Human cardiomyocyte progenitor cell-derived cardiomyocytes display a maturated electrical phenotype.

Cardiomyocyte progenitor cells (CMPCs) can be isolated from the human heart and differentiated into cardiomyocytes in vitro. A comprehensive assessment of their electrical phenotype upon differentiation is essential to predict potential future applications of this cell source. CMPCs isolated from human fetal heart were differentiated in vitro and examined using immunohistochemistry, Western blotting, RT-PCR, voltage clamp and current clamp techniques.

Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction.

Aims: Reduced excitability and gap junction expression are commonly found in electrically remodelled diseased hearts, but their contribution to slow conduction and arrhythmias is unclear. In this study, we have investigated the effect of isolated and combined reductions in membrane excitability and intercellular coupling on impulse propagation and arrhythmogeneity in genetically modified mice.

Methods And Results: Cx43 and Scn5a(1798insD/+) heterozygous (HZ) mice were crossbred to create a mixed offspring: wild-type (WT, n = 15), Cx43 HZ (n = 14), Scn5a(1798insD/+) (Scn5a) HZ (n = 17), and Cx43/Scn5a(1798insD/+) (Cx43/Scn5a) HZ (n = 15) mice.

Effects of childhood trauma on HPA-axis reactivity in women free of lifetime psychopathology.

Exposure to childhood trauma may induce persistent changes in Hypothalamic-Pituitary-Adrenal (HPA)-axis functioning even in the absence of current psychopathology. Because previous studies did not systematically exclude subjects with lifetime psychiatric morbidity, prevalent psychopathology may have confounded the association. In this study we investigated whether women exposed to childhood trauma, but without a history of psychiatric disorders, show alterations in HPA-axis functioning.

Cardiac cell-cell junctions in health and disease: Electrical versus mechanical coupling.

Intercalated discs are the membrane sites where individual cardiomyocytes are connected to each other. Adherens-, desmosomal-, and gap junctions are situated in the intercalated disc and ensure mechanical coupling between cells and enable propagation of electrical impulses throughout the heart. A number of cardiac disorders, for example arrhythmogenic right ventricular dysplasia/cardiomyopathy, have been described in which an impaired mechanical coupling leads to electrical dysfunction, with occurrence of fatal arrhythmias.

Improvement of cardiac efficacy and safety models in drug discovery by the use of stem cell-derived cardiomyocytes.

Background: The pharmaceutical industry suffers from high attrition rates during late phases of drug development. Improved models for early evaluation of drug efficacy and safety are needed to address this problem. Recent developments have illustrated that human stem cell-derived cardiomyocytes are attractive for using as a model system for different cardiac diseases and as a model for screening, safety pharmacology and toxicology.

The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium.

Cardiac sodium channels are responsible for conduction in the normal and diseased heart. We aimed to investigate regional and transmural distribution of sodium channel expression and function in the myocardium. Sodium channel Scn5a mRNA and Na(v)1.

PKG activity causes photoreceptor cell death in two retinitis pigmentosa models.

Photoreceptor degeneration in retinitis pigmentosa is one of the leading causes of hereditary blindness in the developed world. Although causative genetic mutations have been elucidated in many cases, the underlying neuronal degeneration mechanisms are still unknown. Here, we show that activation of cGMP-dependent protein kinase (PKG) hallmarks photoreceptor degeneration in rd1 and rd2 human homologous mouse models.

Rewiring the heart: stem cell therapy to restore normal cardiac excitability and conduction.

The regenerative capacity of the mammalian heart is insufficient to recover from myocardial infarction. Stem cells are currently considered as a promising and valuable tool to replace the, often large, loss of contractile tissue. One of the bottlenecks hampering fast clinical application is the large amount of cells required to replace a single damaged region combined with an appropriate strategy to succeed in homogeneous repair.

Selectivity in enrichment of cAMP-dependent protein kinase regulatory subunits type I and type II and their interactors using modified cAMP affinity resins.

cAMP regulates cellular functions primarily by activating PKA. The involvement of PKAs in various signaling pathways occurring simultaneously in different cellular compartments necessitates stringent spatial and temporal regulation. This specificity is largely achieved by binding of PKA to protein scaffolds, whereby a distinct group of proteins called A kinase anchoring proteins (AKAPs) play a dominant role.

Serum cholesterol, apolipoprotein E genotype and depressive symptoms in elderly European men: the FINE study.

Background: Cohort and case-control studies found that lower serum total cholesterol is associated with depression. It is, however, unclear whether low cholesterol or its lipoprotein fractions are causally related to depression. Using a Mendelian randomization design, the potential association between apolipoprotein E (APOE) genotype (affecting lifetime cholesterol levels) and depressive symptoms was studied.

Photoreceptor cell death mechanisms in inherited retinal degeneration.

Photoreceptor cell death is the major hallmark of a group of human inherited retinal degenerations commonly referred to as retinitis pigmentosa (RP). Although the causative genetic mutations are often known, the mechanisms leading to photoreceptor degeneration remain poorly defined. Previous research work has focused on apoptosis, but recent evidence suggests that photoreceptor cell death may result primarily from non-apoptotic mechanisms independently of AP1 or p53 transcription factor activity, Bcl proteins, caspases, or cytochrome c release.

Differences in distribution of fibrosis in the ventricles underlie dominant arrhythmia vulnerability of the right ventricle in senescent mice.

Mutations that are supposed to affect right (RV) and left ventricular (LV) electrophysiology equally, often reveal dominant conduction slowing and arrhythmia vulnerability in RV. In this study we investigated the mechanism of dominant arrhythmia vulnerability of RV in senescent mice. We performed epicardial ventricular activation mapping on adult and senescent Langendorff perfused hearts.

Triplex protein quantification based on stable isotope labeling by peptide dimethylation applied to cell and tissue lysates.

