Search

Abstract The NLRP3 inflammasome is an intracellular, multiprotein complex that promotes the auto-catalytic activation of caspase-1 and the subsequent maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18. Persistent activation of the NLRP3 inflammasome has been implicated in the pathophysiology of a number of inflammatory and autoimmune diseases, including neuroinflammation, cardiovascular disease, non-alcoholic steatohepatitis, lupus nephritis and severe asthma. Here we describe the preclinical profile of JT002, a novel small molecule inhibitor of the NLRP3 inflammasome. JT002 potently reduced NLRP3-dependent proinflammatory cytokine production across a number of cellular assays and prevented pyroptosis, an inflammatory form of cell death triggered by active caspase-1. JT002 demonstrated in vivo target engagement at therapeutically relevant concentrations when orally dosed in mice and prevented body weight loss and improved inflammatory and fibrotic endpoints in a model of Muckle–Wells syndrome (MWS). In two distinct models of neutrophilic airway inflammation, JT002 treatment significantly reduced airway hyperresponsiveness and airway neutrophilia. These results provide a rationale for the therapeutic targeting of the NLRP3 inflammasome in severe asthma and point to the use of JT002 in a variety of inflammatory disorders.

Macrophage infiltration of adipose tissue during weight gain is a central event leading to the metabolic complications of obesity. However, what are the mechanisms attracting professional phagocytes to obese adipose tissue remains poorly understood. Here, we demonstrate that adipocyte-derived microparticles (MPs) are critical "find-me" signals for recruitment of monocytes and macrophages. Supernatants from stressed adipocytes stimulated the attraction of monocyte cells and primary macrophages. The activation of caspase 3 was required for release of these signals. Adipocytes exposed to saturated fatty acids showed marked release of MPs into the supernatant while common genetic mouse models of obesity demonstrate high levels of circulating adipocyte-derived MPs. The release of MPs was highly regulated and dependent on caspase 3 and Rho-associated kinase. Further analysis identified these MPs as a central chemoattractant in vitro and in vivo. In addition, intravenously transplanting circulating MPs from the ob/ob mice lead to activation of monocytes in circulation and adipose tissue of the wild type mice. These data identify adipocyte-derived MPs as novel "find me" signals that contributes to macrophage infiltration associated with obesity.

Obesity is associated with metabolic perturbations including liver and adipose tissue inflammation, insulin resistance, and type 2 diabetes. Omega-6 fatty acids (ω6) promote and omega-3 fatty acids (ω3) reduce inflammation as they can be metabolized to pro- and anti-inflammatory eicosanoids, respectively. 12/15-lipoxygenase (12/15-LO) enzymatically produces some of these metabolites and is induced by high fat (HF) diet. We investigated the effects of altering dietary ω6/ω3 ratio and 12/15-LO deficiency on HF diet-induced tissue inflammation and insulin resistance. We examined how these conditions affect circulating concentrations of oxidized metabolites of ω6 arachidonic and linoleic acids and innate and adaptive immune system activity in the liver. For 15 weeks, wild-type (WT) mice were fed either a soybean oil-enriched HF diet with high dietary ω6/ω3 ratio (11∶1, HFH), similar to Western-style diet, or a fat Kcal-matched, fish oil-enriched HF diet with a low dietary ω6/ω3 ratio of 2.7∶1 (HFL). Importantly, the total saturated, monounsaturated and polyunsaturated fat content was matched in the two HF diets, which is unlike most published fish oil studies in mice. Despite modestly increased food intake, WT mice fed HFL were protected from HFH-diet induced steatohepatitis, evidenced by decreased hepatic mRNA expression of pro-inflammatory genes and genes involved in lymphocyte homing, and reduced deposition of hepatic triglyceride. Furthermore, oxidized metabolites of ω6 arachidonic acid were decreased in the plasma of WT HFL compared to WT HFH-fed mice. 12/15-LO knockout (KO) mice were also protected from HFH-induced fatty liver and elevated mRNA markers of inflammation and lymphocyte homing. 12/15-LOKO mice were protected from HFH-induced insulin resistance but reducing dietary ω6/ω3 ratio in WT mice did not ameliorate insulin resistance or adipose tissue inflammation. In conclusion, lowering dietary ω6/ω3 ratio in HF diet significantly reduces steatohepatitis.

