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The association between immunoregulatory cytokines, such as interleukin (IL)-10 or IL-35, and dipeptidyl peptidase-4 inhibitor (DPP4i)-related bullous pemphigoid (BP) has not been evaluated. Serum IL-10 and IL-35 levels were measured in 39 patients with BP (24 males and 15 females; 6 DPP4i-related and 33 DPP4i-unrelated BP patients) and 10 healthy controls. The number of CD26 + cells in the dermis around bulla on sections was counted immunohistochemically for 12 patients (six patients with DPP4i-related BP and six randomly sampled patients with DPP4i-unrelated BP). Patients with DPP4i-related BP had lower levels of serum eosinophils (DPP4i-related vs. DPP4i-unrelated BP: 476.1 ± 234.0 vs. 911.3 ± 948.8/μL; p = 0.537) and a higher rate of infiltrating CD26 + cells (32.9 ± 7.1% vs. 15.7 ± 4.4%; p = 0.01). There were no significant differences in serum IL-10 (6.77 ± 0.24 vs. 6.84 ± 0.20 pg/mL), serum IL-35 (2.63 ± 0.17 vs. 2.63 ± 0.21 pg/mL), serum anti-BP180NC16a antibodies (67.31 ± 37.4 vs. 76.18 ± 54.59 U/mL) and Bullous Pemphigoid Disease Area Index before treatment in this study. Serum IL-10 and IL-35 levels do not increase in patients with BP and may not be a candidate for a therapeutic target for BP. An increase in CD26 + cells might be associated with DPP4i-related BP., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In Japan, Buruli ulcer cases are often advanced, requiring surgical treatment. However, extensive debridement is often difficult because of cosmetic and functional sequelae. Moreover, the lesions are complicated and composed of edematous erythema, necrotic ulcer, and erythematous skin lesions caused by a paradoxical reaction, which also make it difficult to perform adequate debridement., Methodology/principal Findings: We performed quantitative polymerase chain reaction (PCR) analysis for IS2404 using 29 samples taken from mapping biopsy. We evaluated the relationship among mycobacterial burden, histopathological findings, and clinical outcomes using 83 tissue samples taken from mapping biopsy and debrided Buruli ulcer. On quantitative PCR, the Cp values of IS2404 amplification were substantially different in each site. The major histological findings could be divided into massive subcutaneous necrosis with scant inflammatory cell infiltration and dense inflammatory cell infiltration. Of the 84 sites, 34 were subjected to repeated histological evaluations. In these sites, histological necrosis did not disappear over time despite standard antibiotic treatment. In contrast, the ulcers were cured and no recurrences were observed without resecting the 11 biopsied sites that lacked histological necrosis. Although quantitative PCR revealed that a lower Cp value of IS2404 was associated with histological massive necrosis, sites that showed lower Cp values clinically did not always need debridement., Conclusion/significance: Our descriptive study revealed that the histological findings and amounts of mycobacterial DNA differed according to the sites despite being found in one lesion. Our results showed that the need for surgical debridement in each site was correlated with histological necrosis without inflammatory cell infiltration, as the inflammation is supposed to represent an active host immune response rather than mycobacterial burden. We suggest that the debridement of lesions with histological necrosis in mapping biopsy may be useful for Japanese cases with unsuccessful standard antibiotic treatment to achieve sufficient clinical improvement., Competing Interests: The authors have declared that no competing interests exist.

Although annular erythema is usually observed as one of the cutaneous manifestations of Sjögren's syndrome or subacute cutaneous lupus erythematosus, autoimmune blistering diseases also present with annular erythema. However, bullous lesions are not always found, and there is a rare type without bullous lesions. We present two cases of autoimmune blistering diseases showing annular erythema without bullous lesions. It is important to perform direct or indirect immunofluorescence examination when we encounter multiple annular erythema.

Background: While the frequency of interleukin (IL)-10-producing B (B10) cells is reported to have an inverse correlation with disease activity in some human autoimmune diseases, the association between B10 cells and autoimmune blistering diseases (AIBD) has not been well evaluated. Although several phenotypes of human regulatory B cells have been proposed, the most appropriate one in AIBD has not been established., Objective: To evaluate B10 cells in AIBD including their phenotypes., Methods: Peripheral blood mononuclear cells were isolated from 39 patients with AIBD, including 14 with pemphigus and 25 with pemphigoid, and 10 healthy controls. We investigated the frequencies of B10 cells and CD19 + CD24 hi CD38 hi B cells using flow cytometry., Results: The frequencies of B10 cells and CD19 + CD24 hi CD38 hi B cells were significantly lower and higher, respectively, in patients with pemphigus compared with healthy controls. Comparing patients with pemphigoid and healthy controls, no significant difference in the frequencies of B10 cells and CD19 + CD24 hi CD38 hi B cells was observed. B10-cell level in pemphigus was not associated with disease severity but inversely correlated with the required dose of steroid for treatment. While no significant difference in the frequency of IL-10-producing cells among CD19 + CD24 hi CD38 hi B cells was observed, in CD9 + and CD27 - B-cell subsets it was significantly decreased in patients with pemphigus compared with healthy controls., Conclusions: Our results suggest the association of B10 cells with pemphigus but not with pemphigoid. The decrease in B10-cell level in pemphigus is partly caused by the lower production of IL-10 in CD9 + and CD27 - B-cell subsets., (© 2016 British Association of Dermatologists.)

