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Detection of the JAK2V617F mutation is essential for diagnosing patients with classical myeloproliferative neoplasms (MPNs). However, detection of the low-frequency JAK2V617F mutation is a challenging task due to the necessity of discriminating between true-positive and false-positive results. Here, we have developed a highly sensitive and accurate assay for the detection of JAK2V617F and named it melting curve analysis after T allele enrichment (MelcaTle). MelcaTle comprises three steps: 1) two cycles of JAK2V617F allele enrichment by PCR amplification followed by BsaXI digestion, 2) selective amplification of the JAK2V617F allele in the presence of a bridged nucleic acid (BNA) probe, and 3) a melting curve assay using a BODIPY-FL-labeled oligonucleotide. Using this assay, we successfully detected nearly a single copy of the JAK2V617F allele, without false-positive signals, using 10 ng of genomic DNA standard. Furthermore, MelcaTle showed no positive signals in 90 assays screening healthy individuals for JAK2V617F. When applying MelcaTle to 27 patients who were initially classified as JAK2V617F-positive on the basis of allele-specific PCR analysis and were thus suspected as having MPNs, we found that two of the patients were actually JAK2V617F-negative. A more careful clinical data analysis revealed that these two patients had developed transient erythrocytosis of unknown etiology but not polycythemia vera, a subtype of MPNs. These findings indicate that the newly developed MelcaTle assay should markedly improve the diagnosis of JAK2V617F-positive MPNs.

During 2012-2013, a total of 4325 host-seeking adult ticks belonging to the genus Ixodes were collected from various localities of Hokkaido, the northernmost island of Japan. Tick lysates were subjected to real-time PCR assay to detect borrelial infection. The assay was designed for specific detection of the Relapsing fever spirochete Borrelia miyamotoi and for unspecific detection of Lyme disease-related spirochetes. Overall prevalence of B. miyamotoi was 2% (71/3532) in Ixodes persulcatus, 4.3% (5/117) in Ixodes pavlovskyi and 0.1% (1/676) in Ixodes ovatus. The prevalence in I. persulcatus and I. pavlovskyi ticks were significantly higher than in I. ovatus. Co-infections with Lyme disease-related spirochetes were found in all of the tick species. During this investigation, we obtained 6 isolates of B. miyamotoi from I. persulcatus and I. pavlovskyi by culture in BSK-M medium. Phylogenetic trees of B. miyamotoi inferred from each of 3 housekeeping genes (glpQ, 16S rDNA, and flaB) demonstrated that the Hokkaido isolates were clustered with Russian B. miyamotoi, but were distinguishable from North American and European B. miyamotoi. A multilocus sequence analysis using 8 genes (clpA, clpX, nifS, pepX, pyrG, recG, rplB, and uvrA) suggested that all Japanese B. miyamotoi isolates, including past isolates, were genetically clonal, although these were isolated from different tick and vertebrate sources. From these results, B. miyamotoi-infected ticks are widely distributed throughout Hokkaido. Female I. persulcatus are responsible for most human tick-bites, thereby I. persulcatus is likely the most important vector of indigenous relapsing fever from tick bites in Hokkaido.

Abstract Background Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice. Methods Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks. Results At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition. Conclusions Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.

Background: The COVID-19 pandemic and associated restrictions on human activities have greatly changed lifestyles, which might have deteriorated the cardiometabolic profile., Objective: This study aimed to examine the effect of the COVID-19 pandemic on the incidence of cardiometabolic risk factors among Japanese workers in fiscal years (FY) 2020 and 2021 compared with the prepandemic period., Method: This study comprised an average of 71 025 employees in Japan who underwent annual health check-ups for at least two successive years from 2015 to 2021. Annual incidence rates from 2016 to 2021 were assessed for obesity, diabetes, hypertension, dyslipidaemia and metabolic syndrome (MetS). The observed incidence rates in 2020 and 2021 were compared with the predicted incidence based on prepandemic trends (2016 to 2019)., Results: Relative to the prepandemic, the incidence of all the outcomes, except for dyslipidaemia, significantly increased in 2020. Between FY 2016 and 2019, the adjusted mean incidence of obesity, diabetes, hypertension, dyslipidaemia and MetS was 5.0%, 1.4%, 5.3%, 17.4% and 7.6%, respectively. In FY 2020, the adjusted incidence (95% CI) of these outcomes increased to 6.02 (5.80 to 6.24), 1.84 (1.73 to 1.96), 6.62 (6.40 to 6.83), 19.31 (18.83 to 19.78) and 8.51 (8.23 to 8.78), which were higher than the predicted incidence of 5.24 (4.99 to 5.49), 1.54 (1.41 to 1.67), 6.02 (5.76 to 6.27), 18.58 (18.00 to 19.16) and 8.05 (7.71 to 8.38) for 2020, respectively. The incidence returned to the prepandemic levels in FY 2021., Conclusion: Results showed a worsening of the cardiometabolic profile during the initial year of the pandemic, which was reverted in the second year to the levels before the pandemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

The opioid system plays crucial roles in modulating social behaviors in both humans and animals. However, the pharmacological profiles of opioids regarding social behavior and their therapeutic potential remain unclear. Multiple pharmacological, behavioral, and immunohistological c-Fos mapping approaches were used to characterize the effects of μ-opioid receptor agonists on social behavior and investigate the mechanisms in naive mice and autism spectrum disorder-like (ASD-like) mouse models, such as prenatally valproic acid-treated mice and Fmr1-KO mice. Here, we report that low-dose morphine, a μ-opioid receptor agonist, promoted social behavior by selectively activating neurons in prosocial brain regions, including the nucleus accumbens, but not those in the dorsomedial periaqueductal gray (dmPAG), which are only activated by analgesic high-dose morphine. Critically, intra-dmPAG morphine injection counteracted the prosocial effect of low-dose morphine, suggesting that dmPAG neural activation suppresses social behavior. Moreover, buprenorphine, a μ-opioid receptor partial agonist with less abuse liability and a well-established safety profile, ameliorated social behavior deficits in two mouse models recapitulating ASD symptoms by selectively activating prosocial brain regions without dmPAG neural activation. Our findings highlight the therapeutic potential of brain region-specific neural activation induced by low-dose opioids for social behavior deficits in ASD.

Regioselective hydroaminative cyclizations of 1,5- and 1,6-diynes via double functionalization of an alkyne carbon were achieved using a phosphine-quinolinolato (PNO) rhodium catalyst. While the reaction of 1,6-diynes with secondary amines provided cyclic 2-aminodienes, phenylene-tethered 1,5-diynes were transformed into benzofulvene derivatives. The reaction is considered to proceed via in situ construction of an aminocarbene ligand, [2 + 2] addition with an internal alkyne moiety, and isomerization to an aminodiene structure. This hydroaminative cyclization proceeds just by heating the substrate with the rhodium catalyst without adding any additive and provides a convenient route to access cyclic 2-aminodiene and aminobenzofulvene derivatives.

