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免疫調節細胞の発現を上方調節および抑制するための方法
No full text[[abstract]]The present application provides a method of upregulating an expression of immumodulatory cells in vitro comprising treating the immumodulatory cells with IL-25 to i
Causal relationships between childhood maltreatment and adult health and socioeconomic outcomes using two-sample mendelian randomization
No full text[[abstract]]Background :Growing evidence suggests that childhood maltreatment is an important risk factor for lifelong negative consequences of health outcomes; however, there has not been a systematic investigation of the impact of childhood maltreatment on health outcomes in adulthood. We aim to investigate the impact of childhood maltreatment on disease burden and health and socioeconomic outcomes in adulthood. Methods: We utilized self-reported data on five subtypes of childhood maltreatment in the UK Biobank = 129,017). We first performed sex-combined and sex-stratified genome-wide association analyses to identify genomic loci associated with specific subtypes of childhood maltreatment. We then performed Mendelian randomization (MR) analyses to identify causal effects of childhood maltreatment on health and socioeconomic outcomes. Results: We identified two novel loci for emotional abuse in sex-combined analysis, one locus for emotional neglect in males, one locus for physical abuse in females, and one locus for sexual abuse in females. MR analyses showed that childhood maltreatment may increase the risk of anxiety disorders, major depressive disorder, migraine, stroke, and type 2 diabetes mellitus in adulthood. MR analysis also suggested childhood maltreatment may increase the costs for healthcare in adulthood, decrease the lifespan, and lead to lower educational attainment. Discussion: Our study elucidates the influence of childhood maltreatment on health outcomes in adulthood, highlighting the enduring influence of childhood maltreatment on lifelong health consequences and their associated healthcare costs. It is important to develop prevention strategies to lower the incidence of childhood maltreatment and provide support and care for victims of childhood maltreatment for better long-term health outcomes in the population
Prognosis of periprosthetic fractures post hip fracture: Unveiling protective role of anti-osteoporotic medication
No full text[[abstract]]Objective: Periprosthetic fractures (PPF) near prior hip fracture fixation implants present formidable challenges due to intricate fracture patterns, implant presence, and compromised patient bone quality. Limited research exists on PPF prognosis in osteoporotic hip fracture patients. While anti-osteoporotic medication (AOM) effectively reduces secondary hip fracture risks, its impact on PPFs remains unexplored. Our study aims to address these gaps by assessing the influence of initiating AOM post-hip fracture on PPF occurrence and investigating PPF prognosis in a nationwide cohort of hip fracture patients. Methods: This nationwide cohort study employs Taiwan’s National Health Insurance Research Database (NHIRD) from January 1, 2016, to December 31, 2018, identifying 48,082 hospitalized hip fracture patients with concomitant procedures. Collected demographics include age, gender, comorbidities, and comedications. AOM use within one year post-hip fracture was examined. Primary outcome: periprosthetic fracture risk post-incident hip fracture. Secondary outcomes: subsequent osteoporotic fractures and PPF patient mortality. Fine and Gray’s subdistribution hazard function explored risk factors and AOM effects on PPF. Results: Among 48,082 patients with incident hip fractures, 30,182 (62.7%) were female, mean age 77.9 ± 10.7 y. Over 5 y, 443 (0.92%) developed PPF, with failure probability ranging from 0.58% (first year) to 1.25% (5-y follow-up). AOM users had lower cumulative PPF incidence at 5 y (0.53 vs. 1.08%). AOM post-hip fracture reduced PPF risk by 50% (HR = 0.5, p < 0.0001). Among 443 PPF patients, 22 (4.97%) had subsequent osteoporotic fractures, and 72 (16.25%) died within one year. Conclusion: PPF following an incident hip fracture escalates the risk of imminent fractures and mortality within a year. Employing AOM post-hip fracture may effectively mitigate the risk of PPF
Association of exercise with melatonin level in community- dwelling older adults
