Purpose in life in patients with rheumatoid arthritis

To evaluate the role of purpose in life among people with rheumatoid arthritis (RA), a questionnaire comprising the Purpose in Life test (PIL) and the purpose in life dimension of the Psychological Well-Being test (PWB-pil) was sent to a random sample of 300 patients with RA. Additional questions comprised sociodemographic and disease characteristics, physical, mental and social functioning, coping (Coping with rheumatic stressors questionnaire), and quality of life (RAND-36). Associations between sociodemographic and disease characteristics, physical, mental and social functioning, and coping on the one side and the two measures of purpose in life on the other side and associations between the two purpose of life measures and physical and mental dimensions of quality of life were assessed by means of univariate and multivariate regression analyses. The response rate was 156 of 300 (52%). The median PIL and PWB-pil scores were 103 (range 63–131) and 82 (41–110), respectively. A lower age, a better mental health status, and an optimistic coping style were significantly associated with both higher PIL and PWB-pil scores, whereas more participation in leisure and/or social activities was associated with a higher PIL score. It was found that the PIL and PWB-pil contributed independently and significantly to the mental component summary scale of the RAND-36. In RA patients, lower age, a better mental health status, an optimistic coping style, and participation in leisure and/or social activities were significantly associated with more sense of purpose in life. Purpose in life pays a significant and independent contribution to the mental component of quality of life. These findings highlight the significance of the concept of purpose in life in patients with RA

Sustained synchronized neuronal network activity in a human astrocyte co-culture system

Impaired neuronal network function is a hallmark of neurodevelopmental and neurodegenerative disorders such as autism, schizophrenia, and Alzheimer's disease and is typically studied using genetically modified cellular and animal models. Weak predictive capacity and poor translational value of these models urge for better human derived in vitro models. The implementation of human induced pluripotent stem cells (hiPSCs) allows studying pathologies in differentiated disease-relevant and patient-derived neuronal cells. However, the differentiation process and growth conditions of hiPSC-derived neurons are non-trivial. In order to study neuronal network formation and (mal) function in a fully humanized system, we have established an in vitro co-culture model of hiPSC-derived cortical neurons and human primary astrocytes that recapitulates neuronal network synchronization and connectivity within three to four weeks after final plating. Live cell calcium imaging, electrophysiology and high content image analyses revealed an increased maturation of network functionality and synchronicity over time for co-cultures compared to neuronal monocultures. The cells express GABAergic and glutamatergic markers and respond to inhibitors of both neurotransmitter pathways in a functional assay. The combination of this co-culture model with quantitative imaging of network morphofunction is amenable to high throughput screening for lead discovery and drug optimization for neurological diseases

Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13)

The ETV6 gene (first identified as TEL) is a frequent target of chromosomal translocations in both myeloid and lymphoid leukemias. At present, more than 40 distinct translocations have been cytogenetically described, of which 13 have now also been characterized at the molecular level. These studies revealed the generation of in-frame fusion genes between different domains of ETV6 and partner genes encoding either kinases or transcription factors. However, in a number of cases-including a t(6;12)(q23;p13), the recurrent t(5;12)(q31;p13), and some cases of the t(4;12)(q11-q12;p13) described in this work-functionally significant fusions could not be identified, raising the question as to what leukemogenic mechanism is implicated in these cases. To investigate this, we have evaluated the genomic regions at 4q11-q12 and 5q31, telomeric to the breakpoints of the t(4;12)(q11-q12;p13) and t(5;12)(q31;p13). The homeobox gene GSH2 at 4q11-q12 and the IL-3/CSF2 locus at 5q31 were found to be located close to the respective breakpoints. In addition, GSH2 and IL-3 were found to be ectopically expressed in the leukemic cells, suggesting that expression of GSH2 and IL-3 was deregulated by the translocation. Our results indicate that, besides the generation of fusion transcripts, deregulation of the expression of oncogenes could be a variant leukemogenic mechanism for translocations involving the 5' end of ETV6, especially for those translocations lacking functionally significant fusion transcripts

The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia.

