bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanistic reasoning and informed consent
Authors: Kennedy Ashley , Malanowski Sarah 
Published: August 2018

AbstractEvidence‐based medicine (EBM) proponents have argued that mechanistic evidence concerning medical treatments should be considered secondary to evidence derived from randomized controlled trials (RCTs). One common criticism of RCTs is that they often do not yield results that are generalizable to clinical practice, and that for clinical practice application, mechanistic evidence is needed. However, proponents of EBM have argued that mechanistic reasoning is often unreliable and thus not very useful. Here we suggest an important role of mechanistic explanation that has been left out of this discussion entirely, namely, its importance in a patient’s decision of whether or not to take certain drugs. We argue that in certain cases, knowing how a treatment works is just as important for the patient as knowing whether it does. In this paper, we explore how and why giving patients mechanistic information can be an important factor in obtaining informed consent for medical treatment, focusing on the example case of hormonal contraceptives.
Mesenchymal COX2‐PG secretome engages NR4A‐WNT signalling axis in haematopoietic progenitors to suppress anti‐leukaemia immunity
Authors: Wu Limei , Amarachintha Surya , Xu Jian , Oley Frank , Du Wei 
Published: August 2018

SummaryThe bone marrow (BM) microenvironment (niche) plays important roles in supporting normal/abnormal haematopoiesis. We investigated the interaction between leukaemic mesenchymal niche and haematopoietic stem and progenitor cells (HSPCs) using the model of Fanconi anaemia (FA), a genetic disorder characterized by BM failure and leukaemia. Healthy donor HSPCs co‐cultured on mesenchymal stromal cells (MSCs) derived from FA patients with acute myeloid leukaemia (AML) exhibited higher human engraftment and myeloid expansion in Non‐obese diabetic severe combined immunodeficiency IL‐2γ−/−/SGM3 recipients. Untargeted metabolomics analysis revealed the progressively elevated prostaglandins (PGs) in the MSCs of FA patients with myelodysplastic syndromes (MDS) and AML. Reduced secretion of PGs subsequent to inflammatory cyclooxygenase 2 (COX2) inhibition ameliorated HSPC/myeloid expansion. Transcriptome analysis demonstrated dysregulation of genes involved in the NR4A family of transcription factors (TFs) and WNT/β‐catenin signalling pathway in FA‐AML‐MSC‐co‐cultured‐CD34+ cells. COX2 inhibition led to significantly decreased NR4A TFs and WNT signalling genes expression. Mechanistically, NR4A1 and NR4A2 synergistically activate the CTNNB1 gene promoter . Knocking down CTNNB1 or NR4A1 in AML‐MSC‐co‐cultured‐CD34+ cells increased leukaemia‐reactive T‐effector cells production and rescued anti‐leukaemia immunity. Together, these findings suggest that specific interactions between leukaemic mesenchymal niche and HSPCs orchestrate a novel COX2/PG‐NR4A/WNT signalling axis, connecting inflammation, cellular metabolism and cancer immunity.
Subjective Well‐Being Decreasing With Age: New Research on Children Over 8
Authors: Casas Ferran , González‐Carrasco Mònica 
Published: August 2018

An increasing number of scientific publications have provided data from different countries suggesting subjective well‐being (SWB) continuously decreases during adolescence. A review of these publications reveals authors have used dissimilar scales in diverse countries. Using data from the international Children's Worlds project (N = 48,040), involving 15 countries, a comparative analysis was performed to determine how mean scores evolve with different SWB scales from the age of 8 onwards. The results support the hypothesis that the tendency of SWB to decrease with age starts at around 10 years of age in most countries, while also confirming that different psychometric scales display different levels of sensitivity to diverse sociocultural contexts and more than one should be used in any research on children and adolescents’ SWB.
Effect of two recombinant Trichinella spiralis serine protease inhibitors on TNBS-induced experimental colitis of mice
Authors: Xu J , Wu L , Yu P , Liu M , Lu Y 
Published: August 2018

