Systematic Analysis of Gene Expression Differences between Left and Right Atria in Different Mouse Strains and in Human Atrial Tissue

Background: Normal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (paired-like homeodomain transcription factor 2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. We therefore systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria. Methods: We compared left and right atrial gene expression in healthy, adult mice of different strains and ages by employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in either atrium were validated by RT-qPCR and Western blot in further animals and in shock-frozen left and right atrial appendages of patients undergoing open heart surgery. Results: We identified 77 genes with preferential expression in one atrium that were common in all strains and age groups analysed. Independent of strain and age, Pitx2c was the gene with the highest enrichment in left atrium, while Bmp10, a member of the TGFb family, showed highest enrichment in right atrium. These differences were validated by RT-qPCR in murine and human tissue. Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria. Several of the genes and gene groups enriched in left atria have a known biological role for maintenance of healthy physiology, specifically the prevention of atrial pathologies involved in atrial fibrillation, including membrane electrophysiology, metabolic cellular function, and regulation of inflammatory processes. Comparison of the array datasets with published array analyses in heterozygous Pitx2c+/2 atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c. Conclusions: Our study reveals systematic differences between left and right atrial gene expression and supports the hypothesis that Pitx2c has a functional role in maintaining ‘‘leftness’’ in the atrium in adult murine and human hearts

Parkinson’s disease dyskinesias possibly relate to greater dopamine transporter losses in the putamen over time

The pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease is incompletely understood. This study was designed to investigate in Parkinson’s patients, whether time-related changes in striatal dopamine transporter availability are associated to the appearance of dyskinesias. 15 Parkinson’s patients had dopamine transporter-specific SPECT imaging with 123I-FP-CIT twice: at baseline (when they were drug naïve) and at follow-up (6.31±2.29 years from baseline), and were followed up clinically every six months. At the end of the study, patients were divided in two groups according to whether they had developed dyskinesias or not. Semi-quantification of 123I-FP-CIT data was performed using the occipital cortex as the reference region. Specific binding ratios were calculated for the putamen and the caudate. During the clinical follow-up, all Parkinson’s patients were treated pharmaceutically. 8 patients developed dyskinesias, while 7 remained nondyskinetic. At baseline, the two groups had similar 123I-FP-CIT specific binding ratio values for the putamen and the caudate (p>0.05). Also, between-group differences in age, disease duration, and Hoehn & Yahr scores were not statistically significant. Over-time, the putaminal 123I-FP-CIT specific binding ratio values in the dyskinetic group decreased significantly (p<0.01). The nondyskinetic patients had smaller reductions (p<0.05) during the same period of time. At follow-up, the dyskinetic patients had significantly higher Hoehn & Yahr scores (p<0.01) and were taking higher levodopa equivalent doses (p<0.001), as compared to the nondyskinetic patients. The development of Parkinson’s dyskinesias is related to a faster progression rate, as reflected by marked putaminal dopamine transporter decreases

Rhythm Control in Heart Failure Patients With Atrial Fibrillation Contemporary Challenges Including the Role of Ablation

AbstractBecause nonpharmacological interventions likely alter the risks and benefits associated with rhythm control, this paper reviews the role of current rhythm control strategies in atrial fibrillation. This report also focuses on the specific limitations of pharmacological interventions and the utility of percutaneous ablation in this growing population of patients with concomitant atrial fibrillation and heart failure

Physical Chemistry of Chloroquine Permeation through the Cell Membrane with Atomistic Detail

We provide a molecular-level description of the thermodynamics and mechanistic aspects of drug permeation through the cell membrane. As a case study, we considered the antimalaria FDA approved drug chloroquine. Molecular dynamics simulations of the molecule (in its neutral and protonated form) were performed in the presence of different lipid bilayers, with the aim of uncovering key aspects of the permeation process, a fundamental step for the drug’s action. Free energy values obtained by well-tempered metadynamics simulations suggest that the neutral form is the only permeating protomer, consistent with experimental data. H-bond interactions of the drug with water molecules and membrane headgroups play a crucial role for permeation. The presence of the transmembrane potential, investigated here for the first time in a drug permeation study, does not qualitatively affect these conclusions

Three-Dimensional Self-Navigated T2 Mapping for the Detection of Acute Cellular Rejection After Orthotopic Heart Transplantation.

T2 mapping is a magnetic resonance imaging technique measuring T2 relaxation time, which increases with the myocardial tissue water content. Myocardial edema is a component of acute cellular rejection (ACR) after heart transplantation. This pilot study compares in heart transplantation recipients a novel high resolution 3-dimensional (3D) T2-mapping technique with standard 2-dimensional (2D) T2-mapping for ACR detection. Consecutive asymptomatic patients (n = 26) underwent both 3D T2 mapping and reference 2D T2 mapping magnetic resonance imaging on the day of endomyocardial biopsy (EMB). 3D T2 maps were obtained at an isotropic spatial resolution of 1.72 mm (voxel volume 5.1 mm(3)). 2D and 3D maps were matched anatomically, and maximum segmental T2 values were compared blinded to EMB results. In addition, all 3D T2 maps were rendered as 3D images and inspected for foci of T2 elevation. T2 values of segments from 2D and reformatted 3D T2 maps agreed (p &gt; 0.5). The highest 2D segmental T2 values were 49.9 ± 4.0 ms (no ACR = 0R, n = 18), 48.9 ± 0.8 ms (mild ACR = 1R, n = 3), and 65.0 ms (moderate ACR = 2R). Rendered 3D T2 maps of cases with 1R showed foci with significantly elevated T2 signal (T2 = 58.2 ± 3.6 ms); 5 cases (28%) in the 0R group showed foci with increased T2 values (&gt;2 SD above adjacent tissue) that were not visible on the 2D T2 maps. This pilot study in a small cohort suggests equivalency of standard segmental analysis between 3D and 2D T2-mapping. 3D T2 mapping provides a spatial resolution that permits detection of foci with elevated T2 in patients with mild ACR

Precision tests of the Standard Model with leptonic and semileptonic kaon decays

We present a global analysis of leptonic and semileptonic kaon decays data, including all recent results by BNL-E865, KLOE, KTeV, ISTRA+, and NA48. Experimental results are critically reviewed and combined, taking into account theoretical (both analytical and numerical) constraints on the semileptonic kaon form factors. This analysis leads to a very accurate determination of Vus and allows us to perform several stringent tests of the Standard Model