Predicting sinusoidal obstruction syndrome after allogeneic stem cell transplantation with the EASIX biomarker panel

No biomarker panel is established for prediction of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), a major complication of allogeneic stem cell transplantation (alloSCT). We compared the potential of the Endothelial Activation and Stress Index (EASIX), based on lactate dehydrogenase, creatinine, and thrombocytes, with that of the SOS/VOD CIBMTR clinical risk score to predict SOS/VOD in two independent cohorts. In a third cohort, we studied the impact of endothelium-active prophylaxis with pravastatin and ursodeoxycholic acid (UDA) on SOS/VOD risk. The cumulative incidence of SOS/VOD within 28 days after alloSCT in the training cohort (Berlin, 2013-2015, n=446) and in the validation cohort (Heidelberg, 2002-2009, n=380) was 9.6% and 8.4%, respectively. In both cohorts, EASIX assessed at the day of alloSCT (EASIX-d0) was significantly associated with SOS/VOD incidence (p<0.0001), overall survival (OS) and non-relapse mortality (NRM). In contrast, the CIBMTR score showed no statistically significant association with SOS/VOD incidence, and did not predict OS and NRM. In patients receiving pravastatin/UDA, the cumulative incidence of SOS/VOD was significantly lower at 1.7% (p<0.0001, Heidelberg, 2010-2015, n=359) than in the two cohorts not receiving pravastatin/UDA. The protective effect was most pronounced in patients with high EASIX-d0. The cumulative SOS/VOD incidence in the highest EASIX-d0 quartiles were 18.1% and 16.8% in both cohorts without endothelial prophylaxis as compared to 2.2% in patients with pravastatin/UDA prophylaxis (p<0.0001). EASIX-d0 is the first validated biomarker for defining a subpopulation of alloSCT recipients at high risk for SOS/VOD. Statin/UDA endothelial prophylaxis could constitute a prophylactic measure for patients at increased SOS/VOD risk

Differential sensitivity of TREK-1, TREK-2 and TRAAK background potassium channels to the polycationic dye ruthenium red

BACKGROUND AND PURPOSE: Pharmacological separation of the background potassium currents of closely related K2P channels is a challenging problem. We previously demonstrated that ruthenium red (RR) inhibits TASK-3 (K2 P 9.1), but not TASK-1 (K2 P 3.1) channels. RR has been extensively used to distinguish between TASK currents in native cells. In the present study, we systematically investigate the RR sensitivity of a more comprehensive set of K2 P channels. EXPERIMENTAL APPROACH: K+ currents were measured by two-electrode voltage clamp in Xenopus oocytes and by whole-cell patch clamp in mouse dorsal root ganglion (DRG) neurons. KEY RESULTS: RR differentiates between two closely related members of the TREK subfamily. TREK-2 (K2 P 10.1) proved to be highly sensitive to RR (IC50 = 0.2 muM), whereas TREK-1 (K2 P 2.1) was not affected by the compound. We identified aspartate 135 (D135) as the target of the inhibitor in mouse TREK-2c. D135 lines the wall of the extracellular ion pathway (EIP), a tunnel structure through the extracellular cap characteristic for K2 P channels. TREK-1 contains isoleucine in the corresponding position. The mutation of this isoleucine (I110D) rendered TREK-1 sensitive to RR. The third member of the TREK subfamily, TRAAK (K2 P 4.1) was more potently inhibited by ruthenium violet, a contaminant in some RR preparations, than by RR. DRG neurons predominantly express TREK-2 and RR-resistant TREK-1 and TRESK (K2 P 18.1) background K+ channels. We detected the RR-sensitive leak K+ current component in DRG neurons. CONCLUSIONS AND IMPLICATIONS: We propose that RR may be useful for distinguishing TREK-2 (K2P 10.1) from TREK-1 (K2P 2.1) and other RR-resistant K2 P channels in native cells

Komplexitätsmanagement in der Produktentwicklung : Holistische Modellierung, Analyse, Visualisierung und Bewertung komplexer Systeme

