bluuebunny/crossref_metadata_2025 huggingface dataset:
Noninvasive biomagnetic detection of intestinal slow wave dysrhythmias in chronic mesenteric ischemia
Authors: Somarajan S. , Muszynski N. D. , Cheng L. K. , Bradshaw L. A. , Naslund T. C. , Richards W. O.
Published: April 2015

Chronic mesenteric ischemia (CMI) is a challenging clinical problem that is difficult to diagnose noninvasively. Diagnosis early in the disease process would enable life-saving early surgical intervention. Previous studies established that superconducting quantum interference device (SQUID) magnetometers detect the slow wave changes in the magnetoenterogram (MENG) noninvasively following induction of mesenteric ischemia in animal models. The purpose of this study was to assess functional physiological changes in the intestinal slow wave MENG of patients with chronic mesenteric ischemia. Pre- and postoperative studies were conducted on CMI patients using MENG and intraoperative recordings using invasive serosal electromyograms (EMG). Our preoperative MENG recordings showed that patients with CMI exhibited a significant decrease in intestinal slow wave frequency from 8.9 ± 0.3 cpm preprandial to 7.4 ± 0.1 cpm postprandial ( P < 0.01) that was not observed in postoperative recordings (9.3 ± 0.2 cpm preprandial and 9.4 ± 0.4 cpm postprandial, P = 0.86). Intraoperative recording detected multiple frequencies from the ischemic portion of jejunum before revascularization, whereas normal serosal intestinal slow wave frequencies were observed after revascularization. The preoperative MENG data also showed signals with multiple frequencies suggestive of uncoupling and intestinal ischemia similar to intraoperative serosal EMG. Our results showed that multichannel MENG can identify intestinal slow wave dysrhythmias in CMI patients.
Effect of dietary protein restriction on renal ammonia metabolism
Authors: Lee Hyun-Wook , Osis Gunars , Handlogten Mary E. , Guo Hui , Verlander Jill W. , Weiner I. David
Published: April 2015

Dietary protein restriction has multiple benefits in kidney disease. Because protein intake is a major determinant of endogenous acid production, it is important that net acid excretion change in parallel during protein restriction. Ammonia is the primary component of net acid excretion, and inappropriate ammonia excretion can lead to negative nitrogen balance. Accordingly, we examined ammonia excretion in response to protein restriction and then we determined the molecular mechanism of the changes observed. Wild-type C57Bl/6 mice fed a 20% protein diet and then changed to 6% protein developed an 85% reduction in ammonia excretion within 2 days, which persisted during a 10-day study. The expression of multiple proteins involved in renal ammonia metabolism was altered, including the ammonia-generating enzymes phosphate-dependent glutaminase (PDG) and phospho enolpyruvate carboxykinase (PEPCK) and the ammonia-metabolizing enzyme glutamine synthetase. Rhbg, an ammonia transporter, increased in expression in the inner stripe of outer medullary collecting duct intercalated cell (OMCDis-IC). However, collecting duct-specific Rhbg deletion did not alter the response to protein restriction. Rhcg deletion did not alter ammonia excretion in response to dietary protein restriction. These results indicate 1) dietary protein restriction decreases renal ammonia excretion through coordinated regulation of multiple components of ammonia metabolism; 2) increased Rhbg expression in the OMCDis-IC may indicate a biological role in addition to ammonia transport; and 3) Rhcg expression is not necessary to decrease ammonia excretion during dietary protein restriction.
Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3
Authors: Fenton Robert A. , Poulsen Søren B. , de la Mora Chavez Samantha , Soleimani Manoocher , Busslinger Meinrad , Dominguez Rieg Jessica A. , Rieg Timo
Published: April 2015

Caffeine is one of the most widely consumed behavioral substances. We have previously shown that caffeine- and theophylline-induced inhibition of renal reabsorption causes diuresis and natriuresis, an effect that requires functional adenosine A1receptors. In this study, we tested the hypothesis that blocking the Giprotein-coupled adenosine A1receptor via the nonselective adenosine receptor antagonist caffeine changes Na+/H+exchanger isoform 3 (NHE3) localization and phosphorylation, resulting in diuresis and natriuresis. We generated tubulus-specific NHE3 knockout mice (Pax8-Cre), where NHE3 abundance in the S1, S2, and S3 segments of the proximal tubule was completely absent or severely reduced (>85%) in the thick ascending limb. Consumption of fluid and food, as well as glomerular filtration rate, were comparable in control or tubulus-specific NHE3 knockout mice under basal conditions, while urinary pH was significantly more alkaline without evidence for metabolic acidosis. Caffeine self-administration increased total fluid and food intake comparably between genotypes, without significant differences in consumption of caffeinated solution. Acute caffeine application via oral gavage elicited a diuresis and natriuresis that was comparable between control and tubulus-specific NHE3 knockout mice. The diuretic and natriuretic response was independent of changes in total NHE3 expression, phosphorylation of serine-552 and serine-605, or apical plasma membrane NHE3 localization. Although caffeine had no clear effect on localization of the basolateral Na+/bicarbonate cotransporter NBCe1, pretreatment with DIDS inhibited caffeine-induced diuresis and natriuresis. In summary, NHE3 is not required for caffeine-induced diuresis and natriuresis.
Defective renal dopamine function and sodium-sensitive hypertension in adult ovariectomized Wistar rats: role of the cytochromeP-450 pathway
Authors: Di Ciano Luis A. , Azurmendi Pablo J. , Colombero Cecilia , Levin Gloria , Oddo Elisabet M. , Arrizurieta Elvira E. , Nowicki Susana , Ibarra Fernando R.
Published: April 2015