The palladium-catalyzed C-H iodination of 1-arylpyridine N -oxides proceeded under electrochemical oxidation conditions using I 2 as an iodine source. The reaction of isoquinoline N -oxides possessing various para - or meta -substituted aryl groups at the 1-position proceeded to give the corresponding iodination products. Electron-donating groups on the aryl group facilitated the reaction to give relatively high yields of the product. The reaction was also found to be applicable to 2-aryl-3-picoline N -oxides.

Palladium-catalyzed electrochemical C(sp 3 )-H acetoxylation to prepare 1,2-diol derivatives was achieved using oxime ethers as exo -directing groups. Various substrates containing alkoxy groups with a methyl branch at the α-position as well as norbornan-2-ol derivative were acetoxylated only using a catalytic amount of Pd(OAc) 2 along with NaOAc/Ac 2 O/AcOH under anodic oxidation conditions.

Aims: This study aimed to develop a cardiovascular disease (CVD) risk model using data from a large occupational cohort., Methods: A risk prediction model was developed using the routine health checkup data of 96,117 Japanese employees (84.0% men) who were 30-64 years of age and had no CVD at baseline. Cox proportional hazards regression models were employed to develop a risk model for assessing the 10-year CVD risk. Measures of discrimination and calibration were used to assess the predictive performance of the model and internal validation was used to examine potential overfitting., Results: During a mean follow-up period of 6.7 years (range, 0.1-11.0 years), 422 cases of incident CVD were confirmed. The final model, which included predictor variables of age, smoking, diabetes, systolic blood pressure, and low- and high-density lipoprotein cholesterol levels, demonstrated a good predictive ability (Harrell's C-statistic, 0.796; 95% confidence interval, 0.775-0.817) with excellent calibration between observed and predicted values. Internal validation revealed minimal overfitting., Conclusions: The developed model can accurately predict the 10-year CVD risk. Because it is based on routine health checkup data, the prediction model can be easily implemented in the workplace. Further studies are required to assess the external validity and transferability of the proposed CVD risk model.

Red meat and processed meat intake has been linked to increased risk of type 2 diabetes; however, evidence from Asia is limited and inconsistent. We prospectively examined the association of intake of total meat and its subtype with type 2 diabetes in a Japanese working population. Participants were 2709 workers aged 18-78 years who reported no history of diabetes when they responded to a health survey for the first time between 2012 and 2019. Dietary intake was assessed using a validated self-administered diet history questionnaire. The incidence of type 2 diabetes was assessed via annual health checkups from baseline through March 2023. Type 2 diabetes was defined as fasting blood glucose ≥ 126 mg/dl, casual blood glucose ≥ 200 mg/dl, HbA1c ≥ 6·5 %, self-report of diabetes or current use of anti-diabetic drugs. Hazard ratios according to tertile of meat intake were estimated using Cox proportional hazards regression. During 16 119 person-years of follow-up, 135 (5·0 %) workers developed type 2 diabetes. Intakes of total meat, red meat, processed meat and poultry were not associated with risk of type 2 diabetes. After adjustment for covariates, hazard ratios for the highest v . lowest tertile of meat intake were 1·01 (95 % CI 0·63, 1·62) for total meat, 1·02 (95 % CI 0·66, 1·58) for red meat, 0·99 (95 % CI 0·65, 1·49) for processed meat and 1·13 (95 % CI 0·71, 1·80) for poultry. Our findings suggest that meat intake is not associated with the risk of type 2 diabetes among Japanese workers.

The Japanese Society of Hypertension updated guidelines for hypertension management (JSH2019), changing the blood pressure (BP) classification. However, evidence is sparse regarding the association of the classification with cardiovascular disease (CVD) events among young to middle-aged workers in Japan. We examined this issue using longitudinal data from Japan Epidemiology Collaboration on Occupational Health Study with a prospective cohort design. Participants were 81,876 workers (aged 20-64 years) without taking antihypertensive medication at baseline. BP in 2011 or 2010 was used as exposure. CVD events that occurred from 2012 to 2021 were retrieved from a within-study registry. Cox regression was used to calculate multivariable-adjusted hazard ratios of CVD events. During 0.5 million person-years of follow-up, 334 cardiovascular events, 75 cardiovascular deaths, and 322 all-cause deaths were documented. Compared with normal BP (systolic BP [SBP] < 120 mmHg and diastolic BP [DBP] < 80 mmHg), multivariable-adjusted hazard ratios (95% confidence intervals) of cardiovascular events were 1.98 (1.49-2.65), 2.10 (1.58-2.77), 3.48 (2.33-5.19), 4.12 (2.22-7.64), and 7.81 (3.99-15.30) for high normal BP (SBP120-129 mmHg and DBP < 80 mmHg), elevated BP (SBP130-139 mmHg and/or DBP80-89 mmHg), stage 1 hypertension (SBP140-159 mmHg and DBP90-99 mmHg), stage 2 hypertension (SBP160-179 mmHg and/or DBP100-109 mmHg), and stage 3 hypertension (SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg), respectively. The highest population attributable fraction was observed in elevated BP (17.8%), followed by stage 1 hypertension (14.1%). The present data suggest that JSH2019 may help identify Japanese workers at a higher cardiovascular risk., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Introduction: Although conventional cigarette smoking has been linked to an increased risk of hearing loss, the association between heated tobacco products (HTPs) and hearing loss is unknown. The objective of this study was to investigate the association between cigarette and HTP use and hearing loss., Methods: This cross-sectional study examined the data of 7769 employees from five companies (Study I) and 34404 employees from a large company (Study II), all participants in the Japan Epidemiology Collaboration on Occupational Health Study. The participants were categorized into five groups based on their self-reported tobacco use: never smokers, former smokers, exclusive cigarette smokers, exclusive users of HTPs, and those who used both cigarettes and HTPs. Hearing levels were measured using pure-tone audiometry at 1 and 4 kHz frequencies. Separate analyses were carried out for each study, and the results were then combined using fixed-effect models to pool the estimates., Results: The analysis included 42173 participants, with a prevalence of 12.9% for exclusive cigarette smoking, 9.8% for exclusive HTP use, and 5.5% for dual use. The pooled adjusted odds ratios with 95% confidence intervals for unilateral hearing loss at 4 kHz were 1.21 (95% CI: 1.10-1.33) for former smokers, 1.83 (95% CI: 1.64-2.05) for exclusive cigarette smokers,1.46 (95% CI: 1.28-1.67) for exclusive HTP users, and 1.66 (95% CI: 1.41-1.96) for dual users, compared to never smokers. Additionally, the adjusted odds ratios for hearing loss at 4 kHz among exclusive cigarette smokers, exclusive HTP users, and dual users increased with the intensity of cigarette/HTP consumption (all p for trend <0.001). No significant associations were found between exclusive HTP use, dual use, and hearing loss at 1 kHz, apart from exclusive cigarette smoking., Conclusions: In this cross-sectional study, associations were found between exclusive cigarette smoking, exclusive HTP use, dual use, and hearing loss, particularly at 4 kHz. Further research is needed to confirm these findings., Competing Interests: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported., (© 2024 Hu H. et al.)

