RESUMEN
Introduction: Colorectal Cancer (CRC) accounts for 9% of cancer deaths globally. Hormonal pathways play important roles in some cancers. This study investigated the association of CRC expression of neurotensin (NTS), NTS receptors 1 and 3 (NTSR1 and NTSR3) and clinical outcomes. Methods: A prospective cohort study which quantifies the protein expression of NTS, NTSR1 and NTSR3 in human CRCs using immunohistochemistry. Expression levels were then compared with clinico-pathological outcome including histological grade, overall survival (OS) and disease-free survival (DFS). Results: Sixty-four patients were enrolled with median follow-up of 44.0 months. There was significantly higher expression of NTS in cancer tissue in CRC with higher T stages (p < 0.01), N stages (p = 0.03), and AJCC clinical stages (p = 0.04). There was significantly higher expression of NTS, NTSR1 and NTSR3 in cancer tissue compared to surrounding normal epithelium (median H-score 163.5 vs 97.3, p < 0.01). There was significantly shorter DFS in individuals with CRC with high levels of NTS compared to lower levels of NTS (35.8 months 95% CI 28.7-42.8 months vs 46.4 months 95% CI 42.2-50.5 months, respectively, p = 0.02). Above median NTS expression in cancer tissue was a significant risk factor for disease recurrence (HR 4.10, 95% CI 1.14-14.7, p = 0.03). Discussion: The expression of NTS and its receptors has the potential to be utilised as a predictive and prognostic marker in colorectal cancer for postoperative selection for adjuvant therapy and identify individuals for novel therapies targeting the neurotensinergic pathways. Conclusions: High NTS expression appears to be associated with more advanced CRC and worse DFS.
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Adenocarcinoma/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/metabolismo , Neurotensina/genética , Receptores de Neurotensina/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neurotensina/metabolismo , Receptores de Neurotensina/metabolismoRESUMEN
We describe what we believe is the first instance of complete COVID-19 testing of all passengers and crew on an isolated cruise ship during the current COVID-19 pandemic. Of the 217 passengers and crew on board, 128 tested positive for COVID-19 on reverse transcription-PCR (59%). Of the COVID-19-positive patients, 19% (24) were symptomatic; 6.2% (8) required medical evacuation; 3.1% (4) were intubated and ventilated; and the mortality was 0.8% (1). The majority of COVID-19-positive patients were asymptomatic (81%, 104 patients). We conclude that the prevalence of COVID-19 on affected cruise ships is likely to be significantly underestimated, and strategies are needed to assess and monitor all passengers to prevent community transmission after disembarkation.
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Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/epidemiología , Neumonía Viral/epidemiología , Navíos , Viaje , Anciano , Infecciones Asintomáticas/epidemiología , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Femenino , Vacaciones y Feriados , Humanos , Masculino , Medicina Naval/estadística & datos numéricos , Pandemias , Neumonía Viral/diagnóstico , Prevalencia , SARS-CoV-2RESUMEN
BACKGROUND: Respiratory viral infection causes chronic obstructive pulmonary disease (COPD) exacerbations. We previously reported increased bronchial mucosa eosinophil and neutrophil inflammation in patients with COPD experiencing naturally occurring exacerbations. But it is unclear whether virus per se induces bronchial mucosal inflammation, nor whether this relates to exacerbation severity. OBJECTIVES: We sought to determine the extent and nature of bronchial mucosal inflammation following experimental rhinovirus (RV)-16-induced COPD exacerbations and its relationship to disease severity. METHODS: Bronchial mucosal inflammatory cell phenotypes were determined at preinfection baseline and following experimental RV infection in 17 Global Initiative for Chronic Obstructive Lung Disease stage II subjects with COPD and as controls 20 smokers and 11 nonsmokers with normal lung function. No subject had a history of asthma/allergic rhinitis: all had negative results for aeroallergen skin prick tests. RESULTS: RV infection increased the numbers of bronchial mucosal eosinophils and neutrophils only in COPD and CD8+ T lymphocytes in patients with COPD and nonsmokers. Monocytes/macrophages, CD4+ T lymphocytes, and CD20+ B lymphocytes were increased in all subjects. At baseline, compared with nonsmokers, subjects with COPD and smokers had increased numbers of bronchial mucosal monocytes/macrophages and CD8+ T lymphocytes but fewer numbers of CD4+ T lymphocytes and CD20+ B lymphocytes. The virus-induced inflammatory cells in patients with COPD were positively associated with virus load, illness severity, and reductions in lung function. CONCLUSIONS: Experimental RV infection induces bronchial mucosal eosinophilia and neutrophilia only in patients with COPD and monocytes/macrophages and lymphocytes in both patients with COPD and control subjects. The virus-induced inflammatory cell phenotypes observed in COPD positively related to virus load and illness severity. Antiviral/anti-inflammatory therapies could attenuate bronchial inflammation and ameliorate virus-induced COPD exacerbations.
