Life-threatening coronary vasospasm in patients with type 2 diabetes with SGLT2 inhibitor-induced euglycemic ketoacidosis: a report of two consecutive cases.

Euglycemic diabetic ketoacidosis (eDKA) has emerged as an adverse event associated with sodium-glucose transporter-2 inhibitors (SGLT2i). We present two consecutive cases of SGLT2i-induced eDKA, both manifested as life-threatening coronary vasospastic angina (VSA). Case 1: A 64-year-old male overweight patient with type 2 diabetes (BMI 28.2 kg/m2), treated with dapagliflozin 5 mg daily for 6 months and a restricted diet for 2 months, experienced loss of consciousness following severe chest pain while driving, resulting in a traffic accident: plasma glucose, 163 mg/dL; urine ketones, (+++); bicarbonate (HCO3-), 13.2 mmol/L; and total ketone body, 1539 µmol/L. Coronary angiography (CAG) performed on day 5 revealed diffusely spastic coronary arteries with 90% stenosis in the right coronary artery, leading to the diagnosis of VSA in the presence of coronary atherosclerosis. Case 2: A 63-year-old male patient with type 2 diabetes (BMI 22.2 kg/m2) experienced severe chest discomfort and faintness following 2 months of chest pain while on dapagliflozin 10 mg daily for 1 year: plasma glucose, 112 mg/dL; urine ketones, (+++); HCO3-, 15.3 mmol/L; and total ketone body, 10,883 µmol/L. CAG performed on day 10 revealed no organic stenosis but diffusely spastic coronary arteries in response to coronary ergonovine infusion, confirming the diagnosis of VSA. SGLT2i has the potential to inhibit acetylcholine and butyrylcholine esterase activities, leading to reduced scavenging of acetylcholine and possible induction of coronary vasospasm. These cases highlight the association between life-threatening VSA and SGLT2i-induced eDKA.

Developing an Artificial Intelligence-Based Pediatric and Adolescent Migraine Diagnostic Model.

Introduction Misdiagnosis of pediatric and adolescent migraine is a significant problem. The first artificial intelligence (AI)-based pediatric migraine diagnosis model was made utilizing a database of questionnaires obtained from a previous epidemiological study, the Itoigawa Benizuwaigani Study. Methods The AI-based headache diagnosis model was created based on the internal validation based on a retrospective investigation of 909 patients (636 training dataset for model development and 273 test dataset for internal validation) aged six to 17 years diagnosed based on the International Classification of Headache Disorders 3rd edition. The diagnostic performance of the AI model was evaluated. Results The dataset included 234/909 (25.7%) pediatric or adolescent patients with migraine. The mean age was 11.3 (standard deviation 3.17) years. The model's accuracy, sensitivity (recall), specificity, precision, and F-values for the test dataset were 94.5%, 88.7%, 96.5%, 90.0%, and 89.4%, respectively. Conclusions The AI model exhibited high diagnostic performance for pediatric and adolescent migraine. It holds great potential as a powerful tool for diagnosing these conditions, especially when secondary headaches are ruled out. Nonetheless, further data collection and external validation are necessary to enhance the model's performance and ensure its applicability in real-world settings.

School-Based Stroke Education Through On-Demand E-learning During Coronavirus Disease 2019 Pandemic: Itoigawa Stroke Awareness Campaign.

