332 research outputs found

    Sentry bioconvertible inferior vena cava filter: Study of stages of incorporation in an experimental ovine model

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    The Sentry inferior vena cava (IVC) filter is designed to provide temporary protection from pulmonary embolism (PE) and then bioconvert to become incorporated in the vessel wall, leaving a patent IVC lumen. Objective. To evaluate the performance and stages of incorporation of the Sentry IVC filter in an ovine model. Methods. Twenty-four bioconvertible devices and 1 control retrievable filter were implanted in the infrarenal IVC of 25 sheep, with extensive daily monitoring and intensive imaging. Vessels and devices were analyzed at early (≤98 days, n = 10) and late (180 ± 30 days, n = 14 study devices, 1 control) termination and necropsy time-points. Results. Deployment success was 100% with all devices confirmed in filtering configuration, there were no filter-related complications, and bioconversion was 100% at termination with vessels widely patent. By 98 days for all early-incorporation analysis animals, the stabilizing cylindrical part of the Sentry frame was incorporated in the vessel wall, and the filter arms were retracted. By 180 days for all late-incorporation analysis animals, the filter arms as well as frames were stably incorporated. Conclusions. Through 180 days, there were no filter-related complications, and the study devices were all bioconverted and stably incorporated, leaving all IVCs patent

    Using Fludarabine to Reduce Exposure to Alkylating Agents in Children with Sickle Cell Disease Receiving Busulfan, Cyclophosphamide, and Antithymocyte Globulin Transplant Conditioning: Results of a Dose De-Escalation Trial

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    AbstractHigh-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide. We conducted a multicenter dose de-escalation trial with the objective of decreasing the doses of busulfan and cyclophosphamide by 50% and 55%, respectively. Using day +28 donor-predominant chimerism as a surrogate endpoint for sustained engraftment, we completed the first 2 of 4 planned levels, enrolling 6 patients at each and reducing the total dose of cyclophosphamide from 200 mg/kg to 90 mg/kg. On the third level, which involved a reduction of i.v. busulfan from 12.8 mg/kg to 9.6 mg/kg, the first 2 patients had host-predominant T cell chimerism, which triggered trial-stopping rules. All 14 patients survive disease-free. No patients suffered severe regimen-related toxicity. Our results suggest BU-FLU-CY-ATG using lower dose CY could be a less toxic yet effective regimen. Further evaluation of this regimen in a full-scale clinical trial is warranted

    Single-molecule visualization of fast polymerase turnover in the bacterial replisome

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    The Escherichia coli DNA replication machinery has been used as a road map to uncover design rules that enable DNA duplication with high efficiency and fidelity. Although the enzymatic activities of the replicative DNA Pol III are well understood, its dynamics within the replisome are not. Here, we test the accepted view that the Pol III holoenzyme remains stably associated within the replisome. We use in vitro single-molecule assays with fluorescently labeled polymerases to demonstrate that the Pol III* complex (holoenzyme lacking the β2 sliding clamp), is rapidly exchanged during processive DNA replication. Nevertheless, the replisome is highly resistant to dilution in the absence of Pol III* in solution. We further show similar exchange in live cells containing labeled clamp loader and polymerase. These observations suggest a concentration-dependent exchange mechanism providing a balance between stability and plasticity, facilitating replacement of replisomal components dependent on their availability in the environment

    Interactive Effects of Climate Change with Nutrients, Mercury, and Freshwater Acidification on Key Taxa in the North Atlantic Landscape Conservation Cooperative Region

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    The North Atlantic Landscape Conservation Cooperative LCC (NA LCC) is a public-private partnership that provides information to support conservation decisions that may be affected by global climate change (GCC) and other threats. The NA LCC region extends from southeast Virginia to the Canadian Maritime Provinces. Within this region, the US National Climate Assessment documented increases in air temperature, total precipitation, frequency of heavy precipitation events, and rising sea level, and predicted more drastic changes. Here, we synthesize literature on the effects of GCC interacting with selected contaminant, nutrient, and environmental processes to adversely affect natural resources within this region. Using a case study approach, we focused on 3 stressors with sufficient NA LCC region-specific information for an informed discussion. We describe GCC interactions with a contaminant (Hg) and 2 complex environmental phenomena-freshwater acidification and eutrophication. We also prepared taxa case studies on GCC- and GCC-contaminant/nutrient/process effects on amphibians and freshwater mussels. Several avian species of high conservation concern have blood Hg concentrations that have been associated with reduced nesting success. Freshwater acidification has adversely affected terrestrial and aquatic ecosystems in the Adirondacks and other areas of the region that are slowly recovering due to decreased emissions of N and sulfur oxides. Eutrophication in many estuaries within the region is projected to increase from greater storm runoff and less denitrification in riparian wetlands. Estuarine hypoxia may be exacerbated by increased stratification. Elevated water temperature favors algal species that produce harmful algal blooms (HABs). In several of the region\u27s estuaries, HABs have been associated with bird die-offs. In the NA LCC region, amphibian populations appear to be declining. Some species may be adversely affected by GCC through higher temperatures and more frequent droughts. GCC may affect freshwater mussel populations via altered stream temperatures and increased sediment loading during heavy storms. Freshwater mussels are sensitive to un-ionized ammonia that more toxic at higher temperatures. We recommend studying the interactive effects of GCC on generation and bioavailability of methylmercury and how GCC-driven shifts in bird species distributions will affect avian exposure to methylmercury. Research is needed on how decreases in acid deposition concurrent with GCC will alter the structure and function of sensitive watersheds and surface waters. Studies are needed to determine how GCC will affect HABs and avian disease, and how more severe and extensive hypoxia will affect fish and shellfish populations. Regarding amphibians, we suggest research on 1) thermal tolerance and moisture requirements of species of concern, 2) effects of multiple stressors (temperature, desiccation, contaminants, nutrients), and 3) approaches to mitigate impacts of increased temperature and seasonal drought. We recommend studies to assess which mussel species and populations are vulnerable and which are resilient to rising stream temperatures, hydrological shifts, and ionic pollutants, all of which are influenced by GCC

