TC10, a Rho family GTPase, is required for efficient axon regeneration in a neuron-autonomous manner.

Intracellular signaling pathways that promote axon regeneration are closely linked to the mechanism of neurite outgrowth. TC10, a signaling molecule that acts on neurite outgrowth through membrane transport, is a member of the Rho family G proteins. Axon injury increases the TC10 levels in motor neurons, suggesting that TC10 may be involved in axon regeneration. In this study, we tried to understand the roles of TC10 in the nervous system using TC10 knock-out mice. In cultured hippocampal neurons, TC10 ablation significantly reduced axon elongation without affecting ordinary polarization. We determined a role of TC10 in microtubule stabilization at the growth cone neck; therefore, we assume that TC10 limits axon retraction and promotes in vitro axon outgrowth. In addition, there were no notable differences in the size and structure of brains during prenatal and postnatal development between wild-type and TC10 knock-out mice. In motor neurons, axon regeneration after injury was strongly suppressed in mice lacking TC10 (both in conventional and injured nerve specific deletion). In retinal ganglion cells, TC10 ablation suppressed the axon regeneration stimulated by intraocular inflammation and cAMP after optic nerve crush. These results show that TC10 plays an important role in axon regeneration in both the peripheral and central nervous systems, and the role of TC10 in peripheral axon regeneration is neuron-intrinsic.

Phosphatase of regenerating liver sensitizes MET to functional activation by hepatocyte growth factor.

Phosphatase of regenerating liver (PRL) is overexpressed in metastatic cancers and actively drives their malignant progression. Many studies on cultured cancer cells have implied PRL overexpression as a stimulant for cellular signaling involved in cell proliferation. However, its role in the tightly adhered and polarized epithelial cells remains largely uncharacterized. In this study, we show that inducible expression of PRL in MDCK normal epithelial cells sensitized MET, the receptor for hepatocyte growth factor (HGF), to functional activation by HGF. We found that PRL expression amplified tyrosine phosphorylation levels of various proteins, among which MET was identified to be the most abundant. This phosphorylation occurred selectively at Y1234/1235 in the activation loop of MET, whereas phosphorylation of Y1349 in the effector-binding site, which is directly involved in downstream signaling, was almost undetectable. Consistently, PRL overexpression by itself did not cause observable alterations at the cellular level. However, when cells were stimulated with HGF, phosphorylation of Y1349 was much more strongly induced in PRL-expressing cells than in control cells. This resulted in robust cell scattering and tubulogenesis, even with low levels of HGF. Collectively, these results demonstrate a unique role of PRL in regulating MET function, which is known to be crucial for remodeling of epithelial tissues and malignant progression of cancers.

Involvement of the Mab21l1 gene in calvarial osteogenesis.

The Mab-21 gene family is crucial for animal development. A deficiency in the Mab-21 genes associates with several defects, including skeletal malformation in mice and humans. In this study, we observed that mice lacking Mab21l1 displayed an unclosed fontanelle, suggesting impaired calvarial bone development. Cells isolated from the calvaria of these mice showed a greater osteoblast differentiation potential as evidenced by the abundance of mineralized bone nodules and higher expression levels of osteogenic markers than wild-type cells. Mab21l1-/- osteoblasts also expressed higher levels of adipocyte genes and interferon-regulated genes at early stages of osteogenesis. Rankl/Opg expression levels were also higher in Mab21l1-/- osteoblasts than in wild-type cells. These data suggest that Mab21l1 is involved in either the regulation of mesenchymal cell proliferation and differentiation or the balance between bone formation and resorption. An alteration in these regulatory machineries, therefore, may lead to insufficient bone formation, causing the bone phenotype in Mab21l1-/- mice.

[Curriculum of the New Certificate Psychiatrist System of the Japanese Board of Psychiatry-What Items are Applied Each Year for Three Years, and How Training Psychiatrists are Evaluated-].

