Colitis-induced alterations in adrenergic control of circular smooth muscle in vitro in rats.

The present study investigated inflammation-induced changes in adrenergic regulation of smooth muscle. Colitis was induced in rats by intrarectal administration of trinitrobenzenesulfonic acid in ethanol. After 4 h (acute) or 7 days (chronic), in vitro isometric tension was measured in strips of circular smooth muscle taken from the distal colon. In controls, the major inhibitory control of smooth muscle responses to nerve stimulation was mediated by nitric oxide and beta adrenergic receptors. There was less evidence of alpha adrenergic control. Studies with the beta3 receptor antagonist cyanopindolol and the beta3 receptor agonist BRL37344 revealed that beta adrenergic regulation of spontaneous contractions and responses to nerve stimulation were mediated primarily by the beta3 adrenoreceptor. Both acute and chronic colitis significantly increased responses to electrical field stimulation. This effect was attributed to a loss of inhibitory nitrergic regulation as well as to selective changes in the beta adrenergic control of colonic circular smooth muscle. Inflammation did not alter alpha adrenergic control. Chronic colitis also decreased the sensitivity to nerve stimulation and pharmacological contractile agents. Acute and chronic inflammation reduced the ability of BRL37344 to inhibit contractions in response to nerve stimulation. In addition, in inflamed colon, BRL37344 was less effective in relaxing carbachol-induced precontractions. Finally, inflammation resulted in a loss of the ability of the cyanopindolol to increase the amplitude of both spontaneous contractions and contractions in response to nerve stimulation. These effects indicated that colitis induced a down-regulation of inhibitory beta3 adrenergic control of colonic smooth muscle function. This loss of adrenergic regulation may contribute to the diarrhea in inflammatory bowel disease.

The role of IL-4 in Heligmosomoides polygyrus-induced alterations in murine intestinal epithelial cell function.

IL-4 and IL-13 promote gastrointestinal worm expulsion, at least in part, through effects on nonlymphoid cells, such as intestinal epithelial cells. The role of IL-4/IL-13 in the regulation of intestinal epithelial function during Heligmosomoides polygyrus (Hp) infection was investigated in BALB/c mice infected with Hp or treated with a long-lasting formulation of recombinant mouse IL-4/alphaIL-4 complexes (IL-4C) for 7 days. Separate groups of BALB/c mice were drug-cured of initial infection and later reinfected and treated with anti-IL-4R mAb, an antagonist of IL-4 and IL-13 receptor binding, or with a control mAb. Segments of jejunum were mounted in Ussing chambers, and short circuit current responses to acetylcholine, histamine, serotonin, PGE2, and glucose were determined. Although only modest changes in epithelial cell function were observed during primary Hp infection, IL-4C or a secondary Hp infection each induced more dramatic changes, including increased mucosal permeability, reduced sodium-linked glucose absorption, and increased Cl- secretory response to PGE2. Some, but not all, effects of IL-4C and Hp infection were dependent on enteric nerves. Hp-induced changes in epithelial function were attenuated or prevented by anti-IL-4R mAb. Thus, IL-4/IL-13 mediate many of the effects of Hp infection on intestinal epithelial cell function and do so both through direct effects on epithelial cells and through indirect, enteric nerve-mediated prosecretory effects. These immune system-independent effector functions of IL-4/IL-13 may be important for host protection against gastrointestinal nematodes.

Etiology and treatment of achalasia in the pediatric age group.

Achalasia in children bears many similarities to the disorder in adults, both in terms of clinical features and in terms of the approach to therapy. Pharmacologic management is of limited temporary benefit until more definitive therapy is undertaken. Intrasphincteric injections of botulinum toxin provides safe but short-term relief from symptoms. Based on our review of the safety and effectiveness of pneumatic dilation, we advocate this procedure as the primary form of definitive therapy for achalasia in children. In patients who do not achieve satisfactory results from a series of graduated pneumatic dilations, Heller myotomy provides safe and effective surgical treatment.

