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BACKGROUND: Mas-related G protein-coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell-mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. OBJECTIVE: We sought to identify and characterize novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease. METHODS: Antagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell-derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-/-) knockout and Mrgprb2em(MRGPRX2) transgenic human MRGPRX2 knock-in mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. RESULTS: MRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 knock-in mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. CONCLUSIONS: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.
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Background: There has been a recent and, for many within the chronic pain space, long-overdue increase in literature that focuses on equity, diversity, inclusion, and decolonization (EDI-D) to understand chronic pain among people who are historically and structurally marginalized. Aims: In light of this growing attention in chronic pain research, we undertook a scoping review of studies that focus on people living with chronic pain and marginalization to map how these studies were carried out, how marginalization was conceptualized and operationalized by researchers, and identify suggestions for moving forward with marginalization and EDI-D in mind to better support people living with chronic pain. Methods: We conducted this scoping review using critical analysis in a manner that aligns with dominant scoping review frameworks and recent developments made to scoping review methodology as well as reporting guidelines. Results: Drawing on 67 studies, we begin with a descriptive review of the literature followed by a critical review that aims to identify fissures within the field through the following themes: (1) varying considerations of sociopolitical and socioeconomic contexts, (2) conceptual conflations between sex and gender, and (3) differing approaches to how people living with chronic pain and marginalization are described. Conclusion: By identifying strengths and limitations in the research literature, we aim to highlight opportunities for researchers to contribute to a more comprehensive understanding of marginalization in chronic pain experiences.
Contexte: La littérature mettant l'accent sur l'équité, la diversité, l'inclusion et la décolonisation (EDI-D) pour mieux comprendre la douleur chronique chez les personnes historiquement et structurellement marginalisées a récemment connu une augmentation, attendue depuis longtemps par de nombreux spécialistes de la douleur chronique.Objectifs: À la lumière de cette attention croissante dans la recherche sur la douleur chronique, nous avons entrepris un examen approfondi des études portant sur les personnes vivant avec une douleur chronique et la marginalisation, afin de déterminer comment ces études ont été menées, comment la marginalisation a été conceptualisée et opérationnalisée par les chercheurs, et de recenser des suggestions pour aller de l'avant en gardant à l'esprit la marginalisation et l'EDI-D afin de mieux soutenir les personnes vivant avec la douleur chronique.Méthodes: Nous avons mené cet examen de la portée en utilisant l'analyse critique, conformément aux cadres dominants et aux développements récents de la méthodologie de l'examen de la portée, ainsi qu'aux lignes directrices relatives aux rapports.Résultats: En nous appuyant sur 67 études, nous commençons par un examen descriptif de la littérature, suivi d'un examen critique visant à déterminer les lacunes dans le domaine, en fonction des thèmes suivants : (1) les diverses interprétations des contextes sociopolitiques et socioéconomiques, (2) les confusions conceptuelles entre sexe et genre, et (3) les approches différentes concernant la manière dont les personnes vivant avec la douleur chronique et la marginalisation sont décrites.Conclusions: En cernant les points forts et les limites de la littérature de recherche, nous visons à mettre en évidence les possibilités pour les chercheurs de contribuer à une meilleure compréhension de la marginalisation dans les expériences de douleur chronique.Abréviations: TUO : trouble lié à l'utilisation d'opioïdes; DSM-5 : Manuel diagnostique et statistique 5; BPI : Questionnaire concis sur la douleur; NIDA : National Institute on Drug Abuse; IASP : Association internationale pour l'étude de la douleur; MTUO : Médicaments pour le trouble lié à l'utilisation des opioïdes; EIQ : Écart interquartile.
