Anti-fibrotic Effects of ONO-EF-345, a Specific Phosphodiesterase IV inhibitor, on Lung Fibroblasts

Phosphodiesterase (PDE) IV inhibitors have been shown to inhibit various inflammatory reactions in pulmonary diseases such as bronchial asthma and chronic obstructive lung diseases (COPD). However, there have been no studies evaluating the effect of PDE IV inhibitors on airway fibrosis, which is a critical feature of airway remodeling in asthma and COPD. We therefore examined whether ONO-EF-345 (ONO), a PDE IV inhibitor, affected the function of lung fibroblasts. ONO suppressed TGF-ß-induced type I collagen (COL1) mRNA expression in lung fibroblasts and also inhibited TGF-ß-induced a- smooth muscle actin (SMA) protein expression. ONO did not affect Smad2 phosphorylation or Smad7 expression. However, ONO reduced JNK and p38 activation, which regulates TGF-ß-induced COL1 expression. These results indicate that PDE IV inhibitors exert anti-fibrotic effects through the JNK and/or p38 pathways

Validation of the Ten-Item Internet Gaming Disorder Test (IGDT-10) based on the clinical diagnosis of IGD in Japan

Background and aims: Although the Ten-Item Internet Gaming Disorder Test (IGDT-10) has been translated into Japanese and widely used, the Japanese version has not previously been validated. We used the clinical diagnosis of IGD as a gold standard for validating the test. Methods: The Japanese version was validated using 244 gamers drawn from the general young population in Japan. Expert interviews using the Japanese version of the Structured Clinical Interview for Internet Gaming Disorder evaluated diagnoses of Internet gaming disorder (IGD). This resulted in a diagnosis of IGD for eight individuals, categorized as the gold standard group. The screening performance of the two Japanese versions with different scoring conditions was examined: the scoring method proposed by the original study (original version) and a less stringent scoring method where responses of either “often” or “sometimes” were regarded as affirmative (modified version). Results: The results of the sensitivity and specificity analyses, the Cronbach’s alpha and the receiver operating characteristics analysis revealed a higher screening performance for the modified versus the original version. The optimum cutoff for the modified version was 5 or more – the sensitivity, specificity, and Youden’s index were 87.5, 85.2, and 72.7%, respectively. The rate of probable IGD using the original and modified versions were 1.8% and 11.3%, respectively. Discussion and conclusion: A less stringent scoring method for the Japanese version of IGDT-10 showed a higher screening performance than the original scoring method. Future studies comprising different ethnic groups and gaming cultures should further examine the suggested scoring method

IL-10 Inhibits Transforming Growth Factor-ß-Induction of Type I Collagen mRNA Expression via Both JNK and p38 Pathways in Human Lung Fibroblasts

Transforming growth factor-ß (TGF-ß) is a key factor for understanding the pathogenesis of fibrotic disorders such as idiopathic pulmonary fibrosis (IPF). We have demonstrated that interleukin-10 (IL-10) suppresses TGF-ß-induced expression of type I collagen (COL1) mRNA in a human lung fibroblast cell line (WI-38). However, the inhibitory mechanism has not yet been clearly elucidated. Thus, in the current study, we investigate the effects of IL-10 blockade of TGF-ß signaling which regulates COL1 mRNA expression. In WI-38 cells, IL-10 inhibits TGF-ß-mediated phosphorylation of both, c-Jun HN2-terminal kinase (JNK) and p38, but does not suppress TGF-ß- mediated phosphorylation of Smad2 or affect TGF-ß-upregulation of Smad7 mRNA expression. In addition, SP600125 and SB203580, specific inhibitors of JNK and p38, respectively, attenuate TGF-ß-induced COL1 mRNA expression in WI-38 cells. These results suggest that IL-10 inhibits TGF-ß-induced COL1 mRNA expression via both JNK and p38 pathways but not Smad pathways in WI-38 cells. This inhibitory mechanism may provide a novel insight into therapeutic strategies for fibrotic disorders such as IPF

Regression of LV hypertrophy by tafamidis

Transthyretin amyloidosis (ATTR) variant is a life-threatening hereditary disease predominantly affecting the peripheral nervous system and heart. Tafamidis, which prevents the deposition of amyloid by stabilizing transthyretin, is available for the treatment of neuropathy and cardiomyopathy of ATTR. However, whether tafamidis could eliminate established amyloid deposits and improve cardiac function remains unknown. We reported a case of regression of left ventricular hypertrophy after tafamidis therapy in a patient with an ATTR variant

Progression of microstructural deterioration in load-bearing immobilization osteopenia

PurposeImmobilization osteopenia is a major healthcare problem in clinical and social medicine. However, the mechanisms underlying this bone pathology caused by immobilization under load-bearing conditions are not yet fully understood. This study aimed to evaluate sequential changes to the three-dimensional microstructure of bone in load-bearing immobilization osteopenia using a fixed-limb rat model.Materials and methodEight-week-old specific-pathogen-free male Wistar rats were divided into an immobilized group and a control group (n = 60 each). Hind limbs in the immobilized group were fixed using orthopedic casts with fixation periods of 1, 2, 4, 8, and 12 weeks. Feeding and weight-bearing were freely permitted. Length of the right femur was measured after each fixation period and bone microstructure was analyzed by micro-computed tomography. The architectural parameters of cortical and cancellous bone were analyzed statistically.ResultsFemoral length was significantly shorter in the immobilized group than in the control group after 2 weeks. Total area and marrow area were significantly lower in the immobilized group than in the control group from 1 to 12 weeks. Cortical bone area, cortical thickness, and polar moment of inertia decreased significantly after 2 weeks. Some cancellous bone parameters showed osteoporotic changes at 2 weeks after immobilization and the gap with the control group widened as the fixation period extended (P < 0.05).ConclusionThe present results indicate that load-bearing immobilization triggers early deterioration of microstructure in both cortical and cancellous bone after 2 weeks

