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Setting: Japan: a low-TB-burden country., Objective: To characterise TB-related technical enquiries received in 2020-2022, and share the lessons learnt., Design: This was a descriptive study., Results: We received 1,898 communications, of which 1,447 (40.2 per month) were classified as technical enquiries, 34% fewer than the 2,197 enquiries received in 2017-2019. The enquiry rates were highest for Shimane (4.32/100,000 population) and Yamanashi (2.59/100,000 population) prefectures, and lowest in Ehime (0.00/100,000 population) and Yamagata (0.09/100,000 population) prefectures. The main organisations the enquirers belonged to were local governments ( n = 989, 68.3%) and healthcare facilities ( n = 242, 16.7%). The enquirers included medical doctors ( n = 236, 16.3%), nurses ( n = 814, 56.3%), and the general public ( n = 141, 9.7%). The most frequent enquiries were about TB diagnosis and treatment, including laboratory diagnosis ( n = 442, 30.6%), followed by the regulatory framework ( n = 216, 14.9%), contact investigation ( n = 151, 10.8%), and TB in foreigners ( n = 112, 7.9%)., Conclusion: During the COVID-19 era, we received two-thirds of technical enquiries compared with 2017-2019, because local health offices were overwhelmed by the pandemic. Since the most frequent enquiries were about diagnosis and treatment of TB, the health ministry of Japan should maintain a few specialised TB institutions with TB physicians to provide technical assistance., Competing Interests: Conflicts of interest: none declared., (© 2024 The Authors.)

Background: Research on the relationship between neuron-specific enolase (NSE) levels and normal organs, particularly the central nervous system, in small cell lung cancer is limited. Therefore, this study aimed to investigate the relationship between positron emission tomography-computed tomography (PET-CT) accumulation at hypothalamic/pituitary regions, tumor activity, and NSE level in limited-stage small cell lung cancer. We retrospectively analyzed patients who were diagnosed with limited-stage small cell lung cancer at Tokyo Medical University Hospital between July 1, 2019, and May 31, 2023, and were treated with chemoradiotherapy or radiotherapy. Leukocytes, erythrocytes, hemoglobin, platelets, total protein, albumin, NSE, and carcinoembryonic antigen were measured in blood samples obtained before treatment initiation. The maximum standardized uptake value (SUVmax), volume, and total lesion glycolysis (TLG) of each hypothalamic /pituitary region, primary tumor, and lymph node metastases were extracted from PET-CT images. The total tumor volume (primary tumor volume plus lymph node metastases volume) and total TLG (primary tumor TLG plus lymph node metastases TLG) were calculated., Results: This study included 19 patients (mean age, 70.1 ± 8.8 years; 13 men and 6 women); the pathology in all patients was small cell lung cancer. Patients were classified into two groups according to the NSE reference value (16.3 ng/mL): six patients having NSE level below the reference value and 13 having NSE level above the reference value. The SUVmax in the hypothalamic/pituitary region was 2.95 in the NSE < 16.3 ng/mL group and 4.10 in the NSE > 16.3 ng/mL group, with a statistically significant difference (p = 0.03). The total tumor volume was 17.8 mL in the NSE < 16.3 ng/mL group and 98.9 mL in the NSE > 16.3 ng/mL group, with a statistically significant difference (p < 0.01). A correlation coefficient of r = 0.458 (p = 0.0486) was observed between SUVmax in the hypothalamus/pituitary and NSE level. A correlation coefficient of r = 0.647 (p < 0.01) was also observed between total tumor volume and NSE level. Finally, a correlation coefficient of r = 0.53 (p = 0.01) was observed between hypothalamic/pituitary TLG and primary tumor TLG., Conclusions: The findings demonstrated a correlation between hypothalamic/pituitary activity and tumor activity, suggesting the prognostic significance of NSE., (© 2024. The Author(s).)

Objective: To investigate the positron emission tomography/computed tomography (PET/CT) findings of T1/T2N0M0 glottic cancer (hereafter referred to as T1/T2) and dose distribution in radiotherapy., Subjects and Methods: We retrospectively collected data from patients diagnosed with T1/T2N0M0 glottic cancer who received radiotherapy. The extent of fluorine-18-fluorodeoxyglucose ( 18 F-FDG) accumulation in primary tumors, maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), tumor volume of primary tumors on PET/CT were compared. Furthermore, the tumor identified on PET/CT was incorporated into the radiotherapy plans. A dummy plan (radiation field 6x6cm, prescription point facing the vertebral body, maximum dose ≤107%, T1/T2 66Gy/33 fractions) was developed for three-dimensional conformal radiotherapy, and the dose distribution of primary tumors was calculated., Results: Twenty-nine patients (27 men and two women) were included; their mean age was 67.2±15.0 years. Increased 18 F-FDG accumulation in primary tumors was observed on PET/CT in 22/29 (78.5%; T1: 14/21 [67%], T2: 8/8 [100%]) patients. The median SUVmax, TLG, and primary tumor volume were significantly different between T1 and T2 (SUVmax, T1: 4.56 vs. T2: 8.43, P=0.035; TLG, T1: 1.01 vs. T2: 3.71 SUVxmL, P<0.01; primary tumor volume, T1: 0.38mL vs. T2: 0.80mL, P=0.01). At a TLG cut-off value of 3.470, the area under the curve was 0.875, sensitivity was 0.875, and specificity was 0.929 for T1-T2 differentiation. In 20 patients with 18 F-FDG accumulation, the minimum radiation dose was significantly different between T1 and T2 (66Gy vs. 64Gy, P<0.01) at the same 66Gy prescription. The minimum radiation dose and primary tumor volume show the correlation value (r=-0.516, P=0.02)., Conclusion: In glottic cancer, T1 and T2 can be differentiated by the extent of 18 F-FDG accumulation in primary tumors on PET/CT. The minimum radiation dose rate decreases as volume increases.

Setting: Japan, an intermediate TB burden country., Objective: To review TB-related technical enquiries received at the Research Institute of Tuberculosis, Japan, from January 2017 to December 2019., Design: This was a cohort study., Results: A total of 2,197 enquiries were analysed. On average, 61.0 enquiries/month (range: 42-81) were received. The enquiry rates were highest for the Yamanashi (4.65/100,000 population) and Ishikawa (4.55) Prefectures, and lowest in the Yamagata (0.46) and Tochigi (0.56) Prefectures. The main organisations the enquirers belonged to were local governments ( n = 1,585, 72.1%) and healthcare facilities ( n = 307, 14.0%). The enquirers were medical doctors ( n = 391, 17.8%), nurses ( n = 1,207, 54.9%), other healthcare professionals ( n = 57, 2.6%), the general public ( n = 168, 7.6%) and others/unknown ( n = 374, 17.0%). The most frequent enquiries were about TB diagnosis and treatment ( n = 501, 22.8%), including laboratory diagnosis ( n = 88, 4.0%), TB treatment in general ( n = 93, 4.2%) and management of comorbidities ( n = 86, 3.9%), followed by contact investigations ( n = 385, 17.5%) and TB in foreigners ( n = 344, 15.7%)., Conclusion: As the most frequent enquiries were about diagnosis and treatment of TB, the health ministry of Japan should maintain a few specialised TB institutions with TB physicians to provide technical assistance., Competing Interests: Conflicts of interest: none declared., (© 2022 The Union.)

Background: In August 2018, a male worker (Pt1) in an office was diagnosed with smear-positive pulmonary tuberculosis (TB). This study aims to characterize the cases found in the TB outbreak in the office., Methods: The risks of TB disease or infection were compared among the staff members by seating locations., Results: A total of 116 current and ex-staff members were investigated, among whom 13 patients with active TB, including Pt1, and 20 with latent TB infection were found by the end of 2020. One-third of the seating groups located at one end of the office that Pt1 belonged to had the highest risk of TB disease (30.8%, 95% confidence interval [CI]: 14.3%-51.8%) and infection (61.5%, 95% CI: 40.6%-79.8%) with a high relative risk of TB infection (6.2, 95% CI: 2.0-18.8) compared to another one-third of the seating groups at the other end of the office that had the lowest risk of active TB (0%, 95% CI: 0%-11.6%) and TB infection (10.0%, 95% CI: 2.1%-26.5%)., Conclusion: The seating groups that Pt1 belonged to had the highest risk of TB disease and infection because the staff members in the groups were exposed to the air containing TB bacilli from Pt1. Local health offices should initiate active case finding using chest X-rays as soon as they are notified of a sputum smear-positive TB case if the delay of the diagnosis is longer than three months., Competing Interests: None

Vicarious reward is a phenomenon in which an individual feels as if he/she has received a reward as the result of watching someone else receive a reward. In this study, we used electroencephalography to investigate brain activity while participants watched a preferred player win a competitive game (Rock-Paper-Scissors game). In the experimental task, movie clips showed right hand of the two players and played Rock-Paper-Scissors game. We asked participants to explicitly support or "cheer" for a specific player, and then examined brain activity associated with vicarious reward. For the observed hand movement, previous findings showed that the event-related desynchronization of mu band (8-14 Hz) appeared at the contra-lateral central electrode to the observed hand (If someone sees the right-hand movement, the left central electrode shows the event-related desynchronization of mu-band). During observation of the player, we detected event-related desynchronization of mu band activity in the contra-lateral central electrode as well as mid-frontal beta band (15-22 Hz) activation when the preferred player won. Furthermore, functional connectivity analysis revealed a strong phase synchronization between the contra-lateral central electrode and mid-frontal electrode in the mu band when participants received the vicarious reward. Cross-frequency coupling analysis revealed functional integration between the mu and beta bands at mid-frontal electrode. These results indicate the interaction of mu band observed at contra-lateral electrode and beta band observed at mid-frontal electrode coupling, suggesting a link between the mirror neuron system and the reward system during vicarious reward., (Copyright © 2019 Inomata, Zama and Shimada.)

