Effect of salt intake on beat‐to‐beat blood pressure nonlinear dynamics and entropy in salt‐sensitive versus salt‐protected rats

Blood pressure exhibits substantial short‐ and long‐term variability (BPV). We assessed the hypothesis that the complexity of beat‐to‐beat BPV will be differentially altered in salt‐sensitive hypertensive Dahl rats (SS) versus rats protected from salt‐induced hypertension (SSBN13) maintained on high‐salt versus low‐salt diet. Beat‐to‐beat systolic and diastolic BP series from nine SS and six SSBN13 rats (http://www.physionet.org) were analyzed following 9 weeks on low salt and repeated after 2 weeks on high salt. BP complexity was quantified by detrended fluctuation analysis (DFA), short‐ and long‐range scaling exponents (αS and αL), sample entropy (SampEn), and traditional standard deviation (SD) and coefficient of variation (CV(%)). Mean systolic and diastolic BP increased on high‐salt diet (P < 0.01) particularly for SS rats. SD and CV(%) were similar across groups irrespective of diet. Salt‐sensitive and ‐protected rats exhibited similar complexity indices on low‐salt diet. On high salt, (1) SS rats showed increased scaling exponents or smoother, systolic (P = 0.007 [αL]) and diastolic (P = 0.008 [αL]) BP series; (2) salt‐protected rats showed lower SampEn (less complex) systolic and diastolic BP (P = 0.046); and (3) compared to protected SSBN13 rats, SS showed higher αL for systolic (P = 0.01) and diastolic (P = 0.005) BP. Hypertensive SS rats are more susceptible to high salt with a greater rise in mean BP and reduced complexity. Comparable mean pressures in sensitive and protective rats when on low‐salt diet coupled with similar BPV dynamics suggest a protective role of low‐salt intake in hypertensive rats. This effect likely reflects better coupling of biologic oscillators.We investigated the non‐linear dynamical properties of blood pressure variability, specifically complexity analysis and detrended fluctuation analysis (DFA), of the systolic and diastolic blood pressure time series in 9 salt sensitive and 6 protected rats. We showed that salt sensitive rats exhibit varying non linear BP dynamics compared to protected rats (smoother time series), irrespective of diet; we also showed the differential impat of salt intake on complexity and DFA metrics in both strains of rats.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/122419/1/phy212823_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/122419/2/phy212823.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/122419/3/phy212823-sup-0001-SupInfo.pd

The effect of completeness of revascularization during CABG with single versus multiple arterial grafts

IntroductionIncomplete coronary revascularization is associated with suboptimal outcomes. We investigated the longâ term effects of Incomplete, Complete, and Supraâ complete revascularization and whether these effects differed in the setting of singleâ arterial and multiâ arterial coronary artery bypass graft (CABG).MethodsWe analyzed 15â year mortality in 7157 CABG patients (64.1â ±â 10.5 years; 30% women). All patients received a left internal thoracic artery to left anterior descending coronary artery graft with additional venous grafts only (singleâ arterial) or with at least one additional arterial graft (multiâ arterial) and were grouped based on a completeness of revascularization index (CRIâ =â number of grafts minus the number of diseased principal coronary arteries): Incomplete (CRIâ â ¤â â 1 [Nâ =â 320;4.5%]); Complete (CRIâ =â 0 [Nâ =â 2882;40.3%]; reference group); and two Supraâ complete categories (CRIâ =â +1[Nâ =â 3050; 42.6%]; CRIâ â ¥â +â 2 [Nâ =â 905; 12.6%]). Riskâ adjusted mortality hazard ratios (AHR) were calculated using comprehensive propensity score adjustment by Cox regression.ResultsIncomplete revascularization was rare (4.5%) but associated with increased mortality in all patients (AHR [95% confidence interval]â =â 1.53 [1.29â 1.80]), those undergoing singleâ arterial CABG (AHRâ =â 1.27 [1.04â 1.54]) and multiâ arterial CABG (AHRâ =â 2.18 [1.60â 2.99]), as well as in patients with 3â Vessel (AHRâ =â 1.37 [1.16â 1.62]) and, to a lesser degree, with 2â Vessel (AHRâ =â 1.67 [0.53â 5.23]) coronary disease. Supraâ complete revascularization was generally associated with incrementally decreased mortality in all patients (AHR [CRIâ =â +1]â =â 0.94 [0.87â 1.03]); AHR [CRIâ â ¥â +2]â =â 0.74 [0.64â 0.85]), and was driven by a significantly decreased mortality risk in singleâ arterial CABG (AHR [CRIâ =â +1]â =â 0.90 [0.81â 0.99]; AHR [CRIâ â ¥â +2]â =â 0.64 [0.53â 0.78]); and 3â Vessel disease patients (AHR [CRIâ =â +1]â =â 0.94 [0.86â 1.04]; and AHR [CRIâ â ¥â +2]â =â 0.75 [0.63â 0.88]) with no impact in multiâ arterial CABG (AHR [CRIâ =â +1]â =â 1.07 [0.91â 1.26]; AHR [CRIâ â ¥â +2]â =â 0.93 [0.73â 1.17]).ConclusionsIncomplete revascularization is associated with decreased late survival, irrespective of grafting strategy. Alternatively, supraâ complete revascularization is associated with improved survival in patients with 3â Vessel CAD, and in singleâ arterial but not multiâ arterial CABG.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146364/1/jocs13810.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146364/2/jocs13810_am.pd

