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2.  Reference value and annual trend of white blood cell counts among adult Japanese population 
Objectives
This study was initiated to establish the reference values (the 95 % lower limit in particular) for white blood cell (WBC) counts in peripheral blood of general Japanese population. Additional attempts were made to examine whether the reference range had changed in the past 100 years, and which factors had induced such change in WBC counts.
Methods
Data employed were WBC counts of >100 thousand apparently healthy Japanese men, collected in 2002 and in 2010, respectively. Information on smoking habits was collected simultaneously.
Results
The distribution of WBC counts was essentially normal. Arithmetic mean (AM) WBC was 6,248 cells/mm3 in 2002 and 6,162 cells/mm3 in 2010. Based on the 2010 observation, 3 × 103 WBCs/mm3 (after rounding of the figure) was identified as the 95 % lower limit of the reference value for the population. No clear age dependency was detected. Smoking induced elevation in WBC, whereas WBC returned to the level of never smokers after quitting for 3 or more years.
Conclusions
Historical review disclosed a secular trend of decrease in WBC in the past 100 years, so that about 8 % of never-smoking men would be considered leukocytopenic according to the conventional cutoff of 4 × 103 cells/mm3 as a screening level. Decreased smoking rates and improved general hygiene are discussed as possible factors for WBC count reduction. Thus, WBC count of 3 × 103 cells/mm3 is recommended as the 95 % lower limit of the reference value for screening cases with reduced WBC counts.
doi:10.1007/s12199-012-0304-8
PMCID: PMC3590320  PMID: 23054993
Annual trend; Japanese; Leukocyte counts; Men; Reference value; White blood cell counts
3.  Serotonin-2C receptor involved serotonin-induced Ca2+ mobilisations in neuronal progenitors and neurons in rat suprachiasmatic nucleus 
Scientific Reports  2014;4:4106.
The hypothalamic suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals, undergoes serotonergic regulation, but the underlying mechanisms remain obscure. Here, we generated a subclone of an SCN progenitor cell line expressing Ca2+ sensors (SCN2.2YC) and compared its 5-HT receptor signalling with that of rat SCN neurons in brain slices. SCN2.2YC cells expressed 5-HT1A/2A/2B/2C, but not 5A/7, while all six subtypes were expressed in SCN tissues. High K+ or 5-HT increased cytosolic Ca2+ in SCN2.2YC cells. The 5-HT responses were inhibited by ritanserin and SB-221284, but resistant to WAY-100635 and RS-127445, suggesting predominant involvement of 5-HT2C for Ca2+ mobilisations. Consistently, Ca2+ imaging and voltage-clamp electrophysiology using rat SCN slices demonstrated post-synaptic 5-HT2C expression. Because 5-HT2C expression was postnatally increased in the SCN and 5-HT-induced Ca2+ mobilisations were amplified in differentiated SCN2.2YC cells and developed SCN neurons, we suggest that this signalling development occurs in accordance with central clock maturations.
doi:10.1038/srep04106
PMCID: PMC3925950  PMID: 24531181
4.  Steady state trials: another valid substitution of counterfactual ideal to measure causal effects 
Objectives
Many traditionally established medical interventions are not examined with randomized trials especially in emergency medicine. We researched what is the scientific basis of the measurement of the causal effect in these interventions and proposed another trial to measure causal effects.
Methods
We deduced steady state trials from the counterfactual model and used Bayesian approaches to estimate causal effects statistically.
Results
When the state of the observed person is fairly steady before an exposure, the ratio of the after-period to the before-period of the exposure is sufficiently small, and changes are obtained in relatively short time, it is possible to postulate that the state of the counterfactual person to be compared is almost equal to the state of the real person before the exposure. Bayesian approaches show that the causal effect of the exposure is estimated even in only one-person steady state trials, when large changes are observed.
Conclusions
Steady state trials are valid methods to measure causal effects and can measure causal effects even in one-person trials. When we can measure the causal effect of interventions with steady state trials, these interventions should be regarded as scientific without use of randomized trials.
doi:10.1007/s12199-012-0312-8
PMCID: PMC3650177  PMID: 23111579
Cross-over trials; Counterfactual model; Steady state; Period ratio; Individual causal effect
5.  Correlation of light transmittance with asthma attack: fine water particles as a possible inducing factor of asthma 
Background and objectives
It has been postulated that air-borne fine water particles (or mist) can induce asthma attacks in asthmatic children. To date, no attempt has been made to quantify the density of air-borne fine water particles with the aim of relating particle density to the etiology of asthma among children. The aim of this study was to investigate the relation of asthma attack frequency and the particle density evaluated in terms of light transmittance.
