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Biomedical subjects

M D Basson

Publications and source records attributed to M D Basson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Association of rectal prolapse with colorectal cancer.

BACKGROUND: Although screening for colorectal cancer facilitates earlier detection and improves survival, cost-effective screening requires identification of patients at high risk for colorectal cancer. Rectal prolapse has not been clearly linked to colorectal carcinoma. Whether patients with rectal prolapse should be screened for colorectal cancer is therefore unclear. METHODS: We retrospectively identified 70 consecutive patients treated for rectal prolapse at a community hospital during a period of 16 years and monitored for an average of 4.4 +/- 2.7 years and 350 patients of similar age treated for chronic unrelated conditions in the same institution during a similar period. We determined their incidence of colorectal cancer and sought demographic correlates. RESULTS: The prevalence of rectosigmoid carcinoma among patients with prolapse was 5.7% during the study. Only 1.4% of the comparative group had colorectal cancer. Thus patients with rectal prolapse exhibited a 4.2-fold (95% confidence interval, 1.1 to 16.0) relative risk for colorectal cancer over the comparative group (p < 0.02). CONCLUSIONS: To the extent to which these patients represent the population of patients with rectal prolapse, routine initial screening of patients with symptomatic rectal prolapse by use of flexible sigmoidoscopy may be appropriate.

Aged↗
PubMed1996

Matrix-specific effect of endothelial control of smooth muscle cell migration.

PURPOSE: Smooth muscle cell (SMC) migration is a critical element in the development of intimal hyperplasia. The effect of endothelial cells (ECs) on SMC migration and the modulation of this cell-to-cell interaction by extracellular matrix is not well understood. METHODS: To examine this relationship SMCs and ECs were cocultured on opposite sides of a semipermeable membrane and were compared with SMCs cultured alone. To assess migration SMCs were plated at confluent density into the center of the membrane with a steel fence. After the fence was removed, SMCs were treated for 2 hours with mitomycin C (20 micrograms/ml) to assess migration independent of proliferation. Cell migration was measured with morphometry. Experiments were performed on plastic and membranes coated with fibronectin or type I collagen (n > or = 8/group). Cell adhesiveness was quantitated by cell attachment and spreading assays. RESULTS: ECs stimulated SMC migration by 187% when compared with SMCs cultured alone on plastic and by 160% when cultured on fibronectin (p < 0.01). Type I collagen stimulated migration of SMCs cultured alone and prevented EC stimulated migration in cocultured SMCs (p < 0.01). Cell adhesiveness was significantly increased in cocultured SMCs compared with SMCs cultured alone regardless of whether cells were cultured on plastic (EC/SMC, 13.5 +/- 0.6 SMCs/high power field vs SMC, 8.9 +/- 0.5, p < 0.01), fibronectin (16.3 +/- 0.8 vs 12.3 +/- 0.7, p < 0.01) or type I collagen (15.5 +/- 1.0 vs 12.4 +/- 0.6, p < 0.01). ECs increased SMC cell spreading on plastic and fibronectin when compared with SMCs cultured alone. No difference in SMC cell spreading was seen in the presence or absence of ECs when cells were cultured on type I collagen. EC-SMC contact was not required; EC-conditioned media alone increased SMC migration by 75% when compared with SMCs cultured alone. Our data suggest that ECs increase SMC migration by a diffusable molecule that may also alter SMC adhesion molecule expression. Extracellular matrix composition can attenuate these effects.

Animals↗
PubMed1995

Modulation of human CACO-2 intestinal epithelial cell phenotype by protein kinase C inhibitors.

Protein kinase C (PKC) isoforms are altered in colon tumors and upon exposure of intestinal mucosa to nutrients. We evaluated the effects of the PKC inhibitors staurosporine and calphostin C on human Caco-2 intestinal epithelial proliferation, motility, and differentiation. Motility was quantitated by monolayer expansion and the brush border enzymes dipeptidyl dipeptidase (DPDD) and alkaline phosphatase (AP) by synthetic substrate digestion. Staurosporine (0.03-1.0 ng/ml) and calphostin C (10(-12) M-10(-4) M) dose-dependently inhibited monolayer expansion and AP but stimulated DPDD. Proliferation was also inhibited but the effects of each inhibitor on motility, AP, and DPDD were preserved after mitomycin C proliferative blockade, suggesting that these effects were proliferation-independent. PKC inhibitors independently inhibit motility, AP and proliferation in human intestinal Caco-2 epithelial cells, but selectively stimulate the small intestinal differentiation marker DPDD. PKC may regulate small intestinal epithelial differentiation.

