Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial.

AIMS: We aimed to improve the retention in treatment and therapeutic outcome of methadone maintenance treatment (MMT) patients by adjusting the oral methadone dose in order to reach a "target" plasma R-methadone level (80-250 ng/mL). METHODS: A multicenter randomized controlled trial was organized. RESULTS: The intention-to-treat statistical analysis showed that repeated dose adjustments performed in order to obtain therapeutic plasma R-methadone levels did not improve retention in treatment of heroin-dependent patients. However, patients having plasma methadone levels in the "target range" at the beginning of the study had a better retention in treatment than controls. Furthermore, patients succeeding in keeping plasma R-methadone target levels (per protocol analysis) remained in treatment and improved their social scores better than controls. -Conclusion: Although the primary endpoint of this study was not demonstrated, a post hoc and a per protocol analysis suggested that patients in MMT with plasma R-methadone concentrations in the target range have a better therapeutic outcome than controls.

Arrays of microLEDs and astrocytes: biological amplifiers to optogenetically modulate neuronal networks reducing light requirement.

In the modern view of synaptic transmission, astrocytes are no longer confined to the role of merely supportive cells. Although they do not generate action potentials, they nonetheless exhibit electrical activity and can influence surrounding neurons through gliotransmitter release. In this work, we explored whether optogenetic activation of glial cells could act as an amplification mechanism to optical neural stimulation via gliotransmission to the neural network. We studied the modulation of gliotransmission by selective photo-activation of channelrhodopsin-2 (ChR2) and by means of a matrix of individually addressable super-bright microLEDs (µLEDs) with an excitation peak at 470 nm. We combined Ca2+ imaging techniques and concurrent patch-clamp electrophysiology to obtain subsequent glia/neural activity. First, we tested the µLEDs efficacy in stimulating ChR2-transfected astrocyte. ChR2-induced astrocytic current did not desensitize overtime, and was linearly increased and prolonged by increasing µLED irradiance in terms of intensity and surface illumination. Subsequently, ChR2 astrocytic stimulation by broad-field LED illumination with the same spectral profile, increased both glial cells and neuronal calcium transient frequency and sEPSCs suggesting that few ChR2-transfected astrocytes were able to excite surrounding not-ChR2-transfected astrocytes and neurons. Finally, by using the µLEDs array to selectively light stimulate ChR2 positive astrocytes we were able to increase the synaptic activity of single neurons surrounding it. In conclusion, ChR2-transfected astrocytes and µLEDs system were shown to be an amplifier of synaptic activity in mixed corticalneuronal and glial cells culture.

Pregnancy outcome in women exposed to antiepileptic drugs: teratogenic role of maternal epilepsy and its pharmacologic treatment.

Infants born to epileptic women treated with antiepileptic drugs (AEDs) have an increased risk of major congenital malformations (MCMs). In order to determine the role of maternal epilepsy we conducted a prospective cohort study on three cohorts of pregnant women: (i) 385 epileptic women treated with AEDs, (ii) 310 non-epileptic women treated with AEDs, (iii) 867 healthy women not exposed to AEDs (control group). The rate of MCMs in the epileptic group (7.7%) was not statistically higher than in the non-epileptic one (3.9%) (p=0.068). The rate in the first group was higher compared to the control group (p=0.001), while the rate in the second one was not (p=0.534). Our data confirm that AEDs therapy is the main cause of the increased risk of malformations in the offspring of epileptic women; however a teratogenic role of the maternal epilepsy itself cannot be excluded.