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Objective Biomarkers of disease activity in lupus nephritis (LN) are in demand. This is because they may be useful in patients who are unable to undergo invasive kidney biopsy, as predictors of renal function, and for early detection of LN recurrence. The focus is on the measurement of urinary chemokines and cytokines, especially in urinary biomarkers, which are non-invasive and simple. In our previous report, we reported that kidney injury molecule-1 (KIM-1) is expressed in injured tubules and that the number of tubular-KIM-expressing positive cells correlates with renal pathology findings and also with urinary (u)-KIM-1 levels. However, there have been no reports examining the effect of u-KIM-1 levels on response to therapy, correlation with renal pathology, and usefulness as a predictor of renal function. Methods U-KIM-1 levels were measured by ELISA in 61 SLE patients. In 38 active LN who underwent renal biopsy, we also examined whether u-KIM-1 levels affected LN disease activity, renal histological findings, and predictors of renal function. Results In SLE patients, proteinuria and u-KIM-1 levels were elevated in active LN compared to inactive LN. U-KIM-1 and proteinuria decreased with intensified treatment. U-KIM-1 levels also correlated with the percentage of glomerular crescent formation in renal pathology. In addition, patients with higher baseline u-KIM-1 levels had significantly higher eGFR and lower LN disease activity at 12 months after treatment intensification. Conclusions These data suggest that u-KIM-1 levels correlate with LN disease activity and renal histopathology findings and may be used as a predictor of treatment response.

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Erythrocytes are deformable cells that undergo progressive biophysical and biochemical changes affecting the normal blood flow. Fibrinogen, one of the most abundant plasma proteins, is a primary determinant for changes in haemorheological properties, and a major independent risk factor for cardiovascular diseases. In this study, the adhesion between human erythrocytes is measured by atomic force microscopy (AFM) and its effect observed by micropipette aspiration technique, in the absence and presence of fibrinogen. These experimental data are then used in the development of a mathematical model to examine the biomedical relevant interaction between two erythrocytes. Our designed mathematical model is able to explore the erythrocyte-erythrocyte adhesion forces and changes in erythrocyte morphology. AFM erythrocyte-erythrocyte adhesion data show that the work and detachment force necessary to overcome the adhesion between two erythrocytes increase in the presence of fibrinogen. The changes in erythrocyte morphology, the strong cell-cell adhesion and the slow separation of the two cells are successfully followed in the mathematical simulation. Erythrocyte-erythrocyte adhesion forces and energies are quantified and matched with experimental data. The changes observed on erythrocyte-erythrocyte interactions may give important insights about the pathophysiological relevance of fibrinogen and erythrocyte aggregation in hindering microcirculatory blood flow., This work was supported by Fundação para a Ciência e a Tecnologia – Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES, Portugal) projects PTDC/EMD-TLM/7289/2020 (all authors), PTDC/BBB-BMD/6307/2014 and UID/BIM/50005/2019 (CSL, FAC, NCS), through Fundos do Orçamento de Estado. JC and RT also thank the support of FEDER funds through the Operational Programme Competitiveness Factors – COMPETE and Fundação para a Ciência e a Tecnologia through the strategic projects UIDB/04564/2020 and UIDP/04564/2020. CSL also acknowledges FCT-MCTES fellowships PD/BD/135045/2017 and COVID/BD/151823/2021, General Programme of the European Molecular Biology Conference – EMBO Short-Term Fellowship 8350, and an EBSA Bursary for a working visit to the University of Southern Denmark to perform the micropipette aspiration technique experiments, as well as Erasmus+ mobility – ERASMUS SMT Student Mobility for Traineeships. AH-M acknowledges support from Ministerio de Ciencia e Innovación (Spain) under project PID2019-106063GB-100 and AGAUR (Generalitat de Catalunya) under project 2017 SGR-1061.

The pathogenesis of acute kidney injury (AKI) is complex and involves various immune and inflammatory responses. Antigen-presenting cells such as macrophages and dendritic cells (DCs) were recently reported to have diverse functions in AKI depending on the pathogenesis and disease phase. Herein, we intraperitoneally administered liposomal clodronate (LC) to lipopoly-saccharide (LPS)-induced AKI model mice in order to deplete antigen-presenting cells (e.g., macrophages and DCs). After the LPS injection, the mice were divided into LC-treated (LPS + LC) and saline-treated groups (LPS), and the immune responses of macrophages and DCs in the acute and recovery phases were evaluated. The LPS + LC-treated group exhibited significantly suppressed renal macrophages and DC infiltration at 18 h and improved survival at 120 h after LPS injection. Via the depletion of macrophages and DC infiltrations, the serum and renal tissue inflammatory cytokines/chemokines were suppressed at 18 h and reversed at 120 h. Tubular kidney injury molecule-1 expression was decreased at 18 h and increased at 120 h. These findings indicate that LC administration suppressed tubular and interstitial injury in the acute phase of AKI and affected delayed tissue repair in the recovery phase. They are important for understanding innate and acquired immune responses in the therapeutic strategy for LPS-induced AKI.