We have previously shown that ovariectomy in adult Wistar rats under normal sodium (NS) intake results in an overexpression of the total Na+-K+-ATPase (NKA) α1-subunit (Di Ciano LA, Azurmendi PJ, Toledo JE, Oddo EM, Zotta E, Ochoa F, Arrizurieta EE, Ibarra FR. Clin Exp Hypertens 35: 475–483, 2013). Upon high sodium (HS) intake, ovariectomized (oVx) rats developed defective NKA phosphorylation, a decrease in sodium excretion, and an increment in mean blood pressure (MBP). Since NKA phosphorylation is modulated by dopamine (DA), the aim of this study was to compare the intracellular response of the renal DA system leading to NKA phosphorylation upon sodium challenge in intact female (IF) and oVx rats. In IF rats, HS caused an increase in urinary DA and sodium, in NKA phosphorylation state, in cytochrome P-4504A (CYP4A) expression, and in 20-HETE production, while MBP kept normal. Blockade of the D1 receptor (D1R) with the D1-like receptor antagonist SCH 23390 in IFHS rats shifted NKA into a more dephosphorylated state, decreased sodium excretion by 50%, and increased MBP. In oVxNS rats, D1R expression was reduced and D3R expression was increased, and under HS intake sodium excretion was lower and MBP higher than in IFHS rats (both P < 0.05), NKA was more dephosphorylated than in IFHS, and CYP4A expression or 20-HETE production did not change. Blockade of D1R in oVxHS rats changed neither NKA phosphorylation state nor sodium excretion or MBP. D2R and PKCα expression did not vary among groups. The alteration of the renal DA system produced by ovariectomy could account for the defective NKA phosphorylation, the inefficient excretion of sodium load, and the development of salt-sensitive hypertension.
ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. I. Stilbene-sensitive Cl−secretion
Authors: Nanami Masayoshi , Lazo-Fernandez Yoskaly , Pech Vladimir , Verlander Jill W. , Agazatian Diana , Weinstein Alan M. , Bao Hui-Fang , Eaton Douglas C. , Wall Susan M.
Published: April 2015

Inhibition of the epithelial Na+channel (ENaC) reduces Cl−absorption in cortical collecting ducts (CCDs) from aldosterone-treated rats and mice. Since ENaC does not transport Cl−, the purpose of the present study was to explore how ENaC modulates Cl−absorption in mouse CCDs perfused in vitro. Therefore, we measured transepithelial Cl−flux and transepithelial voltage in CCDs perfused in vitro taken from mice that consumed a NaCl-replete diet alone or the diet with aldosterone administered by minipump. We observed that application of an ENaC inhibitor [benzamil (3 μM)] to the luminal fluid unmasks conductive Cl−secretion. During ENaC blockade, this Cl−secretion fell with the application of a nonselective Cl−channel blocker [DIDS (100 μM)] to the perfusate. While single channel recordings of intercalated cell apical membranes in split-open CCDs demonstrated a Cl−channel with properties that resemble the ClC family of Cl−channels, ClC-5 is not the primary pathway for benzamil-sensitive Cl−flux. In conclusion, first, in CCDs from aldosterone-treated mice, most Cl−absorption is benzamil sensitive, and, second, benzamil application stimulates stilbene-sensitive conductive Cl−secretion, which occurs through a ClC-5-independent pathway.
Porphyromonas gingivalis Periodontal Infection and Its Putative Links with Alzheimer’s Disease
Authors: Singhrao Sim K. , Harding Alice , Poole Sophie , Kesavalu Lakshmyya , Crean StJohn
Published: April 2015

Periodontal disease (PD) and Alzheimer’s disease (AD) are inflammatory conditions affecting the global adult population. In the pathogenesis of PD, subgingival complex bacterial biofilm induces inflammation that leads to connective tissue degradation and alveolar bone resorption around the teeth. In health, junctional epithelium seals the gingiva to the tooth enamel, thus preventing bacteria from entering the gingivae. Chronic PD involves major pathogens (Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) which have an immune armoury that can circumvent host’s immune surveillance to create and maintain an inflammatory mediator rich and toxic environment to grow and survive. The neurodegenerative condition, AD, is characterised by poor memory and specific hallmark proteins; periodontal pathogens are increasingly being linked with this dementing condition. It is therefore becoming important to understand associations of periodontitis with relevance to late‐onset AD. The aim of this review is to discuss the relevance of finding the keystone periodontal pathogen P. gingivalis in AD brains and its plausible contribution to the aetiological hypothesis of this dementing condition.
Counting Quadratic Nonresidues in Shifted Subsets of the Set of Quadratic Nonresidues for Primesp=4k+1
Authors: Meza-Moreno Rocío , Pineda-Ruelas Mario
Published: April 2015

Letp=4k+1be a prime number andFpthe finite field withpelements. Forx∈1,n,Nxwill denote the set of quadratic nonresidues less than or equal tox. In this work we calculate the number of quadratic nonresidues in the shifted setN(p-1)/2+a.
Requirement of Innate Immunity in Tumor-Bearing Mice Cured by Adoptive Immunotherapy Using Tumor-Draining Lymph Nodes
Authors: Ammori John , Hamzeh Khaled , Graor Hallie , Kim Julian
Published: April 2015