No full text[[abstract]]Summary: Melatonin serves as an endogenous synchronizer of biological rhythms. Age-related changes are evident with a significant reduction in melatonin observed in 24-hour secretion. Melatonin exerts a significant cytoprotective action by buffering free radicals and reversing inflammation. However, few studies have explored the association between physical activity and melatonin level. In this study, we compared melatonin level and actigraphy-derived sleep and activity indicators in older adults across two levels of exercise habit (sedentary-to- light exercise and moderate -to-vigorous exercise), as well as the association of these indicators with melatonin levels. We recruited 104 participants (aged 57– 84 years) who wore a wristwatch device to monitor their activity (MotionWatch 8; CamNtech, Cambridge, UK) for 14 days. Circadian rhythms were estimated using cosinor analysis, lag 1440 mins correlation coefficient, interdaily stability, and non-parametric analysis. Saliva samples were collected every 30 mins from 18:00 pm till one hour before usual bedtime, and maximum melatonin level during this period. A 5-minute Psychomotor Vigilance Task (PVT) was used to evaluate attention. Habits of physical activities were self-reported. Melatonin level was not significantly different between participants with sedentary- to-light and moderate-to-vigorous exercise habits. Analysis showed that participants who had moderate-vigorous exercise habit were older (p = 0.04), having longer sports time (p < 0.001) and WASO (p = 0.02), more occurrence of daytime naps (intradaily variability) (p = 0.05), more fragmentated 24-h sleep-wake cycle (interdaily stability, p = 0.01), and less regular 24h rhythm (lag 1140 mins correlation, p = 0.04). They also showed shorter response time (p = 0.05), and a smaller number of lapses (p = 0.04) in PVT. Regression analysis results showed that weekly exercise time is positively associated with melatonin level. Additionally, a later start hour of M10 is associated with 5.95 pg/ml increase in melatonin level. In consistent, exercise in older adults did not promote a robust sleep- wake cycle but is related to better cognitive function and higher melatonin levels
[[alternative]]DUSP8 promotes IL-9 transcription by inactivating Pur-α leading to asthma and atopic dermatitis
No full text[[abstract]]Dual-specificity phosphatase 8 (DUSP8) is a member of the DUSP family. DUSP8 dephosphorylates and inactivates the kinase JNK. DUSP8 protein levels are predominantly expressed in CD4+ T cells and platelets. DUSP8 dephosphorylates and inactivates specifically JNK in Jurkat T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T-cell-specific DUSP8 conditional knockout (T-DUSP8 cKO, DUSP8f/f;CD4-Cre) mice, mass spectrometry, and chromatin-immunoprecipitation sequencing, we found that DUSP8 stimulated IL-9 gene expression and Th9 differentiation. TGF-β stimulated DUSP8 phosphatase activity in T cells. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-β signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, Il-9 mRNA levels in murine T cells were induced in Pur-α knockout. Reduction of IL-9 levels in T cells of T-DUSP8 cKO mice was reversed by Pur-α heterozygous knockout. Consistently, T-DUSP8 cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in allergy, autoimmune responses, and anti-tumor immunity. Remarkably, DUSP8 overexpression and DUSP8-Pur-α interaction indeed occurred in the peripheral blood T cells of patients with asthma or atopic dermatitis, contributing to IL-9 overproduction in patients’ T cells. Thus, DUSP8 plays a critical role in the pathogenesis of asthma and atopic dermatitis, as well as autoimmune disease and cancer
Gut microbes with the gbu genes determine TMAO production from L-carnitine intake and serve as a biomarker for precision nutrition
No full text[[abstract]]Gut microbial metabolism of L-carnitine, which leads to the production of detrimental trimethylamine N-oxide (TMAO), offers a plausible link between red meat consumption and cardiovascular risks. Several microbial genes, including cntA/B, the cai operon, and the recently identified gbu gene cluster, have been implicated in the conversion of dietary L-carnitine into TMA(O). However, the key microbial genes and associated gut microbes involved in this pathway have not been fully explored. Utilizing the oral carnitine challenge test (OCCT), which specifically measures TMAO production from L-carnitine intake and identifies TMAO producer phenotypes, we compared the abundance of microbial genes between low- and high-TMAO producers across three independent cohorts. Our findings consistently revealed that the gbu gene cluster, rather than cntA/B or the cai operon, was significantly enriched in high-TMAO producers. We further analyzed 292 paired multi-omic datasets from OCCT and shotgun metagenomic sequencing, which demonstrated a significant positive correlation between the abundance of fecal gbu genes and L-carnitine-induced TMAO production, with gbuB showing the strongest correlation. Interestingly, these fecal gbu genes were found to increase with L-carnitine supplementation and decrease with a plant-based diet. Notably, we verified a previously uncultured gbu-containing bacterium, JAGTTR01 sp018223385, as the major contributor to TMA formation in the human gut. We isolated these gbu-containing gut microbes and confirmed their role in TMA/TMAO production using anaerobic incubation and a gnotobiotic mouse model. Using an in-house collection of gbu-containing isolates, we developed a qPCR-based method to quantify fecal gbuB and validated its correlation with L-carnitine-mediated TMAO production as measured by OCCT. Overall, these findings suggest that gbu-containing gut microbes are crucial for TMAO increases following L-carnitine intake and may serve as biomarkers or targets for personalized nutrition
