Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2.

Preventing tumor neovascularisation is one of the strategies recently developed to limit the dissemination of cancer cells and apparition of metastases. Although these approaches could improve the existing treatments, a number of unexpected negative effects have been reported, mainly linked to the hypoxic condition and the subsequent induction of the pro-oncogenic hypoxia inducible factor(s) resulting from cancer cells' oxygen starvation. Here, we checked in vivo on colon cancer cells an alternative approach. It is based on treatment with myo-inositol trispyrophosphate (ITPP), a molecule that leads to increased oxygenation of tumors. We provide evidence that ITPP increases the survival of mice in a model of carcinomatosis of human colon cancer cells implanted into the peritoneal cavity. ITPP also reduced the growth of subcutaneous colon cancer cells xenografted in nu/nu mice. In the subcutaneous tumors, ITPP stimulated the expression of the homeobox gene Cdx2 that is crucial for intestinal differentiation and that also has an anti-tumoral function. On this basis, human colon cancer cells were cultured in vitro in hypoxic conditions. Hypoxia was shown to decrease the level of Cdx2 protein, mRNA and the activity of the Cdx2 promoter. This decline was unrelated to the activation of HIF1α and HIF2α by hypoxia. However, it resulted from the activation of a phosphatidylinositol 3-kinases-like mitogen-activated protein kinase pathway, as assessed by the fact that LY294002 and U0126 restored high Cdx2 expression in hypoxia. Corroborating these results, U0126 recapitulated the increase of Cdx2 triggered by ITPP in subcutaneous colon tumor xenografts. The present study provides evidence that a chemical compound that increases oxygen pressure can antagonize the hypoxic setting and reduce the growth of human colon tumors implanted in nu/nu mice.

Climate change and the green energy paradox: the consequences for twaite shad Alosa fallax from the River Severn, U.K.

A stock-recruitment model with a temperature component was used to estimate the effect of an increase in temperature predicted by climate change projections on population persistence and distribution of twaite shad Alosa fallax. An increase of 1 and 2° C above the current mean summer (June to August) water temperature of 17·8° C was estimated to result in a three and six-fold increase in the population, respectively. Climate change is also predicted to result in an earlier commencement to their spawning migration into fresh water. The model was expanded to investigate the effect of any additional mortality that might arise from a tidal power barrage across the Severn Estuary. Turbine mortality was separated into two components: (1) juvenile (pre-maturation) on their out migration during their first year and on their first return to the river to spawn and (2) post-maturation mortality on adults on the repeat spawning component of the population. Under current conditions, decreasing pre-maturation and post-maturation survival by 8% is estimated to result in the stock becoming extinct. It is estimated that an increase in mean summer water temperature of 1° C would mean that survival pre and post-maturation would need to be reduced by c. 10% before the stock becomes extinct. Therefore, climate change is likely to be beneficial to populations of A. fallax within U.K. rivers, increasing survival and thus, population persistence.

Fully automated image-guided needle insertion: application to small animal biopsies.

The study of biological process evolution in small animals requires time-consuming and expansive analyses of a large population of animals. Serial analyses of the same animal is potentially a great alternative. However non-invasive procedures must be set up, to retrieve valuable tissue samples from precisely defined areas in living animals. Taking advantage of the high resolution level of in vivo molecular imaging, we defined a procedure to perform image-guided needle insertion and automated biopsy using a micro CT-scan, a robot and a vision system. Workspace limitations in the scanner require the animal to be removed and laid in front of the robot. A vision system composed of a grid projector and a camera is used to register the designed animal-bed with to respect to the robot and to calibrate automatically the needle position and orientation. Automated biopsy is then synchronised with respiration and performed with a pneumatic translation device, at high velocity, to minimize organ deformation. We have experimentally tested our biopsy system with different needles.

In vitro and in vivo efficacy of photofrin and pheophorbide a, a bacteriochlorin, in photodynamic therapy of colonic cancer cells.

