Novel analysis of functional relationship linking moyamoya disease to moyamoya syndrome.

Objective: The aim of this study was to elucidate the genetic pathways associated with Moyamoya disease (MMD) and Moyamoya syndrome (MMS), compare the functional activities, and validate relevant related genes in an independent dataset. Methods: We conducted a comprehensive search for genetic studies on MMD and MMS across multiple databases and identified related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments analyses were performed for these genes. Commonly shared genes were selected for further validation in the independent dataset, GSE189993. The Sangerbox platform was used to perform statistical analysis and visualize the results. P＜0.05 indicated a statistically significant result. Results: We included 52 MMD and 51 MMS-related publications and identified 126 and 51 relevant genes, respectively. GO analysis for MMD showed significant enrichment in cytokine activity, cell membrane receptors, enzyme binding, and immune activity. A broader range of terms was enriched for MMS. KEGG pathway analysis for MMD highlighted immune and cellular activities and pathways related to MMS prominently featured inflammation and metabolic disorders. Notably, nine overlapping genes were identified and validated. The expressions of RNF213, PTPN11, and MTHFR demonstrated significant differences in GSE189993. A combined receiver operating characteristic curve showed high diagnostic accuracy (AUC = 0.918). Conclusions: The findings indicate a close relationship of MMD with immune activity and MMS with inflammation, metabolic processes and other environmental factors in a given genetic background. Differentiating between MMD and MMS can enhance the understanding of their pathophysiology and inform the strategies for their diagnoses and treatment.

Genetic Analysis of SCN11A, SCN10A, and SCN9A in Familial Episodic Pain Syndrome (FEPS) in Japan and Proposal of Clinical Diagnostic Criteria.

Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A, SCN10A, and SCN9A, which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A, SCN10A, and SCN9A. In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A, SCN10A, and SCN9A, respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.

Is Japan at low risk for PFAS immunotoxicity?: human biomonitoring study in contaminated areas in Japan.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are now considered global contaminants posing health risks. Recent human biomonitoring data in Japan are presented. METHODS: Human biomonitoring data from Japan, dating back to 2000, were reviewed. In addition, 399 serum samples collected in a primary care clinic in Urayasu City, Okinawa Island-one of the highest PFAS-exposed areas in Japan-between 2021 and 2022 were analyzed. Serum levels of four PFAS were compared with risk levels based on the assessment by Sonne et al. and the European Food Safety Agency. RESULTS: The PFAS levels in the general population from various areas other than Hokkaido (16.1-43.5 ng/mL) are classified at moderate to severe risk for immunotoxicity based on the assessment. CONCLUSIONS: A portion of the Japanese population has had high exposure to PFAS and was at high risk of immunotoxicity, and this situation remained in PFAS-contaminated areas in the 2020s.

Linear isomer but not branched isomers of perfluorooctane sulfonate in plasma is associated with eicosapentaenoic acid, a seafood consumption biomarker.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are global contaminants. Seafood consumption is a possible PFAS exposure route to humans while the isomer specific analysis has not been conducted. METHODS: Perfluorooctane sulfonate (PFOS), perfluoroheptane sulfonate (PFHpS) and perfluorohexane sulfonate (PFHxS) were investigated in residents of Kyoto, Japan (n = 51). The relationship between plasma PFAS and seafood consumption biomarker, the ratio of eicosapentaenoic acid to arachidonic acid (EPA/AA) was examined by multiple regression analysis. RESULTS: Linear PFOS concentrations showed a significant positive correlation with the EPA/AA ratio in plasma samples (ß = 6.80, p = 0.0014). Linear PFHpS was marginally associated with EPA/AA ratio (ß = 0.178, p = 0.0874). Branched PFOS isomers and PFHxS had no associations with EPA/AA ratios. CONCLUSION: Seafood intake may be a significant exposure pathway for PFAS, such as PFOS but the isomers differ.

