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Competing Interests: The authors report no conflicts of interest.

In 1975, a trend began in which applications of MDs to the National Institutes of Health for research funding became less successful than applications from PhDs or MD/PhDs. MD/PhDs were the most successful applicants. Concomitantly, proposals for clinical research were less successful than nonclinical proposals. Since 1975, surgeons have fared disproportionately worse than researchers in other clinical disciplines in obtaining funding from the National Institutes of Health. Despite the efforts of surgical organizations, surgeons continue to fall farther behind in getting National Institutes of Health support for research. The most likely cause of this problem is that the surgical profession has failed to develop and sustain an adequate research workforce.

Objective: The goal of this investigation was to determine the role of calcitonin gene-related peptide (CGRP) in gastric mucosal resistance to ulceration., Summary Background Data: CGRP is a 37-amino acid peptide found in the peripheral ends of afferent gastric neurons. CGRP is known to inhibit acid secretion, stimulate mucosal blood flow, and stimulate release of somatostatin., Methods: The release of CGRP in response to intragastric and intra-arterial administration of capsaicin in the isolated, vascularly perfused rat stomach was measured by radioimmunoassay. The molecular forms of CGRP released were analyzed by gel filtration chromatography. The effect of intravenous CGRP or intragastric capsaicin on gastric ulceration induced by 100 mmol/L HCl and indomethacin was studied in intact and endogenous CGRP-depleted rats., Results: Intra-arterial capsaicin (concentration range, 10(-7) to 10(-5) mol/L) stimulated a prompt and sustained release of immunoreactive CGRP, of which 84% coeluted with rat 1-37 CGRP I by gel filtration. Intragastric capsaicin (range, 10(-5) to 10(-4) mol/L) failed to release CGRP into the vascular perfusate. In intact rats, intragastric capsaicin (10(-6) mol/L) or intravenous CGRP I (10 micrograms/kg/hr) reduced the number and area of mucosal lesions caused by HCl and indomethacin compared with the findings in control rats. Rats depleted of endogenous CGRP were more susceptible to gastric ulceration than were normal rats. Intragastric capsaicin failed to protect the mucosa of CGRP-depleted rats, whereas exogenous intravenous CGRP was effective., Conclusions: These data support the hypothesis that CGRP released from gastric enteric neurons mediates gastric mucosal resistance to ulceration by noxious agents.

The effects of a specific cholecystokinin (CCK) receptor antagonist (L364,718) and a gastrin receptor antagonist (L365,260) on gastrin-releasing peptide-10 (GRP-10)-stimulated pancreatic secretion were investigated in the anesthetized rat. GRP-10 stimulated pancreatic exocrine secretion in a dose-dependent manner. A dose of 1.0 nmol/kg/h elicited a significant increase in pancreatic protein output. L364,718 (2.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous CCK-8 (3.0 nmol/kg/h) on pancreatic secretion, did not suppress the excitatory effect of GRP-10. L365,260 (5.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous gastrin (20 micrograms/kg/h) on gastric acid secretion, did not suppress the excitatory effect of GRP-10 either. We concluded that CCK or gastrin do not mediate the excitatory mechanism of bombesin/GRP on pancreatic secretion. Since CCK and gastrin are the most probable candidates for excitatory mediator of bombesin/GRP, these results support the hypothesis that bombesin/GRP directly stimulates the exocrine pancreas in the rat.

Geranyl-geranyl acetone (GGA), a new acyclic polyisoprenoid, anti-ulcer drug appears to exert its beneficial effect by stimulating bicarbonate secretion from the stomach and pancreas. Its efficacy in stimulating pancreatic bicarbonate is particularly striking, and this study was designed to examine the mechanism for this action. Since it is structurally similar to the side chain of the prostaglandin molecule, its ability to stimulate bicarbonate secretion could be a direct one. On the other hand, the magnitude of pancreatic bicarbonate response (about 50% of maximal response to secretin) suggests it might act by releasing secretin. Two types of experiments were performed in dogs with pancreatic fistulas: first, secretagogue interactions were examined by studying the effect of intraduodenal GGA (8 mg/kg) or its carrier (control) on the dose-response curves to exogenous secretin and cholecystokinin octapeptide (CCK-8); second, the effect of graded doses of intraduodenal GGA on pancreatic bicarbonate and plasma secretin-like immunoreactivity (SLI) responses was tested directly. Pancreatic bicarbonate responses (micromoles per 30 min) were to secretin doses of 32, 125, and 500 ng/kg/h. Without and with GGA, responses were 74 +/- 27, 952 +/- 215, and 2,000 +/- 425 and 599 +/- 110, 1,624 +/- 472, and 2,129 +/- 398 ng/kg/h, respectively. Similarly, the bicarbonate responses to CCK-8 were augmented. Basal plasma SLI was 1.5 +/- 0.6 pM/ml. Peak plasma SLI in response to 2, 4, and 8 mg of GGA intraduodenally were 6.8 +/- 0.7, 8.9 +/- 3.1, and 19.6 +/- 2.7 pM/ml, respectively. It is concluded that GGA is a potent stimulant of pancreatic bicarbonate secretion, and this action appears to be mediated by the release of duodenal secretin.

