Thoracic wall reconstruction for primary malignancies in children: short- and long-term results.

AIM: Primary thoracic wall malignancy is a rare and diverse entity in children. Surgical treatment commonly involves major chest wall resection causing large defects requiring complex reconstruction. In adults, the use of alloplastic and/or xenogenic materials and muscle flap repair is well established. However, literature provides only little information on procedures in children. We report our experience in 8 consecutive children who underwent chest wall resection and reconstruction with regard to surgical treatment and outcome. PATIENTS AND METHODS: Retrospective study of all children with primary malignant chest wall tumors requiring rib resection and reconstruction with prosthetic material performed in our institution between November 2002 and April 2010. Endpoints were postoperative complications and long-term results, focusing on scoliosis defined radiologically by the Cobb angle. RESULTS: 8 children (7 male, 1 female) with a median age of 10.6 (4.1-18.9) years underwent resection of thoracic wall tumors. A mean number of 3 (1-5) ribs were resected. Stability was obtained using rigid prosthetic material (STRATOS™ titanium bar) in 2 patients and/or non-rigid prosthetic material (Goretex® patch in 6 patients, Vicryl® patch in 3 patients, Tutopatch® in 1 patient). A muscular flap was added in 5 patients. Postoperative complications included superficial wound infection (n = 2) and dislocation of a titanium bar necessitating removal in 1 patient. No infections of the prosthetic material were observed. No perioperative mortality occurred. At a mean follow-up of 37.5 (4-97) months, 6 patients were alive. 2 patients died due to early tumor recurrence. Mild scoliosis (Cobb angle 10-20°) was detected in 2 of the surviving patients (33%). CONCLUSION: Surgical reconstruction after resection of malignant thoracic wall tumors using non-rigid prosthetic material is safe and effective in pediatric patients, whereas rigid prosthetic material might dislocate. Scoliosis represents a long-term complication after chest wall reconstruction and should be monitored during routine follow-up.

Laparoscopically assisted ventriculoperitoneal shunt placement in infants with previous multiple abdominal operations.

BACKGROUND: The insertion of a ventriculoperitoneal shunt (VPS) is the treatment of choice in patients with hydrocephalus. However, VPS placement may be difficult in patients with extensive adhesions following prior abdominal interventions. Laparoscopic placement of the abdominal part of the VPS allows controlled adhesiolysis in combination with an optimal shunt placement in patients with a body weight above 5 kg. We investigated the feasibility and safety of laparoscopic VPS placement in young infants who had undergone abdominal operations. PATIENTS AND METHODS: In our institution, 6 children with prior laparotomies (range: 2-9; median 3) received a VPS catheter between 2004 and 2008. The median age was 9 months (range: 2 months-4 years) and the median body weight was 4.5 kg (3.5-8.2 kg). All procedures were laparoscopically assisted and performed simultaneously by an interdisciplinary neurosurgical and a pediatric surgical team. RESULTS: Median operating time was 63 min (35-100 min). In all cases, correct placement of the shunt with sufficient drainage was achieved. Enteral feeding was started on the day of operation in all patients. Median follow-up was 10 months (range: 2 months-3 years). There were no complications except in one patient, who developed shunt dysfunction 4 weeks postoperatively and underwent a laparoscopic shunt revision. CONCLUSION: In our series laparoscopically assisted VPS insertion in low-weight children who had undergone repeated prior abdominal surgery was feasible and had a low complication rate. We recommend laparoscopically assisted VPS insertion in small infants to avoid the complications of alternative techniques, such as open techniques or ventriculoatrial shunt.

Laparoscopic nephroureterectomy in children: a prospective study on Ligasure versus Clip/Ligation.

