Associations of a family history of lupus with the risks of lupus and major psychiatric disorders in first-degree relatives.

BACKGROUND: Genetic factors link psychiatric disorders, particularly major depressive disorder (MDD), bipolar disorder, and obsessive-compulsive disorder (OCD), with systemic lupus erythematosus (SLE). Additionally, maternal SLE is a risk factor for long-term developmental problems, particularly learning disabilities, attention disorders, autism spectrum disorder (ASD) and speech disorders, in children. AIM: We aimed to determine whether first-degree relatives (FDRs) of patients with SLE have increased risks of SLE and major psychiatric disorders. DESIGN AND METHODS: Using the Taiwan National Health Insurance Research Database, we recruited 40 462 FDRs of patients with SLE as well as 161 848 matched controls. The risks of major psychiatric disorders, including schizophrenia, bipolar disorder, OCD, MDD, ASD and attention-deficit/hyperactivity disorder (ADHD), were assessed. RESULTS: The FDRs of patients with SLE had higher risks of SLE (reported as the adjusted relative risk and 95% confidence interval: 14.54; 12.19-17.34), MDD (1.23; 1.12-1.34), ADHD (1.60; 1.55-1.65), OCD (1.41; 1.14-1.74) and bipolar disorder (1.18; 1.01-1.38) compared with controls. Specifically, male FDRs of patients with SLE had higher risks of SLE and bipolar disorder, whereas female FDRs of patients with SLE had higher risks of MDD and OCD. Differences in the familial relationship (i.e. parents, children, siblings and twins) were consistently associated with higher risks of these disorders compared with controls. CONCLUSIONS: The FDRs of patients with SLE had higher risks of SLE, MDD, ADHD, OCD and bipolar disorder than the controls.

Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study.

A previous genetic study has suggested that schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) share common disease-associated genes. However, whether individuals with first-degree relatives (FDRs) with schizophrenia have a higher risk of these major psychiatric disorders requires further investigation. This study used Taiwan's National Health Insurance Research Database and identified 151 650 patients with schizophrenia and 227 967 individuals with FDRs with schizophrenia. The relative risks (RRs) of schizophrenia and other major psychiatric disorders were assessed in individuals with FDRs with schizophrenia. The individuals with FDRs with schizophrenia exhibited higher RRs (95% confidence interval) of major psychiatric disorders, namely schizophrenia (4.76, 4.65-4.88), bipolar disorder (3.23, 3.12-3.35), major depressive disorder (2.05, 2.00-2.10), ASD (2.55, 2.35-2.77) and ADHD (1.31, 1.25-1.37) than were found in the total population. Several sensitivity analyses were conducted to confirm these results. A dose-dependent relationship was observed between the risks of major psychiatric disorders and the numbers of FDRs with schizophrenia. The increased risks of major psychiatric disorders were consistent in different family relationships, namely among parents, offspring, siblings and twins. Our study supports the familial dose-dependent co-aggregation of schizophrenia, bipolar disorder, major depressive disorder, ASD and ADHD, and our results may prompt governmental public health departments and psychiatrists to focus on the mental health of individuals with FDRs with schizophrenia.

Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer.

Colon cancer is the third leading cause of death from cancer worldwide with less than 10% survival rate at the late stage. Although mutations of certain genes have been implicated in familial colon cancer development, the etiology of the majority of colon cancer remains unknown. Herein, we identified TYRO3 as a potential oncogene. Immunohistochemical staining results demonstrated that levels of TYRO3 were markedly elevated in polyps and colon cancer cells and were negatively correlated with prognosis. Overexpression of TYRO3 enhanced cell motility, invasion, anchorage-independent growth and metastatic ability, while knockdown of TYRO3 impaired all these processes. Results from meta-analysis showed that TYRO3 was associated with epithelial-mesenchymal transition (EMT) signatures. Gain-of-function and loss-of-function experiments demonstrated that expression of SNAI1, the master regulator of EMT, was regulated by TYRO3 and played a major role in mediating TYRO3-induced EMT processes. The murine model also demonstrated that Tyro3 and Snai1 were upregulated in the early stage of colon cancer development. To provide a proof-of-concept that TYRO3 is a druggable target in colon cancer therapy, we raised anti-TYRO3 human antibodies and showed that treatment with the human antibody abolished TYRO3-induced EMT process. More importantly, administration of this anti-TYRO3 antibody increased drug sensitivity in primary cultured colon cancer cells and xenografted mouse tumors. These findings demonstrate that TYRO3 is a novel oncogene and a druggable target in colon cancer.

