RESUMEN
BACKGROUND: There is limited research on the dietary behaviours of Canadian children at school, including where students obtain food from during school hours or whether lunch-time food source influences diet quality. METHODS: Nationally representative cross-sectional data from 24-h dietary recalls were analysed from the 2004 Canadian Community Health Survey (n = 4589). Dietary outcomes included school hour and school day dietary intakes and School Healthy Eating Index (S-HEI) scores. Survey-weighted covariate-adjusted linear regression models examined differences in dietary outcomes across lunch-time food source groups. RESULTS: The majority of children (72.8%) reported bringing lunch from home, whereas fewer students obtained lunch from off-campus locations (11.6%), schools (9.6%) or skipped lunch (5.9%). Compared to off-campus lunches, home-packed lunches were significantly higher in fibre, vitamins A, D and C, thiamin, magnesium, iron, grains, vegetables and fruit, but lower in total calories, fat and calories from minimally nutritious foods. Average school hour diet quality required improvement for all age groups, although S-HEI scores did not differ significantly by lunch-time food source among 6-8-year-old children. However, for children age 9-17 years, bringing a home-packed lunch was associated with significantly higher S-HEI scores compared to students obtaining lunch from off-campus locations. After adjusting for age and sex, lunch-time food source was also significantly associated with whole day dietary quality. CONCLUSIONS: Although the nutritional quality of off-campus lunches was lower than home-packed lunches, the quality of foods was suboptimal, regardless of food source. Strategies are needed to enhance access to nutritious foods on campus and improve the nutritional quality of packed lunches, which supply the majority of lunch-time foods consumed by Canadian children.
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Dieta , Conducta Alimentaria , Abastecimiento de Alimentos , Almuerzo , Valor Nutritivo , Instituciones Académicas , Estudiantes , Adolescente , Canadá , Niño , Estudios Transversales , Registros de Dieta , Femenino , Servicios de Alimentación , Humanos , MasculinoRESUMEN
BACKGROUND: Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells. OBJECTIVES: To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques. METHODS: Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways. RESULTS: We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC. CONCLUSIONS: Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.
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Asma/genética , Asma/metabolismo , Miocitos del Músculo Liso/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Péptidos/genética , Acetilcolina/farmacología , Animales , Estudios de Casos y Controles , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Masculino , Glicoproteínas de Membrana , Proteínas de la Membrana/farmacología , Ratones , Ratones Endogámicos BALB C , Contracción Muscular/efectos de los fármacos , Miocitos del Músculo Liso/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Péptidos/metabolismo , Sistema Respiratorio/citología , Venenos de Araña/farmacología , Transcripción GenéticaRESUMEN
BACKGROUND: Coeliac disease (CD) affects approximately 1% of the population in the UK and is managed by the life-long adherence to a strict gluten-free diet (GFD). Adhering to a GFD is practically difficult and not only affects dietary patterns, but also can affect many other aspects of daily life. The present study aimed to investigate the effect of CD and a GFD on dietary habits and quality of life of a cohort of adult biopsy diagnosed coeliac patients who reside in England. METHODS: The cohort was composed of 146 adult biopsy-diagnosed CD patients, who were all members of the Coeliac UK charity. Participants responded to a self-administered questionnaire considering dietary habits and quality of life. A food frequency questionnaire (FFQ) was used to assess dietary compliance. RESULTS: Generally, English CD patients reported to be in good physical and emotional health, although there were reports of anxiety and depression as a result of CD, most likely as a result of exclusion from social and leisure activities. The cohort reported high levels of dietary compliance (96%) which was supported by FFQ responses. However, there were reports of intentional gluten intake during social situations and when eating take-away foods. The FFQ revealed further examples of gluten ingestion, presumably unintentional, particularly through the consumption of breakfast cereals and starch-based sauces such as cheese sauce, custard and ketchup. CONCLUSIONS: The present study revealed that CD affects a wide range of daily activities and that gluten consumption may be more common than anticipated with possible consequences on health.