This study aims to investigate influence of under- and over-treatment on residual stress state induced by HFMI numerically. Finite element simulations were performed using a flat plate model considering S355 where feed rate and the number of hits were varied. To reduce computational time, the mass scaling method was adopted to the simulations. In addition, in order to survey influence of surface removal on residual stress state, electropolishing was conducted after the HFMI simulation. Additional simulations were performed on bead on plate model considering JIS-SM400 in order to investigate applicability of isotropic hardening model for residual stress estimation. From the results, the mass scaling method can result in reducing computational time more than 90% with reasonable good estimation of the residual stresses.The investigations regarding under- and over-treatment reveal that high feed rate mainly influences residual stress state on the treated surface and the number of hits is independent of amount of induced residual stress. Surface removal after the simulation can result in slightly improving the accuracy of the estimated residual stresses. The simulations to bead on plate model give reasonable results in a depth of around 0.2 mm even when the residual stresses due to welding is disregarded.

Objectives Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-inadequate response (IR). Methods We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (n = 54, each group). Results The retention rates at 24 months were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months, the MTX+IGU group’s 28 joint-disease activity score (DAS28) was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group’s good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group’s good-responder percentage (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the estimated glomerular filtration rate from baseline during follow-up. Conclusions IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function should be monitored during follow-up.

This paper investigates the fatigue strength enhancement of two types of peening techniques: hammer peening with impact crack-closure retrofit apparatus and high-frequency mechanical impact (HFMI) treatment on out-of-plane gusset-welded joints made of SBHS700. In this work, fatigue tests were continuously carried out using plate specimens that were removed from a previously tested girder specimen. The results showed that the fatigue strength enhancement of these peening techniques on the welded joints was expected to be at least three classes higher compared with as-welded details with similar dimensions. Unexpectedly, the improvement effect of the hammer peening on one specimen was slightly lower than that of the other specimens. According to SEM observation, the cause of the slight reduction was that due to its weld shape, the distance between the crack initiation point and the treatment edge became greater than 2 mm. Finally, evaluations were performed on available data, including the test results from this study, based on an extended Modified Goodman model to estimate the fatigue limits of HFMI-treated joints. Consequently, the estimation results by the model indicated a good agreement with the fatigue strength enhancement of HFMI treatment and a possibility to be able to assess the enhancement of the hammer peening.

Concerning environmental protection from removal of existing paint containing lead and poly chlorinated biphenyl on existing steel bridges during re-painting, circulating blasted techniques at bridge site using both steel grits and steel shots that can be reused several times have been recently developed and practically used in Japan. The techniques can be upgraded to apply shot peening techniques by controlling treatment that ensures beneficial compressive residual stress. This study investigated an application of shot peening by utilizing circulating blasted techniques using steel rounded shots to welded joints during re-painting of a pilot existing steel bridge. In order to ensure the quality of the shot peening, the surface coverage near welded joints, indicating whether shot media uniformly hit the treatment area, was measured and controlled. After the surface coverage control, to verify the compressive residual stress introduced by the shot peening, the residual stress in the vicinity of weld toes of the pilot bridge was measured by means of X-ray diffraction method. The measurement results indicated that shot peening can introduce compressive residual stress that is the least − 350 MPa at a depth of 100 μm and is kept up to a depth of 400 to 500 μm. In addition, this compressive residual stress was compared with that of plate specimens treated by shot peening under almost the same quality control as the pilot bridge. The compressive residual stress introduced to the specimens agreed well with that of the pilot bridge, and therefore, this result implied that this shot peening could enhance the fatigue strength of welded joints on existing steel bridges.

BackgroundInterleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the ‘cytokine storm’ such as adult-onset Still’s disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group).Patients and MethodsWe enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group.ResultsSerum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and ‘arthralgia or arthritis’ are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83–1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data.ConclusionsIL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.

Objectives In our previous 24-month study, we observed that teriparatide had some advantages over denosumab for bone mineral density (BMD) in glucocorticoid-induced osteoporosis (GIO) patients with prior bisphosphonate treatment. We conducted this extension study to investigate whether the advantage of teriparatide obtained in the first 2 years would be maintained after the switch to denosumab. Materials and Methods We switched patients who had completed 24-month daily teriparatide treatment to denosumab (switch group, n=18) and compared their BMD every 6 months up to 48 months with the group who continued to receive denosumab (denosumab group, n=16). Results At 48 months, the lumbar spine BMD was significantly increased from baseline in both groups (denosumab: 10.4 ± 8.7%, p

It is clear that usages of high-strength steels for steel bridges are effective to reduce weight of the bridges, and therefore, it may lead to the cost reduction of the bridges. However, adoptions of high-strength steels might result in under-matched joints, and significance of under-matched welded joints made of over 700-MPa class steels on fatigue strength and estimation of a local strain approach on the joints are not clear yet. This paper presents fatigue test results of under-matching welded joints made of 800-MPa class steels containing incomplete penetration under higher stress range region. Test results indicate that the fatigue strength in higher stress range region is less than that made of mild-strength steels, and showed that the cause of reduction of fatigue strength is that under-matched welded joints caused strain concentration and ductile crack propagation at around weld roots. This paper also presents applicability of a simple estimation method of the effective notch strain from nominal strain proposed by a previous study, and the estimation method can evaluate the effect of under-matching welded joints under higher stress range region.

