A novel approach towards therapeutic optimization of diclofenac

Con objeto de obtener compuestos con menor toxicidad gástrica que el diclofenaco, se sintetizaron y evaluaron cinco ésteres derivados aminoetílicos N,N-sustituidos derivados del diclofenaco. Estos ésteres se diseñaron para satisfacer el requisito estructural de disponer de una actividad anticolinérgica intacta antes de la separación. Además de bloquear el grupo carboxilo ácido mediante esterificación, esta actividad se incorporó a los ésteres sintetizados, con el beneficio adicional esperado de la reducción de la secreción de ácido gástrico y la consecuente eliminación de la irritación local mediante un mecanismo dual. En este estudio se describen la síntesis, la cinética de la hidrólisis y la actividad biológica de estos ésteres. Todos los derivados de éster permanecieron estables en tampones de pH 2,0 y 7,4 durante un período de tiempo suficiente, lo que aseguró su absorción en estado intacto y la eliminación de la irritación gástrica local producida por el fármaco principal. Se observó una rápida hidrólisis enzimática de todos los derivados en un 80% de suero humano combinado. Se descubrió que los ésteres sintetizados poseían la actividad anticolinérgica propuesta. Se mantuvo la actividad antiinflamatoria en la mayoría de los compuestos y se logró una significativa reducción del potencial ulcerogénico en comparación con el diclofenaco.In an effort for obtaining compounds with lower gastric toxicity than diclofenac, five different N,Ndisubstitutedaminoethyl ester derivatives of diclofenac were synthesized and evaluated. These esters were designed so as to satisfy the structural requirement for them to possess the anticholinergic activity in intact form before cleavage. Besides blocking the acidic carboxyl group by esterification this activity was incorporated into the synthesized esters with an expected additional benefit of having reduced gastric acid secretion and thereby abolishing the local irritation by a dual mechanism. This report describes the synthesis, hydrolysis kinetics and the biological activity of these esters. All the ester derivatives were found to be stable in buffers (pH 2.0 and 7.4) for sufficient time period, assuring them to be absorbed intact and to successfully overcome the local gastric irritation of the parent drug. A fast enzymatic hydrolysis was observed for all the derivatives in 80% pooled human serum. The synthesized esters were found to possess the proposed anticholinergic activity. The anti-inflammatory activity for most of the compounds was retained with a significant reduction in the ulcerogenic potential compared to diclofenac

Power-Gating Technique for Network-on-Chip Buffers

A new approach to reducing leakage power in network-on-chip buffers is presented. The non-uniformity of buffer utilisation is leveraged across the network and power-gating is applied to scarcely utilised buffers. Instead of turning-off the buffers completely, a buffer portion is kept turned-on. This design choice has a significant performance benefit because the buffer is always able to receive network packets. Design aspects and trade-offs in a 45 nm CMOS technology are discussed and results obtained over video application benchmarks are presented. It is shown that it is possible to reduce buffer leakage by 40% without performance penalt

The effect of dietary calcium inclusion on broiler gastrointestinal pH: quantification and method optimization

There is little consensus as to the most appropriate methodology for the measurement of gastrointestinal pH in chickens. An experiment was conducted to establish the optimum sampling method for the determination of broiler digesta pH in birds fed differing levels of dietary calcium. Ross 308 broilers (n = 60) were fed one of two experimental diets, one containing 0.8% monocalcium phosphate and 2% limestone and one containing 0.4% monocalcium phosphate and 1% limestone. Four factors were investigated to determine the most appropriate method of measuring broiler gastrointestinal digesta pH: removal from the tract, prolonged air exposure, altering the temperature of the assay, and controlling the water content of the digesta. The conditions were assessed at bird ages from 7 to 42 d post hatch. Dietary Ca content had no significant effect on in situ pH, but it contributed towards variance in ex situ pH of both gizzard and duodenum digesta

Effects of acute cannabidiol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Background: Some evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due to its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors and the endocannabinoid system in HIV Tat transgenic mice. Methods: Tat transgenic mice (female/male) were injected with CBD (3, 10, 30 mg/kg) and assessed for antinociception, activity, coordination, anxiety-like behavior, and recognition memory. Brains were taken to quantify endocannabinoids, cannabinoid receptors, and cannabinoid catabolic enzymes. Additionally, CBD and metabolite 7-hydroxy-CBD were quantified in the plasma and cortex. Results: Tat decreased supraspinal-related nociception and locomotion. CBD and sex had little to no effects on any of the behavioral measures. For the endocannabinoid system male sex was associated with elevated concentration of the proinflammatory metabolite arachidonic acid in various CNS regions, including the cerebellum that also showed higher FAAH expression levels for Tat(+) males. GPR55 expression levels in the striatum and cerebellum were higher for females compared to males. CBD metabolism was altered by sex and Tat expression. Conclusion: Findings indicate that acute CBD effects are not altered by HIV Tat, and acute CBD has no to minimal effects on behavior and the endocannabinoid system

Two-Fluid Scenario for Dark Energy Models in an FRW Universe-Revisited

In this paper we study the evolution of the dark energy parameter within the scope of a spatially homogeneous and isotropic Friedmann-Robertson-Walker (FRW) model filled with barotropic fluid and dark energy by revisiting the recent results (Amirhashchi et al. in Chin. Phys. Lett. 28:039801, 2011a). To prevail the deterministic solution we select the scale factor $a(t) = \sqrt{t^{n}e^{t}}$ which generates a time-dependent deceleration parameter (DP), representing a model which generates a transition of the universe from the early decelerating phase to the recent accelerating phase. We consider the two cases of an interacting and non-interacting two-fluid (barotropic and dark energy) scenario and obtained general results. The cosmic jerk parameter in our derived model is also found to be in good agreement with the recent data of astrophysical observations under the suitable condition. The physical aspects of the models and the stability of the corresponding solutions are also discussed.Comment: 10 pages, 4 figures. arXiv admin note: substantial overlap with arXiv:1011.394

Identification of new susceptibility loci for osteoarthritis (arcOGEN):a genome-wide association study

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.Arthritis Research UK 1803

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk–outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01–4·94) deaths and 105 million (95·0–116) DALYs for both sexes combined, representing 44·4% (41·3–48·4) of all cancer deaths and 42·0% (39·1–45·6) of all DALYs. There were 2·88 million (2·60–3·18) risk-attributable cancer deaths in males (50·6% [47·8–54·1] of all male cancer deaths) and 1·58 million (1·36–1·84) risk-attributable cancer deaths in females (36·3% [32·5–41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6–28·4) and DALYs by 16·8% (8·8–25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9–42·8] and 33·3% [25·8–42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden

First measurement of Ωc0 production in pp collisions at s=13 TeV

The inclusive production of the charm–strange baryon 0 c is measured for the first time via its hadronic √ decay into −π+ at midrapidity (|y| <0.5) in proton–proton (pp) collisions at the centre-of-mass energy s =13 TeV with the ALICE detector at the LHC. The transverse momentum (pT) differential cross section multiplied by the branching ratio is presented in the interval 2 < pT < 12 GeV/c. The pT dependence of the 0 c-baryon production relative to the prompt D0-meson and to the prompt 0 c-baryon production is compared to various models that take different hadronisation mechanisms into consideration. In the measured pT interval, the ratio of the pT-integrated cross sections of 0 c and prompt + c baryons multiplied by the −π+ branching ratio is found to be larger by a factor of about 20 with a significance of about 4σ when compared to e+e− collisions