Introduction Abdominal angiography procedures such as transarterial chemoembolization (TACE) are essential for hepatocellular carcinoma treatment. One method commonly used is transfemoral access (TFA). However, issues associated with this method, which include postoperative compression of the puncture site and long periods of bed rest, can affect patient satisfaction. Thus, transradial access (TRA), a minimally invasive treatment method that improves treatment quality, was developed for TACE. This retrospective, multicenter study aimed to investigate the efficacy and safety of abdominal angiography using the radial artery approach. Methods In total, 1,601 patients underwent abdominal angiography using TRA and received treatment (radial access for visceral intervention (RAVI)) at 14 institutions in Japan. The treatment time, procedure completion rate, patient satisfaction, and complications were investigated. Results The success rate of RAVI was 99.4%, and the complication rate was 1.2%. Approximately 98.2% of the patients requested the radial artery approach again. There were no significant differences in the success rate of RAVI and the incidence of complications based on the operator's years of experience or the patient's age. Some patients developed minor complications such as puncture site bleeding, hematoma, vascular pain, and vasospasm. Further, serious complications (cerebral infarction (n = 1), cerebellar infarction (n = 1), and aortic dissection (n = 1)) were observed. Conclusion Similar to the conventional TFA, RAVI helped in facilitating peritoneal angiography safely. In abdominal angiography, this method can reduce patient burden and can be widely used in the future from the perspective of clinical benefit., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Sasaki et al.)

In organic reactions, bond-forming and bond-cleaving processes are generally considered to be more important than other processes such as conformational isomerization. We report herein an example where a conformational isomerization process, propeller-like alkene rotation, is considered to determine the selectivity over the reaction pathways. The transition state with the highest energy barrier in some alkylpalladium isomerization (chain walking) events was theoretically indicated to correspond to alkene rotation, while transition states for bond-cleaving β-hydride elimination and bond-forming migratory insertion were not even observed. It was also suggested both theoretically and experimentally that the palladium chain walking over internal carbons in alkyl chains proceeds via cis alkene intermediates rather than thermodynamically more stable trans alkene intermediates, due to their relative difficulty to undergo alkene rotation.

Background/objectives: In addition to the potential effects of nutrients on mood, eating behaviors have been suggested to be associated with depressive symptoms. We investigated the prospective association between the accumulation of unhealthy eating behaviors and depressive symptoms in a Japanese working population., Methods: Participants were 914 workers (aged 19-68 years) who did not have depressive symptoms at baseline (April 2012 and May 2013) and attended a 3-year follow-up survey (April 2015 and May 2016). Unhealthy eating behaviors (skipping breakfast, eating dinner just before bedtime, and snacking after dinner) were assessed at baseline. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale at follow-up. Multiple logistic regression was used to estimate the odds ratio of depressive symptoms (CES-D score ≥16) at follow-up according to the number of unhealthy eating behaviors., Results: In a model with adjustment of background factors, participants having 2-3 unhealthy eating behaviors at baseline had significantly higher risk of developing depressive symptoms (OR, 2.02; 95% CI, 1.21-3.38) compared with those having no such behaviors. After adjustment for occupational and lifestyle factors, the association was slightly attenuated but remained significant (OR, 1.87; 95% CI, 1.10-3.21). This association was further attenuated and became statistically non-significant after additional adjustment for nutritional factors (OR, 1.67; 95% CI, 0.96-2.90)., Conclusions: Our results suggest that the accumulation of unhealthy eating behaviors is associated with an increased risk of depressive symptoms and that this association may be partly ascribed to a lower intake of nutrients with mood-improving effects., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Diabetes and prediabetes have been linked with morbidity or mortality from cardiovascular disease, cancer, or other physical disorders among working-age populations, but less is known about outcomes directly related to labor loss (eg, Tlong-term sickness absence [LTSA] or pre-retirement death due to physical disorders).This prospective study aimed to examine the association of diabetes and prediabetes with the risk of a composite outcome of LTSA and pre-retirement death due to physical disorders. The present study also examined the associations of severe outcomes (LTSA or death) due to specific physical disorders or injuries/external causes in relation to diabetes and prediabetes., Methods: Data were derived from the Japan Epidemiology Collaboration on Occupational Health study. A total of 60,519 workers from 12 companies were followed for 8 years. Diabetes and prediabetes were defined based on the American Diabetes Association criteria. A Cox proportional hazards regression model was used to examine the association between diabetes/prediabetes and severe outcomes due to physical disorders or injuries/external causes., Results: The adjusted hazard ratios of severe outcomes due to all physical disorders were 1.22 (95% confidence interval [CI], 1.02-1.45) and 2.32 (95% CI, 2.04-2.64) for prediabetes and diabetes, respectively. In cause-specific analyses, an increased risk was observed for severe outcomes due to cancers, cardiovascular diseases, diseases of the musculoskeletal system, and injuries/external causes in relation to either or both diabetes and prediabetes., Conclusion: Diabetes and prediabetes were associated with an increased risk of severe outcomes due to physical disorders or injuries/external causes among Japanese workers.

Post-traumatic trigeminal neuropathy (PTTN) is a type of chronic pain caused by damage to the trigeminal nerve. A previous study reported that pretreatment with anti-high mobility group box-1 (HMGB1) neutralizing antibodies (nAb) prevented the onset of PTTN following distal infraorbital nerve chronic constriction injury (dIoN-CCI) in male mice. Clinical evidence indicates a high incidence of PTTN in females. Although our previous study found that perineural HMGB1 is crucial in initiation of PTTN in male mice, it is currently unknown whether HMGB1 is also involved in the pathogenesis of PTTN in female mice. Therefore, in the current study, we examined the effect of anti-HMGB1 nAb on pain-like behavior in female mice following dIoN-CCI surgery. We found that dIoN-CCI surgery enhanced reactivity to mechanical and cold stimuli in female mice, which was suppressed by treatment with anti-HMGB1 nAb. Moreover, the increase in macrophages after dIoN-CCI was significantly attenuated by pretreatment with anti-HMGB1 nAb. Furthermore, anti-HMGB1 nAb treatment inhibited microglial activation in the trigeminal spinal tract nucleus. These data suggest that HMGB1 also plays a crucial role in the onset of PTTN after nerve injury in female mice. Thus, anti-HMGB1 nAb could be a novel therapeutic agent for inhibiting the onset of PTTN in female and male mice.

