Urban versus rural differences of hip fractures among the elderly in Kyoto, Japan: a 10-year study.

Secular changes in the incidence rate of hip fractures were estimated to vary by fracture type, i.e., femoral neck or trochanteric fractures, age, and sex, in urban or rural areas in Kyoto Prefecture, Japan from 2008 to 2017. PURPOSE: Our survey in Kyoto Prefecture from 2008 to 2017 showed that the incidence rate of femoral neck fractures is generally increasing. We investigated the differences between urban and rural areas in the changes of the incidence rate over time of femoral neck and trochanteric fractures during the same period. METHODS: Patients aged 65 years and above who sustained hip fractures between 2008 and 2017 and were treated at one of the participating 11 hospitals were included. The ratio of sick beds for acute-term care at the investigated hospitals to total number of beds in the urban area was 16.5% (1863/11,158) and 30.6% (1863/5623) in the rural area. The change in incidence rate was estimated utilizing the population according to the national census conducted in 2010 and 2015. RESULTS: There were 3559 and 6474 hip fractures in the urban and rural areas, respectively. Femoral neck fractures were 1936 (54.4%) and 2813 (43.5%) in each area. The increase of the population-adjusted numbers was marked by neck fractures in males, in both areas. In women, there was a significant increase in femoral neck fractures in the urban area in those aged 85 years and over. For trochanteric fractures, a significant increase was only found in women aged 65 to 74 years in the rural area. CONCLUSION: A regional difference in the secular changes in incidence rate of hip fractures was found in women, not in men, mostly because neck fractures in women increased in the over 85 group in the urban area.

Hip fractures among the elderly in Kyoto, Japan: a 10-year study.

In Kyoto Prefecture, Japan, the number of hip fractures increased during 2013-2017 compared to 2008-2012. However, the estimated overall incidence rate increased only in femoral neck fractures in men aged ≥75 and women aged ≥85. PURPOSE: The incidence rate of hip fractures in Japan has plateaued or decreased. We investigated the annual hip fracture occurrences in Kyoto Prefecture, Japan, from 2008 to 2017. METHODS: Patients aged 65 years and above who sustained hip fractures between 2008 and 2017 and were treated at one of the participating 11 hospitals were included. The total number of beds in these institutions was 3701, accounting for 21.5% of the 17,242 acute-care beds in Kyoto Prefecture. The change in incidence rate was estimated utilizing the population according to the national census conducted in 2010 and 2015. RESULTS: The total number of hip fractures was 10,060, with 47.5% femoral neck fractures and 52.5% trochanteric fractures. A decrease in number was seen only in trochanteric fractures in the group of 75- to 84-year-old women. The population-adjusted numbers of femoral neck fractures showed a significant increase in all age groups in men, whereas in women, there was an increase in femoral neck fractures in the ≥85 group and trochanteric fractures in the age group 65-74, and a decrease in trochanteric fractures in the age group 75-84. The estimated change in incidence rate showed an increase in femoral neck fractures in men aged ≥75 and women aged ≥85. CONCLUSION: In Kyoto Prefecture, the number of hip fractures increased in the second half of the study period (2013-2017) compared to the first half (2008-2012). However, the incidence rate had not increased, except in femoral neck fractures in men aged ≥75 and women aged ≥85.

A modified Terrono classification for Type 1 thumb deformity in rheumatoid arthritis: a cross-sectional analysis.

The most common thumb deformity in rheumatoid arthritis is Nalebuff Type 1 deformity (boutonniere deformity). Type 1 deformity severely impairs hand function, and this impairment is evaluated by the Terrono classification. In some cases, the Terrono classification incorrectly categorizes advanced thumb deformity into earlier stages. We modified the Terrono classification by assessing the active range of motion of the interphalangeal joint prior to assessing the passive range of movement of the metacarpophalangeal joint. An active range of movement of the interphalangeal joint was strongly correlated with hand function. In 55 hands that we treated between 2004 and 2015, we compared the modified classification with the original Terrono classification. Our modified classification could detect advanced deformity earlier, and was more strongly correlated with hand function. Additionally, correlation analysis showed that advanced Type 1 deformity should be treated first, even in cases with severe ulnar drift. Our results suggest that the modified classification may benefit the treatment of Type 1 deformity, including joint-preserving surgery. Level of evidence: III.