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Enfermedad Celíaca/dietoterapia , Dieta Sin Gluten , Conducta Alimentaria , Calidad de Vida , Anciano , Enfermedad Celíaca/epidemiología , Enfermedad Celíaca/patología , Estudios de Cohortes , Inglaterra/epidemiología , Femenino , Glútenes/administración & dosificación , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Encuestas y CuestionariosRESUMEN
The stages of rice, Oryza sativa L. (Poales: Poaceae), grain maturity that are most susceptible to rice stink bug, Oebalus pugnax (F.), damage have been identified; however, the stage at which they are no longer capable of causing appreciable damage during grain maturity is unclear. The objective of this study was to determine the susceptibility of rice to rice stink bug feeding at different levels of grain maturity and determine an insecticide termination timing. Rice stink bug damage was examined using five levels of grain maturity described as percent of kernels reaching mature straw coloration referred to as hard dough (20, 40, 60, 80, and 100%) across a range of infestation levels using single panicle sleeve cages and large cages. Hybrid and conventional cultivar rice panicles at 20, 40, and 60% hard dough were found to be susceptible to indirect yield loss, as two rice stink bugs per panicle resulted in over 7% peck. In large cage trials, 25 rice stink bugs caused 0.7-1% peck to hybrid and conventional rice plots at 20% hard dough. Much less damage was observed once rice reached 60% hard dough, where peck averages only reached 0.4%. Decreased damage at 60% hard dough was validated using uncaged trials where 0.4% additional peck was observed in unsprayed plots. These data indicate that rice in the early stages of hard dough is susceptible to large levels of indirect yield loss, but unless significant densities of rice stink bug are present at 60% hard dough, no more sampling or applications are necessary.
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Heterópteros , Insecticidas , Oryza , Animales , Grano Comestible , PoaceaeRESUMEN
Glycosaminoglycans (GAG) are essential extracellular matrix molecules which regulate tissue flexibility, a parameter that is reduced in airways of patients with asthma and chronic obstructive pulmonary disease (COPD). We investigated the expression of GAG and their metabolising enzymes in primary human airway smooth muscle cells (ASMC) obtained from healthy donors (controls) and patients with asthma or COPD. Total GAG synthesis was assessed by [(3)H]-glucosamine incorporation. GAG were isolated, purified, fractionated by electrophoresis and characterised using specific GAG-degrading enzymes. Secretion of hyaluronic acid (HA) by ASMC from patients with asthma or COPD was significantly decreased compared with controls. RT-PCR analysis and western blotting revealed that this decrease was associated with a significant reduction in the expression of HA synthase-1 and -2 and a significant increase of hyaluronidase-1. Furthermore, the expression of the HA receptor CD44 was significantly decreased, whereas the receptor for HA-mediated motility was not expressed in asthma or COPD. Our results indicate that there is a decreased expression of HA in asthma and COPD associated with a synergistic regulation of HA metabolising enzymes that may regulate the pathological airway remodelling in these lung diseases.
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Asma/metabolismo , Asma/patología , Ácido Hialurónico/metabolismo , Miocitos del Músculo Liso/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Adulto , Asma/etiología , Estudios de Casos y Controles , Técnicas de Cultivo de Célula , Femenino , Glucuronosiltransferasa/fisiología , Humanos , Hialuronano Sintasas , Hialuronoglucosaminidasa/fisiología , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/etiología , Adulto JovenRESUMEN
The traditional view of the pathophysiology of asthma is that its characteristic features are secondary to a major allergic or immunological dysfunction. However, this does not explain intrinsic asthma, which can occur in the absence of atopy. An alternative view is that an abnormality in the airway smooth muscle cell, which is capable of producing inflammatory, immunological and growth factors as well as molecules, which facilitate interaction with inflammatory cells, is the primary or instigating event. Evidence is rapidly accumulating that the smooth muscle is abnormal, in that it proliferates faster, produces more chemokines and cytokines as well as a different profile of extracellular matrix proteins than its non-asthmatic counterpart. These abnormalities may arise from altered calcium homoeostasis leading to increased mitochondrial biogenesis and/or decreases in the levels of key transcription factors such as CCAAT enhancer binding protein-alpha. Conditions under which smooth muscle is ablated, such as bronchial thermoplasty, may help us to understand more about the contribution of an airway smooth muscle dysfunction to asthma aetiology.
