Coadministration of Atorvastatin Prevents Nitroglycerin-Induced Endothelial Dysfunction and Nitrate Tolerance in Healthy Humans

ObjectivesWe aimed to assess whether concurrent administration of atorvastatin would modify the development of tolerance and endothelial dysfunction associated with sustained nitroglycerin (GTN) therapy in humans.BackgroundAnimal studies have demonstrated that administration of 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors can protect against GTN-induced endothelial dysfunction and tolerance, likely through an antioxidant mechanism.MethodsThirty-six healthy male volunteers were randomized to receive continuous transdermal GTN (0.6 mg/h) and placebo, atorvastatin (80 mg/day) alone, or continuous transdermal GTN (0.6 mg/h) with concurrent atorvastatin (80 mg/day), all for 7 days. On the second visit, forearm blood flow was measured with venous-occlusion strain gauge plethysmography in response to incremental infusions of acetylcholine (7.5, 15, and 30 μg/min). Acetylcholine infusions were coinfused first with saline, and repeated during the coinfusion of vitamin C (24 mg/min). Blood pressure responses to sublingual GTN (400 μg) were assessed on both visits.ResultsAcetylcholine responses in the GTN plus placebo group were significantly attenuated versus those in the GTN plus atorvastatin and atorvastatin groups (p < 0.01). Coinfusion of vitamin C completely restored acetylcholine responses in the GTN plus placebo group (p < 0.01 vs. saline coinfusion), but caused no change in either the atorvastatin or the GTN plus atorvastatin groups. Blood pressure responses to sublingual GTN did not significantly change between visits in subjects receiving GTN plus atorvastatin and atorvastatin alone, but were significantly blunted in the GTN plus placebo group (p < 0.05).ConclusionsThe present findings demonstrate, for the first time in humans, that atorvastatin prevents both GTN-induced endothelial dysfunction and nitrate tolerance, likely by counteracting the GTN-induced increase in oxidative stress

Use of a participatory quality assessment and improvement tool for maternal and neonatal hospital care. Part 2: Review of the results of quality cycles and of factors influencing change

Background Information about the use of the findings of quality assessments in maternal and neonatal (MN) care is lacking and the development of tools capable to effectively address quality gaps is a key priority. Furthermore, little is known about factors that act as barriers or facilitators to change at facility level. Based on the extensive experience made with the WHO Quality Assessment and Improvement MN (QA/QI MN) tool, an overview is provided of the improvements in quality of care (QoC) which were obtained over time and of the factors influencing change. Methods All documented reports on the implementation of the WHO QA/QI MN tool were searched and screened for inclusion. Reports were considered if bringing evidence from both the baseline assessment and the reassessment. Changes were considered in four domains: maternal care, neonatal care, infrastructure and policies, with reference made to WHO maternal and neonatal care standards. The observed improvements were categorized according to intensity and extent across the sample of health facilities. Factors influencing change were categorized into internal and external and further classified as barriers or facilitators. Results. Changes were documented after an average period of 1.2 years from first assessment in 27 facilities belonging to 9 different countries in Central and Eastern Europe (3), Central Asia (3), sub-Saharan Africa (2) and Latin America (1). Improvements were observed in all areas of care but were greater and more frequently observed in areas related to appropriate case management and respectful care for both mothers and newborns. Although widespread across most facilities and countries, the observed improvements were not covering all the quality gaps observed at the baseline assessment nor were always sufficient to achieve standard care. Factors facilitating change as well as barriers were mainly related to the capacity of the managers and head of units to involve and motivate their staff members. Conclusions The use of WHO QA/QI MN tool proved effective in promoting significant changes in quality of care. The review of observed improvements and of factors influencing change at facility level shows that participatory assessment tools that promote a constructive dialogue with hospital managers and staff and support them in acquiring capacity in this role are crucial to implement effective quality cycles

Inhibitory effects of fenofibrate on apoptosis and cell proliferation in human endothelial cells in high glucose

Fenofibrate has beneficial effects on the progression and clinical emergence of atherosclerosis in normoglycemic and in diabetic patients. Given the involvement of endothelium in these processes, we speculated that fenofibrate may influence endothelial cell apoptosis and proliferation, regulators of endothelium integrity. Fenofibrate effects on apoptosis and proliferation were studied in human umbilical vein endothelial cells under normal (5.5 mmol/l, NG) and high (22 mmol/l, HG) glucose with or without fenofibrate (50 micromol/l). Apoptosis was evaluated by annexin V, by poly(ADP-ribose) polymerase protein cleavage, and cyclooxygenase-2 (COX-2), Bax/Bcl-2, and p53 protein levels; proliferation was assessed by determining cell cycle phase distribution and the amounts of the cell cycle regulators E2F1, cyclin D1, E1, and A and the levels of the hyper-phosphorylated form of the retinoblastoma protein (ppRb). HG resulted in increased (p<0.05) apoptosis rate associated with COX-2 protein overexpression, without modification of Bax/Bcl2 ratio and p53 levels. Fenofibrate decreased apoptosis and normalized increased COX-2 expression in HG (p<0.05). Both in HG and NG, fenofibrate dramatically reduced cell proliferation (p<0.05) through a G1/G0 block mediated by the reduction in ppRb and the decrease in E2F1, cyclin E1, A, and D1 protein expression, with a mechanism that, for cyclin E1, occurred at the posttranscriptional level. In conclusion, our data show that fenofibrate reduces apoptosis caused by HG but severely interferes with endothelial cell proliferation both in NG and HG. The resulting effect may influence endothelium integrity in vivo and may impact the outcome of acute complications of atherosclerosis in diabete

