Search

Kotaro Doi,1 Hiroshi Kimura,2 Yukiko T Matsunaga,1 Teruo Fujii,3 Masaomi Nangaku4 1Institute of Industrial Science, The University of Tokyo, Tokyo, Japan; 2Department of Mechanical Engineering, School of Engineering, Tokai University, Kanagawa, Japan; 3The University of Tokyo, Tokyo, Japan; 4Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, JapanCorrespondence: Masaomi Nangaku, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan, Tel/Fax +81358009736, Email mnangaku@m.u-tokyo.ac.jpAbstract: Glomerulopathy, characterized by a dysfunctional glomerular capillary wall, results in proteinuria, leading to end-stage renal failure and poor clinical outcomes, including renal death and increased overall mortality. Conventional glomerulopathy research, including drug discovery, has mostly relied on animal experiments because in-vitro glomerulus models, capable of evaluating functional selective permeability, was unavailable in conventional in-vitro cell culture systems. However, animal experiments have limitations, including time- and cost-consuming, multi-organ effects, unstable reproducibility, inter-species reliability, and the social situation in the EU and US, where animal experiments have been discouraged. Glomerulus-on-a-chip, a new in-vitro organ model, has recently been developed in the field of organ-on-a-chip research based on microfluidic device technology. In the glomerulus-on-a-chip, the podocytes and endothelial cells are co-cultured in a microfluidic device with physical stimuli that mimic the physiological environment to enhance cell function to construct a functional filtration barrier, which can be assessed by permeability assays using fluorescently labeled molecules including inulin and albumin. A combination of this glomerulus-on-a chip technology with the culture technology to induce podocytes and endothelial cells from the human pluripotent stem cells could provide an alternative organ model and solve the issue of animal experiments. Additionally, previous experiments have verified the difference in the leakage of albumin using differentiated podocytes derived from patients with Alport syndrome, such that it could be applied to intractable hereditary glomerulopathy models. In this review, we provide an overview of the features of the existing glomerulus-on-a-chip systems, focusing on how they can address selective permeability verification tests, and the challenges they involved. We finally discuss the future approaches that should be developed for solving those challenges and allow further improvement of glomerulus-on-a-chip technologies.Keywords: glomerulus, podocyte, selective permeability, microfluidic device, organ-on-a-chip

Machiko Matsumoto-Sasaki,1 Kaoruko Simizu,1 Masanobu Suzuki,2 Masaru Suzuki,1 Hirokazu Kimura,1 Yuji Nakamaru,2 Yoichi M Ito,3 Akihiro Honma,2 Satoshi Konno1 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 3Data Science Center, Promotion Unit, Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Sapporo, JapanCorrespondence: Kaoruko Simizu, Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Japan, Tel +81-11-706-5911, Fax +81-11-706-7899, Email okaoru@med.hokudai.ac.jpPurpose: Biologics have been used increasingly for the treatment of severe asthma. However, established guidelines for the selection, switching, or discontinuation of biologics do not exist. We aimed to identify the clinical characteristics of patients with asthma who required switching biologics and the factors associated with switching biologics.Patients and Methods: This was a retrospective study of 42 patients with severe asthma treated with biologics at the Hokkaido University Hospital between 23rd June 2016 and 30th April 2021, when two biologics were available in Japan. We compared the characteristics of subjects who continued and switched biologics. The time to switch the biologics was assessed by type 2 inflammatory biomarkers, pulmonary function indices, and the presence of comorbidities, including the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score and aspirin exacerbated respiratory diseases (AERD), using the Kaplan–Meier method and a multivariate Cox proportional hazards model.Results: Eight and five patients were treated by mepolizumab and benralizumab at baseline, respectively among the 31% (13/42) who switched the biologics. Subjects who required switching biologics were characterized by high blood eosinophil counts, younger age, JESREC scores of 11 points or higher, and AERD. The time taken to switch biologics was significantly shorter in the subgroups with high JESREC scores (≥ 11) or AERD, compared with their counterparts with low JESREC scores or without AERD (both, P < 0.05). JESREC scores of ≥ 11, but not the presence of AERD, were associated with time to switch biologics.Conclusion: The presence of eosinophilic chronic rhinosinusitis based on JESREC scores of ≥ 11 and younger age were factors associated with switching biologics in asthma.Keywords: aspirin-exacerbated respiratory disease, asthma, biologics, comorbidities, eosinophilic chronic rhinosinusitis

