Sinteza N4-(2,4-dimetilfenil) semikarbazona kao inhibitori 4-aminobutirat aminotransferaze

Several 2,4-dimethylphenyl substituted semicarbazones were synthesized in three steps involving aryl urea and aryl semicarbazide formations. The structures were confirmed by spectral and elemental analyses. All the compounds were evaluated for anticonvulsant activity by using a series of test models including maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (scSTY) seizure threshold tests. The compounds were also evaluated for behavioural impairement and depression activity. In the neurochemical investigation, potent compounds were evaluated for their effects on rat brain -aminobutyric acid levels and in vitro -aminobutyrate transaminase (Pseudomonas fluorescens) activity. Preliminary studies suggest these compounds to exhibit anticonvulsant activity via GABA-mediated mechanism.Sintetizirano je nekoliko 2,4-dimetilfenil supstituiranih semikarbazona u tri sintetska koraka koji uključuju aril uree i aril semikarbazide. Strukture spojeva su potvrđene spektroskopskim metoda i elementarnom analizom. Ispitano je antikonvulzivno djelovanje novih spojeva nakon izazivanja konvulzija elektrošokom te supkutanom primjenom pentilentetrazola ili strihnina. Osim toga, testirano je antidepresivno djelovanje te učinak tih spojeva na ponašanje štakora. Praćen je njihov utjecaj na koncentraciju gama-aminomaslačne kiseline (GABA) u mozgu štakora te in vitro na aktivnost gama-aminobutirat transaminaze (Pseudomonas fluorescens). Preliminarni pokusi ukazuju da antikonvulzivno djelovanje ovih spojeva uključuje GABA-ergički sustav

Sinteza N4-(2,4-dimetilfenil) semikarbazona kao inhibitori 4-aminobutirat aminotransferaze

Several 2,4-dimethylphenyl substituted semicarbazones were synthesized in three steps involving aryl urea and aryl semicarbazide formations. The structures were confirmed by spectral and elemental analyses. All the compounds were evaluated for anticonvulsant activity by using a series of test models including maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (scSTY) seizure threshold tests. The compounds were also evaluated for behavioural impairement and depression activity. In the neurochemical investigation, potent compounds were evaluated for their effects on rat brain -aminobutyric acid levels and in vitro -aminobutyrate transaminase (Pseudomonas fluorescens) activity. Preliminary studies suggest these compounds to exhibit anticonvulsant activity via GABA-mediated mechanism.Sintetizirano je nekoliko 2,4-dimetilfenil supstituiranih semikarbazona u tri sintetska koraka koji uključuju aril uree i aril semikarbazide. Strukture spojeva su potvrđene spektroskopskim metoda i elementarnom analizom. Ispitano je antikonvulzivno djelovanje novih spojeva nakon izazivanja konvulzija elektrošokom te supkutanom primjenom pentilentetrazola ili strihnina. Osim toga, testirano je antidepresivno djelovanje te učinak tih spojeva na ponašanje štakora. Praćen je njihov utjecaj na koncentraciju gama-aminomaslačne kiseline (GABA) u mozgu štakora te in vitro na aktivnost gama-aminobutirat transaminaze (Pseudomonas fluorescens). Preliminarni pokusi ukazuju da antikonvulzivno djelovanje ovih spojeva uključuje GABA-ergički sustav

Meta-Analysis of the Alzheimer\u27s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models.

We present a consensus atlas of the human brain transcriptome in Alzheimer\u27s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington\u27s disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

An efficient synthesis of N-substituted 3-nitrothiophen-2-amines

A novel protocol for the synthesis of 3-nitro-N-aryl/alkylthiophen-2-amines in good yields from the reaction of α-nitroketene N,S-aryl/alkylaminoacetals and 1,4-dithiane-2,5-diol in the presence of K2CO3 in refluxing ethanol is described. This transformation generates two C–C bonds in a single operation and presumably proceeds through a reaction sequence comprising 2-mercaptoacetaldehyde generation, nucleophilic carbonyl addition, annelation and elimination steps

Antigen detection assay with parasite specific monoclonal antibodies for diagnosis of lymphatic filariasis