Caco-2 Cells↗
PubMed1995

PYY inhibition of VIP-stimulated ion transport in the rabbit distal ileum.

Vasoactive intestinal polypeptide (VIP) is the pathophysiologic mediator of several small intestinal hypersecretion states. VIP exerts its effect by binding mucosal receptors and ultimately increasing intracellular levels of cAMP. Peptide YY (PYY), a GI hormone concentrated in the distal ileum and colon, has been demonstrated to decrease VIP-mediated secretion in the colon through a specific Y4 mucosal receptor. Characterization of PYY's effect on VIP-stimulated small intestinal secretion may provide a basis for future therapeutic interventions. We hypothesized that ion transport in the small intestine is mediated through a novel Y receptor subtype. We performed Ussing chamber ion transport studies on rabbit ileum using VIP, PYY, and other pancreatic polypeptide (PP)-fold peptides in order to specifically examine: (1) the effects of VIP and PYY on basal and VIP-stimulated short circuit current (Isc), and (2) the changes in VIP-stimulated Isc in response to NPY, PP, leucine31,proline31 neuropeptide Y fragment, ([Leu31,Pro34]NPY) and the carboxy-terminal fragment of NPY (NPY13-36). VIP increased basal Isc in a concentration-dependent manner, while PYY decreased basal Isc. Graded concentrations of PYY decreased VIP-stimulated increases in Isc. PYY added prior to VIP had no effect on VIP-stimulated increases in ISC. Inhibition of VIP-stimulated Isc increases was seen with NPY, but not with [Leu31,Pro34]NPY, PP, or NPY13-36. This distinct pattern of binding affinity characterizes a novel Y receptor subtype. Additionally, increases in Isc by VIP despite pretreatment with PYY suggests that VIP-stimulated ion transport is mediated through mechanisms other than increases in cAMP.

Animals↗
PubMed1995

Specific modulation of intestinal epithelial brush border enzyme expression by a phorbol ester.

Much is known about intestinal epithelial regulation by growth factors and nutrients but the intracellular signals governing cell phenotype are less well understood. In an initial attempt to evaluate the role of protein kinase C in these events, we studied the effects of protein kinase C modulation by the phorbol ester TPA upon the differentiation, motility, and doubling time of the human intestinal epithelial Caco-2 cell line, a common model for enterocytic brush border enzyme expression. We also compared the effects of TPA to those of 4 alpha-phorbol 12,13-didecanoate, which does not modulate protein kinase C activity. Differentiation was studied by quantitating brush order dipeptidyl peptidase (DPDD)-specific activity in protein-matched Caco-2 lysates via synthetic substrate digestion. Alkaline phosphatase (AP) was studied for comparison. Doubling time was assessed by log transformation of serial cell counts and motility by monolayer expansion across type I collagen. TPA (0.03-0.7 micrograms/ml) dose-dependently stimulated DPDD, with a maximal 455 +/- 26% increase at 0.7 micrograms/ml (P < 0.01, n = 5). However, TPA dose-dependently inhibited AP to a maximal 91.6 +/- 0.3% decrease (P < 0.01, n = 5). TPA also dose-dependently prolonged the cell doubling time from 26.5 +/- 0.4 to 64.5 +/- 8.8 hr (n = 20, P < 0.01) with a maximal effect at 1.0 micrograms/ml and inhibited migration with essentially complete ablation of cell motility at 0.1 micrograms/ml (n = 10, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1995

Primary malignant lymphoma of the intestine.

Primary intestinal lymphoma is uncommon but not rare. Its pathology and potential therapy are complex. Its epidemiology has changed radically over the past century, reflecting a sharp surge in the incidence of intestinal lymphoma, particularly that associated with immunosuppression. Recent advances in diagnosis, a new approach to pathologic classification by immunotyping, and a new staging system have influenced therapy. New multimodal therapeutic protocols have improved the prognosis of this once deadly disease.

Clinical Protocols↗
PubMed1994

Glutamine modulates phenotype and stimulates proliferation in human colon cancer cell lines.

