Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing

In chronic pain states, the neurotrophin brain-derived neurotrophic factor (BDNF) transforms the output of lamina I spinal neurons by decreasing synaptic inhibition. Pain hypersensitivity also depends on N-methyl-D-aspartate receptors (NMDARs) and Src-family kinases, but the locus of NMDAR dysregulation remains unknown. Here, we show that NMDAR-mediated currents at lamina I synapses are potentiated in a peripheral nerve injury model of neuropathic pain. We find that BDNF mediates NMDAR potentiation through activation of TrkB and phosphorylation of the GluN2B subunit by the Src-family kinase Fyn. Surprisingly, we find that Cl−-dependent disinhibition is necessary and sufficient to prime potentiation of synaptic NMDARs by BDNF. Thus, we propose that spinal pain amplification is mediated by a feedforward mechanism whereby loss of inhibition gates the increase in synaptic excitation within individual lamina I neurons. Given that neither disinhibition alone nor BDNF-TrkB signaling is sufficient to potentiate NMDARs, we have discovered a form of molecular coincidence detection in lamina I neurons

Open-label study comparing the efficacy and tolerability of aripiprazole and haloperidol in the treatment of pediatric tic disorders

Due to its unique pharmacodynamic properties of dopamine partial agonist activity, and its association with few and mild side effects, aripiprazole is a candidate atypical antipsychotic for patients with tic disorders. This open-label study compared the efficacy and tolerability of aripiprazole with haloperidol, a typical antipsychotic widely used to treat patients with tic disorders. Forty-eight children and adolescents with tic disorders were recruited from the outpatient clinic at South Korea and treated with aripiprazole (initial dose, 5.0 mg/d; maximum dose 20 mg/d) or haloperidol (initial dose, 0.75 mg/d; maximum dose, 4.5 mg/d) for 8 weeks. Treatment efficacy was measured using the yale global tic severity scale (YGTSS), and tolerability was measured using the extrapyramidal symptom rating scale (ESRS) and an adverse effects checklist. Total tic scores as measured by the YGTSS decreased over time in both groups (p < 0.001) without any significant differences between groups. ESRS scores were significantly higher in the haloperidol group during the 4 weeks after commencement of medication (p < 0.05). These results indicate that aripiprazole may be a promising drug in the treatment of children and adolescents with tic disorders. Further controlled studies are needed to determine the efficacy and tolerability of aripiprazole in these patients

European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce

Longitudinal association between motor and obsessive compulsive symptoms in patients with psychosis and their unaffected siblings

Little is known about the co-prevalence of obsessive compulsive symptoms (OCS) and motor symptoms in patients with psychotic disorders. Cross-sectional associations between OCS and motor symptoms were assessed at baseline and at 3years follow-up in patients (n=726) with psychotic disorders and in their unaffected siblings (n=761) from the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Furthermore, longitudinal associations between changes in OCS and motor symptoms were evaluated. At baseline, OCS was not associated with any motor symptom (akathisia, dyskinesia, parkinsonism or dystonia) in patients. At follow-up, patients with OCS reported significantly more akathisia. Dividing the patients into four groupsno OCS, OCS remission with OCS only at baseline, OCS de novo with OCS only at follow-up and a persistent OCS grouprevealed that the OCS de novo group already reported more akathisia at baseline compared to the no-OCS group. At follow-up, both the OCS de novo and the persistent OCS group reported more akathisia. These results remained significant after correcting for relevant confounders clozapine, GAF score, PANSS-negative score and IQ. Motor symptoms at baseline were significantly associated with OCS at follow-up, but not the other way around. In siblings, OCS at baseline was associated with akathisia, but this association was lost at follow-up. Results suggest that motor symptoms might precede co-occurring OCS in patients with psychotic disorders. However, no inference can be made about causality, and further prospective research is needed to investigate this assumption

Effect of cattle slurry pre-treatment by separation and addition of nitrification inhibitors on gaseous emissions and N dynamics: A laboratory study

The application of untreated or treated animal manure to soils can result in increased N and C gaseous emissions contributing to ecosystem change and global warming. In the present study, dairy cattle slurry (liquid manure) was subjected first to pre-treatment by separation using a screw press to obtain a liquid (LF) and a solid fraction (SF). Then, the different fractions and the whole slurry (WS) were combined with two nitrification inhibitors (NI), dicyandiamide (DCD) or 3,4-dimethylpyrazole phosphate (DMPP), were applied to soil to assess the effect of slurry treatment by separation and NI addition on soil N dynamics and CH4, CO2, NH3, NO and N2O emissions. The WS and the two slurry fractions, combined or not with DCD or DMPP, were applied to soil at an equivalent field dosage of 120 kg total N haÿ1 . Controls including a soil only, soil–DCD and soil–DMPP treatments were also included. The mixtures were incubated for 93-d at 20 °C. Results obtained show that NI inhibited nitrification between 16 and 30-d in WS and LF, with DMPP having a longer effect over time compared to DCD. There was no significant effect of NI on nitrification for the SF treatment. Nitrification inhibitors did not significantly affect (P > 0.05) the CH4, CO2 and N2O emissions, but significantly decreased (P < 0.05) NO emissions. Furthermore, the two NIs had a similar effect on gaseous emissions. Throughout the entire experiment, the greatest amount of NO was released from the LF treatment (without NI), while the greatest amount of N2O was released from the SF treatment. Slurry separation had no impact on N emissions, while the combination of this process with one of the two NI led to a small reduction in total N emissions

Topiramate in the Adjunctıve Treatment of Tourette Syndrome: A Case Report

Tourette Syndrome (TS) is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic. In many of the cases, Attention Deficit Hyperactivity Disorder (ADHD) is a frequent comorbid disorder. Many treatment options have been suggested for TS and ADHD comorbidity. In this article, we present a case diagnosed with TS and ADHD whose tics were refractory to many other suggested treatment options for Tic Disorders (TD) and worsened during the use of recommended first-line treatment agents for ADHD, that were significantly reduced by using topiramate. New therapeutic options that would be easily used and with less side effects are needed in the treatment of TD. Topiramate treatment seems like an appropriate option raising hope for the future to be used as monotherapy or in adjuvant treatment for TD. Larger trials with longer follow up are required in this field

Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette's syndrome, Sydenham's chorea, and autoimmune disorders

Background: Some cases of Tourette's syndrome (TS) are hypothesized to be caused by autoantibodies that develop in response to a preceding group A beta hemolytic streptococcal infection