177 research outputs found

    Quantitative scintigraphy with deconvolutional analysis for the dynamic measurement of hepatic function

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    A mathematical technique known as deconvolutional analysis was used to provide a critical and previously missing element in the computations required to quantitate hepatic function scintigraphically. This computer-assisted technique allowed for the determination of the time required, in minutes, of a labeled bilirubin analog (99mTc-disofenin) to enter the liver via blood and exit via bile. This interval was referred to as the mean transit time (MTT). The critical process provided for by deconvolution is the mathematical simulation of a bolus injection of tracer directly into the afferent blood supply of the liver. The raw data required for this simulation are obtained from the intravenous injection of labeled disofenin, a member of the HIDA family of radiopharmaceuticals. In this study, we perform experiments which document that the simulation process itself is accurate. We then calculate the MTT under a variety of experimental conditions involving progressive hepatic ischemia/reperfusion injury and correlate these results with the results of simultaneously performed BSP determinations and hepatic histology. The experimental group with the most pronounced histologic findings (necrosis, vacuolization, disorganization of hepatic cords) also have the most prolonged MTT and BSP half-life. However, both quantitative imaging and BSP testing are able to identify milder degrees of hepatic ischemic injury not reflected in the histologic evaluation. Quantitative imaging with deconvolutional analysis is a technique easily adaptable to the standard nuclear medicine minicomputer. It provides rapid results and appears to be a sensitive monitor of hepatic functional disturbances resulting from ischemia and reperfusion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26699/1/0000247.pd

    Indication for the disappearance of reactor electron antineutrinos in the Double Chooz experiment

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    The Double Chooz Experiment presents an indication of reactor electron antineutrino disappearance consistent with neutrino oscillations. A ratio of 0.944 ±\pm 0.016 (stat) ±\pm 0.040 (syst) observed to predicted events was obtained in 101 days of running at the Chooz Nuclear Power Plant in France, with two 4.25 GWth_{th} reactors. The results were obtained from a single 10 m3^3 fiducial volume detector located 1050 m from the two reactor cores. The reactor antineutrino flux prediction used the Bugey4 measurement as an anchor point. The deficit can be interpreted as an indication of a non-zero value of the still unmeasured neutrino mixing parameter \sang. Analyzing both the rate of the prompt positrons and their energy spectrum we find \sang = 0.086 ±\pm 0.041 (stat) ±\pm 0.030 (syst), or, at 90% CL, 0.015 << \sang  <\ < 0.16.Comment: 7 pages, 4 figures, (new version after PRL referee's comments

    An innovative telemedicine knowledge translation program to improve quality of care in intensive care units: protocol for a cluster randomized pragmatic trial

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    Abstract Background There are challenges to timely adoption of, and ongoing adherence to, evidence-based practices known to improve patient care in the intensive care unit (ICU). Quality improvement initiatives using a collaborative network approach may increase the use of such practices. Our objective is to evaluate the effectiveness of a novel knowledge translation program for increasing the proportion of patients who appropriately receive the following six evidence-based care practices: venous thromboembolism prophylaxis; ventilator-associated pneumonia prevention; spontaneous breathing trials; catheter-related bloodstream infection prevention; decubitus ulcer prevention; and early enteral nutrition. Methods and design We will conduct a pragmatic cluster randomized active control trial in 15 community ICUs and one academic ICU in Ontario, Canada. The intervention is a multifaceted videoconferenced educational and problem-solving forum to organize knowledge translation strategies, including comparative audit and feedback, educational sessions from content experts, and dissemination of algorithms. Fifteen individual ICUs (clusters) will be randomized to receive quality improvement interventions targeting one of the best practices during each of six study phases. Each phase lasts four months during the first study year and three months during the second. At the end of each study phase, ICUs are assigned to an intervention for a best practice not yet received according to a random schedule. The primary analysis will use patient-level process-of-care data to measure the intervention's effect on rates of adoption and adherence of each best practice in the targeted ICU clusters versus controls. Discussion This study design evaluates a new system for knowledge translation and quality improvement across six common ICU problems. All participating ICUs receive quality improvement initiatives during every study phase, improving buy-in. This study design could be considered for other quality improvement interventions and in other care settings. Trial Registration This trial is registered with http://www.clinicaltrials.gov (ID #: NCT00332982

    Cell-to-Cell Stochastic Variation in Gene Expression Is a Complex Genetic Trait

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    The genetic control of common traits is rarely deterministic, with many genes contributing only to the chance of developing a given phenotype. This incomplete penetrance is poorly understood and is usually attributed to interactions between genes or interactions between genes and environmental conditions. Because many traits such as cancer can emerge from rare events happening in one or very few cells, we speculate an alternative and complementary possibility where some genotypes could facilitate these events by increasing stochastic cell-to-cell variations (or ‘noise’). As a very first step towards investigating this possibility, we studied how natural genetic variation influences the level of noise in the expression of a single gene using the yeast S. cerevisiae as a model system. Reproducible differences in noise were observed between divergent genetic backgrounds. We found that noise was highly heritable and placed under a complex genetic control. Scanning the genome, we mapped three Quantitative Trait Loci (QTL) of noise, one locus being explained by an increase in noise when transcriptional elongation was impaired. Our results suggest that the level of stochasticity in particular molecular regulations may differ between multicellular individuals depending on their genotypic background. The complex genetic architecture of noise buffering couples genetic to non-genetic robustness and provides a molecular basis to the probabilistic nature of complex traits