Loss-of-function mutations of the IL36RN gene, encoding interleukin-36 receptor antagonist (IL-36Ra), have been reported as major pathogenic causes of generalized pustular psoriasis (GPP), especially in cases lacking previous histories of psoriasis vulgaris. Palmoplantar pustulosis (PPP), which is traditionally included among GPP-related diseases, has a controversial association with IL36RN. While a negative view about the said association has been recently published from Europe, variations of the IL36RN gene show great ethnic differences. In this study, we performed mutation analysis of the IL36RN gene in 88 Japanese patients with PPP and identified three types of single base substitutions in four patients, namely, p.Pro82Leu in two patients, p.Asn47Ser in one and p.Thr123Met in another. All variations were heterozygous and different from previous European reports. We compared the immunohistochemical findings of IL-36Ra on patients with and without variation of the IL36RN gene; however, no significant differences were observed. Our data and the previous European study suggest that PPP is not associated with mutations of the IL36RN gene., (© 2016 Japanese Dermatological Association.)

Annular erythema with Sjögren's syndrome (AESS) is occasionally found, especially in Asian patients, which is classified into three types. We present a case of Sjögren's syndrome showing various types of AESS with anti-signal recognition particle antibody-positive polymyositis. We successfully treated the eruption and myositis with a low dose of prednisolone. Every onset of annular erythema coincided with elevation of serum creatine kinase levels, which suggests the correlation between the activities of annular erythema and polymyositis., (© 2016 Japanese Dermatological Association.)

We present a refractory case of pemphigus vulgaris that achieved long-term remission after i.v. immunoglobulin treatment (IVIG). We evaluated the fluctuation of circulating interleukin-10-producing B cells (B10 cells) during the course in our case and other three patients with pemphigus treated with IVIG without clinical remission. B10 cells were observed predominantly in CD1d(-) , CD5(-) , CD9(-) and CD27(+) populations among CD19(+) cells in healthy controls, as well as in patients with pemphigus. The frequency of B10 cells among CD19(+) cells increased in our case, but not in the other three patients without clinical remission, which leads to speculation on the association between the increase of B10 cells and the achievement of long-term remission after IVIG treatment., (© 2016 Japanese Dermatological Association.)

Aims: Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort., Methods and Results: The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000-04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively., Conclusion: An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

We present a cases of Merkel cell carcinoma (MCC) with Merkel cell polyomavirus that showed complete regression after biopsy. The exact mechanism of regression in MCC has remained unclear. It has been reported that apoptosis caused by T-cell immunity was implicated in the regression, and programmed cell death 1 (PD-1), an inhibitory receptor, was expressed in approximately half of tumor-infiltrating T cells in MCC. However, the contribution of PD-1-positive cells for the regression of MCC has not been evaluated. We examined the rate of PD-1-positive cells among the peritumoral mononuclear cells, which showed that the percentage of PD-1-positive cells in the case was significantly lower compared with in MCC without regression. We propose that PD-1-positive cells suppress tumor immunity for MCC, and that reduction of PD-1-positive cells may be associated with tumor regression., (© 2015 Japanese Dermatological Association.)

Background: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood., Methods: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies., Results: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer., Conclusion: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Background: The strength of the association between brain tumors in children and residential power-frequency magnetic fields (MF) has varied in previous studies, which may be due in part to possible misclassification of MF exposure. This study aimed to examine this association in Japan by improving measurement techniques, and by extending measurement to a whole week., Methods: This population-based case-control study encompassed 54% of Japanese children under 15 years of age. After excluding ineligible targeted children, 55 newly diagnosed brain tumor cases and 99 sex-, age-, and residential area-matched controls were included in the analyses. The MF exposures of each set of matching cases and controls were measured in close temporal proximity to control for seasonal variation; the average difference was 12.4 days. The mean interval between diagnosis and MF measurements was 1.1 years. The weekly mean MF level was defined as the exposure. The association was evaluated using conditional logistic regression analysis that controlled for possible confounding factors., Results: The odds ratios (95% CI) for exposure categories of 0.1 to 0.2, 0.2 to 0.4, and above 0.4 microT, against a reference category of <0.1 microT, were 0.74 (0.17-3.18), 1.58 (0.25-9.83), and 10.9 (1.05-113), respectively, after adjusting for maternal education. This dose-response pattern was stable when other variables were included in the model as possible confounding factors., Conclusions: A positive association was found between high-level exposure-above 0.4 microT-and the risk of brain tumors. This association could not be explained solely by confounding factors or selection bias.

Objective: The relation between daily maximum temperature and mortality rate has a V-shaped pattern; the mortality rate is lowest at a certain temperature, that is, optimum temperature (OT), and the mortality rate increases when the temperature becomes higher or lower than OT. OT is associated with climate, but the relation between OT and long-term average temperature, which is a frequently used index of climate, had an outlier (Okinawa) even in Japan alone. Our objective is to determine the best climate index for OT estimation., Methods: We obtained death certificate data, meteorological data and population data for Japan from relevant government ministries. All the data obtained were from 1972 to 1995 except for Okinawa's mortality data (1973 to 1995). Using smoothing spline with the degree of freedom fixed to 6, we computed the OTs for 47 prefectures in Japan. These OTs were exhaustively compared with percentiles of daily maximum, average, and minimum temperatures, along with the long-term average temperature., Results: Among the candidates of the best climate index, 80 and 85 percentiles of daily maximum temperatures (Tmax80 and Tmax85) showed the highest correlation coefficient with OT (R>0.9, much higher than the R for the long-term average temperature, i.e., 0.63), and the regression models using Tmax80 and Tmax85 best regressed the OT, that is, the difference between the observed OT and the expected OT was smallest when Tmax80 or Tmax85 was used. Unlike previously used average of daily mean temperature, Tmax80 and Tmax85 made Okinawa a nonoutlier. This characteristic is desirable because Okinawa's being an outlier is due to its maritime climate and the capacity to accommodate a different type of climate may expand the applicability of OT estimation method to wider regions in the world. A direct comparison of OT with Tmax75 to Tmax90 revealed that the difference is smallest for the percentile between Tmax80 and Tmax85., Conclusion: We considered that a daily maximum temperature between Tmax80 and Tmax85 is the best climate index for estimating OT in Japan.

