Search

This paper investigates various aspects of asymmetric connectedness among the stock markets in China, Japan, and Korea. Based on the realized semi-volatility indices, we find that the impact of bad volatility strictly dominates good volatility in generating transmission across the Northeast Asian markets. We also present evidence that the impacts of the U.S. volatility shock on other countries have been due primarily to bad volatility. In the dynamic analysis, we observe highly volatile patterns in the connectedness measures with several peaks during major economic shocks. Most influential episodes of volatility connectedness have been witnessed, inter alia, during the global financial crisis and the European debt crisis. The recent COVID-19 pandemic has also caused turmoil by damaging the health of the global financial market.

Pathogenesis of inflammatory bowel disease (IBD) accompanies disrupted intestinal tight junctions. However, many approaches of therapeutics for IBD are focused only on anti-inflammatory effects and most cellular experiments are based on two-dimensional cell lines which have insufficient circumstances of intestine. Thus, here, we used three-dimensional structure intestinal organoids to investigate effects of metformin in the in vitro IBD condition. In this study, we focused on both tight junctions and the levels of inflammatory cytokines. Metformin enhances the intestinal barrier in injured intestine via upregulation of AMP-activated protein kinase, dysfunction of which contributes to the pathogenesis of intestinal diseases. We aim to investigate the effects of metformin on cytokine-induced injured intestinal organoids. Tumor necrosis factor-alpha (TNF-α) was used to induce intestinal injury in an organoid model, and the effects of metformin were assessed. Cell viability and levels of inflammatory cytokines were quantified in addition to tight junction markers. Furthermore, 4 kDa FITC-dextran was used to assess intestinal permeability. The upregulation of inflammatory cytokine levels was alleviated by metformin, which also restored the intestinal epithelium permeability in TNF-α-treated injury organoids. We confirmed that claudin-2 and claudin-7, representative tight junction markers, were also protected by metformin treatment. This study confirms the protective effects of metformin, which could be used as a therapeutic strategy for inflammatory intestinal diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Non-small-cell lung cancer (NSCLC) shows a high incidence of brain metastases (BM). Early detection is crucial to improve clinical prospects. We trained and validated classifier models to identify patients with a high risk of developing BM, as they could potentially benefit from surveillance brain MRI., Methods: Consecutive patients with an initial diagnosis of NSCLC from January 2011 to April 2019 and an in-house chest-CT scan (staging) were retrospectively recruited at a German lung cancer center. Brain imaging was performed at initial diagnosis and in case of neurological symptoms (follow-up). Subjects lost to follow-up or still alive without BM at the data cut-off point (12/2020) were excluded. Covariates included clinical and/or 3D-radiomics-features of the primary tumor from staging chest-CT. Four machine learning models for prediction (80/20 training) were compared. Gini Importance and SHAP were used as measures of importance; sensitivity, specificity, area under the precision-recall curve, and Matthew's Correlation Coefficient as evaluation metrics., Results: Three hundred and ninety-five patients compromised the clinical cohort. Predictive models based on clinical features offered the best performance (tuned to maximize recall: sensitivity∼70%, specificity∼60%). Radiomics features failed to provide sufficient information, likely due to the heterogeneity of imaging data. Adenocarcinoma histology, lymph node invasion, and histological tumor grade were positively correlated with the prediction of BM, age, and squamous cell carcinoma histology were negatively correlated. A subgroup discovery analysis identified 2 candidate patient subpopulations appearing to present a higher risk of BM (female patients + adenocarcinoma histology, adenocarcinoma patients + no other distant metastases)., Conclusion: Analysis of the importance of input features suggests that the models are learning the relevant relationships between clinical features/development of BM. A higher number of samples is to be prioritized to improve performance. Employed prospectively at initial diagnosis, such models can help select high-risk subgroups for surveillance brain MRI., Competing Interests: Disclosure M.S. reports research funding to institution (but not for this specific project) from Astra Zeneca, honoraria for advisory boards from Astra Zeneca, BMS, MSD/Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Johnson & Johnson, Amgen, Tesaro, Eli Lilly, honoraria for educational lectures from Astra Zeneca, BMS, Novartis, Pfizer, Boehringer Ingelheim, Amgen and Eli Lilly. The authors have no conflicts of interest to report with regard to this project., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Backgrounds: Tumor vascularity plays a fundamental role in cancer progression, including breast cancer. This study aimed to elucidate tumor vascularity and its impact on patient survival in the context of breast cancer subtypes using Hounsfield units (HU) on contrast-enhanced computed tomography (CT)., Materials and Methods: Patients with early-stage breast cancer who completed planned treatment between 2003 and 2013 were retrospectively assessed., Results: The final cohort comprised 440 patients. Of the 440 patients, 262 had estrogen receptor (ER)-positive disease and 119 had human epidermal growth factor receptor 2 (HER2)-overexpressing disease. The tumor-to-aorta ratio of Hounsfield units (TAR) was related to significantly worse recurrence-free interval (RFI) (P < .001) and overall survival (OS) (P < .001) in patients with TAR > 0.33 for RFI and > 0.35 for OS than their counterparts. In the subgroup analysis, the survival disadvantage was limited only to patients with ER-positive and HER2-negative disease (P < .001 for both RFI and OS)., Conclusion: This study showed that TAR, which reflects tumor vascularity, was significantly related to patients' RFI and OS, suggesting its capacity as a feasible biomarker. This study also showed that TAR was associated with the survival in patients with ER-positive and HER2-negative disease., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The ability to catalyze diverse reactions with relevance for chemical and pharmaceutical research and industry has led to an increasing interest in fungal enzymes. There is still an enormous potential considering the sheer amount of new enzymes from the huge diversity of fungi. Most of these fungal enzymes have not been characterized yet due to the lack of high throughput synthesis and analysis methods. This bottleneck could be overcome by means of cell-free protein synthesis. In this study, cell-free protein synthesis based on eukaryotic cell lysates was utilized to produce a functional glycoside hydrolase (GH78) from the soft-rot fungus Xylaria polymorpha (Ascomycota). The enzyme was successfully synthesized under different reaction conditions. We characterized its enzymatic activities and immobilized the protein via FLAG-Tag interaction. Alteration of several conditions including reaction temperature, template design and lysate supplementation had an influence on the activity of cell-free synthesized GH78. Consequently this led to a production of purified GH78 with a specific activity of 15.4 