Healthy life expectancy is an indicator that represents a composite of data on mortality and health status and is defined as the average number of years that a person can expect to live at a certain level of health. To extend people's healthy life expectancy, my colleague and I conducted a variety of epidemiologic research based upon community-based cohort studies and intervention trials. The findings from our prospective cohort studies included blood pressure reference values measured at home, green tea health benefit, Japanese dietary pattern, and feeling ikigai (a sense of life worth living) at daily life.
Based upon these evidence, I have made some proposals toward extension of healthy life expectancy. In 2011, as the Chair of the Planning Committee for the Next National Health Promotion of Ministry of Health, Labor and Welfare (MHLW), I proposed that the Health Japan 21 (second term) should aim to extend healthy life expectancy to exceed the number of years extended in the total life expectancy, thus compressing the duration to be spent in an unhealthy state (compression of morbidity). In the interim evaluation of the Health Japan 21 (second term) in 2018, we were able to demonstrate that this goal is being achieved. Compared with 2010, in 2016, the increase in healthy life expectancy (1.72 years in men and 1.17 years in women) was higher than that of total life expectancy (1.43 years in men and 0.84 years in women). As a result, the duration to be spent in an unhealthy state was reduced by 0.29 years in men and by 0.33 years in women. It is important to note that Japan is the only country that has made progress in achieving compression of morbidity at the national level. We need to maintain this momentum of compressing morbidity.
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and is strongly associated with cardiovascular mortality. Given the pandemic of obesity and diabetes, the elucidation of the molecular underpinnings of DKD and establishment of effective therapy are urgently required. Studies over the past decade have identified the activated renin-angiotensin system (RAS) and hemodynamic changes as important therapeutic targets. However, given the residual risk observed in patients treated with RAS inhibitors and/or sodium glucose co-transporter 2 inhibitors, the involvement of other molecular machinery is likely, and the elucidation of such pathways represents fertile ground for the development of novel strategies. Rho-kinase (ROCK) is a serine/threonine kinase that is under the control of small GTPase protein Rho. Many fundamental cellular processes, including migration, proliferation, and survival are orchestrated by ROCK through a mechanism involving cytoskeletal reorganization. From a pathological standpoint, several analyses provide compelling evidence supporting the hypothesis that ROCK is an important regulator of DKD that is highly pertinent to cardiovascular disease. In cell-based studies, ROCK is activated in response to a diverse array of external stimuli associated with diabetes, and renal ROCK activity is elevated in the context of type 1 and 2 diabetes. Experimental studies have demonstrated the efficacy of pharmacological or genetic inhibition of ROCK in the prevention of diabetes-related histological and functional abnormalities in the kidney. Through a bird's eye view of ROCK in renal biology, the present review provides a conceptual framework that may be widely applicable to the pathological processes of multiple organs and illustrate novel therapeutic promise in diabetology.
Recent studies have clarified the interaction between nervous systems and immunity regarding the manner in which local inflammation is regulated and systemic homeostasis is maintained. The cholinergic anti-inflammatory pathway (CAP) is a neuroimmune pathway activated by vagus nerve stimulation. Following afferent vagus nerve stimulation, signals are transmitted to immune cells in the spleen, including β2-adrenergic receptor-positive CD4-positive T cells and α7 nicotinic acetylcholine receptor-expressing macrophages. These immune cells release the neurotransmitters norepinephrine and acetylcholine, inducing a series of reactions that reduce proinflammatory cytokines, relieving inflammation. CAP contributes to various inflammatory diseases such as endotoxemia, rheumatoid arthritis, and inflammatory bowel disease. Moreover, emerging studies have revealed that vagus nerve stimulation ameliorates kidney damage in an animal model of acute kidney injury. These studies suggest that the link between the nervous system and kidneys is associated with the pathophysiology of kidney injury. Here, we review the current knowledge of the neuroimmune circuit and kidney disease, as well as potential for therapeutic strategies based on this knowledge for treating kidney disease in clinical settings.
