Pyruvate dehydrogenase deficiency: morphological and metabolic effects, creation of animal model to search for curative treatment

The main source of energy for brain and other organs is glucose. To obtain energy for all tissue, glucose has to come through glycolysis; then as pyruvate it is converted to acetyl-CoA by pyruvate dehydrogenase complex (PDC) and finally enters citric acid cycle. What happens when one of these stages become disturb? Mutation in genes encoding subunits of PDC leads to pyruvate dehydrogenase deficiency. Abnormalities in PDC activity result in severe metabolic and brain malformations. For better understanding the development and mechanism of pyruvate dehydrogenase deficiency the murine model of this disease has been created. Studies on a murine model showed similar malformation in brain structures as in the patients suffered from pyruvate dehydrogenase deficiency such as reduced neuronal density, heterotopias of grey matter, reduced size of corpus callosum and pyramids. There is still no effective cure for PDC-deficiency. Promising therapy seemed to be ketogenic diet, which substitutes glucose to ketone bodies as a source of energy. Studies have shown that ketogenic diet decreases lactic acidosis and inhibits brain malformations, but not the mortality in early childhood. The newest reports say that phenylbutyrate increases the level of PDC in the brain, because it reduces the level of inactive form of PDH. Experiments on human fibroblast and zebra fish PDC-deficiency model showed that phenylbutyrate is promising cure to PDC-deficiency. This review summarizes the most important findings on the metabolic and morphological effects of PDC-deficiency and research for treatment therapy

Changes in DNA Sequence and Methylation Contribute to the Predisposition of Schizophrenia: Toward an Epigenetic Therapy

Schizophrenia has a heterogeneous and complex etiology that includes multiple candidate genes affected by a variety of mutational mechanisms including epigenetics, functional pathways, and environmental factors. This chapter mainly focuses on reviewing two sets of studies. The first one is whole‐genome next‐generation sequencing datasets involving monozygotic twins discordant for schizophrenia. The findings suggest that de novo sequence variations may underlie the discordance of monozygotic twins for schizophrenia. Second, whole‐genome DNA methylation study suggesting the role of DNA methylation in the mechanisms of actions of antipsychotic drugs in treating the disorder as well as the manifestation of side effects such as metabolic disorders. Furthermore, we are reporting original research results using next‐generation mitochondrial DNA sequence analysis of a pair of monozygotic twins discordant for schizophrenia as well as their mother. The chapter sheds light on the interplay between sequence variations and epigenetic signatures, including DNA methylation changes, in the etiology and pathophysiology of schizophrenia. Given the dynamic nature of methylation, it may be possible to develop a new treatment strategy for schizophrenia that is based on reversion of genomic methylation. This may involve environmental, dietary, and/or pharmaceutical approaches

Insights into the Origin of DNA Methylation Differences between Monozygotic Twins Discordant for Schizophrenia

BACKGROUND: DNA methylation differences between monozygotic twins discordant for schizophrenia have been previously reported. However, the origin of methylation differences between monozygotic twins discordant for schizophrenia is not clear. The findings here argue that all DNA methylation differences may not necessarily represent the cause of the disease; rather some may result from the effect of antipsychotics. METHODS: Methylation differences in rat brain regions and also in two pairs of unrelated monozygotic twins discordant for schizophrenia have been studied using genome-wide DNA methylation arrays at Arraystar Inc. (Rockville, Maryland, USA). The identified gene promoters showing significant alterations to DNA methylation were then further characterized using ingenuity pathway analysis (Ingenuity System Inc, CA, USA). RESULTS: Pathway analysis of the most significant gene promoter hyper/hypomethylation revealed a significant enrichment of DNA methylation changes in biological networks and pathways directly relevant to neural development and psychiatric disorders. These included HIPPO signaling (p = 3.93E-03) and MAPK signaling (p = 4.27E-03) pathways involving hypermethylated genes in schizophrenia-affected patients as compared to their unaffected co-twins. Also, a number of significant pathways and networks involving genes with hypomethylated gene promoters have been identified. These included CREB signaling in neurons (p = 1.53E-02), Dopamine-DARPP32 feedback in cAMP signaling (p = 7.43E-03) and Ephrin receptors (p = 1.13E-02). Further, there was significant enrichment for pathways involved in nervous system development and function (p = 1.71E-03-4.28E-02). CONCLUSION: The findings highlight the significance of antipsychotic drugs on DNA methylation in schizophrenia patients. The unique pathways affected by DNA methylation in the two pairs of monozygotic twins suggest that patient-specific pathways are responsible for the disease; suggesting that patient-specific treatment strategies may be necessary in treating the disorder. The study reflects the need for developing personalized medicine approaches that take into consideration epigenetic variations between patients

Olanzapine-Induced Methylation Alters Cadherin Gene Families and Associated Pathways Implicated in Psychosis

