Interplay of mechanotransduction, FOXC2, connexins, and calcineurin signaling in lymphatic valve formation.

The directional flow of lymph is maintained by hundreds of intraluminal lymphatic valves. Lymphatic valves are crucial to prevent lymphedema, accumulation of fluid in the tissues, and to ensure immune surveillance; yet, the mechanisms of valve formation are only beginning to be elucidated. In this chapter, we will discuss the main steps of lymphatic valve morphogenesis, the important role of mechanotransduction in this process, and the genetic program regulated by the transcription factor Foxc2, which is indispensable for all steps of valve development. Failure to form mature collecting lymphatic vessels and valves causes the majority of postsurgical lymphedema, e.g., in breast cancer patients. Therefore, this knowledge will be useful for diagnostics and development of better treatments of secondary lymphedema.

Autophagic cell death exists.

The term autophagic cell death (ACD) initially referred to cell death with greatly enhanced autophagy, but is increasingly used to imply a death-mediating role of autophagy, as shown by a protective effect of autophagy inhibition. In addition, many authors require that autophagic cell death must not involve apoptosis or necrosis. Adopting these new and restrictive criteria, and emphasizing their own failure to protect human osteosarcoma cells by autophagy inhibition, the authors of a recent Editor's Corner article in this journal argued for the extreme rarity or nonexistence of autophagic cell death. We here maintain that, even with the more stringent recent criteria, autophagic cell death exists in several situations, some of which were ignored by the Editor's Corner authors. We reject their additional criterion that the autophagy in ACD must be the agent of ultimate cell dismantlement. And we argue that rapidly dividing mammalian cells such as cancer cells are not the most likely situation for finding pure ACD.

Mutual trust and cooperation in the evolutionary hawks-doves game

Using a new dynamical network model of society in which pairwise interactions are weighted according to mutual satisfaction, we show that cooperation is the norm in the hawks-doves game when individuals are allowed to break ties with undesirable neighbors and to make new acquaintances in their extended neighborhood. Moreover, cooperation is robust with respect to rather strong strategy perturbations. We also discuss the empirical structure of the emerging networks, and the reasons that allow cooperators to thrive in the population. Given the metaphorical importance of this game for social interaction, this is an encouraging positive result as standard theory for large mixing populations prescribes that a certain fraction of defectors must always exist at equilibrium.

IRM cardiaque en évolution: de grandes études multicentriques en 2012 [Cardiac MR in development: the large multicenter CMR studies in 2012].

The results of several large multicenter CMR studies were reported in 2012, thus, constantly corroborating the evidence on CMR performance. In this review, we present results of the MR-IMPACT programme and the CE-MARC study, which demonstrated the superiority of perfusion-CMR over gated SPECT for the workup of suspected CAD, the currently available data from the European CMR registry, comprising almost 30,000 patients from 57 participating centers in 15 European countries, and finally, the results of the Advisa-MRI study, which documented the safety of a MRI-compatible pacemaker system. These large trials and others set the basis for the recommendations in the new European guidelines on heart failure to use CMR as a first line method if echocardiographic quality is inadequate or the etiology of heart failure is unclear.

Patient expectations at a multicultural out-patient clinic in Switzerland.

BACKGROUND: Recognizing patient expectation is considered as an important objective for primary care physicians. A number of studies suggest that failure to identify patient expectations can lead to patient dissatisfaction with care, lack of compliance and inappropriate use of medical resources. It has been suggested that identifying patient expectations in multicultural contexts can be especially challenging. OBJECTIVES: The aim of the study was to compare health care expectations of Swiss and immigrant patients attending the out-patient clinic of a Swiss university hospital and to assess physicians' ability to identify their patients' expectations. METHODS: Over a 3-month period, all patients attending the out-patient clinic at a Swiss university hospital were requested to complete pre-consultation surveys. Their physicians were requested to complete post-consultation surveys. Outcome measures were patients' self-rated health, resort to prior home treatment, patients' expectations of the consultation, physicians' perception of their patients' expectations and agreement between patients and physicians. RESULTS: We analysed 343 questionnaires completed by patients prior to their consultation (> 50% immigrants) and 333 questionnaires completed by their physicians after the consultation. Most expectations were shared by all patients. Physicians had inaccurate perceptions of their patients' expectations, regardless of patients' origin. CONCLUSIONS: Our study found no evidence that immigrant patients' expectations differed from those of Swiss patients, nor that physicians had more difficulty identifying expectations of immigrant patients. However, physicians in our study were generally poor at identifying patients' expectations, and therefore inter-group differences may be difficult to detect. Our results point to the need to strengthen physicians' general communication skills which should then serve as a foundation for more specific, cross-cultural communication training.

