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Since February, 2023, the omicron variant has accounted for essentially all new coronavirus infections in Japan. If future infections involve mutant strains with the same level of infectivity and virulence as omicron, the government's basic policy will be to prevent the spread of infection, without compromising socioeconomic activities. Objectives include protecting pregnant women and elderly persons, and focusing on citizens requiring hospitalization and those at risk of serious illness, without imposing new social restrictions. Although the government tries to raise public awareness through education, most people affected by COVID-19 stay at home, and by the time patients become aware of the seriousness of their disease, it has often reached moderate or higher severity. In this review, we discuss why this situation persists even though the disease seems to have become milder with the shift from the delta variant to omicron. We also propose a pathophysiological method to determine the risk of severe illness. This assessment can be made at home in the early stages of COVID-19 infection, using urine analysis. Applicability of this method to drug discovery and development is also discussed. [ABSTRACT FROM AUTHOR]

In Japan, nationwide epidemiological surveys on carbapenem-resistant Enterobacterales (CREs), including comprehensive information, are scarce, with most data available only through public reports. This study analyzed data on the Enterobacterales family collected from nationwide testing centers between January 2016 and December 2022, focusing on isolates that met the criteria for CRE in Japan based on drug susceptibility. We investigated 5,323,875 Enterobacterales isolates of 12 different species; among 4696 (0.09%) CRE strains, the proportion of major CRE isolates was as follows: Escherichia coli, 31.3%; Klebsiella pneumoniae, 28.0%; Enterobacter cloacae, 18.5%; and Klebsiella aerogenes, 6.7%. Moreover, over a 7-year period, Providencia rettgeri, E. cloacae, K. aerogenes, and K. pneumoniae demonstrated relatively high CRE percentages of 0.6% (156/26,185), 0.47% (869/184,221), 0.28% (313/110,371), and 0.17% (1314/780,958), respectively. The number of CRE strains isolated from different samples was as follows: urine, 2390; respiratory specimens, 1254; stool, 425; blood, 252; others, 375. In the broader context, including colonization, the predominant isolates of CREs collected at nationwide testing centers are E. coli and K. pneumoniae. Furthermore, recently, attention has been directed toward less common CRE species, such as Klebsiella oxytoca and Providencia rettgeri, and thus, it might be necessary to continue monitoring these less common species. [ABSTRACT FROM AUTHOR]

Background: This non‐randomized intervention study aimed to evaluate the effect of supplementing infant formula with biotin on biotin metabolism and on development. Methods: We enrolled healthy Japanese infants (n = 84) and assigned them to groups offered Formula A (total biotin, 0.5 μg/100 kcal) or Formula B (total biotin, 2.4 μg/100 kcal) until they were 6 months of age, and completed an additional follow up to age 36 months. Urinary biotin concentrations were measured at 1 and 6 months, and were compared among breast‐fed, Formula A‐fed, and Formula B‐fed infants at each age. In a follow‐up subgroup analysis, we compared scores on the Ages and Stages Questionnaire, version 3 (ASQ‐3), from 9 to 36 months among infants continuously fed Formula A, Formula B, or breastmilk. Results: No adverse events occurred during the intervention period. At 1 month, urinary biotin concentrations were highest in Formula B‐fed infants and lowest in Formula A‐fed infants. At 6 months, Formula B‐fed infants retained higher biotin levels than Formula A‐fed and breast‐fed infants. Both differences were statistically significant (P < 0.05). The breast‐fed, Formula A‐fed, and Formula B‐fed groups had similar ASQ scores at 9–36 months. Conclusions: Biotin supplementation of infant formula contributed to improving biotin status in formula‐fed infants. The results support the official approval of the use of biotin in infant formula by the government of Japan in 2014. [ABSTRACT FROM AUTHOR]

Incidents of food poisoning associated with tetrodotoxin (TTX) contamination occur every year throughout Japan. Here, we determined TTX levels in leftover foods and serum and urine samples from eight food poisoning incidents associated with TTX contamination in Nagasaki, Japan, from 2011 to 2017. Seven food samples associated with four of these food poisoning incidents were classified as weakly toxic 'four samples', moderate-to-strongly toxic 'two samples', and strongly toxic 'one sample'. In comparison with previous reports, TTX was detected at harmful levels in the urine samples, but the grade of poisoning symptoms varied. The patients' time to maximum serum TTX levels 'Tmax' was estimated to be 12-24 h after ingestion of TTX-containing foods. Additionally, serum TTX levels of 19.5 ng/mL or higher within 24 h after ingestion indicated Grade 3 poisoning associated with respiratory abnormalities. These conditions were considered indicators of severe symptoms, while TTX levels of 1-3 ng/ mL relate to the onset and disappearance of symptoms. A negative correlation was found between the logarithm of serum TTX concentration and the time after ingestion for two patients, indicating that the TTX serum levels decreased logarithmically. Furthermore, the TTX serum half-lives 'T1/2' were 17.5 and 23.7 h. The results of this study enhance our understanding of TTX food safety and contribute to TTX risk assessment. [ABSTRACT FROM AUTHOR]

Regular cancer screening is critical for early cancer detection. Cancer screening tends to be burdensome, invasive, and expensive, especially for a comprehensive multi-organ check. Improving the rate and effectiveness of routine cancer screenings remain a challenge in health care. Multi-cancer early detection (MCED) is an exciting concept and a potentially effective solution for addressing current issues with routine cancer screening. In recent years, several technologies have matured for MCED, such as identifying cell-free tumor DNA in blood or using organisms such as Caenorhabditis elegans as a tool for early cancer detection. In Japan, N-NOSE is a commercially available multi-cancer detection test based on the chemotaxis of C. elegans using a urine sample showing 87.5% sensitivity and 90.2% specificity. In this review, we focus on using C. elegans as a powerful biosensor for universal cancer screening. We review N-NOSE clinical research results, spotlighting it as an effective primary cancer screening test. [ABSTRACT FROM AUTHOR]

Recently, Escherichia albertii has been identified as a causative agent of diarrhea in humans and is often misidentified as diarrheagenic Escherichia coli (DEC), a lactose-nondegrading bacterium. In this study, we performed biochemical characterization, gene possession status, drug susceptibility testing, and sequencing analysis of the strains detected in urine samples. One urea-degrading strain was detected in terms of biochemical characteristics, but was found to be nonurea-degrading by another method, leading to conflicting results. All target strains possessed the E. albertii-specific gene, the DEC common gene eae, and the E. coli 16S rRNA gene. In the drug susceptibility test, all urine-derived strains were sensitive to tetracycline (TC), whereas the JCM 17328 strain was resistant to TC, suggesting that TC is effective against urine-derived E. albertii strains. In 16S rRNA sequencing analysis, the E. albertii strains were ranked at the top of homology, but not in the top one, making it difficult to differentiate them from other strains. In summary, if a suspected lactose-nondegrading E. coli strain was isolated from a urine sample, it could be differentiated from E. albertii by the presence of E. albertii-specific genes. [ABSTRACT FROM AUTHOR]

In the end of March 2018, an unprecedented food poisoning incident due to ingestion of the visceral balls of geoduck Panopea japonica occurred in Japan. The patient, presented with symptoms of numbness on the lips and general weakness, was diagnosed as paralytic shellfish poisoning (PSP). The patient immediately treated with the mechanical ventilation recovered and left the hospital after 3 days treatment. Saxitoxins (STXs) in the plasma and urinary samples collected from the patient on the first and second day after hospitalization were analyzed by ultra high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC/MS/MS) and liquid chromatography with post-column fluorescent detection (LC/FLD). The STXs levels of 499.1 and 6.0 μg/L of STX dihydrochloride equivalent (STX·2HCl eq.) were quantitated by LC/FLD in the urinary samples on the first and second day, respectively. In addition, geoducks harvested from the same areas of the PSP causative specimens after the incident were analyzed by LC/FLD, and the results showed the level of STXs in their whole bodies of the geoducks exceeding 0.8 mg STX·2HCl eq./kg which is the maximum levels of STX in CODEX STAN 292–2008. Prominent toxins in STXs that detected in urinary and geoduck samples and identified by UHPLC/MS/MS and LC/FLD were gonyautoxin-1+4 (GTX1+4). These results concluded that the incident was the food poisoning due to STXs accumulated in the geoducks. This is the first PSP case caused by consumption of geoducks in Japan. This is also the first PSP case that causative toxins are detected in urinary samples of patients involved in PSP in Japan. [Display omitted] • A food poisoning incident caused by ingestion of geoducks Panopea japonica occurred in Japan. • We identified GTX1+4 as the main causative toxins by chemical analyses of patient's urine in this poisoning. • Visceral balls from geoducks accumulated a fatal level of STXs. • This is the first human PSP case caused by consumption of geoducks in Japan. [ABSTRACT FROM AUTHOR]

Since April 2021, the plasma aldosterone concentration has been measured by chemiluminescent enzyme immunoassay (CLEIA) in Japan. In the present study, we developed a new CLEIA using a two-step sandwich method to measure the 24-hour urine aldosterone level. We collected 115 urine samples and measured 24-hour urine aldosterone levels employing radioimmunoassay (RIA), CLEIA, and liquid chromatography–tandem mass spectrometry (LC-MS/MS). The results showed that the 24-hour urine aldosterone levels measured using CLEIA and LC-MS/MS were significantly correlated (ρ = 0.992, P < 0.0001). Based on the results of Passing–Bablok regression analysis, the slope was 0.992 and the intercept –19.3. The 24-hour urine aldosterone levels measured using CLEIA and RIA were also significantly correlated (ρ = 0.905, P < 0.0001). However, the aldosterone level measured by CLEIA was lower than that measured by RIA (slope, 0.729; intercept, 120.9). In Japan, a new guideline for primary aldosteronism has been announced, with changes in the aldosterone measurement method. The cutoff values for oral sodium loading test (OSLT) were changed, but clinical verification using real-world urine samples has not been performed. Therefore, we examined the cut-off value of the 24-hour urine aldosterone level after the OSLT. Receiver operating characteristic analysis revealed a cut-off value for primary aldosteronism of 3 μg/day. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the ability of bacterial scatter diagrams generated from the automated urine particle analyzer (UF-1000i, Sysmex, Kobe, Japan) to pre-estimate the treatment efficacy of oral cefalexin in treating women with uncomplicated urinary tract infection (uUTI).Materials and Methods: Over 3 years, women 20-80 years old with symptoms suggestive of uUTI (Urinary Tract Infection Symptoms Assessment symptom score, ,UTISA > 3) and bacteriuria (bacterial count ≥ 100/uL) were enrolled. After informed consent, patients took cephalexin 500mg 4 times/day for 7 days. The voided urine specimens were classified into rods or cocci/mixed group automatically through the built-in software of the UF1000i. Patients were followed up with UTISA on the 3rd day after treatment and returned to the clinic on the 7th day and followed for additional UTISA and urine analysis. Symptom and laboratory improvement were defined as UTISA < 4 and bacterial count < 100/uL, respectively, on the 7th day.Results: Of 99 women (age: 49.91 ±15.32 years) eligible for analysis, 80 were classified as having urine that contained rods and 19 as cocci/mixed. Symptom improvement was observed in 62 women in the rods group and 11 women in the cocci/mixed group (p = 0.08). Laboratory improvement was noted in 64 women in the rods group and 10 women in the cocci/mixed group (p = 0.01). On day 7, treatment success with both symptom and laboratory improvement was more observed in rods than in cocci/mixed group (61.3% vs. 26.3%, p < 0.01).Conclusion: The automatic urine particle analyzer can pre-estimate the treatment response of antibiotics in women with uUTI. [ABSTRACT FROM AUTHOR]

Exposure to low doses of neonicotinoid (NEO) insecticides during pregnancy may have a negative impact on the neurodevelopment of children. Biomarkers are frequently used to investigate the exposure and its health effects in environmental epidemiology. In the present study, we aimed to evaluate the utility of urinary biomarkers of NEO exposure by calculating intra-class correlation coefficients (ICCs). Urine samples were collected from 30 pregnant women who were non-smokers and living in a central part of Japan, between 12 and 22 weeks of gestation. We collected first morning voided (FMV) urine and afternoon spot (PM) urine samples on the same day on five occasions within a 2-week period. The urinary concentrations of NEO and their metabolites (NEO/m) were measured by liquid chromatography–tandem mass spectrometry. Normalisation to the specific gravity and creatinine concentration was used in the calculation of ICC. The number of urine samples required to obtain a reliable biomarker estimate of NEO exposure was calculated. The most frequently detected NEO/m was N -desmethyl-acetamiprid (N-dm-ACE), followed by clothianidin (CLO), thiamethoxam (THX) and dinotefuran (DIN), in both FMV and PM urine samples. The ICC calculations showed poor reproducibility for the measurement of CLO and THX concentrations (ICCs ≤0.25) in both FMV and PM urine samples and for DIN (ICC ≤0.29) in the FMV urine samples, and moderate reproducibility was identified for N-dm-ACE (ICC >0.60) in both FMV and PM urine samples and for DIN (ICC >0.40) in the PM urine samples. A minimum of 1–19 spot urine samples per individual was required to provide a reliable biomarker estimate over a 2 week period. These results suggest that pregnant Japanese women are frequently exposed to NEOs, and that, with the exception of urinary N-dm-ACE, a single measurement of urinary NEO concentrations may not be an appropriate method of characterising overall exposure. • Reproducibility of urinary neonicotinoid biomarkers in Japanese pregnant women was determined. • N-dm-ACE, CLO, THX and DIN were detected in >60% of samples. • Intra-class correlation coefficients ranged from 0.12 to 0.69. [ABSTRACT FROM AUTHOR]

The article presents the case study on Urine Titin N-Fragment as a Biomarker of Muscle Injury for Critical Illness Myopathy, a part of ICU-acquired weakness, held at Hitachi General Hospital in Japan. Titin extends from Z-disc to M-line and serves as a molecular spring and generating passive stiffness. It also highlights the methods which includes Population and setting, Data collection and evaluation and statistical analysis.

Background: Urinary tract infection (UTI) in children is a common illness. The gold standard for UTI diagnosis is urine culture, but it takes a long time and often gives negative results. Currently developed a method of flow cytometry for checking urine sediments. This tool is able to detect leukocytes urine and urine bacteria in quick time. The purpose of this study is to analyze the relationship of urine leukocyte count and the number of urine bacteria using flow cytometry with urine culture in patients with UTI Method: Eighty-four patients were enrolled in this study that consisting of 43 patients with suspected UTI and 43 patients with non-ISK treated at Inpatient Installation, Emergency Installation Department of Health Sciences at Dr.Soetomo General Hospital, Surabaya for 4 months. The examination of urine leukocytes and urine bacteria was using current cytometry method (UF-500i, Sysmex, Japan). While, examination of urine culture using blood agar plate and Mac. Conkey. Results: There was a significant relationship between the number of leukocytes and the number of colonies. The relationship between leukocytes and the number of colonies was weak, this was indicated by Spearman correlation coefficient (rho) value of 0.376. There was a significant relationship between bacteria and the number of colonies. p <0.05. The relationship between the number of urine bacteria and the number of colonies was quite strong indicated by rho = 0.729. Conclusion: There was a relationship between urine leukocyte count and the number of urine bacteria using flow cytometry with a urine culture. [ABSTRACT FROM AUTHOR]

There is a growing appreciation of the importance of determining chemical exposure levels in early childhood, as well as in embryonic and foetal life, which are now widely believed to be essential for gaining insight into potential health risks associated with these chemicals. To facilitate the assessment of exposure to neonicotinoid insecticides (NEOs) in non-toilet-trained children, a new method using disposable diapers (nappies) was developed for the simultaneous determination of the NEOs acetamiprid and its metabolite N-desmethylacetamiprid, clothianidin, dinotefuran, imidacloprid, thiacloprid, and thiamethoxam (NEO biomarkers). The urine absorbed in disposable diapers was extracted with acetone (diaper urine) and was cleaned using a solid-phase extraction column, before analysis with LC-MS/MS. The absolute recoveries of NEO biomarkers were 19–50%. Good results were observed for the linearity of the matrix-matched calibration curves (r2 = 0.983–0.996; concentration range LOQ-20 µg L−1) and the precision of intra-day (% relative standard deviation (%RSD): 3.3–12.7%) and inter-day (%RSD: 4.3–19.5%) analyses. The lowest and highest limits of detection of the developed method were 0.07 µg L−1 for acetamiprid and 0.75 µg L−1 for clothianidin. The developed method was applied for the evaluation of fifty diapered three-year-old children in Japan. Importantly, the study revealed relatively high detection rates for dinotefuran and N-desmethylacetamiprid; 84% and 78% respectively. The highest geometric mean of dinotefuran urinary concentration was 2.01 µg L−1. Thus, a method for determining NEO biomarkers in urine extracted from disposable diapers was established. This is the first report on the simultaneous quantitative analysis of NEO biomarkers of diaper-absorbed urine samples. [ABSTRACT FROM AUTHOR]

• The association between NEO exposures and neurodevelopment was examined. • A total of 8538 mother–child pairs were included in statistical analyses. • No participating women had the estimated daily intake of NEO exceeding the ADI. • Maternal urinary NEO concentrations during pregnancy were not related with child development. Recent studies have reported the effect of neonicotinoid (NEO) exposures on development in human. However, information about the risk of childhood development delays due to NEO exposures is limited. The study aimed to examine the association between NEO exposure and child development up to 4 years of age using data of the Japan Environment and Children's Study. The study employed urinary NEO and metabolite concentrations in the first and second or third trimesters; the Japanese translation of the Ages and Stages Questionnaire (third edition; J-ASQ-3) scores on developmental delay in five domains, namely communication, gross motor skills, fine motor skills, problem solving, and personal-social characteristics from 6 months to 4 years of age; and self-reported questionnaire data. The associations between urinary NEO concentrations and J-ASQ-3 results were analysed using the treed distributed lag mixture model. A total of 8538 participants were included in statistical analyses. The determination rates of urinary acetamiprid- N -desmethyl (dm-ACE), clothianidin (CLO), dinotefuran (DIN) and thiamethoxam (THX) were greater than 50%. Median urinary dm-ACE, CLO, DIN and THX concentrations were 0.34, 0.14, 0.22 and 0.05 ng/ml, respectively, in samples collected during gestational weeks < 23, and 0.28, 0.12, 0.18 and 0.04 ng/ml, respectively, in those collected during gestational weeks ≥ 23. The binomial scores divided by the cut-off values of the J-ASQ were used in the treed distributed lag mixture model. The highest percentage for a domain with a value less than the cut-off value was 'problem solving' at 6 months of age among all the J-ASQ-3 scores (10.5%). There was no statistically significant association between maternal urinary dm-ACE, CLO, DIN and THX concentrations during pregnancy and the J-ASQ-3 results up to 4 years of age. Objective assessment of child development in different populations may be warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

