Effects of low-dose nitrite upon normal, hypoxic and ischaemic vessels

The simple anion inorganic nitrite (NO2 ) has previously been considered a relatively inert nitric oxide (NO) metabolite. However, recent evidence shows that NO2" exhibits an enhanced vasodilator effect in hypoxia. It has been suggested that this effect is mediated by intra-vascular reduction of NO2" to NO by deoxygenated-haemoglobin. This thesis investigated the effects of low-dose NO2" supplementation in man, in three different environments where the actions of NO2" may be potentiated. Firstly, the effect of systemic sodium nitrite (NaNO2) administration upon forearm and pulmonary haemodynamics were assessed in healthy volunteers in both hypoxia and normoxia conditions created by a controlled environmental chamber. The study- infusion resulted in an approximate doubling of plasma NO2", with similar pharmacokinetics observed in both hypoxia and normoxia. Forearm vasodilation occurred in hypoxia but not normoxia. In addition a pulmonary vasodilator effect was present in hypoxia only, and was not dependent upon simultaneous elevation of plasma NO2". The same dose of NaNO2 was given to patients with proven inducible myocardial ischaemia in the second study: a double-blind placebo-controlled clinical trial. Objective markers of myocardial ischaemia were measured by tissue velocity imaging performed during dobutamine stress echocardiography. The results showed that low-dose NaNO2 acts as an anti-ischaemic agent despite no vasodilator effect being present in normoxia. A third set of experiments were performed to assess the potential role of NaNO2 as an ischaemic conditioning agent in a forearm model of ischaemia/reperfusion injury. Here NaNO2 was able to act as a pre-conditioning but not a post-conditioning agent. Two key results subtend this thesis. Firstly, tissue levels of NO2" are more important than intra-vascular levels, as its hypoxia-enhanced actions appear to be modulated from this site. Secondly, NaNO2 may find clinically relevance in the future as a targeted vasodilator, providing a therapeutic effect to tissues in need only

Elder Abuse in the European Union

The rapid rise in persons over age 60 has created a platform for the rise of elder abuse all over the world. Increasing strains on caregivers and the realization that elder abuse is a serious issue have only recently produced research on the topic. In light of this, this presentation evaluates the state of the aging population in the European Union where more research has been done on elder abuse than in other areas of the world. This presentation focuses specifically on elder abuse in Germany and in Greece, as these countries represent the cultural and geographical extremes in Europe today. First, the presentation evaluates the risk factors and forms that elder abuse is taking today in the European Union. The presentation then describes the state of elder abuse in both Germany and Greece, taking into consideration demographics, culture, and current responses. Finally, this presentation evaluates possible steps to implement for effective change in the area of elder abuse

Low-Dose Sodium Nitrite Attenuates Myocardial Ischemia and Vascular Ischemia-Reperfusion Injury in Human Models

