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Biological disease-modifying anti-rheumatic drugs (bDMARDs) against pathogenic proinflammatory cytokines and lymphocytes, such as tumour necrosis factor-α (TNF-α), interleukin-6, T cells and B cell...

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200-5000 mg/g and estimated glomerular filtration rate 25-75 mL/min/1.73m2) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury-related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury-related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function. HJLH and DC are co-primary authors. The DAPA-CKD Trial Committees and Investigators are listed in the Appendix.

BackgroundAchievement of normal physical function is an important outcome for older patients. Previous studies of younger cohorts showed that aging, comorbidities, and joint damage influenced the physical function of patients with RA who achieved clinical remission or low disease activity (LDA). We previously demonstrated that a treat-to-target (T2T) strategy for methotrexate (MTX)-naïve elderly-onset RA (EORA) was effective with an acceptable safety profile. It showed that 60.9% of 197 patients achieved HAQ Disability Index (HAQ-DI) ≤0.5 at three years by following the T2T strategy targeting LDA (1).ObjectivesWe aimed to evaluate associated factors with HAQ-DI in the T2T strategy targeting LDA for patients with EORA during three-year observational period.MethodsTreatment was adjusted to target LDA with conventional synthetic disease-modifying antirheumatic drugs (DMARDs), followed by biological DMARDs (bDMARDs) in 197 MTX-naïve EORA patients (mean age 74.9 years) with moderate-to-high disease activity. HAQ-DI was evaluated at week 0, 24, 52, 76, 104, 128, and 156. To evaluate associated factors with SDAI and HAQ-DI over the 36-month follow-up, Bayesian hierarchical logistic regression modeling was applied for 1067 periods from the 197 patients.ResultsAt baseline, the enrolled 197 patients with EORA who had normal physical function (HAQ-DI ≤0.5) in 29.4%, HAQ-DI >0.5 and In the multilevel logistic model, the association of MTX, bDMARDs, and GC use with changes in SDAI in each period was evaluated. Age, sex, and comorbidities (chronic lung disease, cardiovascular disease, history of malignancy, osteoporosis, history of serious infections, and osteoarthritis) were included as inter-individual factors. The model indicated that the use of bDMARDs was associated with a reduction of the SDAI (ΔSDAI: -9.75, SD 0.75, pThe association of age, sex, the comorbidities, and MTX, bDMARDs, and GC use with physical function in each period was evaluated by the multilevel logistic model. The model indicated that older age (ΔHAQ-DI: 0.03, SD 0.01, p ConclusionThese data indicate that bDMARDs had a central role in reducing disease activity in the T2T strategy targeting LDA in EORA patients. Chronic lung diseases and osteoporosis at baseline were associated with increase in disease activity and worsening of physical function. However, disease activity had a greater impact on physical function than the comorbidities at baseline.References[1]Sugihara T, et al. Rheumatology (Oxford). 2021;60(9):4252-4261Disclosure of Intereststakahiko sugihara Speakers bureau: TS has received honoraria from Abbvie Japan Co., Ltd., AsahiKASEI Co., Ltd., Astellas Pharma Inc., Ayumi Pharmaceutical, Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Mitsubishi-Tanabe Pharma Co., Ono Pharmaceutical, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., and UCB Japan Co. Ltd., Grant/research support from: TS has received research grants from AsahiKASEI Co., Ltd., Daiichi Sankyo., Chugai Pharmaceutical Co., Ltd., and Ono Pharmaceutical., Tatsuro Ishizaki: None declared, Hiroyuki Baba: None declared, Takumi Matsumoto: None declared, Kanae Kubo Speakers bureau: KK has received honoraria from Asahi KASEI, Astellas Pharma, Bristol Myers Squibb, Eisai, AbbVie GK, Boehringer Ingelheim, Daiichi-Sankyo, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma and Nippon Shinyaku., Grant/research support from: KK has received research grants from Asahi KASEI, Mari Kamiya: None declared, Fumio Hirano: None declared, Tadashi Hosoya: None declared, Masayo Kojima Speakers bureau: MK has received speakers bureau from AbbVie, Astellas, Ayumi Pharma, Chugai, Eisai, Eli Lilly, Janssen, Ono Pharmaceutical, Pfizer, Tanabe-Mitsubishi, and Takeda Pharmaceutical Co., Ltd., Nobuyuki Miyasaka: None declared, Masayoshi Harigai Speakers bureau: MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Consultant of: MH is a consultant for AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd. and Teijin Pharma., Grant/research support from: MH has received research grants from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekiui Medical, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd.

