Characteristics of the child behavior checklist in adolescents with depression associated with bipolar disorder.

BACKGROUND: The child behavior checklist-Juvenile bipolar disorder phenotype (CBCL-JBD) has been proposed as a distinct profile specific to children and adolescents who have been diagnosed with bipolar disorder. The objective of this study was to examine whether bipolar disorder youth with depression exhibit the "CBCL-Juvenile bipolar disorder phenotype." METHODS: Thirty-two adolescents, ages 12-18 years, with a depressive episode associated with bipolar I disorder were recruited, and their primary caregivers completed the CBCL. RESULTS: Only the internalizing subscale (mean=70.2, SD=9.7) and total score (mean=71.5, SD=8.9) reached clinical significance (>70). Moreover, the CBCL-JBD profile scores of our subjects (204.6, SD=27.5) did not reach clinical significance (>210). LIMITATIONS: Our subjects differed demographically from those in studies that have confirmed the CBCL-Juvenile bipolar disorder phenotype with regards to sex, age and ADHD comorbidity, thus limiting the interpretability of our comparisons with other studies. Furthermore, our investigation involved a small sample size and did not include a control group, which should be addressed in future studies. CONCLUSIONS: The results of our study suggest that the CBCL-JBD profile is not characteristic of depressed youth with bipolar disorder. Better assessment tools for making an accurate and efficient diagnosis of bipolar disorder are needed so that appropriate treatment can be implemented and significant morbidity and mortality are minimized.

Mutations associated with occult hepatitis B virus infection result in decreased surface antigen expression in vitro.

Occult hepatitis B virus (HBV) infection is characterized by the absence of detectable hepatitis B surface antigen (HBsAg) in the serum, despite detectable HBV DNA. Investigations of the mechanisms underlying the development of occult HBV infection are lacking in the current literature, although viral mutations in the surface region, resulting in decreased HBsAg expression or secretion, represent one potential mechanism. Wild-type HBsAg expression vectors were constructed from genotype-matched chronic HBV sequences. Site-directed mutagenesis was then utilized to introduce three genotype A mutations - M103I, K122R and G145A - associated with occult HBV infection in vivo, alone and in combination, into the wild-type HBsAg vectors. Transfection of Huh7 and HepG2 cell lines was performed, and cell culture supernatants and cell lysates were collected over 7 days to assess the effects of these mutations on extracellular and intracellular HBsAg levels. The G145A mutation resulted in significantly decreased extracellular and intracellular HBsAg expression in vitro. The most pronounced reduction in HBsAg expression was observed when all three mutations were present. The mutations evaluated in vitro in the current study resulted in decreased HBsAg expression and potentially increased hepatic retention and/or decreased hepatic secretion of synthesized HBsAg, which could explain the lack of HBsAg detection that is characteristic of occult HBV infection in vivo.

Measurement of GSTP1 promoter methylation in body fluids may complement PSA screening: a meta-analysis.

BACKGROUND: Prostate-specific antigen (PSA) screening has low specificity. Assessment of methylation status in body fluids may complement PSA screening if the test has high specificity. METHOD: The purpose of this study was to conduct a meta-analysis of the sensitivity and specificity for prostate cancer detection of glutathione-s-transferase-π (GSTP1) methylation in body fluids (plasma, serum, whole blood, urine, ejaculate, and prostatic secretions). We conducted a comprehensive literature search on Medline (Pubmed). We included studies if they met all four of the following criteria: (1) measurement of DNA methylation in body fluids; (2) a case-control or case-only design; (3) publication in an English journal; and (4) adult subjects. Reviewers conducted data extraction independently using a standardised protocol. Twenty-two studies were finally included in this paper. Primer sequences and methylation method in each study were summarised and evaluated using meta-analyses. This paper represents a unique cross-disciplinary approach to molecular epidemiology. RESULTS: The pooled specificity of GSTP1 promoter methylation measured in plasma, serum, and urine samples from negative-biopsy controls was 0.89 (95% CI, 0.80-0.95). Stratified analyses consistently showed a high specificity across different sample types and methylation methods (include both primer sequences and location). The pooled sensitivity was 0.52 (95% CI, 0.40-0.64). CONCLUSIONS: The pooled specificity of GSTP1 promoter methylation measures in plasma, serum, and urine was excellent and much higher than the specificity of PSA. The sensitivity of GSTP1 was modest, no higher than that of PSA. These results suggest that measurement of GSTP1 promoter methylation in plasma, serum, or urine samples may complement PSA screening for prostate cancer diagnosis.

