Non-Vitamin K antagonist oral anticoagulants for mechanical heart valves is the door still open?

The estimated prevalence of mitral or aortic valvular heart disease is ≈2.5% in the general population of Western countries, and is expected to rise with population aging. A substantial proportion of patients with valvular heart disease undergoes surgical valve replacement. Mechanical heart valves are much more durable than bioprostheses, and are thus preferentially implanted in patients with a longer life expectancy, but have the major drawback of requiring lifelong anticoagulation to prevent valve thrombosis because of their higher thrombogenicity. The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing vitamin K antagonists in many settings, including bioprostheses, because of their favorable safety and efficacy profiles. However, mechanical heart valves currently pose an absolute contraindication to NOACs based on the results of a single phase II study comparing dabigatran and warfarin (RE-ALIGN [Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement]). That trial was stopped prematurely because of an excess of both stroke and bleeding with the dabigatran doses tested. Because of such negative findings, research in this area has been halted. We believe that several aspects of both the preclinical studies and the RE-ALIGN trial should be critically reevaluated. In our opinion, 1 single trial with a single NOAC does not represent sufficient evidence for dismissing a therapeutic strategy, anticoagulation with NOACs, that has shown better safety and at least similar efficacy as warfarin in the setting of atrial fibrillation and venous thromboembolism,. Herein, we reevaluate this topic to identify the patient profile that has the greatest likelihood of benefit from some of the NOACs, with a focus on factor Xa inhibitors, thus providing some perspectives for basic and translational research

Microfluidic hydrogel layers with multiple gradients to stimulate and perfuse three-dimensional neuronal cell cultures

We present a simple and easy to handle PDMS microfluidic device for neuronal cell culture studies in three-dimensional hydrogel scaffolds. The hydrogel is structured in parallel layers to reconstruct cell layers close to the natural environment. Dissociated cortical neurons of embryonic rats have been cultured in 0.5% w/v agarose including 0.2% w/v alginate. The cells formed neurite networks through neighboring cell free hydrogel layers. The cell culture showed neurite outgrowth in the microfluidic channel over more than seven days in vitro without perfusion. Culturing neurons in hydrogel layers surrounded by a liquid phase containing culture medium resulted in denser neuronal networks

FFAs and QT intervals in obese women with visceral adiposity: Effects of sustained weight loss over 1 year

We evaluated 66 obese patients grouped by waist-to-hip ratio (WHR) into group A (WHR > 0.85, n = 30) and group B (WHR ≤ 0.85, n = 36), before and after 1 yr of diet-induced weight loss compared with 25 nonobese women. Before diet, the longest values of QT intervals and the highest levels of FFA and catecholamines were in group A (P < 0.01). In obese women (both groups), the corrected QT (QTc); interval correlated with plasma FFA (P < 0.01) and catecholamine (P < 0.02) concentrations. After 1 yr of diet, at the same levels of body weight reduction, the decrement of the QTc interval (P < 0.02), FFA (P < 0.01) and catecholamine (P < 0.02) levels were significantly greater in-group A than group B. In multivariate analysis, the decline of the QTc interval after weight loss was associated with changes in plasma FFA independently of changes in WHR and plasma catecholamines. Our data suggest that the QTc interval is tightly correlated with plasma FFA levels; shortening of cardiac repolarization times in the course of long-lasting weight reduction may reduce the risk of ventricular electrical instability, especially in women with abdominal adiposity

Metabolic syndrome and risk of cancer:a sistematic review and meta-analysis.

