Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function.

Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several small-molecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)--a bicyclic diterpenoid lactone isolated from Andrographis paniculata--and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras.

Functional analysis of human thromboxane synthase polymorphic variants.

BACKGROUND: Thromboxane A synthase (TXAS) metabolizes the cyclooxygenase product prostaglandin (PG) H2 into thromboxane H2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation. Nonsynonymous polymorphisms in the TXAS gene have the potential to alter TXAS activity and affect TXA2 generation. OBJECTIVES: The aim of this study was to assess the functional effects of genetic variants in the TXAS protein, including K258E, L357V, Q417E, E450K, and T451N. METHODS: Wild-type TXAS and the variant proteins were expressed in a bacterial system and purified by affinity and hydroxyapatite chromatography. The two characteristic catalytic activities of TXAS were assayed in each of the purified recombinant proteins: isomerization of PGH2 to TXA2 and fragmentation of PGH2 to 12-hydroxyheptadecatrienoic acid and malondialdehyde. RESULTS: All of the variants showed both isomerization and fragmentation activities. The Km values of the variants ranged from 27 to 52 µmol/l PGH2 (wild-type value: 32 µmol/l PGH2); the Vmax values of the variants ranged from 18 to 40 U/mg (wild-type value: 41 U/mg). The kinetic differences were largest for the L357V variant, whose Vmax/Km ratio was just 27% of the wild-type value. CONCLUSION: The increased Km and decreased Vmax values observed with L357V suggest that this variant may generate less TXA2 at the low levels of PGH2 expected in vivo, raising the possibility of attenuated signaling through the thromboxane pathway.

Mortality and suicide after self-harm: community cohort study in Taiwan.

BACKGROUND: Little is known about outcomes after self-harm in East Asia. AIMS: To investigate mortality after self-harm in a Taiwanese population. METHOD: Between 2000 and 2003, 1083 individuals who self-harmed were identified through a population self-harm register in Nantou County, Taiwan, and followed until 2007 for date and cause of death on a national mortality database. RESULTS: In total, 145 individuals died, 48 through suicide. The risks of all-cause and suicide mortality in the first year were 4.7% and 2.1% respectively, representing 8- and 131-fold age- and gender-standardised increases. Male gender and older age were independent risk factors for both suicide and non-suicide mortality. Use of more lethal methods in the index episode was associated with higher mortality but this was accounted for by gender. CONCLUSIONS: Results in this sample support the recommendation that people with a history of recent self-harm should be a major target for suicide prevention programmes.

Non-fatal repetition of self-harm: population-based prospective cohort study in Taiwan.

BACKGROUND: Repeated self-harm is relatively common and is linked with an elevated risk of eventual suicide. There has been no study of this involving a large sample from the Far East. AIMS: To estimate the risk over the medium term of non-fatal repetition of self-harm and identify predictive factors in those carrying out self-harm. METHOD: A total of 970 individuals who had self-harmed were recruited from a community-based suicide behaviour register system in Nantou, Taiwan from July 2000 to February 2003. Information regarding demography and suicide methods was collected. Individuals were followed-up until December 2005 to examine the risk of repeated self-harm and independent predictive factors. RESULTS: Ninety cohort members had repeated self-harm during the follow-up period (accounting for 131 repeated self-harm episodes in all). The cumulative risks were 5.7% for the first year, 7.8% for the second year and 9.5% for the fourth year. The risk was highest within the first year after the self-harm event. Independent risk factors included female gender and self-cutting as well as self-poisoning with drugs. Effect of younger age was mediated through the choice of methods. CONCLUSIONS: Individuals with self-harm have a high risk of repetition, especially within the first year. Suicide prevention strategies need to focus on intervening with this population to reduce their repetition.

A community-based study of case fatality proportion among those who carry out suicide acts.

OBJECTIVE: To investigate the case fatality proportion and associated factors in those carrying out suicide acts in Nantou, Taiwan. METHOD: Data from 1,171 suicide acts (including 973 with deliberate self harm and 198 completed suicides), identified between July 2000 and February 2003, were collected from a population suicide register in Nantou County, Taiwan. Case fatality proportion and the independent effects of demographic factors and suicide method on case fatality were investigated. RESULTS: The overall case fatality proportion was 16.9%, with higher proportions in men (26.3%) and in those aged 65 and over (37.9%). Hanging was the most lethal method (fatality proportion = 81.5%); pesticide was both commonly used and associated with a high case fatality (fatality proportion = 26.3%). Only age (increased with age) and suicide method were found to be independently associated with the risk of fatality. CONCLUSIONS: Suicide method and older age are independent predictors of the fatality of suicide acts. Suicide prevention strategy and clinical assessment ought to take into account of these two factors. Diminution of pesticide toxicity and control of access to pesticides are important considerations for suicide prevention in rural Taiwan.