Genomic variability associated with the presence of occult hepatitis B virus in HIV co-infected individuals.

Occult hepatitis B virus (O-HBV) infection is characterized by the presence of HBV DNA without detectable hepatitis B surface antigen (HBV DNA+/HBsAg-) in the serum. Although O-HBV is more prevalent during HBV/HIV co-infection, analysis of HBV mutations in co-infected patients is limited. In this preliminary study, HBV PreSurface (PreS) and surface (S) regions were amplified from 33 HIV-positive patient serum samples - 27 chronic HBV (C-HBV) and six O-HBV infections. HBV genotype was determined by phylogenetic analysis, while quasispecies diversity was quantified for the PreS, S and overlapping polymerase regions. C-HBV infections harboured genotypes A, D and G, compared to A, E, G and one mixed A/G infection for O-HBV. Interestingly, nonsynonymous-synonymous mutation values indicated positive immune selection in three regions for O-HBV vs one for C-HBV. Sequence analysis further identified new O-HBV mutations, in addition to several previously reported mutations within the HBsAg antigenic determinant. Several of these O-HBV mutations likely contribute to the lack of detectable HBsAg in O-HBV infection by interfering with detection in serologic assays, altering antigen secretion and/or decreasing replicative fitness.

Response rates to pegylated interferon and ribavirin in HCV/HIV coinfection: a research synthesis.

Several recent trials have determined varying rates of response to pegylated interferon plus ribavirin (peg-IFN + RIB) in hepatitis C virus (HCV)/human immunodeficiency virus-coinfected patients. We sought to identify a pooled response rate and sources of interstudy variability. A literature search was conducted to identify randomized or prospective studies evaluating response rates to peg-IFN + RIB in coinfected patients. A Bayesian hierarchical model was used to estimate overall response rate. Between-study variance was calculated and sensitivity analyses were conducted. Meta-regression was employed to identify sources of between-study variability. The literature search yielded seven studies of 146, which matched keywords and inclusion criteria. The combined patient total was 784. Individual intention-to-treat response rates ranged from 27.3% to 44.2%. The pooled Bayesian estimate of percent response was 33.3%. Significant interstudy heterogeneity was detected. Meta-regression yielded no significant effects of covariates on response rate. Subanalyses by CD4+, HCV viral load and genotype yielded sustained virological response (SVR) odds ratios of 0.73 for low CD4+, 0.41 for high viral load and 0.30 for genotype 1/4. The pooled response rate is not attributable to any one study. Response is poor compared with HCV-monoinfected patients. Interstudy variability is not satisfactorily explained by factors influencing individual response, but may be due to differences between studies unavailable for inclusion in this analysis. However, both genotype 1/4 and high HCV viral load at baseline were significantly associated with a reduction in odds of SVR in pooled subanalysis. Improved treatments are needed in coinfected patients, especially with genotype 1/4 and high viral load.

Steroids for improving recovery following tonsillectomy in children.

