bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Secreted Antigenic Target of 6 kDa of Mycobacterium tuberculosis Stimulates Macrophage Chemoattractant Protein‐1 Production by Macrophages and Its Regulation by p38 Mitogen‐Activated Protein Kinases and Interleukin‐4
Authors: Ma J. , Jung B‐G. , Yi N. , Samten B. 
Published: May 2016

AbstractEarly secreted antigenic target of 6 kDa (ESAT‐6), the major virulence factor of Mycobacterium tuberculosis, affects host immunity and the formation of granulomas likely through inflammatory cytokines. To understand its role in this regard further, we investigated the effect of ESAT‐6 on macrophages by determining the production of macrophage chemoattractant protein (MCP)‐1, a major chemokine associated with tuberculosis pathogenesis, by murine bone marrow‐derived macrophages (BMDMs) and its regulation by protein kinases and cytokines. The results revealed that ESAT‐6, but not Ag85A and culture filtrate protein 10 kDa (CFP10), induced MCP‐1 production by BMDMs dose and time dependently. Inhibition of p38 but not other mitogen‐activated protein kinases (MAPK) and PI3K further enhanced ESAT‐6‐induced MCP‐1 production by BMDMs. Inhibition of p38 MAPK enhanced ESAT‐6‐induced MCP‐1 mRNA accumulation without affecting mRNA stability. ESAT‐6 also induced TNF‐α from BMDMs and MCP‐1 from mouse lung epithelial cells, and these were suppressed by p38 MAPK inhibition, implying cytokine‐ and cell‐specific effect of p38 MAPK inhibition on ESAT‐6‐induced MCP‐1 by macrophages. Pretreatment of BMDMs with IL‐4, but not other cytokines (IL‐2, IL‐10, TNF‐α, IFN‐γ and IL‐1α) further elevated ESAT‐6‐stimulated MCP‐1 production although IL‐4 did not induce MCP‐1 without ESAT‐6. Both p38 MAPK inhibitor and IL‐4 did not show additive effect on ESAT‐6‐induced MCP‐1 protein level despite such effect on MCP‐1 mRNA level was evident. In conclusion, these results indicate a specific role for both p38 MAPK and IL‐4 in ESAT‐6‐induced MCP‐1 production by macrophages and suggest a pathway with significance in tuberculosis pathogenesis.
Fermented Milk Containing Lactobacillus casei Strain Shirota Preserves the Diversity of the Gut Microbiota and Relieves Abdominal Dysfunction in Healthy Medical Students Exposed to Academic Stress
Authors: Kato-Kataoka Akito , Nishida Kensei , Takada Mai , Kawai Mitsuhisa , Kikuchi-Hayakawa Hiroko , Suda Kazunori , Ishikawa Hiroshi , Gondo Yusuke , Shimizu Kensuke , Matsuki Takahiro , Kushiro Akira , Hoshi Ryoutaro , Watanabe Osamu , Igarashi Tomoki , Miyazaki Kouji , Kuwano Yuki , Rokutan Kazuhito 
Published: May 2016

ABSTRACT

Stress-induced abdominal dysfunction is an attractive target for probiotics. To investigate the effects of the probiotic
Lactobacillus casei
strain Shirota on abdominal dysfunction, a double-blind, placebo-controlled trial was conducted with healthy medical students undertaking an authorized nationwide examination for academic advancement. For 8 weeks, until the day before the examination, 23 and 24 subjects consumed an
L. casei
strain Shirota-fermented milk and a placebo milk daily, respectively. In addition to assessments of abdominal symptoms, psychophysical state, and salivary stress markers, gene expression changes in peripheral blood leukocytes and composition of the gut microbiota were analyzed using DNA microarray analysis and 16S rRNA gene amplicon sequence analysis, respectively, before and after the intervention. Stress-induced increases in a visual analog scale measuring feelings of stress, the total score of abdominal dysfunction, and the number of genes with changes in expression of more than 2-fold in leukocytes were significantly suppressed in the
L. casei
strain Shirota group compared with those in the placebo group. A significant increase in salivary cortisol levels before the examination was observed only in the placebo group. The administration of
L. casei
strain Shirota, but not placebo, significantly reduced gastrointestinal symptoms. Moreover, 16S rRNA gene amplicon sequencing demonstrated that the
L. casei
strain Shirota group had significantly higher numbers of species, a marker of the alpha-diversity index, in their gut microbiota and a significantly lower percentage of
Bacteroidaceae
than the placebo group. Our findings indicate that the daily consumption of probiotics, such as
L. casei
strain Shirota, preserves the diversity of the gut microbiota and may relieve stress-associated responses of abdominal dysfunction in healthy subjects exposed to stressful situations.

