Search

Red, green, and blue light InxGa1−xN multiple quantum wells have been grown on GaN/γ-LiAlO2 microdisk substrates by plasma-assisted molecular beam epitaxy. We established a mechanism to optimize the self-assembly growth with ball-stick model for InxGa1-xN multiple quantum well microdisks by bottom-up nanotechnology. We showed that three different red, green, and blue lighting micro-LEDs can be made of one single material (InxGa1-xN) solely by tuning the indium content. We also demonstrated that one can fabricate a beautiful InxGa1-xN-QW microdisk by choosing an appropriate buffer layer for optoelectronic applications.

Mg-doped GaN was grown by plasma-assisted molecular beam epitaxy (PAMBE) on a Fe-doped GaN template substrate by employing a shutter-controlled process. The transition from n-type to p-type conductivity of Mg-doped GaN in relation to the N/Ga flux ratio was studied. The highest p-type carrier concentration in this series was 3.12 × 1018 cm−3 under the most N-rich condition. By modulating the shutters of different effusion cells for the shutter-controlled process, a wide growth window for p-type GaN was obtained. It was found that the presence of Mg flux effectively prevents the formation of structural defects in GaN epi-layers, resulting in the improvement of crystal quality and carrier mobility.

Tumor hypoxia is a common feature in colorectal cancer (CRC), and is associated with resistance to radiotherapy and chemotherapy. Thus, a specifically targeted probe for the detection of hypoxic CRC cells is urgently needed. Carbonic anhydrase 9 (CA9) is considered to be a specific marker for hypoxic CRC diagnosis. Here, a nuclear imaging Indium-111 (111In)-labeled dual CA9-targeted probe was synthesized and evaluated for CA9 detection in in vitro, in vivo, and in human samples. The CA9-targeted peptide (CA9tp) and CA9 inhibitor acetazolamide (AAZ) were combined to form a dual CA9-targeted probe (AAZ-CA9tp) using an automatic microwave peptide synthesizer, which then was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radioisotope (111In) labeling (111In-DOTA-AAZ-CA9tp). The assays for cell binding, stability, and toxicity were conducted in hypoxic CRC HCT15 cells. The analyses for imaging and biodistribution were performed in an HCT15 xenograft mouse model. The binding and distribution of 111In-DOTA-AAZ-CA9tp were detected in human CRC samples using microautoradiography. AAZ-CA9tp possessed good CA9-targeting ability in hypoxic HCT15 cells. The dual CA9-targeted radiotracer showed high serum stability, high surface binding, and high affinity in vitro. After exposure of 111In-DOTA-AAZ-CA9tp to the HCT15-bearing xenograft mice, the levels of 111In-DOTA-AAZ-CA9tp were markedly and specifically increased in the hypoxic tumor tissues compared to control mice. 111In-DOTA-AAZ-CA9tp also targeted the areas of CA9 overexpression in human colorectal tumor tissue sections. The results of this study suggest that the novel 111In-DOTA-AAZ-CA9tp nuclear imaging agent may be a useful tool for the detection of hypoxic CRC cells in clinical practice.

Tumor hypoxia is a common feature in colorectal cancer (CRC), and is associated with resistance to radiotherapy and chemotherapy. Thus, a specifically targeted probe for the detection of hypoxic CRC cells is urgently needed. Carbonic anhydrase 9 (CA9) is considered to be a specific marker for hypoxic CRC diagnosis. Here, a nuclear imaging Indium-111 (

Background This study had two aims: (a) to identify the different patterns of use of home- and community-based services (HCBS) among older adults in Taiwan, and (b) to examine the effects of the different use patterns on HCBS recipients’ use of institutional long-term care services. Methods The study analyzed cohort data from Taiwan's first National 10-Year Long-Term Care Plan database and from National Health Insurance Claim Data. We extracted baseline information on older adults who were first evaluated for and prescribed HCBS from 2010 through 2013 (N = 71,260). We used latent class analysis to specify the underlying subgroups of recipients with similar patterns of HCBS use. We used hierarchical multinomial logistic regression to examine the effect of the different use patterns on the risk of institutional (e.g., nursing home) placement from 4 to 15 months after initial HCBS evaluation. Results Four subgroups of HCBS recipients were identified, with patterns of home-based personal care (PC), home-based personal care and medical care (PC/MC), home-based medical care (MC), and community care services. Compared to the home-based PC/MC group, people in the home-based MC group had lower risk (OR = 0.54) and people in the community care group had higher risk (OR = 1.76) of admission to a nursing home. Conclusions Study findings may provide insights for policy makers regarding the usefulness of integrating medical care and other types of long-term care services into adult day care.

ObjectiveSchizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)–related proteins in N-methyl-D-aspartate receptor–postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia.MethodsWe resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry.ResultsWe identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type.ConclusionOur findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.

Lattice relaxation on wurtzite GaN microdisks grown by plasma-assisted molecular beam epitaxy was systematically studied. The lattice constants of GaN microdisks were evaluated from high-resolution transmission electron microscopy, and the anisotropic strain was then analyzed by observing the microscopic atomic layers. We found that the vertical lattice strain along the c-axis followed a linear relationship, while the lateral lattice strain along the a-axis exhibited a quadratic deviation. The lattice mismatch is about 0.94% at the interface between the GaN microdisks and the &gamma, LiAlO2 substrate, which induces the anisotropic strain during epi-growth.

InyAl1−yN epifilms with alloy compositions (y) ranging from 0.13 to 0.47 were grown on a GaN template using a low-temperature molecular-beam-epitaxy technique. Because of the larger lattice constant of high-indium-content InyAl1−yN epifilm, the compressive stress accumulated during epitaxy. When the compressive stress exceeded the elastic limit of the InyAl1−yN epifilms, a “concave-valley” crack with an equivalent width (~25 nm) was generated to form a prismatic domain. Our calculation and fitting results showed that no cracking occurred when the lattice mismatch was 2.4% because the stress exceeded the elastic limit.

Purpose The purpose of this paper is to examine the association between the cost of debt (COD) and auditor industry expertise using Taiwanese data. Since previous studies (Li et al., 2010) have only examined the relation between industry specialization and COD at the audit firm level in western countries, the authors further examine the association between industry specialization and COD at the individual auditor level in an Asian context. Design/methodology/approach The authors use the interest rate on the firm’s debt as a proxy variable for the COD (Francis, Khurana and Pereira, 2005). The authors adopt three different methods to measure industry specialization, which consist of the auditors’ market share in terms of client sales and number of clients, and client assets. Findings The results indicate that the clients of industry specialists at individual auditor levels have a lower COD. Originality/value First, the authors extend the research of Li et al. (2010) and find that the clients of individual auditor industry specialists also have a lower COD. Second, the authors also believe the evidence on the effects of industry expertise at the individual auditor level may have policy implications for regulators and public investors. Finally, in contrast to works carried out in the US market, the authors provide empirical evidence for the relation between industry specialization and COD in an Asian market.

This article answers the question of whether the adoption of International Financial Reporting Standards (IFRS) reduces the cost of equity capital, with a focus on the tourism industry. We employ a set of global tourism companies and find that mandatory IFRS adoption has a significantly negative relation with the cost of equity capital. However, we find that this relation is varied with different business cultures and geographic areas. Moreover, from interactive analyses of country institutions for the relation between mandatory IFRS adoption and tourism firm’s cost of equity, we show that adopting IFRS complements the deficiencies of various country institutions, such as investor protection, the strength of legal enforcement, and corporate governance.

Indium-incorporation with InxGa1-xN layers on GaN-microdisks has been systematically studied against growth parameters by plasma-assisted molecular beam epitaxy. The indium content (x) of InxGa1-xN layer increased to 44.2% with an In/(In + Ga) flux ratio of up to 0.6 for a growth temperature of 620 &deg, C, and quickly dropped with a flux ratio of 0.8. At a fixed In/(In + Ga) flux ratio of 0.6, we found that the indium content decreased as the growth temperature increased from 600 &deg, C to 720 &deg, C and dropped to zero at 780 &deg, C. By adjusting the growth parameters, we demonstrated an appropriate InxGa1-xN layer as a buffer to grow high-indium-content InxGa1-xN/GaN microdisk quantum wells for micro-LED applications.