Levels and spatial profile of per- and polyfluoroalkyl substances in edible shrimp products from Japan and neighboring countries; a potential source of dietary exposure to humans.

Exposure to per- and polyfluoroalkyl substances (PFAS) is of great concern for human health because of their persistence and potentially adverse effects. Dietary intake, particularly through aquatic products, is a significant route of human exposure to PFAS. We analyzed perfluoroalkyl sulfonic acid (PFSA with carbon numbers from 6 to 8 and 10 (C６-C8, C10)) and perfluorooctanesulfonamide (FOSA), and perfluoroalkyl carboxylic acid (PFCA with carbon numbers from 6 to 15 (C6-C15)) in 30 retail packs of edible shrimps, which included seven species from eight coastal areas of Japan and neighboring countries. The most prevalent compounds were perfluorooctane sulfonate (PFOS, C8) and perfluoroundecanoic acid (PFUnDA, C11), accounting for 46 % of total PFAS. The concentrations ranged from 6.5 to 44 ng/g dry weight (dw) (equivalent to 1.5 to 10 ng/g wet weight (ww)) and varied according to species and location. For example, Alaskan pink shrimp (Pandalus eous) from the Hokuriku coast, Japan contained high levels of long-chain PFCAs (38 ng/g dw (equivalent to 8.7 ng/g ww)), while red rice prawn (Metapenaeopsis barbata) from Yamaguchi, Japan contained a high concentration of PFOS (29 ng/g dw (equivalent to 6.7 ng/g ww)). We also observed regional differences in the PFAS levels with higher concentrations of long-chain PFCAs in Japanese coastal waters than in the South China Sea. The PFAS profiles in shrimp were consistent with those in the diet and serum of Japanese consumers, suggesting that consumption of seafood such as shrimp may be an important source of exposure. The estimated daily intake of sum of all PFAS from shrimp from Japanese coastal water was 0.43 ng/kg body weight/day in average, which could reach the weekly tolerable values (4.4 ng/kg body weight /week) for the sum of the four PFSA set by the EFSA for heavy consumers. The high concentration of PFAS in shrimp warrants further investigation.

Temporal trends in exposure to parabens, benzophenones, triclosan, and triclocarban in adult females in Kyoto, Japan, from 1993 to 2016.

Products used in daily life can contain chemicals such as parabens, benzophenones, triclosan, and triclocarban that have potential endocrine-disrupting effects. Little is known about the temporal trends of exposure levels to some of these chemicals in Japan. Our study assessed the intake and risk associated with exposure to commonly used chemicals. We measured the concentrations of five parabens, four benzophenones, and triclosan and triclocarban in 133 single spot urine samples. The urine samples were collected in 1993, 2000, 2003, 2009, 2011, and 2016 from healthy female residents in Kyoto, Japan. With the exception of methylparaben, ethylparaben, and butylparaben, there were no significant fluctuations in the concentrations of target chemicals over the study period; however, methylparaben, ethylparaben, and butylparaben showed temporal changes in concentrations. Methylparaben concentrations peaked in 2003 with a median value of 309 µg/g creatinine, ethylparaben concentrations peaked in 1993 with a median value of 17.3 µg/g creatinine, and butylparaben showed a decline, with the median values becoming non-detectable in 2009 and 2016. We calculated estimated daily intakes and hazard quotients for each chemical. In the analysis of total samples, 2.3% (3 samples) for butylparaben and 0.8% (1 sample) for propylparaben were found to surpass a hazard quotient of 1. Overall, 3% (n = 4) of the study participants exceeded a hazard index of 1. The potential health risks associated with exposure to butylparaben and propylparaben emphasize the need for further monitoring and research.

Comparison of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA) and perfluorobutane sulfonate (PFBS) removal in a combined adsorption and electrochemical oxidation process.