Complexity is one of the great challenges of our time. Therefore, especially in development, engineers must master the constantly increasing complexity in diverse domains in order to realize product and thus company success. For the appropriate modelling of the many different elements and relations of complex systems, cross-domain, integrative and thus holistic modelling approaches are required, which allow context-related, useful mathematical analysis as well as visualization possibilities in order to enable developers a multi-criteria evaluation of certain action alternatives. However, currently existing approaches are only suitable to a limited extent due to methodological deficits, their high modelling effort, limited analysis and visualization options, or their low support for multi-criteria evaluation. Therefore, this thesis introduces a concept to support developers in holistic complexity management in product development by providing contextually appropriate methods for integrated modelling, analysis, visualization, and evaluation of complex systems for goal-oriented decision making. For effective and efficient application of the methodology, an IT tool is presented that supports developers in their holistic complexity management tasks.Komplexität ist eine der großen Herausforderungen unserer Zeit. Daher müssen Ingenieure besonders in der Entwicklung die stetig steigende Komplexität in diversen Domänen beherrschen, um den Produkt- und damit Unternehmenserfolg zu realisieren. Für die zweckmäßige Modellierung der vielen verschiedenen Elemente und Relationen komplexer Systeme sind domänenübergreifende, integrative und damit holistische Modellierungsansätze erforderlich, welche jeweils kontextbezogen nützliche, mathematische Analyse- sowie Visualisierungsmöglichkeiten erlauben um Entwicklern eine multikriterielle Bewertung bestimmter Handlungsalternativen zu ermöglichen. Derzeit bestehende Ansätze eignen sich hierfür jedoch unter anderem aufgrund methodischer Defizite, ihres hohen Modellierungsaufwands, eingeschränkter Analyse- und Visualisierungsmöglichkeiten oder ihrer geringen Unterstützung bei der multikriteriellen Bewertung nur eingeschränkt. Daher wird in der vorliegenden Arbeit ein Konzept vorgestellt, mit dem Entwickler beim holistischen Komplexitätsmanagement in der Produktentwicklung unterstützt werden, indem kontextbezogen jeweils geeignete Methoden für die integrierte Modellierung, Analyse, Visualisierung und Bewertung komplexer Systeme für eine zielgerichtete Entscheidungsfindung zur Verfügung gestellt werden. Zur effektiven und effizienten Anwendung der Methodik wird ein IT-Werkzeug präsentiert, das Entwickler bei deren Aufgaben im Rahmen des holistischen Komplexitätsmanagements unterstützt

Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Correlations between arm motor behavior and brain function following bilateral arm training after stroke:A systematic review

Background Bilateral training (BT) of the upper limb (UL) might enhance recovery of arm function after stroke. To better understand the therapeutic potential of BT, this study aimed to determine the correlation between arm motor behavior and brain structure/function as a result of bilateral arm training poststroke. Methods A systematic review of quantitative studies of BT evaluating both UL motor behavior and neuroplasticity was conducted. Eleven electronic databases were searched. Two reviewers independently selected studies, extracted data and assessed methodological quality, using the Effective Public Health Practice Project (EPHPP) tool. Results Eight studies comprising 164 participants met the inclusion criteria. Only two studies rated “strong” on the EPHPP tool. Considerable heterogeneity of participants, BT modes, comparator interventions and measures contraindicated pooled outcome analysis. Modes of BT included: in-phase and anti-phase; functional movements involving objects; and movements only. Movements were mechanically coupled, free, auditory-cued, or self-paced. The Fugl-Meyer Assessment (UL section) was used in six of eight studies, however, different subsections were used by different studies. Neural correlates were measured using fMRI and TMS in three and five studies, respectively, using a wide variety of variables. Associations between changes in UL function and neural plasticity were inconsistent and only two studies reported a statistical correlation following BT. Conclusions No clear pattern of association between UL motor and neural response to BT was apparent from this review, indicating that the neural correlates of motor behavior response to BT after stroke remain unknown. To understand the full therapeutic potential of BT and its different modes, further investigation is required

Interleukin (Il)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells

Interleukin (IL)-12 may be secreted as a bioactive T helper type 1 (Th1) cell–inducing heterodimer, as a monomer, or as an antagonistic homodimer. We analyzed the IL-12 produced by mouse splenic dendritic cells (DCs), human thymic DCs, and cultured human monocyte-derived DCs. IL-12 production required both a microbial or T cell–derived stimulus and an appropriate cytokine milieu. The different IL-12 forms were differentially regulated by the cytokines present rather than the stimulus used. IL-4 alone or together with granulocyte/macrophage colony-stimulating factor or interferon γ effectively enhanced the production of the bioactive heterodimer and selectively reduced the antagonistic homodimer of IL-12. Therefore, IL-4, the major Th2-driving cytokine, provides a negative feedback causing DCs to produce the major Th1-inducing cytokine, bioactive IL-12