Objectives: We retrospectively evaluated the retention rate and clinical responses following treatment for rheumatoid arthritis (RA) with iguratimod (IGU) vs. salazosulfapyridine (SASP) as the firs...

Juvenile systemic sclerosis (SSc) is a rare condition that results in various disorders, including growth retardation and learning disabilities in addition to impaired quality of life due to fibrosis and microvascular disorders in multiple organs. Recently, efficacies of immunosuppressants such as cyclophosphamide and mycophenolate mofetil, as well as biological agents, have been reported in adult patients with SSc. However, there has been no consensus in the treatment of juvenile SSc due to its rarity and the fact that skin sclerosis may be self-limiting in some patients. Here, we present a case of 13-year-onset SSc with growth retardation and learning disabilities, in addition to skin sclerosis, interstitial lung disease, and possible myocardial fibrosis that was successfully treated with tocilizumab monotherapy without remarkable adverse reactions. As careful case-by-case management of patient’s growth and education along with standard treatment is needed, the documentation of such case is important for the evaluation of the efficient and safe therapy for juvenile SSc.

Objective: Rheumatoid arthritis (RA) treatments have markedly advanced with the introduction of biological agents, e. g., tumor necrosis factor (TNF) inhibitors. TNF inhibitors are demonstrated to be quite effective in combination with methotrexate (MTX), and sufficient doses of both agents are important to control RA's disease activity. However, not all RA patients can be treated with high-dose MTX due to contraindications related to the antimetabolite action of MTX or to tolerability concerns. In daily practice, this has resulted in reduced effectiveness of TNF inhibitors. We sought to determine whether the concomitant use of dose of MTX affected the clinical effectiveness, retention rate, and side effects of certolizumab pegol (CZP) for treating RA in a real-world setting. CZP is a pegylated–conjugated Fab' fragment of a humanized anti-TNF antibody that has high affinity to TNF.Patients and Methods: We divided Japanese RA patients treated with CZP (n = 95, 25–83 years old) into groups based on those with (n = 65) and without (n = 30) concomitant MTX and those treated with a high dose (≥8 mg, n = 41) or low dose (1– n = 24) of MTX. We retrospectively analyzed the concomitant MTX doses' effects and side effects and the patient retention rate.Results: There were no significant differences among the CZP groups with and without MTX or the groups receiving the high vs. low MTX doses in the retention rate, the low disease activity rate, or the inhibitory effect in radiographic joint damage.Conclusion: CZP has the potential to be a useful biological agent to control RA's disease activity and the bone destruction in patients who cannot tolerate a sufficient MTX dose.

Renal interstitial fibrosis is a common lesion in the process of various progressive renal diseases. Interleukin (IL)-18 is a proinflammatory cytokine that plays an important role in the induction of Th1 responses and is associated with renal interstitial fibrosis, but the mechanism of fibrosis remains unclear. Here we used IL-18 receptor alpha knockout (IL-18Rα KO) mice to investigate the role of an IL-18Rα signaling pathway in renal fibrosis in a murine model of unilateral ureteral obstruction. IL-18 Rα KO mice showed decreased renal interstitial fibrosis and increased infiltration of CD4+ T cells and Foxp3+ regulatory T cells (Tregs) compared to wildtype (WT) mice. The expression of renal transforming growth factor beta 1 (TGF-β1, which is considered an important cytokine in renal interstitial fibrosis) was not significantly different between WT and IL-18Rα KO mice. The adoptive transfer of CD4+ T cells from the splenocytes of IL-18Rα KO mice to WT mice reduced renal interstitial fibrosis and increased the number of Foxp3+ Tregs in WT mice. These results demonstrated that Foxp3+ Tregs have a protective effect in renal interstitial fibrosis via an IL-18R signaling pathway.

Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome has been proposed to describe a clinicoradiological entity manifesting in the joints, skin and bones. We describe a patient with SAPHO syndrome for whom bilateral tonsillectomy was effective for the treatment of arthralgia, which was quantified using multiple pain scales.

