RESUMEN
SETTING: The potential for exposure to indoor radon varies dramatically across British Columbia (BC) due to varied geology. Individuals may struggle to understand their exposure risk and agencies may struggle to understand the value of population-level programs and policies to mitigate risk. INTERVENTION: The BC Centre for Disease Control (BCCDC) established the BC Radon Data Repository (BCRDR) to facilitate radon research, public awareness, and action in the province. The BCRDR aggregates indoor radon measurements collected by government agencies, industry professionals and organizations, and research and advocacy groups. Participation was formalized with a data sharing agreement, which outlines how the BCCDC anonymizes and manages the shared data integrated into the BCRDR. OUTCOMES: The BCRDR currently holds 38,733 measurements from 18 data contributors. The repository continues to grow with new measurements from existing contributors and the addition of new contributors. A prominent use of the BCRDR was to create the online, interactive BC Radon Map, which includes regional concentration summaries, risk interpretation messaging, and health promotion information. Anonymized BCRDR data are also available for external release upon request. IMPLICATIONS: The BCCDC leverages existing radon measurement programs to create a large and integrated database with wide geographic coverage. The development and application of the BCRDR informs public health research and action beyond the BCCDC, and the repository can serve as a model for other regional or national initiatives.
RéSUMé: LIEU: Le potentiel d'exposition au radon à l'intérieur des bâtiments varie beaucoup d'une région à l'autre de la Colombie-Britannique en raison de la géologie variée. Les particuliers peuvent avoir du mal à comprendre leur risque d'exposition, et les organismes, à comprendre l'utilité des programmes et des politiques populationnels pour atténuer le risque. INTERVENTION: Le BC Centre for Disease Control (« le Centre ¼) a créé un organe d'archivage, le BC Radon Data Repository (BCRDR), pour faciliter la recherche, l'information, la sensibilisation du public et l'action liées au radon dans la province. Le BCRDR totalise les relevés du radon à l'intérieur des bâtiments pris par les organismes gouvernementaux, les professionnels et les organismes de l'industrie, ainsi que les groupes de recherche et de revendication. La participation est officialisée par un accord de partage de données qui décrit comment le Centre anonymise et gère les données communes du BCRDR. RéSULTATS: Le BCRDR contient actuellement 38 733 relevés de 18 contributeurs de données. Il continue de croître, avec de nouveaux relevés venant de contributeurs existants et l'ajout de nouveaux contributeurs. Il a servi, entre autres, à créer une carte du radon interactive en ligne pour la Colombie-Britannique, avec des résumés des concentrations régionales, des messages d'interprétation du risque et des informations de promotion de la santé. Sur demande, les données anonymisées du BCRDR sont également disponibles pour diffusion externe. CONSéQUENCES: Le Centre a exploité les programmes de prise de relevés du radon existants pour créer une grande base de données intégrée ayant une vaste couverture géographique. Le développement et les applications du BCRDR éclairent la recherche et l'action en santé publique au-delà du Centre, et l'organe d'archivage peut servir de modèle pour d'autres initiatives régionales ou nationales.
Asunto(s)
Salud Pública , Radón , Contaminación del Aire Interior/prevención & control , Colombia Británica/epidemiología , Bases de Datos Factuales , Comunicación en Salud/métodos , Difusión de la Información , Fuentes de InformaciónRESUMEN
The goal of the present study was to test the Perceptual-Attentional Limitation Hypothesis in children and adults by manipulating the distinctiveness between expressions and recording eye movements. Children 3-5 and 9-11 years old as well as adults were presented pairs of expressions and required to identify a target emotion. Children 3-5 years old were less accurate than those 9-11 years old and adults. All children viewed pictures longer than adults but did not spend more time attending to the relevant cues. For all participants, accuracy for the recognition of fear was lower than for surprise when the distinctive cue was in the brow only. They also took longer and spent more time in both the mouth and brow zones than when a cue was in the mouth or both areas. Adults and children 9-11 years old made more comparisons between the expressions when fear comprised a single distinctive cue in the brow than when the distinctive cue was in the mouth only or when both cues were present. Children 3-5 years old made more comparisons for brow only than both. The results of the present study extend on the Perceptual-Attentional Limitation Hypothesis showing an importance of both decoder and stimuli, and an interaction between decoder and stimuli characteristics.