Methods
The density of fine water particles was quantified by measuring reductions in light transmittance at 250, 365 and 580 nm at an outdoor location when the surroundings were in darkness. The measurements were made at distances varying from 1 to 3 m from the light sources and performed every morning and evening for 1 year. Each day was separated into two half-day units [i.e., morning (from midnight to noon) and afternoon (from noon to midnight)]. The number of asthma attacks among 121 enrolled asthmatic children was counted for each unit. A possible correlation between the transmittance reduction and frequency of asthma attacks was assessed.
Results
A significant difference was observed in the extent of reduction in light transmittance at 365 nm between the units with asthma attacks and those without attacks. Furthermore, the reduction in the transmittance was more evident when more asthma attacks were recorded among the patients. No difference was detected in the reduction in light transmittance at 250 or 580 nm.
Conclusions
These results support the hypothesis that air-borne fine water particles are among the etiological factors that induce asthma attacks in asthmatic children.
doi:10.1007/s12199-010-0164-z
PMCID: PMC2999686  PMID: 21432216
Asthma attack; Fine water particles; Light transmittance; Temperature; Vapor pressure
6.  Comparison of peer-led versus professional-led training in basic life support for medical students 
Background
The effect of peer-led training in basic life support (BLS) in the education of medical students has not been assessed.
Subjects and methods
This study was a randomized controlled trial with a blinded outcome assessor. A total of 74 fourth-year medical students at Ehime University School of Medicine, Japan were randomly assigned to BLS training conducted by either a senior medical student (peer-led group) or a health professional (professional-led group). The primary outcome measure was the percentage of chest compressions with adequate depth (38–51 mm) by means of a training mannequin evaluated 20 weeks after BLS training. Secondary outcome measures were compression depth, compression rate, proportion of participants who could ensure adequate compression depth (38–51 mm) and adequate compression rate (90–110/minute), and retention of BLS knowledge as assessed by 22-point questionnaire.
Results
Percentage chest compressions with adequate depth (mean ± SD) was 54.5% ± 31.8% in the peer-led group and 52.4% ± 35.6% in the professional-led group. The 95% confidence interval (CI) of difference of the means was −18.7% to 22.8%. The proportion of participants who could ensure an adequate mean compression rate was 17/23 (73.9%) in the peer-led group but only 8/22 (36.4%) in the professional-led group (P = 0.011). On the 22-point questionnaire administered 20 weeks after training, the peer-led group scored 17.2 ± 2.3 whereas the professional-led group scored 17.8 ± 2.0. The 95% CI of difference of the means was −1.72 to 0.57.
Conclusion
Peer-led training in BLS by medical students is feasible and as effective as health professional-led training.
doi:10.2147/AMEP.S22948
PMCID: PMC3661254  PMID: 23745089
basic life support; education; training; randomized controlled trial
7.  Past, present, and future of environmental specimen banks 
Environmental specimen banks are an essential part of the infrastructure of environmental sciences. They have various functions: (1) evaluation of governmental environmental policy-making and regulations; (2) a resource for animal health evaluation; (3) research tools to investigate time trends in ecosystems; (4) detection of newly emerging chemicals in the time trends; (5) validations of computer models for environmental phenomena; (6) source identification of contaminants; (7) a tool for food safety; (8) evaluation of genetic selection pressure due to environmental changes. In this review paper, we present a detailed description of the Kyoto University Human Specimen Bank (history, protocol and questionnaires) and provide brief outlines of other representative environmental specimen banks. We then review two illustrative cases in which environmental specimen banks have unveiled insidious contaminations of polybrominated diphenyl ethers and perfluorooctanoic acids. Finally, we give a perspective of new functions for environmental specimen banks in the next 20 years.
doi:10.1007/s12199-009-0101-1
PMCID: PMC2767494  PMID: 19685106
Environmental specimen banks; Food duplicate sample; Human breast milk; Human blood
8.  Paradoxical increases in serum levels of highly chlorinated PCBs in aged women in clear contrast to robust decreases in dietary intakes from 1980 to 2003 in Japan 
Objective
Exposure to polychlorinated biphenyls (PCBs) is considered to have culminated between 1950 and 1970 in Japan, and exposure through diet, the major exposure route, has decreased significantly over the last 10 years. The primary goal of the present study was to investigate the long-term trends and congener profiles of serum and dietary levels of PCBs using historical samples.