Yuki Abe,1 Masaru Suzuki,1 Hiroshi Shima,2 Yusuke Shiraishi,2 Naoya Tanabe,2 Susumu Sato,2 Kaoruko Shimizu,1 Hirokazu Kimura,1 Hironi Makita,1,3 Toyohiro Hirai,2 Satoshi Konno,1 Masaharu Nishimura1,3 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo, 060-8638, Japan; 2Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan; 3Hokkaido Medical Research Institute for Respiratory Diseases, Chuo-ku, Sapporo, 060-0063, JapanCorrespondence: Masaru SuzukiDepartment of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638, JapanTel +81-11-706-5911Fax +81-11-706-7899Email suzumasa@med.hokudai.ac.jpPurpose: Low body mass index (BMI) has been reported to be associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). In contrast, a detailed analysis of the association between body weight change over time and prognosis is not sufficient, particularly in Japanese patients with COPD who have been reported to be much thinner compared to Westerners. This study aimed to investigate the relationship between annual body weight change and long-term prognosis in Japanese patients with COPD in two independent cohorts.Patients and Methods: We analyzed 279 patients with COPD who participated in the Hokkaido COPD cohort study as a discovery cohort. We divided participants into three groups according to quartiles of annual body weight change calculated by the data from the first 5 years: weight loss group ( 0.20 kg/year). The association between annual body weight change and prognosis was replicated in the Kyoto University cohort (n = 247).Results: In the Hokkaido COPD cohort study, the weight loss group had significantly worse mortality than the other groups, whereas there was no difference in BMI at baseline. In the multivariate analysis, annual body weight change was an independent risk factor for all-cause mortality, which was confirmed in the Kyoto University cohort.Conclusion: Annual body weight loss is associated with poor prognosis in Japanese patients with COPD, independent of baseline BMI. Longitudinal assessment of body weight is important for the management of COPD.Keywords: annual body weight change, body mass index, chronic obstructive pulmonary disease, mortality, prognosis, weight loss

Yuki Abe, Masaru Suzuki, Hirokazu Kimura, Kaoruko Shimizu, Hironi Makita, Masaharu Nishimura, Satoshi Konno Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, JapanCorrespondence: Masaru SuzukiDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, JapanTel +81-11-706-5911Fax +81-11-706-7899Email suzumasa@med.hokudai.ac.jpPurpose: Fractional exhaled nitric oxide (FENO) reflects eosinophilic inflammation of the airways. However, the significance of longitudinal assessment of FENO, including its variability, in the clinical course of severe asthma remains unclear. The aim of this study is to examine the association between long-term changes in FENO and the development of exacerbations in severe asthma.Patients and Methods: Among the severe asthma patients enrolled in the Hokkaido Severe Asthma Cohort Study, 100 patients with severe asthma who completed a 3-year follow-up in which FENO was measured annually were included. According to the FENO level at baseline, 1 year, and 2 years, the patients were classified into three groups: the sustained high group (≥ 50 ppb at all three visits), the sustained low group (< 25 ppb at all three visits), and the intermediate group (other). Subjects in the intermediate group were further classified into two groups based on the median value of the coefficient of variation (CV) of FENO during the 3 years (high CV and low CV intermediate groups).Results: The sustained high group experienced shorter exacerbation-free survival and more frequent exacerbations than the sustained low group (median number of exacerbation events, 3 vs 0, p = 0.01). In the intermediate group, the high CV group experienced shorter exacerbation-free survival than the low CV group, and the CV of FENO was an independent contributing factor to the development of exacerbations.Conclusion: Persistence of FENO above 50 ppb over the years as well as the presence of large variations in FENO levels was associated with the development of exacerbations in patients with severe asthma.Keywords: asthma, coefficient of variation, exacerbation, fractional exhaled nitric oxide, longitudinal assessment, variability