Background: Progression of endometriosis is considered estrogen-dependent. Dietary soy isoflavones may affect the risk of endometriosis, and polymorphisms in estrogen receptor genes may modify this association. We examined associations among soy isoflavone intake, estrogen receptor 2 (ESR2) gene polymorphisms and risk of endometriosis., Methods: We recruited women age 20-45 years old who had consulted a university hospital for infertility in Tokyo, Japan in 1999 or 2000. A total of 138 eligible women were diagnosed laparoscopically and classified into 3 subgroups: control (no endometriosis), early endometriosis (stage I-II) and advanced endometriosis (stage III-IV). We measured urinary levels of genistein and daidzein as markers for dietary intake of soy isoflavones, and genotyped ESR2 gene RsaI polymorphisms., Results: Higher levels of urinary genistein and daidzein were associated with decreased risk of advanced endometriosis (P for trend = 0.01 and 0.06, respectively) but not early endometriosis. For advanced endometriosis, the adjusted odds ratio for the highest quartile group was 0.21 (95% confidence interval = 0.06-0.76) for genistein and 0.29 (0.08-1.03) for daidzein, when compared with the lowest group. Inverse associations were also noted between urinary isoflavones and the severity of endometriosis (P for trend = 0.01 for genistein and 0.07 for daidzein). For advanced endometriosis, ESR2 gene RsaI polymorphism appeared to modify the effects of genistein (P for interaction = 0.03)., Conclusions: Dietary isoflavones may reduce the risk of endometriosis among Japanese women.

We examined the association between residential proximity to 60 Hz high voltage (22-500 kV) overhead transmission lines (HVOTLs) and mental health (MH). The subjects were 223 mothers with a mean age of 37 years. The distance from the subject's residence to the closest HVOTL was measured on a map. MH status was assessed by the SF-36 Health Survey, which was scored on a 0-100 point scale, and an individual with a score of 52 points or less was defined as having poor MH. Logistic regression models were used to examine the association between the distance from the subjects' residence to the closest HVOTL and MH status. The prevalence of poor MH was 15%. Among the 223 subjects, 10 lived within 100 m of a HVOTL. The adjusted odds ratios (OR) for poor MH among those who lived 101-300 m or within 100 m from HVOTL were 1.29 (95% confidence interval (CI): 0.35-10.13) and 1.87 (95% CI: 0.35-10.13), respectively, against the reference category (300+ m). MH status was not significantly associated with the distance between the subject's residence and the closest HVOTL.

Residential power-frequency magnetic fields (MFs) were labeled as a possible human carcinogen by the International Agency for Research on Cancer panel. In response to great public concern, the World Health Organization urged that further epidemiologic studies be conducted in high-exposure areas such as Japan. We conducted a population-based case-control study, which covered areas inhabited by 54% of Japanese children. We analyzed 312 case children (0-15 years old) newly diagnosed with acute lymphoblastic leukemia (ALL) or acute myelocytic leukemia (AML) in 1999-2001 (2.3 years) and 603 controls matched for gender, age and residential area. Weekly mean MF level was determined for the child's bedroom. MF measurements in each set of a case and controls were carried out as closely in time as possible to control for seasonal variation. We evaluated the association using conditional logistic regression models. The odds ratios for children whose bedrooms had MF levels of 0.4 microT or higher compared with the reference category (MF levels below 0.1 microT) was 2.6 (95% CI=0.76-8.6) for AML+ALL and 4.7 (1.15-19.0) for ALL only. Controlling for some possible confounding factors did not alter the results appreciably. Even an analysis in which selection bias was maximized did not fully explain the association. Most of the leukemia cases in the highest exposure category had MF levels far above 0.4 microT. Our results provided additional evidence that high MF exposure was associated with a higher risk of childhood leukemia, particularly of ALL., (Copyright (c) 2006 Wiley-Liss, Inc.)

This study evaluates background serum levels of selected organochlorine compounds among Japanese women of reproductive age and investigates whether lifestyle factors, especially dietary factors, may be associated with these levels. A cross-sectional study was performed on 80 Japanese women, aged 26-43 years, who complained of infertility and were confirmed not to have endometriosis. The serum levels of total toxic equivalency (TEQ), 18 polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzofurans (PCDFs), 4 coplanar polychlorinated biphenyls (cPCBs), 36 ortho-substituted polychlorinated biphenyls (PCBs), and 13 chlorinated pesticides or their metabolites were measured and data were collected on the women's age, residence, occupation, body mass index (BMI), smoking and alcohol habit and 6 dietary intakes (fish, meats, rice, vegetables, fruits and dairy products). The serum median level of total TEQ was 25.1 pg TEQ/g lipid, that of PCDDs/PCDFs/cPCBs was 11.5 pmol/g lipid, that of PCBs was 0.46 nmol/g lipid, and that of total pesticides was 1.32 nmol/g lipid. The serum levels of total TEQ, PCDDs/PCDFs/cPCBs, PCBs and pesticides were positively associated with age (P for trend=0.003, 0.01, 0.005 and 0.01, respectively) and frequent fish consumption (P for trend=0.002, 0.003, 0.0003 and 0.006, respectively). Other lifestyle factors were not associated with serum organochlorine levels. The present study suggests that Japanese women who consume fish frequently in their reproductive period tend to accumulate organochlorines in their bodies.