The new certificate psychiatrist system of the Japanese Board of Psychiatry is discussed from the viewpoint of the improvement of the current certificate psychiatrist system. In the new system, training items are applied each year for three years. Actually general items and particular disease items of the current training book are rearranged in the new sys- tem. The results of training psychiatrists are evaluated multi-dimensionally and two-way com- municatively. The instructing doctor evaluates the performance of training psychiatrists at the time of completing the program at all training hospitals and gives some feedback to the psy- chiatrists. Staff with multiple occupations also evaluate the training psychiatrists. The training psychiatrists also evaluate the instructing doctors and training program. The program man- agement committee of each basic training hospital collaborates with the training committee of the cooperative training hospitals to examine and evaluate the training results, and improve the program.

Relationship between quantitative electroencephalogram and interferon-α-induced depression in chronic hepatitis C patients.

BACKGROUND: Quantitative electroencephalogram (qEEG) changes in chronic hepatitis C patients treated with interferon-α (IFN-α) have previously been reported. However, whether IFN-α-induced depression is related to changes in qEEG during IFN-α treatment remains unclear. METHOD: Fifty chronic hepatitis C patients were enrolled and IFN-α was administered intramuscularly at 9 × 10(6) IU daily for the first 4 weeks and then 3 times a week for the next 20 weeks. Serial EEGs obtained before and at 4 weeks after treatment were assessed. The absolute power for each frequency band was determined using qEEG techniques. Differences in the rate of change in absolute power for each of 6 frequency bands (δ, θ1, θ2, α1, α2 and ß) were assessed between patients with and without major depression using the Mann-Whitney U test. When significant differences in the rate of change in absolute power for each frequency band were observed, differences in the rate of change were also assessed between patients with and without psychological complications using the Mann-Whitney U test. RESULTS: Major depression due to psychological complications during IFN-α treatment was reported in 10 out of 50 patients. In the θ1 band, the difference in the rate of change was demonstrated to be significant (p = 0.0036). Moreover, at the central, frontal, parietal, and temporal locations, the rates of change were also significantly different. CONCLUSION: In IFN-α-treated chronic hepatitis C patients who were diagnosed with major depression, qEEG changes were more obvious and widely distributed.

Teratogenic factors affect transcription factor expression.

Chemical compounds are produced every day, many with adverse effects on human health, and hence it is vital to predict the risks to humans simply, rapidly, and accurately. Teratogens have a serious impact on fetal development. This has been studied mainly by phenotypic analysis of experimental animals. However, since phenotypes can vary within different species, we established a new evaluation system based on our recent finding that teratogens influence Hox gene expression in mice. Similarly to the Hox gene expression changes, the expression patterns of several transcription factors involved in development, including the Dlx, Irx, Sall, and T-box families, were altered after 6 h of exposure to retinoic acid (RA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The expression changes in Dlx4, Dlx6, Irx5, Sall2, Sall3, Sall4, Tbx10, and Tbx22 were linked to teratogen-induced phenotypes, and our results indicate that expression changes in developmental transcription factors can help to predict teratogenic risk.

Low Dose of Curcumin Combined with Exercise Synergistically Induces Beige Adipocyte Formation in Mice.

Curcumin (Cur) has various biological effects, including anti-obesity and anti-diabetic properties. However, the molecular mechanisms by which Cur exerts these effects remain unclear. In addition, high doses of Cur have been administered in most animal and human trials to date, due mainly to the poor water solubility of native Cur and its low oral bioavailability. In our previous study, we demonstrated that a highly bioavailable Cur formulation (4.5 mg/kg) induces the formation of beige adipocytes in inguinal white adipose tissue (iWAT) in mice. In the present study, to enhance Cur-mediated beige adipocyte formation and reduce the required functional Cur dose, we investigated whether a low dose of Cur combined with exercise synergistically induced beige adipocyte formation. Cur (1.5 mg Cur/kg, daily) combined with exercise for 4 wk significantly induced beige adipocyte formation in iWAT in mice. This effect was associated with the elevation of interleukin-6 level following subsequent Cur administration combined with exercise. These results indicate that exercise combined with Cur synergistically enhances biological activity and reduces the required Cur dose. These findings suggest that Cur could be used as a dietary supplement during exercise to enhance exercise-mediated health benefits.