Glutamine supplementation has been advocated for patients requiring parenteral nutritional support. However, the direct effect of glutamine on neoplastic cells is poorly understood. We therefore investigated the effects of glutamine on the proliferation, differentiation, and cell-matrix interactions of two human colon carcinoma cell lines (Caco-2 and SW620) adapted to glutamine-free media. Doubling times were calculated by logarithmic transformation of serial cell counts. Alkaline phosphatase, cathepsin C (dipeptidyl peptidase), lactase, and isomaltase expression (markers of differentiation) were assayed by digestion of synthetic substrates. Adhesion to matrix proteins was assessed by colorimetric quantitation of toluidine blue staining of adherent cells. Surface expression of Caco-2 receptors for matrix proteins (integrins) was studied by biotinylation and immunoprecipitation with specific antibodies. Glutamine (1-10 mM) dose-dependently stimulated Caco-2 proliferation on all matrices studied with maximal effect at 7 mM. For instance, Caco-2 doubling time on collagen IV decreased by 57 +/- 0.2% (SE) (P < 0.001). Glutamine inhibited the expression of all four digestive enzymes with maximal inhibition ranging from 10 to 40% (P < 0.05 for all). Adhesion to matrix proteins was markedly diminished (51 +/- 1%, P < 0.01) by glutamine (5 mM) treatment, correlating with decreased alpha 2 and beta 1 integrin subunit surface expression. Glutamine had similar effects on SW620 cells, stimulating proliferation, inhibiting digestive enzyme expression, and diminishing both adhesion and integrin surface expression. Glutamine supplementation modulates the phenotype of at least two human colon carcinoma cell lines, increasing proliferation, decreasing differentiation, and decreasing adhesion to matrix proteins in association with decreased integrin expression. Although the mechanisms of these effects await elucidation, such characteristics would appear to predict more aggressive tumor behavior and raise the possibility that nutritional supplementation with glutamine may be deleterious in patients with cancer.

Alkaline Phosphatase↗
PubMed1994

Effect of tyrosine kinase inhibition on basal and epidermal growth factor-stimulated human Caco-2 enterocyte sheet migration and proliferation.

Mucosal healing requires enterocyte migration (restitution) supplemented by proliferation. Proliferation and migration may be studied independently by thymidine uptake and proliferation-blocked cell migration using human Caco-2 enterocyte monolayers in culture. Since epidermal growth factor (EGF) promotes mucosal healing and the EGF receptor is a tyrosine kinase, we hypothesized that tyrosine kinases might therefore modulate enterocyte migration and proliferation. The tyrosine kinase inhibitors genistein and 2,5-dihydroxymethylcinnamate, which block kinase ATP-binding and substrate-binding sites, respectively, were studied alone and with EGF. Proliferation was blocked with mitomycin. Although each inhibitor decreased basal and EGF-stimulated monolayer expansion when cell proliferation occurred, neither genistein nor 2,5-dihydroxymethylcinnamate decreased migration when proliferation was blocked. However, each inhibitor prevented EGF stimulation of proliferation-blocked migration and thymidine uptake. More substantial inhibition of basal proliferation by genistein correlated with increased protein-linked DNA breaks, which may reflect nonspecific inhibition of DNA topoisomerase activity by genistein. The more specific 2,5-dihydroxymethylcinnamate blocked changes in the alpha 2 integrin subunit organization which may modulate EGF-stimulated migration. Antiproliferative effects of tyrosine kinase inhibitors decrease basal monolayer expansion but true basal enterocyte migration appears independent of tyrosine kinase regulation. However, a specific tyrosine kinase-dependent modulation of cell-matrix interaction inhibits EGF-stimulated migration.

Cell Division↗
PubMed1994

Mucosal healing and adaptation in the small intestine.

The closely related processes of healing and adaptation in the intestinal mucosa are of substantial clinical significance in patients after injury, intestinal surgery, and inflammatory or infectious ulceration, as well as all patients who are fasting. Recent investigations demonstrate that mucosal healing and adaptation are complex processes that seem likely to be regulated by a variety of autocrine and juxtacrine growth factors as well as conventional gut peptides. Further studies of the biology of mucosal healing may permit pharmacological intervention to promote healing and adaptation in the future.

Animals↗
PubMed1993

Biology and management of the midgut carcinoid.