How important are interview methods and questionnaire designs in research on self-reported juvenile delinquency? An experimental comparison of internet vs. paper-and-pencil questionnaires and different definitions of the reference period

There has been relatively little change over recent decades in the methods used in research on self-reported delinquency. Face-to-face interviews and selfadministered interviews in the classroom are still the predominant alternatives envisaged. New methods have been brought into the picture by recent computer technology, the Internet, and an increasing availability of computer equipment and Internet access in schools. In the autumn of 2004, a controlled experiment was conducted with 1,203 students in Lausanne (Switzerland), where "paper-and-pencil" questionnaires were compared with computer-assisted interviews through the Internet. The experiment included a test of two different definitions of the (same) reference period. After the introductory question ("Did you ever..."), students were asked how many times they had done it (or experienced it), if ever, "over the last 12 months" or "since the October 2003 vacation". Few significant differences were found between the results obtained by the two methods and for the two definitions of the reference period, in the answers concerning victimisation, self-reported delinquency, drug use, failure to respond (missing data). Students were found to be more motivated to respond through the Internet, take less time for filling out the questionnaire, and were apparently more confident of privacy, while the school principals were less reluctant to allow classes to be interviewed through the Internet. The Internet method also involves considerable cost reductions, which is a critical advantage if self-reported delinquency surveys are to become a routinely applied method of evaluation, particularly so in countries with limited resources. On balance, the Internet may be instrumental in making research on self-reported delinquency far more feasible in situations where limited resources so far have prevented its implementation.

A Note on Interviewer Performance Measures in centralised CATI Surveys

Interviewer performance with respect to convincing sample members to participate in surveys is an important dimension of survey quality. However, unlike in CAPI surveys where each sample case 'belongs' to one interviewer, there are hardly any good measures of interview performance for centralised CATI surveys, where even single contacts are assigned to interviewers at random. If more than one interviewer works one sample case, it is not clear how to attribute success or failure to the interviewers involved. In this article, we propose two correlated methods to measure interviewer contact performance in centralised CATI surveys. Their modelling must take complex multilevel clustering effects, which need not be hierarchical, into account. Results are consistent with findings from CAPI data modelling, and we find that when comparing effects with a direct ('naive') measure of interviewer contact results, interviewer random effects are largely underestimated using the naive measure.

Surfactant palmitoylmyristoylphosphatidylcholine is a marker for alveolar size during disease.

Two common lung-related complications in the neonate are respiratory distress syndrome, which is associated with a failure to generate low surface tension at the air-liquid interface because of pulmonary surfactant insufficiency, and bronchopulmonary dysplasia (BPD), a chronic lung injury with reduced alveolarization. Surfactant phosphatidylcholine (PC) molecular species composition during alveolarization has not been examined. Mass spectrometry analysis of bronchoalveolar lavage fluid of rodents and humans revealed significant changes in surfactant PC during alveolar development and BPD. In rats, total PC content rose during alveolarization, which was caused by an increase in palmitoylmyristoyl-PC (16:0/14:0PC) concentration. Furthermore, two animal models of BPD exhibited a specific reduction in 16:0/14:0PC content. In humans, 16:0/14:0PC content was specifically decreased in patients with BPD and emphysema compared with patients without alveolar pathology. Palmitoylmyristoyl-PC content increased with increasing intrinsic surfactant curvature, suggesting that it affects surfactant function in the septating lung. The changes in acyl composition of PC were attributed to type II cells producing an altered surfactant during alveolar development. These data are compatible with extracellular surfactant 16:0/14:0PC content being an indicator of alveolar architecture of the lung.