In the rubber hand illusion (RHI), the subject recognizes a fake hand as his or her own. We recently found that the observation of embodied fake hand movement elicited mu-rhythm (8-13 Hz) desynchronization on electroencephalography (EEG), suggesting brain activation in the sensorimotor regions. However, it is known that mu-rhythm desynchronization during action observation is confounded with occipital alpha-rhythm desynchronization, which is modulated by attention. This study examined the independence of brain activities in the sensorimotor and occipital regions relating to the movement observation under the RHI. The invisible participant's left and fake right hands were stroked simultaneously, which was interrupted by unexpected fake hand movements. A mirror-reversed image of the fake hand was shown on a monitor in front of the participant with a delay of 80, 280, or 480 ms. Illusion strength decreased as a function of the delay. EEG independent component analysis (ICA) and ICA clustering revealed six clusters with observation-induced desynchronization of 8-13 Hz frequency band. In the right sensorimotor cluster, mu-rhythm desynchronization was the greatest under the 80-ms delay, while alpha-rhythm desynchronization of the occipital clusters did not show delay-dependence. These results suggest that brain activation in the sensorimotor areas (i.e., mu-rhythm desynchronization) induced by embodied fake hand movement is independent of that in the occipital areas (alpha-rhythm desynchronization)., (Copyright © 2019 Shibuya, Unenaka, Zama, Shimada and Ohki.)

We investigated whether the inferior parietal lobule (IPL) responds in real-time to multisensory inconsistency during movement. The IPL is thought to be involved in both the detection of inconsistencies in multisensory information obtained during movement and that obtained during self-other discrimination. However, because of the limited temporal resolution of conventional neuroimaging techniques, it is difficult to distinguish IPL activity during movement from that during self-other discrimination. We simultaneously conducted electroencephalography (EEG) and near-infrared spectroscopy (NIRS) with the goal of examining IPL activity with a high spatiotemporal resolution during single reaching movements. Under a visual feedback-delay condition, gamma event-related synchronization (γ-ERS), i.e., an increase in gamma (31-47 Hz) EEG power occurred during reaching movements. This γ-ERS is considered to reflect processing of information about prediction errors. To integrate this temporal information with spatial information from the NIRS signals, we developed a new analysis technique that enabled estimation of the regions that show a hemodynamic response characterized by EEG fluctuation present in the visual feedback-delay condition. As a result, IPL activity was explained by γ-ERS specific to visual feedback delay during movements. Thus, we succeeded in demonstrating real-time activation of the IPL in response to multisensory inconsistency. However, we did not find any correlation between either IPL activity or γ-ERS with the sense of agency. Therefore, our results suggest that while the IPL is influenced by prediction error signals, it does not engage in direct processing underlying the conscious experience of making a movement, which is the foundation of self-other discrimination.

Judgment of agency involves the comparison of motor intention and proprioceptive/visual feedback, in addition to a range of cognitive factors. However, few studies have experimentally examined the differences or correlations between delay detection ability and judgment of agency. Thus, the present study investigated the relationship between delay detection ability and agency judgment using the delay detection task and the agency attribution task. Fifty-eight participants performed the delay detection and agency attribution tasks, and the time windows of each measure were analyzed using logistic curve fitting. The results revealed that the time window of judgment of agency was significantly longer than that of delay detection, and there was a slight correlation between the time windows in each task. The results supported a two-step model of agency, suggesting that judgment of agency involved not only comparison of multisensory information but also several cognitive factors. The study firstly revealed the model in psychophysical experiments., Competing Interests: The authors have declared that no competing interests exist.

Mechanical and electrical noise stimulation to the body is known to improve the sensorimotor system. This improvement is related to stochastic resonance (SR), a phenomenon described as a "noise benefit" to various sensory and motor systems. The current study investigated the influence of SR on visuomotor temporal integration and hand motor function under delayed visual feedback in healthy young adults. The purpose of this study was to measure the usefulness of SR as a neurorehabilitation device for disorders of visuomotor temporal integration. Thirty healthy volunteers underwent detection tasks and hand motor function tests under delayed visual feedback, with or without SR. Of the 30 participants, 15 carried out the tasks under delayed visual feedback in the order of SR on-condition, off-condition, off-condition, and on-condition. The remaining 15 participants conducted the experimental tasks in the order of SR off-condition, on-condition, on-condition, and off-condition. Comparisons of the delay detection threshold (DDT), steepness of the delay detection probability curves, box and block test (BBT) scores, and nine-hole peg test (NHPT) scores between the SR on- and off-conditions were performed. The DDT under the SR on-condition was significantly shortened compared with the SR off-condition. There was no significant difference between the SR on- and off-conditions for the steepness of the delay detection probability curves, BBT scores, and NHPT scores. SR improved visuomotor temporal integration in healthy young adults, and may therefore improve movement disorders in patients with impaired visuomotor temporal integration. However, because the current results showed that SR did not improve hand motor function under delayed visual feedback, it may not improve motor function when a large distortion of visuomotor temporal integration is present. Further studies are required considering several limitations of the current study, and future clinical trials are necessary to verify the effects of motor training using SR for the treatment of visuomotor temporal integration disorders., Competing Interests: The authors declare that they have no competing interests.

