Identification of gene pathways implicated in Alzheimer's disease using longitudinal imaging phenotypes with sparse regression

We present a new method for the detection of gene pathways associated with a multivariate quantitative trait, and use it to identify causal pathways associated with an imaging endophenotype characteristic of longitudinal structural change in the brains of patients with Alzheimer's disease (AD). Our method, known as pathways sparse reduced-rank regression (PsRRR), uses group lasso penalised regression to jointly model the effects of genome-wide single nucleotide polymorphisms (SNPs), grouped into functional pathways using prior knowledge of gene-gene interactions. Pathways are ranked in order of importance using a resampling strategy that exploits finite sample variability. Our application study uses whole genome scans and MR images from 464 subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. 66,182 SNPs are mapped to 185 gene pathways from the KEGG pathways database. Voxel-wise imaging signatures characteristic of AD are obtained by analysing 3D patterns of structural change at 6, 12 and 24 months relative to baseline. High-ranking, AD endophenotype-associated pathways in our study include those describing chemokine, Jak-stat and insulin signalling pathways, and tight junction interactions. All of these have been previously implicated in AD biology. In a secondary analysis, we investigate SNPs and genes that may be driving pathway selection, and identify a number of previously validated AD genes including CR1, APOE and TOMM40

CONGRuENTS (COsmic-ray, Neutrino, Gamma-ray and Radio Non-Thermal Spectra). I. A predictive model for galactic non-thermal emission

The total luminosity and spectral shape of the non-thermal emission produced by cosmic rays depends on their interstellar environment, a dependence that gives rise to correlations between galaxies' bulk properties -- star formation rate, stellar mass, and others -- and their non-thermal spectra. Understanding the physical mechanisms of cosmic ray transport, loss, and emission is key to understanding these correlations. Here, in the first paper of the series, we present a new method to compute the non-thermal spectra of star-forming galaxies, and describe an open-source software package -- COsmic-ray, Neutrino, Gamma-ray and Radio Non-Thermal Spectra (CONGRuENTS) -- that implements it. As a crucial innovation, our method requires as input only a galaxy's effective radius, star formation rate, stellar mass, and redshift, all quantities that are readily available for large samples of galaxies and do not require expensive, spatially resolved gas measurements. From these inputs we derive individual, galaxy-by-galaxy models for the background gas and radiation field through which cosmic rays propagate, from which we compute steady state cosmic ray spectra for hadronic and leptonic particles in both the galactic disc and halo by solving the full kinetic equation. We invoke modern models for cosmic ray transport and include all significant emission and loss mechanisms. In this paper we describe the model and validate it against non-thermal emission measured in nearby star-forming galaxies that span four orders of magnitude in star formation rate.Comment: 23 pages, 14 figures, 1 table, accepted for publication in MNRA

The first endovascular repair of an acute type A dissection using an endograft designed for the ascending aorta

Endovascular repair has emerged as a potential alternative to emergency open surgical repair for type A dissection in selected patients, with isolated reports describing the results obtained with a range of devices designed originally for the descending aorta. We believe that we present the first reported repair of an acute ascending aortic dissection using an endovascular stent graft manufactured specifically for the ascending aorta

Multisensory attention training for treatment of tinnitus

Spiegel, D. P. et al. Multisensory attention training for treatment of tinnitus. Sci. Rep. 5, 10802; doi: 10.1038/srep10802 (2015).Tinnitus is the conscious perception of sound with no physical sound source. Some models of tinnitus pathophysiology suggest that networks associated with attention, memory, distress and multisensory experience are involved in tinnitus perception. The aim of this study was to evaluate whether a multisensory attention training paradigm which used audio, visual, and somatosensory stimulation would reduce tinnitus. Eighteen participants with predominantly unilateral chronic tinnitus were randomized between two groups receiving 20 daily sessions of either integration (attempting to reduce salience to tinnitus by binding with multisensory stimuli) or attention diversion (multisensory stimuli opposite side to tinnitus) training. The training resulted in small but statistically significant reductions in Tinnitus Functional Index and Tinnitus Severity Numeric Scale scores and improved attentional abilities. No statistically significant improvements in tinnitus were found between the training groups. This study demonstrated that a short period of multisensory attention training reduced unilateral tinnitus, but directing attention toward or away from the tinnitus side did not differentiate this effect.This work was supported by a grant from Links Research and Grants Corporation to G.D.S