Background.The purpose of this study was to determine the cellular effectors of both the adoptively transferred cells and the tumor-bearing host that participate in the antitumor response to adoptive immunotherapy using culture-activated tumor-draining lymph nodes (TDLNs).Methods.TDLNs harvested from mice with 4T1 carcinoma cells were fractionated to derive the L-selectinlowsubpopulation and activatedex vivoprior toin vitrocytokine release assays and adoptive transfer into BALB/c mice bearing 3-day established subcutaneous tumors. Tumor-bearing recipients were SCID (lacking T, B, and NK cells), Rag2 deficient (lacking T and B cells), and wild-type BALB/c mice.Results.Culture-activated L-selectinlow4T1 TDLN from BALB/c mice secreted significant levels of interferon-gamma in response to 4T1 but not control tumor cellsin vitro. CD4 cells within the adoptively transferred effector cell population contributed significantly to the antitumor effectin vivo. Culture-activated L-selectinlowTDLNs from BALB/c wild-type mice were able to cure Rag2 deficient but not SCID mice bearing 4T1 subcutaneous tumors, suggesting a requirement of NK cells within the innate immune system of the tumor-bearing host during the antitumor response.Conclusions.These results identify the cellular effectors involved in tumor regression following adoptive transfer and demonstrate the requirement for intact innate immunity within the tumor-bearing host.
Efficacy of Acupuncture in Itch: A Systematic Review and Meta-Analysis of Clinical Randomized Controlled Trials
Authors: Yu Chi , Zhang Pei , Lv Zheng-Tao , Li Jing-Jing , Li Hong-Ping , Wu Cai-Hua , Gao Fang , Yuan Xiao-Cui , Zhang Jing , He Wei , Jing Xiang-Hong , Li Man
Published: April 2015

Background. Itch (pruritus) is a sensitive state that provokes the desire to scratch. It is not only a common symptom of skin diseases but it also occurs in some systemic diseases. Clinical studies on the efficacy of the acupuncture therapy in alleviating itch are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking.Objective. This systematic review aims to assess the effectiveness of acupuncture therapy for itch.Materials and Methods. A comprehensive literature search of eight databases was performed up to June 2014, and randomized controlled trials which compared acupuncture therapy and placebo acupuncture or no treatment group were identified. Accordingly, a meta-analysis was conducted.Results. This review included three articles of randomized controlled trials (RCTs) from a total of 2530 articles. The results of Meta-analysis showed that acupuncture therapy was effective to alleviate itch compared with placebo acupuncture and no treatment group.Conclusion. Based on the findings of this systematic review, we cautiously suggest that acupuncture therapy could improve the clinical efficacy of itch. However, this conclusion needs more studies on various ethnic samples to confirm our final conclusion.
Monocytic Tissue Transglutaminase in a Rat Model for Reversible Acute Rejection and Chronic Renal Allograft Injury
Authors: Zakrzewicz Anna , Atanasova Srebrena , Padberg Winfried , Grau Veronika
Published: April 2015

Acute rejection is a major risk factor for chronic allograft injury (CAI). Blood leukocytes interacting with allograft endothelial cells during acute rejection were suggested to contribute to the still enigmatic pathogenesis of CAI. We hypothesize that tissue transglutaminase (Tgm2), a multifunctional protein and established marker of M2 macrophages, is involved in acute and chronic graft rejection. We focus on leukocytes accumulating in blood vessels of rat renal allografts (Fischer‐344 to Lewis), an established model for reversible acute rejection and CAI. Monocytes in graft blood vessels overexpress Tgm2 when acute rejection peaks on day 9 after transplantation. Concomitantly, caspase‐3 is activated, suggesting that Tgm2 expression is linked to apoptosis. After resolution of acute rejection on day 42, leukocytic Tgm2 levels are lower and activated caspase‐3 does not differ among isografts and allografts. Cystamine was applied for 4 weeks after transplantation to inhibit extracellular transglutaminase activity, which did, however, not reduce CAI in the long run. In conclusion, this is the first report on Tgm2 expression by monocytes in vivo. Tgm2 may be involved in leukocytic apoptosis and thus in reversion of acute rejection. However, our data do not support a role of extracellular transglutaminase activity as a factor triggering CAI during self‐limiting acute rejection.
Diabetic Kidney Disease: Pathophysiology and Therapeutic Targets
Authors: Toth-Manikowski Stephanie , Atta Mohamed G.
Published: April 2015

Diabetes is a worldwide epidemic that has led to a rise in diabetic kidney disease (DKD). Over the past two decades, there has been significant clarification of the various pathways implicated in the pathogenesis of DKD. Nonetheless, very little has changed in the way clinicians manage patients with this disorder. Indeed, treatment is primarily centered on controlling hyperglycemia and hypertension and inhibiting the renin-angiotensin system. The purpose of this review is to describe the current understanding of how the hemodynamic, metabolic, inflammatory, and alternative pathways are all entangled in pathogenesis of DKD and detail the various therapeutic targets that may one day play a role in quelling this epidemic.
Radiation Therapy-Induced Cardiovascular Disease Treated by a Percutaneous Approach
Authors: Fiocca Luigi , Coccato Micol , Sirbu Vasile , Vassileva Angelina , Guagliumi Giulio , Musumeci Giuseppe , Terzi Amedeo , Canu Gianluca , Cerchierini Elisa , Cugola Diego , Valsecchi Orazio
Published: April 2015

We report the case of a 51-year-old woman, treated with radiotherapy at the age of two years, for a pulmonary sarcoma. Subsequently she developed severe aortic stenosis and bilateral ostial coronary artery disease, symptomatic for dyspnea (NYHA III functional class). Due to the prohibitive surgical risk, she underwent successful stenting in the right coronary artery and left main ostia with drug eluting stents and, afterwards, transcatheter aortic valve replacement with transfemoral implantation of a 23 mm Edwards SAPIEN XT valve. The percutaneous treatment was successful without complications and the patient is in NYHA II functional class at 2 years’ follow-up, fully carrying out normal daily activities.
Bioelectricity Generation in a Microbial Fuel Cell with a Self‐Sustainable Photocathode
Authors: Liu Ting , Rao Liqun , Yuan Yong , Zhuang Li
Published: April 2015