PURPOSE: The present study was performed to compare dissection of the renal hilar vessels in laparoscopic transabdominal nephrectomy in children using the Endo-Ligasure vessel sealing system versus clip/ligation. PATIENTS AND METHODS: In a prospective and comparative study carried out from February 2003 to April 2004, 10 consecutive patients (group 1) underwent laparoscopic transabdominal nephroureterectomy using clips or intracorporeally performed ligations, respectively. From April 2004 to April 2005, 10 consecutive patients (group 2) underwent the same procedure using the Endo-Ligasure vessel sealing system. Indications for surgery were confirmed non-functioning kidneys secondary to benign unilateral renal disease and no prior surgery. The age and underlying disease distribution and the affected side were not significantly different between the two groups. RESULTS: The operating time was significantly lower in the Endo-Ligasure group (group 1: median 167 vs. group 2: 108 min, p < 0.05). Bleeding of the renal artery occurred due to dislocation of a suture ligation, which was treated laparoscopically with an intracorporeal suture ligation. Blood loss was negligible in all patients. All procedures were completed laparoscopically and recovery was uneventful. CONCLUSIONS: Endo-Ligasure is a beneficial tool in laparoscopic transabdominal nephrectomy. It is safe, effective, and reduces operating times compared to clip application and intracorporeal suturing.

Laparoscopic resection of congenital choledochal cyst, choledochojejunostomy, and extraabdominal Roux-en-Y anastomosis.

BACKGROUND: The feasibility of laparoscopic resection of choledochal cyst and hepaticojejunostomy in children is still unclear. This report presents the author's experience with a first series of patients. METHODS: Data from 11 consecutive children (median age 17.5 months, SD 22, range 2 to 70) with choledochal cyst scheduled for laparoscopy were collected prospectively. There were nine type I and 2 type V cysts according to Todani's classification. All except one patient had intermittent jaundice or recurrent pancreatitis. The laparoscopic technique included excision of the cyst. A Roux-en-Y anastomosis was constructed after exteriorization of the small bowel via the infraumbilical trocar incision. After repositioning of the bowel an end-to-side hepaticojejunostomy was carried out laparoscopically. RESULTS: The procedures were carried out in nine children without intraoperative events and a median duration of 289 min (SD 62). In two patients, the operation was converted after 60 and 90 min due to a lack of overview at the dorsal margin with problems in separation of the portal vein. Oral food intake was started within 2 days and tolerated well in all except one patient, in whom biliar fluid from the drain led to laparoscopic reevaluation on day 1. A small leak was resutured and the patient was discharged on day 5. In one patient, recurrent cholangitis and a dilated Roux-en-Y loop led to correction of some kinking of the loop via laparotomy after 3 months. All other patients are well with bile-stained stools after a mean follow-up of 13 months. CONCLUSIONS: Laparoscopic resection of congenital choledochal cyst and choledochojejunostomy in children is feasible. We feel that there is a considerable learning curve with the technique. Future studies will have to prove the feasibility of laparoscopic Roux-en-Y bowel anastomosis without the need for bowel exteriorization.

Postcholecystectomy syndrome with special regard to children--a review.

The incidence of abdominal symptoms after cholecystectomy in adults is high. Up to one third of the patients consult a doctor because of abdominal complaints within 1 year after the operation. In addition, a higher incidence of colon carcinoma after cholecystectomy has been reported in female patients. This article reviews the known facts on the "postcholecystectomy syndrome". However, little is known about postcholecystectomy symptoms in children. Reports on cholecystectomy in children deal rather with feasibility than long-term outcome. Therapeutic concepts for children with symptomatic gallstone disease should consider the differences in the etiology of gallstone formation between children and adults. Therefore, we recommend a specific concept, including laparoscopic cholecystotomy, for children with temporary disorders causing gallstones, and laparoscopic cholecystectomy for all other patients. The impact of these procedures on postcholecystectomy symptoms in children and the impact of cholecystectomy during childhood on the incidence of right-sided colonic carcinoma remains to be determined.

Evidence for non-neurotensin receptor-mediated effects of xenin (1-25)--focus on intestinal microcirculation.