The Schizosaccharomyces pombe cdc14 gene is required for septum formation and can also inhibit nuclear division.

A conditional heat-sensitive mutation in the cdc14 gene of the fission yeast Schizosaccharomyces pombe results in failure to form a septum. Cells become highly elongated and multinucleate as growth and nuclear division continue in the absence of cell division. This article describes the cloning of the cdc14 gene and the identification of its product, a protein of 240 amino acids, p28cdc14. A null allele of the cdc14 gene shows that the gene is essential for septum formation and completion of the cell-division cycle. Overexpression of the gene product, p28cdc14, causes cell-cycle arrest in late G2 before mitosis. Cells leaking past the block activate p34cdc2 kinase and show condensed chromosomes, but the normal rearrangements of the microtubules and microfilaments that are associated with the transition from interphase to mitosis do not occur. Overexpression of p28cdc14 in mutants, in which the timing of mitosis is altered, suggests that these effects may be mediated upstream of the mitotic inhibitor wee1. These data are consistent with the idea that p28cdc14 may play a role in both the initiation of mitosis and septum formation and, by doing so, be part of the mechanism that coordinates these two cell-cycle events.

Detecting, quantifying and adjusting for publication bias in meta-analyses: protocol of a systematic review on methods.

BACKGROUND: Health professionals and policymakers aspire to make healthcare decisions based on the entire relevant research evidence. This, however, can rarely be achieved because a considerable amount of research findings are not published, especially in case of 'negative' results - a phenomenon widely recognized as publication bias. Different methods of detecting, quantifying and adjusting for publication bias in meta-analyses have been described in the literature, such as graphical approaches and formal statistical tests to detect publication bias, and statistical approaches to modify effect sizes to adjust a pooled estimate when the presence of publication bias is suspected. An up-to-date systematic review of the existing methods is lacking. METHODS/DESIGN: The objectives of this systematic review are as follows:âeuro¢ To systematically review methodological articles which focus on non-publication of studies and to describe methods of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses.âeuro¢ To appraise strengths and weaknesses of methods, the resources they require, and the conditions under which the method could be used, based on findings of included studies.We will systematically search Web of Science, Medline, and the Cochrane Library for methodological articles that describe at least one method of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses. A dedicated data extraction form is developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article. As this will be a qualitative systematic review, data reporting will involve a descriptive summary. DISCUSSION: Results are expected to be publicly available in mid 2013. This systematic review together with the results of other systematic reviews of the OPEN project (To Overcome Failure to Publish Negative Findings) will serve as a basis for the development of future policies and guidelines regarding the assessment and handling of publication bias in meta-analyses.

c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.

The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.

Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances, and opportunities.

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics.

Defining publication bias: protocol for a systematic review of highly cited articles and proposal for a new framework.

BACKGROUND: Selective publication of studies, which is commonly called publication bias, is widely recognized. Over the years a new nomenclature for other types of bias related to non-publication or distortion related to the dissemination of research findings has been developed. However, several of these different biases are often still summarized by the term 'publication bias'. METHODS/DESIGN: As part of the OPEN Project (To Overcome failure to Publish nEgative fiNdings) we will conduct a systematic review with the following objectives:- To systematically review highly cited articles that focus on non-publication of studies and to present the various definitions of biases related to the dissemination of research findings contained in the articles identified.- To develop and discuss a new framework on nomenclature of various aspects of distortion in the dissemination process that leads to public availability of research findings in an international group of experts in the context of the OPEN Project.We will systematically search Web of Knowledge for highly cited articles that provide a definition of biases related to the dissemination of research findings. A specifically designed data extraction form will be developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article.For the development of a new framework we will construct an initial table listing different levels and different hazards en route to making research findings public. An international group of experts will iteratively review the table and reflect on its content until no new insights emerge and consensus has been reached. DISCUSSION: Results are expected to be publicly available in mid-2013. This systematic review together with the results of other systematic reviews of the OPEN project will serve as a basis for the development of future policies and guidelines regarding the assessment and prevention of publication bias.

Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors.

Angio-oedema (AE) is a known adverse effect of angiotensin converting enzyme inhibitor (ACE-I) therapy. Over the past several decades, evidence of failure to diagnose this important and potentially fatal reaction is commonly found in the literature. Because this reaction is often seen first in the primary care setting, a review was undertaken to analyse and document the keys to both diagnostic criteria as well as to investigate potential risk factors for ACE-I AE occurrence. A general review of published literature was conducted through Medline, EMBASE, and the Cochrane Database, targeting ACE-I-related AE pathomechanism, diagnosis, epidemiology, risk factors, and clinical decision making and treatment. The incidence and severity of AE appears to be on the rise and there is evidence of considerable delay in diagnosis contributing to significant morbidity and mortality for patients. The mechanism of AE due to ACE-I drugs is not fully understood, but some genomic and metabolomic information has been correlated. Additional epidemiologic data and clinical treatment outcome predictors have been evaluated, creating a basis for future work on the development of clinical prediction tools to aid in risk identification and diagnostic differentiation. Accurate recognition of AE by the primary care provider is essential to limit the rising morbidity associated with ACE-I treatment-related AE. Research findings on the phenotypic indicators relevant to this group of patients as well as basic research into the pathomechanism of AE are available, and should be used in the construction of better risk analysis and clinical diagnostic tools for ACE-I AE.

Awareness of human immunodeficiency virus screening guidelines is low in emergency departments of western Switzerland.

Background: Human immunodeficiency virus (HIV) prevalence in Switzerland is 0.4% and 30% of HIV patients are diagnosed with CD4 counts <200 cells/microliter. In 2010, the Swiss Federal Office of Public Health (SFOP) published updated guidelines regarding Physician- Initiated Counseling and Testing (PICT) for HIV. In the new guidelines, when acute HIV infection is suspected or HIV is among the differential diagnoses, an HIV test is performed without risk assessment nor prior counseling, unless the patient specifically refuses it. Counseling and verbal consent are still required when the patient asks for an HIV test or belongs to a high risk group. Whist HIV testing in the emergency departments (ED) is recommended, only 1% of patients are currently screened. Lack of awareness among physicians has been cited in the literature as the first barrier to guideline implementation. Objectives: To test if physicians working in EDs of 5 large teaching hospitals in western Switzerland, admitting 175,000 patients / year, were aware of the updated SFOP guidelines. Methods: A survey was delivered to 167 ED physicians in the summer of 2011. The survey consisted of 26 vignettes designed to test whether physicians would request an HIV test according to the new guidelines and if they knew when the PICT strategy was allowed or counseling required. Finally, physicians were asked the number of HIV tests they had requested in the previous 4 weeks, and if they were aware of the new HIV guidelines. Results are presented as mean and standard deviation, median and interquartile range (IQR), or as proportions; Student's t test was used to compare continuous variables; Results: 143 physicians returned the survey (86%); mean age was 32 ± 8 years, and median postgraduate experience of 6 years (IQR 3-12); 52% were male and 17% were attendings. The percentage of correct responses was 60 ± 13% with no difference between attendings and residents (p = 0.31); 2 of the 3 questions with the lowest scores were failure to recognize situations in which HIV testing was indicated, and the third one a failure to recognize acute HIV infection. 82% of physicians were not aware of the new guidelines. The median number of test requests was 1 (IQR 0-2, range 1-10). Conclusion: ED physicians are not aware of current HIV screening guidelines published by the SFOP, and rarely perform HIV tests. An information campaign is required if ED physicians are expected to play a significant role in the reduction of undiagnosed HIV patients.