This study aims to construct an MFC with a photosynthetic algae cathode, which is maintained by self‐capturing CO2 released from the anode and utilizing solar energy as energy input. With this system, a maximum power density of 187 mW/m2 is generated when the anode off gas is piped into the catholyte under light illumination, which is higher than that of 21 mW/m2 in the dark, demonstrating the vital contribution of the algal photosynthesis. However, an unexpected maximum power density of 146 mW/m2 is achieved when the anode off gas is not piped into the catholyte. Measurements of cathodic microenvironments reveal that algal photosynthesis still takes place for oxygen production under this condition, suggesting the occurrence of CO2 crossover from anode to cathode through the Nafion membrane. The results of this study provide further understanding of the algae‐based microbial carbon capture cell (MCC) and are helpful in improving MCC performance.
Antileishmanial Effect of 5,3′-Hydroxy-7,4′-dimethoxyflavanone ofPicramnia gracilisTul. (Picramniaceae) Fruit:In VitroandIn VivoStudies
Authors: Robledo Sara M. , Cardona Wilson , Ligardo Karen , Henao Jéssica , Arbeláez Natalia , Montoya Andrés , Alzate Fernando , Pérez Juan M. , Arango Victor , Vélez Iván D. , Sáez Jairo
Published: April 2015

Species ofPicramniagenus are used in folk medicine to treat or prevent skin disorders, but only few species have been studied for biological activity and chemical composition.P. gracilisTul. is a native species from Central and South America and although its fruits are edible, phytochemical analysis or medicinal uses of this species are not known. In the search of candidates to antileishmanial drugs, this work aimed to evaluate the antileishmanial activity ofP. gracilisTul. inin vitroandin vivostudies. Only ethanolic extract of fruits showed leishmanicidal activity. The majoritarian metabolite was5,3′-hydroxy-7,4′-dimethoxyflavanoneether that exhibited high activity againstL. (V.) panamensis(EC5017.0 + 2.8 mg/mL, 53.7 μM) and low toxicity on mammalian U-937 cells, with an index of selectivity >11.8.In vivostudies showed that the flavanone administered in solution (2 mg/kg/day) or cream (2%) induces clinical improvement and no toxicity in hamsters with CL. In conclusion, this is the first report about isolation of5,3′-hydroxy-7,4′-dimethoxyflavanoneofP. gracilisTul. The leishmanicidal activity attributed to this flavanone is also reported for the first time. Finally, thein vitroandin vivoleishmanicidal activity reported here for5,3′-hydroxy-7,4′-dimethoxyflavanoneoffers a greater prospect towards antileishmanial drug discovery and development.
Protective Effect of Spironolactone on Endothelial-to-Mesenchymal Transition in HUVECs via Notch Pathway
Authors: Chen Xiao , Cai Jiejie , Zhou Xi , Chen Lingzhi , Gong Yongsheng , Gao Zhan , Zhang Huaiqin , Huang Weijian , Zhou Hao
Published: April 2015

Background: Fibrosis results in excessive buildup of extracellular matrix proteins along with abnormalities in structure and is partly derived by a process involving transforming growth factor β (TGF-β) called endothelial-to-mesenchymal transition (EndMT). We investigated whether the aldosterone receptor-blocker spironolactone could abrogate TGF-β-induced fibrosis in EndMT and the underlying mechanism. Methods: Human umbilical vein endothelial cells (HUVECs) were divided into 5 groups for treatment: blank; vehicle control; TGF-β (10 ng/ml); spironolactone (1 μM)+TGF-β; and spironolactone+TGF-β+DAPT (10 μM). Cell chemotaxis was assayed by transwell assay. The expression of CD31 and vimentin was determined by Immunofluorescence staining and western blot analysis. Notch1 protein level was detected by western blot analysis. Results: Spironolactone significantly prevented TGF-β-stimulated EndMT by down-regulate vimentin and up-regulate CD31 in HUVECs (p<0.01).It inhibited cell migration during EndMT (p<0.01). The protective effect of spironolactone against EndMT could be attenuated by blocking the Notch signal pathway with DAPT (p<0.01). Notch signaling was activated and cross-interacted with TGF-β and spironolactone in regulating EndMT in HUVECs and reversed the spironolactone-related signaling by abrogating the antifibrotic actions with decreased Notch1 protein expression (p<0.01). Conclusion: Spironolactone may have a protective role in TGF-β-induced EndMT in HUVECs mediated by the Notch signal pathway.
Telocytes in Pregnancy-Induced Physiological Liver Growth
Authors: Wang Fei , Bei Yihua , Zhao Yingying , Song Yang , Xiao Junjie , Yang Changqing
Published: April 2015

Background/Aims: We previously documented the presence of Telocytes (TCs) in liver and further indicated the potential roles of TCs in liver regeneration after hepatectomy. Pregnancy-induced liver growth, other than liver regeneration after hepatectomy, is a physiological hepatic adaption to meet the enhanced nutritional and metabolic demands. However, the possible roles of TCs in pregnancy-induced liver growth remain unknown. Methods: Pregnant mice were sacrificed at different time points (pregnancy day 0.5, 4.5, 8.5, 10.5, 12.5, 14.5, 16.5, and 18.5). The liver weight was used to evaluate the liver growth during pregnancy. Hepatocytes proliferation was determined by albumin and 5-ethynyl-2'- deoxyuridine (EdU) double immunostaining while TCs were counted by double immunolabeling for CD34/PDGFR-α. Results: Pregnancy-induced liver growth was preceded by increased proliferation of hepatocytes at pregnancy day 4.5, 8.5, 14.5 and 16.5. Furthermore, the number of TCs in liver detected by double immunolabeling for CD34/PDGFR-α was significantly increased at pregnancy day 4.5 and day 14.5, that was coincident with the occurrence of two peaks of hepatic cell proliferation during pregnancy. Conclusion: Our results suggest a possible relationship between TCs and hepatocyte proliferation in pregnancy-induced liver growth.
Calcitonin-Induced Effects on Amniotic Fluid-Derived Mesenchymal Stem Cells
Authors: Morabito Caterina , D'Alimonte Iolanda , Pierdomenico Laura , Pipino Caterina , Guarnieri Simone , Caprara Giusy A. , Antonucci Ivana , Ciccarelli Renata , Marchisio Marco , Pandolfi Assunta , Mariggiò Maria A.
Published: April 2015

