Electrophysiological responses to seizurogenic compounds dependent on E/I balance in human iPSC-derived cortical neural networks.

Construction of in vitro functional assay systems using human-induced pluripotent stem cells (iPSCs) as indicators for evaluating seizure liability of compounds has been anticipated. Imbalance of excitation/inhibition (E/I) inputs triggers seizure; however, the appropriate ratio of E/I neurons for evaluating seizure liability of compounds in a human iPSC-derived neural network is unknown. Here, five neural networks with varying E/I ratios (88/12, 84/16, 74/26, 58/42, and 48/52) were constructed by altering the ratios of glutamatergic (E) and GABA (I) neurons. The responsiveness of each network against six seizurogenic compounds and two GABA receptor agonists was then examined by using six representative parameters. The 52% GABA neuron network, which had the highest ratio of GABA neurons, showed the most marked response to seizurogenic compounds, however, it suggested the possibility of producing false positives. Moreover, analytical parameters were found to vary with E/I ratio and to differ for seizurogenic compounds with different mechanism of action (MoA) even at the same E/I ratio. Clustering analysis using six parameters showed the balance of 84/16, which is the closest to the biological balance, was the most suitable for detection of concentration-dependent change and classification of the MoA of seizurogenic compounds. These results suggest the importance of using a human-iPSC-derived neural network similar to the E/I balance of the living body in order to improve the prediction accuracy in the in vitro seizure liability assessment.

Cumulative incidence of femoral localized periosteal thickening (beaking) preceding atypical femoral fractures in patients with rheumatoid arthritis.

The incidence of localized periosteal thickening (LPT, also termed beaking) of the lateral cortex that often precedes an atypical femoral fracture (AFF) was not high in patients with rheumatoid arthritis (RA) but incomplete AFFs developed in two patients. Higher-dose prednisolone was a significant risk factor for LPT in patients with RA. INTRODUCTION: Atypical femoral fractures (AFFs) are stress fractures; bisphosphonate (BP) use is a major risk factor for the development of such fractures. Localized periosteal thickening (LPT, also termed beaking) of the lateral cortex often precedes a complete or incomplete AFF. We evaluated the incidence of latent LPT in patients with rheumatoid arthritis (RA), to evaluate LPT progression, and to define LPT risk factors. METHODS: A total of 254 patients with RA were included; all underwent annual X-ray evaluation, dual-energy X-ray absorptiometry, and analyses of serum and bone metabolic markers for 2-3 years. LPT of the lateral cortex was sought in femoral X-rays. RESULTS: The incidence of LPT was 2.4% (6/254). Among patients on both BP and prednisolone (PSL) at enrollment, the incidence was 2.3% (3/131). Two femurs of two patients with LPT developed incomplete AFFs; LPT was extensive and associated with endosteal thickening. One patient had been on BP and PSL and microscopic polyangiitis was comorbidity. The other was on a selective estrogen receptor modulator and PSL. A daily PSL dose >5 mg (OR 11.4; 95%CI 2.15-60.2; p = 0.004) and higher-dose methotrexate (OR 1.22; 95%CI 1.01-1.49; p = 0.043) were significant risk factors for LPT. CONCLUSIONS: The incidence of latent LPT was not high (2.4%) but incomplete AFFs developed in two RA patients. Higher-dose PSL because of a comorbid disease requiring glucocorticoid treatment other than RA or refractory RA were risk factors for LPT; X-ray screening for latent LPT would usefully prevent complete AFFs.

Multiple vitamin deficiencies additively increase the risk of incident fractures in Japanese postmenopausal women.