Relationships between exploratory eye movement dysfunction and clinical symptoms in schizophrenia.

AIM: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non-schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). METHODS: The data for the 251 schizophrenia subjects used in the previous discriminant-analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out. RESULTS: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE. CONCLUSION: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.

[Survey on the actual condition of psychiatrists and psychiatric services in Japan. (Part 1): Basic data on number and distribution of psychiatrists].

BACKGROUND: To ensure that psychiatric services adequately meet the needs of the Japanese people, planning a prospective design based on a needs analysis is required. Presently, the distribution of medical resources in Japan is skewed and the priorities of psychiatric services are unclear. OBJECTIVE: To determine the current status of psychiatric services. METHOD: The definition of a psychiatrist was determined by qualified specialists of the Japanese Society for Psychiatry and Neurology (JSPN). Of the 11,169 candidates who applied for the specialist psychiatry examination, 246 were excluded due to a lack of personal information and 4 due to refusal. The remaining 10,919 agreed to allow the verification of their personal data. This study was conducted with the approval of the JSPN. The total number of psychiatrists, their demographic backgrounds, the number of psychiatrists by prefecture, and the number of psychiatrists in each secondary medical care block in Japan were calculated. RESULTS: Of the 10,919 psychiatrists included in this analysis, 2,124 were female and 8,790 were male. Approximately 90% were < 65 years old, and 42% were < 45 years old. Their primary work places were as follows: psychiatric hospitals (n = 5,233, 47.9%); university departments of psychiatry (n=1,353, 12.4%); general hospitals (n = 1,064, 9.7%); psychiatric clinics (n = 2,456, 22.5%); nonpsychiatric clinics (n = 687, 6.3%); and nonclinical work places such as basic science departments (n = 124, 1.1%). The number of psychiatrists per 100,000 inhabitants in each prefecture was determined. The highest numbers of psychiatrists were from Kochi (13.20), Tokyo (12.76), and Tokushima (12.24), and the lowest numbers were from Ibaraki (5.34), Aomori (5.36), and Saitama (5.67). The number of psychiatrists per 100,000 inhabitants in Kochi was 1.48 per area (100 km square), and Tokyo showed the highest at 75.99 psychiatrists per area, followed by Osaka and Kanagawa. The five Tohoku prefectures and Hokkaido had the fewest psychiatrists per area. CONCLUSION: For planning the future management of psychiatric services, continuous investigation of the actual number of psychiatrists and the status of psychiatric services in Japan is required with the constant cooperation of the JSPN.

[Survey on the actual condition of psychiatrists and psychiatric services in Japan. (Part 2): Change in geographical working area and setting of each psychiatrist].

BACKGROUND: The shortage of psychiatrists has recently become a public concern; however, the reason for this shortage has not been clearly discussed or explained on the basis of real data. We assumed that it is not only due to the lack of the absolute number of psychiatrists, but also due to an imbalance in their distribution in geographical working areas and settings. OBJECTIVE: To evaluate the change in distribution of Japanese psychiatrists. METHOD: We analyzed the change in the geographical working area and setting of each psychiatrist from September 2006 to March 2009 using data obtained from psychiatrists who applied for the Board Certification Examination of the Japanese Psychiatric Association. Our data included 6,881 psychiatrists. RESULTS: With regard to the geographical working area, the number of psychiatrists in ordinance-designated cities (urban areas) increased by 2.2%, whereas that in other areas decreased by 3.0%. On examination of work settings, we noted a 16.0% decrease in the number of psychiatric departments in general hospitals and a 20.0% increase in the number of psychiatric clinics. Surprisingly, more than 10% of middle-aged psychiatrists (10.3% of 36 45-year-olds and 12.2% of 46-55-year olds) who worked in general hospitals moved to clinics. CONCLUSION: The present study revealed that, although psychiatrists did not tend to move from rural to urban areas, they showed a tendency to move from general hospitals to psychiatric clinics.

