Pyridoxamine: A novel treatment for schizophrenia with enhanced carbonyl stress.

AIM: The aim of this clinical trial was to obtain proof of concept for high-dose pyridoxamine as a novel treatment for schizophrenia with enhanced carbonyl stress. METHODS: Ten Japanese schizophrenia patients with high plasma pentosidine, which is a representative biomarker of enhanced carbonyl stress, were recruited in a 24-week, open trial in which high-dose pyridoxamine (ranging from 1200 to 2400 mg/day) was administered using a conventional antipsychotic regimen. Main outcomes were the total change in Positive and Negative Syndrome Scale score and the Brief Psychiatric Rating Scale score from baseline to end of treatment at week 24 (or at withdrawal). RESULTS: Decreased plasma pentosidine levels were observed in eight patients. Two patients showed marked improvement in their psychological symptoms. A patient who harbors a frameshift mutation in the Glyoxalase 1 gene also showed considerable reduction in psychosis accompanied with a moderate decrease in plasma pentosidine levels. A reduction of greater than 20% in the assessment scale of drug-induced Parkinsonism occurred in four patients. Although there was no severe suicide-related ideation or behavior, Wernicke's encephalopathy-like adverse drug reactions occurred in two patients and were completely suppressed by thiamine supplementation. CONCLUSION: High-dose pyridoxamine add-on treatment was, in part, effective for a subpopulation of schizophrenia patients with enhanced carbonyl stress. Further randomized, placebo-controlled trials with careful monitoring will be required to validate the efficacy of high-dose pyridoxamine for these patients.

[The International Study of Burnout Syndrome among Psychiatric Trainees (BoSS International) : Findings from Statistical Analysis of the Japanese Data (BoSS Japan)].

BACKGROUND: Burnout is a psychological condition that may occur after being exposed to excessive and prolonged work-related stresses. Previous studies have demonstrated that the rate of burnout among physicians may be higher compared to other occupations ; and espe- cially psychiatric trainees would have a higher risk of burnout because of limited clinical expe- rience, the burden of heavy duties and longer work-hours etc. In this study, we report the findings from Japanese data obtained as part of the international study of burnout syndrome among psychiatric trainees (BoSS International). METHODS: This study was initiated by members of the European Federation of Psychiatric Trainees (EFPT) and the European Psychiatric Association-European Early Career Psychia- trists (EPA-EECP). The total number of participating nations was 22 countries. A national coordinator recruited study collaborators all over Japan and psychiatric trainees working at their medical institutes were invited to participate in BoSS International by e-mail. The sub- jects were requested to answer the on-line questionnaire anonymously. Consent was obtained when making a list of potential participants at each institute and reconfirmed on the first page of the on-line questionnaire. Answering the questionnaire was deemed to constitute consent. RESULTS: Total number of participants to BoSS International was 7,525 from 22 countries and regions. Of them, 1,980 psychiatric trainees fully completed answering the questionnaire (response rate (RR) 26.0%) including 95 Japanese trainees (RR 41.5%). The mean age of 95 Japanese psychiatric trainees (male rate 67.4%) enrolled in BoSS International was 31.8?4.8 year-old. Their mean clinical experience was 2.9 ?4.4 years. The mean weekly working hours were 72.3?27.1, which was the longest of the 22 participating countries/regions ; while weekly clinical supervision by a mentor was only 3.8?9.0 hours. Regarding the severity of burnout, assessed by using the Maslach Burnout Inventory-General Survey (MBI-GS) consisting of three factors (emotional exhaustion, cynicism, and low sense of professional efficacy): 41 Japanese psychiatric trainees (42.0%) meet the criteria of severe burnout syndrome in this study ; with emotional exhaustion scores of 2.20 and higher, and cynicism of 2.00 and higher. Signifi- cant differences were found on the PHQ-9 score and mean length of supervision between those participants with presence and absence of severe burnout syndrome by using Student's t-test. CONCLUSION: Statistical analyses of the whole data (n=1,980) revealed that the risk of burnout was higher for trainees who were younger, without children, and had not opted for psychiatry as a first career choice. Further analyses after adjustment for socio-demographic characteristics and country difference still demonstrated severe burnout was associated with long working hours, less supervision, and not having regular rest. The analyses of Japanese data showed similar tendencies, although statistical significance was not observed. Burnout among psychiatry trainees may be linked to drop-out from the training program and malprac- tice in clinical settings. We should be aware of the higher risk of burnout in residents and the importance of regular and sufficient supervision to prevent burnout.