The lived experiences of brokered brides who have attempted suicide in Taiwan.

AIMS AND OBJECTIVES: The purpose of this study was to explore the lived experiences of brokered brides who have attempted suicide in Taiwan. BACKGROUND: There has been a significant rise in number of brokered brides since the 1970s in Western world and since the 1990s in several Asian countries. However, there is a great lack of research on brokered brides' suicide around the world. DESIGN: A descriptive phenomenological study was used to explore the lived experiences of brokered brides who have attempted suicide. METHODS: Purposive sampling, one-on-one, in-depth with semi-structural interviews were conducted to collect data. Narratives were analysed by Colaizzi's (1978) seven-step method. RESULTS: Data saturation was achieved after interviewing 12 brokered brides. The study group was comprised of females whose average age was 33. Three themes and the sub-themes were: being a chrysalis (loss of support, loneliness, suffering abused experience, loss of self-esteem), death of a chrysalis (loss of hope and seeking salvation) and birth of a chrysalis (regaining hope and sense of self-worth). CONCLUSIONS: These brokered brides suffered from numerous pressures and difficulties in life. Their hopelessness led to suicidal behaviours as a way to get out of trouble. Hence, the need to provide brokered brides with substantial assistance and support in their lives is an issue that cannot be neglected. The results of this study could be used as a reference to provide professionals and the public with a deeper understanding of suicide in this vulnerable group, and provide more appropriate help and care. Relevance to clinical practice. The suffering may be alleviated by giving brokered brides a reliable support system that they so obviously need. Several recommendations have been made, including amendments in terms of policy, society and the services offered by healthcare professionals.

To explore the efficacy of community rehabilitation for facilitating daily function among patients with mental illness.

PURPOSE: To explore the efficacy of community rehabilitation for facilitating daily function among patients with mental illness. DESIGN AND METHODS: A quasi-experimental design was used. Two hundred and sixty-four participants completed a daily living function scale questionnaire and provided disease-related information. FINDINGS: Community rehabilitation was shown to be efficient in helping to stabilize mental illness and enhance daily function. Daily function had a significant and positive correlation with disease stability. PRACTICE IMPLICATIONS: Community rehabilitation for patients with mental illness can effectively stabilize and prevent disability among those with mental illness.

Effect of amphetamine on corrected-QT interval change during methadone maintenance treatment in Taiwan: a prospective cohort study.

INTRODUCTION AND AIMS: Previous studies have suggested that methadone is associated with prolonged corrected-QT (QTc) interval, but published prospective research studies in this area are relatively scarce. This study investigates QTc interval change among methadone maintenance patients and possible associated risk factors. One of the aims is to explore the effect of amphetamines. DESIGN AND METHODS: This prospective cohort study with six-month follow up assesses the effect of methadone on QTc interval among a sample (n = 170) of heroin users in a methadone maintenance treatment program in Taiwan. Demographic data, substance use history, medical history and laboratory studies were collected at study enrollment. Twelve-lead electrocardiograms were performed for all participants both at study enrollment and six months later. RESULTS: The median daily methadone dose was 41 mg. A mean increase of QTc interval (17.1 ms, SD = 50.0, P < 0.001) was found at six-month follow up. QTc interval prolongation in the sample at baseline was 2.9%, and at six months was 12.4%. A positive correlation was found between comorbid amphetamine use frequency in the past month and QTc interval change. Methadone dose was not associated with QTc change. DISCUSSION AND CONCLUSIONS: An increase of mean QTc interval was found among methadone maintenance patients at six-month follow up. Electrocardiogram monitoring should be performed among patients who are at risk of frequently using amphetamines during methadone maintenance treatment.

Positional signaling and expression of ENHANCER OF TRY AND CPC1 are tuned to increase root hair density in response to phosphate deficiency in Arabidopsis thaliana.

Phosphate (Pi) deficiency induces a multitude of responses aimed at improving the acquisition of Pi, including an increased density of root hairs. To understand the mechanisms involved in Pi deficiency-induced alterations of the root hair phenotype in Arabidopsis (Arabidopsis thaliana), we analyzed the patterning and length of root epidermal cells under control and Pi-deficient conditions in wild-type plants and in four mutants defective in the expression of master regulators of cell fate, CAPRICE (CPC), ENHANCER OF TRY AND CPC 1 (ETC1), WEREWOLF (WER) and SCRAMBLED (SCM). From this analysis we deduced that the longitudinal cell length of root epidermal cells is dependent on the correct perception of a positional signal ('cortical bias') in both control and Pi-deficient plants; mutants defective in the receptor of the signal, SCM, produced short cells characteristic of root hair-forming cells (trichoblasts). Simulating the effect of cortical bias on the time-evolving probability of cell fate supports a scenario in which a compromised positional signal delays the time point at which non-hair cells opt out the default trichoblast pathway, resulting in short, trichoblast-like non-hair cells. Collectively, our data show that Pi-deficient plants increase root hair density by the formation of shorter cells, resulting in a higher frequency of hairs per unit root length, and additional trichoblast cell fate assignment via increased expression of ETC1.

