Evidence for a role of volatile amines in the development of neonatal hypergastrinemia.

We investigated the presence of volatile aliphatic amines by fluorescamine and gas chromatographic-head space analysis in human breast milk and amniotic fluid to assess their role in neonatal hypergastrinemia. These volatile nitrogenous amino acid metabolites have been previously demonstrated to stimulate gastrin release in in vivo and in vitro laboratory preparations. In the present study we demonstrated that these gastrin-stimulatory volatile amines were present in significant concentrations in breast milk during the first several weeks after parturition and in amniotic fluid. The individual amines that were identified in both human milk and amniotic fluid samples were methylamine, dimethylamine, ethylamine, trimethylamine, propylamine, isobutylamine, and butylamine. This study provides indirect evidence to support the possibility that the hypergastrinemia measured in the fetus/neonate during the period immediately before and after birth may be attributable, in part, to the ingestion of fluid containing high concentrations of gastrin-stimulating amines.     

Altered Gastrin Regulation in Mice Infected with Helicobacter felis

Altered gastrin expression associated with Helicobacter pylori infection may contribute to the pathogenesis of peptic ulcer disease or gastric cancer in man, but gastrin has not been investigated in a murine model of Helicobacter infection. C57BL/6 mice were inoculated with Helicobacter felis and examined after 4–21 weeks for G and D cell numbers, antral gastrin and somatostatin mRNA, and luminal pH. In H. felis-infected mice, gastrin mRNA declined at four and six weeks after infection to 57% and 23%, respectively, of uninfected control values. Concurrently, somatostatin mRNA showed no change at four weeks and a modest 25% decrease at six weeks after infection. Similar reductions were noted in G and D cell numbers, resulting in a decrease in the G/D cell ratio after mice were infected with H. felis. Infected animals also showed a loss of parietal and chief cells, and an increased gastric pH. H. felis infection in C57BL/6 mice leads to an early suppression of G cell number and gastrin mRNA. These changes precede an alteration in somatostatin cell number and mRNA and, coupled with reductions in parietal and chief cells, may contribute both to severe impairment of gastric acid output and the potential for carcinogenic processes.     

The effects of aspirin on gastric mucosal integrity, surface hydrophobicity, and prostaglandin metabolism in cyclooxygenase knockout mice

BACKGROUND & AIMS: Insight into the role of the different cyclooxygenase isoforms in prostaglandin biosynthesis, surface hydrophobicity, and gastric mucosal barrier integrity can be gained by comparing the effects of luminal damaging agents in wild-type and cyclooxygenase knockout mice. METHODS: Fasted wild-type, cyclooxygenase-1, and cyclooxygenase-2 knockout mice were intragastrically administered saline, 0.6N HCl, or aspirin (aspirin 20 mmol/L) in combination with 0.6N HCl and killed 1 hour later, at which time the gastric lesion score was assessed and biopsy samples were taken for surface, biochemical, and morphological analyses. RESULTS: The gastric mucosa of cyclooxygenase-1 knockout mice was more severely injured by both HCl alone and aspirin/HCl than that of wild-type and cyclooxygenase-2 knockout mice. HCl alone and aspirin/HCl also induced a more profound decrease in surface hydrophobicity in cyclooxygenase-1 knockout mice than in wild-type mice, whereas this surface property was unaffected in cyclooxygenase-2 knockout mice. The gastric injury induced by aspirin/HCl in cyclooxygenase-1 knockout mice could be prevented if the animals were treated with phosphatidylcholine-associated aspirin. Aspirin/HCl, in comparison to saline or HCl alone, induced a 4-6-fold increase in gastric mucosal prostaglandin E(2) concentration in the cyclooxygenase-1 knockout mice, whereas it decreased prostaglandin E(2) levels in wild-type and cyclooxygenase-2 knockout mice. This paradoxical aspirin-induced increase in gastric prostaglandin E(2) in cyclooxygenase-1 knockout mice seemed to correspond to an increase in cyclooxygenase-2 messenger RNA and protein expression. The gastric lesion score seemed to be significantly associated with alterations in surface hydrophobicity but not with mucosal prostaglandin E(2) concentration. CONCLUSIONS: Our evidence on cyclooxygenase knockout mice suggests that aspirin predominantly causes gastric injury by a non-prostaglandin mechanism, perhaps by attenuating surface hydrophobicity, a possibility supported by the low gastric toxicity of phosphatidylcholine/aspirin. However, prostaglandins generated by cyclooxygenase-1 may play an important permissive role in maintaining gastric mucosal barrier integrity. Aspirin seems to paradoxically increase the gastric mucosal prostaglandin E(2) concentration in cyclooxygenase-1 knockout mice, possibly by the induction of cyclooxygenase-2.     

Bombesin Prevents Gastric Injury in the Rat: Role of Gastrin

Bombesin or gastrin-releasing peptide preventsgastric injury by an unknown mechanism. Since exogenousgastrin is a gastroprotective agent, this study wasundertaken to test the hypothesis that gastroprotection by bombesin involves release of endogenousgastrin. Subcutaneous bombesin (10-100 g/kg) dosedependently reduced macroscopic injury to theacid-secreting portion of the stomach caused by 1 ml oforogastric acidified ethanol (150 mM hydrochloric acid-50%ethanol). Blockade of type A cholecystokinin receptorswith intraperitoneal MK-329 (1 mg/kg) reversedintravenous cholecystokinin (5 nmol/kg)-inducedgastroprotection, but not that of bombesin. In contrast,intraperitoneal type B cholecystokinin (gastrin)receptor blockade with L-365,260 (25 mg/kg) diminishedthe protective actions of both subcutaneous bombesin(100 mug/kg) and intravenous gastrin (25 pmol/kg). Inadditional studies, subcutaneous bombesin (10-100g/kg) dose dependently increased serum gastrinlevels (radioimmunoassay). Both the gastroprotectiveactions of bombesin and bombesininduced gastrin releasewere enhanced following immunoneutralization ofendogenous somatostatin with intraperitonealsomatostatin antibody (2 mg). These data indicate thatbombesin prevents gastric injury primarily by release ofendogenous gastrin and both effects are modified byendogenous somatostatin.     