RET (REarranged during Transfection)is activated by DNA rearrangement of the 3′ fragment of the receptor tyrosine kinase gene, namely, RET proto-oncogene, with the 5′ fragment of various genes with putative dimerization domains, such as a coiled coil domain, that are necessary for constitutive activation. RET rearrangements have been detected in a variety of human cancers, including thyroid, lung, colorectal, breast, and salivary gland cancers. Moreover, point mutations in RET are responsible for multiple endocrine neoplasia types 2A and 2B, which can develop into medullary thyroid cancer and pheochromocytoma. Substantial effort is currently being exerted in developing RET kinase inhibitors. RET is also responsible for Hirschsprung's disease, a developmental abnormality in the enteric nervous system. Gene knockout studies have demonstrated that RET plays essential roles in the development of the enteric nervous system and kidney as well as in spermatogenesis. Studies regarding RET continue to provide fascinating challenges in the fields of cancer research, neuroscience, and developmental biology.
Arrest of circulating leukocytes and subsequent diapedesis is a fundamental component of inflammation. In general, the leukocyte migration cascade is tightly regulated by chemoattractants, such as chemokines. Chemokines, small secreted chemotactic cytokines, as well as their G-protein-coupled seven transmembrane spanning receptors, control the migratory patterns, positioning and cellular interactions of immune cells. Increased levels of chemokines and their receptors are found in the blood and within inflamed tissue in patients with rheumatoid arthritis (RA) and vasculitis. Chemokine ligand-receptor interactions regulate the recruitment of leukocytes into tissue, thus contributing in important ways to the pathogenesis of RA and vasculitis. Despite the fact that blockade of chemokines and chemokine receptors in animal models have yielded promising results, human clinical trials in RA using inhibitors of chemokines and their receptors have generally failed to show clinical benefits. However, recent early phase clinical trials suggest that strategies blocking specific chemokines may have clinical benefits in RA, demonstrating that the chemokine system remains a promising therapeutic target for rheumatic diseases, such as RA and vasuculitis and requires further study.
The heart, one of the more complex organs, is composed from a number of differentiated cells. In general, researchers consider that the cardiac cells are derived from the same origin as mesodermal cells, except neural crest cells. However, as the developmental stages proceed, cardiac mesodermal cells are differentiated into various types of cells via cardiac progenitors and demonstrate different programming in transcriptional network and epigenetic regulation in a spatiotemporal manner. In fact, the metabolic feature also changes dramatically during heart development and cardiac differentiation. Researchers reported that each type of cell exhibits different metabolic features that can be used to specifically identify them. Metabolism is a critical process for generating energy and biomass in all living cells and organisms and has been long regarded as a passenger, rather than an active driver, for intracellular status. However, recent studies revealed that metabolism influences self-renewal and cell fate specification via epigenetic changes directly or indirectly. Metabolism mirrors the physiological status of the cell and endogenous cellular activity; therefore, understanding the metabolic signature of each cell type serves as a guide for innovative methods of selecting and differentiating desired cell types. Stem cell biology and developmental biology hold great promise for cardiac regenerative therapy, for which, successful strategy depends on the precise translation of the philosophy of cardiac development in the early embryo to the cell production system. In this review, we focus on the metabolism during heart development and cardiac differentiation and discuss the next challenge to unlock the potential of cell biology for regenerative therapy based on metabolism.
The retina transmits light signals to the brain via a complex structure composed of photoreceptor cells, neurons including ganglion cells, glial cells such as astrocytes and Mueller cells, as well as retinal blood vessels that feed the retina. The retina performs such high-level physiological function and maintains homeostasis effectively through interactions among the cells that form the neurovascular units (NVUs). Furthermore, as a component of the blood‒retinal barrier (BRB), the vascular structure of the retina is functionally based on the NVUs, in which the nervous system and the vascular tissues collaborate in a mutually supportive relationship. Retinal neurons such as ganglion cells and amacrine cells are traditionally considered to be involved only in visual function, but multiple functionality of neurons attracted attention lately, and retinal neurons play an important role in the formation and function of retinal blood vessels. In other words, damage to neurons indirectly affects retinal blood vessels. Diabetic macular edema is the leading cause of vision loss in diabetic retinopathy, and this type of edema results in neurological and vascular disorders. In this article, the regulatory mechanism of retinal capillaries in diabetic macular edema is reviewed from the viewpoint of NVU.