The associations of multiple vitamin deficiencies on incident fractures were uncertain, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. The number of deficiencies was additively associated with incident fracture after adjustment for possible confounding factors including the treatment of osteoporosis. INTRODUCTION: To evaluate the associations of multiple vitamin deficiencies on incident fractures, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. METHODS: This analysis used a subset of the ongoing cohort maintained by a primary care institution. Inclusion criteria of the present study were postmenopausal women aged ≥ 50 years, without vitamin supplementation and secondary osteoporosis. Baseline serum concentrations of 25-hydroxyvitamin D (25(OH)D), undercarboxylated osteocalcin (ucOC), and homocysteine (Hcy) were measured to assess vitamin D, vitamin K, and vitamin B, respectively. Since 25(OH) D positively relates to vitamin D, ucOC and Hcy negatively relate to vitamin K and vitamin B nutrients, respectively, the subjects with lower (25(OH)D) or higher (ucOC or Hcy) values than each median value was defined as subjects with the corresponding vitamin deficiency. Subjects were divided into four groups according to the number of deficiency: no deficiency, single deficiency, double deficiencies, and triple deficiencies. Relationships between the vitamin deficiencies and incident fractures were evaluated by Cox regression analysis. RESULTS: A total of 889 subjects were included in this analysis; their mean and SD age was 68.3 ± 9.5 years, and the follow-up period was 6.3 ± 5.1 years. The numbers of subjects in the four groups were 139 (15.6%), 304 (34.2%), 316 (35.5%), and 130 (14.6%) for the groups with no, single, double, and triple deficiencies, respectively. Incident fractures were observed in 264 subjects (29.7%) during the observation period. The number of deficiencies was significantly associated with incident fracture (hazard ratio 1.25, 95% confidence interval 1.04-1.50, P = 0.018) after adjustment for possible confounding factors including the treatment of osteoporosis. CONCLUSION: Accumulation of vitamin deficiencies was related to incident fractures.

Characterization of patients with systemic lupus erythematosus who meet the diagnostic criteria for TAFRO syndrome.

Purpose TAFRO syndrome is a novel disorder manifesting as fever, anasarca, thrombocytopenia, renal insufficiency and organomegaly, and its etiology has not been clarified. The aim of this study was to elucidate similarities and differences between systemic lupus erythematosus (SLE) and TAFRO syndrome. Methods We examined 46 consecutive patients diagnosed with SLE and determined whether they meet the proposed diagnostic criteria for TAFRO syndrome (2015 version). Results Of the 46 patients with SLE, four (8.7%) also met the TAFRO syndrome criteria (TAFRO-like group). All patients in the TAFRO-like group were males, and their mean age was significantly higher than that of the non-TAFRO group (67.5 ± 8.7 vs. 39.3 ± 18.1 years, p = 0.004). C-reactive protein and γ-glutamyl transpeptidase levels were significantly higher, and frequencies of anti-dsDNA and anti-Sm antibodies were significantly lower in the TAFRO-like than non-TAFRO group. Elder cases (onset age ≥ 50 years) met significantly more categories of the diagnostic criteria for TAFRO syndrome than did those with younger cases. Conclusions Several patients with SLE, especially elder cases, showed features similar to those of TAFRO syndrome. Although exclusion of SLE is needed in the diagnostic criteria for TAFRO syndrome, TAFRO syndrome-like SLE should be considered.

Intake of omega-3 fatty acids contributes to bone mineral density at the hip in a younger Japanese female population.

This study investigated the relationships between intakes of polyunsaturated fatty acids, omega-3 fatty acids, and omega-6 fatty acids and bone mineral density in Japanese women aged 19 to 25 years. Intakes of omega-3 fatty acids (n-3) were positively associated with peak bone mass at the hip. INTRODUCTION: Lifestyle factors such as physical activity and nutrition intake are known to optimize the peak bone mass (PBM). Recently, intake of polyunsaturated fatty acids (PUFAs) has been reported to contribute to bone metabolism. In this study, the relationships of intakes of n-3 and omega-6 (n-6) fatty acids with PBM were evaluated in Japanese female subjects. METHODS: A total of 275 healthy female subjects (19-25 years) having PBM were enrolled, and lumbar and total hip bone mineral density (BMD) and bone metabolic parameters were measured. Dietary intakes of total energy, total n-3 fatty acids, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and total n-6 fatty acids were assessed by a self-administered questionnaire. Physical activity information was also assessed. RESULTS: The mean ± SD age was 20.6 ± 1.4 years, and BMI was 21.2 ± 2.7 kg/m2. BMI and serum bone alkaline phosphatase contributed significantly to lumbar BMD on multiple regression analysis. Intake of n-3 fatty acids and physical activity were also significantly related to total hip BMD. Using EPA or DHA instead of total n-3 fatty acids in the model did not result in a significant result. CONCLUSION: Adequate total n-3 fatty acid intake may help maximize PBM at the hip.