Risk of developing Parkinson's disease among patients with asthma: a nationwide longitudinal study.

BACKGROUND: A cross-sectional retrospective study suggested a link between allergic diseases and Parkinson's disease. However, the temporal association between asthma and Parkinson's disease remains unknown. METHODS: From the Taiwan National Health Insurance Research Database, 10 455 patients who were diagnosed with asthma between 1998 and 2008 and aged ≥45 years and 41 820 age- and sex-matched controls were selected for our study and observed until the end of 2011. Those who developed Parkinson's disease during the follow-up period were identified. We also examined the asthma severity, as indicated by the frequency of admission (times per year) for asthma exacerbation, and the risk of subsequent Parkinson's disease. RESULTS: Patients with asthma had an increased risk of developing Parkinson's disease (hazard ratio [HR]: 3.10, 95% confidence interval [CI]: 2.20-4.36) after we adjusted for demographic data, health system use, medical comorbidities, and medication use. Sensitivity tests yielded consistent findings after we excluded observations on the first year (HR: 2.90, 95% CI: 2.04-4.13) and first 3 years (HR: 2.46, 95% CI: 1.64-3.69). Patients with asthma who had more frequent admissions (times per year) during the follow-up period exhibited a greater risk of subsequent Parkinson's disease (>2: HR: 16.42, 95% CI: 5.88-45.91; 1-2: 12.69, 95% CI: 5.03-31.71; 0-1: HR: 2.92, 95% CI: 1.91-4.49). CONCLUSION: Patients with asthma had an elevated risk of developing Parkinson's disease later in life, and we observed a dose-dependent relationship between greater asthma severity and a higher risk of subsequent Parkinson's disease.

The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response.

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. The top association result in the meta-analysis of response represents SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

Association of CHRNA4 polymorphism with depression and loneliness in elderly males.

The cholinergic receptor, nicotinic, alpha 4 (CHRNA4) gene encodes the neuronal nicotinic acetylcholine receptor alpha-4 subunit. Recent research has shown that a variation in CHRNA4 (rs1044396) affects attention and negative emotionality in normal adults. To determine the link between CHRNA4 variation and cognitive function/depressed mood, this study conducted a genotype-phenotype correlation analysis between the common CHRNA4:rs1044396 variant and several baseline parameters of cognition and depressed mood in 192 elderly male subjects without major psychiatric disorders or dementia. Study findings identified a significant link between the CHRNA4:rs1044396 polymorphism and depression and loneliness in the aged. Compared to carriers of at least one T-allele, carriers of the homozygous C/C genotype described themselves as more depressed and lonely. This is the first evidence which may implicate CHRNA4 in depressed emotions in the elderly.

Gene-gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics.

The use of atypical antipsychotics (AAPs) is associated with increasing the risk of the metabolic syndrome (MetS), which is an important risk factor for cardiovascular disease and diabetes. Two insulin-induced gene (INSIG) isoforms, designated INSIG-1 and INSIG-2 encode two proteins that mediate feedback control of lipid metabolism. In this genetic case-control study, we investigated whether the common variants in INSIG1 and INSIG2 genes were associated with MetS in schizophrenic patients treated with atypical antipsychctics. The study included 456 schizophrenia patients treated with clozapine (n=171), olanzapine (n=91) and risperidone (n=194), for an average of 45.5±27.6 months. The prevalence of MetS among all subjects was 22.8% (104/456). Two single-nucleotide polymorphisms (SNPs) of the INSIG1 gene and seven SNPs of the INSIG2 gene were chosen as haplotype-tagging SNPs. In single-marker-based analysis, the INSIG2 rs11123469-C homozygous genotype was found to be more frequent in the patients with MetS than those without MetS (P=0.001). In addition, haplotype analysis showed that the C-C-C haplotype of rs11123469-rs10185316- rs1559509 of the INSIG2 gene significantly increased the risk of MetS (P=0.0023). No significant associations were found between polymorphisms of INSIG1 gene and MetS, however, INSIG1 and INSIG2 interactions were found in the significant 3-locus and 4-locus gene-gene interaction models (P=0.003 and 0.012, respectively). The results suggest that the INSIG2 gene may be associated with MetS in patients treated with AAPs independently or in an interactive manner with INSIG1.

Comparison of endocrine and cellular mechanisms regulating the corpus luteum of primates and ruminants.

