Tumor necrosis factor receptor-associated factor 3 (TRAF3) is an anti-inflammatory molecule that negatively regulates the non-canonical nuclear factor-κB pathway. Although TRAF3 haploinsufficiency (TRAF3 HI) can influence innate and adaptive immune cells, its effect on inflammatory bowel disease (IBD) development remains unclear. Here, we report the first case of severe early-onset IBD with a novel TRAF3 variant leading to HI, successfully treated with ustekinumab. A 6-year-old girl with a recurrent parotitis, otitis media, tonsilitis, and atopic dermatitis developed IBD involving the stomach, small intestine, and colon. At diagnosis, the immunoglobulin (Ig)G and IgA levels were relatively high, and lymphocyte subsets showed increased counts of plasmablasts, class-switch recombination B cells, and circulating T-follicular helper cells. Treatment with azathioprine and infliximab failed to maintain remission marked by several relapses accompanied by erythema nodosum and arthritis; however, ustekinumab, an anti-interleukin (IL)-12/23p40 antibody, led to long-term clinical remission, normalizing the Ig level and reducing abnormal lymphocyte counts. Whole-exome sequencing revealed a novel heterozygous mutation in TRAF3 [p.(Pro487Leufs*8)], resulting in TRAF3 under-expression. Our case may highlight the contribution of TRAF3 HI to the development of IBD and provide insights into IBD pathophysiology, suggesting the involvement of the IL-12/23-T-follicular helper cell pathway affected by genetic mutations.

BACKGROUND: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. METHODS: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. RESULTS: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer's disease. CONCLUSIONS The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.
Aged ; Alzheimer Disease/genetics* ; Dementia/genetics* ; Environment ; Female ; Humans ; Incidence ; Japan/epidemiology* ; Male ; Middle Aged ; Prevalence ; Prospective Studies ; Risk Factors

Endochondral ossification is the fundamental process of skeletal development in vertebrates. Chondrocytes undergo sequential steps of differentiation, including mesenchymal condensation, proliferation, hypertrophy, and mineralization. These steps, which are required for the morphological and functional changes in differentiating chondrocytes, are strictly regulated by a complex transcriptional network. Biochemical and mice genetic studies identified chondrogenic transcription factors critical for endochondral ossification. The transcription factor sex-determining region Y (SRY)-box 9 (Sox9) is essential for early chondrogenesis, and impaired Sox9 function causes severe chondrodysplasia in humans and mice. In addition, recent genome-wide chromatin immunoprecipitation-sequencing studies revealed the precise regulatory mechanism of Sox9 during early chondrogenesis. Runt-related transcription factor 2 promotes chondrocyte hypertrophy and terminal differentiation. Interestingly, endoplasmic reticulum (ER) stress-related transcription factors have recently emerged as novel regulators of chondrocyte differentiation. Here we review the transcriptional mechanisms that regulate endochondral ossification, with a focus on Sox9.
Animals ; Chondrocytes ; Chondrogenesis ; Chromatin ; Endoplasmic Reticulum ; Gene Regulatory Networks* ; Humans ; Hypertrophy ; Mice ; Miners ; Osteogenesis ; SOX9 Transcription Factor ; Transcription Factors ; Vertebrates

Genetic studies and molecular cloning approaches have been successfully used to identify several transcription factors that regulate the numerous stages of cartilage development. Sex-determining region Y (SRY)-box 9 (Sox9) is an essential transcription factor for the initial stage of cartilage development. Sox5 and Sox6 play an important role in the chondrogenic action of Sox9, presumably by defining its cartilage specificity. Several transcription factors have been identified as transcriptional partners for Sox9 during cartilage development. Runt-related transcription factor 2 (Runx2) and Runx3 are necessary for hypertrophy of chondrocytes. CCAAT/enhancer-binding protein β (C/EBPβ) and activating transcription factor 4 (ATF4) function as co-activators for Runx2 during hypertrophy of chondrocytes. In addition, myocyte-enhancer factor 2C (Mef2C) is required for initiation of chondrocyte hypertrophy, presumably by functioning upstream of Runx2. Importantly, the pathogenic roles of several transcription factors in osteoarthritis have been demonstrated based on the similarity of pathological phenomena seen in osteoarthritis with chondrocyte hypertrophy. We discuss the importance of investigating cellular and molecular properties of articular chondrocytes and degradation mechanisms in osteoarthritis, one of the most common cartilage diseases.
Activating Transcription Factor 4 ; Cartilage Diseases ; Cartilage* ; Chondrocytes ; Cloning, Molecular ; Hypertrophy ; Osteoarthritis ; Sensitivity and Specificity ; Transcription Factors*

