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Background: The rate of suicide attempts by patients with bipolar disorder is high. In addition to patient and country specific factors, environmental factors may contribute to suicidal behavior. Sunlight has multiple diverse impacts on human physiology and behavior. Solar insolation is defined as the electromagnetic energy from the sun striking a surface area on earth. We previously found that a large change in solar insolation between the minimum and maximum monthly values was associated with an increased risk of suicide attempts in patients with bipolar I disorder., Methods: The association between solar insolation and a history of suicide attempts in bipolar disorder was again investigated using an international database with 15% more data and more sites at diverse locations and countries., Results: Data were available from 5641 patients with bipolar I disorder living at a wide range of latitudes in 41 countries in both hemispheres. A large change in solar insolation between the minimum and maximum monthly values was associated with a history of suicide attempts in patients with bipolar I disorder, a replication of our prior analysis. The estimated model also associated state sponsored religion in the onset country, female gender, a history of alcohol or substance abuse, and being part of a younger birth cohort with a history of suicide attempts., Conclusions: A large change between the minimum and maximum monthly values of solar insolation was associated with a history of suicide attempts in bipolar I disorder, replicating our prior research. Physicians should be aware that daylight has wide ranging physiological and psychiatric impacts, and that living with large changes in solar insolation may be associated with an increased suicide risk., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki. Human Ethics and Consent to Participate declarations: not applicable. Competing interests: Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Alcediag, Angelini, Biogen, Beckley-Psytech, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Luye Pharma, Medincell, Merck, Newron, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, Teva, and Viatris, outside the submitted work., (© 2024. The Author(s).)

The COVID-19 pandemic has increased germ aversion, an aversive affective response to a high likelihood of pathogen transmission. While psychological factors are associated with chronic pain, the relationship between germ aversion and chronic pain remains unexplored. This study aimed to examine the relationship between germ aversion and new-onset and prognosis of chronic pain using longitudinal data collected during the COVID-19 pandemic. We conducted web-based surveys of full-time workers at baseline and after three months. Data were collected on demographic characteristics, psychological factors, and chronic pain. Germ aversion was assessed using a modified Perceived Vulnerability to Disease scale. We analyzed responses from 1265 panelists who completed the survey twice. The prevalence of chronic low back pain (CLBP) and chronic neck and shoulder pain (CNSP) was associated with sex, short sleep duration, psychological distress, loneliness, and germ aversion. Stratified analyses showed that germ aversion was a risk factor for CLBP at three months in both individuals with and without CLBP at baseline, and for CNSP at three months in those with CNSP at baseline, even after adjustment for confounders. In conclusion, this preliminary study suggests that high germ aversion is a risk factor for CLBP and CNSP in young and middle-aged workers., (© 2024. The Author(s).)

This study focused on the heterogeneity in progress notes written by physicians or nurses. A total of 806 days of progress notes written by physicians or nurses from 83 randomly selected patients hospitalized in the Gastroenterology Department at Kagawa University Hospital from January to December 2021 were analyzed. We extracted symptoms as the International Classification of Diseases (ICD) Chapter 18 (R00-R99, hereinafter R codes) from each progress note using MedNER-J natural language processing software and counted the days one or more symptoms were extracted to calculate the extraction rate. The R-code extraction rate was significantly higher from progress notes by nurses than by physicians (physicians 68.5% vs. nurses 75.2%; p = 0.00112), regardless of specialty. By contrast, the R-code subcategory R10-R19 for digestive system symptoms (44.2 vs. 37.5%, respectively; p = 0.00299) and many chapters of ICD codes for disease names, as represented by Chapter 11 K00-K93 (68.4 vs. 30.9%, respectively; p < 0.001), were frequently extracted from the progress notes by physicians, reflecting their specialty. We believe that understanding the information heterogeneity of medical documents, which can be the basis of medical artificial intelligence, is crucial, and this study is a pioneering step in that direction., (© 2024. The Author(s).)

Background: Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample., Methods: Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001., Results: The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger., Conclusion: UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition., (© 2023. The Author(s).)

Background: While the symptom of "I am already dead" is a hallmark of Cotard's syndrome, also known as nihilistic delusions, the symptom of "you are already dead" has been neglected., Case Presentation: A woman aged in her 60s diagnosed with schizophrenia was admitted to our hospital for psychotic symptoms, including delusions of reference, delusions of guilt, auditory hallucinations, cenesthetic hallucinations, agitation, depression, suicidal ideation, and catatonia. During hospitalization, her cenesthetic hallucinations progressed to include nihilistic delusions. She described cenesthetic hallucinations along with various delusional descriptions, including the belief that various objects, such as spoons, irons, nails, rulers, bins, and coins, were inside her body and that her body was being burned or in danger of exploding. She also claimed an altered sense of her own body, that her body was larger than normal or reversed. Moreover, she reported nihilistic delusions that her face and body did not exist, that her heart was not functioning, and that she was going to die soon or was already dead. She occasionally refused to eat because of the feeling of being dead. Notably, during a severe episode, she claimed that a doctor in front of her was dead. Clozapine was effective in improving her symptoms. Ultimately, the patient regained her sense of being alive and acknowledged that the doctor was alive., Conclusion: We report the case of a patient presenting with nihilistic delusions regarding both self and others, along with prior cenesthetic hallucinations. Aberrant interoceptive processing could be a potential link between these two forms of nihilistic delusions., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Objective: Corticosteroids can cause psychiatric symptoms known as corticosteroid-induced psychiatric disorders (CIPDs). Little is known regarding the relationship between intravenous pulse methylprednisolone (IVMP) and CIPDs. Therefore, we aimed to examine the relationship between corticosteroid use and CIPDs in this retrospective study., Methods: Patients who were prescribed corticosteroids during their hospitalization at a university hospital and referred to our consultation-liaison service were selected. Patients diagnosed with CIPDs according to the ICD-10 codes were included. The incidence rates were compared between patients receiving IVMP and those receiving any other corticosteroid treatment. The association between IVMP and CIPDs was examined by classifying patients with CIPD into three groups according to the use of IVMP and timing of CIPD onset., Results: Of the 14,585 patients who received corticosteroids, 85 were diagnosed with CIPDs, with an incidence rate of 0.6%. Among the 523 patients who received IVMP, the incidence rate of CIPDs was 6.1% (n = 32), which was significantly higher than that in patients receiving any other corticosteroid treatment. Among the patients with CIPDs, 12 (14.1%) developed CIPDs during IVMP, 19 (22.4%) developed CIPDs after IVMP, and 49 (57.6%) developed CIPDs without IVMP. There was no significant difference in the doses at the time of CIPD improvement among the three groups when we excluded one patient whose CIPD improved during IVMP., Conclusion: Patients receiving IVMP were more likely to develop CIPDs than those who did not receive IVMP. Furthermore, corticosteroid doses at the time of improvement of CIPDs were constant, regardless of IVMP use., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The number of patients who survive for a long time after cancer diagnosis is rapidly increasing; however, such patients experience major problems such as returning to work and changes in their income. This study aimed to determine the extent of income changes of cancer patients during the first year after cancer diagnosis and identify the influencing factors. From November 2019 through January 2020, we conducted a multicenter, self-administered anonymous survey of cancer patients in Kagawa Prefecture, Japan. The number of questionnaires collected was 483 (recovery rate 60.4%), and the number of participants who met the inclusion criteria was 72. Mean year-on-year income level one year since cancer diagnosis was 66% (SD: 32%; median: 70%). Cancer stage ( p = 0.016), employment status at diagnosis ( p = 0.006), and continued employment at the same workplace ( p = 0.001) were associated with income change. Findings from this study showed that cancer patients lost one-thirds of their income one year after their diagnosis. It was related to the stage of their illness, employment status, and continued employment at their workplace just before the diagnosis. Employers should provide cancer patients with the support they need to keep them employed.

