New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis – Implications from the prospective multicenter VADERA II study

Objectives To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. Methods In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. Results In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age 2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. Conclusions Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms. Clinical trial registration number This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483)

Acidic preconditioning protects endothelial cells against apoptosis through p38- and Akt-dependent Bcl-xL overexpression

To analyze the underlying cellular mechanisms of adaptation to ischemia-induced apoptosis through short acidic pretreatment, i.e. acidic preconditioning (APC), Wistar rat coronary endothelial cells (EC) were exposed for 40 min to acidosis (pH 6.4) followed by a 14 h recovery period (pH 7.4) and finally treated for 2 h with simulated in vitro ischemia (glucose-free anoxia at pH 6.4). APC led to a transient activation of p38 and Akt kinases, but not of JNK and ERK1/2 kinases, which was accompanied by significant reduction of the apoptotic cell number, caspase-12/-3 cleavage and Bcl-xL overexpression. These effects of APC were completely abolished by prevention of Akt- or p38-phosphorylation during APC. Furthermore, knock-down of Bcl-xL by siRNA-transfection also abolished the anti-apoptotic effect of APC. Therefore, APC leads to protection of EC against ischemic apoptosis by activation of Akt and p38 followed by overexpression of Bcl-xL, which is a key anti-apoptotic mechanism of APC

Report from Working Group 3: Beyond the standard model physics at the HL-LHC and HE-LHC

This is the third out of five chapters of the final report [1] of the Workshop on Physics at HL-LHC, and perspectives on HE-LHC [2]. It is devoted to the study of the potential, in the search for Beyond the Standard Model (BSM) physics, of the High Luminosity (HL) phase of the LHC, defined as $3$ ab$^{-1}$ of data taken at a centre-of-mass energy of 14 TeV, and of a possible future upgrade, the High Energy (HE) LHC, defined as $15$ ab$^{-1}$ of data at a centre-of-mass energy of 27 TeV. We consider a large variety of new physics models, both in a simplified model fashion and in a more model-dependent one. A long list of contributions from the theory and experimental (ATLAS, CMS, LHCb) communities have been collected and merged together to give a complete, wide, and consistent view of future prospects for BSM physics at the considered colliders. On top of the usual standard candles, such as supersymmetric simplified models and resonances, considered for the evaluation of future collider potentials, this report contains results on dark matter and dark sectors, long lived particles, leptoquarks, sterile neutrinos, axion-like particles, heavy scalars, vector-like quarks, and more. Particular attention is placed, especially in the study of the HL-LHC prospects, to the detector upgrades, the assessment of the future systematic uncertainties, and new experimental techniques. The general conclusion is that the HL-LHC, on top of allowing to extend the present LHC mass and coupling reach by $20-50\%$ on most new physics scenarios, will also be able to constrain, and potentially discover, new physics that is presently unconstrained. Moreover, compared to the HL-LHC, the reach in most observables will, generally more than double at the HE-LHC, which may represent a good candidate future facility for a final test of TeV-scale new physics

Zur Regulation Ischämie induzierter Apoptose koronarer Endothelzellen

In der vorliegenden Arbeit sollte zum einen herausgefunden werden, welcher Bikarbonat-abhängige Transportmechanismus die ischämische Apoptose in Koronarendothelzellen reguliert. SLC4a7 ist mitochondrial lokalisiert, hemmt die durch simulierte Ischämie induzierte Aktivierung des mitochondrialen Apoptosewegs in koronaren Endothelzellen und ist daher eine mögliche Erklärung für die mit Bikarbonat-Transport assoziierte Protektion der Mitochondrien in ischämischen Koronarendothelzellen. Das zweite Teilziel der vorliegenden Arbeit bestand darin, zelluläre Mechanismen der durch azidotische Präkonditionierung induzierten Protektion koronarer Endothelzellen gegenüber Ischämie zu untersuchen. Hier wurde herausgefunden, dass eine azidotische Präkonditionierung koronarer Endothelzellen zu einer Aktivierung der p38- und Akt-Kinasen führt, was eine Überexpression von Bcl-xL zur Folge hat und den über das Endoplasmatische Retikulum vermittelten Apoptoseweg in koronaren Endothelzellen unterdrückt

Inhibition of soluble adenylyl cyclase increases the radiosensitivity of prostate cancer cells

AbstractPharmacological modulation of tumor radiosensitivity is a promising strategy for enhancing the outcome of radiotherapy. cAMP signaling plays an essential role in modulating the proliferation and apoptosis of different cell types, including cancer cells. Until now, the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases. In the present study, the role of an alternative source of cAMP, the intracellular localized soluble adenylyl cyclase (sAC), in the radiosensitivity of prostate cancer cells was investigated. Pharmacological inhibition of sAC activity led to marked suppression of proliferation, lactate dehydrogenase release, and induction of apoptosis. The combination of ionizing radiation with partial suppression of sAC activity (~50%) immediately after irradiation synergistically inhibited proliferation and induced apoptosis. Overexpression of sAC in normal prostate epithelial PNT2 cells increased the cAMP content and accelerated cell proliferation under control conditions. The effects of radiation were significantly reduced in transformed PNT2 cells compared with control cells. Analysis of the underlying cellular mechanisms of sAC-induced radioresistance revealed the sAC-dependent activation of B-Raf/ERK1/2 signaling. In agreement with this finding, inhibition of ERK1/2 in prostate cancer cells enhanced the cytotoxic effect of irradiation. In conclusion, the present study suggests that sAC-dependent signaling plays an important role in the radioresistance of prostate cancer cells. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease

Type 10 adenylyl cyclase mediates mitochondrial Bax translocation and apoptosis of adult rat cardiomyocytes under simulated ischaemia/reperfusion

Aims Apoptosis of cardiomyocytes significantly contributes to the development of post-ischaemic cardiomyopathy. Although mitochondria have been suggested to play a crucial role in this process, the precise mechanisms controlling the mitochondria-dependent apoptosis in cardiomyocytes under ischaemia/reperfusion are still poorly understood. Here we aimed to analyse the role of the soluble adenylyl cyclase (sAC). Methods and results Adult rat cardiomyocytes were subjected to simulated in vitro ischaemia (SI) consisting of glucose-free anoxia at pH 6.4. Apoptosis was detected by DNA laddering, chromatin condensation, and caspases cleavage. SI led to the translocation of sAC to the mitochondria and mitochondrial depolarization followed by cytochrome c release, caspase-9/-3 cleavage and apoptosis during simulated reperfusion (SR). Pharmacological inhibition of sAC during SI, but not during SR, significantly reduced the SI/SR-induced mitochondrial injury and apoptosis. Similarly, sAC knock-down mediated by an adenovirus coding for shRNA targeting sAC prevented the activation of the mitochondrial pathway of apoptosis. Analysis of the link between sAC and apoptosis revealed a sAC and protein kinase A-dependent Bax phosphorylation at Thr(167) and its translocation to mitochondria during SI, which subsequently caused mitochondrial oxygen radical formation followed by cytochrome c release and caspase-9 cleavage during SR. Conclusion These results suggest a key role of sAC in SI-induced mitochondrial Bax translocation and activation of the mitochondrial pathway of apoptosis in adult cardiomyocytes