M -plane GaN thin films were grown on 11° misoriented γ-LiAlO 2 substrates without peeling off or cracking by plasma-assisted molecular beam epitaxy. Because of anisotropic growth kinetics, which leads to an anisotropic compressive in-plane strain in the M -plane GaN films, the surface presents a rough morphology with worse crystal quality. The crystal quality of sample was optimally improved, XRD rocking curve FWHM of which is about 900 arcsec, by raising growth temperature to 800 °C with proper Ga/N flux ratio. As the crystal quality was improved, the polarization ratio decreased from the unity (less than 0.8) which could be attributed to the effect of exciton localization due to the partial increased in-plane strain.

Ideally, continuum of care involves wide-ranging health and long-term care (LTC) services. Taiwan’s National Health Insurance scheme and 10-Year Long-term Care Plan attempts to provide universal and fundamental services of continuum care. However, the accessibility of these services for care recipients remains unclear. This study aims to examine the effectiveness of continuum care in decreasing the healthcare expenditure of LTC recipients using home- and community-based services (HCBS). Data collated from the 2010–2013 Long-Term Care Service Management System (N = 77,251) were subjected to latent class analysis to identify subgroups of recipients using HCBS. Subsequently, the 1-year primary care expenditure after receiving HCBS was compared through generalized linear modeling. Three discrete HCBS subgroups were found: home-based personal care (HP), home-based health care (HH), and community-based care (CC). No difference in the number of visits to doctors and the average primary care expenses was observed between the HP and HH subgroups. However, considering physical and psychosocial confounders, care recipients in the CC subgroup recorded a higher number of visits to doctors (β = 3.05, SD = 0.25, p < 0.05) and lower primary care expenditure (β = -98.15, SD = 43.17, p = 0.02) than the other two subgroups. These findings suggest that LTC recipients in Taiwan may obtain better continuum care only for CC service recipients. Additionally, community-based LTC services may lower the cost of health expenditure after 1 year.

GaN films were grown by plasma-assisted molecular beam epitaxy with a sputtered AlN buffer layer on Si (100) substrate. From the analyses of X-ray diffraction (XRD), transmission electron microscopy (TEM) and photoluminescence (PL) measurements, we showed that the variant M -plane, A -plane and c -plane GaN wurtzite structures can be achieved by the selection of crystalline orientation of sputtered AlN buffer layer and the control of epitaxial growth temperature. We also found that the GaN layer grown on sputtered AlN buffer layer can be converted to GaN zinc-blende structure at the epitaxial growth temperature higher than 750 °C and under Ga-rich condition.

Manuscript Type Empirical Research Question/Issue This study investigates the influence of CEO characteristics on internal control quality in the U. S. Research Findings/Insights Using a sample of 4,374 ExecuComp non-financial firms, we find that CEO entrenchment and age are significantly associated with a material internal control weakness disclosure (MW) under Sarbanes- Oxley Section 404 (SOX 404). Our results demonstrate that entrenchment and age may affect CEOs' behavior in response to the SOX 404 internal control requirements. Theoretical/Academic Implications This study provides empirical support for the influence of CEO characteristics on material internal control weakness. As a result, the effects of internal control mechanisms are likely to be decreased in firms with entrenched and younger CEOs, consistent with entrenchment theory. Practitioner/Policy Implications This study offers insights to regulators and lawmakers interested in the effects of CEO characteristics on internal control weakness. Importantly, it points out that CEO entrenchment and age are likely to affect the strength of internal control mechanisms.

This study examines the effect of disclosure regulation on earnings management using Taiwanese companies conducting transactions with China as the institutional setting. Measuring earnings management by the amount of discretionary accruals (DACCs), the study shows that disclosure regulation mitigates DACCs of Taiwanese firms engaging in related-party transactions with Chinese entities. Following enactment of the disclosure regulation in November 2000, DACCs among Taiwanese enterprises conducting transactions via offshore affiliates dropped. While the disclosure regulation helps to reduce earnings management, this study reports that such effect is asymmetric between high-tech firms and non–high-tech firms. Specifically, the disclosure regulation is effective in reducing earnings management among firms in non–high-tech sectors. However, such effect is not significant among firms in high-tech sectors. This study discusses the implications of empirical findings for corporate management, regulatory agencies, and firm stakeholders.

Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with the various traits of metabolic syndrome (MetS) in the general population. This study investigated whether the common variants in MTTP genes were associated with MetS in schizophrenic patients treated with atypical antipsychotics.The study included 456 hospitalized patients diagnosed with schizophrenia, who had been treated with clozapine (n = 171), olanzapine (n = 91), or risperidone (n = 194) for at least 3 months. Patients were genotyped for the 10 MTTP single-nucleotide polymorphisms.The prevalence of MetS among all subjects was 22.8%. In single-marker-based analysis, the MTTP rs1800591 (-493GT) T-allele carriers were at double the risk for MetS relative to G/G homozygotes. In contrast, the T-allele homozygotes had considerably lower fasting high-density lipoprotein levels than that in the heterozygotes or G-allele homozygotes.Our findings extend and add new information to the existing data regarding the association between MTTP genetic variants and MetS regulation during long-term atypical antipsychotic treatment. The MTTP rs1800591 T allele could be a risk factor for MetS in patients under atypical antipsychotic medication.

The M -plane GaN thin films grown on pre-annealing LiGaO 2 (100) substrates by plasma-assisted molecular-beam epitaxy have been characterized. The LiGaO 2 (100) substrates were annealed in vacuum and in ambient air, respectively. The analyses of X-ray diffraction and Raman scattering measurements indicate that the crystal quality of M -plane GaN thin film grown on air-annealed LiGaO 2 (100) substrate is improved and the compressive stress between M -plane GaN and LiGaO 2 is reduced as well. The experimental results reveal that the thermal annealing LiGaO 2 substrate in air can effectively suppress the formation of lithium-rich surface to grow a high-quality M -plane GaN thin film on LiGaO 2 substrate.

In this paper, we report the growth of M-plane GaN thin films on LiGaO2 (100) substrates pre-annealed in vacuum and in air ambient. The surface of M-plane GaN film grown on the LiGaO2 (100) substrate pre-annealed in air ambient was significantly improved. X-ray diffraction data showed that the M-plane GaN thin film grown on the LiGaO2 (100) substrate pre-annealed in air ambient has better crystal quality than that grown on the LiGaO2 (100) substrate pre-annealed in vacuum. In addition, the strain generated between GaN thin film and LiGaO2 substrate was relaxed when the GaN thin film grew on the LiGaO2 substrate pre-annealed in air ambient. It revealed that the thermal annealing LiGaO2 substrate in air ambient can suppress the formation of lithium-rich surface effectively, and then one can grow a high quality M-plane GaN thin film on the LiGaO2 substrate.

Background: Sudden cardiac death is higher among schizophrenic patients and is associated with parasympathetic hypoactivity. Antipsychotic agents are highly suspected to be a precipitating factor. Thus, we aimed to test if the antipsychotics haloperidol, risperidone and clozapine affect cardiac autonomic function, excluding the confounding effect of altered sleep structure by the drugs. Methods: In this study, haloperidol, risperidone and clozapine were given separately by intraperitoneal injection to male Wistar-Kyoto rats for 5 days. Electroencephalogram (EEG), electromyogram (EMG) and electrocardiographic signals were recorded at baseline and 5 days after drug treatments. Sleep scoring was based on EEG and EMG signals. Cardiac autonomic function was assessed using heart rate variability analysis. Results: Clozapine increased heart rate and suppressed cardiac sympathetic and parasympathetic activity. Cardiac acceleration was more severe during sleep. Haloperidol tended to decrease heart rate while risperidone mildly increased heart rate; however, their effects were less obvious than those of clozapine. There was a significant drug-by-stage interaction on several heart rate variability measures. Conclusion: Taking this evidence as a whole, we conclude that haloperidol has a better level of cardiovascular safety than either risperidone or clozapine. Application of this approach to other psychotropic agents in the future will be a useful and helpful way to evaluate the cardiovascular safety of the various psychotropic medications that are in clinical use.