High and pointed type of femoral localized reaction frequently extends to complete and incomplete atypical femoral fracture in patients with autoimmune diseases on long-term glucocorticoids and bisphosphonates.

Once a localized reaction (beaking) was detected, discontinuation of bisphosphonates (BPs) and switching to vitamin D supplementation or teriparatide therapy effectively improved its shape. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete atypical femoral fracture increased and consideration of prophylactic fixation for such patients was required. INTRODUCTION: Femoral localized reaction (localized periosteal thickening of the lateral cortex, beaking) is reported to precede atypical femoral fractures (AFFs) and to develop in 8-10% of patients with autoimmune diseases taking BPs and glucocorticoids. The aims of the present study were to retrospectively investigate the shapes of localized reaction to consider how to manage the condition. METHODS: Twenty femora of 12 patients with autoimmune diseases who were on BPs and glucocorticoids exhibited femoral localized reaction. The heights of localized reaction were measured and the shapes classified as pointed, arched, and other. Localized reaction changes were divided into three categories: deterioration, no change, and improvement. A severe form of localized reaction was defined; this was associated with prodromal pain, de novo complete AFF, or incomplete AFF with a fracture line at the localized reaction. RESULTS: The mean height of localized reaction was 2.3 ± 0.8 mm (range, 1.0-3.7 mm) and the pointed type was 35%. Localized reaction was significantly higher (3.3 ± 0.8 vs. 2.1 ± 0.7 mm; p = 0.003) and the pointed type more common (78 vs. 27%; p = 0.035) in those with the severe form of localized reaction. Seven patients with localized reactions discontinued BPs just after localized reaction was detected, but five continued on BPs for 2 years. Localized reaction deterioration was more common in patients who continued than discontinued BPs (100 vs. 29%; p = 0.027). After 2 years, all patients had discontinued BPs and localized reaction did not deteriorate further in any patient. CONCLUSIONS: Once a localized reaction was detected, discontinuation of BPs and switching to vitamin D supplementation or teriparatide therapy effectively improved it. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete AFF increased and consideration of prophylactic fixation for such patients was required.

Treatment responses with once-weekly teriparatide therapy for osteoporosis.

UNLABELLED: Monitoring bone mineral density is useful to assess treatment response for osteoporosis, but it does not always reflect fracture prevention. Two types of bone mineral density thresholds were used to analyze data from a once-weekly teriparatide trial, and they appear to be useful indicators of treatment success for osteoporosis. INTRODUCTION: This study aimed to clarify whether the criteria of treatment response could be used to evaluate treatment success with once-weekly teriparatide. METHODS: The data of subjects whose lumbar or femoral neck bone mineral density (BMD) was measured in the TOWER study were included. The least significant change (LSC) and the absolute change were used as the criteria for judgment of treatment success. The correlation between the incidence of fractures and the treatment response was also assessed. RESULTS: There was no significant difference in baseline characteristics between the placebo and teriparatide groups. Once-weekly teriparatide therapy for 72 weeks showed treatment success in 79.2 % of the subjects for lumbar BMD and 44.1 % for femoral neck BMD by LSC and in 50.5 and 39.6 % by absolute change, respectively. A lower incidence of vertebral fracture was observed in patients who achieved treatment success for lumbar BMD. With the LSC, some treatment success was observed in the early phase of treatment, and it increased with treatment duration. CONCLUSIONS: It appears that the LSC could be used as a surrogate efficacy indicator at an earlier stage of treatment, and the absolute criterion of -2.5SD was confirmed as a useful marker of long-term treatment success.