Introduction Raising stroke awareness is important to shorten the interval from onset to consultation. We performed a school-based stroke education by on-demand e-learning during the coronavirus disease 2019 pandemic. Methods We performed on-demand e-learning and distributed the online- and paper-based manga about stroke for students and parental guardians in August 2021. We carried out this in a manner similar to the prior effective online stroke awareness initiatives in Japan. An online post-educational survey in October 2021 was conducted to evaluate the awareness effects by asking participants about their knowledge. We also investigated the modified Rankin Scale (mRS) at the discharge of stroke patients who were treated in our hospital during the before- and after-campaign periods, respectively. Results We distributed the paper-based manga and asked to work on this campaign to all 2,429 students (1,545 elementary school and 884 junior high school students) who lived in Itoigawa. We acquired 261 (10.7%) online responses from the students and 211 (8.7%) responses from their parental guardians. The number of students who chose all correct answers in the survey significantly increased after the campaign (205/261, 78.5%) compared to that before the campaign (135/261, 51.7%) and those of parental guardians showed similar trends (before campaign 93/211, 44.1%; after campaign 198/211, 93.8%). We investigated 282 stroke patients (90 patients before and 192 patients after-campaign period), and their mRS at discharge after-campaign seemed to be improved. Conclusion Only 10.7% of students and 8.7% of the parental guardians worked on the online survey. However, the number of those who chose correct answers about stroke increased after the campaign. After this campaign, the mRS of stroke patients at discharge improved although it was unclear if this is a direct result of this activity.

School-based online survey on chronic headache, migraine, and medication-overuse headache prevalence among children and adolescents in Japanese one city - Itoigawa Benizuwaigani study.

BACKGROUND: We investigated the prevalence of headache, migraine, and medication-overuse headache (MOH) among children and adolescents through a school-based online questionnaire. We also investigated the triggers for migraine among them and the effect of the COVID-19 pandemic on headache frequency. METHODS: Children and adolescents aged 6-17 y.o. completed an online questionnaire. Migraine, MOH was defined as The International Classification of Headache Disorders Third edition. Factor and clustering analyses were performed for migraine triggers. The effect of the coronavirus disease 2019 (COVID-19) pandemic on headache frequency was also asked. RESULTS: Of the 2489 respondents, the prevalence of headache, migraine, and MOH were 36.44%, 9.48%, and 0.44%, respectively. Up to 70% of the respondents with headaches complained of the disturbance to daily life, but about 30% consulted doctors. The migraine triggers were grouped into 5 factors by factor analysis. The sensitivities of the migraineurs against the factors were divided into 3 clusters. Cluster 1 had stronger sensitivity for several triggers. Cluster 2 was sensitive to weather, smartphones, and video games. Cluster 3 had less sensitivity for triggers. Cluster 2 less consulted doctors even though the burden of migraine was enormous. During the COVID-19 pandemic, 10.25% of respondents increased headache attacks, while 3.97% decreased. CONCLUSIONS: This is the first detailed study on headache prevalence in Japanese students from elementary school to high school in one region. The burden of headaches is large among children and adolescents, and the unmet needs of its clinical practice should be corrected.

Headache education by leaflet distribution during COVID-19 vaccination and school-based on-demand e-learning: Itoigawa Geopark Headache Awareness Campaign.

OBJECTIVE: We prospectively performed the Itoigawa Headache Awareness Campaign from August 2021 to June 2022, with two main interventions, and evaluated its effectiveness. BACKGROUND: Headache is a common public health problem, but its burden could be reduced by raising awareness about headache and the appropriate use of acute and prophylactic medication. However, few studies on raising headache awareness in the general public have been reported. METHODS: The target group was the general public aged 15-64. We performed two main interventions synergistically supported by other small interventions. Intervention 1 included leaflet distribution and a paper-based questionnaire about headache during COVID-19 vaccination, and intervention 2 included on-demand e-learning and online survey through schools. In these interventions, we emphasize the six important topics for the general public that were described in the Clinical Practice Guideline for Headache Disorders 2021. Each response among the two interventions' cohorts was collected on pre and post occasions. The awareness of the six topics before and after the campaign was evaluated. RESULTS: We obtained 4016 valid responses from 6382 individuals who underwent vaccination in intervention 1 and 2577 from 594 students and 1983 parents in intervention 2; thus, 6593 of 20,458 (32.2%) of the overall working-age population in Itoigawa city experienced these interventions. The percentage of individuals' aware of the six topics significantly increased after the two main interventions ranging from 6.6% (39/594)-40.0% (1606/4016) to 64.1% (381/594)-92.6% (1836/1983) (p < 0.001, all). CONCLUSIONS: We conducted this campaign through two main interventions with an improved percentage of individuals who know about headache. The two methods of community-based interventions could raise headache awareness effectively. Furthermore, we can achieve outstanding results by doing something to raise disease awareness during mass vaccination, when almost all residents gather in a certain place, and school-based e-learning without face-to-face instruction due to the COVID-19 pandemic.

