Pathophysiology of Anorectal Disorders

描述(由申请人提供)：本研究计划的目标是通过多学科、创新的方法阐明大便失禁(FI)的风险因素和机制，从而加强对女性大便失禁(FI)的预防和管理。虽然目前的概念强调肛门括约肌无力的作用，但我们的流行病学和机械学研究强烈支持FI是由复杂的直肠-肛门感觉运动功能障碍而不是单独的肛门功能障碍引起的假说。我们的具体目标是评估如下假设：(I)接受过子宫切除术的妇女以及FI急性期患者的直肠更加僵硬；(Ii)部分可逆性直肠运动功能障碍主要是由于神经源性而不是肌源性机制导致的；(Ii)急性期FI患者的直肠高敏感性可归因于(Ii)失神经超敏可导致子宫切除术后直肠僵硬；以及(Iii)可乐定可恢复直肠的感觉运动功能，从而改善FI的症状。我们相应的目标是：(I)测量整体和局部直肠应激：在24名无症状和24名急迫性FI患者的直肠气囊扩张过程中，通过同步MRI测量张力关系，同时对照子宫切除术；(IIa)比较阿托品和硝苯地平对56名急迫性FI女性和36名非急迫性FI女性直肠机械性能(即顺应性、容量和对扩张的时相反应)和直肠扩张感觉的急性影响，并对照子宫切除术；(IIB)评估胆碱能激动剂对24名已或未接受子宫切除术的女性直肠感觉运动的影响；以及(Iii)在一项双盲安慰剂对照研究中，研究可乐定对40名FI妇女症状和直肠感觉运动功能的影响。通过测试与一种新疗法相结合的机械性假设，这些研究有望从根本上改变我们对女性FI的理解和管理。 公共卫生相关性：大便失禁(FI)影响10%的绝经后妇女，高达20%。FI可能会造成严重的痛苦，损害日常功能，并有助于制度化。对FI的病理生理学了解甚少，而现有的治疗选择有限，没有循证证据，主要集中在改善肛门括约肌功能。这项建议将增进我们对这些机制的理解，并评估管理金融的新方法。

DESCRIPTION (provided by applicant): The goals of this research program are to enhance the prevention and improve the management of fecal incontinence (FI) in women by clarifying the risk factors and mechanisms for this disorder using multidisciplinary, innovative approaches. While current concepts emphasize the role of anal sphincter weakness, our epidemiological and mechanistic studies strongly support the hypothesis that FI is caused by complex of recto-anal sensorimotor dysfunctions rather than isolated anal dysfunction. Our specific aims are to assess the hypotheses that: (i) The rectum is stiffer in women who have had a hysterectomy and also in women with urge FI; (iia) Partially reversible rectal motor dysfunctions predominantly due to neurogenic rather than myogenic mechanisms contribute to rectal hypersensitivity in women with urge FI; (iib) denervation supersensitivity contributes to increased rectal stiffness after a hysterectomy; and (iii) clonidine will restore rectal sensorimotor functions and thereby improve symptoms in FI. Our corresponding aims are to (i) measure overall and regional rectal stress:strain relationships by simultaneous MRI during rectal balloon distention in 24 asymptomatic women and in 24 women with urge FI, also controlling for hysterectomy; (iia) compare the acute effects of atropine and nifedipine on rectal mechanical properties (i.e., compliance, capacity, and the phasic response to distention) and rectal perception of distention in 56 women with and 36 women without urge FI, also controlling for hysterectomy; (iib) assess the effects of a cholinergic agonist on rectal sensorimotor in 24 women who have or have not had a hysterectomy; and (iii) study the effects of clonidine on symptoms and rectal sensorimotor functions in a double- blind placebo-controlled study of 40 women with FI. By testing mechanistic hypotheses which are integrated with a new therapy, these studies are poised to fundamentally alter our understanding and management of FI in women. Public Health Relevance: Fecal incontinence (FI) affects 10% of all and up to 20% of postmenopausal women. FI can cause significant distress, impair daily functioning, and contribute to institutionalization. The pathophysiology of FI is poorly understood, while available therapeutic options are limited, not evidence-based, and primarily focus on improving anal sphincter function. This proposal will enhance our understanding of the mechanisms and assess novel approaches to manage FI.