Background Strongyloidiasis is a gastrointestinal parasitic infection caused by percutaneous infection with Strongyloides stercoralis. Digestive symptoms such as diarrhea and abdominal pain are the main manifestation, but serious infections such as septicemia, purulent meningitis, and bacterial pneumonia may occur in individuals harboring human T-lymphotropic virus type 1 (HTLV-1) or who are immunocompromised. Although coinfection with Strongyloides stercoralis and HTLV-1 can lead to chronic strongyloidiasis and a disseminated form of the disease, there is a high rate of response to the anthelmintic ivermectin. Case presentation We report a case of strongyloidiasis infection syndrome that was difficult to differentiate from immune reconstitution inflammatory syndrome (IRIS) for various reasons. The patient had been treated with the corticosteroids tacrolimus (Tac) and mycophenolate mofetil (MMF) for systemic lupus erythematosus (SLE) with lupus nephritis and pancytopenia. When the steroid was reduced, she developed cytomegalovirus (CMV) enteritis, and her respiratory status rapidly deteriorated immediately after the withdrawal of Tac and MMF. It was difficult to distinguish immune reconstitution inflammatory syndrome from strongyloidiasis infection syndrome because stool cultures were negative and eosinophils were not increased. Bronchoscopy revealed viable Strongyloides, leading to a diagnosis of strongyloidiasis infection syndrome, but the patient died despite treatment. Conclusions Both corticosteroid therapy and HTLV-1 infection can be associated with a decrease of eosinophils, despite the presence of parasitic infection. In conclusion, even if multiple culture tests are negative, the risk of parasitic infection should be assessed in patients receiving immunosuppressants and steroids even in non-endemic areas.

Yuji Nozaki, Yasuaki Nagare, Chisato Ashida, Daisuke Tomita, Akinori Okada, Asuka Inoue, Koji Kinoshita, Masanori Funauchi, Itaru Matsumura Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan Purpose: We evaluated the clinical responses and radiographic outcomes of 90 patients with rheumatoid arthritis (RA) undergoing continuous or dose-adjusted infliximab treatment over 104weeks.Patients and methods: Patients received 3mg/kg infliximab continuously (the contin group; n=50), or the dose escalation and de-escalation of infliximab (3, 6, and 10mg/kg) from week 14 (the adjusted group; n=40) based on the patient’s Disease Activity Score in 28 joints (DAS28). The retention rate, clinical response, and radiographic assessment were determined at week 104.Results: The contin and adjusted groups’ retention rates at week 104 were 56.8 and 66.7%, and the groups’ low disease activity in the DAS28 was 39.1 and 66.7%, respectively. Remission based on the DAS28 and the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) Boolean-based criteria was significantly increased in the adjusted group. In the radiographic assessment, there was also a significant reduction in the mean changes in total Sharp score. The cumulative rates of any adverse effects showed no significant difference between the groups.Conclusion: In an assessment of adequate DAS28 results, the RA patients who did not respond to the initial dose of infliximab showed improved clinical responses and radiographic assessment after a dose adjustment of infliximab, without an increased risk of serious adverse events. Keywords: rheumatoid arthritis, DAS28, infliximab, mTSS, dose adjustment, REVIVE&nbsp

This study experimentally investigates effect of fatigue strength improvement of the Portable Pneumatic Needle-Peening treatment (PPP treatment) as a needle peening on out-of-plane gusset welded joints by using plate bending fatigue tests. This study also examined effect of the travel speed and the number of treatment passes of the PPP treatment with regards to its fatigue strength improvement. After the fatigue tests, the observation of the fracture surface with Scanning Electron Microscope was carried out in order to clarify the crack initiation. From those test results, it may be concluded that the effect of fatigue strength improvement might be governed by treatment passes with sufficient travel speed. In addition, this study carried out additional fatigue tests that focus on fatigue crack closer by using the PPP treatment. As a result of additional fatigue tests for fatigue crack closure, it might be said that the effect of fatigue crack closure is effective when the distance between fatigue cracks and treatment area is less than 2.0 mm.

Shot-peening recently can be applied to existing steel bridges due to the development of new vacuuming techniques of shots after peening in the construction site. This study experimentally investigates effects of fatigue strength improvement of shot-peening on welded joints. Bending fatigue tests using out-of-plane gusset welded joints specimens were carried out and three type specimens were compared: as-welded, grit-blasted, and shot-peened. In addition, this paper examines differences of fatigue strength improvement effects in case of applying shot-peening to inside of scallop where shots might be difficult to hit perpendicularly to weld toe of welded joints because of narrow space, and the residual stress measurement in order to clarify introducing compressive residual stress were carried out. As a result, it may be concluded that shot-peening can improve fatigue strength of welded joints and its mechanism was identified as extension of crack initiation life and delay crack propagation due to beneficial compressive residual stress in the vicinity of surface layer.

