Glucocorticoid-Treated Mice Are an Inappropriate Positive Control for Long-Term Preclinical Studies in the mdx Mouse

Dmd(mdx) (mdx) mice are used as a genetic and biochemical model of dystrophin deficiency. The long-term consequences of glucocorticoid (GC) treatment on dystrophin-deficient skeletal and heart muscle are not yet known. Here we used systematic phenotyping to assess the long-term consequences of GC treatment in mdx mice. Our investigation addressed not only the effects of GC on the disease phenotype but also the question of whether GCs can be used as a positive control for preclinical drug evaluations.We performed nine pre-clinical efficacy trials (treated N = 129, untreated N = 106) of different durations in 9-to-50-week-old dystrophic mdx mice over a 3-year time period using standardized methods. In all these trials, we used either 1 mg/kg body weight of prednisone or 5 mg/kg body weight of prednisolone as positive controls to compare the efficacy of various test drugs. Data from untreated controls and GC-treated mice in the various trials have been pooled and analyzed to assess the effects of GCs on dystrophin-deficient skeletal and cardiac muscles of mdx mice. Our results indicate that continuous GC treatment results in early (e.g., at 50 days) improvements in normalized parameters such as grip strength, motor coordination and maximal in vitro force contractions on isolated EDL muscle, but these initial benefits are followed by a progressive loss of muscle strength after 100 days. We also found a significant increase in heart fibrosis that is reflected in a significant deterioration in cardiac systolic function after 100 days of treatment.Continuous administration of prednisone to mdx mice initially improves skeletal muscle strength, but further therapy result in deterioration of muscle strength and cardiac function associated with enhanced cardiac fibrosis. These results suggest that GCs may not serve as an appropriate positive control for long-term mdx mouse preclinical trials

The relationship between foot arch measurements and walking parameters in children

BACKGROUND: Walking mechanics are influenced by body morphology. Foot arch height is one aspect of body morphology central to walking. However, generalizations about the relationship between arch height and walking are limited due to previous methodologies used for measuring the arch and the populations that have been studied. To gain the knowledge needed to support healthy gait in children and adults, we need to understand this relationship in unimpaired, typically developing children and adults using dynamic measures. The purpose of the current study was to examine the relationship between arch height and gait in a sample of healthy children and adults using dynamic measures. METHODS: Data were collected from 638 participants (n = 254 children and n = 384 adults) at the Museum of Science, Boston (MOS) and from 18 4- to 8-year-olds at the Motor Development and Motor Control Laboratories. Digital footprints were used to calculate two arch indices: the Chippaux-Smirak (CSI) and the Keimig Indices (KI). The height of the navicular bone was measured. Gait parameters were captured with a mechanized gait carpet at the MOS and three-dimensional motion analyses and in-ground force plates in the Motor Development and Motor Control Laboratories. RESULTS: Linear regression analyses on data from the MOS confirmed that as age increases, step length increases. With a linear mixed effect regression model, we found that individuals who took longer steps had higher arches as measured by the KI. However, this relationship was no longer significant when only adults were included in the model. A model restricted to children found that amongst this sample, those with higher CSI and higher KI values take longer relative step lengths. Data from the Motor Development and Motor Control Laboratories showed that both CSI and KI added to the prediction; children with lower anterior ground reaction forces had higher CSI and higher KI values. Arch height indices were correlated with navicular height. CONCLUSIONS: These results suggest that more than one measure of the arch may be needed elucidate the relationship between arch height and gait.K12 HD055931 - NICHD NIH HHS; K12HD055931 - NICHD NIH HH

Women experience a better long-term immune recovery and a better survival on HAART in Lao People's Democratic Republic.

<p>Abstract</p> <p>Background</p> <p>In April 2003, Médecins Sans Frontières launched an HIV/AIDS programme to provide free HAART to HIV-infected patients in Laos. Although HIV prevalence is estimated as low in this country, it has been increasing in the last years. This work reports the first results of an observational cohort study and it aims to identify the principal determinants of the CD4 cells evolution and to assess mortality among patients on HAART.</p> <p>Methods</p> <p>We performed a retrospective database analysis on patients initiated on HAART between 2003 and 2009 (CD4<200cells/μL or WHO stage 4). We excluded from the analysis patients who were less than 16 years old and pregnant women. To explore the determinants of the CD4 reconstitution, a linear mixed model was adjusted. To identify typical trajectories of the CD4 cells, a latent trajectory analysis was carried out. Finally, a Cox proportional-hazards model was used to reveal predictors of mortality on HAART including appointment delay greater than 1 day.</p> <p>Results</p> <p>A total of 1365 patients entered the programme and 913 (66.9%) received an HAART with a median CD4 of 49 cells/μL [IQR 15–148]. High baseline CD4 cell count and female gender were associated with a higher CD4 level over time. In addition, this gender difference increased over time. Two typical latent CD4 trajectories were revealed showing that 31% of women against 22% of men followed a high CD4 trajectory. In the long-term, women were more likely to attend appointments without delay. Mortality reached 6.2% (95% CI 4.8-8.0%) at 4 months and 9.1% (95% CI 7.3-11.3%) at 1 year. Female gender (HR=0.17, 95% CI 0.07-0.44) and high CD4 trajectory (HR=0.19, 95% CI 0.08-0.47) were independently associated with a lower death rate.</p> <p>Conclusions</p> <p>Patients who initiated HAART were severely immunocompromised yielding to a high early mortality. In the long-term on HAART, women achieved a better CD4 cells reconstitution than men and were less likely to die. This study highlights important differences between men and women regarding response to HAART and medical care, and questions men’s compliance to treatment.</p

