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Polyamines are highly regulated polycations which are essentially involved in cell growth and differentiation. Polyamines in food significantly contribute to the polyamine body pool. Dietary polyamines exert various direct and indirect trophic effects on the rat's immature intestine and play an important role during intestinal maturation. Human milk and that of other mammalians contain relatively high levels of polyamines which are essential luminal growth and maturation factors. The polyamines spermidine and spermine as well as their diamine precursor putrescine are ubiquitous normal constituents of all prokaryotic and eukaryotic cells and are essentially involved in various processes of cell growth and differentiation (Pegg & McCann, 1982; Tabor & Tabor, 1984; Seiler, 1990).

In patients with benign or malignant diseases of the larynx/pharynx causing inadequate oral food intake, maintenance of individual adequate enteral nutrition is a major medical goal. This is particularly important in patients with malignant ENT tumours, where therapeutical measures as radiation or chemotherapy result in further deterioration of nutritional status and consecutively of quality of life and tolerance of therapy. Due to its safe and technically simple route of placement, the PEG has become the preferred enteral route of choice for enteral long-term nutrition world-wide. The technical success rate is > 99% with a procedure-related lethality rate of about 0%. Prospective clinical studies prove the excellent individual subjective acceptance of this method by patients. Indications, contraindications, complications, technical procedures and clinical aspects of PEG placement are described in detail in the present review. Long-term enteral feeding via PEG is accepted as a safe, effective, easy to practise and highly acceptable method with excellent long-term results and thus distinct improvement of nutritional status. Individual decision for PEG placement should be considered much earlier and more frequently in appropriate patients to save and further improve clinical and nutritional status and consecutively quality of life.

The complex damage to health caused by chronic alcohol consumption is evident, and has major consequences both for the individual and society. Besides this relevant health impairment through excessive alcohol use, however, regular moderate use of alcohol has been shown to have various health benefits. In a number of large clinical studies it has been shown that regular moderate consumption of alcohol has a positive influence on overall mortality and can significantly reduce both the primary and secondary incidence and mortality of coronary heart disease. This cardioprotective effect is due primarily to the alcohol itself, since no preferential effect of a particular type of alcoholic beverage has been shown to date. Although a cardioprotective and life-prolonging effect has been shown to be associated with regular moderate use of alcohol, a global recommendation in favor of regular moderate drinking is nevertheless not justifiable at present, because of the well-known considerable risks and potential health hazard associated with drinking.

Adequate enteral nutrition is a major medical goal in patients with inadequate oral food intake caused by various underlying diseases of benign and malignant origin. Due to its safe and technically simple route of placement the PEG has become the preferred enteral route of choice for enteral long-term nutrition world-wide. The incidence of PEG placement is still rapidly increasing. Based on the results of recently published large clinical studies the technical success rate is >99 % with a procedure-related lethal rate of about 0 %. Prospective clinical studies clearly prove the excellent individual subjective acceptance of this method by the patients. Indications, contra-indications, complications and technical procedures of PEG placement are described in detail in the present review. In general, long-term enteral feeding via PEG is accepted as a safe, effective, easy to practice and highly acceptable method with excellent long-term results and distinct improvement of nutritional status. Individual decisions for PEG placement should be considered much earlier and more frequently in appropriate patients to save and further improve quality of life in patients with inadequate oral food intake caused by various benign and malignant diseases.

Background: Modern pancreatin preparations consist of enteric-coated microspheres to protect the enzymes from gastric acid. There are, however, no clinical trials comparing different sizes of pancreatin microspheres with regard to fat excretion and fat intake., Aim: To prove both equivalent efficacy and safety of conventional pancreatin microspheres and smaller pancreatin minimicrospheres in patients with exocrine insufficiency due to chronic pancreatitis., Methods: In this prospective, randomized, double-blind, multicentre, crossover trial, patients with a stool fat excretion of > 7.5 g/day during a placebo period were randomly assigned either to the minimicrosphere/microsphere treatment sequence or vice versa. The primary end-point was the coefficient of fat absorption, which was calculated from fat excretion and fat intake during the course of a standardized diet. Stool weight, clinical symptoms and the safety of the preparations were also evaluated., Results: Thirty-seven patients entered the study, of whom 23 fulfilled the criteria for the crossover period. In the per protocol analysis (n=18), the 90% confidence intervals for the coefficient of fat absorption of both crossover periods lay entirely within the equivalence range (P=0.02). The intention-to-treat analysis revealed similar results, but the equivalence range was slightly missed (P=0.07). Similar results were obtained for the secondary parameters and the reported adverse events., Conclusions: Pancreatin minimicrospheres have been shown to be equally effective as microspheres in improving the coefficient of fat absorption in patients with exocrine insufficiency due to chronic pancreatitis.

Studies of microbial purification of a model waste water containing 4-nitrophenol were carried out in a continuously working aerobic solid-bed reactor. The main emphasis was on the dynamic behaviour of the system after a sudden change in cultivation conditions and on the steady state performance of the reactor as a function of the pollution load. A change from ammonium-free to ammonium-containing medium hardly influenced the nitrophenol degradation. The reactor responded differently to an increase in pollutant load, which was brought about by increasing either the 4-nitrophenol content or the flow of the waste water. Up to a load of 270 mg l-1 h-1 the pollutant was stably and almost completely degraded. At a higher load, only a partial 4-nitrophenol degradation took place. A mathematical model was derived to describe the processes that occurred in the reactor. By segregation into two compartments--the aqueous phase and the biofilm--account was taken of the fact that the pollutant is carried into the biofilm by diffusion and is degraded there. The observed relations between the pollutant load, the pollutant concentration in the outlet of the reactor and the reactor performance agreed with the simulated process behaviour. As the model simulation showed, the incomplete pollutant degradation at a higher reactor load was caused by oxygen limitation.