Endocrine-disrupting chemicals (EDCs) have been proposed as risk factors for endometriosis. Persistent organochlorine compounds, a group of suspected EDCs, are present to some extent in almost all human adipose tissue and blood via the food chain. A few animal studies have confirmed that exposure to these compounds can increase the incidence of endometriosis. In this study, we examined the associations between endometriosis and exposure to selected organochlorine compounds, including 8 polychlorinated dibenzo-p-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), 4 coplanar polychlorinated biphenyls (cPCBs), 36 ortho-substituted polychlorinated biphenyls (PCBs), and 13 chlorinated pesticides or their metabolites. The participants were 139 infertile Japanese women who were examined by laparoscopy and diagnosed as either endometriosis cases (Stages II-IV) or controls (Stages 0-I). The serum levels (lipid adjusted) of the targeted organochlorine compounds were in both 58 cases and 81 controls. There were very few differences in the various levels between endometriosis cases and controls. The total serum toxic equivalency (TEQ) value of PCDDs was significantly higher in the controls than in the cases (P=0.02). No other total TEQ values differed between cases and controls. For PCDDs, PCDFs, cPCBs, and PCBs, the multivariate odds ratio was 0.38 [95% confidence interval (CI), 0.12-1.17] and 0.41 (95% CI, 0.14-1.27) for the third and highest quartiles, respectively, compared to the lowest quartile of total TEQ values. A weak, negative dose-response relationship was evident for total TEQs (P for trend of 0.06). The results of this study provide some evidence that serum levels of these organochlorine compounds are not associated with an increased risk of endometriosis in infertile Japanese women.

Objectives: Health risk assessment and developing measures to deal with global warming (including increased heat waves) have become urgent global issues. In the present study, we measured the personally exposed temperature (Tp) during summer among residents in major Japanese cities to investigate the relation to daily maximum ambient temperature (Tmax), which is generally been used as an index of temperature exposure in epidemiological studies., Methods: Personal exposures to temperature (Tp) were measured for a week with portable monitors (HOBO H8 Loggers, Onset Computer Corporation) for 194 subjects (101 males and 93 females, aged 21-82 years) in 3 cities, i.e., Sapporo, Tokyo and Naha (Okinawa), from July to September, 2003 (73 days)., Results and Discussion: Even on days with a Tmax of 30-35 degrees C, associated with significantly increased risk of mortality in Tokyo, neither average Tp for 7-19 o'clock nor the value for 13-15 o'clock appeared to rise beyond 30 degrees C in Tokyo and 31 degrees C in Naha. It was, thus, apparent that Tp's are generally controlled to not exceed these values at least during daytime, suggesting that they could be regarded as a threshold for heat stress tolerance. On the other hand, although average Tp's for night time (0-7 o'clock) were also found to be asymptomatic at 29 degrees C in Tokyo and 30 degrees C in Naha, they were generally too high to be free from heat stress including sleep disturbance in both cities as indicated in our questionnaire study. For both cities, in days with the Tmax above 30 degrees C, the average Tmin was 26 degrees C, while average and minimum Tp's during the night time were 28 degrees C and 27 degrees C, respectively. The correlation coefficients with Tmax were generally low; 0.35 for average Tp during daytime, 0.42 for Tmin and 0.27 and 0.19 for average and minimum night time Tp, respectively.

The authors measured the exposure to intermediate-frequency (IF: 10 kHz to 30 MHz) electromagnetic fields (EMF) in residential environments. They developed a system to acquire and record waveforms of IF magnetic fields (MFs) and set 5 nanotesla (nT) for the trigger level of acquisition. They operated the system near power lines, railroads, and electrical appliances as possible sources of IF-MFs. Most of the maximum values of magnetic flux density and the time derivative for each wave were below the upper limit of the measurable range of our system (i.e., 53 nT and 10 T/s); these values were much lower than the minimum amplitudes that can theoretically induce heating or membrane excitation within biological systems. Moreover, the amplitudes of the IF-MFs were not related to those of extremely low frequency (ELF) MF measured simultaneously, indicating that IF-MFs do not underlie the associations, observed in several epidemiological studies, between residential exposure to ELF-EMF and childhood cancer.

Background: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations., Methods: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided., Results: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk., Conclusion: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Objectives: To examine whether 50-Hz magnetic fields acutely influence cognitive performance function in humans., Methods: The exposure experiment was conducted in a wooden room with three-axis coils. Twenty young subjects were exposed to circularly polarized 50-Hz/20-mu T magnetic fields for 55 min, during which they were requested to perform four cognitive performance tests for evaluation of simple reaction time, time and accuracy of choice reaction, time perception, and figure perception., Results: No subject detected the existence of the field. Statistical analysis revealed no significant influence of the exposure on the results of the tests., Conclusions: The results indicate that extremely low-frequency electromagnetic fields in the occupational environment are unlikely to interfere with human brain function so much as to lower working efficiency or accuracy.