Background & Aim: High intake of isoflavones has been reported to be associated with decreased prevalence of depressive symptoms. However, no prospective study has examined this association. We prospectively investigated the association between isoflavone intake and depressive symptoms in a Japanese working population., Methods: Participants were 1162 workers (1033 men and 129 women aged 18-68 years) without depressive symptoms at baseline. Dietary intake was assessed using a validated self-administered diet history questionnaire. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Cox proportional hazards regression for interval-censored data was used to estimate the hazard ratio of depressive symptoms (CES-D ≥16) according to the tertile of isoflavone intake with adjustment for covariates., Results: During 5065 person-years of follow-up, 276 (23.8 %) workers were newly identified as having depressive symptoms. Isoflavone intake was not associated with risk of depressive symptoms. After adjustment for lifestyle and dietary factors and baseline CES-D score, the multivariable-adjusted hazard ratios (95 % confidence interval) for the lowest through highest tertile of isoflavone intake were 1.00 (reference), 0.93 (0.66-1.31), and 0.93 (0.62-1.38) (P for trend = 0.70)., Conclusions: Our findings suggest that higher isoflavone intake is not associated with decreased risk of depressive symptoms among Japanese., Competing Interests: Declaration of competing interest None., (Copyright © 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Living alone has been positively associated with the prevalence of depressive symptoms. We examined how a combination of living alone and pet ownership relates to depressive symptoms., Methods: As part of the Japan Epidemiology Collaboration on Occupational Health Study, we conducted a survey on health-related lifestyles, including living arrangements and pet ownership, among 12,763 employees of five companies in 2018-2021. Depressive symptoms were assessed using the 11-item Center for Epidemiological Studies-Depression Scale (cutoff score ≥ 9). A Poisson regression model with a robust variance estimator was used to calculate prevalence ratio and 95% confidence interval (CI) while adjusting for covariates., Results: Among the participants, 30.9% were depressed, 17.7% had pets, and 29.1% lived alone. Compared to individuals living with others but not with a pet, those living alone and not with a pet had a 1.17 times higher prevalence ratio of depressive symptoms (95% CI: 1.08-1.26). The corresponding figures were 1.03 (95% CI: 0.95-1.11) for those living with others and pet(s) and 1.42 (95% CI: 1.18-1.69) for those living alone but with pet(s)., Conclusion: Living alone was significantly associated with a higher prevalence of depressive symptoms. The association was rather stronger among individuals with vs. without pets. Pet ownership may not be associated with decreased depressive symptoms., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Microglia are crucial in induction of central sensitization under a chronic pain state. Therefore, control of microglial activity is important to ameliorate nociceptive hypersensitivity. The nuclear receptor retinoic acid related orphan receptor γ (RORγ) contributes to the regulation of inflammation-related gene transcription in some immune cells, including T cells and macrophages. Their role and function in regulation of microglial activity and nociceptive transduction have yet to be elaborated. Treatment of cultured microglia with specific RORγ inverse agonists, SR2211 or GSK2981278, significantly suppressed lipopolysaccharide (LPS)-induced mRNA expression of pronociceptive molecules interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Intrathecal treatment of naïve male mice with LPS markedly induced mechanical hypersensitivity and upregulation of ionized calcium-biding adaptor molecule (Iba1) in the spinal dorsal horn, indicating microglial activation. In addition, intrathecal treatment with LPS significantly induced mRNA upregulation of IL-1β and IL-6 in the spinal dorsal horn. These responses were prevented by intrathecal pretreatment with SR2211. In addition, intrathecal administration of SR2211 significantly ameliorated established mechanical hypersensitivity and upregulation of Iba1 immunoreactivity in the spinal dorsal horn of male mice following peripheral sciatic nerve injury. The current findings demonstrate that blockade of RORγ in spinal microglia exerts anti-inflammatory effects, and that RORγ may be an appropriate target for the treatment of chronic pain., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Metabolic syndrome (MetS) is associated with cancer risk; however, little is known regarding its relationship with the risk of cancer-related premature death and long-term sick leave (LTSL), which can lead to a substantial loss in working years. The present study aimed to quantify the all-site and site-specific associations between MetS and the risk of severe cancer events (a composite outcome of LTSL and mortality due to cancer) in a large working population in Japan., Methods: We recruited 70,875 workers (59,950 men and 10,925 women), aged 20-59 years, who attended health check-ups in 2011 (10 companies) and 2014 (2 companies). All workers underwent follow up for severe cancer events until March 31, 2020. MetS was defined in accordance with the Joint Interim Statement. Cox regression models were used to quantify the association between baseline MetS and severe cancer events., Results: During 427,379 person-years of follow-up, 523 participants experienced the outcome consisting of 493 LTSLs of which 124 eventually resulted in death, and 30 deaths without taking LTSL. The adjusted hazard ratios (HR) (95% confidence intervals [CI]) for composite severe events due to all-site, obesity-related, and non-obesity-related cancer among those with vs. without MetS were 1.26 (1.03, 1.55), 1.37 (1.04, 1.82), and 1.15 (0.84, 1.56), respectively. In cancer site-specific analyses, MetS was associated with an increased risk of severe events due to pancreatic cancer (HR, 2.06; 95% CI, 0.99-4.26). When mortality was treated solely as the endpoint, the association was significant for all-site (HR, 1.58; 95% CI, 1.10-2.26), and obesity-related (HR, 1.59; 95% CI, 1.00-2.54) cancer. Additionally, a greater number of MetS components was associated with a greater risk of both severe cancer events and cancer-related mortality (P trend < 0.05)., Conclusion: Among Japanese workers, MetS was associated with an increased risk of severe cancer events, especially those due to obesity-linked cancer., (© 2023. The Author(s).)

Background: Metabolic syndrome (MetS) has been associated with various chronic diseases that may lead to long-term sickness absence (LTSA), but there is lacking information on the direct association between MetS and LTSA. The present study aimed to investigate the all-cause and cause-specific associations between MetS and the risk of medically certified LTSA among Japanese workers., Methods: We recruited 67,403 workers (57,276 men and 10,127 women), aged 20-59 years from 13 companies in Japan during their health check-ups in 2011 (11 companies) and 2014 (2 companies), and we followed them for LTSA events (≥30 consecutive days) until March 31, 2020. MetS was defined according to the Joint Interim Statement. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and its 95% confidence intervals (CIs) for LTSA associated with MetS and its components., Results: During 408,324 person-years of follow-up, 2,915 workers experienced LTSA. The adjusted HR for all-cause LTSA was 1.54 (95% CI, 1.41-1.68) among those with MetS compared to those without MetS. In cause-specific analysis, HRs associated with MetS significantly increased for LTSA due to overall physical disorders (1.76); cardiovascular diseases (3.16); diseases of the musculoskeletal system and connective tissue (2.01); cancers (1.24); obesity-related cancers (1.35); mental, behavioral, and neurodevelopmental disorders (1.28); reaction to severe stress and adjustment disorders (1.46); and external causes (1.46). The number of MetS components were also significantly associated with increased LTSA risk., Conclusion: MetS was associated with an increase in the risk of LTSA due to various diseases among Japanese workers.