BACKGROUND: Tonsillectomy continues to be one of the most common surgical procedures performed worldwide. Despite advances in anesthetic and surgical techniques, post-tonsillectomy morbidity remains a significant clinical problem. OBJECTIVES: To assess the clinical efficacy of a single intra-operative dose of dexamethasone in reducing post-tonsillectomy morbidity. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Issue 1, 2002), MEDLINE (from 1966 - February 2002), EMBASE (from 1974 - February 2002) and reference lists of relevant articles. We contacted leading experts for information on any relevant unpublished data. SELECTION CRITERIA: Randomized, double-blind, placebo-controlled trials of a single dose of intravenous, intra-operative corticosteroid for pediatric patients (age < 18 years) who underwent tonsillectomy or adenotonsillectomy were included. DATA COLLECTION AND ANALYSIS: Data regarding the primary outcome measures and measurement tools were extracted by the first author from the published studies. Data regarding study design, patient ages, procedures performed, dose of corticosteroid and method of delivery, as well as methodologic quality were also recorded by the first author. When data were missing from the original publications, the authors were contacted for more information. Data analysis was performed with a random effects model, using the RevMan 4.1 software developed by the Cochrane Collaboration. MAIN RESULTS: Children receiving a single intra-operative dose of dexamethasone (dose range = 0.15 to 1.0 mg/kg; maximum dose range = 8 to 25 mg) were two times less likely to vomit in the first 24 hours than children receiving placebo (RR = 0.54, CI95 = 0.42, 0.69; p < 0.00001). Routine use in four children would be expected to result in one less patient experiencing post-tonsillectomy emesis (RD = -0.25, CI95 = -0.37, -0.13; p = 0.00004). Additionally, children receiving dexamethasone were more likely to advance to a soft/solid diet on post-tonsillectomy day 1 (RR = 1.69, CI95 = 1.02, 2.79; p = 0.04) than those receiving placebo. Due to missing data and varied outcome measurement tools, pain could not be meaningfully analyzed as a distinct outcome measure. REVIEWER'S CONCLUSIONS: The evidence suggests that a single intravenous dose of dexamethasone is an effective, relatively safe and inexpensive treatment for reducing morbidity from pediatric tonsillectomy. No adverse events attributable to dexamethasone were reported in these trials. Additionally, in our 10-year experience of routine use of a single intravenous dose of dexamethasone during pediatric tonsillectomy, there have been no attributable, adverse events. Lastly, we found no reports in the literature of complications from use of a single intravenous dose of corticosteroid during pediatric tonsillectomy.

Vagus nerve stimulation for partial seizures.

BACKGROUND: Vagus nerve stimulation (VNS) has recently been introduced as an adjunct for treating patients with seizures. The aim of this systematic review was to overview the current evidence for the effects of vagus nerve stimulation, when used as an adjunctive treatment for patients with drug-resistant partial epilepsy. OBJECTIVES: To determine the effects of VNS high-level stimulation compared to low-level (presumed subtherapeutic dose) stimulation. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register, MEDLINE (January 1966 to October 2000) and The Cochrane Controlled Trials Register (Cochrane Library Issue 4, 2000). SELECTION CRITERIA: Randomized, double-blind controlled trials of VNS comparing high and low stimulation paradigms. Studies in adults or children with drug-resistant partial seizures. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. The following outcomes were assessed: (a) 50% or greater reduction in total seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. Primary analyses were intention to treat. Sensitivity best and worst case analyses were also undertaken. Summary odds ratios (ORs) were estimated for each outcome. MAIN RESULTS: Results of the overall efficacy analysis show that VNS stimulation using the high stimulation paradigm was significantly better than low stimulation. The overall OR (95% Confidence Interval (CI)) for 50% responders across all studies is 1.93 (1.1,3.3). This effect did not vary substantially and remained statistically significant for both the best and worst case scenarios. Results for the outcome "withdrawal of allocated treatment" suggest that VNS is well tolerated as no significant difference was found between the high and low stimulation groups, and withdrawals were rare. Statistically significant adverse effects associated with implantation (low versus baseline) were hoarseness, cough, pain and paresthesia. Statistically significant adverse effects associated with stimulation (high versus low) were hoarseness and dyspnea, suggesting the implantation is associated with hoarseness, but the stimulation produces additional hoarseness. REVIEWER'S CONCLUSIONS: VNS for partial seizures appears to be an effective and well tolerated treatment. Adverse effects of hoarseness, cough, pain, paresthesias and dyspnea are associated with the treatment but appear to be reasonably well tolerated as dropouts were rare. Typical central nervous system adverse effects of antiepileptic drugs such as ataxia, dizziness, fatigue, nausea and somnolence were not statistically significantly associated with VNS treatment.

