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

Immediate vs. deferred switching from a boosted protease inhibitor (PI/r) based regimen to a Dolutegravir (DTG) based regimen in virologically suppressed patients with high cardiovascular risk or Age ≥50 years: final 96 weeks results of NEAT 022 study

Background Both immediate and deferred switching from a ritonavir-boosted protease inhibitor (PI/r)–based regimen to a dolutegravir (DTG)–based regimen may improve lipid profile. Methods European Network for AIDS Treatment 022 Study (NEAT022) is a European, open-label, randomized trial. Human immunodeficiency virus (HIV)–infected adults aged ≥50 years or with a Framingham score ≥10% were eligible if HIV RNA was <50 copies/mL. Patients were randomized to switch from PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D). Week 96 endpoints were proportion of patients with HIV RNA <50 copies/mL, percentage change of lipid fractions, and adverse events (AEs). Results Four hundred fifteen patients were randomized: 205 to DTG-I and 210 DTG-D. The primary objective of noninferiority at week 48 was met. At week 96, treatment success rate was 92.2% in the DTG-I arm and 87% in the DTG-D arm (difference, 5.2% [95% confidence interval, –.6% to 11%]). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AEs or treatment-modifying AEs. Total cholesterol and other lipid fractions (except high-density lipoprotein) significantly (P < .001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV-infected patients ≥50 years old or with a Framingham score ≥10% was highly efficacious and well tolerated, and improved the lipid profile

Diagnostic challenges of symptomatic uncomplicated diverticular disease

Colonic diverticulosis is a common condition in Western industrialized countries occurring in up to 65% of people over the age of 60 years. Only a minority of these subjects (about 10-25%) experience symptoms, fulfilling Rome III Diagnostic Criteria for irritable bowel syndrome (IBS) diagnosis (IBS-like symptoms) in 10% to 66% of cases. Symptomatic uncomplicated diverticular disease (SUDD) is a syndrome characterized by recurrent abdominal symptoms attributed to diverticula in the absence of macroscopically evident alterations other than the presence of diverticula. Due to the different peak of incidence, the overlap between SUDD and IBS is predominantly present in middle-aged or older patients. In these cases, it is very complex to establish if the symptoms are related to the presence of diverticula or due to an overlapping IBS. In fact, the link between gastrointestinal symptoms and diverticula is unclear, and the mechanism by which diverticula may induce the development of IBS-like symptoms remains to be elucidated. Currently, the etiology and pathophysiology of SUDD, particularly when IBS-like symptoms are present, are not completely understood, and thus these two entities remain a diagnostic challenge not only for the general practitioner but also for the gastroenterologist. Although many issues remain open and unresolved, some minimize the importance of a distinction of these two entities as dietary and pharmacological management may be largely overlapping

Chronic intestinal pseudo-obstruction: A neuropathological approach

Chronic intestinal pseudo-obstruction (CIPO) is a rare syndrome at the extreme end of severe functional bowel disorders. The clinical picture is characterized by a marked impairment of gut propulsive motility, thus mimicking a mechanical obstruction in the absence of any detectable organic cause constricting the gastrointestinal tract. CIPO is still a clinical challenge, and histopathology may be a valuable tool in the diagnostic workup. The histopathological correlates in CIPO include neural, interstitial cells of Cajal (ICC), and/or muscle abnormalities (hence, neuropathy, myopathy and ICC abnormalities), either alone or in combination. Apart from generating a diagnosis, detection of a given histopathological pattern may provide physicians with a guide to prognosis; thus, CIPO patients with an underlying myopathy usually have the poorest outcome compared to those with neuropathy or other patterns. Similar considerations can be applied to genetic forms of CIPO. Peculiar neuropathic/myopathic features, i.e. eosinophilic intraneuronal inclusions in enteric neurons, myenteric/submucosal ganglioneuromas of the enteric nervous system, and a more prominent involvement of the longitudinal rather than the circular layer throughout the gut may suggest CIPO of genetic origin. Another important aspect pertains to the identification of an immune-mediated/inflammatory neuropathy/leiomyositis that can be managed with immunosuppressive drugs. Although still inconclusive, the data published so far are promising and pave the way for future, well-designed trials to test the actual efficacy of immunosuppressive drugs in patients with CIPO due to an underlying inflammatory neuropathy. Future research on gut neuro-ICC-muscular abnormalities is expected to improve diagnostic and therapeutic strategies in patients with CIPO

Is gastroparesis a gastric disease?