Objective: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth., Methods: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer., Results: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001)., Conclusion: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Blood pressure (BP) often rises before surgery. This study investigated whether BP elevation immediately before surgery was associated with adverse outcomes. Medical records of 11,732 patients (average age: 61 years; male: 47.4%) who underwent non-cardiac elective inpatient surgery under general anesthesia at Kagawa University Hospital between January 2011 and June 2019 were reviewed. Differences between the first BP values measured on the day before surgery and the first BP values in the operating room were defined as Δ systolic BP (ΔSBP) and Δ diastolic BP (ΔDBP). The relationships between ΔSBP/ΔDBP and 30-day mortality, 30-day readmission, and over-the-standard length of hospital stay (OSLOS) were assessed. OSLOS was defined as a hospital stay longer than mean+2 standard deviations and was calculated using the Japanese Diagnosis Procedure Combination data. In univariate analysis, the differences in ΔSBP and ΔDBP between the OSLOS and standard LOS groups were both 2 mmHg. In multivariate logistic regression analysis, only ΔDBP was associated with OSLOS. The adjusted odds ratio (95% confidence interval) for the largest quartile was 1.31 (1.02-1.69) (p<0.05). ΔDBP was associated with OSLOS; however, there may be little need to worry about large ΔSBPs and ΔDBPs in clinical practice., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a total upending of our daily lives. While anxiety and depression were frequently reported among the general population, the pandemic's impact on patients with mental health problems remains unknown., Methods: A cross-sectional questionnaire survey involving 1,166 patients was conducted at one psychiatric hospital and one mental health clinic., Results: Symptom deterioration was reported in 23% to 34% of the patients and 9% to 20% reported increase in drug dosage. No significant differences were reported in these items among diagnostic categories. Patients with F 3 (mood disorders) reported more psychological stress during the pandemic's beginning and during the emergency. Patients with F 2 (schizophrenia, schizotypal, and delusional disorders) did online shopping and meetings less frequently, and reported poorer adherence of 3C's, while mask management was stricter in patients with F 4 (neurotic, stress-related, and somatoform disorders). Symptom deterioration was significantly associated with increase in drug dosage, new physical symptoms, anxiety unrelated to COVID-19, stress at the beginning of pandemic, stress during the 'state of emergency', poor adaptability to environmental change, daily life changes, decrease in sleeping time, and decrease in time spent outside., Conclusion: One third of patients reported symptom deterioration during the pandemic, which was associated with stress and daily life changes. Patients with good adaptability to environmental changes might resilient against symptom deterioration. Providing continuous support to help patients manage their daily life in this COVID-19 era may minimize the risk of symptom deterioration.

Clustering of supernumerary centrosomes, which potentially leads to cell survival and chromosomal instability, is frequently observed in cancers. However, the molecular mechanisms that control centrosome clustering remain largely unknown. The centrosomal kinesin KIF24 was previously shown to restrain the assembly of primary cilia in mammalian cells. Here, we revealed that KIF24 depletion suppresses multipolar spindle formation by clustering centrosomes in pancreatic ductal adenocarcinoma (PDAC) cells harboring supernumerary centrosomes. KIF24 depletion also induced hyper-proliferation and improved mitotic progression in PDAC cells. In contrast, disruption of primary cilia failed to affect the proliferation and spindle formation in KIF24-depleted cells. These results suggest a novel role for KIF24 in suppressing centrosome clustering independent of primary ciliation in centrosome-amplified PDAC cells., (© 2022 Mashima et al.)

Objective: In recent years, natural language processing (NLP) techniques have progressed, and their application in the medical field has been tested. However, the use of NLP to detect symptoms from medical progress notes written in Japanese, remains limited. We aimed to detect 2 gastrointestinal symptoms that interfere with the continuation of chemotherapy-nausea/vomiting and diarrhea-from progress notes using NLP, and then to analyze factors affecting NLP., Materials and Methods: In this study, 200 patients were randomly selected from 5277 patients who received intravenous injections of cytotoxic anticancer drugs at Kagawa University Hospital, Japan, between January 2011 and December 2018. We aimed to detect the first occurrence of nausea/vomiting (Group A) and diarrhea (Group B) using NLP. The NLP performance was evaluated by the concordance with a review of the physicians' progress notes used as the gold standard., Results: Both groups showed high concordance: 83.5% (95% confidence interval [CI] 74.1-90.1) in Group A and 97.7% (95% CI 91.3-99.9) in Group B. However, the concordance was significantly better in Group B ( P  = .0027). There were significantly more misdetection cases in Group A than in Group B (15.3% in Group A; 1.2% in Group B, P  = .0012) due to negative findings or past history., Conclusion: We detected occurrences of nausea/vomiting and diarrhea accurately using NLP. However, there were more misdetection cases in Group A due to negative findings or past history, which may have been influenced by the physicians' more frequent documentation of nausea/vomiting., Competing Interests: Declaration of conflicting interests: The author(s) declare the following potential conflicts of interest with respect to the research, authorship and publication of this article: M.T. was an employee of Daiichi Sankyo Co., Ltd. before this study and owns shares in Daiichi Sankyo Co., Ltd. H.Y. was paid advisory fees by Daiichi Sankyo Co., Ltd. M.T. and H.Y.’s interests were reviewed and are managed by Kagawa University in accordance with their conflict-of-interest policies. T.T., A.H., and H.T. are employees of Daiichi Sankyo Co., Ltd. All other authors declare no competing interests., (© The Author(s) 2022.)