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Asma/inmunología , Asma/patología , Músculo Liso/inmunología , Músculo Liso/patología , Asma/fisiopatología , Bronquios/inmunología , Bronquios/patología , Quimiocinas/biosíntesis , Citocinas/biosíntesis , Proteínas de la Matriz Extracelular/biosíntesis , Humanos , Músculo Liso/fisiopatologíaRESUMEN
BACKGROUND: CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on ASM CD40 and OX40L expression. METHODS: CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-alpha and/or IFN-gamma was measured using cell-surface enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Involvement of signalling pathway was investigated with pharmacological inhibitors. Soluble TNF receptor levels were quantified by ELISA. RESULTS: Interferon-gamma and TNF-alpha synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-gamma reduced TNF-alpha-induced OX40L expression to a similar extent in both cell types. TNF-alpha and IFN-gamma induced CD40 via nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-kappaB and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-kappaB, but these were not statistically significant. The reduced OX40L expression with TNF-alpha and IFN-gamma involved extracellular regulated kinase 1/2 activation. CONCLUSION: Asthmatic ASM may modulate airway inflammation locally by increasing CD40 and OX40L expression in response to cytokines. IFN-gamma may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression.
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Asma/inmunología , Antígenos CD40/metabolismo , Interferón gamma/farmacología , Miocitos del Músculo Liso/efectos de los fármacos , Ligando OX40/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Adulto , Anciano , Asma/metabolismo , Antígenos CD40/agonistas , Antígenos CD40/inmunología , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , MAP Quinasa Quinasa 4/efectos de los fármacos , MAP Quinasa Quinasa 4/inmunología , MAP Quinasa Quinasa 4/metabolismo , Persona de Mediana Edad , Miocitos del Músculo Liso/inmunología , FN-kappa B/efectos de los fármacos , FN-kappa B/inmunología , FN-kappa B/metabolismo , Ligando OX40/antagonistas & inhibidores , Ligando OX40/inmunología , Factor de Transcripción STAT3/efectos de los fármacos , Factor de Transcripción STAT3/inmunología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunologíaRESUMEN
The influence of genetic variations in SLC6A4 (serotonin transporter gene) on citalopram treatment of depression using the Sequenced Treatment to Relieve Depression (STAR*D) sample was assessed. Of primary interest were three previously studied polymorphisms: 1) the VNTR variation of the second intron, 2) the indel promoter polymorphism (5HTTLPR or SERT), and 3) a single nucleotide polymorphism (SNP) rs25531. Additionally, SLC6A4 was resequenced to identify new SNPs for exploratory analyses. DNA from 1914 subjects in the STAR*D study were genotyped for the intron 2 VNTR region, the indel promoter polymorphism, and rs25531. Associations of these variants with remission of depressive symptoms were evaluated following citalopram treatment. In white non-Hispanic subjects, variations in the intron 2 VNTR (point-wise P = 0.041) and the indel promoter polymorphism (point-wise P = 0.039) were associated with remission following treatment with citalopram. The haplotype composed of the three candidate loci was also associated with remission, with a global p-value of 0.040 and a maximum statistic simulation p-value of 0.0031 for the S-a-12 haplotype, under a dominant model. One SNP identified through re-sequencing the SLC6A4 gene, Intron7-83-TC, showed point-wise evidence of association, which did not remain significant after correction for the number of SNPs evaluated in this exploratory analysis. No associations between these SLC6A4 variations and remission were found in the white Hispanic or black subjects. These findings suggest that multiple variations in the SLC6A4 gene are associated with remission in white non-Hispanic depressed adults treated with citalopram. The mechanism of action of these variants remains to be determined.