The object of this study is to clarify fatigue limit and fatigue crack growth characteristic of SBHS700 base metal which is 780 MPa class steel. This study carried out the fatigue tests of SBHS700 base metal containing different defect size, and the fatigue limit was compared with that of the conventional steel. Test results indicate that the fatigue limit increased with decrease initial defect size, and can be precisely evaluated by using $$\sqrt {area}$$ parameter model. This paper also presents that crack growth characteristic was almost the same as that of the conventional steel from the observation of striations by using Scanning electron microscope and length of beach marks.

We report a 14-year-old man with Crohn’s disease (CD) who developed right upper arm pain while being treated with the anti-tumor necrosis factor (TNF)-alpha monoclonal antibody, infliximab. There were no symptoms suggestive of active CD, but the inflammatory response was high, and a contrast-enhanced CT showed the occlusion of the right brachial artery. We diagnosed the patient as having Takayasu’s arteritis (TA) and started treatment with corticosteroids, then tapered off the steroids as the symptoms of TA resolved. Later, TA flared up, and his treatment was changed from infliximab to an anti-IL-6 receptor antibody, tocilizumab. The change to TCZ stabilized TA, but exacerbated CD. It is difficult to control both diseases at the same time, and the choice of biologics for treatment must be carefully considered.

Relapsing polychondritis (RP) is a rare autoimmune inflammatory disease characterized by recurrent inflammation and destruction of cartilage. Although auricular chondritis is a characteristic finding in RP, it can be difficult to diagnose in the absence of auricular symptoms. A 64-year-old Japanese male was referred to our hospital with fever and respiratory distress. Contrast-enhanced computed tomography (CT) revealed bronchial wall thickening and we suspected RP; however, he had no auricular symptoms and did not meet the diagnostic McAdam criteria for RP, so we used 18F-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) to search for other cartilage lesions. This analysis revealed FDG accumulation not only in the bronchial walls, but also in the left auricle. Instead of a bronchial biopsy using a bronchoscope, we performed a biopsy of the left auricular cartilage, which is considered a relatively less invasive site. Even though the auricle was asymptomatic, the pathology results revealed chondritis. He was diagnosed with RP, and his symptoms rapidly improved with corticosteroid therapy. A biopsy of asymptomatic auricular cartilage may be useful in the diagnosis of RP. FDG-PET/CT is a powerful tool for the early diagnosis of RP, identifying inflammatory areas even in the absence of symptoms, and guiding the selection of appropriate biopsy sites.

Currently available dynamic surface tension (DST) measurement methods, such as Wilhelmy plate, droplet- or bubble-based methods, still have various experimental limitations such as the large size of the interface, convection in the solution, or a certain “dead time” at initial measurement. These limitations create inconsistencies for the kinetic analysis of surfactant adsorption/desorption, especially significant for ionic surfactants. Here, the “micropipette interfacial area-expansion method” was introduced and validated as a new DST measurement having a high enough sensitivity to detect diffusion controlled molecular adsorption at the air-water interfaces. To validate the new technique, the diffusion coefficient of 1-Octanol in water was investigated with existing models: the Ward Tordai model for the long time adsorption regime (1–100 s), and the Langmuir and Frumkin adsorption isotherm models for surface excess concentration. We found that the measured diffusion coefficient of 1-Octanol, 7.2 ± 0.8 × 10−6 cm2/s, showed excellent agreement with the result from an alternative method, “single microdroplet catching method”, to measure the diffusion coefficient from diffusion-controlled microdroplet dissolution, 7.3 ± 0.1 × 10−6 cm2/s. These new techniques for determining adsorption and diffusion coefficients can apply for a range of surface active molecules, especially the less-characterized ionic surfactants, and biological compounds such as lipids, peptides, and proteins.

Introduction Osteoporosis is one of the serious adverse effects associated with glucocorticoid therapy. Although bisphosphonates have been used for glucocorticoid-induced osteoporosis (GIO), some patients have shown an inadequate response. In such cases, denosumab or teriparatide are used. However, there is no consensus on which of these two drugs is superior. We prospectively compared denosumab's and teriparatide's effects on the bone mineral density (BMD) in GIO patients with prior bisphosphonate treatment. Materials and methods After receiving oral bisphosphonates for ≥2 years, GIO patients with low T-score BMD (, Highlights • We compared the effects of denosumab and teriparatide on BMD in GIO patients with prior bisphosphonate treatment. • At 24 months, teriparatide increased lumbar spine and femoral neck BMD, whereas denosumab increased lumbar spine BMD only. • At 12 months, teriparatide increased lumbar spine and femoral neck BMD more than denosumab. • Teriparatide might have some advantages over denosumab in GIO patients with prior bisphosphonate treatment.