Somatic Symptom Disorder is a specific disorder that is extensively defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5). Although the diagnostic criteria for somatic symptom disorder has archived breakaway from mind-body dualism and simplification for physicians, it remains vague and universally unapplicable. Moreover, despite the DSM-5 removing etiology in diagnosis, there is still a need to determine the etiology for individualized patient treatment. In particular, patients with somatic symptom disorder and relative disorders have psychological pathologies, such as somatization and anxiety about illness, all of which require psychiatric treatment. However, these patients initially visit physicians, not psychiatrists, since their symptoms are somatic, and they are anxious about the possibility of a physical disease. As such, supportive attitude and continuous treatment are important, as they can be performed even without a psychiatric consultation. Furthermore, while the effectiveness of pharmacotherapy is limited for these disorders, psychotherapy has the possibility to bring about a fundamental resolution. Particularly, cognitive behavior therapy or psychoanalytic psychotherapy has been found to be effective; however, they require high motivation and take up much time from the patients. Fortunately, the Morita therapy is especially effective for patients who pay excessive attention to somatic symptoms or are hypochondriacal, which is applicable for outpatients using a comparatively short interview that can even be performed in nonpsychiatric clinical settings.

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries., Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun's electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries)., Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01., Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed., (© 2021. The Author(s).)

Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein-1 (VAP-1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP-1 in TME was investigated in 2 murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP-1-specific inhibitor U-V296 inhibited murine tumor growth by enhancing IFN-γ-producing tumor antigen-specific CD8 + T cells. U-V296 exhibited significant synergistic anti-tumor effects with ICIs. In the TME of mice treated with U-V296, the expression of genes associated with M2-like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H 2 O 2 , an enzymatic product of VAP-1, which promoted the production of IL-4 by mouse Th2 and inhibited IFN-γ by mouse Th1 and human tumor-infiltrating lymphocytes, was decreased in tumors and CD31 + tumor vascular endothelial cells in the TMEs of mice treated with VAP-1 inhibitor. TCGA database analysis showed that VAP-1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL-4, IL4R, and IL-13 expression and a negative correlation with IFN-γ expression. These results indicated that VAP-1 is involved in the immunosuppressive TMEs through H 2 O 2 -associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The SARS-CoV-2 (COVID-19) pandemic has had a tremendous impact on the functionality of health systems and world affairs. We assessed knowledge, attitudes, and practices (KAPs) of healthcare workers (HCWs) in the Democratic Republic of the Congo (DRC). This was a cross-sectional study conducted in 23 referral hospitals located in three towns of the DRC (Lubumbashi, Kamina, Mbuji-Mayi). In total, 613 HCWs were surveyed using the World Health Organization's (WHO's) "Exposure Risk Assessment in the Context of COVID-19" questionnaire. Participants included medical doctors (27.2%) and other categories of HCWs (72.8%). The mean age was 40.3 ± 11.7 years. Over 80% (range: 83-96%) of respondents had sufficient knowledge on each of the three domains: COVID-19 symptoms, disease transmission, and patient care approach. However, attitudes and practices scores were relatively low. Only 27.7% of HCWs were willing to receive a COVID-19 vaccine when it is available, whereas 55% of HCWs complied with good practices; 49.4% wore masks consistently and, surprisingly, only 54.9% used personal protective equipment (PPE) consistently at work and during contact with patients. Knowledge level was positively associated with the use of social media as a primary source of COVID-19-related information and the category of residence, with HCWs from towns already affected by the COVID-19 epidemic being more likely to have positive attitudes (adjusted OR, 1.64; 95%CI, 1.32-2.20) and comply with good practices (aOR, 2.79; 95%CI, 1.93-4.06). This study showed that most Congolese HCWs had sufficient knowledge on COVID-19, whereas the majority did not comply with consistent PPE use. The government of the DRC should urgently take major steps in capacity building for HCWs in outbreak preparedness and supplying hospitals with PPE.

Primary cilia are hair-like projections that protrude from most mammalian cells and mediate various extracellular signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) cells are known to lose their primary cilia, but the relevance of this phenomenon remains unclear. In this study, we generated PDAC-originated Panc1 cells devoid of primary cilia by mutating a centriolar protein, centrosomal protein 164 (CEP164), which is required for ciliogenesis. CEP164 depletion enhanced the clonogenicity of Panc1 cells, along with chemically induced elimination of primary cilia, suggesting that a lack of these organelles promotes PDAC cells proliferation. In addition, the loss of CEP164 altered the cell cycle progression irrespective of absence of primary cilia. We found that CEP164 was co-localized with the GLI2 transcription factor at the mother centriole and controlled its activation, thus inducing Cyclin D-CDK6 expression. Furthermore, CEP164-mutated Panc1 cells were significantly tolerant to KRAS depletion-dependent growth inhibition. This study suggests that CEP164 deficiency is advantageous for PDAC cells proliferation due to not only lack of ciliation but also cilia-independent GLI2-Cyclin D/CDK6 activation, and that CEP164 is a potential therapeutic target for PDAC., (Copyright © 2020 Kobayashi, Tanaka, Mashima, Shoda, Tokuda and Itoh.)

We analyzed the temporal trends and significant changes in apparent energy and macronutrient intakes in the Bangladeshi diet from 1961 to 2017. Due to the lack of a long-running national dietary intake dataset, this study used the Food and Agriculture Organization (FAO)'s old and new food balance sheet dataset. We used the joinpoint regression model and jump model to analyze the temporal trends in apparent energy and macronutrient intakes. The annual percentage change (APC) was computed for each segment of the trends. Bangladesh has experienced a late energy revolution in their dietary history. During the 1960s, 1970s, 1980s, and 1990s, Bangladesh was suffering from substantive calorie deficits, where in apparent energy intake was less than 2200 kcal/day/person. Since the late 1990s, Bangladesh has made significant progress in raising the apparent energy consumption in the diet. Since the late 1970s, apparent fat intake started to increase significantly at a marked rate (APC = 2.16), whereas since the early 1990s, protein intake increased significantly by 1.33% per year. Plant sources have mostly governed the protein and fat intake trends in the Bangladeshi diet since 1960, whereas animal sources began to contribute significantly in protein intake since 1990 (APC = 3.43) and in fat intake since 2000 (APC = 2.88). Bangladesh overcame the substantive calorie deficit condition in the diet from the late 1990s. Excessive carbohydrate intake along with imbalanced and low-quality protein and fat intakes have been the central features in the diet in Bangladesh.

