Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice

Atherosclerosis is a major complication of diabetes. Up to 16 weeks of age, the db/db mouse is insulin-resistant and hyperglycemic and is a good model of Type 2 diabetes. After approximately 16 weeks of age, the mice develop pancreatic beta cell failure that can progress to a Type 1 diabetes phenotype. We have previously shown that glucose increases production of endothelial 12/15 lipoxygenase (12/15LO) products in vitro. In young 10-week-old Type 2 diabetic db/db mice, we found significant elevations in levels of urinary 12/15LO products, 12S-hydroxyeicosatetraenoic acid (12S-HETE) and 13S-hydroxyoctadecaenoic acid (13S-HODE) in vivo compared with C57BLKS/J mice. Using isolated primary aortic endothelial cells (ECs) from db/db mice and WEHI78/24 mouse monocyte cells in static adhesion assays, we found increased WEHI monocyte adhesion to db/db ECs (14 +/- 2 monocytes/field for db/db ECs versus 4 +/- 1 monocytes/field for C57BLKS/J ECs, p < 0.002). Thus, ECs from db/db mice appear to be "pre-activated" to bind monocytes. Analysis of db/db ECs revealed a 2-fold elevation in 12/15LO protein compared with C57BLKS/J EC. To determine that 12/15LO products were responsible for the increased monocyte adhesion observed with db/db ECs, we inhibited expression of murine 12/15LO using either an adenovirus expressing a ribozyme to 12/15LO (AdRZ) or with the 12/15LO inhibitor cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate. Treatment of db/db ECs for 48 h with AdRZ or 4 h with 10 microm cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate significantly reduced monocyte adhesion to db/db endothelium (p < 0.009). Thus, inhibition of the murine 12/15LO in db/db mice significantly reduced monocyte/endothelial interactions. We also found that adhesion of monocytes to diabetic db/db ECs was mediated by interactions of alpha4beta1 integrin on monocytes with endothelial vascular cell adhesion molecule 1 and connecting segment 1 fibronectin and interactions of beta2 integrins with endothelial intercellular adhesion molecule 1. In summary, regulation of the 12/15LO pathway is important for mediating early vascular changes in diabetes. Modulation of the 12/15LO pathway in the vessel wall may provide therapeutic benefit for early vascular inflammatory events in diabetes.     

Role of vagus nerve in postprandial antropyloric coordination in conscious dogs

It is generally believed that gastric emptying of solids is regulated by a coordinated motor pattern between the antrum and pylorus. We studied the role of the vagus nerve in mediating postprandial coordination between the antrum and pylorus. Force transducers were implanted on the serosal surface of the body, antrum, pylorus, and duodenum in seven dogs. Dogs were given either a solid or a liquid meal, and gastroduodenal motility was recorded over 10 h. Gastric emptying was evaluated with radiopaque markers mixed with a solid meal. Dogs were treated with hexamethonium, N(G)-nitro-l-arginine methyl ester (l-NAME), or transient vagal nerve blockade by cooling. A postprandial motility pattern showed three distinct phases: early, intermediate, and late. In the late phase, profound pyloric relaxations predominantly synchronized with giant antral contractions that were defined as postprandial antropyloric coordination. A gastric emptying study revealed that the time at which gastric contents entered into the duodenum occurred concomitantly with antropyloric coordination. Treatment by vagal blockade or hexamethonium significantly reduced postprandial antral contractions and pyloric relaxations of the late phase. l-NAME changed pyloric motor patterns from relaxation dominant to contraction dominant. Solid gastric emptying was significantly attenuated by treatment with hexamethonium, l-NAME, and vagal blockade. Postprandial antropyloric coordination was not seen after feeding a liquid meal. It is concluded that postprandial antropyloric coordination plays an important role to regulate gastric emptying of a solid food. Postprandial antropyloric coordination is regulated by the vagus nerve and nitrergic neurons in conscious dogs.     