Isokinetic Fatigue Characteristics for the Leg Extensors versus Flexors

Maximal isokinetic muscle actions are often used in research studies to examine fatigability and even estimate muscle fiber-type. However, the majority of previous investigations have examined these topics for the leg extensors (i.e., quadriceps), and we are unaware of investigations that have specifically assessed the fatigue characteristics for the flexors (i.e., hamstrings). The purpose of this study was to compare the percent decline values for the leg extensors versus flexors for 50 and 100 repeated, maximal concentric isokinetic muscle actions. Fifteen healthy men (mean ± SD age = 23 ± 3 years; body mass = 94.1 ± 11.9 kg) with previous lower-body strength training experience volunteered to participate in this study. All of the subjects were familiarized with the testing procedures prior to data collection. For data collection, each subject performed 100 repeated, maximal concentric isokinetic muscle actions of the left leg extensors and flexors in a reciprocal manner. Each muscle action was performed at 180 degrees/second through a full 90 degree range of motion. Strong verbal encouragement was provided throughout testing. Percent decline was determined using the mean peak torque values of the initial and final three muscle actions for each muscle group (i.e., extensors versus flexors) and condition (i.e., 50 versus 100 repetitions). A two-way repeated measure analysis of variance was used to examine the data. The mean ± SD percent decline for the leg extensors was 61.8 ± 7.8 and 71.2 ± 6.5% for the 50 and 100 conditions, respectively (Cohen’s d = 1.31). For the leg flexors, these corresponding values were 48.0 ± 12.2 and 54.3 ± 11.7 % (Cohen’s d = 0.53). There was no significant muscle group × condition interaction (p= .114; partial eta squared = .169) There were, however, main effects for both factors. The bonferroni marginal mean pairwise comparisons indicated that when collapsed across condition, the leg extensors fatigued more so than the flexors (66.5 vs. 51.2%). Similarly, when collapsed across muscle group, the percent decline values were greater following 100 (62.8%) versus 50 (54.9%) repetitions. These finding demonstrated greater isokinetic fatigue characteristics for the leg extensors versus flexors. Furthermore, the additional decline in peak torque from repetitions 50-100 was more pronounced for the extensors. We speculate that these findings could be related to differences in muscle fiber-type, lower absolute strength and mass for the posterior aspect of the thigh, and/or unfamiliarity with single-joint testing of the leg flexors

Relationships Between Anthropometric and Performance Variables in Youth: Predictors of Lower-Body Vertical Jump Peak Power

ABSTRACT Anthropometric and physical performance measurements are commonly used for identifying specific physical traits in youth. Laboratory-based tests (e.g., linear velocity transducers), while accurate, provide practical limitations due to high costs and technical necessities. Thus, commonly used field tests may be useful alternatives for assessing fitness/performance characteristics of youth. The purpose of this study was to examine the relationships between anthropometric measures and lower-and upper-body power and strength measures; and to assess the predictive ability of these measures for lower-body vertical jump peak power (PP) output in youth. Thirty-nine pre-adolescent (mean±SD, range: age=7.8±1.7, 5-12 years) children volunteered to participate in this investigation. Subjects were measured for body mass and stature on a calibrated physicians scale. Lower-body PP was assessed using a linear velocity transducer, which was attached to the posterior side of a belt that was securely fastened to the subjects’ waistline. Subjects performed countermovement jumps, starting in a standing position, with hands placed on hips and feet firmly on the ground. Following the descent to the midpoint position and without pause, the subjects exploded upward as hard and fast as possible. Broad jump testing involved subjects performing a countermovement jump in the horizontal direction, on a scaled mat. Maximum isometric hand grip strength of the dominant hand was assessed using a dynamometer. For all testing, 1-2 practice trials were performed, followed by testing consisting of 2-3 trials. The highest trial was used for analyses. Peak power values were normalized to body mass using allometric scaling procedures (PP· body mass-0.67). Pearson correlation (r) and stepwise linear regression analyses were performed to examine the relationships. Results indicated all variables (age, stature, body mass, broad jump and grip strength) were significantly correlated (r=0.38-0.64) to PP. Age was correlated to all variables (r=0.39-0.82) and stature and body mass were correlated to all variables (r=0.37-0.77) except broad jump. Broad jump was correlated only to age (r=0.39) and PP (r=0.38). Linear regression for all variables revealed that stature was the only variable entered into the model (R=0.64; R2=0.41). With the anthropometric variables removed, grip strength was the only variable entered into the model (R=0.57; R2=0.32). These findings suggest that while all the anthropometric and performance variables may be correlated to PP, only stature and grip strength were effective, and thus, necessary to predict PP abilities. Interestingly, broad jump performance was not a good predictor of lower body vertical PP

