András Bálint

Involvement of endogenous CCK and CCK1 receptors in colonic motor function

Cholecystokinin (CCK) is a brain‐gut peptide; it functions both as a neuropeptide and as a gut hormone. Although the pancreas and the gallbladder were long thought to be the principal peripheral targets of CCK, CCK receptors are found throughout the gut. It is likely that CCK has a physiological role not only in the stimulation of pancreatic and biliary secretions but also in the regulation of gastrointestinal motility. The motor effects of CCK include postprandial inhibition of gastric emptying and inhibition of colonic transit. It is now evident that at least two different receptors, CCK1 and CCK2 (formerly CCK‐A and CCK‐B, respectively), mediate the actions of CCK. Both localization and functional studies suggest that the motor effects of CCK are mediated by CCK1 receptors in humans. Since CCK is involved in sensory and motor responses to distension in the intestinal tract, it may contribute to the symptoms of constipation, bloating and abdominal pain that are often characteristic of functional gastrointestinal disorders in general and irritable bowel syndrome (IBS), in particular. CCK1 receptor antagonists are therefore currently under development for the treatment of constipation‐predominant IBS. Clinical studies suggest that CCK1 receptor antagonists are effective facilitators of gastric emptying and inhibitors of gallbladder contraction and can accelerate colonic transit time in healthy volunteers and patients with IBS. These drugs are therefore potentially of great value in the treatment of motility disorders such as constipation and constipation‐predominant IBS.

Role of Different Bombesin Receptor Subtypes Mediating Contractile Activity in Cat Upper Gastrointestinal Tract

Mammalian bombesin-like peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB) are known to increase the motility of different segments in the gut. The present study was carried out to identify the bombesin receptor subtypes mediating the contractions induced by exogenous bombesin-like peptides in muscle strips isolated from cat esophagus, fundus, and duodenum. Both GRP-10 and NMB evoked concentration-dependent contractions in circular strips of esophagus and fundus and in longitudinal strips of the duodenum. These contractions were tetrodotoxin- and atropine-resistant. The potency of NMB in esophageal strips was 33 times higher than that of GRP-10. The NMB-preferring receptor antagonists D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2 (SSocta) and D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH2 (BIM-23127) shifted the NMB and GRP concentration-response curves to the right, while the GRP-preferring receptor antagonist [D-Phe6]Bombesin(6-13)-methyl-ester (BME) did not affect the response to the peptides. Isolated muscle strips from the cat fundus and duodenum showed a higher sensitivity to GRP-10 than to NMB. In both segments, BME shifted the GRP-10 and NMB concentration-response curves to the right, while SSocta had no effect. The antagonism of BME was competitive on duodenal but not competitive on fundic muscle. We conclude that the direct myogenic action of GRP-10 and NMB in the esophagus is mediated mainly via NMB-preferring receptors, while GRP-preferring receptors are responsible for the contractile responses to bombesin-like peptides in feline fundus and duodenum. Our data suggest that the GRP receptor population located on fundic muscle might be nonhomogeneous.

Antisecretory effects of galanin and its putative antagonists M15, M35 and C7 in the rat stomach

The neuropeptide galanin has been reported to have a wide range of biological actions both in the central nervous system and in the gastrointestinal tract. Recent works led to the discovery of selective galanin receptor antagonists including M15 (galanin(1-12)-Pro-substanceP(5-11)-amide), M35 (galanin(1-12)-Pro-bradykinin(2-9)-amide) and C7 (galanin(1-12)-Pro-spantide-amide). These antagonists were shown to competitively inhibit actions of galanin in the central nervous system. The present study was designed to investigate the effect of galanin, M15, M35 and C7 on gastric acid secretion and gastric emptying. Pentagastrin-stimulated gastric acid secretion was inhibited by galanin (0.1-9 nmol x kg(-1) x h(-1), i.v.) in a dose-dependent manner (ID50 = 1.8 +/- 0.3 nmol x kg(-1) x h(-1)). When 9 nmol x kg(-1) x h(-1) galanin infusion was given, inhibition became almost complete. M15, M35 and C7 (1-9 nmol x kg(-1) x h(-1)) did not modify responses of the stomach to galanin, but acted as agonists of galanin on acid secretion. Neither galanin nor its putative antagonists affected the emptying of non-caloric liquids from the stomach. In conclusion, galanin may play an antisecretory role in the regulation of gastric acid secretion but not in the control of gastric emptying of liquids in rats. Its antisecretory action on the stomach is mediated by galanin receptors that are distinct from those in the central nervous system.