This study is a reexamination of the possibility that exposure to extremely low frequency alternating magnetic field (ELF-MF) may influence heart rate (HR) or its variability (HRV) in humans. In a wooden room (cube with 2.7-m sides) surrounded with wire, three series of experiments were performed on 50 healthy volunteers, who were exposed to MFs at frequencies ranging from 50 to 1000 Hz and with flux densities ranging from 20 to 100 microT for periods ranging from 2 min to 12 h. In each experiment, six indices of HR/HRV were calculated from the RR intervals (RRIs): average RRI, standard deviation of RRIs, power spectral components in three frequency ranges (pVLF, pLF and pHF), and the ratio of pLF to pHF. Statistical analyses of results revealed no significant effect of ELF-MFs in any of the experiments, and suggested that the ELF-MF to which humans are exposed in their daily lives has no acute influence on the activity of the cardiovascular autonomic nervous system (ANS) that modulates the heart rate.

The purpose of this study was to examine whether low frequency magnetic field (MF) influences nighttime secretion of hormones, particularly melatonin. Ten healthy males stayed in the experimental room (2.7 m cube with 3 axis Merritt coils) on two separate nights. On one night, subjects were exposed to linearly polarized 50 Hz, 20 microT sinusoidal MF with the third (30%) and the fifth (10%) harmonics and repetitive transient waves (1 burst/s of 1 kHz waves, exponentially attenuated with a duration of 50 ms; initially 100 microT peak), and the other night was for blind control. During the nights (2000-0800 h, including sleeping time, 2300-0700 h), blood samples were collected from the subjects at 1 h intervals for determining the levels of plasma hormones (melatonin, growth hormone (GH), cortisol, prolactin) and at 10 min intervals from 2200 to 0200 h for observing the GH surge induced by sleep. Statistical analyses revealed no significant difference between the 2 nights in the profiles of the four hormones, and the result suggested that extremely low frequency (ELF) or intermediate frequency (IF) MF to which humans are exposed residentially has no acute effect on nighttime secretion of hormones, particularly melatonin., (Copyright 2002 Wiley-Liss, Inc.)

Microperoxidase-11 (MP-11), a heme-containing undecapeptide, derived from horse heart cytochrome c was utilized as a peroxidative catalyst. Catalytic characteristics of MP-11 in hydrophilic organic media were studied using 2,6-dimethoxyphenol as a reducing substrate in a series of organic solvents at various concentrations, indicating that MP-11 was active in water-miscible organic solvents but at least 5% water was compulsory for the catalytic action. Thus, MP-11 was not active in hydrophobic solvents. The pH of the water portion in the media affected the reaction rate. The optimal pH was found to be 9, where a release of protons from either an oxidizing or reducing substrate to the media was facilitated. The decolorization of water-insoluble synthetic dyes by MP-11 in 90% methanol was attempted. MP-11 showed effective decolorization activities against either azo or anthraquinone dyes. The degradation pathway for Solvent Orange 7 was investigated in detail, showing that MP-11 catalyzed the oxidative cleavage of the azo linkage to generate 1,2-naphthoquinone and 2,4-dimethylphenol as key intermediates.

According to our previous study, trimethyltin (TMT), a neurotoxicant, induces the loss of pyramidal neurons in the rat hippocampus, which is preceded by a transient increase in plasma corticosterone concentration. To address whether this transient activation of the hypothalamopituitary-adrenocortical axis is related to neuronal loss in the hippocampus, we evaluated the effects of bilateral adrenalectomy (ADX) and the chronic supplemental treatment of glucocorticoid receptor agonists after ADX on TMT-induced hippocampal damage. Peroral administration of a single dose of TMT (9 mg/kg body wt) induced the extensive loss of CA3 pyramidal neurons and reactive astrocytosis in the hippocampus, as evidenced by results of vimentin and glial fibrillary acidic protein immunohistochemistry, and the effects were profoundly exacerbated by bilateral adrenalectomy. Prolonged administration of corticosterone not only attenuated the exacerbating effects of adrenalectomy but also partially reversed the TMT-induced neuronal loss and reactive astrocytosis. Dexamethasone, but not aldosterone, could be substituted for corticosterone, suggesting a novel neuroprotective action of type II glucocorticoid receptors in the hippocampus., (Copyright 2001 Academic Press.)

Magnetic fields (MF) of 60 Hz at 1.2 microT were previously shown to inhibit the antiproliferative effect of melatonin on MCF-7 cells (Liburdy,R.P., 1993, J. Pimeal Res. 14, 89-97). In addition, three laboratories (Blackman,C.F. and Benane,S.G., 1998; Luben,R.A. and Morgan,A.P., 1998; Morris,J.E., Chrisler,W.B., Miller,D.L., Sasser,L.B. and Anderson,L.E., 1998; 20th Annual Meeting of the Bioelectromagnetics Society, At. Pete Beach, FL) independently reported results consistent with this finding. In this study, we investigated the molecular basis of the biological effects of MF using MCF-7 cells. Only 1a melatonin receptors were identified by the [125I]melatonin binding assay and RT-PCR analysis. Moreover, preceding exposures to MF of 100 microT for 3, 5 and 7 days blocked the melatonin-induced inhibition of cAMP accumulation in a time-dependent manner, while none of the melatonin receptor functions or GTPase and adenylyl cyclase activities were affected. Estrogen-evoked cell proliferation was not altered by MF either. Exposure to 1.2 microT MF exerted the same effects on the melatonin-signaling pathway as that to 100 microT. Thus, this is the first study to provide evidence that MF may cause uncoupling of signal transduction from melatonin receptors to adenylyl cyclase.

