Cyclooxygenase-2-Derived Prostacyclin Protective Role on Endotoxin-Induced Mouse Cardiomyocyte Mortality

Cardiovascular dysfunction characterizes septic shock, inducing multiple organ failure and a high mortality rate. In the heart, it has been shown an up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions with subsequent overproduction of nitric oxide (NO) and eicosanoids. This study is focused on the links between these products of inflammation and cell loss of mouse cardiomyocytes during treatment by the Salmonella typhimurium lipopolysaccharide (LPS) in presence or in absence of NOS or COX inhibitors. LPS induced RelA/NF-κB p65 activation, iNOS and COX-2 up-regulations, resulting in NO and prostacyclin releases. These effects were reversed by the NO-synthase inhibitor and increased by the specific COX-2 inhibitor. Immunostainings with FITC-conjugated anti-Annexin-V and propidium iodide and caspase 3/7 activity assay showed that cardiomyocyte necrosis was inhibited by L-NA during LPS treatment challenge, while apoptosis was induced in presence of both LPS and NS-398. No effect on LPS cellular injury was observed using the specific cyclooxygenase-1 (COX-1) inhibitor, SC-560. These findings strongly support the hypothesis of a link between iNOS-dependent NO overproduction and LPS-induced cell loss with a selective protective role allotted to COX-2 and deriving prostacyclins

LINEARISATION D’UN MODELE DE REACTEUR A BOUES ACTIVEES

Cet article présente une stratégie de linéarisation d’un modèle non linéaire de réacteur à boues activées. Cette stratégie a pour but d’obtenir un modèle linéaire simplifié, pour des fins d’estimation, de commande et d’analyse de stabilité. En appuyant sur un modèle initiale comportant trois variables d’états représentant respectivement : la concentration du substrat biodégradable, la concentration de la biomasse hétérotrophe et la concentration de l’oxygène dissous, une approche systématique de réduction de complexité du modèle est envisagée. Cette approche comprend essentiellement trois étapes. Dans la première étape, une analyse de sensibilité est effectuée dont le but est d’hiérarchiser les variables d’états selon leurs effets sur la réponse du modèle. Par la suite, une procédure de linéarisation est appliquée, basée sur une combinaison linéaire pondérée des termes présentant des non-linéarités dans le système. Les variables identifiées comme non influentes peuvent être ignorées, le modèle s’en trouve avantageusement simplifié. Dans la dernière étape, les paramètres inconnus des termes linéaires trouvés sont identifiés en utilisant un algorithme évolutionnaire. L’avantage principal de la méthode proposée est de conserver la structure générale ainsi que l’ordre du modèle original

Angular versus radial correlation effects on momentum distributions of light two-electron ions

We investigate different correlation mechanisms for two-electron systems and compare their respective effects on various electron distributions. The simplicity of the wave functions used allows for the derivation of closed-form analytical expressions for all electron distributions. Among other features, it is shown that angular and radial correlation mechanisms have opposite effects on Compton profiles at small momenta.Comment: 22 pages, 5 figures, 3 tabl

The large longitudinal spread of solar energetic particles during the January 17, 2010 solar event

We investigate multi-spacecraft observations of the January 17, 2010 solar energetic particle event. Energetic electrons and protons have been observed over a remarkable large longitudinal range at the two STEREO spacecraft and SOHO suggesting a longitudinal spread of nearly 360 degrees at 1AU. The flaring active region, which was on the backside of the Sun as seen from Earth, was separated by more than 100 degrees in longitude from the magnetic footpoints of each of the three spacecraft. The event is characterized by strongly delayed energetic particle onsets with respect to the flare and only small or no anisotropies in the intensity measurements at all three locations. The presence of a coronal shock is evidenced by the observation of a type II radio burst from the Earth and STEREO B. In order to describe the observations in terms of particle transport in the interplanetary medium, including perpendicular diffusion, a 1D model describing the propagation along a magnetic field line (model 1) (Dr\"oge, 2003) and the 3D propagation model (model 2) by (Dr\"oge et al., 2010) including perpendicular diffusion in the interplanetary medium have been applied, respectively. While both models are capable of reproducing the observations, model 1 requires injection functions at the Sun of several hours. Model 2, which includes lateral transport in the solar wind, reveals high values for the ratio of perpendicular to parallel diffusion. Because we do not find evidence for unusual long injection functions at the Sun we favor a scenario with strong perpendicular transport in the interplanetary medium as explanation for the observations.Comment: The final publication is available at http://www.springerlink.co