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Antidepresivos de Segunda Generación/uso terapéutico , Citalopram/uso terapéutico , Trastorno Depresivo Mayor/genética , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Negro o Afroamericano/genética , Alelos , Ensayos Clínicos como Asunto , Trastorno Depresivo Mayor/tratamiento farmacológico , Femenino , Frecuencia de los Genes , Variación Genética , Haplotipos , Hispánicos o Latinos/genética , Humanos , Intrones , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Repeticiones de Minisatélite , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Inducción de Remisión , Análisis de Secuencia de ADN , Resultado del Tratamiento , Población Blanca/genéticaRESUMEN
Grains rich in starch constitute the primary source of energy for both pigs and humans, but there is incomplete understanding of physiological mechanisms that determine the extent of digestion of grain starch in monogastric animals including pigs and humans. Slow digestion of starch to produce glucose in the small intestine (SI) leads to undigested starch escaping to the large intestine where it is fermented to produce short-chain fatty acids. Glucose generated from starch provides more energy than short-chain fatty acids for normal metabolism and growth in monogastrics. While incomplete digestion of starch leads to underutilised feed in pigs and economic losses, it is desirable in human nutrition to maintain consistent body weight in adults. Undigested nutrients reaching the ileum may trigger the ileal brake, and fermentation of undigested nutrients or fibre in the large intestine triggers the colonic brake. These intestinal brakes reduce the passage rate in an attempt to maximise nutrient utilisation, and lead to increased satiety that may reduce feed intake. The three physiological mechanisms that control grain digestion and feed intake are: (1) gastric emptying rate; (2) interplay of grain digestion and passage rate in the SI controlling the activation of the ileal brake; and (3) fermentation of undigested nutrients or fibre in the large intestine activating the colonic brake. Fibre plays an important role in influencing these mechanisms and the extent of their effects. In this review, an account of the physiological mechanisms controlling the passage rate, feed intake and enzymatic digestion of grains is presented: (1) to evaluate the merits of recently developed methods of grain/starch digestion for application purposes; and (2) to identify opportunities for future research to advance our understanding of how the combination of controlled grain digestion and fibre content can be manipulated to physiologically influence satiety and food intake.
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Fibras de la Dieta/farmacología , Ingestión de Alimentos , Metabolismo Energético , Almidón/metabolismo , Porcinos/fisiología , Alimentación Animal/análisis , Animales , Colon/metabolismo , Dieta/veterinaria , Fibras de la Dieta/análisis , Fibras de la Dieta/metabolismo , Digestión , Grano Comestible , Ácidos Grasos Volátiles/metabolismo , Fermentación , Íleon/metabolismo , Respuesta de SaciedadRESUMEN
BACKGROUND: Rhinovirus infection is responsible for considerable morbidity and mortality as the major cause of exacerbations of asthma, and is also known to induce exacerbations of cystic fibrosis and chronic obstructive pulmonary disease. Exacerbations of these diseases are also frequently associated with bacterial and atypical bacterial infection. Alveolar macrophages are the major immune cells in the airways and are important in defence against bacterial infections. METHODS: The authors investigated whether rhinovirus modifies cytokine release, the pattern recognition receptor expression and phagocytosis by human alveolar macrophages in response to bacterial products. RESULTS: Viable rhinovirus was detected in macrophages up to 3 days after exposure and viral RNA expression persisted for 10 days. Infectious but not UV inactivated rhinovirus increased tumour necrosis factor alpha (TNFalpha) and interleukin (IL)8 release by macrophages. In contrast, infectious rhinovirus impaired lipopolysaccharide and lipoteichoic acid induced TNFalpha and IL8 secretion by macrophages. Rhinovirus induced impairment of macrophage antibacterial immune responses did not involve IL10, prostaglandin E(2) or downregulation of Toll-like receptor 2. Furthermore, the macrophage phagocytic response to labelled bacterial particles, but not to latex beads, was impaired. CONCLUSION: The authors have identified impairment of cytokine responses to bacterial lipopolysaccharide and lipoteichoic acid by alveolar macrophages in response to infectious rhinovirus. Virus induced impairment of antibacterial host defence has important implications in the pathogenesis of exacerbations of respiratory diseases.
