The aryl hydrocarbon receptor (AhR) forms a complex with the HSP90‐XAP2‐p23 molecular chaperone when the cells are exposed to toxic compounds. Recently, 1,4‐dihydroxy‐2‐naphthoic acid (DHNA) was ...reported to be an AhR ligand. Here, we investigated the components of the molecular chaperone complex when DHNA binds to AhR. Proteins eluted from the 3‐Methylcolanthrene‐affinity column were AhR‐HSP90‐XAP2‐p23 complex. The AhR‐molecular chaperone complex did not contain p23 in the eluents from the DHNA‐affinity column. In 3‐MC‐treated cells, AhR formed a complex with HSP90‐XAP2‐p23 and nuclear translocation occurred within 30 min, while in DHNA‐treated cells, AhR formed a complex with AhR‐HSP90‐XAP2, and translocation was slow from 60 min. Thus, the AhR activation mechanism may differ when DHNA is the ligand compared to toxic ligands.
When bound to toxic or non‐toxic ligands, aryl hydrocarbon receptors (AhRs) are activated and nuclear translocation occurs; AhRs are bound to molecular chaperone complexes, AhR‐HSP90‐XAP2‐p23 for toxic ligands, whereas for non‐toxic ligands AhR‐HSP90‐ XAP2 for non‐toxic ligands. Toxic and non‐toxic ligand selectivity of AhR depends on the components of the molecular chaperone complex.
Introduction
The healthcare situation of multiple sclerosis (MS) and its course are not being thoroughly investigated in Japan. We aimed to examine the current healthcare situation, including ...treatment and healthcare costs, of MS according to duration since its first diagnosis using Japanese real-world data to determine unidentified healthcare issues at each disease stage.
Methods
This retrospective, non-comparative, non-interventional study used a Japanese nationwide claims database (April 2008–August 2018) comprising 20 million patients from 329 acute care hospitals (as of June 2018). Treatment patterns, comorbidities, healthcare resource utilization, and healthcare costs were analyzed using longitudinal analyses of patients with MS according to duration since the first diagnosis. The time from diagnosis to first treatment was examined using Kaplan–Meier analysis.
Results
We identified 7067 patients with MS mean (standard deviation) age at first diagnosis 45.0 (16.2) years. About 70% of the patients did not receive disease-modifying therapy (DMT) within the first year of diagnosis. The frequency of DMT use decreased in patients with a longer duration since the first diagnosis. MS treatment costs tended to increase with a longer duration from the first diagnosis until 9 years, followed by a tendency to decrease; contrastingly, other healthcare costs tended to increase with duration after decreasing from the year of the first diagnosis to the next year. The frequencies of hospitalizations and hospital visits, healthcare costs—excluding those for MS treatment and tests—and prevalence of comorbidities tended to be higher in patients with a longer duration since the first diagnosis.
Conclusion
A considerable proportion of patients did not receive DMT, suggesting that patients with early-stage MS may lose the opportunity to improve their prognosis through early intervention with DMT. Among patients with a longer duration since the first diagnosis, fewer treatment choices may be available despite the larger clinical and treatment burden.
Aim
This study aimed to investigate the assessment tools dementia specialists use in clinical practice, reasons for their use and assessment‐related factors.
Methods
A questionnaire survey was ...carried out from 15 September 2021 to 20 October 2021 among 1858 dementia specialists in Japan, with responses obtained via mail or using a Web form accessed via a Web address.
Results
Of the 1858 specialists who were sent the questionnaire, 574 responded, yielding a response rate of 32.2%. Almost all respondents stated that the main purposes of neuropsychological testing were to identify the pathophysiology and aid diagnosis. Most respondents identified behavioral and psychological symptoms of dementia as important factors for assessment. The most commonly used tests were the Hasegawa Dementia Scale‐Revised and Mini‐Mental State Examination, often used as screening tools. The Mini‐Mental State Examination, Clock Drawing Test and Cube Copying Test were common assessments carried out directly by specialists. Quality of life and burden of care were less commonly assessed.
Conclusions
Despite the main purpose of carrying out neuropsychological tests on dementia patients is to “understand the pathophysiology” and “aid in diagnosis,” many assessment methods were chosen as screening methods carried out in a short time during clinic hours. The lack of evaluation of care burden and QOL, considered important by specialists, is an issue for the future in treating people with dementia, a life disability. Geriatr Gerontol Int 2024; 24: 102–109.
We surveyed dementia specialists in Japan to identify the assessment tools they use in clinical practice and related factors, such as assessors and time required for each assessment. Our findings hold the potential to drive changes in the selection of screening and detailed assessment tools for treatment planning.
