Autophagy has been implicated in both cell survival and programmed cell death (PCD), and this may explain the apparently complex role of this catabolic process in tumourigenesis. Our previous studies have shown that caspases have little influence on Drosophila larval midgut PCD, whereas inhibition of autophagy severely delays midgut removal. To assess upstream signals that regulate autophagy and larval midgut degradation, we have examined the requirement of growth signalling pathways. Inhibition of the class I phosphoinositide-3-kinase (PI3K) pathway prevents midgut growth, whereas ectopic PI3K and Ras signalling results in larger cells with decreased autophagy and delayed midgut degradation. Furthermore, premature induction of autophagy is sufficient to induce early midgut degradation. These data indicate that autophagy and the growth regulatory pathways have an important relationship during midgut PCD. Despite the roles of autophagy in both survival and death, our findings suggest that autophagy induction occurs in response to similar signals in both scenarios.Cell Death and Differentiation advance online publication, 4 May 2012; doi:10.1038/cdd.2012.43.

OBJECTIVE: The aim of this study was to compare the early adherence patterns for first-generation antipsychotics and second-generation antipsychotics during the first month of treatment for patients newly diagnosed as having schizophrenia.  METHODS: With a random sample from the Taiwan national health insurance database, persons with a schizophrenia diagnosis (ICD-9-CM code 295.X) and a concurrent initial antipsychotic prescription from 1998 to 2006 were defined as being newly treated for schizophrenia. Adherence patterns within one month of diagnosis were categorized into four independent groups: refill, switch, admission, and discontinuation.  RESULTS: Treatment initiated with first-generation or second-generation antipsychotics resulted in similar rates of refill (57% versus 59%). However, patients who started with first-generation antipsychotics were significantly less likely to switch (9% versus 14%) but more likely to discontinue (34% versus 26%) medications than those whose treatment was initiated with second-generation antipsychotics.  CONCLUSIONS: The data substantiated previous observations of the magnitude of adherence problems in Asian populations and highlight the importance of developing new strategies for intervention.(Psychiatric Services 63:504-507, 2012; doi: 10.1176/appi.ps.201100011).

BACKGROUND Hemangioma in infants has a benign self-limited course, but the 10% of cases with complications need further treatment. Successful treatment with propranolol in western countries has been reported over the past few years. We evaluated the efficacy of propranolol for treating infantile hemangioma in Taiwanese newborns and young infants. METHODS Patients below 1 year of age treated with propanolol between November 2009 and March 2011 were enrolled. Demographic data, clinical features, imaging findings, treatment regimens of propranolol, and outcome were investigated. RESULTS Thirteen patients were treated with propranolol at a dose of 2-3 mg/kg/day. Seven (53.8%) patients had solitary hemangioma and six had multiple ones. The indications for treatment were risk of local event in nine patients, functional risk in four, local complication in one, and life-threatening complication in one. The median age for starting propranolol was 4 months (range: 1-11 months). Responses to propranolol, such as decolorization, regression in tumor size, or improvement of hemangioma-associated complications were observed in all patients within 1-2 weeks after treatment. Propranolol-associated adverse effects occurred in two patients. One infant had occasional tachypnea, and the other had occasional pale-looking appearance. The symptoms resolved after dosage tapering. CONCLUSION Propranolol may be a promising therapeutic modality for infantile hemangioma. Therapeutic strategies are needed to evaluate the optimal treatment protocol and long-term adverse effects.

Ginkgolide A, ginkgolide B, ginkgolide C, and ginkgolide J are structurally-related terpene trilactones present in Ginkgo biloba extract. Pregnane X receptor (PXR), glucocorticoid receptor (GR), and constitutive androstane receptor (CAR) regulate the expression of genes involved in diverse biological functions. In the present study, we investigated the effects of individual ginkgolides as single chemical entities on the function of human PXR (hPXR), human GR (hGR), and human CAR (hCAR). In cell-based reporter gene assays, none of the ginkgolides activated hGR or hCAR (wild-type and its SV23, SV24, and SV25 splice variants). Concentration-response experiments showed that ginkgolide A and ginkgolide B activated hPXR and rat PXR to a greater extent than ginkgolide C, whereas ginkgolide J had no effect. As determined by a time-resolved fluorescence resonance energy transfer competitive binding assay, ginkgolide A and ginkgolide B, but not ginkgolide C or ginkgolide J, were shown to bind to the ligand-binding domain of hPXR, consistent with molecular docking data. When compared with SR12813 (a known agonist of hPXR), ginkgolide A and ginkgolide B were considerably less potent in binding to hPXR. These two ginkgolides recruited steroid receptor coactivator-1 to hPXR and increased hPXR target gene (CYP3A4) expression, as assessed by a mammalian two-hybrid assay and real-time polymerase chain reaction, respectively. In conclusion, the individual ginkgolides regulate the function of nuclear receptors in a receptor-selective and chemical-dependent manner. This study identifies ginkgolide A and ginkgolide B as naturally-occurring agonists of hPXR and provides mechanistic insight into the structure-activity relationship in ligand-activation of hPXR.

