101 research outputs found
Parenteral antithrombotic therapy during primary percutaneous coronary intervention
No full textAcute myocardial infarction (AMI) is a major cause of morbidity, mortality and disability worldwide. ST-segment elevation myocardial infarction (STEMI) accounts for 25-40% of AMI presentations. Arterial thrombosis due to atherosclerotic plaque rupture with formation of an occlusive thrombus is the main cause of STEMI. Platelets and coagulation factors are the two principal elements involved in this process. The main goal of STEMI treatment is the early reperfusion. Prompt primary percutaneous coronary intervention (pPCI) together with an appropriate antithrombotic therapy are the treatment of choice in this setting. In this chapter, we provide an overview of currently available parenteral antithrombotic therapies used in patients with STEMI undergoing pPCI
Povijesni identitet umjetnika Schiavona u kritičkoj fortuni prve polovine XX. stoljeća
No full textAutorica se bavi proučavanjem interpretacije povijesnog, simboličkog, regionalnog i nacionalnog umjetničkog identiteta u recepciji Schiavona, najpoznatijih umjetnika-emigranata podrijetlom s istočne obale Jadrana, koji se u hrvatskoj povijesti umjetnosti obrađuju pod zajedničkim imenom protonacionalne zajednice kojoj su pripadali kao umjetnici, a posebice odraza nacionalnih ideologija i političkih kretanja u njihovoj kritičkoj fortuni u razdoblju od početka XX. stoljeća do 1945. godine
The Aftermath of the Orlov Revolt in the Venetian Ionian Islands: Outlaw Nicolin Fortuni and the Question of Russophile Influence
No full textIn 1770, in the immediate aftermath of the Orlov Revolt in the Ottoman Peloponnese, islanders from Zante and Cephalonia, subjects of the Venetian Republic who were involved in the uprising, were driven back to their homelands by the Muslim Albanian contingents that fought against them. Upon their return, these individuals challenged the islands' social order and controlling them became a matter of high priority for the local authorities. One such individual was the peasant Nicolin Fortuni, who, after leading the islanders' invasion of Ottoman Gastouni in March 1770, returned to Zante and became a notorious brigand. A reconstruction of Fortuni's activities after the revolt offers new insights into the birth of Ionian Russophilism before the fall of the Venetian Republic in 1797. © 2022 by The Modern Greek Studies Association
Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model
No full textCopyright © The Author 2012. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Friedreich's ataxia (FRDA) is the most common hereditary ataxia, affecting ∼3 in 100 000 individuals in Caucasian populations. It is caused by intronic GAA repeat expansions that hinder the expression of the FXN gene, resulting in defective levels of the mitochondrial protein frataxin. Sensory neurons in dorsal root ganglia (DRG) are particularly damaged by frataxin deficiency. There is no specific therapy for FRDA. Here, we show that frataxin levels can be upregulated by interferon gamma (IFNγ) in a variety of cell types, including primary cells derived from FRDA patients. IFNγ appears to act largely through a transcriptional mechanism on the FXN gene. Importantly, in vivo treatment with IFNγ increases frataxin expression in DRG neurons, prevents their pathological changes and ameliorates the sensorimotor performance in FRDA mice. These results disclose new roles for IFNγ in cellular metabolism and have direct implications for the treatment of FRDA.AtaxiaUK, National Ataxia Foundation, USA, Friedreich Ataxia Research Alliance
(FARA), USA and Telethon-Italy, FARA, GoFAR, the Wellcome
Trust, the EU FP7 and the Fondazione Telethon
Assessing bleeding in acute coronary syndrome using the Bleeding Academic Research Consortium definition
No full textBackground The Bleeding Academic Research Consortium (BARC) definition was proposed to overcome the heterogeneity among the many bleeding definitions. The aim of this study-level meta-analysis was to explore the incidence of BARC-assessed bleeding in acute coronary syndrome (ACS) studies and to ascertain the relation between these events and variables related to bleeding risk.Methods and ResultsWe searched the literature for studies that reported bleeding events according to BARC criteria in ACS patients. An analysis on heterogeneity between studies in bleeding reports was performed with I2 test. A meta-regression was conducted to explore the relation between different types of BARC bleedings and patient and procedural features. Nine studies were included in the analysis. Overall, BARC 2 rates were higher than BARC 3 or 5 rates (6.3 versus 2.6%). An extremely high level of heterogeneity was detected both for BARC 2 (I2 99.3%) and BARC 3 or 5 (I2 97.5%) bleedings. Increasing age [β coefficient 0.4% (0.2-0.6%); P<0.001] and renal impairment [β coefficient 1 6.5% (1-32.1%); P=0.037] were associated with increased BARC 3 or 5 rates, whereas the use of glycoprotein IIb/IIIa inhibitors was the only factor related to an increased incidence of BARC 2 bleeding [β coefficient 2 2.3% (5.5-39%); P=0.009]. Conclusion The high level of heterogeneity in BARC bleeding reports only partially explained by bleeding risk profile suggests that a regulatory guidance to properly evaluate bleedings and to estimate the risk - benefit in clinical trials investigating different antithrombotic treatments in ACS patients is needed
Primum non nocere: An updated meta-analysis on aspirin use in primary prevention of cardiovascular disease in patients with diabetes