Cellular homeostasis in response to glucose availability is maintained through the tight coordination of various physiological processes, including cell proliferation, transcription, and metabolism. In this study, we use the budding yeast Saccharomyces cerevisiae to identify proteins implicated in carbon source-dependent modulation of physiological processes. We find that the mitotic cyclin Clb4 is required for optimal regulation of glucose-starvation-responsive pathways through the target of rapamycin complex 1. Cells lacking Clb4 are characterized by dysregulation of autophagy and impaired modulation of cell size. Notably, cell viability after prolonged glucose starvation is severely reduced by disruption of Clb4. We conclude that Clb4, in addition to its function in the cell cycle, plays a role in the intracellular adaptation to glucose starvation., (© 2019 Federation of European Biochemical Societies.)

Background: Neurophysiology including P300, that is a typical index of event-related potential, may be potential biomarkers for bipolar disorder (BD) and it can be useful towards elucidating the pathophysiology of BD. However, previous findings from P300 studies were inconsistent due to the heterogeneity of research methods, which make it difficult to understand the neurobiological significance of them. The aim of this study is to conduct a meta-analysis on P300 in patients with BD., Method: A literature search was conducted using PubMed to identify studies that compared P300 event-related potential between patients with BD and healthy controls (HCs). We analyzed P300 indices such as amplitude and latency of P3a and P3b in auditory or visual paradigms. Further, moderator analyses were conducted to investigate the influence of patient characteristics (i.e. history of psychosis, diagnostic subcategories [BD-I/BD-II], and phase of illness [euthymic, manic, or depressive]) on P300 indices., Result: Out of 124 initial records, we included 30 articles (BD: N = 1331; HCs: N = 1818). Patients with BD showed reduced P3a and P3b amplitude in both paradigms and delayed P3b latency in auditory paradigms compared to HCs. There was no influence on the history of psychosis, diagnostic subcategories, or phase of illness on P300 indices., Limitation: The difference in medication use was difficult to control and it may affect the results., Conclusion: This meta-analysis provides evidence for P300 abnormalities in patients with BD compared to HCs. Our results suggest that P300 may be trait markers rather than state markers in this illness., (Copyright © 2019. Published by Elsevier B.V.)

Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder predominantly affecting young men. Characteristic features of an early stage of LHON are peripapillary telangiectatic microangiopathy with optic disc hyperaemia and swelling of the retinal nerve fibre layers. We evaluated the microcirculation of the optic nerve head (ONH) by laser speckle flowgraphy (LSFG) in a 79-year-old man and a 36-year-old woman with LHON. The ONH microcirculation of the tissue area was markedly increased in the early stage in both patients. LSFG may be a useful noninvasive method to suspect individuals to have an early stage of LHON., (© 2018 Taylor & Francis Group, LLC.)

Graft-versus-host disease (GVHD) is a potentially lethal complication of hematopoietic stem cell transplantation (HSCT). GVHD comprises acute and chronic forms. To date, several approaches to treat acute GVHD or chronic GVHD have been reported. However, there is no literature precedent regarding all-in-one methods to address the 2 GVHD types. Severe inflammation in organs affected by GVHD is highly problematic, and vascular adhesion protein-1 (VAP-1) is known to be detrimentally involved in various inflammatory diseases. Based on the previous reports, we envisaged that there would be a link between GVHD and VAP-1, and we strived to create effective therapies for the 2 types of GVHD using a mouse model of GVHD. Our investigation indicated that expression of VAP-1 was elevated in organs disordered by GVHD. Hence, we subsequently attempted to block VAP-1 by using a novel inhibitor. Our results indicate that systemic injection of the inhibitor prevented aberrant influx of inflammatory cells into tissues and thereby mitigate GVHD-elicited inflammation and fibrosis. Collectively, our study suggests that the increased expression of VAP-1 is detrimentally associated with the development of GVHD and that the blockade of VAP-1 could be a promising medical modality to combat the acute and chronic variants.-Mukai, S., Ogawa, Y., Kawakami, Y., Mashima, Y., Tsubota, K. Inhibition of vascular adhesion protein-1 for treatment of graft-versus-host disease in mice.

Background: Patients with Leber hereditary optic neuropathy (LHON) have a progressive decrease of their visual acuity which can deteriorate to <0.1. Some patients can have a partial recovery of their vision in one or both eyes. One prognostic factor associated with a recovery of vision is an early-age onset. The purpose of this study was to determine other clinical factors that are predictive of a good visual recovery., Methods: Sixty-one Japanese LHON patients, with the 11,778 mutation and a mean age of 23.1 ± 12.1 years at the onset, were studied. All patients were initially examined at an acute stage of LHON and were followed for 3 to 10 years. At 1 year after the onset, the lowest visual acuity was <0.1 in all eyes. We studied the following parameters of patients with/without a final visual acuity of ≥ 0.2: sex; heavy consumption of cigarettes and alcohol; taking idebenone; mean age at onset; mean lowest visual acuity; and distribution of the lowest and the final visual acuity., Results: Fifteen (24.6%) of the 61 patients or 25 (20.5%) of the 122 eyes had a recovery of their visual acuity to ≥ 0.2. The mean age at onset of these 15 patients with visual recovery to ≥ 0.2 was 17.5 ± 7.7 years, and that of the 46 patients without visual recovery to ≥ 0.2 was 25.0 ± 12.8 years (P = 0.02, Mann-Whitney U test). The mean lowest visual acuity of the 25 eyes with visual recovery ≥ 0.2 was 0.04, and that of the 97 eyes without visual recovery to ≥ 0.2 was 0.015 (P < 0.001, Mann-Whitney U test). Fifty percent (15/30) of the eyes whose lowest visual acuity was ≥ 0.04 during 1 year after the onset had a visual recovery to ≥ 0.2, while 11% (10/92) of the eyes whose the lowest visual acuity was ≤ 0.03 had a visual recovery to ≥ 0.2 (P < 0.001, χ 2 test). There were no significant differences in the other clinical factors., Conclusion: A final visual acuity of ≥ 0.2 was associated with a less severe reduction of the visual acuity at 1 year after the onset. Our findings can be used to predict the visual prognosis in LHON patients.