Questionnaire-Based Survey during COVID-19 Vaccination on the Prevalence of Elderly's Migraine, Chronic Daily Headache, and Medication-Overuse Headache in One Japanese City-Itoigawa Hisui Study.

BACKGROUND: The prevalence of headache disorders, migraine, chronic daily headache (CDH), and medication-overuse headache (MOH) among the elderly in Japan has not been sufficiently investigated. We performed a questionnaire-based survey and revealed 3-month headache prevalence and headaches' characteristics. METHODS: The population aged over 64 was investigated in Itoigawa during their third coronavirus disease 2019 vaccination. Migraine, MOH was defined as The International Classification of Headache Disorders Third edition. CDH was defined as a headache occurring at least 15 days per month. K-means++ were used to perform clustering. RESULTS: Among 2858 valid responses, headache disorders, migraine, CDH, and MOH prevalence was 11.97%, 0.91%, 1.57%, and 0.70%, respectively. Combined-analgesic and non-opioid analgesic were widely used. Only one migraineur used prophylactic medication. We performed k-means++ to group the 332 MOH patients into four clusters. Cluster 1 seemed to have tension-type headache-like headache characteristics, cluster 2 seemed to have MOH-like headache characteristics, cluster 3 seemed to have severe headaches with comorbidities such as dyslipidemia, stroke, and depression, and cluster 4 seemed to have migraine-like headache characteristics with photophobia and phonophobia. CONCLUSIONS: This is the largest prevalence survey in the Japanese elderly. Headache disorders are still the elderly's burden. Clustering suggested that severe headaches associated with some comorbidities may be unique to the elderly.

Acrylamide-Hemoglobin Adduct Levels in a Japanese Population and Comparison with Acrylamide Exposure Assessed by the Duplicated Method or a Food Frequency Questionnaire.

The levels of hemoglobin adducts of acrylamide (AA-Hb), a biomarker of acrylamide exposure, have not been reported for Japanese subjects. Herein, we determined the AA-Hb levels in a Japanese population and compared them with the estimated dietary intake from the duplicate diet method (DM) and a food frequency questionnaire (FFQ). One-day DM samples, FFQ, and blood samples were collected from 89 participants and analyzed for acrylamide. AA-Hb was analyzed using liquid chromatography tandem mass spectrometry and the N-alkyl Edman method. Participants were divided into tertiles of estimated acrylamide intake and geometric means (GMs) of AA-Hb adjusted for sex and smoking status. A stratified analysis according to smoking status was also performed. The average AA-Hb levels for all participants, never, past, and current smokers were 46, 38, 65, and 86 pmol/g Hb, respectively. GMs of AA-Hb levels in all participants were significantly associated with tertiles of estimated acrylamide intake from DM (p for trend = 0.02) and FFQ (p for trend = 0.04), although no association with smokers was observed. AA-Hb levels reflected smoking status, which were similar to values reported in Western populations, and they were associated with estimated dietary intake of acrylamide when adjusted for sex and smoking status.

Dietary exposure to acrylamide in a group of Japanese adults based on 24-hour duplicate diet samples.

