RESUMEN
BACKGROUND & AIMS: Nonrelaxing pelvic floor dysfunction (N-RPFD), or dyssynergic defecation, is the paradoxical contraction and/or impaired relaxation of pelvic floor and anal muscles during defecation. Few studies have evaluated this disorder in patients with an ileal pouch-anal anastomosis (IPAA). We investigated the frequency of N-RPFD in patients with and without chronic pouchitis following IPAA and the effectiveness of biofeedback therapy within this population. METHODS: We conducted a retrospective study of all patients with an IPAA who underwent anorectal manometry between January 2000 and March 2015 (n = 111). N-RPFD was diagnosed in patients with symptoms consistent with a pouch evacuation disorder and 1 or more of the following abnormal tests: anorectal manometry, balloon expulsion test, barium or magnetic resonance defecography, or external anal sphincter electromyography. Patients who completed biofeedback therapy were identified and assessed to determine symptomatic response. RESULTS: Of the 111 patients evaluated, 83 (74.8%) met criteria for N-RPFD. A significantly higher proportion of patients with chronic pouchitis were diagnosed with N-RPFD than patients without chronic pouchitis (83.3% vs 62.2%, respectively; P = .012). Most patients diagnosed with N-RPFD had abnormal results from the balloon expulsion test (78.3%); 53.0% of patients diagnosed with N-RPFD had abnormal findings from external anal sphincter electromyography, 25.3% had abnormal defecography findings, and 20.5% had abnormal findings from anorectal manometry. Twenty-two patients completed biofeedback therapy: 15 patients (68.2%) had mild-moderate improvement and 5 patients (22.7%) had significant improvement of symptoms. CONCLUSIONS: N-RPFD occurs in almost 75% of patients with an IPAA, especially in patients with chronic pouchitis. Biofeedback seems to be an effective therapy for patients with an IPAA and N-RPFD, but further studies are needed for validation.
Asunto(s)
Ataxia/epidemiología , Trastornos del Suelo Pélvico/epidemiología , Proctocolectomía Restauradora/efectos adversos , Adolescente , Adulto , Anciano , Ataxia/terapia , Biorretroalimentación Psicológica , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Suelo Pélvico/terapia , Prevalencia , Estudios Retrospectivos , Adulto JovenRESUMEN
The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Piridinas/química , Pirimidinas/química , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismoRESUMEN
The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate ß-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.