Group-based exercice training programs for military members presenting musculoskeletal disorders - protocol for a pragmatic randomized controlled trial.

BACKGROUND: Musculoskeletal disorders are a leading cause of morbidity and the most prevalent source of disability among soldiers. Their high prevalence in armed forces and limited ressources have led to problems related to access to physical rehabilitation care. To increase access, supervised group-based exercise programs for the most prevalent musculoskeletal disorders (low back pain, patellofemoral pain, rotator cuff-related shoulder pain or lateral ankle sprain) have been developed at a Canadian Armed forces (CAF) base, but their effectiveness has not been evaluated. The primary objective of this randomized controlled trial is to evaluate the mid- and long-term effects of these group-based training programs on pain severity and functional limitations, in comparison with usual individual physiotherapy care. Secondary objectives include comparing both interventions in terms of health-related quality of life, pain-related fear, and patients' satisfaction. METHODS: One hundred and twenty soldiers with a new medical referral for physiotherapy services for one of the four targeted musculoskeletal disorders will be consecutively recruited. They will be randomly assigned to either group-based training program or usual individual physiotherapy care, and will take part in the assigned 12-week intervention. There will be four evaluation sessions over 26 weeks (baseline, week 6, 12 and 26). At each follow-up, functional limitations, pain severity, health-related quality of life and pain-related fears will be assessed. Patients satisfaction with treatment will also be evaluated at the end of the intervention period. Either two-way repeated measures ANOVA will be used to analyse and compare the effects of the interventions. DISCUSSION: This RCT will determine the effectiveness of group-based training programs compared to usual individual physiotherapy care. This new intervention model could represent an efficient, and more pro-active approach to manage a higher number of soldiers with musculoskeletal disorders. It could improve access to physical rehabilitation care and improve the health of soldiers. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT05235152 ), February 11th 2022.

Considerations for upscaling individual effects of wind energy development towards population-level impacts on wildlife.

The expansion of wind energy poses challenges to policy- and decision-makers to address conflicts with wildlife. Conflicts are associated with impacts of existing and planned projects on wildlife, and associated difficulties of prediction where impacts are subject to considerable uncertainty. Many post-construction studies have demonstrated adverse effects on individuals of various bird and bat species. These effects may come in the form of collision-induced mortality or behavioral or physiological changes reducing the fitness of individuals exposed to wind energy facilities. Upscaling these individual effects to population impacts provides information on the true value of interest from a conservation point of view. This paper identifies methodological issues associated when moving from individual effects to population impacts in the context of wind energy. Distinct methodological approaches to predict population impacts are described using published case studies. The various choices of study design and metrics available to detect significant changes at the population level are further assessed based on these. Ways to derive impact thresholds relevant for decision-making are discussed in detail. Robust monitoring schemes and sophisticated modelling techniques may inevitably be unable to describe the whole complexity of wind and wildlife interactions and the natural variability of animal populations. Still, they will provide an improved understanding of the response of wildlife to wind energy and better-informed policies to support risk-based decision-making. Policies that support the use of adaptive management will promote assessments at the population level. Providing information to adequately balance the development of wind energy with the persistence of wildlife populations.

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment.

UNLABELLED: Human respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cells in vitro. Antivirals acting upstream of RSV polymerase activity (i.e., compounds targeting the fusion protein or the nucleoprotein) reduced viral load immediately postinfection and partially attenuated interferon responses. In contrast, antivirals directed to the RSV polymerase demonstrated activity throughout the viral replication cycle and specifically modulated the RIG-I/mitochondrial antiviral signaling protein (MAVS)/TBK1/IRF3/interferon-stimulated gene (ISG) axis, causing either an upregulation or a downregulation of interferon responses, depending on the mechanism of polymerase inhibition. Notably, polymerase inhibition leading to the accumulation of abortive RNA products correlated with the amplification of interferon-stimulated genes to up to 10 times above normal infection levels. Understanding how antiviral activities and their modulation of innate immunity may affect recovery from RSV infection will help guide the development of safe and effective therapies. IMPORTANCE: RSV circulates seasonally, causing acute lower respiratory disease. Therapeutic interventions with efficacy throughout the viral replication cycle, rapid viral clearance, and prevention of potentially harmful inflammatory responses are desirable. Compounds targeting the RSV polymerase inhibited virus replication late in the viral life cycle and, depending on the functional domain targeted, either attenuated or amplified RIG-I and downstream interferon pathways in infected cells. These data will help guide the development of safe and effective therapies by providing new molecular evidence that the mechanism of inhibition by an antiviral compound can directly impact innate antiviral immune responses in the airway epithelium.