Purpose: To investigate the effect of the vascular adhesion protein-1 (VAP-1) inhibitor RTU-1096 on retinal morphologic changes and ocular inflammation after retinal laser photocoagulation in mice., Methods: C57BL/6JJcl mice were fed a diet containing RTU-1096, a specific inhibitor for VAP-1, or a control diet ad libitum for 7 days. Laser photocoagulation was performed on the peripheral retina of the animals. The semicarbazide sensitive amine oxidase (SSAO) activities in plasma and chorioretinal tissues were measured. Optical coherence tomography (OCT) images were acquired before and at 1, 3, and 7 days after laser photocoagulation, and thickness of the individual retinal layers was measured. Intravitreal leukocyte infiltration was assessed by histologic analysis. The expression level of intercellular adhesion molecule-1 (ICAM-1) in retinal tissues were examined by quantitative real-time PCR., Results: One day after laser photocoagulation, the thickness of the outer nuclear layer (ONL) increased in the laser group compared with in the control group, and RTU-1096 administration abrogated the ONL thickening. Histologic analysis and OCT observation revealed that laser photocoagulation caused infiltration of inflammatory cells and the appearance of hyperreflective foci at the vitreoretinal surface, both of which were suppressed by RTU-1096 administration. In addition, systemic administration of RTU-1096 reduced upregulation of the leukocyte adhesion molecules ICAM-1 in the retina., Conclusions: The current data indicate that VAP-1/SSAO inhibition may be a potential therapeutic strategy for the prevention of macular edema secondary to scatter laser photocoagulation in patients with ischemic retinal diseases such as diabetic retinopathy.

Loss of primary cilia is frequently observed in tumor cells, including pancreatic ductal adenocarcinoma (PDAC) cells, suggesting that the absence of this organelle may promote tumorigenesis through aberrant signal transduction and the inability to exit the cell cycle. However, the molecular mechanisms that explain how PDAC cells lose primary cilia are still ambiguous. In this study, we found that inhibition or silencing of histone deacetylase 2 (HDAC2) restores primary cilia formation in PDAC cells. Inactivation of HDAC2 results in decreased Aurora A expression, which promotes disassembly of primary cilia. We further showed that HDAC2 controls ciliogenesis independently of Kras, which facilitates Aurora A expression. These studies suggest that HDAC2 is a novel regulator of primary cilium formation in PDAC cells., (© 2016 The Authors.)

Purpose: To evaluate the long-term protective effects of transscleral unoprostone (UNO) against retinal degeneration in transgenic (Tg) rabbits (Pro347Leu rhodopsin mutation)., Methods: The UNO release devices (URDs) were implanted into the sclerae of Tg rabbits and ERG, optical coherence tomography (OCT), and ophthalmic examinations were conducted for 40 weeks. Unoprostone metabolites in retina, choroid/RPE, aqueous humor, and plasma from wild-type (Wt) rabbits were measured using liquid chromatography-tandem mass spectrometry. In situ hybridization and immunohistochemistry evaluated the retinal distribution of big potassium (BK) channels, and RT-PCR evaluated the expressions of BK channels and m-opsin at 1 week after URD treatment., Results: The URD released UNO at a rate of 10.2 ±1.0 μg/d, and the release rate and amount of UNO decreased during 32 weeks. Higher ERG amplitudes were observed in the URD-treated Tg rabbits compared with the placebo-URD, or nontreated controls. At 24 weeks after implantation into the URD-treated Tg rabbits, OCT images showed preservation of retinal thickness, and histologic examinations (44 weeks) showed greater thickness of outer nuclear layers. Unoprostone was detected in the retina, choroid, and plasma of Wt rabbits. Retina/plasma ratio of UNO levels were 38.0 vs. 0.68 ng UNO*hour/mL in the URD-treated group versus control (topical UNO), respectively. Big potassium channels were observed in cone, cone ON-bipolar, and rod bipolar cells. Reverse-transcriptase PCR demonstrated BK channels and m-opsins increased in URD-treated eyes., Conclusions: In Tg rabbits, URD use slowed the decline of retinal function for more than 32 weeks, and therefore provides a promising tool for long-term treatment of RP.

It has been suggested that unoprostone isopropyl (UNO) has potent neuroprotective activity in the retina. The effect of sustained transscleral UNO delivery to the posterior segment of the eye on photoreceptor degeneration was evaluated. UNO was loaded into a device made of poly(ethyleneglycol) dimethacrylate by polydimethylsiloxane mold-based UV-curing. The amount of UNO diffusing from these devices was measured using high-performance liquid chromatography. The polymeric devices that released UNO at 1.8 μg/day were implanted on the sclerae of S334ter rats at postnatal 21 days, and electroretinograms (ERGs) were compared with those of topical application and placebo devices. Retinal thickness was evaluated by histological examination. Western blots of specimens 4 weeks after implantation were performed. ERGs showed that the UNO-loaded device prevented the reduction of ERG amplitudes 2 and 4 weeks after implantation, compared with results using a placebo device or topical application. Histological examination showed that the UNO-loaded device prevented the reduction of retinal thickness, and Western blots of specimens indicated that the UNO-loaded device decreased expression of ERK1/2, phosphorylated ERK1/2, and caspase-3. A device that provided sustained UNO administration protected against retinal degeneration in rhodopsin mutant rats, and thus, may have translational potential as a sustainable method to administer drugs to treat retinitis pigmentosa. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1730-1737, 2016., (© 2015 Wiley Periodicals, Inc.)

