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Biomedical subjects

J R Malagelada

Publications and source records attributed to J R Malagelada.

At least 19 recordsLinked to original sources
PubMed1992

Symptomatic responses to stimulation of sensory pathways in the jejunum.

We hypothesized that intestinal afferent pathways inducing perception may be selectively activated by transmucosal electrical nerve stimulation, without disruption of the intrinsic myoelectrical rhythm. Hence, in 12 healthy subjects we measured perception (by a questionnaire) and jejunal slow wave activity (by electromyography), and we randomly applied for 1 min at 5-min intervals graded electrical (15 Hz, 100 microseconds) and mechanical stimuli (balloon distension) in the jejunum up to the respective discomfort threshold. Electrical and mechanical stimuli induced dose-related perception; the perception and discomfort thresholds were 39 +/- 7 and 63 +/- 6 mA and 31 +/- 3 and 49 +/- 5 ml for electrical and mechanical stimuli, respectively. More than one-half of electrical stimuli elicited clinical-type symptoms (abdominal pressure, fullness, colicky or sharp sensation) similar to those induced by mechanical stimuli; the remaining electrical stimuli (38 +/- 10%) induced paresthesia or flutterlike sensation. Similar types of symptoms were perceived with weak and strong stimuli. Jejunal slow wave activity (11.3 +/- 0.4 cycles/min) was not modified by either stimuli. We conclude that activation of intestinal sensory pathways, either by transmucosal nerve stimulation or via mechanoreceptors, induces a similar dose-related symptomatic response, without interfering with the intrinsic myoelectrical activity.

Adult↗
PubMed1992

Dietary manipulation in experimental inflammatory bowel disease.

Eicosanoids are major mediators of defensive and inflammatory processes of the gut mucosa. The activity of the eicosanoid system is modulated by neural and hormonal pathways, but local factors acting within the gastrointestinal lumen may also be involved. We have studied the influence of dietary fatty acids on eicosanoid synthesis by the gastrointestinal mucosa. Since omega-3 fatty acids compete with the omega-6 as precursors of eicosanoid synthesis, we compared the effects of dietary supplementation with either sunflower or cod liver oil as sources of omega-6 or omega-3 fatty acids, respectively. Rats fed with the cod-liver-oil-supplemented diet for four weeks showed high omega-3 and low omega-6 plasma fatty acid levels compared to rats fed with the sunflower oil diet. Synthesis of arachidonic-acid-derived eicosanoids (6-keto-PGF1 alpha, PGE2, TXB2, LTB4, and LTC4) by gastric and intestinal mucosa was found to be lower in the cod liver group as compared to the sunflower group. However, significant generation of eicosapentaenoic-acid-derived eicosanoids (PGE3 and LTC5) was observed only in the cod liver group. We used the (trinitrobenzenesulphonic acid) TNBS model of inflammatory colitis to test the effect of the dietary fat on the development of inflammatory lesions of the bowel. A single intracolonic instillation of the hapten TNBS dissolved in 10% ethanol induces chronic granulomatous lesions of the colonic mucosa that persist for up to 8 weeks. Luminal release of eicosanoid mediators, as measured by intracolonic dialysis, was lower in the cod liver group than in the sunflower group, particularly during the chronic stage of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Duodenal mucosal resistance to intraluminal acid in the rat: role of adaptive cytoprotection.

The duodenal mucosa is normally challenged by intermittent exposure to acid because of periodic gastric emptying. We studied the mechanisms of duodenal adaptation to acid in anesthetized rats. A polyvinyl chloride tube passing through a ligated pylorus was used for duodenal pulse instillations of 1 mL of saline or acid (100 or 400 mumols HCl) at 30-minute intervals. Duodenal lesions were blindly assessed using a combined macroscopic and histological score. Mucosal damage after exposure to saline or 100 mumols HCl was negligible in intact, vagotomized, and indomethacin-pretreated rats, whereas 400 mumols induced noticeable macroscopic and microscopic lesions. Interestingly, in intact and vagotomized rats, previous exposure to a 100-mumols HCl bolus significantly prevented mucosal damage by a subsequent 400-mumols bolus. This effect was not observed in indomethacin-pretreated rats. In these rats, however, intraduodenal instillation of exogenous 16,16-dimethyl prostaglandin E2 (16,16-dm-PGE2) prevented the damage induced by 400 mumols of HCl. A second protocol investigated the luminal release of bicarbonate and PGE2 in response to intraduodenal perfusion with 100 mumols of HCl. Duodenal bicarbonate release was stimulated by acid in all groups, whereas the release of PGE2 increased in intact and vagotomized rats but not in the indomethacin-pretreated group. In summary, these data suggest that adaptive cytoprotection plays a significant role in protecting the duodenal mucosa from acid. Vagal innervation and bicarbonate release do not appear to be as critical as cyclo-oxygenase activity for this mechanism.