Background/Aims: Mesenchymal stem cells from human amniotic fluid (huAFMSCs) can differentiate into multiple lineages and are not tumorigenic after transplantation, making them good candidates for therapeutic purposes. The aim was to determine the effects of calcitonin on these huAFMSCs during osteogenic differentiation, in terms of the physiological role of calcitonin in bone homeostasis. Methods: For huAFMSCs cultured under different conditions, we assayed: expression of the calcitonin receptor, using immunolabelling techniques; proliferation and osteogenesis, using colorimetric and enzymatic assays; intracellular Ca2+ and cAMP levels, using videomicroscopy and spectrophotometry. Results: The calcitonin receptor was expressed in proliferating and osteo-differentiated huAFMSCs. Calcitonin triggered intracellular Ca2+ increases and cAMP production. Its presence in cell medium also induced dose-dependent inhibitory effects on proliferation and increased osteogenic differentiation of huAFMSCs, as also indicated by enhancement of specific markers and alkaline phosphatase activity. Conclusions: These data show that huAFMSCs represent a potential osteogenic model to study in-vitro cell responses to calcitonin (and other members of the calcitonin family). This leads the way to the opening of new lines of research that will add new insight both in cell therapies and in the pharmacological use of these molecules.
Estimation of Detection Rates of Aneuploidy in High-Risk Pregnancy Using an Approach Based on Nuchal Translucency and Non-Invasive Prenatal Testing: A Cohort Study
Authors: Khalil Asma , Mahmoodian Negar , Kulkarni Abhijit , Homfray Tessa , Papageorghiou Aris , Bhide Amar , Thilaganathan Basky
Published: April 2015

Objectives: The aim was to investigate aneuploidy detection using an approach based on nuchal translucency (NT) and non-invasive prenatal testing (NIPT). Methods: This was a cohort study including 5,306 high-risk pregnancies with NT measurements and chorionic villus samples (CVS) tested for full karyotype. Results: The fetal karyotype was normal in 4,172 (78.6%) cases and abnormal in 1,134 (21.4%), including 1,009 with a likely clinically significant adverse outcome. Universal CVS with full karyotyping would lead to the diagnosis of all clinically significant abnormalities. A policy of relying solely on NIPT would have led to the diagnosis of 88.9% of clinically significant abnormalities. A strategy whereby NIPT is the main method, with CVS reserved for cases with NT ≥3.0 mm, would require CVS in 21.7% of cases, identify 94.8% of significant abnormalities and avoid miscarriage in 41 pregnancies compared to CVS for all. Conclusions: A policy of NIPT for increased-risk cases and CVS with full karyotype if the NT was ≥3.0 mm reduced the risk of miscarriage yet still identified 95% of clinically significant aneuploidy.
Addition of eGFR and Age Improves the Prognostic Absolute Renal Risk-Model in 1,134 Norwegian Patients with IgA Nephropathy
Authors: Knoop Thomas , Vågane Ann Merethe , Vikse Bjørn Egil , Svarstad Einar , Magnúsdóttir Bergrún Tinna , Leh Sabine , Varberg Reisæter Anna , Bjørneklett Rune
Published: April 2015

Background: Predicting outcome in individual patients with IgA nephropathy (IgAN) is difficult but important. For this purpose, the absolute renal risk (ARR) model has been developed in a French cohort to calculate the risk of end-stage renal disease (ESRD) and death. ARR (0-3) is scored in individual IgAN patients based on the presence of proteinuria ≥1 g/24 h, hypertension, and severe histopathological lesions (1 point per risk factor). We have validated the ARR model in a Norwegian cohort of IgAN patients and tested whether adding data on initial estimated glomerular filtration rate (eGFR) and age improved prediction. Methods: IgAN patients diagnosed between 1988 and 2012 were identified in the Norwegian Kidney Biopsy Registry, and endpoints were identified by record linkage with the Norwegian Renal Registry (ESRD) and the Population Registry (deaths). Results: We identified 1,134 IgAN patients. The mean duration of follow-up was 10.2 years (range 0.0 to 25.7 years). Two hundred and fifty one patients developed ESRD and there were 69 pre-ESRD deaths. The ARR model significantly stratified the IgAN cohort according to risk of ESRD/death. The inclusion of eGFR and age significantly improved the ARR prognostic model; in the receiver operator characteristics (ROC) analysis, area under the curve (AUC) at 10-years of follow-up increased from 0.79 to 0.89, p < 0.001. Conclusions: ARR is a suitable prognostic model for stratifying IgAN patients according to the risk of ESRD or death. Including initial eGFR and age in the model substantially improved its accuracy in our nationwide cohort.
A 4-Year, Open-Label, Multicenter, Randomized Trial of Genotropin® Growth Hormone in Patients with Idiopathic Short Stature: Analysis of 4-Year Data Comparing Efficacy, Efficiency, and Safety between an Individualized, Target-Driven Regimen and Standard Dosing
Authors: Counts Debra R. , Silverman Lawrence A. , Rajicic Natasa , Geffner Mitchell E. , Newfield Ron S. , Thornton Paul , Carakushansky Mauri , Escobar Oscar , Rapaport Robert , Levitsky Lynne , Rotenstein Deborah , Hey-Hadavi Judith , Wajnrajch Michael P.
Published: April 2015