Objective: The objective of this study was to investigate the descending neural drive to ankle muscles during gait in stroke patients using a coherence analysis of surface electromyographic (EMG) recordings and the relationships of the drive with clinical functions., Methods: EMG recordings of the paired tibialis anterior (TA), medial and lateral gastrocnemius (MG and LG), and TA-LG muscles were used to calculate intramuscular, synergistic, and agonist-antagonist muscle coherence, respectively, in 11 stroke patients and 9 healthy controls. Paretic motor function, sensory function, spasticity, ankle muscle strength, and gait performance were evaluated., Results: Paretic TA-TA and MG-LG beta band (15-30 Hz) coherences were significantly lower compared with the non-paretic side and controls. TA-LG beta band coherence was significantly higher on both sides compared with controls. Paretic TA-TA beta band coherence positively correlated with gait speed, and paretic TA-LG beta band coherence negatively correlated with paretic ankle plantar flexor muscle strength., Conclusions: The intramuscular and synergistic muscle neural drives were reduced during gait on the paretic side in stroke patients. The agonist-antagonist muscle neural drive was increased to compensate for paretic ankle muscle weakness., Significance: Descending neural drive reorganization to agonist-antagonist muscles is important for patients with paretic ankle muscle weakness., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

This paper describes the reversible control of the size of liquid-metal nanoparticles under ultrasonication. Gallium was utilized as a liquid metal, which has a melting point of 29.8 °C. Investigating the effects of ultrasonication (power, time, and temperature) on the formation of gallium nanoparticles revealed that the process is similar to the formation of oil in water (O/W) or water in oil (W/O) emulsions, as the temperature significantly affects the size of the gallium nanoparticles (GaNPs). Under ultrasonication, the balance between the break-up and coalescence of the GaNPs can be adjusted by changing the temperature or adding acid through modulating the natural surface oxide layer (which can be removed with acid) and the stabilizing effect of the surfactant dodecanethiol. Coalescence was predominant at higher temperatures, whereas particle break-up was found to be predominant at lower temperatures. Furthermore, the change in size was accompanied by a shift in the plasmonic absorption of the GaNPs in the UV region., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The chemical chaperone 4-phenylbutyric acid (4-PBA) has potential as an agent for the treatment of neurodegenerative diseases. However, the requirement of high concentrations warrants chemical optimization for clinical use. In this study, novel naphthalene derivatives with a greater chemical chaperone activity than 4-PBA were synthesized with analogy to the benzene ring. All novel compounds showed chemical chaperone activity, and 2 and 5 possessed high activity. In subsequent experiments, the protective effects of the compounds were examined in Parkinson's disease model cells, and low toxicity of 9 and 11 was related to amphiphilic substitution with naphthalene., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We discovered that a reagent comprising a combination of PhBCl2 and nitriles was useful for syntheses of both 3-acylindoles and 1-(1H-indol-3-yl)alkylamine from indoles. The reaction proceeded selectively at the 3-position of indoles providing 3-acylindoles in moderate to high yields on treatment with the above reagent. Furthermore, the reaction provided the corresponding amine products in moderate to high yields after the intermediate imine was reduced by NaBH3CN. These reactions proceeded under mild conditions and are applicable to the formation of indoles functionalized at the 3-position.

To clarify the influence of the fatty acid composition of sebum in acne vulgaris, we investigated the amounts and fatty acid compositions of triglycerides (TG) and free fatty acids (FFA), and the amounts of cutaneous superficial Propionibacterium acnes in acne patients and healthy subjects. The foreheads of 18 female patients, 10 male patients, 10 healthy females and 10 healthy males were studied in a Japanese population. There were significant differences in the amounts of sebum, TG and cutaneous superficial P. acnes, as well as the fatty acid compositions of TG and FFA between acne patients and healthy subjects in females. Their fatty acid compositions were correlated with the amount of TG with or without acne. It was clarified that the fatty acid compositions of TG and FFA depended on the amount of TG, and there were no differences in the fatty acid composition in the presence and absence of acne., (© 2014 Japanese Dermatological Association.)

Controlled transscleral co-delivery of two drugs, edaravone (EDV) and unoprostone (UNO), using a platform that comprises a microfabricated reservoir, controlled-release cover, and drug formulations, which are made of photopolymerized poly(ethyleneglycol) dimethacrylates, shows synergistic retinal neuroprotection against light injury in rats when compared with single-drug-loaded devices. The device would offer a safer therapeutic method than intravitreal injections for retinal disease treatments., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The previous study has shown that repeated D domain-like (Rdd) proteins, a group of novel secretory proteins consisting of repeated domains of a cysteine-rich sequence, are involved in the process of blood vessel formation in Xenopus embryo. We performed further experiments to examine the localization of Rdd proteins in embryogenesis. Detection of tagged Rdd proteins expressed in blastomeres showed that Rdd proteins formed a high molecular weight complex and existed in the extracellular space. A rabbit antibody against the Rdd synthetic peptide identified a single band of 28 kD in embryonic tissue extract. By whole-mount immunostaining analysis, signal was detected in the regions of inter-somites, vitelline veins, and branchial arches at the tailbud stage. Staining of Rdd was remarkably reduced in the embryos injected with vascular endothelial growth factor Morpholino. We suggest that Rdd proteins interact with a molecule(s) associated with vascular precursor cells.

Aims: To study serum levels of soluble vascular adhesion protein (sVAP)-1 in type II diabetic patients with retinopathy., Methods: Serum samples were obtained from 53 consecutive patients, including 14 cases with non-angiogenic ocular diseases, i.e., epiretinal membrane (ERM) and idiopathic macular hole (MH), 19 cases with age-related macular degeneration (AMD), and 20 cases with diabetic retinopathy (DR). Protein levels of sVAP-1, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and vascular endothelial growth factor (VEGF) were determined by enzyme-linked immunosorbent assay. Enzymatic activity of semicarbazide-sensitive amine oxidase (SSAO) was also measured., Results: Serum level of sVAP-1 showed a moderate correlation with SSAO activity in all cases. Patients with DR had higher levels of serum sVAP-1 than subjects with ERM and MH, or those with AMD; however, severity of DR is not related to the serum levels of sVAP-1. Serum sVAP-1 correlated positively with VEGF in patients with DR, but not in those with ERM and MH, or those with AMD. Neither soluble ICAM-1 nor VCAM-1 correlated with VEGF, even in subjects with DR., Conclusion: The current data demonstrate the elevated serum levels of sVAP-1 and correlation between sVAP-1 and VEGF in patients with type II diabetes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A 68-year-old man developed a rapidly-growing right cervical tumor, a biopsy of which allowed for the diagnosis of diffuse large B-cell lymphoma, not otherwise specified. Magnetic resonance imaging demonstrated a right cervical mass lesion of 80 mm in diameter that extended from the medial region of the parotid gland to the posterior region of the neck. While undergoing a chest X-ray in an upright position, he lost consciousness and briefly fell. A transient loss of consciousness recurred while changing his position on the bed, and an electrocardiogram at that time revealed sinus arrest of a seven second duration. This syncope was considered to be a carotid sinus syncope (CSS) induced by the compression of the carotid sinus by his cervical bulky lymphoma. Temporary cardiac pacing was immediately started and rituximab was administered. Three days later, CHOP therapy was started. As his cervical tumor rapidly shrank, the frequency of sensed sinus arrests decreased to zero per day by day 9 of CHOP therapy, resulting into the removal of the pacemaker. In certain cases with CSS due to cervical lymphoma, cardiac pacing, if needed at the onset, is considered to become removable early after chemotherapy in association with tumor shrinkage.

