Role of resveratrol on the cytotoxic effects and DNA damages of iododeoxyuridine and megavoltage radiation in spheroid culture of U87MG glioblastoma cell line

The purpose of this study was to evaluate the effect of resveratrol on cytogenetic damages of iododeoxyuridine (IUdR) and x-ray megavoltage radiation (6 MV) in spheroid model of U87MG glioblastoma cancer cell line using clonogenic and alkaline comet assay. Cells were cultured as spheroids (350 μm) that were treated with 20 μM resveratrol, 1 μM IUdR and 2 Gy of 6 MV x-ray. After treatment, viability of the cells, colony forming ability and the induced DNA damages were examined using trypan blue dye exclusion, colonogenic and alkaline comet assay, respectively. Our results showed that resveratrol could significantly reduce the colony number and induce the DNA damages of the cells treated with IUdR in combination with 6 MV x-ray radiation. That results indicated that resveratrol as an inhibitor of hypoxia inducible factor 1 alpha (HIF-1α) protein in combination with IUdR as a radiosensitizer enhanced the radiosensitization of glioblastoma spheroid cells

Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus

We examined the effects of fluoxetine, a selective serotonin re-uptake inhibitor, of sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, and of combined administration of these agents on morphometric characteristics of principal cells of the murine hippocampus. Fluoxetine (5 mg/kg), sildenafil (2 mg/kg), or a combination of these drugs in the above doses were administered i.p. daily for 2 weeks to male mice. Hippocampal sections (5 mm thick) were stained with hematoxylin/eosin. Both drugs and their combination evoked no considerable changes in the dimensions of pyramidal cells in the CA1 and CA2 areas and in the dentate gyrus (DG), except for a trend toward some decrease of this parameter after fluoxetine injections in the CA1 area. Combined administration of fluoxetine and sildenafil provided significant decreases in the density of pyramidal neurons (their mean number per 10 mm of the slice) in the CA1 area and DG. Isolated administration of fluoxetine resulted in significant but less intense decreases in the density of principal cells in the CA2 area and DG. Possible mechanisms of the effects of the mentioned drugs are discussed. Further studies of interaction between fluoxetine and sildenafil in their effects on morphological and physiological properties of cells in different subregions of the hippocampus are recommended.Ми досліджували вплив флуоксетину (селективного інгібітора зворотного захвату серотоніну), силденафілу (інгібітора фосфодіестерази-5, PDE5) та їх сукупного введення на морфометричні характеристики основних (пірамідних) клітин гіпокампа мишей. Флуоксетин (5 мг/кг), силденафіл (2 мг/кг) або комбінація цих агентів у зазначених дозах уводилися самцям мишей внутрішньоочеревинно щоденно протягом двох тижнів. Зрізи гіпокампа завтовшки 5 мкм забарвлювали гематоксиліном та еозином. Обидві речовини та їх комбінація не викликали значних змін розмірів пірамідний нейронів у зонах CA1, CA2 та зубчастої звивини (ЗЗ), певна тенденція до зменшення зазначеного параметра спостерігалася після ін’єкцій флуоксетину в зоні CA1. Сукупна дія флуоксетину та силденафілу призводила до істотного зменшення щільності пірамідних нейронів (їх середньої кількості з розрахунку на 10 мкм зрізу) у зоні CA1 та ЗЗ. Обговорюються можливі механізми ефектів згаданих агентів. Доцільними є подальші дослідження особливостей взаємодії флуоксетину та силденафілу на морфологічні та фізіологічні характеристики клітин у різних підрозділах гіпокампа

Histidine substitution in the most flexible fragments of firefly luciferase modifies its thermal stability.

Molecular dynamics (MD) at two temperatures of 300 and 340 K identified two histidine residues, His461 and His489, in the most flexible regions of firefly luciferase, a light emitting enzyme. We therefore designed four protein mutants H461D, H489K, H489D and H489M to investigate their enzyme kinetic and thermodynamic stability changes. Substitution of His461 by aspartate (H461D) decreased ATP binding affinity, reduced the melting temperature of protein by around 25 degrees C and shifted its optimum temperature of activity to 10 degrees C. In line with the common feature of psychrophilic enzymes, the MD data showed that the overall flexibility of H461D was relatively high at low temperature, probably due to a decrease in the number of salt bridges around the mutation site. On the other hand, substitution of His489 by aspartate (H489D) introduced a new salt bridge between the C-terminal and N-terminal domains and increased protein rigidity but only slightly improved its thermal stability. Similar changes were observed for H489K and, to a lesser degree, H489M mutations. Based on our results we conclude that the MD simulation-based rational substitution of histidines by salt-bridge forming residues can modulate conformational dynamics in luciferase and shift its optimal temperature activity

Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus

We examined the effects of fluoxetine, a selective serotonin re-uptake inhibitor, of sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, and of combined administration of these agents on morphometric characteristics of principal cells of the murine hippocampus. Fluoxetine (5 mg/kg), sildenafil (2 mg/kg), or a combination of these drugs in the above doses were administered i.p. daily for 2 weeks to male mice. Hippocampal sections (5 mm thick) were stained with hematoxylin/eosin. Both drugs and their combination evoked no considerable changes in the dimensions of pyramidal cells in the CA1 and CA2 areas and in the dentate gyrus (DG), except for a trend toward some decrease of this parameter after fluoxetine injections in the CA1 area. Combined administration of fluoxetine and sildenafil provided significant decreases in the density of pyramidal neurons (their mean number per 10 mm of the slice) in the CA1 area and DG. Isolated administration of fluoxetine resulted in significant but less intense decreases in the density of principal cells in the CA2 area and DG. Possible mechanisms of the effects of the mentioned drugs are discussed. Further studies of interaction between fluoxetine and sildenafil in their effects on morphological and physiological properties of cells in different subregions of the hippocampus are recommended.Ми досліджували вплив флуоксетину (селективного інгібітора зворотного захвату серотоніну), силденафілу (інгібітора фосфодіестерази-5, PDE5) та їх сукупного введення на морфометричні характеристики основних (пірамідних) клітин гіпокампа мишей. Флуоксетин (5 мг/кг), силденафіл (2 мг/кг) або комбінація цих агентів у зазначених дозах уводилися самцям мишей внутрішньоочеревинно щоденно протягом двох тижнів. Зрізи гіпокампа завтовшки 5 мкм забарвлювали гематоксиліном та еозином. Обидві речовини та їх комбінація не викликали значних змін розмірів пірамідний нейронів у зонах CA1, CA2 та зубчастої звивини (ЗЗ), певна тенденція до зменшення зазначеного параметра спостерігалася після ін’єкцій флуоксетину в зоні CA1. Сукупна дія флуоксетину та силденафілу призводила до істотного зменшення щільності пірамідних нейронів (їх середньої кількості з розрахунку на 10 мкм зрізу) у зоні CA1 та ЗЗ. Обговорюються можливі механізми ефектів згаданих агентів. Доцільними є подальші дослідження особливостей взаємодії флуоксетину та силденафілу на морфологічні та фізіологічні характеристики клітин у різних підрозділах гіпокампа

Transcatheter closure of coronary artery fistulae: A literature review

Coronary artery fistulae (CAFs) are anomalous connections that bypass the myocardial capillary bed between 1 or more coronary arteries and other cardiac chambers or other vessels. These fistulae are usually asymptomatic and are, thus, diagnosed incidentally. However, larger CAFs can cause various symptoms such as angina, exertional dyspnea, syncope, palpitation, and even sudden cardiac death. Treatment options include surgical closure and percutaneous transcatheter closure (TCC) with comparable safety and efficacy. The choice of device in TCC depends on the anatomic characteristics of the CAF, the age and size of the patient, the size of the occluded vessel, the appropriate size of the catheter to be used, and the tortuosity of the catheter course to reach the intended point. Herein, we present 4 cases treated via TCC and then offer an in-depth discussion regarding this coronary artery anomaly. © 2020, Tech Science Press. All rights reserved

In-hospital and six-month outcomes of elderly patients undergoing primary percutaneous coronary intervention for acute st-elevation myocardial infarction

