BAFF AND APRIL: a tutorial on B cell survival.

BAFF, a member of the TNF family, is a fundamental survival factor for transitional and mature B cells. BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients. APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role. The BAFF system provides not only potential insight into the development of autoreactive B cells but a relatively simple paradigm to begin considering the balancing act between survival, growth, and death that affects all cells.

Lessons From the Swiss Medical Board Recommendation Against Mammography Screening Programs

When the US Preventive Services Task Force (USPSTF) in 2009 recommended against universal breast cancer screening with mammography in women aged 40 to 49 years, some scientists, radiologists, politicians, and patients strongly objected. The controversy has been called the "mammography wars." The latest chapter in these wars comes from the Swiss Medical Board, which is mandated by the Conference of Health Ministers of the Swiss Cantons, the Swiss Medical Association, and the Swiss Academy of Medical Sciences to conduct health technology assessments. In a February 2014 report, the Swiss Medical Board stated that new systematic mammography screening programs should not be introduced, irrespective of the age of the women, and that existing programs should be discontinued. The board's main argument was that the absolute reduction in breast cancer mortality was low and that the adverse consequences of the screening were substantial. The absolute risk reduction in breast cancer mortality has been estimated by the board at 0.16% for women screened during 6.2 years and followed-up over 13 years, based on the results of a recent Cochrane Review. The adverse consequences include falsepositive test results, overdiagnosis and overtreatment of patients, and high costs, including the expense of follow-up testing and procedures.

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2(Akita/+) and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2(Akita/+) mice and sex-matched littermate controls. Our phenotypic analysis of Ins2(Akita/+) mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

How to measure cortical folding from MR images: a step-by-step tutorial to compute local gyrification index.

Cortical folding (gyrification) is determined during the first months of life, so that adverse events occurring during this period leave traces that will be identifiable at any age. As recently reviewed by Mangin and colleagues(2), several methods exist to quantify different characteristics of gyrification. For instance, sulcal morphometry can be used to measure shape descriptors such as the depth, length or indices of inter-hemispheric asymmetry(3). These geometrical properties have the advantage of being easy to interpret. However, sulcal morphometry tightly relies on the accurate identification of a given set of sulci and hence provides a fragmented description of gyrification. A more fine-grained quantification of gyrification can be achieved with curvature-based measurements, where smoothed absolute mean curvature is typically computed at thousands of points over the cortical surface(4). The curvature is however not straightforward to comprehend, as it remains unclear if there is any direct relationship between the curvedness and a biologically meaningful correlate such as cortical volume or surface. To address the diverse issues raised by the measurement of cortical folding, we previously developed an algorithm to quantify local gyrification with an exquisite spatial resolution and of simple interpretation. Our method is inspired of the Gyrification Index(5), a method originally used in comparative neuroanatomy to evaluate the cortical folding differences across species. In our implementation, which we name local Gyrification Index (lGI(1)), we measure the amount of cortex buried within the sulcal folds as compared with the amount of visible cortex in circular regions of interest. Given that the cortex grows primarily through radial expansion(6), our method was specifically designed to identify early defects of cortical development. In this article, we detail the computation of local Gyrification Index, which is now freely distributed as a part of the FreeSurfer Software (http://surfer.nmr.mgh.harvard.edu/, Martinos Center for Biomedical Imaging, Massachusetts General Hospital). FreeSurfer provides a set of automated reconstruction tools of the brain's cortical surface from structural MRI data. The cortical surface extracted in the native space of the images with sub-millimeter accuracy is then further used for the creation of an outer surface, which will serve as a basis for the lGI calculation. A circular region of interest is then delineated on the outer surface, and its corresponding region of interest on the cortical surface is identified using a matching algorithm as described in our validation study(1). This process is repeatedly iterated with largely overlapping regions of interest, resulting in cortical maps of gyrification for subsequent statistical comparisons (Fig. 1). Of note, another measurement of local gyrification with a similar inspiration was proposed by Toro and colleagues(7), where the folding index at each point is computed as the ratio of the cortical area contained in a sphere divided by the area of a disc with the same radius. The two implementations differ in that the one by Toro et al. is based on Euclidian distances and thus considers discontinuous patches of cortical area, whereas ours uses a strict geodesic algorithm and include only the continuous patch of cortical area opening at the brain surface in a circular region of interest.