IMPORTANCE
A novel clinical trial was conducted with healthy medical students under examination stress conditions. It was demonstrated that the daily consumption of lactic acid bacteria provided health benefits to prevent the onset of stress-associated abdominal symptoms and a good change of gut microbiota in healthy medical students.
Visual dysfunction and its correlation with retinal changes in patients with Parkinson's disease: an observational cross-sectional study
Authors: Polo V , Satue M , Rodrigo M J , Otin S , Alarcia R , Bambo M P , Fuertes M I , Larrosa J M , Pablo L E , Garcia-Martin E 
Published: May 2016

ObjectivesTo evaluate visual dysfunction and its correlation with structural changes in the retina in patients with Parkinson's disease (PD).MethodsPatients with PD (n=37) and controls (n=37) were included in an observational cross-sectional study, and underwent visual acuity (VA), colour vision (using the Farnsworth and Lanthony desaturated D15 colour tests) and contrast sensitivity vision (CSV; using the Pelli-Robson chart and CSV 1000E test) evaluation to measure visual dysfunction. Structural measurements of the retinal nerve fibre layer (RNFL), and macular and ganglion cell layer (GCL) thicknesses, were obtained using spectral domain optical coherence tomography (SD-OCT). Comparison of obtained data, and correlation analysis between functional and structural results were performed.ResultsVA (in all different contrast levels) and all CSV spatial frequencies were significantly worse in patients with PD than in controls. Colour vision was significantly affected based on the Lanthony colour test. Significant GCL loss was observed in the minimum GCL+inner plexiform layer. A clear tendency towards a reduction in several macular sectors (central, outer inferior, outer temporal and superior (inner and outer)) and in the temporal quadrant of the RNFL thickness was observed, although the difference was not significant. CSV was the functional parameter most strongly correlated with structural measurements in PD. Colour vision was associated with most GCL measurements. Macular thickness was strongly correlated with macular volume and functional parameters (r>0.70, p<0.05).ConclusionsPatients with PD had visual dysfunction that correlated with structural changes evaluated by SD-OCT. GCL measurements may be reliable indicators of visual impairment in patients with PD.
Examining the quality of evidence to support the effectiveness of interventions: an analysis of systematic reviews
Authors: Kane Robert L , Butler Mary , Ng Weiwen 
Published: May 2016

ObjectiveThis analysis examines the quality of evidence (QOE) for 1472 outcomes linked to interventions where the QOE was rated in 42 systematic reviews of randomised clinical trials and/or observational studies across different topics.SettingNot applicable.Participants76 systematic reviews.Primary and secondary outcome measuresStrength of evidence ratings by initial reviewers.ResultsAmong 76 systematic reviews, QOE ratings were available for only 42, netting 1472 comparisons. Of these, 57% included observational studies; 4% were rated as high and 12% as moderate; the rest were low or insufficient. The ratings varied by topic: 74% of the surgical study pairs were rated as low or insufficient, compared with 82% of pharmaceuticals and 86% of device studies, 88% of organisational, 91% of lifestyle studies, and 94% of psychosocial interventions.ConclusionsWe are some distance from being able to claim evidence-based practice. The press for individual-level data will make this challenge even harder.
Systematic review of prognostic models for recurrent venous thromboembolism (VTE) post-treatment of first unprovoked VTE
Authors: Ensor Joie , Riley Richard D , Moore David , Snell Kym I E , Bayliss Susan , Fitzmaurice David 
Published: May 2016

ObjectivesTo review studies developing or validating a prognostic model for individual venous thromboembolism (VTE) recurrence risk following cessation of therapy for a first unprovoked VTE. Prediction of recurrence risk is crucial to informing patient prognosis and treatment decisions. The review aims to determine whether reliable prognostic models exist and, if not, what further research is needed within the field.DesignBibliographic databases (including MEDLINE, EMBASE and the Cochrane Library) were searched using index terms relating to the clinical field and prognosis. Screening of titles, abstracts and subsequently full texts was conducted by 2 reviewers independently using predefined criteria. Quality assessment and critical appraisal of included full texts was based on an early version of the PROBAST (Prediction study Risk Of Bias Assessment Tool) for risk of bias and applicability in prognostic model studies.SettingStudies in any setting were included.Primary and secondary outcome measuresThe primary outcome for the review was the predictive accuracy of identified prognostic models in relation to VTE recurrence risk.Results3 unique prognostic models were identified including the HERDOO2 score, Vienna prediction model and DASH score. Quality assessment highlighted the Vienna, and DASH models were developed with generally strong methodology, but the HERDOO2 model had many methodological concerns. Further, all models were considered at least at moderate risk of bias, primarily due to the need for further external validation before use in practice.ConclusionsAlthough the Vienna model shows the most promise (based on strong development methodology, applicability and having some external validation), none of the models can be considered ready for use until further, external and robust validation is performed in new data. Any new models should consider the inclusion of predictors found to be consistently important in existing models (sex, site of index event, D-dimer), and take heed of several methodological issues identified through this review.PROSPERO registration numberCRD42013003494.
Management of problematic behaviours among individuals on long-term opioid therapy: protocol for a Delphi study
Authors: Merlin Jessica S , Young Sarah R , Azari Soraya , Becker William C , Liebschutz Jane M , Pomeranz Jamie , Roy Payel , Saini Shalini , Starrels Joanna L , Edelman E Jennifer 
Published: May 2016

