ABSTRACT
Vagal neurostimulation (VNS) is used for the treatment of epilepsy and major medical-refractory depression. VNS has neuropsychiatric functions and systemic anti-inflammatory activity. The objective of this study is to measure the clinical efficacy and impact of VNS modulation in depressive patients. Six patients with refractory depression were enrolled. Depression symptoms were assessed with the Montgomery-Asberg Depression Rating, and anxiety symptoms with the Hamilton Anxiety Rating Scale. Plasmas were harvested prospectively before the implantation of VNS (baseline) and up to 4 years or more after continuous therapy. Forty soluble molecules were measured in the plasma by multiplex assays. Following VNS, the reduction in the mean depression severity score was 59.9% and the response rate was 87%. Anxiety levels were also greatly reduced. IL-7, CXCL8, CCL2, CCL13, CCL17, CCL22, Flt-1 and VEGFc levels were significantly lowered, whereas bFGF levels were increased (p values ranging from 0.004 to 0.02). This exploratory study is the first to focus on the long-term efficacy of VNS and its consequences on inflammatory biomarkers. VNS may modulate inflammation via an increase in blood-brain barrier integrity and a reduction in inflammatory cell recruitment. This opens the door to new pathways involved in the treatment of refractory depression.
Subject(s)
Depressive Disorder, Treatment-Resistant , Vagus Nerve Stimulation , Humans , Pilot Projects , Depressive Disorder, Treatment-Resistant/psychology , Depression , Treatment Outcome , InflammationABSTRACT
The mechanisms generating cancer-initiating mutations are not well understood. Sonic hedgehog (SHH) pathway activation is frequent in medulloblastoma (MB), with PTCH1 mutations being a common initiating event. Here we investigated the role of the developmental mitogen SHH in initiating carcinogenesis in the cells of origin: granule cell progenitors (GCPs). We delineate a molecular mechanism for tumor initiation in MB. Exposure of GCPs to Shh causes a distinct form of DNA replication stress, increasing both origin firing and fork velocity. Shh promotes DNA helicase loading and activation, with increased Cdc7-dependent origin firing. The S-phase duration is reduced and hyper-recombination occurs, causing copy number neutral loss of heterozygosity-a frequent event at the PTCH1/ptch1 locus. Moreover, Cdc7 inhibition to attenuate origin firing reduces recombination and preneoplastic tumor formation in mice. Therefore, tissue-specific replication stress induced by Shh promotes loss of heterozygosity, which in tumor-prone Ptch1+/- GCPs results in loss of this tumor suppressor-an early cancer-initiating event.
Subject(s)
Cerebellar Neoplasms , Medulloblastoma , Animals , Carcinogenesis/genetics , Cerebellar Neoplasms/genetics , DNA Replication/genetics , Hedgehog Proteins/genetics , Medulloblastoma/genetics , MiceABSTRACT
We report the case of a 23-year-old left-handed woman with medically intractable praxis-induced reflex seizures mainly precipitated by writing. Selective resection of subtle end-of-sulcus cortical dysplasia in the right inferior parietal lobule resulted in freedom from seizures. To the best of our knowledge, this is the first case of praxis-induced reflex seizures mainly precipitated by writing in which a focal lesion was found and treated successfully by surgery.
