Association of anticholinergic drug exposure with the risk of dementia among older adults in Japan: The LIFE Study.

OBJECTIVES: Several studies have investigated that anticholinergic drugs cause cognitive impairment. However, the risk of dementia associated with anticholinergics has not been extensively investigated in the super-aging society of Japan. We conducted this study to assess the association between anticholinergic drugs and the risk of dementia in older adults in Japan. METHODS: This nested case-control study used data from the Longevity Improvement & Fair Evidence Study, which includes claim data in Japan from 2014 to 2020. We included 66,478 cases of diagnosed dementia and 328,919 matched controls aged ≥65 years, matched by age, sex, municipality, and cohort entry year. Primary exposure was the total cumulative anticholinergic drugs prescribed from cohort entry date to event date or matched index date, which was the total standardized daily doses for each patient, calculated by adding the total dose of different types of anticholinergic drugs in each prescription, divided by the World Health Organization-defined daily dose values. Odds ratios for dementia associated with cumulative exposure to anticholinergic drugs were calculated using conditional logistic regression adjusted for confounding variables. RESULTS: The mean (standard deviation) age at index date was 84.3 (6.9), and the percentage of women was 62.1%. From cohort entry date to event date or matched index date, 18.8% of the case patients and 13.7% of the controls were prescribed at least one anticholinergic drug. In the multivariable-adjusted model, individuals with anticholinergic drugs prescribed had significantly higher odds of being diagnosed with dementia (adjusted odds ratio, 1.50 [95% confidence interval, 1.47-1.54]). Among specific types of anticholinergic drugs, a significant increase in risk was observed with the use of antidepressants, antiparkinsonian drugs, antipsychotics, and bladder antimuscarinics in a fully multivariable-adjusted model. CONCLUSIONS: Several types of anticholinergic drugs used by older adults in Japan are associated with an increased risk of dementia. These findings suggest that the underlying risks should be considered alongside the benefits of prescribing anticholinergic drugs to this population.

Economic Status and Mortality in Patients with Alzheimer's Disease in Japan: The Longevity Improvement and Fair Evidence Study.

OBJECTIVES: As more countries are implementing measures to address Alzheimer's disease (AD), it is essential to update the available knowledge on the relationship between economic status and mortality in patients with AD. This study examined the influence of economic status on mortality in Japanese individuals with AD using a medical claims dataset. DESIGN: This was a retrospective cohort study. SETTING AND PARTICIPANTS: Medical claims data from April 2014 to March 2019 were obtained from 13 local cities participating in the Longevity Improvement and Fair Evidence study. The inclusion criteria were patients aged 65 years and older who were newly diagnosed with AD during the study period. METHODS: The outcome was death during the follow-up period. We assessed economic status by household income (middle to high income and low income); data were obtained from the use of the Medical Expenditure Ceiling Application and Standard Copayment Reduction Card (fee reduction card) when receiving an AD diagnosis, as an indicator of low-income status. We performed multivariate Cox proportional hazards analyses to examine the relationship between economic status and mortality; the model was adjusted for age, sex, the Charlson comorbidity index, and antidementia drug use. RESULTS: We identified 39,081 newly diagnosed patients with AD from the Longevity Improvement and Fair Evidence study database (mean age, 83.6 years; female, 67.1%). Of these, 3189 individuals were identified as having a low-income status. After adjusting for possible confounders, low-income status was associated with mortality (hazard ratio, 1.95; 95% confidence interval, 1.84-2.07). CONCLUSIONS AND IMPLICATIONS: Low-income status was associated with substantially poorer prognoses in new AD cases, indicating a need for a thorough examination of medical and nursing care services utilized by low-income individuals with AD and to explore improvement strategies.

Improved assay system for acidic peptide: N-glycanase (aPNGase) activity in plant extracts.

Plant acidic peptide: N-glycanase (aPNGase) release N-glycans from glycopeptides during the degradation process of glycoproteins in developing or growing plants. We have previously developed a new method to detect the aPNGase activity in crude extracts, which is prerequisite for the construction of aPNGase knockout or overexpression lines. However, this method has the disadvantage of requiring de-sialylation treatment and a lectin chromatography. In this study, therefore, we improved the simple and accurate method for detecting aPNGase activity using anion-exchange HPLC requiring neither the desialylation treatment nor the lectin affinity chromatography.

