Serotonin uptake blockers inhibit the firing of presumed serotonergic dorsal raphe neurons in vitro

Some antidepressant drugs are potent inhibitors of neuronal uptake of serotonin. In vivo, these compounds inhibit serotonergic dorsal raphe neuronal firing rates, presumably through increased stimulation of 5-HT1a autoreceptors. We recorded from electrophysiologically identified serotonergic dorsal raphe neurons in rat brain slices and determined the effects of five serotonin uptake blockers on the firing rates of these units in vitro. Each drug decreased the neuronal firing rates in a concentration-dependent manner. IC50 values derived from concentration-response curves are: fluvoxamine, 0.8 μM; sertraline, 1.1 μM; imipramine, 2.7 μM; chlorimipramine, 2.8 μM; and fluoxetine, 4.2 μM. Exposure of brain slices to 10 μM tetrabenazine, a serotonin depleting agent, prior to treatment with serotonin uptake blockers resulted in a rightward shift of the concentration-response curve. In vitro single unit recording allows: (1) direct comparison with neurochemical data obtained in vitro; (2) access to tissue bypassing blood brain barrier and liver enzymes; (3) quick wash out of drug from tissue; and (4) ability to record from single unitsover long periods (hours). This in vitro test provides a fast, simple means of determining neurophysiological effects of potential antidepressant drugs on the serotonin system.     

A multi-feature and multi-channel univariate selection process for seizure prediction.

OBJECTIVE: To develop a prospective method for optimizing seizure prediction, given an array of implanted electrodes and a set of candidate quantitative features computed at each contact location. METHODS: The method employs a genetic-based selection process, and then tunes a probabilistic neural network classifier to predict seizures within a 10 min prediction horizon. Initial seizure and interictal data were used for training, and the remaining IEEG data were used for testing. The method continues to train and learn over time. RESULTS: Validation of these results over two workshop patients demonstrated a sensitivity of 100%, and 1.1 false positives per hour for Patient E, using a 2.4s block predictor, and a failure of the method on Patient B. CONCLUSIONS: This study demonstrates a prospective, exploratory implementation of a seizure prediction method designed to adapt to individual patients with a wide variety of pre-ictal patterns, implanted electrodes and seizure types. Its current performance is limited likely by the small number of input channels and quantitative features employed in this study, and segmentation of the data set into training and testing sets rather than using all continuous data available. SIGNIFICANCE: This technique theoretically has the potential to address the challenge presented by the heterogeneity of EEG patterns seen in medication-resistant epilepsy. A more comprehensive implementation utilizing all electrode sites, a broader feature library, and automated multi-feature fusion will be required to fully judge the method's potential for predicting seizures.     

Functional outcomes of cleft lip surgery. Part IV: Between- and within-participant variables affecting lip vermilion sensory thresholds.

OBJECTIVE: Compare neurosensory assessments for participants with and without a cleft lip; identify between- and within-participant variables affecting sensory thresholds on the vermilion of participants with cleft lip. DESIGN: A parallel group, nonrandomized clinical trial. SUBJECTS: There were 56 participants with cleft lip and 37 noncleft participants. ANALYSIS: Two-point perception and warmth and cool detection thresholds were measured on the right and left sides of the upper and lower vermilion. A cotton-tip stick, stroked across the skin, was used to identify altered sensation. Linear mixed effects modeling was used to examine the effects of between- and within-participant variables on the thresholds. RESULTS: Threshold values on the upper and lower vermilion were similar for cleft and noncleft participants and were unaffected by the presence of a cleft on the side tested. Participants with cleft lip who reported hyposensitive altered sensations had higher two-point thresholds on the upper lip than those who reported hypersensitivity. Participants with cleft lip who reported altered midface sensation had lower warmth detection, but higher cool detection thresholds, on the lower vermilion than participants with cleft lip who did not report altered sensation. Participants with bilateral cleft lip had lower warmth detection thresholds on the upper vermilion than participants with unilateral cleft lip. CONCLUSIONS: Although participants with cleft lip and noncleft participants exhibit similar thermal and two-point discrimination, on average, differences exist among subgroups of participants with cleft lip that may reflect central disturbances in the processing of somatosensory stimuli.     

Adalimumab

? Adalimumab is a subcutaneously administered, recombinant, human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). ? The clinical efficacy and safety of adalimumab in patients with moderate to severe Crohn’s disease has been demonstrated in four pivotal, randomized, double-blind trials (CLASSIC-I, GAIN, CHARM, and CLASSIC-II) that included a total of >1400 patients. ? In the CLASSIC-I trial, adalimumab was significantly more effective than placebo for induction of remission in patients who had not previously received anti-TNF therapy. ? Adalimumab was also more effective than placebo for induction of remission in the GAIN study in patients who had either lost responsiveness or developed intolerance to infliximab. ? The CHARM trial showed that, among patients who responded to open-label adalimumab induction, maintenance therapy with adalimumab 40mg weekly or every other week for up to 1 year was associated with significantly greater remission rates than placebo at weeks 26 and 56. In addition, significantly more adalimumab than placebo recipients achieved corticosteroid-free remission and had complete fistula closure. ? In CLASSIC-II, an extension of the CLASSIC-I trial, patients who were in remission after a short course of adalimumab and were randomized to receive up to 1 year’s treatment with adalimumab 40mg weekly or every other week were significantly more likely to remain in remission than those randomized to receive placebo. ? In general, the tolerability profile of adalimumab in patients with Crohn’s disease was similar to that in patients with rheumatoid arthritis or other approved indications.     

Effects of temperature and aldehyde fixation on tissue water diffusion properties, studied in an erythrocyte ghost tissue model.

Ex vivo biological sample imaging can complement in vivo MRI studies. Since ex vivo studies are typically performed at room temperature, and samples are frequently preserved by fixation, it is important to understand how environmental and chemical changes dictated by ex vivo studies alter the physical and MR properties of a sample. Diffusion and relaxation time measurements were used to assess the effects of temperature change and aldehyde fixation on the biophysical and MR properties of a model biological tissue comprised of erythrocyte ghosts suspended in buffer or agarose gel. Sample temperature was varied between 10 degrees C and 37 degrees C. Diffusion MRI data were analyzed with a biophysically appropriate two-compartment exchange model. Temperature change resulted in a complex alteration of water diffusion properties due to the compartmental nature of tissues and alteration in membrane permeability. Formaldehyde, Karnovsky's solution, and glutaraldehyde all caused statistically significant changes to the biophysical and MR properties of the samples. Fixation caused large decreases in water proton T2, which was restored to near prefixation values by washing free fixative from the samples. Water membrane permeability was also significantly altered by fixation. This study demonstrates that relating in vivo MR data to chemically fixed ex vivo data requires an understanding of the effects of sample preparation.     

Linear response of mutans streptococci to increasing frequency of xylitol chewing gum use: a randomized controlled trial [ISRCTN43479664]

Background  

Xylitol is a naturally occurring sugar substitute that has been shown to reduce the level of mutans streptococci in plaque and saliva and to reduce tooth decay. It has been suggested that the degree of reduction is dependent on both the amount and the frequency of xylitol consumption. For xylitol to be successfully and cost-effectively used in public health prevention strategies dosing and frequency guidelines should be established. This study determined the reduction in mutans streptococci levels in plaque and unstimulated saliva to increasing frequency of xylitol gum use at a fixed total daily dose of 10.32 g over five weeks.