Country actions to meet UN commitments on non-communicable diseases: a stepwise approach.

Strong leadership from heads of state is needed to meet national commitments to the UN political declaration on non-communicable diseases (NCDs) and to achieve the goal of a 25% reduction in premature NCD mortality by 2025 (the 25 by 25 goal). A simple, phased, national response to the political declaration is suggested, with three key steps: planning, implementation, and accountability. Planning entails mobilisation of a multisectoral response to develop and support the national action plan, and to build human, financial, and regulatory capacity for change. Implementation of a few priority and feasible cost-effective interventions for the prevention and treatment of NCDs will achieve the 25 by 25 goal and will need only few additional financial resources. Accountability incorporates three dimensions: monitoring of progress, reviewing of progress, and appropriate responses to accelerate progress. A national NCD commission or equivalent, which is independent of government, is needed to ensure that all relevant stakeholders are held accountable for the UN commitments to NCDs.

ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients.

As culture-based methods for the diagnosis of invasive fungal diseases (IFD) in leukemia and hematopoietic SCT patients have limited performance, non-culture methods are increasingly being used. The third European Conference on Infections in Leukemia (ECIL-3) meeting aimed at establishing evidence-based recommendations for the use of biological tests in adult patients, based on the grading system of the Infectious Diseases Society of America. The following biomarkers were investigated as screening tests: galactomannan (GM) for invasive aspergillosis (IA); β-glucan (BG) for invasive candidiasis (IC) and IA; Cryptococcus Ag for cryptococcosis; mannan (Mn) Ag/anti-mannan (A-Mn) Ab for IC, and PCR for IA. Testing for GM, Cryptococcus Ag and BG are included in the revised EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) consensus definitions for IFD. Strong evidence supports the use of GM in serum (A II), and Cryptococcus Ag in serum and cerebrospinal fluid (CSF) (A II). Evidence is moderate for BG detection in serum (B II), and the combined Mn/A-Mn testing in serum for hepatosplenic candidiasis (B III) and candidemia (C II). No recommendations were formulated for the use of PCR owing to a lack of standardization and clinical validation. Clinical utility of these markers for the early management of IFD should be further assessed in prospective randomized interventional studies.

Genetic analysis of sudden cardiac death victims: a survey of current forensic autopsy practices.

Autopsy-negative sudden cardiac deaths (SCD) seen in forensic practice are most often thought to be the result of sudden arrhythmic death syndrome. Postmortem genetic analysis is recommended in such cases, but is currently performed in only a few academic centers. In order to determine actual current practice, an on-line questionnaire was sent by e-mail to members of various forensic medical associations. The questions addressed routine procedures employed in cases of sudden cardiac death (autopsy ordering, macroscopic and microscopic cardiac examination, conduction tissue examination, immunohistochemistry and electron microscopy, biochemical markers, sampling and storage of material for genetic analyses, toxicological analyses, and molecular autopsy). Some questions concerned the legal and ethical aspects of genetic analyses in postmortem examinations, as well as any existing multidisciplinary collaborations in SCD cases. There were 97 respondents, mostly from European countries. Genetic testing in cases of sudden cardiac death is rarely practiced in routine forensic investigation. Approximately 60% of respondents reported not having the means to perform genetic postmortem testing and 40% do not collect adequate material to perform these investigations at a later date, despite working at university hospitals. The survey demonstrated that many of the problems involved in the adequate investigation of SCD cases are often financial in origin, due to the fact that activities in forensic medicine are often paid by and dependent on the judicial authorities. Problems also exist concerning the contact with family members and/or the family doctor, as well as the often-nonexistent collaboration with others clinicians with special expertise beneficial in the investigation of SCD cases, such as cardiologists and geneticists. This study highlights the importance in establishing guidelines for molecular autopsies in forensic medicine.

Chaperones and proteases: cellular fold-controlling factors of proteins in neurodegenerative diseases and aging.

The formation of toxic protein aggregates is a common denominator to many neurodegenerative diseases and aging. Accumulation of toxic, possibly infectious protein aggregates induces a cascade of events, such as excessive inflammation, the production of reactive oxygen species, apoptosis and neuronal loss. A network of highly conserved molecular chaperones and of chaperone-related proteases controls the fold-quality of proteins in the cell. Most molecular chaperones can passively prevent protein aggregation by binding misfolding intermediates. Some molecular chaperones and chaperone-related proteases, such as the proteasome, can also hydrolyse ATP to forcefully convert stable harmful protein aggregates into harmless natively refoldable, or protease-degradable, polypeptides. Molecular chaperones and chaperone-related proteases thus control the delicate balance between natively folded functional proteins and aggregation-prone misfolded proteins, which may form during the lifetime and lead to cell death. Abundant data now point at the molecular chaperones and the proteases as major clearance mechanisms to remove toxic protein aggregates from cells, delaying the onset and the outcome of protein-misfolding diseases. Therapeutic approaches include treatments and drugs that can specifically induce and sustain a strong chaperone and protease activity in cells and tissues prone to toxic protein aggregations.