16,16-Dimethylprostaglandin E2↗
PubMed1991

Effect of obesity on gastroesophageal resistance to flow in man.

Chronic (obesity) and acute intraabdominal pressure increases appear to favor gastroesophageal reflux, but the mechanism is not completely understood. We hypothesized that it could be due to an alteration in the resistance gradient between the stomach and the gastroesophageal junction, even increasing intragastric resistance above resistance at the gastroesophageal junction. Hence, we used a pneumatic resistometer to measure gastric and gastroesophageal resistance to flow in 11 lean healthy controls and eight morbidly obese individuals without gastroesophageal reflux disease. Resistance was quantified at rest and during acute intraabdominal pressure increases, both in the recumbent and sitting positions. We found that gastroesophageal junction resistance was higher than gastric resistance in lean as well as in obese subjects (P less than 0.001). In obese individuals both gastric and gastroesophageal junction resistance were increased (P less than 0.001), thus a normal gastric-gastroesophageal junction resistance gradient was maintained. Body position did not modify resistance. Acute increases in intraabdominal pressure decreased the gastric-gastroesophageal junction resistance gradient similarly in obese and lean subjects. We conclude that obesity by itself does not appear to predispose to gastroesophageal reflux, but it creates intraabdominal conditions that may favor reflux whenever the gastroesophageal barrier becomes weakened.

Adult↗
PubMed1991

Long-term efficacy of oral cisapride in symptomatic upper gut dysmotility.

We conducted a 12-month trial of cisapride (10 mg three times a day) in 21 patients with gastric stasis due to clinically and manometrically diagnosed gastroparesis (N = 9; seven due to diabetes) or chronic intestinal pseudo-obstruction (N = 12). Radionuclide solid-liquid gastric emptying tests were performed at baseline and at the end of the 12-month period. Symptoms were assessed monthly by diary and every three months by the investigators; frequency and severity of symptoms were scored in a standardized manner. For the whole group of 21 patients, gastric emptying of both solids and liquids improved significantly after one year of cisapride (P less than 0.05). Among chronic intestinal pseudoobstruction patients, there was predominantly an improvement in gastric emptying of solids; in contrast, patients with gastroparesis had a greater improvement in liquid emptying. Total symptom score improved significantly in the gastroparesis group (median score: 8 at baseline vs 6 at one year, P less than 0.05) but not in the chronic intestinal pseudoobstruction patients (median score at baseline 10 vs 9 at one year). Similarly, body weight showed a trend towards improvement in the gastroparesis group. No significant side effects were noted. We conclude that during a 12-month open trial, cisapride was effective in improving gastric emptying in patients with gastric stasis and consistently improved symptoms in those with gastroparesis.

Administration, Oral↗
PubMed1991

Sensorial and intestinointestinal reflex pathways in the human jejunum.

Using an intestinal barostat that maintains a constant pressure within an air-filled bag (12 cm long), the authors have previously shown reflex changes in intestinal tone induced by distention. The aim of this study was to investigate the sensitivity and the responsiveness to such reflexes along the jejunum. Eight healthy volunteers were studied using two barostats operating simultaneously in the proximal and the distal jejunum (located 10 cm and 52 cm caudad to the ligament of Treitz, respectively). With one barostat, standardized distentions (1 minute duration at 10-minute intervals in 4-mm Hg increments) were produced; with the other barostat, intestinal tone was measured as volumetric variations at constant pressure. Perception was scored (0-6) by a questionnaire. The proximal jejunum relaxed in response to distention of the distal jejunum (mean +/- SE, 40% + 7% delta vol; 5.1 + 0.1 perception score at the threshold for discomfort; P less than 0.05 for both). In contrast, the distal jejunum did not respond to distention of the proximal jejunum, whereas the perception scores were similar (10% +/- 5% delta vol; 5.1 +/- 0.1 perception score). Thus, the responsiveness of the proximal jejunum to intestinointestinal reflexes fades distally, whereas intestinal sensitivity to distention remains uniform.

Adult↗
PubMed1991

Enteric neuronal autoantibodies in pseudoobstruction with small-cell lung carcinoma.

