Interplay between electrical activity and bone morphogenetic protein signaling regulates spinal neuron differentiation

A gradient of bone morphogenetic proteins (BMPs) along the dorsoventral axis of the spinal cord is necessary for the specification of dorsal neurons. Concurrently, a gradient of calcium-mediated electrical activity is present in the developing spinal cord but in an opposing ventrodorsal direction. Whether BMPs and electrical activity interact in embryonic spinal neurons remains unknown. We show that BMP decreases electrical activity by enhancing p38 MAPK-mediated negative modulation of voltage-gated sodium channels. In turn, electrical activity affects the phosphorylation status and nuclear level of activated Smads, the canonical components of BMP signaling. This interaction between calcium spike activity and BMP signaling regulates the specification of the dorsal commissural spinal neuron phenotype. The present study identifies an unexpected interplay between BMPs and electrical activity that is critical for decoding the morphogen gradient during spinal neuron differentiation.     

Templates as a method for implementing data provenance in decision support systems

Decision support systems are used as a method of promoting consistent guideline-based diagnosis supporting clinical reasoning at point of care. However, despite the availability of numerous commercial products, the wider acceptance of these systems has been hampered by concerns about diagnostic performance and a perceived lack of transparency in the process of generating clinical recommendations. This resonates with the Learning Health System paradigm that promotes data-driven medicine relying on routine data capture and transformation, which also stresses the need for trust in an evidence-based system. Data provenance is a way of automatically capturing the trace of a research task and its resulting data, thereby facilitating trust and the principles of reproducible research. While computational domains have started to embrace this technology through provenance-enabled execution middlewares, traditionally non-computational disciplines, such as medical research, that do not rely on a single software platform, are still struggling with its adoption. In order to address these issues, we introduce provenance templates – abstract provenance fragments representing meaningful domain actions. Templates can be used to generate a model-driven service interface for domain software tools to routinely capture the provenance of their data and tasks. This paper specifies the requirements for a Decision Support tool based on the Learning Health System, introduces the theoretical model for provenance templates and demonstrates the resulting architecture. Our methods were tested and validated on the provenance infrastructure for a Diagnostic Decision Support System that was developed as part of the EU FP7 TRANSFoRm project.     

Nodal‐mediated epigenesis requires dynamin‐mediated endocytosis

Nodal proteins are diffusible morphogens that drive pattern formation via short‐range feedback activation coupled to long‐range Lefty‐mediated inhibition. In the sea urchin embryo, specification of the secondary (oral‐aboral) axis occurs via zygotic expression of nodal, which is localized to the prospective oral ectoderm at early blastula stage. In mid‐blastula stage embryos treated with low micromolar nickel or zinc, nodal expression expands progressively beyond the confines of this localized domain to encompass the entire equatorial circumference of the embryo, producing radialized embryos lacking an oral‐aboral axis. RNAseq analysis of embryos treated with nickel, zinc, or cadmium (which does not radialize embryos) showed that several genes involved in endocytosis were similarly perturbed by nickel and zinc but not cadmium. Inhibiting dynamin, a GTPase required for receptor‐mediated endocytosis, phenocopies the effects of nickel and zinc, suggesting that dynamin‐mediated endocytosis is required as a sink to limit the range of Nodal signaling. Developmental Dynamics 240:704–711, 2011. © 2011 Wiley‐Liss, Inc.     

中药滴鼻剂临床应用技术规范(草案)

基于对临床中药滴鼻剂应用的数据挖掘,结合临床实际应用情况和现代有关中药滴鼻剂的研究,经学会专家多次论证,形成中药滴鼻剂临床应用技术规范（草案）,包括临床适应症、用药前评估、制备、临床应用前期准备、使用剂量、使用频次、用药疗程、注意事项、不良反应及护理等。以期规范中药滴鼻剂的应用、提高中药滴鼻剂的疗效、减少中药滴鼻剂的不良反应。     

疾病控制机构呼吸道传染病疫情处置应急箱配置标准和操作规程研究

目的:加强卫生应急队伍装备建设,实现卫生应急队伍装备的专业化、规范化及标准化配备,以适应卫生应急工作需要。方法:采用调查表和快速应用程序开发工具(Delphi)研究疾控机构应对呼吸道传染病疫情处置应急箱配置标准和操作规程。结果:省、市、县疾控机构为应对呼吸道传染病疫情处置工作要求和任务,需配备现场个人应急箱、现场应急作业背囊、生物样品采集箱和感染性生物样品运输箱4种应急箱,配备数量要能够分别同时应对省级3起、市级2起和县级2起呼吸道传染病疫情。结论:各级疾控机构要配备一定数量的模块化组合的应急箱,同时制定应急箱标准操作规程和维护管理规程,以满足实际工作需求。     

