Effects of fermented soymilk with Lacticaseibacillus paracasei YIT 9029 on gut microbiota and defecation habits: a randomised, double-blind, placebo-controlled study.

Previous studies have demonstrated that soymilk and Lacticaseibacillus paracasei YIT 9029 (strain Shirota: LcS) each beneficially affect the gut microbiota and defecation habits. To investigate the effects of daily consumption of fermented soymilk containing LcS (FSM), we conducted a randomised, double-blind, placebo-controlled study of 112 healthy Japanese adults with a low faecal Bifidobacterium count. They consumed 100 ml FSM or placebo (unfermented soymilk base) once daily for 4 weeks. Their gut microbiota was analysed by 16S rRNA gene amplicon sequencing and quantitative reverse transcription-polymerase chain reaction (PCR), and faecal short-chain fatty acids (SCFAs) and urinary putrefactive products were assessed during the pre- and post-consumption periods. Defecation habits were examined weekly using a subjective questionnaire. In the post-consumption period, living LcS were not detected in two subjects in the FSM group (n = 57) but were detected in one subject in the SM group (n = 55). The FSM group had a significantly higher number and relative abundance of faecal lactobacilli compared with the placebo group. The relative abundance of Bifidobacterium, alpha-diversity of microbiota, and concentrations of acetate and total SCFAs in faeces were significantly increased in the FSM group, although no significant differences were detected between the groups. The number of defecations and defecation days per week significantly increased in both groups. Subgroup analysis of 109 subjects, excluding 3 with inconsistent LcS detection (2 and 1 subjects in the FSM and SM groups, respectively), revealed that the FSM group (n = 55) had significantly greater increases in faecal acetate concentration compared with the SM group (n = 54) and significant upregulation of pathways related to energy production or glucose metabolism in the gut microbiota. These findings suggest that daily FSM consumption improves the gut microbiota and intestinal environment in healthy adults and may help to maintain health and prevent diseases. Registered at the University Hospital Medical Information Network (UMIN) clinical trials registry under: UMIN 000035612.

Pharmacological considerations in antipsychotic drug selection for prevention of drug-induced dysphagia.

Antipsychotic drugs have the ability to induce dysphagia. The aim of this study was to determine the association between the receptor affinity of antipsychotic drugs and the time-to-onset of dysphagia, and to identify factors that prevent antipsychotic drug-induced dysphagia. We used the receptor affinity of 13 antipsychotic drugs for which data were reported in an in vitro test using human receptors, extracted time-to-onset dysphagia from the Japan Adverse Drug Event Report database, and used data from 46 patients to evaluate the correlation between receptor affinity and time-to-onset of dysphagia. We found a negative correlation between D2 receptor affinity and time-to-onset of dysphagia (r = -0.4572, p = 0.0016), and a positive correlation between H1, M1, and M3 receptor affinity and time-to-onset of dysphagia (r = 0.5006, p = 0.0006; r = 0.4130, p = 0.0059; and r = 0.4149, p = 0.0057, respectively). Antipsychotic drugs with a strong D2 receptor-blocking action may accelerate the onset of dysphagia, whereas a strong H1, M1, and M3 receptor-blocking action may delay the onset of dysphagia. The current study revealed the relationship between the receptor affinity of antipsychotic drugs and the time-to-onset of dysphagia, which should aid in the selection of antipsychotic drugs, while preventing dysphagia.

The dominant limb preferentially stabilizes posture in a bimanual task with physical coupling.

Humans are endowed with an ability to skillfully handle objects, like when holding a jar with the nondominant hand while opening the lid with the dominant hand. Dynamic dominance, a prevailing theory in handedness research, proposes that the nondominant hand is specialized for postural stability, which would explain why right-handed people hold the jar steady using the left hand. However, the underlying specialization of the nondominant hand has only been tested unimanually, or in a bimanual task where the two hands had different functions. Using a dedicated dual-wrist robotic interface, we tested the dynamic dominance hypothesis in a bimanual task where both hands carry out the same function. We examined how left- and right-handed subjects held onto a vibrating virtual object using their wrists, which were physically coupled by the object. Muscular activity of the wrist flexors and extensors revealed a preference for cocontracting the dominant hand during both holding and transport of the object, which suggests proficiency in the dominant hand for stabilization, contradicting the dynamic dominance hypothesis. While the reliance on the dominant hand was partially explained by its greater strength, the Edinburgh inventory was a better predictor of the difference in the cocontraction between the dominant and nondominant hands. When provided with redundancy to stabilize the task, the dominant hand preferentially cocontracts to absorb perturbing forces.NEW & NOTEWORTHY We found that subjects prefer to stabilize a bimanually held object by cocontracting their dominant limb, contradicting the established view that the nondominant limb is specialized toward stabilization.

Endpoint stiffness magnitude increases linearly with a stronger power grasp.

Humans can increase the endpoint stiffness of their arm to reduce self-generated movement variability and to reject unpredictable perturbations from the environment, like during handheld drilling, thereby increasing movement precision. Existing methods to estimate changes in the endpoint stiffness use robotic interfaces to apply position or force perturbations to measure the arm's dynamic response. We propose an alternative method of measuring changes in the power grasp force to estimate adaptations in the magnitude of the arm's endpoint stiffness. To validate our method, we examined how the strength of the power grasp, when holding onto a robotic manipulandum, affected the arm's endpoint stiffness in three different locations of the workspace. The endpoint stiffness magnitude increased linearly with the grasp force, and this linear relationship did not depend on the arm's posture or position in the workspace. The endpoint stiffness may have increased as a combination of greater grasp stiffness and greater arm stiffness, since larger co-contraction was observed in the elbow and shoulder with a stronger grasp. Changes in the grasp force could serve as a metric in assessing how humans adapt their endpoint stiffness magnitude.

Increase in Grasp Force Reflects a Desire to Improve Movement Precision.

Grasping is an action engraved in the human genome, enabling newborn infants to hang from a monkey-bar immediately after birth. The grasp force provides rich information about the brain's control of arm movements. In this study, we tested the hypothesis that the grasp force increases to improve the hand's movement precision during reaching. In two reaching experiments, subjects increased grasp force to suppress movement imprecision that arose from both self-generated motor noise and from an unpredictable environment. Furthermore, the grasp force did not increase constantly, but increased specifically along the movement where the hand's deviation was greatest. The increased grasp was premeditated and was not a reaction to environmental forces, suggesting that the central nervous system has a predictive, state-dependent model of movement precision during reaching. The grasp force provides a high temporal resolution and calibration-less estimate of movement precision adaptation.

Assessment of "look-alike" packaging designs related to medication errors using information technology.

This study aimed to assess the similarity among press-through pack (PTP) sheets of pharmaceutical products in Japan. The appearance of PTPs was assessed using a pharmaceutical design database (PDD) of 2,750 pharmaceutical tablets comprising approximately 40 % of the 6,840 products marketed in Japan. Package sheet color (Sc), tablet color (Tc), character color (Cc), sheet line color (SLc), and upper color (Uc) were used to evaluate the uniformity of PTP sheet design. To assess the risk of misidentification, 1,000 prescriptions for 82,273 cancer patients were retrieved from 21,026,742 records in the claims database of the Japan Medical Data Center Co. Ltd., Tokyo, Japan. The most frequent PTP sheet colors for 143 drugs were Sc (silver), Tc (white), Cc (blue), SLc (none), and Uc (silver). The prescribing pattern of 1000 randomly chosen prescriptions was analyzed. Database records of prescriptions without tablets (n = 69), including only one PTP tablet (n = 292), and those with lack of PDD prescription data (n = 388) were excluded. Eventually, 236 prescriptions were evaluated. Fourteen prescriptions (5.9%) had PTP sheets with five matching elements and 29 had with four matching elements (12.3%). This novel PDD database for information technology concept easily identified similar PTP sheets involved in prescriptions dispensed in 18 % of evaluated cancer patients. The concept seems to be applicable for preventing look-alike dispensing errors.

Optimisation of antithrombin resistance assay as a practical clinical laboratory test: Development of prothrombin activator using factors Xa/Va and automation of assay.