The story starts in Basel at CLINAM in 2013, when I asked Pieter about making nanoparticles and he advised me to "try this solvent-exchange method we have developed for making limit sized particles". We are particularly interested in what are "limit size materials" because we want to test the feasibility of an idea: could we design, make, develop, and test the concept for treating metastatic cancer by, "Putting the Drug in the Cancer's Food? "Limit size" is the size of the cancer's food, ? the common Low Density Lipoprotein, (LDL) ~20 nm diameter. In this contribution to Pieter's LTAA we focus on the "bottom" (nucleation) and the "up" (growth) of "bottom-up design" as it applies to homogeneous nucleation of especially, hydrophobic drugs and the 8 physico-chemical stages and associated parameters that determine the initial size, and any subsequent coarsening, of a nanoparticle suspension. We show that, when made by the rapid solvent-exchange method, the same sized particles can be obtained without phospholipid. Furthermore, the obtained size follows the predictions of classic nucleation theory when the appropriate values for the parameters (surface tension and supersaturation) at nucleation are included. Calculations on dissolution time for nanoparticles reveal that a typical fewmicromolar-solubility, hydrophobic, anti-cancer drug (like Lapatinib, Niclosamide, Abiraterone, and Fulvestrant) of 500 nm diameter would take between 3?7 s to dissolve in an infinite sink like the blood stream; and a 50 nm particle would dissolve in less than a second! And so the nanoparticle design requires a highly water-insoluble drug, and a tight, encapsulating, impermeable lipid:cholesterol monolayer. While the "Y" junction can be used to mix an ethanolic solution with anti-solvent, we find that a "no-junction" can give equally good results. A series of nanoparticles (DiI-fluorescently labeled Triolein-cored and drug-cored nanoparticles of Orlistat) were then tested in well-characterized cell lines for uptake and efficacy as well as a PET-imageable nanoparticle in initial PET-imaging studies in animals for EPR uptake and tumor detection. We show that, while free-drug cannot be optimally administered in vivo, a nanoparticle formulation of orlistat could in principle represent a stable parenteral delivery system. The article ends with a brief discussion of what we see as the way forward in Individualized Medicine from the Diagnostic-Therapeutic ("Diapeutic") side, requiring (18)FDG detection of metastatic lesions, functional imaging of a protein target (e.g. Fatty Acid Synthase) using (11)C acetate, then a PET (or other)-imageable nanoparticle to demonstrate EPR accumulation, and then the administration of the pure-drug nanoparticle taken in by the most aggressive cancer cells in the perivascular space, as they would their "food".

(1) Background: We evaluated the clinical response of iguratimod (IGU) in patients with rheumatoid arthritis (RA) being treated with or without methotrexate (MTX) over 54 weeks. (2) Methods: 106 patients with RA undergoing IGU were retrospectively observed. RA patients were divided into those treated with MTX+IGU (n = 35) and those treated with IGU (n = 71). The primary endpoint was the clinical response of the Disease Activity Score assessing 28 joints with C-reactive protein (DAS28-CRP) differences in the changes from baseline to 54 weeks between MTX+IGU and IGU groups. Secondary endpoints, such as the clinical response, retention rate, and safety, were evaluated. (3) Results: The DAS28-CRP difference in the changes between the two groups were &minus, 0.2. DAS28-CRP were significantly reduced from the baseline in the MTX+IGU and IGU groups (&minus, 1.43 and &minus, 1.20 from baseline, respectively). The retention rates were 71.4% in the MTX+IGU groups and 59.2% in the IGU groups (p = 0.16). Adverse events were observed in a total of 6 (17.1%) MTX+IGU patients and 20 (28.2%) IGU patients (p = 0.21). (4) Conclusions: IGU therapy may be a useful treatment option for patients who cannot be treated with MTX.

Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (R&alpha, ) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18R&alpha, knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18R&alpha, KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-&gamma, levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18R&alpha, KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18R&alpha, signaling pathway. These results suggest that inhibitors of the IL-18/IL-18R&alpha, signaling pathway could become new therapeutic agents for rheumatoid arthritis.

Interleukin (IL)-10, a cytokine with anti-inflammatory effects, is produced by blood cells and cells of various organs. Ischemia-reperfusion injury (IRI) is a systemic inflammatory disease caused by a systemic circulation of pro-inflammatory cytokines and chemokines produced from blood cells or organs damaged by ischemia. Apoptosis, a key event after IRI, is correlated with the degree of injury. Here we investigated the effects and mechanism of IL-10 in renal IRI. Compared to wild-type (WT) mice with a renal IRI, IL-10 knockout (IL-10 KO) mice with IRI demonstrated decreased renal function as represented by blood urea nitrogen and serum creatinine, upregulated early acute kidney injury (AKI) biomarkers such as kidney injury molecule-1 (Kim-1), increased mRNA expression of the pro-inflammatory cytokines IL-1β, IL-6, and IL-18 and a chemokine (regulated on activation, normal T cell expressed and secreted; RANTES), and increased expression of the pro-apoptosis factors Bax and cleaved caspase-3. When tubular epithelial cells (TECs) from IL-10 KO mice were put in a hypoxic state and added with recombinant IL-10, their expression of Bax decreased. Our findings demonstrated that IL-10 suppressed the production of pro-inflammatory cytokines, renal dysfunction, and the expression of pro-apoptosis factors after IRI.