Acrylamide is a probable human carcinogen and known human neurotoxin that can be generated in food through heating. Using a mathematical modelling approach, our previous study estimated long-term average dietary exposure to acrylamide in the Japanese people; however, the validity of these estimates remained unknown. Here, we aimed to obtain a more accurate estimate of acrylamide exposure that would reflect the usual practice of heat processing and consumption of foods in the population. We collected duplicate diet samples and dietary records during 24 h from a group of Japanese adults. A total of 110 duplicate diet samples were analysed for acrylamide by LC-MS/MS. Data from individual dietary records were used to examine the association between dietary acrylamide exposure and consumption of selected food groups (e.g., coffee, tea, confectioneries, and vegetables prepared at high temperature [deep-frying, stir-frying, sautéing, and baking]). Of the 110 homogenised diet samples, 108 contained detectable levels of acrylamide. Dietary exposure to acrylamide ranged from 8 to 1582 ng/kg body weight (bw)/day, with the mean value of 215 ng/kg-bw/day and median value of 143 ng/kg-bw/day. This mean value was higher than the value we previously estimated for Japanese adults using a mathematical approach. Multiple linear regression analysis showed log dietary acrylamide exposure was significantly associated with consumption of coffee and vegetables prepared at high temperature during 24-hr of sampling (adj. R2 = 0.250, p < 0.001). We revealed significant difference in dietary acrylamide exposure between participants who had coffee and vegetables prepared at high temperature (median, 169 ng/kg-bw/day; range, 35-1224 ng/kg-bw/day, n = 42) and those who had none of them (median, 75 ng/kg-bw/day; range, 8-311 ng/kg-bw/day, n = 15) (Steel-Dwass test, p < 0.05).

Estimation of long-term dietary exposure to acrylamide of the Japanese people.

Acrylamide is a probable human carcinogen and known human neurotoxin. This study estimated hypothetical long-term dietary exposure to acrylamide of the Japanese people using probabilistic and deterministic approaches by combining the concentration of acrylamide in foods with the amount and frequency of food consumption in the population. Data included acrylamide concentrations in more than 2400 individual food samples from a national survey and the literature from 2004 to 2013. Food consumption amounts were derived from the data of 24,293 Japanese citizens aged 1 year and older in the 2012 National Health and Nutrition Survey. Median lifetime average dietary exposure to acrylamide was estimated as 147-154 ng/kg body weight (bw)/day (95th percentile, 226-261 ng/kg bw/day). The deterministic estimate of lifetime exposure was 158 ng/kg bw/day and ranged from 119 ng/kg bw/day for the period of life after 60 years old to 409 ng/kg bw/day for the period between 1 and 6 years old. This study found that vegetables cooked at a high temperature, coffee and cooked potato were the major food groups contributing to long-term dietary acrylamide exposure of the Japanese people.

Daily inhalation rate and time-activity/location pattern in Japanese preschool children.

Lack of data on daily inhalation rate and activity of children has been an issue in health risk assessment of air pollutants. This study aimed to obtain the daily inhalation rate and intensity and frequency of physical activity in relation to the environment in Japanese preschool children. Children aged four-six years (n= 138) in the suburbs of Tokyo participated in this study, which involved three days' continuous monitoring of physical activity using a tri-axial accelerometer and parent's completion of a time/location diary during daily life. The estimated three-day mean daily inhalation rate (body temperature, pressure, saturated with water vapor) was 9.9 ± 1.6 m(3) /day (0.52 ± 0.09 m(3) /kg/day). The current daily inhalation rate value of 0.580 m(3) /kg/day proposed for use in health risk assessment in Japan is confirmed to be valid to calculate central value of inhaled dose of air pollutants in five- to six-year-old children. However, the 95th percentile daily inhalation rate of 0.83 m(3) /kg/day based on measurement for five-year-old children is recommended to be used to provide an upper bound estimate of exposure that ensure the protection of all five- to six-year-old children from the health risk of air pollutants. Children spent the majority of their time in sedentary and light level of physical activity (LPA) when indoors, while 85% of their time when outdoors was spent in LPA and moderate-to-vigorous physical activity. The results suggest the need to consider variability of minute respiratory ventilation rate according to the environment for more refined short-term health risk assessment.

Estimation of daily inhalation rate in preschool children using a tri-axial accelerometer: a pilot study.