BACKGROUND: The absence of biallelic TCRγ deletion (ABD) is a characteristic of early thymocyte precursors before V(D)J recombination. The ABD was reported to predict early treatment failure in T-cell acute lymphoblastic leukemia (ALL). This study aimed to investigate its prognostic value in Taiwanese patients with T-cell ALL. PROCEDURE: Forty-five children with T-cell ALL were enrolled from six medical centers in Taiwan. Quantitative DNA polymerase chain reaction (Q-PCR) was performed to check the status of TCRγ deletion. The threshold for homozygous deletions by Q-PCR was defined as a fold-change <0.35. RESULTS: ABD was found in 20 patients [20:45] who had higher incidences of induction failure than those without ABD (P = 0.03; hazard ratio [HR] = 8.13; 95% confidence interval [95% CI] = 1.23-53.77) after multivariate regression analysis. Patents with ABD also had inferior EFS and OS (P = 0.071 and 0.0196, respectively). Multivariate Cox analysis indicated that the association between ABD and overall survival was independent of age and leukocyte count on presentation (P = 0.036; HR = 4.25; 95% CI = 1.10-16.42). CONCLUSIONS: The absence of TCRγ deletion is a predictor of a poor response to induction chemotherapy for pediatric patients with T-cell ALL in Taiwan. Providing patients with T-cell ALL and ABD with alternative regimens may be worthwhile to test in future clinical trials. Pediatr Blood Cancer © 2011 Wiley Periodicals, Inc.

Meandering through the most densely populated metropolitan areas of Taipei, Taiwan, the Danshui River and its tributaries have undergone the construction of 14 wetlands since 2004, as a means to improve water quality. This study was conducted to examine the functional capabilities associated with treating non-point source pollution through these riparian wetlands. Trend analysis was used to differentiate dissolved oxygen, biochemical oxygen demand, suspended solids, ammonia, and Escherichia coli, among 13 sampling sites using both functions of a Mann-Kendall test and a seasonal Mann-Kendall test. The results show that water quality in Taipei metropolitan rivers has been improving since increasing the number of constructed wetlands and connecting households to the public sewage system. The concentration of pollutants such as those influencing biochemical oxygen demand have gradually declined in drought seasons because riparian wetlands contribute a base flow to dilute riverine pollutants. This paper indicates that the creation of treatment systems influences dissolved oxygen conditions at the municipal scale, suggesting that constructed wetlands could stabilize water quality during extreme hydrological events and improve water quality particularly in times of drought.

Despite more than four decades of investigation, the etiology of Kawasaki disease remains obscure, and none of the proposed etiologic theories for the disease have achieved independent confirmation. Clinical and epidemiologic features support an infectious cause, but the etiology remains unclear. The authors present a case of Kawasaki disease associated with Epstein-Barr virus and Mycoplasma pneumoniae infection in a 3.5-y-old boy. He received two doses of intravenous immunoglobulin due to prolonged course of Kawasaki disease but later had complicated autoimmune haemolytic anaemia. His prolonged fever subsided after azithromycin administration. Epstein-Barr virus infection was confirmed by molecular microbiological pathology of cervical lymph node and serological tests. The serological tests for Mycoplasma pneumoniae also revealed a positive result. Thus, it is concluded that Mycoplasma pneumoniae and Epstein-Barr virus infections may occur simultaneously in a child with Kawasaki disease. In addition, autoimmune hemolytic anaemia may be noted in Kawasaki disease patients after high-dose IVIG administration. To the authors' knowledge, this is the first report of Kawasaki disease with Epstein-Barr virus and Mycoplasma pneumoniae in the English-language literature.

