The role of BDNF methylation and Val66Met in amygdala reactivity during emotion processing

Epigenetic alterations of the brain‐derived neurotrophic factor (BDNF) gene have been associated with psychiatric disorders in humans and with differences in amygdala BDNF mRNA levels in rodents. This human study aimed to investigate the relationship between the functional BDNF‐Val⁶⁶Met polymorphism, its surrounding DNA methylation in BDNF exon IX, amygdala reactivity to emotional faces, and personality traits. Healthy controls (HC, n = 189) underwent functional MRI during an emotional face‐matching task. Harm avoidance, novelty seeking and reward dependence were measured using the Tridimensional Personality Questionnaire (TPQ). Individual BDNF methylation profiles were ascertained and associated with several BDNF single nucleotide polymorphisms surrounding the BDNF‐Val⁶⁶Met, amygdala reactivity, novelty seeking and harm avoidance. Higher BDNF methylation was associated with higher amygdala reactivity (x = 34, y = 0, z = ?26, t₍₁₆₆₎ = 3.00, TFCE = 42.39, p_(FWE) = .045), whereby the BDNF‐Val⁶⁶Met genotype per se did not show any significant association with brain function. Furthermore, novelty seeking was negatively associated with BDNF methylation (r = ?.19, p = .015) and amygdala reactivity (r = ?.17, p = .028), while harm avoidance showed a trend for a positive association with BDNF methylation (r = .14, p = .066). The study provides first insights into the relationship among BDNF methylation, BDNF genotype, amygdala reactivity and personality traits in humans, highlighting the multidimensional relations among genetics, epigenetics, and neuronal functions. The present study suggests a possible involvement of epigenetic BDNF modifications in psychiatric disorders and related brain functions, whereby high BDNF methylation might reduce BDNF mRNA expression and upregulate amygdala reactivity.     

Silymarin from Milk Thistle Fruits Counteracts Selected Pathological Changes in the Lenses of Type 1 Diabetic Rats

Diabetes is a metabolic disease affecting many tissues and organs. The main etiological factor for diabetic complications is hyperglycemia and subsequent pathologies, such as oxidative stress. One of the organs susceptible to the development of diabetic complications is the eye with all of its elements, including the lens. The aim of this study was to evaluate the effect of silymarin, an extract obtained from milk thistle fruit husks, on the oxidative stress markers in the lenses of type 1 diabetic rats. The study was performed on male rats in which type 1 diabetes was induced with 60 mg/kg streptozotocin injection. Diabetic animals were treated via an intragastric tube with silymarin at 50 and 100 mg/kg doses for four weeks. Multiple oxidative stress and polyol pathway-related parameters were measured in the lenses, and auxiliary biochemical tests in the serum were conducted. Diabetes induced severe pathological changes both in the lenses and the serum, and silymarin counteracted several of them. Nevertheless, the qualitative analyses encompassing all tested parameters indicate that silymarin slightly improved the overall state of diabetic animals. Upon the obtained results, it can be concluded that silymarin reveals a faint positive effect on the lenses in type 1 diabetic rats.     

Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome

Placental protein 13 (PP13) is a galectin expressed by the syncytiotrophoblast. Women who subsequently develop preterm pre-eclampsia have low first trimester maternal serum PP13 concentrations. This study revealed that third trimester maternal serum PP13 concentration increased with gestational age in normal pregnancies (p < 0.0001), and it was significantly higher in women presenting with preterm pre-eclampsia (p = 0.02) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (p = 0.01) than in preterm controls. Conversely, placental PP13 mRNA (p = 0.03) and protein, as well as cytoplasmic PP13 staining of the syncytiotrophoblast (p < 0.05) was decreased in these pathological pregnancies compared to controls. No differences in placental expression and serum concentrations of PP13 were found at term between patients with pre-eclampsia and control women. In contrast, the immunoreactivity of the syncytiotrophoblast microvillous membrane was stronger in both term and preterm pre-eclampsia and HELLP syndrome than in controls. Moreover, large syncytial cytoplasm protrusions, membrane blebs and shed microparticles strongly stained for PP13 in pre-eclampsia and HELLP syndrome. In conclusion, parallel to its decreased placental expression, an augmented membrane shedding of PP13 contributes to the increased third trimester maternal serum PP13 concentrations in women with preterm pre-eclampsia and HELLP syndrome.     

