Pathophysiology of Anorectal Disorders

肛门直肠疾病的病理生理学

• 批准号: 7595123
• 负责人: ADIL E. BHARUCHA
• 金额: $ 32.11万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595123
• 关键词: Acute; Adrenergic Agonists; Affect; Anus; Atropine; Bethanechol; Biofeedback; Cholinergic Agonists; Clonidine; Communities; Complex; Consensus; Controlled Study; Data; Denervation; Discipline of obstetrics; Disease; Distress; Double-Blind Method; Epidemiology; Fecal Incontinence; Functional disorder; Goals; Hypersensitivity; Hysterectomy; Injury; Institutionalization; L-Type Calcium Channels; Magnetic Resonance Imaging; Measures; Mechanics; Motor; Muscarinic Agonists; Muscarinic Antagonists; Neuropathy; Nifedipine; Patients; Perception; Postmenopause; Prevention; Property; Rectum; Research; Rest; Risk; Risk Factors; Role; Sensorimotor functions; Stress; Symptoms; Techniques; Testing; Therapeutic; United States National Institutes of Health; Vaginal delivery procedure; Woman; anorectal disorder; base; cohort; daily functioning; evidence base; improved; innovation; multidisciplinary; novel; novel strategies; placebo controlled study; pressure; programs; public health relevance; rectal; response; sphincter ani muscle structure; symposium

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.

描述（由申请人提供）：该研究计划的目标是通过使用多学科的创新方法来阐明这种疾病的危险因素和机制，从而增强女性的预防和改善粪便失禁（FI）的管理。尽管当前的概念强调了肛门括约肌弱点的作用，但我们的流行病学和机械研究强烈支持以下假设：FI是由正直 - 肛门感觉运动功能障碍而不是孤立的肛门功能障碍引起的。我们的具体目的是评估：（i）接受子宫切除术以及急于FI的女性的女性中直肠更加严厉； （IIA）部分可逆的直肠运动功能障碍主要是由于神经源性而非肌源性机制导致了急速FI女性的直肠超敏反应。 （IIB）地敏性超敏反应有助于子宫切除术后直肠僵硬的增加； （iii）可乐定将恢复直肠感觉运动功能，从而改善FI的症状。我们相应的目的是（i）测量整体和区域直肠应力：在24名无症状女性直肠球囊延伸期间以及24名患有FI的女性中，同时进行MRI的应变关系，也控制子宫切除术； （IIA）比较阿托品和硝苯地平对直肠机械性能的急性作用（即，依从性，能力和对延伸的阶段反应）和直肠对36名没有敦促FI女性的妇女的延伸感知，也没有敦促FI，也控制子宫切除术； （IIB）评估胆碱能激动剂对24名患有或没有子宫切除术的女性直肠感觉运动的影响； （iii）研究可乐定对40名FI女性的双盲安慰剂对照研究中的症状和直肠感觉运动功能的影响。通过测试与新疗法相结合的机械假设，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：粪便尿失禁（FI）会影响绝经后妇女的10％和多达20％。 FI会引起严重的困扰，损害日常运作，并导致制度化。 FI的病理生理学知之甚少，而可用的治疗选择是有限的，而不是基于证据的，主要专注于改善肛门括约肌的功能。该建议将增强我们对机制的理解，并评估管理FI的新方法。