Defining length stability in paediatric femoral shaft fractures treated with titanium elastic nails.

INTRODUCTION: Optimal paediatric femoral shaft fracture patterns or lengths amenable to titanium elastic nail stabilization have not been well defined. The purpose of this study is to identify radiographic parameters predictive of treatment failure with flexible intramedullary nails based upon fracture morphology. METHODS: A retrospective review was performed of all femoral shaft fractures treated with flexible intramedullary nails over a five-year period. All patients with at least six weeks of postoperative radiographic imaging were included. Fracture characteristics included location, pattern, length, obliquity, angulation, translation and shortening. Postoperative radiographs were reviewed to determine shortening and angulation. RESULTS: There were 58 patients with 60 femoral shaft fractures stabilized with titanium nails, with 46 healing within acceptable parameters and 14 considered malunions. Six of the 14 malunions developed complications requiring early unplanned intervention. No patients in the treatment success group had a complication. Between the treatment success and failure groups, fracture pattern, location, length, obliquity, angulation, translation or shortening were not statistically different. Mean nail canal fill was significantly lower in the failure group (0.72 versus 0.81; p = 0.0146), with a receiver operating characteristic curve identifying canal fill 76% as the optimal threshold. CONCLUSION: This is the first study to measure the length and obliquity of paediatric femoral shaft fractures and to determine their relationship to radiographic alignment after healing. None of the preoperative fracture characteristics were predictive of malalignment or shortening. We recommend the use of larger nail sizes in the treatment of paediatric femoral shaft fractures, especially if there is concern for residual instability. LEVEL OF EVIDENCE: IV.

Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo.

Head-twitch behavior (HTR) is the behavioral signature of psychedelic drugs upon stimulation of the serotonin 5-HT2A receptor (5-HT2AR) in rodents. Following the previous report of a semi-automated detection of HTR based on the dynamics of mouse's head movement, here we present a system for the identification of individual HTR events in a fully automated fashion. The validity of this fully automated HTR detection system was tested with the psychedelic drug DOI in 5-HT2AR-KO mice, and via evaluation of potential sources of false-positive and false-negative HTR events. The increased throughput in data processing achieved via automation afforded the possibility of conducting otherwise time consuming HTR time-course studies. To further assess the versatility of our system, we also explored the pharmacological interactions between 5-HT2AR and the metabotropic glutamate receptor 2 (mGluR2). Our data demonstrate the potentiation effect of the mGluR2/3 antagonist LY341495 on DOI-induced HTR, as well as the HTR-blocking effect of the mGluR2/3 agonist and antipsychotic drug in development LY404039. This fully automated system can contribute to speed up our understanding of 5-HT2AR's pharmacology and its characteristic behavioral outputs in rodents.

Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice.

BACKGROUND: Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis and schizophrenia treatment. Previous findings in mGlu2 knockout (KO) mice suggested that mGlu2 is necessary for head-twitch behavior, a rodent phenotype characteristic of hallucinogenic 5-HT2A receptor agonists. However, the role of mGlu2 in the behavioral effects induced by antipsychotic drugs remains poorly understood. Here, we tested antipsychotic-like behavioral phenotypes induced by the atypical antipsychotic clozapine in mGlu2-KO mice and wild-type control littermates. METHODS: Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5 mg/kg) or vehicle followed by MK801 (0.5 mg/kg), PCP (7.5 mg/kg), amphetamine (6 mg/kg), scopolamine (2 mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated. RESULTS: The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion. CONCLUSION: These findings further support the existence of a functionally relevant crosstalk between 5-HT2A and mGlu2 receptors in different preclinical models of antipsychotic activity.

Reformulating a Pharmacophore for 5-HT2A Serotonin Receptor Antagonists.

Several pharmacophore models have been proposed for 5-HT2A serotonin receptor antagonists. These typically consist of two aromatic/hydrophobic moieties separated by a given distance from each other, and from a basic amine. Although specified distances might vary, the models are relatively similar in their general construction. Because our preliminary data indicated that two aromatic (hydrophobic) moieties might not be required for such action, we deconstructed the serotonin-dopamine antipsychotic agent risperidone (1) into four smaller structural fragments that were thoroughly examined in 5-HT2A receptor binding and functional (i.e., two-electrode voltage clamp (TEVC) and intracellular calcium release) assays. It was apparent that truncated risperidone analogues behaved as antagonists. In particular, 6-fluoro-3-(1-methylpiperidin-4-yl)benzisoxazole (4) displayed high affinity for 5-HT2A receptors (Ki of ca. 12 nM) relative to risperidone (Ki of ca. 5 nM) and behaved as a potent 5-HT2A serotonin receptor antagonist. These results suggest that multiple aromatic (hydrophobic) moieties are not essential for high-affinity 5-HT2A receptor binding and antagonist activity and that current pharmacophore models for such agents are very much in need of revision.