A rapid analytical method for determining 90Sr in urine samples (1–2 L) was developed to assess the internal exposure of workers in a radiological emergency. Strontium in a urine sample was rapidly separated by phosphate co-precipitation, followed by extraction chromatography, and the 90Sr activity was determined by triple quadrupole inductively coupled plasma mass spectrometry (ICP-MS/MS). Measurement in the MS/MS mode with an O 2 reaction gas flow rate 1 mL min−1 showed no tailing of 88Sr at m/z = 90 up to 50 mg L−1 Sr. The interferences of Ge, Se and Zr at m/z = 90 were successfully removed by phosphate co-precipitation, followed by extraction chromatography with a tandem column of Pre-filter, TRU and Sr resin. This analytical method was validated by the results of the analyses of synthetic urine samples (1.2–1.6 L) containing a known amount of 90Sr along with 1 mg of each of Ge, Se, Sr and Zr. The turnaround time for Sr purification from the urine sample and the 90Sr measurement by ICP-MS/MS was about 10 h. The detection limit of 90Sr was approximately 1 Bq per urine sample, which was lower than 15 Bq per urine after a day of intake giving 5 mSv of unplanned exposure of worker limited by Nuclear Regulation Authority of Japan. • Rapid analytical method was developed for determination of 90Sr in urine samples. • 90Sr concentration was measured by ICP-MS/MS with 1 mL min−1 of O 2 gas flow rate in collision/reaction cell. • Interferences from Ge, Se and Zr were observed in 90Sr determination by ICP-MS/MS. • Strontium was rapidly purified from interfering elements by phosphate co-precipitation and extraction chromatography. • Proposed method was applied to internal dosimetry of workers in a radiological emergency. [ABSTRACT FROM AUTHOR]

Synthetic phenolic antioxidants (SPAs) such as 2,6-di- tert -butyl-4-hydroxytoluene (butylated hydroxytoluene, BHT), are used in a wide variety of consumer products, including certain foodstuffs (e.g. fats and oils) and cosmetics. Although BHT is considered generally safe as a food preservative when used at approved concentrations, there is debate whether BHT exposure is linked to cancer, asthma, and behavioral issues in children. Little is known with regard to human exposure to SPAs and the methods to measure these chemicals in urine. In this study, six SPAs and the metabolites were analyzed in 145 urine samples collected from four Asian countries (China, India, Japan, and Saudi Arabia) and the United States. BHT was found in 88% of the urine samples at median and maximum concentrations of 1.26 and 15 ng/mL, respectively. BHT metabolites and butylated hydroxyanisole (BHA) were found in 39% to 89% of the urine samples at a concentration range of

Background: Diuresis has been observed within a week following renal transplantation, suggesting that the procedure causes acute disturbance of renal water homeostasis. Aquaporin (AQP) 1 and AQP2, important proteins for renal water reabsorption, have been identified in urinary extracellular vesicles (uEV-AQP1 and -AQP2), and experimental studies have shown that the presence of uEV-AQP1 and -AQP2 may be an indicator of their levels of expression in the kidney. However, the release patterns of uEV-AQP1 and -AQP2 during the acute phase following renal transplantation are largely unknown.Methods: In this study, we examined the release of uEV-AQP1 and -AQP2 in recipients until 6 days (day 6) after renal transplantation. At Miyazaki prefectural Miyazaki Hospital, Japan, uEVs were obtained from 7 recipients, all of whom had received renal allografts from living donors. uEVs were isolated by differential centrifugation.Results: Immunoblotting analysis showed that the release of uEV-AQP2 was significantly decreased on day 1 in comparison with a control sample (from 3 healthy volunteers), accompanied by high urine output and low urine osmolality. Thereafter, the level increased gradually to the control level by day 6. The release pattern of uEV-AQP1 was similar to that of uEV-AQP2, but the levels did not reach statistical significance in comparison with the control level at any of the time points examined. Evaluation of the relationship between urinary osmolality and uEV-AQPs revealed a significant correlation for uEV-AQP2, but not for uEV-AQP1.Conclusion: These results indicate that acute diuresis after renal transplantation might be due to a decrease in the renal expression of AQP2, whose level can be estimated from the amount released in uEVs. [ABSTRACT FROM AUTHOR]

Abstract Serum ferritin reflects total body iron stores, thus a low serum ferritin is used as a parameter of iron deficiency. In healthy adults in Japan, urine ferritin levels were about 5% of serum ferritin levels, with a correlation coefficient of 0.79. It is not known whether a low urine ferritin could serve as a non-invasive screen for iron deficiency. If so, this might be useful for neonates and young children, avoiding phlebotomy to screen for iron deficiency. However, for urinary ferritin screening to be feasible, ferritin must be measurable in the urine and correlate with serum ferritin. Testing should also clarify whether the iron content of ferritin in serum and urine are similar. In this pilot feasibility study we measured ferritin in paired serum and urine samples of healthy adult males, healthy term neonates, growing preterm neonates, and children who had very high serum ferritin levels from liver disorders or iron overload. We detected ferritin in every urine sample, and found a correlation with paired serum ferritin (Spearman correlation coefficient 0.78 of log 10 -transformed values). These findings suggest merit in further studying urinary ferritin in select populations, as a potential non-invasive screen to assess iron stores. [ABSTRACT FROM AUTHOR]

It is important to grasp a patient's daily sodium intake in the management of chronic kidney disease, as sodium intake is widely recommended at 6 g/day or less. There are multiple equations widely known for estimating the daily sodium excretion from a spot urine sample, but these are aimed at healthy people. There are few reports that validate equations in patients with chronic kidney disease. The purpose of this study is to evaluate whether the amount of measured daily sodium excretion from a sample collected for 24-h urine (24HU) is equal to that of using an equation from a spot urine sample (SU) in patients with chronic kidney disease. One hundred sixty-two patients with chronic kidney disease from Kanagawa Prefecture Shiomidai Hospital, Japan and the Jikei University Kashiwa Hospital, Japan participated in the study. Daily sodium excretion was measured from 24HU and compared with it from SU by using the formula according to Tanaka et al. Sodium excretion by 24HU was 2744 mg/day and estimating daily sodium excretion from SU was 3315 mg/day. The coefficient of determination was 0.17 (p < .001) in multivariate regression analysis. The coefficient of determination was extremely low. Thus, there is a considerable difference between the amount of sodium excretion calculated from a 24HU and that from a SU in patients with chronic kidney disease. [ABSTRACT FROM AUTHOR]

Objective The present study aimed to investigate human papillomavirus (HPV) prevalence and identify risk factors for HPV detection in urine samples among heterosexual men attending urological clinics. Materials and Methods Spot urine samples including initial stream were collected from 845 participants, and the cell pellets were preserved into liquid-based cytological solution. After DNA extraction from each sample, HPV-DNA amplification and genotyping were performed using Luminex multiplex polymerase chain reaction. Participants completed a questionnaire on their age, education, smoking status, sexuality, age of sexual debut, marital status, and present history of sexually transmitted infections. Results Data from 803 patients were included in the analysis. Overall HPV and high-risk (HR) HPV prevalence in urine samples were 6.2% and 3.1%, respectively. HPV and HR-HPV prevalences were the highest in men with urethritis, and were significantly higher than those without urethritis. HPV detection was the most common in men aged 40–49 years, although significant detection differences were not age-related. Urethritis was an independent risk factor for HPV detection from urine samples, with an odds ratio (OR) of 4.548 (95%CI; 1.802–11.476) (p = 0.001). On the other hand, a sub-analysis excluding men with urethritis demonstrated that prostate cancer was a significant risk factor for HPV detection, with OR of 2.844 (95%CI; 1.046–7.732) (p = 0.0410), whereas was not a significant risk for HR-HPV detection in urine samples. Conclusion Prostate cancer may represent a risk factor for HPV detection in the urine of men without urethritis. Registration of clinical trials The authors did not register to Clinical Trial because this is observational and cross-sectional study. [ABSTRACT FROM AUTHOR]

Background and Aim: Epidemiological studies linking insecticide exposure to childhood neurodevelopment have been gaining global attention. Despite the rapid development of the central nervous system in early childhood, studies regarding the biological monitoring of insecticide exposure in diapered children are limited. In this study, we aimed to clarify the concentrations of organophosphate (OP) insecticide metabolites in toddler urine extracted from disposable diapers in Japan.Methods: We recruited diapered children from the Aichi regional subcohort participants of the Japan Environment and Children's Study (JECS) at the time of their 18-month checkup. A total of 116 children wore designated disposable diapers overnight, which were then sent as refrigerated cargo. The urine was extracted from the diapers using acetone and analyzed by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) to determine the concentrations of six dialkyl phosphates (DAPs) (i.e., dimethyl phosphate [DMP], dimethyl thiophosphate [DMTP], dimethyl dithiophosphate [DMDTP], diethyl phosphate [DEP], diethyl thiophosphate [DETP], and diethyl dithiophosphate [DEDTP]). DAP absorption into the diapers was quantified to calculate the urinary DAP concentrations.Results: The DAP recovery using the developed method yielded between 54.2% (DEDTP) and 101.4% (DEP). Within-run precision expressed as the relative standard deviation was between 2.4% and 14.7%, and the between-run precision was between 3.1% and 8.5%. A Bland-Altman analysis confirmed the agreement between the results obtained by the developed method and by the measurements for the corresponding urine without diaper absorption. The geometric means (GM) of urinary DMP, DMTP, DMDTP, DEP, DETP, and total DAPs (ΣDAP) were 3.6, 3.9, 0.9, 6.0, 0.6μg/L, and 137.6 nmol/L, respectively. The GM of DEDTP was not calculated due to its low detection rate.Conclusions: We successfully established a method to measure the DAP concentrations in urine extracted from diapers and this is the first report of these pesticide concentrations in diapered children in Japan. [ABSTRACT FROM AUTHOR]