Background:A framework has been proposed to explain which disease outcomes impact quality of life or well-being in patients with axSpA; this was based on cross-sectional data and patients with radiographic axSpA.1Objectives:To investigate the determinants of patient’s well-being over time, and the influence of contextual factors on these relationships in patients with early axSpA.Methods:Five-year data from DESIR, a cohort of early axSpA, were analysed. Clinical data were collected every 6 months up to 2 years and annually thereafter. X-rays and MRI of the spine and SIJ were performed at baseline, 2, and 5 years. The outcome was BAS-G, the patient’s global assessment of the disease impact on well-being. Generalized estimating equations (GEE) were used to test the relationship between potential explanatory variables from 5 domains (disease activity, physical function, spinal mobility, structural damage, spinal and SIJ inflammation) and BAS-G over 5 years. Longitudinal relationships were analysed using an autoregressive GEE model. Contextual factors (patient’s educational level, gender and age) were tested as potential effect modifiers or confounders.Results:A total of 708 patients were included, mean age 33.7 (SD 8.6) years, 46% male, 41% lower educated. Higher scores of the individual questions of BASDAI on fatigue (Q1) (β [95% CI]: 0.17 [0.13-0.22]), back pain (Q2) (0.51 [0.46-0.56]), peripheral joint pain (Q3) (0.08 [0.04-0.12]) and severity of morning stiffness (Q5) (0.08 [0.03-0.13]), and BASFI (0.14 [0.08-0.19]) were independently associated with a higher BAS-G over time (Table 1). In the autoregressive GEE model, all variables except for the BASDAI Q5 showed true longitudinal associations with BAS-G. Age, gender and educational level were neither effect modifiers nor confounders.Table 1.Factors associated with BAS-G over time.Multivariable GEE modelMultivariable autoregressive GEE model §Coefficient (95% CI)Coefficient (95% CI)BASDAI Q1 (fatigue, 0-10)0.17 (0.13 to 0.22)*0.15 (0.10 to 0.20)*BASDAI Q2 (back pain, 0-10)0.51 (0.46 to 0.56)*0.54 (0.47 to 0.60)*BASDAI Q3 (peripheral joint pain, 0-10)0.08 (0.04 to 0.12)*0.13 (0.08 to 0.19)*BASDAI Q4 (enthesitis, 0-10)0.03 (-0.01 to 0.07)0.02 (-0.04 to 0.08)BASDAI Q5 (severity of morning stiffness, 0-10)0.08 (0.03 to 0.13)*0.06 (-0.01 to 0.13)BASDAI Q6 (duration of morning stiffness, 0-10)0.03 (-0.01 to 0.07)0.05 (-0.01 to 0.11)SJC28 (0-28)0.01 (-0.11 to 0.13)0.10 (-0.11 to 0.31)TJC53 (0-159) ¶-0.01 (-0.02 to 0.01)-0.01 (-0.03 to 0.01)MASES (0-39)0.00 (-0.02 to 0.02)-0.00 (-0.03 to 0.02)CRP (mg/L)0.01 (-0.00 to 0.01)0.00 (-0.01 to 0.01)Any EAM (presence vs absence)-0.05 (-0.21 to 0.11)-0.09 (-0.28 to 0.10)BASFI (0-10)0.14 (0.08 to 0.19)*0.08 (0.00 to 0.16)*BASMI linear (0-10)-0.07 (-0.16 to 0.02)-0.10 (-0.22 to 0.02)mNY grading (0-8)0.01 (-0.03 to 0.06)0.06 (0.01 to 0.12)*mSASSS (0-72)-0.01 (-0.04 to 0.02)0.00 (-0.03 to 0.04)* p-value < 0.05¶ Each joint graded 0-3§Adjusted for the outcome (i.e. BAS-G) one year before, in order to disentangle the cross-sectional and longitudinal relationships between outcomes and allow the interpretation of a longitudinal relationshipConclusion:A higher level of back pain was associated with a worsening of the patient’s well-being in early axSpA, as were, though to a lesser extent, higher levels of fatigue, morning stiffness, peripheral joint pain and physical disability. Contextual factors like age, gender and educational level did not have an impact on these relationships. Thus, the previously proposed framework of disease outcomes also applies to patients with early axSpA and to outcomes over time.References:[1]Machado, P. ARD 2011.Disclosure of Interests:Fumio Hirano Paid instructor for: Ono pharmaceuticals, Astellas Pharma Inc, Sumitomo Dainippon Pharma, Chugai Pharmaceutical Co., Ltd., Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Floris A. van Gaalen: None declared, Robert B.M. Landewé Consultant of: AbbVie; AstraZeneca; Bristol-Myers Squibb; Eli Lilly & Co.; Galapagos NV; Novartis; Pfizer; UCB Pharma, Cecile Gaujoux-Viala: None declared, Sofia Ramiro Grant/research support from: MSD, Consultant of: Abbvie, Lilly, Novartis, Sanofi Genzyme, Speakers bureau: Lilly, MSD, Novartis