Background: Polyamines are essential for cell growth. Dietary and probably gut bacterial derived polyamines contribute significantly to the polyamine body pool., Aims: To evaluate the influence of dietary, luminal polyamines on growth and development of different gastrointestinal organs in normally growing rats., Methods: Male suckling Wistar rats were randomly allocated to four treatment groups: polyamine deficient diet (PDD); PDD plus antibiotics (neomycin 2 g/kg and metronidazole 34 mg/kg); PDD plus polyamine supplementation at normal concentrations; or normal standard laboratory chow. After a six month feeding period 7-10 animals/group were sacrificed., Results: No differences in body weight gain, food consumption, or general behaviour could be observed between the four groups of animals. Feeding of PDD alone or PDD plus antibiotics resulted in a highly significant decrease in organ weight, protein content, and DNA content in small intestinal and colonic mucosa whereas no alterations were found in the liver., Conclusions: Long term feeding of polyamine deficient diets resulted in a significant hypoplasia of small intestinal and colonic mucosa. Dietary, luminal polyamines are important local factors for growth and the development of small intestinal and colonic mucosa.

The microbial degradation of hydrocarbons was studied in an artificially contaminated sandy soil, using a pilot-scale percolator system. After a short lag period, an intensive degradation occurred, which diminished in time and completely stopped in the end, despite large residual contaminations (residues of 56% diesel fuel, 20% n-hexadecane and 3.5% phenanthrene at the initial loadings of each 3000 mg/kg). The remaining pollutant content was influenced by the kind of hydrocarbon but was nearly independent of its initial loading. According to a model-aided analysis of the carbon dioxide production during remediation, the observed stagnation of degradation was caused by a limited bioavailability of the pollutants. The degradation in the soil-free aqueous phase was more extensive than in the soil, which suggests that the limited bioavailability in the soil can be attributed mainly to matrix-dependent rather than substrate-dependent influences. Generally, fine particles and organic matter are mainly responsible for the adsorption of pollutants to the soil matrix. Our sandy soil also bound hydrocarbons adsorptively although it contained neither silty material nor significant amounts of organic matter. As shown by Brunauer Emmett Teller (BET) analysis, the soil particles were covered by micropores, which enlarged the soil surface by a factor of 120 in comparison with the macroscopic surface area. The microporosity is the reason for the hydrocarbons being more strongly adsorbed to the sandy soil than expected.

Chronic pancreatitis is typically characterized by clinical (abdominal pain, steatorrhea, loss of body weight), morphological (calcifications, dilated ductus pancreaticus) as well as functional (maldigestion, diabetes mellitus) parameters. Since the diagnosis of chronic pancreatitis is hampered by the inavailability of early histological confirmation, it is therefore based on morphological (ultrasound, ERP, EUS, CT) and functional (faecal elastase) criteria. Due to the poor correlation between morphological and functional parameters in the early phase of the disease, both are complementary at this stage. While the diagnosis of severe cases of chronic pancreatitis with steatorrhea is hardly a challenge in clinical practice, the differential diagnostic evaluation of mild and moderate cases remains a major clinical problem. ERP remains to be the most sensitive morphological procedure, while determination of faecal elastase is the most sensitive and specific "tubeless" pancreatic function test available today and in the future prove to be rapid, easy to handle and highly practicable in clinical routine.

The amino groups of amino acids, the constituents of proteins, are catabolized in the urea cycle. One intermediate of this cycle, ornithine, is a precursor molecule of polyamines. The influence of dietary protein intake on the production and excretion of polyamines in the urine is yet unclear. The aim of this study was to investigate the excretion of polyamines in the urine following three days of creatine-free, creatine-free and low-polyamine diet in four persons. On the fourth day they were loaded with creatine-free, creatinine-free and low-polyamine high-protein diet (80 g/70 kg body weight). High-protein diet resulted in no increase of urinary polyamine excretion. The low-polyamine diet caused a non-significant decrease in urinary polyamine excretion (by 15%).

Background: Breath tests using stable isotopes of carbon or hydrogen are increasingly becoming established for the evaluation of various gastrointestinal functions, including measurement of exocrine pancreatic insufficiency. We wanted to evaluate the clinical relevance of the non-invasive, non-radioactive 13C-mixed triglyceride breath test in comparison with the secretin-caerulein test as the 'gold standard' of pancreatic function testing and with faecal chymotrypsin and elastase 1 in patients with mild and severe exocrine pancreatic insufficiency., Methods: The secretin-caerulein test, faecal fat analysis, 13C-mixed triglyceride breath test, faecal elastase 1, and chymotrypsin and various morphologic investigations were done in 26 patients with mild (n = 13) or severe (n = 13) exocrine pancreatic insufficiency and 25 patients with gastrointestinal diseases of non-pancreatic origin. Twenty-seven healthy volunteers served as normal controls. After a 12-h fast 200 mg mixed triglyceride (1,3-distearyl,2(carboxyl-13C)octanoyl glycerol) were orally administered with a test meal, and breath samples were taken before and at 30-min intervals for 5 h thereafter, and the increase in 13C/12C isotopic ratio in breath was analysed by mass spectrometry. Various modifications of the test procedure were investigated., Results: Specificity for impaired pancreatic function was higher for faecal elastase (90%) and equal for faecal chymotrypsin (82%) as compared with the various variables of the 13C-mixed triglyceride breath test (69-85%). The sensitivity of the 13C-mixed triglyceride breath test for total and separately for mild and severe exocrine pancreatic insufficiency was higher (total, 69-81%) than that of faecal chymotrypsin (total, 56%) but lower than faecal elastase (total, 92%)., Conclusion: The 13C-mixed triglyceride breath test very sensitively reflects severe exocrine pancreatic insufficiency (steatorrhoea) but has limited sensitivity for the detection of mild cases. With regard to the higher sensitivity and specificity, the higher practicability, and the much lower cost, determination of faecal elastase 1 concentrations is superior to the 13C-mixed triglyceride breath test and therefore remains the most reliable indirect pancreatic function test available today.