Background: Tolvaptan has been approved in Japan for the treatment of hepatic edema. An important consideration in providing a clinical benefit to patients with liver cirrhosis is the improvement of ascites-related clinical symptoms. In the present post hoc analysis, we aimed to identify factors that were predictive of the potency of tolvaptan, and to examine the relationship between changes in initial urine volume and improvement in ascites-related clinical symptoms.Methods: This post hoc analysis was based on three previous phase 2 and 3 clinical trials of tolvaptan in patients with liver cirrhosis. Predictive factors associated with a change in initial urine volume were identified. A change of ≥500 mL from baseline confirmed the pharmacological action of tolvaptan treatment. The relationship between the change in initial urine volume and improvement in ascites-related clinical symptoms was also examined.Results: A total of 152 patients were enrolled in this study. Body weight and BUN were identified as predictive parameters. Among patients with a change in initial urine volume of ≥500 mL, 75 % demonstrated improvement in ascites-related clinical symptoms, while no improvement was seen in those with a change of <500 mL. None of the patients with initial urine volume of <500 mL showed resolution of symptoms.Conclusions: Change in urine volume was affected by both baseline body weight and BUN in tolvaptan-treated subjects. Higher urine output was associated with improvements in ascites-related clinical symptoms. [ABSTRACT FROM AUTHOR]

Background: Non-invasive, prompt, and proper detection tools for kidney graft injuries (KGIs) are awaited to ensure graft longevity. We screened diagnostic biomarkers for KGIs following kidney transplantation using extracellular vesicles (EVs; exosomes and microvesicles) from the urine samples of patients., Methods: One hundred and twenty-seven kidney recipients at 11 Japanese institutions were enrolled in this study; urine samples were obtained prior to protocol/episode biopsies. EVs were isolated from urine samples, and EV RNA markers were assayed using quantitative reverse transcription polymerase chain reaction. Diagnostic performance of EV RNA markers and diagnostic formulas comprising these markers were evaluated by comparison with the corresponding pathological diagnoses., Results: EV CXCL9, CXCL10, and UMOD were elevated in T-cell-mediated rejection samples compared with other KGI samples, while SPNS2 was elevated in chronic antibody-mediated rejection (cABMR) samples. A diagnostic formula developed through Sparse Logistic Regression analysis using EV RNA markers allowed us to accurately (with an area under the receiver operator characteristic curve [AUC] of 0.875) distinguish cABMR from other KGI samples. EV B4GALT1 and SPNS2 were also elevated in cABMR, and a diagnostic formula using these markers was able to distinguish between cABMR and chronic calcineurin toxicity accurately (AUC 0.886). In interstitial fibrosis and tubular atrophy (IFTA) urine samples and those with high Banff chronicity score sums (BChS), POTEM levels may reflect disease severity, and diagnostic formulas using POTEM detected IFTA (AUC 0.830) and high BChS (AUC 0.850)., Conclusions: KGIs could be diagnosed with urinary EV mRNA analysis with relatively high accuracy., (© 2023. The Author(s).)

People who experience natural disasters have a high risk of developing cardiovascular diseases. We investigated the association between the extent of house collapse and urine sodium-to-potassium (UNa/K) ratio of 2011 Great East Japan Earthquake victims. We used the baseline survey data of the Tohoku Medical Megabank Project Community-Based Cohort Study of 29 542 individuals (aged 20-74 years) residing in the affected areas. The UNa/K ratio was calculated using spot urinary electrolyte values. Analysis of covariance was used to calculate the multivariate-adjusted geometric means of the UNa/K ratio in the following groups stratified according to the self-reported extent of house collapse: total collapse (TC), half collapse (HC), partial collapse (PC), and no damage (ND). Multivariable-adjusted odds ratios (ORs) for a high UNa/K ratio were calculated using logistic regression. The TC, HC, PC, and ND groups comprised 5 359 (18.1%), 3 576 (12.1%), 7 331 (24.8%), and 13 276 (44.9%) participants, respectively. The TC (3.33; 95% confidence interval [CI], 3.28-3.38), HC (3.37; 3.30-3.43), and PC (3.32; 3.28-3.37) groups had significantly higher multivariate-adjusted geometric means of the UNa/K ratio than the ND (3.24; 3.21-3.27) group. The multivariable-adjusted ORs (95% CIs) for a high UNa/K ratio in the TC, HC, and PC groups vs. the ND group were 1.07 (0.99-1.15), 1.20 (1.11-1.31), and 1.20 (1.12-1.28), respectively. Similar associations between house collapse and UNa/K ratio were observed for both sexes. We report that victims of a natural disaster tend to have a diet with high sodium-to-potassium ratio., (© 2023. The Author(s).)

Background: Bladder cancer (BCa) is among the most commonly diagnosed malignancies worldwide, and due the high rate of post-operative disease recurrence, it is one of the most prevalent in many countries. The development of non-invasive molecular assays that can accurately detect and monitor BCa would be a major advance, benefiting both patients and healthcare systems. We have previously identified a urinary protein biomarker panel that is being developed for application in at-risk patient cohorts. Here, we investigated the potential utility of the multiplex assay in a Japanese cohort. Methods: The Japanese study cohort collected from urology clinics at two institutions was comprised of a total of 288 subjects. The protein biomarker panel (IL8, MMP9, MMP10, ANG, APOE, SDC1, A1AT, PAI1, CA9, VEGFA) was monitored in voided urine samples collected prior to cystoscopy using a custom multiplex ELISA assay. The diagnostic performance of the biomarker panel was assessed using receiver operator curves, predictive modeling and descriptive statistics. Results: Urinary biomarker concentrations were significantly elevated in cases versus controls, and in cases with high-grade and muscle-invasive tumors. The AUC for the 10-biomarker assay was 0.892 (95 % confidence interval 0.850-0.934), with an overall diagnostic sensitivity specificity of 0.85 and 0.81, respectively. A predictive model trained on the larger institutional cohort correctly identified 99 % of the cases from the second institution. Conclusions: Urinary levels of a 10-biomarker panel enabled discrimination of patients with BCa. The multiplex urinary diagnostic assay has the potential to be developed for the non-invasive detection of BCa in at-risk Japanese patients. [ABSTRACT FROM AUTHOR]

The use of neonicotinoid (NEO) insecticides has increased over the past decade not only in Japan but also worldwide, while organophosphate (OP) and pyrethroid (PYR) insecticides are still conventionally used in agriculture and domestic pest control. However, limited data are currently available on the NEO exposure levels, especially in children, who are particularly vulnerable to environmental toxicants. Thus, the purpose of this study was to characterize the exposure to NEOs, as well as OPs and PYRs, in three-year-old Japanese children by assessing the range, distribution, and seasonal differences of the urinary concentrations of seven NEOs (acetamiprid, clothianidin, dinotefuran, thiacloprid, thiamethoxam, imidacloprid, and nitenpyram); four OP metabolites (dialkylphosphates [DAPs]), including dimethylphosphate, dimethylthiophosphate, diethylphosphate, and diethylthiophosphate; and three PYR metabolites (3-phenoxybenzoic acid, trans -chrysanthemumdicarboxylic acid, and 3-(2,2-dichlorovinyl)-2,2- dimethylcyclopropane carboxylic acid). Urine samples were collected from 223 children (108 males and 115 females) in the summer and winter months. The detection rates of NEOs were 58% for dinotefuran, 25% for thiamethoxam, 21% for nitenpyram, and <16% for all other NEOs. The median and maximum concentrations of the sum of the seven NEOs (ΣNEO) were 4.7 and 370.2 nmol/g creatinine, respectively. Urinary ΣNEO, dimethylphosphate, and all PYR metabolite concentrations were significantly higher in the summer than in the winter (p<0.05). The creatinine-adjusted concentration of ΣNEO significantly correlated with those of all DAPs (p<0.05) but not with those of the PYR metabolites. Moreover, the NEO-detected group showed higher urinary ΣDAP (sum of four OP metabolites) concentrations than the group without NEO detection. These findings suggest that children in Japan are environmentally exposed to the three major insecticide lines, and that the daily exposure sources of NEOs are common to those of OPs. [ABSTRACT FROM AUTHOR]

Background: Although several cross-sectional and intervention studies showed that sodium intake or excretion was associated with blood pressure levels, no prospective study has examined the long-term association between sodium excretion in spot urine and blood pressure changes.Methods: We conducted a prospective study of 889 normotensive subjects (295 men and 594 women, mean age 57.3 years) who underwent the baseline survey including spot urine test in 2005 and the follow-up survey in 2009 to 2011 (mean follow-up period: 5.8 years). We examined the association between sodium concentration in spot urine, a validated index of sodium excretion occurring over 24-h, and blood pressure changes between baseline and follow-up survey in all, non-overweight (body mass index(BMI) ≤ 25 kg/m(2)) and overweight normotensives.Results: For all subjects, sodium concentrations in spot urine were not associated with either systolic or diastolic blood pressure changes. When stratified by BMI at baseline survey, sodium concentrations were positively associated with systolic blood pressure changes in non-overweight subjects, but not in overweight subjects. After adjustment for age, sex, BMI, alcohol intake status, current smoking and estimated glomerular filtration rate, the multivariable-adjusted mean values of the systolic blood pressure change among non-overweight subjects was +7.3 mmHg in the highest quartiles of sodium concentrations, while it was +3.9 mmHg in the lowest quartile (P for difference = 0.021, P for trend = 0.040). After further adjustment of baseline blood pressure levels, the association was slightly weakened; the multivariable-adjusted mean values of the systolic blood pressure changes were +7.0 mmHg and +4.2 mmHg (P for difference = 0.047, P for trend = 0.071).Conclusions: High sodium concentrations in spot urine were associated with subsequent systolic blood pressure increases among non-overweight normotensive individuals. (272 words). [ABSTRACT FROM AUTHOR]