Relative contributions of "pressure pump" and "peristaltic pump" to gastric emptying

The relative contributions to gastric emptying from common cavity antroduodenal pressure difference ("pressure pump") vs. propagating high-pressure waves in the distal antrum ("peristaltic pump") were analyzed in humans by high-resolution manometry concurrently with time-resolved three-dimensional magnetic resonance imaging during intraduodenal nutrient infusion at 2 kcal/min. Gastric volume, space-time pressure, and contraction wave histories in the antropyloroduodenal region were measured in seven healthy subjects. The subjects fell into two distinct groups with an order of magnitude difference in levels of antral pressure activity. However, there was no significant difference in average rate of gastric emptying between the two groups. Antral pressure history was separated into "propagating high-pressure events" (HPE), "nonpropagating HPEs," and "quiescent periods." Quiescent periods dominated, and average pressure during quiescent periods remained unchanged with decreasing gastric volume, suggesting that common cavity pressure levels were maintained by increasing wall muscle tone with decreasing volume. When propagating HPEs moved to within 2-3 cm of the pylorus, pyloric resistance was found statistically to increase with decreasing distance between peristaltic waves and the pylorus. We conclude that transpyloric flow tends to be blocked when antral contraction waves are within a "zone of influence" proximal to the pylorus, suggesting physiological coordination between pyloric and antral contractile activity. We further conclude that gastric emptying of nutrient liquids is primarily through the "pressure pump" mechanism controlled by pyloric opening during periods of relative quiescence in antral contractile wave activity.     

Lack of pyloric interstitial cells of Cajal explains distinct peristaltic motor patterns in stomach and small intestine

The frequency and propagation velocity of distension-induced peristaltic contractions in the antrum and duodenum are distinctly different and depend on activation of intrinsic excitatory motoneurons as well as pacemaker cells, the interstitial cells of Cajal associated with Auerbach's plexus (ICC-AP). Because ICC are critical for coordination of motor activities along the long axis of many regions in the gut, the role of ICC in antroduodenal coordination was investigated. We used immunohistochemistry, electron microscopy, simultaneous multiple electrical recordings in vitro, and videofluoroscopy in vivo in mice and rats. A strongly reduced number of ICC-AP with loss of network characteristics was observed in a 4-mm area in the rat and a 1-mm area in the mouse pyloric region. The pyloric region showed a slow wave-free gap of 4.1 mm in rats and 1.3 mm in mice. Between antrum and duodenum, there was no interaction of electrical activities and in the absence of gastric emptying, there was no coordination of motor activities. When the pyloric sphincter opened, 2.4 s before the front of the antral wave reached the pylorus, the duodenum distended after receiving gastric content and aboral duodenal peristalsis was initiated, often disrupting other motor patterns. The absence of ICC-AP and slow wave activity in the pyloric region allows the antrum and duodenum to have distinct uncoordinated motor activities. Coordination of aborally propagating peristaltic antral and duodenal activity is initiated by opening of the pylorus, which is followed by distention-induced duodenal peristalsis. Throughout this coordinated motor activity, the pacemaker systems in antrum and duodenum remain independent.     

达格列净抑制2型糖尿病小鼠心血管及肾脏并发症的研究

摘要 目的：探讨达格列净对2型糖尿病小鼠心、肾的保护作用。方法：选取24只6周龄的雄性2型糖尿病模型(C57BLKS/J-leprdb/leprdb, db/db)小鼠,随机等分成达格列净投药组和对照组,另选取同周龄雄性非糖尿病的(C57BLKS/J-leprdb/+, db/m)小鼠12只作为正常组。检测小鼠血糖后,从第7周开始对投药组小鼠进行为期10周的达格列净用药,其余小鼠给予同等计量生理盐水,期间定期监测血糖、血压、尿糖以及各项代谢相关指标。投药结束后分离心脏及肾脏组织,组织切片进行染色观察。结果：与对照组相比,投药组达格列净用药后第1周血糖值显著降低(P < 0.01),用药9周后糖耐量测试结果显示血糖值几乎接近正常小鼠组水平,但各组间血压值无明显差异,心肌间质纤维化、炎性细胞浸润、氧化应激水平明显下降,同时肾小球硬化、炎性细胞浸润和氧化应激程度明显得到改善。结论：达格列净用药不仅能显著降低2型糖尿病模型小鼠血糖,还能有效抑制糖尿病引起的心血管及肾损害。     