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Background: With the exponential increase in digital space of social media platforms, a new group called social media influencers are driving online content of polycystic ovary syndrome (PCOS) which eventually influences behaviour and decision-making process. The objective of this study was to identify the top 100 social media (Twitter) influencers and organizations from across the globe who are advocating for PCOS. We further explored the origin and journey of these social media influencers. Methods: We identified the top 100 PCOS influencers and organizations between July and August 2022 using three social network analysis tools- Cronycle, Symplur and SocioViz. These influencers were invited to a semi-structured interview to explore why they chose to become an influencer and the support they have to deliver their online content. Two independent authors coded the anonymised transcripts from these interviews and broad themes were identified by thematic inductive analysis. Results: 95.0% of individual influencers and 80% of organisations are from high-income countries. Most influencers in our study agree that social media is an essential tool in the present day to raise awareness of PCOS. However, they reiterated social media also has significant disadvantages that require consideration and caution. Most influencers were driven by poor personal experience and worked voluntarily to reduce misinformation and improve the experiences of women diagnosed with PCOS in the future. Although there is an interest in working together, there is currently minimal collaborative work between influencers. Conclusion: There is a global inequity of #PCOS influencers online. Establishing standards and support based on evidence may help develop more influencers, especially in low- and middle-income countries, so we can counter misinformation and provide locally acceptable guidance.
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Síndrome del Ovario Poliquístico , Medios de Comunicación Sociales , Humanos , FemeninoRESUMEN
Dramatic reductions in solar, wind, and battery storage costs create new opportunities to reduce emissions and costs in China's electricity sector, beyond current policy goals. This study examines the cost, reliability, emissions, public health, and employment implications of increasing the share of non-fossil fuel ("carbon free") electricity generation in China to 80% by 2035. The analysis uses state-of-the-art modeling with high resolution load, wind, and solar inputs. The study finds that achieving an 80% carbon-free electricity system in China by 2035 could reduce wholesale electricity costs, relative to a current policy baseline, while maintaining high levels of reliability, reducing deaths from air pollution, and increasing employment. In our 80% scenario, wind and solar generation capacity reach 3 TW and battery storage capacity reaches 0.4 TW by 2035, implying a rapid scale up in these resources that will require changes in policy targets, markets and regulation, and land use policies.
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Strong enhancement of molecular circular dichroism (CD) has the potential to enable efficient asymmetric photolysis, a method of chiral separation that has conventionally been impeded by insufficient yield and low enantiomeric excess. Here, we study experimentally how predicted enhancements in optical chirality density near resonant silicon nanodisks boost CD. We use fluorescence-detected circular dichroism (FDCD) spectroscopy to measure indirectly the differential absorption of circularly polarized light by a monolayer of optically active molecules functionalized to silicon nanodisk arrays. Importantly, the molecules and nanodisk antennas have spectrally coincident resonances, and our fluorescence technique allows us to deconvolute absorption in the nanodisks from the molecules. We find that enhanced FDCD signals depend on nanophotonic resonances, in good agreement with simulated differential absorption and optical chirality density, while no signal is detected from molecules adsorbed on featureless silicon surfaces. These results verify the potential of nanophotonic platforms to be used for asymmetric photolysis with lower energy requirements.
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Chirality in Nature can be found across all length scales, from the subatomic to the galactic. At the molecular scale, the spatial dissymmetry in the atomic arrangements of pairs of mirror-image molecules, known as enantiomers, gives rise to fascinating and often critical differences in chemical and physical properties. With increasing hierarchical complexity, protein function, cell communication, and organism health rely on enantioselective interactions between molecules with selective handedness. For example, neurodegenerative and neuropsychiatric disorders including Alzheimer's and Parkinson's diseases have been linked to distortion of chiral-molecular structure. Moreover, d-amino acids have become increasingly recognized as potential biomarkers, necessitating comprehensive analytical methods for diagnosis that are capable of distinguishing l- from d-forms and quantifying trace concentrations of d-amino acids. Correspondingly, many pharmaceuticals and agrochemicals consist of chiral molecules that target particular enantioselective pathways. Yet, despite the importance of molecular chirality, it remains challenging to sense and to separate chiral compounds. Chiral-optical spectroscopies are designed to analyze the purity of chiral samples, but they are often insensitive to