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Suboptimal control of postoperative pain following knee arthroplasty can slow recovery and reduce patient satisfaction. Intraarticular (IA) administration of bupivacaine and ketorolac offers efficient pain control and minimizes opioid consumption. However, the clinical benefits of this approach are short lived due to rapid clearance of drugs from the joint cavity. Here, we describe a poloxamer based thermoresponsive in situ gelling system for the sustained IA delivery of bupivacaine hydrochloride (BH) and ketorolac tromethamine (KT) following knee surgery in an ovine model. Drug loaded formulations were prepared using poloxamer 407, poloxamer 188 and sodium chloride. In vitro characterization was conducted, followed by in vivo evaluation of sustained drug release and safety in an ovine model of knee joint surgery. Rheological studies revealed a Newtonian-like flow of the developed formulation at room temperature, confirming its injectability, followed by a transition to a viscous gel as temperature approached body temperature. The developed formulation successfully sustained the in vivo release of BH for 72 h and KT for 48 h, as determined by circulating drug levels, compared to 24 and 8 h for marketed drug solutions. The concentrations of BH and KT in the synovial fluids at 72 h were 11.5 and 1.8 times that of marketed products, suggesting a significant increase in the IA residence time. The developed formulation induced a comparable inflammatory response compared to the marketed drug solutions, however a significantly higher chondrotoxicity was observed following administration of the gel formulations. Poloxamers based in situ gelling systems are promising delivery platforms for the sustained and localised IA delivery of BH and KT, with potential clinical benefits in managing the postoperative pain following knee arthroplasty.Efficient delivery of highly lipophilic drugs or prodrugs to the mesenteric lymph nodes (MLN) can be achieved following oral administration with lipids. [https://www.selleckchem.com/products/stf-083010.html click here] However, it remains unclear which specific MLN can be targeted and to what extent. Moreover, the efficiency of drug delivery to the retroperitoneal lymph nodes (RPLN) has not been assessed. The aim of this study was to assess the distribution of a highly lipophilic model drug cannabidiol (CBD), known to undergo intestinal lymphatic transport following administration with lipids, into specific MLN and RPLN in rats at various time-points post dosing. In vivo studies showed that at 2 h following administration, significantly higher concentrations of CBD were present in the region second from the apex of the MLN chain. From 3 h following administration, concentrations in all MLN were similar. CBD was also found at substantial levels in RPLN. This study demonstrates that drug concentrations in specific MLN are different, at least at the peak of the absorption process. Moreover, in addition to the MLN, the RPLN may also be targeted by oral route of administration, which may have further implications for treatment of a range of diseases.Cardiovascular diseases rank the top causes of death worldwide, with a substantial increase in women compared to men. Such increase can beexplained by the drastic decrease in 17-β-estradiol hormone during menopause and associated with endothelium-dependent vascular dysfunction. The current treatments for cardiovascular diseases (e.g., hypertension), are only palliative and therefore, feasible, non-invasive options for preventing further vascular damage are needed. The polyphenol ellagic acid (EA) has risen as a candidate with possible vascular protection properties. This study evaluated the effects of EA in small mesenteric arteries of ovariectomized spontaneously hypertensive rats. Our findings showed that EA oral treatment for 4 weeks preserved vasodilation endothelial-dependent in acetylcholine pre-constricted arteries of spontaneously hypertensive rats to the same extent as 17-β-estradiol treatment, an effect that was abolished in the presence of the nitric oxide synthase inhibitor L-NitroG-L-Arginine Methyl Ester. Moreover, EA induced vascular nitric oxide release, by increasing both the activitation site phosphorylation and total levels of the endothelial nitric oxide synthase. Finally, EA decreased superoxide anion while increased total levels of the antioxidant enzymes Superoxide Dismutase 2 and catalase. We concluded that EA has vasodilation properties acting via endothelial nitric oxide synthase activation and a potential antioxidant effect by stimulating the Superoxide Dismutase 2-catalase pathway.The year 2020 brought unprecedented challenges and renewed focus on racial disparities and inequities in the United States. For racial and ethnic minority groups, and in particular African Americans, racial disparities have been a constant presence and threat from the time of slavery through the present day. These racial disparities, sanctioned and maintained by institutional racism, manifest in all aspects of life for African Americans-segregated and unequal education and housing systems, health and mental health care disparities, disproportionally elevated incarceration rates, and, as painfully highlighted this past year, continued vulnerability to acts of violence at the hands of law enforcement. In addition, most recently, there has been a renewed focus on the increased suicide rate for Black youth and its relationship to these racial disparities.1 In a large urban environment, our academic Child Psychiatry Department recognized that progress toward addressing