High-resolution copy number variation analysis of schizophrenia in Japan.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Comparison of mouse and human ankles and establishment of mouse ankle osteoarthritis models by surgically-induced instability.

OBJECTIVE: Prevalence of ankle osteoarthritis (OA) is lower than that of knee OA, however, the molecular mechanisms underlying the difference remain unrevealed. In the present study, we developed mouse ankle OA models for use as tools to investigate pathophysiology of ankle OA and molecular characteristics of ankle cartilage. DESIGN: We anatomically and histologically examined ankle and knee joints of C57BL/6 mice, and compared them with human samples. We examined joints of 8-week-old and 25-month-old mice. For experimental models, we developed three different ankle OA models: a medial model, a lateral model, and a bilateral model, by resection of respective structures. OA severity was evaluated 8 weeks after the surgery by safranin O staining, and cartilage degradation in the medial model was sequentially examined. RESULTS: Anatomical and histological features of human and mouse ankle joints were comparable. Additionally, the mouse ankle joint was more resistant to cartilage degeneration with aging than the mouse knee joint. In the medial model, the tibiotalar joint was markedly affected while the subtalar joint was less degenerated. In the lateral model, the subtalar joint was mainly affected while the tibiotalar joint was less altered. In the bilateral model, both joints were markedly degenerated. In the time course of the medial model, TdT-mediated dUTP nick end labeling (TUNEL) staining and Adamts5 expression were enhanced at early and middle stages, while Mmp13 expression was gradually increased during the OA development. CONCLUSION: Since human and mouse ankles are comparable, the present models will contribute to ankle OA pathophysiology and general cartilage research in future.

An internet-based wearable watch-over system for elderly and disabled utilizing EMG and accelerometer.

An effective way for preventing injuries and diseases among the elderly is to monitor their daily lives. In this regard, we propose the use of a "Hyper Hospital Network", which is an information support system for elderly people and patients. In the current study, we developed a wearable system for monitoring electromyography (EMG) and acceleration using the Hyper Hospital Network plan. The current system is an upgraded version of our previous system for gait analysis (Yoshida et al. [13], Telemedicine and e-Health 13 703-714), and lets us monitor decreases in exercise and the presence of a hemiplegic gait more accurately. To clarify the capabilities and reliability of the system, we performed three experimental evaluations: one to verify the performance of the wearable system, a second to detect a hemiplegic gait, and a third to monitor EMG and accelerations simultaneously. Our system successfully detected a lack of exercise by monitoring the iEMG in healthy volunteers. Moreover, by using EMG and acceleration signals simultaneously, the reliability of the Hampering Index (HI) for detecting hemiplegia walking was improved significantly. The present study provides useful knowledge for the development of a wearable computer designed to monitor the physical conditions of older persons and patients.

A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility.

Reticulon 4 receptor (RTN4R) plays an essential role in regulating axonal regeneration and plasticity in the central nervous system through the activation of rho kinase, and is located within chromosome 22q11.2, a region that is known to be a hotspot for schizophrenia (SCZ) and autism spectrum disorder (ASD). Recently, rare variants such as copy-number variants and single-nucleotide variants have been a focus of research because of their large effect size associated with increased susceptibility to SCZ and ASD and the possibility of elucidating the pathophysiology of mental disorder through functional analysis of the discovered rare variants. To discover rare variants with large effect size and to evaluate their role in the etiopathophysiology of SCZ and ASD, we sequenced the RTN4R coding exons with a sample comprising 370 SCZ and 192 ASD patients, and association analysis using a large number of unrelated individuals (1716 SCZ, 382 ASD and 4009 controls). Through this mutation screening, we discovered four rare (minor allele frequency <1%) missense mutations (R68H, D259N, R292H and V363M) of RTN4R. Among these discovered rare mutations, R292H was found to be significantly associated with SCZ (P=0.048). Furthermore, in vitro functional assays showed that the R292H mutation affected the formation of growth cones. This study strengthens the evidence for association between rare variants within RTN4R and SCZ, and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder.

Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders.

CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.

Fruit of the jambolan tree (Eugenia jambolana Lam.) and experimental diabetes.