the trace enantiomeric excess that might be present in a patient sample, such as blood, urine, or sputum, or pharmaceutical product. Similarly, existing separation schemes to enable enantiopure solutions of chiral products are inefficient or costly. Consequently, most pharmaceuticals or agrochemicals are sold as racemic mixtures, with reduced efficacy and potential deleterious impacts.Recent advances in nanophotonics lay the foundation toward highly sensitive and efficient chiral detection and separation methods. In this Account, we highlight our group's effort to leverage nanoscale chiral light-matter interactions to detect, characterize, and separate enantiomers, potentially down to the single molecule level. Notably, certain resonant nanostructures can significantly enhance circular dichroism for improved chiral sensing and spectroscopy as well as high-yield enantioselective photochemistry. We first describe how achiral metallic and dielectric nanostructures can be utilized to increase the local optical chirality density by engineering the coupling between electric and magnetic optical resonances. While plasmonic nanoparticles locally enhance the optical chirality density, high-index dielectric nanoparticles can enable large-volume and uniform-sign enhancements in the optical chirality density. By overlapping these electric and magnetic resonances, local chiral fields can be enhanced by several orders of magnitude. We show how these design rules can enable high-yield enantioselective photochemistry and project a 2000-fold improvement in the yield of a photoionization reaction. Next, we discuss how optical forces can enable selective manipulation and separation of enantiomers. We describe the design of low-power enantioselective optical tweezers with the ability to trap sub-10 nm dielectric particles. We also characterize their chiral-optical forces with high spatial and force resolution using combined optical and atomic force microscopy. These optical tweezers exhibit an enantioselective optical force contrast exceeding 10 pN, enabling selective attraction or repulsion of enantiomers based on the illumination polarization. Finally, we discuss future challenges and opportunities spanning fundamental research to technology translation. Disease detection in the clinic as well as pharmaceutical and agrochemical industrial applications requiring large-scale, high-throughput production will gain particular benefit from the simplicity and relative low cost that nanophotonic platforms promise.
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Nanopartículas , Fotones , Aminoácidos/química , Dicroismo Circular , Luz , Microscopía de Fuerza Atómica , Microscopía Electrónica de Rastreo , Pinzas Ópticas , EstereoisomerismoRESUMEN
Lymphocyte trafficking out of secondary lymphoid organs is regulated by concentration gradient-dependent interactions between the membrane-derived lysophospholipid signaling molecule sphingosine 1-phosphate (S1P) and the G-protein-coupled receptor, S1P1 Etrasimod is a novel, next-generation, small-molecule, oral S1P receptor modulator in clinical development for the treatment of immune-mediated inflammatory disorders, including ulcerative colitis. In preclinical pharmacology studies, etrasimod was a full agonist of recombinant human (6.1 nM EC50), mouse (3.65 nM EC50), dog (4.19 nM EC50), and monkey (8.7 nM EC50) S1P1 receptors, and a partial agonist of human S1P4 (147 nM EC50) and S1P5 (24.4 nM EC50), with relative efficacies of 63% and 73% of S1P response, respectively; whereas neither agonist nor antagonist activity was observed for human S1P2 or S1P3 A dose-dependent relationship was observed for etrasimod plasma concentration and lymphocyte count in mice, and chronic treatment with etrasimod resulted in attenuation of inflammation in a CD4+CD45RBhigh T-cell transfer mouse model of colitis.
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Acetatos/farmacología , Colitis/tratamiento farmacológico , Colitis/metabolismo , Ciclopentanos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Indoles/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Acetatos/uso terapéutico , Animales , Transporte Biológico/efectos de los fármacos , Recuento de Células , Colitis/inmunología , Ciclopentanos/uso terapéutico , Modelos Animales de Enfermedad , Perros , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Indoles/uso terapéutico , Masculino , RatonesRESUMEN
OBJECTIVES: Most adolescent cases of pelvic inflammatory disease (PID) are diagnosed in the emergency department (ED). An important step to prevent PID-related morbidity among this high-risk population is to quantify prevalence and microbial patterns and identify testing and treatment gaps. METHODS: We performed a retrospective, cross-sectional study of all visits by adolescents to an urban children's ED with an International Classification of Diseases, Ninth Revision, diagnosis of PID in 2012. We used standard descriptive statistics to quantify PID diagnoses, sexually transmitted infections (STI) testing, and treatment. RESULTS: Pelvic inflammatory disease was diagnosed in more than 9% of women with a chief complaint of abdominal/pelvic pain. Most diagnosed cases underwent some STI testing, and 40% tested positive. Seventy percent of cases received antibiotics recommended by the Centers for Disease Control and Prevention. CONCLUSIONS: There is a high prevalence of PID among adolescents in the pediatric ED. Rates of STI testing and appropriate treatment reveal gaps in diagnosis and management, representing a lost opportunity for identification and treatment of PID/STIs among high-risk adolescents.
