The Role of Over-Nutrition and Obesity in Multiple Sclerosis

In countries with high standard of living, lowered risk of infectious diseases is parallel to increased incidence of autoimmune diseases. One of the autoimmune disorders, multiple sclerosis, affects genetically susceptible individuals. Genetic susceptibility is supposed to interact with lifestyle and environmental factors in developing autoimmunity in MS. From this point of view, epigenetics provides the bridge between the external environment and the internal genetic system. In MS, environmental burden can modulate gene expression by epigenetic modification of chromatin components, microRNAs or by subtle changes in DNA methylation. Our paper focuses on describing the epigenetic mechanisms linking environmental factors with pathogenesis of multiple sclerosis. We summarise current knowledge about the role of over-nutrition and obesity as epigenetic factors in multiple sclerosis

Produljen tijek Creutzfeldt -Jakobove bolesti uz opsežnu degeneraciju središnjega živčanog sustava

In Slovak genetic Creutzfeldt-Jakob disease patients with E200K mutation in the prion protein gene the mean duration of clinical stage is significantly shorter in methionine homozygous then in methionine / valine heterozygous patients (3.70±2.00 vs. 7.84±7.30 months). An atypical prolonged course (13 months) of Creutzfeldt-Jakob disease complicated by malignant neuroleptic syndrome in a 48-year-old methionine homozygous carrier of E200K mutation is reported. Progression was documented by computed tomography, magnetic resonance imaging, functional-biochemical magnetic resonance spectroscopy, and electroencephalography. Post mortem neurohistologic findings confirmed the definitive diagnosis of Creutzfeldt-Jakob disease and revealed severe reduction of cerebral and cerebellar cortex with almost complete depletion of neuronal cells. The possible explanation of unusual duration of the disease in genetic Creutzfeldt-Jakob disease is discussed. The importance of early diagnosis and timely therapeutic intervention (when effective treatment becomes available) sufficiently preceding the development of irreversible degenerative changes if the central nervous system is emphasized.Srednje trajanje kliničkog stadija u slovačkih bolesnika s genetskom Creutzfeldt-Jakobovom bolešću s mutacijom EZOOK u genu prionskog proteina (PRNP) značajno je kraće u bolesnika homozigotnih za metionin nego u onih heterozigotnih za metionin/valin (3,70±Z,OO prema 7,84±7,30 mjeseci). Opisuje se atipičan produljeni tijek (13 mjeseci) Creutzfeldt-jakobove bolesti komplicirane malignim neurolepticnim sindromom u 48-godišnjeg nositelja mutacije EZOOK homozigotnog za metionin. Progresija je dokumentirana kompjutoriziranom tomografijom, magnetskom rezonancom, funkcionalno biokemijskom spektroskopijom magnetskom rezonancom i elektroencefalografijom. Neurohistološki nalazi pri obdukciji potvrdili su definitivnu dijagnozu Creutzfeldt-Jakobove bolesti i otkrili teško smanjenje cerebralnog i cerebelarnog korteksa uz gotovo potpun nestanak neuronskih stanica. Raspravlja se o mogućem objašnjenju neuobičajenog trajanja bolesti u slučaju genetske Creutzfeldt-Jakobove bolesti. Naglašava se važnost rane dijagnoze i terapijske intervencije (kad učinkovita terapija bude dostupna), koje ce dostatno prethoditi razvoju zapaženih ireverzibilnih degenerativnih promjena središnjega živčanog sustava

Produljen tijek Creutzfeldt -Jakobove bolesti uz opsežnu degeneraciju središnjega živčanog sustava

In Slovak genetic Creutzfeldt-Jakob disease patients with E200K mutation in the prion protein gene the mean duration of clinical stage is significantly shorter in methionine homozygous then in methionine / valine heterozygous patients (3.70±2.00 vs. 7.84±7.30 months). An atypical prolonged course (13 months) of Creutzfeldt-Jakob disease complicated by malignant neuroleptic syndrome in a 48-year-old methionine homozygous carrier of E200K mutation is reported. Progression was documented by computed tomography, magnetic resonance imaging, functional-biochemical magnetic resonance spectroscopy, and electroencephalography. Post mortem neurohistologic findings confirmed the definitive diagnosis of Creutzfeldt-Jakob disease and revealed severe reduction of cerebral and cerebellar cortex with almost complete depletion of neuronal cells. The possible explanation of unusual duration of the disease in genetic Creutzfeldt-Jakob disease is discussed. The importance of early diagnosis and timely therapeutic intervention (when effective treatment becomes available) sufficiently preceding the development of irreversible degenerative changes if the central nervous system is emphasized.Srednje trajanje kliničkog stadija u slovačkih bolesnika s genetskom Creutzfeldt-Jakobovom bolešću s mutacijom EZOOK u genu prionskog proteina (PRNP) značajno je kraće u bolesnika homozigotnih za metionin nego u onih heterozigotnih za metionin/valin (3,70±Z,OO prema 7,84±7,30 mjeseci). Opisuje se atipičan produljeni tijek (13 mjeseci) Creutzfeldt-jakobove bolesti komplicirane malignim neurolepticnim sindromom u 48-godišnjeg nositelja mutacije EZOOK homozigotnog za metionin. Progresija je dokumentirana kompjutoriziranom tomografijom, magnetskom rezonancom, funkcionalno biokemijskom spektroskopijom magnetskom rezonancom i elektroencefalografijom. Neurohistološki nalazi pri obdukciji potvrdili su definitivnu dijagnozu Creutzfeldt-Jakobove bolesti i otkrili teško smanjenje cerebralnog i cerebelarnog korteksa uz gotovo potpun nestanak neuronskih stanica. Raspravlja se o mogućem objašnjenju neuobičajenog trajanja bolesti u slučaju genetske Creutzfeldt-Jakobove bolesti. Naglašava se važnost rane dijagnoze i terapijske intervencije (kad učinkovita terapija bude dostupna), koje ce dostatno prethoditi razvoju zapaženih ireverzibilnih degenerativnih promjena središnjega živčanog sustava

