University partnership to address the shortage of healthcare professionals in Africa.

The shortage of qualified health professionals is a major obstacle to achieving better health outcomes in many parts of the world, particularly in Africa. The role of health science universities in addressing this shortage is to provide quality education and continuing professional development opportunities for the healthcare workforce. Academic institutions in Africa, however, are also short of faculty and especially under-resourced. We describe the initial phase of an institutional partnership between the Muhimbili University of Health and Allied Sciences (MUHAS) and the University of California San Francisco (UCSF) centred on promoting medical education at MUHAS. The challenges facing the development of the partnership include the need: (1) for new funding mechanisms to provide long-term support for institutional partnerships, and (2) for institutional change at UCSF and MUHAS to recognize and support faculty activities that are important to the partnership. The growing interest in global health worldwide offers opportunities to explore new academic partnerships. It is important that their development and implementation be documented and evaluated as well as for lessons to be shared.

Reciprocal effect of unsulfated and sulfated forms of cholecystokinin-octapeptide on gastric acid secretion in the rat.

The sulfated and unsulfated forms of cholecystokinin-octapeptide (CCK-8) were compared, with respect to their effect on gastric acid secretion, in the rat. Unsulfated CCK-8 stimulated acid secretion in a dose-dependent manner, while the sulfated form was without stimulatory effect; thus, sulfation of the tyrosine residue in the seventh position from the C terminus completely abolished the gastrin-like action of CCK-8. Compared with pentagastrin and human gastrin II, unsulfated CCK-8 gave lower calculated maximal response. While sulfated CCK-8 given alone had no effect on acid secretion, it caused marked inhibition of the plateau response to submaximal pentagastrin. This inhibition was surmountable with higher doses of pentagastrin, suggesting a competitive type of inhibition. It is, therefore, concluded that lack of sulfation of the tyrosine residue in the seventh position does not exclude CCK-8 from occupying the gastrin receptor; but does prevent the hormone-receptor interaction that leads to the secretory response. These observations in the rat are different from those in the dog where desulfation of tyrosine renders the CCK analog, caerulein, ineffective in its ability to stimulate acid secretion.

Substance P inhibits pancreatic exocrine secretion via a neural mechanism.

We investigated the effects of the sensory neuropeptide substance P (SP) on amylase and fluid secretion in the isolated vascularly perfused rat pancreas. SP inhibited CCK-induced amylase release and secretin-induced juice flow via the pancreatic duct in a dose-related fashion. Threshold inhibition occurred following addition of 10(-10) M SP to the perfusate, and maximal inhibition was seen with 10(-8) M SP. The effects of SP were partially blocked by both the neurokinin-1 (NK1) and neurokinin-2 (NK2) receptor antagonists. Atropine and TTX blocked SP-induced effects on both amylase secretion (26 and 63% blockade, respectively) and pancreatic juice flow (21 and 79% blockade, respectively). Excitation of pancreatic sensory nerves using capsaicin (in the absence of SP) inhibited both amylase and pancreatic juice flow via activation of the NK1 receptor. We conclude that SP inhibits exocrine secretion via an indirect neural mechanism.

Molecular insights into the development of the pancreas.

There is general agreement that the exocrine pancreas derives from the endoderm of the embryonic foregut. The cellular origin of the endocrine pancreas has been debated for a long time. A hypothesis existed that the endocrine cells of the pancreas originated from the neural crest of the embryo. The recent application of microdissection of the mouse embryo and an exquisitely sensitive polymerase chain reaction assay (PCR) indicates that both the exocrine and endocrine cells of the pancreas develop from the endoderm of the foregut as evidenced by the expression of genes responsible for acinar enzymes and islet hormones in the foregut at the site where the future pancreatic diverticulum would form. Furthermore, the mesenchyme surrounding the primitive endoderm cells from which the pancreas would form exerts significant regulation of differentiation of the pancreas. In culture or in vivo explants, these endoderm cells differentiate only into islet cells in the absence of mesenchyme. On the other hand, when these cells are cultured in vitro with mesenchyme, they differentiate to form not only islets but also ducts and acini.