Midgut carcinoid tumors derive from gut entoderm. These tumors may cause a complex of symptoms comprising the carcinoid syndrome by secreting a wide variety of bioactive agents in addition to serotonin. Such symptoms generally follow metastases to the liver but may also occur in primary ovarian or retroperitoneal tumors. After localization and biochemical characterization, the bioactivity of these tumors should be blocked by octreotide, sometimes in combination with other pharmacologic antagonists, so that primary resection may be performed safely. If curative resection is impossible, then a cytoreductive management scheme should be employed that includes surgical debulking and hepatic arterial embolization, followed by palliation with octreotide.

Algorithms↗
PubMed1993

Deoxycholate is an important releaser of peptide YY and enteroglucagon from the human colon.

Peptide YY (PYY) and enteroglucagon are hormonal peptides found in endocrine cells of the distal intestinal mucosa. Although it is known that plasma concentrations of both peptides increase in response to feeding, the mechanism by which ingested food causes release of colonic hormones is not understood. The release of PYY and enteroglucagon was measured in response to intraluminal stimuli in 176 patients having investigative colonoscopy. Introduction of air, saline (isotonic and hypertonic), glucose (isotonic and hypertonic), oleic acid (without bile salts), and casein hydrolysate all failed to release PYY but glucose caused a small but significant increase in enteroglucagon concentrations. In contrast with the lack of effect of nutrients, infusion of deoxycholic acid produced a rapid and marked dose responsive increase in plasma PYY concentrations when introduced into the sigmoid colon. PYY release was statistically significant at doses between 3.3 mM to 30 mM; for example 10 mM deoxycholate caused a sixfold increase in plasma PYY concentrations. Infusion of 10 mM deoxycholate into the transverse colon or caecum produced an increase of PYY that was similar to the responses in the sigmoid colon. There was also a significant release of enteroglucagon in response to infusion of this bile salt into the sigmoid colon at doses between 3.3 mM and 30 mM. The enteroglucagon response to 10 mM deoxycholate was similar in all three colonic regions. When oleic acid was added to deoxycholate as an emulsion, the release of PYY and enteroglucagon was similar to that seen with the bile salt alone. These findings suggest that bile salts may play an important part in the control of colonic endocrine function and may explain the increased circulating concentrations of colonic regulatory peptides that are seen in malabsorption states and after small bowel resection in humans.

Aged↗
PubMed1993

Small bowel tumors.

Small bowel tumors include adenocarcinomas, carcinoids, lymphomas, and sarcomas, as well as a variety of benign polyps, which should be excised to rule out malignancy. Although small bowel tumors are traditionally difficult to diagnose, a heightened index of suspicion should be combined with improved diagnostic techniques to increase yield and decrease delays in identification. The management of bioactive carcinoid tumors has rapidly advanced over the past year. Increasing experience with the stable somatostatin analogue octreotide has enabled regulation of hormonal secretion by these tumors both chronically and during acute "carcinoid crisis." In addition, early identification may be facilitated by the use of isotopically labeled variants of the compound. Although the development of sophisticated pharmacotherapeutic probes has improved the management of secretory small intestinal tumors, the prognosis for adenocarcinomas, lymphomas, and sarcomas still primarily reflects on the time of delay in diagnosis and awaits an improved understanding of the pathobiology of these malignant lesions.

Adenocarcinoma↗
PubMed1993

Diagnosis and management of gastrointestinal neuroendocrine tumors.

Neuroendocrine tumors of the gastrointestinal tract pose substantial diagnostic and therapeutic challenges. The numerous biologically active peptides and amines produced by these lesions generate complex clinical syndromes. Unfortunately, little is known regarding the genesis of these lesions. Recent advances in understanding of the pathobiology of these lesions has facilitated characterization of the biochemistry of tumor secretions. Similarly, pharmacological blockade of tumor bioactivity using somatostatin analogs, pharmacotherapeutic probes, or specific antagonists has enhanced treatment options. Effective biochemical palliation of tumor symptoms has in turn motivated a more aggressive approach to cytoreduction of these tumors by surgery or hepatic embolization. The combination of chemical blockade and surgical therapy may permit more extended and symptom-free survival for a significant proportion of patients. We evaluate the basic principles of diagnosis and management of gastrointestinal neuroendocrine tumors.

Gastrointestinal Neoplasms↗
PubMed1993

Clinical applications of gastrointestinal hormones.