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Atención/fisiología , Emociones/fisiología , Movimientos Oculares/fisiología , Miedo/psicología , Reconocimiento en Psicología/fisiología , Percepción Social , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Percepción Visual/fisiología , Adulto JovenRESUMEN
Chlorpromazine (CPZ), a member of the largest class of first-generation antipsychotic agents, is known to cause hepatotoxicity in the form of cholestasis and hepatocellular necrosis in some patients. The mechanism of CPZ hepatotoxicity is unclear, but is thought to result from reactive metabolite formation. The goal of this research was to assess potential cytotoxic mechanisms of CPZ using the accelerated cytotoxicity mechanism screening (ACMS) technique with freshly isolated rat hepatocytes. This study identified CPZ cytotoxicity and inhibition of mitochondrial membrane potential (MMP) to be concentration-dependent. Furthermore, inhibition of cytochrome P450s (CYPs), including CYP2D1 and 1A2, delayed CPZ cytotoxicity, suggesting a role for CYP activation of CPZ to a toxic metabolite(s) in this model. Metabolism studies also demonstrated glucuronide and glutathione (GSH) requirement for CPZ detoxification in hepatocytes. Inactivating the 2-electron reduction pathway, NAD(P)H quinone oxidoreductase (NQO1), caused a significant increase in hepatocyte susceptibility to CPZ, indicating quinoneimine contribution to CPZ cytotoxicity. Nontoxic concentrations of peroxidase/H(2)O(2) (inflammatory model) increased cytotoxicity in CPZ-treated hepatocytes and caused additional mitochondrial toxicity. Inflammation further depleted GSH and increased oxidized glutathione (GSSG) levels. Results suggest activation of CPZ to reactive metabolites by 2 pathways in hepatocytes: (i) a CYP-catalyzed quinoneimine pathway, and (ii) a peroxidase-catalyzed oxidation of CPZ to CPZ radicals.
Asunto(s)
Antipsicóticos/toxicidad , Clorpromazina/toxicidad , Hepatocitos/efectos de los fármacos , Oxidorreductasas de Alcohol/antagonistas & inhibidores , Animales , Antipsicóticos/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Clorpromazina/metabolismo , Citocromo P-450 CYP1A2 , Familia 2 del Citocromo P450 , Citocromos/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Hepatocitos/enzimología , Hepatocitos/metabolismo , Hepatocitos/patología , Inactivación Metabólica , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Formation of the epithelial barrier and apico-basal cell polarity represent two characteristics and mutually dependent features of differentiated epithelial monolayers. They are controlled by special adhesive structures, tight junctions (TJs), and polarity protein complexes that define the apical and the basolateral plasma membrane. The functional interplay between TJs and polarity complexes remains poorly understood. We investigated the role of Scribble, a basolateral polarity protein and known tumor suppressor, in regulating TJs in human intestinal epithelium. Scribble was enriched at TJs in T84 and SK-CO15 intestinal epithelial cell monolayers and sections of normal human colonic mucosa. siRNA-mediated knockdown of Scribble in SK-CO15 cells attenuated development of epithelial barrier and inhibited TJ reassembly independently of other basolateral polarity proteins Lgl-1 and Dlg-1. Scribble selectively co-imunoprecipitated with TJ protein ZO-1, and ZO-1 was important for Scribble recruitment to intercellular junctions and TJ reassembly. Lastly, Scribble was mislocalized from TJs and its expression down-regulated in interferon-gamma-treated T84 cell monolayers and inflamed human intestinal mucosa in vivo. We conclude that Scribble is an important regulator of TJ functions and plasticity in the intestinal epithelium. Down-regulation of Scribble may mediate mucosal barrier breakdown during intestinal inflammation.