U mg - 1 . The results of this study may be foundational for future high throughput fungal enzyme screenings, including substrate spectra analysis and mutant screenings., Competing Interests: Declaration of Interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: With the introduction of new anti-tuberculosis drugs, all-oral regimens with shorter treatment durations for multidrug-resistant tuberculosis have been anticipated. We aimed to investigate whether a new all-oral regimen was non-inferior to the conventional regimen including second-line anti-tuberculosis drugs for 20-24 months in the treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis., Methods: In this multicentre, randomised, open-label phase 2/3 non-inferiority trial, we enrolled men and women aged 19-85 years with multidrug-resistant tuberculosis confirmed by phenotypic or genotypic drug susceptibility tests or rifampicin-resistant tuberculosis by genotypic tests at 12 participating hospitals throughout South Korea. Participants with fluoroquinolone-resistant multidrug-resistant tuberculosis were excluded. Participants were randomly assigned (1:1) to two groups using a block randomisation, stratified by the presence of diabetes and cavitation on baseline chest radiographs. The investigational group received delamanid, linezolid, levofloxacin, and pyrazinamide for 9 months, and the control group received a conventional 20-24-month regimen, according to the 2014 WHO guidelines. The primary outcome was the treatment success rate at 24 months after treatment initiation in the modified intention-to-treat population and the per-protocol population. Participants who were "cured" and "treatment completed" were defined as treatment success following the 2014 WHO guidelines. Non-inferiority was confirmed if the lower limit of a 97·5% one-sided CI of the difference between the groups was greater than -10%. Safety data were collected for 24 months in participants who received a predefined regimen at least once. This study is registered with ClinicalTrials.gov, NCT02619994., Findings: Between March 4, 2016, and Sept 14, 2019, 214 participants were enrolled, 168 (78·5%) of whom were included in the modified intention-to-treat population. At 24 months after treatment initiation, 60 (70·6%) of 85 participants in the control group had treatment success, as did 54 (75·0%) of 72 participants in the shorter-regimen group (between-group difference 4·4% [97·5% one-sided CI -9·5% to ∞]), satisfying the predefined non-inferiority margin. No difference in safety outcomes was identified between the control group and the shorter-regimen group., Interpretation: 9-month treatment with oral delamanid, linezolid, levofloxacin, and pyrazinamide could represent a new treatment option for participants with fluoroquinolone-sensitive multidrug-resistant tuberculosis., Funding: Korea Disease Control and Prevention Agency, South Korea., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This paper responds to a recent critique by Bissett et al. of the fMRI Stop task used in the Adolescent Brain Cognitive Development ℠ Study (ABCD Study®). The critique focuses primarily on a task design feature related to race model assumptions (i.e., that the Go and Stop processes are fully independent). In response, we note that the race model is quite robust against violations of its assumptions. Most importantly, while Bissett raises conceptual concerns with the task we focus here on analyzes of the task data and conclude that the concerns appear to have minimal impact on the neuroimaging data (the validity of which do not rely on race model assumptions) and have far less of an impact on the performance data than the critique suggests. We note that Bissett did not apply any performance-based exclusions to the data they analyzed, a number of the trial coding errors they flagged were already identified and corrected in ABCD annual data releases, a number of their secondary concerns reflect sensible design decisions and, indeed, their own computational modeling of the ABCD Stop task suggests the problems they identify have just a modest impact on the rank ordering of individual differences in subject performance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To systematically review the literature related to the effectiveness of parents' active involvement during painful interventions for their preterm infants., Data Sources: We performed a systematic search of PubMed, EMBASE/Ovid, CINAHL, Livivio, and PsycInfo using the keywords "preterm infants," "pain," and "parents.", Study Selection: Articles were eligible for inclusion if they were published between 2000 and 2021 and reported randomized controlled trials (RCTs) in which preterm infants underwent painful interventions, and parents were present and actively involved in pain-reducing measures., Data Extraction: We used the Consolidated Standards of Reporting Trials (CONSORT) checklist for RCTs for data extraction. We assessed methodologic quality using critical appraisal for RCTs according to the Joanna Briggs Institute., Data Synthesis: In total, 22 articles met the inclusion criteria. These articles reported 19 studies focused on kangaroo/skin-to-skin care, one focused on breastfeeding, and two focused on facilitated tucking. The methods used to evaluate pain in the infant varied substantially. Overall, kangaroo/skin-to-skin care and facilitated tucking resulted in clinically and statistically significant decreases in pain. For breastfeeding, effectiveness was linked to a more mature sucking pattern of the preterm infant., Conclusion: The current evidence suggests that involving parents in pain-reducing measures during painful interventions for their preterm infants is beneficial. However, more research is needed for the different methods of involving parents in pain-reducing measures., (Copyright © 2021 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses. Published by Elsevier Inc. All rights reserved.)

Background: Nicotine and illicit stimulants are very addictive substances. Although associations between grey matter and dependence on stimulants have been frequently reported, white matter correlates have received less attention., Methods: Eleven international sites ascribed to the ENIGMA-Addiction consortium contributed data from individuals with dependence on cocaine (n = 147), methamphetamine (n = 132) and nicotine (n = 189), as well as non-dependent controls (n = 333). We compared the fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) of 20 bilateral tracts. Also, we compared the performance of various machine learning algorithms in deriving brain-based classifications on stimulant dependence., Results: The cocaine and methamphetamine groups had lower regional FA and higher RD in several association, commissural, and projection white matter tracts. The methamphetamine dependent group additionally showed lower regional AD. The nicotine group had lower FA and higher RD limited to the anterior limb of the internal capsule. The best performing machine learning algorithm was the support vector machine (SVM). The SVM successfully classified individuals with dependence on cocaine (AUC = 0.70, p < 0.001) and methamphetamine (AUC = 0.71, p < 0.001) relative to non-dependent controls. Classifications related to nicotine dependence proved modest (AUC = 0.62, p = 0.014)., Conclusions: Stimulant dependence was related to FA disturbances within tracts consistent with a role in addiction. The multivariate pattern of white matter differences proved sufficient to identify individuals with stimulant dependence, particularly for cocaine and methamphetamine., (Copyright © 2021. Published by Elsevier B.V.)

