Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques

The feasibility, safety, and efficacy of liver-directed gene transfer was evaluated in 5 male macaques (aged 2.5 to 6.5 years) by using a recombinant adeno-associated viral (rAAV) vector (rAAV-2 CAGG-hFIX) that had previously mediated persistent therapeutic expression of human factor IX (hFIX; 6%-10% of physiologic levels) in murine models. A dose of 4 × 1012 vector genomes (vgs)/kg of body weight was administered through the hepatic artery or portal vein. Persistence of the rAAV vgs as circular monomers and dimers and high-molecular-weight concatamers was documented in liver tissue by Southern blot analysis for periods of up to 1 year. Vector particles were present in plasma, urine, or saliva for several days after infusion (as shown by polymerase chain reaction analysis), and the vgs were detected in spleen tissue at low copy numbers. An enzyme-linked immunosorption assay capable of detecting between 1% and 25% of normal levels of hFIX in rhesus plasma was developed by using hyperimmune serum from a rhesus monkey that had received an adenoviral vector encoding hFIX. Two macaques having 3 and 40 rAAV genome equivalents/cell, respectively, in liver tissue had 4% and 8% of normal physiologic plasma levels of hFIX, respectively. A level of hFIX that was 3% of normal levels was transiently detected in one other macaque, which had a genome copy number of 25 before abrogation by a neutralizing antibody (inhibitor) to hFIX. This nonhuman-primate model will be useful in further evaluation and development of rAAV vectors for gene therapy of hemophilia B. © 2002 by The American Society of Hematology

Percentile reference values for anthropometric body composition indices in European children from the IDEFICS study

INTRODUCTION: To characterise the nutritional status in children with obesity or wasting conditions, European anthropometric reference values for body composition measures beyond the body mass index (BMI) are needed. Differentiated assessment of body composition in children has long been hampered by the lack of appropriate references. OBJECTIVES: The aim of our study is to provide percentiles for body composition indices in normal weight European children, based on the IDEFICS cohort (Identification and prevention of Dietary-and lifestyle-induced health Effects in Children and infantS). METHODS: Overall 18 745 2.0-10.9-year-old children from eight countries participated in the study. Children classified as overweight/obese or underweight according to IOTF (N = 5915) were excluded from the analysis. Anthropometric measurements (BMI (N = 12 830); triceps, subscapular, fat mass and fat mass index (N = 11 845-11 901); biceps, suprailiac skinfolds, sum of skinfolds calculated from skinfold thicknesses (N = 8129-8205), neck circumference (N = 12 241); waist circumference and waist-to-height ratio (N = 12 381)) were analysed stratified by sex and smoothed 1st, 3rd, 10th, 25th, 50th, 75th, 90th, 97th and 99th percentile curves were calculated using GAMLSS. RESULTS: Percentile values of the most important anthropometric measures related to the degree of adiposity are depicted for European girls and boys. Age-and sex-specific differences were investigated for all measures. As an example, the 50th and 99th percentile values of waist circumference ranged from 50.7-59.2 cm and from 51.3-58.7 cm in 4.5-to < 5.0-year-old girls and boys, respectively, to 60.6-74.5 cm in girls and to 59.9-76.7 cm in boys at the age of 10.5-10.9 years. CONCLUSION: The presented percentile curves may aid a differentiated assessment of total and abdominal adiposity in European children

Measurement of the B0 anti-B0 oscillation frequency using l- D*+ pairs and lepton flavor tags

The oscillation frequency Delta-md of B0 anti-B0 mixing is measured using the partially reconstructed semileptonic decay anti-B0 -> l- nubar D*+ X. The data sample was collected with the CDF detector at the Fermilab Tevatron collider during 1992 - 1995 by triggering on the existence of two lepton candidates in an event, and corresponds to about 110 pb-1 of pbar p collisions at sqrt(s) = 1.8 TeV. We estimate the proper decay time of the anti-B0 meson from the measured decay length and reconstructed momentum of the l- D*+ system. The charge of the lepton in the final state identifies the flavor of the anti-B0 meson at its decay. The second lepton in the event is used to infer the flavor of the anti-B0 meson at production. We measure the oscillation frequency to be Delta-md = 0.516 +/- 0.099 +0.029 -0.035 ps-1, where the first uncertainty is statistical and the second is systematic.Comment: 30 pages, 7 figures. Submitted to Physical Review

