Tohoku Medical and Pharmaceutical University Hospital

IL-17 is a cytokine that induces neutrophil-mediated inflammation, but its role in protective immunity against intracellular bacterial infection remains unclear. In the present study, we demonstrate that IL-17 is an important cytokine not only in the early neutrophil-mediated inflammatory response, but also in T cell-mediated IFN-gamma production and granuloma formation in response to pulmonary infection by Mycobacterium bovis bacille Calmette-Guérin (BCG). IL-17 expression in the BCG-infected lung was detected from the first day after infection and the expression depended on IL-23. Our observations indicated that gammadelta T cells are a primary source of IL-17. Lung-infiltrating T cells of IL-17-deficient mice produced less IFN-gamma in comparison to those from wild-type mice 4 wk after BCG infection. Impaired granuloma formation was also observed in the infected lungs of IL-17-deficient mice, which is consistent with the decreased delayed-type hypersensitivity response of the infected mice against mycobacterial Ag. These data suggest that IL-17 is an important cytokine in the induction of optimal Th1 response and protective immunity against mycobacterial infection.

In this study, we examined the biological action of IL-17 on human non-small cell lung cancer (NSCLC). Although IL-17 had no direct effect on the in vitro growth rate of NSCLC, IL-17 selectively augmented the secretion of an array of angiogenic CXC chemokines, including CXCL1, CXCL5, CXCL6, and CXCL8 but not angiostatic chemokines, by three different NSCLC lines. Endothelial cell chemotactic activity (as a measure of net angiogenic potential) was increased in response to conditioned medium from NSCLC stimulated with IL-17 compared with those from unstimulated NSCLC. Enhanced chemotactic activity was suppressed by neutralizing mAb(s) to CXCL1, CXCL5, and CXCL8 or to CXCR-2 but not to vascular endothelial growth factor-A. Transfection with IL-17 into NSCLC had no effect on the in vitro growth, whereas IL-17 transfectants grew more rapidly compared with controls when transplanted in SCID mice. This IL-17-elicited enhancement of NSCLC growth was associated with increased tumor vascularity. Moreover, treatment with anti-mouse CXCR-2-neutralizing Ab significantly attenuated the growth of both neomycin phosphotransferase gene-transfected and IL-17-transfected NSCLC tumors in SCID mice. A potential role for IL-17 in modulation of the human NSCLC phenotype was supported by the findings that, in primary NSCLC tissues, IL-17 expression was frequently detected in accumulating and infiltrating inflammatory cells and that high levels of IL-17 expression were associated with increased tumor vascularity. These results demonstrate that IL-17 increases the net angiogenic activity and in vivo growth of NSCLC via promoting CXCR-2-dependent angiogenesis and suggest that targeting CXCR-2 signaling may be a novel promising strategy to treat patients with NSCLC.

IL-17A is originally identified as a proinflammatory cytokine that induces neutrophils. Although IL-17A production by CD4(+) Th17 T cells is well documented, it is not clear whether IL-17A is produced and participates in the innate immune response against infections. In the present report, we demonstrate that IL-17A is expressed in the liver of mice infected with Listeria monocytogenes from an early stage of infection. IL-17A is important in protective immunity at an early stage of listerial infection in the liver because IL-17A-deficient mice showed aggravation of the protective response. The major IL-17A-producing cells at the early stage were TCR gammadelta T cells expressing TCR Vgamma4 or Vgamma6. Interestingly, TCR gammadelta T cells expressing both IFN-gamma and IL-17A were hardly detected, indicating that the IL-17A-producing TCR gammadelta T cells are distinct from IFN-gamma-producing gammadelta T cells, similar to the distinction between Th17 and Th1 in CD4(+) T cells. All the results suggest that IL-17A is a newly discovered effector molecule produced by TCR gammadelta T cells, which is important in innate immunity in the liver.