Atypical or second-generation antipsychotics (SGAs) are associated with excessive body weight gain (BWG) and other components of metabolic syndrome. Among all SGAs, clozapine and olanzapine are known to cause the most significant weight gain, followed by risperidone and quetiapine. The genetic variant of tumor necrosis factor α (TNF-α), -308 G>A polymorphism (rs1800629), has been implicated in clozapine-induced BWG in several studies. We hypothesized that TNF-α -308 G>A polymorphism has a general effect on SGA-induced BWG. The present study was conducted to examine the association between TNF-α -308 G>A polymorphism and BWG during treatment for schizophrenia using a variety of second generation antipsychotics (SGAs). A total of 500 patients with schizophrenia treated with clozapine (n=275), olanzapine (n=79) or risperidone (n=146) for an average of 49.9 months were recruited. Subjects with an increase in weight of more than 7% from the baseline before the current SGA treatment to the weight at the survey point were defined as having BWG. The association between TNF-α -308 G>A polymorphism and BWG was studied, and the effect of non-genetic factors such as baseline BMI, SGA treatment duration and SGA type on the association was controlled by logistic regression. The results revealed that there was no significant association between BWG and TNF-α -308 G>A polymorphism (GG/GA/AA or GG/GA+AA) in each separate SGA group or collectively. These findings suggest that TNF-α -308 G>A polymorphism does not play a major role in SGA-induced weight gain.

M-plane GaN thin films have been grown on β-LiGaO2 (100) substrates by plasma-assisted molecular-beam epitaxy. Pure M-plane GaN crystal films have been verified by the measurements of X-ray diffraction, micro-Raman scattering, polarization-dependent photoluminescence and atomic force microscopy. The measurements of X-ray diffraction and micro-Raman scattering exhibited the evidences of large compressive stress on the M-plane GaN thin films. Based on experimental results, we showed that the large compressive stress is the major source leading to the peeling of M-plane GaN thin film off substrate after thermal recycles.

We have grown high-quality InxGa1-xN/GaN triple-quantum-well microdisks on LiAlO2 substrate by plasma-assisted molecular beam epitaxy. The InxGa1-xN/GaN microdisk with a hexagonal shape of oblique face 28o-angle off c-axis was achieved. The mechanism of the termination of awl-shaped growth and the growth rates of GaN-barrier and InxGa1-xN-well were evaluated and confirmed with the triple quantum wells. Based on the growth rates and 28o-angle geometric shape, one can control the finite size of InGaN/GaN microdisks by plasma-assisted molecular beam epitaxy.

Cellular, animal and human studies support the involvement of aberrant NRG-ErbB signaling in the pathogenesis of schizophrenia. The aim of the present study was to examine whether genetic variation in the human ERBB4 gene is associated with susceptibility to schizophrenia. Two hundred and twenty-seven unrelated chronic inpatients with schizophrenia were enrolled in the study, and the genetic variation in the polymorphisms of the ERBB4 gene in the patients was compared with that of the control group, which consisted of 223 subjects free of psychiatric illness. The results showed that one coding-synonymous polymorphism (rs3748962, Val1065Val) was in genotypic (p=0.0027) and allelic (p=0.0007) association with schizophrenia. In comparison with subjects of the rs3748962-TT type, those of the rs3748962-CT and rs3748962-CC types were at 1.74- and 2.64-fold greater risk of schizophrenia (CT vs. TT: OR=1.71 (95% CI=1.15-2.53), p=0.0014; CC vs. TT: OR=2.64 (95% CI=1.37-5.23), p=0.0047), which supports the hypothesis of an additive model of transmission (p=0.0006). Furthermore, the frequency of haplotype ATC of rs3791709-rs2289086-rs3748962 was found to be significantly higher in the patients with schizophrenia than in the controls (case vs. control=36.0% vs. 24.4%, permutation p-value=0.0002). The findings support the involvement of the ERBB4 gene in schizophrenia in Han Chinese.