Circulating human corticotropin-releasing factor-binding protein levels following cortisol infusions.

Corticotropin-releasing factor-binding protein (CRF-BP) is a 37 kDa protein present in the brain and plasma and is known to regulate the actions of CRF. It has been demonstrated that CRF-BP in the brain and the pituitary appears to be positively regulated by glucocorticoids. In this study, the effect of various doses of hydrocortisone infusions on plasma CRF-BP levels was assessed. Four groups of 10 age-matched males received a 100 min infusion of either placebo (saline), 40 microg/kg/h, 300 microg/kg/h or 600 microg/kg/h hydrocortisone. CRF-BP levels were measured via a LIRMA. In addition, levels of plasma ACTH and cortisol were measured by standard radioimmunoassay. As expected, plasma cortisol levels increased and plasma ACTH levels were suppressed following the infusion. When expressed as proportion of pre-infusion baseine, no significant changes in plasma CRF-BP levels were observed following the infusion for all hydrocortisone groups relative to the control group. However, a significant time-averaged positive correlation was found between CRF-BP and cortisol levels at low to moderate, but not high, cortisol levels. The data obtained in this study indicate that CRF binding protein levels within the time course examined may slightly appear to be affected in the peripheral circulation in response to pronounced, sustained hypercortisolemia.

A placebo-controlled, crossover trial of granisetron in SRI-induced sexual dysfunction.

BACKGROUND: Sexual side effects are commonly associated with serotonin reuptake inhibitor (SRI) therapy. The mechanism underlying SRI-induced sexual dysfunction has been hypothesized to be mediated by direct serotonergic effects. Evidence from open-label reports suggests that cyproheptadine, nefazodone, mirtazapine, and mianserin, which block one or more serotonin receptors, may reverse sexual side effects. The current study was a prospective, randomized, crossover trial comparing granisetron, a serotonin-3 antagonist, with placebo in outpatients who developed sexual dysfunction during SRI treatment. METHOD: Thirty-one outpatients who were currently experiencing sexual dysfunction associated with SRIs were randomly assigned to double-blind treatment with granisetron (1-1.5 mg) or placebo for use 1 to 2 hours prior to sexual activity. Patients rated sexual symptoms after each trial using the Sexual Side Effect Scale (SSES). After 4 trials of the medication, patients crossed over to the other treatment for 4 more trials. RESULTS: Twenty patients received at least 1 dose of placebo and granisetron. Analysis by repeated-measures analysis of variance showed no significant effects of granisetron relative to placebo. Significant improvement between baseline and treatment-phase SSES scores was observed for both granisetron (p = .0004) and placebo (p = .0081). The study medication was generally well tolerated. CONCLUSION: The results of this study do not support the efficacy of granisetron (1-2 mg) in the treatment of SRI-associated sexual side effects. A significant placebo response may be associated with the treatment of SRI-induced sexual dysfunction.

Divalproex sodium in sex offenders with bipolar disorders and comorbid paraphilias: an open retrospective study.

BACKGROUND: This study evaluated divalproex response in sex offenders with a bipolar disorder. METHODS: We reviewed the records of all sex offenders who participated in a residential rehabilitative program who received divalproex for treatment of a bipolar disorder. Patients' mood symptoms and, when present, comorbid paraphilic symptoms, were retrospectively assessed using the CGI severity scale. RESULTS: Sex offenders displayed significant improvement in manic symptoms with divalproex treatment. However, there was no significant improvement in paraphilic symptoms in the subset of patients admitting to these symptoms. CONCLUSION: Divalproex may be effective for manic symptoms in sex offenders with a bipolar disorder. However, for bipolar sex offenders with comorbid paraphilias, the drug may not be effective for paraphilic symptoms. LIMITATIONS: This study was limited by its retrospective, open-label design, lack of systematic means of assessing manic and paraphilic symptoms, and small sample size. CLINICAL RELEVANCE: Divalproex may be a helpful adjunct in the treatment of the subset of sex offenders who have a bipolar disorder.

Do steroids reduce morbidity of tonsillectomy? Meta-analysis of randomized trials.