Kai Ushio,1,2 Kazuyoshi Nakanishi,3,4 Yukio Mikami,1,5 Atsuo Yoshino,6 Masahiro Takamura,7 Kazuhiko Hirata,2 Yuji Akiyama,8 Hiroaki Kimura,1,2 Yasumasa Okamoto,6 Nobuo Adachi2,3 1Department of Rehabilitation, Hiroshima University Hospital, Hiroshima, Japan; 2Sports Medical Center, Hiroshima University Hospital, Hiroshima, Japan; 3Department of Orthopedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; 4Department of Orthopedic Surgery, Nihon University School of Medicine, Nihon University, Tokyo, Japan; 5Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan; 6Department of Psychiatry and Neurosciences, Hiroshima University, Hiroshima, Japan; 7Brain, Mind and KANSEI Sciences Research Center, Hiroshima University, Hiroshima, Japan; 8Department of Clinical Radiology, Hiroshima University Hospital, Hiroshima, JapanCorrespondence: Kazuyoshi NakanishiDepartment of Orthopedic Surgery, Nihon University School of Medicine, Nihon University, Oyaguchi-Kamimachi 30-1, Itabashi-Ku, Tokyo 173-8610, JapanTel +81-3-3972-8111Fax +81-3-3957-6186Email nakanishi.kazuyoshi@nihon-u.ac.jpPurpose: Expectation affects pain experience in humans. Numerous studies have reported that pre-stimulus activity in the anterior insular cortex (aIC), together with prefrontal and limbic regions, integrated pain intensity and expectations. However, it is unclear whether the resting-state functional connectivity (rs-FC) between the aIC and other brain regions affects chronic pain. The purpose of this study was to examine the rs-FC between the aIC and the whole brain regions in female patients with severe knee osteoarthritis (OA).Patients and Methods: Nineteen female patients with chronic severe knee OA and 15 matched controls underwent resting-state functional magnetic resonance imaging. We compared the rs-FC from the aIC seed region between the two groups. A disease-specific measurement of knee OA was performed.Results: The aIC showed stronger rs-FC with the right orbitofrontal cortex (OFC), subcallosal area, and bilateral frontal pole compared with controls. The strength of rs-FC between the left aIC and the right OFC was positively correlated with the knee OA pain score (r = 0.49, p = 0.03). The strength of rs-FC between the right aIC and right OFC was positively correlated with the knee OA total score (r = 0.48, p = 0.036) and pain score (r = 0.46, p = 0.049). The OFC, subcallosal area, and frontal pole, together with the aIC, were activated during anticipation of pain stimulus. These areas have been reported as representative pain-related expectation regions.Conclusion: This was the first study to show the stronger rs-FCs between the aIC and other pain-related expectation regions in female patients with severe knee OA. Female sex and preoperative pain intensity are risk factors of persistent postoperative pain after total knee arthroplasty. It is suggested that the functional relationship between pain-related expectation regions affects the formation of severe knee OA and persistent postoperative pain following total knee arthroplasty.Keywords: functional magnetic resonance imaging, chronic pain, insular cortex, orbitofrontal cortex

Nozomu Takei,1,* Masaru Suzuki,1,* Hironi Makita,2 Satoshi Konno,1 Kaoruko Shimizu,1 Hiroki Kimura,1 Hirokazu Kimura,1 Masaharu Nishimura1,2 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Hokkaido Medical Research Institute for Respiratory Diseases, Sapporo, Japan*These authors contributed equally to this workCorrespondence: Masaharu NishimuraDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo 060-8638, JapanTel +81 11 706 5911Fax +81 11 706 7899Email ma-nishi@med.hokudai.ac.jpPurpose: Alpha-1 antitrypsin deficiency is associated with the development of chronic obstructive pulmonary disease (COPD), whereas increased levels of serum alpha-1antitrypsin occur in response to inflammation. The effects of alpha-1 antitrypsin levels on the clinical course of COPD had been unclear. We investigated the association of serum alpha-1 antitrypsin levels with the clinical course of COPD patients based on data from a 10-year prospective cohort study.Patients and methods: We analyzed 278 COPD patients who participated in the Hokkaido COPD cohort study and who did not meet the criteria for alpha-1 antitrypsin deficiency. We divided the subjects into 3 groups according to quartiles of serum alpha-1 antitrypsin levels at baseline: lower group (141 mg/dL, n = 67). The annual change in forced expiratory volume in 1 s (FEV1) and events of COPD exacerbation were monitored during the first 5 years, and mortality was followed-up during the entire 10 years.Results: At baseline, the higher group showed lower body mass index; higher computed tomography emphysema score; lower diffusing capacity; higher levels of acute-phase proteins; and higher blood neutrophil counts. Longitudinal analyses revealed that in the higher group, the annual decline in FEV1 was rapid and the 10-year mortality was higher, but there was no association between serum alpha-1 antitrypsin levels and time to first exacerbation.Conclusion: COPD subjects with higher serum alpha-1 antitrypsin levels were associated with a worse systemic inflammation status and higher 10-year mortality.Keywords: chronic obstructive pulmonary disease, alpha-1 antitrypsin, inflammation, lung function decline, mortality

