Yu Chiau Shyu

Effect of Parenteral Selenium Supplementation in Critically Ill Patients: A Systematic Review and Meta-Analysis

Background It is currently unclear whether parenteral selenium supplementation should be recommended in the management of critically ill patients. Here we conducted a systematic review and meta-analysis to assess the efficacy of parenteral selenium supplementation on clinical outcomes. Methods/Principal Findings Randomized trials investigating parenteral selenium supplementation administered in addition to standard of care to critically ill patients were included. CENTRAL, Medline, EMBASE, the Science Citation Index, and CINAHL were searched with complementary manual searches. The primary outcome was all-cause mortality. Trials published in any language were included. Two authors independently extracted data and assessed trial quality. A third author was consulted to resolve disagreements and for quality assurance. Twelve trials were included and meta-analysis was performed on nine trials that recruited critically ill septic patients. These comprised 965 participants in total. Of these, 148 patients (30.7%) in the treatment groups, and 180 patients (37.3%) in control groups died. Parenteral selenium treatment significantly reduced all-cause mortality in critically ill patients with sepsis (relative risk [RR] 0.83, 95% CI 0.70–0.99, p = 0.04, I2 = 0%). Subgroup analyses demonstrated that the administration schedule employing longer duration (RR 0.77, 95% CI 0.63–0.94, p = 0.01, I2 = 0%), loading boluses (RR 0.73, 95% CI 0.58–0.94, p = 0.01, I2 = 0%) or high-dose selenium treatment (RR 0.77, 95% CI 0.61–0.99, p = 0.04, I2 = 0%) might be associated with a lower mortality risk. There was no evidence of adverse events. Conclusions/Significance Parenteral selenium supplementation reduces risk of mortality among critically ill patients with sepsis. Owing to the varied methodological quality of the studies, future high-quality randomized trials that directly focus on the effect of adequate-duration of parenteral selenium supplementation for severe septic patients are needed to confirm our results. Clinicians should consider these findings when treating this high-risk population. Systematic Review Registration PROSPERO 2011; CRD42011001768

Disruption of the nuclear membrane by perinuclear inclusions of mutant huntingtin causes cell-cycle re-entry and striatal cell death in mouse and cell models of Huntington's disease

Accumulation of N-terminal fragments of mutant huntingtin (mHTT) in the cytoplasm, nuclei and axons of neurons is a hallmark of Huntingtons disease (HD), although how these fragments negatively impact neurons remains unclear. We followed the distribution of mHTT in the striata of transgenic R6/2-J2 HD mice as their motor function declined. The fraction of cells with diffuse, perinuclear or intranuclear mHTT changed in parallel with decreasing motor function. In transgenic mice, medium spiny neurons (MSNs) that exhibited perinuclear inclusions expressed cell-cycle markers typically not seen in the striata of normal mice, and these cells are preferentially lost as disease progresses. Electron microscopy reveals that perinuclear inclusions disrupt the nuclear envelope. The progression of perinuclear inclusions being accompanied by cell-cycle activation and culminating in cell death was also observed in 1° cortical neurons. These observations provide a strong correlation between the subcellular location of mHTT, disruption of the nucleus, re-entry into the cell-cycle and eventual neuronal death. They also highlight the fact that the subcellular distribution of mHTT is highly dynamic such that the distribution of mHTT observed depends greatly on the stage of the disease being examined.

Sumoylation of p45/NF-E2: Nuclear Positioning and Transcriptional Activation of the Mammalian β-Like Globin Gene Locus

ABSTRACT NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells and in mouse fetal liver. By in vitro sumoylation reaction and DNA transfection experiments, we show that the sumoylation occurs at lysine 368 (K368) of human p45/NF-E2. Furthermore, p45 sumoylation enhances the transactivation capability of NF-E2, and this is accompanied by an increase of the NF-E2 DNA binding affinity. More interestingly, we have found that in K562 cells, the β-globin gene loci in the euchromatin regions are predominantly colocalized with the nuclear bodies promyelocytic leukemia protein (PML) oncogenic domains that are enriched with the PML, SUMO-1, RNA polymerase II, and sumoylatable p45/NF-E2. Chromatin immunoprecipitation assays further showed that the intact sumoylation site of p45/NF-E2 is required for its binding to the DNase I-hypersensitive sites of the β-globin locus control region. Finally, we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells.

Chromatin-binding in vivo of the erythroid kruppel-like factor, EKLF, in the murine globin loci

EKLF is an erythroid-specific, zinc finger-containing transcription factor essential for the activation of the mammalian beta globin gene in erythroid cells of definitive lineage. We have prepared a polyclonal anti-mouse EKLF antibody suitable for Western blotting and immunoprecipitation (IP) qualities, and used it to define the expression patterns of the EKLF protein during mouse erythroid development. We have also used this antibody for the chromatin-immunoprecipitation (ChIP) assay. EKLF was found to bind in vivo at both the mouse beta-major-globin promoter and the HS2 site of beta-LCR in the mouse erythroleukemia cells (MEL) in a DMSO-inducible manner. The DMSO-induced bindings of EKLF as well as three other proteins, namely, RNA polymerase II, acetylated histone H3, and methylated histone H3, were not abolished but significantly lowered in CB3, a MEL-derived cell line with null-expression of p45/NF-E2, an erythroid-enriched factor needed for activation of the mammalian globin loci. Interestingly, binding of EKLF in vivo was also detected in the mouse alpha-like globin locus, at the adult alpha globin promoter and its far upstream regulatory element alpha-MRE (HS26). This study provides direct evidence for EKLF-binding in vivo at the major regulatory elements of the mouse beta-like globin gene clusters the data also have interesting implications with respect to the role of EKLF-chromatin interaction in mammalian globin gene regulation.