OBJECTIVES/HYPOTHESIS: The study aims to reconcile conflicting published reports regarding the clinical efficacy of a single intraoperative dose of dexamethasone in reducing post-tonsillectomy morbidity. STUDY DESIGN: Systematic overview (meta-analysis). METHODS: To critically evaluate the existing evidence, we performed a formal meta-analysis of eight double-blinded, randomized, placebo-controlled studies of dexamethasone in pediatric patients undergoing tonsillectomy or adenotonsillectomy. Reduction in postoperative emesis and pain, as well as early return to soft or solid diet, were studied as distinct end points. RESULTS: Children being given a single intraoperative dose of dexamethasone (dosing, 0.15-1.0 mg/kg; maximum dose, 8-25 mg) were two times less likely to vomit in the first 24 hours than children being given placebo (relative risk [RR] = 0.55; 95% confidence interval [CI], 0.41-0.74; P < .0001). Routine use in four children would be expected to result in one less patient having post-tonsillectomy emesis (risk difference [RD] = -0.24; 95% CI, -0.38 to -0.10; P = .0006). In addition, children being given dexamethasone were more likely to advance to a soft or solid diet on post-tonsillectomy day 1 (RR = 1.69; 95% CI, 1.02-2.79; P = .04) than those being given placebo. Because of missing data and varied outcome measures, pain could not be meaningfully analyzed as a distinct end point. CONCLUSION: Given the frequency of tonsillectomy, relative safety and low cost of dexamethasone, and the reduction in postoperative morbidity, we recommend routine use of a single intravenous dose during pediatric tonsillectomy.

An open trial of olanzapine in the treatment of patients with psychotic depression.

Compared to major depression without psychosis, psychotic depression often responds poorly to treatment with tricyclic antidepressants alone. Atypical antipsychotics, which appear to possess thymoleptic properties, may represent a new treatment alternative for patients with psychotic mood disorders. This open-label, pilot study evaluated the efficacy of olanzapine monotherapy in patients with psychotic depression. Seven inpatients who met DSM-IV criteria for a major depressive episode (unipolar) with psychotic features participated in a 10-week open-label trial of olanzapine 10-20 mg/day. The Hamilton Rating Scale for Depression (HRSD), the Scale for the Assessment of Positive Symptoms (SAPS), and the Clinical Global Impression Scale (CGI) were performed at each visit to evaluate clinical response. Four out of the 5 study completers responded during the trial. Overall, there was a statistically significant change between baseline and final visit on the SAPS, HRSD, and the CGI Scale (p < .001). The results of this pilot study suggest that olanzapine may be an effective treatment for some patients with unipolar psychotic depression. However, these observations require replication in randomized, controlled trials.

Age-related alterations in emotional behaviors and amygdalar corticotropin-releasing factor (CRF) and CRF-binding protein expression in aged Fischer 344 rats.

Corticotropin-releasing factor (CRF) coordinates the mammalian response to stress. In the amygdala, the CRF system appears to be responsible, at least in part, for the behavioral responses resulting from stress. Associated with amygdalar CRF is a 37 kDa binding protein (CRF-BP) which may also play a role in regulating stressful stimuli. Aging has been shown to be associated with abnormal neuroendocrine stress systems and little is known with regards to how amygdalar stress systems change with aging. In our study, we have assessed levels of amygdalar CRF and CRF-BP mRNA in Fischer 344 rats of 4, 12 or 24 months of age following 14 days of hourly restraint. Prior to sacrifice, rats were also tested for anxiety-like behaviors on the elevated plus maze. After behavioral testing, rats were perfused with 4% paraformaldehyde and the brains were processed for in situ hybridization. Twenty micron sections were hybridized with a CRF as well as a CRF-BP riboprobe. Following hybridization, tissue sections were oppossed to X-ray film and relative amounts of mRNA in the amygdala were quantitated. Levels of CRF mRNA in the amygdala of 12 and 24 month-old rats following chronic restraint were significantly lower relative to rats which were handled for 14 days. There were no significant differences in amygdalar CRF gene expression between stressed and handled 4 month-old rats. At 12 and 24 months of age but not 4 months, there were also significant effects of restraint associated with decreases in amygdalar CRF-BP gene expression. Furthermore, there were reciprocal decreases in anxiety-like behaviors in the 12 and 24 month-old rats which were significant; the changes in anxiety-like behaviors between restrained vs. handled 4 month-old rats were not significantly different. The decreased gene expression of CRF in the amygdala in concert with decreased anxiety-like behaviors following restraint is consistent with the known behavioral effects of exogenously applied intra-amygdalar CRF. The changes in amygdalar CRF-BP observed may be secondary to the known regulatory effects that CRF exhibits on its binding-protein. These studies have relevance to better understanding the molecular basis of aging related changes in neuroendocrine stress systems.