The clinical relevance of the 13C-starch breath test was evaluated in comparison to the secretin-caerulein test as the "gold standard" of pancreatic function testing, fecal elastase concentration, and fecal chymotrypsin activity in 30 patients with mild (n = 15) or severe (n = 15) exocrine pancreatic insufficiency. 23 patients with gastrointestinal diseases of non-pancreatic origin and 31 healthy volunteers served as controls. 50 g of natural starch of maize were orally administered after a 12-h fast and breath samples were taken before and in 30 min intervals for five hours after oral ingestion and the increase of 13C/12C-isotopic ratio was analyzed by mass spectrometry. Specificity of fecal elastase (93%) and fecal chymotrypsin (93%) for impaired pancreatic function were much higher compared to the various parameters of the 13C-starch breath test (69-74%). Sensitivities of the 13C-starch breath test for all and separately for mild and severe exocrine pancreatic insufficiency were higher (total 70-77%) compared to fecal chymotrypsin (total 60%), but lower compared to fecal elastase (total 93%). With regard to the higher sensitivity and specificity, the higher practicability, and the lower costs determination of fecal elastase concentrations is superior to the 13C-starch breath test and therefore remains to be the most reliable indirect pancreatic function test available today.

Sperm acrosome antigen-1 (SAA-1) is a molecule on the acrosomal cap of sperm from the human and a number of mammalian and lower species. SAA-1 was initially characterized by a monoclonal antibody (mab) AG7 directed against SAA-1. Previous studies indicate that SAA-1 may play an important role in the regulation of the acrosome reaction in the human and other species. Unselected couples seeking infertility treatment were subjected to an analysis of the amount of SAA-1 present on washed husband sperm. Using indirect immunofluorescence as well as radioimmunobinding assay, the expression of SAA-1 on patient spermatozoa was found to be significantly decreased compared to a group of healthy sperm donors. The decrease in SAA-1 did not correlate well with sperm morphology. Couples entered into the study were followed for an average of 12 months, while they received infertility treatment. Most couples conceived after a variable number of treatment cycles. It is concluded that a decrease of SAA-1 expression may contribute to subfertility, which can be overcome by the aid of assisted reproduction.

The present study was designed to investigate the inhibitory potency of the two novel S-adenosylmethionine decarboxylase (SAM-DC) inhibitors MDL 73811 and CGP 48664 on the camostate-induced pancreatic polyamine metabolism and especially intracellular spermidine accumulation as well as pancreatic growth in vivo. Male Wistar rats (180 g) were either treated with (1) the synthetic trypsin inhibitor camostate (200 mg/kg b.w. orally twice daily), (2) camostate+MDL 73811 (100 mg/kg b.w. i.p. twice daily), (3) camostate+CGP 48664 (5 mg/kg b.w. i.p. once daily) or (4) saline as controls. Animals (5-9 per group) were sacrificed after 1, 2 and 5 days of treatment. MDL 73811 caused a long-lasting (> 95%; p < 0.005) inhibition of SAM-DC followed by a significant (p < 0.005) increase in ornithine decarboxylase and putrescine, while spermine was decreased (p < 0.005). In contrast to MDL 73811, CGP 48664 had little effect in vivo. Despite potent inhibition of SAM-DC camostate-stimulated intracellular spermidine accumulation was not prevented by the simultaneous administration of MDL 73811. Consequently organ growth was not affected either. Since de novo synthesis of spermidine was effectively inhibited by MDL 73811, counterregulatory mechanisms (i.e. interconversion pathway, extracellular uptake) had to step in to maintain the intracellular balance of spermidine. The present data support the general concept of the importance of intracellular spermidine accumulation for the maintenance of pancreatic growth in vivo.