Limb apraxia is a higher brain dysfunction that typically occurs after left hemispheric stroke and its cause cannot be explained by sensory disturbance or motor paralysis. The comparison of motor signals and visual feedback to generate errors, i.e., visuo-motor integration, is important in motor control and motor learning, which may be impaired in apraxia. However, in apraxia after stroke, it is unknown whether there is a specific deficit in visuo-motor temporal integration compared to visuo-tactile and visuo-proprioceptive temporal integration. We examined the precision of visuo-motor temporal integration and sensory-sensory (visuo-tactile and visuo-proprioception) temporal integration in apraxia after stroke by using a delayed visual feedback detection task with three different conditions (tactile, passive movement, and active movement). The delay detection threshold and the probability curve for delay detection obtained in this task were quantitative indicators of the respective temporal integration functions. In addition, we performed subtraction and voxel-based lesion-symptom mapping to identify the brain lesions responsible for apraxia and deficits in visuo-motor temporal integration. The behavioral experiments showed that the delay detection threshold was extended and that the probability curve for delay detection was less steep in apraxic patients compared to controls (pseudo-apraxic patients and unaffected patients), only for the active movement condition, and not for the tactile and passive movement conditions. Furthermore, the severity of apraxia was significantly correlated with the delay detection threshold and the steepness of the probability curve in the active movement condition. These results indicated that multisensory (i.e., visual, tactile, and proprioception) feedback was normally temporally integrated, but motor prediction and visual feedback were not correctly temporally integrated in apraxic patients. That is, apraxic patients had difficulties with visuo-motor temporal integration. Lesion analyses revealed that both apraxia and the distortion of visuo-motor temporal integration were associated with lesions in the fronto-parietal motor network, including the left inferior parietal lobule and left inferior frontal gyrus. We suppose that damage to the left inferior fronto-parietal network could cause deficits in motor prediction for visuo-motor temporal integration, but not for sensory-sensory (visuo-tactile and visuo-proprioception) temporal integration, leading to the distortion of visuo-motor temporal integration in patients with apraxia.

Although visuo-motor temporal integration in children is suggested to be related to motor control and motor learning, its relevance is still unclear. On the other hand, visuo-motor temporal integration ability undergoes developmental changes with age. In the current correlational study, we measured manual dexterity and visuo-motor temporal integration ability in 132 children with typical development (age, 4-15 years) and investigated the relationship between the two functions. The Movement Assessment Battery for Children-2nd edition was used as an indicator of manual dexterity. The delay detection threshold (DDT) and steepness of the probability curve for delay detection, which was measured by the delayed visual feedback detection task for self-generated movement, were used as indices of the visuo-motor temporal integration ability. The results indicated significant correlations between manual dexterity/age and DDT/steepness of the probability curve for delay detection. In addition, hierarchical multiple regression analysis showed that both manual dexterity and age significantly contributed to visuo-motor temporal integration, indicating a better fit than when only age was employed as an independent variable. Importantly, there was no interaction effect between age and manual dexterity. These findings were the first to suggest that manual dexterity is a significant predictor of visuo-motor temporal integration ability in children, regardless of age. The present study validated the important relationship between visuo-motor temporal integration and manual dexterity in children. Considering the limitations of the current study, including the non-homogeneous sample, further studies are still warranted to validate the results.

The neurological basis of developmental coordination disorder (DCD) is thought to be deficits in the internal model and mirror-neuron system (MNS) in the parietal lobe and cerebellum. However, it is not clear if the visuo-motor temporal integration in the internal model and automatic-imitation function in the MNS differs between children with DCD and those with typical development (TD). The current study aimed to investigate these differences. Using the manual dexterity test of the Movement Assessment Battery for Children (second edition), the participants were either assigned to the probable DCD (pDCD) group or TD group. The former was comprised of 29 children with clumsy manual dexterity, while the latter consisted of 42 children with normal manual dexterity. Visuo-motor temporal integration ability and automatic-imitation function were measured using the delayed visual feedback detection task and motor interference task, respectively. Further, the current study investigated whether autism-spectrum disorder (ASD) traits, attention-deficit hyperactivity disorder (ADHD) traits, and depressive symptoms differed among the two groups, since these symptoms are frequent comorbidities of DCD. In addition, correlation and multiple regression analyses were performed to extract factors affecting clumsy manual dexterity. In the results, the delay-detection threshold (DDT) and steepness of the delay-detection probability curve, which indicated visuo-motor temporal integration ability, were significantly prolonged and decreased, respectively, in children with pDCD. The interference effect, which indicated automatic-imitation function, was also significantly reduced in this group. These results highlighted that children with clumsy manual dexterity have deficits in visuo-motor temporal integration and automatic-imitation function. There was a significant correlation between manual dexterity, and measures of visuo-motor temporal integration, and ASD traits and ADHD traits and ASD. Multiple regression analysis revealed that the DDT, which indicated visuo-motor temporal integration, was the greatest predictor of poor manual dexterity. The current results supported and provided further evidence for the internal model deficit hypothesis. Further, they suggested a neurorehabilitation technique that improved visuo-motor temporal integration could be therapeutically effective for children with DCD.