We report here a deallylative β-acylalkylation reaction of allylbenzene derivatives with allyl alcohols in the presence of Cp*Rh catalysts. Allylbenzenes possessing pyridyl and pyrazolyl directing groups were converted to β-aryl ketones via the cleavage of C(aryl)-C(allyl) bonds. Synthesis of a quinoline derivative from a β-aryl ketone product bearing a pyrazolyl group was also achieved.

Aims: We aimed to assess the cross-sectional association of heated tobacco product (HTP) use with prediabetes and diabetes., Methods: The present analysis included 8950 workers from 5 companies (Study I) and 31,341 workers from another large company (Study II), who participated in the Japan Epidemiology Collaboration on Occupational Health Study. The participants were divided into five groups: never smokers, past smokers, exclusive HTP users, dual users of cigarettes and HTPs, and exclusive cigarette smokers. Diabetes and prediabetes were defined according to the fasting blood glucose and HbA1c levels and self-reported diabetes treatment, using the American Diabetes Association criteria. We analyzed the data of Study I and II separately, and then pooled these estimates using the fixed-effect models, with adjustment for a wide range of covariates., Results: In this study that included 40,291 participants (mean age, 46.6 years; men, 84.3%), about half of the current tobacco-related product users reported using HTPs. Exclusive HTP users had higher odds of prediabetes (pooled odds ratio 1.36; 95% CI 1.25-1.47) and diabetes (1.68; 95% CI 1.45-1.94) than never smokers. Similarly, dual users also had increased odds of prediabetes (pooled odds ratio, 1.26; 95% CI 1.13-1.39) and diabetes (1.93; 95% CI 1.63-2.29). The strength of these associations was comparable to that of cigarette smokers. We observed significantly higher HbA1c and fasting blood glucose levels among both exclusive HTP users and dual users compared to never smokers., Conclusion: HTP use was associated with an increased likelihood of prediabetes and diabetes. Prospective studies are warranted to confirm the cross-sectional association., (© 2022. Springer-Verlag Italia S.r.l., part of Springer Nature.)

While the hydroboration of alkenes is well established, the corresponding cyclization reaction of dienes remains challenging. Here, we report a new method for hydroboration/cyclization applicable to various 1, n -dienes and hydroboranes. The method features the direct synthesis of borylalkyl cyclopentanes from common 1,6-dienes, which is highlighted by syntheses of elaborated pyrrolidine cores from easily accessible diallylamines. Notably, 1, n -dienes ( n > 6) also undergo five-membered ring formation, offering "remote" hydroboration/cyclization that would be otherwise difficult to achieve.

Here we report an ortho -C-H alkenylation of aromatic ketones with unsymmetric internal alkynes catalyzed by an iron phosphine complex, Fe(PMe 3 ) 4 . The use of a catalytic amount of P t Bu 3 as an additive was found to improve the product yields. The alkenylation proceeds regio- and stereoselectively to give the corresponding styrene derivatives.

In this study, we aimed to evaluate the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) treatment for unresectable hepatocellular carcinoma (HCC) and to analyze the factors affecting overall survival (OS). A total of 69 patients who received Atez/Bev at our institutions for unresectable HCC were enrolled in this study. OS and progression-free survival (PFS) were estimated using the Kaplan−Meier method. Changes in clinical indicators within 3 months were defined as delta (∆) values, and the Cox proportional hazards model was used to identify which ∆ values affected OS. The median OS, PFS, objective response rate, and disease control rate were 12.5 months, 5.4 months, 23.8%, and 71.4%, respectively. During the observational period, 62 patients (92.5%) experienced AEs (hypertension (33.3%) and general fatigue), and 27 patients (47.4%) experienced grade ≥ 3 AEs (hypertension (10.1%) and anemia (7.2%)). There was a significant deterioration in the albumin-bilirubin (ALBI) score (−2.22 to −1.97; p < 0.001), and a reduction in PIVKA-II levels (32,458 to 11,584 mAU/mL; p = 0.040) within 3 months after commencing Atez/Bev. Both the worsening ∆ ALBI score (p = 0.005) and increasing ∆ PIVKA-II (p = 0.049) were significantly associated with the OS of patients.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and social interaction and the presence of restricted, repetitive behaviors. Additionally, difficulties in sensory processing commonly occur in ASD. Sensory abnormalities include heightened or reduced sensitivity to pain, but the mechanism underlying sensory phenotypes in ASD remain unknown. Emerging evidence suggests that microglia play an important role in forming and refining neuronal circuitry, and thus contribute to neuronal plasticity and nociceptive signaling. In the present study, we investigated the age-dependent tactile sensitivity in an animal model of ASD induced by prenatal exposure to valproic acid (VPA) and subsequently assessed the involvement of microglia in the spinal cord in pain processing. Pregnant ICR (CD1) mice were intraperitoneally injected with either saline or VPA (500 mg/kg) on embryonic day 12.5. Male offspring of VPA-treated mothers showed mechanical allodynia at both 4 and 8 weeks of age. In the spinal cord dorsal horn in prenatally VPA-treated mice, the numbers and staining intensities of ionized calcium-binding adapter molecule 1-positive cells were increased and the cell bodies became enlarged, indicating microglial activation. Treatment with PLX3397, a colony-stimulating factor 1 receptor inhibitor, for 10 days resulted in a decreased number of spinal microglia and attenuated mechanical allodynia in adult mice prenatally exposed to VPA. Additionally, intrathecal injection of Mac-1-saporin, a saporin-conjugated anti-CD11b antibody to deplete microglia, abolished mechanical allodynia. These findings suggest that prenatal VPA treatment causes allodynia and that spinal microglia contribute to the increased nociceptive responses., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We aimed to assess the association between heated tobacco product (HTP) use and high-density lipoprotein cholesterol (HDL-C) concentration. Our study included 12,268 workers from five companies (Study I) and 36,503 workers from another large company (Study II). Participants were categorized into five groups: never smokers, past smokers, exclusive HTP users, dual users of cigarettes and HTPs, and exclusive cigarette smokers. We analyzed the data of Studies I and II separately and then pooled these estimates using a fixed-effect model. Of the 48,771 participants, 9.3% were exclusive HTP users, and 6.0% were dual users. Exclusive HTP users had modestly but significantly lower concentrations of HDL-C than never smokers, with the pooled mean difference being - 1.1 (95% CI - 1.5 to - 0.6) mg/dL. Dual users showed a further reduction (mean difference - 3.7 (- 4.2 to - 3.2) mg/dL), which was comparable to that of exclusive cigarette smokers versus never smokers (mean difference - 4.3 (- 4.7 to - 3.9) mg/dL). The pooled odds ratios (95% CIs) of having low HDL-C (< 40 mg/dL for men and 50 mg/dL for women) were 1, 0.99 (0.90-1.11), 1.25 (1.09-1.43), 2.02 (1.76-2.32), and 2.09 (1.88-2.32) for never smokers, past smokers, exclusive HTP users, dual users, and exclusive cigarette smokers, respectively. In conclusion, exclusive HTP users had lower HDL-C concentrations than never smokers, although higher than exclusive cigarette smokers. Moreover, dual users had HDL-C concentrations similar to those in exclusive cigarette smokers., (© 2022. The Author(s).)

