An Adult`s Vitiligo in Estonia: Study of 155 Patients

Background: Vitiligo is a common depigmentary disorder characterized by white patches of the skin, hair and mucous membranes due to selective destruction of melanocytes. Objective: The objective of this study was to analyze the clinical characteristics, coexisting diseases, presence of autoantibodies and autoimmune polyglandular syndrome (APS) in Estonian adult vitiligo patients. Methods:Adult patients with vitiligo were called to participate in the study at the Dermatology Department of Tartu University from January 2005 to July 2008. One hundred fifty five subjects were examined in 141 of those the level of thyroid peroxidase antibodies (TPO-Ab), gastric parietal cell antibodies (PCA), antinuclear antibodies (ANA), antiadrenal cortex antibodies (AAA) and rheumatoid factor (RF) in blood were measured. Results: Study group (mean age 44.9 years, mean age of vitiligo onset 28.5 years, mean duration of vitiligo 16.9 years) consisted of 44 males and 111 females. Vitiligo vulgaris was the most common clinical type (81.3%), followed by acrofacial, focal, segmental and universal vitiligo. Two-thirds of subjects reported a coexisting disease and 36.7% had one or more disease of autoimmune origin. The presence of autoantibodies was established in 49.6%. TPO-Ab was found in 36.9%, PCA in 14.2%, ANA and AAA both in 2.8% and positive RF in 7.8% cases. 17 subjects had APS 3, 35 had subclinical APS 3 and two subjects had APS 4. Conclusions: Vitiligo vulgaris was the most frequent clinical type. Vitiligo was associated with other autoimmune diseases, the presence of autoantibodies in the blood was frequent (especially TPO-Ab) and many subjects had APS

The PRO2268 Gene as a Novel Susceptibility Locus for Vitiligo

Letter to the edito

Polymorphisms in Toll-like receptor genes are associated with vitiligo

Background: The members of Toll-like receptor (TLR) family are responsible for recognizing various molecular patterns associated with pathogens. Their expression is not confined to immune cells and have been detected in skin cells such as keratinocytes and melanocytes. As part of a generated response to pathogens, TLRs are involved in inducing inflammatory mediators to combat these threats. It is therefore not surprising that TLRs have been implicated in inflammatory skin diseases, including atopic dermatitis and psoriasis. Likewise, as key players in autoimmunity, they have been associated with a number of autoimmune diseases. Based on this, the role of TLRs in vitiligo could be suspected, but is yet to be clearly established. Methods: In order to conduct a genetic association analysis, 30 SNPs were selected from TLR1-TLR8 and TLR10 regions to be genotyped in Estonian case-control cohort consisting of 139 vitiligo patients and 307 healthy control individuals. The patients were further analyzed in subgroups based on sex, age of onset, occurrence of vitiligo among relatives, extent of depigmented areas, vitiligo progression activity, appearance of Köbner's phenomenon, existence of halo naevi, and incidence of spontaneous repigmentation. Results: The most notable finding came with SNP rs179020 situated in TLR7 gene, that was associated in entire vitiligo (Padj = 0.0065) and also several subgroup analyses. Other single marker and haplotype analyses pointed to TLR3, TLR4, and TLR10 genes. Conclusions: This study investigated the genetic regions of nine TLR genes in relation to vitiligo susceptibility. The main results were the associations of TLR7 SNPs with vitiligo, while several other associations were obtained from the remaining TLR gene regions. This suggests that in addition to other inflammatory skin diseases, TLRs affect the development of vitiligo, thus making them interesting targets for future research

Glial cell line-derived neurotrophic factor receptor REarranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo

Background Motor symptoms of Parkinson's disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration. Glial cell line-derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons in vitro and in animal models of PD, but the clinical use of GDNF is complicated by its pharmacokinetic properties. The present study aimed to evaluate the neuronal effects of a blood-brain-barrier penetrating small molecule GDNF receptor Rearranged in Transfection agonist, BT13, in the dopamine system. Methods We characterized the ability of BT13 to activate RET in immortalized cells, to support the survival of cultured dopamine neurons, to protect cultured dopamine neurons against neurotoxin-induced cell death, to activate intracellular signaling pathways both in vitro and in vivo, and to regulate dopamine release in the mouse striatum as well as BT13's distribution in the brain. Results BT13 potently activates RET and downstream signaling cascades such as Extracellular Signal Regulated Kinase and AKT in immortalized cells. It supports the survival of cultured dopamine neurons from wild-type but not from RET-knockout mice. BT13 protects cultured dopamine neurons from 6-Hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+)-induced cell death only if they express RET. In addition, BT13 is absorbed in the brain, activates intracellular signaling cascades in dopamine neurons both in vitro and in vivo, and also stimulates the release of dopamine in the mouse striatum. Conclusion The GDNF receptor RET agonist BT13 demonstrates the potential for further development of novel disease-modifying treatments against PD. (c) 2019 International Parkinson and Movement Disorder SocietyPeer reviewe

Promoter polymorphism -119C/G in MYG1 (C12orf10) gene is related to vitiligo susceptibility and Arg4Gln affects mitochondrial entrance of Myg1

