Peer victimization through a trauma lens: Identifying who is at risk for negative outcomes.

Peer victimization is a chronic stressor that occurs within the context of peer interactions and has been robustly associated with numerous negative psychological and social adjustment problems. Although increased frequency of peer victimization has been linked to psychosocial problems, few researchers have studied the role of duration and pervasiveness of victimization (i.e., number of places it occurs). The objective of this study was to examine how frequency, duration, and pervasiveness of peer victimization are associated with youth adjustment. Canadian adolescents (N = 879), ages 12-18 completed an online survey about experiences with peer victimization. Youth also answered questions about internalizing problems, distress, relationship quality with family, friends, and adults in their school and community, as well as academic functioning. Data were analyzed using multinomial logistic regression modeling. Both duration and pervasiveness of peer victimization were predictive of increased internalizing problems, distress, relationship problems, and academic difficulties. Duration and pervasiveness of peer victimization were identified as important factors to consider when predicting youth psychosocial adjustment. By asking questions about these situational factors, parents, teachers, and healthcare providers may more effectively identify youth who are at risk for experiencing mental health problems associated with peer victimization.

Mutagen Synergy: Hypermutability Generated by Specific Pairs of Base Analogs.

UNLABELLED: We tested pairwise combinations of classical base analog mutagens in Escherichia coli to study possible mutagen synergies. We examined the cytidine analogs zebularine (ZEB) and 5-azacytidine (5AZ), the adenine analog 2-aminopurine (2AP), and the uridine/thymidine analog 5-bromodeoxyuridine (5BrdU). We detected a striking synergy with the 2AP plus ZEB combination, resulting in hypermutability, a 35-fold increase in mutation frequency (to 53,000 × 10(-8)) in the rpoB gene over that with either mutagen alone. A weak synergy was also detected with 2AP plus 5AZ and with 5BrdU plus ZEB. The pairing of 2AP and 5BrdU resulted in suppression, lowering the mutation frequency of 5BrdU alone by 6.5-fold. Sequencing the mutations from the 2AP plus ZEB combination showed the predominance of two new hot spots for A·T→G·C transitions that are not well represented in either single mutagen spectrum, and one of which is not found even in the spectrum of a mismatch repair-deficient strain. The strong synergy between 2AP and ZEB could be explained by changes in the dinucleoside triphosphate (dNTP) pools. IMPORTANCE: Although mutagens have been widely studied, the mutagenic effects of combinations of mutagens have not been fully researched. Here, we show that certain pairwise combinations of base analog mutagens display synergy or suppression. In particular, the combination of 2-aminopurine and zebularine, analogs of adenine and cytidine, respectively, shows a 35-fold increased mutation frequency compared with that of either mutagen alone. Understanding the mechanism of synergy can lead to increased understanding of mutagenic processes. As combinations of base analogs are used in certain chemotherapy regimens, including those involving ZEB and 5AZ, these results indicate that testing the mutagenicity of all drug combinations is prudent.

Bone morphogenetic protein 7 sensitizes O6-methylguanine methyltransferase expressing-glioblastoma stem cells to clinically relevant dose of temozolomide.

