The forkhead box O1 (FOXO1) transcription factor is a key regulator of autophagy. In chondrocytes, reduced FOXO1 expression with aging causes osteoarthritis due to dysfunction of autophagy, but the ...mechanisms underlying regulation of FOXO1 expression and the reduction in expression with aging remain unclear. We investigated the mechanism by which transforming growth factor β1 (TGFβ1) signaling regulates the FOXO1–autophagy axis.
Expression of FOXO1 was measured in chondrocytes after TGFβ1 treatment. Immunohistochemistry was performed to estimate the levels of activin receptor-like kinase 5 (ALK5) and FOXO1 in the knee joints of young, middle-aged and old mice. The effects of the ALK5 inhibitor and SMAD3 or SMAD2 knockdown on FOXO1 expression were evaluated. The role of TGFβ1 in autophagy after hydrogen peroxide (H2O2) treatment was analyzed. The protective effect of TGFβ1 against H2O2 treatment was assessed by cell viability assay and TUNEL assay.
TGFβ1 promoted the expression of FOXO1 mRNA and protein. Both ALK5 and FOXO1 expression decreased with aging. ALK5 inhibition and SMAD3 knockdown suppressed induction of FOXO1 expression by TGFβ1, whereas SMAD2 knockdown increased it. TGFβ1 promoted the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3)-I protein via the SMAD3–FOXO1 pathway. Furthermore, under H2O2 treatment, TGFβ1 promoted expression of LC3-II. TGFβ1 pretreatment suppressed cell death of chondrocytes following H2O2 treatment, but this protective effect was abolished by FOXO1 knockdown.
TGFβ1 protects chondrocytes against oxidative stress via the FOXO1–autophagy axis, and a reduction in ALK5 expression might cause reduced FOXO1 expression with aging.
In chronic kidney disease stage 5D, diagnostic usefulness of bone mineral density (BMD) in predicting fracture has not been established because of variable results in previous studies. The reason for ...this may be the heterogeneity of underlying pathogenesis of the fracture.
BMD was measured annually and serum biochemistry monthly for 485 hemodialyzed patients from April 2003 to March 2008, and all fractures were recorded.
Forty-six new episodes of any type of fracture and 29 cases of prevalent spine fracture were recorded. Serum bone-specific alkaline phosphatase (b-AP) was a very useful surrogate marker for any type of incident fracture risk area under curve (AUC) = 0.766, P < 0.0001. A significantly greater risk of any type of incident fracture was associated with parathyroid hormone (PTH) levels either <150 pg/mL hazard ratio (HR) = 3.47, P < 0.01 or >300 pg/mL (HR = 5.88, P < 0.0001) compared with 150-300 pg/mL. Receiver-operating characteristic analysis demonstrated a significant predictive power for incident of any type of fracture by BMD at the total hip (AUC = 0.760, P < 0.0001) and other hip regions in females in the lower PTH group (PTH < 204 pg/mL). BMDs at every site but whole body or lumbar spine had significant power to discriminate prevalent spine fracture regardless of gender or PTH.
Hemodialyzed patients with low or high PTH or increased b-AP had a high fracture risk. BMD by Dual Energy X-ray Absorptiometry (DEXA), especially at the total hip region, was useful to predict any type of incident of fracture for females with low PTH or to discriminate prevalent spine fracture for every patient.
The organizing of magnetic skyrmions shows several forms similar to atomic arrays of solid states. Using Lorentz transmission electron microscopy, we report the first direct observation of a stable ...liquid-crystalline structure of skyrmions in chiral magnet Co8.5Zn7.5Mn4(110) thin film, caused by magnetic anisotropy and chiral surface twist. Elongated skyrmions are oriented and periodically arranged only in the ⟨110⟩ directions, whereas they exhibit short-range order along the ⟨001⟩ directions, indicating a smectic skyrmion state. In addition, skyrmions possess anisotropic interaction with an opposite sign depending on the crystal orientation, in contrast to existing isotropic interaction.
This paper describes a microsimulation program developed to study freeway ramp merging phenomena under congested traffic conditions. The results of extensive macroscopic and microscopic studies are ...used to establish a model for the behavior of merging drivers. A theoretical framework for modeling the ramp and freeway lag driver acceleration-deceleration behavior guided the model development. This methodology uses the stimuli-response psychophysical concept as a fundamental rule and is formulated as a modified form of the conventional car-following models. Data collected at the two merging points are used to calibrate the hypothesized ramp and freeway lag vehicle acceleration models. Drawing on this behavioral model, the freeway merging capacity simulation program (FMCSP) is developed to simulate actual traffic conditions. This model evaluates the capacity of a merging section for a given geometric design and flow condition. Validation of FMCSP is performed using the observed flow, vehicle trajectories, and lane-changing maneuvers. The simulation model is applied to investigate a variety of merging strategies. The results indicated that the FMCSP is capable of simulating the actual traffic conditions of congested freeway ramp merging sections and will aid in the development of traffic management strategies for complex freeway ramp merging areas.
