Family-based association study of the BDNF, COMT and serotonin transporter genes and DSM-IV bipolar-I disorder in children

<p>Abstract</p> <p>Background</p> <p>Over the past decade pediatric bipolar disorder has gained recognition as a potentially more severe and heritable form of the disorder. In this report we test for association with genes coding brain-derived neurotrophic factor (<it>BDNF</it>), the serotonin transporter (<it>SLC6A4</it>), and catechol-O-methyltransferase (<it>COMT</it>).</p> <p>Methods</p> <p>Bipolar-I affected offspring triads (N = 173) were drawn from 522 individuals with 2 parents in 332 nuclear families recruited for genetic studies of pediatric psychopathology at the Clinical and Research Program in Pediatric Psychopharmacology and Adult ADHD at Massachusetts General Hospital.</p> <p>Results</p> <p>We failed to identify an association with the val66 allele in BDNF (OR = 1.23, p = 0.36), the COMT-l allele (OR = 1.27, p = 0.1), or the HTTLPR short allele (OR = 0.87, p = 0.38).</p> <p>Conclusion</p> <p>Our study suggests that the markers examined thus far in <it>COMT </it>and <it>SLC6A4 </it>are not associated with pediatric bipolar disorder and that if the val66met marker in <it>BDNF </it>is associated with pediatric bipolar disorder the magnitude of the association is much smaller than first reported.</p

A randomised controlled trial of cognitive behavioural treatment for obsessive compulsive disorder in children and adolescents

Cognitive behaviour therapy (CBT) for young people with obsessive compulsive disorder (OCD) has become the treatment of first choice. However, the literature is largely based on studies emphasising exposure and response prevention. In this study, we report on a randomised controlled trial of CBT for young people carried out in typical outpatient clinic conditions which focused on cognitions. A randomised controlled trial compares 10 sessions of manualised cognitive behavioural treatment with a 12-week waiting list for adolescents and children with OCD. Assessors were blind to treatment allocation. 21 consecutive patients with OCD aged between 9 and 18 years were recruited. The group who received treatment improved more than a comparison group who waited for 3 months. The second group was treated subsequently using the same protocol and made similar gains. In conclusion, CBT can be delivered effectively to young people with OCD in typical outpatient settings

Are Child and Adolescent Responses to Placebo Higher in Major Depression than in Anxiety Disorders? A Systematic Review of Placebo-Controlled Trials

BACKGROUND: In a previous report, we hypothesized that responses to placebo were high in child and adolescent depression because of specific psychopathological factors associated with youth major depression. The purpose of this study was to compare the placebo response rates in pharmacological trials for major depressive disorder (MDD), obsessive compulsive disorder (OCD) and other anxiety disorders (AD-non-OCD). METHODOLOGY AND PRINCIPAL FINDINGS: We reviewed the literature relevant to the use of psychotropic medication in children and adolescents with internalized disorders, restricting our review to double-blind studies including a placebo arm. Placebo response rates were pooled and compared according to diagnosis (MDD vs. OCD vs. AD-non-OCD), age (adolescent vs. child), and date of publication. From 1972 to 2007, we found 23 trials that evaluated the efficacy of psychotropic medication (mainly non-tricyclic antidepressants) involving youth with MDD, 7 pertaining to youth with OCD, and 10 pertaining to youth with other anxiety disorders (N = 2533 patients in placebo arms). As hypothesized, the placebo response rate was significantly higher in studies on MDD, than in those examining OCD and AD-non-OCD (49.6% [range: 17-90%] vs. 31% [range: 4-41%] vs. 39.6% [range: 9-53], respectively, ANOVA F = 7.1, p = 0.002). Children showed a higher stable placebo response within all three diagnoses than adolescents, though this difference was not significant. Finally, no significant effects were found with respect to the year of publication. CONCLUSION: MDD in children and adolescents appears to be more responsive to placebo than other internalized conditions, which highlights differential psychopathology

Up-regulation of human inducible nitric oxide synthase by p300 transcriptional complex

p300, a ubiquitous transcription coactivator, plays an important role in gene activation. Our previous work demonstrated that human inducible nitric oxide synthase (hiNOS) expression can be highly induced with the cytokine mixture (CM) of TNF-α + IL-1β + IFN-γ. In this study, we investigated the functional role of p300 in the regulation of hiNOS gene expression. Our initial data showed that overexpression of p300 significantly increased the basal and cytokine-induced hiNOS promoter activities in A549 cells. Interestingly, p300 activated cytokine-induced hiNOS transcriptional activity was completely abrogated by deleting the upstream hiNOS enhancer at -5 kb to -6 kb in the promoter. Furthermore, p300 over-expression increased cytokine-induced transcriptional activity on a heterologous minimal TK promoter with the same hiNOS enhancer. Site-directed mutagenesis of the hiNOS AP-1 motifs revealed that an intact upstream (-5.3kb) AP-1 binding site was critical for p300 mediated cytokine-induced hiNOS transcription. Furthermore, our ChIP analysis demonstrated that p300 was binding to Jun D and Fra-2 proteins at -5.3 kb AP-1 binding site in vivo. Lastly, our 3C assay was able to detect a long DNA loop between the hiNOS enhancer and core promoter site, and ChIP loop assay confirmed that p300 binds to AP-1 and RNA pol II proteins. Overall, our results suggest that coactivator p300 mediates cytokine-induced hiNOS transactivation by forming a distant DNA loop between its enhancer and core promoter region

