Adenosine triphosphatases of thermophilic archaeal double-stranded DNA viruses

Peer reviewe

Automatic Atrial Threshold Measurement and Adjustment in Pediatric Patients

Background: Automatic threshold measurement and output adjustment are used as default settings in modern pacemakers. The purpose of the study was to assess Atrial Capture Management (ACM) of Medtronic pacemakers in pediatric patients. Methods: Forty children were enrolled in two centers. Median age was 9.8 years (range 0.8–17.5 years). Half had undergone surgery for congenital heart defects; 45% of patients had an epicardial atrial lead. The pacing indication was atrioventricular block in 82% of patients and sinus node disease in 18%. Manually determined atrial thresholds and ACM measurements were compared. Results: ACM measurements were within the expected variation in 37/40 (93%) of the patients. In one patient the threshold was 0.625-V lower manually than with ACM. One patient had too high an intrinsic atrial rate for ACM to be able to measure threshold. The mean threshold at 0.4 ms was 0.69 ± 0.32 V manually and 0.68 ± 0.35 V with ACM (two-tailed paired t- test, P = 0.52) in all patients. The mean difference was 0.012 V (95% confidence interval: −0.027, 0.053). The mean endocardial threshold was 0.70 ± 0.36 V manually and 0.69 ± 0.38 V with ACM; epicardial threshold was 0.67 ± 0.27 V manually and 0.68 ± 0.32 V with ACM. The difference between the measurements was 0.012 V for endocardial and 0.014 V for epicardial leads. No atrial arrhythmias due to ACM measurements were observed. Conclusions: ACM measures atrial thresholds reliably in pediatric patients with both endocardial and epicardial leads, allowing its use in both. Constant high intrinsic atrial rate may prevent automatic threshold measurement in young children. (PACE 2010; 33:309–313)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79326/1/j.1540-8159.2009.02619.x.pd

The C-Type Lectin of the Aggrecan G3 Domain Activates Complement

Excessive complement activation contributes to joint diseases such as rheumatoid arthritis and osteoarthritis during which cartilage proteins are fragmented and released into the synovial fluid. Some of these proteins and fragments activate complement, which may sustain inflammation. The G3 domain of large cartilage proteoglycan aggrecan interacts with other extracellular matrix proteins, fibulins and tenascins, via its C-type lectin domain (CLD) and has important functions in matrix organization. Fragments containing G3 domain are released during normal aggrecan turnover, but increasingly so in disease. We now show that the aggrecan CLD part of the G3 domain activates the classical and to a lesser extent the alternative pathway of complement, via binding of C1q and C3, respectively. The complement control protein (CCP) domain adjacent to the CLD showed no effect on complement initiation. The binding of C1q to G3 depended on ionic interactions and was decreased in D2267N mutant G3. However, the observed complement activation was attenuated due to binding of complement inhibitor factor H to CLD and CCP domains. This was most apparent at the level of deposition of terminal complement components. Taken together our observations indicate aggrecan CLD as one factor involved in the sustained inflammation of the joint

Learning how to understand complexity and deal with sustainability challenges : A framework for a comprehensive approach and its application in university education

Sustainability challenges such as climate change, biodiversity loss, poverty and rapid urbanization are complex and strongly interrelated. In order to successfully deal with these challenges, we need comprehensive approaches that integrate knowledge from multiple disciplines and perspectives and emphasize interconnections. In short, they aid in observing matters in a wider perspective without losing an understanding of the details. In order to teach and learn a comprehensive approach, we need to better understand what comprehensive thinking actually is. In this paper, we present a conceptual framework for a comprehensive approach, termed the GHH framework. The framework comprises three dimensions: generalism, holism, and holarchism. It contributes to the academic community's understanding of comprehensive thinking and it can be used for integrating comprehensive thinking into education. Also, practical examples of the application of the framework in university teaching are presented. We argue that an ideal approach to sustainability challenges and complexity in general is a balanced, dialectical combination of comprehensive and differentiative approaches. The current dominance of specialization, or the differentiative approach, in university education calls for a stronger emphasis on comprehensive thinking skills. Comprehensiveness should not be considered as a flawed approach, but should instead be considered as important an aspect in education as specialized and differentiative skills. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Indications and management of implantable cardioverter-defibrillator therapy in childhood hypertrophic cardiomyopathy

Sudden cardiac death is the most common mode of death during childhood and adolescence in hypertrophic cardiomyopathy, and identifying those individuals at highest risk is a major aspect of clinical care. The mainstay of preventative therapy is the implantable cardioverter-defibrillator, which has been shown to be effective at terminating malignant ventricular arrhythmias in children with hypertrophic cardiomyopathy but can be associated with substantial morbidity. Accurate identification of those children at highest risk who would benefit most from implantable cardioverter-defibrillator implantation while minimising the risk of complications is, therefore, essential. This position statement, on behalf of the Association for European Paediatric and Congenital Cardiology (AEPC), reviews the currently available data on established and proposed risk factors for sudden cardiac death in childhood-onset hypertrophic cardiomyopathy and current approaches for risk stratification in this population. It also provides guidance on identification of individuals at risk of sudden cardiac death and optimal management of implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy

Bone marrow mesenchymal stem cells do not enhance intra-synovial tendon healing despite engraftment and homing to niches within the synovium

Intra-synovial tendon injuries display poor healing, which often results in reduced functionality and pain. A lack of effective therapeutic options has led to experimental approaches to augment natural tendon repair with autologous mesenchymal stem cells (MSCs) although the effects of the intra-synovial environment on the distribution, engraftment and functionality of implanted MSCs is not known. This study utilised a novel sheep model which, although in an anatomically different location, more accurately mimics the mechanical and synovial environment of the human rotator cuff, to determine the effects of intra-synovial implantation of MSCs

Quantification of Dynamic Morphological Drug Responses in 3D Organotypic Cell Cultures by Automated Image Analysis

Glandular epithelial cells differentiate into complex multicellular or acinar structures, when embedded in three-dimensional (3D) extracellular matrix. The spectrum of different multicellular morphologies formed in 3D is a sensitive indicator for the differentiation potential of normal, non-transformed cells compared to different stages of malignant progression. In addition, single cells or cell aggregates may actively invade the matrix, utilizing epithelial, mesenchymal or mixed modes of motility. Dynamic phenotypic changes involved in 3D tumor cell invasion are sensitive to specific small-molecule inhibitors that target the actin cytoskeleton. We have used a panel of inhibitors to demonstrate the power of automated image analysis as a phenotypic or morphometric readout in cell-based assays. We introduce a streamlined stand-alone software solution that supports large-scale high-content screens, based on complex and organotypic cultures. AMIDA (Automated Morphometric Image Data Analysis) allows quantitative measurements of large numbers of images and structures, with a multitude of different spheroid shapes, sizes, and textures. AMIDA supports an automated workflow, and can be combined with quality control and statistical tools for data interpretation and visualization. We have used a representative panel of 12 prostate and breast cancer lines that display a broad spectrum of different spheroid morphologies and modes of invasion, challenged by a library of 19 direct or indirect modulators of the actin cytoskeleton which induce systematic changes in spheroid morphology and differentiation versus invasion. These results were independently validated by 2D proliferation, apoptosis and cell motility assays. We identified three drugs that primarily attenuated the invasion and formation of invasive processes in 3D, without affecting proliferation or apoptosis. Two of these compounds block Rac signalling, one affects cellular cAMP/cGMP accumulation. Our approach supports the growing needs for user-friendly, straightforward solutions that facilitate large-scale, cell-based 3D assays in basic research, drug discovery, and target validation.</p