MK-801 blocks monoamine transporters expressed in HEK cells

Abstract(+)-MK-801 is known to be a specific non-competitive antagonist of N-methyl-d-aspartate (NMDA) receptors. However, besides having an anticonvulsant effect, this compound possesses a central sympathomimetic effect and an anxiolytic-like action, raising the possibility that (+)-MK-801 might affect monoamine uptake systems. To elucidate this possibility, we investigated the effects of (+)-MK-801 on monoamine transporters expressed in HEK cells. (+)-MK-801 significantly inhibited the uptake of all three monoamine transporters in a dose-dependent manner and the inhibitions were competitive with respect to monoamines. The Ki values of (+)-MK-801 on the norepinephrine, dopamine and serotonin transporters were 3.2 μM, 40 μM and 43 μM, respectively. In addition, (−)-MK-801, a less potent antagonist of NMDA receptors, also inhibited monoamine transporters with a similar potency as that of (+)-MK-801. These results clearly indicate that MK-801, a non-competitive antagonist of NMDA receptors, competitively inhibits monoamine transporters without stereoselectivity

Quality and safety issues related to traditional animal medicine: role of taurine

<p>Abstract</p> <p>Background</p> <p><it>Calculus Bovis</it> (:<it>C.Bovis</it>) is one of the most precious and commonly-used medicinal materials in Japan and China. As the natural occurrence is very rare, a source of supply for <it>C. Bovis</it> is far behind the actual need and great efforts have been taken for some substitutes of natural <it>C. Bovis</it>. Unfortunately, very little information is available on the quality and/or clinical efficacy of medication based on <it>C. Bovis</it>. To ensure sustainable use of traditional therapeutic agents derived from <it>C. Bovis</it>, we felt that several issues needed to be addressed: 1) the source of the <it>C. Bovis</it> materials and quality control; 2) the role of taurine in the efficacy of <it>C. Bovis</it>.</p> <p>Methods</p> <p>Nine samples of natural <it>C. Bovis</it> and its substitutes were collected. ICP-MS was used for elemental analysis and the characterization was performed by principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA) as multivariate approaches. The efficacy of <it>C. Bovis</it> was evaluated for morphology, viability and beating pattern on cultured cardiac myocytes and/or fibroblasts.</p> <p>Results</p> <p>PCA and multi-elemental focus was effective in discriminating <it>C. Bovis</it> samples derived from different habitats. A satisfactory classification using SIMCA was obtained among Australia <it>C. Bovis</it>, other habitats and the substitutes. Australian samples had better batch uniformity than other habitats and were composed of fewer elements. We have used Australian<it> C. Bovis</it> for assessment on its bioactive compounds. Rat cardiac cells incubated with <it>C. Bovis</it> extract (0.01-0.1mg/ml) maintained normal morphology, viability and beating pattern. Cardiac myocytes and fibroblasts treated for 48 h with CA (0.5mM) or DCA (0.1mM) caused cell injury, as reflected by changes in appearance and a reduction of viability detected by the MTS assay. In cardiomyocytes, 0.5 h exposure of CA (0.5mM) markedly decreased the velocity ratio of beating, whereas the simultaneous addition of 1 mM taurine largely prevented the decrease.</p> <p>Conclusions</p> <p>The multi-elemental focus provided some references for the quality control and the efficacy of <it>C. Bovis</it>. Taurine partly attenuated the harmful actions of bile acids. It is plausible that the relationship between taurine and the bile acids contributes to therapeutic effect of <it>C. Bovis</it>.</p

Successful Treatment of MMP-9-Expressing Angiosarcoma with Low-Dose Docetaxel and Bisphosphonate

We describe a 78-year-old Japanese patient with angiosarcoma on the scalp. Interestingly, immunohistochemical staining revealed this tumor as positive for matrix metalloproteinase 9 (MMP-9). After conventional therapy for angiosarcoma with surgical treatment and radiation therapy, we intravenously administered docetaxel at 40 mg/m2 body surface area together with oral administration of 17.5 mg sodium risedronate hydrate. One and a half years after the standard treatment, there was no evidence of local recurrence or metastasis