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Macrófagos Alveolares/inmunología , Infecciones por Picornaviridae/inmunología , Rhinovirus/inmunología , Regulación hacia Abajo , Ensayo de Inmunoadsorción Enzimática , Femenino , Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/inmunología , Bacterias Grampositivas/inmunología , Infecciones por Bacterias Grampositivas/inmunología , Humanos , Inmunidad Celular , Interleucina-8/metabolismo , Lipopolisacáridos/farmacología , Macrófagos Alveolares/virología , Masculino , Persona de Mediana Edad , Fagocitosis/inmunología , Infecciones por Picornaviridae/virología , Ácidos Teicoicos/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: In the healthy lung, airway epithelial cells (AEC) regulate fibroblast proliferation through release of soluble factors, such as prostaglandins and proteins. Fibroproliferative diseases and airway remodelling may result from an inadequate generation of suppressive factors by AEC or the inability of fibroblasts to respond to them appropriately. OBJECTIVE: The aim of this study was to study the effect of primary human AEC on the proliferation of fibroblasts obtained from healthy and fibrotic lungs in an interactive cell culture model. RESULTS: Conditioned medium (CM) from 14 out of 16 AEC lines significantly inhibited proliferation of normal human lung fibroblasts by 51.2+/-6.0%. The proliferation of fibroblasts derived from patients with lung fibrosis was equally inhibited by CM of AEC. The inhibitory effect of AEC-CM was completely reversed when fibroblasts were pre-incubated with 2.5 microm indomethacin. Furthermore, primary human AEC, but not fibroblasts, secrete TGF-beta, and the inhibitory effect of the AEC-CM was blocked by neutralizing anti-TGF-beta antibodies. CONCLUSION: These results demonstrate that AEC actively inhibit the proliferation of both normal and fibrotic fibroblasts via TGF-beta, which induces the prostaglandin E(2) synthesis in fibroblasts. The data indicate that proliferative lung diseases may be treated using the epithelial cell as the target of medication.
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Fibroblastos/metabolismo , Fibrosis Pulmonar/metabolismo , Mucosa Respiratoria/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Western Blotting , Proliferación Celular , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Humanos , Mucosa Respiratoria/inmunologíaRESUMEN
Food banks provide supplemental food to low-income households, yet little is known about the cardiovascular health of food banks members. This study therefore described cardiovascular disease (CVD) risk factors among food bank members and explored associations between food insecurity and CVD risk. Adults ≥18â¯years (nâ¯=â¯77) from three food bank sites in metro Vancouver, British Columbia completed surveys and physical assessments examining a range of socio-demographic variables and CVD risk factors. A composite measure of myocardial infarction (MI) risk called the INTERHEART score was assessed and household food insecurity was measured using the Household Food Security Survey Module. Regression models were used to explore associations between food insecurity and CVD risk measures, including the INTERHEART score. Ninety-seven percent of food bank members reported experiencing food insecurity, 65% were current smokers, 53% reported either chronic or several periods of stress in the past year, 55% reported low physical activity levels and 80% reported consuming fewer than five servings of fruit and vegetables daily. Prevalence of self-reported diabetes and hypertension were 13% and 29% respectively. Fifty-two percent of the sample were at high risk of non-fatal MI. No statistically significant associations were found between increased severity of food insecurity and CVD risk factors among this sample where both severe food insecurity and high CVD risks were prevalent. Food bank members were at elevated risk for CVD compared with the general population. Strategies are needed to reduce prevalence of food insecurity and CVD risk factors, both of which disproportionately affected food bank members.
