RESUMEN
BACKGROUND: Resolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A4 (LXA 4) is an anti-inflammatory, pro-resolution lipid mediator that reduces neuroinflammation in stroke. Since LXA 4 is rapidly inactivated, potent analogs have been synthesized, including BML-111. We hypothesized that post-ischemic, intravenous treatment with BML-111 for 1 week would provide neuroprotection and reduce neurobehavioral deficits at 4 weeks after ischemic stroke in rats. Additionally, we investigated the potential protective mechanisms of BML-111 on the post-stroke molecular and cellular profile. METHODS: A total of 133 male Sprague-Dawley rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) and BML-111 administration was started at the time of reperfusion. Two methods of week-long BML-111 intravenous administration were tested: continuous infusion via ALZET ® osmotic pumps (1.25 and 3.75 µg µl-1 hr-1), or freshly prepared daily single injections (0.3, 1, and 3 mg/kg). We report for the first time on the stability of BML-111 and characterized an optimal dose and a dosing schedule for the administration of BML-111. RESULTS: One week of BML-111 intravenous injections did not reduce infarct size or improve behavioral deficits 4 weeks after ischemic stroke. However, post-ischemic treatment with BML-111 did elicit early protective effects as demonstrated by a significant reduction in infarct volume and improved sensorimotor function at 1 week after stroke. This protection was associated with reduced pro-inflammatory cytokine and chemokine levels, decreased M1 CD40+ macrophages, and increased alternatively activated, anti-inflammatory M2 microglia/macrophage cell populations in the post-ischemic brain. CONCLUSION: These data suggest that targeting the endogenous LXA 4 pathway could be a promising therapeutic strategy for the treatment of ischemic stroke. More work is necessary to determine whether a different dosing regimen or more stable LXA 4 analogs could confer long-term protection.
Asunto(s)
Encéfalo/inmunología , Ácidos Heptanoicos/farmacología , Infarto de la Arteria Cerebral Media , Inflamación/inmunología , Lipoxinas , Accidente Cerebrovascular , Animales , Antiinflamatorios no Esteroideos/farmacología , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/inmunología , Lipoxinas/agonistas , Lipoxinas/inmunología , Masculino , Microglía/efectos de los fármacos , Factores Protectores , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/inmunología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/terapia , TiempoRESUMEN
BACKGROUND: The incidence of Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD) is increasing, and CDI has a negative impact on IBD outcomes with both increased morbidity and mortality. Data are lacking regarding the rate of appropriate testing for CDI at the time of diagnosis. METHODS: We sought to determine the rate of CDI testing and CDI positivity at diagnosis of IBD using data collected through the Ocean State Crohn's and Colitis Area Registry (OSCCAR), a prospective cohort of patients with newly diagnosed IBD. CDI testing and CDI positivity were determined by reviewing the medical records of patients enrolled into the registry and diagnosed with IBD between January 2008 and July 2011. RESULTS: Of 320 enrolled patients, 227 (70.9%) reported diarrhea, and CDI testing was performed for 113 (49.8%) of the 227 patients. CDI testing was not recorded as being performed for the remaining 114 patients who reported having diarrhea. An additional 24 patients were tested for CDI but did not report having diarrhea. Seven (5.1%) of the 137 patients tested for CDI were positive. CONCLUSIONS: Testing for CDI is significantly lower than expected at diagnosis of IBD. Although the prevalence of CDI among tested patients is approximately 5%, a low testing rate suggests a significant quality issue in the diagnosis of IBD, with the potential for delayed diagnosis of CDI.
Asunto(s)
Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/microbiología , Pruebas Diagnósticas de Rutina/métodos , Heces/microbiología , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Infecciones por Clostridium/epidemiología , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/epidemiología , Masculino , Persona de Mediana Edad , New York/epidemiología , Prevalencia , Pronóstico , Estudios Prospectivos , Características de la Residencia , Factores de Riesgo , Adulto JovenRESUMEN
Clostridium difficile infection (CDI) is a common cause of infectious diarrhea and is usually treated with metronidazole or vancomycin. CDI recurs in 15%-30% of patients after the initial episode and in up to 65% after a second episode. Recurrent infections are a challenge to treat, and patients are usually managed with prolonged pulsed or tapered vancomycin. Fecal microbiota transplantation is an alternative treatment that has a 91% rate of success worldwide, with no reported complications. We describe a patient with ulcerative colitis that had been quiescent for more than 20 years who developed a flare of ulcerative colitis after fecal microbiota transplantation, indicating the need for caution in treating CDI with fecal microbiota transplantation in patients with inflammatory bowel disease.
Asunto(s)
Terapia Biológica/efectos adversos , Terapia Biológica/métodos , Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/terapia , Colitis Ulcerosa/patología , Anciano , Humanos , MasculinoRESUMEN
GOALS: We aim to present a data detailing our success with fecal microbiota transplantation (FMT) and to provide a simple treatment protocol. BACKGROUND: Relapse is a common problem in patients treated for Clostridium difficile infection, often requiring prolonged courses of oral vancomycin with limited alternative treatment options. Administration of the entire fecal flora from a healthy individual to restore beneficial physiological species is referred to as FMT (also termed fecal bacteriotherapy or stool transplant). Although introduced over 50 years ago with high cure rates in published case series, FMT is neither routine practice nor widely available to patients. STUDY: Twenty-six patients with relapsing C. difficile infection underwent FMT over a 28-month period. FMT was performed during colonoscopy by direct infusion of minimally processed donor stool. RESULTS: Twenty-four female and 2 male patients underwent FMT. The mean duration of CDI was 12.6 months (range, 4 to 84 mo) before FMT. These patients have been followed for a mean duration of 10.7 months (range, 2 to 30 mo). Twenty-four patients have remained free of significant diarrhea or CDI. One experienced loose stool and resumed vancomycin despite remaining C. difficile negative; she developed CDI recurrence 11 months post-FMT after taking cephalexin. Another had diarrhea 2 months post-FMT. Stool was not tested for C. difficile; she received 1 week of vancomycin and CDI did not recur after this. CONCLUSIONS: FMT through colonoscopy was simple, safe, and 92% effective in preventing further diarrhea or CDI relapse in this group of 26 patients with recurrent CDI.