The activity of 5- to 6-year-old Japanese children (n=29) was monitored for 3 consecutive days, including one weekend day, using an ActivTracer tri-axial accelerometer. The daily inhalation rate and time spent in sedentary, light, or moderate to vigorous levels of physical activity (MVPA) were estimated from the accelerometer measurements based on previously developed regression equations. The 3-day mean daily inhalation rate (STPD) was estimated at 8.3±1.4 m(3) day(-1) in 10 subjects who completed 3 days of monitoring. The time spent in sedentary, light, or MVPA each day was 320, 415, and 81 min day(-1), respectively. Analysis of between-day reliability indicated that 3 days of monitoring with the ActivTracer tri-axial accelerometer provided an acceptable estimate of daily inhalation rate (intra-class correlation coefficient [ICC]=0.892), but low to moderate reliability for the time spent in different levels of activities (ICC=0.43 to 0.58). We observed a significant difference in the daily inhalation rate between weekdays and the weekend day, possibly due to differences in time spent in MVPA. This finding suggests that a weekend day should be included to obtain more reliable estimates of daily inhalation rate using an accelerometer.

Estimation of the respiratory ventilation rate of preschool children in daily life using accelerometers.

Inhalation rate is an essential factor for determining the inhaled dose of air pollutants. Here, accelerometers were used to develop regression equations for predicting the minute ventilation rate (V(E)) to estimate the daily inhalation rate in young children. Body acceleration and heart rate were measured in 29 Japanese preschool children (6 yr of age) during nine different levels of activities (lying down, sitting, standing, playing with plastic bricks, walking, building with blocks, climbing stairs, ball tossing, and running) using the Actical omnidirectional accelerometer, the ActivTracer triaxial accelerometer, and a heart rate monitor. Measurements were calibrated against the V(E) measured by the Douglas bag method. ActivTracer accelerometer measurements gave a strong correlation with V(E) (Pearson's r = 0.913), which was marginally stronger than that for the Actical counts (r = 0.886) and comparable to the correlation between heart rate and logarithmic V(E) (r = 0.909). According to the linear regression equation, the V(E) for lying down, sitting, standing, playing with plastic bricks, walking, and running was overestimated by 14-60% by the Actical and by 14-37% by the ActivTracer. By comparison, for building with blocks, climbing stairs, and ball tossing, the V(E) was underestimated by 19-23% by the Actical and by 13-18% by the ActivTracer. When these three activities were excluded, a stronger correlation was found between the V(E) and ActivTracer measurements (r = 0.949); this correlation was 0.761 for the three excluded activities. Discriminant analysis showed that the ratio between vertical and horizontal acceleration obtained by the ActivTracer could discriminate walking from building with blocks, climbing stairs, and ball tossing with a sensitivity of 75%. The error in estimating V(E) was considerably improved for the ActivTracer measurements by the use of two regression equations developed for each type of activity.

[Correlation analysis of urinary 1-hydroxypyrene levels between children and their mothers with respect to dietary intake].

Vulnerability of children to toxic substances is of great concern due to their susceptibility and specific exposure profiles. In this study, we examined urinary 1-hydroxypyrene (1-OHP) levels in 134 kindergarten children and their mothers in order to assess exposure profiles from foods. Mean concentration of 1-OHP in children (0.083 micromol/mol-creatinine) was 1.8-fold higher than that in mothers (0.046 micromol/mol-creatinine). Nonetheless, a significant correlation was observed between 1-OHP levels in the two groups, which presumably reflected the similarities of diet between child and mother on the day before urine sampling. Moreover, intake of foodstuff, such as meat and/or fish, elevated the urinary 1-OHP levels, apparently due to high cooking temperature. These results demonstrate the importance of exposure assessment of toxic substances (in children via the diet).

[Assessment of exposure to polycyclic aromatic hydrocarbons in Japanese children].

