Pediatric chronic intestinal pseudo-obstruction is a rare disorder characterized by a severe impairment of gastrointestinal motility leading to intestinal obstruction symptoms in the absence of mechanical causes. The diagnosis is usually clinical and diagnostic work is usually aimed to rule out mechanical obstruction and to identify any underlying diseases. Treatment is challenging and requires a multidisciplinary effort. In this manuscript we describe the youngest child successfully treated with the orally administrable, longacting, reversible anti-cholinesterase drug, pyridostigmine. Like other drugs belonging to cholinesterase inhibitors, pyridostigmine enhances gut motility by increasing acetylcholine availability in the enteric nervous system and neuro-muscular junctions. Based on the direct evidence from the reported case, we reviewed the current literature on the use of pyridostigmine in severe pediatric dysmotility focusing on intestinal pseudo-obstruction. The overall data emerged from the few published studies suggest that pyridostigmine is an effective and usually well tolerated therapeutic options for patients with intestinal pseudo-obstruction. More specifically, the main results obtained by pyridostigmine included marked reduction of abdominal distension, reduced need of parenteral nutrition, and improvement of oral feeding. The present case and review on pyridostigmine pave the way for eagerly awaited future randomized controlled studies testing the efficacy of cholinesterase inhibitors in pediatric severe gut dysmotility.

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Post-infectious irritable bowel syndrome is a well-defined pathological entity that develops in about one-third of subjects after an acute infection (bacterial, viral) or parasitic infestation. Only recently it has been documented that an high incidence of post-infectious irritable bowel syndrome occurs after Clostridium difficile infection. However, until now it is not known why in some patients recovered from this infection the gastrointestinal disturbances persist for months or years. Based on our in vitro studies on enteric glial cells exposed to the effects of C. difficile toxin B, we hypothesize that persistence of symptoms up to the development of irritable bowel syndrome might be due to a disturbance/impairment of the correct functions of the enteroglial intestinal network.

BACKGROUND: All the enteric ganglion cells are fully mature by 2 to 5 years of age in human. No one had reported the presentation of immature enteric ganglion cells in elder ones. Colorectal carcinoma is also rare in the adolescent population. The coincidence of these 2 rare events in a 13-year-old boy has never been reported elsewhere, which may suggest some linkage between them.
METHODS: A 13-year-old boy presented with progressive abdominal pain and melena for 3 months. Computed tomography (CT) scan and endoscopic ultrasonography showed significant abnormality in the transverse colon characteristic of marked mural thickening. The biopsy results indicated signet ring cell carcinoma.
METHODS: A 13-year-old male patient with advanced colon signet ring cell carcinoma. In addition, immature but not mature ganglion cells could be observed in almost all of the slices of the resected nontumorous area of the specimen.
METHODS: The transverse colon tumor was resected and the subsequent histopathological examination confirmed the diagnosis of primary colon signet ring cell carcinoma. Then the patient received adjuvant chemotherapy and biological target therapies subsequently.
RESULTS: After 6 cycles of adjuvant chemotherapy and biological target therapies, metastasis was however detected within a year.
CONCLUSIONS: In this case, a 13-year-old male patient with advanced colon signet ring cell carcinoma were presented. Unexpectedly, immature ganglion cells could be observed in almost all of the slices of the resected nontumorous area of the specimen. It is critical to raise medical awareness and improve the diagnosis and treatment of the signet ring cell carcinoma. This malignancy and the immature ganglion cells may be associated, possibly caused by some unidentified genetic defects. Genome sequencing, histopathological examination, and long-term follow-up of young patients with related diseases, would help further reveal the potential relationship between tumorigenesis and ganglion cells\' immaturity, contributing to understanding the molecular mechanisms.

A patient with early achalasia presented spontaneous strong rhythmic non-propulsive contractions at ~7/min, independent of swallows. Our aim was to evaluate characteristics of the rhythmic contractions, provide data on the structure of pacemaker cells in the esophagus and discuss a potential role for interstitial cells of Cajal (ICC) in the origin of rhythmicity. We hypothesize that intramuscular ICC (ICC-IM) are the primary pacemaker cells. The frequency but not the amplitude of the rhythmic contractions was inhibited by the phosphodiesterase inhibitor drotaverine consistent with cAMP inhibiting pacemaker currents in ICC-IM. The frequency increased by wet swallows but not dry swallows, consistent with stretch causing increase in slow wave frequency in ICC-IM. New studies on archival material showed that ICC-IM were present throughout the human esophageal musculature and were not diminished in early achalasia. Although ICC-IM exhibited a low density, they were connected to PDGFRα-positive fibroblast-like cells with whom they formed a dense gap junction coupled network. Nitrergic innervation of ICC was strongly diminished in early achalasia because of the loss of nitrergic nerves. It therefore appears possibly that ICC-IM function as pacemaker cells in the esophagus and that the network of ICC and PDGFRα-positive cells allows for coupling and propagation of the pacemaker activity. Loss of nitrergic innervation to ICC in achalasia may render them more excitable such that its pacemaker activity is more easily expressed. Loss of propagation in achalasia may be due to loss of contraction-induced aboral nitrergic inhibition.