The value of the amylase--creatinine clearance ratio (ACCR) in the diagnosis of postoperative pancreatitis was prospectively assessed. In 77 patients undergoing operations known to have a significant incidence of postoperative pancreatitis (gastric, biliary or pancreatic) i.e. "high risk" group, the ACCR was abnormally elevated postoperatively in 36 patients (47%). However, overt clinical pancreatitis occurred in only eight patients (10%). In 60 other patients undergoing nonabdominal operations (orthiipedic, head and neck, varicose vein surgery etc.) i.e. "low risk" group, the ACCR was abnormally elevated postoperatively in 23 patients (38%). No patient in this group developed clinical pancreatitis. We conclude, therefore, the ACCR is often abnormally elevated nonspecifically following any type of surgery, and cannot be used as evidence of postoperative pancreatitis. These data do suggest, however, that a normal ACCR, especially on successive daily determinations, might help to exclude the diagnosis of postoperative pancreatitis.

This study examines the effect of graded antral distension with acid (0.1 M HCl) or alkali (0.1 M NaHCO3) on pentagastrin-stimulated acid secretion in two groups of dogs. Group A consisted of six dogs provided with innervated antral pouch. In these dogs, the vagal branches to the fundus, as well as the extragastric vagal divisions (hepatic and celiac), were preserved. All of these animals had a gastric fistula in the main stomach, and in two a denervated fundic pouch or Heidenhain pouch was constructed in addition. Group B consisted of four dogs with an innervated antral pouch and gastric fistula. In this latter group, however, parietal cell vagotomy as well as extragastric vagotomy (division of the hepatic and celiac branches) was performed so that the only vagal communication was between the antrum and the CNS. Antral distension with acid caused significant inhibition of pentagastrin-stimulated acid secretion from both the gastric fistula and the Heidenhain pouch in Group A dogs. Antral acidification without distension did not inhibit. Alkaline antral distension in this group caused much less inhibition of acid secretion, but did cause significant increase in circulating immunoreactive gastrin. In Group B dogs, antral distension with neither acid nor alkali caused inhibition of pentagastrin-stimulated acid secretion, indicating that intact vagal supply to the oxyntic mucosa and/or to the extragastric abdominal organs is necessary for the inhibitory mechanism to operate. The results of this study suggest that: a) antral acidification per se does not inhibit pentagastrin-stimulated acid secretion; and b) antral distension with acid, and to a lesser extent with alkali, is inhibitory only if vagal innervation to the fundus and other abdominal viscera is preserved. The observations are compatible with the hypothesis that antral distension activates a neurohumoral inhibitory mechanism releasing the inhibitor reflexly from sites other than the antrum or CNS.

Gastric emptying of liquids and solids was evaluated in ten dogs with gastric fistula before and after either truncal vagotomy, antrectomy, or pyloroplasty. In subsequent operations, the vagotomy group underwent either antrectomy or pyloroplasty, and the antrectomy and pyloroplasty groups were vagotomized. Vagotomy significantly inhibited the emptying of both liquids and solids (p less than 0.001) when the pyloric antrum was intact. When the antropyloric mechanism was removed by antrectomy, the effect of vagotomy was to accelerate the emptying of liquids (p less than 0.05) but to impair the emptying of solids (p less than 0.001). When the pylorus was destroyed by pyloroplasty, vagotomy markedly accelerated the emptying of liquids but had little effect on the emptying of solids. Neither antrectomy nor pyloroplasty had any significant effect on the emptying of solids. Pyloroplasty caused minor acceleration of emptying of liquids while antrectomy had no effect.

We studied the effect of graded antral distension on gallbladder contraction both when gastrin release was promoted (alkaline distension) and when gastrin release was blocked (acid distension) in five dogs provided with innervated antral pouch, chronic bile fistula and gastric fistula. Graded distension of the antrum caused graded gallbladder contraction as evidenced by bilirubin output even when gastrin release was completely suppressed. This nongastrin mechanism of gallbladder contraction is abolished by parenteral atropine and by transthoracic truncal vagotomy. These observations provide evidence for a cholinergic, pyloro-cholecystic reflex for gallbladder contraction that is dependent on intact long vagal pathways. Similar reflex mechanisms have been shown to be initiated by antral distension and to cause pancreatic enzyme secretion (pyloro-pancreatic reflex) or acid secretion from the oxyntic gland area of the stomach (pyloro-oxyntic reflex). It would appear, therefore, that the antrum plays a central role in the integration of upper gastrointestinal function not only through the hormone gastrin but also through neural reflex mechanisms.

The effect of somatostatin (SS-14) was tested in an anesthetized rabbit model of closed-loop ileal obstruction. Experimental groups included (1) immediate treatment (N = 6) receiving SS-14 2,000 pmol X kg-1 X h-1 intravenously (I.V.) beginning at the time of ileal obstruction, (2) delayed treatment (N = 5) receiving SS-14 beginning 6 hours following ileal obstruction, and (3) control (N = 6) receiving only hydration. After 24 hours, all rabbits were killed. Significantly decreased intestinal luminal volume and sodium and potassium output was observed with both immediate and delayed SS-14 treatment when compared to control. Additionally, the gross and microscopic pathologic features of intestinal distension, inflammation, and necrosis seen in control rabbits were absent in rabbits treated with SS-14. The known broad spectrum of physiologic activity of SS-14 on the gastrointestinal tract appeared beneficial in this rabbit model of intestinal obstruction.