Background/Aims: Growth hormone (GH) treatment regimens for children with non-GH-deficient, idiopathic short stature (ISS) have not been optimized. To compare the efficacy, efficiency, and safety of an individualized, target-driven GH regimen with standard weight-based dosing after 4 years of treatment. Methods: This is a 4-year, open-label, multicenter, randomized trial comparing individualized, formula-based dosing of Genotropin® versus a widely used ISS dose of Genotropin®. Subjects were prepubertal, had a bone age of 3-10 years for males and 3-9 years for females, were naive to GH treatment, and had a height standard deviation score (Ht SDS) of -3 to -2.25, a height velocity <25th percentile for their bone age, and peak stimulated GH >10 ng/ml. After the first 2 years, the individualized-dosing group was further randomized to either 0.18 or 0.24 mg/kg/week. Results: At 4 years, subjects in all treatment regimens achieved similar average height gains of +1.3 SDS; however, the individualized dosing regimen utilized less GH to achieve an equivalent height gain. Conclusion: Individualized, formula-based GH dosing, followed by a dose reduction after 2 years, provides a more cost-effective growth improvement in patients with ISS than currently employed weight-based regimens.
The Identification of Stenotrophomonas maltophilia Contamination in Ultrasound Endoscopes and Reproduction of Decontamination Failure by Deliberate Soiling Tests
Authors: Stigt Jos A. , Wolfhagen Maurice J. , Smulders Patricia , Lammers Vera
Published: April 2015

Background: An outbreak of Stenotrophomonas maltophilia was observed in the cultures of bronchial aspirations. After systematic culturing of the scopes and reprocessing the equipment, it turned out to be a pseudo-outbreak caused by a failure of the disinfector to sterilize ultrasound scopes, subsequently resulting in cross infection of the bronchoscopes via the connecting tubes in the dryer. Objectives: To support the above-mentioned findings and to show how different variables influence the decontamination process. Methods: The ultrasound scopes were deliberately contaminated with test soil and subsequently disinfected with peracetic acid (PAA), glutaraldehyde (GA) and hot water. Cultures were taken immediately after disinfection and after 4 days in the drying cabinet. Results: After disinfection with PAA, persistent contamination was observed in the endobronchial ultrasound scope, and after disinfection with PAA and prolonged storage in the drying cabinet, contamination of the endoscopic ultrasound scope persisted. All ultrasound scopes were effectively disinfected with GA. Conclusion: It is concluded that disinfection with PAA fails to decontaminate the small channels of the ultrasound scopes. Prolonged storage in humid conditions seems to enhance the outgrowth of microorganisms. By reassignment of all endoscopes to fixed locations in the drying cabinet, by using disposable connector tubes for the balloon channels, and by using GA instead of PAA, the reprocessing procedure in our hospital was corrected effectively.
High Titer Anti-Basement Membrane Antibodies in a Subset of Patients with Pediatric Systemic Lupus Erythematosus
Authors: Orjuela Alvaro , Suwanichkul Adisak , Canter Debra , Minard Charles G. , Devaraj Sridevi , Hicks M. John , Muscal Eyal , Wenderfer Scott E.
Published: April 2015

Background/Aims: There is a critical need for more noninvasive biomarkers to identify nephritis in patients with systemic lupus erythematosus (SLE). Recent studies in a model mouse and an adult SLE patient cohort suggest that anti-basement membrane antibody levels correlate well with lupus activity and kidney injury. The purpose of this study was to assess the anti-basement membrane reactivity in pediatric SLE (pSLE) patients with or without nephritis. Methods: Auto-antibodies to basement membrane antigens were assessed using an anti-matrigel ELISA. Endpoint titers were measured in pSLE patients and healthy children, as well as in autoimmune and non-immune mice, with good reproducing capabilities. Findings were also analyzed with respect to the presence or absence of nephritis, dsDNA antibodies, and other manifestations of pSLE. Results: MRL/lpr mice developed high-titer anti-matrigel antibodies, whereas C57BL/6 mice did not. In a cohort of 21 pSLE patients and 22 pediatric controls, high-titer anti-matrigel IgG, IgM and IgA antibody levels were specific for pSLE. High-titer anti-matrigel IgG3 levels could distinguish with good sensitivity the 13 pSLE patients with a history of nephritis from the 8 non-renal pSLE patients. High-titer anti-matrigel IgG, IgA, IgM or IgG3 did not correlate with positive anti-double stranded DNA, but defined an overlapping subset of patients. Conclusion: The addition of anti-basement membrane antibody testing to serologic testing in pSLE may help to monitor disease activity or to define important subsets of patients with risks for specific disease manifestations.
PTEN expression in endothelial cells is down-regulated by uPAR to promote angiogenesis
Authors: Unseld Matthias , Chilla Anastasia , Pausz Clemens , Mawas Rula , Breuss Johannes , Zielinski Christoph , Schabbauer Gernot , Prager Gerald
Published: April 2015

