Mutations in RAD21 disrupt regulation of apob in patients with chronic intestinal pseudo-obstruction

Background Aims Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers. Methods We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed. Results We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens. Conclusions Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons. © 2015 by the AGA Institute

Body Contouring Surgery after Bariatric Surgery Improves Long-Term Health-Related Quality of Life and Satisfaction with Appearance: An International Longitudinal Cohort Study Using the BODY-Q

Objective: To examine health-related quality of life (HRQL) and satisfaction with appearance in patients who have undergone bariatric surgery (BS) with or without subsequent body contouring surgery (BCS) in relation to the general population normative for the BODY-Q. Background: The long-term impact of BS with or without BCS has not been established using rigorously developed and validated patient-reported outcome measures. The BODY-Q is a patient-reported outcome measure developed to measure changes in HRQL and satisfaction with appearance in patients with BS and BCS. Methods: Prospective BODY-Q data were collected from 6 European countries (Denmark, the Netherlands, Finland, Germany, Italy, and Poland) from June 2015 to February 2022 in a cohort of patients who underwent BS. Mixed-effects regression models were used to analyze changes in HRQL and appearance over time between patients who did and did not receive BCS and to examine the impact of patient-level covariates on outcomes. Results: This study included 24,604 assessments from 5620 patients. BS initially led to improved HRQL and appearance scores throughout the first postbariatric year, followed by a gradual decrease. Patients who underwent subsequent BCS after BS experienced a sustained improvement in HRQL and appearance or remained relatively stable for up to 10 years postoperatively. Conclusions: Patients who underwent BCS maintained an improvement in HRQL and satisfaction with appearance in contrast to patients who only underwent BS, who reported a decline in scores 1 to 2 years postoperatively. Our results emphasize the pivotal role that BCS plays in the completion of the weight loss trajectory

Widespread eradication of Helicobacter pylori: a debate

Background. Helicobacter pylori eradication is recommended currently only in peptic ulcer patients. The accumulating evidence of a possible pathogenetic role of the germ in other pathological conditions, such as mucosa-associated lymphoid tissue lymphomas and (possibly) also functional dyspepsia and gastric cancer, creates increasing pressure in favor of an expansion of such indication. However, at present, cultural and practical considerations should discourage widespread screening and eradication programs. Methods. The basis for our study is a critical review of the literature. Results. The lack of a sound pathophysiological basis linking H. pylori infection to both dyspeptic symptom perception and gastric cancer risk sharply contrasts with the numerical and clinical relevance of these pathological conditions. Screening tests are not sufficiently cheap, easy, and reliable to be applicable on a large scale. Also, eradication therapies may provide suboptimal therapeutic effects and excessive side effects if applied by physicians who are not prepared culturally. Conclusions. Improvement of pathophysiological, diagnostic, and therapeutic knowledge must be achieved before eradication programs can be proposed on a large scale

Unsolved problems in the management of patients with gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease is a common problem that brings large numbers of patients to physicians every day. It lowers the quality of life of affected individuals and exposes them to potentially dangerous complications. An increasing awareness exists among patients, doctors and authorities about the relevance of this pathological condition. Despite an improved understanding of many aspects of gastro-oesophageal reflux disease, clinical management of several cases is still unsatisfactory. Atypical cases with extra-oesophageal manifestations often defy diagnosis. Even typical symptoms are often misunderstood and considered to be part of the poorly defined area of dyspepsia by both patients and doctors. As a consequence, management remains uncertain for too many cases. If correctly diagnosed, gastro-oesophageal reflux disease can be efficaciously treated with proton pump inhibitors (PPIs). Although standard doses of PPIs can heal mucosal lesions and provide symptom relief in the vast majority of oesophagitis patients, non-oesophagitis symptomatic individuals and those with extra-oesophageal manifestations may fail to respond to similar regimens. Antireflux surgery is a possible alternative to PPI therapy, but it is hampered by complications in a substantial percentage of cases and by sporadic casualties even when performed by experienced surgeons. The high prevalence of gastro-oesophageal reflux disease in the general population and the relatively high management costs should prompt any doctor to seek the best possible therapeutic approach

Fiber and macrogol in the therapy of chronic constipation.

Chronic constipation is a common condition in the general population. Although the majority of affected individuals do not seek medical consultation and search for remedies for their condition in the pharmacy or herbal shops, the actual health burden caused by this condition is extremely high. Many laxatives are available, but patients are often dissatisfied with the therapies adopted, whether prescribed by a doctor or self prescribed, and this leads to further social and health burdens. All of the available guidelines promote initiating the therapy of any type of constipation by ensuring an adequate intake of dietary fiber and water. However, high amounts of insoluble vegetable fiber such as those normally contained in fruits and vegetables, can lead to a further worsening of the digestive symptoms typical of chronic constipation, such as bloating and distension and pain. Better results can be obtained with soluble fibers, such as psyllium. Among the various available laxatives, polyethylene glycol (PEG), or macrogol, is the product which has been most studied and has produced the best results with the least number of side effects. This is an inert not absorbable molecule that, diluted in water, forms an isotonic solution that prevents part of the water from being absorbed, thus increasing the volume of the intestinal contents, reducing the consistency and facilitating transport and evacuation. The combination of psyllium and PEG could combine the advantages of fiber and isotonic solutions and represent an important therapeutic option for patients suffering from chronic constipation