Alterations in spontaneous contractions in vitro after repeated inflammation of rat distal colon.

In inflammatory bowel disease, smooth muscle function reportedly varies with disease duration. The aim of these studies was to determine changes in the control of spontaneous contractions in a model of experimental colitis that included reinflammation of the healed area. The amplitude and frequency of spontaneous contractions in circular smooth muscle were determined after intrarectal administration of trinitrobenzenesulfonic acid in rat distal colon. With the use of a novel paradigm, rats were studied 4 h (acute) or 28 days (healed) after the initial inflammation. At 28 days, rats were studied 4 h after a second inflammation (reinflamed) of the colon. Colitis induced transient increases in the amplitude of spontaneous contractions coincident with a loss of nitric oxide synthase activity. The frequency of contractions was controlled by constitutive nitric oxide in controls. Frequency was increased in healed and reinflamed colon and was associated with a shift in the dominance of neural constitutive nitric oxide synthase control to that of inducible nitric oxide synthase (iNOS). The initial colitis induced a remodeling of the neural control of spontaneous contractions reflecting changes in their regulation by constitutive nitric oxide synthase and iNOS.

Progressive alterations in circular smooth muscle contractility in TNBS-induced colitis in rats.

The present study was designed to investigate inflammation-induced changes in smooth muscle responses to acetylcholine and the tachykinins that may contribute to the abnormal motility associated with inflammatory bowel disease. Colitis was induced in male Sprague-Dawley rats by intrarectal administration of trinitrobenzenesulphonic acid in ethanol. After either 4 h (acute) or 7 days (chronic) the distal colon was taken for in vitro measurement of smooth muscle tension and histological assessment. Acute colitis featured injury and neutrophilic infiltration confined to the mucosa while chronic inflammation showed marked injury, lymphocytic infiltration and muscle thickening. Acute inflammation increased responses to substance P and acetylcholine but decreased responses to neurokinin A. The enhanced response to substance P was dependent on nerves, while the decreased response to neurokinin A reflected a reduction in activity at the level of the smooth muscle. In the saline group, there was evidence of cholinergic interaction with substance P, but not neurokinin A. Substance P modulation of cholinergic nerves was absent in acute inflammation. Responses to all neurotransmitters were decreased in the chronic stage. These data demonstrate progressive changes in the smooth muscle function during acute and chronic colitis that may contribute to the abnormal motility associated with inflammatory bowel disease.

Tachykinergic neurotransmission is enhanced in small intestinal circular muscle in a rabbit model of inflammation.

Previous electrophysiological studies have shown that tachykinin-mediated excitatory junction potentials are enhanced in a ricin model of inflammatory bowel disease. The present study extends these findings by investigating the contractile response to stimulation of noncholinergic nerves and tachykinin agonists. According to rank order potencies, the rabbit ileal circular muscle was neurokinin (NK)1 preferring, and the response to these agonists was down-regulated by acetylcholine and up-regulated by nitric oxide. In ricin-treated tissue, cholinergic and nitridergic modulation was lost; in the presence of atropine and N-nitro-L-arginine methyl ester, or tetrodotoxin, the response to NK1 and NK2 agonists was enhanced. The noncholinergic response to nerve stimulation was predominantly mediated by NK1 receptors, and the enhanced response of ricin-treated tissue to NK1 agonists probably contributes to the increased response to electrical field stimulation observed under these conditions. Increased tachykinin response and loss of control of this response by acetylcholine and nitric oxide are likely to have profound effects on intestinal motility and could contribute to some of the symptomology of inflammatory bowel disease.

Role of sensory afferents in the myoelectric response to acute enteric inflammation in the rabbit.

