Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI.

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population. SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models. RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10-7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue. CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.

BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Will diminishing cochlear delay affect speech perception in noise?

OBJECTIVE: Normal auditory systems appear well habituated to time/phase delays inherent to sound encoding along the hearing organ, sending frequency information non-simultaneously to the central auditory system. Eliminating, or simply perturbing, the cochlear delay might be expected to decrease speech recognition ability, especially under demanding listening conditions. Resources of a larger-scale investigation permitted a preliminary examination of this issue, particularly on a relevant timescale of empirically demonstrated cochlear delays. DESIGN: In a randomized controlled trial study, word recognition was tested for mono-syllabic tokens treated digitally to exacerbate, if not diminish/nullify, such delays. Speech-weighted noise was used to interfere with listening to time-frequency reversed (nominally no delay) versus non-reversed (natural timing) transforms under three treatments of speech tokens: (1) original-digitally recorded; digitally processed to emphasize (2) transient versus (3) quasi-steady-state components. STUDY SAMPLE: Ten normal-hearing young-adult females. RESULTS: The findings failed to demonstrate statistically significant differences between delay conditions for any of the three speech-token treatments. CONCLUSIONS: An algorithm putatively diminishing frequency-dependent cochlear delays failed to systematically deteriorate performance in all subjects for the fixed time-frequency transform, stimulus parameters, and test materials employed. Yet, trends were evident such that some effect of perturbing cochlear delays could not be ruled out completely.

Steady-state analysis of auditory evoked potentials over a wide range of stimulus repetition rates: profile in children vs. adults.

OBJECTIVE: Auditory steady-state responses (ASSR) evoked by recurrent brief tones were assessed over a wide range of stimulus repetition rates apropos the traditionally measured obligatory, transient, auditory evoked potentials. Repetition rates of ≤ 10 Hz have received little attention in the context of the ASSR stimulus-response analysis approach, speculated to provide technical advantages/additional information over more traditional transient stimulus-response paradigms. DESIGN: Magnitudes were measured at repetition rates from 0.75 to 80 Hz, using trains of repeated tone-burst stimuli. STUDY SAMPLE: Twelve normal-hearing children and a reference sample of 25 young adults. RESULTS: Results show that response magnitudes were significantly larger in children than adults at repetition rates of ≤ 5 Hz. Magnitudes were largest at the two lowest repetition rates, following the trends expected from the transient auditory evoked potential (AEP) literature. The harmonic sum is proposed as a more appropriate measure of response magnitude than amplitude of the fundamental alone. CONCLUSIONS: The analysis methods used in this paper may give information that will have applications for clinical testing. Of pragmatic importance is that the stimulus rate profile could be determined without subjective wave identification and/or interpretation, and thus by a method that is inherently more objective than conventional AEP analysis.

Steady-state analysis of auditory evoked potentials over a wide range of stimulus repetition rates in awake vs. natural sleep.

OBJECTIVE: Auditory steady-state responses (ASSR) evoked by recurrent tones were assessed over a wide range of stimulus repetition rates embracing well the traditionally measured transient AEPs. Repetition rates of ≤ 10 Hz have received little attention in the context of the ASSR stimulus-response analysis approach which is speculated to provide technical advantages, if not additional/supplemental information, over more traditional transient stimulus-response paradigms. DESIGN: Magnitudes were measured at repetition rates from 0.75 to 80 Hz, using trains of recurrent tone-burst stimuli. STUDY SAMPLE: Twenty-five normal-hearing adults during sleep and awake. RESULTS: Results show that response magnitudes for adults tested during sleep were significantly larger than those for adults while awake at repetition rates <5 Hz. Magnitudes were largest at the two lowest repetition rates, as expected from corresponding results obtained using conventional methods. CONCLUSIONS: The analysis methods used in this paper may give information that will have applications for clinical testing. Results confirm and extend knowledge of the effects of repetition rate on AEPs over a range embracing the gamut of responses as traditionally classified, specifically at the beginning stages of natural sleep.

Steady-state analysis of auditory evoked potentials over a wide range of stimulus repetition rates: profile in adults.

OBJECTIVE: Quasi-steady-state responses were assessed over a wide range of stimulus repetition rates embracing well the traditionally measured transient AEPs (obligatory auditory evoked potentials of all latencies). Repetition rates of ≤10 Hz have received little attention in the context of the ASSR stimulus-response analysis approach which is speculated to provide technical advantages, if not additional information, over more traditional transient stimulus-response paradigms. DESIGN: A measure introduced and defined as the sum of the response at the stimulus frequency and its harmonics. The magnitude of steady-state responses were measured at repetition rates from 0.75 to 80 Hz, using trains of repeated tone-burst stimuli. STUDY SAMPLE: Twenty-five normal-hearing adults. RESULTS: Results show that the magnitudes of the response across repetition rates are largest at the two lowest rates, following trends expected from the transient AEP literature. Good reliability overall was observed for the harmonic sum. CONCLUSIONS: The analysis methods used in this paper may give information that will have application for clinical testing. Of pragmatic importance is that the rate profile could be determined without subjective wave identification and/or interpretation, and thus by a method that is inherently more objective than conventional AEP tests.

