A multilevel intervention to increase physical activity and improve healthy eating and physical literacy among young children (ages 3-5) attending early childcare centres: the Healthy Start-Départ Santé cluster randomised controlled trial study protocol

Abstract: Background: Childhood obesity is a growing concern for public health. Given a majority of children in many countries spend approximately 30 h per week in early childcare centers, this environment represents a promising setting for implementing strategies to foster healthy behaviours for preventing and controlling childhood obesity. Healthy Start-Départ Santé was designed to promote physical activity, physical literacy, and healthy eating among preschoolers. The objectives of this study are to assess the effectiveness of the Healthy Start-Départ Santé intervention in improving physical activity levels, physical literacy, and healthy eating among preschoolers attending early childcare centers. Methods/Design: This study follows a cluster randomized controlled trial design in which the childcare centers are randomly assigned to receive the intervention or serve as usual care controls. The Healthy Start-Départ Santé intervention is comprised of interlinked components aiming to enable families and educators to integrate physical activity and healthy eating in the daily lives of young children by influencing factors at the intrapersonal, interpersonal, organizational, community, physical environment and policy levels. The intervention period, spanning 6-8 months, is preceded and followed by data collections. Participants are recruited from 61 childcare centers in two Canadian provinces, New Brunswick and Saskatchewan. Centers eligible for this study have to prepare and provide meals for lunch and have at least 20 children between the ages of 3 and 5. Centers are excluded if they have previously received a physical activity or nutrition promoting intervention. Eligible centers are stratified by province, geographical location (urban or rural) and language (English or French), then recruited and randomized using a one to one protocol for each stratum. Data collection is ongoing. The primary study outcomes are assessed using accelerometers (physical activity levels), the Test of Gross Motor Development-II (physical literacy), and digital photography-assisted weighted plate waste (food intake). Discussion: The multifaceted approach of Healthy Start-Départ Santé positions it well to improve the physical literacy and both dietary and physical activity behaviors of children attending early childcare centers. The results of this study will be of relevance given the overwhelming prevalence of overweight and obesity in children worldwide. Trial registration: NCT02375490 (ClinicalTrials.gov registry)

Granulocyte colony-stimulating factor in traumatic spinal cord injury

Granulocyte colony-stimulating factor (G-CSF) is a cytokine used in pharmaceutical preparations for the treatment of chemotherapy induced neutropenia. Evidence from experimental studies indicates that G-CSF exerts relevant activities in the central nervous system (CNS) in particular after lesions. In acute, subacute, and chronic CNS lesions, G-CSF appears to have strong anti-inflammatory, antiapoptotic, antioxidative, myelin-protective, and axon-regenerative activities. Additional effects result in the stimulation of angiogenesis and neurogenesis as well as in bone marrow stem cell mobilization to the CNS. There are emerging preclinical and clinical data indicating that G-CSF is a safe and effective drug for the treatment of acute and chronic traumatic spinal cord injury (tSCI), which we summarize in this review

