Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696]

BACKGROUND: Activation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS. METHODS: The FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest. CONCLUSION: The primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins

Fluvastatin in the first-line therapy of acute coronary syndrome: results of the multicenter, randomized, double-blind, placebo-controlled trial (the FACS-trial)

<p>Abstract</p> <p>Background</p> <p>Statins have been proved to be effective in reduction of mortality and morbidity when started in the early secondary prevention in stabilized patients after acute coronary syndrome (ACS). The safety and efficacy of statin administration directly in the first-line therapy in unstable ACS patients is not clear. The aim of our study was, therefore, to assess the effect of statin treatment initiated immediately at hospital admission of patients with ACS.</p> <p>Methods</p> <p>The trial was stopped prematurely after enrollment of one hundred and fifty-six patients with ACS that were randomized at admission to fluvastatin 80 mg (N = 78) or placebo (N = 78). Study medication was administered immediately after randomization and then once daily for 30 days; all patients were then encouraged to continue in open-label statin therapy and at the end of one-year follow-up 75% in the fluvastatin group and 78% in the placebo group were on statin therapy.</p> <p>Results</p> <p>We did not demonstrate any difference between groups in the level of C-reactive protein, interleukin 6, and pregnancy-associated plasma protein A on Day 2 and Day 30 (primary endpoint). Fluvastatin-therapy, however, significantly reduced one-year occurrence of major adverse cardiovascular events (11.5% vs. 24.4%, odds ratio (OR) 0.40, 95% CI 0.17-0.95, P = 0.038). This difference was caused mainly by reduction of recurrent symptomatic ischemia (7.7% vs. 20.5%, OR 0.32, 95% CI 0.12-0.88, P = 0.037).</p> <p>Conclusions</p> <p>This study failed to prove the effect of fluvastatin given as first-line therapy of ACS on serum markers of inflammation and plaque instability. Fluvastatin therapy was, however, safe and it may reduce cardiovascular event rate that supports immediate use of a statin in patients admitted for ACS.</p> <p>Trial registration</p> <p>NCT00171275</p

Reassessing the Fighting Performance of Conscript Soldiers During the Malvinas/Falklands War (1982)

While the idea is controversial, it is quite possible that, at least under certain circumstances, the fighting effectiveness of a conscript army can equal that of a professional army. For any army, fighting effectiveness is not only influenced by the degree of psychological cohesion among soldiers and officers, but also by the organizational culture of each particular service unit towards the preparation for war and the waging of the conflict itself. The Malvinas (Falklands) War of 1982 demonstrates this very well. In this war, two different types of armies confronted one another: the British army, a professional and all volunteer force, and the Argentine army constituted principally of conscripted soldiers. In this regard, some analysts assert that the British concept was vindicated when a force of British professional soldiers defeated an opposing Argentine force of draftees twice as numerous. Analysts in general have rated the capabilities of the Argentine land forces as poor, although there were exceptions and some units performed very well. These cases deserve to be studied. Notably, the most effective Argentine effort came from some small Army units and one Navy unit, the 5th Marine Battalion. For these units, two primary reasons account for the differences in fighting performance. First, small Army groups fought well because there was cohesion among their components, conscripts, noncommissioned officers, and junior officers, especially by the attitude of the latter. Secondly, in the case of the Marine battalion, its performance was the product not only of good training, but also of the different institutional approach to waging war that the Argentine Navy employed. These, in turn, improved cohesion. By focusing upon these units and their effectiveness, a rather new picture of the Malvinas War comes to light that differs quite substantially from those drawn in the immediate aftermath of the war itself. It should also make us rethink the lessons of the war, including those that surround the professionals versus conscripts controversy

TCT-624 Real-time utilisation of instant wave-free ratio (iFR) is feasible when performed by clinicians: results of the ADVISE in-practice, an international, multi-centre evaluation of iFR in clinical practice

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Carbon Nanofiber versus Graphene-Based Stretchable Capacitive Touch Sensors for Artificial Electronic Skin.

Stretchable capacitive devices are instrumental for new-generation multifunctional haptic technologies particularly suited for soft robotics and electronic skin applications. A majority of elongating soft electronics still rely on silicone for building devices or sensors by multiple-step replication. In this study, fabrication of a reliable elongating parallel-plate capacitive touch sensor, using nitrile rubber gloves as templates, is demonstrated. Spray coating both sides of a rubber piece cut out of a glove with a conductive polymer suspension carrying dispersed carbon nanofibers (CnFs) or graphene nanoplatelets (GnPs) is sufficient for making electrodes with low sheet resistance values (≈10 Ω sq-1). The electrodes based on CnFs maintain their conductivity up to 100% elongation whereas the GnPs-based ones form cracks before 60% elongation. However, both electrodes are reliable under elongation levels associated with human joints motility (≈20%). Strikingly, structural damages due to repeated elongation/recovery cycles could be healed through annealing. Haptic sensing characteristics of a stretchable capacitive device by wrapping it around the fingertip of a robotic hand (ICub) are demonstrated. Tactile forces as low as 0.03 N and as high as 5 N can be easily sensed by the device under elongation or over curvilinear surfaces

Cell Survival from Chemotherapy Depends on NF-κB Transcriptional Up-Regulation of Coenzyme Q Biosynthesis

9 pages and 6 figures.[Background] Coenzyme Q (CoQ) is a lipophilic antioxidant that is synthesized by a mitochondrial complex integrated by at least ten nuclear encoded COQ gene products. CoQ increases cell survival under different stress conditions, including mitochondrial DNA (mtDNA) depletion and treatment with cancer drugs such as camptothecin (CPT). We have previously demonstrated that CPT induces CoQ biosynthesis in mammal cells.[Methodology/Principal Findings] CPT activates NF-κB that binds specifically to two κB binding sites present in the 5′-flanking region of the COQ7 gene. This binding is functional and induces both the COQ7 expression and CoQ biosynthesis. The inhibition of NF-κB activation increases cell death and decreases both, CoQ levels and COQ7 expression induced by CPT. In addition, using a cell line expressing very low of NF-κB, we demonstrate that CPT was incapable of enhancing enhance both CoQ biosynthesis and COQ7 expression in these cells.[Conclusions/Significance] We demonstrate here, for the first time, that a transcriptional mechanism mediated by NF-κB regulates CoQ biosynthesis. This finding contributes new data for the understanding of the regulation of the CoQ biosynthesis pathway.This work was supported by spanish Ministerio de Educacion y Ciencia Grant BFU2005-03017.Peer reviewe

A rare truncating BRCA2 variant and genetic susceptibility to upper aerodigestive tract cancer

© The Author 2015. 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/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Funding This work was supported the National Institutes of Health (R01CA092039 05/05S1) and the National Institute of Dental and Craniofacial Research (1R03DE020116). Notes The authors thank all of the participants who took part in this research and the funders and technical staff who made this study possible. We acknowledge and thank Simone Benhamou (INSERM, France) for sample contributions. We also acknowledge and thank The Cancer Genome Atlas initiative, whose data contributed heavily to this study.Peer reviewedPublisher PD

Obesity, Metabolic Factors and Risk of Different Histological Types of Lung Cancer: A Mendelian Randomization Study

Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01–1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15–2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79–1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84–0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25–2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior

Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 x 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 x 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 x 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers