Effects of Mitochondria-Targeted Antioxidants on Real-time Blood Nitric Oxide and Hydrogen Peroxide Release in Hind Limb Ischemia and Reperfusion

In the body, reperfusion of ischemic tissue with blood causes the release of reactive oxygen species (ROS), in part, from damaged mitochondria leading to endothelial and organ dysfunction. Endothelial dysfunction occurs within 5 min of reperfusion, is common to all vascular beds, and is characterized by increased hydrogen peroxide (H2O2) and decreased nitric oxide (NO) levels in the blood that further exacerbate reperfusion injury. Previous studies have shown that promoting endothelial NO synthase coupling during reperfusion increases blood NO and decreases blood H2O2 levels in hind limb I/R and attenuates myocardial I/R injury (1). This study specifically examines the effects mitochondria-targeted antioxidants, mitoquinone (mitoQ; Fig. 1), a cell permeable coenzyme Q analogue or SS-31 ((D-Arg)-Dmt-Lys-Phe-Amide; Genemed Synthesis, San Antonio, TX) (Fig.1), a cell permeable peptide, on inhibiting H2O2 release and increasing NO bioavailability in hind limb I/R. MitoQ (2) and SS-31 (3,4) are able to concentrate into the inner mitochondrial membrane via an electrical potential gradient or selective diffusion respectively, where they attenuate superoxide and subsequent H2O2 production thus allowing a concurrent increase in NO bioavailability

Tracking system analytic calibration activities for the Mariner Mars 1969 mission

Calibration activity of Deep Space Network in support of Mars encounter phase of Mariner Mars 1969 missio

Cardioprotective Effects of Selective Mitochondrial-Targeted Antioxidants in Myocardial Ischemia/Reperfusion (I/R) Injury

During myocardial ischemia, coronary blood flow interruption deprives cardiomyocytes of oxygen, glucose and fatty acids. Ischemic damage is exacerbated by a burst of reactive oxygen species (ROS) generated at reperfusion when oxygen interacts with damaged mitochondrial electron transport chains (ETC), especially uncoupled complexes I and III (Fig. 1,2). Nicotinamide adenine dinucleotide phosphate oxidase (Nox) activity can also release ROS, inducing additional tissue/organ damage. Surgical intervention or thrombolytic treatments can restore coronary blood flow. However, as blood flow reestablishes, oxidative stress leads to I/R injury. Clinical treatment remains a challenge as no pharmaceutical agents effectively limit I/R-induced damage. Mitochondria are implicated in I/R as a major source of ROS3,4,5. Excess ROS leads to mitochondrial and cardiac contractile dysfunction6. Conventional antioxidants have limited efficacy in myocardial I/R because they are not targeted selectively to where most I/R damage occurs, in mitochondria (Fig. 3)3,4,5. Mitoquinone (mitoQ, MW=600 g/mol), a coenzyme Q analog, easily crosses phospholipid bilayers and is driven by the large electrochemical membrane potential to concentrate mitoQ several hundred-fold within mitochondria. The respiratory chain reduces mitoQ to its active ubiquinol antioxidant form to limit myocardial I/R injury5. The SS-31 (Szeto-Schiller) peptide ((D-Arg)-Dmt-Lys-Phe-Amide, MW=640 g/mol, Genemed Synthesis, Inc., San Antonio, TX) is also of interest since it is cellpermeable, specifically targeted to inner mitochondrial membranes based on its alternating cationic aromatic residue sequence, with an antioxidant dimethyltyrosine moeity. SS peptides scavenge ROS in I/R models. Although mitochondrial-targeted antioxidant pretreatment can effectively limit I/R injury, pretreatment is not always possible in cases of myocardial infarction. Therefore, evaluating cardioprotective efficacy of mitochondrialtargeted antioxidants when given at reperfusion is of high significanc

The Mariner 6 and 7 flight paths and their determination from tracking data

Determination of orbit estimates for Mariner 6 and 7 space probe flight

Cardioprotective Effects of Cell Permeable NADPH oxidase inhibitors in Myocardial Ischemia/Reperfusion Injury

During myocardial ischemia/reperfusion (I/R), the generation of reactive oxygen species (ROS) contributes to post-reperfused cardiac injury and contractile dysfunction. Activation of NADPH oxidase (NOX) during reperfusion generates ROS, and exacerbates I/R injury. We hypothesize that reducing ROS formation through inhibition of NOX will attenuate myocardial I/R injury in isolated perfused rat hearts subjected to I(30min)/R(45min) compared to untreated I/R hearts. The cell-permeable NOX inhibiting peptide, gp91 ds/tat (RKKRRQRRR-CSTRIRRQL-Amide, MW=2452 g/mol, 20μM, n=5), significantly improved post-reperfused cardiac function compared to controls (n=15,

Joint hypermobility in children with idiopathic scoliosis: SOSORT award 2011 winner

<p>Abstract</p> <p>Background</p> <p>Generalized joint hypermobility (JHM) refers to increased joint mobility with simultaneous absence of any other systemic disease. JHM involves proprioception impairment, increased frequency of pain within joints and tendency to injure soft tissues while performing physical activities. Children with idiopathic scoliosis (IS) often undergo intensive physiotherapy requiring good physical capacities. Further, some physiotherapy methods apply techniques that increase joint mobility and thus may be contraindicated.</p> <p>The aim of this paper was to assess JHM prevalence in children with idiopathic scoliosis and to analyze the relationship between JHM prevalence and the clinical and radiological parameters of scoliosis. The methods of assessment of generalized joint hypermobility were also described.</p> <p>Materials and methods</p> <p>This case-control study included 70 subjects with IS, aged 9-18 years (mean 13.2 ± 2.2), Cobb angle range 10°-53° (mean 24.3 ± 11.7), 34 presenting single curve thoracic scoliosis and 36 double curve thoracic and lumbar scoliosis. The control group included 58 children and adolescents aged 9-18 years (mean 12.6 ± 2.1) selected at random. The presence of JHM was determined using Beighton scale complemented with the questionnaire by Hakim and Grahame. The relationship between JHM and the following variables was evaluated: curve severity, axial rotation of the apical vertebra, number of curvatures (single versus double), number of vertebrae within the curvature (long versus short curves), treatment type (physiotherapy versus bracing) and age.</p> <p>Statistical analysis was performed with Statistica 8.1 (StatSoft, USA). The Kolmogorov-Smirnov test, U Mann-Whitney test, Chi²test, Pearson and Spermann correlation rank were conducted. The value <it>p </it>= 0.05 was adopted as the level of significance.</p> <p>Results</p> <p>JHM was diagnosed in more than half of the subjects with idiopathic scoliosis (51.4%), whilst in the control group it was diagnosed in only 19% of cases (<it>p </it>= 0.00015). A significantly higher JHM prevalence was observed in both girls (<it>p </it>= 0.0054) and boys (<it>p </it>= 0.017) with IS in comparison with the corresponding controls. No significant relation was found between JHM prevalence and scoliosis angular value (<it>p </it>= 0.35), apical vertebra rotation (<it>p </it>= 0.86), the number of vertebrae within curvature (<it>p </it>= 0.8), the type of applied treatment (<it>p </it>= 0.55) and the age of subjects (<it>p </it>= 0.79). JHM prevalence was found to be higher in children with single curve scoliosis than in children with double curve scoliosis (<it>p </it>= 0.03).</p> <p>Conclusions</p> <p>JHM occurs more frequently in children with IS than in healthy sex and age matched controls. No relation of JHM with radiological parameters, treatment type and age was found. Systematically searched in IS children, JHM should be taken into account when physiotherapy is planned.</p

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Niestateczne skarpy tamy zbiornika Nova Bystrica

Water reservoir Nova Bystrica is located in the northern part of Slovakia, about 6 kilometers southward of the border with Poland and serves to supply the population with drinking water. Two landslides (slope deformations) have affected a slope adjacent to the water reservoir dam. The distance between the dam left-hand side and the landslides is about 250 m. The first landslide is active; its toe extends to the reservoir water and has destroyed the forest road. The second slope deformation, which is considerably larger than the first one, is a block deformation allocated above the forest road. In the contribution, basing on the ongoing monitoring the authors described the stability of both landslides. According to the slope stability calculations they also analyzed the activity of both landslides and forecasted their further development with regard to the operation of the water reservoir itself. In conclusions there are recommendations for further monitoring of both slope deformations and also there are suggests for additional research works.Zbiornik wodny zapewniający mieszkańcom wodę pitną Nova Bystrica położony jest na północy Słowacji w odległości ok. 6 km od granicy z Polską. Na zboczach przyległych do tamy zbiornika miały miejsce dwa osuwiska. Odległość pomiędzy lewą częścią tamy a miejscem utraty stateczności zbocza wynosiła 250 m. Pierwsze osuwisko jest cały czas aktywne, a jego jęzor wchodzi do zbiornika i niszczy drogę leśną pośrodku zbocza. Drugie osuwisko, o wiele większe niż pierwsze, jest blokową deformacją zlokalizowaną powyżej ww. drogi. Bazując na prowadzonym w tym rejonie monitoringu, autorzy określili stateczność zboczy obu osuwisk. W oparciu o obliczenia wskaźników stateczności, przeanalizowali również aktywność obu osuwisk z uwzględnieniem przyszłych ruchów wody w zbiorniku. We wnioskach podano zalecenia dotyczące dalszego monitoringu deformacji zachodzących na zboczu osuwisk oraz sugestie dalszych prac badawczych w tym zakresie