In the rubber hand illusion (RHI), individuals perceive a fake hand as their own when the hidden real hand and visible fake hand are synchronously stroked. Several RHI studies have reported that visual manipulation of the embodied fake hand inversely affects the perceptual processing of the observer's own hand (e.g., thermal or pain sensitivity). In this study, we examined whether motor manipulation of the fake hand similarly affects the observer's motor system. Our study employed a novel RHI paradigm wherein stroking was interrupted by unexpected movement of the fake hand (i.e., finger spreading) while measuring electroencephalography (EEG). We found that participants often spontaneously moved their hands in accordance with the movement of the fake hand only in the RHI (synchronous) sessions. EEG analyses revealed enhanced neural activation (mu-rhythm desynchronization) of the motor system during observation of the fake hand movement. Moreover, motor activation was greater in the synchronous than in the asynchronous condition and significantly correlated with the feeling of body ownership over the fake hand. These findings provide strong behavioral and neurophysiological evidence of 'motor back projection', in which the movement of an illusory embodied body part is inversely transferred to the sensorimotor system of the observer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Altered limb ownership or heaviness has been observed in patients with hemiplegia, chronic pain, and several other conditions. Although these sensations are thought to be caused by sensorimotor incongruence, few studies have systematically verified this relationship. In addition, it remains unclear whether these subjective sensations affect movement execution. In a psychophysical experiment, we systematically investigated the relationships between sensorimotor integration and subjective limb perception, such as sense of ownership/heaviness, and verified the relationship between subjective limb perception and movement execution. Thirty-nine healthy participants were enrolled, and a visual feedback delay system was used to systematically evoke sensorimotor incongruence. Participants periodically flexed and extended their wrist while seeing a delayed image of their hand under five delay conditions (0, 150, 250, 350, 600ms). During wrist movement, electromyography (EMG) activity in flexor carpi radialis (FCR) was recorded. Also, to analyze the change in muscle activity and movement speed, the values of integral and peak frequency were calculated. To record changes in the subjective limb perception of the altered limb ownership and heaviness, we used a 7-point Likert scale for each participant. We found that altered ownership and heaviness increased with increasing feedback delay. Also, muscle activity and movement speed decreased with visual feedback delay. There was no significant correlation between subjective altered limb perception (i.e., altered limb ownership and heaviness) and muscle activity or movement speed. We systematically demonstrated that limb ownership, heaviness, muscle activation and movement speed were altered by sensorimotor incongruence. However, our study did not reveal the relationships between these factors. These results indicate the existence of different mechanisms governing subjective limb perception and movement execution. In the future, we should consider rehabilitation methods to improve sensorimotor incongruence., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The spectral nonlinearity of an inverse-layer-type silicon (Si) photodiode (PD) in the visible region was investigated. As expected by theoretical calculation, supralinearity and saturation of the Si PD, which are key factors of nonlinearity, were suppressed by applying a reverse voltage above 30 V. Experimentally observed nonlinear behavior depending on the reverse bias was compared to a theoretical model describing supralinearity, including the inner parameters of the Si PD, and these comparison results were in agreement. This theoretical model enables us to quantitatively predict the behavior of the supralinearity of the inverse-layer-type Si PD in various reverse bias conditions. Accurate experimental nonlinearity supported by theoretical predictions will contribute to high-accuracy optical measurement with the Si PD over a wide range of optical power levels and various reverse-bias voltages.

We investigated the relationship between electrophysiological activity and haemodynamic response during motor preparation by simultaneous recording of electroencephalography (EEG) and near-infrared spectroscopy (NIRS). It is still unknown how exactly EEG signals correlate with the haemodynamic response, although the activation in the premotor area during motor preparation has been captured by EEG and haemodynamic approaches separately. We conducted EEG-NIRS simultaneous recordings over the sensorimotor area with a self-paced button press task. Participants were instructed to press a button at their own pace after a cue was shown. The result showed that the readiness potential (RP), a negative slow potential shift occurring during motor preparation, on C3 in the extended 10-20 system occurred about 1000 ms before the movement onset. An increase in concentration of oxyhaemoglobin (oxyHb) in the premotor cortex during motor preparation was also confirmed by NIRS, which resulted in a significant correlation between the amplitude of the RP and the change in oxyHb concentration (Pearson's correlation r(2) = 0.235, p = 0.03). We show that EEG-NIRS simultaneous recording can demonstrate the correlation between the RP and haemodynamic response in the premotor cortex contralateral to the performing hand.

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients.

Background: MicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary., Methodology/principal Findings: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model., Conclusions/significance: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

We have realized a high-detection-efficiency photon number resolving detector at an operating wavelength of about 850 nm. The detector consists of a titanium superconducting transition edge sensor in an optical cavity, which is directly coupled to an optical fiber using an approximately 300-nm gap. The gap reduces the sensitive area and heat capacity of the device, leading to high photon number resolution of 0.42 eV without sacrificing detection efficiency or signal response speed. Wavelength dependent efficiency in fiber-coupled devices, which is due to optical interference between the fiber and the device, is also decreased to less than 1% in this configuration. The overall system detection efficiency is 98%±1% at wavelengths of around 850 nm, which is the highest value ever reported in this wavelength range.

We compare the results of measurements of the nonlinearity of high-power optical fiber powermeters (OFPMs) by two national metrology institutes (NMIs): the National Institute of Standards and Technology (NIST-USA) and the National Metrology Institute of Japan/National Institute of Advanced Industrial Science and Technology (NMIJ/AIST-Japan) at a wavelength of 1480 nm. The nonlinearity and range discontinuity of a commercial OFPM were measured from 1 mW to 500 mW by use of a superposition method (both laboratories) and from 1 mW to 250 mW by use of a comparison method (NMIJ only). Measurement results showed largest differences of less than 1.6 parts in 10(3), which is within the combined expanded (k = 2) uncertainty for both laboratories.