Summary
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease (CD), is a chronic autoimmune disease. Parasitic infections and their products have been shown to have protective effects on autoimmune diseases, including IBD. In this experiment, 96 male BALB/c mice aged 6–8 weeks were divided randomly into two large groups: prevention and therapy. The changes in the various indicators of colitis were detected to demonstrate that Trichinella spiralis serine protease inhibitors can relieve the inflammatory severity of 2,4,6-trinitrobenzenesulphonic acid solution (TNBS)-induced colitis and to explore possible immunological mechanisms. Results showed that the disease activity index (DAI) score, myeloperoxidase (MPO) activity, macroscopic and microscopic damage degrees of colon all decreased significantly, interferon (IFN)-γ expression decreased, interleukin (IL)-4 expression increased, nuclear factor kappa B (NF)-κB expression decreased and the percentage of CD4+CD25+forkhead box protein 3 (FoxP3+) regulatory T cells (Treg) cells in the spleen. MLN increased significantly compared to the phosphate-buffered saline (PBS)/2,4,6-trinitrobenzenesulphonic acid solution (TNB) group. We found the same results with the T. spiralis Kazal-type serine protease inhibitors (TsKaSPI)+TNBS and TsAdSPI+TNBS groups in the large prevention group and the large therapy group, compared to the TNBS+PBS group with the TNBS+TsKaSPI and TNBS+TsAdSPI groups. Immunization with TsKaSPI and TsAdSPI on the CD models showed an intervention effect, possibly because TsKaSPI and TsAdSPI induced a T helper type 2 (Th2)-type immune response and balanced the TNBS-induced Th1-type immune response.
Serum exosomes of chronic gastritis patients infected withHelicobacter pylorimediate IL-1α expression via IL-6 trans-signalling in gastric epithelial cells
Authors: Chen Y , Wang X , Yu Y , Xiao Y , Huang J , Yao Z , Chen X , Zhou T , Li P , Xu C 
Published: August 2018

SummaryEmerging evidence has linked the exosomes to many immunological disorders, including infectious diseases. However, knowledge regarding the role of exosomes in Helicobacter pylori infection is limited. Here, we show that serum exosomes from chronic gastritis patients with H. pylori infection (Hp exosomes) stimulate the expression of the soluble interleukin (IL)-6 receptor (sIL-6R), which is involved in IL-6 trans-signalling in gastric epithelial cells. Interestingly, sIL-6R up-regulates expression of the proinflammatory cytokine IL-1α, and the neutralization of sIL-6R suppresses IL-1α secretion. Thus, Hp exosomes regulate IL-1α expression via sIL-6R-mediated IL-6 trans-signaling. Altogether, this study reveals a novel perspective in which exosomes play a vital role in immunological mechanisms during H. pylori infection.
The benefits of adding metformin to tamoxifen to protect the endometrium—A randomized placebo‐controlled trial
Authors: Davis Susan R. , Robinson Penelope J. , Jane Fiona , White Shane , Brown Kristy A. , Piessens Sofie , Edwards Andrew , McNeilage Jane , Woinarski Jillian , Chipman Mitchell , Bell Robin J. 
Published: August 2018

SummaryBackgroundWe investigated whether metformin prevents tamoxifen‐induced endometrial changes and insulin resistance (IR) after a diagnosis of breast cancer.MethodsThis was a single‐centre, randomized, double‐blind, placebo‐controlled, parallel group trial. Postmenopausal women with hormone receptor‐positive breast cancer taking tamoxifen were randomly allocated to metformin 850 mg or identical placebo, twice daily, for 52 weeks. Outcome measures included double endometrial thickness (ET) measured by transvaginal ultrasound, fasting insulin, glucose and IR estimated by the homeostasis model of assessment (HOMA‐IR).ResultsA total of 112 women were screened and 102 randomized. Results are presented as median (range). The 101 women who took at least one dose of medication were aged 56 (43‐72) years, with 5(0.5‐28) years postmenopause, and had taken tamoxifen for 28.9 (0‐367.4) weeks. The baseline ET was 2.9 mm (1.4‐21.9) for the placebo group (n = 52) and 2.5 mm (1.3‐14.8) for the metformin group (n = 50). At 52 weeks, the median ET was statistically significantly lower for the metformin (n = 36) than for the placebo group (n = 45) (2.3 mm (1.4‐7.8) vs 3.0 (1.2‐11.3); P = 0.05). 13.3% allocated to placebo had an ET greater than 4 mm vs 5.7% for metformin (P = 0.26). There was no endometrial atypia or cancer. Compared with placebo, metformin resulted in significantly greater baseline‐adjusted reductions in weight (P < 0.001), waist circumference (0.03) and HOMA‐IR (P < 0.001).ConclusionsMetformin appears to inhibit tamoxifen‐induced endometrial changes and has favourable metabolic effects. Further research into the adjuvant use of metformin after breast cancer and to prevent EH and cancer is warranted.
Identification of novel immune‐relevant drug target genes for Alzheimer's Disease by combining ontology inference with network analysis
Authors: Han Zhi‐Jie , Xue Wei‐Wei , Tao Lin , Zhu Feng 
Published: August 2018