SUMMARY In image analysis, it is important to detect lines (straight lines) that represent the edges of an object in the image. The most popular technique for line detection is the Hough transform. In this transform, peaks resulting in the accumulator array that are obtained through a voting procedure in the parameter space represent strong evidence that a corresponding line exists in the image. In the voting procedure, large numbers of votes that are far from the peaks are unnecessary and reduce the speed of the transform. In this paper, we propose a method to speed up this process by introducing a procedure in image space that removes lines except for limited directions. This procedure makes it possible to reduce the voting range and to remove unnecessary votes. Experimental results confirm that the proposed method performs effectively.

Nephrotoxicity is a frequent complication of cisplatin-induced chemotherapy, in which T cells are known to promote acute kidney injury (AKI). Apoptosis and necrosis of tubules and inflammatory events also contribute to the nephrotoxicity. A delineation of the mechanisms that underlie the inappropriate renal and tubular inflammation can thus provide important insights into potential therapies for cisplatin-induced AKI. Rho-kinases are known to act as molecular switches controlling several critical cellular functions, including cell migration, cytokine production, and apoptosis. Here, we show that the Rho-kinase inhibitor fasudil attenuated cisplatin nephrotoxicity, resulting in less histological damage, improved renal function, and the infiltration of fewer leukocytes into the kidney. Renal nuclear factor-κB activation and apoptosis were reduced, and the expressions of proinflammatory renal cytokine and chemokine mRNA were decreased. Urinary and renal kidney injury molecule-1 (Kim-1) expression was also reduced, a finding that is consistent with diminished kidney injury. In the current study, we also showed that fasudil could be protective of the impaired tubules. In vitro, fasudil reduced the apoptosis (annexin-V+PI cells) and cytokine production (tumor necrosis factor+ cells) in T cells and the apoptosis (annexin-V+PI cells) and tubular damage (Kim-1+ cells) in proximal tubular cells by flow cytometric analysis. As Rho-kinase plays an important role in promoting cisplatin nephrotoxicity, inhibiting Rho-kinase may be a therapeutic strategy for preventing cisplatin-induced AKI.

Large-scale RC column tests have been performed in Japan at both the E-defense and JR-Tokai test facility and in United States at the University of California, San Diego Large Outdoor Shake Table Testing Facility. Such recent large-scale RC column tests have been compared with results of small-scale RC column tests. As a result, results of these large-scale model experiments show shortcomings in small-scale model experiments. At least one study showed that the small-scale model does not reproduce the observed damage on the large-scale model. Therefore, in order to develop small-scale model experiment results, experiment tests of small-scale model which might agree well with large-scale model should be undertaken. In an authors’ previous study, experimental cyclic loading study on 0.1- and 0.2-scale RC column models was carried out and results have been compared with full- and 0.5-scale RC column models performed in the JR-Tokai test facility. Although the authors’ experimental study clearly shows agreements and differences between large-scale model and small-scale model, the results still remain to be validated with respect to bond behavior between longitudinal steel bars and concrete. This study analyses full-, 0.5-, 0.2-, and 0.1-scale RC columns models using fiber model analyses to investigate the bond behavior analytically. This analytical study focuses on differences in hysteresis curves. Validity of the analysis results was determined by comparing experimental results of full- and 0.5-scale model. It is shown that fiber model analysis results agree well with the full- and 0.5-scale model. Although results of 0.1-scale models, which are scaled correctly for not only steel bar radius but also steel bar ribs, are capable to full- and 0.5scale model, analytical results of 0.2- and 0.1-scale model with different steel bar ribs seem to be less agreements. Therefore, it is shown that one of the causes of shortcomings in small-scale models is the difference of bond behavior between longitudinal steel bars and concrete.

Lupus nephritis is major manifestation of systemic lupus erythematosus and could cause nephrotic syndrome or chronic kidney disease might lead to end-stage renal failure. The pathogenesis of macrophage as well as lymphocyte impairment had been described in lupus nephritis. The interstitial macrophage accumulation and interstitial change or fibrosis is more important than glomerular immunoglobulin deposition or glomerular macrophage accumulation in terms of renal outcome and survival proportion. The expressions of macrophage associated proteins such as CCL2/MCP-1, MIP-1 family and their receptors, CCR2, CCR1 and CCR5 are major target of therapeutic strategy for improving renal illness. The blockade of these chemokines or chemokine receptors ameliorates renal impairment without reducing glomerular immunoglobulin deposition. Deletion of CSF-1 signaling pathway represented more excellent effect in experimental lupus nephritis. The effect of specific antagonist for macrophage associated proteins, specific thyrosine kinase inhibitor for macrophage signaling pathway on glomerulonephritis in lupus prone mice had been reported with evaluation of renal leukocyte infiltration, anti-DNA antibody reduction, the amount of proteinuria, and their survival. The depletion of macrophage could be useful therapeutic tool including M2 macrophage and have synergistic effect with other immunomodulating agents.

