Effects of hydrogen peroxide-induced oxidative stress on the plasma concentration and pharmacokinetics of ketorolac in chicks

The aim was to determine the impact of oxidative stress (OS), induced by hydrogen peroxide (H2O2), on the ketorolac plasma concentration and pharmacokinetics in the chicks. A significant decrease was observed in the total antioxidant status (TAS) measured on day 7th, 10th, and 14th of chicks age by 39, 29, and 41%, respectively compared to the control (H2O) group. By measuring the analgesic median effective dose (ED50), ketorolac’s analgesia amplified 16% in the stressed (H2O2) group. Ketorolac concentration in plasma was investigated at measured multiple times at 0.25, 0.5, 1, 2, 4, and 24 hours after the administration (14 mg/kg, IM) to 110.38, 181.46, 66.24, 13.08, 10.11, and 4.12 µg/ml at the H2O group and significantly elevated in all times measured except 0.25 and 24 h after ketorolac administration by 24, 38, 54, 199, 93, and 59 % to be 136.45, 250.88, 102.03, 39.13, 19.55, and 6.55 µg/ml in the H2O2 group, respectively. The values of AUC0-∞, AUMC0-∞, Cmax, and Kel in the stressed chickens that were administered ketorolac were elevated by 59, 19, 38, and 43%, respectively, whereas other parameters like MRT, t1/2β, Vss, and Cl were reduced by 25, 30, 56, and 37% respectively compared to H2O group. The results showed that the H2O2-inducedOS amplified the analgesic action of ketorolac in a chick model, besides its modification of the plasma concentration and pharmacokinetics of ketorolac

The ER stress transducer IRE1β is required for airway epithelial mucin production

Inflammation of human bronchial epithelia (HBE) activates the endoplasmic reticulum (ER) stress transducer inositolrequiring enzyme 1 (IRE1)α, resulting in IRE1α-mediated cytokine production. Previous studies demonstrated ubiquitous expression of IRE1α and gut-restricted expression of IRE1β.We found that IRE1β is also expressed in HBE, is absent in human alveolar cells, and is upregulated in cystic fibrosis and asthmatic HBE. Studies with Ire1β−/− mice and Calu-3 airway epithelia exhibiting IRE1β knockdown or overexpression revealed that IRE1β is expressed in airway mucous cells, is functionally required for airway mucin production, and this function is specific for IRE1β vs. IRE1α. IRE1β-dependent mucin production is mediated, at least in part, by activation of the transcription factor X-box binding protein-1 (XBP-1) and the resulting XBP-1-dependent transcription of anterior gradient homolog 2, a gene implicated in airway and intestinal epithelial mucin production. These novel findings suggest that IRE1β is a potential mucous cell-specific therapeutic target for airway diseases characterized by mucin overproduction

Long-Term Impact of War on Healthcare Costs: An Eight-Country Study

PMCID: PMC3251588This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021:a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed.FundingBill &amp; Melinda Gates Foundation.<br/