Saturating Nonlinearities of Contrast Response in Human Visual Cortex

Response nonlinearities are ubiquitous throughout the brain, especially within sensory cortices where changes in stimulus intensity typically produce compressed responses. Although this relationship is well established in electrophysiological measurements, it remains controversial whether the same nonlinearities hold for population-based measurements obtained with human fMRI. We propose that these purported disparities are not contingent on measurement type and are instead largely dependent on the visual system state at the time of interrogation. We show that deploying a contrast adaptation paradigm permits reliable measurements of saturating sigmoidal contrast response functions (10 participants, 7 female). When not controlling the adaptation state, our results coincide with previous fMRI studies, yielding nonsaturating, largely linear contrast responses. These findings highlight the important role of adaptation in manifesting measurable nonlinear responses within human visual cortex, reconciling discrepancies reported in vision neuroscience, re-establishing the qualitative relationship between stimulus intensity and response across different neural measures and the concerted study of cortical gain control.SIGNIFICANCE STATEMENT Nonlinear stimulus–response relationships govern many essential brain functions, ranging from the sensory to cognitive level. Certain core response properties previously shown to be nonlinear with nonhuman electrophysiology recordings have yet to be reliably measured with human neuroimaging, prompting uncertainty and reconsideration. The results of this study stand to reconcile these incongruencies in the vision neurosciences, demonstrating the profound impact adaptation can have on brain activation throughout the early visual cortex. Moving forward, these findings facilitate the study of modulatory influences on sensory processing (i.e., arousal and attention) and help establish a closer link between neural recordings in animals and hemodynamic measurements from human fMRI, resuming a concerted effort to understand operations in the mammalian cortex.     

Left atrial appendage size is a marker of atrial fibrillation recurrence after radiofrequency catheter ablation in patients with persistent atrial fibrillation

IntroductionThere are no consistently confirmed predictors of atrial fibrillation (AF) recurrence after catheter ablation. Therefore, we aimed to study whether left atrial appendage volume (LAAV) and function influence the long‐term recurrence of AF after catheter ablation, depending on AF type.MethodsAF patients who underwent point‐by‐point radiofrequency catheter ablation after cardiac computed tomography (CT) were included in this analysis. LAAV and LAA orifice area were measured by CT. Uni‐ and multivariable Cox proportional hazard regression models were performed to determine the predictors of AF recurrence.ResultsIn total, 561 AF patients (61.9 ± 10.2 years, 34.9% females) were included in the study. Recurrence of AF was detected in 40.8% of the cases (34.6% in patients with paroxysmal and 53.5% in those with persistent AF) with a median recurrence‐free time of 22.7 (9.3–43.1) months. Patients with persistent AF had significantly higher body surface area‐indexed LAV, LAAV, and LAA orifice area and lower LAA flow velocity, than those with paroxysmal AF. After adjustment left ventricular ejection fraction (LVEF) <50% (HR = 2.17; 95% CI = 1.38–3.43; p < .001) and LAAV (HR = 1.06; 95% CI = 1.01–1.12; p = .029) were independently associated with AF recurrence in persistent AF, while no independent predictors could be identified in paroxysmal AF.ConclusionThe current study demonstrates that beyond left ventricular systolic dysfunction, LAA enlargement is associated with higher rate of AF recurrence after catheter ablation in persistent AF, but not in patients with paroxysmal AF.     

Microstructure and Mechanical Properties of Ti-25Nb-4Ta-8Sn Alloy Prepared by Spark Plasma Sintering

As the commercially most-used Ti-6Al-4V alloy has a different modulus of elasticity compared to the modulus of elasticity of bone and contains allergenic elements, β-Ti alloy could be a suitable substitution in orthopedics. The spark plasma sintering (SPS) method is feasible for the preparation of materials, with very low porosity and fine-grained structure, leading to higher mechanical properties. In this study, we prepared quaternary Ti-25Nb-4Ta-8Sn alloy using the spark plasma sintering method. The material was also heat-treated in order to homogenize the structure and compare the microstructure and properties in as-sintered and annealed states. The SPS sample had a modulus of elasticity of about 63 ± 1 GPa, which, after annealing, increased to the value of 73 ± 1 GPa. The tensile yield strength (TYS) of the SPS sample was 730 ± 52 MPa, ultimate tensile strength (UTS) 764 ± 10 MPa, and ductility 22 ± 9%. Annealed samples reached higher values of TYS and UTS (831 ± 60 MPa and 954 ± 48 MPa), but the ductility decreased to the value of 3 ± 1%. The obtained results are discussed considering the observed microstructure of the alloy.     