Bayesian consensus-based sample size criteria for binomial proportions

Many sample size criteria exist. These include power calculations and methods based on confidence interval widths from a frequentist viewpoint, and Bayesian methods based on credible interval widths or decision theory. Bayesian methods account for the inherent uncertainty of inputs to sample size calculations through the use of prior information rather than the point estimates typically used by frequentist methods. However, the choice of prior density can be problematic because there will almost always be different appreciations of the past evidence. Such differences can be accommodated a priori by robust methods for Bayesian design, for example, using mixtures or ϵ-contaminated priors. This would then ensure that the prior class includes divergent opinions. However, one may prefer to report several posterior densities arising from a “community of priors,” which cover the range of plausible prior densities, rather than forming a single class of priors. To date, however, there are no corresponding sample size methods that specifically account for a community of prior densities in the sense of ensuring a large-enough sample size for the data to sufficiently overwhelm the priors to ensure consensus across widely divergent prior views. In this paper, we develop methods that account for the variability in prior opinions by providing the sample size required to induce posterior agreement to a prespecified degree. Prototypic examples to one- and two-sample binomial outcomes are included. We compare sample sizes from criteria that consider a family of priors to those that would result from previous interval-based Bayesian criteria.     

A test for the correct specification of marginal structural models

Marginal structural models (MSMs) allow estimating the causal effect of a time-varying exposure on an outcome in the presence of time-dependent confounding. The parameters of MSMs can be estimated utilizing an inverse probability of treatment weight estimator under certain assumptions. One of these assumptions is that the proposed causal model relating the outcome to exposure history is correctly specified. However, in practice, the true model is unknown. We propose a test that employs the observed data to attempt validating the assumption that the model is correctly specified. The performance of the proposed test is investigated with a simulation study. We illustrate our approach by estimating the effect of repeated exposure to psychosocial stressors at work on ambulatory blood pressure in a large cohort of white-collar workers in Québec City, Canada. Code examples in SAS and R are provided to facilitate the implementation of the test.     

Direct development of neurons within foregut endoderm of sea urchin embryos

Although it is well established that neural cells are ectodermal derivatives in bilaterian animals, here we report the surprising discovery that some of the pharyngeal neurons of sea urchin embryos develop de novo from the endoderm. The appearance of these neurons is independent of mouth formation, in which the stomodeal ectoderm joins the foregut. The neurons do not derive from migration of ectoderm cells to the foregut, as shown by lineage tracing with the photoactivatable protein KikGR. Their specification and development depend on expression of Nkx3-2, which in turn depends on Six3, both of which are expressed in the foregut lineage. SoxB1, which is closely related to the vertebrate Sox factors that support a neural precursor state, is also expressed in the foregut throughout gastrulation, suggesting that this region of the fully formed archenteron retains an unexpected pluripotency. Together, these results lead to the unexpected conclusion that, within a cell lineage already specified to be endoderm by a well-established gene regulatory network [Peter IS, Davidson EH (2010) Dev Biol 340:188-199], there also operates a Six3/Nkx3-2-dependent pathway required for the de novo specification of some of the neurons in the pharynx. As a result, neuroendoderm precursors form in the foregut aided by retention of a SoxB1-dependent pluripotent state.     

International collaborative study to evaluate a candidate reference preparation to define an appropriate specified limit of anti-D in intravenous immunoglobulin products

BACKGROUND AND OBJECTIVES: The aim of the study was to evaluate a lyophilized intravenous immunoglobulin (IVIG) preparation containing anti-D (02/228; nominal reciprocal titre of 8) for its suitability to define the maximum limit of anti-D in IVIG products when used in a proposed reference method of direct haemagglutination of papain-treated erythrocytes, in an international collaborative study. MATERIALS AND METHODS: Twenty laboratories tested 02/228 along with a negative control IVIG preparation and four IVIG samples containing different levels of anti-D. Nineteen laboratories performed direct haemagglutination methodology using papain-treated erythrocytes; five of these laboratories and one additional laboratory performed their in-house haemagglutination methodology (all indirect antiglobulin tests). RESULTS: The mode titre of 02/228, obtained by using the proposed reference method, was 8 (62.5% of tests). However, there was wide variation in haemagglutination titres between laboratories for three of the four samples. Correcting the titres of the samples relative to those of the proposed reference preparation reduced the interlaboratory variability and increased the frequency of the mode titres in three out of four samples. The indirect antiglobulin tests also showed wide interlaboratory variability and were less sensitive than the direct method in four laboratories. Eleven of the 14 laboratories that expressed an opinion considered that the level of anti-D in 02/228 was appropriate to define a specified limit. CONCLUSIONS: Our results demonstrate the necessity of using a reference preparation to define the maximum level of anti-D in IVIG products and ensure sufficient sensitivity in haemagglutination testing methodology. On the basis of these results, members of the European Pharmacopoeia Expert Group 6B recommended revision of the appropriate monograph to include this new specification and test. The Food and Drug Administration in the USA intends to adopt the same maximal specification defined by the reference preparation and to recommend the same test for the safety of IVIG products. Preparations 02/228 and 02/226 were also established by the World Health Organization as International Reference Reagents to standardize haemagglutination testing for anti-D in normal IVIG products.