Workaholism, work engagement and child well-being: A test of the spillover-crossover model

This study examines how working parents’ work attitudes (i.e., workaholism and work engagement) are associated with their child’s psychological well-being. Based on the Spillover-Crossover model (SCM), we hypothesize that (a) work-to-family spillover (i.e., work-to-family conflict and facilitation) and (b) employee happiness will sequentially mediate the relationship between parents’ work attitudes and their child’s emotional and behavioral problems. A cross-sectional survey was conducted among Japanese dual-earner couples with pre-school child(ren). On the basis of valid data from 208 families, the hypothesized model was tested using structural equation modeling. For both fathers and mothers simultaneously, workaholism was positively related to work-to-family conflict, which, in turn, was negatively related to happiness. In contrast, work engagement was positively related to work-to-family facilitation, which, in turn, was positively related to happiness. Fathers’ and mothers’ happiness, in turn, were negatively related to their child’s emotional and behavioral problems. Results suggest that parents’ workaholism and work engagement are related to their child’s emotional and behavioral problems in opposite ways, whereby parents’ spillover and happiness mediate this relationship. These findin

Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use

Lymphatic marker podoplanin/D2-40 in human advanced cirrhotic liver- Re-evaluations of microlymphatic abnormalities

<p>Abstract</p> <p>Background</p> <p>From the morphological appearance, it was impossible to distinguish terminal portal venules from small lymphatic vessels in the portal tract even using histochemical microscopic techniques. Recently, D2-40 was found to be expressed at a high level in lymphatic endothelial cells (LECs). This study was undertaken to elucidate hepatic lymphatic vessels during progression of cirrhosis by examining the expression of D2-40 in LECs.</p> <p>Methods</p> <p>Surgical wedge biopsy specimens were obtained from non-cirrhotic portions of human livers (normal control) and from cirrhotic livers (LC) (Child A-LC and Child C-LC). Immunohistochemical (IHC), Western blot, and immunoelectron microscopic studies were conducted using D2-40 as markers for lymphatic vessels, as well as CD34 for capillary blood vessels.</p> <p>Results</p> <p>Imunostaining of D2-40 produced a strong reaction in lymphatic vessels only, especially in Child C-LC. It was possible to distinguish the portal venules from the small lymphatic vessels using D-40. Immunoelectron microscopy revealed strong D2-40 expression along the luminal and abluminal portions of the cell membrane of LECs in Child C-LC tissue.</p> <p>Conclusion</p> <p>It is possible to distinguish portal venules from small lymphatic vessels using D2-40 as marker. D2-40- labeling in lymphatic capillary endothelial cells is related to the degree of fibrosis in cirrhotic liver.</p

Prevention of hypoglycemia by intermittent-scanning continuous glucose monitoring device combined with structured education in patients with type 1 diabetes mellitus : A randomized, crossover trial

Aims: We conducted a randomized, crossover trial to compare intermittent-scanning continuous glucose monitoring (isCGM) device with structured education (Intervention) to self-monitoring of blood glucose (SMBG) (Control) in the reduction of time below range. Methods: This crossover trial involved 104 adults with type 1 diabetes mellitus (T1DM) using multiple daily injections. Participants were randomly allocated to either sequence Intervention/Control or sequence Control/Intervention. During the Intervention period which lasted 84 days, participants used the first-generation FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA) and received structured education on how to prevent hypoglycemia based on the trend arrow and by frequent sensor scanning (≥10 times a day). Confirmatory SMBG was conducted before dosing insulin. The Control period lasted 84 days. The primary endpoint was the decrease in the time below range (TBR; <70 mg/dL). Results: The time below range was significantly reduced in the Intervention arm compared to the Control arm (2.42 ± 1.68 h/day [10.1 %±7.0 %] vs 3.10 ± 2.28 h/day [12.9 %±9.5 %], P = 0.012). The ratio of high-risk participants with low blood glucose index >5 was significantly reduced (8.6 % vs 23.7 %, P < 0.001). Conclusions: The use of isCGM combined with structured education significantly reduced the time below range in patients with T1DM