Although family studies and genome-wide association studies have shown that genetic factors play a role in glaucoma, it has been difficult to identify the specific genetic variants involved. We tested 669 single nucleotide polymorphisms (SNPs) from the region of chromosome 2 that includes the GLC1B glaucoma locus for association with primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) in the Japanese population. We performed a two-stage case-control study. The first cohort consisted of 123 POAG cases, 121 NTG cases and 120 controls: the second cohort consisted of 187 POAG cases, 286 NTG cases, and 271 controls. Out of six SNPs showing significant association with POAG in the first round screening, seven SNPs were tested in the second round. Rs678350 in the HK2 gene coding sequence showed significant allelic (p=0.0027 in Stage Two, 2.7XE-4 in meta-analysis) association with POAG, and significant allelic (p=4.7XE-4 in Stage Two, 1.0XE-5 in meta-analysis) association with NTG. Although alleles in the TMEM182 gene did not show significant association with glaucoma in the second round, subjects with the A/A allele in TMEM182 rs869833 showed worse visual field mean deviation (p=0.01). Even though rs2033008 in the NCK2 gene coding sequence did not show significant association in the first round, it had previously shown association with NTG so it was tested for association with NTG in round 2 (p=0.0053 in Stage Two). Immunohistochemistry showed that both HK2 and NCK2 are expressed in the retinal ganglion cell layer. Once multi-testing was taken into account, only HK2 showed significant association with POAG and NTG in Stage Two. Our data also support previous reports of NCK2 association with NTG, and raise questions about what role TMEM182 might play in phenotypic variability. Our data suggest that HK2 may play an important role in NTG in the Japanese population.

Aim: To investigate the long term effects of cardiac events on renal function, a prospective study of patients with acute myocardial infarction was conducted., Methods: A total of 137 patients with acute myocardial infarction were followed for 1 year. The change of estimated glomerular filtration rate (eGFR) in cardiac patients was compared with that in background-matched controls, and the factors associated with eGFR changes were analyzed., Results: The eGFR decrease was much larger after myocardial infarction, from 73.7 ± 1.9 ml/min/1.73 m2 (mean ± SEM) at baseline to 64.7 ± 1.7 at 1 year, (p < 0.001), compared with that of controls (from 72.8 ± 1.2 to 72.1 ± 1.3, p = 0.305). Multiple regression analysis showed that eGFR change was associated negatively with age, baseline eGFR, proteinuria, and positively with the administration of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, but not the severity of cardiac damage and comorbidities. Longitudinal analysis 1 year before and 2 years after myocardial infarction showed that eGFR decrease was larger during baseline and 6 months after the event (-7.0 ± 1.0)., Conclusions: Renal decline was rapid after myocardial infarction and was affected by clinical characteristics of patients. Careful follow-up of renal function is recommended to prevent the progression of renal and cardiac disease.

Introduction: The purpose of this study was to determine whether topical 0.15% isopropyl unoprostone (IU), a BK-channel activator, could improve or maintain the central retinal sensitivity in patients with middle- to late-stage retinitis pigmentosa (RP). IU was approved for glaucoma and ocular hypertension in 1994. The drug re-profiling strategy is one of the effective ways to develop safe drugs for patients with RP., Methods: A randomized, double-blind, and placebo-controlled phase II safety/efficacy trial was conducted. One hundred and nine patients with middle- to late-stage RP having a visual acuity of ≥0.5 were studied at six ophthalmological centers in Japan. The treatments of IU/day were divided into three groups: placebo group; two-drop group; and four-drop group for 24 weeks. The primary outcome measure was changes in the retinal sensitivity from baseline in the central 2° determined by MP-1 microperimetry (MP-1, Nidek, Japan). The secondary outcomes were changes in best-correct visual acuity, contrast sensitivity, retinal sensitivity of the central 10° by MP-1, mean deviation (MD) by a Humphrey field analyzer (HFA; Carl Zeiss Meditec, Dublin, CA, USA) 10-2, and the Visual Functioning Questionnaire 25 (VFQ-25) questionnaire scores., Results: There was a tendency for a dose-dependent responsiveness in retinal sensitivity in the central 2°, MD, and total VFQ-25 score after 24 weeks of IU instillation by a simple linear regression analysis. A stratified analysis showed a significant dose-dependent responsiveness of the 2° central retinal sensitivity in more advanced patients (P = 0.028). The number of patients having a ≥4 dB decrease in the primary outcome measure was significantly fewer in the four-drop group than in the placebo group (P = 0.02). No adverse reactions were observed., Conclusions: A higher dose of IU can delay progression of the central retinal sensitivity decrease through an improvement of retinal sensitivity.