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Infecciones por Picornaviridae/complicaciones , Infecciones por Picornaviridae/diagnóstico , Infecciones por Picornaviridae/virología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Mucosa Respiratoria/patología , Mucosa Respiratoria/virología , Rhinovirus , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Biomarcadores , Eosinófilos , Femenino , Humanos , Mediadores de Inflamación , Recuento de Leucocitos , Masculino , Neutrófilos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Esputo/citología , Esputo/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
BACKGROUND: The innate immune system senses viral infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in rhinovirus-induced asthma exacerbations in vivo are uncertain. OBJECTIVES: We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after rhinovirus infection in atopic asthmatic patients and control subjects. METHODS: Immunohistochemistry was used to detect expression of IFN-α, IFN-ß, and the PRRs: Toll-like receptor 3, melanoma differentiation-associated gene 5, and retinoic acid-inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after rhinovirus infection. RESULTS: We observed IFN-α/ß deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/ß expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during rhinovirus infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/ß in asthmatic patients during infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during rhinovirus infection. Rhinovirus infection-increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. CONCLUSIONS: Bronchial epithelial IFN-α/ß expression and numbers of subepithelial IFN-α/ß-expressing monocytes/macrophages during infection were both deficient in asthmatic patients. Lower epithelial IFN-α/ß expression was associated with adverse clinical outcomes after rhinovirus infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during infection were also related to greater viral load/illness severity.
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Asma/inmunología , Proteína 58 DEAD Box/inmunología , Regulación de la Expresión Génica/inmunología , Helicasa Inducida por Interferón IFIH1/biosíntesis , Interferón-alfa/inmunología , Interferón beta/inmunología , Infecciones por Picornaviridae/inmunología , Rhinovirus/inmunología , Receptor Toll-Like 3/inmunología , Adulto , Asma/metabolismo , Asma/patología , Biopsia , Bronquios/inmunología , Bronquios/metabolismo , Bronquios/patología , Proteína 58 DEAD Box/biosíntesis , Femenino , Humanos , Helicasa Inducida por Interferón IFIH1/inmunología , Interferón-alfa/metabolismo , Interferón beta/metabolismo , Masculino , Infecciones por Picornaviridae/metabolismo , Infecciones por Picornaviridae/patología , Receptores Inmunológicos , Rhinovirus/metabolismo , Índice de Severidad de la Enfermedad , Receptor Toll-Like 3/biosíntesisRESUMEN
This single-center, randomized, placebo-controlled, four-treatment, four-period crossover study compared the enamel remineralization effects of low- and medium-abrasivity gel-to-foam toothpastes and a reference toothpaste (all 1,450 ppm fluoride as NaF) versus placebo toothpaste (0 ppm fluoride) using a short-term in situ erosion model. Subjects (n = 56) wearing a palatal appliance holding acid-softened bovine enamel specimens brushed their teeth with the test toothpastes. Thereafter, the specimens were removed for analysis of percent surface microhardness recovery (%SMHR) and percent relative erosion resistance (%RER) at 2, 4, and 8 h. Both low- and medium-abrasivity gel-to-foam fluoride toothpastes and the reference toothpaste provided significantly greater %SMHR than placebo at all assessment time points (all p < 0.05). No statistically significant difference of %SMHR was observed between the fluoride treatment groups at any time point. Similarly, all fluoride products provided significantly superior %RER versus placebo (all p < 0.0001), whereas no significant difference of this parameter was noted between the fluoride treatment groups. Increasing numerical improvements of %SMHR and %RER were observed in all four treatment groups over time (2, 4, and 8 h). The present in situ model is a sensitive tool to investigate intrinsic and fluoride-enhanced rehardening of eroded enamel. All three fluoride toothpastes were more efficacious than placebo, and there were no safety concerns following single dosing in this short-term in situ model.