Combination of Exercise and Intake of Amino Acid Mixture Synergistically Induces Beige Adipocyte Formation in Mice.

Exercise combined with dietary factors may have significant effects on the suppression of body fat accumulation. Several trials suggest that amino acid mixtures containing alanine, arginine, and phenylalanine (ARF) combined with exercise can significantly reduce body fat accumulation in overweight adults and high-fat diet-induced obesity in mice. We therefore hypothesized that combining ARF and exercise would significantly induce beige adipocyte formation and that this would contribute to reducing body weight, whereas administration of ARF or exercise alone would not. Administration of ARF (1 g/kg body weight, daily) combined with exercise (5 sessions per week) for 4 wk significantly induced formation of beige adipocytes in inguinal white adipose tissue (iWAT) in mice, although ARF or exercise alone did not. Metabolomic analysis showed that plasma lactate concentration was significantly elevated in the exercise+ARF group relative to the exercise group. Furthermore, lactate dehydrogenase B, which increases redox stress by converting lactate to pyruvate in iWAT and triggers induction of uncoupling protein 1 expression was significantly upregulated in iWAT of the exercise+ARF group. These findings demonstrate the unique effect of ARF combined with exercise for inducing beige adipocyte formation, which may be associated with the suggested lactate-mediated pathway. Appropriate mixtures of amino acids could be used as a dietary supplement before exercise and contributed to increasing energy expenditures.

Exploratory eye movement dysfunction as a discriminator for schizophrenia : a large sample study using a newly developed digital computerized system.

In our previous studies, we identified that exploratory eye movement (EEM) dysfunction appears to be specific to schizophrenia. The availability of a biological marker specific to schizophrenia would be useful for clinical diagnosis of schizophrenia. Consequently, we performed the discriminant analysis between schizophrenics and non-schizophrenics on a large sample using the EEM test data and examined an application of the EEM for clinical diagnosis of schizophrenia. EEM performances were recorded in 251 schizophrenics and 389 non-schizophrenics (111 patients with mood disorders, 28 patients with neurotic disorders and 250 normal controls). The patients were recruited from eight university hospitals and three affiliated hospitals. For this study with a large sample, we developed a new digital computerized version of the EEM test, which automatically handled large amounts of data. We measured four parameters: number of eye fixations (NEF), total eye scanning length (TESL), mean eye scanning length (MESL) and responsive search score (RSS). These parameters of schizophrenics differed significantly from those of the other three groups. The stepwise regression analysis selected the TESL and the RSS as the valid parameters for discriminating between schizophrenics and non-schizophrenics. In the discriminant analysis using the RSS and TESL as prediction parameters, 184 of the 251 clinically diagnosed schizophrenics were discriminated as having schizophrenia (sensitivity 73.3%); and 308 of the 389 clinically diagnosed non-schizophrenic subjects were discriminated as non-schizophrenics (specificity 79.2%). Based on our findings we believe that the EEM measures may be useful for the clinical diagnosis of schizophrenia.

Influence of teratogenic factors on mouse 39 hox gene expression.

In normal development, each gene correctly expresses under temporal and spatial regulation. Teratogenic agents among environmental contaminants induce aberrated gene expression and consequently lead to congenital malformations. Therefore, it is urgent to identify molecular markers for the detection of teratogenic agents' effects.We analyzed mouse 39 hox gene expression in teratogenic factor exposed embryos. We found that 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and retinoic acid (RA) affected differentially expression of hox. Unlike the RA-effects, TCDD led to broad repression of all hox loci. This different effect was also detected in miRNAs (microRNAs) expression in hox loci. Our results indicate that this irregular hox expression is a cause of congenital malformation, and suggest that monitoring of all hox expression works as a marker for environmental contaminants, including teratogenic effects.