Opioid receptor mu 1 gene, fat intake and obesity in adolescence.

Dietary preference for fat may increase risk for obesity. It is a complex behavior regulated in part by the amygdala, a brain structure involved in reward processing and food behavior, and modulated by genetic factors. Here, we conducted a genome-wide association study (GWAS) to search for gene loci associated with dietary intake of fat, and we tested whether these loci are also associated with adiposity and amygdala volume. We studied 598 adolescents (12-18 years) recruited from the French-Canadian founder population and genotyped them with 530 011 single-nucleotide polymorphisms. Fat intake was assessed with a 24-hour food recall. Adiposity was examined with anthropometry and bioimpedance. Amygdala volume was measured by magnetic resonance imaging. GWAS identified a locus of fat intake in the µ-opioid receptor gene (OPRM1, rs2281617, P=5.2 × 10(-6)), which encodes a receptor expressed in the brain-reward system and shown previously to modulate fat preference in animals. The minor OPRM1 allele appeared to have a 'protective' effect: it was associated with lower fat intake (by 4%) and lower body-fat mass (by ∼2 kg, P=0.02). Consistent with the possible amygdala-mediated inhibition of fat preference, this allele was additionally associated with higher amygdala volume (by 69 mm(3), P=0.02) and, in the carriers of this allele, amygdala volume correlated inversely with fat intake (P=0.02). Finally, OPRM1 was associated with fat intake in an independent sample of 490 young adults. In summary, OPRM1 may modulate dietary intake of fat and hence risk for obesity, and this effect may be modulated by subtle variations in the amygdala volume.

Connectivity of stormwater ponds impacts Odonata abundance and species richness.

Context: The successful dispersal of an animal depends, partly, on landscape connectivity. Urbanization poses risks to dispersal activities by increasing hostile land cover types. Objectives: We investigated how connectivity of urban ponds impacted Odonata communities (dragonflies and damselflies), an order of semi-aquatic insects that actively disperse. Methods: We sampled 41 constructed stormwater ponds and 8 natural ponds in a metropolitan area. The effect of connectivity and the quantity of available adjacent habitats was tested at different scales for dragonflies (900 m) and damselflies (300 m), determined by a literature analysis, to account for differences in suborder dispersal capabilities. Results: Lower levels of connectivity and fewer nearest neighbours negatively impacted abundance, species richness, and composition of dragonflies (p values < 0.01, R2 = 0.18-0.70). Adult dragonfly abundance had a stronger positive relationship with connectivity than species richness. In particular, the abundance of adult dragonfly Leucorrhinia frigida, found almost exclusively at natural ponds, had a positive relationship with connectivity. Connectivity and the number of nearest neighbours had no significant impact on damselflies apart from a slight negative relationship between connectivity and species richness (p value = 0.02, R2 = 0.11). Natural ponds had significantly higher levels of connectivity when compared to stormwater ponds. Conclusions: Our results suggest that dragonflies are positively affected by increased connectivity in an urban landscape, with no benefit of connectivity to damselflies at the scale measured. We recommend intentional planning of urban stormwater pond networks, where individual ponds can act as stepping stones, incorporated with strategic inclusion of beneficial land cover types. Supplementary Information: The online version contains supplementary material available at 10.1007/s10980-024-01817-z.

Visceral fat is associated with lower executive functioning in adolescents.

