Gene Deletion of the Kinin Receptor B1 Attenuates Cardiac Inflammation and Fibrosis During the Development of Experimental Diabetic Cardiomyopathy

Objective: Diabetic cardiomyopathy is associated with increased mortality in patients with diabetes mellitus. The underlying pathology of this disease is still under discussion. We studied the role of the kinin B1 receptor on the development of experimental diabetic cardiomyopathy. Research Design and Methods: We utilized B1 receptor knockout mice and investiged cardiac inflammation, fibrosis and oxidative stress after induction of streptozotocin (STZ)-induced diabetes mellitus. Furthermore, the left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes mellitus. Results: B1 receptor knockout mice showed an attenuation of diabetic cardiomyopathy with improved systolic and diastolic function in comparison with diabetic control mice. This was associated with a decreased activation state of the MAP kinase p38, less oxidative stress as well as normalized cardiac inflammation, shown by fewer invading cells and, no increase in matrix metalloproteinase-9 as well as the chemokine CXCL-5. Furthermore, the pro-fibrotic connective tissue growth factor was normalized, leading to a reduction in cardiac fibrosis despite severe hyperglycemia in mice lacking the B1 receptor. Conclusion: These findings suggest that the B1 receptor is detrimental in diabetic cardiomyopathy in that it mediates inflammatory and fibrotic processes. These insights might have useful implications on future studies utilizing B1 receptor antagonists for treatment of human diabetic cardiomyopathy

Unemployment benefits : discursive convergence, distant realities

Production of INCASI Project H2020-MSCA-RISE-2015 GA 691004Unemployment protection systems have certain characteristics in common in Argentina, Uruguay, Spain and Italy: they are compulsory and contributory-proportional, although in Uruguay, it also has a capitalisation supplement. Despite the similarities, they work differently because the context of informal employment chiefly, and unemployment, low salaries and precariousness differ greatly. Consequently, the unemployment protection coverage rate varies. Theories of the Active Welfare State, the Investor State and the reforms of unemployment protection systems have led to a certain modernising language being adopted in these countries: activation, employability, conditionality, lifelong learning, flexibility, which are, among others, words shared with Europe. However, the meanings of these words differ according to the institutional context of each country. In Latin America the welfare state is low institutionalised even almost non-existent, while in Europe it is a diverse institution. Despite this, the four countries share an upward trend in benefit policies, in accordance with the increase in poverty risk

Technology-Enabled Remote Monitoring and Self-Management - Vision for Patient Empowerment Following Cardiac and Vascular Surgery: User Testing and Randomized Controlled Trial Protocol.

BACKGROUND: Tens of thousands of cardiac and vascular surgeries (CaVS) are performed on seniors in Canada and the United Kingdom each year to improve survival, relieve disease symptoms, and improve health-related quality of life (HRQL). However, chronic postsurgical pain (CPSP), undetected or delayed detection of hemodynamic compromise, complications, and related poor functional status are major problems for substantial numbers of patients during the recovery process. To tackle this problem, we aim to refine and test the effectiveness of an eHealth-enabled service delivery intervention, TecHnology-Enabled remote monitoring and Self-MAnagemenT-VIsion for patient EmpoWerment following Cardiac and VasculaR surgery (THE SMArTVIEW, CoVeRed), which combines remote monitoring, education, and self-management training to optimize recovery outcomes and experience of seniors undergoing CaVS in Canada and the United Kingdom. OBJECTIVE: Our objectives are to (1) refine SMArTVIEW via high-fidelity user testing and (2) examine the effectiveness of SMArTVIEW via a randomized controlled trial (RCT). METHODS: CaVS patients and clinicians will engage in two cycles of focus groups and usability testing at each site; feedback will be elicited about expectations and experience of SMArTVIEW, in context. The data will be used to refine the SMArTVIEW eHealth delivery program. Upon transfer to the surgical ward (ie, post-intensive care unit [ICU]), 256 CaVS patients will be reassessed postoperatively and randomly allocated via an interactive Web randomization system to the intervention group or usual care. The SMArTVIEW intervention will run from surgical ward day 2 until 8 weeks following surgery. Outcome assessments will occur on postoperative day 30; at week 8; and at 3, 6, 9, and 12 months. The primary outcome is worst postop pain intensity upon movement in the previous 24 hours (Brief Pain Inventory-Short Form), averaged across the previous 14 days. Secondary outcomes include a composite of postoperative complications related to hemodynamic compromise-death, myocardial infarction, and nonfatal stroke- all-cause mortality and surgical site infections, functional status (Medical Outcomes Study Short Form-12), depressive symptoms (Geriatric Depression Scale), health service utilization-related costs (health service utilization data from the Institute for Clinical Evaluative Sciences data repository), and patient-level cost of recovery (Ambulatory Home Care Record). A linear mixed model will be used to assess the effects of the intervention on the primary outcome, with an a priori contrast of weekly average worst pain intensity upon movement to evaluate the primary endpoint of pain at 8 weeks postoperation. We will also examine the incremental cost of the intervention compared to usual care using a regression model to estimate the difference in expected health care costs between groups. RESULTS: Study start-up is underway and usability testing is scheduled to begin in the fall of 2016. CONCLUSIONS: Given our experience, dedicated industry partners, and related RCT infrastructure, we are confident we can make a lasting contribution to improving the care of seniors who undergo CaVS