OBJECTIVES: To estimate the level of exposure to polycyclic aromatic hydrocarbons (PAHs) in Japanese children by urinary metabolite analysis and the possible contribution of soil ingestion and environmental tobacco smoke (ETS) to PAHs exposure. METHODS: Spot urine samples and questionnaire data were collected from 107 kindergarten children (3-6 yrs) and their mother. The urinary concentration of 1-hydroxypyrene (1-OHP), a biomarker of PAHs exposure, was measured using a high performance liquid chromatography-fluorescence detector. RESULTS: The geometric mean (GM) of urinary 1-OHP concentrations in children was 0.065 mumol/mol-cre (geometric standard deviation=1.88). Parental smoking and time of playing outside (surrogate of soil exposure level) did not increase urinary 1-OHP level. Maternal urinary 1-OHP concentration correlated with, whereas GM (0.038 mumol/mol-cre) was significantly lower than, the urinary 1-OHP concentration in children. The latter might be attributable to greater amount of food intake per body weight for children than for adult. CONCLUSIONS: The contribution of ETS and soil ingestion to PAHs exposure seemed to be small and thus they cannot be the major source of PAHs in Japanese children.

Triaxial accelerometry for assessment of physical activity in young children.

OBJECTIVE: The purpose of the present study was to derive linear and non-linear regression equations that estimate energy expenditure (EE) from triaxial accelerometer counts that can be used to quantitate activity in young children. We are unaware of any data regarding the validity of triaxial accelerometry for assessment of physical activity intensity in this age group. RESEARCH METHODS AND PROCEDURES: EE for 27 girls and boys (6.0 +/- 0.3 years) was assessed for nine activities (lying down, watching a video while sitting and standing, line drawing for coloring-in, playing blocks, walking, stair climbing, ball toss, and running) using indirect calorimetry and was then estimated using a triaxial accelerometer (ActivTracer, GMS). RESULTS: Significant correlations were observed between synthetic (synthesized tri-axes as the vector), vertical, and horizontal accelerometer counts and EE for all activities (0.878 to 0.932 for EE). However, linear and non-linear regression equations underestimated EE by >30% for stair climbing (up and down) and performing a ball toss. Therefore, linear and non-linear regression equations were calculated for all activities except these two activities, and then evaluated for all activities. Linear and non-linear regression equations using combined vertical and horizontal acceleration counts, synthetic counts, and horizontal counts demonstrated a better relationship between accelerometer counts and EE than did regression equations using vertical acceleration counts. Adjustment of the predicted value by the regression equations using the vertical/horizontal counts ratio improved the overestimation of EE for performing a ball toss. DISCUSSION: The results suggest that triaxial accelerometry is a good tool for assessing daily EE in young children.

Dietary exposure to organophosphorus pesticides for young children in Tokyo and neighboring area.

Dietary ingestion is a significant pathway of human exposure to organophosphorus (OP) pesticides. This study aims to determine the occurrence of OP pesticide in the diet of young children in Japan and estimate their exposure. The study was conducted by analyzing duplicate diet samples collected from 33 children aged 3 to 6 years old in Tokyo and the nearby area in Japan. Seven OP pesticides that are mainly used for agriculture in Japan (fenitrothion, trichlorfon, dichlorvos, diazinon, chlorpyrifos, malathion, and EPN) were targeted for analysis. As a result of the study, fenitrothion was frequently found in the week's diet (21%) of children, followed by diazinon (14%), chlorpyrifos (11%), and malathion (4%); the daily intake of pesticides was also estimated to range from < 110 to 180 ng/day, < 70 to 800 ng/day, < 70 to 100 ng/day, and < or = 110 ng/day, respectively. Daily intake of diazinon per kg body weight was relatively higher than other target pesticides and the maximum value was 50 times below the acceptable daily intake set by Japan Ministry of Health and Labor Welfare. Occurrence of malathion in the diet of children in the present study was lower than that reported in 1980s, supposed due to the decreasing level of malathion in wheat and wheat products. Frequent detection of fenitrothion in diet is a significant trend observed in Japan, and is considered due to the high and widespread usage of the pesticide inside of the country.