BACKGROUND AND PURPOSE: Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and also has the potential to increase vascular permeability. Therefore, it may contribute to the recovery of brain cells from ischemic insult through potentiating neovascularization or may exacerbate brain damage by forming brain edema. However, the exact role of this protein in cerebral ischemia is not fully understood. We investigated temporal, spatial, and cellular profiles of the induction of VEGF gene expression after transient focal cerebral ischemia at both mRNA and protein levels. METHODS: We used a transient middle cerebral artery (MCA) occlusion model. Northern blot analysis was performed to assess the chronological pattern of induction and the impact of length of ischemia on mRNA expression. Western blot analysis was performed to ensure the selective detection of immunoreactive VEGF with an antibody. Temporal, spatial, and cellular changes of immunohistochemical VEGF expression were compared with different periods of reperfusion from 1 hour to 7 days after transient MCA occlusion. RESULTS: (1) Northern blot analysis revealed no detectable VEGF mRNA in the control brains. The mRNA became evident at 1 hour after reperfusion, peaked at 3 hours, and then decreased. The length of ischemia from 1 to 3 hours made no differences in the degree and temporal profile of the subsequent induction of VEGF mRNA. (2) Western blot analysis showed no band in the control brain, but two bands with molecular weights of 38 and 45 kD, corresponding to VEGF121 and VEGF165, were induced at 1 hour of reperfusion, peaked at 3 hours of reperfusion, and then decayed. (3) Neurons in the cerebral cortex of the MCA territory expressed VEGF at 1 hour after reperfusion with a peak at 3 hours and then diminished by 1 day. Pial cells of the MCA territory also expressed immunoreactive VEGF from 1 hour of reperfusion that was sustained until 3 to 7 days after reperfusion. CONCLUSIONS: Rapid induction of VEGF gene expression after transient MCA occlusion was demonstrated at both mRNA and protein levels. Cortical neurons and pial cells were the source of VEGF production in this model, but the temporal profiles of the induction between these cells were different. The early but dissociative induction of VEGF between neuronal and pial cells suggests different roles of the protein in their cells after transient MCA occlusion.

The cytokine-inducing activities of fungal polysaccharides were examined in human monocytes in culture, with special reference to CD14 and Toll-like receptors (TLRs). Tumor necrosis factor alpha (TNF-alpha) production by monocytes was markedly induced in a dose-dependent manner upon stimulation with cell walls from Candida albicans and mannan from Saccharomyces cerevisiae and C. albicans, although relatively high concentrations (10 to 100 microg/ml) of stimulants were required for activation as compared with the reference lipopolysaccharide (LPS) (1 to 10 ng/ml). The yeast form C. albicans and its mannan and cell wall fractions exhibited higher TNF-alpha production than respective preparations from the hyphal form. Only slight TNF-alpha production was induced by the S. cerevisiae glucan. The TNF-alpha production triggered by reference LPS and purified fungal mannans required the presence of LPS-binding protein (LBP), and these responses were inhibited by anti-CD14 and anti-TLR4 antibodies, but not by anti-TLR2 antibody. In contrast to the activity of LPS, the activity of purified S. cerevisiae mannan was not inhibited by polymyxin B. These findings suggested that the mannan-LBP complex is recognized by CD14 on monocytes and that signaling through TLR4 leads to the production of proinflammatory cytokines in a manner similar to that induced by LPS.