The Notch signaling pathway consists of several receptors and their ligands Delta and Jagged and is important for embryogenesis, cellular differentiation and proliferation. Activation of Notch ...receptors causes their cleavage yielding cytoplastic domains that translocate into the nucleus to induce target proteins such as the basic-loop-helix proteins Hes and Hey. Here we sought to clarify the significance of the Notch signaling pathway in acute kidney injury using a rat ischemia-reperfusion injury model and cultured NRK-52E cells. Analysis of the whole kidney after injury showed increased expression of Delta-1 and Hes-1 mRNA and protein along with processed Notch-2. Confocal microscopy, using specific antibodies, showed that Delta-1, cleaved Notch-2 and Hes-1 colocalized in the same segments of the injured renal proximal tubules. Recombinant Delta-1 significantly stimulated NRK-52E cell proliferation. Our study suggests that the Delta-1/Notch-2/Hes-1 signaling pathway may regulate the regeneration and proliferation of renal tubules during acute kidney injury.
Introduction
Patients with acquired haemophilia A (AHA) have autoantibodies against factor VIII (FVIII), and may develop spontaneous bleeding that requires treatment with FVIII inhibitor bypassing ...agents such as recombinant activated FVII (rFVIIa, NovoSeven®). However, data regarding the use of rFVIIa are limited.
Aim
To investigate the use, efficacy and safety of rFVIIa for the treatment of AHA by analysis of 10‐year multicentre Japanese postmarketing surveillance data.
Methods
Treatment regimens, haemostatic efficacy and adverse events were recorded for rFVIIa therapy of AHA patients with bleeding episodes. Treatment was evaluated as markedly effective, effective, moderate or ineffective.
Results
Data were collected for 371 bleeding episodes in 132 patients. Bleeding improved after rFVIIa therapy in 92% of episodes (markedly effective in 41%, effective in 10%, moderate in 41%). The response rate was significantly better in patients who received an initial dose of ≥90 μg kg−1 than in those who received an initial dose of <90 μg kg−1. The response rate was also significantly better when rFVIIa was administered earlier after the onset of bleeding. Twelve serious adverse events were recorded in six patients, including five serious thromboembolic events in three patients who were all elderly with significant comorbidities.
Conclusion
This is the largest, single‐country study of rFVIIa therapy in AHA patients reported to date. The Japanese surveillance data show comparable efficacy and safety to prior multinational studies. Doses of 90–120 μg kg−1 and prompt initiation of treatment may be important to achieve good bleeding control.
This paper investigates the effect of heavy commercial vehicles on traffic characteristics and operation of freeway merging sections. Freeways are designed to facilitate the flow of traffic, ...including passenger cars and trucks. The impact of these different vehicle types is not uniform, creating problems in freeway operations and safety, particularly in the vicinity of merging sections. There have been very few studies that are concerned with the traffic behavior and characteristics of heavy vehicles in these situations. Therefore, a three-year study was undertaken to investigate traffic behavior and operating characteristics during the merging process under congested traffic conditions. First extensive traffic data collection captured a wide range of traffic and geometric information using detectors, videotaping, and surveys at several interchanges. The macroscopic detector data were used to identify and quantify the impact of heavy commercial vehicles on the capacity of merging sections. Subsequently, the microscopic data were utilized to establish a model for the behavior of drivers at merging sections. Based on this behavioral model, a microsimulation program was developed to simulate the actual traffic conditions. This model was used to evaluate the capacity of a merging section for a given geometric design and traffic flow condition. In addition, this model was employed to develop a variety of intelligent transport system control strategies that are associated with heavy commercial vehicles with the goal of designing safer and less-congested freeway merging points. The implementation of the proposed control strategies showed significant improvement over the capacity of merging sections.
Objective. Polymorphisms and haplotypes of the peptidylarginine deiminase type 4 gene (PADI4) have been reported to be associated with rheumatoid arthritis (RA) in a Japanese population. However, ...subsequent replication studies showed conflicting results. The aim of this study was to determine whether meta-analysis would prove the existence of the association. Methods. PubMed was searched using the term ‘PADI4’ for articles from the publication of the first study to December 2005. Replication studies that tested the association between PADI4 and RA were reviewed for meta-analysis. The Breslow–Day test for homogeneity across the studies was calculated. The Mantel–Haenszel procedure was used to pool odds ratios (OR) with 95% confidence intervals (CI) to evaluate the association. Results. Six replication studies, one from Japan and five from Europe and North America, fulfilled the selection criteria for inclusion in the meta-analysis. Homogeneity was confirmed across the replication studies. The common OR was 1.14 (95% CI = 1.07–1.21) for allelic distribution. The association was confirmed when only five replication studies in the European descent populations were combined (P = 0.0096, common OR = 1.10). Conclusions. Our meta-analysis showed a positive association between PADI4 and RA not only in the Japanese population but also in populations of European descent.
Summary
Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing ...coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries.
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