tbuckley/cabot-search huggingface dataset:
A multicentre randomised study of intrasphincteric botulinum toxin in patients with oesophageal achalasia
Authors: V Annese
Journal: Gut (2000)

<h3>BACKGROUND</h3> Intrasphincteric injection of botulinum toxin (Botx) has been proposed as treatment for oesophageal achalasia. However, the predictors of response and optimal dose remain unclear. <h3>AIMS</h3> To compare the effect of different doses of Botx and to identify predictors of response. <h3>PATIENTS/METHODS</h3> A total of 118 achalasic patients were randomised to receive one of three doses of Botx in a single injection: 50 U (n=40), 100 U (n=38), and 200 U (n=40). Of those who received 100 U, responsive patients were reinjected with an identical dose after 30 days. Clinical and manometric assessments were performed at baseline, 30 days after the initial injection of botulinum toxin, and at the end of follow up (mean 12 months; range 7–24 months). <h3>RESULTS</h3> Thirty days after the initial injection, 82% of patients were considered responders without a clear dose related effect. At the end of follow up however, relapse of symptoms was evident in 19% of patients who received two injections of 100 U compared with 47% and 43% in the 50 U and 200 U groups, respectively. Using Kaplan-Meier analysis, patients in the 100×2 U group were more likely to remain in remission at any time (p&lt;0.04), with 68% (95% CI 59–83) still in remission at 24 months. In a multiple adjusted model, response to Botx was independently predicted by the occurrence of vigorous achalasia (odds ratio 3.3) and the 100×2 U regimen (odds ratio 3.2). <h3>CONCLUSIONS</h3> Two injections of 100 U of Botx 30 days apart appeared to be the most effective therapeutic schedule. The presence of vigorous achalasia was the principal determinant of the response to Botx.
NFATc1 affects mouse splenic B cell function by controlling the calcineurin–NFAT signaling network
Authors: Sankar Bhattacharyya, Jolly Deb, Amiya K. Patra, Duong Anh Thuy Pham, Wen Chen, Martin Vaeth, Friederike Berberich-Siebelt, Stefan Klein-Hessling, Edward D. Lamperti, Kurt Reifenberg, Julia Jellusova, Astrid Schweizer, Lars Nitschke, Ellen Leich, Andreas Rosenwald, Cornelia Brunner, Swen Engelmann, Ursula Bommhardt, Andris Avots, Martin R. Müller, Eisaku Kondo, Edgar Serfling
Journal: The Journal of Experimental Medicine (2011)

By studying mice in which the Nfatc1 gene was inactivated in bone marrow, spleen, or germinal center B cells, we show that NFATc1 supports the proliferation and suppresses the activation-induced cell death of splenic B cells upon B cell receptor (BCR) stimulation. BCR triggering leads to expression of NFATc1/αA, a short isoform of NFATc1, in splenic B cells. NFATc1 ablation impaired Ig class switch to IgG3 induced by T cell–independent type II antigens, as well as IgG3+ plasmablast formation. Mice bearing NFATc1−/− B cells harbor twofold more interleukin 10–producing B cells. NFATc1−/− B cells suppress the synthesis of interferon-γ by T cells in vitro, and these mice exhibit a mild clinical course of experimental autoimmune encephalomyelitis. In large part, the defective functions of NFATc1−/− B cells are caused by decreased BCR-induced Ca2+ flux and calcineurin (Cn) activation. By affecting CD22, Rcan1, CnA, and NFATc1/αA expression, NFATc1 controls the Ca2+-dependent Cn–NFAT signaling network and, thereby, the fate of splenic B cells upon BCR stimulation.
Visceral Adiposity Index
Authors: Marco C. Amato, Carla Giordano, Massimo Galia, Angela Criscimanna, Salvatore Vitabile, Massimo Midiri, Aldo Galluzzo
Journal: Diabetes Care (2010)