Several organophosphorus compounds such as organophosphate pesticides (OPPs) and trialkylphosphates (TAPs) are suspected to inhibit cholinesterase activities, to affect endocrine systems or to possibly be carcinogenic. To evaluate their adverse effects on health with chronic exposure in the general population, especially in children, we measured the household exposure to OPPs and TAPs by Japanese children via all exposure pathways and the contribution of indoor air quality. First-morning void urine was collected from subjects aged 6 to 15 years (n = 132), and airborne organophosphorus compounds were sampled in the subject's bedroom for 24 h. Airborne levels of nine OPPs and three TAPs and their urinary metabolites were determined. No significant correlations were detected for any compounds between their airborne concentrations and the urinary excretion amounts of their corresponding metabolites. The estimated daily intakes were as follows (median, μg/kg b.w./d): chlorpyrifos, 0.042; diazinon, 0.067; tri-n-butylphosphate, 0.094. The 95th percentiles of the intakes for fenthion, fenitrothion and the above three compounds did not exceed their reference limit values, although one subject had a daily intake of tri-n-butylphosphate that was about twice its reference limit value. The concentration levels of the urinary metabolite of tri-n-butylphosphate in our subjects tended to be higher than those for children in many other countries. The fractions of the amounts absorbed by inhalation to the amounts absorbed via all of the exposure pathways was only 2.3 % (median) for tri-n-butylphosphate. Inhalation did not seem to contribute very much as an absorption pathway of the organophosphorus compounds in these Japanese children while they were at home. The exposure amounts of OPPs were not suggested to be high enough to adversely affect the health of these children at present on the basis of their daily intakes compared to their reference limit values., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Over the past two decades, domestic shipments of glyphosate (Gly), in the form of an ionic salt, have been increasing steadily in Japan. This increase has raising concerns about the effects of chemical exposure on children. The International Agency for Research on Cancer classified Gly as a "probably carcinogenic to humans (Group 2A)" in 2015. The purpose of the current study was to analyze Gly in urine samples of Japanese children to determine temporal changes, seasonal changes, and gender differences.Method: First-morning urine samples were obtained from 50 Japanese children (4-6-year-old) in October of 2006, 2011, and 2015 (total = 150) to investigate the temporal trends in urinary Gly concentrations. Additionally, first-morning urine samples were collected from 3-year-old children in August-September of 2012 (summer; n = 42) and in February of 2013 (winter; n = 42) to investigate the seasonal and gender differences, and the correlations between urinary Gly concentrations and insecticide exposure biomarkers. Urine samples were analyzed to measure for Gly using a liquid chromatography with tandem mass spectrometry (LC-MS/MS).Results: Detectable Gly concentrations were found in 41% of the 234 children. The 75th percentile and maximum concentrations of urinary Gly were 0.20 and 1.33 μg/L, respectively. The urinary Gly concentration in 2015 was significantly higher than in 2006, suggesting that the Gly exposure levels have been increasing. No seasonal or gender-specific differences in urinary Gly concentrations were observed, and no correlation with insecticide exposure biomarkers was found.Conclusion: This study revealed that Gly exposure trends show an increase between 2006 and 2015, and that season and gender were not the exposure-determining factors. Overall, urinary concentrations of Gly were comparable with studies from other countries. [ABSTRACT FROM AUTHOR]

Increased levels of dialkylphosphates (DAP) in maternal urine are associated with a variety of adverse developmental outcomes in children. Although urinary DAP levels are usually considered to be a marker of exposure to organophosphate (OP) pesticides, excretion of DAP may also increase by ingesting preformed DAP. To date, no study has quantitatively assessed the possible contribution of the dietary intake of preformed DAP and OP pesticides to urinary levels of DAP. Therefore, we aimed to estimate the levels of 6 DAPs and 84 OP pesticides in duplicate diet samples and urine samples collected from 73 women living in urban areas of Japan in 2018. DAP and OP pesticides were detected in 94% and 45% of diet samples, while DAP was detected in 100% of urinary samples, respectively. The average daily intake of preformed DAP was significantly higher than that of parent OP pesticides in our participants. Dimethylphosphate and diethylphosphate were predominant in the preformed DAP, and the estimated average daily intake of total amount of DAP was 78.3 nmol. Fruits and vegetables were the major dietary sources of DAP. Dietary intake of DAP was positively associated with urinary DAP levels, suggesting that a considerable amount of urinary DAP was derived from ingesting preformed DAP. Our results show that attributing urinary DAP levels exclusively to OP pesticide exposure would result in a substantial overestimation of the exposure level. Therefore, the urinary levels of DAP may not be suitable for evaluating OP pesticide exposure in the general urban population. [Display omitted] • Duplicate diets were collected from Japanese women of reproductive age. • Diet samples were analyzed for the presence of OP pesticides and DAPs. • The average dietary intake of DAP was much higher than that of OP pesticides. • Dietary DAP intake is associated with urine DAP levels. [ABSTRACT FROM AUTHOR]

Background: Cadmium (Cd) is a wide-spread environmental pollutant with insidious toxicity to kidneys, and children are considered to be a high-risk group. Lead (Pb) is suspected to induce retardation in mental development in children. Daily foods are an important source of both Cd and Pb exposure for general population. Nevertheless, data on dietary exposure of children to Cd and Pb are still scarce in Japan. Objectives: This study was initiated to clarify the extent of exposure of children to Cd. Exposure to Pb, another environmental pollutant element, was also studied in combination. Methods: Twenty-four-hour food duplicates and the first morning urine samples were collected from 296 children (159 boys and 137 girls at the ages of 3-6 years) in 15 kindergartens in Miyagi prefecture on the Pacific coast in north-east Japan; no environmental pollution with Cd has been known in the prefecture. Cd, Pb and iron in food duplicates and Cd in urine were analyzed by inductively coupled plasma-mass spectrometry. α-Microglobulin (α-MG) in urine was measured by the latex method. Log-normal distributions were confirmed for these analytes. Results: The geometric mean (GM) values for dietary intake of Cd and Pb were 11.8 and 2.28 μg/day, or 4.20 and 0.84 μg/kg body weight/week, respectively, for total children studied. No significant difference was detected in dietary Cd and Pb intake between boys and girls of the same age (except for Pb on a μg/day basis at 6 years) as well as of all ages in combination. Trends of increase in Cd and Pb intake were observed parallel to age when calculated on a daily intake basis, but the trends disappeared after correction for body weight. No age-dependent increase was observed in α-MG, despite there was an age-dependent increase in Cd. Conclusions: The dietary intake of Cd and Pb for children studied were 4.20 and 0.84 μg/kg body weight/week, respectively. International comparison of the present results with values reported in literature suggested that exposure of children in Japan was higher with regard to Cd, and lower regarding Pb, reproducing the observation in adult Japanese populations. For better health of children, efforts may be necessary to reduce high dietary exposure to Cd. [ABSTRACT FROM AUTHOR]

Hexanoyl-lysine (HEL), 8-hydroxy-2'deoxyguanosine (8-OHdG), and dityrosine (DT) have served as potential biomarkers for detecting oxidative modified lipids, DNA, and proteins in biological samples, respectively. Whether regular higher levels of consumption of vegetables/fruit (V/F) would decrease oxidative modification of these biomolecules in the body remain unelucidated. To examine the association of regular V/F consumption with the generation of these reactive oxygen species-induced biomarkers, this study evaluated V/F consumption in a school-based sample of teenaged girls (mean age 15.6 ± 1.7 years, n = 103), and quantified the formation of oxidative stress biomarkers in their urine. Only 19.4% and 23.3% of participants reported that they consumed the recommended daily amount of vegetables and fruits, respectively. Individuals who consumed lower levels of fruit (<100g/day) or vegetables (<250g/day) had significantly higher HEL excretion in their urine than those who consumed higher levels of fruit (≥100g/day) ( p < 0.05) or vegetables (≥250g/day) ( p = 0.057). The results of a multiple regression analysis showed that vegetable consumption was an important inhibiting factor of early lipid peroxidation measured as HEL in urine, independent of various confounders (β = - 0.332, p < 0.05). The findings suggest that relatively higher consumption of vegetables would help in the prevention of early lipid peroxidation in adolescents., Competing Interests: The authors declare no conflict of interest.