Muscle cramps are frequently overlooked and worsen the quality of life in patients with chronic liver disease (CLD). Therefore, a valuable biomarker for predicting muscle cramps is required in the clinical setting. This study aimed to investigate whether the serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels, a reliable liver fibrosis marker, could predict muscle cramps in patients with CLD. This retrospective study included 80 patients with CLD. Muscle cramps were assessed using a questionnaire regarding their presence, frequency, pain severity, and duration. The associated predictors were analyzed using logistic regression analysis. The diagnostic accuracy and optimal cutoff values were evaluated using receiver operating characteristic curves. Of the 80 patients, 55% had muscle cramps and showed significantly higher serum M2BPGi levels than those without them (4.54 cutoff index [COI] vs 2.20; P = .001). Multivariate analysis revealed that M2BPGi (odds ratio [ORs], 1.19; 95% confidence interval, 1.003-1.42; P = .046) was independently associated with the presence of muscle cramps. The optimal COI value for predicting muscle cramps was 3.95, and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 61.4%, 80.6%, 79.4%, 63.0%, and 70.0%, respectively. Patients with a COI value ≥3.95 had a 2-fold higher incidence of muscle cramps than patients with a COI value <3.95 (79% vs 37%; P < .001). M2BPGi levels were also associated with the duration of muscle cramps. Serum M2BPGi appears useful as a biomarker for predicting muscle cramps in patients with CLD., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: While it is essential to understand how long is sufficient for return-to-work when designing paid sick-leave systems, little attempt has been done to collect cause-specific information on when and how many of sickness absentees returned to work, became unemployed, or passed away., Methods: We studied the first sick-leave episode of ≥30 consecutive days in those ≤55 years of age during 2012-2013 among employees of 11 Japanese private companies (n = 1,209), which were followed until 2017. Overall and disease-specific cumulative incidences of return-to-work, resignations, and deaths were estimated using competing risk analysis., Results: During the 3.5-year period (follow-up rate: 99.9%), 1,014 returned to work, 167 became unemployed, and 27 died. Overall, return-to-work occurred within 1 year in 74.9% of all absentees and in 89.3% of those who successfully returned to work. Resignation occurred within 1 year in 8.7% of all absentees and in 62.9% of all subjects who resigned. According to ICD-10 chapters, the cumulative incidence of return-to-work ranged from 82.1% for mental disorders (F00-F99) to 95.3% for circulatory diseases (I00-I99). The cumulative incidence of return-to-work due to mental disorders ranged from 66.7% in schizophrenia (F20) to 95.8% in bipolar affective disorders (F31). Death was rarely observed except for cases of neoplasms (C00-D48), of which the cumulative incidence of death reached 14.2% by 1.5 years., Conclusion: Return-to-work and resignations occurred commonly within 1 year of sick leave among long-term sickness absentees in the Japanese private companies. Our findings may assist occupational physicians and employers in developing effective social protection schemes.

While late chronotype and greater social jetlag have been associated with poor dietary behavior among the general population, these associations have not been investigated among workers, who struggle to align their sleep timings with work schedules. We aimed to explore the cross-sectional association of social jetlag and a late chronotype with adherence to a healthy diet among Japanese workers. Participants were 1,435 non-shift workers (18-78 years) who attended a nutritional survey. Social jetlag was defined as the difference in the midpoint of sleep times between weekdays and weekends, while chronotype was estimated using the mid-sleep time on weekends that was corrected with sleep debt on weekdays. We calculated the adherence score of the Japanese Food Guide Spinning Top (JFGST) - healthy diet guidelines for Japanese. Multivariable linear regression analyses were used to calculate the adjusted means and 95% confidence intervals (CI) for adherence scores of social jetlag and chronotype. We found that greater social jetlag was associated with a lower JFGST score. The multivariable-adjusted mean (95% CI) of JFGST scores were 39.7 (39.1-40.2), 38.7 (37.9-39.6), and 38.1 (36.6-39.7) for <1 hour, 1 to <2 hours, and ≥2 hours of social jetlag, respectively ( P-trend  = 0.02). Workers with late chronotypes had significantly lower adherence scores on JFGST [36.3 (34.7-37.8); P-trend  = 0.002]. Results suggest that a late chronotype and social jetlag are inversely associated with adherence to a healthy diet among Japanese workers.

Background & Aims: Limited evidence exists regarding the prospective associations between amino acids and insulin resistance. In addition, amino acids have been suggested to promote insulin resistance with the requirement of obesity in animal studies, but the interaction between amino acids and obesity on the development of insulin resistance has not been examined in epidemiological studies. We aimed to investigate the differences in the prospective associations of serum amino acids with insulin resistance among adults with and without overweight or obesity., Methods: Fasting serum concentrations of 25 amino acids were quantified in 1131 non-diabetic Japanese workers aged 22-71 years at baseline. The homeostasis model assessment of insulin resistance (HOMA-IR) was estimated at baseline and the 3-year follow-up. Generalized linear models were used to assess the associations between amino acids at baseline and HOMA-IR at follow-up with adjustment for potential confounding factors. A Bonferroni-corrected threshold of p = 0.001 was considered significant for multiple tests., Results: The associations for the following amino acids with HOMA-IR at the 3-year follow-up significantly varied by obesity status: isoleucine, valine, tyrosine, alanine, and methionine (all p for interaction <0.05). Higher concentrations of serum isoleucine, valine, tyrosine, and alanine (per 1SD) were significantly associated with higher HOMA-IR levels in overweight/obese participants (multivariable-adjusted β coefficients ranging from 0.09 to 0.12; all p < 0.001), but no association was observed in the underweight/normal-weight participants. The associations for serum methionine were direct among overweight/obese participants, but inverse among underweight/normal-weight participants (all p < 0.001)., Conclusions: This study demonstrated the prospective associations of different individual serum amino acids with insulin resistance, with most pronounced associations being for overweight/obese adults. Our findings support the possibility of heterogeneous effects of individual amino acids, as well as their interplay with obesity in the progression of insulin resistance., Competing Interests: Conflict of interest We have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

High intake of sweet foods such as cakes, cookies, chocolate and ice cream has been reported to be associated with depressive symptoms. However, prospective studies are scarce and no study has been conducted in Asian populations. We prospectively investigated the association between confectionery intake and depressive symptoms in a Japanese working population. Participants were 911 workers (812 men and 99 women; aged 19-68 years) without depressive symptoms at baseline who completed a 3-year follow-up survey. Dietary intake was assessed using a validated self-administered diet history questionnaire. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Multiple logistic regression was used to estimate the OR of depressive symptoms according to tertile of confectionery intake with adjustment for covariates. At the time of the 3-year follow-up survey, 153 (16·8 %) workers were newly identified as having depressive symptoms (CES-D score ≥ 16). Confectionery intake was significantly associated with increased odds of developing depressive symptoms. The multivariable-adjusted OR of depressive symptoms for the highest v . lowest tertile of confectionery intake was 1·72 (95 % CI 1·03, 2·86) after adjustment for covariates including dietary factors such as folate, vitamin B 6 , vitamin B 12 , n -3 PUFA, Mg, Zn and soft drink ( P for trend = 0·012). Our results suggest that confectionery intake is associated with a higher risk of depressive symptoms in a Japanese working population predominantly comprised of men.

