Autonomic abnormalities in patients with primary Sjogren’s syndrome – Preliminary results

Primary Sjogren's syndrome (pSS) is an autoimmune disease affecting exocrine glands and extra-glandular organs. There are conflicting reports on the presence of autonomic dysfunction in pSS and no data are available on the functional status of sympathetic outflow to the vessels and baroreceptor [baroreflex sensitivity (BRS)] control mechanisms. We investigated the cardiac (cBRS) and sympathetic (sBRS) baroreceptor modulation in both time and frequency domains and the cardiovascular autonomic profile in pSS patients compared to healthy controls. Autonomic symptoms were quantified by the Composite Autonomic Symptom Scale (COMPASS31) three-item questionnaire. The EULAR Sjogren's syndrome patient reported index (ESSPRI) questionnaire evaluated the magnitude of pSS clinical symptoms, i.e., fatigue, pain, and sicca symptoms. Electrocardiogram, beat-by-beat arterial pressure (AP) and respiratory activity were continuously recorded in 17 pSS patients and 16 healthy controls, while supine and during 75 degrees head-up tilt. In seven patients and seven controls, muscle sympathetic nerve activity (MSNA) was measured. Spectrum analysis of RR variability provided markers of cardiac vagal modulation (HFRR nu) and sympatho-vagal balance [low frequency (LF)/high frequency (HF)]. The power of LF (0.1 Hz) oscillations of systolic arterial pressure (SAP) variability (LFSAP) evaluated the vasomotor response to sympathetic stimulation. Compared to controls, pSS patients scored higher in total COMPASS31 (p < 0.0001) and all ESSPRI subdomains (fatigue, p = 0.005; pain, p = 0.0057; dryness, p < 0.0001). Abnormal scialometry (<1.5 ml/15 min) and Schirmer tests (<5 mm/5 min) were found in pSS patients and salivary flow rate was negatively associated with ESSPRI dryness (p = 0.0014). While supine, pSS patients had lower SEQ(cBRs) index of cardiac baroreceptor sensitivity, higher HFRRnu (p = 0.021), lower LF/HF (p = 0.007), and greater MSNA (p = 0.038) than controls. No differences were observed in LFSAP between groups. During orthostatic challenge, although LFSAP increased similarly in both groups, MSNA was greater in pSS patients (p = 0.003). At rest pSS patients showed lower cBR control and greater parasympathetic modulation. Furthermore, greater sympathetic nerve activity was observed in pSS patients while supine and in response to gravitational challenge. We hypothesized that such enhanced sympathetic vasoconstrictor activity might reflect an attempt to maintain blood pressure in a setting of likely reduced vascular responsiveness

Transform Autism Education - Final Report

The Transform Autism Education (TAE) project focused on the domain of ‘good autism practice’ in the education of pupils with autism in the UK, Greece and Italy with the overall objectives to:• Research good autism practice in education.• Create professional development programmes in Greece and Italy.• Enhance the knowledge and practice of school staff.• Facilitate the inclusion of autistic children in primary schools in those countries.Funded by the European Commission through Erasmus Plus Key Action 2, Strategic Partnerships scheme, and led by Principal Investigator Dr. Karen Guldberg, the project involved a range of Greek, Italian and UK partners. It employed the Autism Education Trust (AET) collaborative training schemes in the UK as a founding model. While the requirements of each country were distinct, and so necessitated careful adaptations of the materials to their specific needs, what united all aspects of the project was a desire to improve the educational inclusion of autistic children, as well as their general experiences in school and their outcomes

Parkin regulates kainate receptors by interacting with the GluK2 subunit

Although loss-of-function mutations in the PARK2 gene, the gene that encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, the responsible molecular mechanisms remain unclear. Evidence suggests that a loss of parkin dysregulates excitatory synapses. Here we show that parkin interacts with the kainate receptor (KAR) GluK2 subunit and regulates KAR function. Loss of parkin function in primary cultured neurons causes GluK2 protein to accumulate in the plasma membrane, potentiates KAR currents and increases KAR-dependent excitotoxicity. Expression in the mouse brain of a parkin mutant causing autosomal recessive juvenile parkinsonism results in GluK2 protein accumulation and excitotoxicity. These findings show that parkin regulates KAR function in vitro and in vivo, and suggest that KAR upregulation may have a pathogenetic role in parkin-related autosomal recessive juvenile parkinsonism