The cumulative incidence of and risk factors for latent beaking in patients with autoimmune diseases taking long-term glucocorticoids and bisphosphonates.

SUMMARY: The incidence of beaking, which has been reported to precede atypical femoral fracture, was high and increased over 2 years in patients with autoimmune diseases who were taking bisphosphonates and glucocorticoids. Regular femoral X-rays are strongly recommended to screen for beaking, and bisphosphonate drug holidays should be considered. INTRODUCTION: Atypical femoral fractures (AFFs) have been recently recognized as complications associated with bisphosphonate (BP) use. AFFs are considered to be stress fractures; localized periosteal thickening of the lateral cortex is often present at the fracture site; this thickening is termed "beaking." Beaking has been reported to precede AFF. The aims of the present study were to evaluate the incidence of latent beaking in patients with autoimmune diseases taking BPs and glucocorticoids and to identify risk factors for beaking. METHODS: A total of 125 patients with autoimmune diseases who were taking BPs and glucocorticoids was included; 116 patients underwent X-rays and analysis of serum and urine bone metabolic markers annually for 2 years. Mean patient age was 54.5 years; there were 105 (90.5%) females and the mean duration of disease was 13.2 years. Focal lateral cortical thickening in femoral X-rays was defined as beaking. RESULTS: Beaking was detected in 15 femora of 10 patients (8.0%) at the time of recruitment. Over the 2-year observation period, the incidence of beaking increased to 21 femora of 12 patients (10.3%), and a complete AFF at the location of beaking occurred in one patient. Beaking was associated with a longer duration of BP treatment (6.1 ± 1.0 years vs. 5.0 ± 2.9 years, p = 0.01). Age 40-60 years, BP therapy ≥4 years, and diabetes mellitus were significantly associated with beaking. CONCLUSIONS: The incidence of beaking was high, and increased over 2 years, in patients with autoimmune diseases who were taking BPs and glucocorticoids. Regular femoral X-rays are strongly recommended to screen for beaking. Long-term BP/glucocorticoid use was a risk factor for beaking in patients with autoimmune diseases; BP drug holidays should be considered.

Efficacy of weekly teriparatide does not vary by baseline fracture probability calculated using FRAX.

UNLABELLED: The aim of this study was to determine the efficacy of once-weekly teriparatide as a function of baseline fracture risk. Treatment with once-weekly teriparatide was associated with a statistically significant 79 % decrease in vertebral fractures, and in the cohort as a whole, efficacy was not related to baseline fracture risk. INTRODUCTION: Previous studies have suggested that the efficacy of some interventions may be greater in the segment of the population at highest fracture risk as assessed by the FRAX® algorithms. The aim of the present study was to determine whether the antifracture efficacy of weekly teriparatide was dependent on the magnitude of fracture risk. METHODS: Baseline fracture probabilities (using FRAX) were computed from the primary data of a phase 3 study (TOWER) of the effects of weekly teriparatide in 542 men and postmenopausal women with osteoporosis. The outcome variable comprised morphometric vertebral fractures. Interactions between fracture probability and efficacy were explored by Poisson regression. RESULTS: The 10-year probability of major osteoporotic fractures (without BMD) ranged from 7.2 to 42.2 %. FRAX-based hip fracture probabilities ranged from 0.9 to 29.3 %. Treatment with teriparatide was associated with a 79 % (95 % CI 52-91 %) decrease in vertebral fractures assessed by semiquantitative morphometry. Relative risk reductions for the effect of teriparatide on the fracture outcome did not change significantly across the range of fracture probabilities (p = 0.28). In a subgroup analysis of 346 (64 %) participants who had FRAX probabilities calculated with the inclusion of BMD, there was a small but significant interaction (p = 0.028) between efficacy and baseline fracture probability such that high fracture probabilities were associated with lower efficacy. CONCLUSION: Weekly teriparatide significantly decreased the risk of morphometric vertebral fractures in men and postmenopausal women with osteoporosis. Overall, the efficacy of teriparatide was not dependent on the level of fracture risk assessed by FRAX in the cohort as a whole.