The general transcription factor TFIIH contains three ATP-dependent catalytic activities. TFIIH functions in nucleotide excision repair primarily as a DNA helicase and in Pol II transcription initiation as a dsDNA translocase and protein kinase. During initiation, the XPB/Ssl2 subunit of TFIIH couples ATP hydrolysis to dsDNA translocation facilitating promoter opening and the kinase module phosphorylates Pol II to facilitate the transition to elongation. These functions are conserved between metazoans and yeast; however, yeast TFIIH also drives transcription start-site scanning in which Pol II scans downstream DNA to locate productive start-sites. The ten-subunit holo-TFIIH from S. cerevisiae has a processive dsDNA translocase activity required for scanning and a structural role in scanning has been ascribed to the three-subunit TFIIH kinase module. Here, we assess the dsDNA translocase activity of ten-subunit holo- and core-TFIIH complexes (i.e. seven subunits, lacking the kinase module) from both S. cerevisiae and H. sapiens. We find that neither holo nor core human TFIIH exhibit processive translocation, consistent with the lack of start-site scanning in humans. Furthermore, in contrast to holo-TFIIH, the S. cerevisiae core-TFIIH also lacks processive translocation and its dsDNA-stimulated ATPase activity was reduced ~5-fold to a level comparable to the human complexes, potentially explaining the reported upstream shift in start-site observed in vitro in the absence of the S. cerevisiae kinase module. These results suggest that neither human nor S. cerevisiae core-TFIIH can translocate efficiently, and that the S. cerevisiae kinase module functions as a processivity factor to allow for robust transcription start-site scanning., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DJT is a member of the SAB at Dewpoint Therapeutics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Multimodal neuroimaging assessments were utilized to identify generalizable brain correlates of current body mass index (BMI) and predictors of pathological weight gain (i.e., beyond normative development) one year later. Multimodal data from children enrolled in the Adolescent Brain Cognitive Development Study® at 9-to-10-years-old, consisted of structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), resting state (rs), and three task-based functional (f) MRI scans assessing reward processing, inhibitory control, and working memory. Cross-validated elastic-net regression revealed widespread structural associations with BMI (e.g., cortical thickness, surface area, subcortical volume, and DTI), which explained 35% of the variance in the training set and generalized well to the test set (R 2 = 0.27). Widespread rsfMRI inter- and intra-network correlations were related to BMI (R 2 train = 0.21; R 2 test = 0.14), as were regional activations on the working memory task (R 2 train = 0.20; (R 2 test = 0.16). However, reward and inhibitory control tasks were unrelated to BMI. Further, pathological weight gain was predicted by structural features (Area Under the Curve (AUC) train = 0.83; AUC test = 0.83, p < 0.001), but not by fMRI nor rsfMRI. These results establish generalizable brain correlates of current weight and future pathological weight gain. These results also suggest that sMRI may have particular value for identifying children at risk for pathological weight gain., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: To assess the clinical utility of a prototype sequence for metal artifact reduction, the multiacquisition variable-resonance image combination selective (MAVRIC-SL) at 3 T. This sequence allows a surgical prosthesis-dependent reduction in the number of spectral bins. We compared the prototype MAVRIC SL to the conventional two-dimensional fast spin-echo (FSE) sequences and MAVRIC SL images acquired with all spectral bins to those acquired with the optimized number of spectral bins., Methods: MAVRIC SL images were acquired in 25 image sets from August 2017 to April 2018. For each subject, the optimized number of spectral bins was determined using a short spectral calibration scan. The image sets obtained with magnetic resonance imaging that were used for the analysis consisted of MAVRIC-SL proton density (PD)-weighted or short inversion time inversion recovery (STIR) images acquired with all 24 spectral bins, the corresponding images with the optimized number of spectral bins, and the conventional two-dimensional FSE or STIR PD-weighted images. A musculoskeletal radiologist reviewed and scored the images using a five-point scale for artifact reduction around the prosthesis and visualization of the prosthesis and peri-prosthetic tissues. Quantitative evaluation of the peri-prosthetic tissues was also performed. The Wilcoxon rank-sum test was used to test for significance., Results: The MAVRIC SL images enabled a significantly improved reduction in metallic artifacts compared to the conventional two-dimensional FSE sequences. The optimized number of spectral bins ranged from 6 to 20, depending on the prosthesis susceptibility difference, size, and orientation to the B 0 field. The scan times significantly decreased with a reduced number of spectral bins (354.0 ± 139.1 versus 283.0 ± 89.6 s; 20% reduced scan time; p < .05). Compared to the MAVRIC SL images acquired with all 24 bins, the artifact reduction and visualization of the prosthesis and peri-prosthetic tissues on the MAVRIC SL images acquired with calibrated bins were not significantly different., Conclusions: Compared to the MAVRIC SL images acquired with all 24 spectral bins, those acquired with an optimized number of spectral bins can reduce metallic artifacts with no significant image quality degradation while providing reduced scan time., Competing Interests: Declaration of Competing Interest Dr. S.S. Kaushik works for GE Healthcare. MAVRIC SL is a GE Healthcare product., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This study aimed to comprehensively review the available evidence regarding the efficacy of first-line pembrolizumab for advanced/metastatic non-small-cell lung cancer (NSCLC), and to compare pembrolizumab monotherapy versus pembrolizumab plus chemotherapy versus chemotherapy alone., Materials and Methods: A search of the PubMed, EMBASE, and Cochrane Library databases was performed in July 2018, and abstracts from the American Society of Clinical Oncology meetings (2015-2018) were reviewed. Summaries of the results were pooled using a random-effect model to determine the pooled hazard ratio (HR) for progression-free survival (PFS), overall survival (OS), and their 95% confidence intervals (CIs). A network meta-analysis was used to indirectly compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy., Results: A total of 4 relevant phase III trials comprising 2754 patients were identified. Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). In particular, for the subgroup with PD-L1 TPS ≥ 50%, the HR of PFS was 0.49 (95% CI, 0.32-0.76; P = .001), and that of OS was 0.57 (95% CI, 0.45-0.73; P < .001). In terms of PFS, pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy with an HR of PFS 0.52 (95% CI, 0.27-0.99; P = .048) for the subgroup with PD-L1 TPS ≥ 50%., Conclusions: For patients with NSCLC with PD-L1 TPS ≥ 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy in this meta-analysis. To confirm this finding, a prospective phase III trial that directly compares the treatments is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Assays to identify circulating tumor cells (CTCs) might allow for noninvasive and sequential monitoring of lung cancer. We investigated whether serial CTC analysis could complement conventional imaging for detecting recurrences after treatment in patients with locally advanced non-small-cell lung cancer (LA-NSCLC)., Patients and Methods: Patients with LA-NSCLC (stage II-III) who definitively received concurrent chemoradiation were prospectively enrolled, with CTCs from peripheral blood samples identified using an adenoviral probe that detects elevated telomerase activity present in nearly all lung cancer cells. A "detectable" CTC level was defined as 1.3 green flourescent protein-positive cells per milliliter of collected blood. Samples were obtained before, during (at weeks 2, 4, and 6), and after treatment (post-radiation therapy [RT]; at months 1, 3, 6, 12, 18, and 24)., Results: Forty-eight patients were enrolled. At a median follow-up of 10.9 months, 22 (46%) patients had disease recurrence at a median time of 7.6 months post-RT (range, 1.3-32.0 months). Of the 20 of 22 patients for whom post-RT samples were obtained, 15 (75%) had an increase in CTC counts post-RT. In 10 of these 15 patients, CTCs were undetectable on initial post-RT draw but were then detected again before radiographic detection of recurrence, with a median lead time of 6.2 months and mean lead time of 6.1 months (range, 0.1-12.0 months) between CTC count increase and radiographic evidence of recurrence. One patient with an early recurrence (4.7 months) had persistently elevated detectable CTC levels during and after treatment., Conclusion: These results indicate that longitudinal CTC monitoring in patients with LA-NSCLC treated with chemoradiation is feasible, and that detectable CTC levels in many patients meaningfully precede radiologic evidence of disease recurrence., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Facial mimicry, the unconscious imitation of others' affective facial expressions, serves as an important basis for interpersonal communication. Although there are many studies dealing with this phenomenon regarding the interaction between adults, only few experiments have explored facial mimicry in response to affective facial expressions of children. In the following study affect-prototypical video clips of children's and adults' faces were presented to 44 adults while the activity of corrugator supercilii and zygomaticus muscles was electromyographically measured. A discrete mimic reaction was detected in response to each basic affect (fear, disgust, happiness, sadness, surprise and anger). The activity of corrugator supercilii muscle was significantly lower when affective facial expressions of children were presented in contrast to those of adults. In addition, negative correlations between alexithymia and the averaged facial EMG activity were detected., (Copyright © 2019. Published by Elsevier B.V.)