Weekly administrations of the potent carcinogen 1,2-dimethylhydrazine (DMH) predominantly induce carcinoma of the colon by nearly 100% after six months' treatment in rats. Polyamines, and especially the key enzyme of polyamine de novo synthesis ornithine decarboxylase (ODC) are well-known to play an important role in cell growth and tumor carcinogenesis. Male Wistar rats were s. c.-injected with a single dose of 20 mg DMH/kg b. wt. and five to eight animals were sacrificed 4, 8, 12, 24, 72, 120, 168, and 240 hours after injection of DMH or the basic solution, respectively. Additionally, seven animals were simultaneously treated with the ODC inhibitor alpha-difluoromethylornithine (DFMO) and sacrificed seven days after a single DMH injection. A single s. c.-dosage of the colon carcinogen DMH resulted in dissimilar activation patterns of polyamine metabolism in the various organs studied: in distal and less pronounced in proximal colonic mucosa ODC and putrescine are significantly increased seven days after application of DMH and DNA polymerase after ten days; in small intestinal mucosa ODC activity is significantly elevated after seven days and especially S-adenosylmethionine decarboxylase activity is significantly and prolonged increased between twelve and 72 hours after DMH injection; while spermidine/spermine N1-acetyltransferase activity is significantly elevated in liver after 168 and 240 hours, no changes compared to controls are found in the pancreas. DFMO treatment completely prevents DMH-induced activation of polyamine de novo synthesis and DNA polymerase in colon and small intestine. These data prove completely different and -interestingly-late appearing activation patterns of DMH on intracellular polyamine metabolism in various organ systems and further elucidate the complex metabolic changes following carcinogen treatment.

Two cases of different dysfunctions of self-expanding nickel-titanium coil stents are described here. In the first case, a metallic coil stent was placed in a 8-cm circular rigid stenosis of the mid-esophagus caused by a squamous-cell carcinoma (T3 N1 M1), and seven weeks later, the stent lumen was completely occluded by massive tumor ingrowth through inadequtely adapted single coil wires. In the second case, the caudal and cranial ends of the stent became increasingly invaginated after initially adequate stent expansion, resulting in a shortening of the stent to about two-thirds of its intended size, with subsequent complete luminal obstruction at both ends of the stent due to tumor overgrowth. These two examples of different stent dysfunction correspond to similar observations by other investigators. Further investigations in a large series of stent insertions have to be performed before general conclusion can be drawn as to the clinical efficacy of metallic coil stents for endoscopic palliation of esophageal carcinoma.

The indication for initiation of a replacement therapy with pancreatic enzymes in the course of ongoing exocrine pancreatic insufficiency is clinically given with the appearance of loss of body weight, steatorrhea with stool fat excretion of more than 15 g per day, dyspeptic symptoms with strong meteorism, diarrhoea, and subjective misbehaviour caused by chronic pancreatitis, in rare cases with the appearance of maldigestion of proteins and carbohydrates and--under certain circumstances--for the treatment of pain in chronic pancreatitis. Due to the increase of chronic pancreatitis in recent years, the number of patients who necessarily have to be treated with enzyme replacement therapy has increased, too. The adequate replacement therapy with pancreatic enzymes, especially in patients with severe exocrine pancreatic insufficiency, is still a serious problem--requiring sufficient knowledge of the individual pathophysiological circumstances of the patient as well as the various pharmacological aspects of the different types of enzyme drugs. The most important clinical aim of the replacement therapy is the necessity to achieve a sufficient lipase activity in the duodenum. Accordingly the achievement of this aim is the main problem in clinical practice, since the acid-instable lipase is predominantly inactivated by gastric acid and proteases. Furthermore, in many cases an asynchronous gastroduodenal transport of the administered enzyme drug and food is found as a result of inadequate size of the drug or drug particles. In general, the necessary doses of administered enzymes does not follow general rules, but has to be adjusted individually. Recent scientific developments, as the characterization of an acid-stable bacterial lipase, the cloning of human acid-stable lipase, the transfection of human lipase genes by virus-mediated gene transfer as well as the development of very small acid-stable mini microspheres, present interesting new perspectives to further optimize the efficacy of the therapy of exocrine pancreatic insufficiency in the near future.

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.

The present study was designed to investigate the effects of the carcinogenic agent azaserine on the induction of pancreatic and hepatic polyamine metabolism in rats. One single injection of 30 mg azaserine/kg body weight i.p. is known to induce adenoma and subsequently carcinoma, predominantly in the pancreas, after several months. Male Lewis rats were treated with either azaserine (30 mg/kg body weight i.p.) or saline and 5-10 animals per group were sacrificed 2, 6, 9, 12, 18, 24, and 48 h later. Furthermore, animals were simultaneously treated with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) or the polyamine oxidase inhibitor MDL 72527 and killed 6 and 12 h after azaserine injection. The azaserine-induced significant increase in pancreatic putrescine concentrations was accompanied by an increase in spermidine/spermine N1-acetyltransferase but unchanged ODC and was significantly inhibited by N, N'-bis(2,3-butadienyl)putrescine (MDL 72527) but not by DFMO. S-Adenosylmethionine decarboxylase (SAM-DC) activity was significantly decreased in the pancreata of azaserine-treated animals compared to controls. In contrast, the azaserine-induced significant increase in hepatic putrescine was lower and transient, was accompanied by an increase in ODC and SAM-DC, and was completely inhibited by simultaneous DFMO treatment but not by MDL 72527. These data show completely different patterns of activation of polyamine metabolism in the pancreas and in the liver: Azaserine treatment forms putrescine in the liver by de novo synthesis via ODC only, while azaserine-induced pancreatic putrescine is exclusively produced by the interconversion pathway via oxidation of N1-acetylspermidine.