INTRODUCTION: Antithrombin resistance (ATR) is a novel thrombotic risk in abnormal prothrombins. A manual ATR assay using Oxyuranus scutellatus (Ox) venom as a prothrombin activator was established for detecting antithrombin-resistant prothrombin. However, this assay was limited because of Ox snake venom availability and its throughput capacity. Here, we have improved the ATR assay using bovine factors Xa and Va (FXa/Va) as prothrombin activators and have optimised assay conditions for an automated instrument (ACL TOP 500). METHODS: Diluted plasma was incubated with a prothrombin activator mix (phospholipids, CaCl2 , and bovine FXa/Va), followed by inactivation with antithrombin for 10, 20 and 30 minutes. We added a chromogenic substrate S-2238, and assessed changes in absorbance/min at 405 nm. We also adapted assay conditions for ACL TOP 500. RESULTS: Optimum conditions for FXa/Va treatment were 6.25% phospholipids, 5 mM CaCL2 , 0.01 µg/mL FXa and 0.1 µg/mL FVa. ATR assay kinetics with the FXa/Va activator was comparable with that with the Ox activator in heterozygous reconstituted plasma with the recombinant wild-type or antithrombin-resistant prothrombin. Using ACL TOP 500, optimum conditions for the FXa/Va treatment were 10.0% phospholipids, 5 mM CaCl2 , 0.02 µg/mL FXa and 0.2 µg/mL FVa. The automated ATR assay with the FXa/Va activator demonstrated good detectability for antithrombin-resistant prothrombin in plasma from a heterozygous carrier with prothrombin Yukuhashi or Belgrade. CONCLUSION: We optimised the ATR assay with the FXa/Va activator and adapted the assay for ACL TOP 500; the assay showed the ability to clearly detect antithrombin-resistant prothrombin in manual and automated procedures.

Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism.

Essentials Prothrombin Belgrade mutation leads to antithrombin resistance. Clinical and biochemical phenotypes in a large family with this mutation were investigated. In carriers, we detected decreased factor II activity and increased endogenous thrombin potential. Prothrombin Belgrade mutation represents a strong prothrombotic risk factor. SUMMARY: Background The recently reported c.1787G>A mutation in the prothrombin gene leads to Arg596Gln replacement in the protein molecule (prothrombin Belgrade). This substitution impairs binding of antithrombin to thrombin and results in inherited thrombophilia, known as antithrombin resistance. Objectives We aimed to elucidate the clinical and biochemical characteristics of thrombophilia associated with antithrombin resistance in a large Serbian family with the prothrombin Belgrade mutation. Patients and methods Nineteen family members were investigated, among whom 10 were carriers of the c.1787G>A mutation. In all subjects the clinical phenotype was determined and laboratory investigations of hemostatic parameters were performed. Results Six out of the 10 mutation carriers developed thromboembolic events, mainly deep venous and mesenteric vein thrombosis. The median age of the first thrombotic event was 26.5 (12-41) years, whereas the incidence rate of first thrombosis was 2.2% per year. In all mutation carriers prothrombin activity was significantly decreased in comparison with non-carriers, clearly distinguishing each group. However, the presence of the mutation did not affect the prothrombin antigen level in plasma. The endogenous thrombin potential was significantly increased in all carriers in comparison with non-carriers, indicating the presence of blood hypercoagulability. Interestingly, levels of D-dimer and the F1+2 fragment were similar in both groups. Conclusions Although rare, the prothrombin Belgrade mutation represents strong thrombophilia with early onset of thrombosis in the investigated family. According to our results, decreased prothrombin activity may be a simple screening test for detection of this mutation in thrombotic patients.

Numerical study of plasma generation process and internal antenna heat loadings in J-PARC RF negative ion source.

A numerical model of plasma transport and electromagnetic field in the J-PARC (Japan Proton Accelerator Research Complex) radio frequency ion source has been developed to understand the relation between antenna coil heat loadings and plasma production/transport processes. From the calculation, the local plasma density increase is observed in the region close to the antenna coil. Electrons are magnetized by the magnetic field line with absolute magnetic flux density 30-120 Gauss which leads to high local ionization rate. The results suggest that modification of magnetic configuration can be made to reduce plasma heat flux onto the antenna.

Pre-conditioning procedure suitable for internal-RF-antenna of J-PARC RF-driven H⁻ ion source.

The Japan Proton Accelerator Research Complex (J-PARC) cesiated RF-driven H(-) ion source has been successfully operated for about 1 yr. By the world brightest level beam, the J-PARC design beam power of 1 MW was successfully demonstrated. Although no internal-RF-antenna failure, except for the once caused by an excess cesium due to a misoperation, occurred in the operation, many antennas failed in pre-conditionings for the first hundred days. The antenna failure rate was drastically decreased by using an antenna with coating thicker than a standard value and the pre-conditioning procedure repeating 15 min 25 kW RF-power operation and impurity-gas evacuation a few times, before the full power (50 kW) operation.