Methods
Using banked samples collected in 1980, 1995, and 2003 surveys, we determined the daily intakes and serum concentrations of 13 PCB congeners (#74, #99, #118, #138, #146, #153, #156, #163, #164, #170, #180, #182, and #187) in women.
Results
The total daily PCB intake [ng/day, geometric mean (geometric standard deviation)] decreased significantly from 523 (2.5) in 1980 to 63 (3.2) in 2003. The serum total PCB level (ng/g lipid) in women <40 years of age decreased significantly from 185 (1.8) in 1980 to 68 (1.8) in 2003. In contrast, the level in women >50 years of age increased significantly from 125 (1.7) in 1980 to 242 (1.7) in 2003. Specifically, the serum concentrations of hexa (#138, #146, #153, #156, #163, and #164) and hepta (#170, #180, #182, and #187) congeners increased significantly. A comparison of the serum PCB levels of women born from 1940 to 1953 revealed that their serum total PCB level was significantly higher in the 2003 survey [242 (1.7), n = 9] than in the 1995 [128 (2.0), n = 17] surveys. This increase in the total PCB level was attributable to increases in the hepta congener groups.
Conclusion
Present results suggest a decreased rate of elimination of hepta congeners with aging in females, rather than a birth-generation phenomenon.
doi:10.1007/s12199-009-0089-6
PMCID: PMC2711886  PMID: 19568832
Polychlorinated biphenyl; Congener profiles; Diet; Serum; Aging; Decrease in metabolism
9.  Intracellular Calcium Spikes in Rat Suprachiasmatic Nucleus Neurons Induced by BAPTA-Based Calcium Dyes 
PLoS ONE  2010;5(3):e9634.
Background
Circadian rhythms in spontaneous action potential (AP) firing frequencies and in cytosolic free calcium concentrations have been reported for mammalian circadian pacemaker neurons located within the hypothalamic suprachiasmatic nucleus (SCN). Also reported is the existence of “Ca2+ spikes” (i.e., [Ca2+]c transients having a bandwidth of 10∼100 seconds) in SCN neurons, but it is unclear if these SCN Ca2+ spikes are related to the slow circadian rhythms.
Methodology/Principal Findings
We addressed this issue based on a Ca2+ indicator dye (fluo-4) and a protein Ca2+ sensor (yellow cameleon). Using fluo-4 AM dye, we found spontaneous Ca2+ spikes in 18% of rat SCN cells in acute brain slices, but the Ca2+ spiking frequencies showed no day/night variation. We repeated the same experiments with rat (and mouse) SCN slice cultures that expressed yellow cameleon genes for a number of different circadian phases and, surprisingly, spontaneous Ca2+ spike was barely observed (<3%). When fluo-4 AM or BAPTA-AM was loaded in addition to the cameleon-expressing SCN cultures, however, the number of cells exhibiting Ca2+ spikes was increased to 13∼14%.
Conclusions/Significance
Despite our extensive set of experiments, no evidence of a circadian rhythm was found in the spontaneous Ca2+ spiking activity of SCN. Furthermore, our study strongly suggests that the spontaneous Ca2+ spiking activity is caused by the Ca2+ chelating effect of the BAPTA-based fluo-4 dye. Therefore, this induced activity seems irrelevant to the intrinsic circadian rhythm of [Ca2+]c in SCN neurons. The problems with BAPTA based dyes are widely known and our study provides a clear case for concern, in particular, for SCN Ca2+ spikes. On the other hand, our study neither invalidates the use of these dyes as a whole, nor undermines the potential role of SCN Ca2+ spikes in the function of SCN.
doi:10.1371/journal.pone.0009634
PMCID: PMC2835761  PMID: 20224788
10.  Activities of occupational physicians for occupational health services in small-scale enterprises in Japan and in the Netherlands 
Objectives
Occupational health service (OHS) for small-scale enterprises (SSEs) is still limited in many countries. Both Japan and the Netherlands have universal OHS systems for all employees. The objective of this survey was to examine the activities of occupational physicians (OPs) in the two countries for SSEs and to investigate their proposals for the improvement of service.