[Display omitted] • Ubiquitous nonylphenol (NP) exposure in 7-year-old Japanese children (n = 180). • Specific urinary biomarkers OH-NP and oxo-NP detected in 100% and 66% of samples. • Median and maximum daily NP intakes at 0.14 and 0.95 µg/(kg bw*d). • Associations of OH-NP and oxidative stress biomarkers HEL and HNE. • Only slight annual decrease in NP exposure of 4.7% between 2012 and 2017. Nonylphenol (NP) has been under scrutiny for decades due to its endocrine-disrupting properties and its ubiquity in the environment. Despite its widespread occurrence, robust and reliable exposure data are rare. In this study, we used human biomonitoring (HBM) measuring the novel urinary alkyl-chain-oxidized biomarkers OH-NP and oxo-NP to determine NP exposure in 7-year-old Japanese children. The new biomarkers are advantageous over measuring unchanged NP because they are not prone to external contamination. We analyzed 180 first morning void urine samples collected between 2012 and 2017. OH-NP and oxo-NP were detected in 100% and 66% of samples at median concentrations of 2.69 and 0.36 µg/L, respectively. 10-fold concentration differences between OH-NP and oxo-NP are in line with recent findings on human NP metabolism. Based on OH-NP we back-calculated median and maximum NP daily intakes (DI) of 0.14 and 0.95 µg/(kg bw*d). These DIs are rather close to but still below the current provisional tolerable daily intake of 5 µg/(kg bw*d) by the Danish Environmental Protection Agency. Between 2012 and 2017 the DIs decreased by an average of 4.7% per year. We observed no seasonal changes or gender differences and questionnaire data on food consumption, housing characteristics or pesticide use showed no clear associations with NP exposure. Urinary OH-NP was weakly associated with the oxidative stress (lipid peroxidation) biomarkers N -ε-hexanoyl-lysine (HEL) and trans -4-hydroxy-2-nonenal (HNE) (Spearman ρ = 0.30 and 0.22, respectively), but not with 8-hydroxy-2′-deoxyguanosine (8-OHdG). Further research is needed to identify and understand the major sources of NP exposure and to investigate a potential role in oxidative stress. This study is the first to investigate NP exposure in Japanese children based on robust and sensitive HBM data. It is a first step to fill the long-standing gap in quantitative human NP exposure monitoring and risk assessment. [ABSTRACT FROM AUTHOR]

Summary: We evaluated how bone turnover might predict vertebral fracture risk in postmenopausal women over 10 years. After adjusting for age and femoral neck bone mineral density, high bone-specific alkaline phosphatase and total and free deoxypyridinoline at baseline predicted increased vertebral fracture risk in women with ≥ 5 years since menopause. Introduction: The aim was to evaluate the ability of bone turnover markers (BTMs) in predicting vertebral fractures. Methods: Participants in the 1996 baseline survey of the JPOS Cohort Study included 522 postmenopausal women, with no diseases or medications affecting bone metabolism. Vertebral fractures were ascertained in three follow-up surveys (1999, 2002, and 2006). Initial fracture events were diagnosed morphometrically. The Poisson regression model was applied to estimate the rate ratio (RR) of the following log-transformed BTM values at baseline: osteocalcin and bone-specific alkaline phosphatase (BAP) in serum and C-terminal cross-linked telopeptide of type I collagen, total deoxypyridinoline (tDPD), and free deoxypyridinoline (fDPD) in urine. Results: Eighty-three fracture events were diagnosed over a median follow-up period of 10.0 years. RR per standard deviation (SD) (95 % confidence interval) for BAP was 4.38 (1.45, 13.21) among 65 subjects with years since menopause (YSM) < 5 years. RRs per SD (95 % confidence interval) for BAP, tDPD, and fDPD were 1.39 (1.12, 1.74), 1.32 (1.05, 1.67), and 1.40 (1.12, 1.76), respectively, after adjusting for age and femoral neck bone mineral density (FN BMD) among 457 subjects with YSM ≥ 5 years. Of the 451 women followed at least once until 2002, RRs per SD for BAP, tDPD, and fDPD adjusted for age and FN BMD over 6 years were not significantly different from those over 10 years. Conclusion: BAP was associated with vertebral fracture risk among early postmenopausal women. BTMs can predict vertebral fractures independently of BMD among late postmenopausal women over a 10-year follow-up period. [ABSTRACT FROM AUTHOR]

This study examined the effect of the volume of fluid ingested on urine concentrating ability during prolonged heavy exercise in a hot environment at low levels of dehydration. Seven healthy males performed 105 min of intermittent cycle exercise at 70% maximum oxygen uptake (32°C, 60% relative humidity) while receiving no fluid ingestion (NF), voluntary fluid ingestion (VF), partial fluid ingestion equivalent to one-half of body mass loss (PF), and full fluid ingestion equivalent to body mass loss (FF). Fluid (5°C, 3.4% carbohydrate, 10.5 mmol.L-1 sodium) was ingested just before commencing exercise and at 15, 33, 51, 69, and 87 min of exercise, and the total amount of fluid ingested in PF and FF was divided into six equal volumes. During exercise, body mass loss was 2.2 ± 0.2, 1.1 ± 0.5, 1.1 ± 0.2, and 0.1 ± 0.2% in NF, VF, PF, and FF, respectively, whereas total sweat loss was about 2% of body mass in each trial. Subjects in VF ingested 719 ± 240 ml of fluid during exercise; the volume of fluid ingested was 1.1 ± 0.4% of body mass. Creatinine clearance was significantly higher and free water clearance was significantly lower in FF than in NF during exercise. Urine flow rate during exercise decreased significantly in NF. There were significant decreases in creatinine and osmolar clearance and was a significant increase in free water clearance during exercise in NF and VF. Creatinine clearance decreased significantly and free water clearance increased significantly during exercise in PF. There was no statistical change in urinary indices of renal function during exercise in FF. The findings suggest that full fluid ingestion equivalent to body mass loss has attenuated the decline in urine concentrating ability during prolonged heavy exercise in a hot environment at low levels of dehydration. [ABSTRACT FROM AUTHOR]

Summary: This study investigated the effects of a single administration of teriparatide on bone turnover markers in postmenopausal women. Teriparatide caused a transient increase in bone resorption and inhibition of bone formation followed by a subsequent increase in bone formation and a decrease in resorption that lasted at least 1 week. Introduction: This study aims to investigate the effects of a single subcutaneous administration of teriparatide on bone turnover markers to elucidate why once weekly intermittent administration of teriparatide is effective on osteoporosis. Methods: Pharmacokinetics and calcium metabolism and bone turnover parameters were measured in 30 postmenopausal women after two doses of teriparatide (28.2 or 56.5 μg injection) or placebo in a randomized, double-blind, placebo-controlled study. Results: Teriparatide plasma concentration increased in a dose-dependent manner, and the maximum concentration was achieved 1 h after injection. Serum levels of calcium and phosphorus were transiently increased and decreased after teriparatide injection, respectively. Calcium metabolism returned to baseline levels 24 h later. Two days after injection, the serum level of 1,25-dihydroxy vitamin D was increased by ~80 % from baseline for both doses of teriparatide. Serum levels of osteocalcin and procollagen type I N-terminal propeptide decreased during the first 24 h followed by a ~10 % increase for 14 days. The serum level of cross-linked N-telopeptide (NTX) of type I collagen increased during the first 24 h followed by a 10 to 12 % dose-dependent suppression from baseline for 14 days. Urinary cross-linked C-telopeptide of type I collagen changes occurred in the same direction as serum NTX, but not dose dependently. Conclusion: A single administration of teriparatide caused an immediate, transient increase in bone resorption and inhibited bone formation followed by an increase in bone formation and decrease in resorption for ≥1 week. These findings may provide proof for the effect of a once-weekly regimen of teriparatide on bone turnover. [ABSTRACT FROM AUTHOR]

Background: The use of benchmark dose (BMD) and the 95% lower confidence limit of benchmark dose (BMDL) have been gaining popularity not only in experimental studies but also in epidemiological studies including those on toxicology of cadmium (Cd), a ubiquitous hazardous element in the environment. However, the reproducibility of BMD and BMDL values has seldom been examined. Objectives: This study was initiated to determine whether consistent BMD and BMDL values are obtained for similar non-exposed populations, i.e., the populations with no anthropogenic exposure to Cd in a single nation of Japan. Methods: Cd (an exposure marker), α-microglobulin (α-MG), β-microglobulin (β-MG) and N-acetyl-β-D-glucosaminidase (NAG) (three effect markers of tubular dysfunction) levels in the urine of adult Japanese women from five previous publications of this study group were examined. Overall, data were available for 17,375 cases (in 16 prefectures) regarding Cd, α-MG and β-MG, and 6,409 cases (in ten prefectures) regarding NAG. The data were used to calculate BMD and BMDL values taking advantage of the hybrid approach (Budtz-Jǿrgensen et al. in Biometrics 57:698-706, ). It was possible to calculate BMD and BMDL values for α-MG and β-MG for all of the 16 prefectures with 17,375 cases, whereas the values for NAG were successfully calculated for nine prefectures with 5,843 cases. Results: The application gave BMD values of 1.92, 2.46 and 2.32 μg Cd/g cr for α-MG, β-MG and NAG, respectively, and BMDL values of 1.83, 2.32 and 2.09 μg Cd/g cr. Large inter-prefectural variations were observed in the BMD and BMDL; there was about fourfold difference both in BMD and in BMDL calculated for α-MG and β-MG in 16 prefectures, and the variation was greater (i.e., by about sevenfold) in BMD and BMDL for NAG in nine prefectures. A survey of relevant literature revealed variation in BMD and BMDL values of similar folds as observed in the present analyses in five studies of Japanese populations. Multiple regression analyses taking BMD or BMDL as a dependent variable and age, CR concentration and Cd concentration as independent variables showed both BMD and BMDL were significantly influenced by Cd concentration in cases of α-MG and β-MG, whereas BMD and BMDL for NAG was by CR. Conclusions: Even when the analysis was conducted in a single nation, both BMD and BMDL for the Cd effect markers varied by ca. fourfold when examining α-MG or β-MG and the values varied by ca. sevenfold for NAG among Cd-non-exposed populations. The most influential factors in the study population may include urine density and Cd levels in the urine. [ABSTRACT FROM AUTHOR]

