Severe Intestinal Dysmotility Research Articles

Exploring the complexities of megacystis-microcolon-intestinal hypoperistalsis syndrome: insights from genetic studies.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is an uncommon genetic disorder inherited in an autosomal recessive pattern that affects the muscles that line the bladder and intestines. The most common genes associated with MMIHS mutations are ACTG2, LMOD1, MYH11, MYL9, MYLK, and PDCL3. However, the complete genetic landscape of MMIHS still needs to be fully understood. The diagnosis of MMIHS can be challenging. However, advances in prenatal and diagnostic techniques, such as ultrasound and fetal urine analysis, have improved the ability to detect the syndrome early. Targeted next-generation sequencing (NGS) and other diagnostic tests can also diagnose MMIHS. The management of MMIHS involves addressing severe intestinal dysmotility, which often necessitates total parenteral nutrition (TPN), which can lead to complications such as hepatotoxicity and nutritional deficiencies. Multivisceral and intestinal transplantation has emerged as therapeutic options, offering the potential for improved outcomes and enteral autonomy.Understanding the genetic underpinnings of MMIHS is crucial for personalized care. While the prognosis varies, timely interventions and careful monitoring enhance patient outcomes. Genetic studies have given us valuable insights into the molecular mechanisms of MMIHS. These studies have identified mutations in genes involved in the development and function of smooth muscle cells. They have also shown that MMIHS is associated with defects in the signaling pathways that control muscle contraction. Continued research in the genetics of MMIHS holds promise for unraveling the complexities of MMIHS and improving the lives of affected individuals.

TFAP2B Haploinsufficiency Impacts Gastrointestinal Function and Leads to Pediatric Intestinal Pseudo-obstruction.

Background: Pediatric Intestinal Pseudo-obstruction (PIPO) is a congenital enteric disorder characterized by severe gastrointestinal (GI) dysmotility, without mechanical obstruction. Although several genes have been described to cause this disease, most patients do not receive a genetic diagnosis. Here, we aim to identify the genetic cause of PIPO in a patient diagnosed with severe intestinal dysmotility shortly after birth. Methods: Whole exome sequencing (WES) was performed in the patient and unaffected parents, in a diagnostic setting. After identification of the potential disease-causing variant, its functional consequences were determined in vitro and in vivo. For this, expression constructs with and without the causing variant, were overexpressed in HEK293 cells. To investigate the role of the candidate gene in GI development and function, a zebrafish model was generated where its expression was disrupted using CRISPR/Cas9 editing. Results: WES analysis identified a de novo heterozygous deletion in TFAP2B (NM_003221.4:c.602-5_606delTCTAGTTCCA), classified as a variant of unknown significance. In vitro studies showed that this deletion affects RNA splicing and results in loss of exon 4, leading to the appearance of a premature stop codon and absence of TFAP2B protein. Disruption of tfap2b in zebrafish led to decreased enteric neuronal numbers and delayed transit time. However, no defects in neuronal differentiation were detected. tfap2b crispants also showed decreased levels of ednrbb mRNA, a downstream target of tfap2b. Conclusion: We showed that TFAP2B haploinsufficiency leads to reduced neuronal numbers and GI dysmotility, suggesting for the first time, that this gene is involved in PIPO pathogenesis.

Multiple Roles of Ret Signalling During Enteric Neurogenesis.

The majority of the enteric nervous system is formed by vagal neural crest cells which enter the foregut and migrate rostrocaudally to colonise the entire length of the gastrointestinal tract. Absence of enteric ganglia from the distal colon are the hallmark of Hirschsprung disease, a congenital disorder characterised by severe intestinal dysmotility. Mutations in the receptor tyrosine kinase RET have been identified in approximately 50% of familial cases of Hirschsprung disease but the cellular processes misregulated in this condition remain unclear. By lineage tracing neural crest cells in mice homozygous for a knock-in allele of Ret (Ret51/51), we demonstrate that normal activity of this receptor is required in vivo for the migration of enteric nervous system progenitors throughout the gut. In mutant mice, progenitors of enteric neurons fail to colonise the distal colon, indicating that failure of colonisation of the distal intestine is a major contributing factor for the pathogenesis of Hirschsprung disease. Enteric nervous system progenitors in the ganglionic proximal guts of mutant mice are also characterised by reduced proliferation and differentiation. These findings suggest that the functional abnormalities in Hirschsprung disease result from a combination of colonic aganglionosis and deficits in neuronal circuitry of more proximal gut segments. The reduced neurogenesis in the gut of Ret51/51 mutants was reproduced in the multilineage enteric nervous system progenitors isolated from these animals. Correction of the molecular defects of such progenitors fully restored their neurogenic potential in culture. These observations enhance our understanding of the pathogenesis of Hirschsprung disease and highlight potential approaches for its treatment.