Xenin (1-25) has been detected in various locations in mammalians. It has structural similarities with neurotensin and its intestinal effects are claimed to be mediated by neurotensin receptors. It has been shown to influence gastrointestinal motility. The effects of xenin (1-25) on intestinal microvascular perfusion after ischemia/reperfusion have not been investigated yet. Therefore, the superior mesenteric artery was clamped for 40 min in Wistar rats (n=8). Ten minutes prior to reperfusion, intravenous infusion of xenin (1-25) (5 nmol/kg/h) was started. By means of intravital microscopy, microvascular perfusion in the mucosal layer was assessed. Animals (n=8) with and without clamping of the superior mesenteric artery and infusion of the carrier solution served as controls. After ischemia/reperfusion, xenin (1-25) increased the density of perfused microvessels and the capillary red blood cell velocity compared to ischemic controls. Capillary red blood cell velocity was elevated (p<0.05). Xenin (1-25) improved the heterogeneous distribution of mucosal blood flow during reperfusion demonstrated by an increase of both the perfusion index and the percentage of perfused microvessels. We conclude that the effects of xenin (1-25) on intestinal microcirculation are significantly different from those previously described for neurotensin. A more complex effector mechanism must be postulated that may involve other regulatory peptides and receptors.

Differential effects of neurotensin and cholecystokinin on intestinal microcirculation after ischemia-reperfusion.

BACKGROUND: We investigated the effect of neurotensin and cholecystokinin (CCK) on intestinal microcirculation after ischemia-reperfusion. METHOD: Ischemia was induced in Wistar rats by occlusion of the superior mesenteric artery for 40 min. Ten minutes before reperfusion, infusion of either neurotensin or CCK was started. Afterwards, the microhemodynamics of the jejunum were examined by means of intravital microscopy. RESULTS: Ischemia-reperfusion decreased functional capillary density from 873.4+/-18.1 to 362.5+/-8.3 cm(-1) and red blood cell velocity from 0.49+/-0.03 to 0.34+/-0.02 mm/s. Furthermore, leukocyte-endothelium interaction was increased. Neurotensin infusion significantly increased functional capillary density to 483.2+/-9.0 cm(-1) and red blood cell velocity to 0.69+/-0.01 mm/s in the mucosal capillaries compared with ischemic controls. Despite the amelioration of villus perfusion, the number of non-perfused villi significantly increased (11.8+/-3.6%) compared with ischemic controls. CCK infusion also resulted in a significant increase of functional capillary density (535.2+/-7.4 cm(-1)) and red blood cell velocity (0.67+/-0.01 mm/s). In contrast to neurotensin, the number of non-perfused villi was not increased (5.8+/-2.2%). CONCLUSION: We conclude that neurotensin further aggravates perfusion inhomogeneity and stasis when administered during the ischemic period. In contrast, CCK has no negative influence on perfusion homogeneity after ischemia-reperfusion. It may be superior to neurotensin in the reconstitution of normal microvascular perfusion patterns after ischemia-reperfusion.

Impact of gastrin-releasing peptide on intestinal microcirculation after ischemia-reperfusion in rats.

We investigated the effect of gastrin-releasing peptide (GRP) and its antagonist RC-3095 on intestinal microcirculation after ischemia-reperfusion. Intestinal ischemia was induced in female Wistar rats by occlusion of the superior mesenteric artery for 40 min. Ten minutes prior to reperfusion, infusion of GRP or RC-3095 was started. A jejunal segment was exteriorized and the microhemodynamics of the mucosa and submucosa were examined by intravital microscopy and compared both with normal and ischemic controls (without application of the regulatory peptide). Ischemia-reperfusion significantly decreased functional capillary density from 891.2 +/- 14.1 to 398.3 +/- 11.4 cm(-1). Capillary red blood cell velocity was reduced from 0.46 +/- 0.01 to 0.37 +/- 0.01 mm/s (p < 0.05). Furthermore, both sticking and rolling of leukocytes were enhanced. 3.4 +/- 1.1% of the villi were not perfused at all. GRP infusion reversed the microcirculatory ischemia-reperfusion injury by increasing functional capillary density to 669.8 +/- 8.3 cm(-1) and red blood cell velocity to 0.62 +/- 0.01 mm/s (p < 0.05). In addition, application of GRP resulted in a complete absence of stasis (0%) in the villi. Leukocyte-endothelium adherence remained unchanged when compared to the ischemic controls. In contrast, application of RC-3095 caused an aggravation of microcirculatory disturbances demonstrated by a markedly increased number of non-perfused villi (42.5 +/- 4.2%; p < 0.05 vs. ischemic controls) and a significantly reduced functional capillary density (346.2 +/- 8.4 cm(-1), p < 0.05 vs. ischemic controls). In addition, RC-3095 led to an increased permanent leukocyte adherence in postcapillary venules whereas rolling was significantly reduced when compared to normal controls. We conclude that GRP in pharmacological doses has a protective effect on intestinal microcirculation during reperfusion. Furthermore, these data suggest that endogenous GRP may play a decisive role in the maintenance of microvascular integrity during reperfusion.