Primary aldosteronism affects ≈5% to 10% of hypertensive patients and has unilateral and bilateral forms. Most unilateral primary aldosteronism is caused by computed tomography-detectable aldosterone-producing adenomas, which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone-regulating genes. The cause of the most common bilateral form of primary aldosteronism, idiopathic hyperaldosteronism (IHA), is believed to be diffuse hyperplasia of aldosterone-producing cells within the adrenal cortex. Herein, a multi-institution cohort of 15 IHA adrenals was examined with CYP11B2 immunohistochemistry and next-generation sequencing. CYP11B2 immunoreactivity in adrenal glomerulosa harboring non-nodular hyperplasia was only observed in 4/15 IHA adrenals suggesting that hyperplasia of CYP11B2-expressing cells may not be the major cause of IHA. However, the adrenal cortex of all IHA adrenals harbored at least 1 CYP11B2-positive aldosterone-producing cell cluster (APCC) or micro-aldosterone-producing adenomas. The number of APCCs per case (and individual APCC area) in IHA adrenals was significantly larger than in normotensive controls. Next-generation sequencing of DNA from 99 IHA APCCs demonstrated somatic mutations in genes encoding the L-type calcium voltage-gated channel subunit α 1-D ( CACNA1D, n=57; 58%) and potassium voltage-gated channel subfamily J-5 ( KCNJ5, n=1; 1%). These data suggest that IHA may result from not only hyperplasia but also the accumulation or enlargement of computed tomography-undetectable APCC harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in the CACNA1D L-type calcium channel provides a potential actionable therapeutic target that could complement mineralocorticoid blockade and inhibit aldosterone overproduction in some IHA patients.

BACKGROUND: Seroepidemiological studies have revealed that influenza C virus is widely distributed globally. However, because the isolation of this virus is difficult, there have been few reports on its clinical features. METHODS: Between December 1990 and November 2004, 84,946 respiratory-tract specimens were obtained from patients < or = 15 years old. On the basis of the results of isolation of virus, we examined the clinical data on children infected with influenza C virus. RESULTS: Of 170 children infected with influenza C virus, 157 (92.4%) were < 6 years old. Fever (frequency, 90.0%), cough (frequency, 74.1%), and rhinorrhea (frequency, 61.8%) were the most frequent symptoms. The mean duration of fever was 2.88 days (standard deviation, 1.66 days). Of the 170 children, 29 were hospitalized, and 21 (72.4%) of these 29 had lower-respiratory-tract illness such as pneumonia, bronchitis, and bronchiolitis. The rate of hospital admission was significantly higher in children < 2 years old than in children 2-5 years old (30.4% vs. 11.9%; P = .0043). CONCLUSIONS: Influenza C virus is a significant cause of upper-respiratory-tract illness in children < 6 years old, and the risk of complications with lower-respiratory-tract illness is particularly high in children < 2 years old.

There is little evidence examining the relationship between anatomical landmarks, radiological placement of the tunnels and long-term clinical outcomes following anterior cruciate ligament (ACL) reconstruction. The aim of this study was to investigate the reproducibility of intra-operative landmarks for placement of the tunnels in single-bundle reconstruction of the ACL using four-strand hamstring tendon autografts. Isolated reconstruction of the ACL was performed in 200 patients, who were followed prospectively for seven years with use of the International Knee Documentation Committee forms and radiographs. Taking 0% as the anterior and 100% as the posterior extent, the femoral tunnel was a mean of 86% (sd 5) along Blumensaat's line and the tibial tunnel was 48% (sd 5) along the tibial plateau. Taking 0% as the medial and 100% as the lateral extent, the tibial tunnel was 46% (sd 3) across the tibial plateau and the mean inclination of the graft in the coronal plane was 19 degrees (sd 5.5). The use of intra-operative landmarks resulted in reproducible placement of the tunnels and an excellent clinical outcome seven years after operation. Vertical inclination was associated with increased rotational instability and degenerative radiological changes, while rupture of the graft was associated with posterior placement of the tibial tunnel. If the osseous tunnels are correctly placed, single-bundle reconstruction of the ACL adequately controls both anteroposterior and rotational instability.

