118 research outputs found
Common variants at 6p21.1 are associated with large artery atherosclerotic stroke
No full textGenome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10 -8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10 -4; discovery and replication combined OR = 1.21, P = 4.7 × 10 -8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke
Chemogenetic silencing reveals presynaptic Gi/o protein-mediated inhibition of developing hippocampal synchrony in vivo
No full textSummary: Recent advances in understanding how neuronal activity shapes developing brain circuits increasingly rely on Gi/o-dependent inhibitory chemogenetic tools (Gi-DREADDs). However, their mechanisms of action and efficacy in neurons with immature Gi/o signaling are elusive. Here, we express the Gi-DREADD hM4Di in glutamatergic telencephalic neurons and analyze its impact on CA1 pyramidal neurons in neonatal mice. Using acousto-optic two-photon Ca2+ imaging, we report that activation of hM4Di leads to a complete arrest of spontaneous synchrony in CA1 in vitro. We demonstrate that hM4Di does not cause somatic hyperpolarization or shunting but rather mediates presynaptic silencing of glutamatergic neurotransmission. In vivo, inhibition through hM4Di potently suppresses early sharp waves (eSPWs) and discontinuous oscillatory network activity in CA1 of head-fixed mice before eye opening. Our findings provide insights into the role of Gi/o signaling in synchronized activity in the neonatal hippocampus and bear relevance for applying chemogenetic silencing at early developmental stages
Determining outcomes and prognostic factors in ANCA associated vasculitis as a platform for the evaluation of newer treatments
No full textAnti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV) is a multisystem disease with substantial morbidity and mortality despite modem treatment. Longer-term patient outcomes are inadequately defined and new safe therapies arc needed. The aims o[this thesis were to investigate long-term outcomes of patients with AAV, compare two different damage assessment scores and the study of a novel immune-suppressant, deoxyspcrgualin (DSG), in the treatment of relapsing and refractory disease. Survival was studied in 535 newly diagnosed patients recruited to four randomised controlled trials. After a median of 5.2 years 25% deaths occurred with a mortality rate ratio of 2.6 (95% Confidence Interval (Cl) 2.2-3.1 ) compared to an age and sex matched general population. Multivariable analysis showed severely impaired kidney function, advancing age, higher disease activity and white cell count and lower haemoglobin were significant negative prognostic factors. In the same cohort, 38% experienced a relapse. Higher risk for relapse was independently associated with anti-proteinase 3 (anti-PR3) antibodies and cardiovascular involvement whereas impaired kidney function conferred a lower risk. A comparison between the Vasculitis Damage Index (VDI) and the Combined Damage Assessment Index (CDA) showed good correlation between both indices. The CDA was more complex but captured more detail. An international expert panel developed recommendations for the conduct of clinical studies and therapeutic trials in AA V. The following areas were covered: disease definitions, disease activity states, outcome measures, eligibi lity criteria, trial design including relevant end-points and biomarkers. Areas for further research were identified. A prospective open label study in 44 patients with refractory or relapsing granulomatosis with polyangiitis (GPA) treated for six months with DSG showed that 95% achieved either partial Of complete remission. Adverse events were common but rarely led to treatment discontinuation. Prolonged administration of DSG in eleven patients was effective III the majority without the occurrence of unexpected toxicity.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
A cross-sectional study of the Birmingham Vasculitis Activity Score version 3 in systemic vasculitis.