This study focused on three of the most studied PFAS molecules, namely perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA) and perfluorobutane sulfonate (PFBS). They were compared in terms of their adsorption capacity onto graphite intercalated compound (GIC), a low surface area, highly conductive and cheap adsorbent. The adsorption on GIC followed a pseudo second order kinetics and the maximum adsorption capacity using Langmuir was 53.9 µg/g for PFOS, 22.3 µg/g for PFOA and 0.985 µg/g for PFBS due to electrostatic attraction and hydrophobic interactions. GIC was added into an electrochemical oxidation reactor and >100 µg/L PFOS was found to be fully degraded (<10 ng/L) leaving degradation by-products such as PFHpS, PFHxS, PFPeS, PFBS, PFOA, PFHxA and PFBA below 100 ng/L after 5 cycles of adsorption onto GIC for 20 min followed by regeneration at 28 mA/cm2 for 10 min. PFBS was completely removed due to degradation by aqueous electrons on GIC flakes. Up to 98 % PFOA was removed by the process after 3 cycles of adsorption onto GIC for 20 min followed by regeneration at 25 mA/cm2 for 10 min. When PFBS was spiked individually, only 17 % was removed due to poor adsorption on GIC. There was a drop of 3-40 % by treating PFOS, PFOA and smaller sulfonates in a real water matrix under the same electrochemical conditions (20 mA/cm2), but PFOS and PFOA removal percentage were 95 and 68 % after 20 min at 20 mA/cm2.

Role of ABCB1 and ABCB4 in renal and biliary excretion of perfluorooctanoic acid in mice.

BACKGROUND: Perfluorooctanoic acid (PFOA) is one of the major per- and polyfluoroalkyl substances. The role of ATP-binding cassette (ABC) transporters in PFOA toxicokinetics is unknown. METHODS: In this study, two ABC transporters, ABCB1 and ABCB4, were examined in mice with single intravenous PFOA administration (3.13 µmol/kg). To identify candidate renal PFOA transporters, we used a microarray approach to evaluate changes in gene expression of various kidney transporters in Abcb4 null mice. RESULTS: Biliary PFOA concentrations were lower in Abcb4 null mice (mean ± standard deviation: 0.25 ± 0.12 µg/mL) than in wild-type mice (0.87 ± 0.02 µg/mL). Immunohistochemically, ABCB4 expression was confirmed at the apical region of hepatocytes. However, renal clearance of PFOA was higher in Abcb4 null mice than in wild-type mice. Among 642 solute carrier and ABC transporters, 5 transporters showed significant differences in expression between wild-type and Abcb4 null mice. These candidates included two major xenobiotic transporters, multidrug resistance 1 (Abcb1) and organic anion transporter 3 (Slc22a8). Abcb1 mRNA levels were higher in Abcb4 null mice than in wild-type mice in kidney. In Abcb4 null mice, Abcb1b expression was enhanced in proximal tubules immunohistochemically, while that of Slc22a8 was not. Finally, in Abcb1a/b null mice, there was a significant decrease in the renal clearance of PFOA (0.69 ± 0.21 vs 1.1 mL ± 0.37/72 h in wild-type mice). A homology search of ABCB1 showed that several amino acids are mutated in humans compared with those in rodents and monkeys. CONCLUSIONS: These findings suggest that, in the mouse, Abcb4 and Abcb1 are excretory transporters of PFOA into bile and urine, respectively.

History of Changes in the Protocol of Clinical Trial of Zinc Supplementation in Treatment of COVID-19 by Hydroxychloroquine.

An article published in this journal used a randomized controlled trial to evaluate the efficacy of combining chloroquine/hydroxychloroquine (CQ/HCQ) and zinc in the treatment of COVID-19 patients. Findings from this study indicate that zinc supplements did not enhance the clinical efficacy of hydroxychloroquine in improving COVID-19 treatment. Although this finding is consistent with many previous studies, several concerns regarding study protocol and trial registration, including interventions and primary outcomes, have been raised in which the protocol has been changed after the completion of the recruitment.

Association between lignan polyphenol bioavailability and enterotypes of isoflavone metabolism: A cross-sectional analysis.