BACKGROUND: The complex aetiology of most mental disorders involves gene-environment interactions that may operate using epigenetic mechanisms particularly DNA methylation. It may explain many of the features seen in mental disorders including transmission, expression and antipsychotic treatment responses. This report deals with the assessment of DNA methylation in response to an antipsychotic drug (olanzapine) on brain (cerebellum and hippocampus), and liver as a non-neural reference in a rat model. The study focuses on the Cadherin/protocadherins encoded by a multi-gene family that serve as adhesion molecules and are involved in cell-cell communication in the mammalian brain. A number of these molecules have been implicated in the causation of schizophrenia and related disorders. RESULTS: The results show that olanzapine causes changes in DNA methylation, most specific to the promoter region of specific genes. This response is tissue specific and involves a number of cadherin genes, particularly in cerebellum. Also, the genes identified have led to the identification of several pathways significantly affected by DNA methylation in cerebellum, hippocampus and liver. These included the Gα12/13 Signalling (p = 9.2E-08) and Wnt signalling (p = 0.01) pathways as contributors to psychosis that is based on its responsiveness to antipsychotics used in its treatment. CONCLUSION: The results suggest that DNA methylation changes on the promoter regions of the Cadherin/protocadherin genes impact the response of olanzapine treatment. These impacts have been revealed through the identified pathways and particularly in the identification of pathways that have been previously implicated in psychosis

DNA Methylation Differences in Monozygotic Twin Pairs Discordant for Schizophrenia Identifies Psychosis Related Genes and Networks

Background Despite their singular origin, monozygotic twin pairs often display discordance for complex disorders including schizophrenia. It is a common (1%) and often familial disease with a discordance rate of ~50% in monozygotic twins. This high discordance is often explained by the role of yet unknown environmental, random, and epigenetic factors. The involvement of DNA methylation in this disease appears logical, but remains to be established. Methods We have used blood DNA from two pairs of monozygotic twins discordant for schizophrenia and their parents in order to assess genome-wide methylation using a NimbleGen Methylation Promoter Microarray. Results The genome-wide results show that differentially methylated regions (DMRs) exist between members representing discordant monozygotic twins. Some DMRs are shared with parent(s) and others appear to be de novo. We found twenty-seven genes affected by DMR changes that were shared in the affected member of two discordant monozygotic pairs from unrelated families. Interestingly, the genes affected by pair specific DMRs share specific networks. Specifically, this study has identified two networks; “cell death and survival” and a “cellular movement and immune cell trafficking”. These two networks and the genes affected have been previously implicated in the aetiology of schizophrenia. Conclusions The results are compatible with the suggestion that DNA methylation may contribute to the discordance of monozygotic twins for schizophrenia. Also, this may be accomplished by the direct effect of gene specific methylation changes on specific biological networks rather than individual genes. It supports the extensive genetic, epigenetic and phenotypic heterogeneity implicated in schizophrenia

Experimental study of a R290 variable geometry ejector

Ejectors are classified as fluid-dynamics controlled devices where the "component-scale"performances are imposed by the local-scale fluid dynamic phenomena. For this reason, ejector performances (measured by the pressure-entrainment ratio coordinate of the critical point) are determined by the connection of operation conditions, working fluid and geometrical parameters. Given such a connection, variable geometry ejector represents a promising solution to increase the flexibility of ejector-based systems. The present study aims to extend knowledge on variable geometry systems, evaluating the local and global performances of the R290 ejector equipped with a spindle. The prototype ejector was installed at the R290 vapour compression test rig adapted and modified for the required experimental campaign. The test campaign considered global parameter measurements, such as the pressure and the temperature at inlets and outlet ports together with the mass flow rates at both inlet nozzles, and the local pressure drop measurements inside the ejector. In addition, the experimental data were gathered for different spindle positions starting from fully open position the spindle position limited by the mass flow rate inside the test rig with the step of 1.0 mm

Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy

Statistical Analysis of TOTPAR over 2, 4, 6 and 8 h (ANCOVA) (ITT Population) (single-dose phase). (DOCX 16 kb

Electroencephalographic Findings, Antiepileptic Drugs and Risk Factors of 433 Individuals Referred to a Tertiary Care Hospital in Ethiopia

Background: Little is known about the characteristics of electroencephalogram (EEG) findings in epileptic patients in Ethiopia. The objective of this  study was to characterize the EEG patterns, indications, antiepileptic drugs (AEDs), and epilepsy risk factors.Methods: A retrospective observational review of EEG test records of 433 patients referred to our electrophysiology unit between July 01, 2020 and  December 31, 2021.Results: The age distribution in the study participants was right skewed unipolar age distribution for both sexes and the mean age of 33.8 (SD=15.7) years. Male accounted for 51.7%. Generalized tonic clonic seizure was the most common seizure type. The commonest indication for EEG was  abnormal body movement with loss of consciousness (35.2%). Abnormal EEG findings were observed in 55.2%; more than half of them were Interictal epileptiform discharges, followed by focal/or generalized slowing. Phenobarbitone was the commonest AEDs. A quarter (20.1%) of the  patients were getting a combination of two AEDs and 5.2% were on 3 different AEDs. Individuals taking the older AEDs and those on 2 or more AEDs  tended to have abnormal EEG findings. A cerebrovascular disorder (27.4%) is the prevalent risk factor identified followed by brain tumor, HIV  infection, and traumatic head injury respectively.Conclusion: High burden of abnormal EEG findings among epileptic patients referred to our unit. The proportion of abnormal EEG patterns was  higher in patients taking older generation AEDs and in those on 2 or more AEDs. Stroke, brain tumor, HIV infection and traumatic head injury were  the commonest identified epilepsy risk factors