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

Investigation of trends in basin-scale temperature variables

This research paper presents an analysis of temperature variables over the West Banas basin in order to detect the presence of underlying trends employing historical temperature data for three points viz., Abu Road, Mount Abu and Pindwara obtained for a period of 40 years (1981 – 2020) from MERRA-2 database. The study aims to investigate the long-term changes in temperature trends and identify any significant patterns or anomalies in mean, maximum and minimum temperatures at monthly, seasonal and annual timescales at the three locations amounting to a total of 162 series. The trends were evaluated using the Mann-Kendall test, a popular and powerful statistical technique formulated for analysing abnormal distributions. Prior to the application of the trend test, autocorrelated time series were identified and the trend test was modified using a variance correction approach to incorporate the influence of autocorrelations upon the resultant trends. The findings of autocorrelation analysis revealed that 11 of the 162 series were autocorrelated, a majority of which were associated with the temperature series at Abu Road. The results of the trend test showed that 27 out of the 162 series possessed significant trends with the mean and maximum monsoon temperatures in most of the series exhibiting a reducing trend while the minimum temperature appeared to be rising. Overall, the research highlights the importance of monitoring temperature trends, particularly in regions that may be more vulnerable to the impacts of climate change. The findings of this study can inform future climate adaptation strategies and support decision-making processes aimed at mitigating the effects of global warming on the natural and built environment

Chemical composition and larvicidal activities of the essential oil of Zanthoxylum armatum DC (Rutaceae) against three mosquito vectors

Background & objectives: In view of the recently increased interest in developing plant origininsecticides as an alternative to chemical insecticide, this study was undertaken to assess the larvicidalpotential of the essential oil from the seeds of Zanthoxylum armatum DC [syn. Z. alatum Roxb](Rutaceae) against three medically important species of mosquito vectors, Aedes aegypti, Anophelesstephensi and Culex quinquefasciatus.Methods: Essential oil was hydro distilled in the laboratory from the seeds obtained from the marketand the chemical constituents of the oil were determined using GC/GC-MS. Bioefficacy of theessential oil was evaluated under laboratory conditions using III instar mosquito larvae.Results: Among the three mosquito species tested, Cx. quinquefasciatus was the most sensitive(LC50 = 49 ppm) followed by Ae. aegypti (LC50 = 54 ppm) and An. stephensi (LC50 = 58 ppm). GCMSanalysis of the oil revealed at least 28 compounds, consisting mainly of oxygenated monoterpenes(75%) and monoterpenes (22%). Linalool though constituted a major part (57%), failed to produceany appreciable mortality when tested alone.Interpretation & conclusion: From the results it can be concluded that the larvae of the three mosquitospecies were susceptible to the essential oil composition. Such findings would be useful in promotingresearch aiming at the development of new agent for mosquito control based on bioactive chemicalcompounds from indigenous plant sources as an alternative to chemical larvicides

Development and validation of a simplified thoracolumbar spine fracture classification system

STUDY DESIGN : Development and validation of fracture classification system. OBJECTIVE: To develop and validate a Simplified Classification System (SCS) for Thoraco-Lumbar (TL) fractures (SCS – TL fractures). SETTING : Tertiary Spinal Injuries Centre, New Delhi, India METHODS : Based on the International Spinal Cord Society Spine Trauma Study Group (ISCoS STSG, n = 23) experts’ clinical consensus conducted by the senior author and on his own experience, the Denis classification for TL fractures was modified to develop a SCS-TL fractures that could guide the management. After Face and Content validation, Construct validation was done in two stages. First stage analyzed if management of 30 cases of TL fractures, as suggested by the SCS - TL fractures and ISCoS STSG (n = 9) as well as other (n = 5) experts, matched. Second stage was a one year prospective study analyzing if the management suggested matched the management actually carried out by different spine surgeons (n = 10) working at a single institution. RESULTS : In the first stage there was 100% agreement for management (conservative or surgical) as proposed by experts and that suggested by the proposed classification for TL fractures whereas for surgical approach there was 88% agreement. In the second stage, there was 100% agreement for the management as well as surgical approach as carried out at our centre and that proposed by the SCS for TL fractures. CONCLUSIONS : The proposed SCS-TL fractures helps in classifying and in decision making for management of TL fractures. The next phase of validation would involve multicentric reliability studies and prospective application of the SCS- TL fractures.https://www.nature.com/schj2022Orthopaedic Surger

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

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

Elliptic flow of charged particles at midrapidity relative to the spectator plane in Pb–Pb and Xe–Xe collisions

Measurements of the elliptic flow coefficient relative to the collision plane defined by the spectator neutrons v2{ SP} in collisions of Pb ions at center-of-mass energy per nucleon–nucleon pair √ 2.76 TeV and Xe ions at √ sNN = sNN =5.44 TeV are reported. The results are presented for charged particles produced at midrapidity as a function of centrality and transverse momentum for the 5–70% and 0.2–6 GeV/c ranges, respectively. The ratio between v2{ SP} and the elliptic flow coefficient relative to the participant plane v2{4}, estimated using four-particle correlations, deviates by up to 20% from unity depending on centrality. This observation differs strongly from the magnitude of the corresponding eccentricity ratios predicted by the TRENTo and the elliptic power models of initial state fluctuations that are tuned to describe the participant plane anisotropies. The differences can be interpreted as a decorrelation of the neutron spectator plane and the reaction plane because of fragmentation of the remnants from the colliding nuclei, which points to an incompleteness of current models describing the initial state fluctuations. A significant transverse momentum dependence of the ratio v2{ SP}/v2{4} is observed in all but the most central collisions, which may help to understand whether momentum anisotropies at low and intermediate transverse momentum have a common origin in initial state f luctuations. The ratios of v2{ SP} and v2{4} to the corresponding initial state eccentricities for Xe–Xe and Pb–Pb collisions at similar initial entropy density show a difference of (7.0 ±0.9)%with an additional variation of +1.8% when including RHIC data in the TRENTo parameter extraction. These observations provide new experimental constraints for viscous effects in the hydrodynamic modeling of the expanding quark–gluon plasma produced in heavy-ion collisions at the LHC