A two-week workshop to promote cardiovascular disease prevention programs in countries with limited resources.

Training is a crucial tool for building the capacity necessary for prevention and control of cardiovascular diseases (CVDs) in developing countries. This paper summarizes some features of a 2-week workshop aimed at enabling local health professionals to initiate a comprehensive CVD prevention and control program in a context of limited resources. The workshops have been organized in the regions where CVD prevention programs are being contemplated, in cooperation with health authorities of the concerned regions. The workshop's content includes a broad variety of issues related to CVD prevention and control, and to program development. Strong emphasis is placed on "learning by doing," and groups of 5-6 participants conduct a small-scale epidemiological study during the first week; during the second week, they draft a virtual program of CVD prevention and control adapted to the local situation. This practice-oriented workshop focuses on building expertise among anticipated key players, strengthening networks among relevant health professionals, and advocating the urgent need to tackle the emerging CVD epidemic in developing countries.

Management of hepatitis C virus (HCV) infection in drug substitution programs.

BACKGROUND: In Switzerland, intravenous drug use (IDU) accounts for 80% of newly acquired hepatitis C virus (HCV) infections. Early HCV treatment has the potential to interrupt the transmission chain and reduce morbidity/mortality due to decompensated liver cirrhosis and hepatocellular carcinoma. Nevertheless, patients in drug substitution programs are often insufficiently screened and treated. OBJECTIVE/METHODS: With the aim to improve HCV management in IDUs, we conducted a cross sectional chart review in three opioid substitution programs in St. Gallen (125 methadone and 71 heroin recipients). Results were compared with another heroin substitution program in Bern (202 patients) and SCCS/SHCS data. RESULTS: Among the methadone/heroin recipients in St. Gallen, diagnostic workup of HCV was better than expected: HCV/HIV-status was unknown in only 1% (2/196), HCV RNA was not performed in 9% (13/146) of anti-HCV-positives and the genotype missing in 15% (12/78) of HCV RNA-positives. In those without spontaneous clearance (two thirds), HCV treatment uptake was 23% (21/91) (HIV-: 29% (20/68), HIV+: 4% (1/23)), which was lower than in methadone/heroin recipients and particularly non-IDUs within the SCCS/SHCS, but higher than in the, mainly psychiatrically focussed, heroin substitution program in Bern (8%). Sustained virological response (SVR) rates were comparable in all settings (overall: 50%, genotype 1: 35-40%, genotype 3: two thirds). In St. Gallen, the median delay from the estimated date of infection (IDU start) to first diagnosis was 10 years and to treatment was another 7.5 years. CONCLUSIONS: Future efforts need to focus on earlier HCV diagnosis and improvement of treatment uptake among patients in drug substitution programs, particularly if patients are HIV-co-infected. New potent drugs might facilitate the decision to initiate treatment.

Topographic ERP analyses: a step-by-step tutorial review

In this tutorial review, we detail both the rationale for as well as the implementation of a set of analyses of surface-recorded event-related potentials (ERPs) that uses the reference-free spatial (i.e. topographic) information available from high-density electrode montages to render statistical information concerning modulations in response strength, latency, and topography both between and within experimental conditions. In these and other ways these topographic analysis methods allow the experimenter to glean additional information and neurophysiologic interpretability beyond what is available from canonical waveform analyses. In this tutorial we present the example of somatosensory evoked potentials (SEPs) in response to stimulation of each hand to illustrate these points. For each step of these analyses, we provide the reader with both a conceptual and mathematical description of how the analysis is carried out, what it yields, and how to interpret its statistical outcome. We show that these topographic analysis methods are intuitive and easy-to-use approaches that can remove much of the guesswork often confronting ERP researchers and also assist in identifying the information contained within high-density ERP datasets