Influence of Ranitidine and Famotidine on the Intragastric pH-profile in Healthy Volunteers/Randomised cross-over study of ranitidine effervescent tablets (300 mg) versus famotidine film coated tablets (40 mg). A controlled cross-over trial was carried out to compare the duration of time until the onset of action and its intensity following administration of ranitidine (R, Sostril, CAS 76824-35-6) effervescent tablets (300 mg) and famotidine (F, CAS 76824-35-6) film coated tablets (40 mg). Twelve volunteers (4 female, 8 male) participated in the study. The efficacy of the test medications was assessed by pH-metry during 12 h. The evaluation of the measurements showed that a pH-value 3.5 was reached 100 s after administration of R and 3,392 s (56.5 min) after F (p < 0.01). The median pH-values were significantly higher after R during the first 2 h. The AUC-values (area under the curve; pH-time) for 1, 2 and 4 h were calculated by the trapezoid rule. The intake of R resulted in significantly higher areas than that of F. After reaching the pH-value of 3.5 this value remained stable during the complete period of measurement (R = 12 h, F = 11 h). The faster onset of pH-value elevation could correspond clinically with a faster onset of pain relief.

Epidermal growth factor (EGF) is a potent mitogen exerting a variety of biologic effects. While the growth stimulatory effect of EGF is well investigated in the gut, there are conflicting results concerning the growth stimulatory effect of EGF in the pancreas and no data concerning its effect on pancreatic polyamine metabolism in vivo. In the present study male Wistar rats (180 g) were either treated with EGF (20 micrograms/kg b. wt. i.p. every 8 hours) alone, EGF plus the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethyl-ornithine (DFMO), DFMO alone or saline as controls and 9-10 rats per group were killed after 8 hours, 1, and 5 days. To prove the biologic activity of EGF (> 97% purity; HPLC) rats were i.p. injected with 150 micrograms EGF/kg b. wt. and five animals were killed after 2, 4, or 6 hours, respectively and ODC and S-adenosylmethionine decarboxylase (SAM-DC) activities were calculated in the duodenum, ileum, and pancreas. In contrast to the gut neither acute high-dose nor long-term administration of EGF resulted in any stimulation of pancreatic growth or pancreatic polyamine metabolism of rats in vivo.

The prognostic assessment, as well as the individual therapy especially of acute necrotizing pancreatitis, still remains a common clinical problem. Today, conservative intensive care is widely accepted as the most important initial therapeutic measure. Despite various attempts based on different underlying pathophysiological mechanisms, advances in conservative therapeutic concepts over the last few years have remained small. The aim of the following review is to present current concepts of treatment of acute pancreatitis, summarizing the established guidelines for conservative and operative surgical therapy as discussed in further articles of this issue. Furthermore, important recent attempts at therapeutic innovation are discussed, and the prospects for future development presented.

Aim of the present study was to evaluate the relevance of various intracellular regulatory mechanisms of polyamine metabolism in normal and camostate (FOY 305)-induced pancreatic growth in rats. Furthermore it was investigated whether the simultaneous inhibition of the polyamine interconversion pathway by the potent polyamine oxidase inhibitor MDL-72527 together with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) is able to enhance and prolong the only initial and transient inhibitory effects of DFMO on camostate-induced pancreatic growth. Simultaneous administration of DFMO and MDL-72527 resulted in a significant inhibition of the camostate-induced increases in pancreatic putrescine, ODC and DNA over 5 days, while the initial significant inhibition of pancreatic weight, protein content, DNA-polymerase and especially spermidine was absent after 5 days and spermine as well as N1-acetylspermidine were even increased. Diamine oxidase (DAO) activity in pancreas is very low and the potent DAO inhibitor aminoguanidine failed to alter any of the measured parameters except DAO. Therefore, oxidative degradation of putrescine by DAO--which is essential in the gut--is irrelevant in the pancreas. Simultaneous inhibition of the pancreatic polyamine interconversion pathway extended the initial inhibitory effects of DFMO only slightly and failed to exert a potent long-lasting inhibitory effect on spermidine and pancreatic growth.

36 patients (18 males and 18 females, mean age 51 [21-76] years) were prepared for colonoscopy with acupuncture (points: Hegu, Neiguan, Zusanli and Gongsun bilaterally), without acupuncture or pretend acupuncture at points not expected to bring about pain relief. In the 12 acupuncture patients mean pain sensitivity, estimated during the examination by means of a visual analog scale, was significantly (P = 0.003) lower (1.4 +/- 0.4) than in the groups without acupuncture (n = 12; 2.7 +/- 0.3) or pretend acupuncture (n = 12; 3.0 +/- 0.3). In addition, analgesics and sedatives needed to be given significantly less to those with acupuncture (one patient each; P = 0.005) than those without (analgesics to five, sedatives to eight patients) or with pretend acupuncture (analgesics to four, sedatives to five patients). These data demonstrate that pain connected with colonoscopy can be reduced by preceding acupuncture.

The adequate therapy of pancreatic enzyme replacement in patients with exocrine pancreatic insufficiency is still a difficult clinical problem especially in patients following pancreatectomys, with chronic alcoholic pancreatitis or cystic fibrosis. The substitution of lipase to eliminate steatorrhoea is the most important aim but due to its acid lability even the most serious problem in pancreatic enzyme replacement therapy. Various different medications are meanwhile available: conventional preparations from porcine pancreatin or fungal enzymes as rizolipase, enteric-coated tablets or even enteric-coated microspheres or adjunctive therapy with H2-receptor antagonists. While dosage requirements vary widely and therefore have to be tried out individually, the choice of the adequate preparation should be influenced by the realization of the physiological and pathophysiological characteristics of the individual patient and the pharmaceutical characteristics of the different supplements. The advantages and disadvantages of the various medications for enzyme replacement therapy in patients with exocrine pancreatic insufficiency are reviewed in this article.