Introduction: This study aimed to verify the internal consistency and validity of the Japanese version of the 9-item Shared Decision-Making Questionnaire (SDM-Q-9) and investigate the association among patient factors, shared decision-making experienced by patients, and patients' decision conflict during the treatment decision process in primary outpatient settings in Japan.
Methods: Patients who visited a primary care outpatient unit for the first time and completed the Japanese version of SDM-Q-9 and the Decisional Conflict Scale (DCS) immediately after consultation were included. The internal consistency of SDM-Q-9 was assessed using Cronbach's alpha coefficient. Factor analysis and structural equation modeling were used to investigate structural construct validity. The relationship among patient-perceived experiences of shared decision-making, decision conflict, and patient factors was evaluated using correlation analysis.
Results: A total of 131 patients with chronic diseases (55.0% females, 28.2% aged ≥ 70 years) were included in this analysis. Cronbach's alpha for the Japanese version of SDM-Q-9 was 0.917, indicating a high degree of internal consistency. Confirmatory factor analysis indicated that the Japanese version of SDM-Q-9 had a one-factor structure. Spearman's rank correlation analysis indicated that the correlation between SDM-Q-9 and DCS was −0.577 (p < 0.05), indicating a significant inverse correlation and convergent validity. Older age was positively associated with perceived support of the physician in understanding all information.
Conclusions: We confirmed that the Japanese version of SDM-Q-9 was both reliable and valid for use in Japanese primary care settings. In addition, we found a clear association between shared decision-making and decisional conflict of patients.
Introduction: Recent estimates suggest that there is a substantial number of Japanese students with developmental disabilities. This study aimed to examine potential associations between autistic, autistic subcomponents, and attention deficit/hyperactivity disorder (ADHD) traits with student performance (as measured by presenteeism) and class attendance among Japanese university students.
Methods: Participants comprised 721 students from different regions of Japan who completed a self-administered internet survey. Autistic and ADHD traits were measured using an abridged version of the autism spectrum quotient (AQ-Short) and adult ADHD self-report scale (ASRS). Presenteeism, which is an indicator of student performance, was assessed using the modified World Health Organization Health and Work Performance Questionnaire. Class attendance during the past year was self-reported by participants.
Results: Students with high levels of autistic traits and high levels of ADHD traits were significantly more likely to report poor student performance (odds ratio [OR] = 3.07, 95% confidence interval [95% CI]: 1.90–4.96; and OR = 2.13, 95% CI: 1.32–3.42, respectively). Regarding autistic trait subcomponents, students with high levels of preference for routine (OR = 2.39, 95% CI: 1.38–4.13) and high levels of difficulties with social skills (OR = 1.81, 95% CI: 1.03–3.18) were also significantly more likely to report poor student performance. There were borderline significant associations between traits of attention-switching difficulties and poor student performance (OR = 1.78, 95% CI: 1.00–3.15). Regarding ADHD trait subcomponents, students with high levels of inattention (OR = 2.88, 95% CI: 1.32–6.26) were also significantly more likely to report poor student performance. Students with both high levels of autistic traits and high levels of ADHD traits were more likely to report poor student performance than those with high levels of only one trait type. There were, however, no statistically significant associations between these traits and low class attendance risk.
Conclusions: Sickness presenteeism was significantly associated with high levels of both autistic traits and ADHD traits among Japanese university students.
Introduction: This study examined the relationship between health literacy (HL), women's health, and work productivity (i.e., absenteeism or presenteeism) among female workers in Japan.
