Digestive Diseases and Sciences

This study was undertaken to assess a possible role for γ-aminobutyric acid (GABA) in the regulation of intestinal secretion of IgA and IgG antibodies. Rats were immunized with culture supernatant of Aeromonas hydrophila isolate SSU. This culture supernatant contains a number of toxins that may be considered virulence factors. After 24 days of immunization, rats were anesthetized and a 10-cm intestinal segment was intubated and ligated at both ends in situ. The intestinal loop was perfused with phosphate-buffered saline (PBS). The effluents were collected for measurement of IgA and IgG by the ELISA. When compared with the effect of intravenous administration of normal saline in the control group, intravenous injection of GABA (30 mg/kg) resulted in a significant increase of IgA and IgG secretion in the experimental group. These stimulatory effects of GABA on secretion of IgA and IgG were abolished by bicuculline, a GABA-receptor antagonist, and by atropine, indicating that the GABA-stimulated secretion of IgA and IgG was mediated via the GABA receptors and cholinergic muscarinic receptors. These results suggest that GABA may participate in the nervous regulation of intestinal secretion of IgA and IgG antibodies in the rat.

In this paper we have attempted to outline in a general way the important pathways of conduction of pain from, and mechanics of production of pain in, the viscera in the upper part of the abdomen. The general principles involved follow a pattern similar to that encountered in cases of benign lesions of the stomach. We felt that, if gastric carcinoma superficially invades the tissues of the stomach and results in disturbances of its normal mechanics, pain may result. This pain would utilize pathways coursing along the splanchnic vessels. In order to be interpreted as pain, these irregularities in mechanics would require an “adequate” stimulus which, in this case, would be spasm or obstruction. If, on the other hand, the lesion burrows through the gastric wall into the tissues surrounding the organ, pain would be relayed to the spinal cord over the spinal sensory group of nerves and, in this instance, wide distribution and reference of pain may be produced. If the lesion invades the regions of the distribution of the phrenic nerve, pain will be referred into the left side of the thorax and to the “peripheral distribution” of this nerve which would be into the left shoulder and the base of the neck. Such a lesion is usually inoperable. Any stimulus which would initiate the sensation of pain on surfaces of the body also could produce pain in penetrating lesions. Applying these hypotheses to the problem of pain in cases of cancer of the stomach permits an explanation of the apparent paradoxical behavior of distress among patients harboring such lesions. Who, at operation or necropsy has not viewed with surprise tremendous cancers involving most of the stomach which have produced no pain whatsoever? After all, this should be no more the cause of astonishment than to witness surgical procedures on the stomach which caused patients no pain even though only local anesthesia was used. The mechanisms which produce pain in such cases depend on the production of an adequate stimulus, such as stretching or constriction of the circular muscular fibers which would require a mechanical disturbance, such as spasm or obstruction. If cancer does not set in motion this adequate stimulus, it is likely to produce no pain whatsoever. If, on the other hand, there is mechanical disturbance such as interference with normal emptying or invasion of the pylorus, pain or at least a sense of epigastric distress is likely to be one of the earlier manifestations of this disease. Cancer of the pylorus therefore is more often amenable to surgical treatment than are other types of cancer, not only because of its resectability from a physical standpoint but because of the fact that, as a rule, it produces symptoms relatively early. Shift of pain from original to secondary regions among patients who have cancer of the stomach is of varying significance. In the event that the lesion is small, for instance, a penetrating peptic ulcer harboring in its depth malignant degeneration associated with hyperacidity, a shift of pain may not be of very serious significance. If, on the other hand, the lesion is fairly extensive and the patient complains of shifts of pain from the original into secondary regions, the lesion will be found to be inoperable in almost all instances. This, of course, is owing to the fact that cancer has penetrated the wall of the organ and has invaded tissues contiguous to the stomach. The shift of pain, in such instances, is owing to invasion of the spinal sensory nerves. In a general way, it can be said that cancer of the stomach in which gastric chemistry is normal or is elevated is much more likely to produce a painful syndrome than that in which there is no acidity or only a trivial amount of hydrochloric acid. This is probably owing to the fact that the acid acts, as it does in cases of benign gastric lesions, as a trigger mechanism which initiates spasm and this, in turn, is responsible for the sensation of pain. Otherwise stated, with the exception of pyloric lesions which cause early obstruction, the presence of carcinoma of the stomach is suspected most usually by its complications and its systemic effects when the lesion has advanced beyond the bounds of operability.

The validity of pancreatic enzyme substitution therapy in the two months following diagnosis of celiac disease was investigated. Twenty patients (8 males, 12 females), mean age 14.2 months (group A) received an enzyme substitution preparation. The control group (group B) included 20 patients (9 males, 11 females), mean age 14.5 months, treated with placebo. Before starting treatment, we performed a stratification for age, weight-for-age at diagnosis, and degree of pancreatic insufficiency. The therapies were then administered randomly in double-blind fashion. On diagnosis and 30 and 60 days after commencement of a gluten-free diet with identical calorie intake in both groups, a series of anthropometric variables were determined. After 30 days weight increase in group A patients was significantly higher (in grams) than in group B: 1131±461 vs 732±399 (P<0.006). Weight-for-age increase also was greater in group A than in group B: 9.2±5.1% vs 5.0±4.0% (P<0.002). The increase in height Z score, weight-for-height, arm circumference, and subscapular and tricipital fold measurements were greater in group A patients than those in group B, but the difference was not significant. After 60 days of therapy none of the parameters considered were significantly different in the two groups. We concluded that pancreatic enzyme therapy is certainly useful in the first 30 days after diagnosis of celiac disease.