Inhibitory effects and mechanisms of intestinal electrical stimulation on gastric tone, antral contractions, pyloric tone, and gastric emptying in dogs

The aim of this study was to investigate the effects and mechanisms of intestinal electrical stimulation (IES) on gastric tone, antral and pyloric contractions, and gastric emptying in dogs. Female hound dogs were equipped with a duodenal or gastric cannula, and one pair of serosal electrodes was implanted in the small intestine. The study consisted of five different experiments. Liquid gastric emptying was assessed by collection of chyme from the duodenal cannula in a number of sessions with and without IES and with and without N-nitro-l-arginine (l-NNA). Postprandial antral and pyloric contractions were measured with and without IES and in the absence and presence of l-NNA or phentolamine by placement of a manometric catheter into the antrum and pylorus via the duodenal cannula. Gastric tone was assessed by measurement of gastric volume at a constant pressure. Gastric emptying was substantially and significantly delayed by IES or l-NNA compared with the control session. IES-induced delay of gastric emptying became normal with addition of l-NNA. IES reduced gastric tone, which was blocked by l-NNA. IES also inhibited antral contractions (frequency and amplitude), and this inhibitory effect was not blocked by l-NNA but was blocked by phentolamine. IES alone did not affect pyloric tone or resistance, but IES + l-NNA decreased pyloric tone. In conclusion, IES reduces gastric tone via the nitrergic pathway, inhibits antral contractions via the adrenergic pathway, does not affect pyloric tone, and delays liquid gastric emptying. IES-induced delay of gastric emptying is attributed to its inhibitory effects on gastric motility.     

Restraint stress augments postprandial gastric contractions but impairs antropyloric coordination in conscious rats

Central corticotropin-releasing factor (CRF) plays an important role in mediating restraint stress-induced delayed gastric emptying. However, it is unclear how restraint stress modulates gastric motility to delay gastric emptying. Inasmuch as solid gastric emptying is regulated via antropyloric coordination, we hypothesized that restraint stress impairs antropyloric coordination, resulting in delayed solid gastric emptying in conscious rats. Two strain gauge transducers were sutured onto the serosal surface of the antrum and pylorus, and postprandial gastric motility was monitored before, during, and after restraint stress. Antropyloric coordination, defined as a propagated single contraction from the antrum to the pylorus within 10 s, was followed by > or = 20 s of quiescence. Restraint stress enhanced postprandial gastric motility in the antrum and pylorus to 140 +/- 9% and 134 +/- 9% of basal, respectively (n = 6). The number of episodes of antropyloric coordination before restraint stress, 2.4 +/- 0.4/10 min, was significantly reduced to 0.6 +/- 0.3/10 min by restraint stress. Intracisternal injection of the CRF type 2 receptor antagonist astressin 2B (60 microg) or guanethidine partially restored restraint stress-induced impairment of antropyloric coordination (1.6 +/- 0.3/10 min, n = 6). The restraint stress-induced augmentation of antral and pyloric contractions was increased by astressin 2B and guanethidine but abolished by atropine, hexamethonium, and vagotomy. Restraint stress enhanced postprandial gastric motility via a vagal cholinergic pathway. Restraint stress-induced delay of solid gastric emptying is due to impairment of antropyloric coordination. Restraint stress-induced impairment of antropyloric coordination might be mediated via a central CRF pathway.     