<p>Abstract</p> <p>Background</p> <p><it>MYG1 </it>(<it>Melanocyte proliferating gene 1</it>, also C12orf10 in human) is a ubiquitous nucleo-mitochondrial protein, involved in early developmental processes and in adult stress/illness conditions. We recently showed that <it>MYG1 </it>mRNA expression is elevated in the skin of vitiligo patients. Our aim was to examine nine known polymorphisms in the <it>MYG1 </it>gene, to investigate their functionality, and to study their association with vitiligo susceptibility.</p> <p>Methods</p> <p>Nine single nucleotide polymorphisms (SNPs) in the <it>MYG1 </it>locus were investigated by SNPlex assay and/or sequencing in vitiligo patients (n = 124) and controls (n = 325). <it>MYG1 </it>expression in skin biopsies was detected by quantitative-real time PCR (Q-RT-PCR) and polymorphisms were further analysed using luciferase and YFP reporters in the cell culture.</p> <p>Results</p> <p>Control subjects with -119G promoter allele (rs1465073) exhibited significantly higher <it>MYG1 </it>mRNA levels than controls with -119C allele (<it>P </it>= 0.01). Higher activity of -119G promoter was confirmed by luciferase assay. Single marker association analysis showed that the -119G allele was more frequent in vitiligo patients (47.1%) compared to controls (39.3%, <it>P </it>< 0.05, OR 1.37, 95%CI 1.02-1.85). Analysis based on the stage of progression of the vitiligo revealed that the increased frequency of -119G allele occurred prevalently in the group of patients with active vitiligo (n = 86) compared to the control group (48.2% <it>versus </it>39.3%, <it>P </it>< 0.05; OR 1.44, 95%CI 1.02-2.03). Additionally, we showed that glutamine in the fourth position (in Arg4Gln polymorphism) completely eliminated mitochondrial entrance of YFP-tagged Myg1 protein in cell culture. The analysis of available EST, cDNA and genomic DNA sequences revealed that Myg1 4Gln allele is remarkably present in human populations but is never detected in homozygous state according to the HapMap database.</p> <p>Conclusions</p> <p>Our study demonstrated that both <it>MYG1 </it>promoter polymorphism -119C/G and Arg4Gln polymorphism in the mitochondrial signal of Myg1 have a functional impact on the regulation of the <it>MYG1 </it>gene and promoter polymorphism (-119C/G) is related with suspectibility for actively progressing vitiligo.</p

Let’s not forget tautomers

A compound exhibits tautomerism if it can be represented by two structures that are related by an intramolecular movement of hydrogen from one atom to another. The different tautomers of a molecule usually have different molecular fingerprints, hydrophobicities and pKa’s as well as different 3D shape and electrostatic properties; additionally, proteins frequently preferentially bind a tautomer that is present in low abundance in water. As a result, the proper treatment of molecules that can tautomerize, ~25% of a database, is a challenge for every aspect of computer-aided molecular design. Library design that focuses on molecular similarity or diversity might inadvertently include similar molecules that happen to be encoded as different tautomers. Physical property measurements might not establish the properties of individual tautomers with the result that algorithms based on these measurements may be less accurate for molecules that can tautomerize—this problem influences the accuracy of filtering for library design and also traditional QSAR. Any 2D or 3D QSAR analysis must involve the decision of if or how to adjust the observed Ki or IC50 for the tautomerization equilibria. QSARs and recursive partitioning methods also involve the decision as to which tautomer(s) to use to calculate the molecular descriptors. Docking virtual screening must involve the decision as to which tautomers to include in the docking and how to account for tautomerization in the scoring. All of these decisions are more difficult because there is no extensive database of measured tautomeric ratios in both water and non-aqueous solvents and there is no consensus as to the best computational method to calculate tautomeric ratios in different environments

Computational Modeling of Silicate Glasses: A Quantitative Structure-Property Relationship Perspective

This article reviews the present state of Quantitative Structure-Property Relationships (QSPR) in glass design and gives an outlook into future developments. First an overview is given of the statistical methodology, with particular emphasis to the integration of QSPR with molecular dynamics simulations to derive informative structural descriptors. Then, the potentiality of this approach as a tool for interpretative and predictive purposes is highlighted by a number of recent inspiring applications

Three Thousand Years of Continuity in the Maternal Lineages of Ancient Sheep (Ovis aries) in Estonia

lthough sheep (Ovis aries) have been one of the most exploited domestic animals in Estonia since the Late Bronze Age, relatively little is known about their genetic history. Here, we explore temporal changes in Estonian sheep populations and their mitochondrial genetic diversity over the last 3000 years. We target a 558 base pair fragment of the mitochondrial hypervariable region in 115 ancient sheep from 71 sites in Estonia (c. 1200 BC – AD 1900s), 19 ancient samples from Latvia, Russia, Poland and Greece (6800 BC – AD 1700), as well as 44 samples of modern Kihnu native sheep breed. Our analyses revealed: (1) 49 mitochondrial haplotypes, associated with sheep haplogroups A and B; (2) high haplotype diversity in Estonian ancient sheep; (3) continuity in mtDNA haplotypes through time; (4) possible population expansion during the first centuries of the Middle Ages (associated with the establishment of the new power regime related to 13th century crusades); (5) significant difference in genetic diversity between ancient populations and modern native sheep, in agreement with the beginning of large-scale breeding in the 19th century and population decline in local sheep. Overall, our results suggest that in spite of the observed fluctuations in ancient sheep populations, and changes in the natural and historical conditions, the utilisation of local sheep has been constant in the territory of Estonia, displaying matrilineal continuity from the Middle Bronze Age through the Modern Period, and into modern native sheep