Development of electrocardiogram intervals during growth of FVB/N neonate mice

<p>Abstract</p> <p>Background</p> <p>Electrocardiography remains the best diagnostic tool and therapeutic biomarker for a spectrum of pediatric diseases involving cardiac or autonomic nervous system defects. As genetic links to these disorders are established and transgenic mouse models produced in efforts to understand and treat them, there is a surprising lack of information on electrocardiograms (ECGs) and ECG abnormalities in neonate mice. This is likely due to the trauma and anaesthesia required of many legacy approaches to ECG recording in mice, exacerbated by the fragility of many mutant neonates. Here, we use a non-invasive system to characterize development of the heart rate and electrocardiogram throughout the growth of conscious neonate FVB/N mice.</p> <p>Results</p> <p>We examine ECG waveforms as early as two days after birth. At this point males and females demonstrate comparable heart rates that are 50% lower than adult mice. Neonatal mice exhibit very low heart rate variability. Within 12 days of birth PR, QRS and QTc interval durations are near adult values while heart rate continues to increase until weaning. Upon weaning FVB/N females quickly develop slower heart rates than males, though PR intervals are comparable between sexes until a later age. This suggests separate developmental events may contribute to these gender differences in electrocardiography.</p> <p>Conclusions</p> <p>We provide insight with a new level of detail to the natural course of heart rate establishment in neonate mice. ECG can now be conveniently and repeatedly used in neonatal mice. This should serve to be of broad utility, facilitating further investigations into development of a diverse group of diseases and therapeutics in preclinical mouse studies.</p

Small bound for birational automorphism groups of algebraic varieties (with an Appendix by Yujiro Kawamata)

We give an effective upper bound of |Bir(X)| for the birational automorphism group of an irregular n-fold (with n = 3) of general type in terms of the volume V = V(X) under an ''albanese smoothness and simplicity'' condition. To be precise, |Bir(X)| < d_3 V^{10}. An optimum linear bound |Bir(X)|-1 < (1/3)(42)^3 V is obtained for those 3-folds with non-maximal albanese dimension. For all n > 2, a bound |Bir(X)| < d_n V^{10} is obtained when alb_X is generically finite, alb(X) is smooth and Alb(X) is simple.Comment: Mathematische Annalen, to appea

Randomized Trial to Evaluate Tandospirone in Geographic Atrophy Secondary to Age-Related Macular Degeneration: The GATE Study

Purpose To determine the safety and efficacy of AL-8309B (tandospirone) in the management of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) and obtain standardized data on GA lesion growth progression. Design Prospective, controlled, double-masked, randomized, multicenter phase 3 clinical trial. Methods setting: Forty-eight clinical sites. patients: Patients with GA associated with AMD were enrolled. All patients were followed for a minimum of 30 months, and up to 36 months. intervention procedures: Patients were randomized (1:1:1) to receive AL-8309B ophthalmic solution 1.0%, 1.75%, or vehicle, administered as a twice-daily topical ocular drop. main outcome measures: The primary efficacy endpoint was mean annualized lesion enlargement from baseline as assessed with fundus autofluorescence (FAF) imaging. Results A total of 768 eyes of 768 patients were enrolled and treated with AL-8309B 1.0% (n = 250), AL-8309B 1.75% (n = 258), or vehicle (n = 260). An increase in mean lesion size was observed in both the AL-8309B and vehicle treatment groups, and growth rates were similar in all treatment groups. Annualized lesion growth rates were 1.73, 1.76, and 1.71 mm 2 for AL-8309B 1.0%, AL-8309B 1.75%, and vehicle, respectively. Conclusions AL-8309B 1.0% and 1.75% did not affect lesion growth in eyes with GA secondary to AMD. There were no clinically relevant safety issues identified for AL-8309B. The large natural history dataset from this study is a valuable repository for future comparisons

Methodological approaches to determining the marine radiocarbon reservoir effect

The marine radiocarbon reservoir effect is an offset in 14C age between contemporaneous organisms from the terrestrial environment and organisms that derive their carbon from the marine environment. Quantification of this effect is of crucial importance for correct calibration of the &lt;sup&gt;14&lt;/sup&gt;C ages of marine-influenced samples to the calendrical timescale. This is fundamental to the construction of archaeological and palaeoenvironmental chronologies when such samples are employed in &lt;sup&gt;14&lt;/sup&gt;C analysis. Quantitative measurements of temporal variations in regional marine reservoir ages also have the potential to be used as a measure of process changes within Earth surface systems, due to their link with climatic and oceanic changes. The various approaches to quantification of the marine radiocarbon reservoir effect are assessed, focusing particularly on the North Atlantic Ocean. Currently, the global average marine reservoir age of surface waters, R(t), is c. 400 radiocarbon years; however, regional values deviate from this as a function of climate and oceanic circulation systems. These local deviations from R(t) are expressed as +R values. Hence, polar waters exhibit greater reservoir ages (&#948;R = c. +400 to +800 &lt;sup&gt;14&lt;/sup&gt;C y) than equatorial waters (&#948;R = c. 0 &lt;sup&gt;14&lt;/sup&gt;C y). Observed temporal variations in &#948;R appear to reflect climatic and oceanographic changes. We assess three approaches to quantification of marine reservoir effects using known age samples (from museum collections), tephra isochrones (present onshore/offshore) and paired marine/terrestrial samples (from the same context in, for example, archaeological sites). The strengths and limitations of these approaches are evaluated using examples from the North Atlantic region. It is proposed that, with a suitable protocol, accelerator mass spectrometry (AMS) measurements on paired, short-lived, single entity marine and terrestrial samples from archaeological deposits is the most promising approach to constraining changes over at least the last 5 ky BP

