Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system

Previous studies have suggested that risk of psychotic events may be increased in children exposed to methylphenidate (MPH). However, this risk has not been fully examined and the possibility of confounding factors has not been excluded. Patients aged 6-19 years who received at least one MPH prescription were identified using Hong Kong population-based electronic medical records on the Clinical Data Analysis & Reporting System (2001-2014). Using the self-controlled case series design, relative incidence of psychotic events was calculated comparing periods when patients were exposed to MPH with non-exposed periods. Of 20 586 patients prescribed MPH, 103 had an incident psychotic event; 72 (69.9%) were male and 31 (30.1%) female. The mean age at commencement of observation was 6.95 years and the mean follow-up per participant was 10.16 years. On average, each participant was exposed to MPH for 2.17 years. The overall incidence of psychotic events during the MPH exposure period was 6.14 per 10 000 patient-years. No increased risk was found during MPH exposed compared to non-exposed periods (incidence rate ratio (IRR) 1.02 (0.53-1.97)). However, an increased risk was found during the pre-exposure period (IRR 4.64 (2.17-9.92)). Results were consistent across all sensitivity analyses. This study does not support the hypothesis that MPH increases risk of incident psychotic events. It does indicate an increased risk of psychotic events prior to the first prescription of MPH, which may be due to an association between psychotic events and the behavioural and attentional symptoms that led to psychiatric assessment and initiation of MPH treatment

Adult-Age Inflammatory Pain Experience Enhances Long-Term Pain Vigilance in Rats

Background: Previous animal studies have illustrated a modulatory effect of neonatal pain experience on subsequent painrelated behaviors. However, the relationship between chronic pain status in adulthood and future pain perception remains unclear. Methodology/Principal Findings: In the current study, we investigated the effects of inflammatory pain experience on subsequent formalin-evoked pain behaviors and fear conditioning induced by noxious stimulation in adult rats. Our results demonstrated an increase of the second but not the first phase of formalin-induced pain behaviors in animals with a history of inflammatory pain that have recovered. Similarly, rats with persistent pain experience displayed facilitated acquisition and prolonged retention of pain-related conditioning. These effects of prior pain experience on subsequent behavior were prevented by repeated morphine administration at an early stage of inflammatory pain. Conclusions/Significance: These results suggest that chronic pain diseases, if not properly and promptly treated, may have a long-lasting impact on processing and perception of environmental threats. This may increase the susceptibility of patients to subsequent pain-related disorders, even when chronic pain develops in adulthood. These data highlight th

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

Genetic disruption of KLF1 K74 sUMOylation in hematopoietic system promotes healthy longevity in mice

[[abstract]]The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Kruppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1(K74R/K74R) mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1(K74R/K74R) mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8(+) T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1(K74R/K74R) mice extends the lifespan of the wild-type mice. The Klf1(K74R/K74R) mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan

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

[[abstract]]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

Trend, characteristics, and pharmacotherapy of adults diagnosed with attention-deficit/hyperactivity disorder: a nationwide survey in Taiwan

Yu-Shian Cheng,1,2 Yu-Chiau Shyu,3,4 Sheng-Yu Lee,5,6 Shin-Sheng Yuan,7 Chun-Ju Yang,8 Kang-Chung Yang,8,9 Tung-Liang Lee,10 Liang-Jen Wang1 1Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 2Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai’s Home, Kaohsiung, 3Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, 4Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 5Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, 6Department of Psychiatry, College of Medicine and Hospital, National Cheng Kung University, Tainan, 7Institute of Statistical Science, Academia Sinica, 8Institute of Biopharmaceutical Sciences, National Yang-Ming University, 9Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan; 10Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA Objective: Attention-deficit/hyperactivity disorder (ADHD) in adults may result in functional impairment warranting clinical interventions. However, few studies have investigated the diagnosis and treatment rates of adult ADHD in non-Caucasian ethnic groups. This study used nationwide population-based data to investigate the rate of diagnosis, associated characteristics, and pharmacological treatment for adult ADHD in Taiwan. Methods: Adults (age ≥18 years) newly diagnosed with ADHD (n=5,397) between January 2000 and December 2011 were enrolled from the National Health Insurance database in Taiwan. All patients were monitored until December 31, 2011. Patients who received treatment with immediate-release methylphenidate (IR-MPH), osmotic release oral system-methylphenidate (OROS-MPH), and atomoxetine (ATX) were analyzed. Results: The cumulative prevalence of adult ADHD was 0.028%, and the incidence increased 10.9-fold from 2000 to 2011. The male to female ratio was 1.16, and 74.9% of the patients had the inattentive type. Overall, 55% of the patients received drug therapy for ADHD, and the average treatment duration was 478.3 days. Of the total patients, 50.4%, 13.3%, and 1.7% were prescribed with IR-MPH, OROS-MPH, and ATX, for a mean duration of 453.9, 327.7, and 161.4 days, respectively. Conclusion: This population-based study showed an increasing trend in the diagnosis rate of adult ADHD; however, this rate is still low compared with Western countries. Approximately 45% of the adult patients with ADHD never received medication for their ADHD. Continuous efforts are needed to increase public awareness of adult ADHD. Keywords: ADHD, gender difference, epidemiology, drug adherence, comorbidity, non-Caucasia