The tumour suppressor phosphatase and tensin homologue (PTEN), mutated or lost in many human cancers, is a major regulator of angiogenesis. However, the cellular mechanism of PTEN regulation in endothelial cells so far remains elusive. Here, we characterise the urokinase receptor (uPAR, CD87) and its tumour-derived soluble form, suPAR, as a key molecule of regulating PTEN in endothelial cells. We observed uPAR-deficient endothelial cells to express enhanced PTEN mRNA- and protein levels. Consistently, uPAR expression in endogenous negative uPAR cells, down-regulated PTEN and activated the PI3K/Akt pathway. Additionally, we found that integrin adhesion receptors act as trans-membrane signaling partners for uPAR to repress PTEN transcription in a NF-κB-dependent manner. Functional in vitro assays with endothelial cells, derived from uPAR-deficient and PTEN heterozygous crossbred mice, demonstrated the impact of uPAR- dependent PTEN regulation on cell motility and survival. In an in vivo murine angiogenesis model uPAR-deficient PTEN heterozygous animals increased the impaired angiogenic phenotype of uPAR knockout mice and were able to reverse the high invasive potential of PTEN heterozygots. Our data provide first evidence that endogenous as well as exogenous soluble uPAR down-regulated PTEN in endothelial cells to support angiogenesis. The uPAR-induced PTEN regulation might represent a novel target for drug interference, and may lead to the development of new therapeutic strategies in anti-angiogenic treatment.
Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease
Authors: Vranckx Pascal , Leebeek Frank , Tijssen Jan , Koolen Jacques , Stammen Francis , Herman Jean-Paul , de Winter Robbert , van t Hof Arnout , Backx Bianca , Lindeboom Wietze , Kim So-Young , Kirsch Bodo , van Eickels Martin , Misselwitz Frank , Verheugt Freek
Published: April 2015

Patients on rivaroxaban requiring percutaneous coronary intervention (PCI) represent a clinical conundrum. We aimed to investigate whether rivaroxaban, with or without an additional bolus of unfractionated heparin (UFH), effectively inhibits coagulation activation during PCI. Stable patients (n=108) undergoing elective PCI and on stable dual antiplatelet therapy were randomised (2:2:2:1) to a short treatment course of rivaroxaban 10 mg (n=30), rivaroxaban 20 mg (n=32), rivaroxaban 10 mg plus UFH (n=30) or standard peri-procedural UFH (n=16). Blood samples for markers of thrombin generation and coagulation activation were drawn prior to and at 0, 0.5, 2, 6–8 and 48 hours (h) after start of PCI. In patients treated with rivaroxaban (10 or 20 mg) and patients treated with rivaroxaban plus heparin, the levels of prothrombin fragment 1 + 2 at 2 h post-PCI were 0.16 [0.1] nmol/l (median) [interquartile range, IQR] and 0.17 [0.2] nmol/l, respectively. Thrombin–antithrombin complex values at 2 h post-PCI were 3.90 [6.8] μg/l and 3.90 [10.1] μg/l, respectively, remaining below the upper reference limit (URL) after PCI and stenting. This was comparable to the control group of UFH treatment alone. However, median values for thrombin–antithrombin complex passed above the URL with increasing tendency, starting at 2 h post-PCI in the UFH-alone arm but not in rivaroxaban-treated patients. In this exploratory trial, rivaroxaban effectively suppressed coagulation activation after elective PCI and stenting.

Clinical trial registration: Clinical Trials.gov Identifier: NCT01442792 URL: EudraCT. Unique identifier: No: 2011–001094–58.
Endothelial Alpha-Parvin Controls Integrity of Developing Vasculature and Is Required for Maintenance of Cell–Cell Junctions
Authors: Fraccaroli Alessia , Pitter Bettina , Taha Abdallah Abu , Seebach Jochen , Huveneers Stephan , Kirsch Julian , Casaroli-Marano Ricardo P. , Zahler Stefan , Pohl Ulrich , Gerhardt Holger , Schnittler Hans-J. , Montanez Eloi
Published: April 2015

Rationale:

Angiogenesis and vessel integrity depend on the adhesion of endothelial cells (ECs) to the extracellular matrix and to adjacent ECs. The focal adhesion protein α-parvin (α-pv) is essential for vascular development. However, the role of α-pv in ECs in vivo is not known.

Objective:

To determine the function of α-pv in ECs during vascular development in vivo and the underlying mechanisms.

Methods and Results:

We deleted the
α-pv
gene specifically in ECs of mice to study its role in angiogenesis and vascular development. Here, we show that endothelial-specific deletion of α-pv in mice results in late embryonic lethality associated with hemorrhages and reduced vascular density. Postnatal-induced EC-specific deletion of α-pv leads to retinal hypovascularization because of reduced vessel sprouting and excessive vessel regression. In the absence of α-pv, blood vessels display impaired VE-cadherin junction morphology. In vitro, α-pv–deficient ECs show reduced stable adherens junctions, decreased monolayer formation, and impaired motility, associated with reduced formation of integrin-mediated cell–extracellular matrix adhesion structures and an altered actin cytoskeleton.

Conclusions:

Endothelial α-pv is essential for vessel sprouting and for vessel stability.
Health Literacy and Mortality: A Cohort Study of Patients Hospitalized for Acute Heart Failure
Authors: McNaughton Candace D. , Cawthon Courtney , Kripalani Sunil , Liu Dandan , Storrow Alan B. , Roumie Christianne L.
Published: April 2015

Background

More than 30% of patients hospitalized for heart failure are rehospitalized or die within 90 days of discharge. Lower health literacy is associated with mortality among outpatients with chronic heart failure; little is known about this relationship after hospitalization for acute heart failure.