No full textMeta-Analysis Comparing Potent Oral P2Y12 Inhibitors versus Clopidogrel in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention
No full textBackground: In patients with atrial fibrillation (AF) receiving percutaneous coronary intervention (PCI), current guidelines recommend against combining potent oral P2Y12 inhibitors (i.e. ticagrelor or prasugrel) with oral anticoagulant (OAC) therapy, but the evidence is limited. Objective: The aim of this meta-analysis was to compare the efficacy and safety of potent oral P2Y12 inhibitors with clopidogrel in patients receiving OAC therapy for AF after a recent PCI. Methods: Electronic databases were searched for randomized controlled trials (RCT) reporting outcomes according to the P2Y12 inhibitor used. Major or clinically relevant non-major bleeding were the safety endpoints, while the efficacy outcomes were major adverse cardiovascular events (MACE). The potent oral P2Y12 inhibitors prasugrel and ticagrelor were compared with clopidogrel. A subgroup analysis was conducted to evaluate the differences between patients treated with dual antithrombotic therapy (DAT) versus triple antithrombotic therapy (TAT). Results: Four RCTs that included 10,057 patients were included in this analysis. Potent oral P2Y12 inhibitors were associated with a significant increase in major or clinically relevant non-major bleeding compared with clopidogrel (risk ratio [RR] 1.30, 95% confidence interval [CI] 1.06–1.59, p = 0.01; number needed to harm 18, 95% CI 12–36). This finding was consistent regardless of the concomitant antithrombotic therapy (DAT vs. TAT; p = 0.69). The risk of MACE did not differ between potent oral P2Y12 inhibitors and clopidogrel (RR 1.02, 95% CI 0.57–1.82). Conclusions: In patients receiving OAC therapy for AF after a recent PCI, potent oral P2Y12 inhibitors increase the risk of clinically relevant bleeding compared with clopidogrel, with no evident benefit in terms of MACE reduction
Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells
No full textFriedreich’s ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA
Dual versus triple therapy in patients on oral anticoagulants and undergoing coronary stent implantation: A systematic review and meta-analysis
No full textBackground and aims: There is contrasting evidence regarding the optimal antithrombotic regimen after percutaneous coronary stent implantation in patients on oral anticoagulants. A systematic review and meta-analysis was performed to explore the comparative efficacy and safety of dual (an antiplatelet plus an oral anticoagulant) versus triple therapy (dual antiplatelet therapy plus an oral anticoagulant). Methods: We searched the literature for randomized controlled trials (RCTs) or observational studies (OSs) addressing this issue. The efficacy outcomes were all-cause mortality, cardiovascular mortality, myocardial infarction and stent thrombosis. The safety outcomes were major bleeding events and all bleeding events. The analyses were stratified by type of anticoagulant and of antiplatelet used in dual therapy. Results: Four RCTs and ten OSs met our inclusion criteria including a total of 10,126 patients. 5671 patients received triple therapy whereas 4455 received dual therapy. Median follow up was 12 months. There was no difference between dual therapy and triple therapy regarding efficacy outcomes. Dual therapy significantly reduced the risk of major bleeding (RR 0.66; CI 95% 0.52–0.83; P = 0.0005) and of all bleeding events (RR 0.67, CI 95% 0.55–0.80; P < 0.0001). The effect was consistent regardless of the type of antiplatelet and anticoagulant used in dual therapy. Conclusion: Dual antithrombotic therapy after coronary stenting in anticoagulated patients significantly reduces bleeding events compared with triple therapy. Dual therapy might be considered in this setting especially when bleeding risk outweighs ischemic risk, although our study was not sufficiently powered to detect a difference in ischemic endpoints
GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients
No full textFriedreich's ataxia is an autosomal recessive progressive degenerative disorder caused by deficiency of the protein frataxin. The most common genetic cause is a homozygotic expansion of GAA triplets within intron 1 of the frataxin gene leading to impaired transcription. Preclinical in vivo and in vitro studies have shown that interferon gamma (IFNγ) is able to up-regulate the expression of frataxin gene in multiple cell types. We designed a phase IIa clinical trial, the first in Italy, aimed at assessing both safety and tolerability of IFNγ in Friedreich's patients and ability to increase frataxin levels in peripheral blood mononuclear cells. Nine patients (6 female and 3 males aged 21-38 years) with genetically confirmed disease were given 3 subcutaneous escalating doses (100, 150 and 200 μg) of IFNγ (human recombinant interferon 1 b gamma, trade name IMUKIN®), over 4 weeks. The primary end-point was the assessment of the safety and tolerability of IFNγ by means of standard clinical and hematological criteria. The secondary end-point was the detection of changes of frataxin levels in peripheral blood mononuclear cells after each single escalating dose of the drug. IFNγ was generally well tolerated, the main adverse event was hyperthermia/fever. Although, increases in frataxin levels could be detected in a minority of patients, these changes were not significant. A large phase III multicenter, randomized clinical trial with IFNγ in Friedreich's ataxia patients is currently ongoing. This study is expected to conclusively address the clinical efficacy of IFNγ therapy in patients with Friedreich's ataxia
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