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Antibacterianos/uso terapéutico , Enfermedad Inflamatoria Pélvica/tratamiento farmacológico , Enfermedad Inflamatoria Pélvica/epidemiología , Enfermedades de Transmisión Sexual/tratamiento farmacológico , Enfermedades de Transmisión Sexual/epidemiología , Adolescente , Estudios Transversales , Servicio de Urgencia en Hospital , Femenino , Adhesión a Directriz , Humanos , Enfermedad Inflamatoria Pélvica/microbiología , Prevalencia , Estudios Retrospectivos , Centros de Atención Terciaria , Resultado del Tratamiento , Servicios Urbanos de Salud , Adulto JovenRESUMEN
GPR84 is an orphan G-protein coupled receptor, expressed on monocytes, macrophages and neutrophils and is significantly upregulated by inflammatory stimuli. The physiological role of GPR84 remains largely unknown. Medium chain fatty acids (MCFA) activate the receptor and have been proposed to be its endogenous ligands, although the high concentrations of MCFAs required for receptor activation generally exceed normal physiological levels. We identified the natural product embelin as a highly potent and selective surrogate GPR84 agonist (originally disclosed in patent application WO2007027661A2, 2007) and synthesized close structural analogs with widely varying receptor activities. These tools were used to perform a comprehensive study of GPR84 signaling and function in recombinant cells and in primary human macrophages and neutrophils. Activation of recombinant GPR84 by embelin in HEK293 cells results in Gi/o as well as G12/13-Rho signaling. In human macrophages, GPR84 initiates PTX sensitive Erk1/2 and Akt phosphorylation, PI-3 kinase activation, calcium flux, and release of prostaglandin E2. In addition, GPR84 signaling in macrophages elicits Gi Gßγ-mediated augmentation of intracellular cAMP, rather than the decrease expected from Giα engagement. GPR84 activation drives human neutrophil chemotaxis and primes them for amplification of oxidative burst induced by FMLP and C5A. Loss of GPR84 is associated with attenuated LPS-induced release of proinflammatory mediators IL-6, KC-GROα, VEGF, MIP-2 and NGAL from peritoneal exudates. While initiating numerous proinflammatory activities in macrophages and neutrophils, GPR84 also possesses GPR109A-like antiatherosclerotic properties in macrophages. Macrophage receptor activation leads to upregulation of cholesterol transporters ABCA1 and ABCG1 and stimulates reverse cholesterol transport. These data suggest that GPR84 may be a target of therapeutic value and that distinct modes of receptor modulation (inhibition vs. stimulation) may be required for inflammatory and atherosclerotic indications.
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Benzoquinonas/química , Benzoquinonas/farmacología , Macrófagos/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Receptores de Superficie Celular/agonistas , Animales , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Células HEK293 , Humanos , Factores Inmunológicos/química , Factores Inmunológicos/farmacología , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Chameleons are masters of light, expertly changing their color, pattern, and reflectivity in response to their environment. Engineered materials that share this tunability can be transformative, enabling active camouflage, tunable holograms, and novel colorimetric medical sensors. While progress has been made in creating artificial chameleon skin, existing schemes often require external power, are not continuously tunable, and may prove too stiff or bulky for applications. Here, a chemically tunable, large-area metamaterial is demonstrated that accesses a wide range of colors and refractive indices. An ordered monolayer of nanoresonators is fabricated, then its optical response is dynamically tuned by infiltrating its polymer substrate with solvents. The material shows a strong magnetic response with a dependence on resonator spacing that leads to a highly tunable effective permittivity, permeability, and refractive index spanning negative and positive values. The unity-order index tuning exceeds that of traditional electro-optic and photochromic materials and is robust to cycling, providing a path toward programmable optical elements and responsive light routing.
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The discovery of a novel, selective and fully efficacious CB2 agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound 6 was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB2 receptor to avoid tachyphylaxis. Based on its overall favorable preclinical profile, 6 (APD371) was selected for further development for the treatment of pain.