IntroductionGiven the sharp rise in opioid prescribing and heightened recognition of opioid addiction and overdose, opioid safety has become a priority. Clinical guidelines on long-term opioid therapy (LTOT) for chronic pain consistently recommend routine monitoring and screening for problematic behaviours. Yet, there is no consensus definition regarding what constitutes a problematic behaviour, and recommendations for appropriate management to inform front-line providers, researchers and policymakers are lacking. This creates a barrier to effective guideline implementation. Thus, our objective is to present the protocol for a Delphi study designed to: (1) elicit expert opinion to identify the most important problematic behaviours seen in clinical practice and (2) develop consensus on how these behaviours should be managed in the context of routine clinical care.Methods/analysisWe will include clinical experts, defined as individuals who provide direct patient care to adults with chronic pain who are on LTOT in an ambulatory setting, and for whom opioid prescribing for chronic non-malignant pain is an area of expertise. The Delphi study will be conducted online in 4 consecutive rounds. Participants will be asked to list problematic behaviours and identify which behaviours are most common and challenging. They will then describe how they would manage the most frequently occurring common and challenging behaviours, rating the importance of each management strategy. Qualitative analysis will be used to categorise behaviours and management strategies, and consensus will be based on a definition established a priori.Ethics/disseminationThis study has been approved by the Institutional Review Board (IRB) of the University of Alabama at Birmingham (UAB). This study will generate Delphi-based expert consensus on the management of problematic behaviours that arise in individuals on LTOT, which we will publish and disseminate to appropriate professional societies. Ultimately, our findings will provide guidance to front-line providers, researchers and policymakers.
Are self-reported neighbourhood characteristics associated with onset of functional limitations in older adults with or without memory impairment?
Authors: Nguyen Thu T , Rist Pamela M , Glymour M Maria 
Published: May 2016

BackgroundNeighbourhood resources may preserve functional independence in older adults, but little is known about whether benefits differ for individuals with normal and impaired memory. We evaluated the extent to which neighbourhood context was related to onset of instrumental and basic activities of daily living (I/ADL) limitations and whether relationships were modified by memory impairment.MethodsHealth and Retirement Study participants 50+ years of age without baseline I/ADL limitations (n=8726 for IADL and n=8345 for ADL models) were interviewed biennially for up to 8 years. Self-reported neighbourhood characteristics were scaled from 0 (worst) to 1 (best). Memory, assessed by direct and proxy cognitive assessments, was dichotomised at the 20th centile. We used pooled logistic regression models, adjusted for demographics and individual characteristics.ResultsLow neighbourhood physical disorder (OR=0.51 (95% CI: 0.37 to 0.69)), high social cohesion (OR=0.46 (0.34 to 0.62)), and high safety (OR=0.59 (0.46 to 0.76)) were associated with reduced incidence of IADL limitations. These neighbourhood characteristics were also associated with lower incidence of ADL limitations (disorder OR=0.59 (0.43 to 0.81)); social cohesion OR=0.60 (0.45 to 0.81)); safety OR=0.74 (0.58 to 0.93)). High social ties were not related to ADLs (OR=1.01(0.80 to 1.28)) or IADLs (OR=0.93(0.74 to 1.17)). The benefits of these neighbourhood characteristics for ADLs were similar among those with and without memory impairment but primarily observed among those without memory impairment for IADLs.ConclusionsOlder adults living in neighbourhoods with low physical disorder, high social cohesion and high safety experience lower incidence of IADL and ADL limitations. Memory status modified the estimated effects of neighbourhood characteristics on IADL but not ADL limitations.
Communication in palliative care: talking about the end of life, before the end of life
Authors: Brighton Lisa Jane , Bristowe Katherine 
Published: May 2016