Uptake and depuration of gold nanoparticles in Daphnia magna

This study presents a series of short-term studies (total duration 48 h) of uptake and depuration of engineered nanoparticles (ENP) in neonate Daphnia magna. Gold nanoparticles (Au NP) were used to study the influence of size, stabilizing agent and feeding on uptake and depuration kinetics and animal body burdens. 10 and 30 nm Au NP with different stabilizing agents [citrate (CIT) and mercaptoundecanoic acid (MUDA)] were tested in concentrations around 0.5 mg Au/L. Fast initial uptake was observed for all studied Au NP, with CIT stabilized Au NP showing similar rates independent of size and MUDA showing increased uptake for the smaller Au NP (MUDA 10 nm > CIT 10 nm, 30 nm > MUDA 30 nm). However, upon transfer to clean media no clear trend on depuration rates was found in terms of stabilizing agent or size. Independent of stabilizing agent, 10 nm Au NP resulted in higher residual whole-animal body burdens after 24 h depuration than 30 nm Au NP with residual body burdens about one order of magnitude higher of animals exposed to 10 nm Au NP. The presence of food (P. subcapitata) did not significantly affect the body burden after 24 h of exposure, but depuration was increased. While food addition is not necessary to ensure D. magna survival in the presented short-term test design, the influence of food on uptake and depuration kinetics is essential to consider in long term studies of ENP where food addition is necessary. This study demonstrates the feasibility of a short-term test design to assess the uptake and depuration of ENP in D. magna. The findings underlines that the assumptions behind the traditional way of quantifying bioconcentration are not fulfilled when ENPs are studied.Peer reviewed: YesNRC publication: Ye

Expression of p21WAF1 in Astler–Coller stage B2 colorectal cancer is associated with survival benefit from 5FU-based adjuvant chemotherapy

In several, but not all, previous studies, positive p21WAF1 expression has been suggested as an indicator of a good prognosis in patients with stage III/IV colorectal cancer. However, it is not known whether the same is true for stage B2 patients. The purpose of this study is to assess the influence of p21WAF1 expression in tumor cells on disease-free survival (DFS) and overall survival (OS) of Astler–Coller stage B2 and C patients with colorectal cancer who underwent 5-fluorouracil-based adjuvant chemotherapy. Nuclear p21WAF1 was detected by immunohistochemistry in tissue microarrays from 275 colorectal cancers. The expression of p21WAF1 was associated with DFS (p = 0.025) and OS (p = 0.008) in the subgroup of stage B2 patients that was treated with adjuvant chemotherapy. In multivariate analysis, it remained the only independent prognostic parameter in relation to DFS and OS (p = 0.035 and p = 0.02, respectively). In the subgroup of 72 stage B2 patients with positive p21WAF1 expression but not in the subgroup of 61 stage B2 patients with negative p21WAF1 expression, adjuvant chemotherapy was associated with better DFS (85% 5-year survival versus 65% without chemotherapy, p = 0.03) and OS (96% versus 82%, p = 0.014). In the combined stage B2 and C group of patients treated with adjuvant chemotherapy, positive p21WAF1 expression was also associated with better DFS and OS (p = 0.03, p = 0.002, respectively). Expression of p21WAF1 in colorectal tumor cells identifies a subgroup of Astler–Coller stage B2 patients who could benefit significantly from 5FU-based chemotherapy and may improve the selection of patients for adjuvant chemotherapy

Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-Induced Suppression of Cytokine Production

BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT) is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT) in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT) and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-alpha production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin

Timed sequential chemotherapy with concomitant Granulocyte Colony-Stimulating Factor for high-risk acute myelogenous leukemia: a single arm clinical trial

BACKGROUND: The timed-sequential chemotherapy regimen consisting of etoposide, mitoxantrone and cytarabine (EMA) is an effective therapy for relapsed or refractory acute myelogenous leukemia (AML). We postulated that granulocyte colony-stimulating factor (G-CSF) might enhance the cytotoxicity of EMA by increasing the proportion of leukemic blasts in S-phase. We added G-CSF to EMA (EMA-G) for therapy of advanced high-risk AML patients. METHODS: High-risk AML was defined as refractory, relapsed or secondary to either an antecedent hematologic disorder or exposure to cytotoxic agents. The patients were treated with one course of EMA-G consisting of mitoxantrone and cytarabine on days 1–3, and etoposide and cytarabine on days 8–10. G-CSF was started on day 4 and continued until absolute neutrophil count recovered. RESULTS: Thirty patients were enrolled. The median age was 51 years (range, 25–75). Seventeen (61%) patients had unfavorable cytogenetic karyotypes. Twenty (69%) patients had secondary AML. Ten (34%) had relapsed disease. Four (14%) had refractory AML. Three (10%) patients died from febrile neutropenia and sepsis. Major non-hematologic toxicity included hyperbilirubimenia, renal insufficiency, mucositis, diarrhea, nausea and vomiting, skin rash. A complete remission was achieved in 13 (46%) patients. Median overall survival was 9 months (range, 0.5–66). Median relapse-free survival (RFS) for those who had a CR was 3 months (range, 0.5–63) with RFS censored at the time of allogeneic bone marrow transplantation or peripheral stem cell transplantation for 6 of the patients. CONCLUSIONS: EMA-G is a safe and efficacious option for induction chemotherapy in advanced, high-risk AML patients. The activity of EMA may be increased if applied in patients with less advanced disease

Acupuncture for attention deficit hyperactivity disorder (ADHD): study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Attention-deficit/hyperactivity disorder (ADHD) is a common neuro-psychiatric problem, affecting 7-9% of children. Pharmacological interventions are widely used with behavioral treatments in ADHD. Still, the origin of ADHD is unclear, limiting pharmacological effectiveness and making adverse effects common. The use of complementary and alternative medicine (CAM) has increased, especially for developmental and behavioral disorders, such as ADHD. CAM is used by 60-65% of parents of children with ADHD to relieve ADHD-associated symptoms and to avoid the side effects of conventional medication. Acupuncture has been widely used to treat patients with ADHD, but the available evidence of its effectiveness is insufficient. Our aim was to evaluate the effectiveness and safety of acupuncture in patients (both and each treatment naive and conventional therapy children) with ADHD (any subtype) compared to the waitlist control.</p> <p>Methods/Design</p> <p>This study is a waitlist controlled open trial. We used a computer generated randomization scheme. This randomised, controlled trial had two parallel arms (acupuncture, and waitlist group). Each arm consisted of 40 participants. The acupuncture group received acupuncture treatment two times per week for a total of 12 sessions over 6 weeks. Post-treatment follow-up was performed 3 weeks later to complement the 12 acupuncture sessions. Participants in the waitlist group did not receive acupuncture treatments during the first six weeks but were only required to be assessed. After 6 weeks, the same treatments given to the acupuncture group were provided to the waitlist group. The primary outcome of this trial included differences in Korean version of ADHD-Rating Scale (K-ADHD-RS) before randomization, 3 weeks and 6 weeks after randomization, and 3 weeks after completing the treatment.</p> <p>Discussion</p> <p>Subjective measurements, like K-ADHD-RS, are commonly used in ADHD. Although these measurements have adequate reliability and validity, lack of objective assessment in ADHD may lead to some disputes, like parental placebo effects. More objective measurements, like Computerized Neurocognitive function Test (CNT) in this study, are needed in ADHD trials. Furthermore, this trial will provide evidence for the effectiveness of acupuncture as a treatment for ADHD.</p> <p>Trial Registration</p> <p>Clinical Research Information Service (CRiS) KCT0000019</p

Professional Service Utilisation among Patients with Severe Mental Disorders

<p>Abstract</p> <p>Background</p> <p>Generally, patients with serious mental disorders (SMD) are frequent users of services who generate high care-related costs. Current reforms aim to increase service integration and primary care for improved patient care and health-care efficiency. This article identifies and compares variables associated with the use by patients with SMD of services offered by psychiatrists, case managers, and general practitioners (GPs). It also compares frequent and infrequent service use.</p> <p>Method</p> <p>One hundred forty patients with SMD from five regions in Quebec, Canada, were interviewed on their use of services in the previous year. Patients were also required to complete a questionnaire on needs-assessment. In addition, data were collected from clinical records. Descriptive, bivariate, and multivariate analyses were conducted.</p> <p>Results</p> <p>Most patients used services from psychiatrists and case managers, but no more than half consulted GPs. Most patients were followed at least by two professionals, chiefly psychiatrists and case managers. Care access, continuity of care, and total help received were the most important variables associated with the different types of professional consultation. These variables were also associated with frequent use of professional service, as compared with infrequent service use. In all, enabling factors rather than need factors were the core predictors of frequency of service utilisation by patients with SMD.</p> <p>Conclusion</p> <p>This study reveals that health care system organisation and professional practice - rather than patient need profiles - are the core predictors of professional consultation by patients with SMD. The homogeneity of our study population, i.e. mainly users with schizophrenia, recently discharged from hospital, may partly account for these results. Our findings also underscored the limited involvement of GPs in this patient population's care. As comorbidity is often associated with serious mental disorders, closer follow-up by GPs is needed. Globally, more effort should be directed at increasing shared-care initiatives, which would enhance coordination among psychiatrists, GPs, and psychosocial teams (including case managers). Finally, there is a need to increase awareness among health care providers, especially GPs, of the level of care required by patients with disabling and serious mental disorders.</p