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OBJECTIVES: To determine pregnancy risk and receptiveness to emergency department (ED)-based pregnancy prevention interventions among adolescents accessing care in the ED. STUDY DESIGN: Cross-sectional electronic survey of adolescent females in a pediatric ED used to calculate the Pregnancy Risk Index, a validated measure estimating the annual risk of becoming pregnant based on recent sexual activity, contraceptive method(s), method-specific contraceptive failure rates, and interest in receipt of ED-based contraceptive services. RESULTS: Of 229 participants, 219 were not pregnant, and 129 reported sexual experience. Overall, 72.4% (n = 166) endorsed negative pregnancy intentions. The overall Pregnancy Risk Index for the 219 nonpregnant participants was 9.6 (95% CI 6.8-12.4), and was 17.5 (95% CI 12.8-22.2) for the 129 sexually experienced participants. A Pregnancy Risk Index greater than the national average of 5 was associated with older age (aOR 3.0; 95% CI 1.5-5.85), nonprivate insurance (aOR 7.1; 95% CI 1.6-32.1), prior pregnancy (aOR 2.7; 95% CI 1.2-6.0), and chief complaint potentially related to a reproductive health concern (aOR 2.6; 95% CI 1.4-5.1). In this cohort, 85.1% (n = 194) believed that the ED should provide information about pregnancy prevention, the majority of whom (64.9%; n = 148) believed that pregnancy prevention services should be offered at all ED visits. CONCLUSION: This study demonstrates a high unintended pregnancy risk among adolescents accessing care in the ED. Adolescents report interest in receiving pregnancy prevention information and services in the ED, regardless of reason for visit. Strategies to incorporate successfully the provision of reproductive health services into ED care should be explored.
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Anticoncepción/estadística & datos numéricos , Servicio de Urgencia en Hospital/estadística & datos numéricos , Embarazo en Adolescencia/estadística & datos numéricos , Conducta Sexual/estadística & datos numéricos , Adolescente , Estudios Transversales , Femenino , Humanos , Embarazo , Embarazo en Adolescencia/prevención & control , Medición de RiesgoRESUMEN
Manipulating the frequency of electromagnetic waves forms the core of many modern technologies, ranging from imaging and spectroscopy to radio and optical communication. The process of converting photons from higher to lower energy is easily accomplished and technologically widespread. However, upconversion, which is the process of converting lower-energy photons into higher-energy photons, is still a growing field of study with nascent applications and burgeoning interest. Here, we experimentally demonstrate a new photon upconversion technique mediated by hot carriers in plasmonic nanostructures. Hot holes and hot electrons generated via plasmon decay in illuminated metal nanoparticles are injected into an adjacent semiconductor quantum well where they radiatively recombine to emit higher-energy photons. Using GaN/InGaN quantum wells decorated with gold and silver nanoparticles, we show photon upconversion from 2.4 to 2.8 eV. The process scales linearly with illumination power and enables both geometry- and polarization-based tunability. The conversion of plasmonic losses into upconverted optical emission has the potential to impact bioimaging, on-chip wavelength conversion, and high-efficiency photovoltaics.
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OBJECTIVE: To detail the presentation of calcium pyrophosphate deposition disease (CPPD) in the ankle joint. The aim of this case report is to inform health-care practitioners about the presentation of this condition in an uncommon location and discuss the diagnosis, potential treatment, and management strategies for a patient with CPPD. CLINICAL FEATURES: A 36-year-old male patient presented to a chiropractic clinic with an acute, painful, and swollen ankle, which was later diagnosed by plain film radiograph as CPPD. A rheumatology follow-up was recommended and at-home treatment was prescribed to treat acute symptoms and monitor progress. OUTCOME: No chiropractic treatment was provided and the patient has been referred to a rheumatologist for further assessment. The diagnosis of CPPD was confirmed and he was advised to take an anti-inflammatory if symptoms recurred and booked for further follow-up in six months. SUMMARY: Although the presentation is less common, CPPD can present in the ankle joint and mimic other inflammatory disorders. Conservative treatment can be applied to treat acute symptoms and referral to a rheumatologist is suggested to monitor progress of this condition.