IL-13-induced airway mucus production is attenuated by MAPK13 inhibition

Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13–driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases

Impact of Baseline Retinal Nonperfusion and Macular Retinal Capillary Nonperfusion on Outcomes in the COPERNICUS and GALILEO Studies

To evaluate the impact of baseline retinal capillary nonperfusion (RNP) and macular retinal capillary nonperfusion (MNP) status on outcomes at week&nbsp;24 (W24)

Impact of Baseline Retinal Nonperfusion and Macular Retinal Capillary Nonperfusion on Outcomes in the COPERNICUS and GALILEO Studies.

Purpose To evaluate the impact of baseline retinal capillary nonperfusion (RNP) and macular retinal capillary nonperfusion (MNP) status on outcomes at week 24 (W24). Design Post hoc analyses of 2 phase 3, randomized, double-masked, multicenter, sham-controlled studies. Participants Three hundred sixty-six patients with macular edema secondary to central retinal vein occlusion randomized in COPERNICUS and GALILEO. Methods We randomized patients 3:2 to receive intravitreal aflibercept 2 mg every 4 weeks or sham injections until W24. RNP and MNP were assessed by a masked independent reading center. Main Outcome Measures Proportion of patients with 10 disc areas (DA) or more of RNP and any degree of MNP at W24, relative risks of 10 DA or more of RNP or any degree of MNP at W24 developing, change from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by baseline RNP and MNP status, and relationship between baseline RNP and MNP status. Results At baseline, 24.6% of patients showed 10 DA or more of RNP and 72.6% showed MNP, regardless of baseline RNP status. At W24, the pooled proportions of patients in the intravitreal aflibercept and sham groups with 10 DA or more of RNP were 11.6% and 29.0%, respectively (P = 0.0001); the respective proportions with any degree of MNP were 61.2% and 79.5% (P = 0.0008). Relative risks and 95% confidence intervals for intravitreal aflibercept versus sham were 0.4 (0.25–0.62) for 10 DA or more of RNP and 0.8 (0.68–0.90) for MNP, indicating a lower risk for these outcomes with intravitreal aflibercept than with sham. Mean BCVA change was greater in intravitreal aflibercept- versus sham-treated eyes, with less than 10 DA and 10 DA or more of RNP at baseline (+17.5 vs. +0.8 letters and +18.3 vs. −4.1 letters, respectively) and with and without baseline MNP (+15.7 vs. +0.3 letters and +17.1 vs. +0.4 letters, respectively). Agreement between baseline RNP and MNP status was low (κ = 0.12). The proportions of patients with 1 or more ocular serious adverse event in the intravitreal aflibercept- and sham-treated groups, respectively, were 3.2% and 11.3%. Conclusions At W24, visual and anatomic improvements, including perfusion status, were greater in eyes treated with intravitreal aflibercept than in eyes treated with sham, regardless of baseline RNP or MNP status

Multivariable control of a grid-connected wind energy conversion system with power quality enhancement

This document is the Accepted Manuscript version of the following article: Kaddour Fouad, Houari Merabet Boulouiha, Ahmed Allali, Ali Taibi, and Mouloud Denai, ‘Multivariable control of a grid-connected wind energy conversion system with power quality enhancement’, Energy Systems, Vol. 9 (1): 25-57, February 2018. The final publication is available at Springer via: https://doi.org/10.1007/s12667-016-0223-7This paper proposes the design of a multivariable robust control strategy for a variable-speed WECS based on a SCIG. Optimal speed control of the SCIG is achieved by a conventional PI controller combined with a MPPT strategy. DTC-SVM technique based on a simple Clarke transformation is used to control the generator-side three-level converter in the variable speed WECS. The flow of real and reactive power between the inverter and the grid is controlled via the grid real and reactive currents and the DC link voltage using multivariable H∞ control. The overall WECS and control scheme are developed in Matlab/Simulink and the performance of the proposed control strategy is evaluated via a set of simulation scenarios replicating various operating conditions of the WECS such as variable wind speed and asymmetric single grid faults. The power quality of the WECS system under H∞ control control approach is assessed and the results show a significant improvement in the total harmonic distorsion as compared to that achieved with a classical PI control.Peer reviewedFinal Accepted Versio