Prévalence des maladies infectieuses au Centre hospitalier universitaire vaudois [Prevalence of infectious diseases at the Vaud University Hospital Center].

The prevalence of infectious diseases at our hospital (Centre hospitalier universitaire vaudois, Lausanne [CHUV], 900 beds) was studied retrospectively over a two years period (1980-1981). The medical diagnosis of 30203 patients recorded in the computerized medical archives, representing 93% of the patients admitted during the period of observation, was reviewed. To assess the reliability of the computerized data, quality control was carried out through detailed analysis of all the histologically proven appendicitis recorded during 1981. 88% of the histologically proven appendicitis were registered in the computer and the diagnosis was specific in 87% of cases. An infectious disease was the primary reason for admission in 12.8% of the patients (3873) during the study period. Altogether, 20.2% of patients presented with an infection during their hospital stay. Because of the retrospective nature of the study it was not possible to determine whether these additional infections were nosocomially acquired. The organ systems most frequently infected were the respiratory tract (28.5% of all infections), the digestive tract (20.5%), the skin and osteoarticular system (16%) and the urogenital tract (11.6%). An infection was the primary reason for admission of 40.2% of the patients hospitalized in the dermatology service, of 19.7% of patients admitted in internal medicine, of 15-17% of the patients admitted in pediatrics, ENT and general surgery, and of 1-2% of the patients admitted in neurosurgery and radiotherapy. These observations highlight the continuing importance of infectious diseases in a modern hospital, in spite of high socio-economic levels, stringent hygiene and epidemiologic measures, and modern antibiotic availability.

Cytokines in parasitic diseases: the example of cutaneous leishmaniasis.

The essential role of cytokines in parasitic diseases has been emphasised since the in vivo description of the importance of T helper 1 (Th1) and T helper 2 (Th2) CD4+ T cell responses in resistance and susceptibility to infection with L. major in mice. Th1 cells produced IL-2, IFN-gamma and Lymphotoxin T (LT) and Th2 cells produce IL-4, IL-5 and IL-13. In this model of infection the correlation between on the one hand resistance to infection and the development of a Th1 response and on the other hand susceptibility and Th2 cell development allowed the identification of the mechanisms directing the differentiation of CD4+ T cell precursors towards either Th1 type or Th2 type responses. Cytokines are the crucial inducer of functional CD4+ T cell subset differentiation during infection with L. major. IL-12 and IFN-gamma direct the differentiation of Th1 response and IL-4 of a Th2 response. In susceptible mice, careful analysis of IL-4 production during the first days of infection has shown that the IL-4 produced as a result of a very early burst of IL-4 mRNA expression (16 hours) plays a essential role in the maturation of a Th2 CD4+ T cell response by rendering the CD4+ T cell precursors unresponsive to IL-12. Activation of a restricted population of CD4+ T cells expressing the V beta 4 V alpha 8 TCR heterodimer after recognition of a single antigen, the LACK (Leishmania Activated c Kinase) antigen, resulted in this rapid production of IL-4 required for the subsequent CD4+ T cell differentiation. Thus, tolerization of these cells might contribute a strategy for preventing infection with L. major.

Quantifying sediment storage in a high Alpine valley (Turtmanntal, Switzerland)

The determination of sediment storage is a critical parameter in sediment budget analyses. But, in many sediment budget studies the quantification of magnitude and time-scale of sediment storage is still the weakest part and often relies on crude estimations only, especially in large drainage basins (>100km2). We present a new approach to storage quantification in a meso-scale alpine catchment of the Swiss Alps (Turtmann Valley, 110km2). The quantification of depositional volumes was performed by combining geophysical surveys and geographic information system (GIS) modelling techniques. Mean thickness values of each landform type calculated from these data was used to estimate the sediment volume in the hanging valleys and the trough slopes. Sediment volume of the remaining subsystems was determined by modelling an assumed parabolic bedrock surface using digital elevation model (DEM) data. A total sediment volume of 781·3×106?1005·7×106m3 is deposited in the Turtmann Valley. Over 60% of this volume is stored in the 13 hanging valleys. Moraine landforms contain over 60% of the deposits in the hanging valleys followed by sediment stored on slopes (20%) and rock glaciers (15%). For the first time, a detailed quantification of different storage types was achieved in a catchment of this size. Sediment volumes have been used to calculate mean denudation rates for the different processes ranging from 0·1 to 2·6mm/a based on a time span of 10ka. As the quantification approach includes a number of assumptions and various sources of error the values given represent the order of magnitude of sediment storage that has to be expected in a catchment of this size.