Objective Neutrophil extracellular traps (NETs) are composed of DNA and antimicrobial proteins, including myeloperoxidase (MPO). Recent studies have demonstrated that impaired regulation of NETs could trigger an autoimmune response. Propylthiouracil (PTU), an antithyroid drug, is associated with a risk of MPO antineutrophil cytoplasmic antibody (ANCA) production and MPO ANCA-associated vasculitis (MPO AAV). This study was undertaken to clarify the mechanism of MPO ANCA production, using the PTU-induced model of MPO AAV. Methods NETs were induced by treating human neutrophils with phorbol myristate acetate (PMA) in vitro. We examined whether the addition of PTU influenced the NET formation induced by PMA and the degradation of NETs by DNase I, which is regarded as a regulator of NETs. Furthermore, we examined whether NETs generated by the combination of PMA and PTU induced MPO ANCA and MPO AAV in vivo in rats. Results When NETs were induced by PMA with PTU using human neutrophils in vitro, abnormal conformation of NETs was observed. Interestingly, the abnormal NETs were hardly digested by DNase I. Moreover, rats immunized with the abnormal NETs, which had been induced by PMA with PTU using rat neutrophils, produced MPO ANCA and developed pulmonary capillaritis. When rats were given oral PTU with intraperitoneal injection of PMA, pauci-immune glomerulonephritis and pulmonary capillaritis occurred with MPO ANCA production in the serum. Conclusion Our findings indicate that abnormal conformation and impaired degradation of NETs induced by PTU are involved in the pathogenesis of PTU-induced MPO ANCA production and MPO AAV. These findings suggest that disordered NETs can be critically implicated in the pathogenesis of MPO AAV. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine, using the high-performance liquid chromatographic methods recently modified by us, the fate of dietary tryptophan in 17 healthy female Japanese adults who ate self-selected food. The experimental period was 22 days. The habitual intake of tryptophan was 3328.4 μmol/day. 24-hour urine samples were collected at the beginning of the experiment and then once per week. Blood was collected at the beginning and end of the experiment. Levels of tryptophan and its metabolites were measured in blood and urine. Tryptophan, nicotinamide and 2-oxoadipic acid were the major compounds of the blood. The urinary excretion amounts of tryptophan, 5-hydroxyindole-3-acetic acid, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid were about 40, 20, 4, 1, 10, 4, 3, 5 and 20 μmol/day, respectively. [ABSTRACT FROM AUTHOR]

A potential utilization of dietary intervention for reducing hyperuricemia was tested by managing food materials. Within the framework of the Japanese Government's health promotion program, we made recipes that consisted of more protein-rich and less vegetable/fruit-rich materials for the acidic diet and others composed of less protein-rich and more vegetable/fruit-rich materials for the alkaline diet. We have shown that urine alkalization facilitates uric acid excretion. In this study, it has been clarified with simultaneous measurements of both serum and urine uric acid concentration that acidic diets increase serum uric acid together with a decrease of uric acid excretion. The ratio (R) of uric acid clearance/creatinine clearance was calculated. On the third experimental day, the relative R, referring to that of the first day for the acidic diet, became smaller than that for the alkaline diet, indicating that in acidic urine, uric acid excretion is limited by more active reabsorption, compared with that in alkaline urine. Taken together, we tentatively conclude that dietary intervention may well be the safest and the most economical way for the prevention of hyperuricemia. [ABSTRACT FROM PUBLISHER]

Abstract: Background: It has been reported that pomegranate juice significantly increased the AUC of orally administered carbamazepine in rats, which suggests that pomegranate may inhibit the cytochrome P450 3A (CYP3A)–mediated carbamazepine metabolism. Objective: The aim of the present study was to clarify the effect of repeated consumption of pomegranate juice on CYP3A activity by assessing the pharmacokinetics of midazolam, a typical CYP3A probe drug, and its metabolites in healthy volunteers. Methods: An open-label, randomized, single-center, 2-period crossover study was conducted on healthy Japanese volunteers. Each subject received 200 mL of pomegranate juice twice daily for 2 weeks. On day 14, they were administered 15 μg/kg midazolam orally with either pomegranate juice or water. Plasma concentrations and urinary excretions of midazolam, 1′-hydroxymidazolam, and 4-hydroxymidazolam were determined up to 24 hours using LC/MS/MS and analyzed by a noncompartmental method. Results: Sixteen subjects (11 men and 5 women) were enrolled and completed the study. The mean (SD) age was 24.1 (4.8) years (range 22–40), mean body weight was 62.9 (8.8) kg (range 45.6–79.9). Differences in the mean AUC0–∞ were 12.7 (4.4) and 14.2 (6.6) ng/mL/h in pomegranate juice and control groups, respectively (geometric mean ratio: 1.02 [95% CI, 0.95–1.09]; P = 0.40). Differences in Cmax for midazolam did not reach the level of statistical significance (5.1 [1.7] vs 5.0 [2.0] ng/mL, geometric mean ratio: 0.95 [95% CI, 0.79–1.11]; P = 0.68). Excretions of 1′-hydroxymidazolam (P = 0.34) and 4-hydroxymidazolam (P = 0.32) were not significantly altered by ingestion of pomegranate juice. Conclusion: In this small Japanese adult volunteer population receiving single subtherapeutic doses of midazolam, 2 weeks'' consumption of pomegranate juice did not significantly alter the pharmacokinetic profile of midazolam compared with that of the control. Protocol identifier: UMIN000004459. [Copyright &y& Elsevier]

Objectives: The objectives of the present study are to investigate whether cadmium in blood (Cd-B) and cadmium in urine (Cd-U) correlate with each other irrespective of age among general populations and which one of Cd-B or Cd-U correlates more closely with three renal tubular dysfunction markers in urine of α-microglobulin (α-MG-U), β-microglobulin (β-MG-U) and N-acetyl-β- d-glucosaminidase (NAG-U). Methods: Data on two exposure markers (Cd-B and Cd-U) and three effect markers (α-MG-U, β-MG-U and NAG-U) were collected for 1,403 adult women in non-polluted areas all over Japan. Possible significance of correlation between the parameters and dependency on age was examined by simple and multiple regression analysis. Results: Both Cd-B and Cd-U increased as a function of age. The two exposure markers correlated significantly with each other, and the Cd-U over Cd-B ratio also increased as a function of age. Although both Cd-B and Cd-U correlated significantly with the three effect markers, the correlation was closer for Cd-U than for Cd-B. Conclusions: Cd-U rather than Cd-B should be recommended as an exposure marker of choice in Cd biological monitoring of general populations. Effects of aging should be taken into account when evaluating study results. [ABSTRACT FROM AUTHOR]

Summary: In patients with femoral neck fracture, clinical factors, bone metabolism markers (in serum, urine, and bone), bone mineral density, radiographic parameters, and bone histomorphometric parameters were investigated to detect determinants of fragility fracture. The osteocalcin/deoxypyridinoline ratio and osteopontin/calcium ratio of cortical bone were selected as significant predictors. Introduction: Measurement of bone mineral density is widely used to assess bone strength, but this also depends on other bone components and on bone structure. The objective of this study was to investigate risk factors for fracture related to bone quality, the patient's history, and the patient's lifestyle. Methods: Twenty-one patients with femoral neck fracture and 18 patients with osteoarthritis were enrolled. Blood and urine samples were collected on admission to hospital, and bone samples were obtained from femoral necks resected during surgery. Multivariate logistic regression analysis was performed using osteoarthritis and femoral neck fracture as combined variables to assess the influence of alcohol or coffee intake, eating natto (fermented soybeans), osteocalcin and calcium concentrations, the osteocalcin/deoxypyridinoline ratio and osteopontin/calcium ratios of cortical bone and cancellous bone, various bone histomorphometric parameters, the bone mineral density of the lumbar spine and the intact contralateral femoral neck, and various radiographic parameters of the spine Results: By forward stepwise multivariate analysis, the osteocalcin/deoxypyridinoline and osteopontin/calcium ratios of cortical bone were selected as significant factors for fracture (the odds ratios were 0.493 and <0.001, respectively; both P < 0.001). Conclusions: A decrease of osteopontin and osteocalcin in bone is important for promoting vulnerability to hip fracture. [ABSTRACT FROM AUTHOR]

Phase 1 studies of laninamivir, a novel long-acting neuraminidase inhibitor, were carried out to assess its safety, tolerability, and pharmacokinetics after inhaled administration of its prodrug, CS-8958. Healthy male volunteers (total N = 76) participated in double-blind, randomized, placebo-controlled trials and received 5, 10, 20, 40, 80, or 120 mg of a single dose or 20 or 40 mg of a twice-daily dose for 3 days. The clinical and laboratory parameters and plasma and urinary concentrations of CS-8958 and laninamivir for 144 hours post dosing were measured. There were no adverse events related to the test drug. CS-8958 disappeared from plasma with a half-life of about 2 hours, although laninamivir was slowly eliminated from the body, lasting for even up to 144 hours after administration with a half-life of about 3 days. Area under the curve and maximum concentration increased almost linearly with the dose administered. The cumulative urinary excretion amounts of CS-8958 and laninamivir were 2.3% to 3.6% and 10.7% to 14.6% of the dose, respectively. The half-life of the urinary excretion rates of laninamivir at higher single dose is comparable to plasma half-life. CS-8958, when inhaled by healthy volunteers, is well tolerated and exhibits a suitable pharmacokinetic profile, suggesting potential for long-lasting anti-influenza activity. [ABSTRACT FROM PUBLISHER]