Background: The impact of being overweight, as a component of the metabolic syndrome (MetS), for cardiovascular disease (CVD) mortality was investigated and compared with the predictive value of MetS ...by 2 different definitions. Methods and Results: A 12-year prospective study of 30,774 Japanese men and 60,383 women aged 40-79 years was conducted. The multivariate hazard ratio (HR; 95% confidence interval) of total CVD mortality for overweight subjects with ≥2 additional risk factors with reference to subjects with 0 of 4 MetS components was 1.83 (1.41-2.38) for men and 1.90 (1.45-2.49) for women, and for non-overweight subjects with ≥2 additional risk factors 1.75 (1.38-2.24) and 1.97 (1.52-2.55), respectively. The proportion of excess CVD deaths in the latter group was 1.5-fold higher than that in the former group. Multivariate HRs of coronary heart disease and total CVD mortality for MetS by the modified criteria of the American Heart Association/National Heart, Lung, and Blood Institute were 1.62 (1.31-2.00) and 1.23 (1.09-1.39), respectively, for men and 1.32 (1.05-1.65) and 1.12 (1.00-1.25), respectively, for women. The respective HRs for MetS by the International Diabetic Federation definition did not reach statistical significance, except for coronary heart disease in men. Conclusions: Non-overweight individuals with metabolic risk factors, as well as overweight individuals with such factors, should be targeted to reduce the CVD burden in the general population. (Circ J 2009; 73: 1635-1642)
Introduction
Claims databases are preferred for research on multiple sclerosis (MS) as this condition is characterized by low prevalence and long disease course. However, Japanese claims databases ...contain no information on disease severity or disability status of MS. Here, we aimed to explore the possibility of utilizing a principal component analysis (PCA) to estimate MS severity using a Japanese claims database.
Methods
An MS severity score was developed using a PCA. Factors related to functional systems for Expanded Disability Status Scale (EDSS) and higher disease severity (74 diagnoses, 68 drug prescriptions, and 77 procedures) were extracted from the claims database (April 2008–August 2018). The score (PC1 score) was developed for each patient-year—each year from the first diagnosis (excluding the year of the first diagnosis), based on the first principal component of the included factors. Finally, the patient-years were classified into quartiles based on the PC1 score, and demographic information and medical status were analyzed.
Results
The database contained 7067 patients with MS. The highest score group had a higher mean age (55.4 ± 0.2 mean ± standard error years), lower percentage of women (64.4 ± 0.7%), and longer mean disease duration from first diagnosis (8.1 ± 0.1 years) than the lowest score group (43.3 ± 0.2 years, 68.4 ± 0.8%, and 6.0 ± 0.1 years, respectively). In addition, the PC1 score of each patient positively correlated with disease duration from diagnosis.
Conclusion
We developed a PC1 score to indicate MS severity using information from a Japanese claims database. Since changes in demographic features we observed are consistent with findings of previous research, this score might represent MS severity to some extent. Further research is necessary to validate this score with clinical measurement of disability such as the EDSS.
Objective
No head‐to‐head clinical trials have compared ofatumumab with other disease‐modifying therapies (DMTs) available in Japan for patients with relapsing multiple sclerosis (RMS). In this ...study, a network meta‐analysis (NMA) was conducted to compare the efficacy of ofatumumab to other DMTs currently available in Japan for the treatment of patients with RMS.
Methods
Systematic searches were conducted in biomedical databases from inception to June 2020 to identify randomized controlled trials. Only English‐ and Japanese‐language publications describing studies conducted in Japan were included. Trials with sufficiently similar study and patient characteristics were included in a Bayesian NMA. A sensitivity analysis was conducted to explore the impact of potential sources of uncertainty.
Results
Four trials, each comparing a DMT with placebo in a ≥50% Japanese population, were sufficiently similar that comparative efficacy could be assessed for annualized relapse rate (ARR). Ofatumumab numerically reduced ARR compared with fingolimod (rate ratio RR: 0.84, 95% credible interval CrI: 0.20–3.39), dimethyl fumarate (RR: 0.61, 95% CrI: 0.16–2.30), and placebo (RR: 0.41, 95% CrI: 0.12–1.39), but not natalizumab (RR: 1.33, 95% CrI: 0.33–5.45). In a subgroup analysis of Japanese patients only, ofatumumab reduced relapses compared with all other treatments including natalizumab. These results were limited by the lack of studies reporting direct comparisons between included treatments and by heterogenous reporting of outcome data.
Conclusion
These findings, although limited by the paucity of evidence for Japanese patients, suggest that monoclonal antibody therapies (ie, natalizumab and ofatumumab) may provide improved efficacy compared with other DMTs available in Japan for patients with RMS.
With the advancement of small intestinal (double balloon and capsule) endoscopy technology, incidence of small intestinal lesion caused by nonsteroidal anti-inflammatory drugs (NSAIDs) has been known ...to be high. However, therapy for small intestinal mucosal lesion has not yet been developed. Previous studies have shown that heat shock proteins (HSPs) are involved in cytoprotection mediated by their function as a molecular chaperone. In this study, we examined the effect of HSP60 or HSP70 overexpression on hydrogen peroxide-induced (H
2O
2) or indomethacin-induced cell damage in the small intestinal epithelial cells.
cDNA of human HSP60 or HSP70 was transfected to rat small intestinal (IEC-6) cells, and HSP60- or HSP70-overexpressing cells were cloned. IEC-6 cells transfected with vector only were used as control cells. These cells were treated with H
2O
2 (0–0.14
mM) or indomethacin (0–2.5
mM). The cell viability was determined by MTT-assay. Cell necrosis was evaluated by LDH-release assay. Further, apoptosis was evaluated by caspases-3/7 activity and TUNEL assay.