Characterizing prefrontal cortical activity during inhibition task in methamphetamine-associated psychosis versus schizophrenia: a multi-channel near-infrared spectroscopy study.

Methamphetamine abuse and dependence, frequently accompanied by schizophrenia-like psychotic symptoms [methamphetamine-associated psychosis (MAP)], is a serious public health problem worldwide. Few studies, however, have characterized brain dysfunction associated with MAP, nor investigated similarities and differences in brain dysfunction between MAP and schizophrenia. We compared prefrontal cortical activity associated with stop-signal inhibitory task in 21 patients with MAP, 14 patients with schizophrenia and 21 age- and gender-matched healthy controls using a 52-channel near-infrared spectroscopy (NIRS) system. Both the MAP and the schizophrenia groups showed significantly reduced activation in the bilateral ventrolateral prefrontal cortex compared with controls; however, only the MAP group showed reduced activation in the frontopolar prefrontal cortex. The MAP group demonstrated significant positive correlations between task performance and hemodynamic responses in the bilateral ventrolateral, polar and left dorsolateral regions of the prefrontal cortex. The MAP and schizophrenia groups demonstrated a significant difference in the relationship of impulsivity to hemodynamic changes in the bilateral premotor cortex. These findings characterize similarities and differences in prefrontal cortical dysfunction between psychosis associated with methamphetamine and schizophrenia. The reduced hemodynamic changes in the bilateral ventrolateral prefrontal cortex suggest a common underlying pathophysiology of MAP and schizophrenia, whereas those in the frontopolar prefrontal cortex point to an impaired state that is either inherent or caused specifically by methamphetamine use.

Dorsolateral prefrontal hemodynamic responses during a verbal fluency task in hypomanic bipolar disorder.

OBJECTIVES: Neuroimaging studies have suggested prefrontal dysfunction in response to cognitive activation in bipolar disorder (BD). However, its characteristics in manic states have not been well understood. Thus, we compared prefrontal hemodynamic responses during a cognitive task between hypomanic and depressive states in BD. We then longitudinally compared hypomanic and subsequent euthymic states. METHODS: The prefrontal function of 27 patients with BD (11 hypomanic and 16 depressed) and 12 age- and gender-matched healthy controls (HCs) was evaluated using near-infrared spectroscopy (NIRS) during a verbal fluency task (VFT). Hypomanic symptoms were assessed using the Young Mania Rating Scale. Among the 11 hypomanic patients, eight participated in the second NIRS measurement after their hypomanic symptoms resolved. RESULTS: VFT performance did not differ among hypomanic, depressed, and HC groups. Both BD groups exhibited significantly lower activation during the VFT than HCs in the broader bilateral prefrontal cortex. Hemodynamic changes in the left dorsolateral prefrontal cortex (DLPFC) in the hypomanic patients with BD were significantly larger than those in the depressed patients. In addition, hypomanic symptom severity was positively correlated with activation in the left DLPFC and frontopolar cortex in patients with BD. Follow-up measurement of the hypomanic patients revealed that prefrontal activation was decreased after hypomanic symptoms resolved. CONCLUSIONS: Combining cross-sectional and longitudinal assessments, the present results suggest that prefrontal hemodynamic responses associated with cognitive activation differ between hypomanic and depressive states in BD. NIRS measurement could be a useful tool for objectively evaluating state-dependent characteristics of prefrontal hemodynamics in BD.

Social Function and Frontopolar Activation during a Cognitive Task in Patients with Bipolar Disorder.