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABA B Rs shapes inhibitory neurotransmission

Shrm4, a protein expressed only in polarized tissues, is encoded by the KIAA1202 gene, whose mutations have been linked to epilepsy and intellectual disability. However, a physiological role for Shrm4 in the brain is yet to be established. Here, we report that Shrm4 is localized to synapses where it regulates dendritic spine morphology and interacts with the C terminus of GABA B receptors (GABA B Rs) to control their cell surface expression and intracellular trafficking via a dynein-dependent mechanism. Knockdown of Shrm4 in rat severely impairs GABA B R activity causing increased anxiety-like behaviour and susceptibility to seizures. Moreover, Shrm4 influences hippocampal excitability by modulating tonic inhibition in dentate gyrus granule cells, in a process involving crosstalk between GABA B Rs and extrasynaptic \uce-subunit-containing GABA A Rs. Our data highlights a role for Shrm4 in synaptogenesis and in maintaining GABA B R-mediated inhibition, perturbation of which may be responsible for the involvement of Shrm4 in cognitive disorders and epilepsy

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Transform Autism Education - Final Report

The Transform Autism Education (TAE) project focused on the domain of ‘good autism practice’ in the education of pupils with autism in the UK, Greece and Italy with the overall objectives to: • Research good autism practice in education. • Create professional development programmes in Greece and Italy. • Enhance the knowledge and practice of school staff. • Facilitate the inclusion of autistic children in primary schools in those countries. Funded by the European Commission through Erasmus Plus Key Action 2, Strategic Partnerships scheme, and led by Principal Investigator Dr. Karen Guldberg, the project involved a range of Greek, Italian and UK partners. It employed the Autism Education Trust (AET) collaborative training schemes in the UK as a founding model. While the requirements of each country were distinct, and so necessitated careful adaptations of the materials to their specific needs, what united all aspects of the project was a desire to improve the educational inclusion of autistic children, as well as their general experiences in school and their outcomes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The epigenetics of autoimmunity

The etiology of autoimmune diseases remains largely unknown. Concordance rates in monozygotic twins are lower than 50% while genome-wide association studies propose numerous significant associations representing only a minority of patients. These lines of evidence strongly support other complementary mechanisms involved in the regulation of genes expression ultimately causing overt autoimmunity. Alterations in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune diseases. In recent years, several studies both in clinical settings and experimental models proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and other autoimmune diseases, in some cases based on mechanistical observations. We herein discuss what we currently know and what we expect will come in the next future. Ultimately, epigenetic treatments already being used in oncology may soon prove beneficial also in autoimmune disease

Immune-mediated heart disease

The heart involvement in systemic autoimmune diseases represents a growing burden for patients and health systems. Cardiac function can be impaired as a consequence of systemic conditions and manifests with threatening clinical pictures or chronic myocardial damage. Direct injuries are mediated by the presence of inflammatory infiltrate which, even though unusual, is one of the most danger manifestations requiring prompt recognition and treatment. On the other hand, a not well-managed inflammatory status leads to accelerated atherosclerosis that precipitates ischemic disease. All cardiac structures may be damaged with different grades of intensity; moreover, lesions can appear simultaneously or more frequently at a short distance from each other leading to the onset of varied clinical pictures. The pathogenesis of heart damages in systemic autoimmune conditions is not yet completely understood for the great part of situations, even if several mechanisms have been investigated. The principal biochemical circuits refer to the damaging role of autoantibodies on cardiac tissues and the precipitation of immune complexes on endocardium. These events are finally responsible of inflammatory infiltration which leads to subsequent worsening of the previous damage. For these reasons, it appears of paramount importance a regular and deepened cardiovascular assessment to prevent a progressive evolution toward heart failure in patient affected by autoimmune diseases