were significantly enhanced. Biocontrol of Pythium ultimum on cucumber roots required fewer lon mutant cells than wild-type cells. In starved cells, the loss of Lon function prolonged the half-life of the GacA protein. Thus, Lon protease is an important negative regulator of the Gac/Rsm signal transduction pathway in P. protegens.

Design and methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide long-term follow-up cohort.

In Switzerland, organ procurement is well organized at the national-level but transplant outcomes have not been systematically monitored so far. Therefore, a novel project, the Swiss Transplant Cohort Study (STCS), was established. The STCS is a prospective multicentre study, designed as a dynamic cohort, which enrolls all solid organ recipients at the national level. The features of the STCS are a flexible patient-case system that allows capturing all transplant scenarios and collection of patient-specific and allograft-specific data. Beyond comprehensive clinical data, specific focus is directed at psychosocial and behavioral factors, infectious disease development, and bio-banking. Between May 2008 and end of 2011, the six Swiss transplant centers recruited 1,677 patients involving 1,721 transplantations, and a total of 1,800 organs implanted in 15 different transplantation scenarios. 10 % of all patients underwent re-transplantation and 3% had a second transplantation, either in the past or during follow-up. 34% of all kidney allografts originated from living donation. Until the end of 2011 we observed 4,385 infection episodes in our patient population. The STCS showed operative capabilities to collect high-quality data and to adequately reflect the complexity of the post-transplantation process. The STCS represents a promising novel project for comparative effectiveness research in transplantation medicine.

Sensitivity analysis, dominant factors, and robustness of the ECETOC TRA v3, Stoffenmanager 4.5, and ART 1.5 occupational exposure models

Occupational exposure modeling is widely used in the context of the E.U. regulation on the registration, evaluation, authorization, and restriction of chemicals (REACH). First tier tools, such as European Centre for Ecotoxicology and TOxicology of Chemicals (ECETOC) targeted risk assessment (TRA) or Stoffenmanager, are used to screen a wide range of substances. Those of concern are investigated further using second tier tools, e.g., Advanced REACH Tool (ART). Local sensitivity analysis (SA) methods are used here to determine dominant factors for three models commonly used within the REACH framework: ECETOC TRA v3, Stoffenmanager 4.5, and ART 1.5. Based on the results of the SA, the robustness of the models is assessed. For ECETOC, the process category (PROC) is the most important factor. A failure to identify the correct PROC has severe consequences for the exposure estimate. Stoffenmanager is the most balanced model and decision making uncertainties in one modifying factor are less severe in Stoffenmanager. ART requires a careful evaluation of the decisions in the source compartment since it constitutes ∼75% of the total exposure range, which corresponds to an exposure estimate of 20-22 orders of magnitude. Our results indicate that there is a trade off between accuracy and precision of the models. Previous studies suggested that ART may lead to more accurate results in well-documented exposure situations. However, the choice of the adequate model should ultimately be determined by the quality of the available exposure data: if the practitioner is uncertain concerning two or more decisions in the entry parameters, Stoffenmanager may be more robust than ART.

Reducing Cardiovascular Mortality Through Prevention and Management of Raised Blood Pressure: A World Heart Federation Roadmap.

Prospective epidemiological data have shown that blood pressure has a graded, continuous adverse effect on the risk of various forms of CVD (including stroke, myocardial infarction, heart failure, peripheral arterial disease and end-stage renal disease). 'Raised blood pressure' is frequently considered to be any systolic blood pressure greater than 115 mmHg. It accounts for 45% of all heart disease deaths and 51% of all stroke-related deaths [1], which together are the biggest causes of morbidity and mortality worldwide [2,3,4]. Annually, there are >17 million deaths due to CVD worldwide, of which 9.4 million are attributable to complications of raised blood pressure. This highlights the importance of both high-risk and population-based strategies in blood pressure management and control.

Patient-centered Care in Maternity Services: A Critical Appraisal and Synthesis of the Literature.

BACKGROUND: Patient-centered care (PCC) has been recognized as a marker of quality in health service delivery. In policy documents, PCC is often used interchangeably with other models of care. There is a wide literature about PCC, but there is a lack of evidence about which model is the most appropriate for maternity services specifically. AIM: We sought to identify and critically appraise the literature to identify which definition of PCC is most relevant for maternity services. METHODS: The four-step approach used to identify definitions of PCC was to 1) search electronic databases using key terms (1995-2011), 2) cross-reference key papers, 3) search of specific journals, and 4) search the grey literature. Four papers and two books met our inclusion criteria. ANALYSIS: A four-criteria critical appraisal tool developed for the review was used to appraise the papers and books. MAIN RESULTS: From the six identified definitions, the Shaller's definition met the majority of the four criteria outlined and seems to be the most relevant to maternity services because it includes physiologic conditions as well as pathology, psychological aspects, a nonmedical approach to care, the greater involvement of family and friends, and strategies to implement PCC. CONCLUSION: This review highlights Shaller's definitions of PCC as the one that would be the most inclusive of all women using maternity services. Future research should concentrate on evaluating programs that support PCC in maternity services, and testing/validating this model of care.