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Mucosa Intestinal/metabolismo , Proteínas de la Membrana/metabolismo , Uniones Estrechas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Línea Celular , Homólogo 1 de la Proteína Discs Large , Regulación hacia Abajo/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Silenciador del Gen/efectos de los fármacos , Humanos , Inflamación/patología , Interferón gamma/farmacología , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Ratones , Fosfoproteínas/metabolismo , Unión Proteica/efectos de los fármacos , ARN Interferente Pequeño/metabolismo , Uniones Estrechas/efectos de los fármacos , Proteína de la Zonula Occludens-1RESUMEN
BACKGROUND & AIMS: Previous studies have shown that fibrosis developing in chronic experimental colitis is driven by interleukin (IL)-13 signaling via IL-13R alpha(2) and the production of transforming growth factor (TGF)-beta1. In the present study, we sought to determine the fibrogenic downstream events set in motion by such signaling. METHODS: Experimental colitis with late-onset intestinal fibrosis was induced by weekly intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to BALB/c mice. Blockade of IL-13 signaling via IL-13R alpha(2) and TGF-beta1 signaling was achieved by the administration of small interfering RNA or decoy oligonucleotides that target promoter sequences of signaling components of these receptors. Effects of blockade were determined by enzyme-linked immunosorbent assay or Western blotting detecting specific key fibrogenic factors and by measurement of collagen production. RESULTS: Initially, we showed that abrogation of IL-13 activity via blockade of IL-13R alpha(2) and TGF-beta1 signaling results in severe inhibition of expression of colonic insulin-like growth factor (IGF)-I and early growth response gene (Egr)-1, factors known to initiate and sustain fibrosis. We then showed that Egr-1 was necessary early in the fibrotic process for caspase-mediated apoptosis of myofibroblasts and the production of urokinase plasminogen activator, a protein that enhances TGF-beta1 activation. Finally, we showed that IGF-I (together with TGF-beta1) acts later in the process to stimulate myofibroblasts to deposit collagen in the colon. CONCLUSIONS: These studies establish that IL-13 signaling via the IL-13R alpha(2) is a key initiation point for a complex fibrotic program in the colon consisting of TGF-beta1 activation, IGF-I and Egr-1 expression, myofibroblast apoptosis, and myofibroblast production of collagen.
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Colitis/metabolismo , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Interleucina-13/metabolismo , Animales , Apoptosis , Western Blotting , Células Cultivadas , Colitis/inducido químicamente , Colitis/patología , Colon/metabolismo , Colon/patología , Modelos Animales de Enfermedad , Proteína 1 de la Respuesta de Crecimiento Precoz/biosíntesis , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis/metabolismo , Fibrosis/patología , Regulación de la Expresión Génica , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Factor I del Crecimiento Similar a la Insulina/genética , Subunidad alfa2 del Receptor de Interleucina-13/antagonistas & inhibidores , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena de la Polimerasa , ARN/genética , Transducción de Señal , Factor de Crecimiento Transformador beta1/biosíntesis , Factor de Crecimiento Transformador beta1/genética , Ácido Trinitrobencenosulfónico/toxicidad , Dedos de ZincRESUMEN
In previous studies, we described a "counter-immunosurveillance" mechanism initiated by tumor-activated, interleukin-13 (IL-13)-producing natural killer T cells that signal Gr-1(+) cells to produce transforming growth factor-beta(1) (TGF-beta(1)), a cytokine that suppresses the activity of tumor-inhibiting cytolytic CD8(+) T cells. Here, we show that in two tumor models (the CT-26 metastatic colon cancer and the 15-12RM fibrosarcoma regressor models), this counter-surveillance mechanism requires the expression of a novel IL-13 receptor, IL-13R alpha(2), on Gr-1(intermediate) cells, because down-regulation of IL-13R alpha(2) expression or the activator protein-1 signal generated by the receptor via in vivo administration of specific small interfering RNA or decoy oligonucleotides leads to loss of TGF-beta(1) production. Furthermore, acting on prior studies showing that IL-13R alpha(2) expression is induced (in part) by tumor necrosis factor-alpha (TNF-alpha), we show that receptor expression and TGF-beta(1) production is inhibited by administration of a TNF-alpha-neutralizing substance, TNF-alpha R-Fc (etanercept). Taking advantage of this latter fact, we then show in the CT-26 model that counter-immunosurveillance can be inhibited, anti-CT-26-specific CD8(+) cytolytic activity can be restored, and CT-26 metastatic tumor nodules can be greatly decreased by administration of TNF-alpha R-Fc. Corroborative data were obtained using the 15-12RM fibrosarcoma model. These studies point to the prevention of metastatic cancer with an available agent with already known clinically acceptable adverse effects and toxicity.
