Predictive Value of Tpeak – Tend Indices for Adverse Outcomes in Acquired QT Prolongation: A Meta-Analysis

Background: Acquired QT interval prolongation has been linked with malignant ventricular arrhythmias, such as torsade de pointes, in turn predisposing to sudden cardiac death. Increased dispersion of repolarization has been identified as a pro-arrhythmic factor and can be observed as longer Tpeak – Tend interval and higher Tpeak – Tend/QT ratio on the electrocardiogram. However, the values of these repolarization indices for predicting adverse outcomes in this context have not been systematically evaluated.Method: PubMed, Embase and Cochrane Library databases were searched until 14th February 2018, identifying 232 studies.Results: Five studies on acquired QT prolongation met the inclusion criteria and 308 subjects with drug-induced LQTS patients (mean age: 66 ± 18 years old; 46% male) were included in this meta-analysis. Tpeak – Tend intervals were longer [mean difference [MD]: 76 ms, standard error [SE]: 26 ms, P = 0.003; I2 = 98%] and Tpeak – Tend/QT ratios were higher (MD: 0.14, SE: 0.03, P = 0.000; I2 = 29%) in patients with torsade de pointes compared to those without these events.Conclusion: Tpeak – Tend interval and Tpeak – Tend/QT ratio were higher in patients with acquired QT prolongation suffering from torsade de pointes compared to those who did not. These repolarization indices may provide additional predictive value for identifying high-risk individuals

Higher Dispersion Measures of Conduction and Repolarization in Type 1 Compared to Non-type 1 Brugada Syndrome Patients: An Electrocardiographic Study From a Single Center

Background: Brugada syndrome (BrS) is a cardiac ion channelopathy that predisposes affected individuals to sudden cardiac death (SCD). Type 1 BrS is thought to take a more malignant clinical course than non-type 1 BrS. We hypothesized that the degrees of abnormal repolarization and conduction are greater in type 1 subjects and these differences can be detected by electrocardiography (ECG).Methods: Electrocardiographic data from spontaneous type 1 and non-type 1 BrS patients were analyzed. ECG parameters were measured from leads V1 to V3. Values were expressed as median [lower quartile-upper quartile] and compared using Kruskal-Wallis ANOVA.Results: Compared to non-type 1 BrS patients (n = 29), patients with spontaneous type 1 patterns (n = 22) showed similar (P > 0.05) heart rate (73 [64–77] vs. 68 [62–80] bpm), QRS duration (136 [124–161] vs. 127 [117–144] ms), uncorrected QT (418 [393–443] vs. 402 [386–424] ms) and corrected QT intervals (457 [414–474] vs. 430 [417–457] ms), JTpeak intervals (174 [144–183] vs. 174 [150–188] ms), Tpeak− Tend intervals (101 [93–120] vs. 99 [90–105] ms), Tpeak− Tend/QT ratios (0.25 [0.23–0.27] vs. 0.24 [0.22–0.27]), Tpeak− Tend/QRS (0.77 [0.62–0.87] vs. 0.77 [0.69–0.86]), Tpeak− Tend/(QRS × QT) (0.00074 [0.00034–0.00096] vs. 0.00073 [0.00048–0.00012] ms−1), index of Cardiac Electrophysiological Balance (iCEB, QT/QRS, marker of wavelength: 3.14 [2.56–3.35] vs. 3.21 [2.85–3.46]) and corrected iCEB (QTc/QRS: 3.25 [2.91–3.73] vs. 3.49 [2.99–3.78]). Higher QRS dispersion was seen in type 1 subjects (QRSd: 34 [24–66] vs. 24 [12–34] ms) but QT dispersion (QTd: 48 [39–71] vs. 43 [22–94] ms), QTc dispersion (QTcd: 52 [41–79] vs. 46 [23–104] ms), JTpeak dispersion (44 [23–62] vs. 45 [30–62] ms), Tpeak− Tend dispersion (28 [15–34] vs. 29 [22–53] ms) or Tpeak− Tend/QT dispersion (0.06 [0.03–0.08] vs. 0.08 [0.04–0.12]) did not differ between the two groups. Type 1 subjects showed higher (QRSd × Tpeak− Tend)/QRS (25 [19–44] vs. 19 [9–30] ms) but similar iCEB dispersion (0.83 [0.49–1.14] vs. 0.61 [0.34–0.92]) and iCEBc dispersion (0.93 [0.51–1.15] vs. 0.65 [0.39–0.96]).Conclusion: Higher levels of dispersion in conduction and repolarization are found in type 1 than non-type 1 BrS patients, potentially explaining the higher incidence of ventricular arrhythmias in the former group