ランダム化比較試験によるエドキサバン投与下におけるTKA後DVT発生に対するフットポンプの有効性

長崎大学学位論文 [学位記番号]博（医歯薬）甲第986号 [学位授与年月日]平成29年9月20

Vitamin K deficiency, evaluated with higher serum ucOC, was correlated with poor bone status in women

BACKGROUND: An increase in serum undercarboxylated osteocalcin concentrations suggests vitamin K deficiency. Clinical intervention studies suggested that the vitamin K supplementation might contribute to preventing bone loss in postmenopausal women. Evidence on the relationship between serum undercarboxylated osteocalcin (ucOC) levels and bone parameters of quantitative ultrasound (QUS) is limited. We examined the correlation between serum ucOC concentrations and bone status as measured by QUS among middle-aged and older Japanese men and women. METHODS: The subjects were community-dwelling men (n = 358) and women (n = 503) aged ? 40?years in Japan. Heel QUS parameters, including the stiffness index, speed of sound, and broadband ultrasound attenuation, were measured. Serum ucOC concentrations were measured by electrochemiluminescence immunoassay. Grip strength was measured in the dominant hand. Information on alcohol drinking, current smoking, exercise, and menopause in women was collected. RESULTS: Serum ucOC concentrations were significantly associated with age in both sexes. Serum ucOC concentrations in men were higher at ? 80?years than those in the age groups of 40-49, 50-59, and 60-69?years. Serum ucOC concentrations in women were higher in the age groups of 50-59 and 60-69?years than those at 40-49?years. Partial correlation analysis adjusting for covariates (age, body mass index, grip strength, alcohol drinking, current smoking, and exercise in men; age, body mass index, grip strength, alcohol drinking, current smoking, exercise, and menopause in women) showed that serum ucOC concentrations were negatively significantly correlated with all QUS parameters in women. Serum ucOC concentrations were not correlated with them in men. CONCLUSIONS: Vitamin K deficiency, evaluated with higher serum ucOC, was correlated with poor bone status in women

Effect of surface roughness of biomaterials on Staphylococcus epidermidis adhesion

Background: Implant-related infections are caused by adhesion of bacteria to the surface of biomaterials. In this in vitro research, we evaluated the ability of Staphylococcus epidermidis (ATCC35984) to adhere to the surface of solid biomaterials at different levels of roughness below 30 nm Ra and investigated the minimum level of roughness required to promote bacterial adhesion on five kinds of biomaterials: oxidized zirconium-niobium alloy (Oxinium), cobalt-chromium-molybdenum alloy (Co-Cr-Mo), titanium alloy (Ti-6Al-4 V), commercially pure titanium (Cp-Ti) and stainless steel (SUS316L), samples of which were categorized into a fine group and a coarse group according to surface roughness. The test specimens were physically analyzed and the viable bacterial density of the adhered bacteria was quantitatively determined (n = 20).Results: The amount of bacteria that adhered to the biomaterials in the coarse group was higher than those in the fine group. Oxinium, Ti-6Al-4 V and SUS316L in particular demonstrated statistically significant differences between the two groups (P < 0.05). Of the materials, the Co-Cr-Mo specimens exhibited significantly lower amounts of adhered bacteria than the Ti-6Al-4 V, Cp-Ti and SUS316L specimens in the fine group. Similarly, the Co-Cr-Mo specimens in the coarse group exhibited significantly lower values than the other four materials.Conclusions: These results suggest that minimum level of roughness affecting initial bacterial adherence activity differs according to the type of biomaterial used, and that even a surface roughness of below 30 nm Ra in Oxinium, Ti-6Al-4 V and SUS316L can promote bacterial adhesion. Relative hydrophobic Co-Cr-Mo surfaces were less susceptible to bacterial adherence

Early Staphylococcal Biofilm Formation on Solid Orthopaedic Implant Materials: In Vitro Study

Biofilms forming on the surface of biomaterials can cause intractable implant-related infections. Bacterial adherence and early biofilm formation are influenced by the type of biomaterial used and the physical characteristics of implant surface. In this in vitro research, we evaluated the ability of Staphylococcus epidermidis, the main pathogen in implant-related infections, to form biofilms on the surface of the solid orthopaedic biomaterials, oxidized zirconium-niobium alloy, cobalt-chromium-molybdenum alloy (Co-Cr-Mo), titanium alloy (Ti-6Al-4V), commercially pure titanium (cp-Ti) and stainless steel. A bacterial suspension of Staphylococcus epidermidis strain RP62A (ATCC35984) was added to the surface of specimens and incubated. The stained biofilms were imaged with a digital optical microscope and the biofilm coverage rate (BCR) was calculated. The total amount of biofilm was determined with the crystal violet assay and the number of viable cells in the biofilm was counted using the plate count method. The BCR of all the biomaterials rose in proportion to culture duration. After culturing for 2-4 hours, the BCR was similar for all materials. However, after culturing for 6 hours, the BCR for Co-Cr-Mo alloy was significantly lower than for Ti-6Al-4V, cp-Ti and stainless steel (P0.05). These results suggest that surface properties, such as hydrophobicity or the low surface free energy of Co-Cr-Mo, may have some influence in inhibiting or delaying the two-dimensional expansion of biofilm on surfaces with a similar degree of smoothness