AbstractAimsAlzheimer's disease (AD) is one of the leading causes of death in elderly people. Its pathogenesis is greatly associated with the abnormality of immune system. However, only a few immune‐relevant AD drug target genes have been discovered up to now, and it is speculated that there are still many potential drug target genes of AD (at least immune‐relevant genes) to be discovered. Thus, this study was designed to identify novel AD drug target genes and explore their biological properties.MethodsA combinatorial approach was adopted for the first time to discover AD drug targets by collectively considering ontology inference and network analysis. Moreover, a novel strategy limiting the distance of reasoning and in turn reducing noise interference was further proposed to improve inference performance. Potential AD drug target genes were discovered by integrating information of multiple popular databases (TTD, DrugBank, PharmGKB, AlzGene, and BioGRID). Then, the enrichment analyses of the identified drug targets genes based on nine well‐known pathway‐related databases were conducted to explore the function of the identified potential drug target genes.ResultsEighteen potential drug target genes were finally identified, and 13 of them had been reported to be closely associated with AD. Enrichment analyses of these identified drug target genes, based on nine pathway‐related databases, revealed that the enriched terms were primarily focus on immune‐relevant biological processes. Four of those identified drug target genes are involved in the classical complement pathway and process of antigen presenting.ConclusionThe well‐reproducible results showed the good performance of the combinatorial approach, and the remaining five new targets could be a good starting point for our understanding of the pathogenesis and drug discovery of AD. Moreover, this study supported validity of the combinatorial approach integrating ontology inference with network analysis in the discovery of novel drug target for neurological diseases.
Long noncoding RNA HOTAIR promotes renal cell carcinoma malignancy through alpha‐2, 8‐sialyltransferase 4 by sponging microRNA‐124
Authors: Pan Yue , Wu Yongjin , Hu Jialei , Shan Yujia , Ma Jia , Ma Huipeng , Qi Xia , Jia Li 
Published: August 2018

AbstractObjectivesAccumulating evidence demonstrated that the long noncoding RNA (lncRNA) HOTAIR (Hox transcript antisense intergenic RNA) plays key role in renal cell carcinoma (RCC) malignancy, while microRNA‐124 (miR‐124) is a tumour suppressor in RCC. The aim of this work was to assess the biological function of HOTAIR and to explore underlying mechanism involved in HOTAIR/miR‐124/alpha‐2, 8‐sialyltransferase 4 (ST8SIA4) axis‐regulated progression in RCC.Materials and methodsReal‐time PCR analyses and western blots were performed to the levels of HOTAIR, miR‐124 and ST8SIA4 expression in human RCC tissues and RCC cell lines (ACHN and 786‐O). Bioinformatics analysis and dual‐luciferase reporter assay were used to illustrate relationship between HOTAIR and miR‐124 in RCC. Colony formation assays, EdU assays, Ki67 assays and apoptosis assays were taken to evaluate cell proliferation. Tumour xenograft was created to explore the functions of HOTAIR and ST8SIA4 in tumorigenesis in vivo. Migration assays, invasion assays and cell adhesion assays and were also taken to analyse the carcinoma progression.ResultsIn this study, HOTAIR level was confirmed to be significantly upregulated in RCC samples and RCC cell lines compared with those in the paired adjacent tissues and normal renal cell line. Overexpression of HOTAIR promoted the capability of proliferation, migration and invasion in RCC cell lines. HOTAIR directly bound to miR‐124, while miR‐124 mediated the expression of ST8SIA4 in RCC cell lines. ST8SIA4 was upregulated in RCC tissues and RCC cell lines. Ectopic expression of ST8SIA4 modulated the proliferation, migration and invasion of RCC cells. Further results indicated that HOTAIR promoted the proliferation and metastasis as a competing endogenous RNA to regulate ST8SIA4 expression by sponging miR‐124 in RCC.ConclusionsOur results demonstrated that HOTAIR mediated RCC progression in part through miR‐124/ST8SIA4 axis, which functioned as a new prognostic biomarker in RCC.
Diastolic dysfunction in tetralogy of Fallot: Comparison of echocardiography with catheterization
Authors: DiLorenzo Michael , Hwang Wei‐Ting , Goldmuntz Elizabeth , Ky Bonnie , Mercer‐Rosa Laura 
Published: August 2018