Hyperfrontality in patients with schizophrenia during saccade and antisaccade tasks: a study with fMRI.

AIMS: Antisaccadic eye movements, requiring inhibition of a saccade toward a briefly appearing peripheral target, are known to be impaired in schizophrenia. Previous neuroimaging studies have indicated that patients with schizophrenia show diminished activations in the frontal cortex and basal ganglia. These studies used target fixation as a baseline condition. However, if the levels of brain activities at baseline are not compatible between patients and healthy subjects, between-group comparison on antisaccade-related activations is consequently invalidated. One possibility is that patients with schizophrenia may present with greater activation during fixation than healthy subjects. In order to examine this possibility, here we investigated brain activities associated with antisaccade in the two groups without using target fixation at baseline. METHODS: Functional brain images were acquired during prosaccades and antisaccades in 18 healthy subjects and 18 schizophrenia patients using a box-car functional magnetic resonance imaging design. Eye movements were measured during scanning. RESULTS: In the patient group, the elevated activities in the dorsolateral prefrontal cortex (DLPFC) and thalamus, normally seen in antisaccade tasks relative to saccade tasks, were no longer observed. Moreover, in normal subjects, activities in the DLPFC and thalamus were greater during the antisaccade task than during the saccade task. In patients, no such difference was observed between the two tasks, suggesting that these brain regions are likely to be highly activated even by a simple task such as fixation. In particular, the DLPFC and thalamus in patients were not activated at a level commensurate with the difficulty of the tasks presented. CONCLUSIONS: From these results, it is suggested that schizophrenia entails dysfunctions in the fronto-striato-thalamo-cortical network associated with motor function control.

Inhibited autonomy for promoting physical health: qualitative analysis of narratives from persons living with severe mental illness.

BACKGROUND: Autonomy is a key factor in the reduction of inequitable physical healthcare among people with severe mental illness compared with the general population.AimsTo clarify the critical mechanism underlying autonomy in physical health promotion based on the perspectives of people with severe mental illness. METHOD: We employed a conventional content analysis of narrative data from the Healthy Active Lives in Japan (HeAL Japan) workshop meetings. RESULTS: 'Inhibited autonomy' was extracted as a central component and shaped by the users' experiences, both in a healthcare setting and in real life. This component emerged based on the lack of an empowerment mechanism in psychiatric services. CONCLUSIONS: A barrier to the encouragement of autonomy in physical health promotion was found in current psychiatric services. An effective strategy should be explored to foster an empowerment mechanism in psychiatric and mental health services.Declaration of interestNone.

Eye movement and random number in NP lupus evaluation.

We evaluated the vulnerability of central nervous system (CNS) in patients with systemic lupus erythematosus (SLE) using exploratory eye movement analysis and random number generation (RNG), and compared the tests in evaluating CNS vulnerability. Nineteen patients received the tests more than a month after SLE onset in nonpsychotic status. Exploratory eye movements were analyzed using an eye-mark recorder that detects corneal reflection of infrared light, and numbers of eye fixations were counted to calculate responsive search score (RSS). Using digits 0 through 9, 100 numbers were vocally generated at a random fashion. "Seriality score" was calculated from the recorded 100 numbers. RSS of SLE patients was similar to that of normal individuals, irrespective of neuropsychiatric lupus history. Seriality score of patients having a history of neuropsychiatric lupus was higher than that of never having it (p < 0.05). No relations were confirmed between RSS and seriality score. The current study suggested heterogeneous nature of SLE in CNS vulnerability when evaluating with seriality score, but not with RSS. There seemed to be a difference between exploratory eye movement analysis and RNG in evaluating CNS vulnerability. Each test seemed to evaluate different aspects of brain function.

Impairment of exploratory eye movement in schizophrenia patients and their siblings.