Prevalence, correlates, and risk perception of HIV infection among heroin users in Central Taiwan.

We investigated the prevalence and correlated factors of human immunodeficiency virus (HIV) among heroin users attending methadone maintenance treatment (MMT) programs in Central Taiwan, and explored the degree of risk perception of HIV infection among the participants. Our study participants were 781 heroin users seeking treatment at the MMT program at Tsaotun Psychiatric Center in Taiwan. The presence of HIV antibodies was identified by microparticle enzyme immunoassay and confirmed by western blot. Multivariate logistic regression was used to identify the independent correlates of HIV infection. The mean age of the sample was 36.1 years [standard deviation (SD) = 7.6]; of the patients, 710 (90.9%) were men. The prevalence of HIV infection among our study population was 20.7%. Multivariate logistic regression analysis revealed that HIV infection was independently associated with the age of the patients of initial heroin use, heroin injection use, nondrug-related criminal convictions, needle-sharing behaviors, and sharing injection paraphernalia. A strong agreement existed between self-reported HIV serostatus and the results of laboratory analyses, with 88.8% of patients reporting their condition correctly. We found a high rate of HIV infection among patients in the MMT program. Factors associated with HIV infection were mostly related to drug-use behaviors. These findings stress the importance of education regarding drug-risk behaviors.

The influence of media coverage of a celebrity suicide on subsequent suicide attempts.

OBJECTIVE: To investigate the impact of media reporting of a celebrity suicide on subsequent suicide attempts. METHOD: A Poisson time series autoregression analysis was conducted to examine whether there was a significant increase in suicide attempts during the 3-week period after the start of extensive media reporting of a celebrity suicide. The reporting began on May 2, 2005, and lasted about 17 days. To investigate the influence of media reporting on suicide attempts, a structured interview was conducted with 124 suicide attempters identified from 2 counties in Mid Taiwan who had exposure to the media reporting. RESULTS: After controlling for seasonal variation, calendar year, temperature, and humidity, there was a marked increase in the number of suicide attempts during the 3-week period after media reporting began (adjusted relative risk = 1.55, 95% CI = 1.26 to 1.91). Among 124 suicide attempters exposed to the media reports, 23.4% reported an influence from them. There was no relationship between the attempters' ages and the age of the celebrity or the method, but male attempters had a significantly higher risk for such influence. A considerably higher risk for such influence was found among subjects with a history of suicide attempt(s) in the previous year (odds ratio = 52.3, 95% CI = 5.96 to 459.1). CONCLUSIONS: The extensive media reporting of the suicide of a celebrity was followed by an increase in suicide attempts. The effect was particularly marked in individuals with a recent history of a suicide attempt. The results provide further support for the need for more restrained reporting of suicides as part of suicide prevention strategies and for special vigilance for contagious effects of such reporting on people who have carried out recent suicidal acts.

Long-term psychological outcome of 1999 Taiwan earthquake survivors: a survey of a high-risk sample with property damage.

OBJECTIVE: Severe natural disasters can cause long-term psychological impact on the survivors. This study aimed to examine the prevalence and risk factors of posttraumatic stress symptoms and psychiatric morbidity among survivors of the severe earthquake that occurred in Chi-Chi, Taiwan, in September 21, 1999. METHODS: A total of 6412 earthquake survivors whose houses were destroyed by earthquake were recruited about 2 years after the disaster. They completed a self-report questionnaire assessing posttraumatic stress symptoms, psychiatric morbidity, and information of demographics, trauma exposure, and current living status. RESULTS: The estimated rates of posttraumatic stress disorder caseness and psychiatric morbidity were 20.9% and 39.8%, respectively. Psychiatric morbidity occurred mainly in survivors who were female, older, with low education level, and currently living in a prefabricated house. The risk factors for posttraumatic stress disorder caseness were female sex, currently living in a prefabricated house, low education level, and experienced complete destruction of property. CONCLUSION: These results showed that severe earthquake can cause long-term psychological impact in the survivors. The findings of risk factors suggest avenues for targeting postdisaster interventions.