BackgroundRight ventricular (RV) systolic dysfunction has been associated with adverse outcomes in tetralogy of Fallot (TOF). However, the role and etiology of diastolic dysfunction remain incompletely defined. We assessed the association between traditional echocardiographic measures of diastolic function with catheter‐based RV end‐diastolic pressure (RVEDP) and identified clinical characteristics independently associated with diastolic dysfunction.MethodsSingle‐center, retrospective cohort study of surgically repaired TOF patients undergoing cardiac catheterization with echocardiograms within 3 months prior to the catheterization. Tricuspid inflow and tissue Doppler measurements (E/A, E/e′, and deceleration time) defined diastolic dysfunction, graded as impaired relaxation, pseudonormal, or restrictive physiology. Regression analyses tested associations between echocardiographic parameters, RVEDP, and clinical characteristics.ResultsNinety‐four subjects were included. Catheterization age was 8.9 years (interquartile range 4.4, 15.9). RVEDP was 9.5 ± 2.5 mm Hg. Sixty‐one (65%) subjects had echocardiographic evidence of diastolic dysfunction. RVEDP was not associated with echocardiographic parameters of diastolic function (grade of dysfunction, E/e′, or E/A). Higher RVEDP was associated with larger right atrial and RV end‐diastolic area, independently of weight and degree of pulmonary or tricuspid regurgitation, though was not associated with indexed right atrial or RV end‐diastolic area. Greater number of interim procedures was associated with higher RVEDP, E/e′, and the presence of diastolic dysfunction by echocardiography.ConclusionsDiastolic dysfunction, as determined by echocardiography‐derived and catheter‐based (RVEDP) measures, is prevalent in this TOF population. These measures are not associated with each other; therefore, echocardiographic parameters of diastolic function are not reflective of RVEDP. The development of noninvasive parameters that correlate with filling pressures is required.
Prefrontal cortex modulates firing pattern in the nucleus reuniens of the midline thalamus via distinct corticothalamic pathways
Authors: Zimmerman Eric C. , Grace Anthony A. 
Published: August 2018

AbstractThe thalamus has long been recognized for its role in relaying sensory information from the periphery, a function accomplished by its “first‐order” nuclei. However, a second category of thalamic nuclei, termed “higher‐order” nuclei, have been shown instead to mediate communication between cortical areas. The nucleus reuniens of the midline thalamus (RE) is a higher‐order nucleus known to act as a conduit of reciprocal communication between the medial prefrontal cortex (mPFC) and hippocampus. While anatomical and behavioural studies of RE are numerous, circuit‐based electrophysiological studies, particularly those examining the impact of cortical input and the thalamic reticular nucleus (TRN) on RE neuron firing, are sparse. To characterize RE neuron firing properties and dissect the circuit dynamics of the infralimbic subdivision of the mPFC (ilPFC), the TRN and RE, we used in vivo, extracellular, single‐unit recordings in male Sprague Dawley rats and manipulated neural activity using targeted pharmacological manipulations, electrical stimulation and a projection‐specific implementation of designer receptors exclusively activated by designer drugs (DREADDs). We show that ilPFC inhibition reduces multiple burst firing parameters in RE, whereas ilPFC stimulation drives burst firing and dampens tonic firing. In addition, TRN inhibition reduces the number of spontaneously active neurons in RE. Finally, inhibition of ilPFC terminals in RE selectively enhances a subset of burst firing parameters. These findings demonstrate that ilPFC input, both via direct projections and via the TRN, can modulate RE neuron firing pattern in nuanced and complex ways. They also highlight the ilPFC‐TRN‐RE circuit as a likely critical component of prefrontal–hippocampal interactions.
Effects of litter source on the dynamics of particulate organic matter fractions and rates of macroaggregate turnover in different soil horizons
Authors: Parwada C. , Van Tol J. 
Published: August 2018