AIMS: The goal of this study was to determine the frequencies of important allelic variants in the TPMT, NAT2, GST, SULT1A1 and MDR-1 genes in the Egyptian population and compare them with the frequencies in other ethnic populations. METHODS: Genotyping was carried out in a total of 200 unrelated Egyptian subjects. TPMT*2 was detected using an allele-specific polymerase chain reaction (PCR) assay. TPMT*3C and NAT2 variants (*5,*6 and *7) were detected using an allele-specific real-time PCR assay. Detection of GSTM1 and GSTT1 null alleles was performed simultaneously using a multiplex PCR assay. Finally, a PCR-restriction fragment length polymorphism assay was applied for the determination of TPMT*3A (*3B), SULT1A1*2 and MDR-1 (3435T) variants. RESULTS: Genotyping of TPMT revealed frequencies of 0.003 and 0.013 for TPMT*3A and TPMT*3C, respectively. No TPMT*2 or *3B was detected in the analysed samples. The frequencies of specific NAT2 alleles were 0.215, 0.497, 0.260 and 0.028 for *4 (wild-type), *5 (341C), *6 (590A) and *7 (857A), respectively. GSTM1 and GSTT1 null alleles were detected in 55.5% and 29.5% of the subjects, respectively. SULT1A1*2 was detected at a frequency of 0.135. Finally, the frequencies of the wild-type allele (3435C) and the 3435T variant in the MDR-1 gene were found to be 0.6 and 0.4, respectively. CONCLUSIONS: We found that Egyptians resemble other Caucasians with regard to allelic frequencies of the tested variants of NAT2, GST and MDR-1. By contrast, this Egyptian population more closely resemble Africans with respect to the TPMT*3C allele, and shows a distinctly different frequency with regard to the SULT1A1*2 variant. The predominance of the slow acetylator genotype in the present study (60.50%) could not confirm a previously reported higher frequency of the slow acetylator phenotype in Egyptians (92.00%), indicating the possibility of the presence of other mutations not detectable as T341C, G590A and G857A. The purpose of our future studies is to investigate for new polymorphisms, which could be relatively unique to the Egyptian population.

BACKGROUND: Sorafenib, a kinase inhibitor active against various solid tumours, induces oxidative stress and ferroptosis, a new form of oxidative necrosis, in some cancer cells. Clinically-applicable biomarkers that reflect the impact of sorafenib on the redox metabolism of cancer cells are lacking. METHODS: We used gene expression microarrays, real-time PCR, immunoblot, protein-specific ELISA, and gene reporter constructs encoding the enzyme luciferase to study the response of a panel of cancer cells to sorafenib. Tumour explants prepared from surgical hepatocellular carcinoma (HCC) samples and serum samples obtained from HCC patients receiving sorafenib were also used. RESULTS: We observed that genes of the metallothionein-1 (MT1) family are induced in the HCC cell line Huh7 exposed to sorafenib. Sorafenib increased the expression of MT1G mRNA in a panel of human cancer cells, an effect that was not observed with eight other clinically-approved kinase inhibitors. We identified the minimal region of the MT1G promoter that confers inducibility by sorafenib to a 133 base pair region containing an Anti-oxidant Response Element (ARE) and showed the essential role of the transcription factor NRF2 (Nuclear factor erythroid 2-Related Factor 2). We examined the clinical relevance of our findings by analysing the regulation of MT1G in five tumour explants prepared from surgical HCC samples. Finally, we showed that the protein levels of MT1 increase in the serum of some HCC patients receiving sorafenib, and found an association with reduced overall survival. CONCLUSION: These findings indicate that MT1 constitute a biomarker adapted for exploring the impact of sorafenib on the redox metabolism of cancer cells.