The dopamine D3 receptor antagonist nafadotride inhibits development of locomotor sensitization to amphetamine.

Behavioral sensitization is a well-studied model of behavioral plasticity mediated at least in part by dopaminergic systems believed to play an important role in several psychiatric conditions. In the rodent, locomotion is regulated by the opposing balance of D3 and D2 receptors, with D2 activation increasing and D3 stimulation inhibiting locomotion. However, receptor occupancy of D3 dopamine receptors is far greater than D2 or D1 occupancy at typical post-stimulant dopamine concentrations. We therefore hypothesized that tolerance of D3 receptor inhibition of locomotion contributes to the development of sensitization. To test this hypothesis, we examined the effect of the D3 receptor antagonist nafadotride on sensitization. As predicted, nafadotride inhibits augmentation of the locomotion response to repetitive amphetamine. This finding is consistent with the proposed model of adaptive down-regulation of D3 dopamine receptor function contributing to the development of behavioral sensitization.

Placebo effect in randomized, controlled studies of acute bipolar mania and depression.

Randomized, double-blind, placebo-controlled, parallel group clinical trials have been the standard methodology for establishing the efficacy of new treatments for patients with bipolar disorder in manic, mixed, or depressive episodes. We examine the placebo response rate in acute treatment trials of acute mania (and mixed states) and bipolar depression. Also addressed are potential variables associated with placebo response, strategies to minimize placebo response, the optimum duration of placebo-controlled acute treatment trials, possible alternatives to the use of placebo, and the ramifications of these issues with regard to the design of studies in children, adolescents, and older adults with bipolar disorder.

Placebo effect in randomized, controlled maintenance studies of patients with bipolar disorder.

The prevention of mood episodes is an important goal of the maintenance treatment of patients with bipolar disorder. The rate of relapse on placebo compared with that on active treatment is an important issue in the design of future clinical trials of maintenance treatment. We examine the range and time course of placebo relapse rates in studies of patients with bipolar I disorder. In addition, we address the potential variables associated with placebo response, strategies to minimize placebo response, the optimum duration of placebo-controlled maintenance trials, possible alternatives to placebo control groups, and the impact of these considerations in maintenance studies of children, adolescents, and older adults with bipolar disorder.

Antidepressant treatment of fibromyalgia. A meta-analysis and review.

Fibromyalgia is a common musculoskeletal pain disorder associated with mood disorders. Antidepressants, particularly tricyclics, are commonly recommended treatments. Randomized, controlled trials of antidepressants for treatment of fibromyalgia were reviewed by methodology, results, and potential predictors of response. Twenty-one controlled trials, 16 involving tricyclic agents, were identified; 9 of these 16 studies were suitable for meta-analysis. Effect sizes were calculated for measurements of physician and patient overall assessment, pain, stiffness, tenderness, fatigue, and sleep quality. Compared with placebo, tricyclic agents were associated with effect sizes that were substantially larger than zero for all measurements. The largest improvement was associated with measures of sleep quality; the most modest improvement was found in measures of stiffness and tenderness. Further studies are needed utilizing randomized, double-blind, placebo-controlled, parallel designs with antidepressants administered at therapeutic dose ranges, using standardized criteria for fibromyalgia and systematically assessed for co-occurring psychiatric illness.