A critical analysis of three psychological research programs of doping behaviour

Objectives To consider the various specific substances-taking activities in sport an examination of three psychological models of doping behaviour utilised by researchers is presented in order to evaluate their real and potential impact, and to improve the relevance and efficiency of anti-doping campaigns. Design Adopting the notion of a "research program" (Lakatos, 1978) from the philosophy of science, a range of studies into the psychology of doping behaviour are classified and critically analysed. Method Theoretical and practical parameters of three research programs are critically evaluated (i) cognitive; (ii) drive; and (iii) situated-dynamic. Results The analysis reveals the diversity of theoretical commitments of the research programs and their practical consequences. The «cognitive program» assumes that athletes are accountable for their acts that reflect the endeavour to attain sporting and non-sporting goals. Attitudes, knowledge and rational decisions are understood to be the basis of doping behaviour. The «drive program» characterises the variety of traces and consequences on psychological and somatic states coming from athlete's experience with sport. Doping behaviour here is conceived of as a solution to reduce unconscious psychological and somatic distress. The «situated-dynamic program» considers a broader context of athletes' doping activity and its evolution during a sport career. Doping is considered as emergent and self-organized behaviour, grounded on temporally critical couplings between athletes' actions and situations and the specific dynamics of their development during the sporting life course. Conclusions These hypothetical, theoretical and methodological considerations offer a more nuanced understanding of doping behaviours, making an effective contribution to anti-doping education and research by enabling researchers and policy personnel to become more critically reflective about their explicit and implicit assumptions regarding models of explanations for doping behaviour.

A tutorial review of electrical neuroimaging from group-average to single-trial event-related potentials.

This tutorial review details some of the recent advances in signal analyses applied to event-related potential (ERP) data. These "electrical neuroimaging" analyses provide reference-independent measurements of response strength and response topography that circumvent statistical and interpretational caveats of canonical ERP analysis methods while also taking advantage of the greater information provided by high-density electrode montages. Electrical neuroimaging can be applied across scales ranging from group-averaged ERPs to single-subject and single-trial datasets. We illustrate these methods with a tutorial dataset and place particular emphasis on their suitability for studies of clinical and/or developmental populations.

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2(Akita/+) and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2(Akita/+) mice and sex-matched littermate controls. Our phenotypic analysis of Ins2(Akita/+) mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

Involvement of family physicians in structured programs for chronic diseases or multi-morbidity in Switzerland.

The increasing prevalence of chronic diseases and multi-morbidity represents challenges for health systems worldwide. In that perspective, the current organization of healthcare delivery, fragmentation of care, limited use of evidence-based guidelines and patients'insufficient empowerment are some reasons explaining the current limited effectiveness of the management of chronically ill patients. Based on theoretical models such as the Chronic Care Model (CCM), initiatives targeting improvements in the care of patients with chronic diseases have been implemented worldwide since more than a decade. Their development in Switzerland, a health system where more than half of practices are still single handed [6], is only recent and infrequent. Structured programs for patients with chronic diseases or multimorbidity usually propose patient-centered interventions and consider an integrative multidisciplinary approach. Currently, little is known on the existence of such programs and on the role of family physicians (FPs)within these programs, in Switzerland. The objective of this study was to identify and describe current structured programs targeting chronic diseases or multi-morbidity in Switzerland. This may help in examining innovative approaches that are only developed locally but would deserve wider interest for further implementation. We conducted a telephone-based survey between June and November 2013 and contacted systematically key institutions, informants and stakeholders nationwide and in the 26 cantons...

Abolishing mammography screening programs?

Biller-Andorno and Jüni (2014), in a widely debated commentary published in the May 22 issue of the New England Journal of Medicine, accept the concept that mammography every 2 years from age 50 can decrease breast cancer mortality by 20%, that is, from five to four deaths per 1000 women over a 10-year period. Both the absolute and the relative risk of breast cancer death may vary depending on the baseline mortality rates in various populations and on the impact of screening mammography in reducing breast cancer mortality, which may well vary around the 20% estimate adopted. We accept, therefore, that there are still uncertainties in the absolute and relative impact of mammography screening on breast cancer mortality, given the different study schemes and mammography intervals, the differences in populations, and the continuous improvements in technology (Warner, 2011; Independent UK Panel on Breast Cancer Screening, 2012). We also agree on the observation that mammography has an appreciable impact on breast cancer mortality (Bosetti et al., 2012), but clearly a much smaller one on total mortality.