Intraocular lens power calculation using total keratometry and ray tracing in eyes with previous small incision lenticule extraction

Purpose: To assess the IOL power calculation accuracy in post-SMILE eyes using ray tracing and a range of total keratometry based IOL calculation formulae. Observations: Ray tracing showed excellent predictability in IOL power calculation after SMILE and its accuracy was clinically comparable with the Barrett TK Universal II and Haigis TK formula. Conclusions and importance: Incorporating posterior corneal curvature measurements into IOL power calculation after SMILE seems prudent. The ray tracing method as well as selected TK-based formulae yielded excellent accuracy and should be favored in post-SMILE eyes

Intraocular Lens Power Calculation after Small Incision Lenticule Extraction

With more than 1.5 million Small Incision Lenticule Extraction (SMILE) procedures having already been performed worldwide in an ageing population, intraocular lens (IOL) power calculation in post-SMILE eyes will inevitably become a common challenge for ophthalmologists. Since no refractive outcomes of cataract surgery following SMILE have been published, there is a lack of empirical data for optimizing IOL power calculation. Using the ray tracing as the standard of reference - a purely physical method that obviates the need for any empirical optimization - we analyzed the agreement of various IOL power calculation formulas derived from the American Society of Cataract and Refractive Surgeons (ASCRS) post-keratorefractive surgery online calculator. In our study of 88 post-SMILE eyes, the Masket formula showed the smallest mean prediction error [-0.36 +/- 0.32 diopters (D)] and median absolute error (0.33D) and yielded the largest percentage of eyes within +/- 0.50D (70%) in reference to ray tracing. Non-inferior refractive prediction errors and +/- 0.50D accuracies were achieved by the Barrett True K, Barrett True K No History and the Potvin-Hill formula. Use of these formulas in conjunction with ray tracing is recommended until sufficient data for empirical optimization of IOL power calculation after SMILE is available

3D Heads-Up Display vs. Standard Operating Microscope Vitrectomy for Rhegmatogenous Retinal Detachment

Purpose: To assess the efficacy and outcomes of 23-gauge vitreoretinal surgery for rhegmatogenous retinal detachment using a three-dimensional heads-up display (3D HUD) surgical platform as compared to a standard operating microscope (SOM) setting. Design: Retrospective cohort study. Participants: One hundred and forty consecutive eyes of 140 patients with primary retinal detachment. Methods: All eyes underwent 23-gauge pars plana vitrectomy for primary retinal detachment using either a 3D HUD (NGENUITY;Alcon Inc., Fort Worth, Texas, USA;n = 70 eyes) or a SOM setting (n = 70 eyes);in cases of significant cataract, additional phacoemulsification with intraocular lens (IOL) implantation was performed. Minimum follow-up was 2 months. Main Outcome Measures: Primary retinal reattachment rate, rate of proliferative vitreoretinopathy (PVR), best-corrected visual acuity (BCVA), and duration of surgery. Results: There were 70 eyes each in the 3D HUD and the SOM group. Both groups did not differ concerning age (p = 0.70), extent of retinal detachment (p = 0.07), number of retinal tears (p = 0.40), macular involvement (p = 0.99), and preoperative BCVA (p = 0.99). Postoperatively, 3D HUD and SOM were comparable concerning the primary retinal reattachment rate (88.6 vs. 94.3%;p = 0.37), the development of postoperative PVR (12.9% vs. 7.1%;p = 0.40) and final BCVA (0.26 +/- 0.40 vs. 0.21 +/- 0.38 logMAR;p = 0.99). Duration of surgery was significantly longer in the 3D HUD group (66.2 +/- 16.5 vs. 61.2 +/- 17.1 min;p = 0.04), an effect which however vanished after a "learning curve" of the first 35 eyes (p = 0.49). Conclusions: On par results to a conventional operating microscope can be achieved with a 3D HUD setting when performing 23-gauge vitreoretinal surgery for rhegmatogenous retinal detachment, including the primary retinal reattachment rate, the incidence of postoperative PVR and final BCVA. However, duration of surgery might initially be slightly longer with 3D HUD, suggesting the effect of a learning curve