The Eyes Have It: Sex and Sexual Orientation Differences in Pupil Dilation Patterns

Recent research suggests profound sex and sexual orientation differences in sexual response. These results, however, are based on measures of genital arousal, which have potential limitations such as volunteer bias and differential measures for the sexes. The present study introduces a measure less affected by these limitations. We assessed the pupil dilation of 325 men and women of various sexual orientations to male and female erotic stimuli. Results supported hypotheses. In general, self-reported sexual orientation corresponded with pupil dilation to men and women. Among men, substantial dilation to both sexes was most common in bisexual-identified men. In contrast, among women, substantial dilation to both sexes was most common in heterosexual-identified women. Possible reasons for these differences are discussed. Because the measure of pupil dilation is less invasive than previous measures of sexual response, it allows for studying diverse age and cultural populations, usually not included in sexuality research

Inadequate fluid intake in long term care residents: prevalence and determinants

Dehydration is estimated to be present in half of long term care residents, as many do not consume the recommended levels of fluid intake. This study aims to describe fluid intake in long term care residents and identify the factors associated with fluid intake. Data were collected from 622 long term care residents, with a mean age of 86.8 ± 7.8. Total fluid intake was estimated over three non-consecutive days. Potential resident and unit-level variables risk factors for low fluid intake were collected, such as dementia status, activities of daily living, and eating challenges. Average daily fluid intake ranged from 311-2390 mL (1104.1 ± 379.3). Hierarchical regression analysis revealed that fluid intake was negatively associated with increased age, cognitive impairment, eating challenges and increased dining room staffing. Being male and requiring more physical assistance were positively associated with intake. Variables identified to predict intake could help inform strategies and targeted interventions to improve fluid intake

Longitudinal investigation of training status and cardiopulmonary responses in pre- and early-pubertal children

PurposeThe presence of a maturational threshold that modulates children’s physiological responses to exercise training continues to be debated, not least due to a lack of longitudinal evidence to address this question. The purpose of this study was to investigate the interaction between swim-training status and maturity in nineteen trained (T, 10 ± 1 years, −2.4 ± 1.9 years pre-peak height velocity, 8 boys) and fifteen untrained (UT, 10 ± 1 years, −2.3 ± 0.9 years pre-peak height velocity, 5 boys) children, at three annual measurements.MethodsIn addition to pulmonary gas exchange measurements, stroke volume (SV) and cardiac output ( Q˙) were estimated by thoracic bioelectrical impedance during incremental ramp exercise.ResultsAt baseline and both subsequent measurement points, trained children had significantly (P &#60; 0.05) higher peak oxygen uptake (year 1 T 1.75 ± 0.34 vs. UT 1.49 ± 0.22; year 2 T 2.01 ± 0.31 vs. UT 1.65 ± 0.08; year 3 T 2.07 ± 0.30 vs. UT 1.77 ± 0.16 l min−1) and Q˙ (year 1 T 15.0 ± 2.9 vs. UT 13.2 ± 2.2; year 2 T 16.1 ± 2.8 vs. UT 13.8 ± 2.9; year 3 T 19.3 ± 4.4 vs. UT 16.0 ± 2.7 l min−1). Furthermore, the SV response pattern differed significantly with training status, demonstrating the conventional plateau in UT but a progressive increase in T. Multilevel modelling revealed that none of the measured pulmonary or cardiovascular parameters interacted with maturational status, and the magnitude of the difference between T and UT was similar, irrespective of maturational status.ConclusionThe results of this novel longitudinal study challenge the notion that differences in training status in young people are only evident once a maturational threshold has been exceeded