Antipsychotics-induced tardive dyskinesia (TD) has been suggested to be related to altered dopaminergic neurotransmission in the striatum. Melatonin has a modulating effect on dopaminergic neurotransmission in the brain; therefore, the hypothesis of an association between the melatonin receptor genes (MTNR1A, MTNR1B) and antipsychotics-induced TD was examined in this study.Schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale, and only patients who were either free of any abnormal involuntary movement (non-TD group) or who demonstrated persistent TD (TD group) were enrolled. Genotyping of six tagging single nucleus polymorphisms (SNPs) in the melatonin receptor genes (MRNR1A, MTNR1B) was then performed for each subject.Four hundred and eighteen inpatients (TD=256, non-TD=162) fitted the study criteria and underwent TD assessment and genotyping. Individual haplotype analysis showed that the haplotype ATG was significantly associated with non-TD (permutation P=0.037), and the association was also found to be significant by global haplotype analyses (permutation P=0.045).Our results indicated a significant association between the haplotype ATG in the MTNR1A gene and non-TD. Further replication in other countries or other populations is indicated.

Objective The aim of the study was to investigate the association between genetic variation in the tumor necrosis factor-alpha (TNF-alpha) gene and longitudinal weight change during long-term clozapine treatment. Methods Fifty-five patients with refractory schizophrenia treated with clozapine for 8 years were recruited. Gender, age, treatment response to clozapine in the first 14 months, baseline BMI, clozapine dose, concomitant use of mood stabilizers and other antipsychotics, and -308 G > A polymorphism in the human TNF-alpha gene were analyzed using generalized estimating equations. Results In addition to having a lower baseline BMI (p = 0.0013) and a longer treatment time (p = 0.050), the -308 GG carriers gained significantly more weight than the -308 A allele carriers (p = 0.0084) during 8 years of clozapine treatment, after controlling for other non-genetic factors. Conclusions The -308 G > A genetic variant of the TNF-alpha gene is associated with longitudinal weight change during clozapine treatment. Follow-up duration is an important factor to consider when performing pharmacogenetic study of clozapine-induced weight gain.

Dysregulation of glutamate neurotransmission is implicated in the pathphysiology of schizophrenia. Vesicular glutamate transporters (VGLUTs) package glutamate into vesicles in the presynaptic terminal and regulate the release of glutamate. Abnormal VGLUT1 expression has been linked to schizophrenia in postmortem brain studies. The purpose of this study was to investigate the involvement of the human VGLUT1 in the susceptibility to schizophrenia. In this study, we searched for genetic variants in the putative core promoter region and 12 exons (including UTR ends) of the VGLUT1 gene using direct sequencing in a sample of Han Chinese schizophrenic patients (n=376) and non-psychotic controls (n=368) from Taiwan, and conducted a case-control association study. We identified two common SNPs (g.-248G>C (ss159695612) and c.2697C>A (rs1043558)) in the VGLUT1 gene. No differences in the allele and genotype frequencies were detected between the patients and control subjects. Besides, we identified eight patient-specific rare variants in 16 out of 376 patients, including two variants (g.-296A>G (ss159695611) and g.-32Cv>T (ss159695613)) at the core promoter region and 5'UTR, two missense variants (L516M (ss159695617) and P551S (ss159695618)) and three silent variants (E24E (ss159695614), L118L (ss159695615), and P133P (ss159695616)) at protein-coding regions, and one variant (c.2201G>A (ss159695619)) at the 3'UTR. No rare variants were found in 368 control subjects (4.3% versus 0, P=1.5x10(-5)). Although the functional significance of these rare variants remains to be characterized, our study may lend support to the multiple rare mutation hypothesis of schizophrenia, and may provide genetic clues to indicate the involvement of the glutamate transmission pathway in the pathogenesis of schizophrenia.