Severe gastrointestinal dysmotility is a newly recognized paraneoplastic syndrome that occurs with small-cell lung carcinoma. Thirty-four patients with small-cell carcinoma, of whom 5 had chronic intestinal pseudoobstruction and 29 had no digestive symptoms, were studied serologically. Four of the 5 patients with gut dysmotility had immunoglobulin G antibodies reactive with neurons of the myenteric and submucosal plexuses of jejunum and stomach in an indirect immunofluorescence assay. Antibodies of this type were not found in any of the 29 patients who had no gut dysmotility, nor were they found in patients with chronic idiopathic intestinal pseudoobstruction (n = 8), ovarian cancer (n = 20), or epilepsy (n = 4) or in normal subjects (n = 9). In 4 of the patients with paraneoplastic pseudoobstruction, antibodies in highly diluted serum (1:4000-1:8000) bound selectively to nuclei and cytoplasm of neuronal elements in the gut. This novel autoantibody activity suggests that intestinal pseudoobstruction occurring in patients with small-cell carcinoma may have an autoimmune basis. From a clinical standpoint, serological testing offers a simple means for determining which patients with gut dysmotility syndromes may have associated small-cell carcinoma, thereby enabling earlier diagnosis and treatment of the tumor.

Aged↗
PubMed1991

The origin of symptoms on the brain-gut axis in functional dyspepsia.

It was hypothesized that symptoms in functional dyspepsia are originated by an altered mechanism at the brain-gut axis (one or several) in the process of gastric accommodation to a meal. To test the key mechanisms potentially involved in symptomatic gastric accommodation, the sensorial responses (on a 0-10 perception score) and the gastric tone responses (by electronic barostat) to either gastric accommodation (n = 10) or to cold stress (n = 10) were measured in 20 patients with functional dyspepsia and 20 healthy controls. The mechanical accommodation of the stomach to gastric distention (compliance) was similar in patients (52 +/- 8 mL/mm Hg) and controls (57 +/- 6 mL/mm Hg). However, isobaric gastric distention elicited more upper abdominal discomfort in dyspeptics than in controls (perception scores, 4.7 +/- 0.9 vs. 1.1 +/- 0.5, respectively; mean +/- SE; P less than 0.005). Cold stress induced a similar gastric relaxatory response in dyspeptics and controls (delta vol, 145 mL +/- 40 mL vs. 141 mL +/- 42 mL, respectively); hand perception (scores, 8.3 +/- 0.4 vs. 7.9 +/- 0.4, respectively) and autonomic responses were also similar. It is concluded that an abnormal afferent sensorial pathway (altered gastric perception) may be a major mechanism of symptom production in functional dyspepsia.

Adult↗
PubMed1991

Reflex changes in intestinal tone: relationship to perception.

Using an original technique, we demonstrated a modulation of intestinal tonic muscular activity (intestinal tone) by intestino-intestinal reflexes. In 11 healthy volunteers we quantitated intestinal tone variations as changes in the air volume within a flaccid bag (12 cm long) located in the proximal jejunum and maintained at a constant pressure by an electronic barostat. Validation studies with glucagon showed significant intestinal relaxation (117 +/- 10% delta vol; P less than 0.05). In six healthy volunteers, graded balloon distensions (1 min duration at 10-min intervals in 8-ml stepwise increments) were randomly performed 8 cm orad, 8 cm caudad, and 20 cm caudad to the bag of the barostat. Perception was scored (0-6) by a questionnaire. Distensions at the three sites induced similar perception; at the threshold for discomfort (score greater than or equal to 5) distension also induced intestinal relaxatory responses (43 +/- 10%, 34 +/- 5%, and 32 +/- 4% delta vol from orad to caudad, respectively; P less than 0.05 for all). However, while unperceived orad distensions (13 +/- 2 ml) induced reflex relaxation (21 +/- 6% delta vol; P less than 0.05), 20-cm-caudad distensions at higher levels (16 +/- 2 ml, 2.7 +/- 0.5 perception score; P less than 0.05) did not (1 +/- 7% delta vol). This dissociation between perception and intestinal tone reflexes suggests that both responses to intestinal distension are mediated by specific mechanisms.

Adult↗
PubMed1991

Gastrointestinal motor disturbances in functional dyspepsia.