Quantification of beat-to-beat variability of action potential durations in Langendorff-perfused mouse hearts

Beat-to-beat variability in action potential duration (APD) is an intrinsic property of cardiac tissue and is altered in pro-arrhythmic states. However, it has never been examined in mice. Methods: Left atrial or ventricular monophasic action potentials (MAPs) were recorded from Langendorff-perfused mouse hearts during regular 8 Hz pacing. Time-domain, frequency-domain and non-linear analyses were used to quantify APD variability. Results: Mean atrial APD (90% repolarization) was 26.6±3.8 ms and standard deviation (SD) was 1.4±0.8 ms (n=6 hearts). Coefficient of variation (CoV) was 5.9±3.2% and root mean square (RMS) of successive differences in APDs was 0.5±0.2 ms. The peaks for low- and high-frequency were 0.8±0.6 and 2.7±1.1 Hz, respectively, with percentage powers of 37.8±14.5 and 61.5±15.1%. Poincaré plots of APDn+1 against APDn revealed ellipsoid shapes. The ratio of the SD along the line-of-identity (SD2) to the SD perpendicular to the line-of-identity (SD1) was 5.96±1.44. Approximate and sample entropy were 0.45±0.05 and 0.54±0.11, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.73±0.17 and 0.68±0.20, respectively. When compared to atrial APDs, ventricular APDs were longer (ANOVA, P<0.05) and showed lower mean SD, CoV and RMS of successive differences in APDs, lower LF power, high HF power and lower SD1 and SD2 (P<0.05) but no difference in the remaining parameters. Conclusion: Beat-to-beat variability in APD is observed in mouse hearts during regular pacing. Atrial MAPs showed greater degree of variability than ventricular MAPs. Non-linear techniques offer further insights on short-term and long-term variability and signal complexity

Target Site Recognition by a Diversity-Generating Retroelement

Diversity-generating retroelements (DGRs) are in vivo sequence diversification machines that are widely distributed in bacterial, phage, and plasmid genomes. They function to introduce vast amounts of targeted diversity into protein-encoding DNA sequences via mutagenic homing. Adenine residues are converted to random nucleotides in a retrotransposition process from a donor template repeat (TR) to a recipient variable repeat (VR). Using the Bordetella bacteriophage BPP-1 element as a prototype, we have characterized requirements for DGR target site function. Although sequences upstream of VR are dispensable, a 24 bp sequence immediately downstream of VR, which contains short inverted repeats, is required for efficient retrohoming. The inverted repeats form a hairpin or cruciform structure and mutational analysis demonstrated that, while the structure of the stem is important, its sequence can vary. In contrast, the loop has a sequence-dependent function. Structure-specific nuclease digestion confirmed the existence of a DNA hairpin/cruciform, and marker coconversion assays demonstrated that it influences the efficiency, but not the site of cDNA integration. Comparisons with other phage DGRs suggested that similar structures are a conserved feature of target sequences. Using a kanamycin resistance determinant as a reporter, we found that transplantation of the IMH and hairpin/cruciform-forming region was sufficient to target the DGR diversification machinery to a heterologous gene. In addition to furthering our understanding of DGR retrohoming, our results suggest that DGRs may provide unique tools for directed protein evolution via in vivo DNA diversification

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Prospective Home-use Study on Non-invasive Neuromodulation Therapy for Essential Tremor.