Background:In RMDs, the physician’s global assessment (PhGA) is a major factor of treatment decision. It is not well-known which disease manifestations contribute to PhGA in early axSpA and if contextual factors have an impact.Objectives:To investigate determinants of PhGA and the influence of contextual factors on this relationship in patients with early axSpA.Methods:Five-year data from DESIR, a cohort of early axSpA, were analysed. Clinical data were collected every 6 months up to 2 years and annually thereafter. The primary analysis included all patients, and the subgroup analysis patients with follow-up MRI at 2 and/or 5 years. PhGA over 5 years was the outcome of interest. Univariable generalized estimating equation (GEE) models were used to investigate relationships between potential determinants and PhGA. Longitudinal relationships were investigated in autoregressive models. Effect modification by contextual factors (educational level, gender and age) was tested and, if significant, models were stratified. Univariable analyses were chosen to better assess the contributory explanatory effects of each of the determinants in each of the strata.Results:A total of 708 patients were included, mean age 33.7 (SD 8.6) years, 46% male, 41% lower educated. The subgroup consisted of 220 patients with similar characteristics. Higher BASDAI questions 1-6, SJC28, TJC53, Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), CRP and BASMI were associated with a higher PhGA (Table 1). Gender and age were effect modifiers of SJC28; the effect was largest in the younger male stratum (β [95% CI]; 1.07 [0.71, 1.43]), and smallest in the older female stratum (0.13 [0.04, 0.22]) (Figure 1). Autoregressive GEE models revealed the same determinants of PhGA and the same pattern of effect modification by gender and age.Table 1.Factors associated with PhGA over time in gender/age-stratified groups in univariable analysisFemale/Older(n=200)Female/Younger(n=181)Male/Older(n=154)Male/Younger(n=173)Coefficient (95% CI)BASDAI Q1 (fatigue, 0-10)0.39 (0.34, 0.44)0.39 (0.34, 0.44)0.41 (0.35, 0.46)0.46 (0.41, 0.51)BASDAI Q2 (back pain, 0-10)0.49 (0.45, 0.54)0.53 (0.49, 0.57)0.48 (0.43, 0.53)0.58 (0.54, 0.63)BASDAI Q3 (peripheral joint pain, 0-10)0.31 (0.27, 0.36)0.36 (0.31, 0.41)0.32 (0.27, 0.37)0.43 (0.37, 0.48)BASDAI Q4 (enthesitis, 0-10)0.37 (0.33, 0.41)0.42 (0.37, 0.46)0.36 (0.31, 0.41)0.52 (0.47, 0.56)BASDAI Q5 (severity of morning stiffness, 0-10)0.42 (0.37, 0.46)0.45 (0.40, 0.49)0.44 (0.40, 0.49)0.58 (0.54, 0.63)BASDAI Q6 (duration of morning stiffness, 0-10)0.30 (0.25, 0.35)0.35 (0.30, 0.39)0.36 (0.31, 0.41)0.50 (0.45, 0.56)BASMI linear (0-10)0.61 (0.45, 0.78)0.67 (0.48, 0.86)0.49 (0.30, 0.68)0.95 (0.75, 1.15)SJC28 (0-28)0.13 (0.04, 0.22)0.52 (0.31, 0.73)0.58 (0.40, 0.76)1.07 (0.71, 1.43)TJC53 (0-159) ¶0.05 (0.04, 0.06)0.13 (0.11, 0.16)0.13 (0.11, 0.16)0.15 (0.13, 0.18)MASES (0-39)0.10 (0.08, 0.12)0.15 (0.12, 0.17)0.18 (0.14, 0.23)0.30 (0.25, 0.35)CRP (mg/L)0.02 (0.01, 0.04)0.03 (0.01, 0.05)0.06 (0.04, 0.07)0.04 (0.03, 0.05)Any EAM (presence vs absence)-0.13 (-0.49, 0.23)-0.20 (-0.58, 0.19)-0.26 (-0.68, 0.17)-0.28 (-0.69, 0.14)SPARCC-spine (0-414) §0.06 (-0.11, 0.22)0.05 (-0.11, 0.20)0.02 (-0.03, 0.06)0.05 (-0.04, 0.14)SPARCC-SIJ (0-72) §-0.02 (-0.13, 0.09)0.01 (-0.08, 0.10)0.05 (-0.01, 0.11)0.01 (-0.04, 0.06)¶ Each joint graded 0-3§ Coefficients were estimated in the subgroupConclusion:Patient’s subjective symptoms, peripheral arthritis, enthesitis, higher CRP and impaired spinal mobility contribute to explain PhGA in patients with early axSpA irrespective of gender and age. But physicians consider the presence of swollen joints as more important in males than in females.Disclosure of Interests:Fumio Hirano Paid instructor for: Ono pharmaceuticals, Astellas Pharma Inc, Sumitomo Dainippon Pharma, Chugai Pharmaceutical Co., Ltd., Robert B.M. Landewé Consultant of: AbbVie; AstraZeneca; Bristol-Myers Squibb; Eli Lilly & Co.; Galapagos NV; Novartis; Pfizer; UCB Pharma, Floris A. van Gaalen: None declared, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Cecile Gaujoux-Viala: None declared, Sofia Ramiro Grant/research support from: MSD, Consultant of: Abbvie, Lilly, Novartis, Sanofi Genzyme, Speakers bureau: Lilly, MSD, Novartis

The thermal expansion behavior of sintered samples of Gd 1− x Sr x MnO 3 ( X = 0.0–0.4) was studied. The sintered bodies in this system showed negative thermal expansion over a wide temperature range. The detailed crystal structure refinements with respect to temperature showed that the volume of the orthorhombic perovskite lattice monotonically increased with temperature, however, in addition to this, the release of distortion from the Jahn-Teller effect of Mn 3+ ion occurred over a wide temperature range, which brought the negative expansion of the a -axis, although the b - and c -axes increased with temperature. The anomalous thermal expansion is explained by the sum of the effects of the shrinkage of the a -axis and absorption of the b - and c -axes' expansion by the pores in the sintered body.