Since dyspepsia, as clinically defined, may constitute a heterogeneous group of conditions, it comes as no surprise that the pathophysiologic disturbances are diverse in character and prevalence. Furthermore, there is no convincing evidence that gastric and/or intestinal motor abnormalities differ among the clinical subgroups of dyspepsia. It is reasonable to suspect that a dyspeptic patient may have a gastrointestinal motor disturbance, since about half of them have delayed gastric emptying and antral hypomotility. However, proof of such motor disorder requires physiologic investigation. Even then, certainty as to whether motor abnormalities and symptoms have a causal relationship is often difficult to obtain.

Dyspepsia↗
PubMed1991

When and how to investigate the dyspeptic patient.

When and how to investigate the dyspeptic patient is an issue that requires careful analysis and excludes dogmatic assertions. There are several key decision factors that must be considered on a case-by-case basis: who is the patient, what kind of physician cares for the patient, and what level of uncertainty are both patient and physician prepared to accept? These factors determine to a large extent whether reassurance only, a therapeutic trial, or diagnostic investigation will be carried out. The latter may also be stratified at two levels: a basic level at which the aim to exclude major organic disease as the cause of dyspeptic symptoms and a higher level at which more complex imaging and physiologic tests would be carried out to achieve a more precise diagnosis.

Dyspepsia↗
PubMed1991

[Comparative multicentric study of omeprazole versus ranitidine in the treatment of duodenal ulcer].

A total of 158 patients, aged 19-78 years and with endoscopically verified duodenal ulcer of at least 5 mm in maximum diameter were recruited. 79 patients were randomised to treatment with omeprazole, a proton-pump inhibitor of the parietal cell, and 79 patients were treated with ranitidine. This double blind study is the first clinical trial with omeprazole in Spain. Using "intention to treat" analysis there was no difference in healing rates at 2 weeks between the omeprazole group (70%) and the ranitidine group (59%) with p = 0.13. At four weeks, however, omeprazole healed significantly more patients (92%) than ranitidine (76%) with p = 0.005. Using per protocol analysis a similar result was obtained with no significant difference between omeprazole (71%) and ranitidine (63%) at two weeks (p = 0.3) but significantly greater healing on omeprazole at 4 weeks (97%) compared with ranitidine (83%) with p = 0.008. The influence of additional prognostic factors was assessed using a multivariate analysis. At two and four weeks, there was a significant effect of ulcer size on healing rate. At four weeks there was also a significant effect of treatment. Symptom relief was rapid in both treatments but the omeprazole group had significantly fewer days of pain and better patient's overall evaluation than ranitidine group. No serious adverse events were reported. In conclusion omeprazole healed significantly more duodenal ulcers than ranitidine and symptom relief was more rapid during omeprazole therapy.

Adult↗
PubMed1990

Demonstration of intrathecal and systemic morphine and ST-91 effects on fed canine upper gut motility.

We studied the effects of opioid and adrenergic agonists and antagonists given systemically intravenously and intrathecally on postprandial antral and small bowel motility in a chronic conscious dog model. We studied eight dogs with a surgically implanted thoracic spinal intrathecal injection catheter, and six gastrointestinal manometric perfusion catheters. Morphine given intrathecally or intravenously induced propagated clusters of intestinal pressure activity in the fed dogs. The minimal effective dose for morphine was 150 micrograms/kg by the intrathecal route and 450 micrograms/kg by the intravenous route. ST-91 (an alpha 2-adrenergic agonist) profoundly inhibited antral and small intestinal pressure activity with similar minimal effective dose (100 micrograms/kg) and duration of effect for both intravenous and intrathecal routes. Neither naloxone (3000 micrograms/kg) nor combined phentolamine (1500 micrograms/kg) with propranolol (300 micrograms/kg) altered postprandial antral or small intestinal motility. The capacity of pharmacologic agents to block morphine-induced activity fronts when administered in the same compartment (intravenously or intrathecally) was investigated. The minimally effective morphine-antagonist dose for naloxone was similar intrathecally and intravenously (36 micrograms/kg for both routes). ST-91 (100 micrograms/kg) when given intrathecally or intravenously blocked morphine-induced clustered phasic pressure activity while simultaneously abolishing postprandial small intestine phasic pressure activity. These data suggest the presence of opioid and alpha 2-adrenergic receptors in the spinal cord that can modulate gastrointestinal motility in the postprandial state. Pharmacological interactions between these systems occur at spinal and target organ levels.

Adrenergic alpha-Agonists↗
PubMed1990

Participation of thromboxane and other eicosanoid synthesis in the course of experimental inflammatory colitis.