BACKGROUND: Elderly patients constitute a rapidly growing proportion of the population, and hence the increasing rises in the number of patients with ST-segment-elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention (PCI), which is now established as the preferred reperfusion strategy in STEMI patients, has been inadequately investigated in this high-risk group. The aim of the present study was to investigate the in- hospital and 6-month outcomes of primary PCI in elderly patients (� 75 years) with STEMI. METHODS: A total of 100 elderly patients with STEMI including those with cardiogenic shock were included. Primary PCI procedures were performed in a tertiary referral center between 2009 and 2014. In-hospital and 6-month outcomes of patients were recorded and analyzed. RESULTS: The average age of the patients was 79.6 ± 3.8 years (range = 75-90 years) and 27.0 were women. Cardiovascular risk factors and prior events were common. Nearly, half of the patients had three-vessel disease and the left anterior descending artery (LAD) was the most common infarct-related artery. The presence of cardiogenic shock but not the other variables was associated with less anatomic and procedural success (P < 0.001). It was also the major independent predictors of 6-month mortality in the patients aged � 75 years, hazard ratio (HR) = 8.02; 95% confidence interval (CI): 1.75-25.97, P < 0.001. In-hospital mortality was 2.4% in the patients without and 83.0% in those with cardiogenic shock. CONCLUSION: Primary PCI in aged patients could be associated with low complication rates and improved survival if performed in high-volume centers with experienced operators. Considering the very high rate of mortality in patients with cardiogenic shock, there should be measures to treat these patients before the onset of hemodynamic instability. © 2016, Isfahan University of Medical Sciences(IUMS). All rights reserved

Care Recommendations for the Investigation and Management of Children With Skeletal Muscle Channelopathies.

The field of pediatric skeletal muscle channelopathies has seen major new advances in terms of a wider understanding of clinical presentations and new phenotypes. Skeletal muscle channelopathies cause significant disability and even death in some of the newly described phenotypes. Despite this, there are virtually no data on the epidemiology and longitudinal natural history of these conditions or randomized controlled trial evidence of efficacy or tolerability of any treatment in children, and thus best practice care recommendations do not exist. Clinical history, and to a lesser extent examination, is key to eliciting symptoms and signs that indicate a differential diagnosis of muscle channelopathy. Normal routine investigations should not deter one from the diagnosis. Specialist neurophysiologic investigations have an additional role, but their availability should not delay genetic testing. New phenotypes are increasingly likely to be identified by next-generation sequencing panels. Many treatments or interventions for symptomatic patients are available, with anecdotal data to support their benefit, but we lack trial data on efficacy, safety, or superiority. This lack of trial data in turn can lead to hesitancy in prescribing among doctors or in accepting medication by parents. Holistic management addressing work, education, activity, and additional symptoms of pain and fatigue provides significant benefit. Preventable morbidity and sometimes mortality occurs if the diagnosis and therefore treatment is delayed. Advances in genetic sequencing technology and greater access to testing may help to refine recently identified phenotypes, including histology, as more cases are described. Randomized controlled treatment trials are required to inform best practice care recommendations. A holistic approach to management is essential and should not be overlooked. Good quality data on prevalence, health burden, and optimal treatment are urgently needed

Systems Analysis Implicates WAVE2&nbsp;Complex in the Pathogenesis of&nbsp;Developmental Left-Sided Obstructive&nbsp;Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

Role of polymorphisms of the endothelial nitric oxide synthase gene in predicting slow-flow phenomenon after primary percutaneous coronary intervention

Objective: The aim of the present study was to examine the association between 2 polymorphisms of the endothelial nitric oxide (eNOS) gene (-786T>C and +894G>T) and the no-reflow/slow-flow phenomenon in post-primary percutaneous coronary intervention (PPCI) patients. Methods: A total of 103 post-PPCI patients were enrolled. Coronary no-reflow phenomenon was defined as a Thrombolysis in Myocardial Infarction (TIMI) flow grade 0-1 and coronary slow-flow phenomenon (CSFP) was defined as a TIMI flow grade �2. Results: Due to the small number of post-PPCI patients with the no-reflow phenomenon (n=4), the primary comparison was made between CSFP (n=20) and normal flow (n=83) groups. There was a greater frequency of CSFP among carriers of the-786C allele of the eNOS-786T>C polymorphism (odds ratio OR: 3.90; 95% confidence interval CI: 0.87-17.45; p=0.07). However, no such association was detected between the +894T allele of the eNOS +894G>T and CSFP (OR: 0.92; 95% CI: 0.21-3.98; p=0.91). In the adjusted analysis, the-786T>C polymorphism did not reach statistical significance. Conclusion: There was no significant association between CSFP and 2 of the most common polymorphisms of the eNOS gene in post-PPCI patients. © 2020 Turkish Society of Cardiology