    Interactive Effects of Climate Change with Nutrients, Mercury, and Freshwater Acidification on Key Taxa in the North Atlantic Landscape Conservation Cooperative Region

    Get PDF
    The North Atlantic Landscape Conservation Cooperative LCC (NA LCC) is a public–private partnership that provides information to support conservation decisions that may be affected by global climate change (GCC) and other threats. The NA LCC region extends from southeast Virginia to the Canadian Maritime Provinces. Within this region, the US National Climate Assessment documented increases in air temperature, total precipitation, frequency of heavy precipitation events, and rising sea level, and predicted more drastic changes. Here, we synthesize literature on the effects of GCC interacting with selected contaminant, nutrient, and environmental processes to adversely affect natural resources within this region. Using a case study approach, we focused on 3 stressors with sufficient NA LCC regionspecific information for an informed discussion. We describe GCC interactions with a contaminant (Hg) and 2 complex environmental phenomena—freshwater acidification and eutrophication. We also prepared taxa case studies on GCCand GCC-contaminant/nutrient/process effects on amphibians and freshwater mussels. Several avian species of high conservation concern have blood Hg concentrations that have been associated with reduced nesting success. Freshwater acidification has adversely affected terrestrial and aquatic ecosystems in the Adirondacks and other areas of the region that are slowly recovering due to decreased emissions of N and sulfur oxides. Eutrophication in many estuaries within the region is projected to increase from greater storm runoff and less denitrification in riparian wetlands. Estuarine hypoxia may be exacerbated by increased stratification. Elevated water temperature favors algal species that produce harmful algal blooms (HABs). In several of the region\u27s estuaries, HABs have been associated with bird die-offs. In the NA LCC region, amphibian populations appear to be declining. Some species may be adversely affected by GCC through higher temperatures and more frequent droughts. GCC may affect freshwater mussel populations via altered stream temperatures and increased sediment loading during heavy storms. Freshwater mussels are sensitive to un-ionized ammonia that more toxic at higher temperatures. We recommend studying the interactive effects of GCC on generation and bioavailability of methylmercury and how GCC-driven shifts in bird species distributions will affect avian exposure to methylmercury. Research is needed on how decreases in acid deposition concurrent with GCC will alter the structure and function of sensitive watersheds and surface waters. Studies are needed to determine how GCC will affect HABs and avian disease, and how more severe and extensive hypoxia will affect fish and shellfish populations. Regarding amphibians, we suggest research on 1) thermal tolerance and moisture requirements of species of concern, 2) effects of multiple stressors (temperature, desiccation, contaminants, nutrients), and 3) approaches to mitigate impacts of increased temperature and seasonal drought. We recommend studies to assess which mussel species and populations are vulnerable and which are resilient to rising stream temperatures, hydrological shifts, and ionic pollutants, all of which are influenced by GCC

    Early changes in visuospatial episodic memory can help distinguish primary age‐related tauopathy from Alzheimer’s disease

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    From Wiley via Jisc Publications RouterHistory: received 2021-02-08, rev-recd 2021-03-19, accepted 2021-05-01, pub-electronic 2021-05-29Article version: VoRPublication status: PublishedFunder: Alzheimer's Research Trust; Id: http://dx.doi.org/10.13039/501100000319Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265Funder: Unilever; Id: http://dx.doi.org/10.13039/100007190Funder: Economic and Social Research Council; Id: http://dx.doi.org/10.13039/501100000269Funder: Alzheimer's Society; Id: http://dx.doi.org/10.13039/501100000320Funder: Wellcome Trust; Grant(s): 00388

    Outcome of Transplantation for Acute Myelogenous Leukemia in Children with Down Syndrome

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    AbstractData on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to posttransplantation relapse. We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls. The median age at transplantation for DS-AML was 3 years, and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (hazard ratio [HR], 2.84; P < .001; 62% versus 37%) and transplant-related mortality (HR, 2.52; P = .04; 24% versus 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR, 2.86; P < .001; 21% versus 52%) was significantly higher for DS-AML. Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multicenter effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks
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