Degeneration of the Sacroiliac Joint in Hip Osteoarthritis Patients: A Three-Dimensional Image Analysis.

OBJECTIVE: The sacroiliac joint is an important source of low back pain and may be influenced by pathologies in adjoining structures such as the hip or the spine. This study aimed to investigate the influence of hip osteoarthritis on sacroiliac joint degeneration by examining the sacroiliac joints of hip osteoarthritis patients, focusing on the localization and quantity of vacuum phenomena. MATERIALS AND METHODS: The preoperative computed tomography (CT) of 31 female hip replacement candidates (mean age 69.1) and pelvic CT of 34 age-matched controls (mean age 67.9) were used to reconstruct the sacroiliac joints three-dimensionally. The degeneration score of the sacroiliac joints on axial view, as well as the location and volume of vacuum phenomena in the three-dimensionally reconstructed sacroiliac joints, were analyzed. RESULTS: The total sacroiliac joint degeneration scores were similar in hip osteoarthritis patients and controls but the breakdown of the score revealed that joint space narrowing and vacuum phenomena in the sacroiliac joint increase in hip osteoarthritis, while osteophytes decrease. Three-dimensional reconstruction revealed that the volume of vacuum phenomena in the sacroiliac joint was significantly larger in the hip osteoarthritis group and the vacuum areas were localized in the antero-superior region of the sacroiliac joint. CONCLUSION: Our results suggest that hip osteoarthritis and sacroiliac joint degeneration are related, and that with further investigation, the sacroiliac joint may become a new treatment target in hip osteoarthritis.

A new assessment tool for ulnar drift in patients with rheumatoid arthritis using pathophysiological parameters of the metacarpophalangeal joint.

OBJECTIVES: To establish a new assessment tool for ulnar drift (UD) in rheumatoid arthritis (RA). METHODS: We established an observational cohort of 67 patients (134 rheumatoid hands) beginning in 2004. Fifty-two patients (100 hands) had follow-up in 2009 and 37 patients (63 hands) completed follow-up in 2015. UD was evaluated with the Fearnley classification and our scoring method, which assesses four parameters of the metacarpophalangeal joint. Cluster analysis using UD parameters divided hands into groups. Changes in UD over time, correlation of the Fearnley stage and cluster with a functional assessment, and reliability of the parameters were analyzed. RESULTS: UD increased and worsened over time according to the trend test. A dendrogram indicated five clusters would be appropriate. Both the Fearnley classification and cluster were associated with function; however, our method related to function more linearly (R-squared: 0.42). We found one type of hand in which bone destruction precedes the joint dislocation and one type in which joint dislocation progresses with little deviation during UD progression. CONCLUSION: Our UD evaluation appeared to be simple and related to function. Additionally, it enables dividing UD hands into five stages. Thus, our assessment should be beneficial compared to the Fearnley classification in considering treatments of UD.

A PTH-responsive circadian clock operates in ex vivo mouse femur fracture healing site.

