RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein–coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states

Angiogenesis-Related Cytokines, RANKL, and Osteoprotegerin in Multiple Myeloma Patients in relation to Clinical Features and Response to Treatment

An essential cytokine system for the osteoclast biology in multiple myeloma (MM) consists of the receptor of activator of NF-κB ligand (RANKL), its receptor (RANK), and the soluble decoy receptor, osteoprotegerin (OPG). Myeloma cells cause imbalance in OPG/RANKL interactions. We measured serum levels of OPG, soluble (s) RANKL, sRANKL/OPG ratio, markers of disease activity [LDH, CRP, interleukin-6 (IL-6), β2-microglobulin (B2M)], and angiogenic factors [hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], in 54 newly diagnosed MM patients and in 25 of them in plateau phase. All the above values were higher in MM patients compared to controls and decreased in plateau phase. sRANKL and RANKL/OPG were higher with advancing disease stage and skeletal grade. Significant correlations were found among RANKL and RANKL/OPG with HGF, LDH, VEGF, IL-6, and B2M. In conclusion, RANKL and OPG play significant roles in MM pathophysiology, as regulators of bone turnover and mediators of angiogenesis

Risk and protective factors for atrial fibrillation after cardiac surgery and valvular interventions : an umbrella review of meta-analyses

Objective Postoperative atrial fibrillation (POAF) is a common complication affecting approximately one-third of patients after cardiac surgery and valvular interventions. This umbrella review systematically appraises the epidemiological credibility of published meta-analyses of both observational and randomised controlled trials (RCT) to assess the risk and protective factors of POAF. Methods Three databases were searched up to June 2021. According to established criteria, evidence of association was rated as convincing, highly suggestive, suggestive, weak or not significant concerning observational studies and as high, moderate, low or very low regarding RCTs. Results We identified 47 studies (reporting 61 associations), 13 referring to observational studies and 34 to RCTs. Only the transfemoral transcatheter aortic valve replacement (TAVR) approach was associated with the prevention of POAF and was supported by convincing evidence from meta-analyses of observational data. Two other associations provided highly suggestive evidence, including preoperative hypertension and neutrophil/lymphocyte ratio. Three associations between protective factors and POAF presented a high level of evidence in meta-analyses, including RCTs. These associations included atrial and biatrial pacing and performing a posterior pericardiotomy. Nineteen associations were supported by moderate evidence, including use of drugs such as amiodarone, b-blockers, glucocorticoids and statins and the performance of TAVR compared with surgical aortic valve replacement. Conclusions Our study provides evidence confirming the protective role of amiodarone, b-blockers, atrial pacing and posterior pericardiotomy against POAF as well as highlights the risk of untreated hypertension. Further research is needed to assess the potential role of statins, glucocorticoids and colchicine in the prevention of POAF.Funding Agencies|ALF grants (County Council of Ostergotland) [RO818141]</p

Regional differences in presentation characteristics, use of treatments and outcome of patients with cardiogenic shock: Results from multicenter, international registry

Background. Concurrent evidence about cardiogenic shock (CS) characteristics, treatment and outcome does not represent a global spectrum of patients and is therefore limited. The aim of this study was to investigate these regional differences. Methods. To investigate regional differences in presentation characteristics, treatments and outcomes of patients treated with all types of cardiogenic shock (CS) in a single calendar year on a multi-national level. Consecutive patients from 19 tertiary care hospitals in 13 countries with CS who were treated between January 1, 2018 and December 31, 2018 were enrolled in this study. Results. In total, 699 cardiogenic shock patients were included in this study. Of these patients, 440 patients (63%) were treated in European hospitals and 259 (37%) were treated in Non-European hospitals. Female patients (P<0.01) and patients with a previous myocardial infarction (P=0.02) were more likely to present at Non-European hospitals; whereas older patients (P=0.01) and patients with cardiogenic shock due to acute heart failure (P<0.01) were more likely to present at European hospitals. Vasopressor use was more likely in Non-European hospitals (P=0.04), whereas use of mechanical circulatory support (MCS) was more likely in European hospitals (P<0.01). Despite adjustment for relevant confounders, 30-day in-hospital mortality risk was comparably high in CS patients treated in European vs. Non-European hospitals (hazard ratio 1.08, 95% CI 0.84-1.39, P=0.56). Conclusion. Despite marked heterogeneity in characteristics and treatment of CS patients, including fewer use of MCS but more frequent use of vasopressors in Non-European hospitals, 30-day in-hospital mortality did not differ between regions