Fine-tuning to minimize emittances of J-PARC RF-driven H⁻ ion source.

The Japan Proton Accelerator Research Complex (J-PARC) cesiated RF-driven H(-) ion source has been successfully operated for about one year. By the world's brightest level beam, the J-PARC design beam power of 1 MW was successfully demonstrated. In order to minimize the transverse emittances, the rod-filter-field (RFF) was optimized by changing the triple-gap-lengths of each of pairing five piece rod-filter-magnets. The larger emittance degradation seems to be caused by impurity-gases than the RFF. The smaller beam-hole-diameter of the extraction electrode caused the more than expected improvements on not only the emittances but also the peak beam intensity.

Status of the RF-driven H⁻ ion source for J-PARC linac.

For the upgrade of the Japan Proton Accelerator Research Complex linac beam current, a cesiated RF-driven negative hydrogen ion source was installed during the 2014 summer shutdown period, with subsequent operations commencing on September 29, 2014. The ion source has been successfully operating with a beam current and duty factor of 33 mA and 1.25% (500 µs and 25 Hz), respectively. The result of recent beam operation has demonstrated that the ion source is capable of continuous operation for approximately 1100 h. The spark rate at the beam extractor was observed to be at a frequency of less than once a day, which is an acceptable level for user operation. Although an antenna failure occurred during operation on October 26, 2014, no subsequent serious issues have occurred since then.

A Simple fMRI Compatible Robotic Stimulator to Study the Neural Mechanisms of Touch and Pain.

This paper presents a simple device for the investigation of the human somatosensory system with functional magnetic imaging (fMRI). PC-controlled pneumatic actuation is employed to produce innocuous or noxious mechanical stimulation of the skin. Stimulation patterns are synchronized with fMRI and other relevant physiological measurements like electroencephalographic activity and vital physiological parameters. The system allows adjustable regulation of stimulation parameters and provides consistent patterns of stimulation. A validation experiment demonstrates that the system safely and reliably identifies clusters of functional activity in brain regions involved in the processing of pain. This new device is inexpensive, portable, easy-to-assemble and customizable to suit different experimental requirements. It provides robust and consistent somatosensory stimulation, which is of crucial importance to investigating the mechanisms of pain and its strong connection with the sense of touch.

Distinct X chromosomal rearrangements in four haemophilia B patients with entire F9 deletion.

INTRODUCTION: Haemophilia B is an X-linked bleeding disorder caused by a coagulation factor IX gene (F9) abnormality. Numerous F9 defects have been identified to date; however, only a few with an entire F9 deletion have been reported in detail. AIM: To elucidate the cause of severe haemophilia B, we investigated the precise X chromosome abnormalities in four Japanese patients who did not show all amplifications in F9-specific PCR. METHODS: We analysed the patient's genomic DNA using Multiplex ligation-dependent probe amplification (MLPA). To assess the extent of any deletions, we further performed mapping PCRs, inverse PCRs or long-range PCRs and direct sequencing analyses of the X chromosome. RESULTS: We detected entire F9 deletions in four haemophilia B patients and identified the precise deleted regions of the X chromosome including F9. Patient 1 had a 149-kb deletion with breakpoints 90-kb upstream and 30-kb downstream from F9. Patients 2 and 3 showed 273-kb and 1.19-Mb deletions respectively. Patient 4 had two deleted regions: a 1663-bp deletion 1.34-Mb upstream from F9 and a 7.2-Mb deletion including F9. These distinct breakpoints found in four different patients suggest that the mechanism of X chromosome deletion may be different between individuals. Non-allelic homologous recombination (NAHR), microhomology-mediated break-induced replication (MMBIR) or fork stalling and template switching (FoSTeS) may occur in respective X chromosomes of the four haemophilia B patients analysed. CONCLUSIONS: We identified diverse X chromosomal rearrangements in four haemophilia B patients, which might be caused by distinct mechanisms of genomic rearrangement.

Dependence of beam emittance on plasma electrode temperature and rf-power, and filter-field tuning with center-gapped rod-filter magnets in J-PARC rf-driven H(-) ion source.