Bilobalide is a naturally occurring sesquiterpene trilactone with therapeutic potential in the management of ischemia and neurodegenerative diseases such as Alzheimer's disease. In the present study, we investigated the effect of bilobalide on the activity of rat constitutive androstane receptor (rCAR) and rat pregnane X receptor (rPXR) and compared that with human CAR (hCAR) and human PXR (hPXR). Bilobalide activated rCAR in a luciferase reporter gene assay and increased rCAR target gene expression in cultured rat hepatocytes, as determined by the CYP2B1 mRNA and CYP2B enzyme activity (benzyloxyresorufin O-dealkylation) assays. This increase in hepatocyte CYP2B1 expression by bilobalide was not accompanied by a corresponding increase in rCAR mRNA level. In contrast to the activation of rCAR, the activity of rPXR, hCAR, and hPXR was not influenced by this chemical in cell-based reporter gene assays. Consistent with these results, bilobalide did not alter rPXR, hCAR, or hPXR target gene expression in rat or human hepatocytes, as evaluated by the CYP3A23, CYP2B6, CYP3A4 mRNA assays and the CYP3A (testosterone 6β-hydroxylation) and CYP2B6 (bupropion hydroxylation) enzyme activity assays. Bilobalide was not an antagonist of rPXR, hCAR, or hPXR, as suggested by the finding that it did not attenuate rPXR activation by pregnenolone 16α-carbonitrile, hCAR activation by 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime, or hPXR activation by rifampicin in reporter gene assays. In conclusion, bilobalide is an activator of rCAR, whereas it is not a ligand of rPXR, hCAR, or hPXR. Likewise, it is an inducer of rat CYP2B1, but not of rat CYP3A23, human CYP2B6, or human CYP3A4.

Naturally-occurring splice variants of human constitutive androstane receptor (hCAR) exist, including hCAR-SV23 (insertion of amino acids SPTV), hCAR-SV24 (APYLT), and hCAR-SV25 (SPTV and APYLT). An extract of G. biloba was reported to activate hCAR-SV24 and the wild-type (hCAR-WT). However, it is not known whether it selectively affects hCAR splice variants, how it activates hCAR isoforms, and which chemical is responsible for the effects of the extract. Therefore, we evaluated the impact of G. biloba extract on the functionality of hCAR-SV23, hCAR-SV24, hCAR-SV25, and hCAR-WT, and compared it to that of phenobarbital, di-(2-ethylhexyl)phthalate (DEHP), 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), and 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in cell-based reporter gene assays. Among the hCAR splice variants investigated, only hCAR-SV23 was activated by G. biloba extract, and this required co-transfection of a retinoid X receptor-α (RXRα) expression plasmid. The extract activated hCAR-SV23 to a lesser extent than hCAR-WT, but ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, or bilobalide was not responsible for the effects of the extract. CITCO activated hCAR-SV23, hCAR-SV24, and hCAR-WT. By comparison, phenobarbital activated hCAR-WT, whereas DEHP activated hCAR-SV23, hCAR-SV24 (with exogenous RXRα supplementation), and hCAR-WT. TCPOBOP did not affect the activity of any of the isoforms. G. biloba extract and phenobarbital did not bind or recruit coactivators to the ligand-binding domains of hCAR-WT and hCAR-SV23, whereas positive results were obtained with the controls (CITCO for hCAR-WT and DEHP for hCAR-SV23). In conclusion, G. biloba extract activates hCAR in an isoform-selective manner, and hCAR-SV23, hCAR-SV24, and hCAR-WT have overlapping but distinct sets of ligands.

Estrogens have multifaceted roles in mammalian testis. In the present study, we focused on estradiol as a potential regulator of testicular cytochrome P450 1B1 (CYP1B1) expression and investigated the possible mechanisms involved in the estradiol-mediated suppression. CYP1B1 protein levels were measured in the testes of rats that were treated with 17β-estradiol benzoate (1.5 mg/kg) at different stages of development. In addition, CYP1B1 mRNA levels were measured in mouse MA-10 Leydig tumor cells treated with (a) various concentrations of 17β-estradiol benzoate,(b) 17β-estradiol benzoate in the presence of exogenous luteinizing hormone (LH), or (c) 17β-estradiol benzoate in the presence of ICI 182,780, a competitive steroidal antagonist of estrogen receptors (ERs). Treatment of neonatal, pubertal, or adult rats with 17β-estradiol benzoate was associated with a reduction of approximately 90% in testicular CYP1B1 protein content compared to age-matched controls. Treatment of MA-10 cells with 17β-estradiol benzoate (10-500 nM) produced a concentration- and time-dependent decrease in CYP1B1 mRNA levels, but had no effect on LH receptor mRNA levels or on protein kinase A (PKA) activity. However, 17β-estradiol benzoate (10-500 nM), regardless of the concentration tested, failed to attenuate the LH-elicited increase in CYP1B1 mRNA or PKA activity in MA-10 cells that were co-treated with LH and estradiol. Similarly, ICI 182,780 (10-1000 µM) did not reverse the suppressive effect of estradiol on CYP1B1 mRNA expression in MA-10 cells co-treated with estradiol and ICI 182,780. The results indicate that downregulation of testicular CYP1B1 by estradiol was independent of PKA activity and was not mediated by ERs in MA-10 cells.