This study was designed to investigate the efficacy of photodynamic therapy (PDT) in treating colonic cancer in a preclinical study. Photofrin, a porphyrin mixture, and pheophorbide a (Ph a), a bacteriochlorin, were tested on HT29 human colonic tumor cells in culture and xenografted into athymic mice. Their pharmacokinetics were investigated in vitro, and the PDT efficacy at increasing concentrations was determined with proliferative, cytotoxic and apoptotic assessments. The in vivo distribution and pharmacokinetics of these dyes (30 mg/kg, intraperitoneal) were investigated on HT29 tumor-bearing nude mice. The inhibition of tumor growth after a single 100 J/cm2 PDT session was measured by the changes in tumor volume and by histological analysis of tumor necrosis. PDT inhibited HT29 cell growth in culture. The cell photodamage occurred since the time the concentrations of Ph a and Photofrin reached 5.10(-7) M (or 0.3 microg/mL) and 10 microg/mL, respectively. A photosensitizer dose-dependent DNA fragmentation was observed linked to a cleavage of poly(ADP-ribose) polymerase and associated with an increased expression of mutant-type p53 protein. PDT induced a 3-week delay in tumor growth in vivo. The tumor injury was corroborated by histological observation of necrosis 48 h after treatment, with a correlated loss of specific enzyme expression in most of the tumor cells. In conclusion, PDT has the ability to destroy human colonic tumor cells in vitro and in vivo. This tumoricidal effect is likely associated with a p53-independent apoptosis, as HT29 cells express only mutated p53. The current study suggests a preferential use of Photofrin in PDT of colonic cancer because it should be more effective in vivo than Ph a as a consequence of better tumor uptake.

Dual effect of laparoscopy on cell-mediated immunity.

Laparoscopic influence on cell-mediated immunity and tumour evolution is controversial. The objective of the present study was to assess tumour growth and immune patterns after laparoscopy on an experimental study. Lewis rats, bearing an intrapancreatic ductal carcinoma randomly underwent one of the following 2-hour procedures: anaesthesia, laparotomy or CO(2) pneumoperitoneum. Cell-mediated immunity was investigated through determination of serum IL1beta concentrations by ELISA and TNFalpha, IL6 and iNOS gene transcriptions in blood white cells and peritoneal cells by RT-PCR 1 day after operation. Tumour growth and spread patterns were assessed on anatomopathological examination 2 weeks after surgery. Tumour growth and spread were unaffected no matter what procedure was applied, but port-site seeding occurred in half of the cases undergoing laparoscopy. No significant change in acute-phase protein response, represented by IL1beta serum concentration, was found after laparoscopy. TNFalpha, IL6 and inducible NO synthase gene transcriptions were enhanced in blood white cells and depressed in peritoneal immune cells after laparoscopy. In our experimental conditions, cell-mediated immune response to CO(2) pneumoperitoneum seems to be a good systemic immune activation and a less acute peritoneal immune response as opposed to control laparoscopy. This early impairment of peritoneal macrophage immune activity, observed after a long-lasting CO(2) pneumoperitoneum, might be responsible for the high rate of port site recurrence.

Ileal uptake of polyalkylcyanoacrylate nanocapsules in the rat.

The ileal uptake of polyalkylcyanoacrylate nanocapsules (less than 300 nm in diameter) has been investigated in the rat. Iodised oil (Lipiodol) was used as the tracer for X-ray microprobe analysis in scanning electron microscopy. Lipiodol nanocapsules, or an emulsion of Lipiodol, were administered in the lumen of an isolated ileal loop of rat. Lipiodol nanocapsules improved the absorption of the tracer as indicated by increased concentrations of iodine in the mesenteric blood (+27%, P < 0-01, compared with Lipiodol emulsion). Intestinal biopsies were taken at different time points and the samples underwent cryofixation and freeze-drying. The nanocapsules were characterized by their strong iodine emission, and electron microscopy of the biopsy samples revealed nanocapsules in the intraluminal mucus of the non-follicular epithelium, then in the intercellular spaces between enterocytes, and finally the nanocapsules were found within intravillus capillaries. However, nanocapsules were most abundant in the Peyer's patches, where the intestinal epithelium had been crossed by way of the specialized epithelial cells, designated membranous cells, or M cells, and their adjacent absorptive cells. These observations were confirmed quantitatively by measuring iodine concentrations in the various tissue compartments. Ten minutes after the intraluminal administration of Lipiodol nanocapsules, the emission of iodine peaked in the mucus (+77%, P < 0.01), in M cells (+366%, P <0.001), in enterocytes adjacent to M cells (+70%, P < 0.05) and in lymph vessels (+59%, P < 0.05). Polyalkylcyanoacrylate nanocapsules were able to pass through the ileal mucosa of the rat via a paracellular pathway in the non-follicular epithelium, and most predominantly, via M cells and adjacent enterocytes in Peyer's patches.