The role of sensory afferents in inflammation-induced alterations in myoelectric activity in vivo was investigated in the rabbit small intestine. Isolated ileal loops were implanted with serosal electrodes and exposed to ricin or vehicle after pretreatment with 125 mg/kg of subcutaneous (125 mg over 3 days) or intraluminal (640 microM) capsaicin. After 5 h of myoelectric recording, the loops were prepared for histology and for ex vivo generation of eicosanoids. Capsaicin exacerbated mucosal damage after exposure to ricin but did not alter neutrophil infiltration. Subcutaneous capsaicin alone elevated slow-wave frequency and spike events and transiently suppressed the myoelectric response to ricin. In contrast, intraluminal capsaicin alone did not alter myoelectric activity but produced a sustained inhibition of the response to ricin. Eicosanoid production was unchanged by capsaicin alone. Intraluminal capsaicin blocked increases in leukotriene C4 and prostaglandin E2 during inflammation, an effect that paralleled its inhibition of myoelectric activity. Thus the contribution of sensory afferents to altered motility during acute ileitis involves the release of mucosal inflammatory mediators that influence neural control of smooth muscle.

Intestinal motility changes in rats after enteric serotonergic neuron destruction.

The myenteric plexus consists of several subpopulations of morphologically and chemically distinct neurons known to contain a variety of peptides and amines, one of which is serotonin (5-hydroxytryptamine). These neurons are considered essential for nerve-to-nerve transmission. In the present study, we investigated the effect of 5,6- and 5,7-dihydroxytryptamine (5,6-DHT; 5,7-DHT), indoleamine neurotoxins that selectively and irreversibly injure the serotonergic neurons of the myenteric plexus. Treatment with 5,6-, or 5,7-DHT caused marked disruption of the activity front of the migrating myoelectric complex (MMC), increased its duration, and decreased its propagation velocity. At higher doses, 5,7-DHT also reduced the slow-wave frequency. Immunohistochemical techniques showed that tissue from rats treated with 5,7-DHT was depleted of serotonin-like immunoreactivity within the myenteric plexus neurons. Reserpine also caused motility and immunohistochemical changes similar to those induced by the two neurotoxins. Therefore, destruction of enteric serotonergic neurons disrupts the MMC. These studies support the cellular concepts that serotonergic neurons function as interneurons in the myenteric plexus, modulating and processing the neural stimuli, and that serotonin is an important neurotransmitter in the small intestine.

Colonic leiomyoma--an unusual cause of gastrointestinal hemorrhage in childhood. Report of a case.

Leiomyomas of the intestine are rarely found in the pediatric population. The authors' review of the literature revealed only three colonic leiomyomas previously described. The authors present the first reported case of a child with lower gastrointestinal hemorrhage secondary to a colonic leiomyoma. Pathologic aspects of intestinal leiomyomas are discussed along with the difficulty in histologic differentiation from leiomyosarcomas. Wide resection is recommended for spindle cell neoplasms of the intestine owing to difficulty in differentiating benign from malignant tumors.

Morbidity and mortality in children with pyogenic liver abscess.

Review of our experience from 1975 to 1986 and a literature survey disclosed 109 children with pyogenic liver abscess. During this time, newer imaging techniques, especially ultrasonography and computed tomography, facilitated the prompt diagnosis of cystic lesions within the liver parenchyma. The incidence of pyogenic liver abscess at our institution (25 per 100,000 pediatric hospital admissions) was higher than previously reported. Since the majority of abscesses were located in the right lobe of the liver, patients were most effectively treated with percutaneous drainage of the abscess cavity. Staphylococcus aureus was the most common bacterial agent responsible for pyogenic liver abscess; however, anaerobic organisms were noted as a major group of pathogens and represented 27% of our patients. Furthermore, one patient was discovered to have multiple microabscesses of the liver associated with cat-scratch disease; pleomorphic gram-negative bacilli were not cultured. Among the 109 patients, the overall mortality of 15% was considerably better than that for children with PLA before 1975. The improved survival may be related to more prompt diagnosis of pyogenic liver abscess followed by evacuation of the liver abscess and antibiotic therapy.