ObjectivesThe aim of this study was to assess the potential benefits of inorganic nitrite in 2 clinical models: stress-induced myocardial ischemia and whole-arm ischemia-reperfusion.BackgroundInorganic nitrite, traditionally considered a relatively inert metabolite of nitric oxide, may exert vasomodulatory and vasoprotective effects. Despite promising results from animal models, few have shown effectiveness in human model systems, and none have fully translated to the clinical setting.MethodsIn 10 patients with inducible myocardial ischemia, saline and low-dose sodium nitrite (NaNO2) (1.5 μmol/min for 20 min) were administered in a double-blind fashion during dobutamine stress echocardiography, at separate visits and in a random order; long-axis myocardial function was quantified by peak systolic velocity (Vs) and strain rate (SR) responses. In 19 healthy subjects, flow-mediated dilation was assessed before and after whole-arm ischemia-reperfusion; nitrite was given before ischemia or during reperfusion.ResultsComparing saline and nitrite infusions, Vs and SR at peak dobutamine increased in regions exhibiting ischemia (Vs from 9.5 ± 0.5 cm/s to 12.4 ± 0.6 cm/s, SR from −2.0 ± 0.2 s−1 to −2.8 ± 0.3 s−1), whereas they did not change in normally functioning regions (Vs from 12.6 ± 0.4 cm/s to 12.6 ± 0.6 cm/s, SR from −2.6 ± 0.3 s−1 to −2.3 ± 0.1 s−1) (p < 0.001, analysis of variance). With NaNO2, the increment of Vs (normalized for increase in heart rate) increased only in poorly functioning myocardial regions (+122%, p < 0.001). Peak flow-mediated dilation decreased by 43% after ischemia-reperfusion when subjects received only saline (6.8 ± 0.7% vs. 3.9 ± 0.7%, p < 0.01); administration of NaNO2 before ischemia prevented this decrease in flow-mediated dilation (5.9 ± 0.7% vs. 5.2 ± 0.5%, p = NS), whereas administration during reperfusion did not.ConclusionsLow-dose NaNO2 improves functional responses in ischemic myocardium but has no effect on normal regions. Low-dose NaNO2 protects against vascular ischemia-reperfusion injury only when it is given before the onset of ischemia

Genomic analysis of metabolic pathway gene expression in mice

BACKGROUND: A segregating population of (C57BL/6J × DBA/2J)F2 intercross mice was studied for obesity-related traits and for global gene expression in liver. Quantitative trait locus analyses were applied to the subcutaneous fat-mass trait and all gene-expression data. These data were then used to identify gene sets that are differentially perturbed in lean and obese mice. RESULTS: We integrated global gene-expression data with phenotypic and genetic segregation analyses to evaluate metabolic pathways associated with obesity. Using two approaches we identified 13 metabolic pathways whose genes are coordinately regulated in association with obesity. Four genomic regions on chromosomes 3, 6, 16, and 19 were found to control the coordinated expression of these pathways. Using criteria that included trait correlation, differential gene expression, and linkage to genomic regions, we identified novel genes potentially associated with the identified pathways. CONCLUSION: This study demonstrates that genetic and gene-expression data can be integrated to identify pathways associated with clinical traits and their underlying genetic determinants

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

Diversity of Lactase Persistence Alleles in Ethiopia:Signature of a Soft Selective Sweep

The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (-13910(∗)T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene LCT is responsible for lactase persistence and appears to have been under strong directional selection in the last 5,000 years, evidenced by the widespread occurrence of this allele on an extended haplotype. In Africa and the Middle East, the situation is more complicated and at least three other alleles (-13907(∗)G, rs41525747; -13915(∗)G, rs41380347; -14010(∗)C, rs145946881) in the same LCT enhancer region can cause continued lactase expression. Here we examine the LCT enhancer sequence in a large lactose-tolerance-tested Ethiopian cohort of more than 350 individuals. We show that a further SNP, -14009T>G (ss 820486563), is significantly associated with lactose-digester status, and in vitro functional tests confirm that the -14009(∗)G allele also increases expression of an LCT promoter construct. The derived alleles in the LCT enhancer region are spread through several ethnic groups, and we report a greater genetic diversity in lactose digesters than in nondigesters. By examining flanking markers to control for the effects of mutation and demography, we further describe, from empirical evidence, the signature of a soft selective sweep

Electronic structure and light-induced conductivity in a transparent refractory oxide

Combined first-principles and experimental investigations reveal the underlying mechanism responsible for a drastic change of the conductivity (by 10 orders of magnitude) following hydrogen annealing and UV-irradiation in a transparent oxide, 12CaO.7Al2O3, found by Hayashi et al. The charge transport associated with photo-excitation of an electron from H, occurs by electron hopping. We identify the atoms participating in the hops, determine the exact paths for the carrier migration, estimate the temperature behavior of the hopping transport and predict a way to enhance the conductivity by specific doping.Comment: 4 pages including 4 figure