Efficacy and tolerability of subcutaneously administered methotrexate including dose escalation in long-term treatment of rheumatoid arthritis in a Japanese population.

OBJECTIVES: The aim of this article is to evaluate the efficacy and safety of subcutaneously administered methotrexate (MTX) for Japanese patients with active rheumatoid arthritis. METHODS: MTX-naïve patients were randomized in a 1:1 ratio to receive a 12-week administration of either 7.5 mg MTX subcutaneously (MJK101, a prefilled syringe for subcutaneous injection) or 8 mg MTX orally in Part 1 of the trial. The primary end point was a 20% improvement in the American College of Rheumatology criteria (ACR20) at Week 12. In the second part, all enrolled patients received MJK101 weekly for 52 weeks with doses starting from 7.5 to 15 mg with 2.5 mg increments with the option of self-administration of MJK101. RESULTS: The efficacy of MJK101 was comparable to oral MTX following 12 weeks of treatment at the starting doses. A numerically higher ACR20 response rate and fewer adverse events in particular gastrointestinal adverse events were observed. During long-term subcutaneous treatment, MJK101 was well tolerated across all tested doses. Patients clinically improved upon dose escalation. CONCLUSIONS: Subcutaneously applied MTX (MJK101) was efficient and well tolerated over a long-term treatment period in the Japanese population with doses up to 15 mg/week. Subcutaneous administration of MTX is a beneficial option for Japanese patients with rheumatoid arthritis.

Initial memory consolidation and the synaptic tagging and capture hypothesis.

Everyday memories are retained automatically in the hippocampus and then decay very rapidly. Memory retention can be boosted when novel experiences occur shortly before or shortly after the time of memory encoding via a memory stabilization process called "initial memory consolidation." The dopamine release and new protein synthesis in the hippocampus during a novel experience are crucial for this novelty-induced memory boost. The mechanisms underlying initial memory consolidation are not well-understood, but the synaptic tagging and capture (STC) hypothesis provides a conceptual basis of synaptic plasticity events occurring during initial memory consolidation. In this review, we provide an overview of the STC hypothesis and its relevance to dopaminergic signalling, in order to explore the cellular and molecular mechanisms underlying initial memory consolidation in the hippocampus. We summarize electrophysiological STC processes based on the evidence from two-pathway experiments and a behavioural tagging hypothesis, which translates the STC hypothesis into a related behavioural hypothesis. We also discuss the function of two types of molecules, "synaptic tags" and "plasticity-related proteins," which have a crucial role in the STC process and initial memory consolidation. We describe candidate molecules for the roles of synaptic tag and plasticity-related proteins and interpret their candidacy based on evidence from two-pathway experiments ex vivo, behavioural tagging experiments in vivo and recent cutting-edge optical imaging experiments. Lastly, we discuss the direction of future studies to advance our understanding of molecular mechanisms underlying the STC process, which are critical for initial memory consolidation in the hippocampus.

Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory.

Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.

[Optogenetic enhancement of everyday memory.]

Everyday memories are encoded in the hippocampus and decay very rapidly. In contrast, everyday memory with novel experience before or after remains for a long time. Our research group applied optogenetics to behavioural test in mice. We revealed the possibility that non-canonical release of dopamine from the locus coeruleus into the hippocampus change trivial everyday memory to long-term memory.

CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility.

Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. In concordance with this result, electrophysiological analysis in the hippocampal CA1 region disclosed an increased ratio of NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs (NMDA-EPSCs) as well as a stronger inhibition of the NMDA-EPSCs by the GluN2B-selective antagonist ifenprodil in Cdkl5 -/Y mice. Subcellular fractionation of the hippocampus from Cdkl5 -/Y mice revealed a significant increase of GluN2B and SAP102 in the PSD (postsynaptic density)-1T fraction, without changes in the S1 (post-nuclear) fraction or mRNA transcripts, indicating an intracellular distribution shift of these proteins to the PSD. Immunoelectron microscopic analysis of the hippocampal CA1 region further confirmed postsynaptic overaccumulation of GluN2B and SAP102 in Cdkl5 -/Y mice. Furthermore, ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 -/Y mice, suggesting that upregulation of GluN2B accounts for the enhanced seizure susceptibility. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GluN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility, and that aberrant NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of the CDKL5 loss-of-function.

Action of irbesartan on blood pressure and glucose/lipid metabolism, in hemodialysis patients with hypertension.

BACKGROUND: Irbesartan has been reported to have beneficial effects on glucose/lipid metabolism in addition to an antihypertensive effect; however, such effects have not been clarified in hemodialysis (HD) patients. We investigated the effects of irbesartan on blood pressure (BP) as well as glucose/lipid metabolism, in HD patients with hypertension. METHODS: Seventeen HD patients with hypertension, aged 62.7 ± 12.5 years, were treated with daily oral administration of 50 to 100 mg of irbesartan for 12 weeks. Then, the changes of BP as well as glucose metabolism (random serum glucose level and serum glycosylated hemoglobin [HbA1c] level) and lipid metabolism (serum low-density lipoprotein cholesterol [LDL-chol] level, serum high-density lipoprotein cholesterol [HDL-chol] level, and serum triglyceride [TG] level) were evaluated. RESULTS: Irbesartan significantly reduced systolic BP (154.9 ± 12.8 to 139.4 ± 13.1 mmHg (P < 0.01) and diastolic BP (78.9 ± 9.1 to 72.2 ± 9.7 mmHg, P < 0.01). It also reduced LDL-chol (77.6 ± 19.1 to 72.0 ± 18.6 mg/dL, P < 0.05), whereas it did not significantly affect random serum glucose (129.3 ± 46.9 mg/dL to 130.6 ± 47.2 mg/dL), HbA1c (5.58% ± 1.41% to 5.49% ± 1.11%), TG (104.3 ± 65.8 mg/dL to 100.2 ± 59.9 mg/dL), or HDL-chol (44.8 ± 17.1 mg/dL to 45.7 ± 15.6 mg/dL). CONCLUSION: Irbesartan is effective for BP control and may have beneficial effects on lipid metabolism in HD patients.

Efficacy of tocilizumab and evaluation of clinical remission as determined by CDAI and MMP-3 level.

Tocilizumab, a biological agent developed in Japan, is a human anti-interleukin-6 (anti-IL-6) receptor antibody. Rheumatoid arthritis improves with its use. A remission rate of 59% is attainable, as measured by disease activity score 28 (DAS28) in the SAMURAI study. However, in tocilizumab treatment, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels drop to negative values; therefore we sought to utilize a different index for measuring its efficacy. In order to evaluate the effects of tocilizumab we carried out this study using clinical disease activity index (CDAI), as it is not reliant on blood data and would also allow us to determine which markers are present in remission. Twenty-two patients under treatment with tocilizumab participated in this study. Effects of treatment as well as the remission rate were measured by CDAI and DAS28 3 months after initiation of treatment. IL-6 and matrix metalloproteinase-3 (MMP-3) levels were measured at the same time. We studied the clinical efficacy of tocilizumab using DAS28 after treatment; remission as measured by DAS28 was 57.1% at 1 year. However, the remission rate as measured by CDAI was only 19.1% at 1 year. CDAI was not only correlated with DAS28, but also other clinical variables, MMP-3, and IL-6. We conclude that CDAI is effective in measuring clinical response to tocilizumab treatment, and that MMP-3 level is as useful as IL-6 level as an indicator.