The fruit of Indian Eugenia jambolana have been shown to have therapeutic properties, but because the therapeutic potential of a plant is related to the geographic region in which the plant was grown and to the part of the plant used, we investigated Brazilian Eugenia jambolana fruit using the same preparation and experimental methods as have been used in India. The well-established metabolic cage model was used to evaluate the physiological and metabolic parameters associated with streptozotocin-induced diabetes in rats (n=10) which had been administered, by gavage, 50 mg per day of lyophilised Eugenia jambolana fruit-pulp extract for 41 days. We found that, compared to untreated controls, rats treated with the lyophilised fruit-pulp showed no observable difference in body weight, food or water intake, urine volume, glycaemia, urinary urea and glucose, hepatic glycogen, or on serum levels of total cholesterol, HDL cholesterol or triglycerides. No change was observed in the masses of epididymal or retroperitoneal adipose tissue or of soleus or extensor digitorum longus muscles. This lack of any apparent effect on the diabetes may be attributable to the regional ecosystem where the fruit was collected and/or to the severity of the induced diabetes.

Daytime melatonin administration enhances sleepiness and theta/alpha activity in the waking EEG.

It is still controversial whether the pineal hormone melatonin can be characterized as a hypnotic. We therefore measured subjective sleepiness and waking EEG power density in the range of 0.25-20 Hz after a single dose of melatonin (5 mg). During an 8 h mini-constant routine protocol, melatonin administered in a double blind cross-over design to healthy young men at 1300 h or 1800 h increased subjective sleepiness, as rated half-hourly on three different scales (Visual Analogue Scale, Akerstedt Sleepiness Symptoms Check List, Akerstedt Sleepiness Scale) and objective fatigue as evidenced by augmented waking EEG power density in the theta/alpha range (5.25-9 Hz). The increase in subjective sleepiness reached significance 40 min and 90 min after melatonin administration (at 1300 h and 1800 h, respectively) and lasted for 3 h (at 1300 h) and 5 h (at 1800 h). The increase in the theta/alpha frequencies of the waking EEG occurred immediately after melatonin ingestion and stayed significantly higher parallel to the higher sleepiness ratings. However, the EEG changes appeared before the subjective symptoms of sleepiness became manifest. There was a significant correlation between salivary melatonin levels and the timing of increased subjective sleepiness. Melatonin had no effects on mood.

"Eating lightly" and the self-presentation of femininity.

In Experiment 1, male and female subjects were given an opportunity to snack as they participated in a "get-acquainted study" with a same-sex or opposite-sex partner (confederate) whose social desirability was manipulated. Consistent with the hypothesis that women may eat less when motivated to present themselves in a feminine light, female subjects ate significantly less with a desirable male partner than in the remaining three conditions. In contrast, male subjects did not eat more (or less) with a desirable woman, although they did show an overall tendency to eat less with female (vs. male) partners. In Experiment 2, female subjects snacked as they got acquainted with a desirable male partner (confederate). Before this interaction, subjects received feedback indicating that they had either very masculine or very feminine interests. In addition, subjects believed either that their male partner was aware of their gender feedback or that he was unaware. Consistent with predictions derived from Schlenker's (1982) analytic-identity theory of social conduct, subjects in the partner-aware conditions ate less when they had received masculine (vs. feminine) feedback, whereas subjects in the partner-unaware conditions ate less when they had received feminine (vs. masculine) feedback. Implications for understanding eating disorders such as anorexia and bulimia are discussed.

Studies on the genotype-phenotype relation in the hph-1 mouse mutant deficient in guanosine triphosphate (GTP) cyclohydrolase I activity.

The guanosine triphosphate (GTP) cyclohydrolase I (GTP-CHI) catalyses the rate-limiting step in the de novo synthesis of tetrahydrobiopterin, a cofactor of three aromatic amino acid hydroxylases, one of which is phenylalanine hydroxylase. The hph-1 mouse mutant deficient in GTP-CHI activity exhibits hyperphenylalaninemia which peculiarly disappears at 3 weeks of age, thus corresponding to the increase in liver GTP-CHI activity. The present gas chromatographic-mass spectrometric analysis of the phenylalanine and catecholamine metabolisms demonstrated the former metabolism to remain disturbed even in adult hph-1, which demonstrated a metabolic basis for sensitivity to the phenylalanine challenge in adult hph-1. A Northern blot analysis showed the hepatic GTP-CHI RNA expression in hph-1 at 2, 3 and 4 weeks of age to parallel the peculiar time course of the enzyme activity previously reported. No mutation was detected in either the coding region or the 5' flanking region (nt.-1 to -746) of the GTP-CHI gene of the hph-1. Further molecular genetic analyses are therefore required to elucidate the mechanism of the peculiar phenotype of hph-1.