Introduction: The use of the Internet is becoming increasingly important in enabling children and adults to fully participate in society, whether it is learning new skills or connecting with friends and family. Consequently, children's opportunities are increasingly dependent on the Internet. The advance of technological innovations has resulted in more and more ICT devices being available to children, contributing to the deterioration of children and adolescents' health. Methods: The study was designed as an epidemiological, cross-sectional, descriptive-analytical, comparative study. The study was conducted from October 18, 2021, to January 16, 2022, using an online questionnaire accessible through the Microsoft Forms platform. Respondents were able to access the questionnaire via a link or QR code located on the child's consent form for participation in the study, which was previously signed by a parent/guardian. Results: The results of the study showed that school-age children were the most frequent users of smartphones and watches TV, with male respondents spending more time using almost all ICT devices, with the exception of tablets, which were used more frequently by female respondents. The analysis of pain intensity in the use of information and communication technologies revealed that respondents most frequently experienced mild pain, especially in the neck/shoulders and lower extremities. The frequency of eye problems after using ICT devices was found to be occasional, with the most pronounced symptoms being fatigue, tearing, and eyestrain, as well as headaches in one in five respondents. Conclusion: Increasing frequency of ICT device use was associated with higher pain intensity in all anatomic regions. A 1-hour increase in weekly ICT device use also increased the likelihood of pain intensity in all anatomic regions, including eye symptoms and headaches. High exposure to ICT is of concern because it leads to adverse health outcomes for children.

Introduction: information and communication technology (ICT) has multiplied its availability and use, resulting in enormous usage, especially among school-age children, who use it for an average of 7.5 hours per day. The amount of time adolescents spend in front of electronic screens has increased significantly between the ages of 10 and 14, but there are significant gender changes. For boys, this increase is 41.6 minutes per day, while for girls it is 22.7 minutes per day. Methods: The study is designed as an epidemiological, cross-sectional, descriptive-analytic, comparative study. The study will be conducted in the form of an online questionnaire on the Microsoft Forums platform during the period 12/15/2021 to 12/30/2021. Respondents were able to access the request for consent using a link and a QR code, which was previously signed by a parent/guardian giving consent for children to participate in this study. Results: The results of this study show that school-aged children generally use cell phones with a touch screen between 2 and 3 hours daily during the work week (39.2%) and TV (39.5%). Pain caused by ICT use in the past 12 months occurred mainly in the neck/shoulder area (42.4%), while pain in the previous month occurred mainly in the lower extremities (29.1%). Conclusion: Increased use of ICT devices was associated with higher levels of musculoskeletal symptoms. The higher pain burden in various body parts is of concern, and further research on the effects of ICT device use in adolescents is needed and warranted.

Introduction: The assessment of the health-care system by its beneficiaries is based on evaluation of the public perception in regards to the performance of healthcare workers, the functioning of the health system, the effectiveness of health policy measures, and a number of other components. The aim of this study was to determine patients’ trust in the work of physiotherapists and the health-care system; determine the quality of communication between the patient and the physiotherapist and determine the quality of cooperation between healthcare workers in the provision of health services. Methods: The study is descriptive, conducted in five cities: Banja Luka, Bihać, Herceg Novi, Nikšić, and Podujevo. The confidence in health-care questionnaire developed by Calnan and Sanford (2004) was used as a research instrument, containing six areas of research: Attitude toward the patient, Health policy and patient care, Professionalism and expertise, Quality of health care, Communication and information, and Quality of cooperation. Results: The mean age of the subjects was 41 years, 24 females and 26 males. Subjects expressed the greatest satisfaction on subscales I - Attitude toward the patient (27.44 ± 3.59 out of 30) and IV - Quality of health care (36.60 ± 4.19 out of 40), which represents 91.5% of the possible maximum. This is followed by subscale V - Communication and information (20.8 ± 3.17 out of 25) corresponding to 83.2% of the possible maximum, followed by subscale III - Professionalism and expertise (15.68 ± 3.29 out of 20) which represents 78.4% of the possible maximum. Subjects showed the least satisfaction on subscales II - Health policy and patient care (16.94 ± 5.56 out of 25), which represents 67.8% of the possible maximum, and subscales VI - Quality of cooperation (9.94 ± 0.42 out of 15) which corresponds to 66.3% of the possible maximum. Conclusions: The research showed a high degree of satisfaction of subjects in various fields, which indicates a high degree of confidence in the work of physiotherapists and the health-care system. Research on a larger sample in needed for creation and implementation of the guidelines in the strategic documents of the countries in the region and for improvement of health policies and patient care.

Introduction: Work-related musculoskeletal disorders (WRMSDs) are the most common work-related diseases and describe a wide range of degenerative and inflammatory conditions affecting blood vessels, peripheral nerves, joints, ligaments, tendons, and muscles. WRMSDs are becoming an increasing problem in modern society. They are the second biggest cause of short-term or temporary incapacity for work just following a cold. At the workplace, health professionals represent a very vulnerable category in terms of musculoskeletal disorders (MSDs) development. It is estimated that almost one-third of all cases of absence from work among health care professionals are related to MSDs. Studies also show that a large number of health professionals report the occurrence of MSDs in one or more regions of the body, with a problem with the lower back being one of the most common. Methods: This article presents a non-experimental (qualitative) research, or a scientific review of the published literature where the databases were reviewed in which the keywords for the review were: MSDs, work, health, intervention program, and ergonomics. Various databases were used in the preparation of this article, including PubMed, Google Scholar, Medline, Hrčak, Dabar, Science Direct, and Science Citation. Results: The results include a review and analysis of eighteen published scientific articles in the period 2001-2020. The studies published in these articles has been conducted in the United States, Australia, Switzerland, Portugal, Slovenia, Turkey, China, Nigeria, Israel, Tunisia, Iran, Croatia, Taiwan, Bangladesh, Serbia, Macedonia, and Greece. Conclusion: This article should indicate the magnitude of the problems of WRMSDs in health professionals and that this topic is an inexhaustible and very interesting basis for further studies by current and future researchers to create strategies for the prevention and treatment of this disorder and to eliminate its causes.

Prenatal androgen produces many reproductive and metabolic features of polycystic ovary syndrome in female rodents, sheep, and monkeys. We investigated the impact of such prenatal treatment in adult male rats. Pregnant dams received free testosterone (T; aromatizable androgen), dihydrotestosterone (D; nonaromatizable androgen), or vehicle control (C) on embryonic days 16–19. Neither of the prenatal androgen treatments resulted in increased body weight from weaning to age 65 days in males. However, at 65 days, there were significant increases in retroperitoneal (P<0.001 T versus C; P<0.05 D versus C), epididymal (P<0.05 T versus C), and subcutaneous (P<0.01 T versus C) fat pads in prenatally androgenized males. While both androgens altered body composition, subcutaneous fat depots increased only in T males. T males had elevated glucose levels (P<0.01) compared to C males. There were no differences among the three groups in insulin sensitivity, circulating lipid and leptin levels, or hepatic triglyceride content. Real-time PCR analysis of insulin signaling pathway genes in retroperitoneal fat revealed a transcriptional downregulation of adipsin and insulin receptor substrate-1 in T and α-1D adrenergic receptor in D compared to C males. We conclude that transient exposure to androgen excess in utero increases body fat in adult male rats. Only T males exhibit increased circulating glucose levels and subcutaneous fat suggesting that these changes may be mediated by aromatization of androgen to estrogen rather than by direct androgenic actions. [ABSTRACT FROM AUTHOR]