RESUMEN
BACKGROUND AND AIM: We recently conducted a randomized placebo-controlled trial on the efficacy and safety of rikkunshito, a standardized Japanese herbal medicine, for the treatment of functional dyspepsia (FD). The present post-hoc study aimed to evaluate the differences in clinical characteristics between responders and non-responders among FD patients who received rikkunshito for 8 weeks. METHODS: Rikkunshito responders were defined by using a global patient assessment. Candidate predictors included age, gender, smoking, alcohol consumption, body mass index, comorbidity, Helicobacter pylori infection, plasma levels of acyl ghrelin and des-acyl ghrelin, severity of dyspeptic symptoms, FD subgroup, previous medication, and the type of recruiting institution (clinic or hospital). We calculated hazard ratios (HRs) by using Cox regression analysis with the factors that were indicated to be associated with responders. RESULTS: We assigned 83 and 42 patients to responder and non-responder categories, respectively. Lack of alcohol consumption (HR, 2.04; 95% confidence interval, 1.08-3.88) and low plasma des-acyl ghrelin levels (< 177 fmol/mL; HR, 2.42; 95% confidence interval, 1.24-4.73) were significantly associated with the efficacy of rikkunshito. Lack of alcohol consumption was associated with the efficacy of rikkunshito especially among H. pylori-infected participants. On the other hand, the low plasma des-acyl ghrelin was associated with the efficacy of rikkunshito especially among H. pylori-negative participants. CONCLUSIONS: A low baseline level of plasma des-acyl ghrelin was associated with an increased treatment efficacy of rikkunshito against FD. Lack of alcohol consumption was also clinically useful for predicting the response to rikkunshito.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Dispepsia/diagnóstico , Dispepsia/tratamiento farmacológico , Ghrelina/sangre , Evaluación de Procesos y Resultados en Atención de Salud , Fitoterapia , Adulto , Anciano , Consumo de Bebidas Alcohólicas/efectos adversos , Biomarcadores/sangre , Método Doble Ciego , Medicamentos Herbarios Chinos/administración & dosificación , Femenino , Infecciones por Helicobacter , Helicobacter pylori , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The antiatherogenic properties of apoA-IV suggest that this protein may act as an anti-inflammatory agent. We examined this possibility in a mouse model of acute colitis. Mice consumed 3% dextran sulfate sodium (DSS) in their drinking water for 7 days, with or without daily intraperitoneal injections of recombinant human apoA-IV. apoA-IV significantly and specifically delayed the onset, and reduced the severity and extent of, DSS-induced inflammation, as assessed by clinical disease activity score, macroscopic appearance and histology of the colon, and tissue myeloperoxidase activity. Intravital fluorescence microscopy of colonic microvasculature revealed that apoA-IV significantly inhibited DSS-induced leukocyte and platelet adhesive interactions. Furthermore, apoA-IV dramatically reduced the upregulation of P-selectin on colonic endothelium during DSS-colitis. apoA-IV knockout mice exhibited a significantly greater inflammatory response to DSS than did their WT littermates; this greater susceptibility to DSS-induced inflammation was reversed upon exogenous administration of apoA-IV to knockout mice. These results provide the first direct support for the hypothesis that apoA-IV is an endogenous anti-inflammatory protein. This anti-inflammatory effect likely involves the inhibition of P-selectin-mediated leukocyte and platelet adhesive interactions.
Asunto(s)
Antiinflamatorios/metabolismo , Apolipoproteínas A/metabolismo , Colitis/metabolismo , Animales , Antiinflamatorios/inmunología , Apolipoproteínas A/genética , Apolipoproteínas A/inmunología , Colitis/inducido químicamente , Colitis/inmunología , Colitis/patología , Colon/anatomía & histología , Colon/patología , Sulfato de Dextran/administración & dosificación , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Células Epiteliales/citología , Células Epiteliales/metabolismo , Humanos , Indicadores y Reactivos/administración & dosificación , Indicadores y Reactivos/toxicidad , Inflamación/inmunología , Inflamación/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Leucocitos/inmunología , Leucocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Selectina-P/metabolismo , Adhesividad Plaquetaria/fisiología , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismoRESUMEN
A high resistance rate (47.9%) to gatifloxacin (GAT; 8-methoxy fluoroquinolone) in Helicobacter pylori (H. pylori) strains from 48 Japanese patients is observed after unsuccessful H. pylori eradication. A significant association between MICs for GAT equal to or above 1 microg/ml and mutations of the gyrA gene of H. pylori was demonstrated.
Asunto(s)
Antiinfecciosos/farmacología , Girasa de ADN/genética , Fluoroquinolonas/farmacología , Helicobacter pylori/efectos de los fármacos , Mutación , Farmacorresistencia Bacteriana , Femenino , Gatifloxacina , Helicobacter pylori/genética , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana EdadRESUMEN
Although platelets have been implicated in the pathogenesis of human inflammatory bowel diseases, little is known about the magnitude of platelet accumulation in the inflamed bowel, what regulates this process, and its relevance to the overall inflammatory response. In this study, intravital video microscopy was used to monitor the trafficking of platelets and leukocytes and vascular permeability in colonic venules during the development of colonic inflammation induced by 3% dextran sodium sulfate (DSS). Blocking antibodies directed against different adhesion molecules as well as P-selectin-deficient mice were used to define the adhesive determinants of DSS-induced platelet recruitment. DSS induced an accumulation of adherent platelets that was temporally correlated with the appearance of adherent leukocytes and with disease severity. Platelet adhesion and, to a lesser extent, leukocyte adhesion were attenuated by immunoblockade of P-selectin and its ligand P-selectin glycoprotein ligand-1 (PSGL-1), with contributions from both platelet- and endothelial cell-associated P-selectin. DSS induced a rapid and sustained increase in vascular permeability that was greatly attenuated in P-selectin-deficient mice. P-selectin bone marrow chimeras revealed that both endothelial cell- and platelet-associated P-selectin contribute to the P-selectin expression detected in the inflamed colonic microvasculature, with endothelial P-selectin making a larger contribution. Our findings indicate that colonic inflammation is associated with the induction of a prothrombogenic phenotype in the colonic microcirculation, with P-selectin and its ligand PSGL-1 playing a major role in the recruitment of platelets.