BACKGROUND: Obesity, a major risk factor for cardiometabolic disease, is associated with lower cognitive performance from childhood to senescence, especially on tasks of executive function. In the cardiovascular domain, fat stored viscerally rather than elsewhere in the body carries particularly high risk. It is unknown whether this is also true in case of obesity-cognition relationships. The aim of this study was to assess the cross-sectional relationship between visceral fat (VF) and cognitive performance in a community sample of healthy adolescents. METHODS: In a community-based sample of 983 adolescents (12-18 years old, 480 males), VF was quantified using magnetic resonance imaging, total body fat was measured using a multifrequency bioimpedance, and cognitive performance was assessed using a battery of cognitive tests measuring executive function and memory. RESULTS: We found that larger volumes of VF were associated with lower performance on six measures of executive function (P=0.0001-0.02). We also found that the association of VF with executive function was moderated by sex for a subset of measures, such that relationship was present mainly in female subjects and not in male subjects (sex-by-VF interaction: P=0.001-0.04). These relationships were independent of the quantity of total body fat and a number of potential confounders, including age, puberty stage and household income. CONCLUSIONS: Our results suggest that the adverse association between obesity and executive function may be attributed to fat stored viscerally and not to fat stored elsewhere in the body. They also suggest that female subjects compared with male subjects may be more sensitive to the potentially detrimental effects of VF on cognition.

Sexual dimorphism in the adolescent brain: Role of testosterone and androgen receptor in global and local volumes of grey and white matter.

Here we examined sex differences in the volumes of grey and white matter, and in grey-matter "density," in a group of typically developing adolescents participating in the Saguenay Youth Study (n=419; 12-18 years). In male adolescents, we also investigated the role of a functional polymorphism in androgen-receptor gene (AR) in moderating the effect of testosterone on volumes of grey and white matter and grey-matter density. Overall, both absolute and relative volumes of white matter were larger in male vs. females adolescents. The relative grey-matter volumes were slightly larger in female than male adolescents and so was the grey-matter density in a large number of cortical regions. In male adolescents, functional polymorphism of AR moderated the effect of testosterone on relative white- and grey-matter volumes. Following a discussion of several methodological and interpretational issues, we outline future directions in investigating brain-behavior relationships vis-à-vis psychopathology.

A decade of mammalian retinal stem cell research.

Ten years have now passed since the discovery of quiescent neural stem cells within the mammalian retina. Beside the fascinating aspect of stem cell biology in basic science, these cells have also offered hope for the treatment of incurable retinal diseases. The field has thus rapidly evolved, fluctuating between major advances and recurring doubts. In this review, we will retrace the efforts of scientists during this last decade to characterize these cells and to use them in regenerative medicine. We will also highlight advances made in animal models capable of stem cell-mediated retinal regeneration.

Sex differences in the growth of white matter during adolescence.

The purpose of this study was to examine sex differences in the maturation of white matter during adolescence (12 to 18 years of age). We measured lobular volumes of white matter and white-matter "density" throughout the brain using T1-weighted images, and estimated the myelination index using magnetisation-transfer ratio (MTR). In male adolescents, we observed age-related increases in white-matter lobular volumes accompanied by decreases in the lobular values of white-matter MTR. White-matter density in the putative cortico-spinal tract (pCST) decreased with age. In female adolescents, on the other hand, we found only small age-related increase in white-matter volumes and no age-related changes in white-matter MTR, with the exception of the frontal lobe where MTR increased. White-matter density in the pCST also increased with age. These results suggest that sex-specific mechanisms may underlie the growth of white matter during adolescence. We speculate that these mechanisms involve primarily age-related increases in axonal calibre in males and increased myelination in females.

Xath5 participates in a network of bHLH genes in the developing Xenopus retina.

