The favorable kinetics and balance of nebivolol-stimulated nitric oxide and peroxynitrite release in human endothelial cells

Background: Nebivolol is a third-generation beta-blocker used to treat hypertension. The vasodilation properties of nebivolol have been attributed to nitric oxide (NO) release. However, the kinetics and mechanism of nebivolol-stimulated bioavailable NO are not fully understood. Methods: Using amperometric NO and peroxynitrite (ONOO-) nanosensors, β3-receptor (agonist: L-755,507; antagonists: SR59230A and L-748,337), ATP efflux (the mechanosensitive ATP channel blocker, gadolinium) and P2Y-receptor (agonists: ATP and 2-MeSATP; antagonist: suramin) modulators, superoxide dismutase and a NADPH oxidase inhibitor (VAS2870), we evaluated the kinetics and balance of NO and ONOO- stimulated by nebivolol in human umbilical vein endothelial cells (HUVECs). NO and ONOO- were measured with nanosensors (diameter ~ 300 nm) placed 5 ± 2 μm from the cell membrane and ATP levels were determined with a bioluminescent method. The kinetics and balance of nebivolol-stimulated NO and ONOO- were compared with those of ATP, 2-MeSATP, and L-755,507. Results: Nebivolol stimulates endothelial NO release through β3-receptor and ATP-dependent, P2Y-receptor activation with relatively slow kinetics (75 ± 5 nM/s) as compared to the kinetics of ATP (194 ± 10 nM/s), L-755,507 (108 ± 6 nM/s), and 2-MeSATP (105 ± 5 nM/s). The balance between cytoprotective NO and cytotoxic ONOO- was expressed as the ratio of [NO]/[ONOO-] concentrations. This ratio for nebivolol was 1.80 ± 0.10 and significantly higher than that for ATP (0.80 ± 0.08), L-755,507 (1.08 ± 0.08), and 2-MeSATP (1.09 ± 0.09). Nebivolol induced ATP release in a concentration-dependent manner. Conclusion: The two major pathways (ATP efflux/P2Y receptors and β3 receptors) and several steps of nebivolol-induced NO and ONOO- stimulation are mainly responsible for the slow kinetics of NO release and low ONOO-. The net effect of this slow kinetics of NO is reflected by a favorable high ratio of [NO]/[ONOO-] which may explain the beneficial effects of nebivolol in the treatment of endothelial dysfunction, hypertension, heart failure, and angiogenesis

A different ultrastructural face of ribbon synapses in the rat retina

Abstract Ribbon synapses located exclusively within retinal, cochlear and vestibular connections belong to the most interesting cellular structures but their molecular nature and functions had remained unclear. The study has provided a descriptive morphological analysis of rat eye ribbon synapses using high-resolution transmission electron microscopy (TEM). An original collection of untypical, rarely present in the literature sagittal or tangential sections through the single RIBEYE domain of the particular ribbon have been delivered

Outcome of refractory and relapsed acute myeloid leukemia in children treated during 2005-2011 : experience of the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG)

AIM OF THE STUDY: Recent studies showed relatively better outcome for children with refractory (refAML) and relapsed acute myeloid leukemia (relAML). Treatment of these patients has not been unified within Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) so far. The goal of this study is to analyze the results of this therapy performed between 2005–2011. MATERIAL AND METHODS: The outcome data of 16 patients with refAML and 62 with relAML were analyzed retrospectively. Reinduction was usually based on idarubicine, fludarabine and cytarabine with allogenic hematopoietic stem cell transplant (alloHSCT) in 5 refAML and 30 relAML children. RESULTS: Seventy seven percent relAML patients entered second complete remission (CR2). Five-year OS and disease-free survival (DFS) were estimated at 16% and 30%. The outcome for patients after alloHSCT in CR2 (63%) was better than that of those not transplanted (36%) with 5-year OS of 34% vs. 2-year of 7% and 5-year DFS of 40% vs. 12.5%. Second complete remission achievement and alloHSCT were the most significant predictors of better prognosis (p = 0.000 and p = 0.024). The outcome of refAML children was significantly worse than relAML with first remission (CR1) rate of 33%, OS and DFS of 25% at 3 years and 53% at 2 years, respectively. All survivors of refAML were treated with alloHSCT after CR1. CONCLUSIONS: The uniform reinduction regimen of the documented efficacy and subsequent alloHSCT in remission is needed to improve the outcome for ref/relAML children treated within PPLLSG. The focus should be on the future risk-directed both front and second line AML therapy