The psychometric validation of the quality practical experience (QPE) instruments (nurses and student nurse) to evaluate clinical supervision of undergraduate student nurses.

It is important to evaluate stakeholder feedback regarding any change to a clinical supervision model to maintain quality. The Quality Practical Experience (QPE) instruments offer both the nurse on the ward involved with supervising student learning and the student nurse the opportunity to evaluate their satisfaction with the supervision model. This paper reports on the evaluation of the construct validity and the reliability of the QPE instruments measuring nurse and nursing student satisfaction with the clinical supervision model. Methodological design for the reliability and validation of a measuring instrument. The nurse and the student QPE instruments were tested with convenience samples of 488 nurses and 1116 student nurses, respectively. Psychometric tests included internal reliability, test-retest reliability and factor analyses. Exploratory factor analysis for both QPEs supported a three-factor solution; the nurse QPE explained 48% and student nurse QPE 45% of variance. Internal reliability and test-retest reliability were stable over time (nurse QPE ICC = 0.82; student nurse QPE ICC = 0.71). Both QPE instruments were found to be valid and reliable. Feedback from all stakeholders involved with supporting student nurses during clinical placement is important.

Classifying subgroups of chronic low back pain patients based on lifting patterns.

OBJECTIVE: To compare self-reported measures of chronic lower back pain (CLBP) patients who were assigned to 2 subgroups based on their lifting patterns performed during a repetitive lifting task. DESIGN: Cross-sectional study. SETTING: Research laboratory PARTICIPANTS: CLBP subjects (n=81) and pain-free controls (n=53). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Measures of lifting patterns and self-reported disability, pain, and psychosocial aspects. RESULTS: Two CLBP subgroups were found: 1 group that lifts similarly to control subjects (n=35) and 1 group that lifts very differently from controls (n=46). The CLBP group that lifted differently than controls reported higher pain intensity (P=.005), higher pain severity (P=.025), and lower self-efficacy (P=.013) than the CLBP group that lifted similarly to controls. CONCLUSIONS: A classification system based on lifting patterns identified 2 CLBP subgroups that were significantly different on lifting and self-reported measures, indicating the importance of physical functioning measures in classification systems.

Speech signal modification to increase intelligibility in noisy environments.

The role of transient speech components on speech intelligibility was investigated. Speech was decomposed into two components--quasi-steady-state (QSS) and transient--using a set of time-varying filters whose center frequencies and bandwidths were controlled to identify the strongest formant components in speech. The relative energy and intelligibility of the QSS and transient components were compared to original speech. Most of the speech energy was in the QSS component, but this component had low intelligibility. The transient component had much lower energy but was almost as intelligible as the original speech, suggesting that the transient component included speech elements important to speech perception. A modified version of speech was produced by amplifying the transient component and recombining it with the original speech. The intelligibility of the modified speech in background noise was compared to that of the original speech, using a psychoacoustic procedure based on the modified rhyme protocol. Word recognition rates for the modified speech were significantly higher at low signal-to-noise ratios (SNRs), with minimal effect on intelligibility at higher SNRs. These results suggest that amplification of transient information may improve the intelligibility of speech in noise and that this improvement is more effective in severe noise conditions.

Bacterial expression, correct membrane targeting and functional folding of the HIV-1 membrane protein Vpu using a periplasmic signal peptide.

Viral protein U (Vpu) is a type-III integral membrane protein encoded by Human Immunodeficiency Virus-1 (HIV- 1). It is expressed in infected host cells and plays several roles in viral progeny escape from infected cells, including down-regulation of CD4 receptors. But key structure/function questions remain regarding the mechanisms by which the Vpu protein contributes to HIV-1 pathogenesis. Here we describe expression of Vpu in bacteria, its purification and characterization. We report the successful expression of PelB-Vpu in Escherichia coli using the leader peptide pectate lyase B (PelB) from Erwinia carotovora. The protein was detergent extractable and could be isolated in a very pure form. We demonstrate that the PelB signal peptide successfully targets Vpu to the cell membranes and inserts it as a type I membrane protein. PelB-Vpu was biophysically characterized by circular dichroism and dynamic light scattering experiments and was shown to be an excellent candidate for elucidating structural models.

Towards the development of a pediatric ventricular assist device.