OBJECTIVE To individuate a novel sex-specific index, based on waist circumference, BMI, triglycerides, and HDL cholesterol, indirectly expressing visceral fat function. RESEARCH DESIGN AND METHODS Visceral adiposity index (VAI) was first modeled on 315 nonobese healthy subjects. Using two multiple logistic regression models, VAI was retrospectively validated in 1,498 primary care patients in comparison to classical cardio- and cerebrovascular risk factors. RESULTS All components of metabolic syndrome increased significantly across VAI quintiles. VAI was independently associated with both cardiovascular (odd ratio [OR] 2.45; 95% CI 1.52–3.95; P &amp;lt; 0.001) and cerebrovascular (1.63; 1.06–2.50; P = 0.025) events. VAI also showed significant inverse correlation with insulin sensitivity during euglycemic-hyperinsulinemic clamp in a subgroup of patients (Rs = −0.721; P &amp;lt; 0.001). By contrast, no correlations were found for waist circumference and BMI. CONCLUSIONS Our study suggests VAI is a valuable indicator of “visceral adipose function” and insulin sensitivity, and its increase is strongly associated with cardiometabolic risk.
Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21
Authors: Frederick J Sheedy, Eva Palsson-McDermott, Elizabeth J Hennessy, Cara Martin, John J O'Leary, Qingguo Ruan, Derek S Johnson, Youhai Chen, Luke A J O'Neill
Journal: Nature Immunology (2009)
RISK FACTORS FOR SPORT INJURY IN ELEMENTARY SCHOOL CHILDREN: ARE CHILDREN WITH DEVELOPMENTAL COORDINATION DISORDER OR ATTENTION DEFICIT HYPERACTIVITY DISORDER AT GREATER RISK OF INJURY?
Authors: B Tan, R Carnduff, C McKay, J Kang, M Romiti, G Nasuti, K Hurtubise, T Jarus, L Boyd, P Doyle-Baker, B Wilson, C Emery
Journal: British Journal of Sports Medicine (2014)

Background Studies examining risk factors for sport injury in elementary school children are few. The risk of sport injury in special populations including Developmental Coordination Disorder (DCD) and Attention Deficit Hyperactivity Disorder (ADHD) has not been previously examined. Objective To examine risk factors for sport injury in elementary school students (ages 9–12), including special populations (DCD and ADHD). Design Cross-sectional study. Setting A survey was sent home with students in 26 randomly selected Calgary (Canada) elementary schools. Participants Children ages 9–12 years (n=540). Risk factor assessment The primary risk factors of interest were probable DCD (pDCD) and ADHD. Other risk factors considered included age, sex, ethnicity, highest level of parent education, stressful life events (previous year), receiving coaching in at least 1 sport, and body mass index. Main outcome measurements Injury definitions included any sport injury in the previous year and sport injury in the previous year requiring medical attention. Results Based on univariate Poisson regression (adjusted for exposure hours and cluster) the risk of all sport injury in the previous year in typically developing children did not differ from children with either pDCD (n=150, Incidence Rate Ratio (IRR=1.02 [95% CI 0.7–1.5]) or ADHD (n=87, IRR=0.94 [95% CI 0.58–1.55]). Children with ADHD were at a greater risk of sport injury requiring medical attention compared to those without ADHD (IRR: 1.82 [95% CI 1.23–2.68]). No other risk factors were identified based on univariate analysis. Conclusions Children (9–12 years) with pDCD and ADHD were at a similar risk of sport injury in the previous year as typically developing children. Children with ADHD were at an 82% greater risk of sport injury requiring medical attention than children without the disorder. This study will inform the development of injury prevention strategies for future studies in elementary school targeting children with ADHD.
The Costs of a National Health Information Network
Authors: Rainu Kaushal, David Blumenthal, Eric G. Poon, Ashish K. Jha, Calvin Franz, Blackford Middleton, John Glaser, Gilad Kuperman, Melissa Christino, Rushika Fernandopulle, Joseph P. Newhouse, David W. Bates
Journal: Annals of Internal Medicine (2005)

Background: The use of information technology may result in a safer and more efficient health care system. However, consensus does not exist about the structure or costs of a national health information network (NHIN). Objectives: To describe the potential structure and estimate the costs of an NHIN. Design: Cost estimates of an NHIN model developed by an expert panel. Setting: U.S. health care system. Measurements: An expert panel estimated the existing and the expected prevalence in 5 years of critical information technology functionalities. They then developed a model of an achievable NHIN by defining key providers, functionalities, and interoperability functions. By using these data and published cost estimates, the authors determined the cost of achieving this model NHIN in 5 years given the current state of information technology infrastructure. Results: To achieve an NHIN would cost $156 billion in capital investment over 5 years and $48 billion in annual operating costs. Approximately two thirds of the capital costs would be required for acquiring functionalities and one third for interoperability. Ongoing costs would be more evenly divided between functionality and interoperability. If the current trajectory continues, the health care system will spend $24 billion on functionalities over the next 5 years or about one quarter of the cost for functionalities of a model NHIN. Limitations: Because of a lack of primary data, the authors relied on expert estimates. Conclusions: While an NHIN will be expensive, $156 billion is equivalent to 2% of annual health care spending for 5 years. Assessments such as this one may assist policymakers in determining the level of investment that the United States should make in an NHIN.
Adenosine receptor specificity in preconditioning of isolated rabbit cardiomyocytes: evidence of A3 receptor involvement
Authors: S. Armstrong, C. E Ganote
Journal: Cardiovascular Research (1994)