The proto-oncoprotein Bcl-3 is a member of the IkappaB family and is present predominantly in the nucleus. To gain insight into specific nuclear functions of Bcl-3 we have isolated proteins that interact with its ankyrin repeat domain. Using the yeast two-hybrid-system we identified four novel binding partners of Bcl-3 in addition to NF-kappaB p50 and p52, previously known to associate with Bcl-3. The novel Bcl-3 interactors Jab1, Pirin, Tip60 and Bard1 are nuclear proteins which also bind to other transcription factors including c-Jun, nuclear factor I (NFI), HIV-1 Tat or the tumor suppressor and PolII holoenzyme component Brca1, respectively. Bcl-3, p50, and either Bard1, Tip60 or Pirin are sequestered into quarternary complexes on NF-kappaB DNA binding sites, whereas Jab1 enhances p50-Bcl-3-DNA complex formation. Furthermore, the histone acetylase Tip60 enhances Bcl-3-p50 activated transcription through an NF-kappaB binding site, indicating that quarternary complexes containing Bcl-3 interactors modulate NF-kappaB driven gene expression. These data implicate Bcl-3 as an adaptor between NF-kappaB p50/p52 and other transcription regulators and suggest that its gene activation function may at least in part be due to recruitment of the Tip60 histone actetylase.

The popularity of applying filtering theory in the environmental and hydrological sciences passed its first climax in the 1970s. Like so many other new mathematical methods it was simply the fashion at the time. The study of groundwater systems was not immune to this fashion, but neither was it by any means a prominent area of application. The spatial-temporal characteristics of groundwater flow are customarily described by analytical or, more frequently, numerical, physics-based models. Consequently, the state-space representations associated with filtering must be of a high order, with an immediately apparent computational over-burden. And therein lies part of the reason for the but modest interest there has been in applying Kalman filtering to groundwater systems, as reviewed critically in this paper. Filtering theory may be used to address a variety of problems, such as: state estimation and reconstruction, parameter estimation (including the study of uncertainty and its propagation), combined state-parameter estimation, input estimation, estimation of the variance-covariance properties of stochastic disturbances, the design of observation networks, and the analysis of parameter identifiability. A large proportion of previous studies has dealt with the problem of parameter estimation in one form or another. This may well not remain the focus of attention in the future. Instead, filtering theory may find wider application in the context of data assimilation, that is, in reconstructing fields of flow and the migration of sub-surface contaminant plumes from relatively sparse observations.

Temperature rises of various oils were measured in both impact tests and quasi-adiabatic compression tests. A steel ball impacted against an oiled sapphire glass in the impact test. It was found that the maximum temperature rise was 45 °C in impact tests. A close relationship between temperature rise and α amax was found for oils of relatively low viscosity, where α was the pressure-viscosity coefficient and amax was the maximum acceleration of the hammer during impact; namely, the temperature increased with each increase in the product of the contact force and the pressure-viscosity coefficient. In the compression tests, the temperature increased almost linearly with increase in the volumetric strain regardless of the type of oil. The order of the temperature rise for the corresponding oil in each experiment was reversed; i.e. a higher temperature increase was observed for an oil of smaller pressure-viscosity coefficient in the compression test. On the contrary, a higher temperature rise was noted in the case of a larger pressure-viscosity coefficient in the impact test. As far as the temperature rise is concerned for entrapped oil in the impact tests, there exists an optimum combination of viscosity and pressure-viscosity coefficient.

The therapeutic effectiveness of ursodeoxycholic acid (UDCA) for various autoimmune liver diseases strongly indicates that UDCA possesses immunomodulatory activities. Experimental evidence also supports this notion, since, for example, UDCA has been shown to suppress secretion of IL-2, IL-4, and IFN-gamma from activated T lymphocytes, and Ig production from B lymphocytes. To investigate the mechanical background of UDCA-mediated immunomodulation, we asked whether UDCA interacts with the intracellular signal transduction pathway, especially whether it is involved in immunosuppressive glucocorticoid hormone action. For this purpose, we used a cloned Chinese hamster ovary cell line, CHOpMTGR, in which glucocorticoid receptor cDNA was stably integrated. In immunocytochemical analysis, we found that treatment with UDCA promoted the nuclear translocation of the glucocorticoid receptor in a ligand-independent fashion, which was further confirmed by immunoprecipitation assays. Moreover, the translocated glucocorticoid receptor demonstrated sequence-specific DNA binding activity. Transient transfection experiments revealed that treatment of the cells with UDCA marginally enhanced glucocorticoid-responsive gene expression. We also showed that UDCA suppressed IFN-gamma-mediated induction of MHC class II gene expression via the glucocorticoid receptor-mediated pathway. Together, UDCA-dependent promotion of translocation of the glucocorticoid receptor may be associated with, at least in part, its immunomodulatory action through glucocorticoid receptor-mediated gene regulation.

The performance of a stochastic numerical modelling procedure to simulate dispersion of a conservative solute in two-dimensional heterogeneous hydraulic conductivity fields is investigated in a series of numerical experiments, the results of which are compared with theoretical predictions. Random hydraulic conductivity fields are generated with a prescribed statistical structure, a finite difference model is used to obtain the flow field and particle tracking reproduces the dispersive properties. For comparison between stochastic numerical methods and stochastic theories for solute transport, fulfilment of the ergodic requirement is necessary, consequently aspects of simulated solute plume behaviour are investigated with respect to ergodicity. Application of numerical stochastic methods is hampered by the large associated computational burden, which is affected by a range of factors, not least the level of discretisation of the hydraulic conductivity field. The experiments detailed here investigate the effects of hydraulic conductivity discretisation and the effects of initial solute source area for a range of log—permeability variances. An increasing deviation from Dagan's linear theory is observed for increasing coarseness of discretisation. A tendency to ergodic conditions is found for a smaller initial source area than previously reported.