Methods: In February 2018, a web-based, nationwide survey was conducted among registered survey company monitors. The questionnaire included women's HL, absenteeism, presenteeism, health behaviors for menstrual abnormalities and premenstrual syndrome (PMS), and demographic information. Overall, 2,596 monitors were randomly invited, and the survey included the first 2,000 respondents (average age = 35.8 years, SD = 8.1). An analysis of covariance (ANCOVA) was conducted to compare adjusted work productivity between two groups: the low-HL group and the high-HL group. The results were adjusted for age, education, employment status, number of children, and the presence of underlying gynecological diseases. Logistic regression analyses were performed to determine any differences in health behaviors for menstrual abnormalities or PMS between the two groups. The results were adjusted for age, education level, number of children, and employment status.
Results: The ANCOVA showed that the high-HL group had significantly less presenteeism and better performance when experiencing PMS (p < 0.001 and p < 0.013, respectively) compared to the low-HL group after adjusting for covariates. However, the results showed no significant differences in absenteeism between the two groups. Logistic regression showed that the high-HL group had a significantly higher odds ratio (OR) than the low-HL group in terms of health behaviors for menstrual abnormalities or PMS (OR 2.82 and 1.86, respectively) after adjusting for covariates.
Conclusions: Women's HL may contribute to decreased presenteeism and better health behaviors regarding the use of medicine or medical services.
Introduction: Growing evidence indicates the prognostic importance of the crosstalk between cancer cells and stroma through the induction of epithelial-mesenchymal transition (EMT). This study aimed to clarify the prognostic value of evaluating primary tumor histology with the anatomical extent of disease in patients with colorectal liver metastasis (CRLM).
Methods: Prognostic analyses were performed in 411 CRLM patients who underwent hepatectomy at two institutions. Tumors were graded into one of three histological categories based on integrated assessment of EMT-associated histology (HistologyEMT) in primary tumors, i.e., poorly differentiated clusters (PDCs) and desmoplastic reaction (DR).
Results: A prognostic grouping system for the anatomical extent of disease (N stage, liver metastasis number and size, and extrahepatic disease; Gradeanatomical) stratified patients into three groups with different five-year relapse-free survival (RFS) rates after hepatectomy: A, 31% (191 patients); B, 15% (124 patients); and C, 6% (96 patients; P < 0.0001). HistologyEMT (A, G1 PDC and mature-type DR; C, G3 PDC and immature-type DR; and B, others) identified 49, 120, and 242 patients with 46%, 5%, and 22% five-year RFS, respectively (P < 0.0001). Among prognostic factors, the Akaike information criterion was most favorable in Gradeanatomical, followed by HistologyEMT. Multivariate analysis demonstrated that these two factors independently impacted RFS; two-year RFS after hepatectomy in different patient groups had a wide range (10%-76%).
Conclusions: Histological assessment of dedifferentiation and the stromal environment of primary tumors contributed to effective risk stratification of early relapse after hepatectomy, which could be useful to determine clinical management for CRLM patients.
Introduction: A widely used reference range for pulmonary function testing was derived from middle-aged, healthy, non-smoking adults in Japan. This study examined the effect of age-related diseases on pulmonary function tests for older Japanese adults.
Methods: All patients aged ≥65 years who underwent spirometry before general and orthopedic surgeries in Itoigawa General Hospital (Niigata, Japan) from January 2014 to June 2019 were identified, and their charts were reviewed.
Results: This study included 1050 Japanese patients (median age: 75 years). The median spirometric values of vital capacity, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and FEV1/FVC in all patients were 2.66 L [interquartile range; 2.24, 3.25], 2.57 L [2.13, 3.13], 1.98 L [1.66, 2.37], and 77.5% [72.2, 81.9], respectively. Multiple regression analyses revealed that spirometric values were significantly affected by age, body height, sex, smoking status, social dependency, dyslipidemia, diabetes, history of heart failure, peripheral artery disease, end-stage renal disease, neuromuscular disease, and psychiatric disorders. Male sex and height were positively correlated with FVC and FEV1. Other factors, such as a history of heart failure, neuromuscular disease, and independent physical activity, were negatively correlated with FVC and FEV1 to almost the same extent as that of age.
