Heritability of Transforming Growth Factor-ß1 and Tumor Necrosis Factor-Receptor Type 1 Expression and Vitamin D Levels in Healthy Adolescent Twins.

Cytokines and vitamin D both have a role in modulating the immune system, and are also potentially useful biomarkers in mental illnesses such as major depressive disorder (MDD) and schizophrenia. Studying the variability of cytokines and vitamin D in a healthy population sample may add to understanding the association between these biomarkers and mental illness. To assess genetic and environmental contributions to variation in circulating levels of cytokines and vitamin D (25-hydroxy vitamin D: 25(OH)D3), we analyzed data from a healthy adolescent twin cohort (mean age 16.2 years; standard deviation 0.25). Plasma cytokine measures were available for 400 individuals (85 MZ, 115 DZ pairs), dried blood spot sample vitamin D measures were available for 378 individuals (70 MZ, 118 DZ pairs). Heritability estimates were moderate but significant for the cytokines transforming growth factor-ß1 (TGF-ß1), 0.57 (95% CI 0.26-0.80) and tumor necrosis factor-receptor type 1 (TNFR1), 0.50 (95% CI 0.11-0.63) respectively. Measures of 25(OH)D3 were within normal range and heritability was estimated to be high (0.86, 95% CI 0.61-0.94). Assays of other cytokines did not generate meaningful results. These potential biomarkers may be useful in mental illness, with further research warranted in larger sample sizes. They may be particularly important in adolescents with mental illness where diagnostic uncertainty poses a significant clinical challenge.

Dopamine D3 receptor gene variation: impact on electroconvulsive therapy response and ventral striatum responsiveness in depression.

Dysfunction of dopamine D3 receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D3 receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D3 receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a sample of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent samples of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02-0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009; corrected p=0.045) and rs3773679 (uncorrected p=0.009; corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (sample 1: cluster-corrected p=0.002; sample 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli.

Mechanistic considerations for adenosine-lidocaine-magnesium (ALM) in controlling coagulopathy.

Adenosine-lidocaine-magnesium (ALM) mixture is a cardioplegic agent that improves survivability undisputedly in rodents, but not swine, models of hemorrhagic shock. However, despite protection from comorbid coagulopathy being the one common effect reported in both models, the underlying prothrombotic mechanism for ALM has not been fully elucidated. Here, we undertook a component-based approach focusing on individual drugs in the mixture to elaborate on the protective mechanism against coagulopathy within the frames of adenosine signaling and metabolic pathways. Additionally, the translational potential of small and large animal models of hemorrhagic shock for human survival is critically appraised, owing to substantial quantitative/qualitative differences between humans and rodents, particularly regarding the genetics of G protein-coupled receptors (GPCRs) interacting with ALM's constituents.

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain.

BACKGROUND: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. METHODOLOGY: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs.Principal findings/resultsIn a whole-brain analysis, the polymorphism rs1800795 (-174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = -10, z = -15; F(2,286) = 8.54, p(uncorrected) = 0.0002; p(AlphaSim-corrected) = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. CONCLUSIONS/SIGNIFICANCE: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.

The IFN-γ/miniTrpRS signaling axis: An insight into the pathophysiology of osteoporosis and therapeutic potential.

Osteoporosis results from dysregulated bone remodeling with increased osteoclast-mediated destruction of bones. We have recently shown in vitro the truncated tryptophanyl-tRNA synthetase (mini-TrpRS)-dependent action of interferon-gamma (IFN-γ) to promote myeloid lineage multinucleation, a fundamental step in the osteoclast formation. In particular, we found that IFN-γ readily induced monocyte aggregation leading to multinuclear giant cell formation that paralleled marked upregulation of mini-TrpRS. However, blockade of mini-TrpRS with its cognate amino acid and decoy substrate D-Tryptophan prevented mini-TrpRS signaling, and markedly reduced the aggregation of monocytes and multinucleation in the presence of IFN. The cell signaling mechanism executed by mini-TrpRS appears inevitably in any inflammatory environment that involves IFN-γ with outcomes depending on the cell type involved. Here, we elaborate on these findings and discuss the potential role of the IFN-γ/mini-TrpRS signaling axis in osteoporosis pathophysiology, which may eventually materialize in a novel therapeutic perspective for this disease.