Propagation patterns of jejunal motor activity measured by high-resolution water-perfused manometry.

The manometric diagnosis of severe intestinal dysmotility is performed at most institutions using catheters with 2-8 sensors 5-10cm apart. The recent application of high-resolution manometry catheters with closely spaced sensors to other gut segments has been highly successful. The objective of the present study was to determine the feasibility of a jejunal high-resolution manometry method and to carry out a descriptive analysis of normal jejunal motor function. A 36-channel high-resolution water-perfused manometry catheter (MMS-Laborie, Enschede, The Netherlands) was orally placed in the jejunum of 18 healthy subjects (10 men, eight women; 21-38 age range). Intestinal motility was recorded during 5h, 3 during fasting, and 2 after a 450kcal solid-liquid meal. Analysis of motility patterns was supported by computerized tools. All healthy subjects except one showed at least one complete migrating motor complex during the 3h fasting period. Phase III activity lasted 5±1min and migrated aborally at a velocity of 7±3cm/min. High-resolution spatial analysis showed that during phase III each individual contraction propagated rapidly (75±37cm/min) over a 32±10cm segment of the jejunum. During phase II, most contractile activity corresponded to propagated contractile events which increased in frequency from early to late phase II (0.5±0.9 vs 2.5±1.3 events/10min, respectively; p<0.001). After meal ingestion, non-propagated activity increased, whereas propagated events were less frequent than during late phase II. Jejunal motility analysis with high-resolution manometry identifies propagated contractile patterns which are not apparent with conventional manometric catheters.

Nutritional considerations in severe primary chronic small intestinal dysmotility.

To provide an update on the recent evidence underpinning the approach to nutritional care in patients with severe primary chronic small bowel dysmotility. Patients with severe chronic small intestinal dysmotility suffer nutritional and nonnutritional morbidity, both as a result of their underlying polysymptomatic, poorly understood condition and the interventions required. A proportion require artificial nutrition support; however, this is associated with impaired quality of life and associated complications. The approach to nutritional support must therefore engage a multidisciplinary team (MDT) to ensure that decisions to escalate beyond oral nutrition reflect individualised risk-benefit discussions while adopting a holistic approach to symptom management. Since nutritional outcomes are worse in those with the chronic intestinal pseudo-obstruction (CIPO) phenotype, differentiation into CIPO and non-CIPO subgroups, using a pragmatic diagnostic approach rather than invasive/poorly tolerated investigations, can be an important step in achieving nutritional care tailored to the individual. Malnutrition in patients with severe chronic small intestinal dysmotility is multifactorial. Early engagement of a broad team that includes dietitians, psychologists and pain management experts is crucial to achieving the most beneficial and least harmful patient-centred nutritional care outcomes.

The management of adult patients with severe chronic small intestinal dysmotility

Adult patients with severe chronic small intestinal dysmotility are not uncommon and can be difficult to manage. This guideline gives an outline of how to make the diagnosis. It discusses...

Intestinal involvement in amyloidosis is a sequential process.

Gastrointestinal amyloidosis causes dysmotility. A comprehensive histological analysis to explain these symptoms is lacking. Therefore, we systematically examined histological features of intestinal dysmotility in patients with AL and AA amyloidosis, compared to controls. Autopsy tissue material from small bowel and colon was used for histological (semiquantitative) evaluation of the mucosa, blood vessels, muscular layers, enteric nervous system (ENS) and the interstitial cells of Cajal (ICC), using hematoxylin and eosin, periodic acid Schiff, Elastic von Gieson and Congo red staining, and immunohistochemistry with α-smooth muscle actin, HuC/D, S100 and CD117 antibodies, according to guidelines of the Gastro 2009 International Working Group. Amyloid deposits were present in the vascular walls of all amyloidosis patients. In the mucosa, amyloid was found in 67% of AA patients. The muscular layers were involved in 64% of amyloidosis patients, most prominent in AA patients, associated with the presence of polyglucosan inclusion bodies, but not with either abnormal α-actin patterns or fibrosis. Amyloid in the muscularis propria surrounding the myenteric plexus was found, but not inside the myenteric plexus. These deposits might be related to loss of the ICC network, but there was no association with decreased neuronal or nerve fiber density. We hypothesize that intestinal dysmotility in amyloidosis patients is a sequential process: amyloid deposition starts in the vasculature, followed by involvement of the muscular layers, ICC loss, and potentially affect the myenteric plexus. This final stage may be accompanied by clinical symptoms of severe intestinal dysmotility.