Functional and immunocytochemical evidence that galanin is a physiological regulator of human jejunal motility

Abstract The neuropeptide galanin has species-dependent effects on intestinal motility. It has a contractile effect on rat jejunal muscle while it relaxes guinea-pig ileum by inhibiting cholinergic transmission. Its effect on human gut motility has been unknown. Extensive work led to the discovery of selective galanin analogues such as M15 [galanin(1-12)-Pro-substance-P(5-11)], M35 [galanin(1-12)-Pro-bradykinin(2-9)-amide] that competitively inhibit various actions of galanin in the central nervous system. The present study was designed to examine the effect of galanin, M15 and M35 on longitudinal jejunal smooth muscle strips isolated from humans and rats, and to localize galanin-immunoreactivity in human jejunum. Galanin and ACh were equally effective in stimulating contractions of the isolated jejunal muscle: sigmoid curve fitting showed that maximal contractile response to galanin and ACh were 25.7±11.1 mN and 23.7±9.7 in humans, while 8.0±0.6 and 8.1±0.3 mN in rats, respectively. These effects of galanin were not inhibited by either atropine (5×10−6 M) or tetrodotoxin (3×10−6 M). The potency of galanin inducing the contractile actions were similar in humans and rats. Interestingly, neither M15 nor M35 (up to 10−7 M) were able to inhibit the responses of the smooth muscle to galanin. However, both putative galanin receptor antagonists showed agonist effects in our experimental models. In accordance with the functional studies, both the longitudinal and the circular muscle layers were abundant in nerve fibers and varicosities showing galanin immunoreactivity. Our data suggest that galanin is a potent physiological regulator of jejunal contractions in humans. Its action on the jejunum, however, is mediated by galanin receptors that are different from those located in the central nervous system.

Long-Term Clinical Results of Highly Selective Vagotomy Performed Between 1980 and 1990

A retrospective analysis was conducted of 778 patients who underwent highly selective vagotomy between 1980 and 1990. Surgery was performed for duodenal ulcers without any complications in 485 (62.3%) patients; for duodenal ulcers with complications such as stenosis, bleeding, or perforation in 270 (34.7%); for combined duodenal and ventricular ulcers in 12 (1.5%), and for ventricular ulcers alone in 11 (1.4%). Pyloroplasty was additionally performed in the presence of complications only. The incidence of intraoperative complications proved to be as high as 1.4%, occurring in 11 patients, while postoperative complications developed in 247 patients (31.7%). Although the overall mortality was 0.6% (5 patients), the mortality rate of those patients who underwent surgery for uncomplicated ulcer disease was 0.2% only (2 patients). The patients comprised 554 men (71.2%) and 224 women (28.8%) with an average age of 41.4±0.7 years. The average duration of duodenal ulcer disease was 9.5 years, and 643 (83.2%) of the patients were able to be regularly followed up for between 3 and 13 years. Recurrence developed in 62 patients (9.6%): in the duodenum in 57 patients (91.9%), and in the stomach in 5 (8.1%). The rate of recurrence according to sex was 9.4% in men and 10.3% in women, being 42 and 20 patients, respectively. The average duration until recurrence appeared was 27.06±3.44 months. A reoperation proved necessary in 28 of these 62 patients (45.1%). The clinical results were evaluated by means of a modified Visick classification, according to which 81.8% of the patients belonged to groups 1 or 2, 7.9% to group 3, and 10.3% to group 4.

Effects of putative galanin antagonists M35 and C7 on rat exocrine pancreas

Galanin is a neuropeptide having a wide range of biological actions. Recently selective galanin receptor antagonists such as M35 [galanin(1-12)-Pro-bradykinin(2-9)-amide] and C7 [galanin(1-12)-Pro-spantide-amide] have been described. These antagonists have blocked the actions of galanin on flexor reflex, glucose-induced insulin secretion, and acetyicholine release from hippocampus. Our present aim was to investigate whether M35 and C7 can affect galanin-induced inhibition of pancreatic enzyme secretion in rats. Pancreatic enzyme secretion was studied in urethane-anesthetized rats supplied with jugular vein catheter and pancreatic cannula. Amylase secretion evoked by submaximal CCK-8 stimulation was inhibited dose-dependently by galanin in anesthetized rats. Surprisingly, neither M35 nor C7 was able to inhibit the responses of the exocrine pancreas to galanin. However, both putative galanin receptor antagonists behaved as agonists in our experimental models. Our data suggest that the effects of galanin on pancreatic enzyme secretion are not mediated by M35- or C7-sensitive galanin receptors. Therefore, these galanin receptors are different from those described in the central nervous system.

