Expression and Role of IL-1β Signaling in Chondrocytes Associated with Retinoid Signaling during Fracture Healing

The process of fracture healing consists of an inflammatory reaction and cartilage and bone tissue reconstruction. The inflammatory cytokine interleukin-1β (IL-1β) signal is an important major factor in fracture healing, whereas its relevance to retinoid receptor (an RAR inverse agonist, which promotes endochondral bone formation) remains unclear. Herein, we investigated the expressions of IL-1β and retinoic acid receptor gamma (RARγ) in a rat fracture model and the effects of IL-1β in the presence of one of several RAR inverse agonists on chondrocytes. An immunohistochemical analysis revealed that IL-1β and RARγ were expressed in chondrocytes at the fracture site in the rat ribs on day 7 post-fracture. In chondrogenic ATDC5 cells, IL-1β decreases the levels of aggrecan and type II collagen but significantly increased the metalloproteinase-13 (Mmp13) mRNA by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. An RAR inverse agonist (AGN194310) inhibited IL-1β-stimulated Mmp13 and Ccn2 mRNA in a dose-dependent manner. Phosphorylated extracellular signal regulated-kinases (pERK1/2) and p-p38 mitogen-activated protein kinase (MAPK) were increased time-dependently by IL-1β treatment, and the IL-1β-induced p-p38 MAPK was inhibited by AGN194310. Experimental p38 inhibition led to a drop in the IL-1β-stimulated expressions of Mmp13 and Ccn2 mRNA. MMP13, CCN2, and p-p38 MAPK were expressed in hypertrophic chondrocytes near the invaded vascular endothelial cells. As a whole, these results point to role of the IL-1β via p38 MAPK as important signaling in the regulation of the endochondral bone formation in fracture healing, and to the actions of RAR inverse agonists as potentially relevant modulators of this process

Community-based clinical education increases motivation of medical students to medicine of remote area : comparison between lecture and practice

In this study, we administered a questionnaire to medical students to evaluate the effect of community-based clinical education on their attitudes to community medicine and medicine in remote area. Questionnaires were given 4 times to all the students from first-year to sixth-year. Of 95 students, 65 students (68.4%) who completed all questionnaires, were used in this study. The intensity of students’ attitudes was estimated by using visual analogue scale. The intensity of interest, a sense of fulfillment and passion in medicine of remote area was significantly increased　after the community-based practice. On the other hand, the level of understanding in medicine in remote area was increased by the lecture not by the practice. The intensity of desire both to become a generalist and a specialist was significantly increased when the grade went up. Most of sixth-year students desired to have abilities of a generalist and a specialist simultaneously. This study shows that the community-based practice is more meaningful in increasing motivation in medicine in remote area than the lecture, and suggests that it is　important to prepare more courses to　experience community medicine to increase the number of physicians who desire to work in remote area

Optimal dose of brexpiprazole for augmentation therapy of antidepressant-refractory depression: a systematic review and dose-effect meta-analysis.

BACKGROUND Brexpiprazole augmentation is an effective treatment strategy for antidepressant-refractory depression, but its optimal dosage remains unclear. AIMS To find the optimal dosage of brexpiprazole as augmentation of other antidepressants. METHODS We searched multiple electronic databases (from inception to September 16th, 2021) to identify double-blind, randomized placebo-controlled fixed-dose trials evaluating brexpiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder not adequately responding to one or more antidepressant treatment. Our outcomes of interest at 8 weeks (range 4-12 weeks) were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects) and acceptability (dropouts for any reason). We performed a random-effects, one-stage dose-effect meta-analysis with restricted cubic splines. RESULTS Six studies met the inclusion criteria, including 1,671 participants in total. The dose-efficacy curve showed an increase up to doses around 2 mg (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.12-2.06) and then a decreasing trend through the higher licensed dose up to 3 mg (OR 1.40, 95%CI 0.95-2.08). The shape of the dose-tolerability curve was comparable to that of the efficacy and the dose-acceptability curve showed a monotonic increasing trend but both had wide confidence bands. CONCLUSIONS One to two mg of brexpiprazole as augmentation treatment may achieve an optimal balance between efficacy, tolerability, and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies limit the reliability of the results. Further research is required to validate the findings. This article is protected by copyright. All rights reserved