We examined the function of basic-helix-loop-helix (bHLH) transcription factors during retinal neurogenesis. We identified Xath5, a Xenopus bHLH gene related to Drosophila atonal, which is expressed in the developing Xenopus retina. Targeted expression of Xath5 in retinal progenitor cells biased the differentiation of these cells toward a ganglion cell fate, suggesting that Xath5 can regulate the differentiation of retinal neurons. We examined the relationship between the three bHLH genes Xash3, NeuroD, and Xath5 during retinal neurogenesis and found that Xash3 is expressed in early retinoblasts, followed by coexpression of Xath5 and NeuroD in differentiating cells. We provide evidence that the expression of Xash3, NeuroD, and Xath5 is coupled and propose that these bHLH genes regulate successive stages of neuronal differentiation in the developing retina.

The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies.

Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small molecule nucleoside analog GS-441524 is a molecular precursor to a pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We determined that GS-441524 was non-toxic in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. We determined the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an experimental FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity.

Isolation and embryonic expression of Xel-1, a nervous system-specific Xenopus gene related to the elav gene family.

We have identified a new member of the elav gene family in Xenopus laevis. This gene, Xel-1, like the other elav-related genes, encodes a putative RNA-binding protein that contains three RNA Recognition Motifs and is solely expressed in the nervous system. Xel-1 is most likely the Xenopus homologue of Hel-N1, one of the three known human genes related to elav. Xel-1 is not expressed in early neural precursors but rather in differentiating neurons of the central nervous system, as well as in the cranial and the spinal ganglion cells. Xel-1 thus appears to be an early differentiation marker for both the central and the peripheral nervous system of Xenopus laevis.

Xenopus elav-like genes are differentially expressed during neurogenesis.

In Xenopus, three neural-specific elav-like genes (ELGs) have been identified, elrB/Xel-1, elrC and elrD. With the aim to highlight possible differences in the regulation of these genes, we compared their expression patterns during development. We had previously shown that elrB is expressed from the early tailbud stage onwards, in both the central and peripheral nervous system. Here we show that both elrC and elrD are expressed earlier than elrB in the developing neural tube and the cranial ganglia, with different temporal specificities. Double in situ hybridizations on brain cross-sections allowed us to define precisely the expression domains of elrB, elrC and elrD in the brain at the tailbud stage. What emerges from this study is a differential distribution of ELGs transcripts in the hindbrain. Also, double labeling with a motor neuron marker shows that in stage 41 tailbud embryos, elrD remains strongly expressed in motor neurons whereas elrC is mostly expressed in non-motor neuron cells.

Molecular recapitulation: the growth of the vertebrate retina.

In postembryonic lower vertebrates, the ciliary marginal zone (CMZ) of the retina is a continuously growing zone in the central nervous system. By studying the cellular and molecular biology of the cells in this region, we have discovered that the CMZ can be divided into several zones, from peripheral to central, which reflect different stages of development of retinal stem cells. Based on the behavior of the cells and on the genes expressed in different regions, we propose here that cellular development in the CMZ recapitulates in space what happens in embryonic retinal development in time.

Misexpression of the RNA-binding protein ELRB in Xenopus presumptive neurectoderm induces proliferation arrest and programmed cell death.

Proteins of the ELAV/Hu family share the presence of three RNA binding domains. In Xenopus, three nervous system-specific elav/Hu related genes, elrB, elrC and elrD, have been identified so far. The temporally regulated expression patterns of elrB, elrC and elrD suggest their involvement at different steps of neural differentiation. In the present study we misexpressed elrB by RNA injection in early Xenopus embryos and analyzed morphologically and molecularly its effects on neural development. We showed that heterochronous expression of elrB in presumptive neurectoderm down-regulates the expression of neural markers, such as N-tubulin, as well as that of other Xenopus elav-like genes, elrC and elrD, whereas ectopic expression of elrB in presumptive mesoderm has no effect on MyoD. Misexpression of elrB also induces severe defects in neural tube development, associated with massive cell loss resulting from early cell cycle arrest and programmed cell death. Our results are discussed in the context of early neural differentiation.

Visceral fat enhances blood pressure reactivity to physical but not mental challenges in male adolescents.