Functional neuromuscular impairment in severe intestinal dysmotility.

Chronic intestinal pseudo-obstruction (CIPO) and enteric dysmotility (ED) are severe intestinal motility disorders usually associated with underlying neuromuscular abnormalities. To evaluate the in vitro neuromuscular function of patients with severe intestinal motility disorders. Full-thickness intestinal biopsies (16 jejunum and 3 ileum) obtained from patients with CIPO (n=10) and ED (n=9) were studied using muscle bath and microelectrode techniques. Control samples (n=6 ileum and n=6 jejunum) were used to establish the range of normality. Fourteen parameters were defined to assess muscle contractility and nerve-muscle interaction: five to evaluate smooth muscle and interstitial cells of Cajal (ICC) and nine to evaluate inhibitory neuromuscular transmission. For each sample, a parameter was scored 0 if the value was inside the normal range or a value of 1 if it was outside. Patients' samples (CIPO/ED) had more abnormal parameters than controls (P<0.001 for both jejunum and ileum). Functional abnormalities were found to be heterogeneous. The most prevalent abnormality was a decreased purinergic neuromuscular transmission, which was detected in 43.8% of jejunal samples. Abnormalities of neuromuscular intestinal function are detected in vitro in severe intestinal dysmotility. However, consistent with the heterogeneity of the disease pathophysiology, functional impairment cannot be attributed to a single mechanism. Specifically, defects of purinergic neuromuscular transmission may have an important role in motility disorders of the gastrointestinal tract.

Loss of alpha-smooth muscle actin expression associated with chronic intestinal pseudo-obstruction in a young Miniature Bull Terrier

BackgroundChronic intestinal pseudo-obstruction (CIPO) is a rare clinical syndrome in veterinary medicine characterized by severe intestinal dysmotility without evidence of mechanical occlusion of the intestinal lumen. The exact pathogenesis of CIPO is unknown.Case presentationA 1-year-old male Miniature Bull Terrier dog was presented with a history of chronic weight loss, regurgitation, lethargy, vomiting and diarrhea. The dog was submitted for exploratory laparotomy. A full thickness intestinal biopsy was taken and a CIPO was suspected. The clinical condition deteriorated and the dog was euthanized. At gross examination the small intestine was severely dilated. Histologically severe fibrosis of the submucosa and severe atrophy of the tunica muscularis were present in small intestine and colon. Immunohistochemical examination with a panel of antibodies for gastro-intestinal neuromuscular disease-associated antigens revealed a severely reduced expression of alpha-smooth muscle actin in the tunica muscularis.ConclusionsThis case report describes the gross, histological and immunohistochemical findings of CIPO affecting a 1-year-old Miniature Bull Terrier; on the basis of these findings a myopathic form of CIPO is hypothesized in this case.

Complex gastroschisis: Clinical spectrum and neonatal outcomes at a referral center