CCN2 Is Required for the TGF-β Induced Activation of Smad1 - Erk1/2 Signaling Network

Connective tissue growth factor (CCN2) is a multifunctional matricellular protein, which is frequently overexpressed during organ fibrosis. CCN2 is a mediator of the pro-fibrotic effects of TGF-β in cultured cells, but the specific function of CCN2 in the fibrotic process has not been elucidated. In this study we characterized the CCN2-dependent signaling pathways that are required for the TGF-β induced fibrogenic response. By depleting endogenous CCN2 we show that CCN2 is indispensable for the TGF-β-induced phosphorylation of Smad1 and Erk1/2, but it is unnecessary for the activation of Smad3. TGF-β stimulation triggered formation of the CCN2/β3 integrin protein complexes and activation of Src signaling. Furthermore, we demonstrated that signaling through the αvβ3 integrin receptor and Src was required for the TGF-β induced Smad1 phosphorylation. Recombinant CCN2 activated Src and Erk1/2 signaling, and induced phosphorylation of Fli1, but was unable to stimulate Smad1 or Smad3 phosphorylation. Additional experiments were performed to investigate the role of CCN2 in collagen production. Consistent with the previous studies, blockade of CCN2 abrogated TGF-β-induced collagen mRNA and protein levels. Recombinant CCN2 potently stimulated collagen mRNA levels and upregulated activity of the COL1A2 promoter, however CCN2 was a weak inducer of collagen protein levels. CCN2 stimulation of collagen was dose-dependent with the lower doses (<50 ng/ml) having a stimulatory effect and higher doses having an inhibitory effect on collagen gene expression. In conclusion, our study defines a novel CCN2/αvβ3 integrin/Src/Smad1 axis that contributes to the pro-fibrotic TGF-β signaling and suggests that blockade of this pathway may be beneficial for the treatment of fibrosis

Strategies for blocking the fibrogenic actions of connective tissue growth factor (CCN2): From pharmacological inhibition in vitro to targeted siRNA therapy in vivo

Connective tissue growth factor (CCN2) is a major pro-fibrotic factor that frequently acts downstream of transforming growth factor beta (TGF-β)-mediated fibrogenic pathways. Much of our knowledge of CCN2 in fibrosis has come from studies in which its production or activity have been experimentally attenuated. These studies, performed both in vitro and in animal models, have demonstrated the utility of pharmacological inhibitors (e.g. tumor necrosis factor alpha (TNF-α), prostaglandins, peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, statins, kinase inhibitors), neutralizing antibodies, antisense oligonucleotides, or small interfering RNA (siRNA) to probe the role of CCN2 in fibrogenic pathways. These investigations have allowed the mechanisms regulating CCN2 production to be more clearly defined, have shown that CCN2 is a rational anti-fibrotic target, and have established a framework for developing effective modalities of therapeutic intervention in vivo

Integrated pest management of Tuta absoluta: practical implementations across different world regions

The South American tomato pinworm, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae), has invaded most Afro-Eurasian countries and is threatening worldwide tomato production. Various strategies have been developed and implemented to manage this pest. Here, we present a timely review on the up-to-date development and practical implementation of integrated pest management (IPM) programs for tomato crops across different world regions infested by T. absoluta. While insecticide resistance is a growing concern, biological control via releasing or conserving arthropod natural enemies and sex pheromone-based biotechnical control are the most successful management practices. Agronomic control-related research is an emerging area where the soil fertilization and/or irrigation, as well as breeding of resistant cultivars, has the potential to enhance IPM effectiveness. Grower survey responses in the native areas (i.e., South America), early-invaded areas (i.e., first report between 2006 and 2012) and newly invaded areas (i.e., first report after 2012) showed that the control programs evolved along with the areas and time since invasion. Growers in the early-invaded areas shifted more rapidly from chemical control to biological control compared to those from the native area. In all concerned regions, the pest control failure risk following chemical insecticide applications and the high cost associated with either biological or biotechnical control methods have been the greatest concerns for growers. The information gathered from the native and/or early-invaded areas may help achieve a more effective management in newly invaded areas. Lastly, researchers are expected to break the bottlenecks of some key issues that would enable lowering application cost of novel biorational alternative management options