OBJECTIF: Expliquer en détail la présentation de la chondrocalcinose articulaire (CCA) dans l'articulation de cheville. Cet exposé de cas a pour but d'informer les professionnels de la santé à propos de la présentation de ce trouble dans un endroit inhabituel et de discuter du diagnostic, du traitement potentiel et des stratégies de prise en charge pour un patient atteint de CCA. CARACTÉRISTIQUES CLINIQUES: Un patient de 36 ans se présente à une clinique de chiropratique avec une cheville enflée avec douleur aiguë, trouble qu'on a plus tard diagnostiqué au moyen d'un cliché sans préparation comme étant une CCA. On a recommandé un suivi en rhumatologie et prescrit un traitement à domicile pour traiter les symptômes aigus et surveiller la progression. RÉSULTAT: On n'a pas fourni de traitement chiropratique et le patient a été envoyé à un rhumatologue pour une évaluation plus poussée. Le diagnostic de CCA a été confirmé; on lui a conseillé de prendre un anti-inflammatoire si les symptômes réapparaissaient et on a planifié un suivi six mois plus tard. RÉSUMÉ: Bien que la présentation soit moins commune, la CCA peut se présenter dans l'articulation de cheville et imiter d'autres affections inflammatoires. Un traitement conservateur peut permettre de soigner les symptômes aigus et on recommande d'envoyer le patient voir un rhumatologue pour surveiller la progression du trouble.
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The Mental Health Commission of Canada defines peer support as "a supportive relationship between people who have a lived experience in common in relation to a mental health challenge or illness related to their own mental health or that of a loved one" (Sunderland et al. 2013: 11). In Ontario, a key resource for peer support is the Ontario Peer Development Initiative (OPDI), which is an umbrella organization of mental health Consumer/Survivor Initiatives (CSIs) and peer support organizations across the province of Ontario. Member organizations are run by and for people with lived experience of a mental health or addiction issue and provide a wide range of services and activities within their communities. The central tenet of member organizations is the common understanding that people can and do recover with the proper supports in place and that peer support is integral to successful recovery. Nationally, Peer Support Accreditation and Certification Canada has recently been established. The relatively new national organization focuses on training and accrediting peer support workers. This paper focuses on a range of diverse peer support groups and CSIs that operate in London and surrounding areas.
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Consejo , Servicios de Salud Mental , Grupo Paritario , Apoyo Social , Humanos , Trastornos Mentales/rehabilitación , Modelos Organizacionales , OntarioRESUMEN
The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.
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Analgésicos no Narcóticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Inflamación/tratamiento farmacológico , Microsomas Hepáticos/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirazoles/farmacología , Receptor Cannabinoide CB2/agonistas , Administración Oral , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/química , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Inflamación/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Osteoartritis/metabolismo , Dolor/metabolismo , Pirazoles/administración & dosificación , Pirazoles/química , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
BACKGROUND: For people with mental illness (psychiatric survivors), seeking and securing employment involves personal, social, and environmental factors. In Canada, psychiatric survivors are under-represented in the workforce, and services can help by tailoring their supports to help make the most gains in employment. OBJECTIVE: Determine whether individual socio-demographic and health factors predict seeking and securing employment among psychiatric survivors. METHODS: A community sample of psychiatric survivors from a Southwestern Ontario region participated in this study. Stepwise logistic regression was used to analyze data from 363 participants who had completed a variety of questionnaires to ascertain individual characteristics and employment outcomes. RESULTS: Health service utilization, living circumstances, homelessness, substance use issues, general health, social integration, ethnicity, having children under 18, and being a student emerged as significant predictors of seeking and securing work. Other commonly accepted human capital indicators, such as education and age, were not predictive of employment search behavior and outcomes. CONCLUSIONS: Individual characteristics that predict employment search and success outcomes for psychiatric survivors include aspects related to treatment and living circumstances, which stands in contrast to predictors of employment for the general population, suggesting that employment support services may need to be tailored to psychiatric survivors specifically.
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Empleo/estadística & datos numéricos , Trastornos Mentales , Enfermos Mentales/estadística & datos numéricos , Adulto , Escolaridad , Composición Familiar , Femenino , Estado de Salud , Personas con Mala Vivienda/estadística & datos numéricos , Humanos , Masculino , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/psicología , Servicios de Salud Mental/estadística & datos numéricos , Persona de Mediana Edad , Ontario , Características de la Residencia , Participación Social , Trastornos Relacionados con Sustancias/rehabilitación , Sobrevivientes/estadística & datos numéricosRESUMEN
APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.
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S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.