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Remineralización Dental , Pastas de Dientes/farmacología , Animales , Bovinos , Estudios Cruzados , Fluoruros , Humanos , Fluoruro de SodioRESUMEN
PURPOSE: To compare the efficacy of an anhydrous dentifrice containing 0.454% w/w stannous fluoride and a negative control dentifrice containing 1,000 ppm fluoride, as sodium monofluorophosphate, at reducing dentin hypersensitivity over 8 weeks with twice-daily brushing. METHODS: This was a randomized, examiner-blind, parallel, two treatment group, stratified (by maximum baseline Schiff sensitivity score), 8-week clinical study carried out at a single site in 119 healthy subjects with at least two sensitive teeth, who met all study criteria at the screening and baseline visits. Clinical assessments of sensitivity to evaporative (air) [with Schiff sensitivity score and visual analogue scale (VAS)] and tactile (Yeaple probe) stimuli were employed to compare the efficacy of the test dentifrice containing 0.454% w/w stannous fluoride to the negative control dentifrice at reducing sensitivity after 4 and 8 weeks treatment. RESULTS: Of the 119 subjects randomized to study treatment, 113 completed the study. At 4 and 8 weeks, between treatment analyses found the test dentifrice to be significantly better than the negative control dentifrice in relieving dentin hypersensitivity for all measures (Schiff: P < 0.0001 at 4 and 8 weeks; VAS score: P = 0.0003 at 4 weeks, P < 0.0001 at 8 weeks; tactile threshold: P = 0.0138 at 4 weeks, P < 0.0001 at 8 weeks).
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Dentífricos/uso terapéutico , Sensibilidad de la Dentina , Manejo del Dolor/métodos , Fluoruros de Estaño/uso terapéutico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: The ability of a dentifrice containing the bioactive material calcium sodium phosphosilicate (CSPS) to remineralise the surface of dentine and physically occlude patent tubules was investigated in a 20 day in situ randomised clinical study. METHODS: Changes in surface microhardness and surface topography of dentine specimens treated for 5, 10, 15 and 20 days, twice daily with either a dentifrice containing 5% CSPS or a fluoride-only containing placebo dentifrice were compared. The substantivity of any mineral deposits formed on the surface of dentine were investigated by the application of an intra-oral dietary acid challenge twice daily during the final 10 days of treatment. RESULTS: After 5 and 10 days of treatment, the dentine samples in both treatment groups demonstrated an increase in surface microhardness. After 10 days of treatment the increase in surface hardness was directionally greater for the specimens treated with 5% CSPS dentifrice. Introducing an intra-oral acid exposure resulted in a reduction in surface microhardness which was significantly greater for the specimens treated with the placebo dentifrice compared to the dentifrice containing 5% CSPS, at day 20. Occlusion of the patent tubules was evident at each time-point and was significantly greater for the 5% CSPS containing dentifrice on days 5 and 10. On day 15 both dentifrices demonstrated the same degree of occlusion. CONCLUSION: This in situ study demonstrated that dentifrice containing 5% CSPS may have potential to mineralise and occlude the dentine in the oral environment. CLINICAL SIGNIFICANCE: This work provides evidence of potential agents that can be used to reduce the pain of dentine hypersensitivity when formulated into dentifrice and applied as part of a normal oral hygiene routine.
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Dentífricos/uso terapéutico , Silicatos/uso terapéutico , Remineralización Dental/métodos , Dentina/efectos de los fármacos , Dentina/metabolismo , Sensibilidad de la Dentina/tratamiento farmacológico , Fluoruros/farmacología , Fluoruros/uso terapéutico , Humanos , Método Simple CiegoRESUMEN
BACKGROUND: The nature of bronchial mucosal inflammation and its physiologic and clinical significance in rhinovirus-induced asthma exacerbations is unclear. We investigated bronchial mucosal inflammatory response and its association with physiologic and clinical outcomes in an experimental model of rhinovirus-induced asthma exacerbations. METHODS: We used immunohistochemistry methods to detect phenotypes of inflammatory cells infiltrating the bronchial mucosa before and after experimental rhinovirus infection in 10 subjects with asthma and 15 normal subjects. RESULTS: Compared with baseline, rhinovirus infection significantly increased the number of epithelial (P = .005) and subepithelial (P = .017) neutrophils in subjects with asthma only and subepithelial CD68+ macrophages in both subjects with asthma (P = .009) and normal subjects (P = .018) but more so in those with asthma (P = .021). Numbers of CD45+, CD68+, and CD20+ cells; neutrophils; and eosinophils at day 4 postinfection were positively associated with virus load (r = 0.50-0.72, P = .016-0.03). At acute infection in subjects with asthma, CD4+ cells correlated with chest symptom scores (r = 0.69, P = .029), the fall in the 10% fall in FEV1 (PC10) correlated with neutrophils (r = -0.89, P = .029), the PC10 correlated inversely with CD4+ (r = -0.67, P = .023) and CD8+ cells (r = -0.65, P = .03), the 20% fall in FEV1 was inversely associated with CD20+ cells (r = -0.65, P = .03), and higher epithelial CD8+ cell counts were significantly associated with a greater maximum fall in FEV1 (r = -0.72, P = .03), whereas higher subepithelial mast cell counts were significantly associated with a lower maximum percent fall in peak expiratory flow (r = 0.8, P = .024). CONCLUSIONS: In subjects with asthma, rhinovirus infection induces bronchial mucosal neutrophilia and more severe monocyte/macrophage infiltration than in normal subjects. Airway neutrophils, eosinophils, and T and B lymphocytes during infection are related to virus load and physiologic and clinical severity, whereas mast cells are related to greater lung function.