Frontal midline theta rhythm in young healthy adults.

In this study, we examined the relationship between the frontal midline (Fm) theta rhythm that appears when a healthy subject is engaged in mental tasks and the theta rhythm which appears in the frontal region of healthy subjects during light drowsiness. The samples for this study were obtained from 465 EEGs of healthy Japan Air Self Defense Force personnel. The 39 who had frontal theta rhythm during light drowsiness were selected to be included in the theta group. For the control group, 34 subjects were randomly selected from the remaining 426 without frontal theta rhythm. When these subjects were reexamined, the rate of appearance of the frontal midline theta rhythm which appears during light drowsiness was 87.2% in the theta group and 0% in the control group. The rate of appearance of the Fm theta was 94.9% in the theta group and 3.0% in the control group. The two types of frontal theta rhythms closely resembled each other in frequency (94.6%) and distribution (83.8%). Except for the results of the hypomania (Ma) scores, there was no remarkable difference between the two groups when the MMPI was administered. The results of our study suggest that there is a close correlation between the frontal theta rhythm that appears during light drowsiness and the Fm theta.

Anti-HCV related to HCV PCR and risk factors analysis in a blood donor population of central Brazil.

Data concerning HCV infection in Central Brazil are rare. Upon testing 2,350 voluntary blood donors from this region, we found anti-HCV prevalence rates of 2.2% by a second generation ELISA and 1.4% after confirmation by a line immunoassay. Antibodies against core, NS4, and NS5 antigens of HCV were detected in 81.8%, 72.7%, and 57.5%, respectively, of the positive samples in the line immunoassay. HCV viremia was present in 76.6% of the anti-HCV-positive blood donors. A relation was observed between PCR positivity and serum reactivity in recognizing different HCV antigens in the line immunoassay. The majority of the positive donors had history of previous parenteral exposure. While the combination of ALT > 50 IU/l and anti-HBc positivity do not appear to be good surrogate markers for HCV infection, the use of both ALT anti-HCV tests is indicated in the screening of Brazilian blood donors.

Behavioral consultation with difficult to treat psychiatric patients.

Behavioral procedures have proven efficacious in the ward-wide treatment of psychiatric inpatients. These procedures are often recommended and administrated by behaviorally oriented staff who work as consultants. While numerous published reports show that behavioral consultation is effective for changing patients' targeted behavior, few data show whether it affects recidivism and other general indicators of patients' functioning. The present report describes group and case study data for 7 patients regarding the effects of behavioral consultation on frequency and duration of hospital admissions, distress upon readmission, proportion of time spent at regressive versus autonomous privilege levels, and other molar indices of patients' functioning.

Validity of the MMPI-2 and Beck Depression Inventory for making decisions of organ allocation in renal transplantation.

Psychosocial factors are presented which affect clinical decision-making regarding the allocation of renal organs. Patients were rated as being either High Risk or Low Risk transplant candidates. High Risk candidates were scored as being significantly different from the Low Risk candidates on many psychosocial variables. Interestingly, significant differences were not found between these two groups on either the MMPI-2 or the Beck Depression Inventory. The validity of using information from these inventories to allocate organs is discussed.

Validity and clinical scale comparisons between the MMPI and MMPI-2 with psychiatric inpatients.

This study was designed to investigate the comparability of the original MMPI (1950) and the MMPI-2 (1989) with a psychiatric patient population. 34 male and 3 female patients, shortly after admission to one of two acute psychiatry units, completed the old and revised versions of the MMPI. Paired t tests indicated but scant differences for raw scores, while many more differences were found among T scores for validity, clinical, and supplemental scales. Analyses, however, showed all scales on the two forms to be highly correlated. Analysis of the high-point and two-point codes across the two administrations also showed relative stability, although the proportion of Scales 2 (Depression) and 8 (Schizophrenia) decreased, while those for Scales 6 (Paranoia) and 7 (Psychasthenia) increased markedly in the MMPI-2 protocols. Examination of each version's discriminability among mood- and thought-disordered subsamples suggested that the MMPI provides slightly better delineation between diagnostic classes. Discriminant function analyses showed that there were essentially no differences between the two forms in the accurate classification of clinical and nonclinical groups. The findings reported here provide support for the MMPI-2; despite modification, the newer form retains the advantages of the original MMPI. Differences found here may be unique to psychiatric patients and their patterns of MMPI/MMPI-2 equivalence and may not generalize to other special populations.