An organoid is a complex, multi-cell three-dimensional (3D) structure that contains tissue-specific cells. Epithelial stem cells, which are marked by leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), have the potential for self-renewal and expansion as organoids. However, in the case of intestinal organoids from Lgr5-EGFP-IRES-CreERT2 transgenic mice, in vitro expansion of the Lgr5 expression is limited in a culture condition supplemented with essential proteins, such as epidermal growth factor (E), noggin (N), and R-spondin 1 (R). In this study, we hypothesized that self-renewal of Lgr5+ stem cells in a 3D culture system can be stimulated by defined compounds (CHIR99021, Valproic acid, Y-27632, and A83-01). Our results demonstrated that dissociated single cells from organoids were organized into a 3D structure in the four compounds containing the ENR culture medium in a 3D and two-dimensional (2D) culture system. Moreover, the Lgr5 expression level of organoids from the ENR- and compound-containing media increased. Furthermore, the conversion of cultured Lgr5+ stem cells from 2D to 3D was confirmed. Therefore, defined compounds promote the expansion of Lgr5+ stem cells in organoids., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background & Aims: Dietetic interventions contribute to certain health objectives and other outcomes, but are mostly part of a multimodal and multidisciplinary approach what makes evaluating the actual effects of dietitians' involvement rather complex. Although monitoring and outcome evaluation (M&OE) can provide routine data to prove the effectiveness of dietetic interventions, this has not been established yet in different dietetic settings., Methods: A comprehensive framework for M&OE in dietetics was developed by dietetic experts from five European higher education institutes for dietetics in the course of the EU sponsored project "Improvement of Education and Competences in Dietetics (IMPECD)"., Results: Firstly, clear definitions on M&OE are proposed to facilitate the use of consistent terminology, with a specific emphasis on the term "impact" covering macro-level outcomes such as cost-effectiveness. Secondly, the Dietetic Care Process (DCP) was merged into a logic model to demonstrate the position of M&OE in relation to intervention planning and implementation, in both group and individual settings. Thirdly, selecting the appropriate indicators is indispensable to monitor and evaluate outcomes, and requires a high level of dietitians' critical reasoning. A categorized overview of indicators is provided to support this process. Lastly, the consortium developed a checklist to give dietitians a handle on what elements could be included in their M&OE plan and trigger them to perform M&OE in practice., Conclusions: Innovative M&OE models may help dietitians to demonstrate their effectiveness in improving clinical outcomes and justify their role in health care., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study analyzes fishers', managers' and scientists' opinions on management measures to facilitate the initiation of management processes towards more sustainable small-scale seagrass fisheries in Zanzibar, Tanzania. The results show that most fishers and managers agreed on the need to include seagrasses specifically in future management. There was further agreement on dragnets being the most destructive gears, and the use of dragnets being a major threat to local seagrass ecosystems. Gear restrictions excluding illegal dragnets were the favored management measure among fishers. Differences between fishers and managers were found concerning seaweed farming, eutrophication and erosion being potential threats to seagrass meadows. A majority of the interviewed fishers were willing to participate in monitoring and controls, and most fishers thought that they themselves and their communities would benefit the most from establishing seagrass management. Co-managed gear restrictions and the inclusion of different key actos in the management process including enforcement are promising starting points for management implementation., (Copyright © 2017. Published by Elsevier Ltd.)

A 13-year-old male castrated pomeranian cross was referred for evaluation of episodes of collapse and a suspected cardiac mass. The presence of a mass at the base of the heart within the pericardial space was confirmed by echocardiography. Additional diagnostics included computed tomography, ultrasound-guided fine-needle aspirate, and thoracic radiographs. The mass was surgically debulked and diagnosed as myxosarcoma via histopathology. This case report describes the diagnostic imaging, laboratory findings, and short-term positive clinical outcome of a dog with a myxosarcoma in a previously undescribed location., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Reirradiation of thoracic malignancies is a treatment challenge, with concerns for toxicity and the inability to deliver definitive doses. Intensity modulated proton therapy (IMPT) may allow safe delivery of a higher dose of radiation to the tumor while minimizing toxicities., Methods and Materials: Between 2011 and 2016, 27 patients who received IMPT for reirradiation of thoracic malignancies with definitive intent were retrospectively analyzed. Patients were included if they received a prior thoracic radiation course. All doses were recalculated to an equivalent dose in 2-Gy fractions (EQD2). Patients received IMPT to a median dose of 66 EQD2 Gy (range, 43.2-84 Gy) for recurrence of thoracic cancer (93%) or sequentially after a course of thoracic stereotactic ablative radiation therapy (7%)., Results: Twenty-two patients (81%) were treated for non-small cell lung cancer. The median time to reirradiation was 29.5 months. At a median follow-up for all patients of 11.2 months (25.9 surviving patients), the median overall survival was 18.0 months, with a 1-year overall survival of 54%. Four patients (15%) experienced an in-field local failure (LF), with a 1-year freedom from LF rate of 78%. The 1-year freedom from locoregional failure and 1-year progression-free survival rates were 61% and 51%, respectively. Patients who received 66 EQD2 Gy or higher had improved 1-year freedom from LF (100% vs 49%; P = .013), 1-year freedom from locoregional failure (84% vs 23%; P = .035), and 1-year progression-free survival (76% vs 14%; P = .050). Reirradiation was well tolerated, with only 2 patients (7%) experiencing late grade 3 pulmonary toxicity, and none with grade 3 or higher esophagitis. There were no grade 4-5 toxicities., Conclusions: These data represent the largest series of patients treated with IMPT for definitive reirradiation of thoracic cancers. They demonstrate that IMPT provided durable local control with minimal toxicity and suggest that higher doses may improve outcomes., (Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Prostate cancer (PCa) currently is the second most diagnosed cancer in men and the second most cause of cancer death after lung cancer in Western societies. This sets the necessity of modelling prostatic disorders to optimize a therapy against them. The conventional approach to investigating prostatic diseases is based on two-dimensional (2D) cell culturing. This method, however, does not provide a three-dimensional (3D) environment, therefore impeding a satisfying simulation of the prostate gland in which the PCa cells proliferate. Cryogel scaffolds represent a valid alternative to 2D culturing systems for studying the normal and pathological behavior of the prostate cells thanks to their 3D pore architecture that reflects more closely the physiological environment in which PCa cells develop. In this work the 3D morphology of three potential scaffolds for PCa cell culturing was investigated by means of synchrotron X-ray computed micro tomography (SXCμT) fitting the according requirements of high spatial resolution, 3D imaging capability and low dose requirements very well. In combination with mechanical tests, the results allowed identifying an optimal cryogel architecture, meeting the needs for a well-suited scaffold to be used for 3D PCa cell culture applications. The selected cryogel was then used for culturing prostatic lymph node metastasis (LNCaP) cells and subsequently, the presence of multi-cellular tumor spheroids inside the matrix was demonstrated again by using SXCμT., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Locally advanced breast cancer (LABC) is a major problem, especially in developing countries. The standard treatment for LABC is neoadjuvant chemotherapy, with or without anti-Her2 therapy, followed by surgery, radiotherapy, and adjuvant systemic treatment if appropriate. However, there are few data in the literature addressing alternatives when neoadjuvant chemotherapy fails to reduce the tumour for surgery., Materials and Methods: We conducted a retrospective study including all patients who had non-metastatic LABC treated with neoadjuvant chemotherapy and who were not eligible for surgical resection; these patients were submitted to salvage radiotherapy (RTX) between January 2000 and December 2012 at the Brazilian National Cancer Institute., Results: Fifty-seven patients were included, with a median age of 51 (23-72) years. The most frequent clinical stages were IIIA and IIIB, corresponding to 19.3% and 70.2%, respectively; mean tumour size was 8.74 (3-18) cm, and 44 patients (77.2%) had nodal involvement. Chemotherapeutic regimens containing anthracyclines were prescribed to 98.2% of the patients. Fifteen patients (26.3%) received taxanes and anthracyclines. Radiation