The Reelin (RELN) gene is associated with executive function in healthy individuals.

Executive functions such as set-shifting and maintenance are cognitive processes that rely on complex neurodevelopmental processes. Although neurodevelopmental processes are mainly studied in animal models and in neuropsychiatric disorders, the underlying genetic basis for these processes under physiological conditions is poorly understood. We aimed to investigate the association between genetic variants of the Reelin (RELN) gene and cognitive set-shifting in healthy young individuals. The relationship between 12 selected single nucleotide polymorphisms (SNPs) of the RELN gene and cognitive set-shifting as measured by perseverative errors using the modified card sorting test (MCST) was analysed in a sample of N=98 young healthy individuals (mean age in years: 22.7 ± 0.19). Results show that in individual MANCOVA analyses two of five significant SNPs (rs2711870: F(2,39)=7.14; p=0.0019; rs2249372: F(2,39)=6.97; p=0.002) withstood Bonferroni correction for multiple testing (corrected p-value: p=0.004). While haplotype analyses of the RELN gene showed significant associations between three haplotypes and perseverative error processing in various models of inheritance (adjusted for age, gender, BDI, MWTB IQ), the GCT haplotype showed the most robust finding with a recessive model of inheritance (p=2.32 × 10(-5)) involving the functional SNP rs362691 (Leu-Val amino acid change). Although our study strongly suggests the involvement of the RELN gene in cognitive set-shifting and maintenance, our study requires further exploration as well as replication of the findings in larger samples of healthy individuals and in clinical samples with neuropsychiatric disorders.

Prevalence, epidemiological aspects and clinical importance of TT virus infection in Slovakia.

The aim of the study was to assess the prevalence, clinical impact and importance of different risk factors of transmission of TTV infection in Slovakia using two PCR methods. Sera of 426 adult persons were examined. TTV DNA was identified by PCR using primers from N22 and untranslated region (UTR) respectively. The established prevalence of TTV tested with N22 and UTR primers according to patients groups was: acute hepatitis of unknown etiology 4 resp. 28 of 37, acute hepatitis B 3 resp. 29 of 38, chronic hepatitis B 11 resp. 41 of 44, chronic hepatitis C 10 resp. 93 of 102, hemodialysis patients 13 resp. 72 of 72, health care workers 0 resp. 27 of 33, control group 8 resp. 83 of 100. Using N22 primers, TTV infection occurred more frequently in chronic hepatitis B group compared with health care workers, if UTR primers were used the group of hemodialysis patients differed significantly from both acute hepatitis groups, health care workers and controls (p < 0.05). From possible risk factors hemodialysis and transfusion count showed notable differences. Bilirubin and aminotransferase levels did not differ between TTV positive and negative groups. No pathogenetic role of TT virus in liver injury was confirmed.

Dysbindin (DTNBP1)--a role in psychotic depression?

Previous studies yielded evidence for dysbindin (DTNBP1) to impact the pathogenesis of schizophrenia on the one hand and affective disorders such as bipolar or major depressive disorder (MDD) on the other. Thus, in the present study we investigated whether DTNBP1 variation was associated with psychotic depression as a severe clinical manifestation of MDD possibly constituting an overlapping phenotype between affective disorders and schizophrenia. A sample of 243 Caucasian inpatients with MDD (SCID-I) was genotyped for 12 SNPs spanning 92% of the DTNBP1 gene region. Differences in DTNBP1 genotype distributions across diagnostic subgroups of psychotic (N = 131) vs. non-psychotic depression were estimated by Pearson Chi(2) test and logistic regression analyses adjusted for age, gender, Beck Depression Inventory (BDI) and the Global Assessment of Functioning Scale (GAF). Overall, patients with psychotic depression presented with higher BDI and lower GAF scores expressing a higher severity of the illness as compared to depressed patients without psychotic features. Four DTNBP1 SNPs, particularly rs1997679 and rs9370822, and the corresponding haplotypes, respectively, were found to be significantly associated with the risk of psychotic depression in an allele-dose fashion. In summary, the present results provide preliminary support for dysbindin (DTNBP1) gene variation, particularly SNPs rs1997679 and rs9370822, to be associated with the clinical phenotype of psychotic depression suggesting a possible neurobiological mechanism for an intermediate trait on the continuum between affective disorders and schizophrenia.