Biomedical subjects

Sonia Franciosi

Publications and source records attributed to Sonia Franciosi.

5 recordsLinked to original sources

PubMed2026

Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification.

BACKGROUND AND AIMS: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. METHODS: The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. RESULTS: A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE. CONCLUSIONS: These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Humans↗

PubMed2006

Broad-spectrum effects of 4-aminopyridine to modulate amyloid beta1-42-induced cell signaling and functional responses in human microglia.

We investigated the modulating actions of the nonselective K(+) channel blocker 4-aminopyridine (4-AP) on amyloid beta (Abeta(1-42))-induced human microglial signaling pathways and functional processes. Whole-cell patch-clamp studies showed acute application of Abeta(1-42) (5 mum) to human microglia led to rapid expression of a 4-AP-sensitive, non-inactivating outwardly rectifying K(+) current (I(K)). Intracellular application of the nonhydrolyzable analog of GTP, GTPgammaS, induced an outward K(+) current with similar properties to the Abeta(1-42)-induced I(K) including sensitivity to 4-AP (IC(50) = 5 mm). Reverse transcriptase-PCR showed a rapid expression of a delayed rectifier Kv3.1 channel in Abeta(1-42)-treated microglia. Abeta(1-42) peptide also caused a slow, progressive increase in levels of [Ca(2+)](i) (intracellular calcium) that was partially blocked by 4-AP. Chronic exposure of human microglia to Abeta(1-42) led to enhanced p38 mitogen-activated protein kinase and nuclear factor kappaB expression with factors inhibited by 4-AP. Abeta(1-42) also induced the expression and production of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, the chemokine IL-8, and the enzyme cyclooxygenase-2; 4-AP was effective in reducing all of these pro-inflammatory mediators. Additionally, toxicity of supernatant from Abeta(1-42)-treated microglia on cultured rat hippocampal neurons was reduced if 4-AP was included with peptide. In vivo, injection of Abeta(1-42) into rat hippocampus induced neuronal damage and increased microglial activation. Daily administration of 1 mg/kg 4-AP was found to suppress microglial activation and exhibited neuroprotection. The overall results suggest that 4-AP modulation of an Abeta(1-42)-induced I(K) (candidate channel Kv3.1) and intracellular signaling pathways in human microglia could serve as a therapeutic strategy for neuroprotection in Alzheimer's disease pathology.

4-Aminopyridine↗

PubMed2004

IL-8 enhancement of amyloid-beta (Abeta 1-42)-induced expression and production of pro-inflammatory cytokines and COX-2 in cultured human microglia.

The effects of the chemokine IL-8 on amyloid beta peptide (Abeta(1-42))-induced responses in cultured human microglia were investigated using RT-PCR, ELISA and immunocytochemistry. Abeta(1-42) (5 microM) applied for 8 h induced the expression and increased the production of the pro-inflammatory cytokines IL-6, IL-1beta, TNF-alpha, the inducible enzyme COX-2 and chemokine IL-8. Microglial treatment with IL-8 added (at 100 ng/mL) with Abeta(1-42) led to enhancement in both expression and production of all of these pro-inflammatory factors compared with peptide alone. Stimulation with IL-8 itself was effective in increasing microglial expression of pro-inflammatory cytokines, IL-8 and COX-2, however, had no effect on protein levels of all these factors. The expression of the anti-inflammatory cytokines IL-10 and TGFbeta(1) remained unchanged from basal levels with stimulation using either Abeta(1-42), IL-8 or the peptide together with IL-8. The actions of IL-8 to potentiate Abeta(1-42)-induced inflammatory mediators may have particular relevance to Alzheimer disease brain which exhibits elevated levels of the chemokine.

Adjuvants, Immunologic↗

PubMed2004

Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus.

Minocycline, a second-generation tetracycline compound, has been examined as a neuroprotectant in beta-amyloid (A beta)-injected rat hippocampus. At 7 days post-injection, A beta(1-42) caused a significant loss of granule cell layer neurons (28% reduction) compared to control uninjected hippocampus. Hippocampal injection of A beta peptide also led to marked gliosis with numbers of microglia (increased by 26-fold) and immunoreactivity of astrocytes (increased by 11-fold) relative to control, as determined from immunohistochemical analysis. Intraperitoneal administration of minocycline significantly reduced neuronal loss induced by A beta(1-42) (by 80%) and also diminished numbers of microglia (by 69%) and astrocytes (by 36%) relative to peptide alone. Peptide injection increased expression of cyclooxygenase-2 (COX-2) in most (about 70%) of granule cells, a subset (about 20%) of microglia, but not in astrocytes; in the presence of minocycline, COX-2 immunostaining was abolished in microglia. The results from this study suggest that minocycline may have efficacy in the treatment of AD.

Amyloid beta-Peptides↗

PubMed2002

Interferon-gamma acutely induces calcium influx in human microglia.

The acute actions of the cytokine, interferon-gamma (IFN-gamma), on intracellular calcium [Ca(2+)](i) levels in human microglia were investigated. In the presence of a calcium-containing physiological solution (Ca(2+)-PSS), IFN-gamma caused a progressive increase in [Ca(2+)](i) to a plateau level with a mean rate of increase of 0.81 +/- 0.17 nM/s and mean amplitude of 102 +/- 12 nM (n = 67 cells). Washout of the cytokine did not alter the plateau established with IFN-gamma in Ca(2+)-PSS; however, introduction of a Ca(2+)-free PSS diminished [Ca(2+)](i) to baseline levels. The decrease in [Ca(2+)](i) with Ca(2+)-free PSS would indicate that the response to IFN-gamma was mediated by an influx pathway. This result was confirmed in separate experiments showing the lack of an induced change in [Ca(2+)](i) with IFN-gamma applied in Ca(2+)-free PSS. The increase in [Ca(2+)](i) induced in Ca(2+)-PSS was reduced to near baseline levels when the external solution contained low Cl(-) in the maintained presence of IFN-gamma suggesting that cellular depolarization inhibited the cytokine mediated entry pathway. The compound SKF96365, which blocks store operated influx of Ca(2+) in human microglia, was ineffective in altering the increase in [Ca(2+)](i), however, La(3+) completely inhibited the Ca(2+) response induced by IFN-gamma. Whole-cell patch clamp studies showed no effect of IFN-gamma to alter outward currents and inward rectifier K(+) currents. The influx of Ca(2+) may serve a signaling role in microglia linking IFN-gamma to functional responses of the cells to infiltrating T lymphocytes into the central nervous system (CNS) during inflammatory processes.

Calcium↗