The very limited options available to treat ventricular failure in children with congenital and acquired heart diseases have motivated the development of a pediatric ventricular assist device at the University of Pittsburgh (UoP) and University of Pittsburgh Medical Center (UPMC). Our effort involves a consortium consisting of UoP, Children's Hospital of Pittsburgh (CHP), Carnegie Mellon University, World Heart Corporation, and LaunchPoint Technologies, Inc. The overall aim of our program is to develop a highly reliable, biocompatible ventricular assist device (VAD) for chronic support (6 months) of the unique and high-risk population of children between 3 and 15 kg (patients from birth to 2 years of age). The innovative pediatric ventricular assist device we are developing is based on a miniature mixed flow turbodynamic pump featuring magnetic levitation, to assure minimal blood trauma and risk of thrombosis. This review article discusses the limitations of current pediatric cardiac assist treatment options and the work to date by our consortium toward the development of a pediatric VAD.

The PediaFlow pediatric ventricular assist device.

The very limited options available to treat ventricular failure in patients with congenital and acquired heart diseases have motivated the development of a pediatric ventricular assist device (VAD). Our effort involves a consortium consisting of the University of Pittsburgh, Carnegie Mellon University, Children's Hospital of Pittsburgh, World Heart Corporation, and LaunchPoint Technologies, LLC. The overall aim of our program is to develop a highly reliable, biocompatible VAD for chronic support (6 months) of the unique and high-risk population of children between 3 kg and 15 kg (patients from birth to 2 years of age). The innovative pediatric VAD we are developing (PediaFlow) is based on a miniature mixed-flow turbodynamic pump featuring magnetic levitation, with the design goal being to assure minimal blood trauma and risk of thrombosis. This article discusses the limitations of current pediatric cardiac assist treatment options and the work to date by our consortium toward the development of a pediatric VAD.

The use of splines to calculate jerk for a lifting task involving chronic lower back pain patients.

Motion differences in a repetitive lifting task have been described previously using differences in the timing of body angle changes during the lift. These timing changes relied on small differences of motion and are difficult to measure. The purpose of this study was to evaluate shoulder jerk (rate of change of acceleration) in a repetitive lifting task as an alternative parameter to detect differences of motion between controls and chronic lower back pain (CLBP) patients and to measure the impact of a rehabilitation program on jerk. The jerk calculation was a noisy measure, since jerk is the third derivative of position; consequently a simulation was performed to evaluate smoothing methods. Woltring's generalized cross-validation spline produced the best estimates of the third derivative and was fit to subject data. The root mean square (rms) amplitude of jerk was used for comparison. Significant group differences were found. CLBP patients performed lifts with lower jerk values than controls and, as the task progressed, both groups increased jerk. After completion of a rehabilitation program, CLBP patients performed lifts with greater rms jerk. In general, patients performed lifts with lower jerk values than controls, suggesting that pain impacts lifting style.

In vitro evaluation of multiobjective hemodynamic control of a heart-assist pump.

Ventricular assist devices now clinically used for treatment of end-stage heart failure require responsive and reliable hemodynamic control to accommodate the continually changing demands of the body. This is an essential ingredient to maintaining a high quality of life. To satisfy this need, a control algorithm involving a trade-off between optimal perfusion and avoidance of ventricular collapse has been developed. An optimal control strategy has been implemented in vitro that combines two competing indices: representing venous return and prevalence of suction. The former is derived from the first derivative of diastolic flow with speed, and the latter derived from the harmonic spectra of the flow signal. The responsiveness of the controller to change in preload and afterload were evaluated in a mock circulatory simulator using a HeartQuest centrifugal blood pump (CF4b, MedQuest Products, Salt Lake City, UT). To avoid the need for flow sensors, a state estimator was used, based on the back-EMF of the actuator. The multiobjective algorithm has demonstrated more robust performance as compared with controllers relying on individual indices.

Local cerebral blood flow measured by xenon-enhanced CT during cryogenic brain edema and intracranial hypertension in monkeys.

We developed a closed-skull model of freeze injury-induced brain edema, a model classically thought to produce vasogenic edema, and observed the natural course of changes in edema and blood flow using xenon-enhanced computed tomography (CT) in five rhesus monkeys before and for up to 6 h post insult. Intracranial pressure (ICP) gradually rose throughout the duration of the experiment. CT scans and CBF images permitted direct observation of the evolution of the lesion and revealed early ischemia in the periphery of the injury zone that progressed over time in association with edema. Frequency histogram analysis of local CBF (ICBF) demonstrated subtle but potentially important changes in distribution of ICBF between and within hemispheres at various times post insult. Changes in ICBF distribution were phasic and dissociated from increases in ICP in the latter stages of injury. The Xe/CT CBF method can be used to evaluate the effects of injury and therapy on CBF in this and other models of acute brain injury.

Comparison of mania and depression after brain injury: causal factors.