Cystadenoma and cystadenocarcinoma are rare tumors of the pancreas. While these cystic neoplasms neither present any typical clinical symptoms nor cause any specific changes in laboratory parameters, great emphasis is laid on imaging procedures for the diagnosis of these pancreatic tumors. Tumor size, localization and the typical cystic character are well-documented by ultrasound and contrast-enhanced computed tomography. Furthermore, CT could contribute to distinguish between serous and mucinous cystadenoma of the pancreas because of typical features of both tumors. Angiography presents a further suitable diagnostic method, while ERCP findings are rather unspecific and non-homogenous. Furthermore, ultrasound guided fine-needle biopsy should be carried out in unclear cases to confirm the diagnosis.

Four patients with benign serous cystadenoma, one with mucinous cystadenoma, and three with mucinous cystadenocarcinoma treated in the university hospital of Göttingen between 1985 and 1988 were investigated. The main initial symptoms of these cystic tumors were abdominal pain (7/8), weight loss (3/8), maldigestion (3/8), and palpable abdominal mass (3/8), while laboratory investigations revealed nonspecific alterations (elevated ESR, mild hypochromic anemia). CA 19-9 was elevated in two patients, one of whom had cystadenocarcinoma; CEA also was elevated in this patient only. In all cases size, localization, and cystic character of the tumors were shown clearly by sonography and computed tomography; fine needle biopsy helped to distinguish between serous and mucinous cystadenoma in four of six cases. Because of their malignant potential, total extirpation of mucinous cystic tumors is the treatment of choice, while serous cystadenomas are benign and therefore may be treated conservatively in uncomplicated cases or high-risk patients.

Cystic neoplasms are rare but in the last ten years more frequently detected tumors of the pancreas. The clinical symptoms as abdominal pain, abdominal mass, diarrhoea or weight loss are rather unspecific. There are no typical laboratory findings. Localization, size and cystic character of these tumors are well documented by ultrasound or abdominal computed tomography while typical features in CT as well as US-guided fine needle biopsy may contribute to further differentiation of the tumors. Exocrine and endocrine pancreatic function are frequently weakened which might falsly lead to the diagnosis of chronic pancreatitis. Because of their malignant potential mucinous cystadenoma should be treated by complete surgical resection while serous cystadenoma are exclusively benign and might therefore be treated conservatively in uncomplicated cases or high-risk patients. The prognosis of pancreatic cystadenocarcinoma is obviously better compared to adenocarcinoma of the pancreas.

We investigated the total, free, and acetylated polyamine concentrations in pancreatic tissue, serum, and urine of 20 patients with pancreatic cancer, 30 healthy volunteers, and 40 patients with nonmalignant, gastrointestinal diseases by reversed-phase liquid chromatography. Tissue concentrations in carcinoma compared to histologically unaffected pancreas were significantly higher for putrescine, elevated for cadaverine, and nearly identical for spermidine and spermine, while N1-acetylspermidine was detectable in cancer tissue only. With the exception of free spermine in urine and total spermine in serum, all other polyamines were significantly elevated in the urine and serum of cancer patients compared to healthy controls. These data support the concept that polyamines play an important role in rapidly growing tissues. However, nonmalignant gastrointestinal diseases partly showed similar elevations. Because of this low specificity, polyamines are of little value only as diagnostic markers of pancreatic carcinoma. Since polyamine concentrations normalized in patients after curative operation while they were further elevated in patients with tumor relapse or metastases, polyamines might play a clinical role in predicting therapeutic success or indicating relapse of the tumor. A significant linear correlation of polyamine concentrations and the size of the tumor was found while a significant correlation to CEA, CA 19-9, and CA 125 or the presence of organ metastases did not exist.

Cholecystokinin (CCK), gastrin, cerulein, and other analogs are known to stimulate the growth of the rat pancreas. In the present study, we compared the trophic action of a member of this gastrin/CCK family, the amphibian peptide cerulein, with a member of the structurally unrelated neurotensin/xenopsin group, the amphibian peptide xenopsin. For this purpose, 0.56 nmols/kg cerulein, 1.0 nmols/kg xenopsin, or normal saline were injected intraperitoneally three times a day in 28 rats for 3 d. Pancreatic weight, DNA, and incorporation of 3H-thymidine into DNA were determined. In another study, pancreatic weight, DNA, and the polyamines, putrescine, spermidine, and spermine, were determined after a single dose of 2.7 nmol/kg cerulein, 4.5 nmol/kg xenopsin, or saline. The polyamines were measured by reverse-phase HPLC and post-column derivatization. Cerulein increased pancreatic weight, stimulated 3H-thymidine incorporation into DNA, and raised putrescine concentrations significantly, but led to a significant reduction of pancreatic DNA concentration. Xenopsin also stimulated 3H-thymidine incorporation into DNA, but did not affect pancreatic weight, DNA concentration, or the polyamines during the 4 h of the experiment. These findings suggest that cerulein, in the dose and intervals applied, initiated hyperplasia and induced hypertrophy of the pancreas, whereas xenopsin only initiated hyperplasia. These results, together with the dissimilar secretory effects of the two peptide families, may be the expression of a dissimilar mode of action. However, it cannot be excluded that, since cerulein is more potent than xenopsin, the differences also are owing to dosage. We conclude that cerulein and xenopsin, which both have trophic effects on the pancreas, may act by different mechanisms.