Encephalitis seldom causes paraparesis as the initial symptom. Here, we report a case of steroid-responsive bilateral frontal cortical encephalitis involving leg motor areas in a patient who presented with paraparesis on admission. Interestingly, the initial paraparesis evolved into an acute disseminated encephalomyelitis (ADEM)-like illness and optic neuritis, and the patient was found to be positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. A 46-year-old man experienced transient dizziness in early September 2008. Brain MRI retrospectively showed a slight fluid attenuation inversion recovery (FLAIR) high-intensity lesion involving the left frontal cortex (figure 1). One week later, the patient experienced a focal motor seizure in the right leg that subsequently generalised. Thereafter, he gradually developed headache and paraparesis over the course of a week. On admission, he presented with paraparesis without other neurological deficits, but the spinal MRI was normal. An electroencephalogram revealed that there were no epileptic discharges. A cerebrospinal fluid (CSF) examination revealed elevated leucocytes (56 /µL; 93% mononuclear cells, 3% polymorphonuclear leucocytes) and normal protein (36 mg/dL) and glucose (59 mg/dL) levels. The myelin basic protein (MBP) and glial fibrillary acidic protein levels in the CSF were not elevated. Cell-based assays for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, anti-voltage-gated potassium channel (VGKC) antibodies, anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibodies and anti-γ-aminobutyric acid-B receptor (GABA(B)R) antibodies in the CSF were negative. Blood and CSF examinations for infectious central nervous system (CNS) CNS diseases, collagen diseases, vasculitis, Behcet disease, sarcoidosis, lymphoma, paraneoplastic syndrome, vitamin B deficiency and Hashimoto encephalopathy were unremarkable. Figure 1 Upper panel: axial fluid attenuation inversion recovery (FLAIR) images (1.5 T; TR 6000 ms, TE 105 ms). (A) Brain MRI at …

IL-28 is a recently described antiviral cytokine. In this study, we investigated the biological effects of IL-28 on tumor growth to evaluate its antitumor activity. IL-28 or retroviral transduction of the IL-28 gene into MCA205 cells did not affect in vitro growth, whereas in vivo growth of MCA205IL-28 was markedly suppressed along with survival advantages when compared with that of controls. When the metastatic ability of IL-28-secreting MCA205 cells was compared with that of controls, the expression of IL-28 resulted in a potent inhibition of metastases formation in the lungs. IL-28-mediated suppression of tumor growth was mostly abolished in irradiated mice, indicating that irradiation-sensitive cells, presumably immune cells, are primarily involved in the IL-28-induced suppression of tumor growth. In vivo cell depletion experiments displayed that polymorphonuclear neutrophils, NK cells, and CD8 T cells, but not CD4 T cells, play an equal role in the IL-28-mediated inhibition of in vivo tumor growth. Consistent with these findings, inoculation of MCA205IL-28 into mice evoked enhanced IFN-gamma production and cytotoxic T cell activity in spleen cells. Antitumor action of IL-28 is partially dependent on IFN-gamma and is independent of IL-12, IL-17, and IL-23. IL-28 increased the total number of splenic NK cells in SCID mice and enhanced IL-12-induced IFN-gamma production in vivo and expanded spleen cells in C57BL/6 mice. Moreover, IL-12 augmented IL-28-mediated antitumor activity in the presence or absence of IFN-gamma. These findings indicate that IL-28 has bioactivities that induce innate and adaptive immune responses against tumors.

BACKGROUND AND PURPOSE: To compare the predictive power of self-measured home blood pressure (HBP) and casual blood pressure (CBP) for stroke risk in relation to the Joint National Committee 7 (JNC-7) classification. METHODS: HBP and CBP measurements were taken in 1702 subjects (> or =40 years) without a history of stroke, who were followed up for an average of 11 years. Subjects were classified into 4 groups on the basis of either HBP or CBP, according to the JNC-7 criteria: group 1 (HBP <115/75 mm Hg; CBP <120/80 mm Hg); group 2 (115/75< or =HBP<135/85 mm Hg; 120/80< or =CBP<140/90 mm Hg); group 3 (135/85< or =HBP<150/95 mm Hg; 140/90< or =CBP<160/100 mm Hg); and group 4 (HBP> or =150/95 mm Hg; CBP > or =160/100 mm Hg). Groups 2, 3, and 4 were further divided into 2 subgroups (a and b): those without and with cardiovascular disease risks, respectively. The risk of the first stroke in these groups was examined by the Cox hazards model adjusted for age and sex. RESULTS: The stroke risk in groups 3b and 4b (defined by HBP and CBP) was 2 to 5x higher than that in group 1 with significant differences. The risk in groups 2a, 3a, and even 4a was not significantly different from that in group 1 by the CBP-based classification, but the risk in group 4a was significantly higher than that in group 1 by the HBP-based classification, which also showed a stepwise increase in risk from groups 2a to 4a. CONCLUSIONS: The JNC-7 classification had a stronger predictive power using HBP-based classification compared with CBP-based classification, suggesting the usefulness of HBP in the management of hypertension.