RANKL is known to play an important role in activating osteoclasts and advancing the progress of osteoporosis. However, little is known about the effect of bisphosphonates on glucocorticoid-induced RANKL expression in human cells. Our study was intended to clarify effects of bisphosphonates on glucocorticoid-induced RANKL expression in human cells.Human T lymphoblastic cell line Jurkat and human osteosarcoma cell line MG-63 were used for the following experiments. RANKL expression in two cell lines was measured using reverse transcription polymerase chain reaction (RT-PCR) analysis and enzyme immunoassay (EIA). Luciferase assays using pGRE-Luc were also performed.In Jurkat and MG-63 cells, dexamethasone induced expression of soluble RANKL (sRANKL) protein in supernatants and RANKL mRNA in cells. Moreover, bisphosphonates, but not cyclooxygenase inhibitors, repressed dexamethasone-induced sRANKL protein production. By contrast, glucocorticoid receptor-driven transcriptional activity was not inhibited by bisphosphonates.Glucocorticoid induced RANKL expression in human cells derived from T lymphocytes and osteoblasts. Bisphosphonates inhibited glucocorticoid-induced RANKL expression, suggesting that these effects might be a new therapeutic mechanism for bisphosphonates.

To examine the effect of thrombin on nuclear factor (NF)-kappaB activation and cell proliferation in synovial cells from patients with rheumatoid arthritis (RA).Using cultured human synovial cells from patients with RA, electrophoretic mobility shift assay, [3H]thymidine incorporation assay, and MTT assay were performed. We tested the upregulatory effects of thrombin on NF-kappaB activation and cell proliferation. The effect of thrombin on degradation of IkappaB was analyzed by Western blot.Thrombin transiently induced DNA-binding activity of NF-kappaB, followed by degradation of IkappaBalpha, but not IkappaBbeta1. Moreover, synovial cell proliferation was stimulated by thrombin in a dose dependent manner. The kinetics of synovial cell proliferation induced by thrombin were almost parallel to those of NF-kappaB activation. Supershift analysis revealed that thrombin induced DNA-binding complexes were made up principally of the p65 and p50 Rel family members. Further, protein kinase C inhibitor calphostin C repressed thrombin induced NF-kappaB activation and cell proliferation in synovial cells.Thrombin stimulates synovial cell proliferation involved in NF-kappaB activation, at least in part, through a protein kinase C mediated pathway, possibly indicating that thrombin plays an important role in synovial hyperplasia in RA.

In inflamed periodontal lesions, dense infiltration of lymphocytes is usually observed in the extravascular periodontal connective tissue, adjacent to gingival fibroblasts. Our previous study revealed that activated lymphocytes can adhesively interact with gingival fibroblasts in vitro. In the present study, we investigated whether gingival fibroblasts are activated through direct interaction with lymphoid cells by monitoring the expression of inflammatory cytokine mRNA in human gingival fibroblasts (HGF). Co-culture with various human lymphoid cells in vitro resulted in a marked increase in the expression of IL-1alpha, IL-1beta, and IL-6 mRNA by the HGF. In addition, expression of the mRNA of the IL-1beta-converting enzyme (ICE), which is essential to produce the mature form of IL-1beta, was constitutively observed in the HGF, suggesting that mature IL-1beta is produced by these cells. When HGF were cultured with the culture supernatant of the lymphoid cells, the increase in the inflammatory cytokine mRNA expression was not observed. Similarly, when HGF and lymphoid cells were cultured in the same well but separated by a membrane which prevented direct contact between the cells, no increase in inflammatory cytokine mRNA expression was observed. These results strongly indicate that direct interaction between these heterotypic cell types transduces activation signals into HGF that induce an increase in inflammatory cytokine mRNA expression. Furthermore, IL-1beta mRNA expression in the HGF was synergistically increased when HGF directly interacted with lymphoid cells in the presence of exogeneous IL-1beta. The present study demonstrates that direct interaction between HGF and lymphoid cells stimulates HGF to increase inflammatory cytokine mRNA expression, and raises the possibility that heterotypic cell-cell interaction may facilitate local inflammatory reactions.

CD44 functions as a receptor for various extracellular matrices and plays crucial roles in homotypic and heterotypic cell-cell interactions. Recently, the molecular structure of CD44 has been extensively analyzed and multiple isoforms produced by alternative splicing of messenger RNA have been identified. In this study, we examined the expression of CD44 isoforms on different cell types isolated from periodontal tissue. In order to examine tissue differences in CD44 isoform expression, we established in vitro cell culture of human gingival fibroblasts (HGF), human periodontal ligament cells (HPDL) and human gingival epithelial cells (HGEC). These cells all expressed CD44 protein and messenger RNA. However, immunoprecipitation and Northern blot analysis revealed that HGEC expressed larger CD44 isoforms than HGF and HPDL. Reverse transcription-polymerase chain reaction with primers flanking the insertion site of alternatively spliced exons was used to study details of the heterogeneity. All cells examined expressed a major band in the absence of alternatively spliced exons and additional larger bands. In particular, HGEC contained more abundant high molecular mass species. In vitro stimulation by IL-1 beta, TNF alpha or phorbol 12-myristate 13-acetate induced an increase in total CD44 messenger RNA in HGF but not change in overall patterns of CD44 isoform expression. However, the isoform expression of HGEC was sensitive to cell density. The amount of larger isoform was decreased by culturing cells beyond confluence. These findings suggest that CD44 isoform expression is cell type-specifically regulated in periodontium and altered according to growth phase of HGEC.

