Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis

Remyelination requires innate immune system function, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory NF-κB-dependent activation in phagocytes occurs rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88). MyD88-deficient mice and zebrafish were not only impaired in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of TNF-α in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new premyelinating oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is required for myelin debris degradation, for inflammation resolution, and for initiating the generation of new oligodendrocytes

ПРЕДРЕПЕРФУЗИОННАЯ ПОРТАЛЬНО-АРТЕРИАЛЬНАЯ ПЕРФУЗИЯ ТРАНСПЛАНТАТА ПЕЧЕНИ РАСТВОРОМ HTK, CОДЕРЖАЩИМ ТАКРОЛИМУС, УМЕНЬШАЕТ ЧАСТОТУ ВОЗНИКНОВЕНИЯ РАННЕЙ ДИСФУНКЦИИ ТРАНСПЛАНТАТА ПЕЧЕНИ

It was shown that Tacrolimus (Tac) can suppress infl ammation and immune response involved in liver ischemia-reperfusion injury (IRI) (Kristo I., Transpl Int., 2011). Aim. We hypothesize that back-table arterial and portal liver perfusion with Tac can infl uence the incidence and severity of early allograft dysfunction (EAD). A prospective randomized study was conducted (ClinicalTrials.gov Identifi er: NCT01887171).Materials and methods. Criteria of the inclusion: First liver transplantation from DBD donor with sequential portal-arterial reperfusion. At back-table portal vein and hepatic artery were perfused each by 500 ml of HTK solution containing 20 ng/ml Tac during 10–15 min followed by portal fl ushing with 200 ml 5% solution of Albumin containing 20 ng/ml Tac and by resting of liver in effl uent. No Tac was added in the control group. Primary Outcome: EAD (Olthoff KM, et al. Liver Transpl. 2010) and severe EAD (P.R.Salvalaggio, et al. Transpl. Proceedings, 2012).Results. No difference was found between groups (main vs. control) in terms of MELD (16 vs. 16), steatosis (10 vs. 10%), ballooning (45 vs. 40%) of liver grafts, recipient age (50 vs. 50 y.o.), warm ischemia time (50 vs.50 min) and total ischemia time (482.5 vs. 485.0 min). Median donor age was higher in the main group (44.5 vs. 39.0 y.o.). The overall rate of EAD was 27.9%. EAD rate was signifi cantly lower in the main group (6/43 vs. 18/43; p = 0.003). The rate of moderate-to-severe EAD was lower in the main group (1/43 vs. 10/43; p = 0.009). The median levels of AST and ALT in 24 h after reperfusion were signifi cantly lower in the intervention group (1004 vs. 1596; p = 0.03 and 449 vs. 759; p = 0.057).Conclusion. Portal and arterial back-table liver perfusion with HTK solution with Tacrolimus may contribute to lower EAD incidence and severity.В предыдущих исследованиях было показано, что такролимус может подавлять воспаление и иммунный ответ во время ишемически-реперфузионного повреждения трансплантата печени (Kristo I., Transpl Int., 2011).Цель исследования. Оценить влияние back-table портальной и артериальной перфузии раствором HTK и альбумина, содержащим такролимус, на частоту и выраженность ранней дисфункции трансплантата печени.Материалы и методы. Для достижения поставленной цели было организовано интервенционное проспективное рандомизированное исследование (ClinicalTrials.gov Identifi er: NCT01887171) в двух параллельных группах по 43 пациента. Критерии включения: первичная ортотопическая трансплантация печени от донора со смертью мозга с последовательной портально-артериальной реперфузией. В основной группе на операции back-table выполняли перфузию воротной вены под давлением 40–60 см водяного столба раствором HTK в объеме 500 мл c содержанием такролимуса 20 нг/мл, а затем перфузию печеночной артерии 500 мл такого же раствора под давлением 40–50 мм рт. ст., перед имплантацией графта в воротную вену вводили 200 мл 5% раствора альбумина c содержанием такролимуса 20 нг/мл. В контрольной группе такролимус не был добавлен.Результаты. Группы были сопоставимы (основная против контрольной соответственно) по баллу MELD, стеатозу, баллонной дистрофии трансплантатов печени, возрасту реципиента, времени тепловой ишемии и общему времени ишемии. Средний возраст донора был выше в основной группе (44,5 против 39 лет). Общая частота ранней дисфункции аллографта (РДА) была 27,9%. Частота РДА была значительно ниже в основной группе (6/43 против 18/43, р = 0,003), также частота тяжелой РДА была значимо ниже в основной группе (1/43 против 10/43; р = 0,009). Средний уровень АСТ и АЛТ через 24 ч после реперфузии были значительно ниже в основной группе (1004 против 1596; р = 0,03 и 449 против 759, р = 0,057).Заключение. Применение инфузии раствора HTK и альбумина с такролимусом в воротную вену и печеночную артерию во время подготовки донорской печени к имплантации позволяет уменьшить частоту и выраженность ранней дифункции трансплантата печени