Rat exocrine pancreatic secretion by vagal stimulation occurs via multiple mediators.

The vagus is a mixed nerve containing cholinerrgic and non-cholinergic neurons. Vagal fibers interact with peptidergic neurons of the enteric nervous system which stain immunohistochemically for cholecystokinin, vasoactive intestinal polypeptide, and gastrin releasing peptide. The contribution of these peptidergic neurons in the pancreatic response to vagal stimulation is unknown. We tested the effect of specific inhibitor of these stimulants against vagally mediated exocrine secretion in rats. The response to vagal stimulation was blocked significantly by each of the following: the ganglionic blocker hexamethonium (100% inhibition); the muscarinic, cholinergic blocker atropine (85% inhibition); the specific cholecystokinin-A receptor blocker (91% inhibition); and a vasoactive intestinal polypeptide polyclonal antibody (89% inhibition). This observation is consistent with the hypothesis that potentiating interactions among several agonists mediate the vagal response. Our study, however, dose not exclude acetylcholine as the final common mediator.

Intrapancreatic cholecystokinin mediates vagally stimulated exocrine secretion from the rat pancreas.

Although cholecystokinin is localized within neuronal fibres of the pancreas, a physiological role for intrapancreatic cholecystokinin has not been identified. The strategy of this study was to elicit pure vagal stimulation electrically, and to use specific receptor antagonists to identify the mediators of exocrine pancreatic secretion. We conclude that vagal stimulation of the rat pancreas involves ganglionic neurotransmission and release of acetylcholine and cholecystokinin from intrapancreatic, postganglionic fibres. To our knowledge, this is the first study to demonstrate a physiological role for intrapancreatic cholecystokinin.

Neuroendocrine tumors: common presentations of uncommon diseases.

In recent decades, isolation of the peptides secreted by gastrointestinal neuroendocrine tumors has greatly advanced our understanding of the pathophysiology of the syndromes resulting from over-production of these biologically active compounds. Early detection of these lesions permits localization and surgical extirpation prior to the development of mestastatic disease. In 1995, early detection of gastrointestinal neuroendocrine tumors hinges on an appropriate index of suspicion on the part of the primary care physician. The prompt recognition of the typical clinical constellations of symptoms associated with these tumors is essential to their timely diagnosis and management.

Epidermal growth factor stimulates the restitution of rat gastric mucosa in vitro.

Epidermal growth factor (EGF) is mitogenic to gastric mucosal cells, protects against gastric mucosal injury induced by ulcerogenic agents, and stimulates cell migration in many systems. Restitution, the rapid re-establishment of mucosal integrity following damage, involves epithelial cell migration and can be monitored by measuring the transmucosal potential difference (PD) of tissue mounted in an Ussing chamber. The role of EGF in restitution is poorly characterized. To assess the effect of exogenous EGF on restitution, samples of rat gastric mucosa were mounted in an Ussing chamber with a solution of 10 nM EGF bathing either the mucosal or serosal surface. Matched control tissues from the same animals were untreated. Mucosal damage was induced by exposure of tissues to hyperosmolar sodium chloride. Restitution following injury was monitored by measuring the recovery of transmucosal PD, which reflects the degree of mucosal integrity. Undamaged mucosa maintained a PD of approximately -30 mV for several hours (mucosa negative with respect to serosa). Mucosal exposure to 1.2 M NaCl for 2 min reduced the PD to near 0 mV. Thereafter, the PD returned in approximately 60 min to plateau at a value representing maximal recovery. Tissues mucosally treated with 10 nM EGF recovered following damage to a maximum of 60.2 +/- 5.1% of pre-exposure PD, while matched controls recovered to only 46.2 +/- 5.8%, a significant difference. Tissues serosally treated with EGF recovered to 61.0 +/- 3.2% and matched controls recovered to 51.1 +/- 2.9%, also a significant difference. These results suggest that both serosally and mucosally applied EGF stimulates the restitution of rat gastric mucosa in vitro.

