BACKGROUNDA previous phase I study showed that the infusion of autologous Tregs expanded ex vivo into patients with recent-onset type 1 diabetes (T1D) had an excellent safety profile. However, the ...majority of the infused Tregs were undetectable in the peripheral blood 3 months postinfusion (Treg-T1D trial). Therefore, we conducted a phase I study (TILT trial) combining polyclonal Tregs and low-dose IL-2, shown to enhance Treg survival and expansion, and assessed the impact over time on Treg populations and other immune cells.METHODSPatients with T1D were treated with a single infusion of autologous polyclonal Tregs followed by one or two 5-day courses of recombinant human low-dose IL-2 (ld-IL-2). Flow cytometry, cytometry by time of flight, and 10x Genomics single-cell RNA-Seq were used to follow the distinct immune cell populations' phenotypes over time.RESULTSMultiparametric analysis revealed that the combination therapy led to an increase in the number of infused and endogenous Tregs but also resulted in a substantial increase from baseline in a subset of activated NK, mucosal associated invariant T, and clonal CD8+ T cell populations.CONCLUSIONThese data support the hypothesis that ld-IL-2 expands exogenously administered Tregs but also can expand cytotoxic cells. These results have important implications for the use of a combination of ld-IL-2 and Tregs for the treatment of autoimmune diseases with preexisting active immunity.TRIAL REGISTRATIONClinicalTrials.gov NCT01210664 (Treg-T1D trial), NCT02772679 (TILT trial).FUNDINGSean N. Parker Autoimmune Research Laboratory Fund, National Center for Research Resources.
Summary
Using the nationwide health insurance claims database, we found that the age-standardized hip fracture incidence rates in Japan indicated significant increase in males but no significant ...change in females during 2012–2015. The fracture risk in subjects aged 75–84 years indicated decrease in females but no change in males.
Introduction
Nationwide registry data on hip fractures have not yet been established in Japan. Using the newly developed National Database of Health Insurance Claims (NDB), which covers the entire Japanese population, we investigated the incidence rates of hip fractures and the associated regional differences. We also assessed the frequency of osteoporosis prescriptions, bone turnover marker (BTM) level, and bone mineral density (BMD) measurements.
Methods
The annual numbers of hip fractures, osteoporosis prescriptions, and BTM level and BMD measurements by prefecture from 2012 to 2015 were obtained from NDB data. We calculated the standardized claims-data ratio (SCR) in each prefecture.
Results
The age-standardized incidence rates from 2012 to 2015 indicated no significant change in females and significant increase in males (
p
value for trend; 0.920, 0.002, respectively). The fracture risk decreased in females aged 75–84 years and indicated no increase in females aged 85–89 years during 2012–2015, while the fracture risk indicated no change in males aged 75–84 years and increased in males aged 85–89 years. The frequency of osteoporosis prescriptions, BTM level measurements, and BMD measurements in the general population in the corresponding period increased with statistical or marginal significance in females and males. West–east regional differences were observed in the incidence rates; the highest SCR values in the western prefectures were approximately double the lowest values in the eastern prefectures.
Conclusions
The age-standardized hip fracture incidence rates indicated no significant change in females and significant increase in males in Japan from 2012 to 2015.
Abstract
Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a ...blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response.
We report that prospectively isolated, human CNS stem cells grown as neurospheres (hCNS-SCns) survive, migrate, and express differentiation markers for neurons and oligodendrocytes after longterm ...engraftment in spinal cord-injured NOD-scid mice. hCNS-SCns engraftment was associated with locomotor recovery, an observation that was abolished by selective ablation of engrafted cells by diphtheria toxin. Remyelination by hCNS-SCns was found in both the spinal cord injury NOD-scid model and myelin-deficient shiverer mice. Moreover, electron microscopic evidence consistent with synapse formation between hCNS-SCns and mouse host neurons was observed. Glial fibrillary acidic protein-positive astrocytic differentiation was rare, and hCNS-SCns did not appear to contribute to the scar. These data suggest that hCNS-SCns may possess therapeutic potential for CNS injury and disease.
Summary
FRAX® is widely used to evaluate fracture risk of individuals in clinical settings. However, FRAX® prediction accuracy is not sufficient, and improvement is desired. Trabecular bone score, a ...bone microarchitecture index, may improve FRAX® prediction accuracy for major osteoporotic fractures in community-dwelling elderly Japanese men.
Introduction
To improve fracture risk assessment in clinical settings, we evaluated whether the combination of FRAX® and Trabecular Bone Score (TBS) improves the prediction accuracy of major osteoporotic fractures (MOFs) in elderly Japanese men compared to FRAX® alone.