Lignan polyphenols derived from plants are metabolized by bacteria in the gut to mammalian lignans, such as enterolactone (ENL) and enterodiol (END). Mammalian lignan intake has been reported to be associated with obesity and low blood glucose levels. However, the factors that are responsible for individual differences in the metabolic capacity for ENL and END are not well understood. In the present study, the effects of enterotypes of isoflavone metabolism, equol producers (EQP) and O-desmethylangolensin producers (O-DMAP), on lignan metabolism were examined. EQP was defined by urinary daidzein (DAI) and equol concentrations as log(equol/DAI) ≥ -1.42. O-DMAP was defined by urinary DAI and O-DMA concentrations as O-DMA/DAI > 0.018. Isoflavone and lignan concentrations in urine samples from 440 Japanese women were measured by gas chromatography-mass spectrometry. Metabolic enterotypes were determined from the urinary equol and O-DMA concentrations. Urinary END and ENL concentrations were compared in four groups, combinations of EQP (+/-) and O-DMAP (+/-). The urinary lignan concentration was significantly higher in the O-DMAP/EQP group (ENL: P<0.001, END: P<0.001), and this association remained significant after adjusting for several background variables (END: ß = 0.138, P = 0.00607 for EQP and ß = 0.147, P = 0.00328 for O-DMAP; ENL: ß = 0.312, P<0.001 for EQP and ß = 0.210, P<0.001 for O-DMAP). The ENL/END ratio was also highest in the O-DMAP/EQP group, indicating that equol and O-DMA metabolizing gut bacteria may be involved in lignan metabolism. In conclusion, urinary lignan concentrations were significantly higher in groups containing either EQP or O-DMAP than in the non-EQP/non-O-DMAP group. The variables and participants in this study were limited, which the possibility of confounding by other variables cannot be ruled out. However, there are no established determinants of lignan metabolism to date. Further research is needed to determine what factors should be considered, and to examine in different settings to confirm the external validity.

Association between urinary zinc excretion and isoflavone-metabolizing enterotypes among Japanese females: a cross-sectional study.

BACKGROUND: Zinc absorption and competition among gut bacteria have been reported in animal studies. Thus, gut bacteria may modify zinc availability in humans. Metabolism of intestinal bacteria is known to be necessary for the activation of several phytoconstituents in the body. For example, equol, a typical substance of soybean isoflavone, is produced by intestinal bacteria metabolizing daidzein and the enterotype is one of distinct ones among Japanese population. The difference in the intestinal microflora can modify the bioavailability of zinc. In this study, we examined urinary zinc concentrations in adult female equol producers (EQPs). METHODS: Urine samples from women participating in health examinations in Miyagi, Okinawa, Kyoto, Kochi, and Hokkaido prefectures were used; from total 17,484 samples, approximately 25 samples were randomly selected for each age group from 30 to 60 years per region (subsample: n = 520), and 520 samples with available urinary zinc concentration (determined by flame atomic absorption analysis) and enterobacterial type were analyzed. EQP was defined as log(equol/daidzein) ≥ -1.42, and urinary concentrations were corrected for creatinine concentration. Urinary zinc concentrations were compared by Student's t-test and multiple regression analyses. RESULTS: The geometric mean urinary zinc concentration (µg/g-Cr) was lower in EQP than in non-EQP (p = 0.0136 by t-test after logarithm transformation). On the other hand, there was no correlation between urinary zinc concentration with daidzein (r = -0.0495, P = 0.436) and equol concentrations (r = -0.0721, P = 0.256). There was a significant negative association between urinary zinc concentration and EQP (ß = -0.392, P = 0.0311) after adjusting with other potential confounding variables, such as daidzein intake. CONCLUSIONS: The results suggest that gut bacteria that produce equol are involved in the metabolism of zinc. Based on previous studies, the bacteria that affect the metabolism of both substances are thought to be Enterococcus. Future studies are expected to identify specific intestinal bacteria for zinc availability and understand individual differences in the effects of micronutrients.