BACKGROUND: Temozolomide (TMZ) is an oral DNA-alkylating agent used for treating patients with glioblastoma. However, therapeutic benefits of TMZ can be compromised by the expression of O6-methylguanine methyltransferase (MGMT) in tumor tissue. Here we used MGMT-expressing glioblastoma stem cells (GSC) lines as a model for investigating the molecular mechanism underlying TMZ resistance, while aiming to explore a new treatment strategy designed to possibly overcome resistance to the clinically relevant dose of TMZ (35 µM). METHODS: MGMT-expressing GSC cultures are resistant to TMZ, and IC50 (half maximal inhibitory concentration) is estimated at around 500 µM. Clonogenic GSC surviving 500 µM TMZ (GSC-500 µM TMZ), were isolated. Molecular signatures were identified via comparative analysis of expression microarray against parental GSC (GSC-parental). The recombinant protein of top downregulated signature was used as a single agent or in combination with TMZ, for evaluating therapeutic effects of treatment of GSC. RESULTS: The molecular signatures characterized an activation of protective stress responses in GSC-500 µM TMZ, mainly including biotransformation/detoxification of xenobiotics, blocked endoplasmic reticulum stress-mediated apoptosis, epithelial-to-mesenchymal transition (EMT), and inhibited growth/differentiation. Bone morphogenetic protein 7 (BMP7) was identified as the top down-regulated gene in GSC-500 µM TMZ. Although augmenting BMP7 signaling in GSC by exogenous BMP7 treatment did not effectively stop GSC growth, it markedly sensitized both GSC-500 µM TMZ and GSC-parental to 35 µM TMZ treatment, leading to loss of self-renewal and migration capacity. BMP7 treatment induced senescence of GSC cultures and suppressed mRNA expression of CD133, MGMT, and ATP-binding cassette drug efflux transporters (ABCB1, ABCG2), as well as reconfigured transcriptional profiles in GSC by downregulating genes associated with EMT/migration/invasion, stemness, inflammation/immune response, and cell proliferation/tumorigenesis. BMP7 treatment significantly prolonged survival time of animals intracranially inoculated with GSC when compared to those untreated or treated with TMZ alone (p = 0.0017), whereas combination of two agents further extended animal survival compared to BMP7 alone (p = 0.0489). CONCLUSIONS: These data support the view that reduced endogenous BMP7 expression/signaling in GSC may contribute to maintained stemness, EMT, and chemoresistant phenotype, suggesting that BMP7 treatment may provide a novel strategy in combination with TMZ for an effective treatment of glioblastoma exhibiting unmethylated MGMT.

Evolution of Staphylococcus aureus under vancomycin selective pressure: the role of the small-colony variant phenotype.

Staphylococcus aureus small-colony variants (SCVs) often persist despite antibiotic therapy. Against a 10(8)-CFU/ml methicillin-resistant S. aureus (MRSA) (strain COL) population of which 0%, 1%, 10%, 50%, or 100% was an isogenic hemB knockout (Ia48) subpopulation displaying the SCV phenotype, vancomycin achieved maximal reductions of 4.99, 5.39, 4.50, 3.28, and 1.66 log10 CFU/ml over 48 h. Vancomycin at ≥16 mg/liter shifted a population from 50% SCV cells at 0 h to 100% SCV cells at 48 h, which was well characterized by a Hill-type model (R2>0.90).

Macitentan for the treatment of pulmonary arterial hypertension.

OBJECTIVE: To review the pharmacology, safety, and efficacy of macitentan. DATA SOURCES: PubMed, EMBASE, and ClinicalTrials.gov were searched using the terms macitentan and ACT-064992. STUDY SELECTION AND DATA EXTRACTION: Phase II and III trials were reviewed in our primary analysis; data from phase I trials and other studies were reported as applicable. DATA SYNTHESIS: Macitentan is a dual endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH). Current treatment options for PAH include 2 other ERAs, phosphodiesterase type 5 inhibitors, prostanoids, and calcium channel blockers. Recently published guidelines do not assert a preference for individual agents. Two trials evaluated the safety and efficacy of macitentan. The phase II study was a 12-month placebo-controlled trial involving patients with idiopathic pulmonary fibrosis; the primary end point was change in forced vital capacity. No significant treatment effect was observed. The phase III study was a placebo-controlled trial involving patients with PAH. The primary end point was time to first occurrence of a composite of outcomes, including all-cause death and PAH worsening. Over a median period of 115 weeks, macitentan 10 mg and 3 mg daily significantly reduced morbidity and mortality. Commonly reported adverse effects included worsening of PAH, peripheral edema, upper-respiratory-tract infection, and anemia. CONCLUSIONS: Macitentan represents the latest addition to the PAH armamentarium. Compared with other ERAs, clinical advantages may include fewer contraindications, use in hepatic impairment, and once-daily administration. However, further comparative studies are necessary to ascertain its place in therapy.

Safety of low doses of quetiapine when used for insomnia.