No full textOBJECTIVE: Assessment of disease activity in vasculitis can be achieved using the BVAS, a clinical checklist of relevant symptoms, signs and features of active disease. The aim of this study was to revalidate the BVAS version 3 (BVAS v. 3) in a cohort of patients with systemic vasculitis. METHODS: A total of 238 patients with vasculitis from seven countries in Europe were evaluated at a single time point. Spearman's correlation coefficients were calculated between BVAS v. 3 scores, vasculitis activity index (VAI), physician's global assessment (PGA), the physician's treatment decision, CRP and the vasculitis damage index (VDI) to demonstrate that the BVAS v. 3 measures disease activity. RESULTS: WG (63%), Churg-Strauss syndrome (9%) and microscopic polyangiitis (9%) were the most common diagnoses. The BVAS v. 3 showed convergent validity with the VAI [ρ = 0.82 (95% CI 0.77, 0.85)], PGA [ρ = 0.85 (95% CI 0.81, 0.88)] and the physician's treatment decision [ρ = 0.54 (95% CI 0.44, 0.62)]. There was little or no correlation between BVAS v. 3 and the CRP level [ρ = 0.18 (95% CI 0.05, 0.30)] or with the VDI [ρ = -0.10 (95% CI 0.22, 0.03)]. The inter-observer reliability was very high with an intra-class correlation coefficient (ICC) of 0.996 (95% CI 0.990, 0.998) for the total BVAS v. 3 score. CONCLUSION: The BVAS v. 3 has been evaluated in a large cohort of patients with vasculitis and the important properties of the tool revalidated. This study increases the utility of the BVAS v. 3 in different populations of patients with systemic vasculitis
POS0246 SEQUENTIAL RITUXIMAB AND MEPOLIZUMAB IN EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS
No full textBackgroundRituximab (RTX) is an effective remission-induction treatment in ANCA-associated vasculitides (AAVs). Some reports have suggested that it might be effective also in Eosinophilic Granulomatosis with Polyangiitis (EGPA), to induce and maintain remission of vasculitic manifestations [1,2]. However, its effects for preventing respiratory relapses seem to be poor. Mepolizumab (Mepo) (both 100 and 300mg/month) is effective in improving respiratory manifestations and lung function, while partially controlling also systemic activity [3,4]. Isolated case reports further indicate that the sequential therapy with RTX and Mepo might be effective [5-7].ObjectivesThe study aimed to investigate the efficacy and safety of a therapeutic regimen based on sequential RTX and Mepo for the control of EGPA.MethodsA multicenter, retrospective, cohort study was conducted on adult patients diagnosed with EGPA according to the ACR classification criteria [8] or MIRRA trial criteria [3]. Only patients who received induction therapy with RTX (any dosage), and subsequent treatment with Mepo (100-300 mg/4 weeks) within 12 months from last RTX administration were included. Patients receiving other induction therapies between RTX and Mepo were excluded. The effectiveness of sequential RTX and Mepo was assessed in terms of disease activity (by the Birmingham Vasculitis Activity Score, BVAS) and daily corticosteroid dosage. Safety data were also collected.ResultsThirty-four EGPA patients treated with sequential RTX and Mepo were included (59% females, median age of 51 years (IQR 40-58); 41% ANCA positive).In most cases (26/34; 76%), RTX was started at the dosage of 1g q2w, and all except two patients had active disease at time of RTX beginning [median BVAS of 9 (IQR 6-14)]. Specifically, most patients started RTX for the control of systemic manifestations (19/34; 56%), or of both systemic and respiratory symptoms (11/34; 32%). All except one patient were receiving oral corticosteroids, at a median dosage of 25 mg/day (10-38).Mepo was started after a median of 14 months (6-23) from RTX initiation and after a median of 5 months (IQR 3-11) from the last RTX administration. Mepo was used at the dosage of 100mg/4 weeks in 32/34 (94%), mostly for the control of respiratory manifestations (25/34, 74%). At the time of starting Mepo, the median BVAS was 4 (2-8), and median prednisolone dose 10 mg/day (7-15). After a median follow-up of 28 months (IQR 23-33) from starting Mepo, the median BVAS decreased to 1.5 (IQR 0-4) and the median corticosteroid