Neurotensin-related regulation of the postprandial lower-oesophageal-sphincter pressure.

BACKGROUND: Ingestion of food has been shown to modulate the lower-oesophageal-sphincter pressure (LESP). Fat is especially effective in decreasing the postprandial LESP. As there is good evidence that neurotensin (NT) is able to decrease the LESP, we conducted the present trial to determine whether NT could possibly be a mediator of the fat-induced decrease of the LESP. METHODS: Six half-breed dogs were fitted for cervical side-to-side oesophagostomy to allow repeated oesophageal intubation; plasma NT immunoactivity was recorded during infusion of NT and after intragastric instillation of 200 ml of a fat solution. Experiments were repeated, with the specific NT antibody GN25 administered intravenously. RESULTS: The optimal dose of NT required to simulate a postprandial situation was 50 pmol/kg/h. Infusion of this NT dose led to a statistically significant decrease of the LESP. Simultaneous administration of the NT antibody (immunoneutralisation) significantly inhibited this effect. Intragastric fat decreased the LESP and increased plasma NT. Immunoneutralisation of endogenously released NT led to an earlier restoration of baseline LESP, but this effect was not statistically significant. CONCLUSIONS: NT and intragastric fat modulate the LESP. NT appears to mediate the postprandial, fat-induced decrease of the LESP. Research with specific NT-receptor antagonists is necessary to determine the exact role of NT and other regulatory peptides in this context.

Is delayed gastric emptying following pancreaticoduodenectomy related to pylorus preservation?

BACKGROUND: Delayed gastric emptying (DGE) is the most frequent postoperative complication after pylorus-preserving pancreaticoduodenectomy (PPPD). This prospective, non-randomized study was undertaken to determine whether the incidence of DGE may be reduced by modifying the original reconstructive anatomy with a retrocolic duodenojejunostomy towards an antecolic duodenojejunostomy. PATIENTS AND METHODS: The study was comprised of 51 patients who underwent PPPD between August 1994 and November 1997. The operation was carried out as originally described but was modified by performing the duodenojejunostomy antecolically. Clinical data were recorded prospectively, with special regard to DGE. RESULTS: After PPPD, the nasogastric tube could be removed at a median of 2 days (range 1-22 days) postoperatively; in two patients, the nasogastric tube was reinserted because of vomiting and nausea. A liquid diet was started at a median of 5 days (3-11 days); the patients were able to tolerate a full, regular diet at a median of 10 days (7-28 days). The overall incidence of DGE was 12% (n=6). No postoperative complications other than DGE were exhibited by 36 patients (71%). In this group, DGE was only seen in one patient (3%). In the second group, where postoperative complications other than DGE occurred (n=15), five patients (30%) exhibited DGE (P=0.002). CONCLUSIONS: DGE after PPPD seems to be of minor clinical importance following uncomplicated surgery. When taking the results into consideration, it can be said that, despite the lack of a control group, antecolic duodenojejunostomy might be the key to a low incidence of DGE after PPPD. In our experience, DGE is linked to the occurrence of other postoperative complications rather than to pylorus preservation.

On the role of gastrin-releasing peptide in meal-stimulated exocrine pancreatic secretion.