EHL oil film thickness measurements for rape seed oil, camellia oil. olive oil. castor oil and glycerol have been carried out by optical interferometry. The experimental results showed that the central film thickness of castor oil and glycerol under rolling conditions was 0.5-0.9 times thinner compared with the Hamrock - Dowson central film thickness formula. This fact was considered to be attributed to their poor wettability at the liquid/solid interface, which was estimated by observing the contact angle with the aid of a goniometer. Furthermore, the largest contact angle of glycerol was lowered by adding surfactant and brought about an increase in film thickness. It is suggested that the interfacial phenomena near the inlet side of the EHL contact region affects the EHL central film thickness, in particular, in case of vegetable oils and glycerol. Further, comparing oils with equal viscosity grades, vegetable oils with lower pressure-viscosity coefficients show lower traction coefficients than the paraffinic mineral oils. The effect of wettability on the traction coefficient was unrecognized.

This paper deals with diagrams for estimation of the film thickness at point contacts based upon observation by means of optical interference at pressures, sufficiently high to cause solidification of lubricants. The observed minimum film thickness at rolling contact is plotted here in the form the Greenwood's parameter H K min = h min /(αan O u) 2 / 3 R 1 / 3 . This serves to estimate the minimum thickness with sufficient accuracy under wide conditions of circular and elliptic contacts. It is noted that in the solidification ranges VE (viscoelastic) and EP (elastic-plastic) larger thickness is formed. The upper parts of these thickness curves are limited by the boundary of the PR (piezoviscous-rigid) range defined by Houpert.

Primary biliary cirrhosis is known as an autoimmune chronic cholestatic disease and characterized by various immunological abnormalities. Especially, the aberrant expression of major histocompatibility complex (MHC) class I antigens on hepatocytes has been considered to have a pivotal role in the pathogenesis and progression of the disease. However, the underlying mechanism of this aberrant expression of MHC class I molecules has not yet been clarified. In the present study we showed that MHC class I immunoreactivities were increased by treatment with chenodeoxycholic acid (CDCA) in the human hepatoma cell line HLE. Moreover, CDCA treatment of the cells increased the steady-state levels of MHC class I mRNA. Since CDCA is one of major constituents of endogenous bile acids in cholestasis, these results suggest that intrahepatic cholestasis, which is almost inevitably associated with PBC, increases both production and surface expression of MHC class I antigens in hepatocytes.

Flow cytometry analysis was performed to investigate the modifications to the T lymphocytes in peripheral blood, the spleen, and two intrahepatic lymphocyte fractions--the intrahepatic lymphocyte fraction 1 (IHL Fr.1), which is easily washed out from the liver by perfusion of collagenase solution, and the intrahepatic lymphocyte fraction 2 (IHL Fr.2), which remains in the liver after the perfusion--occurring in the liver regeneration process after partial hepatectomy of mice. The following findings were obtained: 1) The nontreated murine liver contains Thy 1.2+ cells, alpha beta TCR+ cells, gamma delta TCR+ cells, CD4+ cells, and CD8+ cells. 2) The percentage of each T-cell subset in IHL Fr.1 shows an intermediate value between that in the peripheral blood lymphocytes (PBL) and that in the IHL Fr.2. 3) One day after partial hepatectomy, the Thy 1.2+ cells, alpha beta TCR+ whole cells, and CD4+ cells in IHL Fr.2 all showed a transient, yet significant, decrease, but did not reveal any major change in the other fractions. 4) Both the alpha beta TCR dull+ cells and the CD8+ cells showed practically no change after partial hepatectomy in any of the fractions. This indicates that the alpha beta TCR dull+ cell/alpha beta TCR+ whole cell and the CD8+ cell/CD4+ cell ratios show a significant increase 1 day after partial hepatectomy only in the IHL Fr.2. Double-positive cells, which were scarcely found in the spleen of nontreated mice, appeared in the spleen after partial hepatectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

A 43-year-old man who presented parkinsonism due to pontine and extrapontine myelinolysis was reported. Late in February, 1990, the patient presented suffered from a flu-like illness and was seen at a community hospital. Physical finding showed the pigmentation on the whole body and hypotension, and laboratory examination revealed severe electrolyte imbalance (serum sodium 100 mEq/l, serum potassium 6.9 mEq/l, serum chloride 68 mEq/l) and hypoglycemia (postprandial serum glucose 78 mg/dl). Given these results, adrenal failure was strongly suspected. Prompt correction of electrocyte imbalance was performed by the infusion of sodium chloride, and four days later the serum sodium level reached 131 mEq/l. On the other hand, the patient was noticed lethargic and showed parkinsonism i.e., rest tremor, cog-wheel rigidity, and hypokinesia. Fourteen days after the onset of neurological abnormalities, the patient was referred to our hospital for further evaluation of parkinsonism. Additionally, neurological examination revealed dysphagia, mutism and positive pyramidal tract sign. On admission brain computed tomography was unremarkable, but on the 14th hospital day it showed low density area in the pons. Brain magnetic resonance imaging also showed a striking increase in T2-weighted signal from the pons, the midbrain, and the bilateral thalamus. Based on these findings, a diagnosis of parkinsonism due to pontine and extrapontine myelinolysis was made, and levodopa therapy was started. After the initiation of levodopa therapy, improvement of tremor, rigidity, and hypokinesia ensued with marked functional benefit, and the patient was discharged on the 49th hospital day. Levodopa was stopped three weeks after discharge but, all neurological abnormalities were not recurrent.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral administration of a hot-water extract (Folin) of bamboo grass (Sasa albomarginata MakinoShibata) significantly reduced the incidence of water-immersion and restraint stress-, ethanol-induced and indomethacin-induced gastric ulcers in rats. Histological examination of the Folin-treated gastric mucosa showed that microscopic blood clots overlaid the superficial epithelium, maintaining the cellular integrity of gastric mucosa, especially against stress ulcer. In addition, Folin suppressed the incidence of hyperaemia and a decline of acid mucopolysaccharides in the ethanol-induced ulcer. Folin suppressed a release of histamine from rat mast cells, and stabilized erythrocytes and accelerated their agglutination under acid conditions. These results suggest that a microscopic haemostatic effect of Folin reinforced by a membrane-stabilizing effect might be responsible for the prevention of the gastric lesions.