Abe Y, Suzuki M, Shima H, et al. Int J Chron Obstruct Pulmon Dis. 2021;16:3243–3253. The authors have advised there is an error with the ethics approval number of Kyoto University on pages 3245 and 3252. On page 3245, Kyoto University Cohort section, last sentence, the text “(E182 and R03112)” should read “(E182, R0311-2, and R1660-1)”. On page 3252, Ethics Approval and Informed Consent section, the text “(E182 and R0311-2)” should read “(E182, R0311-2, and R1660-1)”. The authors apologize for these errors. Read the original article

Yoshika Kurokawa,1 Hideko Sone,1 Tin-Tin Win-Shwe,1 Yang Zeng,1 Hiroyuki Kimura,2 Yosuke Koyama,1 Yusuke Yagi,2 Yasuto Matsui,3 Masashi Yamazaki,4 Seishiro Hirano1 1Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Tsukuba, Ibaraki, 2Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 3Department of Environmental Engineering, Kyoto University Graduate School of Engineering, Kyoto, 4TIA Center Office, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan Abstract: Dendrimers have been expected as excellent nanodevices for brain medication. An amine-terminated polyamidoamine dendrimer (PD), an unmodified plain type of PD, has the obvious disadvantage of cytotoxicity, but still serves as an attractive molecule because it easily adheres to the cell surface, facilitating easy cellular uptake. Single-photon emission computed tomographic imaging of a mouse following intravenous injection of a radiolabeled PD failed to reveal any signal in the intracranial region. Furthermore, examination of the permeability of PD particles across the blood–brain barrier (BBB) in vitro using a commercially available kit revealed poor permeability of the nanoparticles, which was suppressed by an inhibitor of caveolae-mediated endocytosis, but not by an inhibitor of macropinocytosis. Physicochemical analysis of the PD revealed that cationic PDs are likely to aggregate promptly upon mixing with body fluids and that this prompt aggregation is probably driven by non-Derjaguin–Landau–Verwey–Overbeek attractive forces originating from the surrounding divalent ions. Atomic force microscopy observation of a freshly cleaved mica plate soaked in dendrimer suspension (culture media) confirmed prompt aggregation. Our study revealed poor transfer of intravenously administered cationic PDs into the intracranial nervous tissue, and the results of our analysis suggested that this was largely attributable to the reduced BBB permeability arising from the propensity of the particles to promptly aggregate upon mixing with body fluids. Keywords: PAMAM dendrimer, nanomaterial, aggregation, blood–brain barrier

Yasunori Oda,1 Nobuhisa Kanahara,2 Hiroshi Kimura,1 Hiroyuki Watanabe,2 Kenji Hashimoto,3 Masaomi Iyo1 1Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; 2Division of Medical Treatment and Rehabilitation, 3Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan Background/aim: Dopamine supersensitivity psychosis (DSP), clinically characterized by unstable and severe psychosis or tardive dyskinesia and often categorized as treatment-resistant schizophrenia, is promoted by long-term antipsychotic treatment. An upregulation of the dopamine D2 receptor caused by antipsychotic(s) is involved in the development of DSP. The present study explored the potential roles of G protein-coupled receptor kinase 6 (GRK6) and β-arrestin 2 (ARRB2) that are involved in the trafficking of DRD2 in patients with DSP. Methods: We conducted a genetic association study of GRK6/ARRB2 between the patients with DSP episodes [DSP(+) group: N=108] and the patients without DSP(-) episodes [DSP(-) group: N=169] from the total group of patients (N=333). Based on the patients’ treatment history, a DSP episode was defined as withdrawal psychosis, developed tolerance to antipsychotic effect, and tardive dyskinesia (the remaining 56 patients were excluded due to insufficient information). Results: The results revealed that none of the allelic or genotyping distributions of five single nucleotide polymorphisms (SNPs) of GRK6 and three SNPs of ARRB2 showed any significant difference between the DSP(+) and DSP(-) groups. Conclusion: The results suggest that the SNP analyses of these two molecules fail to classify patients into the potential clinical subtype of DSP(+) or DSP(-) group. However, since GRK6 and ARRB2 are surely involved in dopamine D2 receptor metabolism, further studies based on prospective observations of the onset of DSP under specific antipsychotic treatments are needed. Keywords: antipsychotic, dopamine D2 receptor, tardive dyskinesia, treatment-resistant