Effects of repetitive transcranial magnetic stimulation on poststroke hemineglect: A systematic review and network meta-analysis of randomized controlled trials
No full text[[abstract]]BACKGROUND: Although various repetitive transcranial magnetic stimulation (rTMS) and theta burst stimulation (TBS) protocols are used, their comparative effectiveness for treating poststroke hemineglect remains unassessed. OBJECTIVE: To investigate rTMS and TBS effects on clinical outcomes in poststroke hemineglect through a systematic review and network meta-analysis. METHODS: We searched PubMed, EMBASE, and Cochrane Library databases up to March 7, 2024, for trials on rTMS or TBS in poststroke hemineglect. Included studies involved rTMS or TBS with different protocols, sham, or no stimulation, assessing hemineglect severity or impact. The quality of the included studies was evaluated using the PEDro scale. The network meta-analysis was performed using ShinyNMA (version 1.01). RESULTS: We analyzed 13 studies with 309 participants. All studies included participants who had experienced right hemisphere stroke. All included studies had a fair to good quality based on PEDro score evaluation. Protocols included continuous TBS (cTBS), high-frequency rTMS (HF-rTMS), and low-frequency rTMS (LF-rTMS) targeting both contralesional and lesional sites. HF-rTMS on the lesional site significantly improved short-term results on the line bisection test and Catherine Bergego Scale; LF-rTMS on the contralesional site improved short-term line bisection; and cTBS on the contralesional site improved long-term line bisection. No severe adverse events or significant inconsistencies were reported. CONCLUSIONS: Our findings indicate that HF-rTMS targeting the lesional site is the preferred therapeutic approach for the short-term management of poststroke hemineglect. LF-rTMS directed at the contralesional site is a practical alternative. Moreover, cTBS targeting the contralesional site is a viable option because of its long-term effect
Autonomic function and change in functional capacity in older adults: A longitudinal investigation
No full text[[abstract]]Functional capacity is an important objective health metric, and relies on the maintenance of physiological homeostasis. Autonomic nervous system is known to coordinates the maintenance of multi-organ homeostasis. The objective of this study was to examine the association of autonomic nervous system function with functional capacity in adults aged 55 years and older. A cohort of 542 adults (mean age of 70.1 years) received repeated measurements of heart rate variability, an autonomic nervous system function marker, and chair rise time, a functional capacity measure. Linear mixed models analysis showed that 1 SD lower powers in low-frequency range at baseline was associated with a 0.11 (95% CI 0.01–0.21) s/year faster increase in chair rise time during the follow-up, whereas 1 SD increase in powers in high-frequency range and 1 SD decrease in the ratio of powers in low-frequency range to powers in high-frequency range during the follow-up were associated with a 0.22 (95% CI 0.06–0.39) s and 0.17 (95% CI 0.01–0.33) s increase in chair rise time. In conclusion, autonomic nervous system function and its changes were longitudinally associated with changes in functional capacity in older adults
Method of stimulating TLR9-activated immune response
No full text[[abstract]]A method of stimulating a TLR9-activated immune response or enhancing a TLR9-activated immune response to an antigen is disclosed herein. TLR9 is the cellular receptor for CpG-ODN, and current developed CpG-ODN has low activity to rabbit TLR9. Here, the method of stimulating TLR9-activated immune response by administering an effective amount of immunogenic composition comprising an antigen and a CpG-ODN comprising GACGTT or AACGTT motif was demonstrated to have potent immunostimulatory activity to rabbit TLR9, and capable of boosting a less toxic and potent antibody response in rabbits
[[alternative]]Gamma-polyglutamic acid-based intraocular irrigation solutions
No full text[[abstract]]환자의 안구조직을 관류하는데 충분한 양의 안과용 관류액에 관한 것으로, a) 관류액의 농도를 높이는데 충분히 효율적인 양의 감마-폴리글루탐산(감마-PGA) 및/또는 이들의 염, 및 b) 환자의 안구조직을 관류하는데 사용되는 감마-PGA 및/또는 이들의 염의 안과용으로 수용 가능한 수성의 부형제를 포함하는 안과용 관류액에 대하여 기재하였다. 또한, 안구수술 동안의 스트레스로 인한 환자의 안구조직 손상을 줄이는데 사용되는 안과용 관류액 및 약제 키트도 기재하였다