Risk governance in organizations

Dieses Buch dokumentiert 10 Jahre Risk-Governance-Forschung an der Universität Siegen. In 50 Beiträgen reflektieren Forscher und Praktiker Risk Governance vor dem Hintergrund ihrer eigenen Forschungen und/oder Erfahrungen und geben jeweils einen Entwicklungsimpuls für die Zukunft der Risk Governance. Das Buch zeigt die große Bandbreite und Tiefe des Forschungsgebietes auf und diskutiert Grundannahmen, Implementierungsfragen, die Rolle der Risk Governance als Transformationsmotor, ihre Wirkung in den verschiedenen betrieblichen Funktionen, Entwicklungsperspektiven und den Beitrag der Risk Governance zu einer nachhaltigen Ausrichtung von Unternehmen.This book documents 10 years of risk governance research at the University of Siegen. In 50 contributions, researchers and practitioners reflect on risk governance against the background of their own research and/or experience and provide a development impetus for the future of risk governance. The book shows the wide range and depth of the research field and discusses basic assumptions, implementation issues, the role of risk governance as transformation engine, its impact in the various operational functions, development perspectives, and the contribution of risk governance to a sustainable orientation of companies

De novo Assembly of a 40 Mb Eukaryotic Genome from Short Sequence Reads: Sordaria macrospora, a Model Organism for Fungal Morphogenesis

Filamentous fungi are of great importance in ecology, agriculture, medicine, and biotechnology. Thus, it is not surprising that genomes for more than 100 filamentous fungi have been sequenced, most of them by Sanger sequencing. While next-generation sequencing techniques have revolutionized genome resequencing, e.g. for strain comparisons, genetic mapping, or transcriptome and ChIP analyses, de novo assembly of eukaryotic genomes still presents significant hurdles, because of their large size and stretches of repetitive sequences. Filamentous fungi contain few repetitive regions in their 30–90 Mb genomes and thus are suitable candidates to test de novo genome assembly from short sequence reads. Here, we present a high-quality draft sequence of the Sordaria macrospora genome that was obtained by a combination of Illumina/Solexa and Roche/454 sequencing. Paired-end Solexa sequencing of genomic DNA to 85-fold coverage and an additional 10-fold coverage by single-end 454 sequencing resulted in ∼4 Gb of DNA sequence. Reads were assembled to a 40 Mb draft version (N50 of 117 kb) with the Velvet assembler. Comparative analysis with Neurospora genomes increased the N50 to 498 kb. The S. macrospora genome contains even fewer repeat regions than its closest sequenced relative, Neurospora crassa. Comparison with genomes of other fungi showed that S. macrospora, a model organism for morphogenesis and meiosis, harbors duplications of several genes involved in self/nonself-recognition. Furthermore, S. macrospora contains more polyketide biosynthesis genes than N. crassa. Phylogenetic analyses suggest that some of these genes may have been acquired by horizontal gene transfer from a distantly related ascomycete group. Our study shows that, for typical filamentous fungi, de novo assembly of genomes from short sequence reads alone is feasible, that a mixture of Solexa and 454 sequencing substantially improves the assembly, and that the resulting data can be used for comparative studies to address basic questions of fungal biology