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Asma/inmunología , Resfriado Común/inmunología , Neumonía/inmunología , Neumonía/virología , Rhinovirus , Adulto , Asma/virología , Resfriado Común/complicaciones , Comorbilidad , Eosinófilos/patología , Femenino , Humanos , Pulmón/fisiopatología , Pulmón/virología , Linfocitos/patología , Macrófagos Alveolares/patología , Masculino , Mastocitos/patología , Neutrófilos/patología , Rhinovirus/aislamiento & purificación , Índice de Severidad de la Enfermedad , Carga ViralRESUMEN
Patients with chronic obstructive pulmonary disease (COPD) often suffer other concomitant disorders, such as cardiovascular diseases and metabolic disorders, that influence significantly (and independently of lung function) their health status and prognosis. Thus, COPD is not a single organ condition, and disturbances of a complex network of interorgan connected responses occur and modulate the natural history of the disease. Here, we propose a novel hypothesis that considers a vascularly connected network with (1) the lungs as the main external sensor of the system and a major source of "danger signals"; (2) the endothelium as an internal sensor of the system (also a potential target tissue); and (3) two key responding elements, bone marrow and adipose tissue, which produce both inflammatory and repair signals. According to the model, the development of COPD, and associated multimorbidities (here we focus on cardiovascular disease as an important example), depend on the manner in which the vascular connected network responds, adapts, or fails to adapt (dictated by the genetic and epigenetic background of the individual) to the inhalation of particles and gases, mainly in cigarette smoke. The caveats and limitations of the hypothesis, as well as the experimental and clinical research needed to test and explore the proposed model, are also briefly discussed.
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Tejido Adiposo/fisiopatología , Médula Ósea/fisiopatología , Pulmón/fisiopatología , Modelos Biológicos , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Tejido Adiposo/metabolismo , Biomarcadores/metabolismo , Médula Ósea/metabolismo , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Humanos , Inflamación/metabolismo , Inflamación/fisiopatología , Pulmón/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Transducción de SeñalRESUMEN
PURPOSE: To compare the efficacy of a 0.454% w/w stannous fluoride containing anhydrous dentifrice and a negative control dentifrice containing 1,000 ppm fluoride (as sodium monofluorophosphate) at reducing dentin hypersensitivity over an 8-week period, following twice daily brushing. METHODS: This was a randomized, examiner blind, two-treatment arm, stratified (by maximum baseline Schiff sensitivity score), parallel design, single-site study in 118 subjects, who had at least two sensitive teeth, and met all the criteria at the screening and baseline visit. The study was conducted in Las Vegas, NV, USA. Tactile threshold (Yeaple Probe) and evaporative (air-blast) sensitivity (with Schiff sensitivity scale) were employed as clinical measures to compare the efficacy of the test dentifrice containing 0.454% w/w stannous fluoride to the negative control (Colgate Cavity Protection) at reducing sensitivity at Weeks 4 and 8. RESULTS: 117 subjects completed the clinical study. At the 4- and 8-week time points, between treatment analyses demonstrated the test dentifrice to be significantly better at relieving subjects' sensitivity, for both validated clinical measures, compared to the negative control (at 4 weeks Schiff P < 0.0001 tactile threshold P < 0.0001; at 8 weeks Schiff P < 0.0001; tactile threshold P < 0.0001).
