Understanding the role of contrasting urban contexts in healthy aging: an international cohort study using wearable sensor devices (the CURHA study protocol).

BACKGROUND: Given the challenges of aging populations, calls have been issued for more sustainable urban re-development and implementation of local solutions to address global environmental and healthy aging issues. However, few studies have considered older adults' daily mobility to better understand how local built and social environments may contribute to healthy aging. Meanwhile, wearable sensors and interactive map-based applications offer novel means for gathering information on people's mobility, levels of physical activity, or social network structure. Combining such data with classical questionnaires on well-being, physical activity, perceived environments and qualitative assessment of experience of places opens new opportunities to assess the complex interplay between individuals and environments. In line with current gaps and novel analytical capabilities, this research proposes an international research agenda to collect and analyse detailed data on daily mobility, social networks and health outcomes among older adults using interactive web-based questionnaires and wearable sensors. METHODS/DESIGN: Our study resorts to a battery of innovative data collection methods including use of a novel multisensor device for collection of location and physical activity, interactive map-based questionnaires on regular destinations and social networks, and qualitative assessment of experience of places. This rich data will allow advanced quantitative and qualitative analyses in the aim to disentangle the complex people-environment interactions linking urban local contexts to healthy aging, with a focus on active living, social networks and participation, and well-being. DISCUSSION: This project will generate evidence about what characteristics of urban environments relate to active mobility, social participation, and well-being, three important dimensions of healthy aging. It also sets the basis for an international research agenda on built environment and healthy aging based on a shared and comprehensive data collection protocol

Melatonin improves muscle function of the dystrophic mdx(5Cv) mouse, a model for Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe X-linked muscle-wasting disease caused by the absence of the cytoskeletal protein dystrophin. In addition to abnormal calcium handling, numerous studies point to a crucial role of oxidative stress in the pathogenesis of the disease. Considering the impressive results provided by antioxidants on dystrophic muscle structure and function, we investigated whether melatonin can protect the mdx(5Cv) mouse, an animal model for DMD. Male mdx(5Cv) mouse pups were treated with melatonin by daily intraperitoneal (i.p.) injection (30 mg/kg body weight) or by subcutaneous (s.c.) implant(s) (18 or 54 mg melatonin as Melovine(®) implants) from 17/18 to 28/29 days of age. Isometric force of the triceps surae was recorded at the end of the treatment. The i.p. treatment increased the phasic twitch tension of mdx(5Cv) mice. The maximal tetanic tension was ameliorated by 18 mg s.c. and 30 mg/kg i.p. treatments. Melatonin caused the dystrophic muscle to contract and relax faster. The force-frequency relationship of melatonin-treated dystrophic mice was shifted to the right. In accordance with improved muscle function, melatonin decreased plasma creatine kinase activity, a marker for muscle injury. Melatonin treatment increased total glutathione content and lowered the oxidized/reduced glutathione ratio, indicating a better redox status of the muscle. In light of the present investigation, the therapeutic potential of melatonin should be further considered for patients with DMD

Environnement résidentiel et vieillissement en santé : le rôle de l’activité physique et de la participation sociale

International audienceDemographic aging one of the major challenges of the 21 st century. It raises the issue of “healthy aging”, a process of helping elderly people remain in good health and independent as long as possible. The influence of environmental factors on this process can vary depending on individuals and their behaviour. The entanglement of these factors represents a theoretical as well as a methodological challenge. This paper aims to i) quantify the associations between the physical and social environment of elderly peoples’ neighbourhoods with their healthy aging, and ii) assess if their physical activity and their social participation are mediating this relation. The results show that, although some characteristics of the neighbourhood relating to the reputation, access to services, and social cohesion are associated with healthy aging, there is limited support for the idea that behaviour mediates the relation between context and health.Le vieillissement démographique est un des défis majeurs du 21 e siècle. Il pose directement la question du « vieillissement en santé », un processus aidant les personnes âgées à rester en bonne santé et indépendantes le plus longtemps possible. L’influence des facteurs environnementaux sur ce processus peut varier selon les individus et leurs comportements. L’enchevêtrement de ces facteurs représente un défi autant théorique que méthodologique. Cet article a pour objectifs i) de quantifier les associations entre l’environnement physique et social du quartier des personnes âgées et leur vieillissement en santé et ii) d’examiner si leur activité physique et leur participation sociale jouent un rôle de médiation dans ces associations. Si certaines caractéristiques du quartier relatives à la réputation, l’accès aux services, et la cohésion sociale sont associées au vieillissement en santé, il existe un soutien limité à l’idée que les comportements tiennent un rôle d’intermédiaire dans cette relation