BACKGROUND: It is important to understand the neural basis of functional impairments in patients with bipolar disorder (BD) in order to be able to address the recovery. Recently, neurocognitive impairment emerged as a predictor of psychosocial function. A number of functional brain imaging studies have shown that social function is associated with activation of the prefrontal cortex during a cognitive task in healthy adults, and in patients with major depressive disorder and schizophrenia. However, few studies have been conducted in patients with BD. METHODS: We performed multichannel near-infrared spectroscopy (NIRS) imaging to investigate the activation of the prefrontal cortex during a verbal fluency task (VFT). We also used the Social Adaptation Self-Evaluation Scale (SASS) to assess social functioning in patients with BD. Thirty-three depressed patients with BD and 65 age-, gender- and task performance-matched healthy controls (HCs) participated in this study. RESULTS: Depressed patients with BD showed reduced activation in the broader bilateral prefrontal cortex during the VFT compared to HCs. Moreover, a significant positive correlation was observed between the total SASS scores and right prefrontal activation in patients with BD. In the SASS subscores, the interest and motivation factor was also positively correlated with frontopolar activation. CONCLUSIONS: These results suggest an association between social function and prefrontal activation in depressed patients with BD. The present study provides evidence that NIRS imaging could be helpful in understanding the neural basis of social function.

Prefrontal dysfunction associated with a history of suicide attempts among patients with recent onset schizophrenia.

Suicide is a major cause of death in patients with schizophrenia, particularly among those with recent disease onset. Although brain imaging studies have identified the neuroanatomical correlates of suicidal behavior, functional brain activity correlates particularly in patients with recent-onset schizophrenia (ROSZ) remain unknown. Using near-infrared spectroscopy (NIRS) recording with a high-density coverage of the prefrontal area, we investigated whether prefrontal activity is altered in patients with ROSZ having a history of suicide attempts. A 52-channel NIRS system was used to examine hemodynamic changes in patients with ROSZ that had a history of suicide attempts (n = 24) or that lacked such a history (n = 62), and age- and sex-matched healthy controls (n = 119), during a block-design letter fluency task (LFT). Patients with a history of suicide attempts exhibited decreased activation in the right dorsolateral prefrontal cortex compared with those without such a history. Our findings indicate that specific regions of the prefrontal cortex may be associated with suicidal attempts, which may have implications for early intervention for psychosis.

A capillary holder for scanning detection of capillary isoelectric focusing with laser-induced fluorescence.

A holder for a 12 cm long capillary was designed for scanning LIF detection of CIEF. The polyimide coat of a fused-silica capillary has been removed, and 1.5 mm diameter flanges have been attached near both ends. The holder is fixed on the stage of a fluorescence microscope via a translational stage, and a capillary guide is directly fixed on the microscope stage. The guide has a groove and a pressure plate for the capillary to slide in. The holder has two pulling plates with slits of 1 mm to accept the capillary just inside the flanges. The slits and the groove of the guide have been aligned. The motion of the translational stage brings the pulling plate into contact with the flange at the pulled side, and slides the capillary through the guide. The other end of the capillary is free and produces no strain on the capillary. When the motion of the stage is reversed, an unstrained contact is achieved at the other end. The baseline noise from scanning was only 50% larger than that without scanning. The fluorescence-signal variation during scanning was about 4% of the total signal, which was about twice that without scanning.

Isoelectric focusing in a microfluidically defined electrophoresis channel.

A new form of microchip isoelectric focusing that allows efficient coupling with pretreatment processes is reported. The sample is conveyed in a carrier ampholyte solution to the separation channel that is connected at both ends by two V-shaped lead channels, which supply electrode solutions to the connection point and complete the electrical connection to off-chip electrodes. The relatively high electric conductivity of the electrode solutions compared with that of the pH gradient enables focusing with a 2% loss of applied voltage at the electrodes using the lead channels. A glass microchip was constructed specifically for this configuration. The channel wall was coated with polydimethylacrylamide, and the IEF chip was operated in a chip holder equipped with on-chip connector valves. A plug of fluorescence-labeled peptide p I markers with p I values ranging from 3.64 to 9.56 with carrier ampholyte solution (pH 3-10) was introduced into the separation channel. When the plug reached the channel segment (24 mm in length) between the connection points with the electrolyte lead channels, isoelectric focusing was started after filling the lead channels with electrolyte solutions. The peptide markers were observed using scanning fluorescence detection. The entire range of the pH gradient was established in the segment after approximately 2 min. Isoelectric focusing of three consecutively injected sample plugs containing different p I markers was demonstrated.