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Dentífricos/uso terapéutico , Sensibilidad de la Dentina/prevención & control , Fluoruros de Estaño/uso terapéutico , Adulto , Anciano , Análisis de Varianza , Femenino , Fluoruros/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Fosfatos/uso terapéutico , Seguridad , Umbral Sensorial , Método Simple Ciego , Adulto JovenRESUMEN
BACKGROUND: Increased airway smooth muscle (ASM) is a feature of established asthma in schoolchildren, but nothing is known about ASM in preschool wheezers. OBJECTIVE: We sought to determine endobronchial biopsy specimen ASM area fraction in preschool wheezers and its association with asthma at school age. METHODS: ASM area, reticular basement membrane thickness, and mucosal eosinophil and ASM mast cell values were quantified in endobronchial biopsy specimens previously obtained from preschool children undergoing clinically indicated bronchoscopy: severe recurrent wheezers (n=47; median age, 26 months) and nonwheezing control subjects (n=21; median age, 15 months). Children were followed up, and asthma status was established at age 6 to 11 years. Preschool airway pathology was examined in relation to asthma at school age. RESULTS: Forty-two (62%) of 68 children had 1 or more evaluable biopsy specimens for ASM. At school age, 51 of 68 children were followed up, and 15 (40%) of 37 preschool wheezers had asthma. Children who had asthma and an evaluable biopsy specimen had increased preschool ASM area fraction (n=8; median age, 8.2 years [range, 6-10.4 years]; median ASM, 0.12 [range, 0.08-0.16]) compared with that seen in children without asthma (n=24; median age, 7.3 years [range, 5.9-11 years]; median ASM, 0.07 [range, 0.02-0.23]; P=.007). However, preschool reticular basement membrane thickness and mucosal eosinophil or ASM mast cell values were not different between those who did or did not have asthma at school age. CONCLUSION: Increased preschool ASM is associated with those children who have asthma at school age. Thus a focus on early changes in ASM might be important in understanding the subsequent development of childhood asthma.
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Asma/diagnóstico , Asma/patología , Bronquios/patología , Músculo Liso/patología , Ruidos Respiratorios/fisiopatología , Asma/inmunología , Biopsia , Bronquios/inmunología , Broncoscopía , Niño , Preescolar , Diagnóstico Precoz , Eosinófilos/inmunología , Eosinófilos/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Mastocitos/inmunología , Mastocitos/patología , Músculo Liso/inmunología , Pruebas de Función Respiratoria , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Ruidos Respiratorios/inmunologíaRESUMEN
BACKGROUND: Cysteinyl leukotriene 1 (CysLT1) receptor expression is known to be increased in the airway mucosa of patients with asthma, especially during exacerbations; however, nothing is known of its expression in COPD. METHODS: We applied immunohistochemistry and in situ hybridization to endobronchial biopsies to determine inflammatory cell CysLT1 receptor protein and mRNA expression in the following: (1) 15 nonsmoker control subjects (NSC), (2) 16 smokers with moderate to severe COPD in its stable phase (S-COPD), and (3) 15 smokers with COPD hospitalized for a severe exacerbation (SE-COPD). RESULTS: The total number of bronchial mucosal inflammatory cells (CD45+) and those expressing CysLT1 receptor protein were significantly greater in SE-COPD (CysLT1 receptor protein: median [range] = 139 [31-634]) as compared with S-COPD (32 [6-114]) or NSC (16 [4-66]) (P < .001 for both). CysLT1 receptor gene expression showed similar differences. A greater proportion of CD451 cells expressed CysLT1 receptor protein in SE-COPD (median [range] = 22% [8-81]) compared with S-COPD (10% [4-32]) (P < .03) or NSC (7% [1-19]) (P < .002). In SE-COPD, the relative frequencies of CysLT1 receptor-expressing cells were as follows: tryptase1 mast cells > CD681 monocytes/macrophage > neutrophils > CD201 B lymphocytes = EG21 eosinophils. Moreover, there were positive correlations between the numbers of cells expressing CysLT1 receptor protein and the numbers of CD451 cells (r = 0.78; P < .003) and tryptase1 mast cells (r = 0.62; P < .02). CONCLUSIONS: Bronchial mucosal CysLT1 receptor-positive inflammatory cells are present in the bronchial mucosa in COPD in greatest number in those experiencing a severe exacerbation.