[Outcome of schizophrenia--extended observation (more than 30 years) of 129 typical schizophrenic cases [III]].

We had already made a report on outcome of schizophrenia (1986). The patients, 129 typical schizophrenia, were continuously observed over 30 years in the Kawagoe Dojinkai Hospital. Recently, we again evaluated their prognoses according to the same criteria as adopted in the first report, and divided them into the following five groups. [symbol: see text]: completely remitted group (21 persons, 16.3%), [symbol: see text]: almost remitted cases now holding jobs (23 persons, 17.8%), [symbol: see text]: Slightly remitted group showing good adjustment at home or hospital (41 persons, 31.8%), [symbol: see text]: maladjusted cases always showing an unfavorable condition (25 persons, 19.4%), x : incurable cases (19 persons, 14.7%). 1) In the last 8 years, there were 30 persons (23.3% of the whole patients) who showed prognostic changes (10 persons improved, 20 persons worsen). While the second group ([symbol: see text]) has seen fewer persons (12 persons down) than previous study, the third group ([symbol: see text]) has seen more persons (9 persons up). Each three groups, that is, the first two groups ([symbol: see text] + [symbol: see text], 44 persons, 34.1%), the third group ([symbol: see text], 41 persons, 31.8%), and the forth and fifth groups ([symbol: see text] + x, 44 persons, 34.1%) accounted for a third of the whole patients. It is after 32 years on the average (extending from 21 to 50 years) from the onset of illness that they showed prognostic changes. 2) Generally speaking, catatonic patients had favorable prognoses, hebephrenic patients unfavorable ones, and paranoid patients medium ones. But 4 improved persons in the forth and fifth groups were all hebephrenic type. 3) 17 among the 30 persons who showed prognostic changes were unstable type. They took a wave-like course. 4) 27 of all the 129 patients were dead. 25 were dead from disease mentioned below. Malignancy (8 persons), Cerebral vascular disease, Pneumonia and Diabetes (3 persons), Heart-failure (2 persons), Ileus, Myocardial infarction, Hepato-cirrhosis, Gastric ulcer, Tuberculosis and Natural death (1 person). 2 persons committed suicide. 5) Outcome of 45 patients who discontinued our medical therapy became clear as follows. [symbol: see text] + [symbol: see text]: 18 persons (40.0%), [symbol: see text]: 9 persons (20.0%), [symbol: see text] + x : 18 persons (40.0%). A smaller percentage of the patients belongs to the third group ([symbol: see text]) than that of our patients who were continuously followed by us.

Synchronous phosphorylation of CPI-17 and MYPT1 is essential for inducing Ca(2+) sensitization in intestinal smooth muscle.

BACKGROUND: Myosin phosphatase activity is regulated by mechanisms involving the phosphorylation of CPI-17 and MYPT1, primarily based on studies with tonic-type vascular smooth muscles. This study examined how these mechanisms contribute to the regulation of contraction of a phasic-type intestinal smooth muscle. METHODS: Phosphorylation levels, tension, and Ca(2+) sensitization was detected in rat ileal smooth muscle. Key Results In rat ileal smooth muscle, phosphorylation level of CPI-17 at Thr(38) and MYPT1 at Thr(853) , but not MYPT1 at Thr(696) , were increased with carbachol (1µmolL(-1) ) accompanied with muscle contraction. The PKC inhibitor Go6976 (1µmol L(-1) ) inhibited the carbachol-induced phosphorylation of CPI-17, whereas the Rho-associated kinase (ROCK) inhibitor, Y-27632 (10µmol L(-1) ) inhibited the carbachol-induced phosphorylation of both CPI-17 and MYPT1. Application of Go6976 or Y-27632 alone inhibited the carbachol-induced contraction; however, the combined application of these inhibitors did not inhibit the contraction in an additive manner. In ß-escin-permeabilized ileal strip, treatment with antiphosphorylated antibodies for CPI-17 at Thr(38) and MYPT1 at Thr(853) and Thr(696) alone almost completely abolished the Ca(2+) sensitization due to carbachol with GTP. CONCLUSIONS & INFERENCES: In conclusion, receptor stimulation increases the Ca(2+) sensitivity of contractile elements through CPI-17 phosphorylation via the PKC/ROCK pathways and MYPT1 phosphorylation via the ROCK pathway, when these mechanisms operate cooperatively and/or synchronously in intestinal smooth muscle.