The Orbit of the Eclipsing X-ray Pulsar EXO 1722-363

With recent and archival Rossi X-Ray Timing Explorer (RXTE) X-ray measurements of the heavily obscured X-ray pulsar EXO 1722-363 (IGR J17252-3616), we carried out a pulse timing analysis to determine the orbital solution for the first time. The binary system is characterized by a_x sin(i) = 101 +/- 3 lt-s and P_orb = 9.7403 +/- 0.0004 days (90% confidence), with the precision of the orbital period being obtained by connecting datasets separated by more than 7 years (272 orbital cycles). The orbit is consistent with circular, and e < 0.19 at the 90% confidence level. The mass function is 11.7 +/- 1.2 M_sun and confirms that this source is a High Mass X-ray Binary (HMXB) system. The orbital period, along with the previously known ~414 s pulse period, places this system in the part of the Corbet diagram populated by supergiant wind accretors. Using previous eclipse time measurements by Corbet et al. and our orbital solution, combined with the assumption that the primary underfills its Roche lobe, we find i > 61 degrees at the 99% confidence level, the radius of the primary is between 21 R_sun and 37 R_sun, and its mass is less than about 22 M_sun. The acceptable range of radius and mass shows that the primary is probably a supergiant of spectral type B0I-B5I. Photometric measurements of its likely counterpart are consistent with the spectral type and luminosity if the distance to the system is between 5.3 kpc and 8.7 kpc. Spectral analysis of the pulsar as a function of orbital phase reveals an evolution of the hydrogen column density suggestive of dense filaments of gas in the downstream wake of the pulsar, with higher levels of absorption seen at orbital phases 0.5-1.0, as well as a variable Fe K_alpha line.Comment: Submitted to ApJ, 11 pages, 11 figure

Linear Progression for Increased External Loads during Strength Training

Improvements in muscular strength require an individual to train with progressively increased external loads over time. While it is well documented that the initial adaptations to strength training occur rapidly, previous researchers have not thoroughly examined the most effective means of inducing these changes. The purpose of this study was to examine the ability to add 2.27 kg to the barbell for 20 consecutive training sessions, and to compare these responses between the sexes. Thirty-four subjects ([mean ± SD age = 23 ± 3 years] men, n = 17; women, n = 17) participated in this study. The subjects were taught how to perform the barbell deadlift exercise, and received individual instruction and verbal feedback regarding their technique throughout the entire investigation. The subjects visited the laboratory twice per week for ten weeks. The external loads corresponded to the maximum weight that each subject could use to perform five sets of five repetitions with correct technique. If five sets of five repetitions were performed, 2.27 kg were added to the barbell for the following training session. The mean external load for each training session was recorded. The data were analyzed with bivariate regression and repeated measures analyses of variance (ANOVAs). The mean ± SD external loads used in this study increased from 66.2 ± 22.3 to 123.1 ± 21.8 kg for the men and 37.8 ± 7.0 to 70.7 ± 12.2 for the women. The results from the repeated measures ANOVAs indicated that men were able to add 2.27 kg to the barbell for 17 consecutive training sessions. For the women, however, the progress stalled at roughly week six. As a result, the coefficient of determination for the external load versus training session number relationship was r2 = .960 for the men and r2 = .881 for the women. These findings demonstrated that adding 2.27 kg to the barbell for each training session was an effective method for progressively increasing the external load over a ten week period. Many of the women had a difficult time with this gradual increase after week six, however, suggesting that smaller absolute changes with fractional plates (e.g., 0.91 kg) may be necessary

Effects of a Ten Week Barbell Deadlift Training Program on Vertical Jump Height in College-Aged Women

The barbell deadlift is a large muscle mass exercise that primarily involves extension at the hip and knee joints. Although it is often incorporated into strength training programs with a variety of other exercises (e.g., back squat), no previous studies have examined the effects of deadlift training on strength or power adaptations. The purpose of this investigation was to examine the effects of a ten week barbell deadlift training program on vertical jump height in previously untrained women. Twenty-eight women (mean ± SD age = 22 ± 2 years) were randomly assigned to either the training group (n = 17) or the control group (n = 11). The training group visited the laboratory for supervised exercise twice per week for ten weeks. Each training session involved five sets of the barbell deadlift, and each set utilized the heaviest external load that allowed for five repetitions with proper exercise technique. If all repetitions were performed with correct technique, additional weight (≤ 2.27 kg) was added to the barbell during the next training session. The control group was asked to refrain from lower-body exercise throughout the course of the study. Vertical jump height was assessed with a Vertec before and after the ten week intervention. An analysis of covariance (ANCOVA) was used to examine the data, and the pretest and posttest values were used as the covariate and dependent variable, respectively. The ANCOVA indicated that the posttest mean for the training group (42.5 cm) was significantly greater than that for the control group (39.0 cm) after adjusting for the pretest vertical jump height scores (p = .012, η² = .229). The effect size for the unadjusted mean increase for the training group (3.6 cm) was considered small-to-moderate (Cohen’s d = .37). These findings demonstrated that a ten week exercise training program using only the barbell deadlift significantly improved vertical jump height in college-aged women