dose was 50 Gy divided into 25 fractions; 43 patients (75.4%) had their tumours downsized by RTX and underwent mastectomy. Overall survival (OS) was 38 (23-52) months. Patients who were submitted to surgery had an OS of 49 (28-70) months and those who were not eligible for mastectomy after radiotherapy had an OS of 18 (9-27) months., Conclusion: This retrospective study confirms that RTX is an effective treatment to downsize LABC tumours with low or no response to chemotherapy, thereby enabling surgical resection which may improve overall patient outcome., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: This study aims to compare fat fraction of lumbar vertebrae between cancer and non-cancer patients, using the two-point modified Dixon (mDixon) turbo spin-echo (TSE) MRI with flexible echo times and multipeak fat spectral model., Materials and Methods: Fat fraction was calculated from fat and water images reconstructed by the mDixon TSE technique. Fat fraction of fat-water phantoms measured with the mDixon TSE method was compared with actual fat percentages. Patients who had undergone mDixon spine MRI and dual-energy X-ray absorptiometry within one year and had no bone metastasis were divided into cancer (n=7) and non-cancer (n=23) groups. Fat fraction and bone mineral density (BMD) were compared between the two groups., Results: Fat fraction of phantoms measured with mDixon MRI was highly correlated with their actual fat percentages (P<0.01, R(2)=0.93). Fat fraction of lumbar vertebrae was significantly lower in cancer patients (58.27±3.16%) than in non-cancer patients (70.48±1.83%) (P<0.01). BMD was not different between cancer (0.912±0.057g/cm(2)) and non-cancer patients (0.876±0.032g/cm(2)) (P=0.58). Fat fraction and BMD showed no significant correlation (P=0.95, R=0.006)., Conclusions: A two-point mDixon TSE method for assessing fat fraction was reliable. Fat fraction of morphologically normal lumbar vertebrae was significantly lower in cancer patients compared to non-cancer patients, using the two-point mDixon TSE technique., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Species sensitivity evaluation represents an approach to avoid chronic toxicity testing of aquatic vertebrates in accordance with the animal welfare concept of the EU chemicals regulation. In this study a data set of chemicals is analysed for relative species sensitivity between Daphnia and fish in chronic testing to evaluate under what condition chronic fish tests can be waived without underestimating the environmental hazard. Chronic fish toxicity is covered in 84% of the evaluated substances by the chronic invertebrate test and an assessment factor of 50. Thus, animal testing can be avoided in environmental hazard assessment for many chemicals. Moreover, it is shown that species sensitivity in chronic testing is associated with species sensitivity in acute testing. The more sensitive species in chronic testing is predicted with a high probability if a species is >5x more sensitive in acute testing. If substances are comparable or more toxic to Daphnia in acute testing than to fish chronic fish toxicity is covered by the chronic Daphnia test and an assessment factor of 50 in about 95% of the evaluated cases. To provide decision support for the regulation of chemicals a categorization scheme on relative sensitivity comparison is presented., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Cardiac contractility was evaluated using standard inotropic agents in rats. We compared indices of cardiac contractility, i.e. LV dP/dt max from telemetry while simultaneously collecting EF (ejection fraction) and FS (fractional shortening) measures from echocardiography., Methods: Male Wistar rats were instrumented with telemetry devices for measurements of blood pressure and left ventricular pressure. Milrinone (PDE III inhibitor) and verapamil (L-type calcium channel blocker) at doses of 0, 3, 10, and 30 mg/kg were administered orally using a 4 × 4 Latin square crossover study design. Telemetry data were recorded at predose and continuously for 24h post-dose. Echocardiographic evaluations were conducted once at predose and at 1 and 2h after milrinone or verapamil administration, respectively. During the recording of echocardiograms, telemetry data were collected simultaneously. Blood samples were also collected to confirm plasma drug exposure., Results: As expected, milrinone increased LV dP/dt max, EF and FS while verapamil decreased LV dP/dt max, EF and FS. Linear regression analysis showed a positive correlation between LV dP/dt max and EF or FS (P<0.001) with both test agents. A change in LV dP/dt max of 1000 mmHg/s was found to correspond with a change in EF and FS of 13 and 16%, respectively, in the telemetered rat., Discussion: The correlation between contractility indices assessed by telemetry and echocardiographic methods in rat models has not received much attention to date. Our results with two reference compounds demonstrate that both methods are sensitive to alterations in contractility induced by inotropic agents administered to rats. The high degree of correlation between changes in LV dP/dt max and EF or FS in the rat enables a translational-element of clinical relevance following changes in contractility indices when measured with telemetry devices in preclinical studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Waterbirds can reallocate a considerable amount of nutrients within agricultural fields and between agriculture sites and wetlands. However their effects on biogeochemical cycles have rarely been quantified. We estimated bird numbers, diet (from stable isotope analysis), food supply, and the food consumption on rice fields by overwintering waterbirds in one of the most important areas for rice production in southwestern Europe and a key area for various migrating and resident waterbird species. Herein, we modelled the nutrient (N and P) recycling in rice fields, and their transport to reservoirs. The energy consumption by waterbirds (96,605±18,311 individuals) on rice fields during winter averaged at 89.9±39.0 kJ·m(-2), with its majority (89.9%) belonging to foraging on rice seeds. Thus, the birds removed about 26% of rice seeds leftover after harvest (estimated in 932.5±504.7 seeds·m(-2) in early winter) wherein common cranes and dabbling ducks (four species) were the most important consumers. Waterbirds foraging and roosting in the rice fields recycled more than 24.1 (1.0 kg·ha(-1)) of N and an additional 5.0 tons (0.2 kg·ha(-1)) of P in the Extremadura's rice fields during winter. Additionally, we estimated that 2.3 tons of N and 550 kg of P were removed from rice fields and transported to reservoirs. The seasonal foraging of wildlife should result in a direct benefit for rice farmers by improving nutrient recycling through defecation by waterbirds with respect to artificial fertilisation. Additionally, rice fields located in the cranes' core wintering areas can provide sufficient food supply to induce habitat shift from their traditional wintering habitat in 'dehesas' to rice fields, which causes indirect socioeconomic benefit through reduced acorn consumption by cranes. Our modelling approach may thus be especially helpful for management decisions regarding rice agroecosystems in areas which are also important for the conservation of migratory waterbirds., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: To report vision-threatening ocular manifestations of primary Sjögren's syndrome (SS)., Design: Retrospective review., Participants: Consecutive patients evaluated at an SS center between January 2007 and May 2011., Methods: Data collection was completed in March 2013. The 2002 American-European consensus criteria were used for diagnosis of SS., Main Outcome Measures: Frequency of extraglandular ocular findings and timing of their diagnosis relative to that of SS and dry eye were assessed., Results: One hundred sixty-three patients were included. Almost all patients (98%) had a history of dry eye for an average of 10.4 years (median, 7.9 years) before presentation. One or more extraglandular ocular manifestations were present in 40 patients (25%), and vision-threatening findings were present in 22 patients (13%). Twelve patients (55%) with a vision-threatening ocular finding did not have a diagnosis of SS at presentation. Sixty-eight patients (42%) had extraglandular systemic manifestations of SS. Patients with vision-threatening ocular findings were 3.9 times more likely to have systemic involvement (95% confidence interval, 1.4-11.0; P = 0.010). Peripheral neuropathy, interstitial nephritis, and vasculitis were more common in those with vision-threatening ocular findings compared with patients without (P < 0.05 for all)., Conclusions: These results from a tertiary referral-based cohort demonstrate that primary SS frequently is associated with ocular and systemic complications. Dry eye precedes these findings on average by 1 decade. Therefore, ophthalmologists should consider assessing for SS in patients with clinically significant dry eye., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Kappa is a widely used measure of agreement. However, it may not be straightforward in some situation such as sample size calculation due to the kappa paradox: high agreement but low kappa. Hence, it seems reasonable in sample size calculation that the level of agreement under a certain marginal prevalence is considered in terms of a simple proportion of agreement rather than a kappa value. Therefore, sample size formulae and nomograms using a simple proportion of