Plant perception of β-aminobutyric acid is mediated by an aspartyl-tRNA synthetase

Specific chemicals can prime the plant immune system for augmented defense. β-aminobutyric acid (BABA) is a priming agent that provides broad-spectrum disease protection. However, BABA also suppresses plant growth when applied in high doses, which has hampered its application as a crop defense activator. Here we describe a mutant of Arabidopsis thaliana that is impaired in BABA-induced disease immunity (ibi1) but is hypersensitive to BABA-induced growth repression. IBI1 encodes an aspartyl-tRNA synthetase. Enantiomer-specific binding of the R enantiomer of BABA to IBI1 primed the protein for noncanonical defense signaling in the cytoplasm after pathogen attack. This priming was associated with aspartic acid accumulation and tRNA-induced phosphorylation of translation initiation factor eIF2α. However, mutation of eIF2α-phosphorylating GCN2 kinase did not affect BABA-induced immunity but relieved BABA-induced growth repression. Hence, BABA-activated IBI1 controls plant immunity and growth via separate pathways. Our results open new opportunities to separate broad-spectrum disease resistance from the associated costs on plant growth

Enzyme sequestration as a tuning point in controlling response dynamics of signalling networks

Signalling networks result from combinatorial interactions among many enzymes and scaffolding proteins. These complex systems generate response dynamics that are often essential for correct decision-making in cells. Uncovering biochemical design principles that underpin such response dynamics is a prerequisite to understand evolved signalling networks and to design synthetic ones. Here, we use in silico evolution to explore the possible biochemical design space for signalling networks displaying ultrasensitive and adaptive response dynamics. By running evolutionary simulations mimicking different biochemical scenarios, we find that enzyme sequestration emerges as a key mechanism for enabling such dynamics. Inspired by these findings, and to test the role of sequestration, we design a generic, minimalist model of a signalling cycle, featuring two enzymes and a single scaffolding protein. We show that this simple system is capable of displaying both ultrasensitive and adaptive response dynamics. Furthermore, we find that tuning the concentration or kinetics of the sequestering protein can shift system dynamics between these two response types. These empirical results suggest that enzyme sequestration through scaffolding proteins is exploited by evolution to generate diverse response dynamics in signalling networks and could provide an engineering point in synthetic biology applications

Anthropometry and body composition in ethnic Japanese and Caucasian adolescent girls: Considerations on ethnicity and menarche

Objective: This study aimed to compare the various anthropometric and body composition parameters based on the ethnicity and the absence or presence of menarche.Design: A cross-sectional study with incomplete sampling, using the subject as the evaluation unit.Subjects: the final sample of 550 subjects was composed of 122 Japanese and 179 Caucasian premenarcheal adolescents, and 72 Japanese and 177 Caucasian postmenarcheal adolescents.Methods: the variables of body composition were measured through the following methods: bioelectrical impedance analysis, near-infrared interactance (NIR), Slaughter cutaneous skinfold equations and body mass index. Weight, height and sitting height were also evaluated.Results: the Japanese pre- and postmenarcheal girls presented lower weight and height values when compared with the Caucasian girls. in general, the Japanese premenarcheal girls presented less fat and fat-free mass than the premenarcheal Caucasian girls. This fact was demonstrated through NIR results. Conversely, the Japanese postmenarcheal adolescents accumulated more fat than their Caucasian counterparts. However, significant differences were solely encountered in the values of cutaneous skinfold percent body fat. With regard to menarche, it was verified that, regardless of ethnicity, all the anthropometric and body composition variables reached higher values among postmenarcheal adolescents when compared with premenarcheal adolescents.Conclusion: Different results of weight and height between the ethnic groups may bring back the discussion concerning separate growth curves for different ethnic groups. the results of the body composition analysis indicated high adiposity levels among postmenarcheal adolescents.Universidade Federal de São Paulo, Escola Paulista Med, Dept Postgrad Nutr, BR-04020060 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Prevent Med, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Postgrad Nutr, BR-04020060 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Prevent Med, São Paulo, BrazilWeb of Scienc