CD4-positive T cells and M2 macrophages dominate the peritoneal infiltrate of patients with encapsulating peritoneal sclerosis

Background Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). Previously, it has been shown that infiltrating CD4-positive T cells and M2 macrophages are associated with several fibrotic conditions. Therefore, the characteristics of the peritoneal cell infiltrate in EPS may be of interest to understand EPS pathogenesis. In this study, we aim to elucidate the composition of the peritoneal cell infiltrate in EPS patients and relate the findings to clinical outcome. Study Design, Setting, and Participants We studied peritoneal membrane biopsies of 23 EPS patients and compared them to biopsies of 15 PD patients without EPS. The cellular infiltrate was characterized by immunohistochemistry to detect T cells(CD3-positive), CD4-positive (CD4+) and CD8-positive T cell subsets, B cells(CD20-positive), granulocytes(CD15-positive), macrophages(CD68-positive), M1(CD80-positive), and M2(CD163-positive) macrophages. Tissues were analysed using digital image analysis. Kaplan-Meier survival analysis was performed to investigate the survival in the different staining groups. Results The cellular infiltrate in EPS biopsies was dominated by mononuclear cells. For both CD3 and CD68, the median percentage of area stained was higher in biopsies of EPS as opposed to non-EPS patients (p<0.001). EPS biopsies showed a higher percentage of area stained for CD4 (1.29%(0.61-3.20)) compared to CD8 (0.71%(0.46-1.01), p = 0.04), while in the non-EPS group these cells were almost equally represented (respectively 0.28% (0.05-0.83) versus 0.22%(0.17-0.43), p = 0.97). The percentage of area stained for both CD80 and CD163 was higher in EPS than in non-EPS biopsies (p<0.001), with CD163+ cells being the most abundant phenotype. Virtually no CD20-positive and CD15-positive cells were present in biopsies of a subgroup of EPS patients. No relation was found between the composition of the mononuclear cell infiltrate and clinical outcome. Conclusions A characteristic mononuclear cell infiltrate consisting of CD4+ and CD163+ cells dominates the peritoneum of EPS patients. These findings suggest a role for both CD4+ T cells and M2 macrophages in the pathogenesis of EPS

Single Versus Multi-Center Surgeons\u27 Risk-Adjusted Mitral Valve Repair Procedural Outcomes

The purpose of this study is to explore strategies to improve mitral valve repair (MVr) outcomes. This research explores postoperative outcomes of patients undergoing MVr surgery by single center surgeons versus patients of multicenter surgeons. Specific outcomes of interest include 30-day operative mortality, major operative complications (e.g., deep sternal wound infection, permanent stroke, renal dysfunction requiring dialysis, reoperation, and prolonged ventilation), length of stay, and 30-day readmissions. In brief, the serisk-adjusted outcome rates for surgeons that perform mitral valve repair procedures will be compared for surgeons that operate at a single center [i.e. SC surgeons] versus multiple centers [i.e. MC surgeons]. The overarching study hypothesis is: H(0) There will be no difference in the risk-adjusted outcome rates between surgeons that operate at a single center [i.e. SC surgeons] versus multiple centers [i.e. MC surgeons]. Based on prior research, however, it is anticipated that single center surgeons may have superior outcomes compared to multi-center surgeons

Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis

Background and Aims Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy. Approach and Results To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL(-/-)) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2(-/-)) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL(-/-) mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and beta-oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2(-/-) mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E-2 accumulation in the intestine and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation. Conclusions Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis

MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial.

PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC

Anchoring tools to communities: insights into perceptions of flood informational tools from a flood-prone community in Louisiana, USA

The lack of community-relevant flood informational resources and tools often results in inadequate and divergent understandings of flood risk and can impede communities' ability to function cohesively in the face of increasing flood threats. The current study reports on a set of workshops that the authors conducted with various groups (citizens, city engineers and planners, realtors and builders, and media representatives) within a flood prone community to evaluate how novel hydroinformatic tools that include hydrodynamic modeling, geospatial visualization, and socioeconomic analysis can enhance understanding of flood risk and engagement in flood risk mitigation among diverse community members. The workshops were designed to help identify stakeholder preferences regarding key functionality needed for integrated hydroinformatic technologies and socioeconomic analyses for flood risk reduction. Workshop participants were asked to use and comment on examples of prototype flood risk informational tools, such as: (1) flood damage estimation tool, (2) drivability and emergency accessibility tool, and (3) community-scale social and economic metrics tool. Data gathered from workshops were analyzed using qualitative analysis based on a grounded-theory approach. Data were coded by hand based on themes identified by the research team and incorporated deviant case analysis to ensure minority opinions was represented. The study results are focused on the following main themes and how flood tools can address them: (1) improving the understanding of flood risk and engagement in flood risk mitigation, (2) reducing the gap between individual and community risk, (3) challenges in communicating flood risk information, (4) enhancing relevance to and engagement of the community, and (5) enabling actionable information. Our research demonstrates the need for community-anchored tools and technologies that can illustrate local context, include local historical and simulated events at multiple levels of community impact, enable analyses by flood professionals while also providing simplified tools of use by citizens, and allow individuals to expand their knowledge beyond their homes, businesses, and places of work

ASCR/HEP Exascale Requirements Review Report

This draft report summarizes and details the findings, results, and recommendations derived from the ASCR/HEP Exascale Requirements Review meeting held in June, 2015. The main conclusions are as follows. 1) Larger, more capable computing and data facilities are needed to support HEP science goals in all three frontiers: Energy, Intensity, and Cosmic. The expected scale of the demand at the 2025 timescale is at least two orders of magnitude -- and in some cases greater -- than that available currently. 2) The growth rate of data produced by simulations is overwhelming the current ability, of both facilities and researchers, to store and analyze it. Additional resources and new techniques for data analysis are urgently needed. 3) Data rates and volumes from HEP experimental facilities are also straining the ability to store and analyze large and complex data volumes. Appropriately configured leadership-class facilities can play a transformational role in enabling scientific discovery from these datasets. 4) A close integration of HPC simulation and data analysis will aid greatly in interpreting results from HEP experiments. Such an integration will minimize data movement and facilitate interdependent workflows. 5) Long-range planning between HEP and ASCR will be required to meet HEP's research needs. To best use ASCR HPC resources the experimental HEP program needs a) an established long-term plan for access to ASCR computational and data resources, b) an ability to map workflows onto HPC resources, c) the ability for ASCR facilities to accommodate workflows run by collaborations that can have thousands of individual members, d) to transition codes to the next-generation HPC platforms that will be available at ASCR facilities, e) to build up and train a workforce capable of developing and using simulations and analysis to support HEP scientific research on next-generation systems.Comment: 77 pages, 13 Figures; draft report, subject to further revisio

Adenosine preconditioning attenuates hepatic reperfusion injury in the rat by preventing the down-regulation of endothelial nitric oxide synthase

BACKGROUND: Previous work has suggested that in the liver, adenosine preconditioning is mediated by nitric oxide. Whether the endothelial isoform of nitric oxide synthase plays a part in this mechanism has however not yet been investigated. METHODS: Wistar rats were used (6 in each group) – Groups: (1) sham, (2) ischemia-reperfusion, (3) adenosine + ischemia-reperfusion, (4) endothelial isoform inhibitor + adenosine + ischemia-reperfusion. RESULTS: Using immunohistochemistry, this study has revealed a decrease in the expression of endothelial nitric oxide synthase following hepatic ischemia-reperfusion. This was prevented by adenosine pre-treatment. When an inhibitor of endothelial nitric oxide synthase was administered prior to adenosine pre-treatment, pre-conditioning did not occur despite normal expression of endothelial nitric oxide synthase. CONCLUSIONS: These findings suggest that adenosine attenuates hepatic injury by preventing the downregulation of endothelial nitric oxide synthase that occurs during ischemia-reperfusion

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo