1,227 research outputs found

    Nitric oxide precursors and congenital heart surgery: A randomized controlled trial of oral citrulline

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    ObjectiveThe study sought to determine whether citrulline supplementation, a precursor to nitric oxide synthesis, is safe and efficacious in increasing plasma citrulline concentrations and decreasing the risk of postoperative pulmonary hypertension.Study DesignForty children, undergoing cardiopulmonary bypass and at risk for pulmonary hypertension, were randomized to receive 5 perioperative doses (1.9 g/m2 per dose) of either oral citrulline or placebo. Plasma citrulline and arginine concentrations were measured at 5 time points. Measurements of systemic blood pressure and presence of pulmonary hypertension were collected.ResultsMedian citrulline concentrations were significantly higher in the citrulline group versus the placebo group immediately postoperatively (36 μmol/L vs 26 μmol/L, P = .012) and at 12 hours postoperatively (37 μmol/L vs 20 μmol/L, P = .015). Mean plasma arginine concentrations were significantly higher in the citrulline group versus the placebo group by 12 hours postoperatively (36 μmol/L vs 23 μmol/L, P = .037). Mean systemic blood pressure did not differ between groups (P = .53). Postoperative pulmonary hypertension developed in 9 patients, 6 of 20 (30%) in the placebo group and 3 of 20 (15%) in the citrulline group (P = .451), all of whom had plasma citrulline concentrations less than age-specific norms. Postoperative pulmonary hypertension did not develop in patients who demonstrated plasma citrulline concentrations in excess of 37 μmol/L (P = .036).ConclusionsOral citrulline supplementation safely increased plasma citrulline and arginine concentrations compared with placebo after cardiopulmonary bypass. Postoperative pulmonary hypertension did not occur in children with naturally elevated citrulline levels or elevations through supplementation. Oral citrulline supplementation may be effective in reducing postoperative pulmonary hypertension

    Exercise and Caloric Restriction Alter the Immune System of Mice Submitted to a High-Fat Diet

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    As the size of adipocytes increases during obesity, the establishment of resident immune cells in adipose tissue becomes an important source of proinflammatory mediators. Exercise and caloric restriction are two important, nonpharmacological tools against body mass increase. To date, their effects on the immune cells of adipose tissue in obese organisms, specifically when a high-fat diet is consumed, have been poorly investigated. Thus, after consuming a high-fat diet, mice were submitted to chronic swimming training or a 30% caloric restriction in order to investigate the effects of both interventions on resident immune cells in adipose tissue. These strategies were able to reduce body mass and resulted in changes in the number of resident immune cells in the adipose tissue and levels of cytokines/chemokines in serum. While exercise increased the number of NK cells in adipose tissue and serum levels of IL-6 and RANTES, caloric restriction increased the CD4+/CD8+ cell ratio and MCP-1 levels. Together, these data demonstrated that exercise and caloric restriction modulate resident immune cells in adipose tissues differently in spite of an equivalent body weight reduction. Additionally, the results also reinforce the idea that a combination of both strategies is better than either individually for combating obesity.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilUniv São Paulo, Sch Arts Sci & Humanities, BR-03828000 São Paulo, BrazilUniv São Paulo, Inst Biomed Sci, Lab Transplantat Immunobiol, Dept Immunol, BR-05508900 São Paulo, BrazilUniv Fed Pelotas, Sch Nutr, Dept Nutr, BR-96010610 Pelotas, RS, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilFAPESP: 2011/03528-0Web of Scienc

    A New Class of Changing-Look LINERs

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    We report the discovery of six active galactic nuclei (AGN) caught "turning on" during the first nine months of the Zwicky Transient Facility (ZTF) survey. The host galaxies were classified as LINERs by weak narrow forbidden line emission in their archival SDSS spectra, and detected by ZTF as nuclear transients. In five of the cases, we found via follow-up spectroscopy that they had transformed into broad-line AGN, reminiscent of the changing-look LINER iPTF 16bco. In one case, ZTF18aajupnt/AT2018dyk, follow-up HST UV and ground-based optical spectra revealed the transformation into a narrow-line Seyfert 1 (NLS1) with strong [Fe VII, X, XIV] and He II 4686 coronal lines. Swift monitoring observations of this source reveal bright UV emission that tracks the optical flare, accompanied by a luminous soft X-ray flare that peaks ~60 days later. Spitzer follow-up observations also detect a luminous mid-infrared flare implying a large covering fraction of dust. Archival light curves of the entire sample from CRTS, ATLAS, and ASAS-SN constrain the onset of the optical nuclear flaring from a prolonged quiescent state. Here we present the systematic selection and follow-up of this new class of changing-look LINERs, compare their properties to previously reported changing-look Seyfert galaxies, and conclude that they are a unique class of transients well-suited to test the uncertain physical processes associated with the LINER accretion state.Comment: Submitted to ApJ, 31 pages, 17 Figures (excluding Appendix due to file size constraints but will be available in electronic version

    Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: Potential therapy for postoperative pulmonary hypertension

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    ObjectivePulmonary hypertension may complicate surgical correction of congenital heart defects, resulting in increased morbidity and mortality. We have previously shown that plasma levels of the nitric oxide precursors citrulline and arginine drop precipitously after congenital cardiac surgery and that oral citrulline supplementation may be protective against the development of pulmonary hypertension. In this study, we assessed the safety and pharmacokinetic profile of intravenous citrulline as a potential therapy for postoperative pulmonary hypertension.MethodsThe initial phase of this investigation was a dose-escalation study of intravenously administered citrulline in infants and children undergoing one of five congenital cardiac surgical procedures (phase 1). The primary safety outcome was a 20% drop in mean arterial blood pressure from the baseline pressure recorded after admission to the intensive care unit. Based on our previous work, the target circulating plasma citrulline trough was 80 to 100 μmol/L. Each patient was given two separate doses of citrulline: the first in the operating room immediately after initiation of cardiopulmonary bypass and the second 4 hours later in the pediatric intensive care unit. Stepwise dose escalations included 50 mg/kg, 100 mg/kg, and 150 mg/kg. After model-dependent pharmacokinetic analysis, we enrolled an additional 9 patients (phase 2) in an optimized dosing protocol that replaced the postoperative dose with a continuous infusion of citrulline at 9 mg/(kg·h) for 48 hours postoperatively.ResultsThe initial stepwise escalation protocol (phase 1) revealed that an intravenous citrulline dose of 150 mg/kg given after initiation of cardiopulmonary bypass yielded a trough level of in the target range of approximately 80 to 100 μmol/L 4 hours later. The postoperative dose revealed that the clearance of intravenously administered citrulline was 0.6 L/(h·kg), with a volume of distribution of 0.9 L/kg and estimated half-life of 60 minutes. Because of the short half-life, we altered the protocol to replace the postoperative dose with a continuous infusion of 9 mg/(kg·h). An additional 9 patients were studied with this continuous infusion protocol (phase 2). Mean plasma citrulline levels were maintained at approximately 125 μmol/L, with a calculated clearance of 0.52 L/(h·kg). None of the 17 patients studied had a 20% drop in mean arterial blood pressure from baseline.ConclusionsIn this first report of the use of intravenous citrulline in humans, we found citrulline to be both safe and well tolerated in infants and young children undergoing congenital cardiac surgery. Because of the rapid clearance, the optimal dosing regimen was identified as an initial bolus of 150 mg/kg given at the initiation of cardiopulmonary bypass, followed 4 hours later by a postoperative infusion of 9 mg/(kg·h) continued up to 48 hours. Using this regimen, plasma arginine, citrulline, and nitric oxide metabolite levels were well maintained. Intravenous citrulline needs to be studied further as a potential therapy for postoperative pulmonary hypertension

    Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European male aging study (EMAS)

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    <p>Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.</p> <p>Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.</p> <p>Design, Setting, and Participants: Men aged 40–79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.</p> <p>Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.</p> <p>Results: A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.</p> <p>Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.</p&gt

    Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European male aging study (EMAS)

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    <p>Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.</p> <p>Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.</p> <p>Design, Setting, and Participants: Men aged 40–79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.</p> <p>Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.</p> <p>Results: A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.</p> <p>Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.</p&gt

    Improving Prediction of Favourable Outcome After 6 Months in Patients with Severe Traumatic Brain Injury Using Physiological Cerebral Parameters in a Multivariable Logistic Regression Model.

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    BACKGROUND/OBJECTIVE: Current severe traumatic brain injury (TBI) outcome prediction models calculate the chance of unfavourable outcome after 6 months based on parameters measured at admission. We aimed to improve current models with the addition of continuously measured neuromonitoring data within the first 24 h after intensive care unit neuromonitoring. METHODS: Forty-five severe TBI patients with intracranial pressure/cerebral perfusion pressure monitoring from two teaching hospitals covering the period May 2012 to January 2019 were analysed. Fourteen high-frequency physiological parameters were selected over multiple time periods after the start of neuromonitoring (0-6 h, 0-12 h, 0-18 h, 0-24 h). Besides systemic physiological parameters and extended Corticosteroid Randomisation after Significant Head Injury (CRASH) score, we added estimates of (dynamic) cerebral volume, cerebral compliance and cerebrovascular pressure reactivity indices to the model. A logistic regression model was trained for each time period on selected parameters to predict outcome after 6 months. The parameters were selected using forward feature selection. Each model was validated by leave-one-out cross-validation. RESULTS: A logistic regression model using CRASH as the sole parameter resulted in an area under the curve (AUC) of 0.76. For each time period, an increased AUC was found using up to 5 additional parameters. The highest AUC (0.90) was found for the 0-6 h period using 5 parameters that describe mean arterial blood pressure and physiological cerebral indices. CONCLUSIONS: Current TBI outcome prediction models can be improved by the addition of neuromonitoring bedside parameters measured continuously within the first 24 h after the start of neuromonitoring. As these factors might be modifiable by treatment during the admission, testing in a larger (multicenter) data set is warranted

    Ernst Freund as Precursor of the Rational Study of Corporate Law

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    Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe
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