Methods
Questionnaires on types and sizes of the industries they serve, allocation of service hours (current and desired), sources of information for occupational health activities etc. were mailed in 2006 to 461 and 335 Japanese and Dutch OPs, respectively, who have served in small- and medium-scale enterprises. In practice, 107 Japanese (23%) and 106 Dutch physicians (32%) replied, respectively.
Results and Conclusions
Total service time per month was longer for OPs in the Netherlands than OPs in Japan. Japanese OPs spent more hours for health and safety meetings, worksite rounds, and prevention of overwork-induced ill health (14–16% each). Dutch OPs used much more hours for the guidance of absent workers (48%). Thus, service conditions were not the same for OPs in the two countries. Nevertheless, both groups of OPs unanimously considered that employers are the key persons for the improvement of OHS especially in SSEs and their education is important for better OHS. The conclusions should be taken as preliminary, however, due to study limitations including low response rates in both groups of physicians.
doi:10.1007/s00420-010-0514-6
PMCID: PMC2836247  PMID: 20130904
Education; Employer; Occupational physician; Occupational health services; Small-scale enterprises
11.  Phospholipase C-β4 Is Essential for the Progression of the Normal Sleep Sequence and Ultradian Body Temperature Rhythms in Mice 
PLoS ONE  2009;4(11):e7737.
Background
The sleep sequence: i) non-REM sleep, ii) REM sleep, and iii) wakefulness, is stable and widely preserved in mammals, but the underlying mechanisms are unknown. It has been shown that this sequence is disrupted by sudden REM sleep onset during active wakefulness (i.e., narcolepsy) in orexin-deficient mutant animals. Phospholipase C (PLC) mediates the signaling of numerous metabotropic receptors, including orexin receptors. Among the several PLC subtypes, the β4 subtype is uniquely localized in the geniculate nucleus of thalamus which is hypothesized to have a critical role in the transition and maintenance of sleep stages. In fact, we have reported irregular theta wave frequency during REM sleep in PLC-β4-deficient mutant (PLC-β4−/−) mice. Daily behavioral phenotypes and metabotropic receptors involved have not been analyzed in detail in PLC-β4−/− mice, however.
Methodology/Principal Findings
Therefore, we analyzed 24-h sleep electroencephalogram in PLC-β4−/− mice. PLC-β4−/− mice exhibited normal non-REM sleep both during the day and nighttime. PLC-β4−/− mice, however, exhibited increased REM sleep during the night, their active period. Also, their sleep was fragmented with unusual wake-to-REM sleep transitions, both during the day and nighttime. In addition, PLC-β4−/− mice reduced ultradian body temperature rhythms and elevated body temperatures during the daytime, but had normal homeothermal response to acute shifts in ambient temperatures (22°C–4°C). Within the most likely brain areas to produce these behavioral phenotypes, we found that, not orexin, but group-1 metabotropic glutamate receptor (mGluR)-mediated Ca2+ mobilization was significantly reduced in the dorsal lateral geniculate nucleus (LGNd) of PLC-β4−/− mice. Voltage clamp recordings revealed that group-1 mGluR-mediated currents in LGNd relay neurons (inward in wild-type mice) were outward in PLC-β4−/− mice.
Conclusions/Significance
These lines of evidence indicate that impaired LGNd relay, possibly mediated via group-1 mGluR, may underlie irregular sleep sequences and ultradian body temperature rhythms in PLC-β4−/− mice.
doi:10.1371/journal.pone.0007737
PMCID: PMC2770323  PMID: 19898623
12.  Using vital signs to diagnose impaired consciousness: cross sectional observational study 
BMJ : British Medical Journal  2002;325(7368):800-802.
Objectives
To determine whether any vital signs can be used to quickly identify brain lesions in patients with impaired consciousness.
Design
Cross sectional observational study.
Setting
Emergency department of an urban hospital, Japan.
