bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperleucocytosis in paediatric acute myeloid leukaemia – the challenge of white blood cell counts above 200 × 109/l. The NOPHO experience 1984–2014
Authors: Zeller Bernward , Glosli Heidi , Forestier Erik , Ha Shau‐Yin , Jahnukainen Kirsi , Jónsson Ólafur G. , Lausen Birgitte , Palle Josefine , Hasle Henrik , Abrahamsson Jonas ,   the NOPHO AML working group
Published: May 2017

SummaryHyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0–18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC >200 × 10/l). Eighty‐six patients (10%) had WBC 100–199 × 109/l and 57 (6%) had WBC ≥200 × 109/l. Patients with WBC ≥200 × 109/l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 × 109/l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty‐six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.
The inward rectifier current inhibitor PA‐6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models
Authors: Ji Yuan , Varkevisser Rosanne , Opacic Dragan , Bossu Alexandre , Kuiper Marion , Beekman Jet D M , Yang Sihyung , Khan Azinwi Phina , Dobrev Dobromir , Voigt Niels , Wang Michael Zhuo , Verheule Sander , Vos Marc A , van der Heyden Marcel A G 
Published: May 2017

Background and PurposeThe density of the inward rectifier current (IK1) increases in atrial fibrillation (AF), shortening effective refractory period and thus promoting atrial re‐entry. The synthetic compound pentamidine analogue 6 (PA‐6) is a selective and potent IK1 inhibitor. We tested PA‐6 for anti‐AF efficacy and potential proarrhythmia, using established models in large animals.Experimental ApproachPA‐6 was applied i.v. in anaesthetized goats with rapid pacing‐induced AF and anaesthetized dogs with chronic atrio‐ventricular (AV) block. Electrophysiological and pharmacological parameters were determined.Key ResultsPA‐6 (2.5 mg·kg−1·10 min−1) induced cardioversion to sinus rhythm (SR) in 5/6 goats and prolonged AF cycle length. AF complexity decreased significantly before cardioversion. PA‐6 accumulated in cardiac tissue with ratios between skeletal muscle : atrial muscle : ventricular muscle of approximately 1:8:21. In SR dogs, PA‐6 peak plasma levels 10 min post infusion were 5.5 ± 0.9 μM, PA‐6 did not induce significant prolongation of QTc and did not affect heart rate, PQ or QRS duration. In dogs with chronic AV block, PA‐6 did not affect QRS but lengthened QTc during the experiment, but not chronically. PA‐6 did not induce TdP arrhythmias in nine animals (0/9) in contrast to dofetilide (5/9). PA‐6 (200 nM) inhibited IK1, but not IK,ACh, in human isolated atrial cardiomyocytes.Conclusion and ImplicationsPA‐6 restored SR in goats with persistent AF and, in dogs with chronic AV block, prolonged QT intervals, without inducing TdP arrhythmias. Our results demonstrate cardiac safety and good anti‐AF properties for PA‐6.
Positive Affectivity and Fear Trajectories in Infancy: Contributions of Mother–Child Interaction Factors
Authors: Gartstein Maria A. , Hancock Gregory R. , Iverson Sydney L. 
Published: May 2017

Fear and positive emotionality were considered in a growth modeling context. Mothers, primarily Caucasian (91.9%) and of middle socioeconomic status, participated in play interactions with infants at 4 months (N = 148). Infant fear and positive affectivity were evaluated at 6, 8, 10, and 12 months of age. A linear trajectory was superior in explaining growth for parent report and observation‐based indicators of positive affectivity and parent report of fearfulness; a piecewise model explained the nonlinear growth of observation‐based fear. Responsiveness in mother–infant interactions emerged as a significant predictor of the fear trajectory, with higher sensitivity predicting lower levels of observed fear. Reciprocity, tempo, emotional tone, and intensity of mother–infant interactions also made significant contributions to temperament development; however, analyses addressing these were exploratory.
Butyrate and retinoic acid imprint mucosal-like dendritic cell development synergistically from bone marrow cells
Authors: Qiang Y , Xu J , Yan C , Jin H , Xiao T , Yan N , Zhou L , An H , Zhou X , Shao Q , Xia S 
Published: May 2017