Serum pepsinogen (sPG) levels are used in gastric cancer screening programs. However, modification of sPG levels by smoking habit, according to the status of Helicobacter pylori (H. pylori) infection has been little investigated. This study investigated the effects of smoking on serum levels of pepsinogen I (PG I), pepsinogen II (PG II), and gastrin by IgG titer of antibody against H. pylori (Hp-IgG titer) using the data from 356 current-smokers and 262 non-smokers (133 never-smokers and 129 ex-smokers) in a cross-sectional study of 618 men aged 40 to 49 years. PG I, PG II, PG I / PG II ratio and gastrin were significantly associated with Hp-IgG titer in never-smokers [Spearman's correlation coefficient (95% confidence interval): 0.23 (0.07, 0.39), 0.52 (0.41, 0.63), -0.40 (-0.54,-0.27), and 0.25 (0.10, 0.41), respectively]. However, the correlation coefficients of PG I and PG II decreased in current-smokers, 0.02 (-0.1, 0.13) and 0.32 (0.22, 0.42), respectively. In H. pylori seronegative and low titer cases, the mean PG I level was significantly (P < 0.01) higher in current-smokers, compared with non-smokers. However, in high titer cases, the mean PG I level was lower in current-smokers. Mean PG II and gastrin levels, and PG I / PG II ratio did not differ according to smoking habits by Hp-IgG titer. The gastrin level was significantly correlated with PG II, but not PG I. These data indicate that current smoking influences the serum PG I level depending on Hp-IgG titer and the associations between sPGs and Hp-IgG titer. Gastrin is not involved in the modification of PG I levels by smoking.

The possible effects of repeated night-time exposure to an extremely low frequency magnetic field (ELF-MF) on melatonin were investigated in nine healthy male subjects aged 23-37 yr. The 16-week experiment consisted of 3 weeks of pre-exposure, 11 weeks of night-time exposure to MF generated from a nonheated electric sheet (ES), and 2 weeks of post-exposure recovery observation. The average MF intensity (rms, mainly 50 Hz AC) on the surface of the sheet was 0.7 microT at the head, 8.3 microT at the waist, and 3.5 microT at the feet of the subject. For each of the urine samples collected 5 times a day on scheduled sampling days, the urinary excretion rate (ng/h) of melatonin was determined, and 24 h rhythms were extracted for each subject and each experimental period (pre-exposure, first half and latter half exposure, and post-exposure periods) by the method of complex cosine curve fitting. Although estimates of the peak height, acrophase, and total daily amount of melatonin were characterized by significant variations among individual subjects, they did not reveal any statistically significant difference between exposure periods and nonexposure periods. Thus, the present study indicates that any profound effect of the MF originating from an ES on nocturnal melatonin production and its circadian rhythm is unlikely., (Copyright 2001 Wiley-Liss, Inc.)

To understand the actual viewpoints of children about daily life and the environment, the authors, adopting a participatory strategy, visited 21 classes of Japanese school children, improved in a stepwise process their ways of question-asking, and developed "WIFY"(what is important for you); a set of interactive questions composed of a basic question and three accompanying instructions. In applying WIFY, 59 fourth graders, 22 in Nagasaki, Japan and 37 in Beijing, China, reported their viewpoints in each of classroom settings. In both settings, when children were allowed to communicate with each other by the use of WIFY answering sheet, spontaneous exchanges arose and continued. WIFY itself is supposed to bring out and enhance mutual collaboration and spontaneous networking. In this instance, WIFY functioned as a communication tool. When answering sheets were collected and obtained responses were analyzed as cases, a rather materialistic view was suggested among Japanese children and a more disciplined view, which put much value on school and home, was suggested among Chinese children. Further studies are needed to confirm the changing environmental views of children from the collaborative research framework.

We analyzed the effectiveness of stereotactic radiosurgery (SRS) for recurrent astrocytic tumors histologically. Five patients were followed by pathological examination after radiosurgery treatment of recurrent astrocytic tumors. Histological diagnoses at the time of the last operation before SRS were Daumas-Duport grade II in two patients and grade IV (glioblastoma) in three patients. No histological diagnoses at the time of SRS were identified in any patients. Contrast enhanced lesions enlarged gradually on magnetic resonance (MR) images after SRS, and local control by SRS was judged as progressive disease radiologically in all patients. Four of five patients received re-operation after SRS, and the other patient died without re-operation and underwent post-mortem examination. After SRS, Ki-67 labeling indices (LIs) of recurrent astrocytomas initially diagnosed as grade II were 2.6% and 1.1%. These LIs were relatively lower than those of the control group of patients with recurrent grade II astrocytomas that were not treated by SRS. Ki-67 LIs of three glioblastomas after SRS were 23.5%, 18.6%, and 17.8%. These LIs were significantly lower than those before SRS (2.3%, 4.5%, and 0.9%). In the autopsy case, there was a significant difference between the LI of tumor cells in the radiosurgically treated region (0.9%) and that in the untreated region (29.2%). These results suggest that the proliferative potential of malignant astrocytic tumors in the radiosurgically treated area is reduced after SRS, and that radiological enlargement of enhanced lesions on MR images is due to propagation of the residual tumor cells that were not covered by radiosurgical target volume or to radiation necrosis. SRS may be a useful therapeutic tool in multidisciplinary treatment of malignant gliomas.