Participants
529 consecutive patients (mean age 65 years) presenting with impaired consciousness (score <15 on the Glasgow coma scale) during 2000.
Main outcome measures
The receiver operating characteristic curve was used to quantify the relation between the vital signs on arrival and the final diagnosis of a brain lesion. Stratum specific likelihood ratios were calculated to define strata with optimal discriminating power.
Results
312 (59%) had a brain lesion which accounted for the impaired consciousness. The area under the receiver operating curve for systolic blood pressure was 0.90 (SE 0.01), indicating significantly higher accuracy (P<0.01) in the identification of a brain lesion than using diastolic pressure 0.82 (0.02) or pulse rate 0.63 (0.03). Likelihood ratios for systolic blood pressure lower than 90 mm Hg were less than 0.04, and those for systolic pressure higher than 170 mm Hg were greater than 6.09.
Conclusions
Systolic blood pressure is useful for diagnosing brain lesions in patients with impaired consciousness.
What is already known on this topicBrain imaging and neurological examination of patients with impaired consciousness are often a waste of time and resources and can delay correct diagnosisWhat this paper addsSystolic blood pressure distinguishes patients with impaired consciousness who are at high risk from those who are at low risk of an organic brain lesionGeneral use of systolic blood pressure in the diagnosis of impaired consciousness may have clinical and economic benefits
PMCID: PMC128944  PMID: 12376438
13.  Lower fiducial limit of urinary metabolite level as an index of excessive exposure to industrial chemicals 
Imamura, T., and Ikeda, M. (1973).British Journal of Industrial Medicine,30, 289-292. Lower fiducial limit of urinary metabolite level as an index of excessive exposure to industrial chemicals. Utilization of the lower fiducial limit (P = 0·10), rather than the mean, as an index of excessive exposure to industrial chemicals is discussed. Cases of exposure to trichloroethylene, phenol, and toluene are used to illustrate this approach.
PMCID: PMC1009526  PMID: 4723791
14.  Urinary excretion of total trichloro-compounds, trichloroethanol, and trichloroacetic acid as a measure of exposure to trichloroethylene and tetrachloroethylene 
Ikeda, M., Ohtsuji, H., Imamura, T., and Komoike, Y. (1972).Brit. J. industr. Med.,29, 328-333. Urinary excretion of total trichloro-compounds, trichloroethanol, and trichloroacetic acid as a measure of exposure to trichloroethylene and tetrachloroethylene. To investigate the relation between trichloroethylene and tetrachloroethylene concentrations in working environments and metabolite concentrations in urine, a series of surveys was conducted at 17 workshops where the vapour concentration in the air of each workshop was relatively constant. Urine samples collected from 85 male workers were analysed for total trichloro-compounds (TTC), and trichloroacetic acid (TCA). Trichloroethanol (TCE) was estimated by difference. Statistical analyses of the data revealed that the urinary concentrations of both TTC and TCE were proportional to the atmospheric concentration of trichloroethylene. The concentration of TCA was also related to the vapour concentration up to 50 p.p.m. but not at higher concentrations. Further calculations suggested that only one-third of the trichloroethylene absorbed through the lungs was excreted in the urine during working time.
In tetrachloroethylene exposure, urinary metabolite levels increased until the atmospheric concentration of the solvent reached 50 to 100 p.p.m., but little increase occurred at higher concentration. This observation was further confirmed by experimental exposure of rats. The toxicological significance of changes in the metabolism of the two solvents is discussed in relation to the possible necessity of reducing the threshold limit value from the current value of 100 p.p.m.
PMCID: PMC1009432  PMID: 5044605
15.  A comparative study of the excretion of Fujiwara reaction-positive substances in urine of humans and rodents given trichloro- or tetrachloro-derivatives of ethane and ethylene 
Ikeda, M., and Ohtsuji, H. (1972).Brit. J. industr. Med.,29, 99-104. A comparative study or the excretion of Fujiwara reaction-positive substances in urine of humans and rodents given trichloro- or tetrachloro-derivatives of ethane and ethylene. 1,1,1-Trichloroethane, 1,1,2- trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, trichloroethylene, and tetrachloroethylene were administered to rats and mice as vapours at 200 p.p.m. for 8 hours and urine was collected for 48 hours. The urine was analysed by the Fujiwara reaction for total trichlorocompounds (TTC), trichloroacetic acid (TCA), and trichloroethanol (TCE). All compounds except 1,1,2-trichloroethane yielded substantial TCA and TCE but 1,1,1,2-tetrachloroethane and trichloroethylene much more than the rest. The results obtained during two periods of 48 hours after intraperitoneal injection were similar. The variations in the amounts of metabolites are shown to be consistent with the vapour pressures of the solvents (compounds with high vapour pressures are lost from the lungs before being metabolized) and with their known chemical properties, according to which 1,1,1-trichlorocompounds should yield TCE and TCA readily, whereas 1,1,2-chlorocompounds should not.