This study was designed to investigate the clinical relevance of polyamine determination in human tissue, serum, and urine as diagnostic markers in the diagnosis or postoperative control of patients with gastrointestinal cancer. Total, free, and acetylated polyamines were measured simultaneously in tissue, serum, and urine of patients with esophageal (n = 16), gastric (n = 40), pancreatic (n = 20) or colorectal (n = 50) carcinoma, in 40 patients with non-malignant gastrointestinal diseases, and 30 healthy volunteers. Though sensitivity of polyamines for gastrointestinal cancer proved to be high, non-malignant gastrointestinal diseases partly showed similar elevated polyamine concentrations in urine and serum which resulted in a low specificity of polyamines for gastrointestinal cancer. Therefore polyamines are not suitable as diagnostic markers in tumor screening. Furthermore, since polyamine concentrations in serum and urine normalized after curative operation while they were further increased and elevated in patients with proven relapse of the tumor or metastases, polyamines might be of clinical value in postoperative monitoring of therapeutical success or predicting relapse of the tumor.

This study was designed to investigate the role of ornithine decarboxylase (ODC) and polyamines in pancreatic adaptation. Cholecystokinin (CCK) is well-known to be a potent trophic stimulus on the pancreas. On the other hand, the oral application of the synthetic trypsin inhibitor camostate results in an extensive release of endogenous CCK in rats. alpha-difluoromethylornithine (DFMO), an irreversible and specific inhibitor of ODC, was applied simultaneously to elucidate the essential role of polyamines in pancreatic growth. Camostate feeding (200 mg/kg b.wt. orally twice a day) resulted in a rapid elevation of ODC activity already after 2 hours, reaching a maximum after 6 hours (about 200fold above controls) followed by a significant increase in putrescine after 4 hours and spermidine after 24 hours while spermine remained unchanged. The trophic parameters increased as expected in following time-course: thymidine kinase (12 hours), DNA polymerase (12 hours), protein (24 hours), pancreatic weight (24 hours) and DNA (5 days). DFMO (2% in drinking water + 3 x 300 mg/kg b.wt. i.p. during daytime) was not able to prevent but significantly delayed and reduced the camostate-induced increase in ODC and polyamines as well as the trophic parameters. These data indicate an essential role for ODC and polyamines in camostate-induced pancreatic growth and hormonal mediated pancreatic adaptation.

The patterns of activity of the nucleolus organizer regions (NORs) in the spermatogeneses of ten species of all non-mammalian classes of vertebrates and one species of the cephalochordates were investigated with the silver (Ag)-staining technique. The Ag-stainability of the NORs is a measure of the transcriptional activity of the ribosomal RNA genes. In all species, there is a very similar pattern of NOR-activity in the various stages of spermatogenesis. The qualitative analysis of the Ag-stainability of the NORs was in very good agreement with the results obtained for mammals: Ag-stained NORs are detectable during the entire meiotic prophase up to the pachytene stage, completely absent in the meiotic metaphases I and II, and again demonstrable in early spermatid nuclei. The results confirm the occurrence of postmeiotic reactivation of the RNA genes. The preferential inhibition of rRNA synthesis by low doses of actinomycin D induced a rapid decline of the Ag-stainability of the postmeiotically reactivated NORs. The significance of the evolutionary conservation of the postmeiotic NOR-reactivation is discussed.

The effect of cyclosporine A (CsA) and alpha-difluoromethylornithine (DFMO) on the camostate-induced increase in pancreatic ornithine decarboxylase (ODC) activity and polyamine biosynthesis has been studied in vivo. Six hours after application of the synthetic trypsin inhibitor camostate (200 mg/kg b wt orally) pancreatic ODC activity increased about 140-fold and putrescine concentration about ninefold. CsA inhibited the elevation of both parameters in a dose-dependent manner. CsA pretreatment for 3 d with doses of 7.5, 10.0, and 12.5 mg/kg b wt orally once a day and consecutive CsA blood levels 24 h after the last CsA application of 751 +/- 62, 968 +/- 70, and 1,395 +/- 79 ng/mL, respectively, resulted in a complete inhibition of the camostate-stimulated increase in pancreatic ODC activity and putrescine concentration in vivo. DFMO (2% in drinking water and additionally 300 mg/kg b wt intraperitoneally at 8 AM, 12 noon, and 4 PM) inhibited the increase in both, ODC activity, and putrescine, significantly in an equipotent degree as 2.5 mg CsA/kg b wt, whereas higher doses of CsA proved to be more effective than DFMO in the chosen subtoxic dose. In all cases, no significant changes in pancreatic spermidine and spermine concentration, DNA and protein content, or pancreatic and body weight were observed. It is concluded that CsA in doses used for immunosuppression in clinical practice is a very potent and more effective inhibitor of ODC activity and polyamine synthesis in vivo than DFMO. This ODC inhibitory effect of CsA is a further detail to elucidate the up to now incompletely understood mechanisms of action of this immunosuppressive agent.