Summary
Accumulating data show that the phenotypes and functions of distinctive mucosal dendritic cells (DCs) in the gut are regulated by retinoic acid (RA). Unfortunately, the exact role of butyrate in RA-mediated mucosal DC differentiation has not been elucidated thoroughly to date. Mucosal-like dendritic cell differentiation was completed in vitro by culturing bone marrow cells with growth factors [granulocyte–macrophage colony-stimulating factor (GM-CSF/interleukin (IL)-4], RA and/or butyrate. The phenotypes, cytokine secretion, immune functions and levels of retinal dehydrogenase of different DCs were detected using quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. The results showed that RA-induced DCs (RA-DCs) showed mucosal DC properties, including expression of CD103 and gut homing receptor α4β7, low proinflammatory cytokine secretion and low priming capability to antigen-specific CD4+ T cells. Butyrate-treated RA-DCs (Bu-RA-DCs) decreased CD11c, but increased CD103 and α4β7 expression. Moreover, the CD4+ T priming capability and the levels of retinal dehydrogenase of RA-DCs were suppressed significantly by butyrate. Thus, butyrate and retinoic acid have different but synergistic regulatory functions on mucosal DC differentiation, indicating that immune homeostasis in the gut depends largely upon RA and butyrate to imprint different mucosal DC subsets, both individually and collectively.
Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives
Authors: Costa N , Marques O , Godinho S I , Carvalho C , Leal B , Figueiredo A M , Vasconcelos C , Marinho A , Moraes-Fontes M F , Gomes da Costa A , Ponte C , Campanilho-Marques R , Cóias T , Martins A R , Viana J F , Lima M , Martins B , Fesel C 
Published: May 2017

Summary
Forkhead box P3 (FoxP3)+ regulatory T cells (Tregs) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+FoxP3+CD45RO–CD31+ recent thymic emigrant Tregs. This first component effect influenced the proportions of circulating CD4+FoxP3highCD45RO+ activated Tregs. (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive Tregs, SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs, but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg-directed therapies can be monitored more effectively when taking this distinction into account.
Tanshinone IIA ameliorates chronic arthritis in mice by modulating neutrophil activities
Authors: Zhang S , Huang G , Yuan K , Zhu Q , Sheng H , Yu R , Luo G , Xu A 
Published: May 2017

SummaryRheumatoid arthritis (RA) is a chronic immune inflammatory disease mediated by the influx of immune cells into the synovial joint space. As Tanshinone IIA (TIIA) has potent anti-oxidant and anti-inflammatory activities, we used the adjuvant-induced arthritis (AA) murine model of RA to investigate the impact of TIIA on RA and immune cell activation. The anti-arthritic activity of TIIA was investigated in an adjuvant-induced arthritis model of RA in mice. Myeloperoxidase and neutrophil elastase expression levels were assessed in ankle joints by immunohistochemistry analysis. Immune cell infiltration was evaluated in air pouch experiments. Proinflammatory cytokines expression levels were determined by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays. Neutrophil extracellular traps (NETs) were assessed by immunostaining and confocal microscopy. Treatment with TIIA alleviated cartilage erosion and neutrophil infiltration in the ankle joints of AA mice and reduced proinflammatory cytokine expression levels in sera. TIIA suppressed interleukin-6 and tumour necrosis factor-α expression and release in neutrophils and promoted neutrophil apoptosis. TIIA also inhibited the NET formation of neutrophils. Our findings demonstrated that TIIA can ameliorate RA effectively by targeting neutrophils, indicating that TIIA may act as a potential therapeutic for RA.
Level of vascular tie and its effect on functional outcome 2 years after anterior resection for rectal cancer
Authors: Kverneng Hultberg D. , Afshar A. A. , Rutegård J. , Lange M. , Haapamäki M. M. , Matthiessen P. , Rutegård M. 
Published: May 2017

AbstractAimPrevious research indicates that high tie of the inferior mesenteric artery during anterior resection for rectal cancer might be associated with an increased risk of postoperative functional disturbances. The goal of this population‐based retrospective cohort study was to further investigate that association.MethodPatients who underwent anterior resection for rectal cancer from April 2011 to September 2012 were identified through the Swedish Colorectal Cancer Registry. Bowel and urogenital function were assessed by a postal questionnaire 2 years after surgery. Information on the level of mesenteric tie and clinical variables was retrieved from the registry. The outcome was defined as any defaecatory, urinary or sexual dysfunction as reported by the patient. The association between high tie and the outcome was evaluated with multivariable logistic and linear regression with adjustment for confounders, such as sex, body mass index, comorbidity and preoperative radiation.ResultsWith a response rate of 86%, 805 patients were included in the study. Of these, 46% were operated with high tie. After adjustment for confounders, high tie did not affect the risk of faecal incontinence (OR 0.85; 95% CI 0.59–1.22), urinary incontinence (OR 0.94; 95% CI 0.63–1.41) or various aspects of sexual dysfunction (erectile dysfunction, anejaculation, dyspareunia and coital vaginal dryness). However, an association between high tie and defaecation at night was detected (OR 1.44; 95% CI 1.02–2.03).ConclusionThis study does not support that the level of vascular tie influences the risk of major defaecatory, urinary or sexual disturbances 2 years after anterior resection for rectal cancer.
Crop wild relatives range shifts and conservation in Europe under climate change
Authors: Aguirre‐Gutiérrez Jesús , van Treuren Rob , Hoekstra Roel , van Hintum Theo J.L. 
Published: May 2017