Migrating myoelectric complex demonstrated in four avian species.

The migrating myoelectric complex (MMC) is demonstrated in four avian species: three gallinaceous birds (Gallus, Phasianus, Coturnix) and an owl (Strix). The complex in birds is strikingly similar to the MMC that is known in mammalian species. It has the same basic pattern of quiescence, followed by a period of irregular spike activity, then a period of intense regular spike activity, and finally a return to quiescence. The frequency and duration of avian MMCs are similar to those of mammals, but the propagation velocity and slow-wave frequency are slower. Granivorous birds (Gallus, Phasianus) and carnivores (Strix) exhibit the same basic motility patterns whether in the fed or fasted states. Interspecific differences occur, however, in the details of frequency, propagation velocity, duration, and slow-wave frequency. The closely related galliforms (chickens, pheasants) are more similar to each other in MMC characteristics than either is to the more distantly related owls.

Abnormal gastroduodenal motility in children and adolescents with recurrent functional abdominal pain.

To determine whether motor activity of the stomach and proximal small intestine is a factor in recurrent abdominal pain in adolescents, we prospectively investigated eight patients with recurrent abdominal pain and compared them with seven normal adolescents. All patients underwent a detailed examination to exclude other known organic causes of the pain. The gastroduodenal motor activity during fasting was studied with a semiconductor recording probe. The recordings were analyzed for periodicity, duration, and propagation velocity of the activity front of the migrating motor complex. The amplitude of the antral and duodenal contractions was also determined. The patients with recurrent abdominal pain had more frequent migrating motor complexes, but these were shorter in duration and moved more slowly down the intestine (slower propagation velocities). The patients also had high-pressure duodenal contractions that were associated with abdominal pain during the study period. These studies suggest that altered intestinal motility may be the underlying mechanism of recurrent abdominal pain in some children.

Lack of efficacy of thickened feeding as treatment for gastroesophageal reflux.

The efficacy of thickened feedings for the treatment of gastroesophageal reflux in infancy was evaluated. Fifty-two infants were examined with prolonged pH monitoring of the distal esophagus after feedings of apple juice or apple juice thickened with rice cereal. All infants had a minimum of three feedings of both thickened and unthickened juice. The recordings of distal esophageal pH were analyzed for the percent of time the pH was less than 4 in the first 2 hours after each feeding. The infants were maintained in the following positions after feeding: prone (n = 29), prone-board with the head elevated 30 degrees from horizontal (n = 29), supine (n = 7), and unrestricted (n = 21). We found no significant difference in the percent of time with reflux with thickened versus unthickened feedings except in those infants maintained in the 30-degree prone position. In the first 2 hours after eating thickened juice, infants maintained in this position had increased esophageal reflux time (P less than 0.006). Further analysis revealed that 33% of the infants had a greater than 30% increase in esophageal reflux time after thickened feedings. Our study suggests that the immediate effect of thickened feedings on gastroesophageal reflux in infants is unpredictable.

Migrating action potential complex: unmasked by 6-hydroxydopamine.

We have previously described the myoelectric characteristics of a single moving ring contraction, the migrating action potential complex (MAPC), in rabbit ileal loops exposed to certain bacteria or their enterotoxins. The MAPC is thought to act as a defense mechanism of the host, clearing unwanted substances from the lumen. In the present study, 6-hydroxydopamine, a substance that selectively destroys adrenergic varicosities containing the neurotransmitter norepinephrine, unmasked the MAPC from the activity front of the migrating motor complex in an unanesthetized rat model. The animals developed diarrhea and lost weight. The study suggests that the MAPC may also be a physiological complex and under the modulation of the enteric nervous system. The MAPC may not be seen under normal control conditions because the complex migrates with the activity front and is under inhibitory control. Destroying the inhibitory mechanisms unmasked the MAPC from the activity front of the migrating motor complex and allowed neural transmission of the ring contraction.