dosage to 5 mg/day (2.5-5), with 7/34 (21%) patients being off steroids. At last follow-up, most patients were off-RTX (28/34), typically due to stable disease remission (20/34; 59%).Both RTX and Mepo were well-tolerated; 5 patients had adverse events on RTX (none serious), and 5 on Mepo (including one serious infection).ConclusionSequential use of RTX and Mepo seems to be effective for remission induction and maintenance in EGPA.References[1]Emmi, Ann Rheum Dis, 2018[2]Teixeira, RMD Open, 2019 3. Wechsler, NEJM, 2017[4]Bettiol, Arthritis Rheumatol, 2021[5]Shiroshita, Respir Med Case Rep, 2018[6]Higashitani, Mod Rheumatol Case Rep, 2021[7]Afiari, Cureus 2020[8]Masi, Arthritis Rheum, 1990Table 1.Effectiveness of sequential RTX and Mepo in the 34 patients included in the studyRTX beginningMepo beginningLast follow-upMedian time elapsed (IQR)-14 months (6-23) from RTX beginning28 months (23-33) from Mepo beginningDosage1g q2w (26/34);100mg/4 weeks (32/34)6 patients off Mepo; 28 patients off RTX375mg/m2 for 4 weeks (8/34)300mg/4 weeks (2/34)Reason for treatment beginning (manifestations)Systemic (19/34);Respiratory (25/34);-Systemic + respiratory (11/34);Systemic (4/34);Only respiratory (3/34);Remission maintenance (5/34)Other (1/34)BVAS (median, IQR)9 (6-14)4 (2-8)1.5 (0-4)Prednisolone dosage (median, IQR), mg/day25 (10-38)10 (7-15)5 (2.5-5)Disclosure of InterestsAlessandra Bettiol: None declared, Maria Letizia Urban: None declared, Federica Bello: None declared, Davide Fiori: None declared, Irene Mattioli: None declared, Giuseppe Lopalco: None declared, Florenzo Iannone: None declared, Allyson Egan: None declared, Luca Moroni: None declared, Lorenzo Dagna Consultant of: Consultation honoraria from GSK outside the current work, Marco Caminati: None declared, Simone Negrini: None declared, Paolo Cameli: None declared, Marco Folci: None declared, Paola Toniati: None declared, Roberto Padoan: None declared, Oliver Flossmann: None declared, Roser Solans-Laqué: None declared, Laura Losappio: None declared, Jan Schroeder Consultant of: Advisory Board fees from AstraZeneca and GSK, Marc André: None declared, Laura Moi: None declared, paola parronchi Consultant of: Consultation honoraria from GSK and Novartis, Fabrizio Conti: None declared, Savino Sciascia: None declared, David Jayne Consultant of: Consultant for Astra-Zeneca, Aurinia, BMS, Boehringer-Ingelheim, Chemocentryx, Chugai, CSL, GSK, Infla-RX, Janssen, Novartis, Roche/Genentech, Takeda and Vifor, Augusto Vaglio Consultant of: Consultation honoraria from GSK outside the current work, Giacomo Emmi Consultant of: Consultation honoraria from GSK outside the current work</jats:sec
Jeg-3 Human Choriocarcinoma-Induced Immunosuppression: Downregulation of Interleukin-2, Interleukin-2 Receptor α-Chain, and Its Jak/Stat Signaling Pathway
No full textRemission in antineutrophil cytoplasmic antibody-associated systemic vasculitis.
No full textThe definition of remission in patients with systemic vasculitis must be distinguished from the term "cure," which implies that patients are well and not requiring ongoing therapy. Remission should be defined using a standardised approach to measuring clinical disease activity, and the definition should be qualified by the duration of the remission and the type of maintenance therapy required to sustain remission. Remission is an important goal of management in the systemic vasculitides and is achievable in most patients. Maintenance of remission is a more difficult target, and evidence from studies of patients with antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis indicates that durable, lasting remission is unlikely to occur. Despite good disease control, damage or scarring from disease or its treatment is a common finding and is a separate outcome from remission. Future studies of vasculitis therapies should address the concept of rapid and sustained disease control, so that patients spend most of their time in a state of good health, with minimal damage
Factors influencing remission, relapse, renal failure and mortality in patients with systemic vasculitis
No full textEular recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis
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