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The essential features of persistent severe asthma include structural changes in the airway wall (remodelling). It is not known whether these are the sequelae of chronic inflammation or indeed its initiators. Several transcription factors have been implicated in the inflammatory process in asthma, including the glucocorticoid receptor (GR), NFkappaB, Activator Protein-1 (AP-1), Nuclear Factor of Activated T-cells (NF-AT), cyclic AMP Response Element Binding Protein and more recently, the CCAAT/Enhancer Binding Protein (C/EBP), Peroxisome Proliferator-activated Receptor (PPAR) and the bZIP transcription factor, Nrf2. Could a pathological de-regulation of one of these transcription factors explain the broad spectrum of asthma pathology and can their modulation lead to better symptom control? Although some of the transcription factors seem to be valid targets (NFkappaB, Nrf2 or STAT6) or tools (PPARgamma, -alpha and C/EBP-alpha) for new therapeutic approaches, since many transcription factors play a central role in tissue and organ homeostasis, a longterm general suppression or overexpression, would cause severe side effects in other organs. Cell type specific application of decoy or antisense oligonucleotides for NFkappaB, Nrf2 or STAT6, or specific agonists for PPARgamma and -alpha may help to control the inflammatory response in lung epithelial cells and infiltrated immune cells, but additional, unwanted, effects on other resident cells of the lung cannot be excluded and a beneficial effect over known anti-asthma drugs has first to be proven. In order to progress with such novel therapeutic strategies, the only option seems to be to link transcription factor inhibitors/activators to a cell type specific delivery system.
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Asma/tratamiento farmacológico , Factores de Transcripción/fisiología , Animales , Asma/etiología , Proteínas Potenciadoras de Unión a CCAAT/fisiología , Factor de Transcripción GATA3/fisiología , Humanos , FN-kappa B/fisiología , PPAR gamma/fisiología , Factor de Transcripción STAT6/fisiología , Factor de Transcripción AP-1/fisiología , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
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Alelos , Pruebas Genéticas/normas , Farmacogenética/normas , Terminología como Asunto , Genes , Pruebas Genéticas/tendencias , Variación Genética , Humanos , Farmacogenética/tendencias , Medicina de PrecisiónRESUMEN
PURPOSE: Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) is a noninvasive technique for spatial characterization of biochemical markers in tissues. We measured the relative tumor concentrations of these biochemical markers in children with recurrent brain tumors and evaluated their potential prognostic significance. PATIENTS AND METHODS: (1)H-MRSI was performed on 27 children with recurrent primary brain tumors referred to our institution for investigational drug trials. Diagnoses included high-grade glioma (n = 10), brainstem glioma (n = 7), medulloblastoma/peripheral neuroectodermal tumor (n = 6), ependymoma (n = 3), and pineal germinoma (n = 1). (1)H-MRSI was performed on 1. 5-T magnetic resonance imagers before treatment. The concentrations of choline (Cho) and N-acetyl-aspartate (NAA) in the tumor and normal brain were quantified using a multislice multivoxel method, and the maximum Cho:NAA ratio was determined for each patient's tumor. RESULTS: The maximum Cho:NAA ratio ranged from 1.1 to 13.2 (median, 4.5); the Cho:NAA ratio in areas of normal-appearing brain tissue was less than 1.0. The maximum Cho:NAA ratio for each histologic subtype varied considerably; approximately equal numbers of patients within each tumor type had maximum Cho:NAA ratios above and below the median. Patients with a maximum Cho:NAA ratio greater than 4.5 had a median survival of 22 weeks, and all 13 patients died by 63 weeks. Patients with a Cho:NAA ratio less than or equal to 4.5 had a projected survival of more than 50% at 63 weeks. The difference was statistically significant (P =.0067, log-rank test). CONCLUSION: The maximum tumor Cho:NAA ratio seems to be predictive of outcome in children with recurrent primary brain tumors and should be evaluated as a prognostic indicator in newly diagnosed childhood brain tumors.
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Neoplasias Encefálicas/diagnóstico , Espectroscopía de Resonancia Magnética/métodos , Adolescente , Adulto , Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Niño , Preescolar , Humanos , Recurrencia Local de Neoplasia , Proyectos Piloto , Pronóstico , ProtonesRESUMEN
A patient had angiographic and computed tomographic features of a dissecting aneurysm of the extracranial internal carotid artery, with intracranial extension into the cavernous sinus. Isolated abducens nerve palsy resolved without treatment, within a two-month period.