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Bronquios/patología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , ARN Mensajero/metabolismo , Receptores de Leucotrienos/genética , Receptores de Leucotrienos/metabolismo , Adulto , Anciano , Bronquios/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/etiología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Fumar/genética , Fumar/metabolismo , Fumar/patologíaRESUMEN
OBJECTIVES: To investigate the dentine occlusion and acid resistance of dentifrices developed to treat dentine hypersensitivity. METHODS: This was a single centre, single blind, randomised, split mouth, four treatments, two period crossover, in situ study in healthy subjects. Subjects wore buccal intra-oral appliances each fitted with four dentine samples over four consecutive days with one study product applied per appliance; 8% strontium acetate in silica base, 1040 ppm sodium fluoride (Sensodyne(®) Rapid Relief), 8% arginine, calcium carbonate, 1450 ppm sodium monofluorophosphate (Colgate Sensitive Pro-Relief(®)), 1450 ppm sodium fluoride (control paste) and water. On days 3 and 4, two agitated grapefruit juice challenges (ex vivo) occurred for 1 min. At the end of each treatment day 1 dentine sample was removed from each appliance for scanning electron microscopy (SEM). The extent of tubule occlusion was measured using an examiner-based visual scoring index (three trained examiners). RESULTS: In total, 28 subjects ((12 males and 16 females with a mean age of 34.7 years (SD 8.41 years)) completed the study. On day 2, both test dentifrices demonstrated significantly better dentine tubule occlusion than water (p < 0.0001) and control paste (8% strontium p = 0.0003 and 8% arginine p = 0.0019). After 3 and 4 days of twice daily brushing with acid challenges on days 3 and 4 the strontium-based dentifrice demonstrated significantly better dentine occlusion than all other treatments (p < 0.0001). CONCLUSIONS: Strontium acetate and arginine-based dentifrice result in statistically significant dentine tubular occlusion compared to controls, but the arginine-based dentifrice is more susceptible to acid challenge. CLINICAL SIGNIFICANCE: Erosive beverages are an important aetiology in DH by exposing dentine tubules. Their consumption has increased significantly over the past decade in the UK. This 4-day in situ study investigated the properties of commercially available dentifrices designed to occlude dentine tubules and their resistance to an agitated acid challenge.
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Dentífricos/uso terapéutico , Desensibilizantes Dentinarios/uso terapéutico , Dentina/efectos de los fármacos , Acetatos/uso terapéutico , Adulto , Arginina/uso terapéutico , Bebidas , Carbonato de Calcio/uso terapéutico , Bebidas Gaseosas , Ácido Carbónico/efectos adversos , Ácido Cítrico/efectos adversos , Citrus paradisi , Citrus sinensis , Estudios Cruzados , Dentina/ultraestructura , Femenino , Fluoruros/uso terapéutico , Humanos , Masculino , Microscopía Electrónica de Rastreo , Fosfatos/uso terapéutico , Método Simple Ciego , Fluoruro de Sodio/uso terapéutico , Estroncio/uso terapéuticoRESUMEN
A comparison of the desensitising efficacy of two commercially available dentifrices with different modes of action was conducted in a randomised, examiner-blind, two-arm, parallel group, 8-week, longitudinal clinical study. Dentifrice A, (Sensodyne Multi Action Iso-Active), contained 50000 ppm KNO(3) and 1450 ppm fluoride as NaF. Dentifrice B, Colgate Sensitive Pro-Relief, contained a combination of 80000 ppm arginine, bicarbonate, calcium carbonate, and 1450 ppm fluorine as NaMFP. Subjects (N = 110), stratified into two groups (N = 55), brushed twice-daily for 60 s, over an 8-week period. Sensitivity status, compliance, and safety were determined at 1, 2, 4, and 8 weeks. A fixed-effects ANCOVA statistical model was applied to the Intent-To-Treat population using a two-sided 5% significance level. After 8 weeks, the treatment groups using Dentifrice A and Dentifrice B exhibited mean reductions from baseline of 49% and 45% in air sensitivity visual analogue scale (VAS) score, 61% (both) in examiner-based Schiff Sensitivity score, and clinically significant reductions in tactile pain threshold; all reductions were statistically significant (P < 0.0001). Both treatment groups also exhibited significant reductions across all sensitivity measures at 1, 2, and 4 weeks (P ≤ 0.0059, Dentifrice A; P ≤ 0.0137, Dentifrice B).