agreement rather than a kappa under certain marginal prevalences are proposed., Methods: A sample size formula was derived using the kappa statistic under the common correlation model and goodness-of-fit statistic. The nomogram for the sample size formula was developed using SAS 9.3., Results: The sample size formulae using a simple proportion of agreement instead of a kappa statistic and nomograms to eliminate the inconvenience of using a mathematical formula were produced., Conclusions: A nomogram for sample size calculation with a simple proportion of agreement should be useful in the planning stages when the focus of interest is on testing the hypothesis of interobserver agreement involving two raters and nominal outcome measures., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Interest in global health and international electives is growing among Emergency Medicine (EM) residents in the United States (US). The majority of EM residency programs offer opportunities for international electives. The degree of participation among residents and type of support provided by the residency program, however, remains unclear., Study Objectives: To explore the current state of global health education among EM residents who participate in international electives., Methods: A 12-question survey was e-mailed to the program directors of the 192 EM residency programs in the US. The survey included questions about the number of residents participating in international electives and the types of preparation, project requirements, supervision, and feedback participating residents receive., Results: The response rate was 53% with 102 responses. Seventy-five of 102 (74%) programs reported that at least one resident participated in an international elective in the 2010-2011 academic year. Forty-three programs (42%) report no available funding to support any resident on an international elective. Residents receive no preparation for international work in 41 programs (40%). Only 25 programs (26%) required their residents to conduct a project while abroad. Forty-nine programs (48%) reported no formal debriefing session, and no formal feedback was collected from returning residents in 57 of 102 (59%) programs., Conclusion: The majority of EM residencies have residents participating in international electives. However, the programs report variable preparation, requirements, and resident supervision. These results suggest a need for an expanded and more structured approach to international electives undertaken by EM residents., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To develop and validate a new risk-of-bias tool for nonrandomized studies (NRSs)., Study Design and Setting: We developed the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). A validation process with 39 NRSs examined the reliability (interrater agreement), validity (the degree of correlation between the overall assessments of RoBANS and Methodological Index for Nonrandomized Studies [MINORS], obtained by plotting the overall risk of bias relative to effect size and funding source), face validity with eight experts, and completion time for the RoBANS approach., Results: RoBANS contains six domains: the selection of participants, confounding variables, the measurement of exposure, the blinding of the outcome assessments, incomplete outcome data, and selective outcome reporting. The interrater agreement of the RoBANS tool except the measurement of exposure and selective outcome reporting domains ranged from fair to substantial. There was a moderate correlation between the overall risks of bias determined using RoBANS and MINORS. The observed differences in effect sizes and funding sources among the assessed studies were not correlated with the overall risk of bias in these studies. The mean time required to complete RoBANS was approximately 10 min. The external experts who were interviewed evaluated RoBANS as a "fair" assessment tool., Conclusions: RoBANS shows moderate reliability, promising feasibility, and validity. The further refinement of this tool and larger validation studies are required., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Abdominal aortic aneurysms (AAA) are a growing problem worldwide, yet there is no known medical therapy. The pathogenesis involves degradation of the elastic lamina by two combined mechanisms: increased degradation of elastin by matrix metalloproteinases (MMP) and decreased formation of elastin due to apoptosis of vascular smooth muscle cells (VSMC). In this study, we set out to examine the potential role of stem cells in the attenuation of AAA formation by inhibition of these pathogenetic mechanisms. Muscle-derived stem cells from murine skeletal muscles were isolated and stimulated with PDGF-BB in vitro for differentiation to VSMC-like progenitor cells (VSMC-PC). These cells were implanted in to elastase-induced AAAs in rats. The cell therapy group had decreased rate of aneurysm formation compared to control, and MMP expression at the genetic, protein and enzymatic level were also significantly decreased. Furthermore, direct implantation of VSMC-PCs in the intima of harvested aortas was visualized under immunofluorescent staining, suggesting that these cells were responsible for the inhibition of MMPs and consequent attenuation of AAA formation. These results show a promising role of stem cell therapy for the treatment of AAAs, and with further studies, may be able to reach clinical significance., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Delaying childbirth increases the proportion of advanced maternal age pregnancies. This increases the number of pregnancies requiring invasive prenatal testing. Prenatal diagnosis of chromosomal aneuploidies and monogenic disorders requires fetal cells obtained through invasive procedures (i.e. chorionic villus sampling and amniocentesis). These procedures carry a risk of fetal loss, which causes anxiety to at-risk couples. Intact fetal cells entering maternal circulation have raised the possibility of non-invasive prenatal diagnosis. Rarity of fetal cells, however, has made it challenging. Fetal nucleated red blood cells are ideal candidate target cells because they have limited lifespan, contain true representation of fetal genotype, contain specific fetal cell identifiers (embryonic and fetal globins), and allow interrogation with chromosomal fluorescence in-situ hybridisation and possibly with array comparative genomic hybridisation. The utility of fetal nucleated red blood cells in non-invasive prenatal diagnosis has not reached clinical application because of the inconsistencies in enrichment strategies and rarity of cells., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that has been reported to reduce the risk of developing Alzheimer's disease (AD). Its preventive effects in AD are likely pleiotropic as ibuprofen displays both anti-inflammatory activity by inhibition of cyclooxygenases and anti-amyloidogenic activity by modulation of γ-secretase. In order to study the anti-inflammatory properties of ibuprofen independent of its anti-amyloidogenic activity, we performed a long-term treatment study with ibuprofen in 5XFAD mice expressing a presenilin-1 mutation that renders this AD model resistant to γ-secretase modulation. As expected, ibuprofen treatment for 3 months resulted in a reduction of the inflammatory reaction in the 5XFAD mouse model. Importantly, an unchanged amyloid beta (Aβ) plaque load, an increase in soluble Aβ42 levels, and an aggravation of some behavioral parameters were noted, raising the question whether suppression of inflammation by nonsteroidal anti-inflammatory drug is beneficial in AD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Prostate cancer patients face important treatment decisions. The role of adjuvant and salvage radiotherapy (RT) is now less controversial in terms of the timing of the treatment after radical prostatectomy, because few randomized trials demonstrated the benefit of early RT in terms of biochemical control and improved survival., Purpose: To evaluate the informational needs of prostate patients referred to Odette Cancer Centre for post-prostatectomy adjuvant or salvage RT. In addition, we investigated how social determinants of health, such as income and education affected these needs., Methods: A needs assessment questionnaire was developed and piloted among 10 prostate cancer patients. A 4-point Likert scale was used to examine patients' knowledge and understanding of various aspects of post-prostatectomy RT., Results: The most frequent patient response corresponded to having "some" knowledge about the topic (Likert scale 3), except for two items, which included knowledge about survival rates for different treatment options and management of side effects related to radiation treatment (Likert scale 2: "a little"). No causative relationship was found between the patients' income and/or education, and their knowledge of various treatment aspects., Conclusions: This study demonstrated that even though our patients had some knowledge about prostate cancer and its treatments, they may still require more information regarding the management of RT-related side effects, local recurrence, and survival rates after post-prostatectomy RT. These findings will be used to conduct a thorough informational needs assessment to aid in the future development and testing of an educational tool for patients with prostate cancer after radical prostatectomy, that will assist them in making decisions about their adjuvant or salvage treatment options., (Copyright © 2011. Published by Elsevier Inc.)

