Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

Mining the human phenome using allelic scores that index biological intermediates

J. Kaprio ja M-L. Lokki työryhmien jäseniä.It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.Peer reviewe

Chronic disease research in Europe and the need for integrated population cohorts

The burden of chronic disease in Europe is characterized by several positive trends, but also some major new challenges. On one hand there has been an important and consistent reduction in mortality, particularly in young and middle age that has led to a substantial increase in life expectancy in all 28 countries within the EU (EU28) in the last 40 years. Even within the relatively recent period of 2003–2013, there was an increase in life expectancy of 3.2 years for men and 2.5 years for women overall in the EU (Fig. 1) [1]. While these trends represent a major success in public health, they hide less positive developments, including major health disparities. Across Europe major differences in life expectancy exist, of over 10 years for men and over 7 years for women (Table 1) [1]. These differences are most extreme between southern Mediterranean Europe and the countries of central Europe and the Baltic region

The Pathogenesis and Therapy of Muscular Dystrophies

Current molecular genomic approaches to human genetic disorders have led to an explosion in the identification of the genes and their encoded proteins responsible for these disorders. The identification of the gene altered by mutations in Duchenne and Becker muscular dystrophy was one of the earliest examples of this paradigm. The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them. The identification of the protein dystrophin has led to a new understanding of the muscle cell membrane and the proteins involved in membrane stability, as well as new candidate genes for additional forms of muscular dystrophy. Animal models identified with naturally occurring mutations and developed by genetic manipulation have furthered the understanding of disease progression and underlying pathology. The biochemistry and molecular analysis of patient samples have led to the different dystrophin-dependent and -independent therapies that are currently close to or in human clinical trials. The lessons learned from decades of research on dystrophin have benefited the field of human genetics

The Pathogenesis and Therapy of Muscular Dystrophies

Current molecular genomic approaches to human genetic disorders have led to an explosion in the identification of the genes and their encoded proteins responsible for these disorders. The identification of the gene altered by mutations in Duchenne and Becker muscular dystrophy was one of the earliest examples of this paradigm. The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them. The identification of the protein dystrophin has led to a new understanding of the muscle cell membrane and the proteins involved in membrane stability, as well as new candidate genes for additional forms of muscular dystrophy. Animal models identified with naturally occurring mutations and developed by genetic manipulation have furthered the understanding of disease progression and underlying pathology. The biochemistry and molecular analysis of patient samples have led to the different dystrophin-dependent and -independent therapies that are currently close to or in human clinical trials. The lessons learned from decades of research on dystrophin have benefited the field of human genetics

Muscle regeneration in dystrophin-deficient <it>mdx </it>mice studied by gene expression profiling

Abstract Background Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is lethal. In contrast, dystrophin-deficient mdx mice recover due to effective regeneration of affected muscle tissue. To characterize the molecular processes associated with regeneration, we compared gene expression levels in hindlimb muscle tissue of mdx and control mice at 9 timepoints, ranging from 1–20 weeks of age. Results Out of 7776 genes, 1735 were differentially expressed between mdx and control muscle at at least one timepoint (p mdx mouse. Based on functional characteristics such as membrane localization, signal transduction, and transcriptional activation, 166 differentially expressed genes with possible functions in regeneration were analyzed in more detail. The majority of these genes peak at the age of 8 weeks, where the regeneration activity is maximal. The following pathways are activated, as shown by upregulation of multiple members per signalling pathway: the Notch-Delta pathway that plays a role in the activation of satellite cells, and the Bmp15 and Neuregulin 3 signalling pathways that may regulate proliferation and differentiation of satellite cells. In DMD patients, only few of the identified regeneration-associated genes were found activated, indicating less efficient regeneration processes in humans. Conclusion Based on the observed expression profiles, we describe a model for muscle regeneration in mdx mice, which may provide new leads for development of DMD therapies based on the improvement of muscle regeneration efficacy.</p