Polymorphisms of glutathione-S-transferase M1, T1, P1 and the risk of prostate cancer: a case-control study

<p>Abstract</p> <p>Background</p> <p>It has been suggested that polymorphisms in glutathione-<it>S</it>-transferases (GST) could predispose to prostate cancer through a heritable deficiency in detoxification pathways for environmental carcinogens. Yet, studies linking <it>GST </it>polymorphism and prostate cancer have so far failed to unambiguously establish this relation in patients. A retrospective study on healthy, unrelated subjects was conducted in order to estimate the population <it>GST </it>genotype frequencies in the Slovak population of men and compare our results with already published data (GSEC project-Genetic Susceptibility to Environmental Carcinogens). A further aim of the study was to evaluate polymorphisms in <it>GST </it>also in patients with prostate cancer in order to compare the evaluated proportions with those found in the control subjects.</p> <p>Methods</p> <p>We determined the <it>GST </it>genotypes in 228 healthy, unrelated subjects who attended regular prostate cancer screening between May 2005 and June 2007 and in 129 histologically verified prostate cancer patients. Analysis for the <it>GST </it>gene polymorphisms was performed by PCR and PCR-RFLP.</p> <p>Results</p> <p>We found that the <it>GST </it>frequencies are not significantly different from those estimated in a European multicentre study or from the results published by another group in Slovakia. Our results suggest that <it>Val/Val </it>genotype of <it>GSTP1 </it>gene could modulate the risk of prostate cancer, even if this association did not reach statistical significance. We did not observe significantly different crude rates of the <it>GSTM1 </it>and <it>GSTT1 </it>null genotypes in the men diagnosed with prostate cancer and those in the control group.</p> <p>Conclusion</p> <p>Understanding the contribution of <it>GST </it>gene polymorphisms and their interactions with other relevant factors may improve screening diagnostic assays for prostate cancer. We therefore discuss issues of study feasibility, study design, and statistical power, which should be taken into account in planning further trials.</p

Spatial variability and reproducibility of GABA‐edited MEGA‐LASER 3D‐MRSI in the brain at 3 T

The reproducibility of gamma‐aminobutyric acid (GABA) quantification results, obtained with MRSI, was determined on a 3 T MR scanner in healthy adults. In this study, a spiral‐encoded, GABA‐edited, MEGA‐LASER MRSI sequence with real‐time motion–scanner‐instability corrections was applied for robust 3D mapping of neurotransmitters in the brain. In particular, the GABA+ (i.e. GABA plus macromolecule contamination) and Glx (i.e. glutamate plus glutamine contamination) signal was measured. This sequence enables 3D‐MRSI with about 3 cm3 nominal resolution in about 20 min. Since reliable quantification of GABA is challenging, the spatial distribution of the inter‐subject and intra‐subject variability of GABA+ and Glx levels was studied via test–retest assessment in 14 healthy volunteers (seven men–seven women). For both inter‐subject and intra‐subject repeated measurement sessions a low coefficient of variation (CV) and a high intraclass correlation coefficient (ICC) were found for GABA+ and Glx ratios across all evaluated voxels (intra−/inter‐subject: GABA+ ratios, CV ~ 8%–ICC > 0.75; Glx ratios, CV ~ 6%–ICC > 0.70). The same was found in selected brain regions for Glx ratios versus GABA+ ratios (CV varied from about 5% versus about 8% in occipital and parietal regions, to about 8% versus about 10% in the frontal area, thalamus, and basal ganglia). These results provide evidence that 3D mapping of GABA+ and Glx using the described methodology provides high reproducibility for application in clinical and neuroscientific studies

Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells

Leucine is an essential, ketogenic amino acid with proteinogenic, metabolic, and signaling roles. It is readily imported from the bloodstream into the brain parenchyma. Therefore, it could serve as a putative substrate that is complementing glucose for sustaining the metabolic needs of brain tumor cells. Here, we investigated the ability of cultured human cancer cells to metabolize leucine. Indeed, cancer cells dispose of leucine from their environment and enrich their media with the metabolite 2-oxoisocaproate. The enrichment of the culture media with a high level of leucine stimulated the production of 3-hydroxybutyrate. When 13C6-leucine was offered, it led to an increased appearance of the heavier citrate isotope with a molar mass greater by two units in the culture media. The expression of 3-methylcrotonyl-CoA carboxylase (MCC), an enzyme characteristic for the irreversible part of the leucine catabolic pathway, was detected in cultured cancer cells and human tumor samples by immunoprobing methods. Our results demonstrate that these cancer cells can catabolize leucine and furnish its carbon atoms into the tricarboxylic acid (TCA) cycle. Furthermore, the release of 3-hydroxybutyrate and citrate by cancer cells suggests their capability to exchange these metabolites with their milieu and the capability to participate in their metabolism. This indicates that leucine could be an additional substrate for cancer cell metabolism in the brain parenchyma. In this way, leucine could potentially contribute to the synthesis of metabolites such as lipids, which require the withdrawal of citrate from the TCA cycle