BACKGROUND: As Japan's population continues to age, it is estimated that the number of people aged ≥75 years will exceed 20 million by 2025. Furthermore, over the past 10 years, we have not reduced the difference between life expectancy and healthy life expectancy. Therefore, the extension of healthy life expectancy and the development of a healthy society are the most urgent issues. In terms of medical care, the changing times have inevitably led to changes in disease structures and medical demands; therefore, the medical delivery system has had to be changed to meet these demands. As dementia rapidly increases, it is important to address "frailty," a condition in which people become more vulnerable to environmental factors as they age, and there is a need to provide services to older people, particularly the old-old, that emphasize quality of life in addition to medical care. To realize a super-aged society that will remain vigorous and vibrant for many years, we need to rethink the future of Japanese medicine and healthcare, and the state of society. CURRENT SITUATION AND PROBLEMS: Disparity between healthy life expectancy and average life expectancy in the realization of a healthy society It is a challenge to build a society with a long and healthy life expectancy through comprehensive prevention and management of lifestyle-related diseases, as well as the elucidation of the factors that explain sex differences in healthy life expectancy, based on the recognition that lifestyle-related diseases in midlife are risk factors for frailty and dementia in old age. Challenges in medical care for building a super-aged and healthy society The challenges include promoting clinical guidelines suitable for older people, including lifestyle-related disease management, promoting comprehensive research on aging (basic research, clinical research and community collaboration research), and embodying a paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care." Furthermore, the key to the future of integrated community care is the development of a comprehensive medical care system for older people in each region and the development of the next generation of medical personnel. Dissemination of frailty prevention measures in a super-aged society The concept of frailty encompasses the meaning of multifacetedness and reversibility; therefore, a comprehensive approach is required, including the renewal of conventional prevention activities in each region, such as the nutritional status of older people, physical activity including exercise, and various opportunities for social participation and participation conditions. Challenges of an unstable diet and undernutrition in older people According to the National Health and Nutrition Examination Survey of Japan, energy and protein intakes are low in Japanese people aged ≥75 years; particularly in people aged ≥80 years, low and insufficient intake of nutrients are prominent. Undernutrition in older people is increasing and is more pronounced in women. There are multiple factors behind this, including social factors, such as living alone, eating alone, poverty and other social factors, as well as problems with access to food security. Pharmacotherapy for older people: measures against polypharmacy In addition to the problems of adverse drug events, drug interactions, duplication of effects and the presence of drugs that "require particularly careful administration," it is also necessary to take measures against polypharmacy in older people, as well as medical economic issues, such as high drug costs and large amounts of remaining drugs. Barriers to this measure include multiple medical institution visits for each disease, lack of coordination between professions, and lack of understanding by patients and families. Role of local communities in a healthy society The decline in the working-age population is also a major challenge; however, we need to make a shift to use this declining birthrate and aging population as an opportunity rather than a crisis. As we look ahead to the coming of the 100-year age of life, we rethink the creation of a comprehensive society and community, and aim to create an age-free society where everyone can play an active role and live in peace, regardless of age. CONTENTS OF THE PROPOSAL: In this report, we have put together a vision for the future of an aging Japanese society from a broader perspective of how the environment and local communities should be, rather than simply from the perspective of individual health. We aim to convey this proposal to the Ministry of Health, Labor and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, the Cabinet Office, and various professional organizations. The paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care" should be promoted for the development of a healthy society While further promoting pre-emptive medical care in the medical care for older people, the development of multidisciplinary medical guidelines appropriate for older people should be promoted at the same time. In addition, we should promote basic aging research, clinical research (including the long-term care field) and transitional research that cover regional areas. Furthermore, while promoting the paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care," the development of various comprehensive medical treatment systems for older people and the strengthening of integrated community care systems should be promoted. Development of the next generation of medical personnel to comprehensively deal with geriatric care, including training geriatric specialists, should be promoted As the number of older people with multimorbidities and frailty rapidly increases in the future, we should promote the development of the next generation of medical personnel who can comprehensively handle medical care for older people, including training leading geriatricians in cooperation with multiple professions in the integrated community care system to provide sufficient medical care. Countermeasures for frailty in older people should be promoted from medical and community planning perspectives To address frailty, which requires comprehensive evaluation and intervention, the three pillars of frailty prevention (nutrition, exercise and social participation) should be incorporated and addressed as part of community development within each municipality, taking into account local characteristics. In particular, it is necessary to revise the way of thinking about nutrition management in older people and the guidelines of the societies in the field. In addition, it is important to strengthen industry-academia-government-private partnerships in each region, taking into account not only medical issues, but also social factors, and encourage the development of momentum in the entire region regarding measures against undernutrition in older people. Polypharmacy measures should be promoted in pharmacotherapy for older people It is necessary to promote cooperation between physicians and pharmacists, establish other multiprofessional cooperation systems, and develop medical and long-term care insurance systems to support this. It is also essential to change the public's mindset, and awareness-raising activities at all levels are required, including the enhancement of educational materials for medical caregivers and the general public. In addition, the economic impact of healthcare using big data should be timely clarified. Innovation in medical and urban planning perspectives should be promoted In the future, it will be necessary to modify and update multidisciplinary approaches such as social participation (e.g. participation in a salon) with a view to innovation in both medical care and community development, especially on the idea of a symbiotic community. In addition, industry-academia-government-private partnership is necessary, including all aforementioned, such as places where people can play an active role in the rest of their lives (such as employment), promotion of human connections, promotion of technology to support older people and support for daily life. Geriatr Gerontol Int 2021; 21: 601-613.

Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding noncancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital. All specimens underwent exome sequencing and the somatic genetic alterations were identified. We divided the cases into three clusters based on the mutation spectra. Clinical characteristics such as age of onset and endometriosis are similar among the clusters but one cluster shows mutations related to APOBEC activation, indicating its contribution to subset of OCCC cases. There are three hypermutated cases (showing 12-fold or higher somatic mutations than the other 45 cases) and they have germline and somatic mismatch repair gene alterations. The frequently mutated genes are ARID1A (66.7%), PIK3CA (50%), PPP2R1A (18.8%), and KRAS (16.7%). Somatic mutations important for selection of chemotherapeutic agents, such as BRAF, ERBB2, PDGFRB, PGR, and KRAS are found in 27.1% of OCCC cases, indicating clinical importance of exome analysis for OCCC. Our study suggests that the genetic instability caused by either mismatch repair defect or activation of APOBEC play critical roles in OCCC carcinogenesis.

BACKGROUND AND PURPOSE: [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc.This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine. METHODS: Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members. RESULTS: A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs. CONCLUSIONS: Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

This article describes a rapid UPLC-MS/MS method to quantitate novel bile acids in biological fluids and the evaluation of their diagnostic potential in Niemann-Pick C (NPC). Two new compounds, NPCBA1 (3β-hydroxy,7β-N-acetylglucosaminyl-5-cholenoic acid) and NPCBA2 (probably 3β,5α,6β-trihydroxycholanoyl-glycine), were observed to accumulate preferentially in NPC patients: median plasma concentrations of NPCBA1 and NPCBA2 were 40- and 10-fold higher in patients than in controls. However, NPCBA1 concentrations were normal in some patients because they carried a common mutation inactivating the GlcNAc transferase required for the synthesis of this bile acid. NPCBA2, not containing a GlcNAc moiety, is thus a better NPC biomarker.

