A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: study protocol for a randomized controlled trial.

BACKGROUND: Cardiac arrest causes ischaemic brain injury. Arterial carbon dioxide tension (PaCO2) is a major determinant of cerebral blood flow. Thus, mild hypercapnia in the 24 h following cardiac arrest may increase cerebral blood flow and attenuate such injury. We describe the Carbon Control and Cardiac Arrest (CCC) trial. METHODS/DESIGN: The CCC trial is a pilot multicentre feasibility, safety and biological efficacy randomized controlled trial recruiting adult cardiac arrest patients admitted to the intensive care unit after return of spontaneous circulation. At admission, using concealed allocation, participants are randomized to 24 h of either normocapnia (PaCO2 35 to 45 mmHg) or mild hypercapnia (PaCO2 50 to 55 mmHg). Key feasibility outcomes are recruitment rate and protocol compliance rate. The primary biological efficacy and biological safety measures are the between-groups difference in serum neuron-specific enolase and S100b protein levels at 24 h, 48 h and 72 h. Secondary outcome measure include adverse events, in-hospital mortality, and neurological assessment at 6 months. DISCUSSION: The trial commenced in December 2012 and, when completed, will provide clinical evidence as to whether targeting mild hypercapnia for 24 h following intensive care unit admission for cardiac arrest patients is feasible and safe and whether it results in decreased concentrations of neurological injury biomarkers compared with normocapnia. Trial results will also be used to determine whether a phase IIb study powered for survival at 90 days is feasible and justified. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000690853 .

Biological impact assessment of nanomaterial used in nanomedicine. Introduction to the NanoTEST project.

Therapeutic nanoparticles (NPs) are used in nanomedicine as drug carriers or imaging agents, providing increased selectivity/specificity for diseased tissues. The first NPs in nanomedicine were developed for increasing the efficacy of known drugs displaying dose-limiting toxicity and poor bioavailability and for enhancing disease detection. Nanotechnologies have gained much interest owing to their huge potential for applications in industry and medicine. It is necessary to ensure and control the biocompatibility of the components of therapeutic NPs to guarantee that intrinsic toxicity does not overtake the benefits. In addition to monitoring their toxicity in vitro, in vivo and in silico, it is also necessary to understand their distribution in the human body, their biodegradation and excretion routes and dispersion in the environment. Therefore, a deep understanding of their interactions with living tissues and of their possible effects in the human (and animal) body is required for the safe use of nanoparticulate formulations. Obtaining this information was the main aim of the NanoTEST project, and the goals of the reports collected together in this special issue are to summarise the observations and results obtained by the participating research teams and to provide methodological tools for evaluating the biological impact of NPs.

Biological evidence supports an early and complex emergence of the Isthmus of Panama.

The linking of North and South America by the Isthmus of Panama had major impacts on global climate, oceanic and atmospheric currents, and biodiversity, yet the timing of this critical event remains contentious. The Isthmus is traditionally understood to have fully closed by ca. 3.5 million years ago (Ma), and this date has been used as a benchmark for oceanographic, climatic, and evolutionary research, but recent evidence suggests a more complex geological formation. Here, we analyze both molecular and fossil data to evaluate the tempo of biotic exchange across the Americas in light of geological evidence. We demonstrate significant waves of dispersal of terrestrial organisms at approximately ca. 20 and 6 Ma and corresponding events separating marine organisms in the Atlantic and Pacific oceans at ca. 23 and 7 Ma. The direction of dispersal and their rates were symmetrical until the last ca. 6 Ma, when northern migration of South American lineages increased significantly. Variability among taxa in their timing of dispersal or vicariance across the Isthmus is not explained by the ecological factors tested in these analyses, including biome type, dispersal ability, and elevation preference. Migration was therefore not generally regulated by intrinsic traits but more likely reflects the presence of emergent terrain several millions of years earlier than commonly assumed. These results indicate that the dramatic biotic turnover associated with the Great American Biotic Interchange was a long and complex process that began as early as the Oligocene-Miocene transition.