Background Growing evidence suggests that dysregulation of N-methyl- d -aspartate receptor (NMDAR)-mediated glutamate neurotransmission may be involved in the pathophysiology of schizophrenia. The NMDAR is a heteromeric protein complex consisting of subunits from three subfamilies (NR1, NR2A, 2B, 2C, 2D and NR3A, 3B). The unique ability of NR3A to modulate the NMDAR function makes it an attractive candidate gene of schizophrenia. The purpose of this study was to investigate the involvement of the gene encoding the human NR3A subunit (GRIN3A) in the liability to schizophrenia. Methods We searched for genetic variants in the putative core promoter region and all the exons (including UTR ends) of the GRIN3A gene in 333 Han Chinese patients with schizophrenia and 369 control subjects from Taiwan using direct polymerase chain reaction (PCR) autosequencing, and assessed their association with schizophrenia. Results We identified 22 single nucleotide polymorphisms (SNPs) in the GRIN3A gene in this sample. SNP- and haplotype-based analyses showed no association of these 22 SNPs with schizophrenia. Nevertheless, we identified two missense mutations (D133N and Q1091H), one nonsense mutation (R1024X), and two synonymous mutations (Y873Y and E889E) of the GRIN3A gene in 6 out of 333 (1.8%) patients, while no rare mutations were found in 369 control subjects (p = 0.011, Fisher's exact test, one-tailed). In silico analysis showed that the R1024X and Q1091H mutations are possibly damaging. Conclusions Although the functional significance of these mutations remains to be characterized, our study indicates that rare mutations in the GRIN3A gene may contribute to the pathogenesis of schizophrenia in certain patients.

Adiponectin, an adipocyte-derived hormone controlling lipid and carbohydrate metabolism, has been suggested to be a biomarker for metabolic syndrome in the general population. This study investigated the association between adiponectin levels and metabolic syndrome in patients treated with atypical antipsychotics.Anthropometric and metabolic parameters and serum adiponectin levels were assessed in hospitalized patients with schizophrenia who had used the same atypical antipsychotic for at least 3 months. Retrospective reviews of the patients' medical records were conducted to obtain demographic data and pretreatment characteristics.The study included 567 schizophrenia patients treated with clozapine (n=231), olanzapine (n=94) and risperidone (n=242), for an average of 45.8+/-27.8 months. The prevalence of metabolic syndrome among all subjects was 23.8%. The clozapine group had a higher prevalence of metabolic syndrome (28.7%) than did the olanzapine (24.2%) and risperidone groups (19.5%) (P=0.039), and the clozapine group had lower levels of adiponectin (8.46+/-6.02 mg/mL) than did the olanzapine (10.26+/-4. 9 mg/mL) and risperidone groups (10.69+/-7.43 mg/mL) (P=0.001). Adiponectin level was negatively correlated with body mass index (BMI) increase after initiation of antipsychotic treatment. Cross-sectional regression analysis showed that age (OR,=1.042, P=0.001), BMI (OR=1.404, P0.0001), and adiponectin level (OR=0.862, P0.0001) were significant factors in the presence of metabolic syndrome. Significant predictors of metabolic syndrome were age at initiation of antipsychotic treatment (OR=1.04, P=.007), BMI at initiation of antipsychotic treatment (OR=1.44, P0.0001), BMI increase after initiation of antipsychotic treatment (OR=1.40, P0.0001), and adiponectin level (OR=0.86, P0.0001).Lower levels of adiponectin and weight gain after taking antipsychotics are associated with higher risk of metabolic syndrome in patients taking atypical antipsychotics.

Dysregulation of the immune response has been proposed as a precipitating factor of schizophrenia, and human leukocyte antigens (HLA) play a critical role in regulating the cascade of immunological reaction. Hence, many studies have investigated the relationship between the HLA system and schizophrenia. HLA is a complex gene family that contains several highly polymorphic genes, while the HLA-A gene is the most often studied gene to be associated with schizophrenia in the literature. A recent study reported that the interaction of the HLA-A10 allele and Chlamydial infection was highly associated with schizophrenia in a German population, which prompted us to investigate whether the HLA-A gene was also associated with schizophrenia in our population. Using a sequencing-based HLA typing method, we determined the HLA-A genotypes in 377 Han Chinese patients with schizophrenia (214 males, 163 females) and 321 non-psychotic Han Chinese control subjects (164 males, 157 females) from Taiwan. In total, 26 DNA-defined HLA-A alleles were identified in this sample. However, no significant differences of these allelic frequencies were found between the patients and the control subjects, suggesting that the HLA-A gene was unlikely a major risk factor of schizophrenia in this sample. As different populations have different HLA polymorphisms, an examination of the relationship of other HLA genes and schizophrenia in our population, with a larger sample size, is warranted in the future.