The contribution of gastrin-releasing peptide (GRP) in the physiologic pancreatic response to a meal is unknown. We therefore investigated whether immunoneutralization of GRP could influence the exocrine pancreatic response to a meal as well as plasma concentrations of the peptide hormones neurotensin (NT) and cholecystokinin (CCK). Modified Herrera fistulas were implanted in five mongrel dogs. After a standard meal, we analyzed plasma NT, CCK, and GRP, and protein and enzyme (amylase, lipase, trypsin) content of exocrine pancreatic juice. An unspecific rabbit immunoglobulin solution was administered intravenously as a control. This experiment was repeated with a specific anti-GRP-immunoglobulin. The i.v. administration of the anti-GRP-antibody significantly inhibited meal-stimulated pancreatic secretion. Integrated protein output decreased from 58.4 to 36.8 g/180 min (p < 0.05), as did amylase (2,102 to 1,145 KU/180 min; p < 0.05), lipase (2,258 to 1,172 KU/180 min; p < 0.05), and trypsin (5,321 to 4,990 U/180 min). Postprandially released NT decreased from 8,271 to 5,825 pmol/180 min (p < 0.05). In contrast, integrated amounts of CCK remained relatively stable with 473 to 611 pmol/180 min. The neuropeptide GRP is one of the biologically important regulatory factors influencing meal-stimulated pancreatic secretion, as well as the postprandial plasma level of the peptide hormone NT in the dog. These mentioned effects of postprandially released GRP seem not to be mediated by CCK in an endocrine manner.

On the effect of xenin and xenin fragments on exocrine pancreas secretion in vivo.

A stimulatory effect on exocrine pancreas secretion could be demonstrated with high concentrations of the 25-amino-acid peptide xenin in non-anesthetized dogs. This peptide has been isolated from gastric mucosa and it is part of a structural coat protein. It has close structural similarities to neurotensin. The longer C-terminal fragments xenin-(13--25) and xenin-(18--25) are essential for the stimulation of exocrine pancreas secretion in vivo. The smaller peptide fragments xenin-(21--25) and xenin-(22--25) failed to stimulate the pancreas as well as the N-terminal peptide fragment xenin-(1--23). The stimulatory effects of xenin may be mediated via neural neurotensin pathways, because neurotensin receptor blockade abolished the stimulatory effect on pancreatic secretion. Cholinergic pathways are not involved, because atropine had no inhibiting effect.

Evaluation of a cacao drink as a simple oral stimulus to assess gallbladder contraction.

UNLABELLED: Gallbladder contractility plays an important role in the pathogenesis of gallstones and in the course of cholelithiasis. Furthermore, a functioning gallbladder is an important condition for performing a successful disolution of gallstones by bile acids. Therefore, a reliable simple physiological test is desired to assess gallbladder contractility. In ten volunteers gallbladder contraction was stimulated by 50 g chocolate, 330 ml cacao drink or in comparison by intramuscular injection of 0.3 microgram/kg ceruletide. Gallbladder volume was measured sonographically and CCK in serum was determined by radioimmunoassay (RIA) after 0, 15, 30 and 45 min. Additionally gallbladder contraction was determined in 20 patients with symptomatic gallstones using cacao drink on ceruletide. In health volunteers remaining gallbladder volume after 30 min was 28% +/- 5% using ceruletide and 37% +/- 7% using cacao. Stimulation by chocolate resulted in a remaining volume of 59% +/- 12% after 45 min only. Simultaneously to gallbladder contraction an increase of CCK in serum was registered. 30 min after cacao CCK had increased from 0.9 to 3.3 pmol/l. Using chocolate an increase of CCK amounted to 2.1 pmol/l after 45 min only. In patients with gallstones the positive predictive value of the cacao test for a functioning gallbladder was 91% and the negative predictive value was 78% in comparison to the unphysiologic stimulation by ceruletide injection. CONCLUSION: Cacao test but not chocolate is suitable and reliable to assess gallbladder contraction in patients with symptomatic gallstones.

[Significance of regulatory peptide GRP for microcirculation of the small intestine after ischemia/reperfusion]. / Die Bedeutung des regulatorischen Peptides GRP für die Mikrozirkulation des Dünndarmes nach Ischämie/Reperfusion.

With the use of intravital fluorescence microscopy we demonstrate, that GRP in pharmacological doses reduces ischemia/reperfusion injury in the rat. As mechanism we discuss a precapillary vasodilation that has a protective effect on the capillary system downstream. A direct influence on leukocyte-endothelium interaction in post-capillary venules could not be shown. In addition, we show that even the GRP endogenously released plays an important role for the regulation of microvascular perfusion after ischemia/reperfusion injury.