AbstractAimClimate change is expected to have a great impact on the distribution of wild flora around the world. Wild plant species are an important component of the genetic resources for crop improvement, which is especially important in face of climate change impacts. Still, many crop wild relatives (CWRs) are currently threatened in their natural habitat and are poorly represented in gene bank collections. To guide in situ conservation measures and to prioritize species for ex situ conservation, predictions are needed about future species distributions as a result of climate change.LocationEurope.MethodsUsing species occurrence data and present and future climatic information, we investigated the possible impacts of future climate change on the European distribution of a selection of CWRs red‐listed in the Netherlands using a species distribution modelling framework. The representation of the CWRs in European protected areas was investigated for the current and future climatic conditions. The models were created based on an optimistic (RCP 2.6) and pessimistic (RCP 8.5) climate change scenario.ResultsA shift in distribution range, mostly towards northern locations, was observed for all investigated species. A loss of distribution area of up to 61.10% (full dispersal assumption) and 68.91% (no dispersal) according to RCP 2.6 was observed for some species. A distribution area loss of up to 90.92% (full dispersal) and 98.36% (no dispersal) was predicted for the most affected species under the RCP 8.5. Based on the predicted distribution in protected areas, present occupation in nature reserves appeared to be no guarantee for the species’ future protection and persistence.Main conclusionsWe conclude that in situ conservation measures, ignoring the effects of climate change, will not be effective for many CWRs and that large‐scale ex situ conservation actions are needed to safeguard CWRs.
The mid‐distance dispersal optimum, evidence from a mixed‐model climate vulnerability analysis of an edaphic endemic shrub
Authors: Pérez‐García Nora , Thorne James H. , Domínguez‐Lozano Felipe 
Published: May 2017

AbstractAimPredicting accurate species responses to climate change in fragmented landscapes is challenging in conservation biogeography. We assessed the role of dispersal, including long‐distance dispersal (LDD), for the long‐term persistence of a rare plant species (Vella pseudocytisus subsp. paui) under current climate conditions and four future climate scenarios; and analysed the effect of competition for its regional survival.LocationEster Iberian system, Aragón, Spain.MethodsWe used BioMove, a linked modelling platform that integrates demographic, dispersal and competition features with biogeographic predictions of range dynamics, and whose results can inform risk assessments and conservation planning. We linked Vella's population dynamics and habitat suitability models with its well‐documented life history traits and ecological characteristics to enhance our understanding of its inherent vulnerability to dispersal, competitive interactions and climate change.ResultsWe found thresholds in the effect of long dispersal distances on population persistence, suggesting a mid‐distance optimum, which reduces mortality risk associated with the increasing proportion of LDD seeds. Moreover, increasing the proportion of LDD propagules reduces Vella's ability to compete in currently occupied and nearby unoccupied habitats by reducing the number of local recruitments.Main conclusionsWhereas LDD ability is generally assumed to be beneficial for the long‐term persistence of plant species in fragmented landscapes, our results suggest that moderate to high distances between new colonization increase the species’ dispersal‐related mortality. Higher numbers of LDD events reduce the number of local propagules in established populations, reducing regional survival for Vella. Moreover, associated range shifts of potentially better climate‐adapted competitors could prevent Vella individuals from colonizing new climatically suitable habitats. These findings can support development of more efficient conservation management strategies for establishing new population patches to mitigate population losses due to climate change. Our findings may also apply as a framework for other narrowly distributed endemic shrub species, particularly edaphic endemics.
Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity‐related metabolic disease
Authors: Abegg Kathrin , Bernasconi Lara , Hutter Melanie , Whiting Lynda , Pietra Claudio , Giuliano Claudio , Lutz Thomas A. , Riediger Thomas 
Published: May 2017

AimsGhrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand‐independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR‐IA) might be effective for the treatment of obesity‐related metabolic disease, we tested 2 novel synthetic compounds GHSR‐IA1 and GHSR‐IA2.Materials and MethodsIn functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR‐IA1 and GHSR‐IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet‐induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids.ResultsBoth compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR‐IA1 increased metabolic rate in chow‐fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR‐IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair‐fed and vehicle‐treated mice. GHSR‐IA2‐treated DIO mice showed decreased blood lipids. GHSR‐IA1 treatment markedly decreased HS in DIO mice.ConclusionsOur study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity‐related metabolic disorders including diabetes mellitus.
Deregulated expression of long non‐coding RNA UCA1 in multiple myeloma
Authors: Sedlarikova Lenka , Gromesova Barbora , Kubaczkova Veronika , Radova Lenka , Filipova Jana , Jarkovsky Jiri , Brozova Lucie , Velichova Roberta , Almasi Martina , Penka Miroslav , Bezdekova Renata , Stork Martin , Adam Zdenek , Pour Ludek , Krejci Marta , Kuglík Petr , Hajek Roman , Sevcikova Sabina 
Published: May 2017

AbstractObjectivesLong non‐coding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that are not translated into proteins. They are involved in pathogenesis of many diseases including cancer and have a potential to serve as diagnostic and prognostic markers. We aimed to investigate lncRNA expression profiles in bone marrow plasma cells (BMPCs) of newly diagnosed multiple myeloma (MM) patients in comparison to normal BMPCs of healthy donors (HD) in a three‐phase biomarker study.MethodsExpression profile of 83 lncRNA was performed by RT2 lncRNA PCR Array (Qiagen), followed by quantitative real‐time PCR using specific TaqMan non‐coding RNA assays analyzing 84 newly diagnosed MM patients and 25 HD.ResultsOur analysis revealed dysregulation of two lncRNAs; NEAT1 (sensitivity of 55.0% and specificity of 79.0%) and UCA1 (sensitivity of 85.0% and specificity of 94.7%). UCA1 levels correlated with albumin and monoclonal immunoglobulin serum levels, cytogenetic aberrations, and survival of MM patients.ConclusionOur study suggests a possible prognostic impact of UCA1 expression levels on MM patients.
Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations
Authors: Patsalos Philip N. , Zugman Miguel , Lake Charlotte , James Anthony , Ratnaraj Neville , Sander Josemir W. 
Published: May 2017

SummaryObjectiveGiven that only the free non–protein‐bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine‐epoxide and N‐desmethyl clobazam), using standardized methodology and under set conditions.MethodsThe protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein‐bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.ResultsGabapentin and pregabalin are non–protein‐bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N‐desmethyl‐clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7–74.8%).SignificanceThese data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine‐epoxide and N‐desmethyl‐clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.
Predicting dose sparing benefit and bleeding risk of pharmacokinetic‐based personalized prophylactic dosing of factor VIII products
Authors: Tegenge M. A. , Yang H. , Forshee R. A. 
Published: May 2017

BackgroundPreviously published factor VIII (FVIII) pharmacokinetic (PK)‐based dosing approaches employ fixed infusion interval with a wide dose range that may lead to increased risk of bleeding, excessive doses or decreased health‐related quality of life.AimThe objectives of the study includes (i) personalizing infusion interval in lieu of fixed infusion, (ii) constraining dose within the range of 10‐50 IU/kg and (iii) characterizing bleeding risk of PK‐based dosing in comparison with empiric standard doses.MethodsPatient demographics and PK parameters for conventional FVIII products were obtained from published literatures. Subject‐specific PK parameters were derived from FVIII activities vs time data generated through simulation.ResultsOur data indicated approximately 4%, 38%, 37% and 20% of the subjects can be dosed with infusion interval of every 24, 48, 72 and 96 hours, respectively, for maintaining a target 1 IU/dL FVIII level within the dose range of 10‐50 IU/kg. Maintaining an alternative trough value of 3 or 5 IU/dL requires more frequent infusion. The predicted median probability of bleeding risk per year was 35.7% (range, 11%‐49%) for PK‐based dosing maintaining 1 IU/dL. Predicted median bleeding risk was 37.9% (0%‐74%), 32.8% (0%‐72%) and 26.7% (0%‐70%) for standard dosing of 20, 30 and 50 IU/kg, respectively. PK‐based dosing resulted in a dose sparing benefit compared to standard dose of 30 or 50 IU/kg three times per week.ConclusionThe results of the study demonstrate the feasibility of individualizing infusion interval, restricting FVIII dose, trough and peak concentration within an acceptable range.