Intestinal ganglioneuromatosis (GN) is an uncommon disease of the enteric nervous system (ENS) and its pathogenesis remains unclear. Here we describe a unique case of diffuse GN of the intestinal wall associated with colon adenocarcinoma occurring in a 38-year-old female. Because it is well-known that glial cell line-derived neurotrophic factor (GDNF) and its receptor components, GDNF family receptor-alpha 1 (GFR-alpha 1) and RET receptor tyrosine kinase, play a crucial role in the development of ENS, their expression was analyzed by immunohistochemistry. Interestingly, GDNF as well as a related neurotrophic factor, neurturin (NTN), were expressed at high levels in adenocarcinoma cells whereas expression of GFR alpha 1 and RET was undetectable in them. In contrast, GFR-alpha 1 showed positive staining in both proliferating ganglion cells and glial cells, and RET immunoreactivity was found mainly in ganglion cell bodies. These findings suggested that GDNF and NTN expression in adenocarcinoma cells may play an important role in the pathogenesis of GN.

BACKGROUND: The pathophysiological basis of diabetic gastroparesis is poorly understood, in large part due to the almost complete lack of data on neuropathological and molecular changes in the stomachs of patients. Experimental models indicate various lesions affecting the vagus, muscle, enteric neurons, interstitial cells of Cajal (ICC) or other cellular components. The aim of this study was to use modern analytical methods to determine morphological and molecular changes in the gastric wall in patients with diabetic gastroparesis.
METHODS: Full thickness gastric biopsies were obtained laparoscopically from two gastroparetic patients undergoing surgical intervention and from disease-free areas of control subjects undergoing other forms of gastric surgery. Samples were processed for histological and immunohistochemical examination.
RESULTS: Although both patients had severe refractory symptoms with malnutrition, requiring the placement of a gastric stimulator, one of them had no significant abnormalities as compared with controls. This patient had an abrupt onset of symptoms with a relatively short duration of diabetes that was well controlled. By contrast, the other patient had long standing brittle and poorly controlled diabetes with numerous episodes of diabetic ketoacidosis and frequent hypoglycemic episodes. Histological examination in this patient revealed increased fibrosis in the muscle layers as well as significantly fewer nerve fibers and myenteric neurons as assessed by PGP9.5 staining. Further, significant reduction was seen in staining for neuronal nitric oxide synthase, heme oxygenase-2, tyrosine hydroxylase as well as for c-KIT.
CONCLUSIONS: We conclude that poor metabolic control is associated with significant pathological changes in the gastric wall that affect all major components including muscle, neurons and ICC. Severe symptoms can occur in the absence of these changes, however and may reflect vagal, central or hormonal influences. Gastroparesis is therefore likely to be a heterogeneous disorder. Careful molecular and pathological analysis may allow more precise phenotypic differentiation and shed insight into the underlying mechanisms as well as identify novel therapeutic targets.

The Interstitial Cells of Cajal (ICC) are responsible for rhythmic electrical activity. A paralytic ileus is present in gastroschisis (GS), a malformation due to a defective closure of the abdominal wall through which part of the intestine herniates during pregnancy. In experimental GS, ICC morphological immaturity was shown in the rat foetus at-term but it could not be demonstrated whether differentiation is accomplished post-natally. For this purpose we morphologically investigated ICC, as well as enteric neurons and smooth muscle cells, in a case of human GS at birth and 1 month later when peristaltic activity had initiated. A 36 weeks gestation female was born by c/section with prenatal diagnosis of GS and possible volvulus of the herniated intestine. At birth, the necrotic intestine was resected and both ileostomy and colostomy were performed. The intestine continuity was restored after 4 weeks. Intestinal specimens, taken during both operations at the level of the proximal stoma, were immunostained with c-kit, neuron-specific-enolase and alpha-smooth-muscle-actin antibodies and some processed for electron microscopy. ICC were present at the myenteric plexus only. At birth, these cells were rare and ultrastructurally immature; 1 month later, when partial enteral feeding was tolerated, they formed rows or groups and many of them were ultrastructurally differentiated. Neurons and smooth muscle cells, immature at birth, had developed after 1 month. Therefore, ICC differentiation, as well as that of neurons and smooth muscle cells, is delayed at birth and this might explain the paralytic ileus in GS. One month later, differentiation quickly proceeded at all cellular levels paralleling the increasing tolerance of enteral nutrition.

Previously no functional study has been available for the mechanism of constipation in familial amyloid polyneuropathy (FAP). We performed a gut function test in a 78-year-old woman with transthyretin-type FAP who had severe constipation. The gut function test showed a prolonged colonic transit time, a low anal pressure at rest and upon squeezing, loss of the spontaneous phasic rectal contractions, and weak abdominal strain. All these abnormalities suggested a peripheral autonomic dysfunction, corresponding to the enteric neuropathy that was confirmed upon autopsy.

Experimental evidence indicates that chronic mechanical sub-occlusion of the intestine may damage the enteric nervous system (ENS), although data in humans are lacking. We here describe the first case of enteric degenerative neuropathy related to a congenital obstruction of the gut. A 3-year and 9-mo old girl began to complain of vomiting, abdominal distension, constipation with air-fluid levels at plane abdominal radiology. Her subsequent medical history was characterized by 3 operations: the first showed dilated duodeno-jejunal loops in the absence of occlusive lesions; the second (2 years later) was performed to obtain full-thickness biopsies of the dilated intestinal loops and revealed hyperganglionosis at histopathology; the third (9 years after the hyperganglionosis was identified) disclosed a Ladd\'s band which was removed and the associated gut malrotation was corrected. Repeated intraoperative full-thickness biopsies showed enteric degenerative neuropathy along with reduced interstitial cells of Cajal network in dilated loops above the obstruction and a normal neuromuscular layer below the Ladd\'s band. One year after the latest surgery the patient tolerated oral feeding and did well, suggesting that congenital (partial) mechanical obstruction of the small bowel in humans can evoke progressive adaptive changes of the ENS which are similar to those found in animal models of intestinal mechanical occlusion. Such ENS changes mimic neuronal abnormalities observed in intestinal pseudo-obstruction.