Highlights of Twentieth Century Surgery in Hungary

On a cold winter morning, in November 1914 a Russian officer was running through the barracks of the camp of the AustrianHungarian prisoners of war in Siberia. He was desperately looking for a prisoner, a Hungarian physician-officer, otologist Robert Barany. At last he found the doctor and handed him a telegram that had just arrived from Sweden. Dr. Barany opened the telegram and saw that it contained the announcement that he was awarded the Nobel Prize. Prince Charles of Sweden, President of the Swedish Red Cross Organization, contacted Prince Konstantin of Russia, President of the Russian Academy of Sciences, asking for his help to release Dr. Barany, but the attempt was unsuccessful. However, Dr. Barany was transported from the camp to a hospital in Kazan. Doctor Barany had suffered from a childhood tuberculosis infection in one of his legs, and as a consequence his walk was imperfect the rest of his life. Here, in Kazan, the Russian army doctor, a general, while examining his Hungarian colleague noted this minor alteration. “Ah, you are wounded,” he said. Dr. Barany protested: “I am not wounded.” The Russian officer refused to accept the remark, telling his patient: “To determine who is wounded and who is not, that’s my job and not yours!” Hence Dr. Barany was released as a war-disabled ex-serviceman, and in September 1916 he was able to attend the Nobel Prize ceremony in Sweden. This true story reflects how much Hungarian life and science were affected by the politics of the twentieth century. Hungary, situated in the eastern part of central Europe is 93,000 km after being reduced to a third of its former territory as a result of the Treaty of Trianon, which put an end to World War I. There are 15 million Hungarians living around the world, 5 million of them outside Hungary. The Magyars arrived in the Carpathian Basin in 896 AD. During the years 2000 and 2001 we celebrated not only the turn of a new millennium but also the 1000th anniversary of the coronation of our first King, St. Stephen, who laid the foundations of Hungarian statehood and the acceptance of Christianity in Hungary. The medical profession has been honored and appreciated even from the earliest times in the history of the nation. On the Hungarian royal crown (called the “Holy Crown”) one can find the portraits of the famous twin brothers who were respected physicians during the Middle Ages, the martyrs St. Cosmas and St. Damian. To evaluate Hungarian surgery during the twentieth century we must go back to previous times.

Intraabdominal abscess managed successfully via the laparoscopic approach.

A rare complication of laparoscopic fundoplication-an intraabdominal abscess located between the fundus and the caudate lobe of the liver-is described. A 41-year-old man had undergone a laparoscopic Nissen-Rossetti fundoplication for longstanding gastroesophageal reflux disease. On the 5th postoperative day, the patients general condition became worse, and he developed intermittent-remittent fever (40 degrees C), an elevated white blood cell count (WBC), and an accelerated sedimentation rate. Evidence of leakage was excluded by Gastrografin swallow. The diagnosis was finally revealed by means of ultrasound and computed tomography (CT) scan, which showed an intraabdominal fluid collection with an air cap of ~10 cm in diameter situated between the diaphragmatic crura, the caudate lobe of the liver, and the gastric fundus. The location did not allow semi-invasive management of the abscess, such as ultrasound or CT-guided puncture and drainage. On the 8th postoperative day, a laparoscopic exploration was performed utilizing the previous port sites. The adhesions were easily dissected, and evacuation of ~300 ml of white, dense fluid, and lavage and drainage were performed without intraabdominal dissemination of pus. The patient was discharged on the 12th postoperative day free of symptoms. Microbiological examination of the pus showed the presence of Peptostreptococcus. The patient remained symptom free. At 8 weeks postoperatively, barium swallow, endoscopy, 24-h pH monitoring, and stationary manometry of the esophagus yielded normal results. Because there was no direct evidence of leakage at the fundus, the development of the abscess was concluded to be due to the use of deep transmucosal stitches rather than seromuscular ones to create the wrap. The nonabsorbable multifilament suture material passing through the entire gastric wall could have facilitated bacterial contamination of the operative field.