Accelerated recovery of 5-fluorouracil-damaged bone marrow after rosiglitazone treatment

Our preliminary data indicate that rosiglitazone may be myeloprotective. We investigated whether it can modify bone marrow recovery. Five-day pre-treatment with rosiglitazone significantly accelerated recovery of 5-fluorouracil-damaged bone marrow in mice. Frequency and femoral content of granulocyte-macrophage progenitors reached mean baseline faster in pre-treated groups than in 5-fluorouracil-treated controls. Consequently, neutropenia was milder. Five-day insulin pre-treatment had similar effects in vivo. Insulin supports in vitro hematopoiesis. The observed myeloprotection demonstrated the importance of insulin in vivo. Clinical use of insulin to moderate myelotoxicity is impractical but rosiglitazone, an insulin sensitizer, could offer hope. Although rosiglitazone tends to increase plasma insulin levels, the significant myeloprotection was partly due to direct effects on progenitors. In vitro rosiglitazone enhanced the survival of both murine progenitor and human mobilized blood stem cells in the presence of 5-fluorouracil, the effect of which was neutralized by a peroxisome-proliferator-activated receptor-gamma antagonist.     

Gesundheit und Frühe Hilfen: Die intersektorale Kooperation im Blick der Forschung

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Frühe Hilfen sind Angebote für Familien mit Kindern bis zum Alter von 3&nbsp;Jahren. Sie leisten einen Beitrag zur...     

The chondrocyte channelome: A narrative review

Chondrocytes are the main cells in the extracellular matrix (ECM) of articular cartilage and possess a highly differentiated phenotype that is the hallmark of the unique physiological functions of this specialised load-bearing connective tissue. The plasma membrane of articular chondrocytes contains a rich and diverse complement of membrane proteins, known as the membranome, which defines the cell surface phenotype of the cells. The membranome is a key target of pharmacological agents and is important for chondrocyte function. It includes channels, transporters, enzymes, receptors, and anchors for intracellular, cytoskeletal and ECM proteins and other macromolecular complexes. The chondrocyte channelome is a sub-compartment of the membranome and includes a complete set of ion channels and porins expressed in these cells. Many of these are multi-functional proteins with “moonlighting” roles, serving as channels, receptors and signalling components of larger molecular assemblies. The aim of this review is to summarise our current knowledge of the fundamental aspects of the chondrocyte channelome, discuss its relevance to cartilage biology and highlight its possible role in the pathogenesis of osteoarthritis (OA). Excessive and inappropriate mechanical loads, an inflammatory micro-environment, alternative splicing of channel components or accumulation of basic calcium phosphate crystals can result in an altered chondrocyte channelome impairing its function. Alterations in Ca²⁺ signalling may lead to defective synthesis of ECM macromolecules and aggravated catabolic responses in chondrocytes, which is an important and relatively unexplored aspect of the complex and poorly understood mechanism of OA development.     

The influence of glucocorticoid receptor single nucleotide polymorphisms on outcome after haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation (HSCT) remains the only cure for most haematological malignancies, however, the mortality rate remains high. Complications after HSCT include relapse, graft versus host disease (GvHD), graft rejection and infection. Over the last few years several groups, have demonstrated that non‐HLA gene polymorphisms can be predictive of outcome after HSCT. Since the glucocorticoid cortisol is pivotal in the regulation of the immune system, we decided to examine single nucleotide polymorphisms (SNPs; rs6198, rs33388 and rs33389) within the glucocorticoid receptor (GR) and correlate with HSCT outcome. The training set consisted of patients (n = 458) who underwent HSCT for acute leukaemia between 1983 and 2005. In the recipients, the absence of the ACT haplotype and absence of the T allele of rs33388 were associated with decreased OS and the absence of the ACT haplotype, the absence of the T allele of rs33388 and the presence of the ATA haplotype were associated with increased risk of relapse. In addition, the presence of the ACT haplotype in the recipient showed a trend to be associated with increased risk of chronic graft versus host disease (cGvHD). The patients in this cohort received mainly myeloablative conditioning (n = 327). The SNPs in the glucocorticoid receptor were then investigated in a validation set (n = 251) of HSCT patients transplanted for acute leukaemia from 2006. This cohort contained significantly more patients that had received reduced intensity conditioning (RIC). Some of the results could be validated in these patients. However, contrary to the training set, the absence of the haplotype ACT in the donor in this cohort was associated with increased risk of cGvHD. Differences in the conditioning were shown to influence the results. These results are the first to associate GR SNPs with HSCT outcome and demonstrate the inherent problems of replicating SNP association studies in HSCT, due to different pre‐transplant regimens.