Biological Flora of the British Isles: Ambrosia artemisiifolia

1. This account presents information on all aspects of the biology of Ambrosia artemisiifolia L. (Common ragweed) that are relevant to understanding its ecology. The main topics are presented within the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, history, and conservation, impacts and management. 2. Ambrosia artemisiifolia is a monoecious, wind-pollinated, annual herb native to North America whose height varies from 10 cm to 2.5 m according to environmental conditions. It has erect, branched stems and pinnately lobed leaves. Spike-like racemes of male capitula composed of staminate (male) florets terminate the stems, while cyme-like clusters of pistillate (female) florets are arranged in groups the axils of main and lateral stem leaves. 3. Seeds require prolonged chilling to break dormancy. Following seedling emergence in spring, the rate of vegetative growth depends on temperature, but development occurs over a wide thermal range. In temperate European climates, male and female flowers are produced from summer to early autumn (July to October). 4. Ambrosia artemisiifolia is sensitive to freezing. Late spring frosts kill seedlings and the first autumn frosts terminate the growing season. It has a preference for dry soils of intermediate to rich nutrient level. 5. Ambrosia artemisiifolia was introduced into Europe with seed imports from North America in the 19th century. Since World War II, it has become widespread in temperate regions of Europe and is now abundant in open, disturbed habitats as a ruderal and agricultural weed. 6. Recently, the N. American ragweed leaf beetle (Ophraella communa) has been detected in southern Switzerland and northern Italy. This species appears to have the capacity to substantially reduce growth and seed production of A. artemisiifolia. 7. In heavily infested regions of Europe, A. artemisiifolia causes substantial crop-yield losses and its copious, highly allergenic pollen creates considerable public health problems. There is consensus among models that climate change will allow its northward and up-hill spread in Europe.

Inference of Evolutionary Forces Acting on Human Biological Pathways.

Because natural selection is likely to act on multiple genes underlying a given phenotypic trait, we study here the potential effect of ongoing and past selection on the genetic diversity of human biological pathways. We first show that genes included in gene sets are generally under stronger selective constraints than other genes and that their evolutionary response is correlated. We then introduce a new procedure to detect selection at the pathway level based on a decomposition of the classical McDonald-Kreitman test extended to multiple genes. This new test, called 2DNS, detects outlier gene sets and takes into account past demographic effects and evolutionary constraints specific to gene sets. Selective forces acting on gene sets can be easily identified by a mere visual inspection of the position of the gene sets relative to their two-dimensional null distribution. We thus find several outlier gene sets that show signals of positive, balancing, or purifying selection but also others showing an ancient relaxation of selective constraints. The principle of the 2DNS test can also be applied to other genomic contrasts. For instance, the comparison of patterns of polymorphisms private to African and non-African populations reveals that most pathways show a higher proportion of nonsynonymous mutations in non-Africans than in Africans, potentially due to different demographic histories and selective pressures.

In-vivo brain neuroimaging provides a gateway for integrating biological and clinical biomarkers of Alzheimer's disease.

PURPOSE OF REVIEW: Only 5% of the Alzheimer's cases are explained by genetic mutations, whereas the remaining 95% are sporadic. The pathophysiological mechanisms underlying sporadic Alzheimer's disease are not well understood, suggesting a complex multifactorial cause. This review summarizes the recent findings on research aiming to show how biomarkers can be used for revealing the underlying mechanisms of preclinical stage Alzheimer's disease and help in their diagnosis. RECENT FINDINGS: The undisputed successful publicly accessible repositories provide longitudinal brain images, clinical, genetic and proteomic information of Alzheimer's disease. By combining with increasingly sophisticated data analysis methods, it is a great opportunity for searching new biomarkers. Innovative studies validated theoretical models of disease progression demonstrating the sequential ordering of well-established biomarkers. Novel observations shed light on the interaction between biomarkers to confirm that disease progression is related to multiple pathological factors. A typical example is the tau-associated neuronal toxicity that can be additionally potentiated by amyloid β peptides. To increase further the complexity, studies report specific impact of common genetic variants that can be traced from childhood through middle age up to the symptomatic onset of Alzheimer's disease. SUMMARY: The discovery of efficient therapies to prevent the disease or modify the progression of disease requires a more thorough understanding of the underlying biological processes. Neuroimaging, genetic and proteomic biomarkers for Alzheimer's disease are critically discussed and proposed to be included in clinical descriptions and diagnostic guidelines.

Biological variation of established and novel biomarkers for atherosclerosis: Results from a prospective, parallel-group cohort study.