Eicosanoids, as modulators of inflammation, may be involved in the pathogenesis of inflammatory bowel disease. We investigated their potential role in a rat model of chronic granulomatous colonic inflammation induced by trinitrobenzene sulphonic acid. Luminal eicosanoid release was quantified in vivo using a dialysis bag placed into the distal colon. We tested the effect of drugs known to modify inflammatory activity or arachidonic acid metabolism. Three days after intracolonic injection of trinitrobenzene sulphonic acid at different dose levels, the dialysates showed a highly significant increase of prostaglandin E2, 6-keto-prostaglandin F1 alpha, thromboxane B2 (TXB2), and leukotriene B4, compared with levels in controls not subjected to the toxic agent. Remarkably, the release of TXB2 continued to increase during the stage of chronic inflammation (up to day 21), whereas the levels of the remainder eicosanoids declined. Treatment with prednisone or 5-aminosalicylic acid reduced TXB2 levels in the chronic stage of the inflammatory disease and improved the morphological damage as assessed macroscopically and histologically. Moreover, two selective thromboxane synthetase inhibitors, OKY 1581 and R70416, significantly reduced the development of chronic inflammatory lesions in the colon while inhibiting the release of TXB2. Our results indicate that (1) luminal release of thromboxane increases in the chronic stage of colonic inflammation, (2) anti-inflammatory treatment reduces tissue damage and thromboxane release, and (3) selective thromboxane synthetase inhibition improves the course of the disease in our experimental model.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Dietary fish oil reduces progression of chronic inflammatory lesions in a rat model of granulomatous colitis.

Eicosanoids are modulators of defensive and inflammatory processes in the gut mucosa, and may be involved in the pathogenesis of chronic inflammatory lesions of the bowel. As omega-3 fatty acids compete with the omega-6 as precursors of eicosanoid synthesis, we compared the effects of dietary supplementation with either sunflower (source of omega-6) or cod liver (source of omega-3) oil on the development of chronic granulomatous lesions in the rat colon. After four weeks on the supplemented diets, plasma omega-6 fatty acid content was significantly higher in the sunflower group, while omega-3 fatty acids predominated in the cod liver group. Inflammatory colitis was then induced by intracolonic administration of trinitrobenzene sulphonic acid. Luminal eicosanoid release, as measured by radioimmunoassay of intracolonic dialysis fluid, increased significantly after the challenge in both groups. Generation of prostaglandin E2 (PGE2) and leucotriene B4 (LTB4) peaked by day 3 and thereafter declined; thromboxane B2 (TXB2), instead, continued to increase from day 3 to 20 in sunflower fed rats, whereas this change was blunted in cod liver animals. The rats were killed 20, 30, or 50 days after the induction of colitis, and the colonic lesions were scored macroscopically (adhesions to surrounding tissues, strictures, ulcerations, and wall thickness) and histologically (ulceration, inflammation, depth of the lesions, and fibrosis). In cod liver animals, the damage score was markedly reduced by day 30, and inflammation and ulceration were almost absent by day 50. In conclusion, a fish oil diet prevents the increase in thromboxane in the chronic state of inflammation and shortens the course of the colonic disease by diminishing both the severity of the lesions and their progression to chronicity.

Animals↗
PubMed1979

Different gastric, pancreatic, and biliary responses to solid-liquid or homogenized meals.

We have compared responses to an ordinary solid-liquid (S) meal and to a homogenized (H) meal of identical composition (sirloin steak, bread, butter, ice cream with chocolate syrup, and water) by measuring simultaneously postprandial gastric, pancreatic, and biliary functions by marker-perfusion techniques. Responses to each (S or H) meals differed strikingly both in magnitude and pattern. S meals elicited a stronger early gastric secretory response (acid, pepsin, and volume) which compensated for faster initial emptying and resulted in higher gastric acidity and volume than after H meals. Further, nutrients ingested with S meals were emptied at a slower rate than H (as evidenced by a more gradual decline in intragastric buffer and osmolality, as well as time required for complete emptying of the meal). This, in turn, prolonged pancreatic and biliary responses since stimulation of these organs continued for as long as meal was delivered into the duodenum. However, early biliary outputs (gallbladder response) were less after S than H, probably because nutrients entered the duodenum more slowly and were initially diluted by rapidly emptying water. The physical characteristics of each meal (encompassing appearance, taste, and form of ingestion) probably accounted for early differences in digestive responses. Later, interactions between gastric (motor and secretory), pancreatic, and biliary functions played a major role. Our findings suggest that gastric, pancreatic, and biliary responses to liquid test meals introduced into the stomach may differ substantially from the presumably more physiological response to ordinary solid-liquid meals.

Adult↗