Background: Lymphatic filariasis is a painful and profoundly disfiguring disease. Infection is usually acquired in childhood but its visible manifestations occur later in life, causing temporary or permanent disability. The importance of developing effective assays to diagnose, monitor and evaluate human lymphatic filariasis has been emphasized by the WHO. Methods: High-affinity monoclonal antibodies (mAbs) specific for recombinant filarial antigen WbSXP-1 were developed. An ELISA based capture assay using monoclonal and polyclonal antibodies for WbSXP-1 was used for detection of circulating filarial antigen. Results: High-affinity monoclonal antibodies (mAbs) were developed that specifically binds both W. bancrofti and B. malayi mf antigens. Two mAbs (1F6H3 and 2E12E3) of subclass IgG2a and IgM showed high affinity, avidity and reactivity to recombinant and mf native antigen. Both the mAbs were used in combination as capture antibodies and polyclonal as detection antibody to develop the assay. The assay showed very high sensitivity towards W. bancrofti mf positive samples compared to endemic normal samples (P<0.0001). Conclusion: A capture assay using high-affinity monoclonal antibodies for WbSXP-1 was developed for the detection of filarial circulating antigen in clinical samples from bancroftian infection. Besides, this would also help in epidemiological studies in endemic areas of filarial infections. (C) 2011 Elsevier B.V. All rights reserved

Ligamentum teres lesions are associated with poorer patient outcomes in a large primary hip arthroscopy cohort of 1,935 patients

Purpose: To retrospectively evaluate the prevalence and characteristics of ligamentum teres (LT) lesions identified in a single-surgeon hip arthroscopy cohort and to compare surgical outcomes of those with, and without, identified LT lesions. Methods: Patients who underwent primary hip arthroscopy between 2005 and 2018 in one surgeon's clinic were identified. Those with a history involving extra-articular scoping or any previous surgery on the ipsilateral hip were excluded. Patient-reported outcome measures completed before and after surgery included the Hip Disability and Osteoarthritis Outcome Score, Nonarthritic Hip Score, and 12-item International Hip Outcome Tool. Conversion to hip joint replacement was ascertained through a national register. Results: A total of 1,935 primary hip arthroscopies (from 1,607 different patients) were included in this study. In total, 323 LT lesions were identified. Those with LT lesions were older than those without (40.3 ± 11.3 years compared with 33.9 ± 12.1 years; P < .001), and more frequently female (58.2% vs 41.8%; P = .001). Hips with lesions had a smaller lateral center-edge angle than other hips (33.0 ± 6.8° vs 34.1 ± 6.0°; P = .004). All patient-reported outcome measures improved significantly (P < .001) from pre- to post-surgery for patients with and without LT lesions. However, patients with LT lesions reported less improvement in the 12-item International Hip Outcome Tool (difference –5.60; P = .004) and in Hip Disability and Osteoarthritis Outcome Score symptoms (–4.41; P = .004), sports (–7.81; P < .001), and quality of life subscales (–8.85; P < .001) than those without lesions. Hips with LT lesions also had a 6.2% 2-year rate of subsequent hip replacement (20/323 hips) compared with those without lesions (0.9%; 14/1612 hips; P < .001). Conclusions: In this single-surgeon hip arthroscopy cohort, identification of LT lesions was associated with poorer patient-reported outcomes and increased likelihood of conversion to arthroplasty within 2 years. These findings suggest a poorer prognosis for patients with LT injury compared with those without. Level of Evidence: Level III, retrospective cohort study.Published versionM.J.B. and C.J.B. report grants from Stryker South Pacific, outside the submitted work

Atropisomerism in 3-arylthiazolidine-2-thiones. A combined dynamic NMR and dynamic HPLC study

Sterically hindered 3-arylthiazolidine-2-thiones were prepared by a solvent-free reaction with arylisothiocyanates and 1,4-dithiane-2,5-diol. Atropisomerism was observed in two compounds (3 and 4, aryl = 1-naphthyl and 2-methylnaphth-1-yl), whose rotational energy barriers were measured using dynamic NMR and dynamic HPLC. The experimental analyses were supported by DFT calculations. Thermally stable atropisomers were obtained by dehydration of compounds 3 and 4 and the absolute configuration of the atropisomers of compound 6 was determined by theoretical simulation of the ECD and VCD spectra