RESUMEN
BACKGROUND: Studies in cystic fibrosis (CF) generally focus on inflammation present in the airway lumen. Little is known about inflammation occurring in the airway wall, the site ultimately destroyed in end-stage disease. OBJECTIVE: To test the hypothesis that inflammatory patterns in the lumen do not reflect those in the airway wall of children with CF. METHODS: Bronchoalveolar lavage (BAL) fluid and endobronchial biopsies were obtained from 46 children with CF and 16 disease-free controls. BAL cell differential was assessed using May-Gruenwald-stained cytospins. Area profile counts of bronchial tissue immunopositive inflammatory cells were determined. RESULTS: BAL fluid from children with CF had a predominance of neutrophils compared with controls (median 810×10(3)/ml vs 1×10(3)/ml, p<0.0001). In contrast, subepithelial bronchial tissue from children with CF was characterised by a predominance of lymphocytes (median 961 vs 717 cells/mm(2), p=0.014), of which 82% were (CD3) T lymphocytes. In chest exacerbations, BAL fluid from children with CF had more inflammatory cells of all types compared with those with stable disease whereas, in biopsies, only the numbers of lymphocytes and macrophages, but not of neutrophils, were higher. A positive culture of Pseudomonas aeruginosa was associated with higher numbers of T lymphocytes in subepithelial bronchial tissue (median 1174 vs 714 cells/mm(2), p=0.029), but no changes were seen in BAL fluid. Cell counts in BAL fluid and biopsies were positively correlated with age but were unrelated to each other. CONCLUSION: The inflammatory response in the CF airway is compartmentalised. In contrast to the neutrophil-dominated inflammation present in the airway lumen, the bronchial mucosa is characterised by the recruitment and accumulation of lymphocytes.
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Bronquios/patología , Fibrosis Quística/inmunología , Neumonía/complicaciones , Adolescente , Factores de Edad , Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Biopsia , Líquido del Lavado Bronquioalveolar/citología , Niño , Preescolar , Fibrosis Quística/complicaciones , Fibrosis Quística/patología , Fibrosis Quística/fisiopatología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Lactante , Subgrupos Linfocitarios/inmunología , Masculino , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/patología , Infecciones Oportunistas/fisiopatología , Neumonía/inmunología , Neumonía/patología , Neumonía/fisiopatología , Pruebas de Función Respiratoria , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Capacidad Vital/fisiologíaRESUMEN
BACKGROUND: The bronchial epithelium and underlying reticular basement membrane (RBM) have a close spatial and functional inter-relationship and are considered an epithelial-mesenchymal trophic unit (EMTU). An understanding of RBM development is critical to understanding the extent and time of appearance of its abnormal thickening that is characteristic of asthma. METHODS: RBM thickness and epithelial height were determined in histological sections of cartilaginous bronchi obtained postmortem from 47 preterm babies and infants (median age 40 weeks gestation (22 weeks gestation-8 months)), 40 children (2 years (1 month-17 years)) and 23 adults (44 (17-90) years) who had died from non-respiratory causes, and had no history of asthma. RESULTS: The RBM was visible by light microscopy at 30 weeks gestation. RBM thickness increased in successive age groups in childhood; in infants (r=0.63, p<0.001) and in children between 1 month and 17 years (r=0.82, p<0.001). After 18 years, RBM thickness decreased with increasing age (r=-0.42, p<0.05). Epithelial height showed a similar relationship with age, a positive relationship from preterm to 17 years (r=0.50, p<0.001) and a negative relationship in adulthood (r=-0.84, p<0.0001). There was a direct relationship between epithelial height and RBM thickness (r=0.6, p<0.001). CONCLUSIONS: The RBM in these subjects was microscopically identifiable by 30 weeks gestation. It thickened during childhood and adolescence. In adults, there was either no relationship with age, or a slow reduction in thickness in older age. Developmental changes of RBM thickness were accompanied by similar changes in epithelial height, supporting the close relationship between RBM and epithelium within the EMTU.