The circadian clock contains clock genes including Bmal1 and Period2, and it maintains an interval rhythm of approximately 24 hours (the circadian rhythm) in various organs including growth plate and articular cartilage. As endochondral ossification is involved not only in growth plate but also in fracture healing, we investigated the circadian clock functions in fracture sites undergoing healing. Our fracture models using external fixation involved femurs of Period2::Luciferase knock-in mice which enables the monitoring of endogenous circadian clock state via bioluminescence. Organ culture was performed by collecting femurs, and fracture sites were observed using bioluminescence imaging systems. Clear bioluminescence rhythms of 24-hour intervals were revealed in fracture healing sites. When parathyroid hormone (PTH) was administered to fractured femurs in organ culture, peak time of Period2::Luciferase activity in fracture sites and growth plates changed, indicating that PTH-responsive circadian clock functions in the mouse femur fracture healing site. While PTH is widely used in treating osteoporosis, many studies have reported that it contributes to improvement of fracture healing. Future studies of the role of this local clock in wound healing may reveal a novel function of the circadian timing mechanism in skeletal cells.

Prediction of radiographic progression in synovitis-positive joints on maximum intensity projection of magnetic resonance imaging in rheumatoid arthritis.

Contrast-enhanced magnetic resonance imaging with maximum intensity projection (MRI-MIP) is an easy, useful imaging method to evaluate synovitis in rheumatoid hands. However, the prognosis of synovitis-positive joints on MRI-MIP has not been clarified. The aim of this study was to evaluate the relationship between synovitis visualized by MRI-MIP and joint destruction on X-rays in rheumatoid hands. The wrists, metacarpophalangeal (MP) joints, and proximal interphalangeal (PIP) joints of both hands (500 joints in total) were evaluated in 25 rheumatoid arthritis (RA) patients. Synovitis was scored from grade 0 to 2 on the MRI-MIP images. The Sharp/van der Heijde score and Larsen grade were used for radiographic evaluation. The relationships between the MIP score and the progression of radiographic scores and between the MIP score and bone marrow edema on MRI were analyzed using the trend test. As the MIP score increased, the Sharp/van der Heijde score and Larsen grade progressed severely. The rate of bone marrow edema-positive joints also increased with higher MIP scores. MRI-MIP imaging of RA hands is a clinically useful method that allows semi-quantitative evaluation of synovitis with ease and can be used to predict joint destruction.

Parathyroid hormone resets the cartilage circadian clock of the organ-cultured murine femur.

BACKGROUND AND PURPOSE: The circadian clock governs endogenous day-night variations. In bone, the metabolism and growth show diurnal rhythms. The circadian clock is based on a transcription-translation feedback loop composed of clock genes including Period2 (Per2), which encodes the protein period circadian protein homolog 2. Because plasma parathyroid hormone (PTH) levels show diurnal variation, we hypothesized that PTH could carry the time information to bone and cartilage. In this study, we analyzed the effect of PTH on the circadian clock of the femur. PATIENTS AND METHODS: Per2::Luciferase (Per2::Luc) knock-in mice were used and their femurs were organ-cultured. The bioluminescence was measured using photomultiplier tube-based real-time bioluminescence monitoring equipment or real-time bioluminescence microscopic imaging devices. PTH or its vehicle was administered and the phase shifts were calculated. Immunohistochemistry was performed to detect PTH type 1 receptor (PTH1R) expression. RESULTS: Real-time bioluminescence monitoring revealed that PTH reset the circadian rhythm of the Per2::Luc activity in the femurs in an administration time-dependent and dose-dependent manner. Microscopic bioluminescence imaging revealed that Per2::Luc activity in the growth plate and the articular cartilage showed that the circadian rhythms and their phase shifts were induced by PTH. PTH1R was expressed in the growth plate cartilage. INTERPRETATION: In clinical practice, teriparatide (PTH (1-34)) treatment is widely used for osteoporosis. We found that PTH administration regulated the femoral circadian clock oscillation, particularly in the cartilage. Regulation of the local circadian clock by PTH may lead to a more effective treatment for not only osteoporosis but also endochondral ossification in bone growth and fracture repair.

MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development.