The prototype rf-driven H(-) ion-source with a nickel plated oxygen-free-copper (OFC) plasma chamber, which satisfies the Japan Proton Accelerator Research Complex (J-PARC) 2nd stage requirements of a H(-) ion beam current of 60 mA within normalized emittances of 1.5 π mm mrad both horizontally and vertically, a flat top beam duty factor of 1.25% (500 µs × 25 Hz) and a life-time of more than 50 days, was reported at the 3rd international symposium on negative ions, beams, and sources (NIBS2012). The experimental results of the J-PARC ion source with a plasma chamber made of stainless-steel, instead of nickel plated OFC used in the prototype source, are presented in this paper. By comparing these two sources, the following two important results were acquired. One was that the about 20% lower emittance was produced by the rather low plasma electrode (PE) temperature (TPE) of about 120 °C compared with the typically used TPE of about 200 °C to maximize the beam current for the plasma with the abundant cesium (Cs). The other was that by using the rod-filter magnets with a gap at each center and tuning the gap-lengths, the filter-field was optimized and the rf-power necessary to produce the J-PARC required H(-) ion beam current was reduced typically 18%. The lower rf-power also decreases the emittances.

Operation and development status of the J-PARC ion source.

A cesium-free H(-) ion source driven with a LaB6 filament is being operated at the Japan Proton Accelerator Research Complex (J-PARC) without any serious trouble since the restoration from the March 2011 earthquake. The H(-) ion current from the ion source is routinely restricted approximately 19 mA for the lifetime of the filament. In order to increase the beam power at the linac beam operation (January to February 2013), the beam current from the ion source was increased to 22 mA. At this operation, the lifetime of the filament was estimated by the reduction in the filament current. According to the steep reduction in the filament current, the break of the filament was predicted. Although the filament has broken after approximately 10 h from the steep current reduction, the beam operation was restarted approximately 8 h later by the preparation for the exchange of new filament. At the study time for the 3 GeV rapid cycling synchrotron (April 2013), the ion source was operated at approximately 30 mA for 8 days. As a part of the beam current upgrade plan for the J-PARC, the front end test stand consisting of the ion source and the radio frequency quadrupole is under preparation. The RF-driven H(-) ion source developed for the J-PARC 2nd stage requirements will be tested at this test stand.

Two is better than one: physical interactions improve motor performance in humans.

How do physical interactions with others change our own motor behavior? Utilizing a novel motor learning paradigm in which the hands of two - individuals are physically connected without their conscious awareness, we investigated how the interaction forces from a partner adapt the motor behavior in physically interacting humans. We observed the motor adaptations during physical interactions to be mutually beneficial such that both the worse and better of the interacting partners improve motor performance during and after interactive practice. We show that these benefits cannot be explained by multi-sensory integration by an individual, but require physical interaction with a reactive partner. Furthermore, the benefits are determined by both the interacting partner's performance and similarity of the partner's behavior to one's own. Our results demonstrate the fundamental neural processes underlying human physical interactions and suggest advantages of interactive paradigms for sport-training and physical rehabilitation.

Multidirectional lip-closing force in adults with mandibular deviation.

The purpose of this study was to investigate the relationship between multidi-rectional lip-closing force and facial soft tissue morphology in adults with mandibular deviation. Fifteen Japanese adults with mandibular deviation participated in this study. The deviation value was defined as the horizontal distance between soft tissue menton and the facial midline. The side of the soft tissue menton relative to the facial midline was defined as the deviated side and the opposite side as the non-deviated side. The signals of directional lip-closing force (DLCF) were investigated in 8 directions. Total lip-closing force (TLCF) was calculated by adding DLCFs in 8 directions. Correlations and differences between the variables were analysed statistically. Significant positive correlations between TLCF and DLCFs were determined in six directions with the exception of the horizontal direction. Significant positive correlations for seven pairs of opposing DLCFs were found. The lower non-deviated DLCF was smaller than the three pairs of opposing lip-closing forces. Negative significant correlation was found between the deviation value and the upper deviated DLCF (P < 0·05). In individuals with mandibular deviation, lip-closing force in the lower non-deviated direction was found to be smaller than the opposing lip-closing forces. When mandibular deviation was greater, the upper deviated lip-closing force was smaller.