The corpus luteum (CL) is a transient endocrine organ that is essential for maintenance of pregnancy in both ruminants and primates. The cellular and endocrine mechanisms that regulate the CL in these species have commonalities and some distinct and intriguing differences. Both species have similar cellular content with large luteal cells derived from the granulosa cells of the follicle, small luteal cells from follicular thecal cells, and large numbers of capillary endothelial cells that form the vasculature that has an essential role in optimal CL function. Intriguingly, the large luteal cells in ruminants grow larger than in primates and acquire a capacity for high constitutive progesterone (P4) production that is independent of stimulation from LH. In contrast, the primate CL and the granulosa lutein cells from primates continue to require stimulation by LH/CG throughout the luteal phase. Although the preovulatory follicle of women and cows had similar size and steroidogenic output (10 to 20 mg/h), the bovine CL had about ten-fold greater P4 output compared to the human CL (17.4 vs. 1.4 mg/h), possibly due to the development of high constitutive P4 output by the bovine large luteal cells. The continued dependence of the primate CL on LH/CG/cAMP also seems to underlie luteolysis, as there seems to be a requirement for greater luteotropic support in the older primate CL than is provided by the endogenous LH pulses. Conversely, regression of the ruminant CL is initiated by PGF from the nonpregnant uterus. Consequently, the short luteal phase in ruminants is primarily due to premature secretion of PGF by the nonpregnant uterus and early CL regression, whereas CL insufficiency in primates is related to inadequate luteotropic support and premature CL regression. Thus, the key functions of the CL, pregnancy maintenance and CL regression in the absence of pregnancy, are produced by common cellular and enzymatic pathways regulated by very distinct luteotropic and luteolytic mechanisms in the CL of primates and ruminants.

Genetic and functional analyses describe a novel 730delG mutation in the KEL gene causing K0 phenotype in a Taiwanese blood donor.

AIMS/OBJECTIVES: The purpose of this study was to explore the molecular basis of the K0 phenotype of a Taiwanese blood donor found to have anti-Ku alloantibodies. BACKGROUND: With respect to Kell blood group antigens, almost all Taiwanese have the (K-, k+) phenotype. MATERIALS AND METHODS: Alloantibody identification and KEL antigen typing were performed. Enzymatic function assays were carried out to detect the Kell glycoprotein on RBCs. The KEL genes were sequenced to detect genetic variation. To determine the origin of this novel allele, family studies were conducted. RESULTS: The alloantibody was identified as anti-Ku. The donor was typed K0 . The KEL gene-sequencing data revealed that this K0 donor is a compound heterozygote with two different null alleles. He bears a novel 730delG mutation in one allele. Family studies suggested that the donor inherited the 730delG mutation from his father. The endothelin-converting activity assay indicated that his RBCs had no functional Kell glycoprotein. Other family members who had only one null allele with the 730delG mutation had the phenotype (K-, k+). CONCLUSION: For blood transfusion safety, it is important to establish an effective screening algorithm to identify rare phenotypes, such as the K0 phenotype, and to establish a database of rare blood groups.

Contamination of Salmonella Schwarzengrund cells in chicken meat from traditional marketplaces in Taiwan and comparison of their antibiograms with those of the human isolates.

Salmonella Schwarzengrund is one of the infective Salmonella serotypes for humans and food animals, such as poultry and swine. Because consumption of foods containing salmonellae due to cross contamination or inadequate cooking may lead to human salmonellosis, in this report, the prevalence of Salmonella Schwarzengrund contamination in chicken meat samples purchased from different traditional marketplaces in Taiwan between 2000 and 2006 was investigated. In addition, 228 Salmonella Schwarzengrund strains isolated from these chicken meat samples and 30 human isolates obtained between 2004 and 2006 were compared for their antimicrobial susceptibility. Results showed that the prevalence of Salmonella Schwarzengrund contamination in raw chicken meat samples was 30.5%. Of all of the Salmonella isolates from chicken meat, Salmonella Schwarzengrund accounted for 39.3%. On the other hand, of the total Salmonella strains isolates from humans between 2004 and 2006, Salmonella Schwarzengrund accounted for 2.8%. All these chicken meat isolates and human isolates were multidrug-resistant and demonstrated high resistance to ampicillin, gentamicin, kanamycin, streptomycin, tetracycline, nalidixic acid, trimethoprim-sulfamethoxazole, and chloramphenicol. For gentamicin and kanamycin, however, the resistance gradually declined. The antibiogram study may indicate the abuse of some antibiotics for both humans and chickens. Also, transmission of Salmonella Schwarzengrund strains between humans and food of animal origin is possible.