Advances in the management of patients with Zollinger-Ellison syndrome.

A detailed description of recent advances in the management of patients with Zollinger-Ellison syndrome (ZES) is presented. The clinical presentation is reviewed, and newer diagnostic tools, both preoperative and intraoperative, are discussed. An update on surgical management is presented, including indications for abdominal exploration, intraoperative localization techniques, surgical excision, and the approach to patients with metastases or in whom no tumor is found. New strategies in the medical management of ZES also are reviewed. An update on patient survival is presented, and a review of the management of patients with multiple endocrine neoplasia type 1 and ZES is discussed.

Calcitonin gene-related peptide (CGRP) upregulates the restitution of rat gastric mucosa in vitro.

Calcitonin gene-related peptide (CGRP) is a neuropeptide with many significant effects on gastrointestinal function. Among these are gastroprotective effects such as inhibition of acid secretion and increase in gastric mucosal blood flow. To evaluate whether CGRP has a direct protective effect on gastric mucosa, we examined the influence of the peptide on restoration of mucosal integrity following mild damage. Mucosal integrity was assayed by measurement of the transmucosal potential difference of tissue mounted in an Ussing chamber perfusion system. Undamaged mucosa maintained a potential difference of approximately -64 mV in both control tissues and tissues serosally treated with CGRP. Damage was induced by exposure of the gastric mucosa to solutions of 0.5, 1.0, and 2.0 M sodium chloride. Each of the hyperosmolar solutions caused mucosal injury as evidenced by a rapid decrease in PD, with the most concentrated solution causing the greatest decrease and the slowest and least complete recovery. CGRP treatment led to a significantly more complete recovery of PD when injury was caused by 0.5 M but not by either 1.0 or 2.0 M NaCl. We conclude that CGRP is capable of directly enhancing recovery of mucosal integrity after mild but not severe damage of rat gastric mucosa in vitro.

Neuroendocrine gut neoplasms. Important lessons from uncommon tumors.

OBJECTIVE: To review our experiences in order to high-light some important lessons learned in the treatment of patients with neuroendocrine gut neoplasms. DESIGN: Retrospective analysis of case series of 70 patients with neuroendocrine gut neoplasms treated between 1983 and 1993. The clinical features of individual patients illustrate lessons in surgical treatment. SETTING: University hospitals with tertiary care referral practice. INTERVENTIONS: The main intervention was abdominal exploration in 43 patients, with resection of the primary tumor in 39 and of hepatic metastases in four. MAIN OUTCOME MEASURES: To describe the tumors seen and to identify major lessons learned. RESULTS: Of 70 patients with neuroendocrine tumors treated, 31 had carcinoid tumors, 10 each had insulinomas and gastrinomas, five had vipomas, nine had non-functioning islet cell tumors, three had glucagonomas, and one each had somatostatinoma and a possible cholecystokinin-secreting tumor (or CCKoma). Important lessons learned include: (1) the importance of preoperative tumor localization; (2) in multiple endocrine neoplasia, type I syndrome, the tumor found may not be the one responsible for the patient's symptoms; (3) solitary sporadic tumors secreting multiple peptides may mimic multiple tumors in multiple endocrine neoplasia, type I syndrome; (4) one needs to be prepared for the unexpected, such as the carcinoid crisis; (5) resection may sometimes be necessary even with advanced local disease; and (6) selected patients may benefit from pancreaticoduodenectomy. CONCLUSIONS: These rare tumors are interesting in their clinical presentation and can be challenging in their treatment.

Laminin mediates the restitution of rat gastric mucosa in vitro.