Objectives: To investigate the association of diabetes and prediabetes with long-term sickness absence (LTSA) due to mental disorders or specific mental disorders., Methods: A prospective cohort study was conducted using data from the Japan Epidemiology Collaboration on Occupational Health Study. A total of 62,065 workers who received health check-ups in 2011 (nine companies) or 2014 (two companies) and were followed up to March 31, 2020 were included in this study. Diabetes status was defined based on the American Diabetes Association criteria, and diabetes was differentiated into diabetes with/without anti-diabetic treatment for additional analysis. A Cox proportional hazards regression model was used to investigate these associations., Results: During maximum 8-year follow-up period, 1024 participants underwent LTSA due to mental disorders. The adjusted hazard ratio (aHR) and corresponding 95% confidence interval (CI) of LTSA due to all mental disorders were 1.10 (0.88-1.38) and 1.45 (1.07-1.98) for prediabetes and diabetes, respectively. Diabetic individuals with/without treatment were both at a high risk of LTSA due to mental disorders. For specific mental disorders, diabetes was associated with a higher risk of LTSA due to reaction to severe stress and adjustment disorders (aHR = 3.02, 95% CI = 2.01-4.52) while it was marginally associated with LTSA due to depressive episode (aHR = 1.25, 95% CI = 0.98-1.60). Prediabetes was also associated with LTSA due to reaction to severe stress and adjustment disorders (aHR = 1.41, 95% CI = 1.08-1.84)., Conclusions: The present study suggests the importance of screening diabetes status and providing psychological support for decreasing the risk of LTSA due to mental disorders within working populations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The specimen collection and subsequent pathological diagnosis of malignant biliary stricture (MBS) are difficult. This study aimed to determine whether the cell block (CB) method using overnight-stored bile is useful in the diagnosis of MBS. This trial was a single-arm prospective study involving a total of 59 patients with suspected MBS. The primary endpoint was cancer detectability and accuracy using the CB method, and a comparison with the detectability and accuracy achieved with bile cytology was made. The immunohistochemical sensitivity for maspin and p53 was also investigated in the CB and surgical specimens. We were able to collect bile from all 59 patients, and 45 of these patients were clinically diagnosed with MBS. The cancer detectability using the CB method (62.2%) was significantly higher than that using cytology (37.8%) ( p = 0.0344). When CB was combined with biopsy, the rates of cancer detectability (75.6%) and accuracy (81.4%) increased. In eight patients who received surgical therapy, maspin- and p53-immunohistochemistry was applied to the surgical and CB specimens, and cancer cells in both specimens showed positive cytoplasmic and nuclear staining for maspin and nuclear staining for p53. The CB method is, thus, useful for detecting malignancy (UMIN000034707).