Kaoru Araki-Sasaki,1,2 Atsuko Fukumoto,1 Yasuhiro Osakabe,3 Hideya Kimura,1 Shinichiro Kuroda1 1Nagata Eye Clinic, Nara, Japan; 2Department of Ophthalmology, Japan Community Health Care Organization, Hoshigaoka Medical Center, Osaka, Japan; 3Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan Abstract: The purpose of this study was to describe the clinical characteristics of fungal keratitis caused by Candida albicans in an eye after Descemet stripping automated endothelial keratoplasty (DSAEK). A 72-year-old male with a history of three trabeculectomies, cataract surgery, and two DSAEK procedures developed a corneal ulcer in his right eye two years after his last DSAEK. Fungal keratitis was most likely related to the immunosuppressive conditions that occurred due to the previous operations, the continuous use of steroid eye drops, and the use of disposable soft contact lenses. A smear and culture from the ulcer detected Candida albicans. Slit-lamp examination showed the characteristic feature was the presence of interface infiltrates located between the host and the graft cornea and in the enlarged area around the ulcer. Two weeks after intense antimycotic treatments with voriconazole, miconazole, and natamycin, perforation of the cornea occurred and further therapeutic penetrating keratoplasty was required. Histological analysis revealed an accumulation of infiltrated cells and fibrotic tissue. The poor prognosis for fungal keratitis that occurs in eyes after undergoing DSAEK may be related to the rapid expansion of inflammatory cells through the interface between the host and the graft. In eyes that develop fungal keratitis after DSAEK, special attention should be paid to the possibility that perforation could occur in these patients. Keywords: DSAEK, Candida albicans, fungal keratitis, keratomycosis, post-operative infection

Hiromi Kimura, Akemi Osaki, Rui Kawashima, Takeshi Inoue, Shin Nakagawa, Katsuji Suzuki, Satoshi Asakura, Teruaki Tanaka, Yuji Kitaichi, Takuya Masui, Nobuki Kitagawa, Yuki Kako, Tomohiro Abekawa, Ichiro Kusumi, Hiroyoshi Yamanaka, Kenzo Denda, Tsukasa KoyamaDepartment of Psychiatry, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanBackground: The bipolar-unipolar distinction in patients with a major depressive episode is the most important issue related to the diagnosis and treatment of mood disorders, but remains unresolved. This study was undertaken to compare bipolar and unipolar depression on Rorschach testing using the Comprehensive System with reference to healthy Japanese controls.Methods: Patients with bipolar or unipolar depression who had undergone the Rorschach test for routine clinical purposes were followed up naturalistically for a long period. Based on diagnostic confirmation after long-term follow-up, scores on this test for patients with bipolar and unipolar depression were compared with those published elsewhere for healthy Japanese controls.Results: The bipolar depression group showed significantly higher scores or positive findings in five variables of the Rorschach test, ie, WSum6, DR2 > 0, (CF + C) > FC + 2, PureC > 1, and Populars > 7, as assessed using the Comprehensive System, than did the unipolar depression group and healthy controls. These scores did not differ between the unipolar depression and control groups.Conclusion: The results of this study show thought disorder or cognitive slippage and marked laxness in modulating emotion in bipolar depression, indicating the psychopathological characteristics of bipolar disorder.Keywords: bipolar depression, bipolar disorder, Rorschach test, thought disorder, unipolar depression

Static experiments are performed to confirm the COD method that is the only method to measure the energy release rate of fast propagating cracks just after bifurcation. The crack opening displacement (COD) of the mother cracks of bifurcated cracks is measured in static condition by Moiré interferometry. Thin notches are used instead of cracks. The bifurcation angle is 13.5 degrees that is the same as the angle of bifurcation of fast propagating cracks in PMMA. The measured CODs are proportional to the square root of the distance from the nominal tip of the mother notch. Stress intensity factor of the bifurcated notch is obtained from the measured CODs through the formula of the COD of single cracks. The experimental results say that the stress intensity factor of a bifurcated crack has the same value as that of the single crack whose length is the same as that of the bifurcated crack. This is caused by the small bifurcation angle of 13.5 degrees. It is concluded that the COD method is correct to measure the energy release rate of rapidly bifurcating cracks.

Magnetic structures of the noncentrosymmetric magnet Sr2MnSi2O7 were examined through neutron diffraction for powder and single‐crystalline samples, as well as magnetometry measurements. All allowed magnetic structures for space group P421m with the magnetic wavevector qm = (0, 0, ½) were refined via irreducible representation and magnetic space group analyses. The compound was refined to have in‐plane magnetic moments within the magnetic space group Cmc21.1′c (No. 36.177) under zero field, which can be altered to P212121.1′c (No. 19.28) above μ0H = 0.067 (5) T to align induced weak‐ferromagnetic components within one layer on the ab plane. All refined parameters are provided following the recent framework based upon the magnetic space group, which better conveys when exchanging crystallographic information for commensurate magnetic structures. [ABSTRACT FROM AUTHOR]