Disease Rescue and Increased Lifespan in a Model of Cardiomyopathy and Muscular Dystrophy by Combined AAV Treatments

The BIO14.6 hamster is an excellent animal model for inherited cardiomyopathy, because of its lethal and well-documented course, due to a spontaneous deletion of delta-sarcoglycan gene promoter and first exon. The muscle disease is progressive and average lifespan is 11 months, because heart slowly dilates towards heart failure.Based on the ability of adeno-associated viral (AAV) vectors to transduce heart together with skeletal muscle following systemic administration, we delivered human delta-sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis in skeletal muscle. Motor ability and cardiac functions were completely rescued. However, BIO14.6 hamsters having less than 70% of fibers recovering sarcoglycan developed cardiomyopathy, even if the total rescued protein was normal. When we used serotype 2/8 in combination with serotype 2/1, lifespan was extended up to 22 months with sustained heart function improvement.Our data support multiple systemic administrations of AAV as a general therapeutic strategy for clinical trials in cardiomyopathies and muscle disorders

Improving hypertension management through pharmacist prescribing; the rural alberta clinical trial in optimizing hypertension (Rural RxACTION): trial design and methods

<p>Abstract</p> <p>Background</p> <p>Patients with hypertension continue to have less than optimal blood pressure control, with nearly one in five Canadian adults having hypertension. Pharmacist prescribing is gaining favor as a potential clinically efficacious and cost-effective means to improve both access and quality of care. With Alberta being the first province in Canada to have independent prescribing by pharmacists, it offers a unique opportunity to evaluate outcomes in patients who are prescribed antihypertensive therapy by pharmacists.</p> <p>Methods</p> <p>The study is a randomized controlled trial of enhanced pharmacist care, with the unit of randomization being the patient. Participants will be randomized to enhanced pharmacist care (patient identification, assessment, education, close follow-up, and prescribing/titration of antihypertensive medications) or usual care. Participants are patients in rural Alberta with undiagnosed/uncontrolled blood pressure, as defined by the Canadian Hypertension Education Program. The primary outcome is the change in systolic blood pressure between baseline and 24 weeks in the enhanced-care versus usual-care arms. There are also three substudies running in conjunction with the project examining different remuneration models, investigating patient knowledge, and assessing health-resource utilization amongst patients in each group.</p> <p>Discussion</p> <p>To date, one-third of the required sample size has been recruited. There are 15 communities and 17 pharmacists actively screening, recruiting, and following patients. This study will provide high-level evidence regarding pharmacist prescribing.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00878566">NCT00878566</a>.</p

The GCP molecular marker toolkit, an instrument for use in breeding food security crops

Crop genetic resources carry variation useful for overcoming the challenges of modern agriculture. Molecular markers can facilitate the selection of agronomically important traits. The pervasiveness of genomics research has led to an overwhelming number of publications and databases, which are, nevertheless, scattered and hence often difficult for plant breeders to access, particularly those in developing countries. This situation separates them from developed countries, which have better endowed programs for developing varieties. To close this growing knowledge gap, we conducted an intensive literature review and consulted with more than 150 crop experts on the use of molecular markers in the breeding program of 19 food security crops. The result was a list of effectively used and highly reproducible sequence tagged site (STS), simple sequence repeat (SSR), single nucleotide polymorphism (SNP), and sequence characterized amplified region (SCAR) markers. However, only 12 food crops had molecular markers suitable for improvement. That is, marker-assisted selection is not yet used for Musa spp., coconut, lentils, millets, pigeonpea, sweet potato, and yam. For the other 12 crops, 214 molecular markers were found to be effectively used in association with 74 different traits. Results were compiled as the GCP Molecular Marker Toolkit, a free online tool that aims to promote the adoption of molecular approaches in breeding activities

Insights on the Neuromagnetic Representation of Temporal Asymmetry in Human Auditory Cortex.