OBJECTIVE: To evaluate the safety of low doses of quetiapine when used for insomnia. DATA SOURCES: A literature search was performed using PubMed and EMBASE (January 1990-November 2011) using the terms quetiapine, insomnia, sleep, low-dose, subtherapeutic, safety, and weight gain. STUDY SELECTION AND DATA EXTRACTION: Two prospective trials were identified that evaluated the effect of quetiapine in primary insomnia. In addition, 2 retrospective cohort studies were identified that evaluated the safety of low doses of quetiapine when used for insomnia. Several case reports on adverse effects with low doses of the drug were also included. DATA SYNTHESIS: Quetiapine is commonly used off-label for treatment of insomnia. When used for sleep, doses typically seen are less than the Food and Drug Administration-recommended dosage of 150-800 mg/day; those evaluated in the studies reviewed here were 25-200 mg/day). At recommended doses, atypical antipsychotics such as quetiapine are associated with metabolic adverse events (diabetes, obesity, hyperlipidemia). Adverse effects in the prospective trials were patient-reported and were minor, including drowsiness and dry mouth; however, the trials were limited by their small sample size and short duration. The retrospective cohort studies found that quetiapine was associated with significant increases in weight compared to baseline. Serious adverse events identified from case reports included fatal hepatotoxicity, restless legs syndrome, akathisia, and weight gain. CONCLUSIONS: There are potential safety concerns when using low-dose quetiapine for treatment of insomnia. These concerns should be evaluated in further prospective studies. Based on limited data and potential safety concerns, use of low-dose quetiapine for insomnia is not recommended.

Anticholinergic use in children and adolescents after initiation of antipsychotic therapy.

BACKGROUND: Second-generation antipsychotics (SGAs) are thought to have a lower likelihood of inducing extrapyramidal symptoms (EPS) than are first-generation antipsychotics (FGAs). Clinical observations suggest that younger patients may be more sensitive to SGA-associated EPS than are adults and require therapy with anticholinergic agents. OBJECTIVE: To determine the proportion of patients 5-18 years of age who received anticholinergic therapy during the initial stages of antipsychotic treatment, as well as to compare anticholinergic utilization across patients receiving aripiprazole, risperidone, and quetiapine, SGAs previously identified as the most commonly prescribed at the academic institution studied. METHODS: Patients 5-18 years of age who were initiating a course of an antipsychotic between January 1, 2005, and September 1, 2008, were identified in a retrospective review of prescription and medical records. Data on demographic characteristics, antipsychotic and anticholinergic utilization, indications, diagnoses, and concomitant medications were collected from the medical record. Only the first therapeutic course of an antipsychotic identified was analyzed. Anticholinergic utilization at antipsychotic initiation and after 30 days was assessed. RESULTS: A total of 235 antipsychotic treatment courses were identified. Of these, 152 patients met our inclusion criteria. Anticholinergic utilization at any time during the first 30 days of treatment was identified in 32 patients (21%), while EPS was documented for 12 patients (8%). FGA or polypharmacy (simultaneous use of >or=2 scheduled antipsychotic) use versus SGA use (OR 18.98; 95% CI 4.74 to 75.95) was the primary characteristic significantly associated with anticholinergic utilization within 30 days after initiation. Of the most commonly used SGAs, risperidone was the drug with which anticholinergics were most frequently prescribed (p = 0.03). CONCLUSIONS: Anticholinergic prescribing exceeded the incidence of EPS, as documented in the medical record (21% vs 8%), and differed across individual medications and antipsychotic class. Utilization of FGAs or polypharmacy was a key predictor of anticholinergic use.

An examination of the moderating effects of neurophysiology on treatment outcomes from cognitive training in schizophrenia-spectrum disorders.