Human sebocytes express prostaglandin E2 receptors EP2 and EP4 but treatment with prostaglandin E2 does not affect testosterone production.

BACKGROUND: Prostaglandins (PG) play an important role in cutaneous homeostasis. Among other skin cells, human sebocytes express cyclooxygenases and can produce PGE(2). Various prostanoid receptors have been demonstrated in epidermis and hair follicles, while limited data are available regarding their expression in sebaceous glands. In addition, the interaction between PGE(2) and androgenesis remains largely unclear. OBJECTIVES: To examine the expression of PGE(2) receptor (EP) and PGF(2alpha) receptor (FP) in human sebocytes and the influence of PGE(2) or PGF(2alpha) on testosterone production. METHODS: A reverse transcription-polymerase chain reaction study was used to detect the expression of EP subtypes and FP. A testosterone radioimmunoassay was used to measure the amount of testosterone in the supernatant of cultured SZ95 sebocytes treated with PGE(2) or PGF(2alpha) alone or in the presence of various androgen precursor substrates. RESULTS: SZ95 sebocytes expressed mainly EP2 and EP4 but not EP3 or FP. Testosterone production was not induced by PGE(2) or PGF(2alpha), alone or in the presence of cholesterol. PGE(2) did not affect androgenesis in cultured sebocytes. CONCLUSIONS: The expression patterns of prostanoid receptors differ between sebocytes, hair follicles and epidermis. The effects of PGE(2) and PGF(2alpha) on the proliferation, lipogenesis and inflammation of sebocytes appear not to be associated with androgenesis.

Predictors of mortality in patients with pyogenic liver abscess.

BACKGROUND: Pyogenic liver abscess (PLA) is uncommon but potentially life-threatening. The objective of this study was to identify the prognostic factors for PLA. METHODS: The medical records of 253 patients, 148 men and 105 women with a mean age of 56.4 years (SD : 15.0 years), who were hospitalised due to a PLA between January 1995 and June 2007 were reviewed. The underlying medical disorders, clinical signs and symptoms, laboratory values, imaging studies, microbiological features, treatments, morbidity and mortality were recorded. Factors related to in-hospital case fatality were analysed. RESULTS: The mean Acute Physiology And Chronic Health Evaluation (APACHE) II score at admission in patients with PLA was 8.7 points (SD 5.4 points). The most common co-existing disease was diabetes mellitus (41.9%), followed by biliary stone disorders (32.0%). Klebsiella pneumoniae was the most frequent pathogen, followed by Escherichia coli. The in-hospital case-fatality rate was 9.1%. Multivariate analysis revealed that gas-forming abscess (p=0.019), multi-drug resistant isolates (p=0.026), anaerobic infection (p=0.045), blood urea nitrogen level >7.86 mmol/l (p=0.004), and APACHE II score > or =15 (p= 0.004) were associated with mortality. CONCLUSIONS: The prognosis of PLA may depend chiefly on the severity of the basic physical condition and underlying pathology. As the primary treatment for PLA is not completely effective, a more aggressive approach should be considered, especially for patients with poor prognosis.

Glycogen synthase kinase-3beta gene is associated with antidepressant treatment response in Chinese major depressive disorder.

Evidence suggests that glycogen synthase kinase-3beta (GSK3B) activity is increased significantly in the brain of patients with major depressive disorders (MDD). Inhibition of GSK3B is thought to be a key feature in the therapeutic mechanism of antidepressants. To investigate whether common genetic variants in the GSK3B gene are associated with MDD and the therapeutic response to antidepressants, four polymorphisms (rs334558 (-50 T>C), rs13321783 (IVS7+9227 A>G), rs2319398 (IVS7+11660 G>T) and rs6808874 (IVS11+4251 T>A)) of the GSK3B gene were genotyped in 230 Chinese MDD patients and 415 controls. Among the MDD patients, 168 accepted selective serotonin reuptake inhibitor (SSRI) (fluoxetine or citalopram) antidepressant treatment and therapeutic evaluation for 4 weeks and 117 for 8 weeks. Significant association with MDD was not shown in the alleles and genotypes of single loci or four-locus haplotypes. However, three of the four polymorphisms investigated were significantly associated with 4-week antidepressant therapeutic effect (P=0.002-0.011). Of the four-locus haplotype analysis, the GSK3B TAGT carriers showed a poorer response to antidepressants in 4-week (P<0.0001) and 8-week (P=0.015) evaluation compared with other haplotype groups and would quite likely be the non-remitter to 8-week antidepressant treatment (P=0.006). Our findings show, for the first time, that GSK3B genetic variants play a role in the SSRI antidepressant therapeutic response and support the hypothesis that drugs regulating GSK3B activity may represent a novel treatment strategy for MDD.