On the mechanism of gastroduodenal motility inhibition under psychogenic stress in rabbits

In experiments on unanaesthetized rabbits, myoelectric activity (contractile activity index) in antral and pyloric parts of the stomach and in two sites of proximal duodenum was studied under stress induced by fastening rabbit to a table in supine position. The stressor impact induced inhibition of contractile activity in antrum and pylorus. The duodenal contractile activity after initial complete suppression overshot its initial level. Blockade of beta1/beta2-adrenoceptor with propranolol and blockade of alpha2-adrenoceptor with yohimbine did not influence qualitatively the pattern of the stressor responses of antrum and pylorus, and of the postpyloric part of duodenum. In conditions of unselective blockade of alpha-adrenoceptor with dihydroergotoxin there was no initial complete inhibition of duodenal contractile activity, and its strengthening was more expressed than in the control experiments. The received data indicate that the stressor inhibition of antral and pyloric contractile activity possibly results from activation of non-adrenergic inhibitory neurons of the enteric nervous system. The initial short-term suppression of duodenal motility resulted from its "adrenergic" inhibition which can also be a factor limiting the manifestation of stimulating effect of the humoral agent on the duodenal motility. In the period after release of the animal, index of antral and pyloric contractile activity did not significantly differ from its initial level; after beta1/beta2-adrenoceptor blockade in antral and after alpha2-adrenoceptor blockade or nonselective alpha-blockade in antral and pyloric parts of the stomach, there was decrease of contractile activity compared with its initial level; after alpha2- or beta1/beta2-adrenoceptor blockade there was no poststressor exceeding of the initial level of the duodenal contractile activity, observed in the control experiments.     

Comprehensive miRNome and in silico analyses identify the Wnt signaling pathway to be altered in the diabetic liver

Aberrant microRNA expression patterns underlie the pathogenesis of diverse diseases, however in a disease as complex as diabetes where the liver exhibits deregulations of normal metabolic processes, the status and role of microRNAs are not yet completely understood. In a step towards unraveling this correlation, we assessed the global microRNA expression profiles in the control and diabetic (db/db) mice liver. These db/db mice were on a C57BLKS/J background and they exhibit diabetic phenotypes that are remarkably similar to those in humans. microRNA microarray profiling revealed 11 miRNAs to be up-regulated and 2 to be down-regulated in the db/db mice liver. Predicted targets of these differentially expressed microRNAs were retrieved from miRanda and TargetScan and the maximum number of commonly predicted targets mapped onto the Wnt signaling pathway that is otherwise conventionally associated with organogenesis and development. Towards validation of this prediction, we found that major components of the Wnt signaling pathway are inhibited in the db/db mice liver. A significant number of these down-regulated genes of the Wnt signaling pathway are predicted targets to the up-regulated miRNAs and specifically our results show that miR-34a and miR-22 decreased the protein levels of their targets. Overexpression of miR-34a and miR-22 and also inhibition of Wnt signaling using specific inhibitors led to increased lipid accumulation in HepG2 cells. Our data suggest that the Wnt signaling pathway could contribute towards the deregulated hepatic behavior in these animals and an altered hepatic miRNA signature could be playing a regulatory role herein.     

Effect of small intestinal resection on somatostatin binding to cytosol of rabbit gastric mucosa

Small bowel resection in the rabbit increased gastric (fundus and antrum) somatostatin content and decreased the number of somatostatin binding sites (but not their corresponding affinity values) in gastric (fundus and antrum) cytosol three weeks after surgery. Five weeks after resection the number of somatostatin binding sites at both fundic and antral levels as well as antral somatostatin content returned towards control values whereas the fundic concentration of the peptide remained increased. Present results together with the known inhibitory role of somatostatin on various gastric functions suggest that the gastric alterations showed by animals subjected to small bowel resection may be due, at least in part, to the observed decrease of the number of gastric somatostatin binding sites.     