The Japanese adult cardiovascular database (JACVSD) contains details of all adult cardiovascular surgeries performed in Japan. This database has the potential to make data from all of Japan available to the world in the future. However, it is time consuming to enter several items from an individual terminal for all cases ; adding further pressure to already busy routine work. In our facilities, an original system using Filemaker Pro has been developed and used since 2004. This system has various functions integrated into it, and currently, the input system of JACVSD has been added. As a result, it becomes possible to automatically enter more than half the data of JACVSD, and excellent results can be reported. Intellectual property rights have been owed by Nihon University since 2007.

Prevalence of age-dependent diseases such as asthma is confounded not only by aging effects but also by cohort and period effects. Age-period-cohort (APC) analysis is commonly performed to isolate the effects of these three factors from two-way tables of prevalence by age and birth cohort. However, APC analysis suffers from technical difficulties such as non-identifiability problems. We isolated the effects of these three factors in a step-by-step manner by analyzing Japan's school health data collected from 1984 to 2004 focusing on asthma prevalence among school children aged 6-17 years consisting of 30 birth cohorts (entering classes). We verified the accuracy of our method showing high agreement of the observed age-, period- and cohort-specific data and the data predicted by our method. The aging effects were found to follow cubic equations whose multinomial coefficients were determined by an optimization technique. The obtained aging effect curves of age-specific asthma prevalence showed that boys reach the peak prevalence at 13 and girls at 14, declining markedly afterward. The cohort effects, defined as the arithmetic asthma prevalence means for ages 6-17 years, showed consistent upward trends for the 30 birth cohorts born in 1968-97 for both sexes. The period effects showed a consistent decline since 1984 but abruptly increased in 1999 and then declined again. We were not able to identify the exact cause of the increase in 1999, therefore, this should be examined in the future studies. Because the cohort effects show no sign of leveling off yet, asthma prevalence will likely increase in the foreseeable future.

Enterovesical fistula is a relatively uncommon complication of colorectal and pelvic malignancies, diverticulitis, inflammatory bowel disease, radiotherapy, and trauma in Asian countries. A case of vesico-ileosigmoidal fistula and a literature review of this disease in Japan are presented. A 70-yr-old male was referred with complaints of urinary pain and pneumaturia. On admission, urinary tract infection and pneumaturia were presented. A barium enema demonstrated multiple diverticulum in his sigmoid colon and the passage of contrast medium into the bladder and ileum. Under the diagnosis of vesico-ileosigmoidal fistula due to suspected diverticulitis of the sigmoid colon, sigmoidectomy and partial resection of the ileum with partial cystectomy were performed. The histopathology revealed diverticulosis of the sigmoid colon with diverticulitis and development of a vesico-ileosigmoidal fistula. No malignant findings were observed. Until the year 2000, a total of 173 cases of vesico-sigmoidal fistula caused by diverticulitis had been reported in Japan. Pneumaturia and fecaluria are the most common types, presenting symptoms in 63% of the cases. Computed tomography, with a sensitivity of 40% to 100%, is the most commonly used diagnostic study. For patients with vesico-sigmoidal fistula, resection of the diseased sigmoid colon and partial cystectomy with primary anastomosis are the safest and most acceptable procedures, leading to the best results.
Aged ; Anastomosis, Surgical ; Bladder Fistula/*etiology/*pathology/surgery ; Colon, Sigmoid/pathology ; Cystectomy ; Diverticulitis/*complications/*pathology/surgery ; Human ; Ileum/pathology ; Male

Primary end-to-side anastomoses between the left upper pulmonary vein and left atrium performed in 21 puppies with continuous 5-0 polydioxanone (PDS) or polypropylene (PRO). Animals were sacrificed at 1, 7 and 28 days after operation. Stenosis occurred in one of 5 animals of the PDS group at 7 days and 28 days respectively, and one of 5 animals of the PRO group at 28 days. There was no significant difference between the two groups in terms of anastomosis patency. Histological examination showed slight tissue reaction and fibrosis surrounding the sutures in both groups. This study suggests that the absorbable monofilament suture material, in particular PDS, is useful for the repair of low pressure circulatory system and will not cause the stenosis of the anastomotic site.