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Bronquios/crecimiento & desarrollo , Mucosa Respiratoria/crecimiento & desarrollo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Membrana Basal/anatomía & histología , Membrana Basal/crecimiento & desarrollo , Estatura/fisiología , Peso Corporal/fisiología , Bronquios/anatomía & histología , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Persona de Mediana Edad , Mucosa Respiratoria/anatomía & histología , Caracteres Sexuales , Adulto JovenRESUMEN
BACKGROUND: Relationships between early deficits of lung function, infant airway pathology and outcome in symptomatic infants are unclear. A study was undertaken to determine the associations between early lung function, airway histology and inflammation in symptomatic infants with the continuance of respiratory symptoms, lung function and subsequent use of inhaled asthma medication at the age of 3 years. METHODS: 53 children who underwent lung function measurements and bronchoscopy following referral to a specialist children's hospital for recurrent lower respiratory symptoms at a mean age of 1 year were followed up at 3 years of age. Assessments were made of respiratory symptoms during the previous year, lung function by oscillometry and atopy by skin prick testing. Individual data on the purchase of asthma medications were obtained from the Social Insurance Institution for the 12 months preceding the follow-up visit. RESULTS: 50 children (94%) were re-evaluated, of whom 40 had ongoing airway symptoms. 11/39 (28%) who underwent successful oscillometry had reduced lung function, 31/50 (62%) used inhaled corticosteroids (ICS) regularly and 12/50 (24%) used ICS intermittently. Abnormal lung function at infancy was associated with ongoing airway symptoms (p<0.001) and with the purchase of ICS (p=0.009) and ß agonists (p=0.002). Reticular basement membrane thickness in infancy and the numbers of mucosal mast cells, but not eosinophils, correlated significantly with the amount of ICS purchased at 3 years (p=0.003 and p=0.018, respectively). CONCLUSIONS: Reduced lung function, thickening of the reticular basement membrane and increased density of mucosal mast cells in infancy are associated with respiratory morbidity and treatment needs at age 3 years in this highly selected group of children.
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Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Asma/fisiopatología , Pulmón/fisiopatología , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/patología , Membrana Basal/patología , Biopsia , Bronquios/patología , Broncodilatadores/uso terapéutico , Broncoscopía , Budesonida/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Hipersensibilidad Inmediata/fisiopatología , Lactante , Masculino , Pronóstico , Mucosa Respiratoria/patología , Ruidos Respiratorios/fisiopatología , Pruebas CutáneasRESUMEN
Pulmonary disease is the most important cause of morbidity and mortality in cystic fibrosis (CF). Most patients with CF die from respiratory failure with extensive airway destruction. Airway remodelling, defined as structural airway wall changes, begins early in life in CF but the sequence of remodelling events in the disease process is poorly understood. Airway remodelling in CF has traditionally been thought to be solely the consequence of repeated cycles of inflammation and infection. However, new evidence obtained from developmental, physiological and histopathological studies suggests that there might instead be multiple mechanisms leading to airway remodelling in CF including (1) changes related to infection and inflammation; (2) changes specific to CF as a result of CF transmembrane conductance regulator (CFTR) dysfunction in the airway wall, independent of infection and inflammation; and (3) protective responses to (1) and/or (2). Recent advances in bronchoscopic techniques have allowed airway mucosal (endobronchial) biopsies to be taken in children and even infants. Endobronchial biopsy studies may provide insight into the role and relative contribution of the different mechanisms of airway remodelling in CF, with the main limitation that they assess only changes in proximal large airways and not in peripheral small airways from where CF disease is thought to originate. Findings from biopsy studies could encourage the development of novel therapeutic strategies targeting structural changes in addition to infection and inflammation.
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Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Fibrosis Quística/fisiopatología , Neumonía/etiología , Adolescente , Adulto , Biopsia , Bronquios/patología , Niño , Preescolar , Fibrosis Quística/complicaciones , Fibrosis Quística/patología , Humanos , Lactante , Recién Nacido , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/patología , Neumonía/patología , Neumonía/fisiopatología , Adulto JovenRESUMEN
The relative roles of the endosomal TLR3/7/8 versus the intracellular RNA helicases RIG-I and MDA5 in viral infection is much debated. We investigated the roles of each pattern recognition receptor in rhinovirus infection using primary bronchial epithelial cells. TLR3 was constitutively expressed; however, RIG-I and MDA5 were inducible by 8-12 h following rhinovirus infection. Bronchial epithelial tissue from normal volunteers challenged with rhinovirus in vivo exhibited low levels of RIG-I and MDA5 that were increased at day 4 post infection. Inhibition of TLR3, RIG-I and MDA5 by siRNA reduced innate cytokine mRNA, and increased rhinovirus replication. Inhibition of TLR3 and TRIF using siRNA reduced rhinovirus induced RNA helicases. Furthermore, IFNAR1 deficient mice exhibited RIG-I and MDA5 induction early during RV1B infection in an interferon independent manner. Hence anti-viral defense within bronchial epithelium requires co-ordinated recognition of rhinovirus infection, initially via TLR3/TRIF and later via inducible RNA helicases.