AIMS: Previous family, adoption and twin studies of schizophrenia have shown that genetic factors contribute significantly to the risk of schizophrenia. The aim of the present study was therefore to investigate whether exploratory eye movement (EEM) abnormalities are related to the genetic markers linked to schizophrenia. METHODS: Twenty-three probands with schizophrenia, 23 of their healthy siblings (23 proband-sibling pairs), and 43 unrelated normal controls performed EEM tasks. Two parameters were measured: (i) number of eye fixations in responsive search (NEFRS) and (ii) responsive search score (RSS). RESULTS: Abnormalities in NEFRS and RSS were more frequent in schizophrenia probands than in their unaffected siblings and in normal controls, and were also more frequent in the healthy siblings than in normal controls. Thus, the EEM test performances of the healthy siblings were intermediate between those of the probands with schizophrenia and those of normal controls. CONCLUSION: Abnormalities of the EEM test parameters may be related to the genetic etiology of schizophrenia. The use of EEM parameters as an endophenotype for schizophrenia may facilitate linkage and association studies in schizophrenia.

Relationship between exploratory eye movement, P300, and reaction time in schizophrenia.

AIMS: Exploratory eye movement (EEM), P300 and reaction time (RT) tests may relate to the important parts of information processing in the human brain. Therefore the aim of the present study was to compare EEM, P300 and RT test data in schizophrenic and normal control groups to investigate whether schizophrenic patients have information processing abnormalities. In addition, the potential correspondence between the three tests was examined in order to investigate the information processing dysfunctions seen in schizophrenic patients. METHODS: The EEM, P300 and RT performances were recorded in 34 schizophrenic and 36 normal control subjects. Ten parameters were measured: four from the EEM test (number of eye fixations, total eye scanning length, cognitive search score and responsive search score [RSS]); two from the P300 test (amplitude and latency); and four from the RT test (simple reaction time, index of reaction time crossover [IRT-crossover], set index and coefficient of variation). RESULTS: These parameters in the schizophrenic patients differed significantly from those in the control group. Additionally, there was a significant correlation between the RSS and the IRT-crossover in the schizophrenic patients. CONCLUSION: The present group comparisons (schizophrenia vs normal controls) are consistent with previous studies in that the abnormalities in EEM, P300 and RT tests in schizophrenic patients were able to be replicated. Moreover, based on the former psychological theory, it is reasonable to propose that the RSS is associated with the IRT-crossover. The present results may contribute to elucidation of the pathophysiological signature of schizophrenia.

Measurement of development of cognitive and attention functions in children using continuous performance test.

AIM: The development of attention function in children is still not sufficiently clear. Although it is difficult to objectively assess attention function, continuous performance tests (CPT) can be used to objectively assess cognitive function along with attention. The development of cognitive and attention functions was examined in children using a CPT. METHODS: A total of 541 healthy girls aged 5-12 years participated. Ten parameters were calculated: numbers of cancellations for either target stimuli (T-cancel) or non-target stimuli (N-cancel), numbers of omission errors (Omission) and commission errors (Commission), hit rate (Hit), false alarm rate (False), mean reaction time for correct response (RT), coefficient of variance for mean reaction time (CVRT), sensitivity index (d'), and lnbeta. RESULTS: The parameters were divided into three types based on pattern of change. T-cancel, False, and Commission, which are related to inhibition of response, N-cancel, Hit, and Omission, which are related to inattention to stimuli, and CVRT, which is related to stability of processing time, exhibited significant change until 5 or 6 years of age. d', which is related to ability to discriminate between target or non-target, exhibited significant change until 8 years of age. RT, which is related to processing time, exhibited significant change until 11 years of age. lnbeta exhibited no significant differences among age groups. CONCLUSIONS: These findings indicate that inhibition function, inattention to stimuli, and stability of processing time develop first. Discrimination ability subsequently increases based on these developments, and finally processing time is reduced.