Methods
Two thousand and twelve community-dwelling men aged ≥65 years completed the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Baseline Study comprising lumbar spine (LS) and femoral neck areal bone mineral density (aBMD) measurements, and interviews regarding clinical risk factors required to estimate 10-year risk of MOF (hip, spine, distal forearm, and proximal humerus) using the Japanese version of FRAX® (v.3.8). TBS was calculated for the same vertebrae used for LS-aBMD with TBS iNsight software (v.2.1). MOFs that occurred during the follow-up period were identified by interviews or mail and telephone surveys. Prediction accuracy of a logistic model combining FRAX® score and TBS compared to FRAX® alone was evaluated by area under receiver-operating characteristic curves (AUCs), as well as category-free integrated discrimination improvement (IDI) and net reclassification improvement (NRI).
Results
We identified 22 men with MOFs during 8140 person-years (PY) of follow-up among 1872 men; 67 men who suffered from fractures other than MOFs were excluded. Participants with MOFs had significantly lower TBS (
p
= 0.0015) and higher FRAX® scores (
p
= 0.0089) than those without. IDI and NRI showed significant improvements in reclassification accuracy using FRAX® plus TBS compared to FRAX® alone (IDI 0.006 (
p
= 0.0362), NRI 0.452 (
p
= 0.0351)), although no difference was observed in AUCs between the two.
Conclusions
TBS may improve MOF prediction accuracy of FRAX® for community-dwelling elderly Japanese men.
Summary
We found that community-dwelling women with 25-hydroxyvitamin D levels <20 ng/mL compared to levels ≥20 ng/mL indicated increased risks for clinical, non-vertebral, and fragility fractures ...during 5 years. Furthermore, the increased risks of non-vertebral fractures remained significant in 10 and 15 years after adjusting for age and bone mineral density.
Introduction
We examined whether total 25-hydroxyvitamin D (25OHD) levels are associated with fracture risk over 15 years in a Japanese female cohort.
Methods
Of 1437 community-dwelling women aged ≥50 years in the baseline survey, 1236 provided information regarding fractures during a 15-year follow-up period. The analysis included 1211 women without early menopause or diseases affecting bone metabolism.
Results
Over 15 years, 269 clinical (224 non-vertebral, 149 fragility) fracture events were confirmed. Incidence rates categorized by 25(OH)D levels (<10, 10–20, 20–30, and ≥30 ng/mL) indicated a significant divergence for any clinical fractures in 5 years (log rank test
p
= 0.016) and for non-vertebral fractures in 5, 10, and 15 years (
p
< 0.001,
p
= 0.001,
p
= 0.017, respectively). Hazard ratios (HRs) for 25(OH)D levels <10 and 10–20 ng/mL compared to levels ≥30 ng/mL during 5 years indicated significances for clinical fractures (HR 4.93 with
p
= 0.009, HR 3.00 with
p
= 0.034) and for non-vertebral fractures (HR 6.55 with
p
= 0.005, HR 3.49 with
p
= 0.036). Those with levels <20 ng/mL compared to those with levels ≥20 ng/mL indicated significant increased risks for clinical fractures (HR 1.72 with
p
= 0.010), non-vertebral fractures (HR 2.45 with
p
< 0.001), and fragility fractures (HR 2.00 with
p
= 0.032) in 5 years. The HR of non-vertebral fractures for levels <20 ng/mL remained significant during 15 years (HR 1.42 with
p
= 0.012) after adjustment for age and femoral neck bone mineral density.
Conclusions
Low 25(OH)D levels, especially <20 ng/mL, were associated with elevated fracture risks in Japanese women.
Summary
Risk of fracture due to glucocorticoid-induced osteoporosis (GIO) can be reduced by anti-osteoporosis (OP) medications. The proportion of patients on long-term glucocorticoid therapy who ...received anti-OP medications according to the GIO management guidelines has increased in recent years, but is still suboptimal.
Introduction
Adherence of physicians to guidelines for glucocorticoid (GC)-induced osteoporosis (GIO) management is currently unclear. This study aimed to clarify the state of guideline adherence by physicians in Japan and identify factors associated with guideline adherence using a nationwide health insurance claims database (NDBJ).
Methods
Patients aged ≥ 50 years who were prescribed GC for ≥ 90 days after 180 days without a GC prescription and who were followed up for osteoporosis (OP) management for the subsequent 360 days during the period spanning 2012–2018 were selected from the NDBJ. Guideline adherence was evaluated with the proportion of patients who received OP management as recommended by the Japanese guidelines. Information on previous vertebral and hip fractures, dementia, and polypharmacy was obtained. Factors associated with OP management were evaluated by logistic regression analysis.
Results
A total of 512,296 patients were considered to be at high risk of fracture according to the guidelines. Proportions of patients receiving OP management (BMD testing or anti-OP medications) have increased in recent years. In 2017, 33.7% of men and 55.3% of women received OP management in the initial 90 days of GC therapy. Female sex, previous anti-OP medications, polypharmacy, and higher GC dose were significantly associated with receiving OP management, while dementia showed an inverse association. A prior history of hip fracture, a strong risk factor for future fracture, was not significantly associated with receiving OP management.