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Nervio Abducens , Disección Aórtica/complicaciones , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de los Nervios Craneales/etiología , Parálisis/etiología , Adulto , Disección Aórtica/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Arteria Carótida Interna/diagnóstico por imagen , Seno Cavernoso/diagnóstico por imagen , Femenino , Humanos , RadiografíaRESUMEN
Inherited forms of ataxia and absence seizures in mice have been linked to defects in voltage-dependent calcium channel subunits. However, a correlation between the sites of neuronal dysfunction and the impact of the primary lesion upon calcium channel subunit expression or function has not been clearly established. For example, the mutation in stargazer mice has pleiotropic consequences including synaptic alterations in cerebellar granule cells, hippocampal CA3/mossy fibers, and cortical neurons in layer V that, presumably, lead to ataxia and seizures. Genetic analysis of stargazer mice determined that the defective gene encodes a protein expressed in brain (gamma2) with limited homology to the skeletal muscle L-type calcium channel gamma1 subunit. Although additional gamma isoforms have been subsequently identified primarily in neural tissue, little was known about the proteins they encode. Therefore, this study explored the distribution and biochemical properties of gamma2 and other gamma isoforms in wild-type and stargazer brain. We cloned human gamma2, gamma3, and gamma4 isoforms, produced specific anti-peptide antibodies to gamma isoforms and characterized both heterologously expressed and endogenous gamma. We identified regional specificity in the expression of gamma isoforms by western analysis and immunohistochemistry. We report for the first time that the mutation in the stargazer gene resulted in the loss of gamma2 protein. Furthermore, no compensatory changes in the expression of gamma3 or gamma4 protein were evident in stargazer brain. In contrast to other voltage-dependent calcium channel subunits, gamma immunostaining was striking in that it was primarily detected in regions highly enriched in excitatory glutamatergic synapses and faintly detected in cell bodies, suggesting a role for gamma in synaptic functions. Sites of known synaptic dysfunction in stargazer (the hippocampal CA3 region, dentate gyrus, and cerebellar molecular layer) were revealed as relying primarily upon gamma2, as total gamma isoform expression was dramatically decreased in these regions. Electron microscopy localized anti-gamma antibody immunostaining to dendritic structures of hippocampal mossy fiber synapses, with enrichment at postsynaptic densities. To assess the association of native gamma with voltage-dependent calcium channel or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits, gamma isoforms (gamma2, gamma3 and gamma4) were detergent solubilized from mouse forebrain. Antibodies against a highly conserved C-terminal epitope present in gamma2, gamma3 and gamma4 immunoprecipitated voltage-dependent calcium channel subunits (alpha1B), providing the first in vivo evidence that gamma and voltage-dependent calcium channels form stable complexes. Furthermore, both anti-gamma2 antibodies and anti-alpha1B antibodies independently immunoprecipitated the AMPA receptor subunit, GluR1, from mouse forebrain homogenates. In summary, loss of gamma2 immunoreactivity in stargazer is precisely localized so as to contribute to previously characterized synaptic defects. The data in this paper provide compelling evidence that gamma isoforms form complexes in vivo with voltage-dependent calcium channels as well as AMPA receptors, are selectively and differentially expressed in neuronal processes, and localize primarily to dendritic structures in the hippocampal mossy fiber region.