PORTAL AND ARTERIAL FLUSHING WITH HTK AND TACROLIMUS CAN ATTENUATE THE INCIDENCE OF EARLY LIVER ALLOGRAFT DYSFUNCTION

It was shown that Tacrolimus (Tac) can suppress infl ammation and immune response involved in liver ischemia-reperfusion injury (IRI) (Kristo I., Transpl Int., 2011). Aim. We hypothesize that back-table arterial and portal liver perfusion with Tac can infl uence the incidence and severity of early allograft dysfunction (EAD). A prospective randomized study was conducted (ClinicalTrials.gov Identifi er: NCT01887171).Materials and methods. Criteria of the inclusion: First liver transplantation from DBD donor with sequential portal-arterial reperfusion. At back-table portal vein and hepatic artery were perfused each by 500 ml of HTK solution containing 20 ng/ml Tac during 10–15 min followed by portal fl ushing with 200 ml 5% solution of Albumin containing 20 ng/ml Tac and by resting of liver in effl uent. No Tac was added in the control group. Primary Outcome: EAD (Olthoff KM, et al. Liver Transpl. 2010) and severe EAD (P.R.Salvalaggio, et al. Transpl. Proceedings, 2012).Results. No difference was found between groups (main vs. control) in terms of MELD (16 vs. 16), steatosis (10 vs. 10%), ballooning (45 vs. 40%) of liver grafts, recipient age (50 vs. 50 y.o.), warm ischemia time (50 vs.50 min) and total ischemia time (482.5 vs. 485.0 min). Median donor age was higher in the main group (44.5 vs. 39.0 y.o.). The overall rate of EAD was 27.9%. EAD rate was signifi cantly lower in the main group (6/43 vs. 18/43; p = 0.003). The rate of moderate-to-severe EAD was lower in the main group (1/43 vs. 10/43; p = 0.009). The median levels of AST and ALT in 24 h after reperfusion were signifi cantly lower in the intervention group (1004 vs. 1596; p = 0.03 and 449 vs. 759; p = 0.057).Conclusion. Portal and arterial back-table liver perfusion with HTK solution with Tacrolimus may contribute to lower EAD incidence and severity

Managing criticalities of e-health IoT systems

Lately, Internet-based solutions, brought by the Internet of Things (IoT) and cloud computation and storage technologies, have been driving revolutionary approaches in innumerable domains, including the sensitive domain of healthcare. Indicatively, real-time diagnosis of medical issues, telemedicine, remote monitoring of patients, as well as computer-assisted smart transportation in case of emergencies, are anticipated as Systems-of-Systems (SoS) that can execute several applications of different criticality, thus necessitating mission-critical and non-critical peripheral components. Therefore, managing the criticality of a specific component, application or service in such an environment, is of fundamental importance. In this respect, this paper discusses an approach to identify and model criticalities of healthcare IoT systems, as a first step to effectively manage them in system implementation and deployment. To do so, it explains the mixed-criticality characteristics of such systems, describing two principal use cases, that stem from the combination of novel technologies with classic health care practices, namely (a) a remote elderly monitoring platform, as well as (b) a smart ambulance system. The main cricalities anticipated in such systems are described, as well as open areas for future research are also identified. 2017 IEEE.The authors wish to acknowledge the Qatar National Research Fund project EMBIoT (Proj. No. NPRP 9-114-2-055) project, under the auspices of which the work presented in this paper has been carried out

Compassion Focused Group Therapy for people with a diagnosis of Bipolar Affective Disorder: A feasibility study

Background: Compassion focused therapy (CFT) is an evolutionary informed, biopsychosocial approach to mental health problems and therapy. It suggests that evolved motives (e.g., for caring, cooperating, competing) are major sources for the organisation of psychophysiological processes which underpin mental health problems. Hence, evolved motives can be targets for psychotherapy. People with certain types of depression are psychophysiologically orientated towards social competition and concerned with social status and social rank. These can give rise to down rank-focused forms of social comparison, sense of inferiority, worthlessness, lowered confidence, submissive behaviour, shame proneness and self-criticism. People with bipolar disorders also experience elevated aspects of competitiveness and up rank status evaluation. These shift processing to a sense of superiority, elevated confidence, energised behaviour, positive affect and social dominance. This is the first study to explore the feasibility of a 12 module CFT group, tailored to helping people with a diagnosis of bipolar disorder understand the impact of evolved competitive, status-regulating motivation on their mental states and the value of cultivating caring and compassion motives and their psychophysiological regulators. Methods: Six participants with a history of bipolar disorder took part in a CFT group consisting of 12 modules (over 25 sessions) as co-collaborators to explore their personal experiences of CFT and potential processes of change. Assessment of change was measured via self-report, heart rate variability (HRV) and focus groups over three time points. Results: Although changes in self-report scales between participants and across time were uneven, four of the six participants consistently showed improvements across the majority of self-report measures. Heart rate variability measures revealed significant improvement over the course of the therapy. Qualitative data from three focus groups revealed participants found CFT gave them helpful insight into: how evolution has given rise to a number of difficult problems for emotion regulation (called tricky brain) which is not one’s fault; an evolutionary understanding of the nature of bipolar disorders; development of a compassionate mind and practices of compassion focused visualisations, styles of thinking and behaviours; addressing issues of self-criticism; and building a sense of a compassionate identity as a means of coping with life difficulties. These impacted their emotional regulation and social relationships. Conclusion: Although small, the study provides evidence of feasibility, acceptability and engagement with CFT. Focus group analysis revealed that participants were able to switch from competitive focused to compassion focused processing with consequent improvements in mental states and social behaviour. Participants indicated a journey over time from ‘intellectually’ understanding the process of building a compassionate mind to experiencing a more embodied sense of compassion that had significant impacts on their orientation to (and working with) the psychophysiological processes of bipolar disorder