Conclusions
Although guideline adherence by physicians has increased in recent years, it remains suboptimal. Further efforts to improve guideline adherence are necessary.
Trial registration number
The present study is not registered.
Summary
Trabecular bone score (TBS), a surrogate measure of bone microarchitecture, represents fracture risk independently of bone density. We present normative TBS values from a representative ...population study of Japanese women. This database would enhance our understanding of trabecular bone microarchitecture and improve osteoporosis management.
Introduction
TBS is a texture parameter that quantifies local variation in gray level distribution within dual-energy X-ray absorptiometry (DXA) images of the lumbar spine. While TBS is associated with fracture risk independently of areal bone mineral density (aBMD), normative TBS values have only been reported for Caucasian women. This study provides age-specific normative values of TBS from a representative sample of Japanese women.
Methods
We randomly selected 4,550 women aged 15–79 years from 7 areas throughout Japan. Women younger than 20 years and those with any medical history which might affect bone metabolism were excluded, and the remaining 3,069 with at least two assessable vertebrae from the first to the fourth vertebrae were subjected to analysis. TBS values were calculated from spine DXA images using TBS iNsight software (Med-Imaps, France). Age-related models of TBS were constructed using piecewise linear regression analysis.
Results
Participant age, body mass index (BMI), spine aBMD, and TBS (mean ± SD) were 48.7 ± 16.8 years, 22.9 ± 3.4, 0.888 ± 0.169 g/cm
2
, and 1.187 ± 0.137, respectively. A three-piece linear regression model of TBS on age explained 70.7 % of the total variance in TBS and comprised very small age-related changes in the youngest segment of the regression line, rapid loss in the middle segment, and small loss in the oldest segment. TBS was lower in Japanese women than in Caucasian women across all age ranges, with the difference increasing with age up through 65 years.
Conclusions
The normative values of TBS for Japanese women presented here would enhance our understanding of trabecular bone microarchitecture and help improve the management of osteoporosis.
Shiverer-immunodeficient (Shi-id) mice demonstrate defective myelination in the central nervous system (CNS) and significant ataxia by 2 to 3 weeks of life. Expanded, banked human neural stem cells ...(HuCNS-SCs) were transplanted into three sites in the brains of neonatal or juvenile Shi-id mice, which were asymptomatic or showed advanced hypomyelination, respectively. In both groups of mice, HuCNS-SCs engrafted and underwent preferential differentiation into oligodendrocytes. These oligodendrocytes generated compact myelin with normalized nodal organization, ultrastructure, and axon conduction velocities. Myelination was equivalent in neonatal and juvenile mice by quantitative histopathology and high-field ex vivo magnetic resonance imaging, which, through fractional anisotropy, revealed CNS myelination 5 to 7 weeks after HuCNS-SC transplantation. Transplanted HuCNS-SCs generated functional myelin in the CNS, even in animals with severe symptomatic hypomyelination, suggesting that this strategy may be useful for treating dysmyelinating diseases.
Objectives
Few prospective cohort studies have evaluated the relationship between dairy product intake frequency and risk of osteoporotic fractures in Asians. This study aimed to investigate the ...association between habitual dairy product intake and risk of osteoporotic fractures.
Design
Secondary analysis of prospective cohort study.
Setting
Five municipalities of Japan.
Participants
This study included 1,429 postmenopausal Japanese women (age ≥45 years at baseline).
Measurements
Baseline milk-intake frequency was obtained using nurse-administered questionnaires. Intakes of yogurt and cheese, and estimated calcium intake, were assessed using a validated food frequency questionnaire. Osteoporotic fracture was defined as a clinical fracture diagnosed using radiography. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.
Results
Over a median follow-up period of 15.1 years (interquartile range IQR, 10.1–15.4 years; total, 18,118 person-years), 172 women sustained at least one osteoporotic fracture. The proportions of participants with milk intakes <1, 1, and ≥2 cups/d were 34.4%, 48.0%, and 17.6%, respectively. After adjustment for age, frequency of yogurt intake, frequency of cheese intake, body mass index, history of osteoporotic fractures, and frequency of natto intake, the HRs compared with that for milk intake <1 cup/d were 0.71 (95% CI: 0.51–0.98) and 0.57 (95% CI: 0.35–0.92) for 1 cup/d and ≥2 cups/d, respectively. After adjustment for bone mineral density, HR significance for milk intakes ≥2 cups/d remained significant. Yogurt and cheese intakes were not related to the risk of osteoporotic fractures.
Conclusion
High habitual milk intake, but not a habitual yogurt or cheese intake is associated with a decreased risk of osteoporotic fractures, independent of bone mineral density, in postmenopausal Japanese women.
PDF