Role of E2F1\u2013Cyclin E1-Cyclin E2 Circuit in Human Coronary Smooth Muscle Cell Proliferation and Therapeutic Potential of Its Downregulation by siRNAs

Aberrant coronary vascular smooth muscle cell (CSMC) proliferation is a pivotal event underlying intimal hyperplasia, a phenomenon impairing the long-term efficacy of bypass surgery and angioplasty procedures. Consequently research has become focused on efforts to identify molecules that are able to control CSMC proliferation. We investigated downregulation of CSMC growth by small interfering RNAs (siRNAs) targeted against E2F1, cyclin E1, and cyclin E2 genes, whose contribution to CSMC proliferation is only now being recognized. Chemically synthesized siRNAs were delivered by two different transfection reagents to asynchronous and synchronous growing human CSMCs cultivated either in normo- or hyperglycemic conditions. The depletion of each of the three target genes affected the expression of the other two genes, demonstrating a close regulatory control. The clearest effects associated with the inhibition of the E2F1\u2013cyclin E1/E2 circuit were the reduction in the phosphorylation levels of the retinoblastoma protein pRB and a decrease in the amount of cyclin A2. At the phenotypic level the downmodulation of CSMC proliferation resulted in a decrease of S phase matched by an increase of G1-G0 phase cell amounts. The antiproliferative effect was cell\u2013donor and transfectant independent, reversible, and effective in asynchronous and synchronous growing CSMCs. Importantly, it was also evident in hyperglycemia, a condition that underlies diabetes. No significant aspecific cytotoxicity was observed. Our data demonstrate the interrelation among E2F1\u2013cyclin E1-cyclin E2 and the pivotal role this circuit exerts in CSMC proliferation. Additionally, our work validates the concept of utilizing anti\u2013E2F1\u2013cyclin E1-cyclin E2 siRNAs to develop a potential novel therapy to control intimal hyperplasia

HLA GENOTYPES AND DISEASE SEVERITY ASSESSED BY MAGNETIC RESONANCE IMAGING FINDINGS IN PATIENTS WITH MULTIPLE SCLEROSIS.

The objective of the study was to examine the relationship between HLA genotypes and disease severity as measured by brain MRI quantitative markers of demyelinating and destructive pathology in patients with multiple sclerosis (MS). We studied 100 patients with MS and 122 age, sex-, ethnic- and residence-matched controls. The DNA extraction and the genomic typing (A, B, DRB1 and DQB1 loci) were obtained with sequence-specific oligonucleotide method, using a commercially available reversible line blot assay (INNO-LIPA). All patients underwent a 1.5 tesla MRI examination of the brain. Disease severity was assessed by clinical (Expanded Disability Status Scale (EDSS)) and MRI (T2- and T1-lesion load (LL) and brain parenchymal fraction (BPF)) outcome measures. HLA-DQB1* 02 (OR 19.9, 95% C. I. 16.2-24.3, uncorrected (uncorr)- p<0.00001, corr-p<0.0006), -DQB1*03 (OR 16.8, 95% C. I. 13.6-20.5, uncorr-p<0.00001, corrp< 0.0006), -DRB1*15 (OR 4.6, 95% C. I. 3.7-5.6, uncorr-p= 0.0001, corr-p=0.006), and -DRB1*03 (OR 3.9, 95% C. I. 3.2-4.8, uncorr-p=0.0001, corr-p= 0.006) alleles were associated with MS. T2-, T1-LL, BPF and EDSS were not significantly different according to the carrier status of these HLA alleles. No differences were found in the ratios of disease severity/disease duration according to the HLA carrier status. Multiple regression analysis showed that a higher T2-LL was associated with the presence of DRB1*04 (uncorr-R2=0.15, p=0.006 and corr-R2=0.11, p=0.025) and B7 alleles (uncorr-R2=0.08, p=0.02 and corr-R2=0.07, p=0.018), T1-LL was associated with B7 (uncorr-R2=0.30, p<0.0001 and corr-R2=0.27, p=0.0001) and DRB1*12 (uncorr-R2=0.25, p<0.0001 and corr-R2=0.21, p=0.0002) alleles, whereas the BPF was predicted only by the presence of DRB1*12 allele (uncorr-R2=0.24, p=0.002 and corr-R2=0.20, p=0.004). The study findings suggest that some HLA alleles may predict the destructive pathological processes visible on MRI. Since the size of the sample studied is relatively small, further studies are needed to draw any firm conclusion about genotype/phenotype correlation in patients with MS

Charge transport properties of CdMnTe radiation detectors

Growth, fabrication and characterization of indium-doped cadmium manganese telluride (CdMnTe) radiation detectors have been described. Alpha-particle spectroscopy measurements and time resolved current transient measurements have yielded an average charge collection efficiency approaching 100 %. Spatially resolved charge collection efficiency maps have been produced for a range of detector bias voltages. Inhomogeneities in the charge transport of the CdMnTe crystals have been associated with chains of tellurium inclusions within the detector bulk. Further, it has been shown that the role of tellurium inclusions in degrading charge collection is reduced with increasing values of bias voltage. The electron drift velocity was calculated from the rise time distribution of the preamplifier output pulses at each measured bias. From the dependence of drift velocity on applied electric field the electron mobility was found to be μn = (718 ± 55) cm2/Vs at room temperature