Highlights: This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients. Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use. Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey. Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TETRAS) and 68% (BF-ADL) of \u27severe\u27 or \u27moderate\u27 patients improving to \u27mild\u27 or \u27slight\u27. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported. Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients

Heterozygous Mutation of Drosophila Opa1 Causes the Development of Multiple Organ Abnormalities in an Age-Dependent and Organ-Specific Manner

Optic Atrophy 1 (OPA1) is a ubiquitously expressed dynamin-like GTPase in the inner mitochondrial membrane. It plays important roles in mitochondrial fusion, apoptosis, reactive oxygen species (ROS) and ATP production. Mutations of OPA1 result in autosomal dominant optic atrophy (DOA). The molecular mechanisms by which link OPA1 mutations and DOA are not fully understood. Recently, we created a Drosophila model to study the pathogenesis of optic atrophy. Heterozygous mutation of Drosophila OPA1 (dOpa1) by P-element insertion results in no obvious morphological abnormalities, whereas homozygous mutation is embryonic lethal. In eye-specific somatic clones, homozygous mutation of dOpa1 causes rough (mispatterning) and glossy (decreased lens deposition) eye phenotypes in adult Drosophila. In humans, heterozygous mutations in OPA1 have been associated with mitochondrial dysfunction, which is predicted to affect multiple organs. In this study, we demonstrated that heterozygous dOpa1 mutation perturbs the visual function and an ERG profile of the Drosophila compound eye. We independently showed that antioxidants delayed the onset of mutant phenotypes in ERG and improved larval vision function in phototaxis assay. Furthermore, heterozygous dOpa1 mutation also caused decreased heart rate, increased heart arrhythmia, and poor tolerance to stress induced by electrical pacing. However, antioxidants had no effects on the dysfunctional heart of heterozygous dOpa1 mutants. Under stress, heterozygous dOpa1 mutations caused reduced escape response, suggesting abnormal function of the skeletal muscles. Our results suggest that heterozygous mutation of dOpa1 shows organ-specific pathogenesis and is associated with multiple organ abnormalities in an age-dependent and organ-specific manner

Submicron Structures Technology and Research

Contains reports on ten research projects.Joint Services Electronics Program (Contract DAAG29-83-K-0003)Joint Services Electronics Program (Contract DAAL03-86-K-0002)National Science Foundation (Grant ECS82-05701)National Science Foundation (Grant ECS85-06565)Lawrence Livermore Laboratory (Subcontract 2069209)National Science Foundation (Grant ECS85-03443)U.S. Air Force - Office of Scientific Research (Grant AFOSR-85-0154)National Aeronautics and Space Administration (Grant NGL22-009-638)National Science Foundation (through KMS Fusion, Inc.)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0908

Multifunctional Role of Bcl-2 in Malignant Transformation and Tumorigenesis of Cr(VI)-Transformed Lung Cells

B-cell lymphoma-2 (Bcl-2) is an antiapoptotic protein known to be important in the regulation of apoptosis in various cell types. However, its role in malignant transformation and tumorigenesis of human lung cells is not well understood. We previously reported that chronic exposure of human lung epithelial cells to the carcinogenic hexavalent chromium Cr(VI) caused malignant transformation and Bcl-2 upregulation; however, the role of Bcl-2 in the transformation is unclear. Using a gene silencing approach, we showed that Bcl-2 plays an important role in the malignant properties of Cr(VI)-transformed cells. Downregulation of Bcl-2 inhibited the invasive and proliferative properties of the cells as well as their colony forming and angiogenic activities, which are upregulated in the transformed cells as compared to control cells. Furthermore, animal studies showed the inhibitory effect of Bcl-2 knockdown on the tumorigenesis of Cr(VI)-transformed cells. The role of Bcl-2 in malignant transformation and tumorigenesis was confirmed by gene silencing experiments using human lung carcinoma NCI-H460 cells. These cells exhibited aggressive malignant phenotypes similar to those of Cr(VI)-transformed cells. Knockdown of Bcl-2 in the H460 cells inhibited malignant and tumorigenic properties of the cells, indicating the general role of Bcl-2 in human lung tumorigenesis. Ingenuity Pathways Analysis (IPA) revealed potential effectors of Bcl-2 in tumorigenesis regulation. Additionally, using IPA together with ectopic expression of p53, we show p53 as an upstream regulator of Bcl-2 in Cr(VI)-transformed cells. Together, our results indicate the novel and multifunctional role of Bcl-2 in malignant transformation and tumorigenesis of human lung epithelial cells chronically exposed to Cr(VI)