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Ataxia/metabolismo , Encéfalo/metabolismo , Canales de Calcio Tipo L/genética , Epilepsia/metabolismo , Ratones Mutantes Neurológicos/metabolismo , Sinapsis/metabolismo , Animales , Especificidad de Anticuerpos , Ataxia/genética , Ataxia/fisiopatología , Encéfalo/fisiopatología , Encéfalo/ultraestructura , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo N/genética , Canales de Calcio Tipo N/metabolismo , Señalización del Calcio/genética , Dendritas/metabolismo , Dendritas/ultraestructura , Epilepsia/genética , Epilepsia/fisiopatología , Expresión Génica/fisiología , Hipocampo/metabolismo , Hipocampo/ultraestructura , Inmunohistoquímica/métodos , Ratones , Ratones Mutantes Neurológicos/anomalías , Microscopía Electrónica , Datos de Secuencia Molecular , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores AMPA/genética , Receptores AMPA/metabolismo , Homología de Secuencia de Aminoácido , Sinapsis/ultraestructuraRESUMEN
1. Phosphoramidon (10 microM) markedly increased the contractile response to endothelin-3 in human and rabbit bronchus in vitro. In human tissue the contractile response to 0.3 microM endothelin-3 was significantly increased from 54 +/- 12% to 137 +/- 34% (of the response to 1 nM acetylcholine) in the presence of phosphoramidon. Similarly, in rabbit isolated bronchus, the endothelin-3-induced response was increased from 34 +/- 5% to 61 +/- 7%. 2. In addition, the potency (as measured by EC30 values) of this peptide in human and rabbit airways was significantly augmented in the presence of the enzyme inhibitor. The geometric mean EC30 value was decreased from 53 nM (95% CI:15, 190) to 8 nM (95% CI:3, 23) in human bronchus and from 150 nM (95% CI:89, 250) to 23 nM (95% CI:11, 50) in rabbit tissue. 3. Neither the potency nor the response (at 0.3 microM) to endothelin-3 in canine bronchial rings was altered after incubation of the tissue in phosphoramidon. 4. A previous study carried out in human airways has implied that the difference in potency between endothelin-1 and endothelin-3 may be attributed to a heterogeneous endothelin receptor population. The results of our study, while also demonstrating this difference in potency, have shown that this marked difference, as well as that obvious in rabbit airway tissue can be abolished in the presence of phosphoramidon. 5. Phosphoramidon produced no change in the cumulative concentration-response curve for endothelin-1 in airway tissue from the three species studied. 6. These results suggest that a phosphoramidon-sensitive enzyme (probably neutral endopeptidase) found in lung, may be responsible for local degradation of endothelin-3, but not endothelin-l in human and rabbit isolated bronchus.
Asunto(s)
Broncoconstricción/efectos de los fármacos , Endotelinas/farmacología , Glicopéptidos/farmacología , Animales , Perros , Sinergismo Farmacológico , Endotelinas/administración & dosificación , Glicopéptidos/administración & dosificación , Humanos , Técnicas In Vitro , Neprilisina/antagonistas & inhibidores , ConejosRESUMEN
1 The peptides endothelin-1 (ET-1) and endothelin-2 (ET-2) elicited potent and sustained contractions of human isolated bronchus and pulmonary artery. 2 ET-1 is one of the most potent contractile agonists investigated in these tissues with an EC50 value of 18.3 nM (95% confidence interval: 12.9, 25.9 nM: n = 26) in bronchus and 3.2 nM (95% confidence interval: 0.4, 23.9 nM; n = 5) in the arterial preparation. 3 ET-1 is 2.5 times more potent than ET-2 in both the airway and vascular tissues, and both forms of the peptide have geometric mean EC50 values 5 times greater than in the isolated bronchial tissue than in the pulmonary artery. 4 Neither pretreatment with the voltage-dependent calcium (VDC) channel antagonist verapamil (10 microM) nor with indomethacin (25 microM) significantly altered the response curve to ET-1 in human isolated bronchus. Removal of calcium from the Krebs-Henseleit solution did not affect ET-1-induced responses. 5 Specific binding on the smooth muscle of human airway and pulmonary arterial tissue to both ET-1 and ET-2 was detected in autoradiographic studies. There appeared to be no difference between the peptides in the location nor the density of binding sites. 6 We conclude that contraction of human bronchial tissue by ET-1 is not dependent upon influence of extracellular calcium nor release of prostaglandins or thromboxane A2. It is likely that the action of ET-1 in this tissue is due to binding of this peptide to specific receptors located on the smooth muscle.