BACKGROUND: Biomarkers are a promising tool for the management of patients with atherosclerosis, but their variation is largely unknown. We assessed within-subject and between-subject biological variation of biomarkers in peripheral artery disease (PAD) patients and healthy controls, and defined which biomarkers have a favorable variation profile for future studies. METHODS: Prospective, parallel-group cohort study, including 62 patients with stable PAD (79% men, 65±7years) and 18 healthy control subjects (44% men, 57±7years). Blood samples were taken at baseline, and after 3-, 6-, and 12-months. We calculated within-subject (CVI) and between-subject (CVG) coefficients of variation and intra-class correlation coefficient (ICC). RESULTS: Mean levels of D-dimer, hs-CRP, IL-6, IL-8, MMP-9, MMP-3, S100A8/A9, PAI-1, sICAM-1, and sP-selectin levels were higher in PAD patients than in healthy controls (P≤.05 for all). CVI and CVG of the different biomarkers varied considerably in both groups. An ICC≥0.5 (indicating moderate-to-good reliability) was found for hs-CRP, D-Dimer, E-selectin, IL-10, MCP-1, MMP-3, oxLDL, sICAM-1 and sP-selectin in both groups, for sVCAM in healthy controls and for MMP-9, PAI-1 and sCD40L in PAD patients. CONCLUSIONS: Single biomarker measurements are of limited utility due to large within-subject variation, both in PAD patients and healthy subjects. D-dimer, hs-CRP, MMP-9, MMP-3, PAI-1, sP-selectin and sICAM-1 are biomarkers with both higher mean levels in PAD patients and a favorable variation profile making them most suitable for future studies.

Biological interpretation of genome-wide association studies using predicted gene functions.

The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.

Evaluation du risque de récidive dans les expertises pénales: quels outils? Quets indicateurs? Quelles pratiques [Risk assessment in forensic psychiatric reports: what kind assessment instrument? What indicator? What practical?].

Here we present results of studies conducted by the Research Unit of Legal Psychiatry and Psychology of Lausanne about risk assessment and protective factors in the evaluation of violence recidivism. It aims to help experts in considering the relevance and use of tools at their disposal. Particular attention is given to the significance of protective factors and impulsive dimensions, as to the inter-raters process that leads to the final deliberations.

EEG as an Indicator of Cerebral Functioning in Postanoxic Coma.

Postanoxic coma after cardiac arrest is one of the most serious acute cerebral conditions and a frequent cause of admission to critical care units. Given substantial improvement of outcome over the recent years, a reliable and timely assessment of clinical evolution and prognosis is essential in this context, but may be challenging. In addition to the classic neurologic examination, EEG is increasingly emerging as an important tool to assess cerebral functions noninvasively. Although targeted temperature management and related sedation may delay clinical assessment, EEG provides accurate prognostic information in the early phase of coma. Here, the most frequently encountered EEG patterns in postanoxic coma are summarized and their relations with outcome prediction are discussed. This article also addresses the influence of targeted temperature management on brain signals and the implication of the evolution of EEG patterns over time. Finally, the article ends with a view of the future prospects for EEG in postanoxic management and prognostication.

The paracaspase MALT1: biological function and potential for therapeutic inhibition.

The paracaspase MALT1 has a central role in the activation of lymphocytes and other immune cells including myeloid cells, mast cells and NK cells. MALT1 activity is required not only for the immune response, but also for the development of natural Treg cells that keep the immune response in check. Exaggerated MALT1 activity has been associated with the development of lymphoid malignancies, and recently developed MALT1 inhibitors show promising anti-tumor effects in xenograft models of diffuse large B cell lymphoma. In this review, we provide an overview of the present understanding of MALT1's function, and discuss possibilities for its therapeutic targeting based on recently developed inhibitors and animal models.

On evaluating the accuracy and biological plausibility of diffusion MRI tractograms

In diffusion MRI, traditional tractography algorithms do not recover truly quantitative tractograms and the structural connectivity has to be estimated indirectly by counting the number of fiber tracts or averaging scalar maps along them. Recently, global and efficient methods have emerged to estimate more quantitative tractograms by combining tractography with local models for the diffusion signal, like the Convex Optimization Modeling for Microstructure Informed Tractography (COMMIT) framework. In this abstract, we show the importance of using both (i) proper multi-compartment diffusion models and (ii) adequate multi-shell acquisitions, in order to evaluate the accuracy and the biological plausibility of the tractograms.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.