Influences of following factors upon the severity of asperity contacts and the life-to-pitting were investigated using rolling/sliding contact of two rollers; (1) the nature of drive, i.e., drive ratio of 1:1, one of 29:28 and friction drive, (2) characteristics of surface topography, (3) slide/sweep ratio. As results, combined effects of these factors were found and the conclusive remarks were consistent with the results of gear tests which were carried out using gear ratios 1:1 and 27:25. The authors discuss the mechanism of pitting from the point of view of the asperity interaction.

As a fundamental investigation of gas/liquid two-phase lubrication under reciprocating conditions, the behaviour of oil films between a reciprocating plate and a stationary optical flat was observed. It was found that under reciprocating conditions the dynamic behaviour of oil films with free boundaries was influenced by complicated interfacial phenomena, showing creep, notching and separation of their contours. Analysis of the results clarified the influencing factors and the inherent conditions in the characteristics types of film contours

The actual ball behaviour during one cage revolution was investigated by using a new measuring method for three-dimensional ball motion. From the experimental results, periodic ball motion with slip was recognized and according to the differences in ball behaviour distinct peripheral regions of the bearing could be discerned.

Recently, a new method for measuring ball motions three dimensionally was developed by one of the present authors and its principle was reported in the previous paper. Before its practical applications were examined, the calibration tests were carried out and the outputs obtained by this new method were compared with the values expected theoretically. By compensating for some undesirable effects, it was confirmed that the outputs were sufficient to analyse actual ball motions within an experimental error of 5%. In order to demonstrate its usefulness, an example of experimental results obtained by this new technique is shown.

Using a modified Timken machine, the effect of the addition of different phosphate esters to paraffinic base oils on their lubricating performance was investigated. The aryl phosphate ester tricresyl phosphate (TCP) has a greater resistance to scuffing than the alkyl phosphate ester trioctyl phosphate (TOP) when used as a lubricant. In contrast, base oils containing TOP are superior to those containing TCP, although phosphate esters are effective only in base oils of higher viscosity than the esters. The lubricating performance of high viscosity base oils containing TOP is improved by coupling the ability of TOP to form a beneficial surface film with the ability of the base oils to build up thick oil films. The addition of TCP, which has a higher adsorption ability but a lower reactivity than TOP, seems, however, to prevent the formation of the oxide film which is formed with base oils alone owing to the marked ability of TCP to adhere to a metal surface. In addition, because of the low reactivity of TCP, iron phosphate is hardly formed. Consequently, the addition of TCP increases the scuffing load of the base oils but has the disadvantage of increasing the coefficient of friction.

Using a series of straight mineral oils with a variety of molecular weight distributions failure loads of spur gears with gear ratios 27:25 and 1:1 were investigated. The failure loads in the case of the synchronous engagement 1:1 were considerably higher than those in the asynchronous engagement 27:25 as a result of imprinting of asperities of harder teeth on softer engaged teeth. The correlation among the results was found to be quite regular, showing the beneficial effect of wide-ranged oils in the molecular weight distribution. Summarizing the obtained results, it is concluded that the failure loads of narrow-ranged oils were conditioned by their viscosity grades, and that those of wide-ranged oils increased further with the aid of oxide film formation on teeth. Results of four-ball tests and two-disk tests previously carried out under mild conditions using the same narrow-ranged and wide-ranged oils show the similar feature to those of the gear tests.

The authors carried out an experimental investigation on the fatigue failure of engine bearings by means of a combination of a slider and bearing metal on a reciprocating bed. Cracks were generated under the condition of mixed lubrication in the vicinity of the contact areas at the stroke ends of the reciprocating bed, where the friction force abruptly increased and reversed its direction. A unique relation similar to the usual fatigue curve was obtained by plotting the friction force against the cycles to failure in place of normal load. The conclusion was further confirmed by an experiment using another testing machine generating an alternating tangent force without sliding.

In order to investigate the effect of solid particles in lubricating oils, systematic research was carried out using a four-ball machine. The effects of hardness, concentration of particles and viscosity of oil were specially taken into consideration. Softer particles like metal powder do not penetrate into the contact surfaces, but accumulate at the front of the contact area and disturb the formation of an oil film, causing a slight amount of abrasion. On the other hand, particles such as quartz powder or carborundum are easily introduced into the contact area, causing marked increase in abrasion. There is a straightforward relationship between the area of impression and the concentration of particles. The test with the Timken machine gives similar results.