Plasma concentrations of cholecystokinin and neurotensin in patients with cystic fibrosis.

BACKGROUND: Regulation of pancreatic exocrine secretion is controlled by vagovagal reflexes and hormones. A negative feedback control mechanism exists between the intraduodenal protease concentration and pancreatic enzyme secretion. In man cholecystokinin (CCK) is the major regulator of postprandial pancreatic enzyme secretion. There is a 50% reduction of meal-stimulated secretion by the specific CCK receptor antagonist loxiglumide, whereas atropine completely blocks postprandial secretion. Neurotensin is released postprandially by nerval reflexes and fat. It has been claimed that both hormones are increased in patients with pancreatic insufficiency. METHODS: We investigated CCK and neurotensin levels in patients with cystic fibrosis and pancreatic insufficiency. In 35 patients (2-24 years old) with cystic fibrosis with steatorrhea and in 15 patients (1.5-24 years old) with cystic fibrosis without pancreatic insufficiency pre- and post-prandial CCK and neurotensin plasma levels were measured 3 days after pancreatic enzyme therapy had been withdrawn. Nine patients (3-14 years old) who had no complaint of abdominal disease served as controls. RESULTS: Basal and postprandial CCK plasma levels did not differ statistically in the three groups, whereas basal and postprandial neurotensin levels were significantly increased in the cystic fibrosis groups. The severity of the disease had no effect on the neurotensin levels. CONCLUSIONS: Cystic fibrosis patients with severe pancreatic insufficiency did not have increased CCK plasma levels, suggesting that a CCK-mediated feedback mechanism of pancreatic enzyme secretion does not operate in our patients. In contrast, basal and postprandial neurotensin plasma levels were significantly increased in patients with cystic fibrosis but were independent of the severity of the pancreatic insufficiency.

Relaxant effect of xenin on rat ileum is mediated by apamin-sensitive neurotensin-type receptors.

The action of xenin, a novel 25-residue peptide of the neurotensin (NT)/xenopsin family, was investigated in isolated rat ileal muscle strips and in dispersed longitudinal smooth muscle cells of rat small intestine in vitro. Xenin relaxes KCl-precontracted ileal strips dose dependently (1 nM-3 microM). The order of potency of the investigated peptides was as follows: xenopsin = NT = xenin > neuromedin N. Kinetensin was inactive. Tetrodotoxin, hexamethonium, tetraethylammonium, 4-aminopyridine, and NG-nitro-L-arginine did not influence the relaxant effects of xenin or NT, whereas the K+ channel blocker apamin nearly abolished their effects. Desensitization against one of the peptides or blockade of NT receptors by SR-48692 prevented the effect of xenin and NT. Structure-activity experiments revealed that the COOH-terminal part of the molecules of xenin and NT is essential for biological activity. Experiments with isolated dispersed smooth muscle cells and binding studies on intestinal smooth muscle cell membranes confirmed and extended the results obtained with muscle strips. In conclusion, xenin relaxes rat ileal smooth muscle via a muscular NT-type apamin-sensitive receptor.

Red kidney bean lectin is a potent cholecystokinin releasing stimulus in the rat inducing pancreatic growth.

BACKGROUND: Lectins are proteins capable of specific binding to carbohydrates without altering their covalent structure. As an essential part of plants they are ingested in our daily diet. By binding to glycosyl side chains of receptors lectins can mimic or inhibit the action of the ligand. Oral administration of phytohaemagglutinin (PHA) in rats dose dependently induces growth of the small intestine and the pancreas by an unknown mechanism. AIMS: To investigate the mechanism of PHA induced intestinal and pancreatic growth. METHODS: Thirty day old male rats were pairfed for 10 days with lactalbumin as a control diet or lactalbumin plus PHA or purified soybean trypsin inhibitor (STI) as a positive control (42 mg/rat/day) with or without 20 micrograms of the cholecystokinin A (CCK-A) antagonist MK 329. To investigate further the effect of PHA on CCK release intestinal mucosal cells were isolated from rats which were continuously perfused in a perfusion apparatus. CCK release into the medium was assayed. RESULTS: PHA and STI significantly stimulated growth of the pancreas and the small intestine. MK 329 blocked this growth effect in the pancreas but not in the small intestine. In vivo, PHA significantly increased CCK plasma levels from 0.75 to 6.67 (SEM 2.23) compared with 2.3 (0.35) pM in the control group. In addition, in vitro PHA dose dependently stimulated CCK release with a maximal effect at 100 ng/ml. CONCLUSION: In vivo and in vitro PHA is a potent stimulus for CCK release in the rat, thereby inducing pancreatic growth, whereas intestinal growth is stimulated by a CCK independent mechanism.