Serotonergic modulation of murine fundic tone

Fundic tone is maintained through a balance of excitatory and inhibitory input to fundic smooth muscle. The aim of this study was to determine the role of serotonin (5-HT) and 5-HT receptors in modulating murine fundic tone. Muscle strips were prepared from the murine fundus. Intracellular recordings were made from circular smooth muscle cells, and the effects of 5-HT on tone and excitatory and inhibitory junction potentials evoked by electrical field stimulation (EFS) were determined. 5-HT induced a concentration-dependent contraction and smooth muscle depolarization that was tetrodotoxin resistant. The 5-HT(1B/D) receptor antagonists GR-127935 and BRL-155172 significantly inhibited 5-HT-induced contractions. The 5-HT(1B/D) agonist sumatriptan contracted murine fundic muscle. The 5-HT(1A) receptor agonist buspirone relaxed fundic smooth muscle, and the relaxation was inhibited by WAY-100135 but not by N(omega)-nitro-l-arginine or tetrodotoxin. 5-HT enhanced both the excitatory and inhibitory responses to EFS. The 5-HT(3) receptor antagonist MDL-72222 partly inhibited both the excitatory and inhibitory response elicited by EFS, whereas the 5-HT(4) receptor antagonist GR-113808 partly inhibited the EFS-evoked inhibitory response. The 5-HT reuptake inhibitor fluoxetine contracted smooth muscle strips, a contraction that was partially inhibited by GR-127935 and abolished by tetrodotoxin. In conclusion, the data suggest that 5-HT modulates murine fundic contractile activity through several different receptor subtypes. Sustained release of 5-HT maintains fundic tone through postjunctional 5-HT(1B/D) receptors. 5-HT(3) receptors modulate excitatory neural input to murine fundic smooth muscle, and both 5-HT(3) and 5-HT(4) receptors modulate inhibitory neural input to murine fundic smooth muscle.     

Metabolic responses to leptin in obese db/db mice are strain dependent

Obese, diabetic C57BL/Ks db/db mice that lack the long-form leptin receptor exhibit no decrease in body weight or food intake when treated with leptin. Here we compared responses to leptin in two strains of db/db mice: C57BL/6J mice that are hyperglycemic and hyperinsulinemic and C57BL/Ks that are hyperglycemic and normo- or hypoinsulinemic. Chronic intraperitoneal infusion of 10 microgram leptin/day partially reversed hyperglycemia in C57BL/6J male mice but exaggerated the diabetic state of female mice. Bolus intraperitoneal injections of 40 microgram leptin/day did not effect glucose in either strain of male db/db mice, whereas chronic intraperitoneal infusion of 20 microgram leptin/day significantly reduced fasting blood glucose in male mice from both strains, especially C57BL/6J mice. Food intake, body weight, rectal temperature, and body fat did not change. Chronic intraperitoneal infusion of 10 microgram leptin/day significantly reduced body fat in lean db/+ C57BL/6J but not in C57BL/Ks mice. Thus peripherally administered leptin is active in mice that have only short-form leptin receptors, and the response is dependent on the method of leptin administration and the background strain.     

Motions of Alexis St. Martin's stomach

In addition to studies on the action of gastric juice, William Beaumont studied the motility of Alexis St. Martin's stomach. He documented the nature of fundal and antral motility and how antral contractions might convert an admixture of solid food and gastric juice into a uniform homogenous semifluid. Beaumont described forcible contractions of the antrum, closure of the pylorus during antral contraction, and the discriminatory nature of the pylorus. Beaumont may also have made the first observations of the gastric motor component of the interdigestive migrating motor complex.     