Few studies have prospectively examined endogenous hormone levels as risk factors for breast cancer. The present study compares prediagnostic hormone levels using stored serum from breast cancer cases and controls selected from the Life Span Study population of the Radiation Effects Research Foundation in Hiroshima and Nagasaki, Japan. Stored serum samples collected in 1968-1970 were assayed for 72 women subsequently diagnosed with breast cancer and 150 control subjects in 72 case-control sets matched on age, date of blood collection, exposure, radiation dose, and city. Serum levels were determined for sex hormone binding globulin, total estradiol (E2), bioavailable E2, dehydroepiandrosterone sulfate, and prolactin. Matched case-control comparisons of hormone levels were carried out by conditional logistic regression and were adjusted for menopausal status at the time of blood drawing. The odds ratio per unit log change in bioavailable E2 was 2.2 [95% confidence interval (CI), 1.02-5.31 for all subjects, and 2.3 (95% CI, 0.55-6.8) and 2.1 (95% CI, 0.55-9.7), respectively, based only on premenopausal or postmenopausal serum. The estimated odds ratios in each quintile of bioavailable E2 level, using the lowest quintile as referent, were 1.00, 1.89, 1.43, 3.45, and 3.37 (P for trend = 0.035). For sex hormone binding globulin, the overall odds ratio was 0.58 (95% CI, 0.14-2.26), and 1.00 (95% CI, 0.19-5.45) and 0.21 (95% CI, 0.02-1.88) based on premenopausal and postmenopausal serum, respectively. This study offers further prospective support for the hypothesis that a high level of biologically available E2 is a risk factor for the subsequent development of breast cancer.

The prevalence of nocturia among Japanese community-dwelling adults was associated with insomnia, taking into account other correlates of insomnia.

Prevalences of periodic limb movement-like and restless legs-like symptoms among Japanese adults were investigated. The latter symptom was significantly associated with insomnia.

It has been reported that matrix metalloproteinases (MMPs) are highly expressed in malignant glioma cells and that this increased expression may facilitate the invasiveness of tumor cells. The authors investigated the expression and enzymatic activity of MMPs in rat brain during the growth of malignant gliomas at different time intervals. C6 rat glioma cells were unilaterally implanted into rat cerebral hemispheres. After 7 or 14 days, these brain tissues were prepared for SDS-PAGE zymography, Western blotting, immunohistochemistry, and in situ zymography. SDS-PAGE zymography and Western blotting revealed that the expression of proMMP-2 in rat brains with C6 glioma cells was significantly higher than that in normal or the sham-operated rat brains, and that the activated form of MMP-2 was detected only in the former but not in the latter. On immunohistochemistry, C6 glioma cells presenting invasive growth into the rat brain parenchyma and vessels demonstrated MMP-2 immunoreactivity. On in situ zymography, foci of invasive C6 glioma cells in rat brain tissue showed gelatinolytic activity. These results suggest that expression and activation of MMP-2 may be one of the crucial steps for glioma cell invasion into the brain parenchyma in vivo.

Serum concentrations of carotenoids, alpha-tocopherol, fatty acids, and thiobarbituric acid-reactive substances (TBARS) were measured in 217 Japanese residents of Japan, and in 99 Japanese and 100 Caucasian residents of the US, aged from 50 y to 74 y. In females, serum values of carotenoids such as beta-carotene (BC) and zeaxanthin & lutein (ZL) were highest among Japanese in Japan, followed by Japanese in the US and Caucasians in the US. In males, these values, except for serum BC values, were also highest among Japanese in Japan. Moreover, serum values of n-3 polyunsaturated fatty acids (n-3PUFAs) such as eicosapentaenoic acid and docosahexaenoic acid were significantly higher among Japanese in Japan than among Japanese and Caucasians in the US in both sexes. In contrast, serum values of n-6 polyunsaturated fatty acids such as linoleic acid and arachidonic acid were lowest among Japanese in Japan. For women, serum levels of n-9 unsaturated fatty acids were lowest among Japanese living in Japan. Serum TBARS values were highest among Japanese in Japan, followed by Japanese in the US and Caucasians in the US. A significant positive correlation was observed between serum values of TBARS and n-3 PUFAs among Japanese both in Japan and in the US. Serum TBARS values showed a significant inverse relationship with the serum values of BC and ZL among Japanese in Japan and with those of BC among Japanese in the US. These relationships were not always observed among Caucasians in the US. The results of this study suggest that the high TBARS values among Japanese in Japan may depend in part on lipid peroxidation induced in vitro by n-3PUFAs, while high reduction of lipid peroxidation could be expected among Japanese in Japan with high antioxidants such as BC and ZL. In conclusion, serum levels of nonprovitamin A carotenoids such as ZL may be a useful intake marker of vegetables. Dietary intakes of dark green vegetables and fish rich in n-3PUFAs might be more important in the prevention of some sites of cancer and of ischemic heart disease.

The production of amyloid beta protein precursor (APP), which is a potent inhibitor of matrix metalloproteinases and serine proteinases, in human astrocytic tumors (n = 17) and normal brain tissues (n = 3) was investigated. We found proteinase inhibitory activity at around 120 kD by trypsin reverse zymography in the culture media of explant cultures of anaplastic astrocytomas and glioblastomas, but not in those of astrocytomas and normal brain tissues. Immunohistochemistry using a monoclonal antibody against human APP demonstrated that APP was detectable mainly in tumor and endothelial cells. Semiquantative analysis of western blotting revealed that immunoreactivity for APP in the culture media of tumor explant cultures appeared to be increased associated with the malignancy of astrocytic tumors. These findings suggest that APP production may be related to the malignant progression of human astrocytic tumors.