    Bare Bones Pattern Formation: A Core Regulatory Network in Varying Geometries Reproduces Major Features of Vertebrate Limb Development and Evolution

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    BACKGROUND: Major unresolved questions regarding vertebrate limb development concern how the numbers of skeletal elements along the proximodistal (P-D) and anteroposterior (A-P) axes are determined and how the shape of a growing limb affects skeletal element formation. There is currently no generally accepted model for these patterning processes, but recent work on cartilage development (chondrogenesis) indicates that precartilage tissue self-organizes into nodular patterns by cell-molecular circuitry with local auto-activating and lateral inhibitory (LALI) properties. This process is played out in the developing limb in the context of a gradient of fibroblast growth factor (FGF) emanating from the apical ectodermal ridge (AER). RESULTS: We have simulated the behavior of the core chondrogenic mechanism of the developing limb in the presence of an FGF gradient using a novel computational environment that permits simulation of LALI systems in domains of varying shape and size. The model predicts the normal proximodistal pattern of skeletogenesis as well as distal truncations resulting from AER removal. Modifications of the model's parameters corresponding to plausible effects of Hox proteins and formins, and of the reshaping of the model limb, bud yielded simulated phenotypes resembling mutational and experimental variants of the limb. Hypothetical developmental scenarios reproduce skeletal morphologies with features of fossil limbs. CONCLUSIONS: The limb chondrogenic regulatory system operating in the presence of a gradient has an inherent, robust propensity to form limb-like skeletal structures. The bare bones framework can accommodate ancillary gene regulatory networks controlling limb bud shaping and establishment of Hox expression domains. This mechanism accounts for major features of the normal limb pattern and, under variant geometries and different parameter values, those of experimentally manipulated, genetically aberrant and evolutionary early forms, with no requirement for an independent system of positional information

    Loss of RNA–Dependent RNA Polymerase 2 (RDR2) Function Causes Widespread and Unexpected Changes in the Expression of Transposons, Genes, and 24-nt Small RNAs

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    Transposable elements (TEs) comprise a substantial portion of many eukaryotic genomes and are typically transcriptionally silenced. RNA–dependent RNA polymerase 2 (RDR2) is a component of the RNA–directed DNA methylation (RdDM) silencing pathway. In maize, loss of mediator of paramutation1 (mop1) encoded RDR2 function results in reactivation of transcriptionally silenced Mu transposons and a substantial reduction in the accumulation of 24 nt short-interfering RNAs (siRNAs) that recruit RNA silencing components. An RNA–seq experiment conducted on shoot apical meristems (SAMs) revealed that, as expected based on a model in which RDR2 generates 24 nt siRNAs that suppress expression, most differentially expressed DNA TEs (78%) were up-regulated in the mop1 mutant. In contrast, most differentially expressed retrotransposons (68%) were down-regulated. This striking difference suggests that distinct silencing mechanisms are applied to different silencing templates. In addition, >6,000 genes (24% of analyzed genes), including nearly 80% (286/361) of genes in chromatin modification pathways, were differentially expressed. Overall, two-thirds of differentially regulated genes were down-regulated in the mop1 mutant. This finding suggests that RDR2 plays a significant role in regulating the expression of not only transposons, but also of genes. A re-analysis of existing small RNA data identified both RDR2–sensitive and RDR2–resistant species of 24 nt siRNAs that we hypothesize may at least partially explain the complex changes in the expression of genes and transposons observed in the mop1 mutant

    Comparison of Muscle Transcriptome between Pigs with Divergent Meat Quality Phenotypes Identifies Genes Related to Muscle Metabolism and Structure

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    Background: Meat quality depends on physiological processes taking place in muscle tissue, which could involve a large pattern of genes associated with both muscle structural and metabolic features. Understanding the biological phenomena underlying muscle phenotype at slaughter is necessary to uncover meat quality development. Therefore, a muscle transcriptome analysis was undertaken to compare gene expression profiles between two highly contrasted pig breeds, Large White (LW) and Basque (B), reared in two different housing systems themselves influencing meat quality. LW is the most predominant breed used in pig industry, which exhibits standard meat quality attributes. B is an indigenous breed with low lean meat and high fat contents, high meat quality characteristics, and is genetically distant from other European pig breeds. Methodology/Principal Findings: Transcriptome analysis undertaken using a custom 15 K microarray, highlighted 1233 genes differentially expressed between breeds (multiple-test adjusted P-value,0.05), out of which 635 were highly expressed in the B and 598 highly expressed in the LW pigs. No difference in gene expression was found between housing systems. Besides, expression level of 12 differentially expressed genes quantified by real-time RT-PCR validated microarray data. Functional annotation clustering emphasized four main clusters associated to transcriptome breed differences: metabolic processes, skeletal muscle structure and organization, extracellular matrix, lysosome, and proteolysis, thereb
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