Chronic tachygastrial electrical stimulation reduces food intake in dogs

Objective: Tachygastria is known to be associated with gastric hypomotility. This study investigated the effect of tachygastrial electrical stimulation (TES) on food intake and its effects on gastric motility. Research Methods and Procedures: Five experiments were performed to study the effects of TES on gastric slow waves, gastric tone, accommodation, and antral contractions, gastric emptying, acute food intake, and chronic food intake in dogs. Results: TES at tachygastrial frequencies induced tachygastria and reduced normal slow waves. TES significantly reduced gastric tone or induced gastric distention, impaired gastric accommodation, and inhibited antral contractions. TES significantly delayed gastric emptying. Acute TES reduced food intake but did not induce any noticeable symptoms. Chronic TES resulted in a 20% reduction in food intake, and the effect of TES was found to be related to specific parameters. Discussion: TES at the distal antrum results in a significant reduction in food intake in dogs, and this inhibitory effect is probably attributed to TES‐induced reduction in proximal gastric tone, gastric accommodation, antral contractility, and gastric emptying. These data suggest a therapeutic potential of the specific method of TES for obesity.     

The Influence of Antral Ulcers on Intramural Gastric Nerve Projections Supplying the Pyloric Sphincter in the Pig (Sus scrofa domestica)—Neuronal Tracing Studies

BackgroundGastric ulcerations in the region of antrum pylori represent a serious medical problem in humans and animals. Such localization of ulcers can influence the intrinsic descending nerve supply to the pyloric sphincter. The pyloric function is precisely regulated by intrinsic and extrinsic nerves. Impaired neural regulation could result in pyloric sphincter dysfunction and gastric emptying malfunction. The aim of the study was to determine the effect of gastric antral ulcerations on the density and distribution of intramural gastric descending neurons supplying the pyloric sphincter in pigs.Conclusions/SignificanceObtained results revealed for the first time significant impact of antral ulcerations on intramural descending nerve pathways supplying the pyloric sphincter in pigs, animals of increasing value in biomedical research and great economic importance.     

Self-renewal of the human gastric epithelium: new insights from expression profiling using laser microdissection

The gastric mucosa is subject to continual bidirectional renewal by differentiation from stem and transit amplifying cells. It was the aim of this study to characterize the self-renewal of the human gastric mucosa and its two major types of glands in the fundus and antrum, respectively. Three characteristic regions (pit, proliferative, and lower neck regions) were isolated from fundic and antral units by the use of laser microdissection, and expression profiles concerning 15 marker genes were generated by RT-PCR analysis. The surface mucous cells (SMCs) of fundic and antral units differed in their expression of at least four secretory genes, i.e., gastric lipase, TFF3, FCGBP, and lysozyme. The maturation of mucous neck cells was shown to occur stepwise, first towards a mucous phenotype followed by a serous differentiation step. Also, a stepwise maturation of both the antral SMCs and antral gland cells was observed. Additionally, the presence of gastric lipase was also demonstrated for the first time in antral gland cells. In conclusion, the different expression profiles of SMCs of the fundic and antral units could be the basis for the different self-renewal rates of fundic and antral SMCs and could influence the spatial organization of the bacterial microbiota within the various parts of the gastric mucosa.     

Physiological effects of superoxide dismutase on altered visual function of retinal ganglion cells in db/db mice

Background

The C57BLKS/J db/db (db/db) mouse is a widely used type 2 diabetic animal model, and this model develops early inner retinal neuronal dysfunction beginning at 24 weeks. The neural mechanisms that mediate early stage retinal dysfunction in this model are unknown. We evaluated visual response properties of retinal ganglion cells (RGCs) during the early stage of diabetic insult (8, 12, and 20 wk) in db/db mice and determined if increased oxidative stress plays a role in impaired visual functions of RGCs in 20 wk old db/db mice.