ATF3 (Activating transcription factor 3), a member of the CREB/ATF family, can be induced by stress and growth factors in mammalian cells, and is thought to play an important role in the cardiovascular system. However, little is currently known about how the induction of ATF3 is regulated, except that the JNK pathway is involved. Here, we investigated the differential roles of the MAPK pathways involved in TNFalpha (tumour necrosis factor alpha)-induced ATF3 expression in vascular endothelial cells. In human umbilical vein endothelial cells, the expression of constitutively active MKK7 (MAPK kinase 7) increased the number of ATF3-positive cells, and dominant negative MKK7 suppressed the TNFalpha-induced expression of ATF3, indicating a requirement for the JNK pathway. In contrast, the expression of constitutively active or dominant negative MEK1/2 (MAPK/ERK kinase 1/2) suppressed or enhanced TNFalpha-mediated induction of ATF3, respectively. In support of this, the MEK1/2 specific inhibitor U0126 enhanced the expression of ATF3 induced by TNFalpha. Furthermore, the ERK pathway inhibits the TNFalpha-mediated induction of ATF3 mRNA, but not its stability, suggesting the involvement of ERK activity in the transcriptional regulation of the ATF3 gene. Our results suggest that TNFalpha-induced ATF3 gene expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells.

Stress-activated protein kinase (SAPK) pathway-regulating phosphatase 1 (SKRP1) has been identified as a member of the mitogen-activated protein kinase (MAPK) phosphatase (MKP) family that interacts physically with the MAPK kinase (MAPKK) MKK7, a c-Jun N-terminal kinase (JNK) activator, and inactivates the MAPK JNK pathway. Although these findings indicated that SKRP1 contributes to the precise regulation of JNK signaling, it remains to be elucidated how SKRP1 is integrated into this pathway. We report that SKRP1 also plays a scaffold role for the JNK signaling, judged by the following observations. SKRP1 selectively formed the stable complexes with MKK7 but not with MKK4 and biphasically regulated the MKK7 activity and MKK7-induced gene transcription in vivo. Co-precipitation analysis between SKRP1 and MKK7-activating MAPKK kinases (MAPKKKs) revealed that SKRP1 also interacted with the MAPKKK, apoptosis signal-regulating kinase 1 (ASK1), but not with MAP kinase kinase kinase 1 (MEKK1). Consistent with these findings, SKRP1 expression increased the ASK1-MKK7 complexes in a dose-dependent manner and specifically enhanced the activation of MKK7 by ASK1. Thus, our findings are, to our knowledge, the first evidence to show that an MKP also functions as a scaffold protein for the particular MAPK signaling.

Mitogen-activated protein kinases (MAPKs) are activated in response to various extracellular stimuli, and their activities are regulated by upstream activating kinases and protein phosphatases such as MAPK phosphatases (MKPs). We report the identification and characterization of a novel MKP termed SKRP1 (SAPK pathway-regulating phosphatase 1). It contains an extended active site sequence motif conserved in all MKPs but lacks a Cdc25 homology domain. Immunoblotting analysis revealed that SKRP1 is constitutively expressed, and its transcripts of 4.0 and 1.0 kb were detected in almost tissues examined. SKRP1 was highly specific for c-Jun N-terminal kinase (JNK) in vitro and effectively suppressed the JNK activation in response to tumor necrosis factor alpha or thapsigargin. Endogenous SKRP1 was present predominantly in the cytoplasm and co-localized with JNK. However, SKRP1 does not bind directly to its target JNK, but co-precipitation of SKRP1 with the MAPK kinase MKK7, a JNK activator, was found in vitro and in vivo. Furthermore, we found that SKRP1 did not interfere with the co-precipitation of MKK7 with JNK. Together, our findings indicate that SKRP1 interacts with its physiological substrate JNK through MKK7, thereby leading to the precise regulation of JNK activity in vivo.

Mitosis utilizes a number of kinesin-related proteins (KRPs). Here we report the identification of a novel KRP termed KRMP1, which has a deduced 1780-amino acid sequence composed of ternary domains. The amino-terminal head domain is most similar to the kinesin motor domain of the MKLP-1 subfamily and has an intrinsic ATPase activity that is diminished by substituting the consensus Lys-168 with Arg. The central stalk domain is predicted to form a long alpha-helical coiled-coil, and can interact with each other in vivo. An in vivo labeling experiment revealed that KRMP1 is phosphorylated, and we also found that the region within the tail domain containing Thr-1604 as the cdc2 kinase phosphorylation site differs from the bimC box conserved in the bimC subfamily of KRPs. Immunofluorescence analysis showed that endogenous KRMP1 was localized predominantly to the cytoplasm during interphase and dispersed throughout the cell during mitosis. Consistent with this finding, overexpressed KRMP1 was detected in a complicated nuclear or cytoplasmic pattern reflecting multiple nuclear localization/export signals. Furthermore, KRMP1 interacted with the mitotic peptidyl-prolyl isomerase Pin1 in vivo, and an in vitro interaction was detected between the tail domain of KRMP1 and the WW domain of Pin1. Overexpression of KRMP1 caused COS-7 cells to arrest at G(2)-M, and co-expression of Pin1 reversed this effect, indicating their physiological interaction. Together, our results suggest that KRMP1 is a mitotic target regulated by Pin1 and vice versa.