Mastermind-like 1 (MAML1) is a transcriptional co-activator in the Notch signaling pathway. Recently, however, several reports revealed novel and unique roles for MAML1 that are independent of the Notch signaling pathway. We found that MAML1 enhances the transcriptional activity of runt-related transcription factor 2 (Runx2), a transcription factor essential for osteoblastic differentiation and chondrocyte proliferation and maturation. MAML1 significantly enhanced the Runx2-mediated transcription of the p6OSE2-Luc reporter, in which luciferase expression was controlled by six copies of the osteoblast specific element 2 (OSE2) from the Runx2-regulated osteocalcin gene promoter. Interestingly, a deletion mutant of MAML1 lacking the N-terminal Notch-binding domain also enhanced Runx2-mediated transcription. Moreover, inhibition of Notch signaling did not affect the action of MAML1 on Runx2, suggesting that the activation of Runx2 by MAML1 may be caused in a Notch-independent manner. Overexpression of MAML1 transiently enhanced the Runx2-mediated expression of alkaline phosphatase, an early marker of osteoblast differentiation, in the murine pluripotent mesenchymal cell line C3H10T1/2. MAML1(-/-) embryos at embryonic day 16.5 (E16.5) had shorter bone lengths than wild-type embryos. The area of primary spongiosa of the femoral diaphysis was narrowed. At E14.5, extended zone of collagen type II alpha 1 (Col2a1) and Sox9 expression, markers of chondrocyte differentiation, and decreased zone of collagen type X alpha 1 (Col10a1) expression, a marker of hypertrophic chondrocyte, were observed. These observations suggest that chondrocyte maturation was impaired in MAML1(-/-) mice. MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development.

DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Krüppel-like factor 15 gene expression.

Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (GR) in adipogenesis have not been well characterized yet. Here, we show that inhibition of GR activity using the GR antagonist RU486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (MEF) differentiation into adipocytes. Moreover, in MEFs isolated from GR knockout (GR(null)) and GR(dim) mice deficient in GR DNA-binding activity, adipogenesis was blocked. We identified glucocorticoid response element sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation. Moreover, transfection of MEFs with siRNA for KLF15 significantly attenuated the expressions of adipogenic-marker genes and the lipid accumulation. Our results provide a new mechanism for understanding glucocorticoids-dependent adipogenesis and that GR promotes adipogenesis via KLF15 gene expression as a transcriptional direct target.

The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line.

Using deep sequencing (deepCAGE), the FANTOM4 study measured the genome-wide dynamics of transcription-start-site usage in the human monocytic cell line THP-1 throughout a time course of growth arrest and differentiation. Modeling the expression dynamics in terms of predicted cis-regulatory sites, we identified the key transcription regulators, their time-dependent activities and target genes. Systematic siRNA knockdown of 52 transcription factors confirmed the roles of individual factors in the regulatory network. Our results indicate that cellular states are constrained by complex networks involving both positive and negative regulatory interactions among substantial numbers of transcription factors and that no single transcription factor is both necessary and sufficient to drive the differentiation process.

Identification of NR5A1 (SF-1/AD4BP) gene expression modulators by large-scale gain and loss of function studies.

Nuclear receptor subfamily 5, group A, member 1 (NR5A1 previously known as SF-1/AD4BP) is a transcription factor involved in the development of adrenal/gonadal tissues and steroidogenic lineage cell differentiation in adult somatic stem cells. To understand the cellular signaling network that regulates NR5A1 gene expression, loss of function screening with an siRNA kinome library, and gain of function screening with an addressable full-length cDNA library representing one quarter of the human genome was carried out. The NR5A1 gene expression was activated in mesenchymal stem cells by siRNA directed against protein kinase C (PKC)-delta, erb-B3, RhoGAP (ARHGAP26), and hexokinase 2, none of which were previously known to be involved in the NR5A1 gene expression. Among these, we identified crosstalk between erb-B3 and PKC-delta signaling cascades. In addition, the gain of function studies indicated that sex-determining region Y (SRY)-box 15 (SOX15), TEA domain family member 4, KIAA1257 (a gene of unknown function), ADAM metallopeptidase with thrombospondin type 1 motif 6, Josephin domain containing 1, centromere protein, TATA box-binding protein-associated factor 5-like RNA polymerase, and inducible T-cell co-stimulator activate NR5A1 gene expression. These results provide new insights into the molecular mechanisms of NR5A1 gene expression.