Stable isotope labeling is at present one of the most powerful methods in quantitative proteomics. Stable isotope labeling has been performed at both the protein as well as the peptide level using either metabolic or chemical labeling. Here, we present a straightforward and cost-effective triplex quantification method that is based on stable isotope dimethyl labeling at the peptide level.

Transmural dispersion of refractoriness and conduction velocity is associated with heterogeneously reduced connexin43 in a rabbit model of heart failure.

Background: Heterogeneity of repolarization and conduction is a potential source of arrhythmogenesis. In heart failure (HF), intercellular coupling is reduced and heterogeneities may become evident because of reduced intercellular coupling.

Objective: This study sought to investigate connexin43 (Cx43) expression, conduction velocity (CV), refractoriness and inducibility of arrhythmias at multiple sites of the left ventricle during HF.

In calcineurin-induced cardiac hypertrophy expression of Nav1.5, Cx40 and Cx43 is reduced by different mechanisms.

Alterations in expression levels of Na(v)1.5, Cx43 and Cx40 have been frequently reported in cardiac disease and are associated with the development of arrhythmias, but little is known about the underlying molecular mechanisms. In this study we investigated electrical conduction and expression of Na(v)1.

Sialoadhesin expression in intact degenerating retinas and following transplantation.

Purpose: Resident microglial cells normally do not express sialoadhesin (Sn; a sialic acid-binding receptor), whereas recruited inflammatory macrophages have been shown to do so. The expression of Sn was examined in the course of photoreceptor cell degeneration and after transplantation.

Methods: Sn expression was analyzed in retinas of rd1 and rds mice.

Progenitor cells isolated from the human heart: a potential cell source for regenerative therapy.

Background: In recent years, resident cardiac progenitor cells have been identified in, and isolated from the rodent heart. These cells show the potential to form cardiomyocytes, smooth muscle cells, and endothelial cells in vitro and in vivo and could potentially be used as a source for cardiac repair. However, previously described cardiac progenitor cell populations show immature development and need co-culture with neonatal rat cardiomyocytes in order to differentiate in vitro.

Mental health of Dutch peacekeeping veterans 10-25 years after deployment.

Objective: This report describes the mental health of Dutch peacekeeping veterans, 10--25 years after deployment, and its association with deployment-related traumatic events.

Method: We randomly selected a group of 1046 peacekeeping veterans, who participated in military missions in Lebanon, former Yugoslavia, and various other missions between 1979 and 1997. We sent a questionnaire assessing current levels of psychological distress (Brief Symptom Inventory--BSI), and a questionnaire assessing trauma related to deployment.

Adrenergic regulation of conduction velocity in cultures of immature cardiomyocytes.

During cardiac maturation, increased exposure of the heart to circulating catecholamines correlates with increased conduction velocity and growth of the heart. We used an in vitro approach to study the underlying mechanisms of adrenergic stimulation induced changes in conduction velocity. By combining functional measurements and molecular techniques, we were able to demonstrate that the increased conduction velocity after beta-adrenergic stimulation is probably not caused by changes in intercellular coupling.

rd1 Mouse retina shows an imbalance in the activity of cysteine protease cathepsins and their endogenous inhibitor cystatin C.

Purpose: To compare in vivo levels, spatial localization, and in vitro secretion of cysteine protease cathepsins and cystatin C (cysC) in the retinal degeneration 1 (rd1) mouse model of retinitis pigmentosa and control (wt) mouse retinas.

Methods: The spatial localization, protein contents, cysC levels and cathepsin-B, -S, and -L activities in wt and rd1 retinas at postnatal (PN) days 2, 7, 14, 21, and 28 were analyzed by immunostaining, spectrophotometry, ELISA, and fluorescence spectrophotometry. The in vitro secretion of cysC and cysteine proteases by PN7 retinal explants into the conditioned medium (RCM) was quantified.

Dominant arrhythmia vulnerability of the right ventricle in senescent mice.

Background: Several cardiac disorders affect the right ventricle (RV) and left ventricle (LV) equally, but nevertheless, RV vulnerability to conduction slowing and arrhythmias exceeds that of the LV.

Objective: This study sought to assess the mechanism of dominant RV arrhythmia vulnerability in senescent mice as a model of general reduced myocardial integrity.

Methods: Epicardial ventricular activation mapping was performed on senescent (22 months) and adult (3 months) Langendorff perfused mouse hearts.

Natural and sexual selection against hybrid flycatchers.

While sexual selection is generally assumed to quickly cause or strengthen prezygotic barriers between sister species, its role in causing postzygotic isolation, through the unattractiveness of intermediate hybrids, is less often examined. Combining 24 years of pedigree data and recently developed species-specific molecular markers from collared (Ficedula albicollis) and pied (Ficedula hypoleuca) flycatchers and their hybrids, we were able to quantify all key components of fitness. To disentangle the relative role of natural and sexual selection acting on F1 hybrid flycatchers, we estimated various fitness components, which when combined represent the total lifetime reproductive success of F1 hybrids, and then compared the different fitness components of F1 hybrids to that of collared flycatchers.

Lysosome mediated Kir2.1 breakdown directly influences inward rectifier current density.

The inward rectifier current generated by Kir2.1 ion channel proteins is primarily responsible for the stable resting membrane potential in various excitable cell types, like neurons and myocytes. Tight regulation of Kir2.

Does trauma cause lasting changes in HPA-axis functioning in healthy individuals?

Although the majority of people who are exposed to traumatic events do not develop psychopathology, trauma has often been associated with increased vulnerability to psychiatric disorders. In addition, alterations in the HPA-axis have been demonstrated in patients with trauma-related psychiatric disorders. We hypothesize that trauma causes dysregulation of the HPA-axis.