Effect of asbestos exposure on differentiation and function of cytotoxic T lymphocytes

Asbestos exposure is known to cause malignant mesothelioma, which is associated with poor prognosis. We focused on and examined the effect of asbestos exposure on the differentiation and function of cytotoxic T lymphocytes (CTLs). CTLs have the ability to specifically attack tumor cells after being differentiated from naïve CD8 T cells following antigen stimulation. Exposure to chrysotile B asbestos suppressed the differentiation of CTLs during the mixed lymphocyte reaction (MLR) and was associated with a decrease in proliferation of CD8 T cells. Additionally, in an effort to investigate the mechanism associated with suppressed CTL differentiation upon exposure to asbestos, we focused on IL-2, a cytokine involved in T cell proliferation. Our findings indicated that insufficient levels of IL-2 are not the main cause for the suppressed induction of CTLs by asbestos exposure, although they suggest potential improvement in the suppressed CTL function. Furthermore, the functional properties of peripheral blood CD8 lymphocytes from asbestos-exposed individuals with pleural plaque (PP) and patients with malignant mesothelioma (MM) were examined. MM patients showed lower perforin levels in CD8 lymphocytes following stimulation compared with PP-positive individuals. The production capacity of IFN-γ in the MM group tended to be lower compared with healthy volunteers or PP-positive individuals. In an effort to determine whether chronic and direct asbestos exposure affected the function of CD8 T cells, cultured human CD8 T cells were employed as an in vitro model and subjected to long-term exposure to chrysotile (CH) asbestos. This resulted in decreased levels of intracellular perforin and secreted IFN-γ. Those findings underlie the possibility that impaired CD8 lymphocyte function is caused by asbestos exposure, which fail to suppress the development of MM. Our studies therefore reveal novel effects of asbestos exposure on CTLs, which might contribute towards the development and implementation of an effective strategy for the prevention and cure of malignant mesothelioma.

Cytokine alteration and speculated immunological pathophysiology in silicosis and asbestos-related diseases

This review is partly composed of the presentation "Cytokine alteration and speculated immunological pathophysiology in silicosis and asbestos-related diseases" delivered during the symposium "Biological effects of fibrous and particulate substances and related areas" organized by the Study Group of Fibrous and Particulate Studies of the Japanese Society of Hygiene and held at the 78th Annual Meeting in Kumamoto, Japan. In this review, we briefly introduce the results of recent immunological analysis using the plasma of silica and asbestos-exposed patients diagnosed with silicosis, pleural plaque, or malignant mesothelioma. Thereafter, experimental background and speculation concerning the immunological pathophysiology of silica and asbestos-exposed patients are discussed.

Immunological alterations found in mesothelioma patients and supporting experimental evidence

It is common knowledge that exposure to asbestos causes asbestos-related diseases, such as asbestosis, lung cancer and malignant mesothelioma, not only in people who have had long-term contact with asbestos in their work environment but also in residents living near factories that handle asbestos. Since the summer of 2005, these revelations turned into a large medical problem and caused and social unrest. We have focused on the immunological effects of both asbestos and silica on the human immune system. In this brief review, we introduce immunological alterations found in patients with malignant mesothelioma and describe the experimental background in which these were found. Analyzing the immunological effects of asbestos may improve our understanding of the biological effects of asbestos.

Keynote lecture in the 13th Japanese Society of Immunotoxicology (JSIT 2006) : -Pathophysiological Development and Immunotoxicology: what we have found from research related to silica and silicate such as asbestos-

Silica and silicates may disturb immune functions such as autoimmunity and tumor immunity, because people who are exposed to the materials sometimes develop autoimmune and malignant diseases, respectively. Although silica-induced disorders of autoimmunity have been explained as adjuvant-type effects of silica, more precise analyses are needed and should reflect the recent progress in immunomolecular findings. A brief summary of our investigations related to the immunological effects of silica/asbestos is presented. Recent advances in immunomolecular studies led to detailed analyses of the immunological effects of asbestos and silica. Both affect immuno-competent cells and these effects may be associated with the pathophysiological development of complications in silicosis and asbestos-exposed patients such as the occurrence of autoimmune disorders and malignant tumors, respectively. In addition, immunological analyses may lead to the development of new clinical tools for the modification of the pathophysiological aspects of diseases such as the regulation of autoimmunity or tumor immunity using cell-mediated therapies, various cytokines, and molecule-targeting therapies. In particular, as the incidence of asbestos-related malignancies is increasing and such malignancies have been a medical and social problem since the summer in 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate the nation wide anxiety about these malignancies.

Keynote Lecture in the 13th Japanese Society of Immunotoxicology (JSIT 2006)

Silica and silicates may disturb immune functions such as autoimmunity and tumor immunity, because people who are exposed to the materials sometimes develop autoimmune and malignant diseases, respectively. Although silica-induced disorders of autoimmunity have been explained as adjuvant-type effects of silica, more precise analyses are needed and should reflect the recent progress in immunomolecular findings. A brief summary of our investigations related to the immunological effects of silica/asbestos is presented. Recent advances in immunomolecular studies led to detailed analyses of the immunological effects of asbestos and silica. Both affect immuno-competent cells and these effects may be associated with the pathophysiological development of complications in silicosis and asbestos-exposed patients such as the occurrence of autoimmune disorders and malignant tumors, respectively. In addition, immunological analyses may lead to the development of new clinical tools for the modification of the pathophysiological aspects of diseases such as the regulation of autoimmunity or tumor immunity using cell-mediated therapies, various cytokines, and molecule-targeting therapies. In particular, as the incidence of asbestos-related malignancies is increasing and such malignancies have been a medical and social problem since the summer in 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate the nation wide anxiety about these malignancies.