International trends in clozapine use: a study in 17 countries

There is some evidence that clozapine is significantly underutilised. Also, clozapine use is thought to vary by country, but so far no international study has assessed trends in clozapine prescribing. Therefore, this study aimed to assess clozapine use trends on an international scale, using standardised criteria for data analysis.

Diagnostic performance of alpha-fetoprotein, lens culinaris agglutinin-reactive alpha-fetoprotein, des-gamma carboxyprothrombin, and glypican-3 for the detection of hepatocellular carcinoma: a systematic review and meta-analysis protocol

BackgroundDiagnosis of early-stage hepatocellular carcinoma (HCC) followed by curative resection or liver transplantation offers the best chance for long-term patient survival. Clinically, ultrasonography has suboptimal sensitivity for detecting early-stage HCC. Several serological tests including alpha-fetoprotein (AFP), the ratio of lens culinaris agglutinin-reactive alpha-fetoprotein to total AFP (AFP-L3/AFP), des-gamma carboxyprothrombin (DCP), and glypican-3 (GPC-3) have been widely investigated as diagnostic biomarkers for early-stage HCC in at-risk populations. However, these tests are not recommended for routine HCC screening. Our objective is to determine the diagnostic performance of AFP, AFP-L3/AFP, DCP, and GPC-3 for the detection of HCC, particularly early-stage tumors meeting the Milan criteria.Methods/designWe will include cross-sectional studies that consecutively or randomly recruit target populations. We will search the Cochrane Library, Medline, Embase, Science Citation Index, and the Chinese National Knowledge Infrastructure. We will also search the MEDION and ARIF databases to identify diagnostic systematic reviews that include primary studies. Reference lists of relevant reviews will be searched for additional trials. Language restrictions will not be applied. Two reviewers will independently screen study eligibility and extract data. Methodological quality will be assessed according to the revised tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Two authors will apply the QUADAS-2 assessment to all the included studies, and any discrepancies will be resolved by the third author. The following test characteristics will be extracted into 2 × 2 tables for all included studies: true positives, false positives, true negatives, and false negatives. Study-specific estimates of sensitivity and specificity with 95% confidence intervals will be displayed in forest plots. When possible, we will use the bivariate random-effects model or the Rutter and Gatsonis hierarchical summary receiver operating characteristic model for statistical analysis. To investigate heterogeneity, we will include study designs, population characteristics, test characteristics, and types of reference standard as the study-level variables.DiscussionOur systematic review will allow patients, clinicians, and researchers to determine the diagnostic performance of AFP, AFP-L3/AFP, DCP, and GPC-3 for the detection of early-stage HCC and the potential roles of these diagnostic biomarkers in the existing diagnostic pathways.Systematic Review Registration: PROSPERO 2013; CRD42013003879

Attention-deficit hyperactivity disorder, its treatment with medication and the probability of developing a depressive disorder: A nationwide population-based study in Taiwan

OBJECTIVE The purpose of this study is to determine the risk of developing depressive disorders by evaluating children with attention-deficit/hyperactivity disorder (ADHD) in comparison to controls that do not have ADHD, as well as to analyze whether the medications used to treat ADHD, methylphenidate (MPH) and atomoxetine (ATX), influence the risk of depression. METHODS A group of patients newly diagnosed with ADHD (n=71,080) and age- and gender-matching controls (n=71,080) were chosen from Taiwans National Health Insurance database during the period of January 2000 to December 2011. Both the patients and controls were monitored through December 31, 2011. We also explore the potential influence of the length of MPH and ATX treatment on developing depressive disorders. RESULTS The ADHD patients showed a significantly increased probability of developing a depressive disorder when compared to the control group (ADHD: 5.3% vs. CONTROLS 0.7%; aHR, 7.16, 99% CI: 6.28-8.16). Regarding treatment with MPH, a longer MPH use demonstrates significant protective effects against developing a depressive disorder (aOR, 0.91, 99%CI: 0.88-0.94). However, the duration of ATX treatment could not be significantly correlated with the probability of developing a depressive disorder. LIMITATIONS The database employed in this study lacks of comprehensive clinical information for the patients with ADHD. Potential moderating factors between ADHD and depression were not considered in-depth in this study. CONCLUSIONS The results of this study reveal that youths diagnosed with ADHD have a greater risk of developing depressive disorders. Long-term treatment with MPH correlated to the reduced probability of developing a depressive disorder among youths with ADHD.