Conclusions: These data will provide clinically useful information to accurately interpret pulmonary function test results in older Japanese adults.
Introduction: The Japanese packaging instructions for methadone prohibit dose escalation within 7 days of administration initiation as this may result in overdose and subsequent adverse events. However, for terminal cancer patients, evaluation of the effects of methadone may be desirable within 7 days because they have limited prognoses. We aimed to determine the possibility of estimating the adequateness of methadone earlier than the 7th day by investigating the onset timing of analgesic effects and adverse events of methadone in Japanese terminal cancer patients.
Methods: Japanese terminal cancer patients who started taking methadone in Ashiya Municipal Hospital were enrolled from January 1, 2013 to February 28, 2019. Verbal rating scale (VRS) scores on pain and adverse events before and after methadone administration (on days 3, 5, and 7) were retrospectively investigated from medical records.
Results: We enrolled 25 patients, of which 20 (80.0%) received methadone until day 7. The VRS score (mean ± standard deviation) on pain was significantly reduced to 0.90 ± 0.55 on day 3, compared with 1.65 ± 0.67 before the administration of methadone (p < 0.05). The mean VRS scores did not differ significantly on days 3, 5, and 7. Additionally, of the 23 patients who received methadone until day 3, 20 (87.0%) showed an analgesic effect on day 3 and 17 (85.0%) received methadone without experiencing serious adverse events until day 7.
Conclusions: The adequateness of methadone in Japanese terminal cancer patients could be determined before day 7, considering the high analgesia incidence and few adverse events 3 days after the methadone administration under careful observation by a physician experienced in methadone administration. However, as this is a preliminary study, the relationship between pharmacokinetic parameters and analgesic effects was not evaluated. Further studies involving pharmacokinetics and multicenter prospective studies are required to support these findings.
Introduction: Though a combination of proximal femoral fracture and mental illness is likely, the management of this combination is not well established. The aim of this study was to clarify the current disposition of acute care and rehabilitation for patients with this combination of conditions at our institution.
Methods: We retrospectively analyzed the records of 192 patients hospitalized in the psychiatric ward who present with a proximal femoral fracture and an antecedent mental illness. We investigated walking ability prior to injury and after surgery, at discharge from our institution, using the Functional Independence Measure (FIM) score.
Results: Although patients in the psychiatric ward demonstrated postoperative hospital stays approximately 10 days longer than those in the orthopedic ward, more than half of the patients in the psychiatric ward were discharged from our institution with a functional level of complete dependence for walking ability. In addition, nearly 90% of the patients studied were transferred to a psychiatric hospital where no physical therapy or rehabilitation was provided to the inpatients.
Conclusions: At our institution, patients with proximal femoral fracture and antecedent mental illness tended to be discharged with complete dependence in walking ability, often to a psychiatric hospital without physical therapy or rehabilitation. We hope this paper will draw attention to the need for rehabilitation in these patients.
A 66-year-old female, whom received a pulmonary vein (PV) isolation (PVAI) with linear ablation of the carina lines between the superior and inferior PVs of both the right and left PVs for atrial fibrillation (AF), was admitted to receive a radiofrequency catheter ablation (RFCA) of symptomatic drug-refractory atrial tachycardia (AT). The EnSiteTM analysis by the AdvisorTM HD Grid catheter during the AT could easily detect that the carina between the right superior and inferior PVs exhibited a low voltage area (< 0.5 mV), in addition to the fact that the electrical activation turned around the right PVs in a figure 8, even though mapping was performed during AT. This AT was steadily terminated, after commencing the radiofrequency energy delivery to the carina of the right PVs.