Patients who developed secondary mania after brain injury (N = 17) had a significantly greater frequency of injury to right hemisphere areas connected with the limbic system than poststroke patients with major depression (N = 31), who had injury primarily in the left frontal cortex and basal ganglia. For patients without mood disturbance after brain injury (N = 28), the location of the lesion was not significant. Secondary mania patients also had a significantly greater frequency of family history of affective disorder than did the other two groups. These results suggest that an interaction between injury to certain areas of the right hemisphere and genetic factors or other neuropathological conditions produces secondary mania.

Lateralization of dementia of depression in stroke patients.

In a group of stroke patients with left-hemisphere lesions, those with major depression performed significantly below nondepressed patients on four of nine cognitive domains examined with a neuropsychological test battery. Among patients with right-hemisphere stroke, those with major depression did not perform below nondepressed patients on any of the nine cognitive domains. The differential effect of depression on cognitive performance between left- and right-hemisphere lesion groups could not be accounted for by demographic variables, neurological symptoms, lesion location, or lesion size. Poststroke major depression appeared to produce a decline in cognitive performance or dementia of depression that depended on the laterality of the lesion.

Mania after brain injury. A controlled study of causative factors.

Eleven patients who developed manic syndromes after brain injury (secondary mania) were studied. Six patients had depressive episodes before mania and five had a definite or possible family history of affective disorder. Eight had lesions involving limbic areas, and nine had right hemisphere involvement. In addition to focal brain injury, mean values for bifrontal and third ventricle/brain ratios of manic patients were significantly increased when compared with non-manic patients who had lesions matched for cause, location, volume, and time since injury. Results indicate that the confluence of either anterior subcortical atrophy and a focal lesion of a limbic or limbic-connected region of the right hemisphere, or genetic loading and a limbic-connected right hemisphere lesion may account for the rare occurrence and specific factors necessary to produce secondary mania.

Body motion during repetitive isodynamic lifting: a comparative study of normal subjects and low-back pain patients.

To quantify performance differences between patients with low-back pain (LBP) and a control group during their performance of a repetitive isodynamic lifting task. Case-control study was done. LBP patients were recruited and tested at an outpatient ambulatory chronic pain rehabilitation program before treatment was begun. Fifty-three LBP patients who had prolonged back pain and 53 age and gender matched pain-free control subjects. Overall lifting performance measures included weight lifting and number of lifts completed; kinematic measures of hip and knee movements during lifting were described by hyperbolic tangent models, and included static measures of starting and ending angles, and dynamic measures of midpoint, falltime, and lift speed. Control subjects completed significantly more lifts and lifted more weight than patients. Starting hip flexion was greater for controls and starting knee flexion was greater for patients, indicating that patients used more of a leg lift. Patients and controls also differed significantly on dynamic measures, particularly lifting speed and hip and knee temporal midpoints. Major static and dynamic motion differences were found between LBP patients and controls as they performed repetitive lifting under a constant load. These findings indicate that body motion parameters, in addition to more common strength and endurance measures, are necessary to describe the impact of persistent LBP on a person's lifting abilities.

Subchronic toxicity of chlorine dioxide and related compounds in drinking water in the nonhuman primate.

Subchronic toxicities of ClO2, NaClO2, NaClO3 and NH2Cl were studied in the African Green monkeys (Cercopithecus aethiops). The chemicals were administered in drinking water during 30-60 days subchronic rising dose protocols. The only unexpected and significant toxic effect was elicited by ClO2; this chemical inhibited thyroid metabolism in the animals at a dose of ca. 9.0 mg/kg/day. A statistically significant decrease of serum thyroxine occurred after the fourth week of exposure to 100 mg/l.concentration. The extent of thyroid suppression was dose dependent in each individual monkey, and was reversible after cessation of exposure. NaClO2 and NaClO3 failed to elicit similar effects in doses up to ca. 60 mg/kg/day. Also, NaClO4 or NH2Cl did not cause T-4 suppression in doses of 10 mg/kg/day. The selective thyroid effect of ClO2 was unexplained and it appeared to be paradoxical since ClO2 was rapidly reduced by the oral and gastric secretions to nonoxidizing species (presumably Cl-). No evidence of thyroid effects were detected in the serum of human volunteers who ingested approximately 1 mg/l. of ClO2 in drinking water as a result of routine use in the community water treatment process. Sodium chlorite induced dose-dependent oxidative stress on hematopoesis, causing decreased hemoglobin and red cell count and increased methemoglobin content. At the same time, serum transaminase (SGPT) levels showed significant subclinical elevation. The hematologic effects of NaClO2 rebounded during exposure indicating compensatory hemopoietic activity taking effect during oxidative stress. Sodium chlorate and chloramine did not induce detectable hematologic changes in the animals.