Methodology/Principal Findings

In vitro extracellular single-unit recordings from RGCs in wholemount retinas were performed. The receptive field size, luminance threshold, and contrast gain of the RGCs were investigated. Although ON- and OFF-RGCs showed a different time course of RF size reduction, by 20 wk, the RF of ON- and OFF-RGCs were similarly affected. The LT of ON-RGCs was significantly elevated in 12 and 20 wk db/db mice compared to the LT of OFF-RGCs. The diabetic injury also affected contrast gains of ON- and OFF-RGCs differently. The generation of reactive oxidative species (ROS) in fresh retina was estimated by dihydroethidium. Superoxide dismutase (SOD) (300 unit/ml) was applied in Ames medium to the retina, and visual responses of RGCs were recorded for five hours. ROS generation in the retinas of db/db mice increased at 8wk and continued to progress at 20 wk of ages. In vitro application of SOD improved visual functions in 20 wk db/db mice but the SOD treatment affected ON- and OFF-RGCs differently in db/m retina.

Conclusions/Significance

The altered visual functions of RGCs were characterized by the reduced RF center size, elevated LT, and attenuated contrast gain in 12 and 20 wk db/db mice, respectively. These altered visual functions could, at least partly, be due to oxidative stress since in vitro application of SOD effectively improves visual functions.     

Amplification and invasiveness of epithelial progenitors during gastric carcinogenesis in trefoil factor 1 knockout mice

Abstract. Objective: It is not known whether or not epithelial progenitors of the pyloric antrum are involved in gastric carcinogenesis. Normally, these progenitors give rise to two main cell lineages: pit and gland mucous cells. This study was designed to examine the changes that occur in pyloric antral mucous cell lineages and their progenitors during development of gastric adenoma and carcinoma in trefoil factor 1 (TFF1) knockout mice. Materials and methods: Pyloric antral mucosal tissues of TFF1 knockout mice at ages from 3 days to 17 months were processed for histochemical analysis using Ulex europaeus and Grifforia simplifolica lectins as markers for pit and gland mucous cells, respectively. The dividing epithelial progenitors were identified by using immunohistochemical and electron microscopy techniques. Results: TFF1 loss was associated with amplification of both mucus‐secreting pit and gland cells. Both lectins examined bound not only to mature mucous cells, but also to most of epithelial progenitors which gradually amplified with age and frequently were seen in mitosis. Analysis of 12‐ to 17‐month‐old TFF1‐deficient stomachs revealed occasional groups of poorly differentiated mucosal cells with features similar to those of epithelial progenitors (or stem cells), in the basal portion of the antral mucosa. These cells eventually invaded the muscularis mucosa while maintaining some capacity to differentiate. Conclusion: This study shows that the progenitors of pit and gland mucous cells contribute to gastric carcinogenesis in the pyloric antrum of TFF1 knockout mice, strongly supporting the concept of stem cell origin of cancer.     

Gastrin release after truncal vagotomy in fistula dogs: Hypersensitivity to bombesin but not bethanechol

Integrated gastrin response was measured by the serial changes in serum immunoreactive gastrin after various stimuli in three dogs with gastric fistula and highly selective fundic vagotomy, who were then subjected to truncal vagotomy. Truncal vagotomy eliminated the gastrin as well as the gastric acid response to vagal excitation by 2-deoxy-glucose, but did not significantly change the responses to bethanechol (20 or 120 μg/kg/hr by IV infusion). Acid output was the same with bombesin or its nonapeptide in the dogs with fundic vagotomy as it was after subsequent truncal vagotomy, but gastrin release was very much increased by truncal vagotomy. For a 3-hour infusion of bombesin integrated gastrin release was 65 and 143 ng/ml/min and for its nonapeptide 43 and 109 ng/ml/min in the dogs with fundic and truncal vagotomy respectively. The marked hypersensitivity of the gastrin response after truncal vagotomy to bombesin but not to a cholinergic agonist suggests that the antral denervation led to a post-denervation hyper-response to the putative transmitter, bombesin, and that the vagal release of antral gastrin may thus represent a peptidergic neurohormonal mechanism. Also, a long half-life of effect suggests that bombesin binds avidly to its receptors.