Aim of the studyTo evaluate the outcomes of neonates with complex gastroschisis (GC), and correlate outcomes with each type of complication. MethodsRetrospective review of patients with complex GC owing to prenatal and/or postnatal abdominal complications; 2008–2016. Primary outcomes: time to discontinue parenteral nutrition (off-PN), length of stay (LOS) and neonatal survival. Main resultsWe treated 58 patients with complex gastroschisis owing to abdominal complications, which were: intestinal necrosis at birth (n=9), intestinal atresia (n=16), medical necrotizing enterocolitis (NEC) (n=15), surgical NEC (n=1), in utero volvulus (n=1), vanishing gastroschisis (n=2), severe intestinal dysmotility (n=1), delayed abdominal closure (n=3), abdominal compartment syndrome (n=2) and hiatal hernia/severe gastroesophageal reflux disease (GERD; n=11). The off-PN time and LOS of the whole group were 92 (35–255) and 119 (42–282) days, significantly longer than those of a demographically equivalent contemporaneous series of 125 patients with uncomplicated gastroschisis (off-PN 32 [12–105] days [p<0.001]; LOS 41 [18–150] days [p<0.001]). Patients with intestinal necrosis at birth or with intestinal atresia had the longest off-PN and LOS times (133 [38–255] / 157 [43–282] and 114 [36–222] / 143 [42–262] days, respectively), followed by patients with complications of the abdominal wall closure (n=5) (69 [43–93] / 89 [58–110] days), patients with hiatal hernias/severe GERD who required fundoplication (63 [35–84] / 89 [57–123] days) and patients who developed medical NEC (67 [35–103] / 76 [50–113] days). Short-bowel syndrome/PN-dependence occurred in 6/58 (10%) patients (2 vanishing gastroschisis, 1 in utero volvulus, 2 intestinal atresias and 1 bowel necrosis at birth). There were no neonatal mortalities. ConclusionGastroschisis can be complicated by a wide variety of prenatal and postnatal events. The most severe outcomes occur in patients with bowel necrosis at birth, intestinal atresias, or vanishing gastroschisis. Complications, however, did not affect neonatal survival in our experience. Level of evidenceIII.

Comparison between small bowel manometric patterns and full-thickness biopsy histopathology in severe intestinal dysmotility.

Intestinal manometry is the current standard for direct evaluation of small bowel dysmotility. Patients with abnormal motility can either be diagnosed of pseudo-obstruction when there are radiological findings mimicking mechanical intestinal obstruction or of enteric dysmotility when these findings are absent. The aim of the present study was to prospectively compare small bowel manometric abnormalities with histopathological findings in intestinal full-thickness biopsies in patients with severe dysmotility disorders. We investigated 38 patients with intestinal manometry and a subsequent full-thickness intestinal biopsy. Manometric recordings were read by 4 investigators and a diagnostic consensus was obtained in 35 patients. Histopathological analysis, including specific immunohistochemical techniques of small bowel biopsies was performed and compared to manometric readings. Patients with abnormal intestinal manometry had abnormal histopathological findings in 73% of cases. However, manometric patterns did not match with the specific neuromuscular abnormalities. Among patients with a neuropathic manometry pattern and abnormal histopathology, only 23% had an enteric neuropathy, whereas 62% had neuromuscular inflammation, and 15% an enteric myopathy. On the other hand, patients with a myopathic manometry pattern all had abnormal histopathology, however, none of them with signs of enteric myopathy. Small bowel dysmotility detected by intestinal manometry is often associated with abnormal neuromuscular findings in full-thickness biopsies. However, there is no correlation between the specific manometric patterns and the histopathological findings.

Chronic intestinal pseudo-obstruction in a child with Treacher Collins syndrome

Treacher Collins syndrome (TCS) mainly presents with severe craniofacial developmental abnormalities characterized by a combination of bilateral downward-slanting palpebral fissures, colobomas of the lower eyelids, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss. It is due to mutations in Treacher Collins syndrome 1 (TCOF1) (5q32-q33.1) and Polymerase RNA 1 polypeptides D and C (POLR1D [13q12.2], and POLR1C [6p21.1]) genes, which are responsible for increased neuroepithelial apoptosis during embryogenesis resulting in the lack of neural crest cells involved in facial bone and cartilage formation. Altered function of the upper digestive tract has been reported, whereas severe dysmotility disorders have never been reported. We describe here the first case of TCS associated with histologically proven chronic intestinal pseudo-obstruction (CIPO) in humans. Case presentatios A 12-year-old boy with TCS due to TCOF1 gene deletion experienced nutritional difficulties and digestive intolerance from birth. CIPO was suspected during childhood because of severe intestinal dysmotility leading to enteral-jejunal nutrition intolerance and dependence on total parenteral nutrition. Diagnosis of CIPO with nervous abnormalities was histologically confirmed on a surgical rectal biopsy that showed enlarged ganglionic myenteric plexus. At the age of 9 years, an isolated colonic stenosis without dilatation responsible for severe abdominal pain and altered quality of life led to digestive derivation contributing to rapid disappearance of chronic abdominal pain. At the age of 12 years, the patient was still dependent on total home parenteral nutrition 7 days a week to maintain regular growth velocity. Recently, mice studies have pointed out the role played by TCOF1 in ganglionic cell migration in the foregut, suggesting that the synergistic haploinsufficiency of Tcof1 and Pax3, a transcription factor regulating the RET gene involved in disorders of neural crest cell development, probably results in colonic aganglionosis and may explain the association described here between TCS and CIPO. This case may correspond to this possible mechanism in humans. These findings and our clinical report suggest that CIPO may be assessed as unusual digestive manifestations in TCS with TCOF1 deletion.