Attention-deficit/hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: A nationwide population-based study in Taiwan

This study estimated the risk of developing psychotic disorders by comparing children with ADHD to non-ADHD controls, and to examine whether methylphenidate (MPH) treatment influences the risks of psychotic disorders. A nationwide cohort of patients who were newly diagnosed with ADHD (n=73,049) and age- and gender-matched controls (n=73,049) were selected from Taiwans National Health Insurance database from January 2000 to December 2011. All participants were observed until December 31, 2011. Cox regression models were used to estimate the effects of ADHD diagnosis and MPH use on subsequent outcomes. Having a diagnosis of any psychotic disorder and of schizophrenia were set as two different outcomes and were analyzed separately. Compared to the control group, the ADHD group showed significantly increased risk of developing any psychotic disorder (adjusted hazard ratio [aHR], 5.20; 95% confidence interval [CI], 4.30-6.30) and schizophrenia (aHR, 4.65; 95% CI, 3.59-6.04). Compared to ADHD patients without psychosis, patients with ADHD who developed psychosis had significantly older age at first diagnosis of ADHD (9.4±3.3years vs. 10.6±4.0years). Among patients with ADHD, MPH use significantly increased the risk of developing any psychotic disorder (aHR, 1.20; 95% CI, 1.04-1.40), but did not increase the risk of developing schizophrenia (aHR, 1.16; 95% CI, 0.94-1.42). The results indicated that previous diagnoses of ADHD are a powerful indicator of developing psychotic disorders. Nevertheless, the specific mechanisms of the relationships between ADHD, MPH use and psychotic disorders need further elucidation in future clinical studies.

A systematic review and meta‐analysis of adjuvant interferon therapy after curative treatment for patients with viral hepatitis‐related hepatocellular carcinoma

The efficacy of adjuvant interferon treatment for the management of patients with viral hepatitis‐related hepatocellular carcinoma (HCC) following curative treatment is controversial. We have conducted a systematic review with meta‐analysis to assess the effects of adjuvant interferon therapy on survival outcomes. Randomized and nonrandomized studies (NRSs) comparing adjuvant interferon treatment with the standard of care for viral hepatitis‐related HCC after curative treatment were included. CENTRAL, Medline, EMBASE and the Science Citation Index were searched with complementary manual searches. The primary outcomes were recurrence‐free survival (RFS) and overall survival (OS). Nine randomized trials and 13 NRSs were included in the meta‐analysis. These nine randomized trials included 942 participants, of whom, 490 were randomized to the adjuvant interferon treatment group and 452 to the control group. The results of meta‐analysis showed unexplained heterogeneity for both RFS and OS. The 13 NRSs included 2214 participants, of whom, 493 were assigned to the adjuvant interferon treatment group and 1721 to the control group. The results of meta‐analysis showed that, compared with controls, adjuvant interferon treatment significantly improved the RFS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.52–0.84, I2 = 29%] and OS (HR 0.43, 95% CI 0.34–0.56, I2 = 0%) of patients with hepatitis C virus‐related HCC following curative treatment. There was little evidence for beneficial effects on patients with hepatitis B virus‐related HCC. Future research should be aimed at clarifying whether the effects of adjuvant interferon therapy are more prominent in hepatitis C patients with sustained virological responses.

Subcellular Transport of EKLF and Switch-On of Murine Adult βmaj Globin Gene Transcription

ABSTRACT Erythroid Krüppel-like factor (EKLF) is an essential transcription factor for mammalian β-like globin gene switching, and it specifically activates transcription of the adult β globin gene through binding of its zinc fingers to the promoter. It has been a puzzle that in the mouse, despite its expression throughout the erythroid development, EKLF activates the adult βmaj globin promoter only in erythroid cells beyond the stage of embryonic day 10.5 (E10.5) but not before. We show here that expression of the mouse βmaj globin gene in the aorta-gonad-mesonephros region of E10.5 embryos and in the E14.5 fetal liver is accompanied by predominantly nuclear localization of EKLF. In contrast, EKLF is mainly cytoplasmic in the erythroid cells of E9.5 blood islands in which βmaj is silenced. Remarkably, in a cultured mouse adult erythroleukemic (MEL) cell line, the activation of the βmaj globin gene by dimethyl sulfoxide (DMSO) or hexamethylene-bis-acetamide (HMBA) induction is also paralleled by a shift of the subcellular location of EKLF from the cytoplasm to the nucleus. Blockage of the nuclear import of EKLF in DMSO-induced MEL cells with a nuclear export inhibitor repressed the transcription of the βmaj globin gene. Transient transfection experiments further indicated that the full-sequence context of EKLF was required for the regulation of its subcellular locations in MEL cells during DMSO induction. Finally, in both the E14.5 fetal liver cells and induced MEL cells, the β-like globin locus is colocalized the PML oncogene domain nuclear body, and concentrated with EKLF, RNA polymerase II, and the splicing factor SC35. These data together provide the first evidence that developmental stage- and differentiation state-specific regulation of the nuclear transport of EKLF might be one of the steps necessary for the switch-on of the mammalian adult β globin gene transcription.