OBJECTIVE - Available evidence supports the emerging hypothesis that metabolic syndrome may be associated with the risk of some common cancers. We did a systematic review and meta-analysis to assess the association between metabolic syndrome and risk of cancer at different sites. RESEARCH DESIGN AND METHODS - We conducted an electronic search for articles published through October 2011 without restrictions and by reviewing reference lists from retrieved articles. Every included study was to report risk estimates with 95% CIs for the association between metabolic syndrome and cancer. RESULTS - We analyzed 116 datasets from 43 articles, including 38,940 cases of cancer. In cohort studies in men, the presence of metabolic syndrome was associated with liver (relative risk 1.43, P < 0.0001), colorectal (1.25, P < 0.001), and bladder cancer (1.10, P = 0.013). In cohort studies in women, the presence of metabolic syndrome was associated with endometrial (1.61, P = 0.001), pancreatic (1.58, P < 0.0001), breast postmenopausal (1.56, P = 0.017), rectal (1.52, P = 0.005), and colorectal (1.34, P = 0.006) cancers. Associations with metabolic syndrome were stronger in women than in men for pancreatic (P = 0.01) and rectal (P = 0.01) cancers. Associations were different between ethnic groups: we recorded stronger associations in Asia populations for liver cancer (P = 0.002), in European populations for colorectal cancer in women (P = 0.004), and in U.S. populations (whites) for prostate cancer (P = 0.001). CONCLUSIONS - Metabolic syndrome is associated with increased risk of common cancers; for some cancers, the risk differs betweens sexes, populations, and de finitions of metabolic syndrome

Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease

Abstract Background Valvular heart disease (VHD) and atrial fibrillation (AF) often coexist. Phase III trials comparing non–vitamin K antagonist oral anticoagulants (NOACs) with warfarin excluded patients with moderate/severe mitral stenosis or mechanical heart valves, but variably included patients with other VHD and valve surgeries. Objectives This study aimed to determine relative safety and efficacy of NOACs in patients with VHD. Methods We performed a meta-analysis of the 4 phase III AF trials of the currently available NOACs versus warfarin in patients with coexisting VHD to assess pooled estimates of relative risk (RR) and 95% confidence intervals (CIs) for stroke/systemic embolic events (SSEE), major bleeding, intracranial hemorrhage (ICH), and all-cause death. Results Compared with warfarin, the rate of SSEE in patients treated with higher-dose NOACs was lower and consistent among 13,585 patients with (RR: 0.70; 95% CI: 0.58 to 0.86) or 58,098 without VHD (RR: 0.84; 95% CI: 0.75 to 0.95; interaction p = 0.13). Major bleeding in patients on higher-dose NOACs versus warfarin was similar and consistent among patients with (RR: 0.93; 95% CI: 0.68 to 1.27) or without VHD (RR: 0.85; 95% CI: 0.70 to 1.02; interaction p = 0.63 for VHD/no-VHD difference). Intracranial hemorrhage was lower with higher-dose NOACs than with warfarin irrespective of VHD (RR: 0.47; 95% CI: 0.24 to 0.93, and 0.49; 95% CI: 0.41 to 059, respectively; interaction p = 0.91). No protective effect of higher-dose NOACs in preventing all-cause death seemed to be present in patients with VHD versus without VHD (RR:1.01; 95% CI: 0.90 to 1.14 vs. RR: 0.88; 95% CI: 0.82 to 0.94, respectively; interaction p = 0.03). Conclusions High-dose NOACs provide overall efficacy and safety similar in AF patients with or without VHD

Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms

Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy (OBX) model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed altered voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 μg/kg/infusion). To this aim, olfactory-bulbectomized (OBX) and sham-operated (SHAM) Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous [fixed ratio 1 (FR-1)] schedule of reinforcement in 2 h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behavior after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5-10 mg/kg), did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg) did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2) reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens (NAc) of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive-like state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats

Climate change adaptation cycle for pilot projects development in small municipalities: The northwestern Italian regions case study

More than half of the European population live in small and medium size municipalities, where climate adaptation planning is an under-researched topic within the climate change field. Many constraints might hinder the implementation of adaptation pilot projects due to lack of economic, knowledge, and technical available resources. Local institutions find difficulties in building a coherent local adaptation planning and design processes with international and national frameworks. In this context, this article proposes a methodology based on the available international frameworks to support the small communities with the aim to implement adaptation pilot projects within different sectors. In doing so, this paper tests a climate change adaptation cycle for pilot projects development in small municipalities; the first in Italy for small municipalities under 20.000 inhabitants. The proposed methodology could lead local adaptation initiatives in climate change risk assessment by supporting the research communities in developing a coherent vision for the local territories and to identify proper oriented measures to enhance demonstrative pilot projects and to increase the level of resilience in small municipalities, avoiding maladaptation