Isolated intestinal neuronal dysplasia Type B (IND-B) in Japan: results from a nationwide survey.

PURPOSE: Intestinal neuronal dysplasia Type B (IND-B) has been proposed to be an allied disorder of Hirschsprung's disease (ADHD). The original histological criteria included hyperganglionosis, giant ganglia, ectopic ganglion cells and an increased AChE activity in the lamina propria. The criteria for IND-B have been gradually revised. The present diagnostic criteria are [1] more than 20 % of the submucosal ganglia contain nine or more ganglion cells and [2] the patient is older than 1 year. To clarify the current status of IND-B in Japan, a nationwide retrospective cohort study was performed. METHODS: Questionnaires were sent to 161 major institutes of pediatric surgery and gastroenterology in Japan. RESULTS: A total of 355 cases of ADHD were collected, including 18 cases of IND-B (5 %). Based on original criteria, 13 out of 18 cases were diagnosed as IND-B. However, only four cases met the current criteria. Three of the four patients (75 %) required pull-through operation. All of the patients exhibited giant ganglia and ganglioneuromatosis-like hyperplasia of the myenteric plexus. CONCLUSIONS: IND-B cases matching the current criteria are thought to be quite rare and they are associated with marked hyperplasia of the myenteric plexus. "True" IND-B is a rare and intractable disease.

Prognostic value of power doppler ultrasonography for equine superficial digital flexor tendon injury in thoroughbred racehorses.

The potential value of hypervascularity detected with power Doppler ultrasonography (PDU) within equine superficial digital flexor tendon (SDFT) as a prognostic factor of SDFT injury is not clear. The purpose of this study was to test the hypothesis that hypervascularity within SDFT is one of the risk factors for subsequent severe SDFT injury and to evaluate the prognostic value. A prospective cohort study of 97 Thoroughbred racehorses without any clinical signs of SDFT injury was conducted. Six variables of age, body weight, sex, the cross-sectional area of SDFT, PDU signal within SDFT and experience of steeplechase were assessed for the possibility of risk factors of subsequent SDFT injury in follow-up period of 1 year. Multivariable logistic regression analyses were used for assessment of the odds ratios (ORs) and 95 % confidence intervals (CIs) of SDFT injury. Multivariable logistic regression analysis revealed that the PDU signal within SDFT was a risk factor for the development of SDFT injury in follow-up period (P = 0.017). The adjusted OR of SDFT injury was significantly higher in PDU positive group than in PDU negative group (OR 3.17, 95 % CIs 1.20-8.35). Although further studies are required, these results would be useful for early detection and/or prevention of development for clinical severe SDFT injury.

Overweight/obesity and underweight are both risk factors for osteoporotic fractures at different sites in Japanese postmenopausal women.

UNLABELLED: This cohort study of 1,614 postmenopausal Japanese women followed for 6.7 years showed that overweight/obesity and underweight are both risk factors for fractures at different sites. Fracture risk assessment may be improved if fracture sites are taken into account and BMI is categorized. INTRODUCTION: The effect of body mass index (BMI) on fracture at a given level of bone mineral density (BMD) is controversial, since varying associations between BMI and fracture sites have been reported. METHODS: A total of 1,614 postmenopausal Japanese women were followed for 6.7 years in a hospital-based cohort study. Endpoints included incident vertebral, femoral neck, and long-bone fractures. Rate ratios were estimated by Poisson regression models adjusted for age, diabetes mellitus, BMD, prior fracture, back pain, and treatment by estrogen. RESULTS: Over a mean follow-up period of 6.7 years, a total of 254 clinical and 335 morphometric vertebral fractures, 48 femoral neck fractures, and 159 long-bone fractures were observed. Incidence rates of vertebral fracture in underweight and normal weight women were significantly lower than overweight or obese women by 0.45 (95 % confidence interval: 0.32 to 0.63) and 0.61 (0.50 to 0.74), respectively, if BMD and other risk factors were adjusted, and by 0.66 (0.48 to 0.90) and 0.70 (0.58 to 0.84) if only BMD was not adjusted. Incidence rates of femoral neck and long-bone fractures in the underweight group were higher than the overweight/obese group by 2.15 (0.73 to 6.34) and 1.51 (0.82 to 2.77) and were similar between normal weight and overweight/obesity. CONCLUSIONS: Overweight/obesity and underweight are both risk factors for fractures at different sites. Fracture risk assessment may be improved if fracture sites are taken into account and BMI is categorized.

Effect of Zr on microstructure of metallic glass coatings prepared by gas tunnel type plasma spraying.

Metallic glass is one of the most attractive advanced materials, and many researchers have conducted various developmental research works. Metallic glass is expected to be used as a functional material because of its excellent physical and chemical functions such as high strength and high corrosion resistance. However, the application for small size parts has been carried out only in some industrial fields. In order to widen the industrial application fields, a composite material is preferred for the cost performance. In the coating processes of metallic glass with the conventional deposition techniques, there is a difficulty to form thick coatings due to their low deposition rate. Thermal spraying method is one of the potential candidates to produce metallic glass composites. Metallic glass coatings can be applied to the longer parts and therefore the application field can be widened. The gas tunnel plasma spraying is one of the most important technologies for high quality ceramic coating and synthesizing functional materials. As the gas tunnel type plasma jet is superior to the properties of other conventional type plasma jets, this plasma has great possibilities for various applications in thermal processing. In this study, the gas tunnel type plasma spraying was used to form the metallic glass coatings on the stainless-steel substrate. The microstructure and surface morphology of the metallic glass coatings were examined using Fe-based metallic glass powder and Zr-based metallic glass powder as coating material. For the mechanical properties the Vickers hardness was measured on the cross section of both the coatings and the difference between the powders was compared.

Serum level of pepsinogen significantly associated with gastric distress induced by amino-bisphosphonates.

UNLABELLED: To elucidate whether serum levels of pepsinogens are associated with the occurrence of gastrointestinal adverse events induced by amino-bisphosphonates (amino-BP), the serum levels of pepsinogen were measured in amino-BP users. Our results indicate that measurement of pepsinogen I is useful in predicting gastric distress induced by amino-BP in osteoporosis. INTRODUCTION: To elucidate whether serum levels of pepsinogens are associated with the occurrence of gastrointestinal adverse events induced by amino-BP, the serum levels of pepsinogen I and II were measured in amino-BP users. METHODS: When the patients complained of gastric distress symptoms during the first 6 months after amino-BP use resulting in discontinuation of the drug, endoscopical examinations were performed to assess whether gastric lesions were present. A total of 223 amino-BP users were enrolled in the study, of which 47 patients refused to take the drug due to gastric distress symptoms. The remaining 176 patients did not complain of any gastric distress. RESULTS: Among 47 patients, eight patients showed obvious gastric lesions such as gastric or duodenal ulcers and acute gastric mucosal lesions in the endoscopical examination. The remaining 39 patients did not show any gastric lesions. The possible confounding factors, such as a Helicobactor pylori infection or concurrent use of ulcerogenic agents, did cause not affect gastric distress in amino-BP users. The serum pepsinogen I level was significantly associated with severity of the gastric lesion 46.8 ± 27.7, 60.8 ± 32.4, and 103.4 ± 49.2 ng/ml for patients without any gastric distress, with gastric distress accompanied no gastric lesions, and with gastric distress accompanied gastric lesions, respectively. CONCLUSIONS: ROC analysis revealed that the cutoff value of pepsinogen I for expectation of gastric regions was 76.8 ng/ml. The results clearly indicate that measurement of pepsinogen I may be useful in predicting gastric distress induced by amino-BP in osteoporosis.

Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1-34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys.

