RESUMEN
INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a common clinical syndrome with high mortality and long-term morbidity. To date there is no effective pharmacological therapy. Aspirin therapy has recently been shown to reduce the risk of developing ARDS, but the effect of aspirin on established ARDS is unknown. METHODS: In a single large regional medical and surgical ICU between December 2010 and July 2012, all patients with ARDS were prospectively identified and demographic, clinical, and laboratory variables were recorded retrospectively. Aspirin usage, both pre-hospital and during intensive care unit (ICU) stay, was included. The primary outcome was ICU mortality. We used univariate and multivariate logistic regression analyses to assess the impact of these variables on ICU mortality. RESULTS: In total, 202 patients with ARDS were included; 56 (28%) of these received aspirin either pre-hospital, in the ICU, or both. Using multivariate logistic regression analysis, aspirin therapy, given either before or during hospital stay, was associated with a reduction in ICU mortality (odds ratio (OR) 0.38 (0.15 to 0.96) P = 0.04). Additional factors that predicted ICU mortality for patients with ARDS were vasopressor use (OR 2.09 (1.05 to 4.18) P = 0.04) and APACHE II score (OR 1.07 (1.02 to 1.13) P = 0.01). There was no effect upon ICU length of stay or hospital mortality. CONCLUSION: Aspirin therapy was associated with a reduced risk of ICU mortality. These data are the first to demonstrate a potential protective role for aspirin in patients with ARDS. Clinical trials to evaluate the role of aspirin as a pharmacological intervention for ARDS are needed.
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Aspirina/uso terapéutico , Unidades de Cuidados Intensivos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Mortalidad Hospitalaria , Humanos , Oportunidad Relativa , Estudios Prospectivos , Análisis de Regresión , Síndrome de Dificultad Respiratoria/mortalidad , RiesgoRESUMEN
Studies of potential biomarkers of acute lung injury (ALI) have provided information relating to the pathophysiology of the mechanisms of lung injury and repair. The utility of biomarkers remains solely among research tools to investigate lung injury and repair mechanisms. Because of lack of sensitivity and specificity, they cannot be used in decision making in patients with ALI or acute respiratory distress syndrome. The authors reviewed known biomarkers in context of their major biologic activity. The continued interest in identifying and studying biomarkers is relevant, as it provides information regarding the mechanisms involved in lung injury and repair and how this may be helpful in identifying and designing future therapeutic targets and strategies and possibly identifying a sensitive and specific biomarker.
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Lesión Pulmonar Aguda/sangre , Citocinas/sangre , Inflamación/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Lesión Pulmonar Aguda/metabolismo , Biomarcadores/sangre , Biomarcadores/metabolismo , Coagulación Sanguínea , Citocinas/metabolismo , Endotelio/metabolismo , Epitelio/metabolismo , Fibrinólisis , Humanos , Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Alveolos Pulmonares/metabolismoRESUMEN
INTRODUCTION: Oral yeasts are an important component of the resident microbial ecology of the oral cavity, but they are also associated with various forms of oral candidosis, such as denture stomatitis. Although Candida albicans is the predominant oral fungal pathogen, other species may also play an integral role in pathogenesis. The aim of this study was to examine the mycological ecology in patients with denture stomatitis, using an improved sampling technique, to determine whether species diversity and species quantity were related to oral pathology. METHODS: Thirty-seven patients attending the Glasgow Dental Hospital were enrolled in this study following informed consent. A full clinical history was obtained, including details of their oral hygiene practices and the levels of erythema based on Newton's classification scale. Oral rinse, denture sonicate, and swab samples were taken, which were processed for quantitative and qualitative analysis of oral yeasts. RESULTS: The proportion of patients with no inflammation or Newton's Types I, II, and III were 31, 33, 25, and 14%, respectively. Denture sonication was a superior sampling procedure, with statistically greater quantities of yeasts isolated using this methodology (P < 0.01). The predominant oral yeasts isolated were C. albicans (75%) and Candida glabrata (30%), which were isolated in higher proportions in patients with the highest grades of inflammation (100 and 80%), and in combination from 80% of these patients. CONCLUSIONS: This study has demonstrated that mixed C. albicans and C. glabrata biofilms may play an important role in the pathogenesis associated with severe inflammation in denture wearers.
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Candida albicans/aislamiento & purificación , Candida glabrata/aislamiento & purificación , Candidiasis Bucal/diagnóstico , Estomatitis Subprotética/microbiología , Anciano , Anciano de 80 o más Años , Biopelículas , Candidiasis Bucal/clasificación , Estudios de Cohortes , Recuento de Colonia Microbiana , Limpiadores de Dentadura/uso terapéutico , Dentadura Completa/microbiología , Eritema/microbiología , Humanos , Hiperplasia , Persona de Mediana Edad , Higiene Bucal , Saccharomyces cerevisiae/aislamiento & purificación , Fumar , Estomatitis Subprotética/clasificación , Cepillado DentalRESUMEN
Gene transcripts and enzyme activities were quantified for a selection of functionally important aminopeptidases at 2-day intervals throughout the first 72 days of development in the Pacific oyster Crassostrea gigas. Leucine aminopeptidase (LAP) and cathepsin B (CathB) gene transcripts were quantified using fluorogenic ('real time') PCR. LAP and CathB gene transcripts were detected at all time points. The proportion of CathB transcripts remained essentially constant and low throughout development (Ct<35). The proportion of LAP transcripts was often similar (Ct<30), but with a distinct peak in transcript abundance at day 19 (Ct approximately 23). CathB and cathepsin D (CathD) enzyme activities were measured biochemically. Whilst CathD activity peaked at day 19, LAP and CathB activities both peaked at day 24. The closely coupled increase in transcript and enzyme activity for LAP indicates regulation at the transcriptional level. Alternatively, the peak in enzyme activity for CathB without enhanced transcriptional activity suggests post-transcriptional regulation. Similar mechanisms of regulation for LAP and CathB have been observed in both plants and mammals, indicating widespread conservation.
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Catepsina B/metabolismo , Catepsina D/metabolismo , Leucil Aminopeptidasa/metabolismo , Ostreidae/enzimología , Transcripción Genética , Animales , Catepsina B/genética , Catepsina D/genética , Cartilla de ADN , Activación Enzimática , Regulación del Desarrollo de la Expresión Génica , Leucil Aminopeptidasa/genética , Ostreidae/genética , Ostreidae/crecimiento & desarrolloRESUMEN
On the basis of histamine release from rat peritoneal mast cells, an octadecapeptide was isolated from the skin extract of the Northern Leopard frog (Rana pipiens). This peptide was purified to homogeneity using reversed-phase high performance liquid chromatography and found to have the following primary structure by Edman degradation and pyridylethylation: LVRGCWTKSYPPKPCFVR, in which Cys(5) and Cys(15) are disulfide bridged. The peptide was named peptide leucine-arginine (pLR), reflecting the N- and C-terminal residues. Molecular modeling predicted that pLR possessed a rigid tertiary loop structure with flexible end regions. pLR was synthesized and elicited rapid, noncytolytic histamine release that had a 2-fold greater potency when compared with one of the most active histamine-liberating peptides, namely melittin. pLR was able to permeabilize negatively charged unilamellar lipid vesicles but not neutral vesicles, a finding that was consistent with its nonhemolytic action. pLR inhibited the early development of granulocyte macrophage colonies from bone marrow stem cells but did not induce apoptosis of the end stage granulocytes, i.e. mature neutrophils. pLR therefore displays biological activity with both granulopoietic progenitor cells and mast cells and thus represents a novel bioactive peptide from frog skin.
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Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Arginina/química , Leucina/química , Péptidos/química , Péptidos/farmacología , Adyuvantes Inmunológicos/aislamiento & purificación , Secuencia de Aminoácidos , Animales , Arginina/aislamiento & purificación , Calcio/metabolismo , Cromatografía en Agarosa , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Cisteína/química , Bases de Datos Factuales , Relación Dosis-Respuesta a Droga , Histamina/metabolismo , Humanos , L-Lactato Deshidrogenasa/metabolismo , Leucina/aislamiento & purificación , Mastocitos/metabolismo , Meliteno/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Neutrófilos/metabolismo , Biosíntesis de Péptidos , Péptidos/aislamiento & purificación , Unión Proteica , Conformación Proteica , Rana pipiens , Análisis de Secuencia de Proteína , Piel/química , Temperatura , Factores de TiempoRESUMEN
The aim of this study was to compare the concentrations of itraconazole in serum and saliva after treatment with itraconazole cyclodextrin solution or itraconazole capsules in Candida-associated denture stomatitis patients without evidence of immunodeficiency. Forty patients were randomly assigned to receive either itraconazole cyclodextrin solution or itraconazole capsules, both at a dosage of 100 mg bd for 15 days. On completion of treatment palatal erythema was assessed and an oral rinse and imprint cultures were collected. Serum and saliva samples were collected at the same time and itraconazole concentrations measured using reverse-phase high-performance liquid chromatography. Itraconazole susceptibilities of Candida albicans and Candida glabrata strains isolated at baseline were measured by a broth microdilution method. Serum itraconazole concentrations achieved did not differ significantly between the two preparations (P = 0.39) although a significantly higher number of patients in the itraconazole cyclodextrin group (P < 0.001) had detectable levels of itraconazole in their saliva compared with the capsule group. Mycologically cured patients had slightly, though not significantly (P = 0.28), higher serum itraconazole concentrations than those from whom yeasts were not eradicated. It was concluded that both formulations of itraconazole were equally effective in treatment of denture stomatitis. Among immunocompetent patients, the absorption of the liquid preparation is no greater than that of the capsules. Therapeutic success in this group was achieved with lower serum itraconazole concentrations than have been reported for immunocompromised groups.
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Antifúngicos/administración & dosificación , Antifúngicos/sangre , Candidiasis/tratamiento farmacológico , Itraconazol/administración & dosificación , Itraconazol/sangre , Estomatitis Subprotética/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candida/metabolismo , Candidiasis/sangre , Candidiasis/metabolismo , Candidiasis/microbiología , Cápsulas , Formas de Dosificación , Femenino , Humanos , Itraconazol/farmacocinética , Itraconazol/uso terapéutico , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Saliva/metabolismo , Soluciones , Estomatitis Subprotética/sangre , Estomatitis Subprotética/metabolismo , Estomatitis Subprotética/microbiologíaRESUMEN
This study investigated the efficacy of a cyclodextrin solution of itraconazole in the treatment of Candida-associated denture stomatitis. It was found that the liquid and capsule preparations of itraconazole were equally effective adjuncts in the treatment of this condition. However, the side effect profile indicates that capsules are the preferred formulation.
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Antifúngicos/uso terapéutico , Ciclodextrinas , Itraconazol/uso terapéutico , Estomatitis Subprotética/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antifúngicos/efectos adversos , Cápsulas , Química Farmacéutica , Femenino , Humanos , Itraconazol/efectos adversos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVES: To compare fluconazole capsules (50 mg daily for 14 days) and itraconazole capsules (100 mg daily for 15 days) in the treatment of denture stomatitis, using objective clinical and mycological outcome measures. METHODS: Twenty complete denture wearers with denture stomatitis were enrolled. At baseline, palatal erythema was measured with an electro-optical instrument, a denture disc specimen was collected from the fitting surface of the denture for culture and an oral rinse and imprint cultures were collected for mycological culture. Ten patients received fluconazole capsules (50 mg daily for 14 days) and 10 received itraconazole capsules (100 mg daily for 15 days). Palatal erythema was reassessed and the microbiological specimens re-collected on day 14. RESULTS: The most common form of denture stomatitis seen in this group of patients was Newton's Type II. All patients responded to advice to leave their dentures out at night but there was a poor overall improvement in denture hygiene. There was an objective reduction in palatal erythema following treatment with both fluconazole and itraconazole. A wide range of yeasts were isolated from the mouths of all the denture stomatitis patients before treatment. C. albicans was the most common isolate. A mycological cure was achieved in only five of the 20 patients, one in the fluconazole group and four in the itraconazole group. A further eight patients in the fluconazole group and three in the itraconazole group had reduced yeast counts by the second visit. CONCLUSION: Fluconazole and itraconazole were of comparable efficacy in the treatment of denture stomatitis, on the basis of reduction in palatal erythema and mycological culture.
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Antifúngicos/uso terapéutico , Candidiasis Bucal/tratamiento farmacológico , Dentadura Completa Superior/efectos adversos , Fluconazol/uso terapéutico , Itraconazol/uso terapéutico , Estomatitis Subprotética/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Candida/aislamiento & purificación , Candida albicans/aislamiento & purificación , Candidiasis Bucal/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estomatitis Subprotética/etiologíaRESUMEN
This study evaluated the sensitivity and reproducibility of an optical instrument, the Erythema Meter, for quantifying erythema of palatal mucosa. The instrument is based on the principle that haemoglobin in the vasculature selectively absorbs green light but has little effect on red light and allows derivation of an 'erythema index'. Non-clinical investigations were carried out by taking a series of Erythema Meter readings from each colour block on a red check-standard used by graphic artists for colour reproduction. For clinical assessment, 20 dentate patients with healthy palatal mucosa and 40 complete denture wearers (20 with denture stomatitis and 20 with healthy palatal mucosa) were enrolled, and palatal erythema determined both visually and using the Erythema Meter. Two weeks later the Erythema Meter readings for the 40 patients with healthy palatal mucosa were repeated, to allow assessment of the reproducibility of the Erythema Meter scores. The median erythema index was 12 (range 2-38) for dentate patients with healthy palatal mucosa and 5 (range 0-29) for denture wearers with healthy palatal mucosa. For denture stomatitis patients the median erythema index was 95 (range 36-117). The overall reproducibility coefficient was 88%. Visual scoring correlated poorly with the Erythema Meter scores for those with moderate degrees of erythema. The Erythema Meter provides an objective and reproducible means of measuring the degree of erythema of the palatal mucosa.
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Colorimetría/instrumentación , Eritema/diagnóstico , Mucosa Bucal/patología , Estomatitis Subprotética/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Dentadura Completa/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hueso Paladar , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estomatitis Subprotética/etiologíaRESUMEN
BACKGROUND: Multiple sensory neuropeptides are present in human airways and may contribute to diseases such as asthma. This study quantified and characterised substance P (SP), neurokinin A (NKA), and calcitonin gene related peptide (CGRP) immunoreactivity in bronchoalveolar lavage fluid in asthmatic and normal subjects. METHODS: Using specific radioimmunoassay (RIA), SP, NKA and CGRP were measured in bronchoalveolar lavage fluid from asthmatic subjects (n = 5), normal subjects (n = 5), atopic non-asthmatic subjects (n = 6), and asthmatic subjects four hours after allergen challenge (n = 12). Peptide immunoreactivity was characterised using high performance liquid chromatography (HPLC) and RIA. RESULTS: No SP or CGRP immunoreactivity was detected in any of the fractions from samples after extraction, HPLC, and RIA. Non-specific binding resulted in spurious SP immunoreactivity being detected in bronchoalveolar lavage fluid when no extraction process was employed. NKA was detected in significant amounts in asthmatic (median 550, range 425-625 pg/ml) and normal subjects (median 725, range 350-1425 pg/ml). The level of NKA was significantly higher in the asthmatic subjects after allergen challenge (median 750, range 350-1250 pg/ml) than in unchallenged asthmatic subjects (median 600, range 425-600 pg/ml, p < 0.01). CONCLUSIONS: Extraction and characterisation of peptides from bronchoalveolar lavage fluid must be performed to ensure that the measured immunoreactivity represents target peptide. NKA is present in bronchoalveolar lavage fluid in high concentrations and is the predominant tachykinin. The concentrations of NKA are similar in normal subjects and subjects with mild asthma.
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Asma/metabolismo , Líquido del Lavado Bronquioalveolar/química , Neuroquinina A/análisis , Adolescente , Adulto , Pruebas de Provocación Bronquial , Broncoconstrictores , Péptido Relacionado con Gen de Calcitonina/análisis , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Cloruro de Metacolina , Radioinmunoensayo , Estadísticas no Paramétricas , Sustancia P/análisisRESUMEN
BACKGROUND: Metachromatic cells obtained from asthmatic subjects demonstrate increased spontaneous and stimulated histamine release in vitro. Their ability to synthesize and store proinflammatory cytokines has focused renewed interest on their role in asthma. OBJECTIVE: The late asthmatic response provides a useful model of clinical asthma. The aim of the study was to examine metachromatic cell derived mediators and histamine releasability in vitro after in vivo allergen exposure in atopic subjects with and without asthma and relate them to the type of physiological response observed. METHODS: Bronchoalveolar lavage (BAL) cells were obtained 4 h after challenge from asthmatics exhibiting a single early response (EAR, n = 5), a dual response (LAR, n = 7), unchallenged (basal, n = 5), atopic non-asthmatic (ANA, n = 6) and non-atopic non-asthmatics (normal, n = 5). BAL histamine and tryptase concentrations and in vitro histamine release (HR) after stimulation with anti-IgE, allergen, A23187, conconavalin A and substance P were compared. RESULTS: Metachromatic cell numbers were lower in normal controls compared with all asthmatic groups and in LAR compared with EAR. Metachromatic cell derived mediators were higher in asthmatic compared with normal subjects. Spontaneous HR in LAR (20.5 +/- 5.0%) was lower than EAR (29.5 +/- 3.9%) and ANA (30.2 +/- 1.4%) (P < 0.05). No differences were seen in stimulated HR between EAR and LAR. HR in ANA stimulated with anti-IgE was greater than LAR (P < 0.05). HR in ANA stimulated with anti-IgE was greater than LAR (P < 0.05). After stimulation with ionophore A23187 (1 microM), release was greater in LAR compared with basal (P < 0.05) and no different at 5 microM. All subject groups responded to substance P (SP) but was significantly more in the asthmatic subjects compared to normal controls (P < 0.05). Allergen challenge did not modify the response of asthmatic subjects to SP. CONCLUSION: Functional differences in metachromatic cell reactivity are present in atopic subjects 4h after in vivo allergen exposure which relate to the physiological response observed after this time and suggest that there is ongoing metachromatic cell degranulation subjects who subsequently develop LAR.
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Alérgenos/inmunología , Asma/inmunología , Líquido del Lavado Bronquioalveolar/citología , Liberación de Histamina/inmunología , Adolescente , Adulto , Alérgenos/farmacología , Anticuerpos Antiidiotipos/farmacología , Basófilos/citología , Basófilos/efectos de los fármacos , Basófilos/metabolismo , Pruebas de Provocación Bronquial , Quimasas , Concanavalina A/farmacología , Femenino , Humanos , Mediadores de Inflamación/farmacocinética , Recuento de Leucocitos , Masculino , Mastocitos/citología , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Serina Endopeptidasas/farmacocinética , Sustancia P/farmacología , Factores de Tiempo , TriptasasRESUMEN
OBJECTIVE AND DESIGN: This study examined whether bradykinin and neurokinin A activate human pulmonary mast cells retrieved by bronchoalveolar lavage (BAL). SUBJECTS: BAL samples were obtained at routine bronchoscopy from 14 unpreselected patients. METHODS: Histamine release experiments were performed using substance P, neurokinin A, bradykinin (peptides 25 and 50 microM), compound 48/80 (0.75-10 micrograms/ml) and A23187 (1 microM). Statistical analyses were performed using the paired Student's t-test and Pearson's linear correlation coefficient. RESULTS: Compound 48/80 induced release was significantly lower than that induced by the other secretagogues (p < 0.05). Neurokinin A and bradykinin induced release correlated significantly with substance P induced release (p < 0.01), suggesting similar mechanisms of action. No correlations were observed between neurokinin A or bradykinin-induced release and the non-peptide stimuli studied. CONCLUSIONS: The mechanism of neurokinin A- and bradykinin-induced bronchoconstriction is not yet clear but our data suggest an indirect effect mediated by mast cell degranulation.
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Bradiquinina/farmacología , Líquido del Lavado Bronquioalveolar/citología , Liberación de Histamina , Mastocitos/efectos de los fármacos , Mastocitos/fisiología , Neuroquinina A/farmacología , Calcimicina/farmacología , Femenino , Humanos , Ionóforos/farmacología , Masculino , Persona de Mediana Edad , Sustancia P/farmacología , p-Metoxi-N-metilfenetilamina/farmacologíaAsunto(s)
Líquido del Lavado Bronquioalveolar/citología , Liberación de Histamina/efectos de los fármacos , Mastocitos/efectos de los fármacos , Sustancia P/toxicidad , Antibacterianos/farmacología , Antimetabolitos/farmacología , Antimicina A/farmacología , Asma/etiología , Asma/metabolismo , Tampones (Química) , Calcio/metabolismo , Tos/etiología , Tos/metabolismo , Desoxiglucosa/farmacología , Glucosa/farmacología , Humanos , Mastocitos/metabolismoRESUMEN
1. Neuropeptide-induced histamine release is thought to occur via receptor-independent mechanisms, with net charge and lipophilicity being important factors. 2. In this study, the histamine releasing ability of neuropeptide Y (NPY), two C-terminal segments of NPY and 13 centrally truncated NPY analogues was examined. These results were compared with the ability of the peptides to bind to the Y2 receptor in the rabbit kidney membrane model and with their hypotensive actions in the anaesthetized-rat model. 3. All analogues tested, with the exception of [Glu4,25,33,35]-NPY(1-4)-Ahx-(25-36) and [Asp4,25,33,35]NPY(1-4)-Ahx-(25-36) which were devoid of histamine releasing activity, evoked a dose-dependent histamine release but there were marked differences between the peptides. The native peptide was the least active. 4. Histamine release was not linked to the ability of the peptides to displace NPY from Y2 receptors. There was a statistical correlation between the hypotensive effects expressed as ED10 values (mumol kg-1, which induced a blood pressure decrease of 10 mmHg) and the EC25 for histamine release (r = 0.62, P = 0.04), although histamine release may not be the sole determinant of the alterations in blood pressure. 5. There was a strong negative correlation between EC25 for histamine release and net positive charge (r = -0.93, P = 5.7 x 10(-7), i.e. increasing the net positive charge caused greater histamine release. However, there was a 12 fold difference in activity amongst the most positively charged analogues (+5). Helicity did not correlate with histamine releasing ability. 6. In the development of NPY-related drugs the avoidance of compounds with net positive charge is recommended.
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Presión Sanguínea/efectos de los fármacos , Liberación de Histamina/efectos de los fármacos , Mastocitos/efectos de los fármacos , Neuropéptido Y/análogos & derivados , Neuropéptido Y/farmacología , Animales , Fenómenos Químicos , Química Física , Dicroismo Circular , Técnicas In Vitro , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Mastocitos/metabolismo , Conejos , Ratas , Receptores de Neuropéptido Y/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Mast cell activation by polycationic substances is believed to result from a direct activation of G protein alpha subunits and it was suggested that the adaption of amphipathic, alpha-helical conformations would allow the peptide to reach the cytosolic compartment to interact with G proteins (Mousli et al., 194, Immunopharmacology 27, 1, for review). We investigated the histamine-releasing activity of model peptides as well as analogues of magainin 2 amide and neuropeptide Y with different amphipathicities and alpha-helix content on rat peritoneal mast cells. Amphipathic helicity is not a prerequisite for mast cell activation. Moreover, non-helical magainin peptides with high histamine-releasing activity were less active in the liberation of carboxyfluoresceine from negatively charged liposomes, indicating that peptide-induced mast cell activation and peptide-induced membrane perturbation do not correlate. In contrast to the negligible influence of the secondary structure, amino acid configuration may exert a striking influence on peptide-induced mast cell activation. Thus histamine-release by substance P was markedly impaired when the L-amino acids in the positively charged N-terminal region were replaced by D-amino acids, with [D-Arg1)substance P being the most inactive substance P diastreoisomer.
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Péptidos Catiónicos Antimicrobianos , Liberación de Histamina/efectos de los fármacos , Mastocitos/efectos de los fármacos , Neuropéptido Y/análogos & derivados , Sustancia P/análogos & derivados , Proteínas de Xenopus , Secuencia de Aminoácidos , Animales , Liposomas , Magaininas , Mastocitos/metabolismo , Datos de Secuencia Molecular , Neuropéptido Y/farmacología , Péptidos/farmacología , Estructura Secundaria de Proteína , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sustancia P/farmacologíaRESUMEN
Substance P elicits histamine release from human skin and rodent mast cells. Since neuropeptide-mediated reflexes may be important in asthma, we examined the ability of substance P to stimulate human mast cells obtained at bronchoalveolar lavage (BAL). BAL samples were obtained at routine bronchoscopy from 35 non-preselected patients. Histamine release experiments were performed in a standard manner using substance P and the calcium ionophore A23187. Both substance P (50 microM) and A23187 caused histamine release (median 26.7% range 6.2-62.8% and 32.1%, 7.7-56.8% respectively) which was significantly greater (P < 0.0001) than the spontaneous release (median 15.6%, range 4.1-33.4%), i.e. that in the absence of any stimulus. Substance P induced histamine release was via an energy dependent process and was blocked by preincubation with antimycin A. A significant correlation was observed between substance P induced release and spontaneous release but was not observed with A23187 induced release. Mast cell counts correlated significantly with substance P induced release but not with spontaneous or A23187 induced release. The substance P induced histamine secretion was elicited at similar concentrations to those used with rodent and human skin mast cells. Asthma is associated with increased numbers of mast cells which have both increased spontaneous and stimulated secretory responses. Thus, in vivo, the bronchoconstrictor action of substance P may in part result from activation of mast cells in the bronchial lumen.
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Liberación de Histamina/efectos de los fármacos , Pulmón/fisiopatología , Mastocitos/efectos de los fármacos , Sustancia P/farmacología , Calcimicina/farmacología , Recuento de Células , Humanos , Masculino , Mastocitos/metabolismo , Persona de Mediana Edad , Enfermedades Respiratorias/fisiopatología , Fumar , Irrigación TerapéuticaRESUMEN
Substance P (SP) stimulates human skin and rodent mast cells. Since neuropeptide-mediated reflexes may be important in asthma, the ability of SP to stimulate human mast cells obtained at bronchoalveolar lavage (BAL) was examined. Routine BAL (n = 22) samples were obtained and histamine release experiments performed in a standard manner. Spontaneous histamine release was bimodally distributed (Group A, high spontaneous release/Group B, normal spontaneous release). Further, Group A had significantly elevated corrected SP-induced histamine release compared to Group B but the corrected calcium ionophore A23187-induced responses were similar. No differences were found in clinical history, age, lavage return or total cell numbers between groups. However, differential cell counts revealed significantly elevated mast cell numbers in Group A providing further evidence for altered mast cell responsivity associated with mast cell hyperplasia. In asthma, BAL mast cells have increased spontaneous and stimulated secretory responses; thus, in asthma SP may also stimulate pulmonary mast cells.
Asunto(s)
Líquido del Lavado Bronquioalveolar/citología , Mastocitos/efectos de los fármacos , Sustancia P/farmacología , Anciano , Calcimicina/farmacología , Femenino , Liberación de Histamina/efectos de los fármacos , Humanos , Técnicas In Vitro , Masculino , Mastocitos/metabolismo , Persona de Mediana EdadRESUMEN
This study investigated the relationship between the adaptation, apical location and gap width of the cervical margin of proximal amalgam restorations. Three hundred and seventeen proximal cervical margins were studied in 243 extracted teeth. The restorations were categorized as 'flush fitting'; 'small overhang', or 'large overhang', based on examination with a Cross calculus probe. After trimming the overhangs to make the restorations flush with the tooth surface, the gap width was measured. In addition, the location of the cavity margin was measured relative to the amelocemental junction (ACJ), and the data were further grouped according to whether the restoration finished apical to the ACJ, less than 1.5 mm coronal to it, or more than 1.5 mm coronal to it. All measurements were made with a Reflex Microscope. Analysis of variance with the Scheffé multiple range test indicated that: the mean gap width of large overhanging restorations was significantly greater than that of small overhanging or flush fitting restorations (P < 0.001); the mean gap width of restorations which finished on the root surface was significantly greater than that of those restorations which finished on the enamel surface at more than 1.5 mm from the ACJ (P < 0.002); and large overhanging restorations were located further apically than small overhanging restorations which were, in turn, located further apically than flush fitting restorations (P < 0.0001). Furthermore, discriminant analysis indicated that the location of the cervical margin had more influence on gap width than the presence of an overhang (R2 = 3.6%; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)