Nrf2 activation promotes resistance to chemical carcinogenesis in animal models, but activating mutations in Nrf2 also confer malignant characters to human cells by activating antioxidative/detoxifying enzymes and metabolic reprogramming. In this study, we examined how these contradictory activities of Nrf2, cancer chemoprevention and cancer cell growth enhancement, can be reconciled in an established mouse model of urethane-induced lung carcinogenesis. Using Keap1-knockdown (kd) mice, which express high levels of Nrf2, we found that urethane was rapidly excreted into the urine, consistent with an upregulation in the expression of urethane detoxification genes. Consequently, urethane-induced tumors were significantly smaller and less frequent in Keap1-kd mice than in wild-type mice. In contrast, tumor cells derived from Keap1-kd mice and transplanted into nude mice exhibited higher tumorigenicity compared with cells derived from wild-type mice. To identify the factors contributing to the tumor growth phenotype in the transplantation model, we performed a microarray analysis and found that many antioxidative stress genes were upregulated in the Keap1-kd-derived tumors. Therefore, we suggest that Nrf2 activation in cancer cells enhances their tumorigenicity, but global Nrf2 activation, as in Keap1-kd mice, simultaneously enhances anticancer immunity, thereby suppressing the growth potential of Keap1-kd tumors. Our findings provide relevant insight into the dual role of Nrf2 in cancer and warrant further studies of Nrf2 function during different stages of carcinogenesis. Cancer Res; 76(10); 3088-96. ©2016 AACR.

The prognostic significance of white-coat hypertension (WCHT) is controversial, and different findings on self-measured home measurements and 24-h ambulatory monitoring make identifying WCHT difficult. We examined whether individuals with partially or completely defined WCHT, as well as masked hypertension, as determined by different out-of-office blood pressure measurements, have a distinct long-term stroke risk. We followed 1464 participants (31.8% men; mean age, 60.6±10.8 years) in the general population of Ohasama, Japan, for a median of 17.1 years. A first stroke occurred in 212 subjects. Using sustained normal blood pressure (events/n=61/776) as a reference, adjusted hazard ratios for stroke (95% confidence intervals; events/n) were 1.38 (0.82-2.32; 19/137) for complete WCHT (isolated office hypertension), 2.16 (1.36-3.43; 29/117) for partial WCHT (either home or ambulatory normotension with office hypertension), 2.05 (1.24-3.41; 23/100) for complete masked hypertension (both home and ambulatory hypertension with office normotension), 2.08 (1.37-3.16; 38/180) for partial masked hypertension (either home or ambulatory hypertension with office normotension), and 2.46 (1.61-3.77; 42/154) for sustained hypertension. When partial WCHT and partial masked hypertension groups were further divided into participants only with home hypertension and those only with ambulatory hypertension, all subgroups had a significantly higher stroke risk (adjusted hazard ratio ≥1.84, P≤0.04). In conclusion, impacts of partial WCHT as well as partial masked hypertension for long-term stroke risk were comparable to those of complete masked hypertension or sustained hypertension. We need both home and 24-h ambulatory blood pressure measurements to evaluate stroke risk accurately.

OBJECTIVE: To clarify the prevalence and clinical characteristics of neuromyelitis optica spectrum disorders (NMOSD) in Japan and compare them with those in other ethnic populations. METHODS: Data processing sheets were sent to all related institutions in northern Japan and were collected from April to May 2016. Prevalence was determined on March 31, 2016, using the 2015 International Panel for NMO Diagnosis criteria. RESULTS: The crude prevalence was 4.1/100,000 (95% confidence interval 2.2-6.9) for NMOSD in northern Japan, with a significantly higher number of female than male patients (female: male 12:2). The positivity for anti-aquaporin-4 antibody was 78.6%, and the mean age at onset was 45.2 years. All patients were subjected to preventive therapy in the form of treatment with steroids or immunosuppressive agents. CONCLUSIONS: Our results showed that the prevalence of NMOSD in the Japanese population is similar to that in Caucasians.