Excretion of metabolites from men exposed intermittently to vapours of tetrachloroethylene and trichloroethylene were also studied. Both gave enough TCE and TCA, but trichloroethylene gave considerably more, in accordance with its relative instability to oxidation.
PMCID: PMC1009358  PMID: 5060252
16.  Quantitative relationship between atmospheric phenol vapour and phenol in the urine of workers in Bakelite factories 
Ohtsuji, H., and Ikeda, M. (1972).Brit. J. industr. Med.,29, 70-73. Quantitative relationship between atmospheric phenol vapour and phenol in the urine of workers in Bakelite factories. A survey in Bakelite factories revealed that the urinary level of total phenol, free plus conjugated, increased in proportion to the phenol concentration to which the subject was exposed in his working environment. This indicates that analysis of urine for phenol is valuable for the monitoring of exposure to phenol in air.
The results also suggest that the human lung takes up phenol very efficiently. The increase in urinary phenol was entirely attributable to conjugated phenol; regardless of exposure, no significant change was observed in free phenol concentration. Ethereal sulphate or ethereal glucuronide had poor validity as an index of exposure.
PMCID: PMC1009353  PMID: 5060248
17.  Excretion kinetics of urinary metabolites in a patient addicted to trichloroethylene 
Ikeda, M., Ohtsuji, H., Kawai, H., and Kuniyoshi, M. (1971).Brit. J. industr. Med.,28, 203-206. Excretion kinetics of urinary metabolites in a patient addicted to trichlorethylene. A male Japanese subject, single, aged 38, who worked at a workshop washing metal parts with trichloroethylene, was admitted to our clinic due to addiction to the solvent. Analyses of urine revealed the presence of up to 160 μg/ml of trichloro-compounds (mostly trichloroacetic acid) which gradually disappeared in three weeks as the psychotic symptoms cleared up. The excretion half-lives of trichloroethylene metabolites for the initial rapid phase (succeeding slow phase in parentheses) were 5·8 (49·7) hours for trichloroethanol, 22·5 (72·6) hours for trichloroacetic acid, and 7·5 (72·6) hours for total trichloro-compounds.
PMCID: PMC1009267  PMID: 5572691
18.  A rapid colorimetric method for the determination of phenylglyoxylic and mandelic acids: Its application to the urinalysis of workers exposed to styrene vapour 
Ohtsuji, H., and Ikeda, M.(1970).Brit. J. industr. Med.,27, 150-154. A rapid colorimetric method for the determination of phenylglyoxylic and mandelic acids. Its application to the urinalysis of workers exposed to styrene vapour. A rapid colorimetric method has been developed for the determination of the styrene metabolites, phenylglyoxylic and mandelic acids, in urine. Ether extracts of acidified urine containing the two acids were evaporated to dryness in a test tube, and a mixture of sulphuric acid and formalin (100:1, v/v) was added for colour development. Factors necessary to convert optical extinction to gravimetric units were determined. When urinesamples from workers exposed to up to 30 ppm of styrene were analysed for phenylglyoxylic and mandelic acids together with hippuric acid, it was found that the phenylglyoxylic acid level provided the most sensitive index of styrene exposure and that the optical extinction at 350 nm was practically proportional to phenylglyoxylic acid concentration. No significant increase in hippuric acid levels was observed.
PMCID: PMC1009089  PMID: 5448524
19.  Neuronal influence on peripheral circadian oscillators in pupal Drosophila prothoracic glands 
Nature Communications  2012;3:909-.