Although one third to one half of refractory schizophrenic patients responds to clozapine, however, there are few evidences currently that could predict clozapine response before the use of the medication. The present study aimed to train and validate artificial neural networks (ANN), using clinical and pharmacogenetic data, to predict clozapine response in schizophrenic patients. Five pharmacogenetic variables and five clinical variables were collated from 93 schizophrenic patients taking clozapine, including 26 responders. ANN analysis was carried out by training the network with data from 75% of cases and subsequently testing with data from 25% of unseen cases to determine the optimal ANN architecture. Then the leave-one-out method was used to examine the generalization of the models. The optimal ANN architecture was found to be a standard feed-forward, fully-connected, back-propagation multilayer perceptron. The overall accuracy rate of ANN was 83.3%, which is higher than that of logistic regression (LR) (70.8%). By using the area under the receiver operating characteristics curve as a measure of performance, the ANN outperformed the LR (0.821+/-0.054 versus 0.579+/-0.068; p

Abnormal dopamine signal transduction is implicated in the pathophysiology of schizophrenia. A recent study showed that prostate apoptosis response 4 protein (Par-4) interacts with dopamine D2 receptor and plays an important role in dopamine signaling. Par-4 knockout mice showed depression-like behavior, suggesting that Par-4 gene may be associated with mental disorders in human. The study was aimed to determine whether the PRKC, apoptosis, WT1, regulator gene (PAWR) that encodes the human homolog of Par-4 protein is a susceptibility gene for schizophrenia. We systematically screened for mutations at the 5' untranslated region (5'UTR) and all the exonic regions of the PAWR gene in a sample of Han Chinese schizophrenic patients from Taiwan. We identified two missense single nucleotide polymorphisms (SNPs) that are in strong linkage in our sample (D'=0.98), i.e. P78R at exon 2 and I199M at exon 3, respectively. SNP- and haplotype-based analysis showed that these two variants are associated with schizophrenia; there is an overrepresentation of RR homozygotes of P78R (OR=2.00, 95% CI=1.05-3.83) and MM homozygotes of I199M (OR=1.81, 95% CI=0.95-3.54) in schizophrenic patients as compared to control subjects. When subjects were divided by gender, the association is specifically with female patients (OR=2.94 for RR and OR=2.7 for MM), but not with male patients. Our results indicate that the PAWR gene is associated with schizophrenia in our population, and this study provides genetic evidence to support the dopamine hypothesis of schizophrenia.

Schizophrenia is a severe mental disorder that requires lifelong treatment, and therefore information on the cardiovascular safety and tolerance of antipsychotics is of significant clinical importance. Atypical antipsychotics have been used to treat schizophrenia patients since the 1990s, and more and more patients have been switched to these from typical antipsychotics; however, there is still no accessible evaluation tool for assessing cardiovascular safety. In this study, we used a computer-assisted 5-min measurement of resting heart rate variability (HRV) in schizophrenia patients who were switched to atypical antipsychotic agents (amisulpride and olanzapine) due to severe side effects (tardive dyskinesia). In 15 patients who switched to amisulpride and 18 to olanzapine, HRV was evaluated before the medication was switched, and patients were followed up every month for 3 months after the switch. Frequency-domain analyses of short-term and stationary respiratory rate (RR) intervals were performed to evaluate low-frequency power (LF; 0.04–0.15 Hz), high-frequency power (HF; 0.15–0.40 Hz), the ratio of LF to HF (LF/HF), and LF in normalized units (LF%). Our results showed significant increases in the mean, variance and HF of RR intervals in the amisulpride group, but not in the olanzapine group. These results indicate that amisulpride has a more vagotonic effect, suggesting greater cardiovascular safety as compared with olanzapine when subjects are switched from typical antipsychotic agents.