Unlabelled: Superficial radial nerve injury, incomplete release of the first extensor compartment, palmar subluxation of the tendons and painful scar are the main reasons for persistent pain and dysfunction after open release. We therefore asked whether the endoscopic release of the first extensor compartment is advantageous over the open release in terms of subjective pain and disability, complication and aesthetic appearance., Methods: Fifty wrists treated with either open release (26 wrists) or endoscopic release (24 wrists) of the first extensor compartment in case of de Quervain's disease were included. All patients were evaluated at a minimum of 1-year follow-up using visual analogue scale (VAS) pain ratings and the Disabilities of Arm, Shoulder and Hand (DASH) score., Results: The average operating time of endoscopic release was 4 min longer than that of open release. The mean VAS pain score was improved from an initial 6.4 to 0.5 in the open release group and from 6.7 to 0.1 in the endoscopic release group. The mean DASH score was improved from 60.1 to 6.8 in the open release group and from 64.4 to 1.5 in the endoscopic release group. No clinically significant difference was found between the two groups regarding subjective VAS pain and DASH scores at the last follow-up. In the open release group, superficial radial nerve injuries (five wrists), significant scar tenderness (three) and unsightly scar (six) were identified., Conclusions: Endoscopic release of the extensor compartment seems to be an effective and safe procedure in patients with de Quervain's disease who are unresponsive to non-operative treatments, despite a little increase in operation time., (Copyright © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Cargos destined to enter or leave the cell nucleus are typically transported by receptors of the importin β family to pass the nuclear pore complex. The yeast Saccharomyces cerevisiae comprises 14 members of this protein family, which can be divided in importins and exportins. The Ran GTPase regulates the association and dissociation of receptors and cargos as well as the transport direction through the nuclear pore. All receptors bind to Ran exclusively in its GTP-bound state and this event is restricted to the nuclear compartment. We determined the Ran-GTP binding properties of all yeast transport receptors by biosensor measurements and observed that the affinity of importins for Ran-GTP differs significantly. The dissociation constants range from 230 pM to 270 nM, which is mostly based on a variability of the off-rate constants. The divergent affinity of importins for Ran-GTP suggests the existence of a novel mode of nucleocytoplasmic transport regulation. Furthermore, the cellular concentration of β-receptors and of other Ran-binding proteins was determined. We found that the number of β-receptors altogether about equals the amounts of yeast Ran, but Ran-GTP is not limiting in the nucleus. The implications of our results for nucleocytoplasmic transport mechanisms are discussed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Rheumatoid arthritis (RA) is a chronic inflammatory disease caused by inflammation of the synovial membrane, leading in turn to articular cartilage destruction. In this work, injectable tyramine modified hyaluronic acid (HA-Tyr) hydrogels were developed for the treatment of RA. HA-Tyr conjugate was synthesized by amide bond formation between carboxyl groups of HA and amine groups of tyramine. Then, HA-Tyr hydrogels were prepared by radical crosslinking reaction using H(2)O(2) and horse-radish peroxidase. Intra-articular injection of HA-Tyr hydrogels encapsulating dexamethasone (DMT) as a model drug resulted in successful treatment of RA with reduced interlukine-6, prostaglandin E2 and four types of cytokine levels in collagen-induced arthritis animal models. Histological analysis with hematoxylin and eosin (H&E) staining also confirmed the therapeutic effect of injectable HA-Tyr hydrogels with DMT. Taken together, the injectable HA-Tyr hydrogels were thought suitable to be developed as a therapeutically effective drug carrier for the treatment of RA., (Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Preeclampsia is one of the leading causes of maternal and fetal/neonatal mortality and morbidity worldwide. Therefore, widely applicable and affordable tests are needed to make an early diagnosis before the occurrence of the clinical symptoms. Circulating cell-free nucleic acids in plasma and serum are novel biomarkers with promising clinical applications in different medical fields, including prenatal diagnosis. Quantitative changes of cell-free fetal (cff)DNA in maternal plasma as an indicator for impending preeclampsia have been reported in different studies, using real-time quantitative PCR for the male-specific SRY or DYS 14 loci. In case of early onset preeclampsia, elevated levels may be already seen in the first trimester. The increased levels of cffDNA before the onset of symptoms may be due to hypoxia/reoxygenation within the intervillous space leading to tissue oxidative stress and increased placental apoptosis and necrosis. In addition to the evidence for increased shedding of cffDNA into the maternal circulation, there is also evidence for reduced renal clearance of cffDNA in preeclampsia. As the amount of fetal DNA is currently determined by quantifying Y-chromosome specific sequences, alternative approaches such as the measurement of total cell-free DNA or the use of gender-independent fetal epigenetic markers, such as DNA methylation, offer a promising alternative. Cell-free RNA of placental origin might be another potentially useful biomarker for screening and diagnosis of preeclampsia in clinical practice. Fetal RNA is associated with subcellular placental particles that protect it from degradation. Its levels are ten-fold higher in pregnant women with preeclampsia compared to controls. In conclusion, through the use of gender-independent sequences, the universal incorporation of fetal nucleic acids into routine obstetric care and into screening or diagnostic settings using combined markers may soon become a reality. Effort has now to be put into the establishment of standardized and simplified protocols for the analysis of these biomarkers in a clinical setting., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Nitric oxide (NO) generated by the inducible isoform of nitric oxide synthase (iNOS) is involved in complex immunomodulatory and antitumoral mechanisms and has been described to have multiple beneficial microbicidal, antiviral and antiparasital effects. However, dysfunctional induction of iNOS expression seems to be involved in the pathophysiology of several human diseases. Therefore iNOS has to be regulated very tightly. Modulation of expression, on both the transcriptional and post-transcriptional level, is the major regulation mechanism for iNOS. Pathways resulting in the induction of iNOS expression vary in different cells or species. Activation of the transcription factors NF-kappaB and STAT-1alpha and thereby activation of the iNOS promoter seems to be an essential step for the iNOS induction in most human cells. However, at least in the human system, also post-transcriptional mechanisms involving a complex network of RNA-binding proteins build up by AUF1, HuR, KSRP, PTB and TTP is critically involved in the regulation of iNOS expression. Recent data also implicate regulation of iNOS expression by non-coding RNAs (ncRNAs)., (Copyright 2010 Elsevier Inc. All rights reserved.)