Purpose: To determine whether polymorphisms in the Toll-like receptor 4 (TLR4) gene are associated with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and exfoliation glaucoma (XFG) in Japanese individuals., Design: Genetic association study., Setting: Multicenter study., Study Population: One hundred eighty-four unrelated Japanese patients with POAG, 365 unrelated patients with NTG, and 109 unrelated patients with XFG from 5 hospitals., Procedures: Genomic DNA was extracted from leukocytes of the peripheral blood, and 8 polymorphisms in the TLR4 genes were amplified by polymerase chain reaction (PCR) and directly sequenced. Allele and genotype frequencies and the inferred haplotypes were estimated., Main Outcome Measures: Differences in allele and genotype frequencies and haplotypes between subjects with POAG, NTG, and XFG., Results: The allele frequency of rs2149356 of the TLR4 gene in the POAG, NTG, and XFG groups was the most significantly different from that of the control group (minor allele frequency 0.446, 0.395, 0.404, vs 0.308; P = .000058, P = .0030, and P = .015). The allele frequencies of the 5 TLR4 SNPs were higher in all of the glaucoma groups than that in the control group. The statistics of genotypes of TLR4 were approximately the same for all allele frequencies. The haplotypic frequencies with Tag SNPs studied earlier showed that only POAG was statistically significant. Other haplotypes, such as rs10759930, rs1927914, rs1927911, and rs2149356, had higher statistical significance (overall P = .00078 in POAG, overall P = .018 in NTG, and overall P = .014 in XFG)., Conclusions: This study demonstrated that TLR4 polymorphisms are associated with NTG in the Japanese, and they also play a role in the pathogenesis of POAG and XFG., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Limited data are available concerning long-term results of imatinib therapy in patients with advanced gastrointestinal stromal tumors. We aimed to clarify the long-term outcomes of imatinib therapy in Japanese patients with advanced gastrointestinal stromal tumors., Methods: A prospective, observational study of imatinib therapy for unresectable and metastatic gastrointestinal stromal tumors was conducted in our institution. Imatinib was initiated at a dose of 400 mg daily and continued until disease progression. Safety, efficacy and long-term tolerability and survival were evaluated in an intent-to-treat population. The median follow-up period in this study was 68 months., Results: Seventy patients were enrolled between December 2001 and December 2009. Treatment-related Grade 3/4 adverse events occurred in 49 patients (70.0%). Although 14 patients required adverse effect management with hospitalization, only 5 patients (7.1%) withdrew from the treatment owing to imatinib intolerance. The tumor response and clinical benefit rates were 61.4 and 85.7%, respectively. Thirty-seven patients (52.9%) maintained the treatment at 400 mg daily imatinib, whereas 33 patients (47.1%) had their dose reduced to 300 mg daily or less. The overall survival rate at 5 years was 60.9% and the median survival time was 70 months. The median progression-free survival time of all the 70 enrolled patients was 30 months. Seven patients (10.0%) suffered from second malignancies, including three patients with genitourinary carcinomas., Conclusions: Despite the need for dose reduction, the long-term results of imatinib therapy for advanced gastrointestinal stromal tumors were good in Japanese patients. Physicians should pay attention to the occurrence of second malignancies during imatinib therapy for gastrointestinal stromal tumor patients.

Purpose: Vascular adhesion protein (VAP)-1, a multifunctional molecule with adhesive and enzymatic properties, is expressed at the surface of vascular endothelial cells of mammals. It also exists as a soluble form (sVAP-1), which is implicated in oxidative stress via its enzymatic activity. This study explores a link between increased level of sVAP-1 and oxidative stress in proliferative diabetic retinopathy (PDR) with a focus on mechanistic components to form sVAP-1 by shedding from retinal endothelial cells., Methods: Protein levels of sVAP-1 and N epsilon-(hexanoyl)lysine (HEL), an oxidative stress marker, in the vitreous samples from patients with PDR or non-PDR were measured by ELISA. The mechanism of VAP-1 shedding under diabetic condition, exposure to high glucose and/or inflammatory cytokines, was explored using cultured retinal capillary endothelial cells., Results: Protein level of sVAP-1 was increased and correlated with HEL in the vitreous fluid of patients with PDR. Retinal capillary endothelial cells released sVAP-1 when stimulated with high glucose or inflammatory cytokines, such as TNF-α and IL-1β in vitro. Furthermore, matrix metalloproteinase-2 and -9, type IV collagenases, were the key molecules to mediate the protein cleavage of VAP-1 from retinal capillary endothelial cells., Conclusions: Our data for the first time provide evidence on the link between sVAP-1 and type IV collagenases in the pathogenesis of PDR.

Purpose: Vascular adhesion protein (VAP)-1 is an adhesion molecule elucidated as a mediator of the leukocyte recruitment cascade. The purpose of this study was to investigate the role of VAP-1 in ocular inflammatory neovascularization using a mouse laser-induced choroidal neovascularization (CNV) model., Methods: CNV was induced with 532 nm laser irradiation in C57BL/6 mice, and production of VAP-1 protein in the retinal pigment epithelium (RPE) choroid during CNV formation was examined. CNV animals were treated with the specific VAP-1 inhibitor U-V002 or vehicle solution, and the volume of CNV tissue was evaluated with volumetric measurements. Macrophage infiltration into the CNV lesions was evaluated using two different techniques, flatmount staining and real-time polymerase chain reaction (PCR) for F4/80. The protein levels of intercellular adhesion molecule (ICAM)-1, monocyte chemoattractant protein (MCP)-1, P-selectin, and vascular endothelial growth factor (VEGF) in the RPE-choroid were measured with enzyme-linked immunosorbent assay (ELISA)., Results: VAP-1 inhibition significantly suppressed CNV formation in a dose-dependent manner and reduced macrophage infiltration into CNV lesions. Furthermore, VAP-1 blockade decreased the expression of ICAM-1 and MCP-1, both of which play a pivotal role in macrophage recruitment., Conclusions: Our data suggest VAP-1 has an important role during ocular inflammatory neovascularization through leukocyte recruitment. VAP-1 inhibition may be a novel and potent therapeutic strategy in treating CNV formation.

Background: A cluster of proinflammatory cytokines plays an important role in the development of various renal diseases, and the expression of these cytokines is genetically modified. To examine the association between polymorphisms of proinflammatory cytokine genes and albuminuria, a cross-sectional study was conducted in the general population., Methods: Single nucleotide polymorphisms (SNPs) in six proinflammatory cytokine genes, including interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, CC chemokine ligand 1 (CCL1) and monocyte chemoattractant protein-1 (MCP-1), were genotyped in 2927 Japanese subjects. Urine albumin-creatinine ratio (UACR) was measured in morning spot urine samples., Results: Albuminuria (UACR ≥ 30 mg/g) was significantly associated with the A/A + A/G genotype at rs2069852 in the IL-6 gene (P = 0.01) and the A/A genotype at rs228269 in the CCL1 gene (P = 0.002). Multivariate analysis with adjustment for traditional risk factors showed that these genotypes independently predicted albuminuria [odds ratio (OR) 1.782, 95% confidence interval (CI) 1.171-2.712, P = 0.007 for the A/A + A/G genotype at rs2069852 in IL-6, and OR 1.432, 95% CI 1.128-1.770, P = 0.003 for the A/A genotype at rs228269 in CCL1]. The prevalence of albuminuria and the UACR were increased along with the increase of risk genotypes., Conclusions: This study revealed that SNPs in the IL-6 and CCL1 genes were associated with albuminuria, and the combination of these genotypes had an additive effect on the prevalence and severity of albuminuria. This indicates that genetic factors influencing inflammatory responses may affect the development of renal injury in the Japanese general population.