586 research outputs found
Correctors of mutant CFTR enhance subcortical cAMP-PKA signaling through modulating ezrin phosphorylation and cytoskeleton organization
The most common mutation of the cystic fibrosis transmembrane regulator (CFTR) gene, F508del, produces a misfolded protein resulting in its defective trafficking to the cell surface and an impaired chloride secretion. Pharmacological treatments partially rescue F508del CFTR activity either directly by interacting with the mutant protein and/or indirectly by altering the cellular protein homeostasis. Here, we show that the phosphorylation of ezrin together with its binding to phosphatidylinositol-4,5-bisphosphate (PIP2) tethers the F508del CFTR to the actin cytoskeleton, stabilizing it on the apical membrane and rescuing the sub-membrane compartmentalization of cAMP and activated PKA. Both the small molecules trimethylangelicin (TMA) and VX-809, which act as 'correctors' for F508del CFTR by rescuing F508del-CFTR-dependent chloride secretion, also restore the apical expression of phosphorylated ezrin and actin organization and increase cAMP and activated PKA submembrane compartmentalization in both primary and secondary cystic fibrosis airway cells. Latrunculin B treatment or expression of the inactive ezrin mutant T567A reverse the TMA and VX-809-induced effects highlighting the role of corrector-dependent ezrin activation and actin re-organization in creating the conditions to generate a sub-cortical cAMP pool of adequate amplitude to activate the F508del-CFTR-dependent chloride secretion
DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes
Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS
Management of pregnancy in autoimmune rheumatic diseases: maternal disease course, gestational and neonatal outcomes and use of medications in the prospectiveItalian P-RHEUM.it study
Objectives To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it. Methods Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018-2023). Maternal and infant information were collected in a web-based database. Results We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress. Conclusions Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures
COVID-19 in rheumatic diseases in Italy: first results from the Italian registry of the Italian Society for Rheumatology (CONTROL-19)
OBJECTIVES:
Italy was one of the first countries significantly affected by the coronavirus disease 2019 (COVID-19) epidemic. The Italian Society for Rheumatology promptly launched a retrospective and anonymised data collection to monitor COVID-19 in patients with rheumatic and musculoskeletal diseases (RMDs), the CONTROL-19 surveillance database, which is part of the COVID-19 Global Rheumatology Alliance.
METHODS:
CONTROL-19 includes patients with RMDs and proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) updated until May 3rd 2020. In this analysis, only molecular diagnoses were included. The data collection covered demographic data, medical history (general and RMD-related), treatments and COVID-19 related features, treatments, and outcome. In this paper, we report the first descriptive data from the CONTROL-19 registry.
RESULTS:
The population of the first 232 patients (36% males) consisted mainly of elderly patients (mean age 62.2 years), who used corticosteroids (51.7%), and suffered from multi-morbidity (median comorbidities 2). Rheumatoid arthritis was the most frequent disease (34.1%), followed by spondyloarthritis (26.3%), connective tissue disease (21.1%) and vasculitis (11.2%). Most cases had an active disease (69.4%). Clinical presentation of COVID-19 was typical, with systemic symptoms (fever and asthenia) and respiratory symptoms. The overall outcome was severe, with high frequencies of hospitalisation (69.8%), respiratory support oxygen (55.7%), non-invasive ventilation (20.9%) or mechanical ventilation (7.5%), and 19% of deaths. Male patients typically manifested a worse prognosis. Immunomodulatory treatments were not significantly associated with an increased risk of intensive care unit admission/mechanical ventilation/death.
CONCLUSIONS:
Although the report mainly includes the most severe cases, its temporal and spatial trend supports the validity of the national surveillance system. More complete data are being acquired in order to both test the hypothesis that RMD patients may have a different outcome from that of the general population and determine the safety of immunomodulatory treatments
Abdominal drainage after elective colorectal surgery: propensity score-matched retrospective analysis of an Italian cohort
background: In italy, surgeons continue to drain the abdominal cavity in more than 50 per cent of patients after colorectal resection. the aim of this study was to evaluate the impact of abdominal drain placement on early adverse events in patients undergoing elective colorectal surgery. methods: a database was retrospectively analysed through a 1:1 propensity score-matching model including 21 covariates. the primary endpoint was the postoperative duration of stay, and the secondary endpoints were surgical site infections, infectious morbidity rate defined as surgical site infections plus pulmonary infections plus urinary infections, anastomotic leakage, overall morbidity rate, major morbidity rate, reoperation and mortality rates. the results of multiple logistic regression analyses were presented as odds ratios (OR) and 95 per cent c.i. results: a total of 6157 patients were analysed to produce two well-balanced groups of 1802 patients: group (A), no abdominal drain(s) and group (B), abdominal drain(s). group a versus group B showed a significantly lower risk of postoperative duration of stay >6 days (OR 0.60; 95 per cent c.i. 0.51-0.70; P < 0.001). a mean postoperative duration of stay difference of 0.86 days was detected between groups. no difference was recorded between the two groups for all the other endpoints. conclusion: this study confirms that placement of abdominal drain(s) after elective colorectal surgery is associated with a non-clinically significant longer (0.86 days) postoperative duration of stay but has no impact on any other secondary outcomes, confirming that abdominal drains should not be used routinely in colorectal surgery
Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign
Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come
ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice
Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.Peer reviewe
Multidifferential study of identified charged hadron distributions in -tagged jets in proton-proton collisions at 13 TeV
Jet fragmentation functions are measured for the first time in proton-proton
collisions for charged pions, kaons, and protons within jets recoiling against
a boson. The charged-hadron distributions are studied longitudinally and
transversely to the jet direction for jets with transverse momentum 20 GeV and in the pseudorapidity range . The
data sample was collected with the LHCb experiment at a center-of-mass energy
of 13 TeV, corresponding to an integrated luminosity of 1.64 fb. Triple
differential distributions as a function of the hadron longitudinal momentum
fraction, hadron transverse momentum, and jet transverse momentum are also
measured for the first time. This helps constrain transverse-momentum-dependent
fragmentation functions. Differences in the shapes and magnitudes of the
measured distributions for the different hadron species provide insights into
the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb
public pages
Study of the decay
The decay is studied
in proton-proton collisions at a center-of-mass energy of TeV
using data corresponding to an integrated luminosity of 5
collected by the LHCb experiment. In the system, the
state observed at the BaBar and Belle experiments is
resolved into two narrower states, and ,
whose masses and widths are measured to be where the first uncertainties are statistical and the second
systematic. The results are consistent with a previous LHCb measurement using a
prompt sample. Evidence of a new
state is found with a local significance of , whose mass and width
are measured to be and , respectively. In addition, evidence of a new decay mode
is found with a significance of
. The relative branching fraction of with respect to the
decay is measured to be , where the first
uncertainty is statistical, the second systematic and the third originates from
the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb
public pages
Measurement of the ratios of branching fractions and
The ratios of branching fractions
and are measured, assuming isospin symmetry, using a
sample of proton-proton collision data corresponding to 3.0 fb of
integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The
tau lepton is identified in the decay mode
. The measured values are
and
, where the first uncertainty is
statistical and the second is systematic. The correlation between these
measurements is . Results are consistent with the current average
of these quantities and are at a combined 1.9 standard deviations from the
predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb
public pages
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