SummarySoil texture influences the transformation of soil organic matter (SOM), and depletion and reduction in the number of macroaggregates. However, the extent of changes in SOM in response to its quality and mechanisms of stabilization in different types of soil texture is unclear. We evaluated changes in SOM during a 30‐week incubation experiment using seven soils mixed with two sources of litter; Vachellia karroo (Hayne) Banfi & Galasso leaf and Zea mays L. stover. We hypothesized that changes in intraparticulate organic matter (iPOM) are influenced by litter quality • soil type • time interactions, which affect rates of turnover of macroaggregates. A completely randomized design was used in arranging soil jars in the incubator. Free light fractions and coarse and fine iPOM within macroaggregates (>250 μm) decreased exponentially from week 1 to 30 and were significantly (P < 0.05) affected by litter source • soil horizon • time interactions. Trends of changes in fine iPOM fractions were the same in macroaggregates and microaggregates (P < 0.05). The greatest changes in POM fractions occurred 8 weeks after litter incorporation. Both V. karroo leaf and Z. mays stover stabilized macroaggregates during the first 8 weeks after incubation; thereafter they lost their influence. Therefore, we needed to reapply fresh litter after this period. Changes in iPOM fractions and macroaggregate turnover were specific to a soil type, suggesting that different sources of litter have different stabilizing effects in macroaggregates. Soil macroaggregate stabilization and changes in iPOM could be used as indicators to apply more appropriate management practices for soil protection or productivity.HighlightsDoes the source of organic matter affect transformation rates of different intraparticulate organic matter in the soil?
Degradation of organic matter into very fine particulate matter also increases the rate of turnover of macroaggregates.
Soil type • litter source interactions greatly influenced the rate of transformation from coarse to fine intraparticulate fractions.
Effects of litter quality on dynamics of POM fractions in aggregates and macroaggregate turnover were horizon specific.
Beneficial effects of bilateral subthalamic stimulation on alexithymia in Parkinson's disease
Authors: Dafsari H. S. , Ray‐Chaudhuri K. , Mahlstedt P. , Sachse L. , Steffen J. K. , Petry‐Schmelzer J. N. , Dembek T. A. , Reker P. , Barbe M. T. , Visser‐Vandewalle V. , Fink G. R. , Timmermann L. 
Published: August 2018

Background and purposeSubthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL) and motor and non‐motor symptoms in advanced Parkinson's disease (PD). However, its effect on alexithymia and its relationship to other neuropsychiatric symptoms and QoL in PD is unclear.MethodsIn this prospective, observational study of 39 patients with PD undergoing STN‐DBS, we examined the Parkinson's Disease Questionnaire‐8 (PDQ‐8), 20‐item Toronto Alexithymia Scale (TAS‐20), Hospital Anxiety and Depression Scale (HADS), Self‐Report Manic Inventory (SRMI), Apathy Evaluation Scale (AES), Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living, UPDRS motor examination and UPDRS complications (UPDRS‐II/‐III/‐IV) and levodopa‐equivalent daily dose (LEDD) pre‐operatively and at 5‐month follow‐up. Outcome changes were tested with Wilcoxon signed‐rank or paired t‐test when parametric tests were applicable and corrected for multiple comparisons. The relationship between outcome changes was explored with bivariate correlations. Additionally, partial correlations between PDQ‐8 and TAS‐20 were computed controlling for HADS, SRMI and AES change scores. Predictor analyses for PDQ‐8 improvement were calculated for all baseline parameters.ResultsThe baseline prevalence of alexithymia was 17.9%. We observed significant beneficial effects of STN‐DBS on PDQ‐8, TAS‐20, HADS, UPDRS‐II, ‐III and ‐IV scores and significant LEDD reduction. The correlation between TAS‐20 and PDQ‐8 improvements remained significant after controlling for all other aforementioned outcomes. Predictor analyses for PDQ‐8 improvement were significant for PDQ‐8 and TAS‐20.ConclusionsThis is the first report of beneficial effects of STN‐DBS on alexithymia. Alexithymia was significantly associated with QoL outcome independent of anxiety, depression, mania and apathy. Our study highlights the importance of alexithymia for holistic assessments of DBS outcomes.
Patient's perception: shorter and more severe prodromal phase in GBA‐associated PD
Authors: Zimmermann M. , Gaenslen A. , Prahl K. , Srulijes K. , Hauser A.‐K. , Schulte C. , Csoti I. , Berg D. , Brockmann K. 
Published: August 2018

BackgroundPrevalence and time of occurrence of prodromal symptoms of Parkinson's disease (PD) in relation to the onset of classical motor manifestation varies between patients. Possible modifying factors might be different genetic architectures predisposing to varying burden of manifestations.ObjectivesTo characterize the prodromal phase in PD patients with heterozygous mutations in the GBA gene compared to PD patients without GBA mutation.MethodsIn a retrospective design, 151 participants [47 PD patients carrying a GBA mutation (PDGBA), 52 idiopathic PD patients (PDidiopathic), 52 healthy elderly (CON)] underwent a validated structured interview designed to assess prevalence and time of occurrence of prodromal symptoms.ResultsPDGBA showed a higher prevalence of prodromal symptoms and almost simultaneous occurrence of non‐motor and early motor symptoms shortly before PD diagnosis whereas PDidiopathic reported a longer prodromal phase starting with non‐motor symptoms.ConclusionThe short and severe prodromal phase in PDGBA might call for shorter assessment intervals in yet premanifest GBA mutation carriers.