BACKGROUND: Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore, there is a necessity of characterizing the preclinical models from a molecular point of view. Selective reaction monitoring (SRM) has already shown promise in preclinical and clinical studies for multiplex measurement of diagnostic, prognostic and treatment-related biomarkers. METHODS: We have established an SRM assay for multiplex analysis of 7 enzymes of the glycolysis pathway which is already known to be affected in human schizophrenia and in the widely-used acute PCP rat model of schizophrenia. The selected enzymes were hexokinase 1 (Hk1), aldolase C (Aldoc), triosephosphate isomerase (Tpi1), glyceraldehyde-3-phosphate dehydrogenase (Gapdh), phosphoglycerate mutase 1 (Pgam1), phosphoglycerate kinase 1 (Pgk1) and enolase 2 (Eno2). The levels of these enzymes were analyzed using SRM in frontal cortex from brain tissue of PCP treated rats. RESULTS: Univariate analyses showed statistically significant altered levels of Tpi1 and alteration of Hk1, Aldoc, Pgam1 and Gapdh with borderline significance in PCP rats compared to controls. Most interestingly, multivariate analysis which considered the levels of all 7 enzymes simultaneously resulted in generation of a bi-dimensional chart that can distinguish the PCP rats from the controls. CONCLUSIONS: This study not only supports PCP treated rats as a useful preclinical model of schizophrenia, but it also establishes that SRM mass spectrometry could be used in the development of multiplex classification tools for complex psychiatric disorders such as schizophrenia.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Biomodd: The integration of art into transdisciplinary research practices

Biomodd is an artistic project with the potential for supporting transdisciplinary practices in blended virtual and in-person environments. After describing the project components, we discuss the collaborative process of idea generation and participant engagement.In this paper, we argue for the integration of collaborative art practice in transdisciplinary (TD) research to generate ideas and engage researchers and non-academic stakeholders. We draw on the virtual and in-person (hybrid) participation of members of the TD collective Space Ecologies Art and Design (SEADS) during Biomodd, an art installation that addresses global challenges in ecology, humanity, technology, and technological waste. Using survey responses, diaries, and meeting minutes, we reflect on the process, methods and ideation during Biomodd and map them to the concept of the “idea journey” discussed by Jill E. Perry-Smith and Pier Vittorio Mannucci. We find that while in-person ideation was driven by utility, materiality, and emergence, the hybrid mode provided favorable conditions for a feedback loop of expansive, individual experimentation and online sharing

Morbidity related to defunctioning ileostomy closure after ileal pouch-anal anastomosis and low colonic anastomosis

Purpose Defunctioning ileostomies are widely performed in order to prevent or treat anastomotic leakage after colorectal surgery. The aim of the present study was to determine morbidity related to stoma closure and to identify predictive factors of a complicated postoperative course. Methods A consecutive series of 138 patients were retrospectively analyzed after stoma reversal. Data collection included general demographics and surgery-related aspects. Morbidity related to stoma closure was retrieved from our prospectively collected registry of complications. Results In 74 of 138 patients, defunctioning ileostomy was performed after restorative proctocolectomy and ileal pouchanal anastomosis (IPAA). The remaining ileostomies (n=64) were constructed after a low colorectal or coloanal anastomosis. A total of 46 complications were recorded in 28 patients resulting in an overall complication rate of 20.3%. Anastomotic leakage rate was 4.3%, and reoperation rate was 8.0%. The number of complications according to the Clavien-Dindo classification was 5 for grade I (10.9%), 26 for grade II (56.5%), 13 for grade III (28.3%), 1 for grade IV (2.2%), and 1 for grade V (2.2%). Multivariate analysis revealed a significantly higher ASA score in the complicated group (P=0.015, odds ratio 2.6, 95% confidence interval 1.2-5.6). Conclusions Closure of a defunctioning ileostomy is associated with 20% morbidity and a reoperation rate of 8%. There is an urgent need for criteria on which a more selective use of a defunctioning ileostomy after low colonic anastomosis or IPAA can be based given its associated morbidit

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group

Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains 651% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the assessment of PD-L1/SP142 immunohistochemistry and TILs. Ten pathologists evaluated PD-L1/SP142 expression in a proficiency test comprising 28 primary TNBCs, as well as PD-L1/SP142 expression and levels of TILs in 49 distant TNBC metastases with various localizations. Interobserver agreement for PD-L1 status (positive versus negative) was high in the proficiency test: the corresponding scores as percentages showed good agreement with the consensus diagnosis. In TNBC metastases, there was substantial variability in PD-L1 status at the individual patient level. For one in five patients, the chance of treatment was essentially random, with half of the pathologists designating them as positive and half negative. Assessment of PD-L1/SP142 and TILs as percentages in TNBC metastases showed poor and moderate agreement, respectively. Additional training for metastatic TNBC is required to enhance interobserver agreement. Such training, focusing on metastatic specimens, seems worthwhile, since the same pathologists obtained high percentages of concordance (ranging from 93% to 100%) on the PD-L1 status of primary TNBCs

RegaDB: Community-driven data management and analysis for infectious diseases

Summary: RegaDB is a free and open source data management and analysis environment for infectious diseases. RegaDB allows clinicians to store, manage and analyse patient data, including viral genetic sequences. Moreover, RegaDB pr

Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving

The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery

Contains fulltext : 96401.pdf (publisher's version ) (Open Access