Methods and Results

Patients hospitalized for acute heart failure and discharged home between November 2010 and June 2013 were followed through December 31, 2013. Nurses administered the Brief Health Literacy Screen at admission; low health literacy was defined as Brief Health Literacy Screen
≤
9. The primary outcome was all‐cause mortality. Secondary outcomes were time to first rehospitalization and, separately, time to first emergency department visit within 90 days of discharge. Cox proportional hazards models determined their relationships with health literacy, adjusting for age, gender, race, insurance, education, comorbidity, and hospital length of stay. For the 1379 patients, average age was 63.1 years, 566 (41.0%) were female, and 324 (23.5%) had low health literacy. Median follow‐up was 20.7 months (interquartile range 12.8 to 29.6 months), and 403 (29.2%) patients died. Adjusted hazard ratio for death among patients with low health literacy was 1.32 (95%
CI
1.05, 1.66,
P
=0.02) compared to Brief Health Literacy Screen >9. Within 90 days of discharge, there were 415 (30.1%) rehospitalizations and 201 (14.6%) emergency department visits, with no evident association with health literacy.

Conclusions

Lower health literacy was associated with increased risk of death after hospitalization for acute heart failure. There was no evident relationship between health literacy and 90‐day rehospitalization or emergency department visits.
Lexicalization and Generative Power in CCG
Authors: Kuhlmann Marco , Koller Alexander , Satta Giorgio
Published: April 2015

The weak equivalence of Combinatory Categorial Grammar (CCG) and Tree-Adjoining Grammar (TAG) is a central result of the literature on mildly context-sensitive grammar formalisms. However, the categorial formalism for which this equivalence has been established differs significantly from the versions of CCG that are in use today. In particular, it allows restriction of combinatory rules on a per grammar basis, whereas modern CCG assumes a universal set of rules, isolating all cross-linguistic variation in the lexicon. In this article we investigate the formal significance of this difference. Our main result is that lexicalized versions of the classical CCG formalism are strictly less powerful than TAG.
Efficient Global Learning of Entailment Graphs
Authors: Berant Jonathan , Alon Noga , Dagan Ido , Goldberger Jacob
Published: April 2015

Entailment rules between predicates are fundamental to many semantic-inference applications. Consequently, learning such rules has been an active field of research in recent years. Methods for learning entailment rules between predicates that take into account dependencies between different rules (e.g., entailment is a transitive relation) have been shown to improve rule quality, but suffer from scalability issues, that is, the number of predicates handled is often quite small. In this article, we present methods for learning transitive graphs that contain tens of thousands of nodes, where nodes represent predicates and edges correspond to entailment rules (termed entailment graphs). Our methods are able to scale to a large number of predicates by exploiting structural properties of entailment graphs such as the fact that they exhibit a “tree-like” property. We apply our methods on two data sets and demonstrate that our methods find high-quality solutions faster than methods proposed in the past, and moreover our methods for the first time scale to large graphs containing 20,000 nodes and more than 100,000 edges.
A Statistical Parsing Framework for Sentiment Classification
Authors: Dong Li , Wei Furu , Liu Shujie , Zhou Ming , Xu Ke
Published: April 2015

We present a statistical parsing framework for sentence-level sentiment classification in this article. Unlike previous works that use syntactic parsing results for sentiment analysis, we develop a statistical parser to directly analyze the sentiment structure of a sentence. We show that complicated phenomena in sentiment analysis (e.g., negation, intensification, and contrast) can be handled the same way as simple and straightforward sentiment expressions in a unified and probabilistic way. We formulate the sentiment grammar upon Context-Free Grammars (CFGs), and provide a formal description of the sentiment parsing framework. We develop the parsing model to obtain possible sentiment parse trees for a sentence, from which the polarity model is proposed to derive the sentiment strength and polarity, and the ranking model is dedicated to selecting the best sentiment tree. We train the parser directly from examples of sentences annotated only with sentiment polarity labels but without any syntactic annotations or polarity annotations of constituents within sentences. Therefore we can obtain training data easily. In particular, we train a sentiment parser, s.parser, from a large amount of review sentences with users' ratings as rough sentiment polarity labels. Extensive experiments on existing benchmark data sets show significant improvements over baseline sentiment classification approaches.
Evaluating Human Pairwise Preference Judgments
Authors: Dras Mark
Published: April 2015

Human evaluation plays an important role in NLP, often in the form of preference judgments. Although there has been some use of classical non-parametric and bespoke approaches to evaluating these sorts of judgments, there is an entire body of work on this in the context of sensory discrimination testing and the human judgments that are central to it, backed by rigorous statistical theory and freely available software, that NLP can draw on. We investigate one approach, Log-Linear Bradley-Terry models, and apply it to sample NLP data.
Improved Spread–Error Relationship and Probabilistic Prediction from the CFS-Based Grand Ensemble Prediction System
Authors: Abhilash S. , Sahai A. K. , Borah N. , Joseph S. , Chattopadhyay R. , Sharmila S. , Rajeevan M. , Mapes B. E. , Kumar A.
Published: April 2015

This study describes an attempt to overcome the underdispersive nature of single-model ensembles (SMEs). As an Indo–U.S. collaboration designed to improve the prediction capabilities of models over the Indian monsoon region, the Climate Forecast System (CFS) model framework, developed at the National Centers for Environmental Prediction (NCEP-CFSv2), is selected. This article describes a multimodel ensemble prediction system, using a suite of different variants of the CFSv2 model to increase the spread without relying on very different codes or potentially inferior models. The SMEs are generated not only by perturbing the initial condition, but also by using different resolutions, parameters, and coupling configurations of the same model (CFS and its atmosphere component, the Global Forecast System). Each of these configurations was created to address the role of different physical mechanisms known to influence error growth on the 10–20-day time scale. Last, the multimodel consensus forecast is developed, which includes ensemble-based uncertainty estimates. Statistical skill of this CFS-based Grand Ensemble Prediction System (CGEPS) is better than the best participating SME configuration, because increased ensemble spread reduces overconfidence errors.