Expression of Transcripts Selective for GABA Neuron Subpopulations across the Cortical Visuospatial Working Memory Network in the Healthy State and Schizophrenia

金沢大学医薬保健総合研究域医学系 / Graduate School of Medical SciencesPMID: 30247542Visuospatial working memory (WM), which is impaired in schizophrenia, depends on a distributed network including visual, posterior parietal, and dorsolateral prefrontal cortical regions. Within each region, information processing is differentially regulated by subsets of γ-aminobutyric acid (GABA) neurons that express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). In schizophrenia, WM impairments have been associated with alterations of PV and SST neurons in the dorsolateral prefrontal cortex. Here, we quantified transcripts selectively expressed in GABA neuron subsets across four cortical regions in the WM network from comparison and schizophrenia subjects. In comparison subjects, PV mRNA levels declined and SST mRNA levels increased from posterior to anterior regions, whereas VIP mRNA levels were comparable across regions except for the primary visual cortex (V1). In schizophrenia subjects, each transcript in PV and SST neurons exhibited similar alterations across all regions, whereas transcripts in VIP neurons were unaltered in any region except for V1. These findings suggest that the contribution of each GABA neuron subset to inhibitory regulation of local circuitry normally differs across cortical regions of the visuospatial WM network and that in schizophrenia alterations of PV and SST neurons are a shared feature across these regions, whereas VIP neurons are affected only in V1.Embargo Period 12 month

統合失調症の認知機能障害とパルブアルブミンニューロンにおけるKCNS3発現低下

金沢大学医薬保健研究域医学系Subjects with schizophrenia (SZ) have lower expression levels of KCNS3, the gene encoding voltage-gated potassium channel subunit selectively expressed in the subset of cortical GABA neurons that express parvalbumin (PV), compared with unaffected comparison subjects. As voltage-gated potassium channels affect neuronal excitability, we hypothesized that the deficits in KCNS3 expression contribute to lower expression levels of neural activity-dependent genes, such as EGR1, EGR2, BDNF, NPTX2 and PVALB, in the cerebral cortex of SZ subjects. To test this hypothesis, we evaluated the expression of Egr1, Egr2, Bdnf, Nptx2, and Pvalb by real-time PCR in the cortex of mice with genetically introduced lower Kcns3 expression in PV neurons. However, none of these genes exhibited a significantly altered expression in these mice, indicating that lower KCNS3 expression in PV neurons does not affect activity levels of cortical circuitries in schizophrenia.統合失調症の大脳皮質において、パルブアルブミン陽性の抑制性ニューロンにおけるカリウムチャネルサブユニット遺伝子KCNS3の発現低下が、大脳皮質神経回路の活動性に影響を及ぼし神経活動依存性遺伝子EGR1, EGR2, BDNF, NPTX2, PVALBの低下を起こしている可能性を評価するために、Kcns3の発現を低下させた遺伝子改変マウスの大脳皮質にてこれらの遺伝子の発現を調べた。その結果、いずれの遺伝子においても有意な発現変化は認められなかった。統合失調症では、パルブアルブミン陽性細胞におけるKCNS3の発現低下は、大脳皮質神経回路の活動性変化の上流メカニズムでないことが示された。研究課題/領域番号:20K16668, 研究期間(年度):2020-04-01 – 2022-03-31出典：研究課題「統合失調症の認知機能障害とパルブアルブミンニューロンにおけるKCNS3発現低下」課題番号20K16668（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-20K16668/20K16668seika/）を加工して作

