Blunted apoptosis of erythrocytes in mice deficient in the heterotrimeric G-protein subunit Gαi2

Putative functions of the heterotrimeric G-protein subunit Gαi2-dependent signaling include ion channel regulation, cell differentiation, proliferation and apoptosis. Erythrocytes may, similar to apoptosis of nucleated cells, undergo eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure. Eryptosis may be triggered by increased cytosolic Ca2+ activity and ceramide. In the present study, we show that Gαi2 is expressed in both murine and human erythrocytes and further examined the survival of erythrocytes drawn from Gαi2-deficient mice (Gαi2−/−) and corresponding wild-type mice (Gαi2+/+). Our data show that plasma erythropoietin levels, erythrocyte maturation markers, erythrocyte counts, hematocrit and hemoglobin concentration were similar in Gαi2−/− and Gαi2+/+ mice but the mean corpuscular volume was significantly larger in Gαi2−/− mice. Spontaneous PS exposure of circulating Gαi2−/− erythrocytes was significantly lower than that of circulating Gαi2+/+ erythrocytes. PS exposure was significantly lower in Gαi2−/− than in Gαi2+/+ erythrocytes following ex vivo exposure to hyperosmotic shock, bacterial sphingomyelinase or C6 ceramide. Erythrocyte Gαi2 deficiency further attenuated hyperosmotic shock-induced increase of cytosolic Ca2+ activity and cell shrinkage. Moreover, Gαi2−/− erythrocytes were more resistant to osmosensitive hemolysis as compared to Gαi2+/+ erythrocytes. In conclusion, Gαi2 deficiency in erythrocytes confers partial protection against suicidal cell death

Blunted apoptosis of erythrocytes in mice deficient in the heterotrimeric G-protein subunit Gαi2

Putative functions of the heterotrimeric G-protein subunit Gαi2-dependent signaling include ion channel regulation, cell differentiation, proliferation and apoptosis. Erythrocytes may, similar to apoptosis of nucleated cells, undergo eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure. Eryptosis may be triggered by increased cytosolic Ca2+ activity and ceramide. In the present study, we show that Gαi2 is expressed in both murine and human erythrocytes and further examined the survival of erythrocytes drawn from Gαi2-deficient mice (Gαi2−/−) and corresponding wild-type mice (Gαi2+/+). Our data show that plasma erythropoietin levels, erythrocyte maturation markers, erythrocyte counts, hematocrit and hemoglobin concentration were similar in Gαi2−/− and Gαi2+/+ mice but the mean corpuscular volume was significantly larger in Gαi2−/− mice. Spontaneous PS exposure of circulating Gαi2−/− erythrocytes was significantly lower than that of circulating Gαi2+/+ erythrocytes. PS exposure was significantly lower in Gαi2−/− than in Gαi2+/+ erythrocytes following ex vivo exposure to hyperosmotic shock, bacterial sphingomyelinase or C6 ceramide. Erythrocyte Gαi2 deficiency further attenuated hyperosmotic shock-induced increase of cytosolic Ca2+ activity and cell shrinkage. Moreover, Gαi2−/− erythrocytes were more resistant to osmosensitive hemolysis as compared to Gαi2+/+ erythrocytes. In conclusion, Gαi2 deficiency in erythrocytes confers partial protection against suicidal cell death.Fil: Bissinger, Rosi. Eberhard Karls Universität Tübingen; AlemaniaFil: Lang, Elisabeth. Universitat Dusseldorf; AlemaniaFil: Ghashghaeinia, Mehrdad. Eberhard Karls Universität Tübingen; AlemaniaFil: Singh, Yogesh. Eberhard Karls Universität Tübingen; AlemaniaFil: Zelenak, Christine. Charité Medical University; AlemaniaFil: Fehrenbacher, Birgit. Eberhard Karls Universität Tübingen; AlemaniaFil: Honisch, Sabina. Eberhard Karls Universität Tübingen; AlemaniaFil: Chen, Hong. Eberhard Karls Universität Tübingen; AlemaniaFil: Fakhri, Hajar. Eberhard Karls Universität Tübingen; AlemaniaFil: Umbach, Anja T.. Eberhard Karls Universität Tübingen; AlemaniaFil: Liu, Guilai. Eberhard Karls Universität Tübingen; AlemaniaFil: Rexhepaj, Rexhep. Universitat Bonn; AlemaniaFil: Liu, Guoxing. Eberhard Karls Universität Tübingen; AlemaniaFil: Schaller, Martin. Eberhard Karls Universität Tübingen; AlemaniaFil: Mack, Andreas F.. Eberhard Karls Universität Tübingen; AlemaniaFil: Lupescu, Adrian. Eberhard Karls Universität Tübingen; AlemaniaFil: Birnbaumer, Lutz. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Lang, Florian. Eberhard Karls Universität Tübingen; AlemaniaFil: Qadri, Syed M.. Eberhard Karls Universität Tübingen; Alemania. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentin

Integrated care for older multimorbid heart failure patients:protocol for the ESCAPE randomized trial and cohort study

ESCAPE Evaluation of a patient-centred biopsychosocial blended collaborative care pathway for the treatment of multimorbid elderly patients. Therapeutic Area Healthcare interventions for the management of older patients with multiple morbidities. Aims Multi-morbidity treatment is an increasing challenge for healthcare systems in ageing societies. This comprehensive cohort study with embedded randomized controlled trial tests an integrated biopsychosocial care model for multimorbid elderly patients. Hypothesis A holistic, patient-centred pro-active 9-month intervention based on the blended collaborative care (BCC) approach and enhanced by information and communication technologies can improve health-related quality of life (HRQoL) and disease outcomes as compared with usual care at 9 months. Methods Across six European countries, ESCAPE is recruiting patients with heart failure, mental distress/disorder plus ≥2 medical co-morbidities into an observational cohort study. Within the cohort study, 300 patients will be included in a randomized controlled assessor-blinded two-arm parallel group interventional clinical trial (RCT). In the intervention, trained care managers (CMs) regularly support patients and informal carers in managing their multiple health problems. Supervised by a clinical specialist team, CMs remotely support patients in implementing the treatment plan—customized to the patients' individual needs and preferences—into their daily lives and liaise with patients' healthcare providers. An eHealth platform with an integrated patient registry guides the intervention and helps to empower patients and informal carers. HRQoL measured with the EQ-5D-5L as primary endpoint, and secondary outcomes, that is, medical and patient-reported outcomes, healthcare costs, cost-effectiveness, and informal carer burden, will be assessed at 9 and ≥18 months. Conclusions If proven effective, the ESCAPE BCC intervention can be implemented in routine care for older patients with multiple morbidities across the participating countries and beyond

Neue Methoden und Ergebnisse zur Erfassung der Lebensqualität von Herzinsuffizienzpatienten

Einleitung: Die Lebensqualität ist bei Patienten mit Herzinsuffizienz stark eingeschränkt. Die vorliegende Arbeit präsentiert neue Methoden und Ergebnisse zur Erfassung der Lebensqualität von Herzinsuffizienzpatienten mit Fokus auf biopsychosoziale Zusammenhänge. Zielstellung: Das erste Ziel war die Validierung des „Fragebogens zur Erfassung des subjek-tiven körperlichen Wohlbefindens“ (KWB16, Engl. FEW16) bei Patienten mit Herzinsuffizienz. Das zweite Ziel war herauszufinden, ob Biomarkerwerte nach akuter Dekompensation einer Herzinsuffizienz (ADHF) mit der Lebensqualität ein Jahr später assoziiert sind. Ein drittes Ziel war die Untersuchung des Wissensstandes über Herzinsuffizienz in der Allgemeinbevölkerung. Methodik: Der FEW16, ein neuer Fragebogen zur Erfassung der Lebensqualität, wurde an einem Kollektiv von Herzinsuffizienzpatienten durch statistische Testung und Vergleich mit etablierten Fragebögen für Depression und Lebensqualität validiert. In dieser Untersuchung erhielt die Therapiegruppe körperliches Training zusätzlich zur Standardtherapie, die Vergleichs-gruppe erhielt nur die Standardtherapie. In der zweiten Untersuchung wurde mittels logistischer Regression und receiver operating characteristic analyses untersucht, ob die Biomarker N-terminal pro-brain-type natriuretic peptide (NT-proBNP) und midregional pro-adrenomedullin (MR-proANP) die Lebensqualität ein Jahr nach Hospitalisierung wegen akuter Dekompensation vorhersagen können. Mit der dritten Studie wurde die Entwicklung des Kenntnisstands über Herzinsuffizienz in der Allgemeinbevölkerung über die Jahre 2007, 2012 und 2015 untersucht. Ergebnisse: Der FEW16 zeigte sich valide und verwendbar, die Änderungssensitivität war jedoch nicht optimal. In der Ex-DHF-P-Studie maß der FEW16 eher das allgemeine Wohlbefinden als nur das körperliche und bezog stark psychische Faktoren des Wohlbefindens ein. NT-proBNP und MR-proANP sind mit wenigen anderen patientenspezifischen Faktoren unabhängige Prädiktoren der Lebensqualität ein Jahr nach Hospitalisierung wegen akuter Dekompensation. Der Kenntnisstand über Herzinsuffizienz in der Bevölkerung war nicht gut und hat sich zwischen 2007 und 2015 nicht verbessert. Diskussion: Das Wissen in der Bevölkerung über Herzinsuffizienz reicht nicht aus, um eine frühe Attribuierung von Symptomen zu der Erkrankung und dadurch Präsentation beim Arzt mit früher Behandlung zu gewährleisten. Da diese essentiell ist, um die Langzeitprognose möglichst günstig beeinflussen zu können, muss es noch mehr Anstrengungen geben, um die Menschen gezielt auf diese Erkrankung aufmerksam zu machen. Der FEW16 kann verwendet werden, um die Lebensqualität von Herzinsuffizienzpatienten einzuschätzen, für den Verlauf eignen sich bereits etablierte Testverfahren besser. Drei Modelle um NT-proBNP und MR-proANP ergänzen die Prädiktion der postdekompensativen Mortalität durch diese beiden Biomarker um die der Lebensqualität, die ein eigenständiger Faktor für die Prognose der Erkrankung ist.Introduction: Quality of life (QoL) is an independent predictor for the prognosis in heart failure (HF). This thesis presents novel methods and findings on QoL in HF patients with a focus on biopsychosocial interrelations. Aims: The first aim was to validate the “Questionnaire for the assessment of physical well-being” (dt. KWB16, Engl. FEW16) for patients with heart failure. The second aim was to assess possible associations between biomarkers after ADHF and QoL after one year. The third aim was to determine the level of knowledge on heart failure in the general population. Methods: The FEW16 was statistically tested and compared to established questionnaires for depression and QoL in a collective of HF patients with preserved ejection fraction with or without physical exercise in addition to standard treatment. The second study tested the biomarkers NT-proBNP and MR-proANP for their association with Qol one year after hospitali-zation for acute decompensation of HF using logistic regression and receiver operating charac-terristic analyses. The third study compared the extent of HF awareness in a subset of the general German population in the years 2007, 2012 and 2015. Results: The FEW16 is a valid and usable questionnaire, its sensitivity to change however was suboptimal. In Ex-DHF-P, the FEW16 measured the general well-being rather than the physical well-being and it overall showed a strong implementation of psychological factors. NT-proBNP and MR-proANP and few other patient-specific factors are independent predictors of QoL one year after hospitalization for ADHF. The awareness on HF in the German population was insufficient and did not improve between 2007 and 2015. Discussion: Knowledge on HF in the general population is not sufficient to assure an early attribution of symptoms to the disease triggering early presentation at the physician and treatment. Early treatment but is essential for a better prognosis. Therefore, it is still necessary to improve campaigns to further raise HF awareness. The FEW16 can be used to assess QoL in HF patients. Three models around NT-proBNP and MR-proANP complement the prediction of mortality through these biomarkers after decompensation with the prediction of QoL, which is an independent predictor for the prognosis of HF itself

Stimulation of Eryptosis by Cryptotanshinone

Background/Aims: Cryptotanshinone, a component of Salvia miltiorrhiza Bunge roots, may trigger suicidal death or apoptosis of tumor cells and has thus been recommended for the prevention and treatment of malignancy. On the other hand, Cryptotanshinone has been shown to counteract apoptosis of neurons and hepatocytes. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and phosphatidylserine translocation to the erythrocyte surface. Eryptosis may be triggered by increase of cytosolic Ca2+-activity ([Ca2+]i). The present study explored whether Cryptotanshinone stimulates eryptosis. Methods: Forward scatter was taken as measure of cell volume, annexin V binding for identification of phosphatidylserine-exposing erythrocytes and Fluo3-fluorescence for determination of [Ca2+]i. Results: A 48 h exposure of human erythrocytes to Cryptotanshinone (10 µM) was followed by significant decrease of forward scatter, significant increase of the percentage annexin-V-binding cells and significant increase of [Ca2+]i. The effect of Cryptotanshinone (1 µM) on annexin-V-binding was virtually abrogated by removal of extracellular Ca2+. Conclusion: Cryptotanshinone is a powerful stimulator of suicidal erythrocyte death or eryptosis, which is effective mainly, if not exclusively, by stimulation of Ca2+ entry