Effects of the SGLT2 inhibitor dapagliflozin on cardiac function evaluated by impedance cardiography in patients with type 2 diabetes. Secondary analysis of a randomized placebo-controlled trial

Cardiovascular outcome trials have documented a strong benefit of sodium glucose cotransporter-2 inhibitors (SGLT2i) on the risk of hospitalization for heart failure (HF) in patients with type 2 diabetes (T2D) with or without established cardiovascular disease or prior history of HF. The mechanisms, however, are not entirely clear. We aimed to evaluate whether treatment with SGLT2i affected cardiac function using impedance cardiography (ICG) in a randomized placebo-controlled trial

Comparative effectiveness of dapagliflozin vs DPP-4 inhibitors on a composite endpoint of HbA1c, body weight and blood pressure reduction in the real world

Background: Treatment of type 2 diabetes (T2D) should aim at preventing or delaying complications through the control of glycaemia and cardiovascular risk factors. We herein compared the SGLT-2 inhibitor dapagliflozin vs DPP-4 inhibitors (DPP-4i) on a composite endpoint of glycaemic and extraglycaemic effectiveness. Methods: This was a multicentre, retrospective real-world study conducted at 56 outpatient clinics in Italy. We collected data on patients newly started on dapagliflozin or DPP-4i in 2015-2017. The primary endpoint was the proportion of patients attaining a simultaneous reduction of HbA1c ≥0.5%, body weight ≥2 kg, systolic blood pressure (SBP) ≥2 mmHg. Confounding by indication was addressed by propensity score matching (PSM) or multivariable adjustment (MVA). Results: Patients initiating dapagliflozin (n = 2091) or DPP-4i (n = 2144) differed for most clinical characteristics. After PSM, two well-balanced groups of 1149 patients each were compared. The primary endpoint was reached in a greater proportion of patients who received dapagliflozin (17.6%) compared to DPP-4i (11.7%), with a relative risk of 1.50 (1.21-1.86; P <.001). Similar results were obtained in the as-treated and intention-to-treat datasets or using MVA in place of PSM. The beneficial effect of dapagliflozin was mainly due to its greater effectiveness on body weight and, to a lesser extent, on SBP. The change in HbA1c did not differ between groups. Conclusions: T2D patients initiating the SGLT2i dapagliflozin had a greater probability of attaining a composite endpoint of clinically relevant reductions in HbA1c, body weight and SBP, compared to similar patients initiating a DPP-4i in the same period and healthcare setting

Maize plants produce direct resistance elicited by Tetranychus urticae Koch (Acari: Tetranychidae).

Plants can be attacked by a wide variety of herbivores. Thus, developing protective mechanisms for resistance against these agents is an advantage for survival and reproduction. Over the course of evolution, many resistance mechanisms against herbivory have been developed by the plants. Induced direct and indirect resistance mechanisms can manifest in plants after herbivore attack. The two-spotted spider mite Tetranychus urticae is not a pest of maize crops (Zea mays), despite being reported infesting plants that may have resistances against this herbivore. We tested the hypothesis that maize plants would be able to induce direct resistance against T. urticae after, evaluating the effect of T. urticae infestation in maize plants on the development and reproduction of conspecifics. We tested induced direct resistance performing infestation and measuring biological parameters upon a second infestation. Maize plants, 40 days after sowing, were divided into two groups: 30 not infested by T. urticae (clean plants clean) and, 30 infested by the spider mite. Infestation of maize plants by T. urticae reduced the conspecific female adult survival. However, no change in the survival of immature or reproduction was observed. These results suggest the induction of induced direct resistances in maize by T. urticae. This is first report of direct resistance induction in Z. mays by the two-spotted spider mite T. urticae

Efeito do cultivo de milho Bt sobre a comunidade de formigas de solo.

Resumo

Diabetes Causes Bone Marrow Autonomic Neuropathy and Impairs Stem Cell Mobilization via Dysregulated p66Shc and Sirt1

Diabetes compromises the bone marrow (BM) microenvironment and reduces circulating CD34 + cells. Diabetic autonomic neuropathy (DAN) may impact the BM, because the sympathetic nervous system (SNS) is prominently involved in BM stem cell trafficking. We hypothesize that neuropathy of the BM affects stem cell mobilization and vascular recovery after ischemia in diabetes. We report that, in patients, cardiovascular DAN was associated with fewer circulating CD34 + cells. Experimental diabetes (STZ and Ob/Ob ) or chemical sympathectomy in mice resulted in BM autonomic neuropathy, impaired Lin - cKit + Sca1 + (LKS) cell and endothelial progenitor cells (EPC, CD34 + Flk1 + ) mobilization and vascular recovery after ischemia. DAN increased expression of p66Shc and reduced expression of Sirt1 in mice and humans. p66Shc KO in diabetic mice prevented DAN in the BM, and rescued defective LKS cell and EPC mobilization. Hematopoietic Sirt1 KO mimicked the diabetic mobilization defect, while hematopoietic Sirt1 overexpression in diabetes rescued defective mobilization and vascular repair. Through p66Shc and Sirt1 , diabetes and sympathectomy elevated the expression of various adhesion molecules, including CD62L . CD62L KO partially rescued the defective stem/progenitor cell mobilization. In conclusion, autonomic neuropathy in the BM impairs stem cell mobilization in diabetes with dysregulation of the lifespan regulators p66Shc and Sirt1