Roles of mTOR and JNK in serine phosphorylation, translocation, and degradation of IRS-1.

In 3T3-L1 adipocytes, insulin or anisomycin stimulated phosphorylation of IRS-1 at Ser(307) and Ser(636/639), both of which were partially reduced by the mTOR inhibitor, rapamycin, or the JNK inhibitor, SP600125, and were further inhibited by a combination of them. Interestingly, anisomycin-induced p70(S6K) phosphorylation was reduced by SP600125, while insulin-induced p70(S6K) phosphorylation was not. Furthermore, unlike insulin, anisomycin failed to elicit translocation or degradation of IRS-1. These results indicate that mTOR and JNK play roles in phosphorylating IRS-1 serine residues, and that insulin and anisomycin are different in terms of the relationship of activation between mTOR and JNK, and the effects on IRS-1 localization and stability.

Air pollution and young children's inhalation exposure to organophosphorus pesticide in an agricultural community in Japan.

Assessment of airborne organophosphorus pesticides in houses of young children (1-6 years old) and childcare facilities was conducted following pesticide applications in an agricultural community in Japan. Trichlorfon and fenitrothion, applied in two separate periods, were frequently detected from outdoor and indoor air. Dichlorvos, the primary degradation product of trichlorfon, was also detected after the application of trichlorfon. Both the outdoors and indoor concentration of applied pesticide were shown to increase with decreasing distance from the pesticide-applied farm. Indoor concentration of these pesticides significantly correlated with outdoor concentration (p=0.001 for trichlorfon and p=0.001 for fenitrothion), indicating infiltration of applied pesticide inside. Ratio of indoor to outdoor concentration (I/O ratio) of fenitrothion was higher for houses with windows open during the application than those with closed windows (median value: 0.74 vs. 0.16, p=0.003). However, a similar trend was not observed for trichlorfon as well as dichlorvos in the first period. Dichlorvos was found to have a higher I/O ratio than trichlorfon during the period, and clear correlation between indoor concentrations of dichlorvos and those of trichlorfon suggested increased decomposition of trichlorfon in the indoor environment. Daily inhalation exposure estimated by using the fixed measurement data and time-activity questionnaire ranged from 0 to 35 ng/kg/day for trichlorfon, from 0 to 26 ng/kg/day for dichlorvos, and from 0 to 44 ng/kg/day for fenitrothion. Median inhalation exposure from indoor air accounted for 74%, 86.3%, and 45% of the daily inhalation exposure, respectively. For kindergarteners or nursery school children, inhalation exposure at childcare facilities was comparable with or more than that at home, indicating that pollution level at childcare facilities had potential of high impact on children's exposure. Estimated daily inhalation exposures were inversely correlated to the proximity of their activity location to the pesticide-applied farm.

Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages.

Inhalation of particulate cobalt has been known to induce interstitial lung disease. There is growing evidence that apoptosis plays a crucial role in physiological and pathological settings and that the ubiquitin-proteasome system is involved in the regulation of apoptosis. Cadmium, the same transitional heavy metal as cobalt, has been reported to accumulate ubiquitinated proteins in neuronal cells. On the basis of these findings, we hypothesized that cobalt would induce apoptosis in the lung by disturbance of the ubiquitin-proteasome pathway. To evaluate this, we exposed U-937 cells and human alveolar macrophages (AMs) to cobalt chloride (CoCl(2)) and examined their apoptosis by DNA fragmentation assay, 4',6-diamidino-2'-phenylindol dihydrochloride staining, and Western blot analysis. CoCl(2) induced apoptosis and accumulated ubiquitinated proteins. Exposure to CoCl(2) inhibited proteasome activity in U-937 cells. Cobalt-induced apoptosis was mediated via mitochondrial pathway because CoCl(2) released cytochrome c from mitochondria. These results suggest that cobalt-induced apoptosis of AMs may be one of the mechanisms for cobalt-induced lung injury and that the accumulation of ubiquitinated proteins might be involved in this apoptotic process.