Metacarpal trabecular bone varies with distinct hand-positions used in hominid locomotion

Trabecular bone remodels during life in response to loading and thus should, at least in part, reflect potential variation in the magnitude, frequency and direction of joint loading across different hominid species. Here we analyse the trabecular structure across all non-pollical metacarpal distal heads (Mc2-5) in extant great apes, expanding on previous volume of interest and whole-epiphysis analyses that have largely focussed on only the first or third metacarpal. Specifically, we employ both a univariate statistical mapping and a multivariate approach to test for both inter-ray and interspecific differences in relative trabecular bone volume fraction (RBV/TV) and degree of anisotropy (DA) in Mc2-5 subchondral trabecular bone. Results demonstrate that while DA values only separate Pongo from African apes (Pan troglodytes, Pan paniscus, Gorilla gorilla), RBV/TV distribution varies with the predicted loading of the metacarpophalangeal (McP) joints during locomotor behaviours in each species. Gorilla exhibits a relatively dorsal distribution of RBV/TV consistent with habitual hyper-extension of the McP joints during knuckle-walking, whereas Pongo has a palmar distribution consistent with flexed McP joints used to grasp arboreal substrates. Both Pan species possess a disto-dorsal distribution of RBV/TV, compatible with multiple hand postures associated with a more varied locomotor regime. Further inter-ray comparisons reveal RBV/TV patterns consistent with varied knuckle-walking postures in Pan species in contrast to higher RBV/TV values toward the midline of the hand in Mc2 and Mc5 of Gorilla, consistent with habitual palm-back knuckle-walking. These patterns of trabecular bone distribution and structure reflect different behavioural signals that could be useful for determining the behaviours of fossil hominins

Snake Bite in South Asia: A Review

Snake bite is one of the most neglected public health issues in poor rural communities living in the tropics. Because of serious misreporting, the true worldwide burden of snake bite is not known. South Asia is the world's most heavily affected region, due to its high population density, widespread agricultural activities, numerous venomous snake species and lack of functional snake bite control programs. Despite increasing knowledge of snake venoms' composition and mode of action, good understanding of clinical features of envenoming and sufficient production of antivenom by Indian manufacturers, snake bite management remains unsatisfactory in this region. Field diagnostic tests for snake species identification do not exist and treatment mainly relies on the administration of antivenoms that do not cover all of the important venomous snakes of the region. Care-givers need better training and supervision, and national guidelines should be fed by evidence-based data generated by well-designed research studies. Poorly informed rural populations often apply inappropriate first-aid measures and vital time is lost before the victim is transported to a treatment centre, where cost of treatment can constitute an additional hurdle. The deficiency of snake bite management in South Asia is multi-causal and requires joint collaborative efforts from researchers, antivenom manufacturers, policy makers, public health authorities and international funders

FACT, the Bur Kinase Pathway, and the Histone Co-Repressor HirC Have Overlapping Nucleosome-Related Roles in Yeast Transcription Elongation

Gene transcription is constrained by the nucleosomal nature of chromosomal DNA. This nucleosomal barrier is modulated by FACT, a conserved histone-binding heterodimer. FACT mediates transcription-linked nucleosome disassembly and also nucleosome reassembly in the wake of the RNA polymerase II transcription complex, and in this way maintains the repression of ‘cryptic’ promoters found within some genes. Here we focus on a novel mutant version of the yeast FACT subunit Spt16 that supplies essential Spt16 activities but impairs transcription-linked nucleosome reassembly in dominant fashion. This Spt16 mutant protein also has genetic effects that are recessive, which we used to show that certain Spt16 activities collaborate with histone acetylation and the activities of a Bur-kinase/Spt4–Spt5/Paf1C pathway that facilitate transcription elongation. These collaborating activities were opposed by the actions of Rpd3S, a histone deacetylase that restores a repressive chromatin environment in a transcription-linked manner. Spt16 activity paralleling that of HirC, a co-repressor of histone gene expression, was also found to be opposed by Rpd3S. Our findings suggest that Spt16, the Bur/Spt4–Spt5/Paf1C pathway, and normal histone abundance and/or stoichiometry, in mutually cooperative fashion, facilitate nucleosome disassembly during transcription elongation. The recessive nature of these effects of the mutant Spt16 protein on transcription-linked nucleosome disassembly, contrasted to its dominant negative effect on transcription-linked nucleosome reassembly, indicate that mutant FACT harbouring the mutant Spt16 protein competes poorly with normal FACT at the stage of transcription-linked nucleosome disassembly, but effectively with normal FACT for transcription-linked nucleosome reassembly. This functional difference is consistent with the idea that FACT association with the transcription elongation complex depends on nucleosome disassembly, and that the same FACT molecule that associates with an elongation complex through nucleosome disassembly is retained for reassembly of the same nucleosome