This study was designed to investigate changes of ornithine decarboxylase and polyamines during pancreatic adaptation in response to feeding of the synthetic protease inhibitor camostate. alpha-Difluoromethylornithine, an irreversible and specific inhibitor of ornithine decarboxylase, was applied simultaneously to elucidate the essential role of polyamines in pancreatic growth. Cholecystokinin (CCK) plasma levels in camostate-fed rats increased from basal values of 3-4 pmol/l to a maximal level of 27.4 pmol/l after 2h; they then decreased up to 12 h but remained elevated above controls throughout the 30-day experiments. In the camostate group pancreatic ornithine decarboxylase activity was elevated after 2 h, reaching a maximum after 6 h (1,858.5 pmol 14CO2/h/mg DNA, about 200-fold above controls) followed by a significant increase in putrescine after 4 h and spermidine after 24 h while spermine remained unchanged. The trophic parameters increased in the following time sequence: thymidine kinase (12 h), DNA polymerase (12 h), protein (24 h), pancreatic weight (24 h) and DNA (5 days). alpha-Difluoromethylornithine significantly delayed and reduced the camostate-induced increase in ornithine decarboxylase activity and polyamine concentrations as well as the trophic parameters. Application of the CCK receptor antagonist L-364,718 resulted in complete inhibition of the increases in ornithine decarboxylase, polyamines and all trophic parameters. These data indicate an important role for ornithine decarboxylase and polyamines in camostate-induced pancreatic growth and hormonal mediated pancreatic adaptation in rats.

A highly sensitive and precise method for the determination of the polyamines putrescine, cadaverine, spermidine and spermine and all their monoacetyl derivatives in a single analysis in human and animal urine, serum and tissue samples is described. For polyamine separation, an ion-pairing reversed-phase high-performance liquid chromatographic (HPLC) method is used, followed by post-column derivatization with o-phthalaldehyde and consecutive fluorescence detection. Urine and serum samples are purified with a Bond Elut silica cartridge. The detection limit for polyamines is 0.5-1.0 pmol and excellent linearity is achieved in the range from 3 pmol up to more than 10 nmol. The influence of some modifications of different analytical steps such as the temperature of the HPLC column and the derivatization reaction coil and the o-phthalaldehyde flow-rate is described. Quality control data and measurements of the reproducibility of the method are presented. In order to establish a rapid analytical method for easy routine use, all steps for preparation and quantitative analysis are minimized. This method was applied to the determination of total polyamines in human urine and serum hydrolysate and of free and acetylated polyamines in human urine and pancreatic tissue of the rat. Values for normal polyamine concentrations in the urine and serum of fifteen male and fifteen female healthy volunteers and in the pancreas of ten normal rats are presented.

Acute and long-term changes of ornithine decarboxylase and polyamines during pancreatic adaptation in response to cholecystokinin administration (1 microgram kg-1 body wt every 8 h) were studied in rats. alpha-difluoromethylornithine, an irreversible and specific inhibitor of ornithine decarboxylase, was applied simultaneously to elucidate the essential role of polyamines in pancreatic growth. In the cholecystokinin-treated animals ornithine decarboxylase activity was increased after 2 h, reached a maximum after 8 h (444.6 pmol 14CO2 h-1 mg-1 DNA, about 65-fold greater than controls, P less than 0.001) followed by a significant increase of putrescine after 6 h and spermidine after 24 h while spermine remained unchanged. The trophic parameters increased in the following time sequence: thymidine kinase (12 h), DNA polymerase (24 h), pancreatic weight (2 days), protein (2 days) and DNA (5 days). alpha-difluoromethylornithine significantly delayed the increase in ornithine decarboxylase, putrescine and spermidine as well as all trophic parameters. Increases in ornithine decarboxylase, polyamines and all trophic parameters were completely inhibited by simultaneous application of the CCK receptor antagonist L-364,718. These data indicate an important role for ornithine decarboxylase and polyamines in cholecystokinin-induced pancreatic growth in rats.

We investigated the trophic effect on the pancreas of male Wistar rats fed up to 20 days with either raw soybean flour (RSF) containing an active trypsin inhibitor or heat-inactivated soybean flour (HSF). The concentrations of the polyamines putrescine, spermidine, and spermine in the pancreas as well as cholecystokinin (CCK) concentrations in arterial and portal vein plasma were measured. Plasma CCK concentrations were measured by a sensitive radioimmunoassay specific for the sulfated region of CCK, whereas polyamine concentrations are determined by reversed phase high-performance liquid chromatography. The levels of CCK in both arterial and portal vein plasma were significantly higher in RSF- compared with HSF-fed rats, the concentration in the portal vein being twice as high compared with the aorta. A significant increase in pancreatic weight and protein content was positively correlated to an increase in putrescine and spermidine in the pancreas of RSF-fed rats compared with HSF-fed controls, whereas the spermine content did not differ between the two groups. The pancreatic DNA content in RSF-fed rats was significantly above control values of day 20 only. These data support the hypothesis that the trophic effect of soybean trypsin inhibitor on the pancreas is mediated by CCK and that polyamines might play an important role in CCK-induced pancreatic growth.

Total, free, and acetylated polyamine concentrations were investigated in gastric or esophageal tissue, serum, and urine of 40 patients with gastric and 16 patients with esophageal cancer, 40 patients with non-malignant gastrointestinal diseases, and 30 healthy volunteers by means of automated reversed-phase liquid chromatography. In both types of carcinoma polyamine levels were highly elevated in tissue, serum, and urine as compared with healthy controls, which supports the concept that polyamines play an important role in proliferating tissues. However, non-malignant gastrointestinal diseases partly showed similar elevations. A significant linear correlation of polyamines in both carcinomas was found for erythrocyte sedimentation rate but not for tumor stage, tumor size, localization, carcinoembryonic antigen, CA 19-9, and CA 125. It is concluded that owing to its low specificity, polyamine determination in serum and urine has no clinical relevance in the screening for gastric or esophageal carcinoma.