Dibekacin sulfate (DKB) dissolved in physiological saline J.P. was administered to rats intraperitoneally and rabbits intravenously for subacute 35-day toxicity test. The results were as follows: I. Wistar-strain rats (1) All the animals of both male and female died in the group with 500 mg/kg. (2) In general conditions stretching physical positions, decrease in spontaneous movements, decrease in respiration rates, unsteady steps of walking and muscular relaxation developed in the groups of high doses of either sex. The effects through the administration of this drug were also noted on the progress of body weights and food intakes in the groups of high doses. (3) In the hematological and histopathological studies, degenerative and reparative changes of tubular epithelia were evidently noted in the groups which were administered more than 100 mg/kg of DKB in both male and female. No pathological findings were noted in administration groups less than 20 mg/kg. (4) Microscopically, slight inflammatory changes were noted in the bladder of the male groups of high doses and the direct stimulative effects on the peritoneum due to intraperitoneal administration were noted but slightly in the serous membrane of the liver, spleen and the gastrointestinal tracts. (5) Judging from the above-mentioned results, "the maximal non toxic dose" through the intraperitoneal administration to rats of this drug was assumed 20 mg/kg in either sex. II. Albino rabbits (1) Neither remarkable change in the general conditions nor death was noted in each administration group. (2) The increase in the mean body weight in each group was almost similar to the control value. They consumed the amounts of food given. (3) The specific abnormal finding was not noted in the hematology and biochemical tests of serum or urine. (4) Since no change was noted on ERG in each rabbits, we estimate there is no effect to the visual organs. (5) In histopathological study, several changes revealed in some organs through the macroscopic findings, organ weights and microscopic findings but they were no more the serious changes attributable to administration. (6) We estimate "the maximal non effective dose" in this test was 10 mg/kg.

A 54-year-old male complaining mainly of pain in the right terminal rib area was admitted to hospital for hepatic tumor examination. Cholangiocarcinoma was diagnosed by various imaging techniques, and the patient was started on a program of daily oral administrations of 600 mg of UFT after abdominal arterial injection of 30 mmg of MMC. The tumor continued to decrease in size on CT image during two years of UFT administration. The patient continues to be monitored as an outpatient. A marked reduction in the size of a cholangiocarcinoma was observed in the case, and administration of UFT has proved effective in prolonging life for over two years.

Mutagenicity of MT-141, a new cephamycin, was evaluated by in vitro and in vivo assays. MT-141 did not induce mutations of the test strains, Escherichia coli WP2 (uvr A) and Salmonella typhimurium TA1535, TA1537, TA1538, TA100 and TA98, with and without metabolic activation in vitro. In bone marrow micronucleus assay with male mice, MT-141 showed no induction of micronucleated polychromatic erythrocyte at 6 hours and 30 hours after administration. In addition MT-141 was found not to cause any dominant lethal effects on male mice for 8 weeks after administration.

Although so far a number of studies concerning the mechanical aspects of the running-in process in tribology have been carried out, a little attention has been attracted to the tribochemical aspects of the running-in process. In order to clarify this question, first the authors dealt with the effect of the oxide film formation under repeated four-ball tests, where the tribochemical running-in process played a significant role. The results were presented at the 6th Leeds-Lyon Symposium in 1979. At the next stage, combinations of repeated four-ball tests of squalane with and without DBDS-additive were investigated. For the purpose of examination of surface films formed on the rubbing surfaces, X-ray microanalysis, X-ray photoelectron spectroscopy (ESCA) and electron diffraction technique have been used. It is concluded that the effect of DBDS should be considered also in connection with its contribution to the oxide film formation

The toxic effects of dibekacin sulfate (DKB) in male and female rats were examined in chronic toxicity test (intraperitoneal injection), and the following results were obtained. 1) No death was noted in both male and female. 2) In general conditions, the excretion of soft or diarrheal stool was noted in groups of more than 20 mg/kg of either sex. The mean body weight was less than the control during a certain period in the male group of 40 mg/kg and in the female group of 20 mg/kg. But, in the food intakes, no particular change was noted in each group of either sex. 3) In the auricle reflex, no abnormality was noted in each group of either sex. 4) In the hematological test, the findings such as an increase of BUN, anemia, etc. were noted in the groups more than 10 mg/kg of male and more than 20 mg/kg of female. 5) In the histopathological study, evident degenerative changes of renal tubular epithelia were noted in the groups which were administered more than 20 mg/kg of DKB in both male and female, but no evident pathological findings due to the renal failure were noted in the groups of less than 10 mg/kg. Several slight changes of the thyroid gland noted in a few rats of DKB administration group of both male and female seemed to be artifact, and inflammatory changes owing to intraperitoneal injection were occasionally noted in the peritoneum of DKB injected animals. 6) Considering the above results, "the maximal non effective dose" was estimated to be 10 mg/kg in both male and female.

Against 17 Gram-negative bacteria, excluding Proteus species, the difference between cefminox and cefotaxime was significant in terms of MIC distribution, in favour of cefotaxime, but was not significant in terms of ED50 distribution. Against 22 Proteus species, the difference between cefminox and cefotaxime was not significant in terms of MIC distribution, but was significant for ED50 distribution, in favour of cefminox. The difference between cefminox and cefoperazone was not significant for either MIC or ED50 distribution against 17 Gram-negative bacteria, but was significant against 22 Proteus species, in favour of cefminox. The distribution of rank of the ED50/MIC ratios for cefminox was significantly lower than those for cefotaxime and cefoperazone, indicating that cefminox showed lower ED50 values than expected from the MIC values.