UNLABELLED: Improvements in total content of enzymatic cross-linking, the ratio of hydroxylysine-derived enzymatic cross-links, and non-enzymatic advanced glycation end product cross-link formation from once-weekly administration of hPTH(1-34) for 18 months in OVX cynomolgus monkeys contributed to the improvement of bone strength. INTRODUCTION: Parathyroid hormone (PTH) is used for the treatment of osteoporosis. To elucidate the contribution of material properties to bone strength after once-weekly treatment with hPTH(1-34) in an ovariectomized (OVX) primate model, the content of collagen and enzymatic immature, mature, and non-enzymatic cross-links, collagen maturity, trabecular architecture, and mineralization in vertebrae were simultaneously estimated. METHODS: Adult female cynomolgus monkeys were divided into four groups (n = 18-20 each) as follows: SHAM group, OVX group, and OVX monkeys given once-weekly subcutaneous injections of hPTH(1-34) either at 1.2 or 6.0 µg/kg (low- or high-PTH groups) for 18 months. The content of collagen, enzymatic and non-enzymatic cross-linking pentosidine, collagen maturity, trabecular architecture, mineralization, and cancellous bone strength of vertebrae were analyzed. RESULTS: Low-PTH and high-hPTH treatments increased the content of enzymatic immature and mature cross-links, bone volume (BV/TV), and trabecular thickness, and decreased pentosidine, compared with the OVX group. Stepwise logistic regression analysis revealed that BV/TV, the content of total enzymatic cross-links, and calcium content independently affected ultimate load (model R (2) = 0.748, p < 0.001) and breaking energy (model R (2) = 0.702, p < 0.001). BV/TV was the most powerful and enzymatic cross-link content was the second powerful determinant of both ultimate load and breaking energy. The most powerful determinant of stiffness was the enzymatic cross-link content (model R (2) = 0.270, p < 0.001). CONCLUSION: Once-weekly preventive administration of hPTH(1-34) increased the total contents of immature and mature enzymatic cross-links, which contributed significantly to vertebral cancellous bone strength.

Dark-bright mixing of interband transitions in symmetric semiconductor quantum dots.

In photoluminescence spectra of symmetric [111] grown GaAs/AlGaAs quantum dots in longitudinal magnetic fields applied along the growth axis, we observe in addition to the expected bright states also nominally dark transitions for both charged and neutral excitons. We uncover a strongly nonmonotonic, sign-changing field dependence of the bright neutral exciton splitting resulting from the interplay between exchange and Zeeman effects. Our theory shows quantitatively that these surprising experimental results are due to magnetic-field-induced ±3/2 heavy-hole mixing, an inherent property of systems with C(3v) point-group symmetry.

Effects of bone mineral density of the lumbar spine and prevalent vertebral fractures on the risk of immobility.

SUMMARY: To clarify the contribution of osteoporosis to future immobilization, a prospective observational study was carried out on Japanese postmenopausal women. The prevalence of low bone mineral density (BMD) and vertebral fracture were independent risks for future immobilization. INTRODUCTION: Immobilization by hip fracture requires more medical care and higher costs. Osteoporosis increases the risk of hip fracture, but there is little data linking osteoporosis and immobilization in postmenopausal Japanese women. METHODS: The study participants consisted of postmenopausal ambulatory volunteers. Baseline information such as BMD, prevalent fractures, comorbidities, pain in the body, and variables were obtained from 1993, and time course of occurrence of immobilization was observed until 2008. RESULTS: A total of 1,312 participants were enrolled and were observed for a total of 6.7 +/- 4.1 years. A total of 75 subjects suffered immobilization. In multivariate analysis to calculate the Cox's hazard ratio of baseline parameters for immobilization, four independent variables were observed: age (hazard ratio, 1.52 [95% CI, 1.29 to 1.80], p = 0.000), pain in the body (2.54 [1.42 to 4.89, p = 0.001]), low BMD (1.83 [1.10 to 3.13, p = 0.020]), and dementia (3.58 [91.80 to 6.76, p = 0.001]). The hazard ratio of prevalent vertebral fracture was 1.98 (1.20 to 3.30, p = 0.007) instead of low BMD of above model. CONCLUSION: These results indicate that low BMD and prevalent vertebral fracture pose an independent risk for future immobilization in postmenopausal Japanese women.