An international registry on autoinflammatory diseases: the Eurofever experience.

OBJECTIVE: To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project. METHODS: A web-based registry collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms. RESULTS: 1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofever registry. Most of the patients (1388; 74%), reside in western Europe, 294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosis of a monogenic autoinflammatory diseases have been enrolled; genetic analysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3-76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997. CONCLUSIONS: A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment, and to perform large scale comparative studies between different conditions.

Comparison of molecular signatures from multiple skin diseases identifies mechanisms of immunopathogenesis.

The ability to obtain gene expression profiles from human disease specimens provides an opportunity to identify relevant gene pathways, but is limited by the absence of data sets spanning a broad range of conditions. Here, we analyzed publicly available microarray data from 16 diverse skin conditions in order to gain insight into disease pathogenesis. Unsupervised hierarchical clustering separated samples by disease as well as common cellular and molecular pathways. Disease-specific signatures were leveraged to build a multi-disease classifier, which predicted the diagnosis of publicly and prospectively collected expression profiles with 93% accuracy. In one sample, the molecular classifier differed from the initial clinical diagnosis and correctly predicted the eventual diagnosis as the clinical presentation evolved. Finally, integration of IFN-regulated gene programs with the skin database revealed a significant inverse correlation between IFN-β and IFN-γ programs across all conditions. Our study provides an integrative approach to the study of gene signatures from multiple skin conditions, elucidating mechanisms of disease pathogenesis. In addition, these studies provide a framework for developing tools for personalized medicine toward the precise prediction, prevention, and treatment of disease on an individual level.

Immune sensing of nucleic acids in inflammatory skin diseases.

Endosomal and cytosolic nucleic acid receptors are important immune sensors required for the detection of infecting or replicating viruses. The intracellular location of these receptors allows viral recognition and, at the same time, avoids unnecessary immune activation to self-nucleic acids that are continuously released by dying host cells. Recent evidence, however, indicates that endogenous factors such as anti-microbial peptides have the ability to break this protective mechanism. Here, we discuss these factors and illustrate how they drive inflammatory responses by promoting immune recognition of self-nucleic acids in skin wounds and inflammatory skin diseases such as psoriasis and lupus.

Fructose and metabolic diseases: new findings, new questions.

There has been much concern regarding the role of dietary fructose in the development of metabolic diseases. This concern arises from the continuous increase in fructose (and total added caloric sweeteners consumption) in recent decades, and from the increased use of high-fructose corn syrup (HFCS) as a sweetener. A large body of evidence shows that a high-fructose diet leads to the development of obesity, diabetes, and dyslipidemia in rodents. In humans, fructose has long been known to increase plasma triglyceride concentrations. In addition, when ingested in large amounts as part of a hypercaloric diet, it can cause hepatic insulin resistance, increased total and visceral fat mass, and accumulation of ectopic fat in the liver and skeletal muscle. These early effects may be instrumental in causing, in the long run, the development of the metabolic syndrome. There is however only limited evidence that fructose per se, when consumed in moderate amounts, has deleterious effects. Several effects of a high-fructose diet in humans can be observed with high-fat or high-glucose diets as well, suggesting that an excess caloric intake may be the main factor involved in the development of the metabolic syndrome. The major source of fructose in our diet is with sweetened beverages (and with other products in which caloric sweeteners have been added). The progressive replacement of sucrose by HFCS is however unlikely to be directly involved in the epidemy of metabolic disease, because HFCS appears to have basically the same metabolic effects as sucrose. Consumption of sweetened beverages is however clearly associated with excess calorie intake, and an increased risk of diabetes and cardiovascular diseases through an increase in body weight. This has led to the recommendation to limit the daily intake of sugar calories.

Assessing dystrophies and other muscle diseases at the nanometer scale by atomic force microscopy.

AIM: Atomic force microscopy nanoindentation of myofibers was used to assess and quantitatively diagnose muscular dystrophies from human patients. MATERIALS & METHODS: Myofibers were probed from fresh or frozen muscle biopsies from human dystrophic patients and healthy volunteers, as well as mice models, and Young's modulus stiffness values were determined. RESULTS: Fibers displaying abnormally low mechanical stability were detected in biopsies from patients affected by 11 distinct muscle diseases, and Young's modulus values were commensurate to the severity of the disease. Abnormal myofiber resistance was also observed from consulting patients whose muscle condition could not be detected or unambiguously diagnosed otherwise. DISCUSSION & CONCLUSION: This study provides a proof-of-concept that atomic force microscopy yields a quantitative read-out of human muscle function from clinical biopsies, and that it may thereby complement current muscular dystrophy diagnosis.