Suicidal ideation and burnout among psychiatric trainees in Japan.

AIM: Burnout is a psychological condition that may occur in all workers after being exposed to excessive work-related stresses. We investigated suicidal ideation and burnout among Japanese psychiatric trainees as a part of the Burnout Syndrome Study (BoSS) International. METHODS: In the Japanese branch, 91 trainees fully completed suicide ideation and behaviour questionnaire (SIBQ) and Maslach Burnout Inventory-General Survey (MBI-GS). RESULTS: Passive suicidal ideation was reported by 38.5% of Japanese trainees and 22.0% of them had experienced active suicidal ideation. The burnout rate among Japanese subjects was 40.0%. These results were worse compared to the all 1980 trainees who fully completed the main outcome measure in BoSS International, 25.9%, 20.4% and 36.7%, respectively. CONCLUSIONS: Our results suggest a higher risk of suicide among Japanese residents. Japan has a higher suicide rate than other countries. Early detection of, and appropriate intervention for, suicidal ideation is important in preventing suicide in psychiatry residents.

Association between longitudinal changes in prefrontal hemodynamic responses and social adaptation in patients with bipolar disorder and major depressive disorder.

BACKGROUND: Patients with affective disorders exhibit changes in regional brain function and show abnormal social adaptation. However, to our knowledge, no near-infrared spectroscopy (NIRS) study has examined the relationship between these two phenomena longitudinally. This study examined the region-specific functional abnormality associated with bipolar disorder (BD) and major depressive disorder (MDD), and the association between particular longitudinal changes in regional activation and social adaptation. METHODS: We evaluated frontotemporal functioning during a verbal fluency test (VFT) for patients with BD (N=18), those with MDD (N=10), and healthy controls (HCs; N=14) using NIRS. NIRS measurements and the Social Adaptation Self-evaluation Scale (SASS) were administered twice with an interval of approximately 6 months. RESULTS: The BD and MDD groups showed lesser activation than the HCs in the bilateral ventro-lateral prefrontal cortex and the anterior part of the temporal cortex (VLPFC/aTC). Longitudinal changes in SASS scores were positively associated with the extent of change in left VLPFC/aTC activation in the BD group and with right VLPFC/aTC activation in the MDD group. LIMITATIONS: Our small sample size limited statistical power, and the effect of medication and multiple comparisons cannot be excluded, although these effects were considered in the interpretation of the present results. CONCLUSION: Longitudinal increases of VLPFC/aTC activation were associated with improvement in social adaptation in patients with BD and those with MDD. NIRS measurement could be a useful tool for objective evaluation of changes in social adaptation in BD and MDD.

Development of a pressure-driven injection system for precisely time controlled attoliter sample injection into extended nanochannels.

The rapidly developing interest in nanofluidics, which is used to examine liquids on an order that ranges from an attoliter to a femtoliter, correlates with the recent interest in decreased sample amounts, such as in the field of single-cell analysis. For general nanofluidic analysis, the fact that a pressure-driven flow does not limit the choice of solvents (aqueous or organic) is an important aspect. In this paper, an automated injection system using a pressure-driven flow for several hundred nanometer-sized channels (extended nanochannels) is described. By automatically, and independently, switching four pressure lines using solenoid valves controlled by a sequencer with a time resolution of 10 ms, 550 aL sample band in minimum was reproducibly injected under normal phase conditions. The reproducibility of the band injection was improved by one order when compared with the previous injection method, which enables determination of time zero for injection. These facts are essential for the further band analysis in nanochannels, where diffusion is dominant. This injection system using pressure-driven flow can be used with any kind of solvent, which should make it a significant tool for nanofluidic applications, such as immunoassay, DNA analysis, and chromatography.

Experimental investigation of droplet acceleration and collision in the gas phase in a microchannel.