Over 80 peptides and amines secreted by more than 20 different types of neuroendocrine cells scattered throughout the gut have been identified. The physiologic function and clinical relevance of many of these hormones await elucidation. Nevertheless, the clinical use of these agents in either diagnostic or therapeutic modalities has greatly expanded the appreciation of the relevance of many of these peptides to malignant and nonmalignant pathobiology.

Carcinoid Tumor↗
PubMed1992

Differential modulation of vascular cell integrin and extracellular matrix expression in vitro by TGF-beta 1 correlates with reciprocal effects on cell migration.

In vitro, BAEC and BASMC migratory phenotypes are known to be reciprocally modulated by both soluble factors and extracellular matrix proteins. In addition, integrin matrix receptors mediate endothelial and smooth muscle cell attachment and migration. To further elucidate these phenomena, we studied the effects of TGF-beta 1 on integrin expression by vascular BASMC and BAEC in tissue culture. TGF-beta 1 upregulated mRNA levels and surface pools of BASMC beta 3 integrin classes without modulating beta 1 integrin mRNA levels or expression of beta 1 integrin organization. In contrast to its effects on BASMC, TGF-beta 1 increased BAEC mRNA levels and surface expression of beta 1 and beta 3 integrins without altering their organization. Conversely, extracellular matrix components (fibronectin, laminin, and fibrinogen) organized cell surface integrins in both BASMC and BAEC without affecting the size of their cell surface pools. These data are consistent with the hypothesis that SMC and EC behavior in neointimal lesions may be modulated, in part, through a coordination of soluble factor and extracellular matrix protein regulation of integrin surface expression and organization.

Animals↗
PubMed1992

Surgical therapy of acute esophageal variceal hemorrhage.

Options for the management of patients with acute variceal hemorrhage must be compared for their ability to stop bleeding and prevent rebleeding, for their safety, and for their impact on hepatic reserve. Pharmacologic treatment may stop bleeding in up to 50% of patients, but cannot prevent rebleeding. Balloon tamponade controls bleeding in 90% of patients but is only transiently effective and may cause complications. Immediate sclerotherapy may stop acute bleeding and may provide chronic control with repeated treatments. However, patients who fail to respond to such measures must be submitted for surgical intervention. Emergency portosystemic shunt or esophageal transection represent the current procedures of choice for these patients. Surgery may also prove more cost effective than repeated sclerotherapy as primary therapy in a select group of patients with a high risk of rebleeding. Ultimately, however, primary pharmacologic therapy or hepatic transplantation to correct the pathophysiology underlying the esophageal variceal hemorrhage must be developed and refined if the natural history of this disease is to be substantially altered.

Acute Disease↗
PubMed1992

Human enterocyte (Caco-2) migration is modulated in vitro by extracellular matrix composition and epidermal growth factor.

The modulation of enterocyte sheet migration was studied using Caco-2 cells, a well-differentiated human colonic cell line. Although Caco-2 cells attached and spread equivalently over collagen types I, III, IV, and V and laminin, migration over laminin was significantly slower than migration over the collagen types. Fibronectin was a poor substrate for attachment, spreading, and migration. Epidermal growth factor (EGF) stimulated migration over laminin but did not alter Caco-2 migration over collagen or fibronectin. This effect was independent of cell proliferation, which was stimulated equivalently on both laminin and collagen I. Expression and organization of cell surface receptors for matrix (integrins) were studied using antibodies specific for beta and alpha integrin subunits. Integrin surface expression was assessed by immunoprecipitation of surface 125iodinated control and EGF-treated cells. Beta 1 surface pools did not change substantially in any condition studied. Alpha 1 subunit pools were decreased after EGF treatment on collagen I but alpha 1 pools increased after EGF treatment on laminin. Surface pools of alpha 2 subunits were increased following EGF treatment whether cells were cultured on laminin or collagen I. However, traditional immunofluorescent and laser confocal imaging demonstrated substantial differences in the character of alpha 2 subunit organization between collagen and laminin in the migrating cell front. Furthermore, a functional antibody to the alpha 2 subunit inhibited EGF stimulation of migration over laminin without substantial effects on basal migration over laminin or collagen I. Thus, EGF appears to exert a matrix-specific effect on enterocyte migration by modulation of integrin expression and organization.

Cell Movement↗