Rhythmic expression of period (per) and timeless (tim) genes in central circadian pacemaker neurons and prothoracic gland cells, part of the peripheral circadian oscillators in flies, may synergistically control eclosion rhythms, but their oscillatory profiles remain unclear. Here we show differences and interactions between peripheral and central oscillators using per-luciferase and cytosolic Ca2+ reporter (yellow cameleon) imaging in organotypic prothoracic gland cultures with or without the associated central nervous system. Isolated prothoracic gland cells exhibit light-insensitive synchronous per-transcriptional rhythms. In prothoracic gland cells associated with the central nervous system, however, per transcription is markedly amplified following 12-h light exposure, resulting in the manifestation of day–night rhythms in nuclear PER immunostaining levels and spontaneous Ca2+ spiking. Unlike PER expression, nuclear TIM expression is associated with day–night cycles that are independent of the central nervous system. These results demonstrate that photoreception and synaptic signal transduction in/from the central nervous system coordinate molecular 'gears' in endocrine oscillators to generate physiological rhythms.
In the fruit fly Drosophila, changes in expression of circadian clock genes are believed to control eclosion. Morioka and colleagues show that transcriptional oscillations of the clock gene, period, in prothoracic gland cells are amplified by photic inputs from the central nervous system.
doi:10.1038/ncomms1922
PMCID: PMC3621432  PMID: 22713751
21.  Significance of urinary hippuric acid determination as an index of toluene exposure 
Ikeda, Masayuki, and Ohtsuji, Hatsue (1969).Brit. J. industr. Med.,26, 244-246. Significance of urinary hippuric acid determination as an index of toluene exposure. Urine samples from 118 male workers in photogravure printing factories were analysed for hippuric acid. The urinary levels of hippuric acid were proportional to the environmental concentrations of toluene, although within wide variations. The urinary concentration of hippuric acid corresponding to 200 p.p.m. of toluene was 3·5 g./litre (specific gravity 1·016) or 4·3 g./g. creatinine.
PMCID: PMC1008946  PMID: 5794951
22.  Hippuric acid, phenol, and trichloroacetic acid levels in the urine of Japanese subjects with no known exposure to organic solvents 
Ikeda, M., and Ohtsuji, H. (1969).Brit. J. industr. Med.,26, 162-164. Hippuric acid, phenol, and trichloroacetic acid levels in the urine of Japanese subjects with no known exposure to organic solvents. Urine samples from 36 male and 30 female university students and 31 male factory workers with no known exposure to industrial organic solvents were analysed for hippuric acid, phenol, and trichloroacetic acid, which are the major metabolites of toluene, benzene, and trichloroethylene respectively. The normal levels were less than 1·4 g./l. for hippuric acid, less than 80 mg./l. for phenol, and less than 1 mg./l. for trichloroacetic acid. No evidence was obtained to suggest that correction for urine concentration with either specific gravity or creatinine concentration minimizes individual variation of metabolite levels.
PMCID: PMC1008913  PMID: 5780109
23.  A Method for Determination of Trichloroethanol and Trichloroacetic Acid in Urine 
When trichloroacetic acid (TCA) and trichloroethanol (TCE) in the urine of human subjects, rabbits, rats, and guinea-pigs were determined by Seto and Schultze's (1956) method, the recovery of TCE, added to urine, varied widely from 81·3% in guinea-pig urine to 16·2% in rat urine. To obtain the maximum recovery of added TCE, Seto and Schultze's method was further modified to give satisfactory results (recovery rate of 95·9 to 98·5%) when applied to human urine as well as to the urine of the above species of animals. Urine samples from human subjects as well as from rats exposed to trichloroethylene were analysed by this modified method. The results showed that the ratio of TCE to TCA varies as a function of environmental trichloroethylene concentration, indicating that the determination of total trichlorocompounds gives a better index of trichloroethylene exposure than does the determination of TCA alone.
PMCID: PMC1008775  PMID: 5690921
24.  Excretion of P-Nitrophenol and p-Aminophenol in the Urine of a Patient Exposed to Nitrobenzene 
An account is given of a patient who had chronic exposure to nitrobenzene and in whom the metabolites, p-nitrophenol and p-aminophenol, were present in the urine. A method of separative determination of these two substances in urine is described.
PMCID: PMC1038356  PMID: 14180479

Results 1-24 (24)