We developed a novel microfluidic system, termed a micro-droplet collider, by utilizing the spatial-temporal localized liquid energy to realize chemical processes, which achieved rapid mixing between droplets having a large volume ratio by collision. In this paper, in order to clarify the characteristics of the micro-droplet collider, dynamics of droplet acceleration, stationary motion and collision in the gas phase in a microchannel were experimentally investigated with visualized images using a microscope equipped with a high-speed camera. The maximum velocity of 450 mm s(-1) and acceleration of 1500 m s(-2) of a 1.6 nL water droplet were achieved at an air pressure of 100 kPa. Measurement results of dynamic contact angles of droplets indicated that wettability of the surface played an important role in the stability of droplet acceleration and collision. We found that the bullet droplet penetrated into the target droplet at collision, which differed from bulk scale. The deformation of the droplet was strongly suppressed by the channel structure, thus stable collision and efficient utilization of the droplet energy were possible. These results are useful for estimating the localized energy, for improving the system in order to realize extreme performance, and for extending the applications of microfluidic devices.

Pathway to psychiatric care in Japan: A multicenter observational study.

BACKGROUND: This study examines pathways to psychiatric care in Japan using the same method as the collaborative study carried out in 1991 under the auspices of the World Health Organization. METHODS: Thirteen psychiatric facilities in Japan were involved. Of the 228 patients who contacted psychiatric facilities with any psychiatric illness, eighty four visiting psychiatric facilities for the first time were enrolled. Pathways to psychiatric care, delays from the onset of illness to treatment prior to reaching psychiatrists were surveyed. RESULTS: Thirty three patients (39.4%) directly accessed mental health professionals, 32 patients (38.1%) reached them via general hospital, and 13 patients (15.5%) via private practitioners. The patients who consulted mental health professionals as their first carers took a longer time before consulting psychiatrists than the patients who consulted non-mental health professionals as their first carers. The patients who presented somatic symptoms as their main problem experienced longer delay from the onset of illness to psychiatric care than the patients who complained about depressive or anxiety symptoms. Prior to the visit to mental health professionals, patients were rarely informed about their diagnosis and did not receive appropriate treatments from their physicians. Private practitioners were more likely to prescribe psychotropics than physicians in general hospitals, but were less likely to inform their patients of their diagnosis. CONCLUSION: This first pathway to psychiatric care study in Japan demonstrated that referral pathway in Japan heavily relies on medical resources. The study indicates possible fields and gives indications, underlining the importance of improving skills and knowledge that will facilitate the recognition of psychiatric disorders presenting with somatic and depressive symptoms in the general health care system and by private practitioners.

Fully automated two-dimensional electrophoresis system for high-throughput protein analysis.

We developed a fully automated electrophoresis system for rapid and highly reproducible protein analysis. All the two-dimensional (2D) electrophoresis procedures including isoelectric focusing (IEF), on-part protein staining, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and in situ protein detection were automatically completed. The system comprised Peltiert devices, high-voltage generating devices, electrodes, and three disposable polymethylmethacrylate (PMMA) parts for IEF, reaction chambers, and SDS-PAGE. Because of miniaturization of the IEF part, rapid IEF was achieved in 30 min. A gel with a tapered edge gel on the SDS-PAGE part realized a connection between the parts without use of a gluing material. A biaxial conveyer was employed for the part relocation, sample introduction, and washing processes to realize a low-maintenance and cost-effective automation system. Performances of the system and a commercial minigel system were compared in terms of detected number, resolution, and reproducibility of the protein spots. The system achieved high-resolution comparable to the minigel system despite shorter focusing time and smaller part dimensions. The resulting reproducibility was better or comparable to the performance of the minigel system. Complete 2D separation was achieved within 1.5 h. The system is practical, portable, and has automation capabilities.

A self-contained polymeric 2-DE chip system for rapid and easy analysis.

We developed a polymeric 2-DE chip system. The chip consisted of an IEF region, an SDS-PAGE region, a valveless connection port, and a sample introduction port. A "junction structure" as a valveless connection port, which allowed separating and connecting the first- and second-dimensional gels, was fabricated between their regions. A "solution inlet" as a sample introduction port was fabricated to perform the liquid and sample introductions without solution leakage. Simultaneous sample monitoring was performed using the on-chip detection system. The performances of the system were demonstrated using commercially available proteins as a standard specimen and tissue-extracted proteins as the real samples. All procedures were employed without any movement of relocation part. This new 2-D separation system realized improved labor-intensive operations and a reduced experimental time.