Prp4 is a protein kinase of Schizosaccharomyces pombe identified through its role in pre-mRNA splicing, and belongs to a kinase family including mammalian serine/arginine-rich protein-specific kinases and Clks, whose substrates are serine/arginine-rich proteins. We cloned human PRP4 (hPRP4) full-length cDNA and the antiserum raised against a partial peptide of hPRP4 recognized 170-kDa polypeptide in HeLa S3 cell extracts. Northern blot analysis revealed that hPRP4 mRNA was ubiquitously expressed in multiple tissues. The extended NH(2)-terminal region of hPRP4 contains an arginine/serine-rich domain and putative nuclear localization signals. hPRP4 phosphorylated and interacted with SF2/ASF, one of the essential splicing factors. Indirect immunofluorescence analysis revealed that endogenous hPRP4 was distributed in a nuclear speckled pattern and colocalized with SF2/ASF in HeLa S3 cells. Furthermore, hPRP4 interacted directly with Clk1 on its COOH terminus, and the arginine/serine-rich domain of hPRP4 was phosphorylated by Clk1 in vitro. Overexpression of Clk1 caused redistribution of hPRP4, from the speckled to the diffuse pattern in nucleoplasm, whereas inactive mutant of Clk1 caused no change of hPRP4 localization. These findings suggest that the NH(2)-terminal region of hPRP4 may play regulatory roles under an unidentified signal transduction pathway through Clk1.

We have developed a method for visualizing phosphorylation of proteins in living cells using a novel fluorescent indicator composed of two green fluorescent protein (GFP) variants joined by the kinase-inducible domain (KID) of the transcription factor cyclic adenosine monophosphate (cAMP)-responsive element binding protein (CREB). Phosphorylation of KID by the cAMP-dependent protein kinase A (PKA) decreased the fluorescence resonance energy transfer (FRET) among the flanking GFPs. By transfecting COS-7 cells with an expression vector encoding this indicator protein (termed ART for cAMP-responsive tracer), we were able to visualize activation dynamics of PKA in living cells.

We report a new family with hereditary factor X deficiency. The propositus had a markedly prolonged prothrombin time, a mild prolongation of activated partial thromboplastin time and a clotting time activated by Russell's viper venom. Factor X activity in plasma was 3 u/dl (normal range 56-138 u/dl). Factor X antigen level was 61 u/dl. Molecular analysis revealed a homozygous mutation, Glu (GAG) to Gln (CAG) at residue 32 which normally undergoes gamma-carboxylation within the gamma-carboxyglutamic acid rich domain. The genotypes of family members completely correlated with their factor X activities. It is suggested that the Glu32 to Gln mutation is the molecular basis for the abnormal factor X in this family.

Plasminogen activator inhibitor-1 (PAI-1) plays an inhibitory role in the fibrinolytic enzyme system and is associated with thrombotic diseases. The gene for PAI-1 has an insertion/deletion polymorphism at the promoter region, the 4G/5G polymorphism, which is related to differences in transcription activity in vitro. Association of the 4G/5G polymorphism with plasma PAI-1 levels, however, has not been uniformly reported. We evaluated the relationship between the 4G/5G polymorphism and plasma PAI-1 antigen levels in 104 Japanese males not taking lipid-lowering drugs and without non-insulin-dependent (type 2) diabetes mellitus or coronary artery disease. The genotype frequency was 37.5%, 50.0%, and 12.5% for 4G/4G, 4G/5G, and 5G/5G genotypes, respectively, which differs from that reported for healthy Caucasian males (P < 0.01), with the 4G allele more frequently found in the Japanese population. No association was found between the 4G/5G polymorphism and plasma PAI-1 antigen levels. Multiple regression analysis revealed a significant (P < 0.01) contribution of triglyceride (TG) levels to variations in plasma PAI-1 antigen levels. The correlation between TG levels and plasma PAI-1 antigen levels was not 4G/5G genotype-specific. These findings suggest that PAI-1 4G/5G polymorphism is not associated with plasma PAI-1 antigen levels among healthy Japanese males and that TG levels correlate to plasma PAI-1 antigen levels in all PAI-1 4G/5G genotypes.

A beamline which serves for calibrating transfer standard light sources (deuterium lamps, excimer lamps, Xe lamps etc.) in the UV and VUV regions is being constructed. The synchrotron radiation from the electron storage ring TERAS (750 MeV) is used as a primary standard of spectral radiant intensity. In order to use synchrotron radiation as a primary standard, the electron beam and synchrotron radiation beam parameters need to be evaluated. Uncertainties of synchrotron radiation flux evaluated by measurements of the magnetic flux density, the position of the electron orbital plane, the electron beam size and the distance from the synchrotron radiation tangent point to the detector system are expected to be about 0.003, 0.01, 0.05 and 0.1%, respectively.