BACKGROUND: Impairments in neurocognition and community functioning are core features of schizophrenia and cognitive training techniques have been developed with the aim of improving these impairments. While cognitive training has produced reliable improvements in neurocognition and functioning, little is known about factors that moderate treatment response. Electroencephalographic (EEG) measures provide a neurophysiological indicator of cognitive functions that may moderate treatment outcomes from cognitive training. METHODS: Data from a clinical trial comparing two cognitive training approaches in schizophrenia-spectrum disorders were utilized in the current report. Cluster analysis was conducted to identify participant clusters based on baseline P300, mismatch negativity (MMN), and theta power during an n-back task, and the EEG measures were also examined as continuous predictors of treatment response. RESULTS: Three clusters were identified based on the baseline EEG variables; however, there were no significant differences in treatment response across the three clusters. Higher P300 amplitude and theta power during the n-back at baseline were significantly associated with greater improvements in a cognitive composite score post-treatment. None of the EEG measures were significantly associated with treatment outcomes in specific cognitive domains or community functioning. Change in EEG measures from baseline to post-treatment was not significantly associated with durability of cognitive or functional change at 12-week follow-up. CONCLUSIONS: Clusters derived from the EEG measures were not significantly associated with either neurocognitive or functional outcomes. P300 and n-back theta power may be associated with learning-related processes, which are important for acquisition and retention of skills during cognitive training programs. Future research should aim to identify at an individual level who is likely to respond to specific forms of cognitive enhancement.

Electronic media use and addiction among youth in psychiatric clinic versus school populations.

OBJECTIVE: Electronic media use is highly prevalent among today's youth, and its overuse in the general population has been consistently associated with the presence of psychiatric symptoms. In contrast, little information exists about electronic media use among youth with psychiatric disorders. Our study aims to compare patterns of television and computer and gaming station use among youth in psychiatric clinic and community-based school populations. METHOD: Surveys were completed by 210 youth and parents, from school (n = 110) and psychiatric clinic (n = 100) populations. Duration and frequency of television, video gaming, and nongaming computer activities were ascertained, along with addictive features of use. Descriptive and comparative analyses were conducted, with a statistical threshold of P < 0.05. RESULTS: Quantitative and qualitative differences were identified between the patterns of use reported by the 2 groups. The mean reported daily duration of exposure to electronic media use was 6.6 hours (SD 4.1) for the clinic sample and 4.6 hours (SD 2.6) for the school sample (P < 0.01). Self-reported rates of addictive patterns related to computer and gaming station use were similar between the 2 populations. However, the clinically based sample favoured more violent games, with 29% reporting playing mature-rated games, compared with 13% reported by the school-based sample (P = 0.02). Youth with externalizing disorders expended greater time video gaming, compared with youth with internalizing disorders (P = 0.01). CONCLUSIONS: Clinically based samples of youth with mental illnesses spend more time engaged in electronic media activities and are more likely to play violent video games, compared with youth in the general population. Further research is needed to determine the long-term implications of these differences.

Unlabeled uses of factor VIIa (recombinant) in pediatric patients.

PURPOSE: Unlabeled uses of factor VIIa (recombinant) in pediatric patients are reviewed. SUMMARY: Factor VIIa (recombinant) is currently approved for the treatment and prevention of bleeding in patients with hemophilia A or B and inhibitors of coagulation factors, acquired hemophilia, or congenital factor VII deficiency. Use of this agent has expanded to include unlabeled indications, including bleeding unrelated to coagulation factor deficiencies in infants, children, and adolescents without congenital hemophilia. Results of a search of the English-language medical literature for relevant articles primarily included case reports and retrospective reviews, with few randomized clinical trials. Reasons for use of factor VIIa (recombinant) included bleeding associated with acquired coagulopathies or congenital disorders resulting in coagulopathies, hepatic failure, surgery, and bleeding associated with prematurity, malignancies, and trauma. In most reports, conventional therapies were used with limited or no success. Factor VIIa (recombinant) was most commonly used in patients with coagulopathies or hemorrhage secondary to surgical procedures, primarily cardiopulmonary bypass and liver transplantation, as well as intracranial hemorrhage. In general, higher mortality rates were reported in medical versus surgical patients. The lowest rates of complete response were seen in younger patients and patients with trauma. A decrease in the requirement of blood product transfusion after the use of factor VIIa (recombinant) versus standard therapies or placebo was commonly observed but was not statistically significant in many cases. CONCLUSION: Given the lack of well-designed controlled studies, current evidence is inconclusive regarding the safety and efficacy of factor VIIa (recombinant) for unlabeled indications in pediatric patients.