EPIGENETICS, RESILIENCE, COMORBIDITY AND TREATMENT OUTCOME

Personalized or precision medicine is a relatively new promising concept which is gaining momentum in all branches of medicine including psychiatry and neurology. Psychiatry and neurology are medical specialties dealing with diagnosis, prevention and treatment of brain disorders which are the main causes of years lived with disability worldwide as well as shortened life. Despite a huge progress in clinical psychopharmacology and neuropharmacology, the treatment outcome for many psychiatric disorders and neurologic diseases has remained unsatisfactory. With aging, comorbidities are more the rule, than an exception and may significantly influence on the final treatment outcome. Epigenetic modulation, resilience and life style are key determinants of the health and very important issues for understanding therapeutic mechanisms and responses. There is a hope that epigenetic profiling before treatment could be used in near future to increase the likelihood of good treatment response by selecting the appropriate medication. The aim of this paper is to offer an overview of the main aspects of epigenetic modulation, resilience and comorbidities and their role in developing the concept of personalized medicine. While waiting for more precise and reliable treatment guidelines it is possible to increase treatment effectiveness in psychiatry and neurology by enhancing individual resilience of patients and managing comorbidities properly

A NOVEL DISEASE-CAUSING NF1 VARIANT IN A CROATIAN FAMILY WITH NEUROFIBROMATOSIS TYPE 1

Neurofibromatosis type 1 (NF1) is the most common autosomal dominant neurocutaneous syndrome with the estimated prevalence ranging from 1 in 3000 to 1 in 4000 individuals and wide phenotypical variability. NF1 is caused by autosomal dominant heterozygous mutations in the neurofibromin gene which is located on the chromosome 17 (17q11.2). Phenotypically, NF1 patients have a very heterogeneous clinical phenotype. In this study, a novel frameshift NF1 variant was identified in a Croatian family with NF1 (mother and two daughters). The novel variant c. 4482_4483delTA leads to sequence change that creates a premature translational stop signal (p.His1494Glnfs*7) in the NF1 gene. Our study showed that even when the same germline NF1 variant has been identified, there is still huge phenotypic variability in patients even within the same family, and it makes prognosis of the disease more complex. The development of next-generation sequencing technologies which allow rapid and accurate identification of disease-causing mutations becomes crucial for molecular characterization of NF1 patients as well as for patient follow-up, in the context of genetic counseling and clinical management of patients

RNA Sequencing of Human Peripheral Blood Cells Indicates Upregulation of Immune-Related Genes in Huntington's Disease

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a trinucleotide repeat expansion in the Huntingtin gene. As disease-modifying therapies for HD are being developed, peripheral blood cells may be used to indicate disease progression and to monitor treatment response. In order to investigate whether gene expression changes can be found in the blood of individuals with HD that distinguish them from healthy controls, we performed transcriptome analysis by next-generation sequencing (RNA-seq). We detected a gene expression signature consistent with dysregulation of immune-related functions and inflammatory response in peripheral blood from HD cases vs. controls, including induction of the interferon response genes, IFITM3, IFI6 and IRF7. Our results suggest that it is possible to detect gene expression changes in blood samples from individuals with HD, which may reflect the immune pathology associated with the disease

Convergence of miRNA Expression Profiling, α-Synuclein Interacton and GWAS in Parkinson's Disease

miRNAs were recently implicated in the pathogenesis of numerous diseases, including neurological disorders such as Parkinson's disease (PD). miRNAs are abundant in the nervous system, essential for efficient brain function and play important roles in neuronal patterning and cell specification. To further investigate their involvement in the etiology of PD, we conducted miRNA expression profiling in peripheral blood mononuclear cells (PBMCs) of 19 patients and 13 controls using microarrays. We found 18 miRNAs differentially expressed, and pathway analysis of 662 predicted target genes of 11 of these miRNAs revealed an over-representation in pathways previously linked to PD as well as novel pathways. To narrow down the genes for further investigations, we undertook a parallel approach using chromatin immunoprecipitation-sequencing (ChIP-seq) analysis to uncover genome-wide interactions of α-synuclein, a molecule with a central role in both monogenic and idiopathic PD. Convergence of ChIP-seq and miRNomics data highlighted the glycosphingolipid biosynthesis and the ubiquitin proteasome system as key players in PD. We then tested the association of target genes belonging to these pathways with PD risk, and identified nine SNPs in USP37 consistently associated with PD susceptibility in three genome-wide association studies (GWAS) datasets (0.46≤OR≤0.63) and highly significant in the meta-dataset (3.36×10−4<p<1.94×10−3). A SNP in ST8SIA4 was also highly associated with PD (p = 6.15×10−3) in the meta-dataset. These findings suggest that several miRNAs may act as regulators of both known and novel biological processes leading to idiopathic PD

Regulation of healthcare ethics committees in Europe

In this article, the question is discussed if and how Healthcare Ethics Committees (HECs) should be regulated. The paper consists of two parts. First, authors from eight EC member countries describe the status quo in their respective countries, and give reasons as to the form of regulation they consider most adequate. In the second part, the country reports are analysed. It is suggested that regulation of HECs should be central and weak. Central regulation is argued to be apt to improve HECs’ accountability, relevance and comparability. To facilitate biomedical citizenship and ethical reflection, regulation should at the same time be weak rather than strict. Independence of HECs to deliberate about ethical questions, and to give solicited and unsolicited advice, should be supported and only interfered with by way of exception. One exception is when circumstances become temporary adversarial to ethical deliberation in healthcare institutions. In view of European unification, steps should be taken to develop consistent policies for both Eastern and Western European countries

A Practical Platform for Blood Biomarker Study by Using Global Gene Expression Profiling of Peripheral Whole Blood

Background: Although microarray technology has become the most common method for studying global gene expression, a plethora of technical factors across the experiment contribute to the variable of genome gene expression profiling using peripheral whole blood. A practical platform needs to be established in order to obtain reliable and reproducible data to meet clinical requirements for biomarker study. Methods and Findings: We applied peripheral whole blood samples with globin reduction and performed genome-wide transcriptome analysis using Illumina BeadChips. Real-time PCR was subsequently used to evaluate the quality of array data and elucidate the mode in which hemoglobin interferes in gene expression profiling. We demonstrated that, when applied in the context of standard microarray processing procedures, globin reduction results in a consistent and significant increase in the quality of beadarray data. When compared to their pre-globin reduction counterparts, post-globin reduction samples show improved detection statistics, lowered variance and increased sensitivity. More importantly, gender gene separation is remarkably clearer in post-globin reduction samples than in pre-globin reduction samples. Our study suggests that the poor data obtained from pre-globin reduction samples is the result of the high concentration of hemoglobin derived from red blood cells either interfering with target mRNA binding or giving the pseudo binding background signal. Conclusion: We therefore recommend the combination of performing globin mRNA reduction in peripheral whole blood samples and hybridizing on Illumina BeadChips as the practical approach for biomarker study