Restitution, the rapid re-establishment of mucosal integrity following damage, involves cell migration and can be monitored by measuring transmucosal potential difference of tissue mounted in an Ussing chamber. The involvement of extracellular matrix proteins and matrix receptors was examined in the restitution of rat gastric mucosa. Undamaged mucosa maintained a potential difference of -32.7 +/- 2.2 mV for several hours. Mucosal exposure to 0.6 M NaCl for 1 min reduced this to -3.3 +/- 1.4 mV in 2-3 min. Thereafter, the potential difference returned in 60 min to plateau at -28.9 +/- 1.3 mV (88.5 +/- 3.6% of pre-exposure). Tissues mucosally treated with 1:100 anti-laminin antiserum maximally recovered following damage to 65.6 +/- 6.6% of pre-exposure potential difference (PD), while those treated with 1:100 anti-collagen IV or anti-fibronectin antisera recovered to 88.8 +/- 9.7% and 86.3 +/- 3.2%, respectively. Only the anti-laminin result was significantly different from controls. The anti-laminin effect was abolished by pre-incubation of the anti-laminin antiserum with purified rat laminin, suggesting that the effect was laminin specific. In experiments involving matrix protein receptors, tissues treated with alpha-lactalbumin, a protein altering the substrate specificity of cell surface laminin receptor/enzyme beta-1,4-galactosyltransferase, maximally recovered following damage to only 49.3 +/- 7.7% of pre-exposure PD, which was significantly different from controls, while those treated with anti-beta 1 integrin recovered to 85.0 +/- 9.7%. Our data suggest that laminin is involved in mediation of gastric mucosal restitution, possibly via beta-1,4-galactosyltransferase.

Vagal regulation of acid secretion and gastrin release.

The vagus nerve plays a central role in the regulation of gastric acid secretion and gastrin release. The current understanding of the mechanisms involved in vagal regulation of acid secretion and gastrin release is reviewed. Thyrotropin-releasing hormone from the medullary raphe nuclei appears to be the central excitatory mediator of vagal action in the dorsal motor nucleus. Vagal stimulation of the parietal cell occurs through M3 cholinergic receptors and via the release of histamine and gastrin from enterochromaffin-like cells and G-cells, respectively. Somatostatin exerts a tonic basal inhibition of both the parietal cell and the G-cell. Vagal stimulation suppresses somatostatin release from delta cells, thereby "disinhibiting" these cells.

A role for calcitonin gene-related peptide in protection against gastric ulceration.

OBJECTIVE: The goal of this investigation was to determine the role of calcitonin gene-related peptide (CGRP) in gastric mucosal resistance to ulceration. SUMMARY BACKGROUND DATA: CGRP is a 37-amino acid peptide found in the peripheral ends of afferent gastric neurons. CGRP is known to inhibit acid secretion, stimulate mucosal blood flow, and stimulate release of somatostatin. METHODS: The release of CGRP in response to intragastric and intra-arterial administration of capsaicin in the isolated, vascularly perfused rat stomach was measured by radioimmunoassay. The molecular forms of CGRP released were analyzed by gel filtration chromatography. The effect of intravenous CGRP or intragastric capsaicin on gastric ulceration induced by 100 mmol/L HCl and indomethacin was studied in intact and endogenous CGRP-depleted rats. RESULTS: Intra-arterial capsaicin (concentration range, 10(-7) to 10(-5) mol/L) stimulated a prompt and sustained release of immunoreactive CGRP, of which 84% coeluted with rat 1-37 CGRP I by gel filtration. Intragastric capsaicin (range, 10(-5) to 10(-4) mol/L) failed to release CGRP into the vascular perfusate. In intact rats, intragastric capsaicin (10(-6) mol/L) or intravenous CGRP I (10 micrograms/kg/hr) reduced the number and area of mucosal lesions caused by HCl and indomethacin compared with the findings in control rats. Rats depleted of endogenous CGRP were more susceptible to gastric ulceration than were normal rats. Intragastric capsaicin failed to protect the mucosa of CGRP-depleted rats, whereas exogenous intravenous CGRP was effective. CONCLUSIONS: These data support the hypothesis that CGRP released from gastric enteric neurons mediates gastric mucosal resistance to ulceration by noxious agents.