A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity

Hirschsprung disease (HSCR) is characterized by absence of enteric neurons from the distal colon and severe intestinal dysmotility. To understand the pathophysiology and genetics of HSCR we developed a unique zebrafish model that allows combined genetic, developmental and in vivo physiological studies. We show that ret mutant zebrafish exhibit cellular, physiological and genetic features of HSCR, including absence of intestinal neurons, reduced peristalsis, and varying phenotype expressivity in the heterozygous state. We perform live imaging experiments using a UAS-GAL4 binary genetic system to drive fluorescent protein expression in ENS progenitors. We demonstrate that ENS progenitors migrate at reduced speed in ret heterozygous embryos, without changes in proliferation or survival, establishing this as a principal pathogenic mechanism for distal aganglionosis. We show, using live imaging of actual intestinal movements, that intestinal motility is severely compromised in ret mutants, and partially impaired in ret heterozygous larvae, and establish a clear correlation between neuron position and organised intestinal motility. We exploited the partially penetrant ret heterozygous phenotype as a sensitised background to test the influence of a candidate modifier gene. We generated mapk10 loss-of-function mutants, which show reduced numbers of enteric neurons. Significantly, we show that introduction of mapk10 mutations into ret heterozygotes enhanced the ENS deficit, supporting MAPK10 as a HSCR susceptibility locus. Our studies demonstrate that ret heterozygous zebrafish is a sensitized model, with many significant advantages over existing murine models, to explore the pathophysiology and complex genetics of HSCR.

Altered expression of retinoblastoma 1 in Hirschsprung's disease

PurposeThe retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development, and has been widely documented to be inactivated in human cancer. A recent study using RB1 knockout mice suggested a new role for RB1 in the normal regulation of the enteric nervous system (ENS), because of knockout mice showing ENS abnormalities and severe intestinal dysmotility. The aim of our study was to investigate the expression of RB1 in the normal human colon and in Hirschsprung's disease (HD). Materials and methodsHD tissue specimens (n=10) were collected at the time of pull-through surgery, while colonic control samples were obtained at the time of colostomy closure in patients with imperforate anus (n=10). Immunolabeling of RB1 was visualized using confocal microscopy to assess protein distribution, while western blot analysis was undertaken to quantify RB1 protein expression. ResultsImmunohistochemistry revealed RB1 co-localized with platelet derived growth factor receptor alpha-positive (PDGFRα+) cells, nitrergic neurons and glia in controls and the ganglionic region of HD, with a marked reduction in the aganglionic HD specimens. Western blotting revealed a marked decrease in RB1 protein expression in the aganglionic region of HD colon compared to ganglionic and normal controls. ConclusionWe provide evidence of the presence of RB1 expression in the human colon in HD. As RB1 is known to colocalize with nitrergic neurons, the decreased expression of RB1 in the aganglionic bowel is most likely a secondary phenomenon because of the deficient nitrergic innervation in HD.

A Novel Mutation in Nucleoporin 35 Causes Murine Degenerative Colonic Smooth Muscle Myopathy

Chronic intestinal pseudo-obstruction (CIPO) is a rare but life-threatening disease characterized by severe intestinal dysmotility. Histopathologic studies in CIPO patients have identified several different mechanisms that appear to be involved in the dysmotility, including defects in neurons, smooth muscle, or interstitial cells of Cajal. Currently there are few mouse models of the various forms of CIPO. We generated a mouse with a point mutation in the RNA recognition motif of the Nup35 gene, which encodes a component of the nuclear pore complex. Nup35 mutants developed a severe megacolon and exhibited a reduced lifespan. Histopathologic examination revealed a degenerative myopathy that developed after birth and specifically affected smooth muscle in the colon; smooth muscle in the small bowel and the bladder were not affected. Furthermore, no defects were found in enteric neurons or interstitial cells of Cajal. Nup35 mice are likely to be a valuable model for the subtype of CIPO characterized by degenerative myopathy. Our study also raises the possibility that Nup35 polymorphisms could contribute to some cases of CIPO.