Asunto(s)
Carcinoma/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Fibrosarcoma/tratamiento farmacológico , Vigilancia Inmunológica/efectos de los fármacos , Subunidad alfa2 del Receptor de Interleucina-13/antagonistas & inhibidores , ARN Interferente Pequeño/uso terapéutico , Animales , Carcinoma/inmunología , Carcinoma/mortalidad , Carcinoma/patología , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/inmunología , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Regulación hacia Abajo , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Femenino , Fibrosarcoma/inmunología , Fibrosarcoma/mortalidad , Fibrosarcoma/prevención & control , Interleucina-13/metabolismo , Interleucina-13/farmacología , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Factor de Crecimiento Transformador beta1/metabolismo , Células Tumorales CultivadasRESUMEN
The intestinal epithelium of the adult gut supports a complex, dynamic microbial ecosystem and expresses highly fucosylated glycans on its surface. Uncolonized gut contains little fucosylated glycan. The transition toward adult colonization, such as during recovery from germ-free status or from antibiotic treatment, increased expression of fucosylated epitopes in the colonic epithelium. This increase in fucosylation is accompanied by induction of fut2 mRNA expression and alpha1,2/3-fucosyltransferase activity. Colonization stimulates ERK and JNK signal transduction pathways, resulting in activation of transcription factors ATF2 and c-Jun, respectively. This increases transcription of fut2 mRNA and expression of alpha1,2/3-fucosyltransferase activity, resulting in a highly fucosylated intestinal mucosa characteristic of the adult mammalian gut. Blocking the ERK and JNK signaling cascade inhibits the ability of colonization to induce elevated fut2 mRNA and fucosyltransferase activity in the mature colon. Thus pioneer-mutualist symbiotic bacteria may utilize the ERK and JNK signaling cascade to induce the high degree of fucosylation characteristic of adult mammalian colon, and we speculate that this fucosylation facilitates colonization by adult microbiota.
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Colon/microbiología , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Fucosiltransferasas/fisiología , Mucosa Intestinal/microbiología , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Transducción de Señal/fisiología , Simbiosis , Animales , Vida Libre de Gérmenes , Ratones , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
To investigate the immunopathogenesis of inflammation-associated fibrosis, we analyzed the chronic colitis and late-developing fibrosis occurring in BALB/c mice administered weekly doses of intrarectal 2,4,6-trinitrobenzene sulfonic acid. We showed first in this model that an initial Th1 response involving IL-12p70 and IFN-gamma subsides after 3 wk to be supplanted by an IL-23/IL-25 response beginning after 4-5 wk. This evolution is followed by gradually increasing production of IL-17 and cytokines ordinarily seen in a Th2 response, particularly IL-13, which reaches a plateau at 8-9 wk. In vitro stimulation studies suggest that this IL-13 production is dependent on IL-23 and IL-25, but not on IL-12p70. We then show that IL-13 production results in the induction of an IL-13R formerly thought to function only as a decoy receptor, IL-13Ralpha(2), and this receptor is critical to the production of TGF-beta(1) and the onset of fibrosis. Thus, if IL-13 signaling through this receptor is blocked by administration of soluble IL-13Ralpha(2)-Fc, or by administration of IL-13Ralpha(2)-specific small interfering RNA, TGF-beta(1) is not produced and fibrosis does not occur. These studies show that in chronic 2,4,6-trinitrobenzene sulfonic acid colitis, fibrosis is dependent on the development of an IL-13 response that acts through a novel cell surface-expressed IL-13R to induce TGF-beta(1). A similar mechanism may obtain in certain forms of human inflammatory bowel disease.