Home parenteral nutrition provision modalities for chronic intestinal failure in adult patients:An international survey

Background & aims: The safety and effectiveness of a home parenteral nutrition (HPN) program depends both on the expertise and the management approach of the HPN center. We aimed to evaluate both the approaches of different international HPN-centers in their provision of HPN and the types of intravenous supplementation (IVS)-admixtures prescribed to patients with chronic intestinal failure (CIF). Methods: In March 2015, 65 centers from 22 countries enrolled 3239 patients (benign disease 90.1%, malignant disease 9.9%), recording the patient, CIF and HPN characteristics in a structured database. The HPN-provider was categorized as health care system local pharmacy (LP) or independent home care company (HCC). The IVS-admixture was categorized as fluids and electrolytes alone (FE) or parenteral nutrition, either commercially premixed (PA) or customized to the individual patient (CA), alone or plus extra FE (PAFE or CAFE). Doctors of HPN centers were responsible for the IVS prescriptions. Results: HCC (66%) was the most common HPN provider, with no difference noted between benign-CIF and malignant-CIF. LP was the main modality in 11 countries; HCC prevailed in 4 European countries: Israel, USA, South America and Oceania (p < 0.001). IVS-admixture comprised: FE 10%, PA 17%, PAFE 17%, CA 38%, CAFE 18%. PA and PAFE prevailed in malignant-CIF while CA and CAFE use was greater in benign-CIF (p < 0.001). PA + PAFE prevailed in those countries where LP was the main HPN-provider and CA + CAFE prevailed where the main HPN-provider was HCC (p < 0.001). Conclusions: This is the first study to demonstrate that HPN provision and the IVS-admixture differ greatly among countries, among HPN centers and between benign-CIF and cancer-CIF. As both HPN provider and IVS-admixture types may play a role in the safety and effectiveness of HPN therapy, criteria to homogenize HPN programs are needed so that patients can have equal access to optimal CIF care

Two tank-mix adjuvants effect on yield and quality attributes of wheat treated with growth retardants. Two tank-mix adjuvants effect on yield and quality attributes of wheat treated with growth retardants Aplicação combinada de retardadores de crescimento

ABSTRACT The objective of this study was to evaluate the quality of seeds and yield of winter wheat under different retardants application. The two years field trials on winter wheat were carried out in the Institute of Plant Protection -National Research Institute in Poznan (Polan

Effect of Chlorocholine Chloride and Triazoles – Tebuconazole and Flusilazole on Winter Oilseed Rape (Brassica Napus Var. Oleifera L.) in Response to the Application Term and Sowing Density

Abstract: Winter oilseed rape is strongly responsive to changes in the plant density. Any change in plant density significantly affects the morphological characteristics and yield of the crop. In addition, plant growth habit can be modified by the use of plant growth regulators. Apart from plant growth regulators like eg. chlorocholine chloride some triazoles have dual properties (fungicide and plant growth regula-tor) eg. tebuconazole. The trials were carried out in the years 2006–2008 at the Institute of Plant Protection – National Research Institute in Poznan (Poland). The treatments consisted of chlorocholine chloride, tebuconazole and flusilazole applied in spring at the growth stage BBCH 30 and BBCH 50 of winter oilseed rape. The field trials were conducted with two sowing densities of winter oilseed rape: 60 seeds/ m2 and 120 seeds/m2. The vegetation seasons varied according to the weather conditions, and the second testing year was characterised by drought in May and June. In the experiments plant height, SPAD units, number of siliques per plant, seed number per silique, weight of thousand seeds, yield, protein and fat content in the seeds were estimated. The increase of silique numbers per plant appeared only at the lower sowing density as a result of the application of tebuconazole or a mixture of tebuconazole with CCC. Flusilazole had a positive impact on seed number per silique. At both sowing densities, changes in the weight of a thousand seeds under the influence of the test preparations, were observed only in that year which had wet weather conditions. A more favourable effect of the test substances on the weight of a thou-sand seeds was obtained at the lower sowing density. All the tested substances positively affected SPAD unit values at the lower sowin