The aim was to further characterise an experimental model of preconditioning of isolated rabbit cardiomyocytes and to determine the role of adenosine receptor subtypes in initiation of the protective response.Isolated myocytes were subjected to 5 min preincubation in the presence or absence of glucose and various agonists and antagonists of adenosine receptors. Ischaemic pelleting was preceded by a 30 min postincubation period. Rate and extent of injury during ischaemia was determined by sequential sampling of the pelleted cells and assessment of trypan blue permeability following 85 mOsm swelling.Myocytes were preconditioned with a 30-50% reduction of injury by a 5 min glucose-free preincubation. Substitution of 5 mM pyruvate for glucose during preincubation did not prevent the protective response. Protection was maintained over a 60-180 min postincubation period. Protection was blocked by 100 microM of the non-specific adenosine A1/A2 antagonist SPT, both when added only during preincubation or only into the ischaemic pellet. Calphostin C, a specific protein kinase C inhibitor at 200 nM, added to the ischaemic pellet blocked protection. Preincubation with R-PIA, the adenosine A1 agonist, did not precondition at an A1 selective dose of 1 microM, but did at 100 microM. The selective A2 agonist CGS 12680 (1 microM) did not precondition. The selective A1/A3 adenosine agonist, APNEA, preconditioned at 1 microM and 200 nM dose levels. Preconditioning induced either by 200 nM APNEA or by glucose-free preincubation was not blocked by 200 nM or 10 microM of the A1 antagonist DPCPX, which has extremely low affinity for A3 receptors, but was blocked by 1 microM of the A1/A3 adenosine antagonist BW 1433U83.Preconditioning can be induced in isolated myocytes by a 5 min preincubation/30 min postincubation protocol, and a similar protection induced by adenosine agonists with A3, but not A1 selectivity. Preconditioning is blocked by non-selective or selective A1/A3 adenosine antagonists and a specific protein kinase C inhibitor, but not by A1 antagonists with little affinity for A3 receptors. The results suggest that preconditioning in isolated rabbit myocytes requires participation of adenosine receptors with agonist/antagonist binding characteristics of the A3 subtype, and is likely to be mediated by activation of protein kinase C.
Incorporation of Carvedilol into PAMAM-functionalized MWNTs as a sustained drug delivery system for enhanced dissolution and drug-loading capacity
Authors: Xin Zheng, Tianyi Wang, Haitao Jiang, Yuting Li, Tongying Jiang, Jinghai Zhang, Siling Wang
Journal: Asian Journal of Pharmaceutical Sciences (2013)

The purpose of this study was to develop poly(amidoamine) (PAMAM)-functionalized multi-walled carbon nanotubes (MWNTs) loaded with a poorly water-soluble drug, intended to improve the drug-loading capacity, dissolution and design a sustained release system. MWNTs were modified with a carboxyl group by acid treatment and then complex with PAMAM. PAMAM-MWNTs were investigated as a scaffold for loading the model drug, Carvedilol (CAR), using three different methods (the fusion method, the incipient wetness impregnation method, and the solvent method). The effects of different pore size, specific surface area and physical state were systematically studied using FT-IR, TGA, SEM, DSC, nitrogen adsorption, XPS and XRD. All the samples made by PAMAM-MWNTs to load the drug had a marked effect on the drug-loading capacity as well as drug dissolution, especially the Ⅱ-30%.
Localization of sequence variations in PGC-1α influence their modifying effect in Huntington disease
Authors: Hong Van B Che, Silke Metzger, Esteban Portal, Carolin Deyle, Olaf Riess, Huu Phuc Nguyen
Journal: Molecular Neurodegeneration (2011)