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Colitis/inmunología , Colitis/patología , Interleucina-13/metabolismo , Receptores de Interleucina-13/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Colitis/inducido químicamente , Fibrosis , Interferón gamma/metabolismo , Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/antagonistas & inhibidores , Subunidad alfa2 del Receptor de Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Ratones , Ratones Endogámicos BALB C , Fosforilación , ARN Interferente Pequeño/farmacología , Receptores de Interleucina-13/antagonistas & inhibidores , Receptores de Interleucina-13/genética , Proteína smad3/metabolismo , Proteína smad7/metabolismo , Células TH1/inmunología , Factor de Crecimiento Transformador beta1/genética , Ácido Trinitrobencenosulfónico/toxicidadRESUMEN
Vitamin A supplementation has consistently reduced infant mortality and the severity of pathogen-induced diarrhea. The mechanism by which vitamin A modulates the mucosal immune response to produce these effects remains poorly defined. To address this issue, stools collected during the summer months from 127 Mexican children 5-15 mo old enrolled in a larger, randomized, double-blind, placebo-controlled, vitamin A supplementation trial were screened for interleukin (IL)-4, IL-6, interferon-gamma (IFN-gamma), and gastrointestinal pathogens. Fecal cytokine values were categorized into 3 levels (undetectable,
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Diarrea/inmunología , Suplementos Dietéticos , Inmunidad Mucosa/efectos de los fármacos , Vitamina A/farmacología , Animales , Ascariasis/inmunología , Ascaris/aislamiento & purificación , Estatura , Peso Corporal , Control de Enfermedades Transmisibles , Diarrea/parasitología , Heces/parasitología , Femenino , Humanos , Lactante , Masculino , México , Factores Socioeconómicos , Células TH1/microbiología , Células Th2/inmunologíaRESUMEN
Necrotizing enterocolitis (NEC) is a major inflammatory disease of the premature human intestine that can be prevented by glucocorticoids if given prenatally before the 34th wk of gestation. This observation suggests that a finite period of steroid responsiveness exists as has been demonstrated in animal models. Human intestinal xenografts were used to determine whether a glucocorticoid responsive period exists in the developing human intestine. Developmental responsiveness was measured by lactase activity and inflammatory responsiveness by IL-8, IL-6, and monocyte chemotactic protein-1 (MCP-1) induction after an endogenous (IL-1 beta) or exogenous (LPS) proinflammatory stimulus, respectively. Functional development of ileal xenografts were monitored for 30 wk posttransplantation, and the lactase activity recapitulated that predicted by in utero development. Cortisone acetate accelerated the ontogeny of lactase at 20 wk (immature) but the effect was lost by 30 wk (mature) posttransplant. Concomitant with accelerated maturation, the IL-8 response to both IL-1 beta and LPS was significantly dampened (from 6- to 3-fold) by glucocorticoid pretreatment in the immature but not mature xenografts. The induction of IL-8 was reflected at the level of IL-8 mRNA, suggesting transcriptional regulation. The excessive activation of IL-8 in the immature gut was mediated by a prolonged activation of ERK and p38 kinases and nuclear translocation of NF-kappa B due to low levels of I kappa B. Steroid pretreatment in immature intestine dampens activation of all three signaling pathways in response to proinflammatory stimuli. Therefore, accelerating intestinal maturation by glucocorticoids within the responsive period by accelerating functional and inflammatory maturation may provide an effective preventive therapy for NEC.
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Cortisona/análogos & derivados , Enterocolitis Necrotizante/prevención & control , Enterocolitis Necrotizante/fisiopatología , Glucocorticoides/farmacología , Íleon/embriología , Íleon/crecimiento & desarrollo , Animales , Niño , Preescolar , Cortisona/farmacología , Humanos , Íleon/patología , Lactante , Recién Nacido , Inflamación , Interleucina-8/biosíntesis , Interleucina-8/farmacología , Ratones , Ratones SCID , Transducción de Señal , Transcripción Genética , Trasplante HeterólogoRESUMEN
Samples of three brands of commercial "Sweet Acidophilus Milk" were obtained directly from the processors and evaluated periodically for microbial, chemical, and flavor changes during 23-24 days of storage at 4 ± 2 C. Counts of Lactobacillus acidophilus decreased from 2.6 × 106-6.4 × 106/ml initially to 5.1 × 104-3.1 × 106/ml at the end of the study. Several samples dropped below 2 × 106 viable L. acidophilus before the pull date was reached. Final contaminant counts were 106 - 106/ml in all samples, but rate of decline of L. acidophilus was not directly related to growth of contaminants. Titratable acidity and pH changed very little, and yeast and mold growth was minor. Notable off-flavors developed in 14-21 days.