Effect of high frequency peening treatment with a small radius tip pin, which is less than 3mm radius tip pin, still remains unclear, although the effect of ultrasonic impact treatment on fatigue strength has been investigated. The objective of this study is to investigate the effect of ultrasonic peening with a 1.5mm radius tip pin on fatigue strength of out-of-plane gusset welded joints. Plate bending fatigue tests of those joints carried out. The results show that the peening can improve fatigue strength, when mean stress does not change or already changes before the peening is carried out. It also shows that the effect of the ultrasonic impact peening become less with increasing mean stress after the ultrasonic peening was carried out, and when the ultrasonic peening is not sufficient for the weld toe.

Although many studies related to seismic repair performance of strain-hardening fiber-reinforced cement-based composites (SHCC) based on cyclic loaded small-scale RC column models have been performed in Japan, most of the studies may not be difficult to evaluate the seismic repair performance considering the size-effect. Therefore, the seismic repair performance of SHCC considering the size effect was still unsolved problems and more experimental studies for either a full-scale RC column or the small-scaled RC column which may reproduce the full-scale model are needed.

The T-cell immunoglobulin mucin 1, also known as kidney injury molecule-1, modulates CD4+ T-cell responses and is also expressed by damaged proximal tubules within the kidney. Both Th subset imbalance (Th1/Th2/Th17) and regulatory T-cell and B-cell alterations contribute to the pathogenesis of autoimmune disease. This study investigated the effects of an inhibitory anti-T-cell immunoglobulin mucin 1 antibody (RMT1–10) in lupus-prone MRL- Faslprmice. MRL- Faslprmice were treated with RMT1–10 or a control antibody intraperitoneally twice weekly from 3 mo of age for 16 wk. RMT1–10 treatment significantly improved survival, limited the development of lymphadenopathy and skin lesions, preserved renal function and decreased proteinuria, reduced serum anti-DNA antibody levels, and attenuated renal leukocyte accumulation. Th1 and Th17 cellular responses systemically and intrarenally were reduced, but regulatory T and B cells were increased. RMT1–10 treatment also reduced glomerular immunoglobulin and C3 deposition and suppressed cellular proliferation and apoptosis. Urinary excretion and renal expression of kidney injury molecule-1 was reduced, reflecting diminished interstitial injury. As RMT1–10 attenuated established lupus nephritis, manipulating immune system T-cell immunoglobulin mucin 1 may represent a therapeutic strategy in autoimmune diseases affecting the kidney.

Objective Biomarkers of disease activity in lupus nephritis (LN) are needed. Ideally, such biomarkers would be capable of detecting early sub-clinical disease and could be used to gauge response to therapy, thus obviating the need for serial renal biopsies. Much of the focus in the search for LN biomarkers has been on the measurement of urinary chemokines and cytokines in LN patients. However, these have yet to be widely implemented in clinical practice. Kidney injury molecule-1 (Kim-1) is expressed in damaged tubules, but whether urinary (u) and tubular (t)-Kim-1 could serve as a biomarker of active LN is unknown. To investigate the disease activity and histological findings in LN, we evaluated u-Kim-1 levels and t-Kim-1 cells in patients with systemic lupus erythematosus (SLE). Method We measured u-Kim-1 levels and stained t-Kim-1 expression in 57 patients with LN using an ELISA and immunohistochemistry staining. Patients were classified into two groups (active LN, n = 37; inactive LN, n = 20) based on the presence of active renal disease according to the renal SLE disease activity index. correlations of clinical, laboratory data, and histological findings with urinary and t-Kim-1 expression were assessed. Result The u-Kim-1 levels were significantly correlated with the expression of t-Kim-1 ( R = 0.64; P = 0.004) in the SLE patients. The active LN patients exhibited elevated u-Kim-1 levels compared to the inactive LN patients. The number of t-Kim-1 cells was also correlated with histological findings (both glomerular and interstitial inflammation). The u-Kim-1 levels were also correlated with proteinuria and tubular damage in the active LN group. The number of t-Kim-1 cells at baseline was significantly correlated with the estimated glomerular filtration rate ( R = 0.72; P = 0.005) and serum creatinine ( R = 0.53; P = 0.005) after 6–8 months of treatment. Conclusion These data suggest the potential use of the u-Kim-1 levels to screen for active LN and for the estimation of t-Kim-1 expression in renal biopsies to predict renal damage, ongoing glomerular nephritis and tubulointerstitial inflammation, and tubular atrophy.