Asunto(s)
Plaquetas/fisiología , Colitis/fisiopatología , Colon/irrigación sanguínea , Animales , Anticoagulantes/farmacología , Permeabilidad Capilar/fisiología , Adhesión Celular/fisiología , Colitis/sangre , Sulfato de Dextran/farmacología , Expresión Génica , Inflamación/fisiopatología , Leucocitos/fisiología , Masculino , Glicoproteínas de Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Selectina-P/fisiología , Fenotipo , Vénulas/fisiopatologíaRESUMEN
Human inflammatory bowel diseases (IBD) are associated with significant alterations in intestinal blood flow, the direction and magnitude of which change with disease progression. The objectives of this study were to determine the time course of changes in colonic blood perfusion that occur during the development of dextran-sodium-sulfate (DSS)-induced colonic inflammation and to address the mechanisms that may underlie these changes in blood flow. Intravital microscopy was used to quantify blood flow (from measurements of vessel diameter and red blood cell velocity) in different-sized submucosal arterioles of control and inflamed colons in wild-type (WT) mice. A significant (18-30%) reduction in blood flow was noted in the smallest arterioles (<40 microm diameter) on days 4-6 of DSS colitis. The arteriolar responses to bradykinin in control and DSS-treated WT mice revealed an impaired endothelium-dependent, but not endothelium-independent, vasodilation in the inflamed colon. However, this impaired vasodilatory response to bradykinin after DSS treatment was not evident in mutant mice that overexpress Cu,Zn-superoxide dismutase. Rescue of the bradykinin-induced vasodilation during DSS colitis was also observed in mice that are genetically deficient in the NAD(P)H oxidase subunit gp91(phox). These findings indicate that the decline in blood flow during experimental colitis may result from a diminished capacity of colonic arterioles to respond to endogenous endothelium-dependent vasodilators like bradykinin and that NAD(P)H oxidase-derived superoxide plays a major role in the induction of the inflammation-induced endothelium-dependent arteriolar dysfunction.
Asunto(s)
Colitis/fisiopatología , Colon/irrigación sanguínea , Animales , Arteriolas/fisiología , Bradiquinina/farmacología , Colitis/inducido químicamente , Colon/efectos de los fármacos , Depresión Química , Sulfato de Dextran , Frecuencia Cardíaca , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasas/metabolismo , Papaverina/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
In dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice the relationship between the amount of ingested DSS and the severity of colitis has not been systematically investigated. We examined whether (1) the severity of colitis is DSS load-dependent, and (2) there is a critical DSS load required to reliably induce colitis. DSS load was calculated as: (drinking volume (ml) x [DSS (g)/100 ml])/body weight (g). A minimum DSS load > or = 30 mg/g body weight over 7 days resulted in a significantly elevated colonic myeloperoxidase (MPO) activity, compared to mice receiving less DSS and controls (P < 0.05). Histomorphologic data correlated with MPO activity and revealed significantly higher damage scores once the DSS load was > or = 30 mg/g body weight. Our findings demonstrate the importance of monitoring DSS load in this model of experimental colitis.
Asunto(s)
Colitis/inducido químicamente , Colitis/patología , Colon/efectos de los fármacos , Sulfato de Dextran/efectos adversos , Sulfato de Dextran/farmacología , Animales , Biopsia con Aguja , Colon/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inmunohistoquímica , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Probabilidad , Distribución Aleatoria , Valores de Referencia , Análisis de Regresión , Factores de Riesgo , Especificidad de la EspecieRESUMEN
Although gastric cancer formation with H. pylori in Mongolian gerbils was recently reported, the same inoculation procedure did not result in cancer formation in other animals such as mice. Disturbed regulation of apoptosis and cell proliferation are known to link the multistep process of carcinogenesis. The present study is designed to examine the level of gastric epithelial cell apoptosis in Mongolian gerbils colonized with the H. pylori (Sydney strain: SS1) in comparison with that in mice. Mice (C57BL/6) and Mongolian gerbils were orally inoculated with SS1 and the stomachs were examined 9 and 18 months later. MPO activity increased persistently in gerbils, but increased transiently in mice. While the levels of DNA fragmentation, caspase-3 activity, and the number of TUNEL-positive cells increased significantly in mice, such parameters were attenuated in gerbils. On the other hand, the number of PCNA-positive cells increased after SS1 inoculation only in Mongolian gerbils, suggesting the enhancement of cell turnover in H. pylori-colonized gerbils. In conclusion, the SS1-induced increase in gastric mucosal apoptosis observed in mice was attenuated significantly in Mongolian gerbils, suggesting the causative role for the higher incidence of gastric carcinogenesis in this animal.