Sub-acute delayed failure of subthalamic DBS in Parkinson's disease: the role of micro-lesion effect.

OBJECTIVE: To study delayed failure after subthalamic nucleus (STN) deep brain stimulation in Parkinson's disease (PD) patients. METHODS: Out of 56 consecutive bilaterally STN-implanted PD patients, we selected subjects who, after initial clinical improvement (1 month after surgery), lost benefit (delayed failure, DF). RESULTS: Five patients developed sub-acutely severe gait disorders (DF). In 4/5 DF patients, a micro-lesion effect, defined as improvement without stimulation, was observed; immediate post-operative MRI demonstrated electrode located above or behind to the STN. CONCLUSIONS: Patients presenting micro-lesion effect should be carefully monitored, as this phenomenon can mask electrodes misplacement and evolution in DF

Topographical body fat distribution links to amino acid and lipid metabolism in healthy non-obese women.

Visceral adiposity is increasingly recognized as a key condition for the development of obesity related disorders, with the ratio between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) reported as the best correlate of cardiometabolic risk. In this study, using a cohort of 40 obese females (age: 25-45 y, BMI: 28-40 kg/m(2)) under healthy clinical conditions and monitored over a 2 weeks period we examined the relationships between different body composition parameters, estimates of visceral adiposity and blood/urine metabolic profiles. Metabonomics and lipidomics analysis of blood plasma and urine were employed in combination with in vivo quantitation of body composition and abdominal fat distribution using iDXA and computerized tomography. Of the various visceral fat estimates, VAT/SAT and VAT/total abdominal fat ratios exhibited significant associations with regio-specific body lean and fat composition. The integration of these visceral fat estimates with metabolic profiles of blood and urine described a distinct amino acid, diacyl and ether phospholipid phenotype in women with higher visceral fat. Metabolites important in predicting visceral fat adiposity as assessed by Random forest analysis highlighted 7 most robust markers, including tyrosine, glutamine, PC-O 44∶6, PC-O 44∶4, PC-O 42∶4, PC-O 40∶4, and PC-O 40∶3 lipid species. Unexpectedly, the visceral fat associated inflammatory profiles were shown to be highly influenced by inter-days and between-subject variations. Nevertheless, the visceral fat associated amino acid and lipid signature is proposed to be further validated for future patient stratification and cardiometabolic health diagnostics.

Genetics of essential tremor.

Essential tremor (ET) is a prevalent condition manifesting with progressive action tremor. Although ET was traditionally viewed as a sporadic disease, a significant proportion of cases report a positive family history of tremor. Autosomal dominant inheritance can be demonstrated in many families. Previously, genome-wide linkage studies in families mapped three loci for ET, hereditary essential tremor-1 (ETM1), ETM2 and ETM3. However, no causal mutation has been replicated in candidate genes within these loci, including dopamine D3 receptor (DRD3) and HS1-binding protein 3 (HS1BP3). Recently, the first genome-wide association study in ET followed by replication studies conducted in diverse populations identified a significant association between the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) SNP rs9652490 and risk for ET Although further novel variants were indentified in LINGO1 and its paralog LINGO2 that may be associated with risk for ET, the pathogenic mechanisms involved remain elusive. Given the possibility that ET as a complex trait may be influenced by the combined effects of rare variants, novel high-throughput technologies sequencing all exons across the genome (exome sequencing) or the whole genome (genome sequencing) may become crucial in understanding/deciphering the genetic background of ET.

The efficiency of a carbamazepine-mianserin combination scheme in opiate detoxification.

A recent comparative randomized double-blind study has suggested the utility of a carbamazepine/mianserin combination as a treatment for opiate withdrawal. The aim of the present study was to explore the feasibility and efficiency of this combination under naturalistic conditions. Five hundred and fifty mostly polysubstance abusing patients treated with a standardized scheme combining carbamazepine and mianserin were assessed with regard to deviations to the protocol, used co-medications and retention in treatment.Three hundred and sixty three patients (66.0%) received the carbamazepine/mianserin combination as specified by the standardized protocol. In 350 patients (63.7%) the whole 10 days was completed. The most frequently used p.r.n. medications were for anxiety (47.5%) and insomnia (54.5%).The treatment of opiate withdrawal with a carbamazepine/mianserin combination scheme in an inpatient setting seems to be feasible and applicable with few adaptations to most patients, and may represent an interesting treatment option for multidrug users.