Association study of polymorphisms in post-synaptic density protein 95 (PSD-95) with schizophrenia.

The postsynaptic density protein 95 (PSD-95) - the prototype of this family - is a modular protein that enables anchoring of NMDA receptors, modulates NMDA receptor sensitivity to glutamate and coordinates NMDA receptor-related intracellular processes. Since hypofunction of NMDA receptors has been implicated in the pathophysiology of schizophrenia, we explored the hypothesis that genetic variants of the PSD-95 gene were associated with a diagnosis of schizophrenia. Three PSD-95 polymorphisms were studied in a sample population of 248 people with schizophrenia and 208 normal controls. One polymorphism (rs373339) was not informative in our Chinese population while the other two polymorphisms (rs2521985 and rs17203281) were analysed with chi-square tests and haplotype analysis. Results demonstrated that the two informative polymorphisms are in strong linkage disequilibrium with each other. Neither single marker nor haplotype analysis revealed an association between variants at the PSD-95 locus and schizophrenia, suggesting that it is unlikely that the PSD-95 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further genetic studies in schizophrenia with other PSD-95-like molecules that interact with the glutamate system are suggested.

Expression of sex-determining genes in human sebaceous glands and their possible role in the pathogenesis of acne.

BACKGROUND: The human skin, especially the sebaceous gland, is a steroidogenic organ similar to the gonads and adrenal cortex, possessing all the enzymes required for steroid sex-hormone synthesis and metabolism. Factors regulating cutaneous steroidogenesis associated with disease status remain largely unknown. OBJECTIVE: We hypothesized that transcription factors involved in sex formation and regulation of steroidogenesis in the classical steroidogenic organs are also expressed in the sebaceous glands. Their possible role in the pathogenesis of acne were investigated. METHODS: We used reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization and Western blotting to analyse the expression of SF-1, WT-1, SRY, SOX-9 and DAX-1 mRNAs and their proteins in cultured human sebocytes and the facial skin of acne patients. RESULTS: The in situ hybridization study showed SOX-9 mRNA mainly localized in basal keratinocytes, the basal layer of the sebaceous glands and eccrine glands. Immortalized human sebaceous gland cells (SZ95) expressed mRNA for SOX-9, WT-1 and DAX-1 but not for SF-1 or SRY. The expression of DAX-1 protein was slightly inhibited by 10(-6) m oestradiol (E2) at 6 h but enhanced by 10(-6) m dihydrotestosterone (DHT) at 48 h. The facial expression of SOX-9 seemed to be higher in the acne-prone male patients, while DAX-1 was stronger in subjects without acne, although both were statistically insignificant. CONCLUSION: Our findings confirm the expression of some sex-determining genes in human sebaceous glands. Further studies on a larger patient population including the normal controls are needed to elucidate the functional significance of these transcription factors in the pathogenesis of acne.

Association study of polymorphisms in glycine transporter with schizophrenia.

Glycine acts as an obligatory co-agonist with glutamate on N-methyl-D-aspartate (NMDA) receptors. Brain glycine availability is determined by glycine transporters (GlyT1 or SLC6A9), which mediate glycine reuptake into nerve terminals. Since hypofunction of NMDA receptors has been implicated in the pathophysiology of schizophrenia, this study tests the hypothesis that GlyT1 genetic variants confer susceptibility to schizophrenia. Four GlyT1 polymorphisms were studied in a sample population of 249 people with schizophrenia and 210 normal controls. One polymorphism (rs16831541) was not informative in our Chinese population while the other three polymorphisms (rs1766967, rs2248632 and rs2248253) were analysed with chi-square tests and haplotype analysis. Significant linkage disequilibrium was obtained among the three polymorphisms. Neither single marker nor haplotype analysis revealed an association between variants at the GlyT1 locus and schizophrenia, suggesting that it is unlikely that the GlyT1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further studies with other GlyT1 variants, relating either to schizophrenia, psychotic symptoms or to therapeutic response in schizophrenia, are suggested.