精神疾患死後脳における分子発現変化の脳内分布解明のための内部標準遺伝子同定

精神疾患の分子基盤の理解には、患者および健常者から得られた死後脳の複数の領域における遺伝子発現評価が必要である。本研究では、死後脳における遺伝子発現の正確な定量に必要な1)RNAの保存状態の評価および2)発現の安定した内部標準遺伝子の同定を患者と健常者の大脳皮質4領域より抽出したRNAを用いて行った。RNAの保存状態は、患者では脳の前方で高く後方で低い傾向を認めたが、対照者ではこのような領域間の差を認めなかった。さらに、一般的に使用されている８種類の内部標準遺伝子から疾患の有無および領域の違いにより影響を受けにくいものとしてPPIA, GAPDH, PSMB2を同定した。Understanding molecular bases of neural network dysfunction in psychiatric disorders depends on the analysis of gene expression across multiple cortical regions in postmortem brains. The accuracy of such evaluation depends on RNA integrity and the stability of expression of internal control transcripts (normalizers) across diagnostic statuses as well as across different cortical regions. In this study, we measured the RNA integrity in multiple cortical regions and assessed the expression stability of eight potential normalizers, using cortical RNA samples obtained from control and schizophrenia subjects. RIN was comparable across the different regions in control subjects, whereas it was higher in anterior association cortices than in posterior visual cortices in schizophrenia subjects. Among the eight normalizers, cyclophilin, glyceraldehyde-3-phosphatase dehydrogenase, proteasome subunit beta-2 exhibited the most stable expression across diagnostic statuses.研究課題/領域番号:17K16372, 研究期間(年度):2017-04-01 - 2019-03-3

Preliminary preventive protocol from first trimester of pregnancy to reduce preterm birth rate for dichorionic–diamniotic twins

Objective: The preterm birth rate of twins is reportedly higher than that of single pregnancies. We performed preliminary preventive interventions at our center focused on evaluating the risk of each case before 14 weeks of gestation to reduce the spontaneous preterm birth rate. Materials and methods: The participants included 184 dichorionic–diamniotic twins delivered at our center during the 8 years from 2006. We evaluated each patient regarding high-risk status (at least 1 additional factor as follows: threatened abortion, history of chorioamnionitis, cervicitis, and bacterial vaginosis), based on available evidence; patients deemed high risk gave their informed consent and underwent treatment for cervicitis and cerclage if indicated. We divided the patients into two groups depending on whether the management was initiated before (Group A) or after (Group B) 14 weeks. We further divided Group A into three: Group 1 underwent treatment for cervicitis, Group 2 underwent cervical cerclage in addition to treatment for cervicitis, and Group 3 did not undergo preventive treatment. We retrospectively compared the preterm birth rates of the two groups, and we also compared them between the higher-risk group (Group 1 + 2) and the no additional risk group (Group 3) in Group A. Results: The spontaneous preterm birth rate < 36 weeks was significantly lower in Group A (4/90; 4.4%) than in Group B (18/94; 19.1%) (p = 0.001). However, there were no significant differences between Group 1 + 2 and Group 3 (2/42 vs. 2/46). Focusing on the spontaneous preterm birth rate < 34 weeks, Group A had a lower rate than Group B (2/90; 2.2% vs. 13/94; 13.8%, p = 0.0012). Conclusion: Even though this was a preliminary study, the results are promising, and we propose custom-made management for dichorionic–diamniotic twins: (1) earlier management from before 14 weeks; (2) high-risk selection for cervicitis and a short cervix; and (3) intervention with anti-inflammatory agents and cerclage if indicated

Interlaboratory evaluation of LC–MS-basedbiomarker assays: supplementary materials

Validation of biomarker assays is crucial for effective drug development and clinical applications.Interlaboratory reproducibility is vital for reliable comparison and combination of data from differentcenters. This review summarizes interlaboratory studies of quantitative LC–MS-based biomarker assaysusing reference standards for calibration curves. The following points are discussed: trends in reports,reference and internal standards, evaluation of analytical validation parameters, study sample analysisand normalization of biomarker assay data. Full evaluation of these parameters in interlaboratory studiesis limited, necessitating further research. Some reports suggest methods to address variations in biomarkerassay data among laboratories, facilitating organized studies and data combination. Method validationacross laboratories is crucial for reducing interlaboratory differences and reflecting target biomarkerresponses.</p

Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

Introduction Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methods We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.Results Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (&gt;90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.Conclusions Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting