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1.
Dig Liver Dis ; 56(3): 468-476, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37770282

RESUMO

BACKGROUND AND AIMS: Hepatitis C virus (HCV) management in Inflammatory Bowel Disease (IBD) is uncertain. The ECCO guidelines 2021 recommended HCV treatment but warn about the risk of IBD reactivation. We aimed to evaluate 1) the effectiveness and safety of direct-acting antivirals (DAAs) in IBD; 2) the interaction of DAAs with IBD drugs. METHODS: Multicentre study of IBD patients and HCV treated with DAAs. Variables related to liver diseases and IBD, as well as adverse events (AEs) and drug interactions, were recorded. McNemar's test was used to assess differences in the proportion of active IBD during the study period. RESULTS: We included 79 patients with IBD and HCV treated with DAAs from 25,998 IBD patients of the ENEIDA registry. Thirty-one (39.2 %) received immunomodulators/biologics. There were no significant differences in the percentage of active IBD at the beginning (n = 11, 13.9 %) or at the 12-week follow-up after DAAs (n = 15, 19 %) (p = 0.424). Sustained viral response occurred in 96.2 % (n = 76). A total of 8 (10.1 %) AEs occurred and these were unrelated to activity, type of IBD, liver fibrosis, immunosuppressants/biologics, and DAAs. CONCLUSIONS: We demonstrate a high efficacy and safety of DAAs in patients with IBD and HCV irrespective of activity and treatment of IBD.


Assuntos
Produtos Biológicos , Hepatite C Crônica , Hepatite C , Doenças Inflamatórias Intestinais , Humanos , Antivirais/efeitos adversos , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C/tratamento farmacológico , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Produtos Biológicos/uso terapêutico
2.
Acta Ortop Mex ; 37(1): 19-24, 2023.
Artigo em Espanhol | MEDLINE | ID: mdl-37857393

RESUMO

INTRODUCTION: revision total knee arthroplasty (TKA) is a challenging procedure that requires proper alignment, restoration of bone loss, and prevention of instability. Modern revision systems offer progressive implant constriction with multiple options for offset, augmentation, and fixation stems. OBJECTIVE: to evaluate the clinical outcomes of a modular implant with hybrid fixation in revision TKA with a minimum follow-up of two years. MATERIAL AND METHODS: we retrospectively included all revision TKA surgeries performed between September 2018 and September 2019, using the same implant. Patient demographics, comorbidities, and data on bone defects were recorded. Clinical outcomes were assessed using subjective roles and Maudsley scores and the Knee Society Score (KSS). Complications during follow-up were also documented. RESULTS: a total of 23 patients were analyzed, comprising 65% females and 35% males, with a median age of 71.1 years. Bone defects following implant removal were classified as F2.T2 in 39.13% of cases, F1.T2 in 8.69%, and F1.T1 in the remaining 52.17%. There were significant improvements in the KSS score (preoperative: 53 points, postoperative: 79 points; p < 0.001). Three (13%) complications were reported, two of which were directly related to the surgery, and two patients required subsequent revision surgery. The 2-year survival rate was 91.3%. CONCLUSION: the use of a modular implant with hybrid fixation in revision TKA demonstrated a high 2-year survival rate, significant improvements in clinical scores, and a low incidence of short-term complications. These findings support the efficacy and safety of this approach, providing favorable clinical outcomes and high patient satisfaction.


INTRODUCCIÓN: la artroplastía total de rodilla (ATR) de revisión es un procedimiento desafiante que requiere alineación adecuada, restauración ósea y estabilidad. Los sistemas modernos de revisión ofrecen opciones de implantes modulares con fijación híbrida. OBJETIVO: evaluar los resultados clínicos de un implante modular de fijación híbrida con seguimiento mínimo de dos años. MATERIAL Y MÉTODOS: se incluyeron retrospectivamente cirugías de revisión de ATR realizadas entre Septiembre de 2018 y Septiembre de 2019 con el mismo implante. Se registraron datos demográficos, comorbilidades y se evaluaron los resultados clínicos utilizando puntuaciones subjetivas y la Knee Society Score (KSS). RESULTADOS: se analizaron 23 pacientes (65% mujeres, 35% hombres; edad mediana: 71.1 años). Los defectos óseos posteriores a la extracción del implante se clasificaron como F2.T2 en 39.13% de los casos, F1.T2 en 8.69%, y F1.T1 en 52.17%. Se observaron mejoras significativas en la puntuación de la KSS (preoperatoria: 53 puntos, postoperatoria: 79 puntos; p < 0.001). Se registraron tres (13%) complicaciones totales, dos relacionadas directamente con la cirugía, y dos casos requirieron una nueva cirugía de revisión. La tasa de supervivencia a los dos años fue de 91.3%. CONCLUSIÓN: el uso del implante modular con fijación híbrida en la revisión de ATR mostró una alta tasa de supervivencia a dos años, mejoras significativas en las puntuaciones clínicas y baja incidencia de complicaciones a corto plazo. Estos resultados respaldan la eficacia y seguridad de este enfoque, proporcionando resultados clínicos favorables y alta satisfacción del paciente.


Assuntos
Artroplastia do Joelho , Prótese do Joelho , Masculino , Feminino , Humanos , Idoso , Artroplastia do Joelho/métodos , Articulação do Joelho/cirurgia , Estudos Retrospectivos , Reoperação/métodos , Resultado do Tratamento
3.
Acta ortop. mex ; 37(1): 19-24, ene.-feb. 2023. tab, graf
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1556725

RESUMO

Resumen: Introducción: la artroplastía total de rodilla (ATR) de revisión es un procedimiento desafiante que requiere alineación adecuada, restauración ósea y estabilidad. Los sistemas modernos de revisión ofrecen opciones de implantes modulares con fijación híbrida. Objetivo: evaluar los resultados clínicos de un implante modular de fijación híbrida con seguimiento mínimo de dos años. Material y métodos: se incluyeron retrospectivamente cirugías de revisión de ATR realizadas entre Septiembre de 2018 y Septiembre de 2019 con el mismo implante. Se registraron datos demográficos, comorbilidades y se evaluaron los resultados clínicos utilizando puntuaciones subjetivas y la Knee Society Score (KSS). Resultados: se analizaron 23 pacientes (65% mujeres, 35% hombres; edad mediana: 71.1 años). Los defectos óseos posteriores a la extracción del implante se clasificaron como F2.T2 en 39.13% de los casos, F1.T2 en 8.69%, y F1.T1 en 52.17%. Se observaron mejoras significativas en la puntuación de la KSS (preoperatoria: 53 puntos, postoperatoria: 79 puntos; p < 0.001). Se registraron tres (13%) complicaciones totales, dos relacionadas directamente con la cirugía, y dos casos requirieron una nueva cirugía de revisión. La tasa de supervivencia a los dos años fue de 91.3%. Conclusión: el uso del implante modular con fijación híbrida en la revisión de ATR mostró una alta tasa de supervivencia a dos años, mejoras significativas en las puntuaciones clínicas y baja incidencia de complicaciones a corto plazo. Estos resultados respaldan la eficacia y seguridad de este enfoque, proporcionando resultados clínicos favorables y alta satisfacción del paciente.


Abstract: Introduction: revision total knee arthroplasty (TKA) is a challenging procedure that requires proper alignment, restoration of bone loss, and prevention of instability. Modern revision systems offer progressive implant constriction with multiple options for offset, augmentation, and fixation stems. Objective: to evaluate the clinical outcomes of a modular implant with hybrid fixation in revision TKA with a minimum follow-up of two years. Material and methods: we retrospectively included all revision TKA surgeries performed between September 2018 and September 2019, using the same implant. Patient demographics, comorbidities, and data on bone defects were recorded. Clinical outcomes were assessed using subjective roles and Maudsley scores and the Knee Society Score (KSS). Complications during follow-up were also documented. Results: a total of 23 patients were analyzed, comprising 65% females and 35% males, with a median age of 71.1 years. Bone defects following implant removal were classified as F2.T2 in 39.13% of cases, F1.T2 in 8.69%, and F1.T1 in the remaining 52.17%. There were significant improvements in the KSS score (preoperative: 53 points, postoperative: 79 points; p < 0.001). Three (13%) complications were reported, two of which were directly related to the surgery, and two patients required subsequent revision surgery. The 2-year survival rate was 91.3%. Conclusion: the use of a modular implant with hybrid fixation in revision TKA demonstrated a high 2-year survival rate, significant improvements in clinical scores, and a low incidence of short-term complications. These findings support the efficacy and safety of this approach, providing favorable clinical outcomes and high patient satisfaction.

4.
O.F.I.L ; 31(4): 386-391, 2021.
Artigo em Espanhol | IBECS | ID: ibc-224754

RESUMO

Objetivos: Implantar un programa de optimización del uso de antimicrobianos (PROA) para intervenir en el uso de antimicrobianos. Analizar el impacto de las intervenciones mediante indicadores basados en el consumo.Métodos: Fase 1. Creación equipo PROA: nombramiento; asesoramiento externo; formación; desarrollo programa informático. Fase 2. Análisis indicadores de consumo: estudio retrospectivo de intervención cuasi-experimental con evaluación pre-post: se evaluaron los indicadores del uso de antimicrobianos basados en el consumo en fase no-intervención y en fase intervención. El programa PROA consistió en un modelo de intervención no restrictivo.Resultados: Se formó e implantó el equipo PROA como órgano estructural y organizativo para la consulta, intervención y vigilancia del uso de antimicrobianos. Durante la fase intervención se realizaron 134 recomendaciones: terapia secuencial (12,69%), cambio de antimicrobiano/desescalada terapéutica (31,34%), suspensión de tratamiento antimicrobiano (55,97%); el grado de aceptación fue del 67,16%. Se analizaron 13 indicadores. En 11 de ellos se observó mejoría: consumo global antibacterianos (-2,26%), consumo global antifúngicos sistémicos (-40,60%), consumo carbapenémicos (-22,63%), consumo fluoroquinolonas (-16,52%), ratio macrólidos i.v./fluoroquinolonas respiratorias i.v. (17,49%), ratio metronidazol/carbapenémicos + piperacilina-tazobactam (15,82%), consumo fosfomicina (69,21%), ratio agentes anti-SASM/agentes anti-SARM (45,14%), ratio amoxicilina-clavulánico/piperacilina-tazobactam (24,38%), diversificación betalactámicos antipseudomónicos (7,61%), ratio fluconazol/equinocandinas (8,74%). Los indicadores en los que se obtuvo resultado negativo fueron: terapia secuencial (-8,89%), ratio amoxicilina/amoxicilina-clavulánico (-4,03%). ... (AU)


Objectives: Implementation of a program for optimizing the use of antibiotics (PROA) to manage the use of antimicrobials. Analyse the impact through indicators based on consumption.Methods: Phase 1. Creation of PROA: appointment; external advice; training; software development. Phase 2. Consumption indicators analysis: interventional, quasi-experimental, retrospective study with pre-post evaluation: indicators based on consumption were evaluated in non-intervention phase and in intervention phase. PROA consisted of a non-restrictive intervention model.Results: PROA was formed and implemented as a structural and managing body for the advice, intervention and monitoring of the use of antimicrobials. During the intervention phase, 134 recommendations related to sequential therapy IV/PO (12.69%), change of antimicrobial/de-escalation (31.34%), discontinuation of antimicrobial treatment (55.97%) were made; the degree of acceptance was 67.16%. 13 indicators based on consumption were analysed. 11 of them led to an improvement: antibacterials global consumption (-2.26%), systemic antifungals global consumption (-40.60%), carbapenems consumption (-22.63%), fluoroquinolones consumption (-16.52%), macrolide IV/ respiratory fluoroquinolones IV ratio (17.49%), metronidazole/carbapenem + piperacillin-tazobactam ratio (15.82%), fosfomycin consumption (69.21%), anti-MSSA agents/anti-MRSA agents ratio (45.14%), amoxicillin-clavulanic/piperacillin-tazobactam ratio (24.38%), diversification antipseudomonic beta-lactam (7.61%), fluconazole/echinocandins ratio (8.74%). Indicators with negative result were: sequential therapy IV/PO (-8.89%), amoxicillin/amoxicillin-clavulanic ratio (-4.03%). ... (AU)


Assuntos
Humanos , Gestão de Antimicrobianos , Anti-Infecciosos/uso terapêutico , Antibacterianos , Automedicação , Indicadores de Qualidade em Assistência à Saúde
6.
Rev. esp. pediatr. (Ed. impr.) ; 71(6): 339-343, nov.-dic. 2015. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-148698

RESUMO

La gastroenterologia pediátrica es una especialidad amplia que incluye las patologías del tubo digestivo, pancreas e hígado, ademas de la nutrición infantil. En los ultimos años, ha adquirido relevancia la realización de técnicas complementarias como la endoscopia digestiva, la videofluoroscopia y el analisis corporal por impedanciometría. La Unidad de Gastroenterologia, Hepatologia y Nutrición Pediátrica del Hospital Infantil Miguel Servet es Unidad de referencia de la Comunidad de Aragón. En este artículo se refleja la estructura, pruebas complementarias y la actividad asistencial, docente e investigadora (AU)


Pediatric Gastroenterology and Nutrition is an intricate speciality that involves the gastrointestinal tract, liver and pancreas pathologies, but also, the children’s nutrition. In our speciality, every year it’s becoming more important to perform examination procedures, as endoscopy, videofluoroscopy or bioelectrical impedance analysis. The Miguel Servet Children’s Hospital Pediatric Gastroenterology, Hepatology and Nutrition Unit is a reference unit in the Aragon Community. This paper shows the Unit structure, the examination procedures and our teaching and research activity (AU)


Assuntos
Humanos , Masculino , Feminino , Criança , Gastroenterologia/educação , Hospitais Pediátricos/organização & administração , Fibrose Cística/genética , Estágio Clínico/métodos , Endoscopia do Sistema Digestório/métodos , Nutrição Parenteral/enfermagem , Hepatopatias/patologia , Gastroenterologia/métodos , Gastroenterologia , Hospitais Pediátricos/história , Fibrose Cística/metabolismo , Estágio Clínico/normas , Endoscopia do Sistema Digestório , Nutrição Parenteral/normas , Hepatopatias/metabolismo
7.
An. sist. sanit. Navar ; 32(3): 423-437, sept.-dic. 2009. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-81678

RESUMO

Los bisfosfonatos son unos fármacos ampliamenteutilizados principalmente para la osteoporosis y tambiénen oncología. Un efecto secundario o complicación delos mismos, desconocida hasta el año 2003, es la osteonecrosisde los maxilares. Se revisan, en este trabajo, lascaracterísticas químicas de los distintos bisfosfonatos,su posible mecanismo de acción, la potencia relativa, losproductos comerciales existentes en el mercado farmacéuticoespañol y sus indicaciones; igualmente se repasala osteonecrosis de los maxilares en sus comienzos, suconcepto, sus estadios clínicos, la razón por la que estapatología aparece en los maxilares, sus factores de riesgo,su incidencia, la actitud a tomar por los dentistas conlos pacientes que toman bisfosfonatos, el tratamiento yla posible predicción de la osteonecrosis(AU)


Bisphosphonates are widely used drugs, primarilyfor osteoporosis and also in oncology. A drug-inducedside effect or complication, which only recently cameto light in 2003, is osteonecrosis of the jaw. This studyreviews the chemical characteristics of the variousbisphosphonates, their possible mechanism of action,relative potency, the commercial products available onthe spanish pharmaceutical market and the indicationsfor bisphosphonate treatment. The study also considersosteonecrosis of the jaw with regard to its onset,concept, clinical stages, why this pathology affects thejaws, its risk factors, incidence, the attitude to be adoptedby dentists with patients taking bisphosphonates, aquick review of the treatment and the possible predictionof osteonecrosis(AU)


Assuntos
Humanos , Difosfonatos/efeitos adversos , Osteonecrose/induzido quimicamente , Doenças Maxilares/induzido quimicamente , Osteoporose/complicações , Osteoporose/tratamento farmacológico , Fatores de Risco
8.
An Sist Sanit Navar ; 32(3): 413-21, 2009.
Artigo em Espanhol | MEDLINE | ID: mdl-20094102

RESUMO

Bisphosphonates are widely used drugs, primarily for osteoporosis and also in oncology. A drug-induced side effect or complication, which only recently came to light in 2003, is osteonecrosis of the jaw. This study reviews the chemical characteristics of the various bisphosphonates, their possible mechanism of action, relative potency, the commercial products available on the spanish pharmaceutical market and the indications for bisphosphonate treatment. The study also considers osteonecrosis of the jaw with regard to its onset, concept, clinical stages, why this pathology affects the jaws, its risk factors, incidence, the attitude to be adopted by dentists with patients taking bisphosphonates, a quick review of the treatment and the possible prediction of osteonecrosis.


Assuntos
Difosfonatos/efeitos adversos , Doenças Maxilomandibulares/induzido quimicamente , Osteonecrose/induzido quimicamente , Idoso , Feminino , Humanos , Pessoa de Meia-Idade
9.
An. sist. sanit. Navar ; 25(1): 59-69, ene. 2002. tab, graf
Artigo em Es | IBECS | ID: ibc-20166

RESUMO

El objetivo del presente trabajo es dar a conocer las causas de las extracciones dentales en el Servicio Navarro de Salud-Osasunbidea (SNS-O). Durante 6 meses se registraron todas las extracciones dentales realizadas en las consultas de Odontología del SNS-O en Pamplona. Se registraron datos por cada extracción realizada. Se anotó la edad y sexo del paciente, el diente extraído y la causa de la exodoncia. Las causas que se consideraron fueron: periodoncia, caries, mixta, ortodoncia, fractura y otras. Se realizaron 4.259 extracciones; el 62,1 por ciento se efectuaron en hombres y el 37,9 por ciento en mujeres (proporción diferente de la población general, p < 0,0001). La edad media fue 53,14 años (DE = 16,77 años; IC 95 por ciento: 52,62 a 53,66 años). Se extrajeron por caries el 49,9 por ciento, por causas periodontales el 33,7 por ciento, por causas mixtas el 3,6 por ciento, por ortodoncia el 1,6 por ciento, por fractura el 0,7 por ciento, por otras causas el 10,4 por ciento. Hubo diferencias estadísticamente significativas en la distribución por sexos de las exodoncias por causa periodontal (p = 0,0001), ortodoncia (p < 0,0001) y otras causas (p = 0,0009). La edad media de las exodoncias por periodoncia, acumuladas en dientes anteriores, fue mayor que por caries (p < 0,0001), acumuladas en dientes posteriores. La edad media de las exodoncias por ortodoncia fue de 20,16 años (p < 0,0001 con todas las demás causas). (AU)


Assuntos
Adolescente , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Criança , Humanos , Cirurgia Bucal/estatística & dados numéricos , Extração Dentária/estatística & dados numéricos , Fraturas dos Dentes/complicações , Cárie Dentária/complicações , Espanha/epidemiologia , Distribuição por Idade , Centros de Saúde
10.
An Sist Sanit Navar ; 25(1): 59-69, 2002.
Artigo em Espanhol | MEDLINE | ID: mdl-12861304

RESUMO

The aim of this paper is to show the causes of the dental extractions in the Navarra Health Service-Osasunbidea. For 6 months all the dental extractions carried out in the clinics of the Navarra Health Service in Pamplona were registered. Data was registered for each extraction carried out. A note was made of the age and sex of the patient, the tooth extracted and the cause of the exodontia. The causes considered were: periodontia, caries, mixed causes, orthodontia, fracture and others. 4,259 extractions were carried out; 62.1% were on men and 37.9% on women (significatively different from the general population, p < 0.0001). The average age was 53.14 years (SD = 16.77 years, 95% CI: 52.62 to 53.66 years). 49.9% of extractions were due to caries, 33.7% for periodontal reasons, 3.6% for mixed causes, 1.6% for orthodontia, 0.7% because of fracture, and 10.4% for other causes. There were statistically significant differences in the distribution by sexes of the exodontias due to periodontia (p = 0.0001), orthodontia (p < 0.0001) and other causes ((p = 0.0009). The average age of the exodontias due to periodontia, accumulated in the front teeth, was greater than that for caries (p < 0.0001), accumulated in the back teeth. The average age of the exodontias due to orthodontia was 20.16 years (p < 0.0001 with all of the other causes).

13.
J Neurochem ; 77(3): 896-903, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11331418

RESUMO

In the gustatory system, the recognition of sugars, amino acids and bitter-tasting compounds is the function of specialized G protein-coupled receptors. Recently, two members of novel subfamily of G protein-coupled receptors were proposed to function as taste receptors based on their specific expression in taste receptor cells. Here, we report the identification of a third member, T1R3, of this family of receptors. T1R3 maps near the telomere of mouse chromosome 4 rendering it a candidate for the Sac locus, a primary determinant of sweet preference in mice. Consistent with its candidacy for the Sac locus, T1R3 displays taste receptor cell-specific expression. In addition, taster and non-taster strains of mouse harbor different alleles of T1R3.


Assuntos
Receptores de Superfície Celular/análise , Receptores Acoplados a Proteínas G , Paladar , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico , Expressão Gênica , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Mucosa Olfatória/química , Sinais Direcionadores de Proteínas , Ratos , Receptores de Superfície Celular/química , Receptores de Superfície Celular/genética , Alinhamento de Sequência , Paladar/genética , Papilas Gustativas/química , Língua/citologia
14.
Acta pediatr. esp ; 58(7): 397-401, jul. 2000. tab
Artigo em Es | IBECS | ID: ibc-9750

RESUMO

Objetivo: Evaluar nutricionalmente una fórmula de bajo grado de hidrólisis proteica (FBGH). Material y métodos: Se realiza un estudio comparativo de un grupo de lactantes alimentados con una fórmula FBGH a base de hidrolizado de proteínas del suero (grupo FBGH) (n= 31) con un grupo control alimentado con lactancia materna (grupo LM) (n= 16). Se compara entre ambos grupos el peso, talla, perímetro craneal (PC) y braquial (PB) a la edad de recién nacido, 1, 2 y 4 meses. Asimismo, se llevó a cabo un estudio bioquímico del estado nutricional proteico a la edad de 4 meses mediante determinación de prealbúmina, proteína por cientofiadora del retinol, fibronectina y somatomedina-C, y nivel de aminoácidos en sangre. Resultados: No se encontraron diferencias significativas en la evaluación antropométrica entre el grupo FBGH y el LM. Las proteínas de vida media corta investigadas eran más elevadas en el grupo FBGH, siendo esto especialmente significativo para la prealbúmina (17,8 ñ 5,7 frente al 14,7 ñ 4 mg/100 mL del grupo LM; p= 0,025). Por otra parte, se han registrado diferencias significativas en el nivel de metionina en sangre a la edad de 4 meses entre el grupo FBGH (22,3 ñ 16,8 umol/ L) y el LM (14,7 ñ 10,6 umol/L) (p= 0,025). Asimismo, se observa una diferencia casi significativa entre la cifra de treonina en el grupo FBGH (125,9 ñ 61,9 umol/L) y el LM (103,83 ñ 52 umol/L) (p= 0,08). Conclusiones: Las diferencias encontradas en los niveles de aminoácidos y de proteínas de vida media corta entre el grupo FBGH y el LM hacen necesario que la administración de estos alimentos especiales se controle desde el punto de vista nutricional y se restrinja su indicación a las situaciones clínicas que lo precisen (AU)


Assuntos
Lactente , Humanos , Recém-Nascido , Alimentos Formulados , Hidrólise , Proteínas , Estudos de Casos e Controles , Estado Nutricional , Pré-Albumina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Aminoácidos/sangue , Metionina/sangue , Treonina/sangue , Fibronectinas/sangue , Aleitamento Materno , Peso-Estatura , Circunferência Braquial , Proteínas de Ligação ao Retinol/metabolismo
15.
Biochemistry ; 38(29): 9366-72, 1999 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-10413511

RESUMO

The mammalian bombesin receptor subfamily of G protein-coupled receptors currently consists of the gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor, and bombesin receptor subtype 3. All three receptors contain a conserved aspartate residue (D98) at the extracellular boundary of transmembrane domain II and a conserved arginine residue (R309) near the extracellular boundary of transmembrane domain VII. To evaluate the functional role of these residues, site-directed GRP-R mutants were expressed in fibroblasts and assayed for their ability to both bind agonist and catalyze exchange of guanine nucleotides. Alanine substitution at GRP-R position 98 or 309 reduced agonist binding affinity by 24- and 56-fold, respectively, compared to wild-type GRP-R. Single swap GRP-R mutations either resulted in no receptor expression in the membrane (D98R) or the protein was not able to bind agonist (R309D). In contrast, the double swap mutation (D98R/R309D) had high-affinity agonist binding, reduced from wild-type GRP-R by only 6-fold. In situ reconstitution of urea-extracted membranes expressing either wild-type or mutant (D98A or R309A) GRP-R with G(q) indicated that alanine substitution greatly reduced G protein catalytic exchange compared to wild-type GRP-R. The D98R/R309D GRP-R had both a higher intrinsic basal activity and a higher overall catalytic exchange activity compared to wild-type; however, the wild-type GRP-R produced a larger agonist-stimulated response relative to the double swap mutant. Taken together, these data show that GRP-R residues D98 and R309 are critical for efficient coupling of GRP-R to G(q). Furthermore, our findings are consistent with a salt bridge interaction between these two polar and oppositely charged amino acids that maintains the proper receptor conformation necessary to interact with G proteins.


Assuntos
Arginina/metabolismo , Ácido Aspártico/metabolismo , Espaço Extracelular/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Receptores da Bombesina/metabolismo , Células 3T3 , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Animais , Arginina/genética , Ácido Aspártico/genética , Catálise , Células Clonais , Proteínas de Ligação ao GTP/genética , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Guanosina Difosfato/metabolismo , Ligantes , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/genética , Estrutura Terciária de Proteína , Receptores da Bombesina/biossíntese , Receptores da Bombesina/genética
16.
J Biol Chem ; 274(17): 11573-81, 1999 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-10206964

RESUMO

We used an in situ reconstitution assay to examine the receptor coupling to purified G protein alpha subunits by the bombesin receptor family, including gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R), and bombesin receptor subtype 3 (BRS-3). Cells expressing GRP-R or NMB-R catalyzed the activation of squid retinal Galphaq and mouse Galphaq but not bovine retinal Galphat or bovine brain Galphai/o. The GRP-R- and NMB-R-catalyzed activations of Galphaq were dependent upon and enhanced by different betagamma dimers in the same rank order as follows: bovine brain betagamma > beta1gamma2 >> beta1gamma1. Despite these qualitative similarities, GRP-R and NMB-R had distinct kinetic properties in receptor-G protein coupling. GRP-R had higher affinities for bovine brain betagamma, beta1gamma1, and beta1gamma2 and squid retinal Galphaq. In addition, GRP-R showed higher catalytic activity on squid Galphaq. Like GRP-R and NMB-R, BRS-3 did not catalyze GTPgammaS binding to Galphai/o or Galphat. However, BRS-3 showed little, if any, coupling with squid Galphaq but clearly activated mouse Galphaq. GRP-R and NMB-R catalyzed GTPgammaS binding to both squid and mouse Galphaq, with GRP-R activating squid Galphaq more effectively, and NMB-R also showed slight preference for squid Galphaq. These studies reveal that the structurally similar bombesin receptor subtypes, in particular BRS-3, possess distinct coupling preferences among members of the Galphaq family.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Receptores da Bombesina/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação , Bovinos , Primers do DNA , Decapodiformes , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cinética , Camundongos , Dados de Sequência Molecular , Receptores da Bombesina/classificação , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos
17.
J Biol Chem ; 273(22): 13613-24, 1998 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-9593699

RESUMO

Bombesin (Bn) receptor subtype 3 (BRS-3) is an orphan receptor that is a predicted member of the heptahelical G-protein receptor family and so named because it shares a 50% amino acid homology with receptors for the mammalian bombesin-like peptides neuromedin B (NMB) and gastrin-releasing peptide. In a recent targeted disruption study, in which BRS-3-deficient mice were generated, the mice developed obesity, diabetes, and hypertension. To date, BRS-3's natural ligand remains unknown, its pharmacology unclear, and cellular basis of action undetermined. Furthermore, there are few tissues or cell lines found that express sufficient levels of BRS-3 protein for study. To define the intracellular signaling properties of BRS-3, we examined the ability of [D-Phe6,beta-Ala11,Phe13, Nle14]Bn-(6-14), a newly discovered peptide with high affinity for BRS-3, and various Bn receptor agonists and antagonists to alter cellular function in hBRS-3-transfected BALB 3T3 cells and hBRS-3-transfected NCI-H1299 non-small cell lung cancer cells, which natively express very low levels of hBRS-3. This ligand stimulated a 4-9-fold increase in [3H]inositol phosphate formation in both cell lines under conditions where it caused no stimulation in untransfected cells and also stimulated an increase in [3H]IP1, [3H]IP2, and 3H]IP3. The elevation of [3H]IP was concentration-dependent, with an EC50 of 20-35 nM in both cell lines. [D-Phe6,beta-Ala11,Phe13,Nle14]Bn-(6-14) stimulated a 2-3-fold increase in [Ca2+]i, a 3-fold increase in tyrosine phosphorylation of p125(FAK) with an EC50 of 0.2-0.7 nM, but failed to either stimulate increases in cyclic AMP or inhibit forskolin-stimulated increases. None of nine naturally occurring Bn peptides or three synthetic Bn analogues reported to activate hBRS-3 did so with high affinity. No high affinity Bn receptor antagonists had high affinity for the hBRS-3 receptor, although two low affinity antagonists for gastrin-releasing peptide and NMB receptors, [D-Arg1,D-Trp7,9, Leu11]substance P and [D-Pro4,D-Trp7,9,10]substance P-(4-11), inhibited hBRS-3 receptor activation. The NMB receptor-specific antagonist D-Nal,Cys,Tyr,D-Trp,Lys,Val, Cys,Nal-NH2 inhibited hBRS-3 receptor activation in a competitive fashion (Ki = 0.5 microM). Stimulation of p125(FAK) tyrosine phosphorylation by hBRS-3 activation was not inhibited by the protein kinase C inhibitor, GF109203X, or thapsigargin, alone or in combination. These results show that hBRS-3 receptor activation increases phospholipase C activity, which causes generation of inositol phosphates and changes in [Ca2+]i and is also coupled to tyrosine kinase activation, but is not coupled to adenylate cyclase activation or inhibition. hBRS-3 receptor activation results in tyrosine phosphorylation of p125(FAK), and it is not dependent on activation of either limb of the phospholipase C cascade. Although the natural ligand is not a known bombesin-related peptide, the availability of [D-Phe6,beta-Ala11, Phe13,Nle14]Bn-(6-14), which functions as a high affinity agonist in conjunction with hBRS-3-transfected cell lines and the recognition of three classes of receptor antagonists including one with affinity of 0.5 microM, should provide important tools to assist in the identification of its natural ligand, the development of more potent selective receptor antagonists and agonists, and further exploration of the signaling properties of the hBRS-3 receptor.


Assuntos
Receptores da Bombesina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células 3T3 , Animais , Bombesina/análogos & derivados , Bombesina/farmacologia , Peptídeo Liberador de Gastrina/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Receptores da Bombesina/agonistas , Receptores da Bombesina/antagonistas & inibidores
18.
J Biol Chem ; 273(26): 15927-32, 1998 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-9632639

RESUMO

Three mammalian bombesin receptor subtypes have been characterized: the gastrin-releasing peptide receptor (GRP-R), the neuromedin B receptor (NMB-R), and bombesin receptor subtype 3 (BRS-3). In a previous report we identified four amino acids that are critical for high affinity binding of bombesin and gastrin-releasing peptide (GRP) to the GRP-R. These four amino acids are conserved in all species variants of the GRP-R and NMB-R which bind bombesin with high affinity, but they are diverged in BRS-3, the bombesin receptor subtype that binds bombesin with much lower affinity. Substituting these four divergent amino acids in BRS-3 for the conserved amino acids in either GRP-R or NMB-R increased the affinity of the mutated BRS-3 (4DeltaBRS-3) for bombesin compared with wild-type BRS-3. We hypothesized that the same four amino acids might be critical for high affinity NMB binding to the NMB-R. In this study we confirm this hypothesis by showing that the affinity of NMB is increased in a mutant BRS-3 receptor (4DeltaBRS-3) that contains these four substitutions resulting in an affinity that is close to the affinity of wild-type NMB-R for NMB. In contrast, these four amino acid substitutions in BRS-3 did not result in the formation of a high affinity binding site for the recently described non-peptide NMB-R antagonist PD168368.


Assuntos
Aminoácidos/metabolismo , Neurocinina B/análogos & derivados , Receptores da Bombesina/metabolismo , Células 3T3 , Sequência de Aminoácidos , Animais , Sítios de Ligação , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Neurocinina B/química , Neurocinina B/metabolismo , Estrutura Secundária de Proteína , Ratos , Receptores da Bombesina/antagonistas & inibidores , Alinhamento de Sequência , Relação Estrutura-Atividade
19.
Eur J Pharmacol ; 343(2-3): 275-87, 1998 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-9570477

RESUMO

Four subtypes of bombesin receptors are identified (gastrin-releasing peptide receptor, neuromedin B receptor, the orphan receptor bombesin receptor subtype 3 (BB3 or BRS-3) and bombesin receptor subtype 4 (BB4)), however, only the pharmacology of the gastrin-releasing peptide receptor has been well studied. This lack of data is due in part to the absence of a general ligand. Recently we have discovered a ligand, 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) that binds to BRS-3 receptors. In this study we investigate its ability to interact with all four bombesin receptor subtypes. In rat pancreatic acini containing only gastrin-releasing peptide receptor and in BB4 transfected BALB cells, this ligand and 125I-[Tyr4]bombesin, the conventional gastrin-releasing peptide receptor ligand, gave similar results for receptor number, affinity for bombesin and affinity for the unlabeled ligand. In neuromedin B receptor transfected BALB cells, this ligand and 125I-[D-Tyr0]neuromedin B, the generally used neuromedin B receptor ligand, gave similar results for receptor number, neuromedin B affinity or the unlabeled ligand affinity. Lastly, in BRS-3 transfected BALB cells, only this ligand had high affinity. For all four bombesin receptors this ligand had an affinity of 1-8 nM and was equal or greater in affinity than any other specific ligands for any receptor. The unlabeled ligand is specific for gastrin-releasing peptide receptors on rat pancreatic acini and did not inhibit binding of 125I-cholecystokinin octapeptide (125I-CCK-8), 125I-vasoactive intestinal peptide (125I-VIP) or 125I-endothelin to their receptors. The unlabeled ligand was an agonist only at the gastrin-releasing peptide receptor in rat acini and did not interact with CCK(A) receptors or muscarinic M3 acetylcholine receptors to increase [3H]inositol phosphates. These results demonstrate 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) is a unique ligand with high affinity for all subtypes of bombesin receptors. Because of the specificity for bombesin receptors, this ligand will be a valuable addition for such pharmacological studies as screening for bombesin receptor agonists or antagonists and, in particular, for investigating BRS-3 cell biology, a receptor for which no ligand currently exists.


Assuntos
Bombesina/metabolismo , Receptores da Bombesina/metabolismo , Células 3T3 , Animais , Bombesina/análogos & derivados , Células CHO , Cricetinae , Radioisótopos do Iodo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pâncreas/citologia , Pâncreas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores da Bombesina/classificação
20.
J Biol Chem ; 272(41): 26062-71, 1997 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-9325344

RESUMO

An orphan receptor discovered in 1993 was called bombesin receptor subtype 3 (BRS-3) because of 47-51% amino acid identity with bombesin (Bn) receptors. Its pharmacology is unknown, because no naturally occurring tissues have sufficient receptors to allow studies. We made two cell lines stably expressing the human BRS-3 (hBRS-3). hBRS-3 was overexpressed in the human non-small cell lung cancer cells, NCI-H1299, and the other was made in Balb 3T3 cells, which lack endogenous BRS-3. [D-Phe6,beta-Ala11,Phe13, Nle14]Bn-(6-14) (where Nle represents norleucine) was discovered to have high potency for stimulating inositol phosphate formation in both cell lines. [125I-D-Tyr6,beta-Ala11,Phe13, Nle14]Bn-(6-14) bound to both cell lines with high affinity. Neither Bn nor 14 other naturally occurring Bn peptides bound to hBRS-3 with a Kd <1000 nM. Twenty-six synthetic peptides that are high affinity agonists or antagonists at other bombesin receptors had an affinity >1000 nM. Guanosine 5'-(beta,gamma-imido)triphosphate inhibited binding to both cells due to a change in receptor affinity. These results demonstrate hBRS-3 has a unique pharmacology. It does not interact with high affinity with any known natural agonist or high affinity antagonist of the Bn receptor family, suggesting the natural ligand is either an undiscovered member of the Bn peptide family or an unrelated peptide. The availability of these cell lines and the hBRS-3 ligand should facilitate identification of the natural ligand for BRS-3, its pharmacology, and cell biology.


Assuntos
Receptores da Bombesina/metabolismo , Células 3T3 , Animais , Northern Blotting , Southern Blotting , Bombesina/análogos & derivados , Bombesina/metabolismo , Bombesina/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Ensaio Radioligante , Receptores da Bombesina/efeitos dos fármacos , Receptores da Bombesina/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transfecção , Células Tumorais Cultivadas
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