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

International audienceAbstract The identification of novel regulators of tumor progression is a key challenge to gain knowledge on the biology of small intestinal neuroendocrine tumors (SI‐NETs). We recently identified the loss of the axon guidance protein semaphorin 3F as a protumoral event in SI‐NETs. Interestingly the expression of its receptor neuropilin‐2 (NRP‐2) was still maintained. This study aimed at deciphering the potential role of NRP‐2 as a contributor to SI‐NET progression. The role of NRP‐2 in SI‐NET progression was addressed using an approach integrating human tissue and serum samples, cell lines and in vivo models. Data obtained from human SI‐NET tissues showed that membranous NRP‐2 expression is present in a majority of tumors, and is correlated with invasion, metastatic abilities, and neovascularization. In addition, NRP‐2 soluble isoform was found elevated in serum samples from metastatic patients. In preclinical mouse models of NET progression, NRP‐2 silencing led to a sustained antitumor effect, partly driven by the downregulation of VEGFR2. In contrast, its ectopic expression conferred a gain of aggressiveness, driven by the activation of various oncogenic signaling pathways. Lastly, NRP‐2 inhibition led to a decrease of tumor cell viability, and sensitized to therapeutic agents. Overall, our results point out NRP‐2 as a potential therapeutic target for SI‐NETs, and will foster the development of innovative strategies targeting this receptor. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Predictive factors of long‐term follow‐up attendance in very long‐term childhood cancer survivors

International audienceBackground: Long-term follow-up (LTFU) clinics have been developed but only some childhood cancer survivors (CCS) attend long-term follow-up (LTFU).Objective: To identify factors that influence LTFU attendance.Methods: Five-year CCS treated for a solid tumor or lymphoma in Gustave Roussy before 2000, included in the FCCSS cohort (French Childhood Cancer Survivor Study), aged >18 years and alive at the date of the LTFU Clinic opening (January 2012) were invited to a LTFU visit. Factors associated with attendance at the LTFU clinic between 2012 and 2020 were estimated using logistic regression analyses. Analyses included different types of factors: clinical (tumor characteristics, cancer treatments, late effects), medical (medical expenses were used as a proxy of survivor’s health status), social (deprivation index based on census-tract data relating to income, educational level, proportion of blue-collar workers, and unemployed people living in the area of residence), and spatial (distance to the LTFU clinic).Results: Among 2341 CCS contacted (55% males, mean age at study, 45 years; SD ± 10 years; mean age at diagnosis, 6 years; SD ± 5 years), 779 (33%) attended at least one LTFU visit. Initial cancer-related factors associated with LTFU visit attendance were: treatment with both radiotherapy and chemotherapy (odds ratio [OR], 4.02; 95% CI, 2.11–7.70), bone sarcoma (OR, 2.43; 95% CI, 1.56–3.78), central nervous system primitive tumor (OR, 1.65; 95% CI, 1.02–2.67), and autologous hematopoietic cell transplant (OR, 2.07; 95% CI, 1.34-3.20). Late effects (OR, 1.70; 95% CI, 1.31–2.20), highest medical expenses (OR, 1.65; 95% CI, 1.22–2.22), living in the most advantaged area (OR vs. the most deprived area = 1.60; 95% CI, 1.15–2.22), and shorter distance from LTFU care center (<12 miles) also increased attendance.Conclusions: Patients who are apparently healthy as well as socially disadvantaged and living far away from the center are less likely to attend LTFU care.

Urocortins improve dystrophic skeletal muscle structure and function through both PKA- and Epac-dependent pathways.