Background: Helicobacter pylori infection and atrophic gastritis (AG) are markedly more prevalent in Japan than in other industrialized countries, however, the reasons for such a high prevalence are not fully understood. To add to information on H. pylori infection and its association with AG, the authors studied Japanese living in less developed countries., Methods: Cross-sectional surveys were conducted of randomly selected Japanese residents aged 40-59 years in São Paulo, Brazil and Lima, Peru. Serum IgG antibody to H. pylori and pepsinogen I (PGI) and II (PGII) were measured as markers of AG., Results: The prevalence of H. pylori infection was similar in both populations, 77% (95% CI: 70-83) in São Paulo and 75% (95% CI: 65-82) in Lima, and was within the range of five populations in Japan from our previous study. However, the prevalence of AG, defined by PGI < 70 ng/ml and PGI/PGII < 3.0 was more prevalent among Japanese in São Paulo (39% [95% CI: 32-47]), than Japanese in Lima (18% [95% CI: 12-27]). This difference was not explained by sex, age, generation or H. pylori infection., Conclusions: Helicobacter pylori infection among Japanese in less developed countries was similar to Japanese in Japan, although prevalence of AG varied. Factors other than H. pylori infection are important in the development of AG among Japanese.

Binding properties of lignin peroxidase (LiP) from the basidiomycete Phanerochaete chrysosporium against a synthetic lignin (dehydrogenated polymerizate, DHP) were studied with a resonant mirror biosensor. Among several ligninolytic enzymes, only LiP specifically binds to DHP. Kinetic analysis revealed that the binding was reversible, and that the dissociation equilibrium constant was 330 microM. The LiP-DHP interaction was controlled by the ionization group with a pKa of 5.3, strongly suggesting that a specific amino acid residue plays a role in lignin binding. A one-electron transfer from DHP to oxidized intermediates LiP compounds I and II (LiPI and LiPII) was characterized by using a stopped-flow technique, showing that binding interactions of DHP with LiPI and LiPII led to saturation kinetics. The dissociation equilibrium constants for LiPI-DHP and LiPII-DHP interactions were calculated to be 350 and 250 microM, and the first-order rate constants for electron transfer from DHP to LiPI and to LiPII were calculated to be 46 and 16 s-1, respectively. These kinetic and spectral studies strongly suggest that LiP is capable of oxidizing lignin directly at the protein surface by a long-range electron transfer process. A close look at the crystal structure suggested that LiP possesses His-239 as a possible lignin-binding site on the surface, which is linked to Asp-238. This Asp residue is hydrogen-bonded to the proximal His-176. This His-Asp...proximal-His motif would be a possible electron transfer route to oxidize polymeric lignin.

Changes in cerebral hemodynamics and metabolism following cerebral revascularization were evaluated using positron emission tomography (PET). Ten patients who had received nonsurgical treatment for 3-6 months for minor completed stroke underwent superficial temporal artery to middle cerebral artery (STA-MCA) bypass surgery. All patients showed no extensive infarction on MR, and responsible vascular lesions were detected in the anterior circulation. A PET study of cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate for oxygen (CMRO2), and cerebral metabolic rate for glucose (CMRGlu) measurements was performed before and 1.5 months after surgery using a steady state technique. Angiographically, anastomotic sites were patent in all patients. Seven patients showed neurological improvement after surgery and the others showed no improvement. The decreases in CBF, CMRO2 and CMRGlu recovered to some extent not only on the lesion side but also on the contralateral side after surgery. The increase in OEF values on the lesion side subsequently decreased after surgery. CMRO2 and CMRGlu showed parallel changes. It is concluded that the metabolic improvement afforded by the cerebral revascularization resulted in the neurological improvement, and that PET study is a powerful method for evaluating patients with cerebral occlusive diseases.

To clarify the relation between neuronal protection against ischaemia and calcium/calmodulin-dependent protein kinase II (CaM kinase II) activity, we investigated temporal alterations of the kinase activity in the hippocampus after transient forebrain ischaemia under neuroprotective conditions, employing the gerbil bilateral carotid artery occlusion model. The hippocampal CA1 neuronal density at 2 hours after 5 minutes of forebrain ischaemia was 214.7 +/- 25.8/mm (mean +/- S.D.), and did not differ from the control significantly; however, it decreased to 11.7 +/- 4.2/mm at 7 days after the ischaemia. The neuronal density at 7 days after the ischaemia was 185.1 +/- 18.5 under the hypothermic conditions, 128.7 +/- 19.6 with the brief ischaemic pretreatment, 65.0 +/- 13.4 with administration of MK-801, and 20.5 +/- 4.2 with the repetitive hyperthermic pretreatment, respectively. The Ca2+/calmodulin-dependent activity of CaM kinase II in the hippocampal cytosolic fraction was decreased to 47.5% of the control value at 2 hours after the ischaemia, when CA1 neuronal death was not observed. In contrast, the activity was 98.8% of the control under the hypothermic conditions, 91.4% with the brief ischaemic pretreatment, 71.2% with administration of MK-801, and 47.9% with the repetitive hyperthermic pretreatment, respectively. These results indicated that the preservation of the Ca2+/calmodulin-dependent activity of cytosolic CaM kinase II after ischaemia parallelled the neuroprotective effect in the gerbil hippocampus. Thus, it is suggested that the preservation of the activity may be involved in the mechanism of neuronal protection against ischaemia.