Effect of neurotensin on pancreatic growth and pancreatic polyamine metabolism in rats.

The neuropeptide neurotensin is known to play a role in the regulation of exocrine pancreatic secretion, but actually there are conflicting results as to whether or not neurotensin exerts a trophic response on the pancreas and there are no data concerning its effect on pancreatic polyamine metabolism. In the present study, acute and long-term effects of various intraperitoneal dosages of neurotensin that resulted in mildly supraphysiological and even unphysiological high plasma concentrations of neurotensin were studied. Furthermore, neurotensin was simultaneously administered with cholecystokinin (1 microgram CCK-8/kg body wt ip every 8 h) for five days. The administration of neurotensin resulted in an acute significant decrease of pancreatic amylase and trypsinogen concentrations (p < 0.001), which indirectly confirms the potent effect of neurotensin on pancreatic exocrine secretion. In contrast to that, neither during the short-term study (100 micrograms neurotensin/kg body wt ip every 8 h for 2, 4, 6, 8, 16, and 24 h) nor during the long-term study (1 microgram, 100 micrograms, or 200 micrograms neurotensin/kg body wt ip three or eight times daily for 10 d) did neurotensin administration result in any increase of the various parameters of pancreatic growth and polyamine metabolism. Simultaneous administration of neurotensin and CCK failed to alter or further increase the known stimulatory effect of CCK on pancreatic polyamine metabolism and pancreatic growth after 5 d of treatment. These data indicate that neither alone nor in combination with cholecystokinin did various dosages of neurotensin exert any significant stimulation on pancreatic growth or the parameters of pancreatic polyamine metabolism.

Physiological augmentation of amino acid-induced insulin secretion by GIP and GLP-I but not by CCK-8.

It was the aim of this study to test insulinotropic actions of cholecystokinin octapeptide (CCK-8), gastric inhibitory polypeptide (GIP), and glucagon-like peptide I (GLP-I)-(7--36) amide at basal glucose but physiologically elevated amino acid concentrations. Therefore, in nine fasting healthy volunteers, an amino acid mixture was infused intravenously (12.6 g/h over 120 min). On separate occasions, from 30 to 120 min, placebo (0.9% NaCl-1% human serum albumin), synthetic sulfated CCK-8 (0.5 pmol.kg-1.min-1), human GIP (1 pmol.kg-1.min-1), or GLP-I-(7--36) amide (0.3 pmol.kg-1.min-1) was infused intravenously to mimic physiological increments after a meal. The amino acid infusion lead to a small increment in plasma glucose from 4.8 +/- 0.2 to 5.0 +/- 0.2 mmol/l and significantly elevated insulin and C-peptide concentrations. GIP and GLP-I-(7--36) amide further stimulated insulin (1.8-fold, P = 0.0001 and 0.004, respectively) and C-peptide (1.3-fold, P = 0.0003 and 0.013, respectively), with a subsequent slight reduction in plasma glucose (P < 0.0001). Insulin and C-peptide then decreased again in parallel. CCK-8 was without effect on insulin and C-peptide levels. In conclusion, GIP and GLP-I-(7--36) amide are not only able to interact with elevated plasma glucose but are insulinotropic also with physiologically raised amino acid concentrations. Such an interaction could play a role after the ingestion of mixed meals. Cholecystokinin, on the other hand, is not a physiological incretin also under these conditions.