Mutations in RAD21 Disrupt Regulation of APOB in Patients With Chronic Intestinal Pseudo-Obstruction

Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with noevidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers. 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. 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. 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.

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility

Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon. Neuronally mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in 'area under the curve'. Prucalopride increased cholinergically mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30-100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 μM) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3-7, each concentration). Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction.

Mechanisms of abdominal distension in severe intestinal dysmotility: abdomino‐thoracic response to gut retention

We previously showed that abdominal distension in patients with functional gut disorders is due to a paradoxical diaphragmatic contraction without major increment in intraabdominal volume. Our aim was to characterize the pattern of gas retention and the abdomino-thoracic mechanics associated with abdominal distension in patients with intestinal dysmotility. In 15 patients with manometrically proven intestinal dysmotility, two abdominal CT scans were performed: one during basal conditions and other during an episode of severe abdominal distension. In 15 gender- and age-matched healthy controls, a basal scan was performed. In basal conditions, patients exhibited more abdominal gas than healthy subjects, particularly in the small bowel, and the volume significantly increased during an episode of distension. During episodes of abdominal distension, the increase in abdominal content was associated with increased girth and antero-posterior abdominal diameter, as well as a cephalic displacement of the diaphragm, which reduced the height of the lung. The consequent reduction in the air volume of the lung was attenuated by an increase in the antero-posterior diameter of the chest. Abdominal distension in patients with severe intestinal dysfunction is related to marked pooling of gut contents, particularly in the small bowel. This increase in content is accommodated within the abdominal cavity by a global and coordinated abdomino-phreno-thoracic response, involving an accommodative ascent of the diaphragm and a compensatory expansion of the chest wall.

Enteric Nervous System Impairment in Gastroschisis

After surgical repair of gastroschisis, most neonates exhibit severe intestinal dysmotility. We hypothesized that impaired development of the enteric nervous system or interstitial cells of Cajal (ICC) network contributes to impaired intestinal motility in gastroschisis. We evaluated this hypothesis in a rat model of gastroschisis. Gastroschisis was created surgically in rat fetuses on gestational day 18, under general anesthesia, and small bowel was harvested on day 22. Intestinal weight-to-length (IW/L) ratio, and small-bowel wall thickness were assessed. Specimens were processed for hematoxylin-eosin staining or immunohistochemistry with specific markers for neuronal cells (Hoxb5), glial cells (GFAP, S100), and ICCs (c-kit). Myenteric plexus maturation was assessed morphologically and compared with sham and control fetuses. Stage of development of the myenteric plexus was graded from 1 (mature) to 3 (very immature) comparatively with specimens from E16 to E22 control fetuses. Compared with sham-operated or control fetuses, gastroschisis was associated with increases in mean intestinal weight/intestinal length (IW/L) ratio, and mean thicknesses of the total, muscular, and submucosal layers of the small-bowel wall. The myenteric plexus were present in the small bowel from fetuses with gastroschisis, however all exhibited abnormal myenteric plexus maturation. Thus, of the gastroschisis fetuses, 55% had an aspect similar to the immature myenteric plexus of E19-E20 fetuses and 45% to the very immature mesenteric plexus observed in E16-E18 fetuses. When compared with sham and control groups, ICCs were less abundant in eviscerated small bowel in the gastroschisis group and often exhibited weak c-kit staining or an abnormally round shape without branches. Hoxb5, a marker for enteric neuroblasts and neuronal precursors, was expressed similarly in myenteric plexuses in all groups. S100 or GFAP staining showed the presence of glial cells within the myenteric plexuses in all groups. The S100 expression level was similar in all groups. In contrast, the GFAP expression level was higher in the gastroschisis group than in the sham and control groups. Our results suggest that delayed maturation of the enteric nervous system combined with impaired ICC network development may largely explain the intestinal dysmotility seen in neonates with gastroschisis.

Percutaneous gastrojejunostomy in children: efficacy and safety

Transgastric jejunal intubation via gastrostomy (GJ) can be indicated when enteral nutrition via gastrostomy is not possible. Between 2001 and 2008, the authors prospectively assessed the outcomes in 29 patients...