Recent reports have suggested that polymorphisms in the human paraoxonase (HUMPONA) gene may be a genetic risk factor for coronary artery disease (CAD) in white populations. However, this association has not yet been confirmed in other ethnic populations. We studied 75 Japanese patients with CAD, whose coronary lesions were confirmed by angiography, and 115 Japanese control subjects with no history of CAD and a normal resting electrocardiogram. The assays for genotyping the two polymorphisms in the HUMPONA gene (192Arg/Gln and 55Leu/Met) were based on changes in restriction enzyme digestion patterns. For codon 192, the frequencies of the Arg-coding allele (B allele) in both patients and control subjects were much higher than those from published results of whites (.26 to .31), and the difference between patients (.74) and control subjects (.59) was statistically significant (P = .002). The patient group had a higher proportion of Arg/Arg (B/B) homozygotes (52.0% vs 32.2%, P = .006). For codon 55, the frequencies of the Leu-coding allele in control subjects and patients were much higher (.91 and .93, respectively) than those published results for whites, but there was no difference between Japanese control subjects and Japanese patients. When subjects with the 55Leu/Leu genotype only were analyzed, 192Arg/Arg homozygotes were still significantly more frequent in the patients than in the control subjects (55.4% vs 37.2%, P = .024), and the frequency of the 192Arg allele was also higher in patients than control subjects (P = .013). Logistic regression analysis including conventional coronary risk factors revealed that 192Arg is an independent risk factor for CAD. Thus, in the Japanese, the association of CAD with the 192Arg variant of HUMPONA (B-type enzyme) is similar to that reported for whites, although the allele frequencies for 192Arg and 55Leu are much higher in the former than the latter population.

Background: Platelets play pivotal roles in coronary thrombosis, and antiplatelet therapies are widely used for coronary artery disease (CAD). However, the effects of genetic variation in platelets on CAD are poorly understood. We have assessed the association between CAD and polymorphisms in a platelet receptor for von Willebrand factor, the glycoprotein (GP) Ib/IX complex, which mediates shear stress-dependent platelet activation., Methods and Results: Genotypes of the alpha-chain of the receptor (GP Ib alpha, 145Thr/Met) were determined in 91 patients with myocardial infarction (MI) or angina pectoris whose lesions were confirmed by coronary angiography as well as in 105 individuals from the general population with no history of angina or other heart diseases and normal resting ECGs. There was no homozygote for Met/Met in either the control or patient groups. The prevalence of the Thr/Met genotype (T/M) in all patients was not significantly different from that in the control group. However, the frequency of T/M was significantly higher in patients aged < or = 60 years (31.8%) than in control subjects aged < or = 60 years (16.0%; P<.05, odds ratio=2.5). An association was also demonstrated between CAD and the other polymorphism of GP Ib alpha, a variable number of tandem repeats of a 13-amino acid sequence, which is known to be linked to the 145Thr/Met polymorphism. There was an association between the frequency of the T/M genotype and the angiographic severity of CAD: 11.1% for Gensini score < 40 versus 50.0% for Gensini score > or = 40 (P=.0015). There was no difference in the distribution of GP Ib alpha genotypes between patients with MI and those with angina pectoris., Conclusions: This study suggests that the presence of the Met allele in GP Ib alpha is a risk factor for the prevalence and severity of CAD in individuals aged < or = 60 years. The results need to be confirmed in a large-scale study of incident case subjects and matching control subjects.

The cardiovascular protective effects of estrogen are known to be mediated by its beneficial effects on lipid metabolism and its direct actions on the vessel wall. The latter can be mediated by a specific receptor for estrogen present on smooth muscle cells and endothelial cells. The gene for the receptor (the classic estrogen receptor [ER]) has three known polymorphisms, Pvu II, Xba I, and B-variant polymorphisms, which are reportedly associated with receptor expression and altered receptor function and with some disorders including breast cancer, hypertension, and spontaneous abortion. However, the significance of genetic variations of the ER in vascular diseases has not been reported. We have examined the association between coronary artery disease (CAD) and the three polymorphisms in ER. Genotypes (P1/P2, X1/X2, and B-wild type/B-variant type) were determined in 87 men and postmenopausal women with myocardial infarction or angina pectoris whose lesions were confirmed by coronary angiography, as well as from 94 control individuals from the general population with no coronary heart disease and normal resting ECG. For B-variant polymorphism, all individuals examined had B-wild type, which contrasts with the reported allele frequency for B-variant type (0.1) in the white population. Genotype distributions and allele frequencies of Pvu II or Xba I polymorphisms were not significantly different between control subjects and patients (P > .05 for Pvu II or Xba I genotypes; P > .05 for Pvu II or Xba I allele frequencies). When the allele frequencies were analyzed separately by sex, there was still no statistically significant difference for both polymorphisms (P > .05 for men; P > .05 for women). No association was found between the polymorphisms and the angiographic severity of CAD. Total cholesterol, triglyceride, or HDL-cholesterol levels were not significantly different among ER genotypes. These findings suggest that the three polymorphisms in ER are not associated with the prevalence and severity of CAD and that the polymorphisms are unrelated to the serum lipid levels in control subjects and patients.

Resistance to activated protein C (APC), recently reported to be the most prevalent inherited cause of thrombosis among Caucasians, is associated with a single point mutation in the coagulation factor V gene. We investigated the prevalence of APC resistance and the factor V gene mutation (R506Q) in 34 consecutive Japanese patients with venous thrombosis or pulmonary thromboembolism and 63 control subjects. Three of the 33 patients examined (9%) had an APC ratio below the 5th percentile of control values (2.27), but all were above 2.0. The factor V mutation (R506Q) was not detected in the 29 patients studied, including the 3 patients whose APC ratios were below 2.27, or in 53 controls. In a tissue factor-based factor V assay to detect APC resistance recently described by Le et al. (Blood 1995;85:1704-1711), all patients studied were found to be normal including the three with a low APC ratio. We conclude that APC resistance and factor V gene mutation are less prevalent in Japan than in several European countries.