Normal pregnancy is associated with a systemic maternal inflammatory reaction, including the activation of peripheral blood monocytes. This reaction is exaggerated in pre-eclampsia, a severe placenta-dependent disorder of pregnancy specific to humans. It has been suggested that placental syncytiotrophoblast membrane microparticles (STBM), which are released into the peripheral blood, may contribute to the maternal response. The aim of this study was to investigate the inflammatory properties of STBM generated by four different approaches on primary human monocytes in vitro. Cellular viability, phenotype and functional response were analysed. STBM isolated by mechanical dissection and STBM generated from villous explant cultures incubated in hypoxic conditions had only minor influences on the monocytic phenotype and failed to induce a proinflammatory response. By contrast, STBM washed from the maternal side of a placental cotyledon and STBM shed by explants cultured in air up-regulated cell surface expression of the adhesion molecule CD54 and induced the production of interleukin (IL)-8, IL-6 and IL-1beta. Cytokine production was time- and dose-dependent. Our study, therefore, suggests that monocyte activation in normal pregnancy and pre-eclampsia may be induced by STBM released by the placenta. The higher amounts of STBM circulating in maternal blood in pre-eclampsia might lead to the excessive maternal inflammatory reaction., (2009 Elsevier Ltd. All rights reserved.)

Objective: To investigate associations between active and passive coping, psychiatric symptoms of depression and anxiety, and quality of life in women with polycystic ovary syndrome (PCOS). To assess the relative contribution of these coping strategies to reduced quality of life in an attempt to clarify the possible relevance of coping for impaired psychosocial well-being in PCOS., Design: Internet-based survey., Participants: 448 German women with PCOS., Methods: Coping (Freiburg Questionnaire of Coping-with-Illness), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), and quality of life (Short Form 12 Health Survey [SF-12]) were assessed in an Internet-based survey. Correlation and regression analyses were conducted., Results: In women with PCOS, passive coping was significantly associated with greater anxiety (r= .65; p < .001), depression (r= .61; p < .001), and reduced psychological quality of life (r=-.64, p < .001). In stepwise multiple regression analyses, passive coping, together with depression, anxiety and body mass index (BMI), explained 50.1% of the SF-12 psychological sum score, while active coping did not enter any regression model., Conclusion: Data suggested that faced with the diagnosis of PCOS, passive coping may constitute a maladaptive strategy associated with anxiety and depression symptoms and compromised quality of life. Hence, efforts to incorporate psychosocial aspects into counselling and care for women with PCOS should take coping strategies into consideration. Nurses and other health care providers may help to improve coping strategies through education and psychosocial support in women with PCOS.

Preimplantation genetic diagnosis (PGD) is usually used to establish a non-affected pregnancy for those couples facing a genetic risk of having an affected child. However, an invasive test is still recommended to all PGD patients due to the risk of misdiagnosis. The discovery of cell-free fetal DNA in maternal plasma provides the possibility for noninvasive prenatal diagnosis. Studies have shown that fetal single-gene disorders can be detected in cell-free fetal DNA by the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) assay with single-allele base extension reaction (SABER) approach or by the size-fractionation approach, whereby cell-free fetal DNA is enriched on the basis of its smaller size compared with maternal DNA fragments. Recent studies have indicated that a combination of the two approaches increases the accuracy of detection. This study combined the two methods and examined fetal paternally inherited gene mutations in maternal plasma obtained from four PGD-conducted pregnancies. The presence or absence of mutations was correctly detected in all cases. This combined method could be used for risk-free prenatal diagnosis of diseases caused by single-gene mutations, and in particular for couples who undergo PGD who opt not to perform invasive prenatal confirmation due to the risk of abortion.

It has recently been reported that high concentrations of circulating cell-free (ccf) nucleic acids in plasma and serum could be used as biomarkers for non-invasive monitoring a wide variety of malignant and benign proliferations and inflammatory conditions. Endometriosis is one of the most common benign gynaecological proliferations with inflammatory activation in premenopausal women. Real-time multiplex polymerase chain reaction was used for synchronized quantification of the glyceraldehyde-3-phosphate dehydrogenase gene sequence in nuclear DNA (nDNA) and the ATP synthase-8 gene sequence in mitochondrial DNA (mtDNA). DNA was extracted from 500 microl serum and plasma of 19 cases with endometriosis to measure the total amount of ccf nDNA and ccf mtDNA. The concentration of ccf nDNA in plasma was significantly higher in the endometriosis group than in the control group (P = 0.046). The cut-off value selected by a receiver operating characteristic curve could provide a sensitivity of 70% and a specificity of 87% to discriminate between the minimal or mild cases and normal controls. The finding of significantly increased concentrations of ccf nDNA in plasma of patients with endometriosis suggests that ccf nDNA might be a potential biomarker for developing non-invasive diagnostic test in endometriosis.

The clinical features of the maternal syndrome of pre-eclampsia can be explained by generalised maternal endothelial cell dysfunction, which is a part of a more global maternal systemic inflammatory response. There is growing evidence that these effects are associated with the shedding of cellular debris, including syncytiotrophoblast microparticles (STBM), cell-free DNA and mRNA, from the surface of the placenta (syncytiotrophoblast) into the maternal circulation. The increased shedding of this debris seen in pre-eclampsia is believed to be caused by placental ischaemia, reperfusion and oxidative stress. This study was carried out to determine whether uterine contractions during labour and subsequent placental separation lead to an acute increase in the release of placental debris into the maternal circulation. To assess the effects of labour, samples were taken from 10 normal pregnant (NP) and 10 pre-eclamptic (PE) women at varied time points. Similarly to assess the effects of placental delivery, plasma samples were taken from 10 NP and 10 PE women undergoing elective caesarean section. There was a significant increase in the shedding of STBM in pre-eclampsia which was not seen in normal pregnancy and there was a small rise in STBM levels at placental separation in both normal pregnant and pre-eclamptic women undergoing caesarean section, but the differences were not significant. However, levels of placental cell-free corticotrophin releasing hormone mRNA were significantly increased in labour in both normal pregnancy and pre-eclampsia and were still high 24 h after delivery in the pre-eclamptic women. There was no significant increase in fetal or total DNA in labour, but the overall levels of total DNA (maternal and fetal) was increased in labour in pre-eclampsia compared to normal labour. The enhanced shedding of STBM and CRH mRNA in pre-eclampsia labour may have a role in cases of postpartum worsening of pre-eclampsia.