Cystatin C is a sensitive marker for detecting a reduced glomerular filtration rate when assessing chronic kidney disease in patients with rheumatoid arthritis and secondary amyloidosis.

OBJECTIVE: Chronic kidney disease is a predictor of end-stage renal disease, and evaluating the glomerular filtration rate (GFR) is necessary to make a definite diagnosis. We assessed the utility of serum cystatin C (cysC) for identifying a reduced GFR in patients who have rheumatoid arthritis (RA) with secondary amyloidosis. METHODS: Fifty patients with RA and secondary amyloidosis (mean age 60.9+/-11.2 years; 45 women) were evaluated. The revised 24-h creatinine clearance (r24-hC(Cr)), which was determined by multiplying the original value by 0.719, was used as a reference for the GFR. The screening potential of the serum cysC and some estimates of the GFR calculated from the serum cysC (cysC-eGFR: eGFR(Hoek) and eGFR(Rule)) for detecting a reduced GFR (r24-hC(Cr)<60 mL/min/1.73 m(2)) were analysed. RESULTS: Both cysC-eGFRs were strongly correlated with the r24-hC(Cr) (eGFR(Hoek), r=0.846, p<0.001; eGFR(Rule), r=0.820, p<0.001). The difference between the average eGFR(Rule) (37.1+/-31.2 mL/min/1.73m(2)) and average r24-hC(Cr) (35.3+/-30.9 mL/min/1.73 m(2)) was small, whereas eGFR(Hoek) and sCr-eGFR were higher than eGFR(Rule) and r24-hC(Cr). In receiver operating characteristic (ROC) curve analyses of a reduced GFR, serum cysC gave a greater area under the curve (AUC=0.958) than the sCr-eGFR (0.939-0.942). The specificity and positive predictive value (PPV) reached 100% when serum cysC >1.365 mg/L was used. CONCLUSIONS: Serum cysC can identify a reduced GFR more accurately than sCr-eGFRs. Serum cysC >1.09 mg/L (i.e. eGFR(Rule)<60 mL/min/1.73 m(2)) could be a marker of a reduced GFR, and serum cysC >1.365 mg/L would strongly suggest a reduced GFR in patients who have RA with secondary amyloidosis.

Tubulointerstitial nephritis with IgM-positive plasmacytoid large lymphocyte infiltration in a patient with primary biliary cirrhosis and Sjögren's syndrome.

We report a 38-year-old woman diagnosed with tubulointerstitial nephritis (TIN) on renal biopsy, followed by being diagnosed with primary biliary cirrhosis (PBC) and Sjögren's syndrome (SS). Immunohistochemically, the cellular infiltrates in TIN were mainly composed of small lymphocytes and IgM-positive plasmacytoid large lymphocytes. IgM-positive plasmacytoid large lymphocytes were not identical with, but colocalized with CD3- or CD20-positive lymphocytes. TIN in patients with PBC is very rare and little is known about immunohistochemical characteristics of infiltrating cells in this setting. To our knowledge, this is the first report demonstrating predominant infiltrating of IgM-positive plasmacytoid large lymphocytes in TIN due to PBC and SS.

Ultra-narrow emission from single GaAs self-assembled quantum dots grown by droplet epitaxy.

We realized ultra-narrow excitonic emission from single GaAs/AlGaAs quantum dots (QDs) grown by a refined droplet epitaxy technique. We found that uncapped quantum dots can be annealed at 400 degrees C without major changes in their morphology, thus enabling an AlGaAs capping layer to be grown at that temperature. Consequently, we demonstrate a fourfold reduction of the linewidth of the emission together with an increased recombination lifetime, compared to the conventional droplet epitaxial QDs. The averaged linewidth of neutral excitons measured by micro-photoluminescence on single quantum dots was around 35 microeV.