Post-traumatic trigeminal neuropathy (PTTN) is a chronic sensory disorder that afflicts patients with nerve injury caused by orofacial and dental surgery or cervicofacial trauma. Currently, effective treatment strategies for PTTN are lacking, and patients treated with conventional drugs for PTTN experience adverse effects such as drowsiness and drug addiction. In the present study, we investigated whether mirogabalin, a novel gabapentinoid, could be an effective treatment for PTTN induced by distal infraorbital nerve chronic constriction injury (dIoN-CCI) in the mouse. Increased facial grooming time and hyper-responsiveness to acetone were observed in dIoN-CCI mice. These pain-related behaviors were attenuated by intraperitoneal injection of mirogabalin. In particular, mirogabalin significantly diminished the increase in facial grooming time. The analgesic effect of mirogabalin injection started 45 min after the injection and persisted for 6 h. Additionally, 10 mg/kg mirogabalin did not affect locomotor activity in the open field test, suggesting that it does not cause sedation. Together, the current findings suggest that mirogabalin could be a valuable therapeutic drug for PTTN following orofacial surgeries without sedative side effects., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The inflammatory response related to surgery is considered surgical inflammation. Most anesthetic agents directly or indirectly suppress the immune response. However, the intravenous anesthetics pentobarbital and ketamine were reported to inhibit the lipopolysaccharide-induced inflammatory response such as cytokines formation. Neurogenic inflammation is inflammation originating from the local release of inflammatory mediators, such as substance P (SP), by primary afferent neurons after noxious stimuli like surgery. Thus, in this study, we examined whether pentobarbital and ketamine suppress SP release from cultured dorsal root ganglion (DRG) neurons. DRG cells were dissected from male Wistar rats. Released SP was measured by radioimmunoassay. We demonstrated that higher concentrations of pentobarbital (100-1,000 μM) significantly inhibited capsaicin (100 nM)-induced, but not high K + (50 mM)-induced, SP release from DRG cells, although a high concentration of ketamine (1 mM) did not. This study revealed that pentobarbital functions between the activation of vanilloid receptor subtype 1 (TRPV1) receptors, to which capsaicin selectively binds, and the opening of voltage-operated Ca 2+ channels (VOCC) in the nerve endings. Therefore, the anti-inflammatory action of pentobarbital is mediated through different mechanisms than those of ketamine. Thus, the inhibitory effect of pentobarbital on SP release from peripheral terminals may protect against neurogenic inflammation after surgery., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This study aimed to investigate the cross-sectional association between serum sodium and blood pressure at baseline and, more importantly, investigate the prospective association between serum sodium and the risk of incident hypertension. We used data from 1 638 workers aged 18 to 71 years who participated in 2015-2016 survey of the Furukawa Nutrition and Health Study. During a maximum follow-up of 3 years, 229 participants developed hypertension. Multivariable linear regression models were used to evaluate the cross-sectional association. The Cox proportional hazards model was used to calculate the hazard ratio and 95% confidence interval of incident hypertension across quartiles of serum sodium (137-140, 141-142, 143, and 144-147 mmol/L). In the cross-sectional analysis, we did not observe a significant association between serum sodium and blood pressure at baseline. In the prospective analysis, the multivariable-adjusted hazard ratios (95% confidence intervals) for incident hypertension were 1.03 (0.71-1.51), 1.35 (0.87-2.08), and 1.46 (0.97-2.20) for the upper three quartiles of the serum sodium levels compared with the lowest quartile (P for trend=0.02). When serum sodium was treated as a continuous variable, the multivariable-adjusted hazard ratio for hypertension was 1.10 (1.03-1.18). The association was slightly attenuated after additionally adjusting for baseline blood pressure, with a hazard ratio of 1.08 (1.00-1.16) for a 1 mmol/L increase in serum sodium. In conclusion, an elevated serum sodium level was associated with an increased risk of developing hypertension, suggesting that serum sodium could be a potential risk factor for hypertension., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Parkinson's disease (PD) patients often complain of pain, but this problem has been neglected and is poorly understood. High mobility group box-1 (HMGB1), an alarmin/damage-associated molecular patterns protein, is increased in the cerebrospinal fluid in PD patients. However, little is known of the relationship between HMGB1 and pain associated with PD. Here, we investigated the role of central HMGB1 in the regulation of nociceptive hypersensitivity in a mouse model of PD. Male ddY mice were microinjected unilaterally with 6-hydroxydopamine (6OHDA) into the striatum. These hemi-PD mice were treated with anti-HMGB1 neutralizing antibody (nAb; 10 µg in 10 µL) by intranasal (i.n.) administration. The mechanical hypersensitivity of the hind paws was evaluated with the von Frey test. Spinal microglial activity was analyzed by immunostaining for ionized calcium-binding adapter molecule 1. The 6OHDA-administered mice displayed unilateral loss of dopamine neurons in the substantia nigra and mechanical hypersensitivity in both hind paws. Moreover, spinal microglia were activated in these hemi-PD mice. Twenty-eight days after the 6OHDA injections, repeated i.n., but not systemic, treatment with anti-HMGB1 nAb inhibited the bilateral mechanical hypersensitivity and spinal microglial activation. However, the anti-HMGB1 nAb did not ameliorate the dopamine neuron loss. Moreover, intracerebroventricular injection with recombinant HMGB1 induced mechanical hypersensitivity. These findings indicate that HMGB1 is involved in the maintenance of nociceptive symptoms in hemi-PD mice via spinal microglial activation. Therefore, central HMGB1 may have potential as a therapeutic target for pain associated with PD., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Although several cross-sectional studies have described an inverse association between green tea consumption and depressive symptoms, only one study has prospectively investigated this association. We investigated the cross-sectional and prospective associations between green tea consumption and depressive symptoms in a working population in Japan. Participants were 1987 workers who participated in the baseline survey for a cross-sectional association, and 916 participants who did not have depressive symptoms at baseline who responded to both the baseline and follow-up surveys for a prospective association. Green tea consumption was evaluated with a validated self-administered diet history questionnaire. Depression symptoms were evaluated with the Center for Epidemiologic Studies Depression (CES-D) scale. Multiple logistic regression was conducted to estimate the odds ratio of depressive symptoms based on green tea consumption. In the cross-sectional analysis, green tea consumption was not associated with the prevalence of depression symptoms. Moreover, consumption at baseline was not associated with depression symptoms after 3 years; the multivariable-adjusted odds ratio of depressive symptoms for ≥2 cups/day of green tea was 1.12 (95% confidence interval 0.65-1.91) compared with <4 cups/week after adjustment for covariates including dietary factors (trend p = 0.67). Our results suggest that there is no association of consumption of green tea with symptoms of depression in Japanese.

As spinal microglia have a critical role in the development of chronic pain, regulation of their activity is essential for pain relief. Previous study has shown that stimulation of the REV-ERB nuclear receptors in the spinal dorsal horn produces antinociception in animal models of both inflammatory and neuropathic pain. However, the involvement of spinal microglia in the antinociceptive action of REV-ERBs remains to be elucidated. In the current study, we found that intrathecal treatment with the REV-ERB agonist SR9009 significantly blocked the increase in ionized calcium-binding adaptor molecule immunoreactivity in the spinal dorsal horn of mice following intrathecal administration of lipopolysaccharide and peripheral sciatic nerve ligation. Furthermore, both Rev-erbα and Rev-erbβ mRNAs were expressed in cultured rat spinal microglia. Treatment of cultured rat spinal microglia with SR9009 significantly blocked the lipopolysaccharide-induced increase in interleukin (IL)-1β and IL-6 mRNA expression. In conclusion, the current findings suggest that REV-ERBs negatively regulate spinal microglial activity and might contribute to the REV-ERB-mediated antinociceptive effect in the spinal dorsal horn., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background & Aim: Dairy products may play a beneficial role against metabolic syndrome; however, epidemiological evidence is scarce in Asian populations, who consume less dairy than Western populations. We prospectively investigated the association between dairy product intake, both overall and by fat content, and metabolic syndrome in a Japanese working population., Methods: Participants were 1014 workers (aged 19-68 years) without metabolic syndrome at baseline who completed a 3-year follow-up survey. Dietary intake was assessed using a validated self-administered diet history questionnaire. Metabolic syndrome was defined according to the Joint Interim Statement (JIS) criteria. Multiple logistic regression was used to estimate the odds ratio of metabolic syndrome according to tertile of total, low-fat, and full-fat dairy product intake with adjustment for covariates., Results: At the 3-year follow-up, 66 (6.5%) workers were newly identified as having metabolic syndrome. A trend towards decreased odds of developing metabolic syndrome was observed among those in the highest tertile of total and full-fat dairy product intake: multivariable-adjusted odds ratio for the highest versus lowest tertile was 0.54 (95% CI 0.26-1.12; P for trend = 0.094) for total dairy products and 0.50 (95% CI 0.24-1.05; P for trend = 0.038) for full-fat dairy products. Low-fat dairy intake was not associated with metabolic syndrome., Conclusions: Our results suggest that higher intake of full-fat, but not low-fat, dairy products may be associated with a lower risk of metabolic syndrome among Japanese., Competing Interests: Declaration of competing interest None., (Copyright © 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

A novel method for catalytic remote bismetalation of alkene substrates by the addition of dimetal reagents is accomplished by using chain walking. In the presence of a palladium catalyst, the reaction of various 1, n -dienes and diborons were converted into cyclopentane derivatives with two boryl groups at remote positions via facile regioselective transformation of an unactivated sp 3 C-H bond to a C-B bond. Sequential construction of three distant bonds, which is difficult to achieve by any method, was accomplished for the reactions of 1, n -dienes ( n ≥ 7).

Palladium-catalyzed remote arylative substitution was achieved for the reaction of arylboronic acids with alkenes possessing a distant acetoxy group to provide arylation products having an alkene moiety at the remote position. The use of β-acetoxy elimination as a key step in the catalytic cycle allowed for regioselective formation of unstabilized alkenes after chain walking. This reaction was applicable to various arylboronic acids as well as alkene substrates., (© 2021 Wiley-VCH GmbH.)