In Duchenne muscular dystrophy, the absence of dystrophin causes progressive muscle wasting and premature death. Excessive calcium influx is thought to initiate the pathogenic cascade, resulting in muscle cell death. Urocortins (Ucns) have protected muscle in several experimental paradigms. Herein, we demonstrate that daily s.c. injections of either Ucn 1 or Ucn 2 to 3-week-old dystrophic mdx(5Cv) mice for 2 weeks increased skeletal muscle mass and normalized plasma creatine kinase activity. Histological examination showed that Ucns remarkably reduced necrosis in the diaphragm and slow- and fast-twitch muscles. Ucns improved muscle resistance to mechanical stress provoked by repetitive tetanizations. Ucn 2 treatment resulted in faster kinetics of contraction and relaxation and a rightward shift of the force-frequency curve, suggesting improved calcium homeostasis. Ucn 2 decreased calcium influx into freshly isolated dystrophic muscles. Pharmacological manipulation demonstrated that the mechanism involved the corticotropin-releasing factor type 2 receptor, cAMP elevation, and activation of both protein kinase A and the cAMP-binding protein Epac. Moreover, both STIM1, the calcium sensor that initiates the assembly of store-operated channels, and the calcium-independent phospholipase A(2) that activates these channels were reduced in dystrophic muscle by Ucn 2. Altogether, our results demonstrate the high potency of Ucns for improving dystrophic muscle structure and function, suggesting that these peptides may be considered for treatment of Duchenne muscular dystrophy

The anticancer drug tamoxifen counteracts the pathology in a mouse model of duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a severe disorder characterized by progressive muscle wasting,respiratory and cardiac impairments, and premature death. No treatment exists so far, and the identification of active substances to fight DMD is urgently needed. We found that tamoxifen, a drug used to treat estrogen-dependent breast cancer, caused remarkable improvements of muscle force and of diaphragm and cardiac structure in the mdx(5Cv) mouse model of DMD. Oral tamoxifen treatment from 3 weeks of age for 15 months at a dose of 10 mg/kg/day stabilized myofiber membranes, normalized whole body force, and increased force production and resistance to repeated contractions of the triceps muscle above normal values. Tamoxifen improved the structure of leg muscles and diminished cardiac fibrosis by~ 50%. Tamoxifen also reduced fibrosis in the diaphragm, while increasing its thickness,myofiber count, and myofiber diameter, thereby augmenting by 72% the amount of contractile tissue available for respiratory function. Tamoxifen conferred a markedly slower phenotype to the muscles.Tamoxifen and its metabolites were present in nanomolar concentrations in plasma and muscles,suggesting signaling through high-affinity targets. Interestingly, the estrogen receptors ERa and ERb were several times more abundant in dystrophic than in normal muscles, and tamoxifen normalized the relative abundance of ERb isoforms. Our findings suggest that tamoxifen might be a useful therapy for DMD

The duration of symptoms does not correlate with rotator cuff tear severity or other patient-related features: a cross-sectional study of patients with atraumatic, full-thickness rotator cuff tears

INTRODUCTION: The purpose of this cross-sectional study is to determine if the duration of symptoms influences the features seen in patients with atraumatic full thickness rotator cuff tears. Our hypothesis is that increasing duration of symptoms will correlate with more advanced findings of rotator cuff tear severity on MRI, worse shoulder outcome scores, more pain, decreased range of motion, and less strength. METHODS: 450 patients with full thickness rotator cuff tears were enrolled in a prospective cohort study to assess the effectiveness of nonoperative treatment and factors predictive of success. Duration of patient symptoms were divided into four groups: ≤3 months, 4–6 months, 7–12 months, and >12 months. Data collected at patient entry into the study included: 1.) Demographic data, 2.) History and physical exam data, 3.) Radiographic imaging data, and 4.) Validated patient reported measures of shoulder status. Statistical analysis included a univariate analysis with Kruskal-Wallis test and Pearson tests to identify statistically significant differences in these features for different durations of symptoms RESULTS: Longer duration of symptoms does not correlate with more severe rotator cuff disease. Duration of symptoms was not related to weakness; limited range of motion; tear size; fatty atrophy; or validated patient reported outcome measures. CONCLUSIONS: There is only a weak relationship between the duration of symptoms and features associated with rotator cuff disease. LEVEL OF EVIDENCE: Level III, Cross Sectional Stud