Cell viability after H
2O
2 or indomethacin treatment was significantly higher in HSP60-overexpressing cells compared with that in control cells and HSP60-overexpressing cells. Apoptotic cells were also reduced in HSP60-overexpressing.
Conclusion: These results indicate that HSP60 plays an important role in protecting small intestinal mucosal cells from H
2O
2-induced or indomethacin-induced cell injury. HSP70-overexpressing cells did not show anti-apoptotic ability.
These findings possibly suggest that function of each HSP is different in the small intestine. Therefore, for the therapy of small intestinal mucosal lesion, HSP60-induction therapy could be a new therapeutic strategy.
Background
To investigate the pathophysiology of reflux laryngitis, an experimental model is required.
Aim
The aim of this study is to establish an animal model of reflux esophago-laryngitis, ...modifying our previously reported model of chronic acid reflux esophagitis.
Methods
The modified chronic acid reflux esophagitis (m-RE) group (
n
= 10), in which the duodenum was wrapped with 2.5 mm of Nelaton catheter, was not treated with any drugs. Also postoperatively, two treatment groups (
n
= 10 in each) received different dosages of rabeprazole (RPZ): 1.0 mg/kg/day (RPZ 1.0 group) or 10.0 mg/kg/day (RPZ 10.0 group). As a control group (
n
= 5), other rats underwent sham operation. The esophagus and larynx were resected on day 14 after the operation, and ulcer score of the esophagus was assessed. The epithelial thickness and leukocyte infiltration of the supraglottic and subglottic laryngeal mucosae were investigated. The number of interleukin (IL)-1β-positive cells was also counted and defined as the IL-1β labeling index.
Results
In the m-RE group, the epithelial thickness, leukocyte infiltration, and IL-1β labeling index of the supraglottic and subglottic laryngeal mucosae were increased compared with controls (
P
< 0.01). In the RPZ groups, not only the ulcer score of esophagus but also the epithelial thickness, leukocyte infiltration, and IL-1β labeling index of both the supraglottic and subglottic laryngeal mucosae were decreased dose-dependently relative to the m-RE group (
P
< 0.05).
Conclusions
Our modified chronic acid reflux esophagitis model proved useful in establishing a rat reflux esophago-laryngitis model, with both pathological laryngeal findings and reflux esophagitis shown to be improved by administration of a proton pump inhibitor.
α-Helical peptides, such as T-20 (enfuvirtide) and C34, derived from the gp41 carboxyl-terminal heptad repeat (C-HR) of HIV-1, inhibit membrane fusion of HIV-1 and the target cells. Although T-20 ...effectively suppresses the replication of multi-drug resistant HIV variants both in vitro and in vivo, prolonged therapy with T-20 induces emergence of T-20 resistant variants. In order to suppress the emergence of such resistant variants, we introduced charged and hydrophilic amino acids, glutamic acid (E) and lysine (K), at the solvent accessible site of C34. In particular, the modified peptide, SC34EK, demonstrates remarkably potent inhibition of membrane fusion by the resistant HIV-1 variants as well as wild-type viruses. The activity was specific to HIV-1 and little influenced by serum components. We found a strong correlation between the anti-HIV-1 activities of these peptides and the thermostabilities of the 6-helix bundles that are formed with these peptides. We also obtained the crystal structure of SC34EK in complex with a 36 amino acid sequence (N36) comprising the amino-terminal heptad repeat of HIV-1. The EK substitutions in the sequence of SC34EK were directed toward the solvent and generated an electrostatic potential, which may result in enhanced α-helicity of the peptide inhibitor. The 6-helix bundle complex of SC34EK with N36 appears to be structurally similar to that of C34 and N36. Our approach to enhancing α-helicity of the peptide inhibitor may enable future design of highly effective and specific HIV-1 inhibitors.
Minimal sequence of potential HIV-1 fusion inhibitors was identified using glycoprotein gp41-derived peptides containing α-helix-inducible EK motifs. One of the N-terminal motifs was replaced with an ...α-helix-inducible motif containing 2-aminoisobutyric acids.
Emergence of multi-drug resistant HIV-1 is a serious problem for AIDS treatment. Recently, the virus-cell membrane fusion process has been identified as a promising target for the development of novel drugs against these resistant variants. In this study, we identified a 29-residue peptide fusion inhibitor, SC29EK, which shows activity comparable to the previously reported inhibitor SC35EK. Some residues in SC29EK not required for interaction with virus gp41 heptad repeat 1 (HR1) were replaced with a non-proteinogenic amino acid, 2-aminoisobutyric acid (Aib), to stabilize the α-helix structure and to provide resistance to peptidases.
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