Increased microvascular permeability in early stage of dextran sulfate sodium-induced colitis: its interaction with lansoprazole binding sites.

To clarify the microvascular changes and the effector sites of lansoprazole during the formation of colitis, the dextran sulfate sodium (DSS)-induced colitis was induced by the oral administration for 3 and 7 days. The alteration of the microvascular permeability was estimated by the intraaortic infusion of FITC-dextran. The effector sites of 3H-lansoprazole were examined by the intraaortic infusion of the radiolabelled compound and the autoradiographic procedure of water-soluble compounds. As a result, marked increase of the microvascular permeability was detected three days after DSS treatment near the inflammatory cells in the tip portion of the colonic mucosa. 3H-lansoprazole in the control rat colon was localized in the goblet cells, while in DSS-treated rats, 3H-lansoprazole was accumulated in the cytoplasm of the mesenchymal cells, and most of them coincided with polymorphonuclear leucocytes and macrophages.

[Genome-wide analysis for transcriptional regulation of chondrogenesis-related genes].

Transcriptional factor Sox9 plays a central role in development of chondrogenesis with stage specificity and in tissue specificity. Sox9 with a number of transcriptional cofactors is a critical regulator in genes such as COL2, chondorocyte specific gene. We report here our new large scale approaches : 1) Whole mount in situ hybridization (WISH), 2) High through-put human cDNA transfection assay. These genome-wide approaches have a possibility of discovery for new transcription factors in chondrogenesis.

Lansoprazole binding to the neutrophils in dextran sulfate sodium-induced rat colitis.

To clarify the effector sites of lansoprazole in the colonic mucosa during the formation of colitis, dextran sulfate sodium-induced colitis was induced by the oral administration of 3% aqueous solution for 3 and 7 days. The effector sites of [3H]lansoprazole were examined by the intra-aortic infusion of the radiolabelled compound and the autoradiographic tracing of water-soluble compounds. As a result, the [3H]lansoprazole binding in the control rat colon was negligible, while in dextran sulfate sodium-treated rats specific binding sites of [3H]lansoprazole were recognized in the cytoplasm of the mesenchymal cells, and most of them coincided with polymorphonuclear leucocytes and macrophages.

Pelvic lymphocyst infection associated with maternally inherited diabetes mellitus.

A 45-year-old woman with 20-year history of diabetes mellitus was admitted to our hospital because of high fever and abdominal pain. Radical hysterectomy and bilateral pelvic lymphadenectomy had been performed 4 months before admission for invasive cervical cancer. On admission, elastic hard tumors were palpable in the lower abdomen. Laboratory examination showed positive C-reactive protein (CRP), anemia and renal dysfunction. Computed tomography (CT) revealed several lymphocysts in the pelvis. She was diagnosed with infection of pelvic lymphocysts. Since her mother also had diabetes associated with deafness, we examined mitochondrial DNA in leukocytes and detected an A to G transition at the nucleotide position of 3243 (A3243G mutation). She was diagnosed as maternally inherited diabetes mellitus and deafness (MIDD). Puncture of the cysts followed by administration of antibiotics resulted in marked improvement of symptoms and laboratory findings. This is a rare case of pelvic lymphocyst infection in a patient with a mitochondrial disorder. Although the exact mechanism of infection is not clear, MIDD may represent an unusual risk factor for infection, and further investigation is necessary to assess the influence of mitochondrial dysfunction on the immune system. Pelvic lymphocyst infection should be considered in the differential diagnosis of abdominal pain and fever in patients with MIDD after abdominal surgery.