The long-term maintenance and acute induction of sucrase activity were studied under a variety of defined dietary conditions during the adult life-span of the Sprague-Dawley rat. Rats were fed chow, 74% carbohydrate, 56% carbohydrate, or 22% carbohydrate diets, from 44 to 106 weeks of age. Sucrase specific activity was measured in enterocytes isolated from the proximal, middle, and distal small intestine at 52, 86, and 104 weeks of age. Sucrase specific activity was correlated with the carbohydrate content of the diet but not affected by age throughout the adult life-span. In a second experiment, the acute induction of sucrase following a 48-hr fast was studied in 58- and 116- week-old rats. The increase in sucrase specific activity following refeeding was not different in the adult and aged rats. The results suggest that the carbohydrate-digesting capacity of the small intestine enterocyte of the Sprague-Dawley rat is not impaired during the aging process.

Rare pancreatic endocrine tumors consisting of both exocrine and endocrine components have been reported sporadically. We investigated the ductal and acinar differentiation in pancreatic endocrine tumors. In immunohistochemical studies of 28 pancreatic endocrine tumors, staining with anti-carcinoembryonic antigen (CEA) or CA19-9 antibody indicated ductal differentiation, while staining with anti-amylase or anti-trypsin antibody indicated acinar differentiation. K-ras gene mutations and p53 gene alterations also were studied. Ten tumors were immunoreactive for CEA or CA19-9. Five tumors diffusely immunoreactive for CEA or CA19-9, in addition to endocrine markers, were diagnosed as duct–endocrine cell tumors of the pancreas. Two tumors diffusely immunoreactive for CEA or CA19-9 and also for pancreaticogut hormones as well as endocrine markers were diagnosed as duct–acinar–endocrine cell tumors. These tumors showed uniform histologic features and synchronous ductal, acinar, and endocrine differentiation, distinct from the coexisting different cellular populations seen in collision tumors. All tumors were malignant. These duct–endocrine cell tumors or duct–acinar–endocrine cell tumors of the pancreas may be derived from a stem cell that retains the capability of expressing either an exocrine or endocrine phenotype. Only one K-ras gene mutation and no p53 gene alterations were detected in these tumors, which suggests that they constitute an entity with a different origin than ductal carcinomas.

Complex and conflicting relationships between epidermal growth factor (EGF), estrogens (E), androgens (A), and related receptors (EGF-R, E-R, A-R) have been reported in different biological situations associated with cell proliferation. There is also evidence that EGF and sex hormone receptors may be involved in normal and neoplastic growth of the gastrointestinal mucosa. In this study, we investigated the behavior of EGF receptors and sex hormone and related receptors, duringN-methyl-N'-nitro-N-nitrosoguanidine (NG) -induced gastric carcinogenesis in Sprague-Dawley male rats. Four groups of 15 rats each (10 NG-treated and five controls) were sacrificed after 1, 20, 30, and 40 weeks of treatment. Gastric tissue from each rat was processed for receptor status (number and affinity) and proliferative activity. A significant and progressive decrease of A-R and EGF-R was observed starting from the 20th week, while no change of E-R occurred throughout the experiment. Cell proliferation in the gastric mucosa of NG-treated rats increased after 30 weeks of treatment. These data indicate that NG treatment is able to modify the receptor status of gastric mucosa in rats.

We studied the sequential immunohistochemicalappearance of androgen-dependent carbonic anhydrase (CAIII) during the development of ethanol-induced liverinjury using liver samples from castrated andnoncastrated male micropigs. In castrated micropigs, thebaseline expression of CA III was either low or absent,while distinct positive immunoreactions were found inzone 3 hepatocytes at 5 and 12 months after the initiation of the ethanol diet. The CA IIIenzyme and protein adducts of lipid peroxidation-derivedaldehydic products, malondialdehyde and4-hydroxynonenal, appeared together in the perivenousregion, suggesting that the enzyme functions in anoxidative environment. The positive staining became moreabundant and widespread during the progression ofalcoholic liver disease. After 12 months, CA III was significantly more abundant in both theethanol-fed noncastrated and castrated micropigs than inthe control animals (P < 0.001, P < 0.05,respectively). CA III content was strikingly high in the ethanol-fed noncastrated animals, consistentwith a potential role of androgens in the regulation ofethanol-induced CA III expression. The strongly positiveCA III immunoreactions in the ethanol-fed noncastrated micropigs were associated with scant evidenceof aldehydic protein adducts and minimal histopathology.Thus, enhanced expression of CA III during ethanolconsumption may also account in part for gender differences in the susceptibility foralcohol-induced liver injury.

This work studied the effects of hydrocortisone treatment in experimental acute pancreatitis on cytokines, phospholipase A2, and breakdown products of arachidonic acid and survival. Edematous and necrotizing pancreatitis were induced in Wistar rats by cerulein hyperstimulation and retrograde intraductal infusion of sodium taurocholate, respectively. Hydrocortisone (10 mg/kg) was administered intravenously 10 minutes after induction of acute pancreatitis. Serum was assayed for phospholipase A2; interleukin (IL) 1β, IL-6, IL-10, thromboxane B2; Prostaglandin E2; and leukotriene B4 at five different time points. A significant release of inflammatory mediators was seen only in the severe model. Hydrocortisone powerfully suppressed arachidonic acid breakdown products and only mildly attenuated the systemic increase of phospholipase A2 and pro- and antiinflammatory cytokines. The mortality rate after 72 hr in the severe model was 86%. Hydrocortisone treatment reduced mortality to 13% (P = 0.001; Fisher's exact test). Hydrocortisone seems to be effective in the treatment of the early systemic inflammatory response syndrome associated with severe acute pancreatitis.