Muscarinic receptor subtypes - search for selective agonists and antagonists

Since the late eighties five muscarinic receptor subtypes (m1 - m5) have been cloned and four of them (M1 - M4) have also been pharmacologically characterized. However, there is still a lack of potent muscarinic agonists and antagonists, which are highly selective for one muscarinic receptor subtype over all other subtypes. For the treatment of Alzheimer's disease, M1-selective agonists capable of penetrating into the CNS are needed. It is hypothezised that such substances would not only improve memory and cognitive ability, but also delay the progression of the disease. In our laboratory, the functionally M1-selective quaternary ammonium compound McN-A-343 has been used as a starting point for the design of such CNS active muscarinic ligands. Structure-activity relationship studies led to the tertiary amine 4-(4-fluorophenylcarbamoyloxy)-2-butynylpyrrolidine (4-F-PyMcN), which was found to stimulate M1 receptors with some functional selectivity. In order to increase the potency and selectivity of 4-F-PyMcN several new derivatives were synthezised and pharmacologically characterized in different functional assays as well as in binding and biochemical (PI turnover) studies. The most promising results were obtained with (S)-4-(4-fluorophenylcarbamoyloxy)-1-methyl-2-butynylpyrrolidine (4-F-MePyMcN). Due to its potent partial agonistic activity at M1 receptors and its M2-antagonistic properties leading to an increase of acetylcholine release by blockade of M2 autoreceptors, this compound may be considered as an important tool for future drug research of cognitive disorders. M2 receptor antagonists may also be used for the treatment of Alzheimer's disease, furthermore in the therapy of supraventricular bradycardia and for quantifying M2 receptors in the CNS with PET imaging. In the search for antagonists which clearly differentiate M2 from other muscarinic receptors, we investigated the two enantiomers of the widely used H1-antihistaminic drug dimethindene. (S)-Dimethindene proved to be a potent M2-selective antagonist with lower affinities for the M1, M3 and M4 receptors. In addition, the (S)-enantiomer was more potent than the (R)-enantiomer in all muscarinic assays. Interestingly, the stereoselectivity was inverse at histamine H1 receptors, the (R)-enantiomer being the eutomer. M3 receptor antagonists may be useful in the treatment of spastic disorders of the gastrointestinal, urogenital and respiratory tract as well as for the relief of glandular hypersecretion. In previous studies, hexahydro-difenidol (HHD) and its sila-analogue, hexahydro-sila-difenidol (HHSiD), as well as the antiparkinsonian drug trihexyphenidyl (THP) were found to be valuable tools for the discrimination of M3 and M2 receptors. In order to further assess the structural requirements (including stereochemical aspects) of the above-mentioned compounds for potency and selectivity, a series of HHD and THP analogues as well as of the corresponding silicon and germanium derivatives (sila- and germa-substitution) were studied. The (R)-enantiomers displayed higher affinities and selectivities than the corresponding (S)-isomers. The enantioselectivity of some of these analogues is best explained by the concept of the four-binding-subsite model suggesting that the differences in affinity of the (R)- and (S)-enantiomers at muscarinic receptors are due to opposite binding of the phenyl and the cyclohexyl ring to the preferring subsites. Surprisingly, there was no significant difference between the Si and Ge analogues indicating a strongly pronounced Si/Ge bioisosterism in this series of compounds. The related carbon derivatives, however, showed higher receptor affinities as well as greater stereoselectivities at all muscarinic receptors studied compared with the silicon and germanium analogues. © 1996 Elsevier B.V. All rights reserved.SCOPUS: ar.kinfo:eu-repo/semantics/publishe

Diagnosis of Constitutional Mismatch Repair-deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents

Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are non-informative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD.publisher: Elsevier articletitle: Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents journaltitle: Gastroenterology articlelink: http://dx.doi.org/10.1053/j.gastro.2015.06.013 content_type: article copyright: Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.status: publishe

Organizational perspectives on outdoor talking therapy: Towards a position of ‘environmental safe uncertainty’

OBJECTIVES: There is growing support within the therapy professions for using talking therapy in alternative environments, such as outdoor spaces. The aim of the present study was to further understand how the organizational culture in clinical psychology may prevent or enable practitioners to step outside the conventional indoor consulting room. DESIGN: Informed grounded theory methodology was used within a pragmatist philosophy. METHODS: Participants (N = 15; nine male, six female) were identified using theoretical sampling. The sample consisted of experts and leaders within the profession of clinical psychology (e.g., heads of services, training programme directors, chairs of professional bodies, and developers of therapy models; M years in the profession = 34.80, SD = 9.77). One‐to‐one interviews and analysis ran concurrently over 9 months (April–December 2020). Mason’s model of safe uncertainty was drawn upon to illuminate and organize themes. RESULTS: The main themes comprised organizational factors that either support a practitioner in maintaining a position of curiosity and flexibility towards the environment where therapy is located (‘environmental safe uncertainty’), or push them towards adopting a more fixed position (‘environmental certainty’). Themes included influences from therapy traditions, accessibility of alternative environments, internalized risk, workplace subcultures, business models, biomedical approaches, and the COVID‐19 pandemic. CONCLUSIONS: Whether therapy is located in a consulting room, outdoors, clients’ homes, or digitally, practitioners, clients, and services are encouraged to maintain a position of environmental safe uncertainty. PRACTITIONER POINTS: The therapy process and outcomes are influenced by the physical environment in which talking therapy is situated. Practitioners have often remained fixed in their preferred therapy environment, such as the indoor consulting room, without exploring the potential benefits of alternative environments or involving the client in this decision‐making (i.e., ‘environmental certainty’). Outdoor environments, as well as other alternatives to the consulting room (e.g., digital, home visits, and public places), can support access to therapy, subsequent engagement, and therefore health care equity. Practitioners and clients are encouraged to adopt a position of ‘environmental safe uncertainty’, which is defined as having openness, critical curiosity, and collaboration regarding the therapy environment and the possibility of other environments being more conducive to therapy