Background: Gastroparesis is a digestive syndrome characterized by delayed gastric emptying (GE) and by symptoms that are suggestive of gastroduodenal motor disorders. There are three grades of gastroparesis of increasing severity: (a) mild gastroparesis; (b) compensated gastroparesis; and (c) gastric failure. GE abnormalities are partially related to symptom type and severity, and other mechanisms may be involved. Aim: To investigate enteric dysmotility (ED) in patients with suspected gastroparesis. Methods: Patients with symptoms suggestive of gastroparesis were consecutively included in the study and underwent a 13 C-octanoic acid GE breath test and small bowel manometry (SBM). Clinical features were recorded using predefined, validated questionnaires at entry. Key Results: The study enrolled 88 patients (71 women; mean age: 37.8&nbsp;±&nbsp;14.3&nbsp;years). Gastric emptying was delayed in 25 patients (28.4%), and 70 patients (79.5%) presented small bowel motor abnormalities including bursts, abnormal activity fronts, inability to respond to meal ingestion, and hypocontractility. Gastric emptying was delayed in 24 of the 70 patients with ED (34.3% vs 5.5% of patients with normal SBM). Enteric dysmotility was detected in 24 of 25 patients (96%) with delayed GE. Patients with and without delayed GE showed similar moderate/severe gastroparesis manifestations, but patients with ED significantly more often had moderate/severe gastroparesis manifestations than patients with normal SBM (grade 1:14% vs 39%, grade 2:62% vs 56%, grade 3:24% vs 5%, respectively). Conclusions and Inferences: Enteric dysmotility was more frequent than delayed GE in patients with symptoms suggestive of gastroparesis. Gastroparesis severity was associated with small bowel motor abnormalities but not with delayed GE

Probiotics and irritable bowel syndrome: rationale and clinical evidence for their use.

Growing evidence suggests a potential role of intestinal microbiota in irritable bowel syndrome (IBS) pathophysiology and symptom generation. Earlier studies based on classic microbiologic techniques hypothesized the presence of qualitative changes in intestinal microbiota in IBS patients. Recently, studies with molecular techniques have provided evidence of significant changes in microbial profiles in IBS and that the composition may be correlated with certain symptoms reported by patients. Although these studies are far from being exhaustive and conclusive they provide promising results that deserve further investigation. In addition, initial evidence indicated the presence of increased amounts of bacteria in the upper small intestine of IBS patients, a condition know as small intestinal bacterial overgrowth. However, the results of these studies have provided contradictory results suggesting that this area requires further work. These qualitative and quantitative changes in intestinal microbiota may induce different effects on the intestinal mucosa including mucosal barrier defects and immune activation which may contribute to symptom generation. Studies in IBS patients have attempted to target changes in intestinal microflora with different therapeutic approaches, such as the use of prebiotics, probiotics, synbiotics, and nonabsorbable and systemic antibiotics. Overall, the results obtained in probiotic clinical trials suggest some beneficial effect over placebo in the relief of IBS symptoms. However, these results, although encouraging, should be confirmed in larger well-designed, placebo-controlled studies. A number of open questions remain to be addressed, including the dose, type, and time of administration of probiotics

Delayed gastric emptying in functional dyspepsia

Functional dyspepsia is a complex syndrome with a poorly defined pathophysiology, resulting in uncertainties in its therapeutic approach. Abnormalities in gastrointestinal motility and sensitivity alone or combined seem to play a role in a substantial subgroup of patients. Drugs capable of prokinetic effects, such as antidopaminergics (eg, metoclopramide, domperidone, levosulpiride) and serotonin 5-HT4 receptor agonists (eg, tegaserod) can be potentially used in the treatment of dyspeptic patients. Furthermore, 5-HT4 receptor agonists do not appear to increase the gastric fundus tone which may also contribute to improved symptoms in subsets of patients. Alosetron, a 5-HT3 receptor antagonist, has been investigated mainly in irritable bowel syndrome, and the few studies performed in functional dyspepsia have provided conflicting results. Erythromycin and related derivatives, the motilides, represent another class of prokinetic compounds able to accelerate gastric emptying and potentially indicated in functional dyspepsia. The stimulatory effect on fundic tone and the occurrence of tachyphilaxis hamper the efficacy of these drugs in the long-term treatment. κ-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but there are few available results and most are inconclusive. Results are also needed to prove efficacy of antidepressants (tricyclic agents and 5-HT reuptake inhibitors). Future clinical trials should be performed so that the formal structure required by good clinical practice can be adapted to detect significant effects in subgroups of patients with functional dyspepsia. Therapy should be ideally targeted to the different pathophysiologic abnormalities of these subgroups. The identification of the mechanisms leading to symptom generation should facilitate the development of newer and more effective therapeutic strategies in functional dyspepsia