racial disparities would be impeded without raising awareness and taking individual and collective action to identify implicit bias, power, and privilege differentials, and systemic racism inherent within academic medicine and our own lived experiences. This letter describes the development of such examination through facilitated dialogues on race and antiracism in our department.The COVID-19 pandemic has exacerbated some of the most pressing social problems and structural inequities, with a disproportionate impact on some of the most vulnerable youth. The goal of this article is to raise awareness among child mental health professionals of the ways in which the pandemic has likely exacerbated the commercial sexual exploitation of children in the United States. A second goal is to promote child mental health professionals' ability to identify and care for these resilient yet underresourced youth.In this issue, readers can review a multisite, double-blind, randomized, controlled trial (DBRCT) of vortioxetine for adolescent major depression (AMD) by Findling et al.1 The investigators deserve credit for this industry-sponsored study's several innovations initial treatment following current guidelines, efforts to reduce placebo response rates (PRRs), and creation of both placebo- and active-control arms. The Journal deserves our respect for its commitment to highlighting these innovations, despite the trial's negative result. It is essential to perform treatment studies in adolescents, and this study underscores the fallacy of presuming that drugs showing efficacy in adults will be as effective in our patients.As our society becomes more sensitized to the reach and extent of structural racism embedded in our institutions, it is important that we do serious and intentional work to undo the harmful policies and practices resulting from this multicentury process. Structural racism is both endemic and epidemic in nature. As relates to children's mental health, there is literature that supports the presence of serious racial/ethnic disparities in both the quantity and quality of children' mental health services as a result of structural racism in our service system.1,2.School attendance problems (SAPs) include full-day and partial absences (eg, missing classes, tardiness) as well as difficulties going to or remaining in school. SAPs also include nonparticipation in distance/hybrid learning formats or lack of access to necessary technology or equipment. SAPs are particularly prevalent among students of color, students in poverty, students with disabilities, English language learners, and migrant populations. SAPs are often part of a complicated clinical picture of mental health (eg, emotional, neurodevelopmental, conduct disorders) and somatic (eg, abdominal, cardiovascular, respiratory problems) challenges. These challenges are exacerbated by disparities in socioeconomic status, childhood adversities, family structure, and neighborhood-level factors that have an impact on mental health outcomes.1 SAPs have serious negative consequences in childhood (eg, lower academic achievement, greater risk of dropout) and in adulthood (eg, lower lifetime earning potential, greater occupational and mental health problems). Unfortunately, underrepresented youth with SAPs often have less access to proper care, especially psychiatric care.Tuberculosis infection caused by the contagious pathogen Mycobacterium tuberculosis (MTB) is one of the ancient diseases in the world. The problem of drug resistance is a difficulty in tuberculosis treatment. MTB engendered epigenetic changes play vital parts in escaping the host immune response and bring about the persistence as well as bacterial expansion. This article describes the epigenetic changes that occur in the pathogen MTB and its host during infection, including DNA methylation, histone modification and microRNA, and summarizes their research progress in drug discovery and tuberculosis diagnosis, providing new ideas and strategies to combat against drug-resistant tuberculosis.Hedgehog, a developmental morphogen, and its downstream signalling have recently been associated with metabolic control. Sonic hedgehog signalling (Shh) is a significant pathway that regulates various events during the growth and development of embryos. The dysregulation of the Shh pathway has been implicated in many physiological and pathological processes, including adipocyte differentiation, cancer, diabetes and obesity. Researchers have proved that pharmacological modulation of the Shh pathway might help to improve better outcomes in metabolic disorders. A systemic review was conducted through various search engines to understand the molecular nature of Shh Pathway in Metabolic Disorders and its therapeutic implication in the future. However, we could find that by studying the crosstalk between various pathways, such as Wnt/ β-catenin, TGF (transforming growth factor β), mTOR, and notch with Sonic hedgehog, a close link between the pathogenesis of different metabolic disorders. Understanding the importance of these molecular interlinking networks will provide a rational basis that influences its activity. This article discusses the changes and modifications that happen due to up-or down-regulation of various transcription factors in the Shh pathway. The study attempts to provide a complete overview of the main signalling events involved with canonical and non-canonical Hedgehog signalling and the increasingly complicated regulatory modalities related to Hedgehog for regulating metabolism. Further, it investigates the possible approaches needed to treat metabolic disorders for better results.