Huntington disease (HD) is caused by a polyglutamine expansion of more than 35 units in the huntingtin protein. This expanded repeat length inversely correlates with the age-at-onset (AAO), however, additional genetic factors apart from the expanded CAG repeat size are thought to influence the course and the AAO in HD. Until now, among others, the gene encoding PCG-1α (PPARGC1A) was shown to modify the AAO in two independent, however small, populations. PGC-1α is involved in the induction of various mechanisms regulating mitochondrial biogenesis and oxidative stress defence. Furthermore, several studies have linked impairment of its function and/or its expression to HD pathogenesis. As the identification of distinct modifiers in association studies is largely dependent on the size of the observed population, we investigated nine different single nucleotide polymorphisms (SNPs) in PPARGC1A in order to replicate the disease modifying effect in more than 800 European HD patients and to identify an association with AAO in HD.Two SNPs, one in the promoter and one in the transcribed region of the gene, showed a significant effect on the AAO. While the minor allele of SNP rs7665116 (g.38570C), located in the transcribed gene region, was associated with a delay in disease onset, especially in HD patients with Italian ancestry, the minor allele of SNP rs2970870 (g.-1437C) in the promoter region leads to an earlier onset of HD in its homozygous state. Additionally, global testing of haplotype block 2, which covers the main part of the transcribed region of the gene, revealed an association between block 2 haplotypes and the disease onset.Therefore, our results indicate opposing modifying influences of two SNPs within one gene on AAO and support the idea that PGC-1α dysfunction is involved in HD pathology.
Nebulised hypertonic saline in bronchiolitis: take it with a pinch of salt
Authors: Steve Cunningham, Stefan Achim Unger
Journal: Thorax (2014)

Nebulised hypertonic saline is attractive as a therapy for acute viral bronchiolitis. Thick and sticky secretions in oedematous airways induce breathlessness and poor feeding as a hallmark of the disease. Loosening secretions with this simple therapy could prevent admission to hospital, or speed recovery and discharge. In a condition with no current acute therapeutic options, this would be welcome indeed.1 ,2 Hypertonic saline changes mucous rheology, and when used in cystic fibrosis, has good—if modest—effect.3

In bronchiolitis, hypertonic saline has had a promising start. Early trials demonstrated appealing benefits with reduction in length of stay by up to 25%.4 A Cochrane review, last updated in 2013, concludes with a recommendation to use hypertonic saline in bronchiolitis to reduce length of stay in hospitalised patients.5

Hypertonic Saline in acute Bronchiolitis RCT and Economic evaluation (SABRE), printed in this issue,6 is the largest reported study for the use of nebulised hypertonic saline infants hospitalised with bronchiolitis. Importantly, the study protocol challenges head on the difficulties with using a placebo control when testing a nebulised intervention. As it cannot be assumed that nebulised normal saline (0.9%) will have no clinical effect, the non-intervention arm in SABRE was the current standard of care in the UK— i.e., no regular use of epinephrine, salbutamol or 0.9% saline that were nebulised in all previous studies testing hypertonic saline in bronchiolitis. By necessity, that made the trial open label, which leaves a study open to criticism of potential confounding bias. In this case, however, the weight of evidence to date in favour of hypertonic saline and the desperate need for something to work in bronchiolitis, might suggest any anticipated bias would have been in favour of the intervention. Yet, the open label design did not favour the intervention: nebulised hypertonic saline …
12 Active immunization after liver transplantation for HBV related liver disease: Failure to induce HBV-specific humoral and cellular immune responses
Authors: J. Rosenau, N. Hooman, K. Rifai, T. Solga, H.L. Tillmann, E. Grzegowski, B. Nashan, J. Klempnauer, C. Trautwein, C. Strassburg, H. Wedemeyer, M.P. Manns
Journal: Journal of Hepatology (2004)
Autonomous growth potential of leukemia blast cells is associated with poor prognosis in human acute leukemias
Authors: Ying Yan, Eric A Wieman, Xiuqin Guan, Ann A Jakubowski, Peter G Steinherz, Richard J O'Reilly
Journal: Journal of Hematology & Oncology (2009)

We have described a severe combined immunodeficiency (SCID) mouse model that permits the subcutaneous growth of primary human acute leukemia blast cells into a measurable subcutaneous nodule which may be followed by the development of disseminated disease. Utilizing the SCID mouse model, we examined the growth potential of leukemic blasts from 133 patients with acute leukemia, (67 acute lymphoblastic leukemia (ALL) and 66 acute myeloid leukemia (AML)) in the animals after subcutaneous inoculation without conditioning treatment. The blasts displayed three distinct growth patterns: "aggressive", "indolent", or "no tumor growth". Out of 133 leukemias, 45 (33.8%) displayed an aggressive growth pattern, 14 (10.5%) displayed an indolent growth pattern and 74 (55.6%) did not grow in SCID mice. The growth probability of leukemias from relapsed and/or refractory disease was nearly 3 fold higher than that from patients with newly diagnosed disease. Serial observations found that leukemic blasts from the same individual, which did not initiate tumor growth at initial presentation and/or at early relapse, may engraft and grow in the later stages of disease, suggesting that the ability of leukemia cells for engraftment and proliferation was gradually acquired following the process of leukemia progression. Nine autonomous growing leukemia cell lines were established in vitro. These displayed an aggressive proliferation pattern, suggesting a possible correlation between the capacity of human leukemia cells for autonomous proliferation in vitro and an aggressive growth potential in SCID mice. In addition, we demonstrated that patients whose leukemic blasts displayed an aggressive growth and dissemination pattern in SClD mice had a poor clinical outcome in patients with ALL as well as AML. Patients whose leukemic blasts grew indolently or whose leukemia cells failed to induce growth had a significantly longer DFS and more favorable clinical course.
Clinical priority setting
Authors: O. F. Norheim
Journal: BMJ (2008)

Twelve years ago (<i>BMJ</i> 1996;312:1553-4) the <i>BMJ</i> argued that health systems needed to be explicit about rationing and published articles describing different ways of rationing fairly. Here a clinician, two ethicists (doi:10.1136/bmj.a1850), and four health economists (doi:10.1136/bmj.a1872) discuss how their ideas have developed—and been put into practice—since then
Pulmonary embolism: CT signs and cardiac biomarkers for predicting right ventricular dysfunction
Authors: T. Henzler, S. Roeger, M. Meyer, U.J. Schoepf, J.W. Nance, D. Haghi, W.E. Kaminski, M. Neumaier, S.O. Schoenberg, C. Fink
Journal: European Respiratory Journal (2011)

The aim of this study was to prospectively evaluate the accuracy of quantitative cardiac computed tomography (CT) parameters and two cardiac biomarkers (N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) and troponin I), alone and in combination, for predicting right ventricular dysfunction (RVD) in patients with acute pulmonary embolism. 557 consecutive patients with suspected pulmonary embolism underwent pulmonary CT angiography. Patients with pulmonary embolism also underwent echocardiography and NT-pro-BNP/troponin I serum level measurements. Three different CT measurements were obtained (right ventricular (RV)/left ventricular (LV) axial , RV/LV 4-CH and RV/LV volume ). CT measurements and NT-pro-BNP/troponin I serum levels were correlated with RVD at echocardiography. 77 patients with RVD showed significantly higher RV/LV ratios and NT-pro-BNP/troponin I levels compared to those without RVD (RV/LV axial 1.68±0.84 versus 1.00±0.21; RV/LV 4-CH 1.52±0.45 versus 1.01±0.21; RV/LV volume 1.97±0.53 versus 1.07±0.52; serum NT-pro-BNP 6,372±2,319 versus 1,032±1,559 ng·L −1 ; troponin I 0.18±0.41 versus 0.06±0.18 g·L −1 ). The area under the curve for the detection of RVD of RV/LV axial , RV/LV 4-CH , RV/LV volume , NT-pro-BNP and troponin I were 0.84, 0.87, 0.93, 0.83 and 0.70 respectively. The combination of biomarkers and RV/LV volume increased the AUC to 0.95 (RV/LV volume with NT-pro-BNP) and 0.93 (RV/LV volume with troponin I). RV/LV volume is the most accurate CT parameter for identifying patients with RVD. A combination of RV/LV volume with NT-pro-BNP or troponin I measurements improves the diagnostic accuracy of either test alone.
Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney
Authors: Ildikó Toma, Jung Julie Kang, Arnold Sipos, Sarah Vargas, Eric Bansal, Fiona Hanner, Elliott Meer, János Peti-Peterdi
Journal: Journal of Clinical Investigation (2008)

Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease in developed countries. A classic hallmark of early diabetes mellitus includes activation of the renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation is elusive. Here we identified a paracrine signaling pathway in the kidney in which high levels of glucose directly triggered the release of the prohypertensive hormone renin. The signaling cascade involved the local accumulation of succinate and activation of the kidney-specific G protein–coupled metabolic receptor, GPR91, in the glomerular endothelium as observed in rat, mouse, and rabbit kidney sections. Elements of signal transduction included endothelial Ca2+, the production of NO and prostaglandin (PGE2), and their paracrine actions on adjacent renin-producing cells. This GPR91 signaling cascade may serve to modulate kidney function and help remove metabolic waste products through renal hyperfiltration, and it could also link metabolic diseases, such as diabetes, or metabolic syndrome with RAS overactivation, systemic hypertension, and organ injury.