Valproate (VPA) is an anti-epileptic and mood-stabilizing drug with a broad range of action and which mechanism of action still remains in part elusive. Recently the discovery that VPA modifies the epigenome increasing the transcriptional rate of target genes raises the issue of understanding the exact role of this mechanism. In this work we tested the possibility that VPA could modify the epigenome of lymphomonocytes (PBMC) obtained from epileptic patients chronically treated in monotherapy with VPA and phenobarbital. Acetyl-histone H3 expression was assessed by western blotting and global DNA methylation by incorporation of [(3)H]dCTP. A significant increase in histone acetylation and a correlated decrease of global DNA methylation was shown at VPA therapeutically relevant plasma concentrations. This effect was drug-related, since it was not demonstrated in PBMC obtained from phenobarbital-treated patients. Moreover, a VPA dose response curve was performed on PBMC obtained from healthy controls, demonstrating an increase of acetyl-histone H3 content. We suggest that the epigenetic properties of VPA expressed on PBMC at these concentrations might be operative in different tissues, with possible implications for the field of neuropsychiatric disorders.

Glutamate is the major mediator of excitatory signaling in the mammalian central nervous system (CNS) and it has recently been described to have a central role in the transduction of sensory input in the peripheral nervous system (PNS), too. However, functional glutamatergic systems are expressed by peripheral non-neural tissues as well, such as heart, kidney, lungs, ovary, testis, blood and skin. Interestingly, glutamatergic alterations have been repeatedly described in these tissues in various neuropsychiatric diseases. Here we will review evidence suggesting that glutamate measurements obtained from sampling ex vivo peripheral cells can permit the assessment of the dynamics of glutamate release, uptake, receptor-mediated signaling, synthesis and degradation, and mirror homologous dysfunctions operative within the CNS in each single patient. Among all the available cell types we will focus on leukocytes, platelets and fibroblasts that can be easily obtained from patients multiple times without concerns related to post-mortem changes. Finally, we will briefly review another possibility, offered by testing plasma (and CSF) glutamate levels, allowing the indirect investigation of glutamate-mediated crosstalk between central and peripheral compartments. Technical pitfalls of these biomarkers will be contextually emphasized.

Abstract A potential role for macroautophagy dysfunction in the pathogenesis of amyotrophic lateral sclerosis (ALS) was hypothesized after the demonstration that selected markers are up-regulated in post mortem samples obtained from both patients and animal models of disease. We hypothesized that a putative dysfunction of this catabolic pathway could be operative also in peripheral blood mononuclear cells (PBMC) obtained from ALS patients, since these cells represent an accessible model for studying molecular pathogenesis events in neuropsychiatric disorders. Beclin-1 and LC3II immunoreactivity were assessed in PBMC from 15 ALS patients and 15 controls by Western blot analysis. The expression of Atg12 mRNA was also assessed by real-time PCR. No significant difference was observed for all these parameters between patients and controls, although PBMC displayed a clear macroautophagy induction following exposure to rapamycin and lithium. Finally, we excluded a putative interference of riluzole demonstrating that LC3II immunoreactivity did not change in riluzole-treated SH-SY5Y neuroblastoma cells. In conclusion, the results of our pilot study do not support the idea of a systemic macroautophagic dysfunction in ALS, although they confirm that PBMC are a suitable peripheral marker for monitoring the effects of drugs interfering with this catabolic pathway.

The hand pronation phenomenon due to a pyramidal tract lesion is a sign commonly used for identifying a mild paresis, but the first descriptions of this maneuver seem to have been only partially investigated by the historians of neuroscience. Here we illustrate that this sign was most probably originally described by Adolf Strümpell (1853-1925) in 1901 and subsequently re-proposed by the illustrious French neurologist Joseph Babinski (1857-1932) in 1907, although with a slightly different focus of application. Finally, the Pronationsphaenomen was analyzed in detail in the subsequent work of Nikolaus Gierlich (1865-1944), a less-known German neurologist who tried one of the first detailed reports of the phylogenetic significance of this sign, publishing a paper in 1925. These works are reported here, detailing the existing discrepancies, along with notes on the relevant surrounding historical context. In particular, the undervalued contribution of Gierlich to the history of neuroscience and to the phylogenetic approach to semeiotics is analyzed in more detail and acknowledged.

The SCA17 clinical phenotype includes characteristics associated with cerebellar and cortical atrophy such as ataxia, dementia, epilepsy, chorea and parkinsonian features. Here we describe the case of a 38-year-old male presenting with ataxia, cognitive impairment and seizures, who was found to carry 43 repeats on one allele of the TATA-binding protein (TBP) gene. Therefore, genetic analysis of TBP gene triplets was performed on the patient's entire family, identifying three asymptomatic carriers of the same allele. A neuroradiological phenotype appeared to segregate with this allele, suggesting that it may play at least a contributory role in the determination of SCA17.