Cytochrome P450 2D6 genotype and methadone steady-state concentrations

A genetic polymorphism of cytochrome P450 2D6 has been described with the existence of poor (zero functional genes), extensive (one or two functional genes), and ultrarapid metabolizers (three or more functional genes). The authors measured the steady-state trough (R)- (i.e., the active enantiomer), (S)-, and (R,S)-methadone plasma levels in opiate-dependent patients receiving methadone maintenance treatment (MMT) and genotyped them for cytochrome P4502D6. The patients' medical records were reviewed to assess the outcome of the MMT with regard to the absence of illicit opiate consumption and to the absence of withdrawal complaints in ultrarapid and poor metabolizers. Of 256 patients included, 18 were found to be poor metabolizers, 228 to be extensive metabolizers, and 10 to be ultrarapid metabolizers. Significant differences were found between genotypes for (R)- (p = 0.024), (S)- (p = 0.033), and (R,S)-methadone (p = 0.026) concentrations to dose-to-weight ratios. For (R)-methadone, a significant difference was found between ultrarapid metabolizers and poor metabolizers (p = 0.009), with the median value in the former group being only 54% of the median value in the latter group. These results confirm the involvement of cytochrome P450 2D6 in methadone metabolism. Although the difference was nonsignificant (p = 0.103), 13 (72%) of the 18 poor metabolizers and only 4 (40%) of the 10 ultrarapid metabolizers were considered successful in their treatment. More studies are needed to examine the influence of the ultrarapid metabolizer status on the outcome of the MMT.

Overview of primary monogenic dystonia.

Primary monogenic forms of dystonia manifest solely or mainly with dystonia; they have been linked to a number of genes and loci and assigned "DYT" numbers. The pure dystonia syndrome early-onset primary dystonia (DYT1) manifests with dominantly-inherited generalized dystonia, often with focal onset in a limb. DYT1 is caused by a GAG deletion in the TOR1A gene. Mutations in the THAP1 gene cause DYT6, a form of pure dystonia that primarily involves cranio-cervical and upper limb muscles. Patients with the dystonia plus syndrome DYT5 display levodopa-responsive dystonia sometimes associated with tremor or parkinsonism (DYT5a, mutations in GCH1); a more severe phenotype with psychomotor involvement can be seen in recessive forms (DYT5b with TH mutations, SPR-deficiency syndrome). Other forms of dystonia plus syndromes include myoclonic dystonia (DYT11) and rapid-onset dystonia-parkinsonism (DYT12). Finally, paroxysmal exertion-induced dystonia (DYT18, GLUT1 deficiency) is caused by mutations in the SLC2A1 gene (DYT9 and DYT18). It is part of the paroxysmal dystonia group and manifests with paroxystic movements sometimes associated with seizures and psychomotor developmental delay.

Genetics of Parkinson's disease: the yield.

The discovery of genes implicated in familial forms of Parkinson's disease (PD) has provided new insights into the molecular events leading to neurodegeneration. Clinically, patients with genetically determined PD can be difficult to distinguish from those with sporadic PD. Monogenic causes include autosomal dominantly (SNCA, LRRK2, VPS35, EIF4G1) as well as recessively (PARK2, PINK1, DJ-1) inherited mutations. Additional recessive forms of parkinsonism present with atypical signs, including very early disease onset, dystonia, dementia and pyramidal signs. New techniques in the search for phenotype-associated genes (next-generation sequencing, genome-wide association studies) have expanded the spectrum of both monogenic PD and variants that alter risk to develop PD. Examples of risk genes include the two lysosomal enzyme coding genes GBA and SMPD1, which are associated with a 5-fold and 9-fold increased risk of PD, respectively. It is hoped that further knowledge of the genetic makeup of PD will allow designing treatments that alter the course of the disease.

L'induction rapide du sevrage par des antagonistes des opiacés sous anesthésie: une alternative dans le traitement de la dépendance aux opiacés [Rapid induction of withdrawal with opiate antagonists under anesthesia: an alternative to treatment of opiate dependence?]

Rapid induction of withdrawal by opiate antagonists under anesthesia is an opiate detoxification technique. This technique is useful to reduce intensity and duration of withdrawal. Therefore, this technique represents an alternative strategy in the treatment of opiate addicted patients. This paper attempts to present a brief history of this technique, and a critical review of related issues.

Depressive disorder moderates the effect of the FTO gene on body mass index.

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant (P<0.0057), with PsyCoLaus giving supportive evidence for five SNPs (P-values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity.

Evaluation du projet EVITA: rapport final

Le projet EVITA (EValuation Indication, Traitement ambulatoire, Accompagnement) s'inscrit dans le Plan cantonal d'action Alcool (2007-2012), lui-même en conformité avec le Plan national Alcool (2007-2011). Ce projet est un mandat du Service de la santé publique qui a pour objectif la mise en oeuvre et l'évaluation d'un dispositif cantonal d'indication et de suivi (DCIS) constituant une porte d'entrée unique. Le DCIS est constitué d'un partenariat entre la Fondation vaudoise contre l'alcoolisme (FVA) et le Centre de traitement en alcoologie (CTA) du CHUV. C'est l'Unité d'évaluation de programmes de prévention (UEPP) de l'Institut universitaire de médecine sociale et préventive (IUMSP) qui a été chargée par le CTA, mandant, de l'évaluation du projet EVITA et qui en a rédigé le protocole. [Introduction, p. 5]