AbstractIncreasing evidence demonstrates the benefits of early end-of-life care discussions with patients with life-threatening illness and their families. However, these conversations often do not occur. This review explores some of the many barriers faced by clinicians in relation to end-of-life care discussions, including prognostic uncertainty, fear of causing distress, navigating patient readiness and feeling unprepared for these conversations. The value of core clinical communication skills, potential strategies for improvement and areas for future research are also discussed. It is essential that clinicians offer patients facing life-threatening illness, and those close to them, the opportunity to discuss end-of-life issues in line with their information and decision-making preferences. With a growing and ageing global population, supporting both generalist and specialist providers of palliative care in this task is key. With careful preparation, fears of undertaking these discussions should not be a barrier to initiating them.
Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas
Authors: Droog Marjolein , Nevedomskaya Ekaterina , Kim Yongsoo , Severson Tesa , Flach Koen D. , Opdam Mark , Schuurman Karianne , Gradowska Patrycja , Hauptmann Michael , Dackus Gwen , Hollema Harry , Mourits Marian J. , Nederlof Petra , van Boven Hester , Linn Sabine C. , Wessels Lodewyk , van Leeuwen Flora E. , Zwart Wilbert 
Published: May 2016

Abstract
Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERα binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERα binding sites proximal to genes involved in classical ERα target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERα and FOXA1 together with the enhancer-enriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERα expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERα are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773–84. ©2016 AACR.
Cell Cycle–Dependent Mechanisms Underlie Vincristine-Induced Death of Primary Acute Lymphoblastic Leukemia Cells
Authors: Kothari Anisha , Hittelman Walter N. , Chambers Timothy C. 
Published: May 2016

Abstract
Microtubule-targeting agents (MTA), such as the taxanes and vinca alkaloids, are used to treat a variety of cancers due to their ability to perturb microtubule dynamics. In cell culture, MTAs exert their anticancer effects primarily by causing mitotic arrest and cell death. However, accumulating indirect evidence suggests that MTAs may exert their cytotoxicity in human tumors by interfering with interphase microtubules. In this study, we sought to develop and characterize an experimental system in which to test the hypothesis that MTAs induce cell death during interphase. Primary adult acute lymphoblastic leukemia (ALL) cells treated with vincristine only weakly exhibited colocalization between mitotic and apoptotic markers and major characteristics of mitotic death, such as an increase in cells with 4N DNA content before the appearance of cells with &lt;2N DNA content, suggesting a mixed response. Therefore, we separated ALL cells into distinct phases of the cell cycle by centrifugal elutriation, labeled cells with 5-ethynyl-2′-deoxyuridine (EdU), and then treated each population with vincristine. Cells isolated during G1 underwent cell death without evidence of EdU uptake, indicating that the cytotoxic effects of vincristine took place during G1. Conversely, cells isolated during S or G2–M phases underwent death following mitotic arrest. Thus, vincristine induces distinct death programs in primary ALL cells depending on cell-cycle phase, and cells in G1 are particularly susceptible to perturbation of interphase microtubules. Primary ALL cells may therefore provide a powerful model system in which to study the multimodal mechanisms underlying MTA-induced cell death. Cancer Res; 76(12); 3553–61. ©2016 AACR.
Selenium- or Vitamin E–Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT
Authors: Chan June M. , Darke Amy K. , Penney Kathryn L. , Tangen Catherine M. , Goodman Phyllis J. , Lee Gwo-Shu Mary , Sun Tong , Peisch Sam , Tinianow Alex M. , Rae James M. , Klein Eric A. , Thompson Ian M. , Kantoff Philip W. , Mucci Lorelei A. 
Published: May 2016

Abstract
Background: Epidemiologic studies and secondary analyses of randomized trials supported the hypothesis that selenium and vitamin E lower prostate cancer risk. However, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no benefit of either supplement. Genetic variants involved in selenium or vitamin E metabolism or transport may underlie the complex associations of selenium and vitamin E.
Methods: We undertook a case–cohort study of SELECT participants randomized to placebo, selenium, or vitamin E. The subcohort included 1,434 men; our primary outcome was high-grade prostate cancer (N = 278 cases, Gleason 7 or higher cancer). We used weighted Cox regression to examine the association between SNPs and high-grade prostate cancer risk. To assess effect modification, we created interaction terms between randomization arm and genotype and calculated log likelihood statistics.
Results: We noted statistically significant (P &lt; 0.05) interactions between selenium assignment, SNPs in CAT, SOD2, PRDX6, SOD3, and TXNRD2, and high-grade prostate cancer risk. Statistically significant SNPs that modified the association of vitamin E assignment and high-grade prostate cancer included SEC14L2, SOD1, and TTPA. In the placebo arm, several SNPs, hypothesized to interact with supplement assignment and risk of high-grade prostate cancer, were also directly associated with outcome.
Conclusion: Variants in selenium and vitamin E metabolism/transport genes may influence risk of overall and high-grade prostate cancer, and may modify an individual man's response to vitamin E or selenium supplementation with regards to these risks.
Impact: The effect of selenium or vitamin E supplementation on high-grade prostate cancer risk may vary by genotype. Cancer Epidemiol Biomarkers Prev; 25(7); 1050–8. ©2016 AACR.