BACKGROUND: Excess visceral fat is a major risk factor for hypertension. Enhanced blood pressure (BP) reactivity and delayed BP recovery from physical and mental challenges predict future hypertension. OBJECTIVES: Determine whether visceral fat is associated with higher BP reactivity and delayed BP recovery from physical and mental challenges during adolescence. METHODS: In a community-based sample of 283 male and 308 female adolescents, we measured visceral fat with magnetic resonance imaging, total body fat with bioimpedance, and beat-by-beat BP with a Finometer at rest and during physical (10-min standing) and mental (2-min math stress) challenges. RESULTS: Males vs. females showed greater BP reactivity and no differences in BP recovery from either type of challenges. Visceral fat was positively associated with BP reactivity to standing up only and in males only (+8.4 ± 3.6 mmHg per 1 log cm(3) of visceral fat, P = 0.008), and this association was independent of total body fat. No association was seen between visceral fat and BP recovery from either type of challenge in either sex. All these associations were independent of age, puberty stage, height and initial BP. CONCLUSIONS: Adolescent males vs. females demonstrate greater BP reactivity but similar BP recovery from physical and mental challenges. Excess visceral fat enhances BP reactivity to physical but not mental challenges in males only.

Synthesis of methotrexate prodrugs as an approach for drug targeting.

Eleven methotrexale-alpha-peptides containing arginine (MTX-Arg), asparagine (MTX-Asn), cysteine (MTX-Cys), glutamine (MTX-Gln), histidine (MTX-His), lysine (MTX-Lys), methionine (MTX-Met), phenylalanine (MTX-Phe), proline (MTX-Pro), tryptophan (MTX-Trp) and tyrosine (MTX-Tyr) were produced by solid phase synthesis using the Fmoc method. Purity of the MTX derivatives was assessed by capillary zone electrophoresis (CZE). An enzymatic assay was then developed using CZE for monitoring the hydrolysis of the MTX-alpha-peptides by bovine pancreatic carboxypeptidase A (CP-A) leading to the release of free MTX. MTX-Phe appeared to be the most suitable substrate for CP-A out of the eleven tested with a hydrolysis rate comparable to that of hippuryl-L-phenylalanine, a natural substrate for CP-A. In vitro assays on a human ovarian teratocarcinoma cell line (CRL-1572), showed that MTX-Phe was non toxic, but when combined with 1 mU of CP-A, MTX-Phe cytotoxicity was enhanced considerably showing only two times less pharmacological activity than MTX. These results suggest that MTX-Phe is a potent prodrug and could be used in a drug targeting model combining monoclonal antibodies coupled with CP-A for a more specific approach in cancer therapy.

Subcellular distribution of Xenopus XEL-1 protein, a member of the neuron-specific ELAV/Hu family, revealed by epitope tagging.

Drosophila and vertebrate elav/Hu genes are involved in the development and the maintenance of the nervous system. They all encode proteins that contain three RNA recognition motifs (RRM) and are thus expected to play a role in RNA metabolism. Drosophila ELAV and RBP9 proteins were reported to be exclusively distributed in nuclei of neurons, whereas known human Hu proteins display a bipartite nuclear and cytoplasmic distribution. We have previously isolated a member of this family in Xenopus, Xel-1, that is exclusively expressed in neural tissues from the early tailbud stage onward. In the present study, we report on the subcellular distribution of XEL-1 protein using myc epitope tagging, a strategy allowing the study of a single member of the ELAV/Hu family. We show that the subcellular distribution of exogenous XEL-1 protein in neural tissues depends on developmental stages. In the neural tube at the neurula stage, where endogenous Xel-1 is not expressed, exogenous tagged XEL-1 protein is localized in both the nucleus and the cytoplasm. At the tailbud stage, where endogenous Xel-1 is expressed, exogenous tagged XEL-1 protein is localized essentially in the cytoplasm of neural tube cells. In contrast, exogenous Drosophila ELAV protein localizes to the nucleus at all stages in Xenopus embryos. The variability in the subcellular localization of ELAV/Hu proteins in different species may have functional implications.