Tamoxifen treatment of oligozoospermia: a re-evaluation of its effects including additional sperm function tests

Summary Because of previous contradictory results, we reevaluted the effects of tamoxifen on 29 men presenting with idiopathic oligozoospermia. To determine whether a possible increase in sperm concentration might be correlated with an improvement of sperm quality, the hamster ovum penetration (HOP) test and the hypo-osmotic swelling (HOS) test were included as additional tests of sperm function. Patients were treated with tamoxifen (20 mg/day) for 3 months. From 4 weeks until the end of the study, tamoxifen had a significant effect (P<0.001) on blood levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and estradiol (E₂). Prolactin (PRL) concentrations were not altered significantly (P>0.05). There was no significant improvement (P>0.05) of conventional semen parameters (volume, concentration, motility, morphology), and of HOP and HOS test results. The lack of correlation between a rise in hormone levels and improvement of sperm quality suggests that tamoxifen is of questionable value in men with idiopathic oligozoospermia.     

Über Vorkommen und Bedeutung von myo-epithelialen Zellen (Myothelien) in Tumoren

Zusammenfassung Die in Schweißdrüsen, Speicheldrüsen und Brustdrüsen vorkommenden Myothelien (myoepitheliale Zellen, Korbzellen) sind eine eigentümliche Zellart, die morphologisch, histochemisch und funktionell Eigenschaften vereint, die sonst nur getrennt, in epithelialen und mesenchymalen Zellen vorkommen. Dieses Doppelgesicht drückt sich in einem von den begleitenden Epithelzellen verschiedenen Verhalten bei regressiven und progressiven Veränderungen aus. Im Aufbau bestimmter, in gleicher Weise in den drei erwähnten Organen vorkommenden Tumoren (Mischtumoren, Cylindromen, Adenomyotheliomen) spielen Myothelien eine formbestimmende Rolle und sind imstande, weitere, in normalen Zellen nicht vorhandene mesenchymale Differenzierungen hervorzubringen, wie die Bildung von Schleim, Knorpel und sogar Knochen. Auch am Aufbau von bösartigen Tumoren sind sie beteiligt und können, wenn sie allein das Bild beherrschen, zu Tumoren führen, die histologisch Sarkome, histogenetisch aber epitheliale Tumoren darstellen.

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On the Occurrence and Significance of Myoepithelial Cells (Myothelia) in Tumors

Summary The myothelia (myoepithelial cells, basket cells) which are found in sudoriferous, salivary and mammary glands represent a peculiar cell type, combining morphological, histochemical, and functional qualities, which elsewhere occur only individually in epithclial or mesenchymal cells. This twofold nature is also apparent in the course of progressive and regressive changes when the myothelia differ in their behaviour from the secretory epithelial cells of the glands.The myothelia take part in the formation and influence the structure of somebenign tumors occurring in identical fashion in these glands [mixed tumors of the salivary gland type, cylindromas (adenoid cystic carcinomas), adenomyotheliomas], tumors capable of producing mesenchymal differentiations not to be found in the normal myothelia such as mucus, cartilage, and even osteoid and bone. Myothelia also play a role inmalignant tumors and may sometimes—if they dominate the histological picture—produce tumors which, from a histological viewpoint, represent sarcomas, but which are histogenetically of epithelial origin.

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Mit Unterstützung des Landesamtes für Forschung in NRW.     

Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome

BACKGROUND: Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant nephrotic syndrome (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes for end-stage renal disease (ESRD) in the first two decades of life. Sporadic mutations in the Wilms' tumor suppressor gene WT1 have been found to be present in patients with SRNS in association with Wilms' tumor (WT) and urinary or genital malformations, as well as in patients with isolated SRNS. METHODS: To further evaluate the incidence of WT1 mutations in patients with NS we performed mutational analysis in 115 sporadic cases of SRNS and in 110 sporadic cases of steroid-sensitive nephrotic syndrome (SSNS) as a control group. Sixty out of 115 (52%) patients with sporadic SRNS were male, 55/115 (48%) were female. Sex genotype was verified by haplotype analysis. Mutational analysis was performed by direct sequencing and by denaturing high-performance liquid chromatography (DHPLC). RESULTS: Mutations in WT1 were found in 3/60 (5%) male (sex genotype) cases and 5/55 (9%) female (sex genotype) cases of sporadic SRNS, and 0/110 (0%) sporadic cases of SSNS. One out of five female patients with mutations in WT1 developed a WT, 2/3 male patients presented with the association of urinary and genital malformations, 1/3 male patients presented with sexual reversal (female phenotype) and bilateral gonadoblastoma, and 4/5 female patients presented with isolated SRNS. CONCLUSION: According to the data acquired in this study, patients presenting with a female phenotype and SRNS and male patients presenting with genital abnormalities should especially be screened to take advantage of the important genetic information on potential Wilms' tumor risk and differential therapy. This will also help to provide more data on the phenotype/genotype correlation in this patient population.