Dyspeptic symptoms and gastric emptying in the irritable bowel syndrome

OBJECTIVES: Irritable bowel syndrome (IBS) and dyspepsia often overlap. Delayed gastric emptying has been reported in IBS patients, although conflicting results exist. Whether overlapping dyspepsia correlates with gastric emptying abnormalities in IBS patients has not been clarified. This study aimed to evaluate gastric emptying of solids and its relationship with dyspeptic symptoms in IBS patients. METHODS: A total of 146 IBS outpatients seen in a referral center were evaluated for dyspeptic symptoms using a validated questionnaire. Gastric emptying of solids was evaluated scintigraphically in all patients and in 50 healthy controls. RESULTS: Overlapping dyspepsia was diagnosed in 96 (66%) IBS patients. On average, gastric emptying rates were lower in IBS patients (mean ± SEM, 33% ± 1%/h) compared with controls (40% ± 2%/h; p < 0.01). Specifically, gastric emptying was delayed in IBS patients with overlapping dyspepsia (31% ± 1%/h; p < 0.01), whereas IBS patients without dyspeptic complaints showed gastric emptying rates (37% ± 2%/h) that were similar to those of healthy controls (40% ± 2%/h). Relevant postprandial fullness (OR = 4.7, 95% CI = 1.8-12.5) and relevant nausea (OR = 3.3, 95% CI 1.2-9.3) were independently associated with delayed gastric emptying. CONCLUSIONS: IBS patients without overlapping dyspepsia have normal gastric emptying of solids. A significant association exists in IBS patients between delayed gastric emptying and overlapping relevant postprandial fullness and nausea

Clinical use of manometry for the diagnosis of intestinal motor abnormalities

Digestive symptoms suggestive of intestinal motor disorders, such as abdominal pain and distension, fullness, vomiting, constipation and diarrhoea, are very common and non-specific, and may be clinical manifestations of both organic and functional diseases. Both radiology and endoscopy are important in the diagnosis of structural gastrointestinal lesions that can affect motility and offer indirect signs of impaired gastrointestinal functions, but the diagnosis of gut motility disorders currently relies on the manometric assessment of contractile activities. Small bowel manometry helps to identify normal motility features and consequently to identify abnormal motor patterns. Small bowel manometry can help to differentiate mechanical obstruction from pseudo-obstruction and neurogenic from myogenic motor disorders. Manometry is an invasive technique which is not well accepted by patients and requires specific skills from investigators. Also, manometric assessment is limited to referral centres with a specific interest in the field of digestive functions, in general, and motility, in particular. Only patients who remain undiagnosed after extensive traditional work-up and fail repeated courses with medical therapy should be referred for the manometric test. Understanding the underlying pathophysiologic mechanisms of abnormal motility and developing new therapies are the goals of the current research in this fascinating field of medicine

Diagnosing and treating dyspepsia. Current practice and new developments

No abstract availabl

Natural history of chronic idiopathic intestinal pseudo-obstruction in adults: a single center study.

BACKGROUND & AIMS: Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare disease characterized by episodes resembling mechanical obstruction in the absence of organic, systemic, or metabolic disorders. Intestinal motor abnormalities have long been identified in CIIP patients. Little is known of the natural history of the disease in adults. This study evaluated the clinical course of CIIP over time. METHODS: Fifty-nine consecutive CIIP patients without underlying collagen, vascular diseases, or mitochondrial cytopathies were evaluated between 1985 and 2001. Family history, onset of digestive symptoms, previous surgeries, episodes suggestive of subacute intestinal obstruction, digestive symptoms, body mass index, and feeding habits were recorded. Small bowel manometry was performed by a perfusion technique, and abnormal motor patterns were visually identified. Full-thickness biopsies were available in 11 cases and were processed for immunohistochemical analysis of myogenic and neurogenic components of the gut wall. RESULTS: Patients were prospectively followed up for a median of 4.6 years (range, 1-13 years). Diagnosis was often made several years after symptom onset (median, 8 years). Thus, the majority of patients (88%) underwent useless and potentially dangerous surgeries (mean, 2.96 per patient). Manometry invariably showed abnormal motor patterns. Pathologic findings included neuropathies in all investigated cases and abnormalities of interstitial cells of Cajal in 5 of 11 cases. Long-term outcome was generally poor despite surgical and medical therapies; 4 patients died of disease-related complications, 4 underwent small bowel transplantation, almost one third required long-term home parenteral nutrition, and two thirds had some sort of nutritional limitations. CONCLUSIONS: CIIP is a severe, often unrecognized disease characterized by disabling and potentially life-threatening complications over time