Communication sounds are typically asymmetric in time and human listeners are highly sensitive to this short-term temporal asymmetry. Nevertheless, causal neurophysiological correlates of auditory perceptual asymmetry remain largely elusive to our current analyses and models. Auditory modelling and animal electrophysiological recordings suggest that perceptual asymmetry results from the presence of multiple time scales of temporal integration, central to the auditory periphery. To test this hypothesis we recorded auditory evoked fields (AEF) elicited by asymmetric sounds in humans. We found a strong correlation between perceived tonal salience of ramped and damped sinusoids and the AEFs, as quantified by the amplitude of the N100m dynamics. The N100m amplitude increased with stimulus half-life time, showing a maximum difference between the ramped and damped stimulus for a modulation half-life time of 4 ms which is greatly reduced at 0.5 ms and 32 ms. This behaviour of the N100m closely parallels psychophysical data in a manner that: i) longer half-life times are associated with a stronger tonal percept, and ii) perceptual differences between damped and ramped are maximal at 4 ms half-life time. Interestingly, differences in evoked fields were significantly stronger in the right hemisphere, indicating some degree of hemispheric specialisation. Furthermore, the N100m magnitude was successfully explained by a pitch perception model using multiple scales of temporal integration of auditory nerve activity patterns. This striking correlation between AEFs, perception, and model predictions suggests that the physiological mechanisms involved in the processing of pitch evoked by temporal asymmetric sounds are reflected in the N100m

Soluble Rhesus Lymphocryptovirus gp350 Protects against Infection and Reduces Viral Loads in Animals that Become Infected with Virus after Challenge

Epstein-Barr virus (EBV) is a human lymphocryptovirus that is associated with several malignancies. Elevated EBV DNA in the blood is observed in transplant recipients prior to, and at the time of post-transplant lymphoproliferative disease; thus, a vaccine that either prevents EBV infection or lowers the viral load might reduce certain EBV malignancies. Two major approaches have been suggested for an EBV vaccine- immunization with either EBV glycoprotein 350 (gp350) or EBV latency proteins (e.g. EBV nuclear antigens [EBNAs]). No comparative trials, however, have been performed. Rhesus lymphocryptovirus (LCV) encodes a homolog for each gene in EBV and infection of monkeys reproduces the clinical, immunologic, and virologic features of both acute and latent EBV infection. We vaccinated rhesus monkeys at 0, 4 and 12 weeks with (a) soluble rhesus LCV gp350, (b) virus-like replicon particles (VRPs) expressing rhesus LCV gp350, (c) VRPs expressing rhesus LCV gp350, EBNA-3A, and EBNA-3B, or (d) PBS. Animals vaccinated with soluble gp350 produced higher levels of antibody to the glycoprotein than those vaccinated with VRPs expressing gp350. Animals vaccinated with VRPs expressing EBNA-3A and EBNA-3B developed LCV-specific CD4 and CD8 T cell immunity to these proteins, while VRPs expressing gp350 did not induce detectable T cell immunity to gp350. After challenge with rhesus LCV, animals vaccinated with soluble rhesus LCV gp350 had the best level of protection against infection based on seroconversion, viral DNA, and viral RNA in the blood after challenge. Surprisingly, animals vaccinated with gp350 that became infected had the lowest LCV DNA loads in the blood at 23 months after challenge. These studies indicate that gp350 is critical for both protection against infection with rhesus LCV and for reducing the viral load in animals that become infected after challenge. Our results suggest that additional trials with soluble EBV gp350 alone, or in combination with other EBV proteins, should be considered to reduce EBV infection or virus-associated malignancies in humans

Evidence for Nearby Supernova Explosions

Supernova explosions are one of the most energetic--and potentially lethal--phenomena in the Universe. Scientists have speculated for decades about the possible consequences for life on Earth of a nearby supernova, but plausible candidates for such an event were lacking. Here we show that the Scorpius-Centaurus OB association, a group of young stars currently located at~130 parsecs from the Sun, has generated 20 SN explosions during the last 11 Myr, some of them probably as close as 40 pc to our planet. We find that the deposition on Earth of 60Fe atoms produced by these explosions can explain the recent measurements of an excess of this isotope in deep ocean crust samples. We propose that ~2 Myr ago, one of the SNe exploded close enough to Earth to seriously damage the ozone layer, provoking or contributing to the Pliocene-Pleistocene boundary marine extinction.Comment: 4 pages, 2 figures. Replaced by final version to appear in Physical Review Letter