This prospective study, in the very early phase after initiation of glucocorticoid (GC) treatment, showed that alendronate was effective in suppressing accelerated bone resorption and subsequent decrease in bone mineral density (BMD) at the lumbar spine of patients with high-dose GC treatment. How bisphosphonates affect bone metabolism and BMD of patients with high-dose GC in the early phase, especially within 1 month is unclear. We examined the prospective effects of daily 5 mg alendronate on bone metabolism and BMD in 20 patients with high-dose GC (at least 40 mg prednisolone/day) and compared them to 34 high-dose GC-treated patients without alendronate. Serum levels of calcium decreased at day 28 in the alendronate group. Urinary calcium excretion significantly increased after day 7 in both groups. The increase in serum parathyroid hormone (PTH) level at day 7 in the control group was not observed in the alendronate group, but PTH levels increased at day 28 and month 3 in the alendronate group. As for the bone turnover markers, the serum osteocalcin level decreased in both alendronate and control groups, but serum bone-type alkaline phosphatase levels did not show significant changes. Although the urinary type I collagen cross-linked N-telopeptide (NTX) level showed significant increases on days 7 and 28 in the control group; such early increases in urinary NTX were not observed in the alendronate group. Thereafter, the urinary NTX levels fell slowly in the alendronate group significantly. BMD at the lumbar spine significantly decreased from month 1 in the control group, whereas in the alendronate group, BMD at the lumbar spine maintained almost the same level at all time points observed. Alendronate was effective in suppressing bone resorption and subsequent BMD decrease at the lumbar spine in patients with high-dose GC treatment. [ABSTRACT FROM AUTHOR]

We evaluated the effect of environmental, low-level exposure to heavy metals during pregnancy, as estimated by urine analysis, on birth size of the newborns. Spot urine samples were collected from unexposed 78 pregnant women in Tokyo during 2007 and 2008. The urinary concentrations of beryllium (Be), copper (Cu), arsenic (As), zinc (Zn), selenium (Se), molybdenum (Mo), cadmium (Cd), tin (Sn), antimony (Sb), and lead (Pb) were measured by ICP-MS. The birthweight (BW), length (BL) and head circumference (HC) of the newborns delivered to the subjects were measured and relationship with urinary metal concentration was examined. The geometric mean concentration of urinary Be, Cu, As, Zn, Se, Mo, Cd, Sn, Sb, and Pb were 0.031, 12.8, 393, 76.9, 37.6, 79.0, 0.766, 0.232, < 0.21, 0.483 μ g g-creatinine- 1, respectively. The mean birth size of the newborn was close to the national average value in Japan. Stepwise multiple regression analysis using birth size as a dependent variable and urinary metal concentrations and covariates as independent variables extracted urinary Cd with a significant negative standardized partial regression coefficient (β) for BW along with gestational age and maternal BMI. For HC, Sn was selected with a negative β. The present study suggested that even a low-level Cd body burden of general population has slight but significant negative effect on BW. [ABSTRACT FROM AUTHOR]

Background: Recent studies showed that serum and urinary neutrophil gelatinase-associated lipocalin (NGAL) represents a novel, sensitive, specific biomarker for early detection of acute kidney injury. However, the clinical significance of measuring serum and urinary NGAL on chronic renal diseases remains unclear. Methods: In this study, we measured serum and urinary NGAL levels in patients with several common pediatric renal diseases such as renal dysfunction (estimated glomerular filtration rate < 90 mL/min/1.73 m2), proliferative glomerulonephritis, steroid-resistant and steroid-sensitive nephrotic syndrome, and tubular dysfunction. Results: Urinary NGAL level was significantly increased compared with the control in all of these disease groups except in patients with a remission stage of steroid-sensitive nephrotic syndrome, although a significant increase in serum NGAL level was observed in the renal dysfunction group only. Both serum and urinary NGAL levels showed significant inverse correlations with an estimated glomerular filtration rate in the analysis with total subjects, and also in the analysis with the renal dysfunction group in urinary NGAL. In proteinuric patients, the extent of proteinuria significantly correlated with urinary NGAL level. In patients with tubular dysfunction, the increase of urinary NGAL level was remarkable compared with the other disease groups. Conclusion: These results indicated that urinary NGAL level is a better biomarker for chronic renal diseases in children than serum NGAL level, although multiple pathological mechanisms should be considered in evaluating these NGAL values. [ABSTRACT FROM AUTHOR]

Background: The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is in clinical development for the treatment of type 2 diabetes mellitus (T2DM). In previous studies in non-Japanese populations, linagliptin showed potential as a once-daily oral antidiabetic drug. Objective: This study investigated the tolerability, pharmacokinetics, and pharmacodynamics of linagliptin in healthy adult male Japanese volunteers, in compliance with Japanese regulatory requirements for new drugs intended for use in humans. Methods: This was a Phase I, randomized, doubleblind, placebo-controlled study in healthy volunteers. Linagliptin or placebo was administered as single escalating doses of 1, 2.5, 5, and 10 mg, or as multiple escalating doses of 2.5, 5, and 10 mg once daily for 12 days. Three quarters of subjects in each dose group were randomized to active drug and one quarter to placebo. Blood and urine samples for determination of pharmacokinetic parameters were obtained before administration of the first dose of study drug and at regular time points after administration, with more frequent blood sampling on days 1 and 12 in subjects receiving multiple doses. Inhibition of DPP-4 activity and plasma concentrations of glucagon-like peptide-1 (GLP-1) and glucose were also determined. Tolerability was assessed throughout the study based on physical examinations, 12-lead ECGs, and standard laboratory tests. Results: Eight subjects were enrolled in each dose group, 6 receiving active drug and 2 receiving placebo. Baseline demographic characteristics were comparable in the single-dose groups (mean [SD] age, 24.5 [3.6] years; mean weight, 61.2 [6.2] kg; mean height, 171.5 [5.3] cm) and multiple-dose groups (mean age, 25.4 [3.7] years; mean weight, 61.6 [5.2] kg; mean height, 170.9 [4.9] cm). Linagliptin displayed nonlinear pharmacokinetics. Total systemic exposure (AUC and Cmax) increased in a manner that was less than dose proportional. Tmax ranged from 1.50 to 6.00 hours, and elimination t½ ranged from 96.9 to 175.0 hours. Total CL increased with increasing dose (from 140 mL/min in the 1-mg group to 314 mL/min in the 10-mg group), as did apparent Vd (from 1260 to 3060 L with doses up to 10 mg). Steady state was attained within 2 to 3 days. The accumulation t½ ranged from ∼10 to 15 hours. The accumulation ratio with multiple dosing was <1.5 and decreased with increasing dose (∼1.2 in the 10-mg dose). Urinary excretion increased with increasing dose and over time in all dose groups, although it did not exceed 7% in any dose group on day 12. Linagliptin inhibited plasma DPP-4 activity in a dose-dependent manner. Mean DPP-4 inhibition was ≥80% over 24 hours after a single dose of 10 mg and after multiple doses of 5 and 10 mg for 12 days. Postprandial plasma GLP-1 concentrations increased from preprandial concentrations by 2- to 4-fold after administration of single doses and by 2- to 2.5-fold on day 12 after administration of multiple doses. Baseline (premeal) plasma GLP-1 concentrations were higher on day 12 than on day 1 in all linagliptin groups. A total of 3 adverse events were reported in 1 subject each: an increase in histamine concentration in a subject receiving a single dose of linagliptin 5 mg, vasovagal syncope in a subject receiving a single dose of linagliptin 10 mg, and pharyngitis in a subject receiving multiple doses of linagliptin 10 mg. None of these events was considered drug related. No episodes of hypoglycemia occurred during the study. Conclusions: In this short-term study in healthy adult male Japanese volunteers, multiple oral doses of linagliptin inhibited plasma DPP-4 activity and elevated active GLP-1 concentrations in a dose-dependent manner, with no episodes of hypoglycemia. Multiple dosing of linagliptin for 12 days was well tolerated and exhibited a pharmacokinetic/pharmacodynamic profile consistent with a once-daily regimen. Clinical studies in Japanese patients with T2DM appear to be warranted. [Copyright &y& Elsevier]

Literature survey has suggested that cadmium (Cd) in the general environment is more abundant in the northern part of the coast on the sea of Japan. The present survey was initiated to examine if the exposure to Cd in the area has been higher than other parts of Japan, and if so, the higher exposure has been associated with tubular dysfunction among the local residents. In three prefectures of Akita, Yamagata and Ishikawa in the region, adult women (about 700 subjects per prefecture) were invited to participate in the survey. Each of the participants provided informed consents, offered spot urine samples and filled questionnaires (on age etc.). The urine samples were analyzed for Cd, α1-microglobulin (α1-MG), β2-microglobulin (β2-MG) and N-acetyl-β- d-glucosaminidase, together with creatinine and specific gravity. The results were combined with published data on two other prefectures of Niigata and Toyama (both in the area), as well as Japan as a whole (all Japan-A excluding Niigata prefecture, which was studied separately in the present study), and subjected to analysis for possible difference from all Japan-A in terms of the levels of internal Cd burden, and prevalence of β2-MG-uria. Geometric means (GMs) for urinary Cd in the five prefectures were in a range from a low of 1.20 to a high of 2.65 μg/l, being higher than the GM (0.99 μg/l) for all Japan-A. GMs for α1-MG (2.15–2.80 mg/l) and β2-MG (99–107 μg/l) were only slightly higher or even lower than all Japan-A values depending on the prefectures. Elevation in the prevalence of β2-MG-uria was significant in Akita prefecture, but the elevation in β2-MG was not associated with elevation in Cd in urine. Literature survey on general population Cd epidemiology showed that Cd, α1-MG and β2-MG levels in urine of the residents in the five prefectures were within the levels reported for non-polluted areas, and such was also the case for prevalence of β2-MG-uria. In an over-all evaluation, no clear-cut evidence was available for increased prevalence of Cd exposure-associated renal tubular dysfunction among general populations in the five prefectures in the northern part on the coast of Sea of Japan than in other prefectures in Japan, despite moderate elevation in urinary Cd levels. [ABSTRACT FROM AUTHOR]