EAN Guideline on Palliative Care of People with Severe, Progressive Multiple Sclerosis

Background and Purpose: Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. Methods: This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients–Intervention– Comparator–Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20m without resting (Expanded Disability Status Scale score >6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. Results: Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient’s wish to hasten death, symptom management, multidisciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommendations (33 weak, 1 strong) and seven good practice statements were devised. Conclusions: The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation:TTVguideIT

Background: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. Methods: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. Discussion: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents.</p

Untersuchungen zum Einfluss verschiedener Selenverbindungen auf das Proteom von murinem Kolongewebe mittels 2D-Gelelektrophorese

Die Effekte des Spurenelementes Selen (Se) auf die Gesundheit als auch bei Erkrankungen werden in der Literatur kontrovers diskutiert. Um das Wissen der Se-vermittelten Wirkungen zu erweitern wurde ein Fütterungsversuch mit drei Se-Verbindungen (Selenit, Selenat, Selenomethionin) in je zwei Konzentrationen (150 μg Se/ kg Diät; 750 μg Se/ kg Diät) im Vergleich zu einem Se-Mangel durchgeführt. In den anschließenden 2D-DIGE-Experimenten wiesen die Se-Verbindungen einen heterogenen Einfluss auf das Gesamt- als auch Redoxproteom des murinen Kolongewebes auf. Ein weiterer Fütterungsversuch mit GPx2-KO-Mäusen konnte zusätzlich einen Einfluss des GPx2-KO sowie einer Selenit-Supplementierung im Vergleich zum Wildtyp bzw. zum Se-Mangel auf das murine Kolonproteom aufzeigen. Die Identifizierung neuer durch Se regulierte Proteine im murinen Kolongewebe erweitert das Verständnis der physiologischen Rolle von Se.The effects of the trace element selenium (Se) on health and diseases are controversial in the literature. In order to expand the knowledge of the Se-mediated effects, a feeding experiment with three Se compounds (selenite, selenate, selenomethionine) in two concentrations (150 μg Se/ kg diet; 750 μg Se/ kg diet) compared to a Se deficiency was carried out. In the subsequent 2D-DIGE experiments, the Se compounds showed a heterogeneous influence on the total and redox proteome of the murine colon tissue. Another feeding attempt with GPx2-KO mice showed an additional influence of GPx2-KO and selenite supplementation compared to the wild type or Se deficiency on the murine colon proteome. The identification of new Se-regulated proteins in murine colon tissue enhances understanding of the physiological role of Se

Hydrogen peroxide – production, fate and role in redox signaling of tumor cells

Hydrogen peroxide (H2O2) is involved in various signal transduction pathways and cell fate decisions. The mechanism of the so called “redox signaling” includes the H2O2-mediated reversible oxidation of redox sensitive cysteine residues in enzymes and transcription factors thereby altering their activities. Depending on its intracellular concentration and localization, H2O2 exhibits either pro- or anti-apoptotic activities. In comparison to normal cells, cancer cells are characterized by an increased H2O2 production rate and an impaired redox balance thereby affecting the microenvironment as well as the anti-tumoral immune response. This article reviews the current knowledge about the intracellular production of H2O2 along with redox signaling pathways mediating either the growth or apoptosis of tumor cells. In addition it will be discussed how the targeting of H2O2-linked sources and/or signaling components involved in tumor progression and survival might lead to novel therapeutic targets

Individual effects of different selenocompounds on the hepatic proteome and energy metabolism of mice

Background: Selenium (Se) exerts its biological activity largely via selenoproteins, which are key enzymes for maintaining the cellular redox homeostasis. However, besides these beneficial effects there is also evidence that an oversupply of Se might increase the risk towards developing metabolic disorders. To address this in more detail, we directly compared effects of feeding distinct Se compounds and concentrations on hepatic metabolism and expression profiles of mice. Methods: Male C57BL6/J mice received either a selenium-deficient diet or diets enriched with adequate or high doses of selenite, selenate or selenomethionine for 20 weeks. Subsequently, metabolic parameters, enzymatic activities and expression levels of hepatic selenoproteins, Nrf2 targets, and additional redox-sensitive proteins were analyzed. Furthermore, 2D-DIGE-based proteomic profiling revealed Se compound-specific differentially expressed proteins. Results: Whereas heterogeneous effects between high concentrations of the Se compounds were observed with regard to body weight and metabolic activities, selenoproteins were only marginally increased by high Se concentrations in comparison to the respective adequate feeding. In particular the high-SeMet group showed a unique response compromising higher hepatic Se levels in comparison to all other groups. Accordingly, hepatic glutathione (GSH) levels, glutathione S-transferase (GST) activity, and GSTpi1 expression were comparably high in the high-SeMet and Se-deficient group, indicating that compound-specific effects of high doses appear to be independent of selenoproteins. Conclusions: Not only the nature, but also the concentration of Se compounds differentially affect biological processes. General significance: Thus, it is important to consider Se compound-specific effects when supplementing with selenium.The peer-reviewed version: [http://cer.ihtm.bg.ac.rs/handle/123456789/3035