Circulating Progenitor Cell Count for Cardiovascular Risk Stratification: A Pooled Analysis

Background: Circulating progenitor cells (CPC) contribute to the homeostasis of the vessel wall, and a reduced CPC count predicts cardiovascular morbidity and mortality. We tested the hypothesis that CPC count improves cardiovascular risk stratification and that this is modulated by low-grade inflammation. Methodology/Principal Findings: We pooled data from 4 longitudinal studies, including a total of 1,057 patients having CPC determined and major adverse cardiovascular events (MACE) collected. We recorded cardiovascular risk factors and high-sensitive C-reactive protein (hsCRP) level. Risk estimates were derived from Cox proportional hazard analyses. CPC count and/or hsCRP level were added to a reference model including age, sex, cardiovascular risk factors, prevalent CVD, chronic renal failure (CRF) and medications. The sample was composed of high-risk individuals, as 76.3% had prevalent CVD and 31.6% had CRF. There were 331 (31.3%) incident MACE during an average 1.7±1.1 year follow-up time. CPC count was independently associated with incident MACE even after correction for hsCRP. According to C-statistics, models including CPC yielded a non-significant improvement in accuracy of MACE prediction. However, the integrated discrimination improvement index (IDI) showed better performance of models including CPC compared to the reference model and models including hsCRP in identifying MACE. CPC count also yielded significant net reclassification improvements (NRI) for CV death, non-fatal AMI and other CV events. The effect of CPC was independent of hsCRP, but there was a significant more-than-additive interaction between low CPC count and raised hsCRP level in predicting incident MACE. Conclusions/Significance: In high risk individuals, a reduced CPC count helps identifying more patients at higher risk of MACE over the short term, especially in combination with a raised hsCRP level

Stepwise Optimization of the Procedure for Assessment of Circulating Progenitor Cells in Patients with Myocardial Infarction

The number and functional activity of circulating progenitor cells (CPCs) is altered in diabetic patients. Furthermore, reduced CPC count has been shown to independently predict cardiovascular events. Validation of CPCs as a biomarker for cardiovascular risk stratification requires rigorous methodology. Before a standard operation protocol (SOP) can be designed for such a trial, a variety of technical issues have to be addressed fundamentally, which include the appropriate type of red blood cell lysis buffer, FMO or isotype controls to identify rare cell populations from background noise, optimal antibody dilutions and conditions of sample storage. We herein propose improvements in critical steps of CPC isolation, antigenic characterization and determination of functional competence for final application in a prospective investigation of CPCs as a biomarker of outcome following acute myocardial infarction.In this validation study, we refined the standard operating procedure (SOP) for flow cytometry characterisation and functional analysis of CPCs from the first 18 patients of the Progenitor Cell Response after Myocardial Infarction Study (ProMIS). ProMIS aims to verify the prognostic value of CPCs in patients with either ST elevation or non-ST elevation myocardial infarction with or without diabetes mellitus, using cardiac magnetic resonance imaging (MRI) for assessment of ventricular function as a primary endpoint. Results indicate crucial steps for SOP implementation, namely timely cell isolation after sampling, use of appropriate lysis buffer to separate blood cell types and minimize the acquisition events during flow cytometry, adoption of proper fluorophore combination and antibody titration for multiple antigenic detection and introduction of counting beads for precise quantification of functional CPC activity in migration assay.With systematic specification of factors influencing the enumeration of CPC by flow cytometry, the abundance and migration capacity of CPCs can be correctly assessed. Adoption of validated SOP is essential for refined comparison of patients with different comorbidities in the analysis of risk stratification

Defesa direta elicitada por Tetranychus urticae Koch (Acari: Tetranychidae) em milho Bt.

Direct and indirect induced defense mechanisms against herbivores can be manifested in maize (Zea mays L.) plants. Furthermore, there are constitutive defenses in which plants continuously express resistance traces. In recent decades has increased the production of transgenic maize plants that constitutively express proteins with insecticide action (Bt maize). The increase of the use of transgenic maize cultivars with the Bt (Bacillus thuringiensis) gene demand studies that evaluate the impacts caused by this technology on plant defense mechanisms and their impact on non-targeted organisms, as the two-spotted spider mite Tetranychus urticae Koch (Acari: Tetranychidae). We tested the hypothesis that Bt maize plants (expressing Cry1F protein) would be capable of inducing direct defenses to T. urticae after being attacked by these mites. Thus, we used plants of a commercial maize hybrid (30F35 Hx - expressing Cry1F protein) and plants of its respective non-Bt isogenic line (control). We compared the survival and reproductive performances of T. urticae on plants of both lines that were previously infested with conspecifics and on plants that did not suffer pre-infestations. The previous infestation of maize plants by T. urticae did not impacted the survival and reproductive abilities of adult and immature forms of the conspecific in both genotypes. These results suggest that, Bt maize expressing the Cry1F insecticidal protein, does not interfere in the induction of direct defense by the T. urticae when compared with conventional maize plants