Human pancreatic carcinoma cells are sensitive to photodynamic therapy in vitro and in vivo.

BACKGROUND: The aim of this study was to assess the efficiency of photodynamic therapy (PDT) on human pancreatic cancer cells in vitro and in an animal model. METHODS: Human pancreatic tumour cell lines were submitted to PDT with pheophorbide a (Ph a), a chlorophyll derivative, in culture and after grafting into athymic mice. Ph a was tested in culture (10-10-10-5 mol/l) with a 5-J/cm2 energy treatment and on tumour-bearing Nude mice (30 mg/kg intraperitoneally) with a 100-J/cm2 PDT session. The effect of PDT was assessed in vitro using proliferative, apoptotic and clonogenic tests and in vivo on tumour growth and on the induction of tumour necrosis. RESULTS: PDT inhibited tumour cell growth in culture by affecting DNA integrity. This tumour cell photodamage started at low concentration (10-7 mol/l) as corroborated by clonogenic and tumour growth tests. A strong necrosis was achieved in vivo with a single PDT session. CONCLUSION: PDT destroyed human pancreatic carcinoma after low photosensitizer supply and weak energy application. It exerted this tumoricidal effect via apoptosis induction with a gentle protocol, and apoptosis and/or necrosis with a stronger protocol.

Increased tumor growth and spread after laparoscopy vs laparotomy: influence of tumor manipulation in a rat model.

BACKGROUND: The use of laparoscopy for assessment and treatment of malignant tumors remains controversial. The aim of this study was to evaluate the impact of tumor manipulation during laparoscopy compared with that of conventional laparotomy on growth and spread of an intraperitoneal tumor in the rat in a randomized, controlled trial. METHODS: Thirty 2-month-old male Lewis rats received a single-site intrapancreatic inoculation of a ductal adenocarcinoma. Fourteen days after cancer implanting, two groups of six animals each underwent a laparotomy (30 min 6 mmHg CO2 pneumoperitoneum). The tumor was manipulated in the one group, and exclusively visualized in the other. In two other groups, a midline laparotomy with (n = 6) or without (n = 6) tumor manipulation was performed. Animals in the control group (n = 6) underwent no procedure. Tumor volume, tumor mass, local regional invasion incidence, lymph node involvement, and liver and lung metastases were evaluated on 28-day tumors. RESULTS: No difference in tumor growth and spread was observed between laparoscopy and laparotomy when tumor manipulation was not carried out. Tumor manipulation increased tumor growth significantly in the laparotomy group, but not in the laparoscopy one. Tumor metastases were correlated to tumor growth and increased significantly after manipulation in both groups. There was no port-site or conventional wound seeding in either the surgical procedure. CONCLUSIONS: This study showed that manipulation is the main factor acting on tumor dissemination in both laparoscopy and laparotomy. Laparoscopic surgery had a beneficial effect on local tumor growth compared with laparotomy in the case of tumor manipulation. This beneficial effect of laparoscopic surgery may be related to a better preservation of immune function in the early postoperative period.

Role of nitric oxide in pancreatic tumour growth: in vivo and in vitro studies.

Nitric oxide (NO), an endogenous free radical, has been implicated in a wide range of biological functions. NO is generated enzymatically from the terminal guanidinonitrogen of L-arginine by nitric oxide synthase (NOS). Despite intensive investigations, the role of NO--either as the primary product of the L-arginine/NOS pathway or provided from the NO donor sodium nitroprusside (SNP)--in carcinogenesis and tumour cell growth remains unclear and controversial. The objective of this study was to examine the growth effects of NO on a ductal pancreatic adenocarcinoma in the rat and on a human pancreatic tumour cell line (HA-hpc2). In vivo, both SNP and endogenous induction of NO by endotoxins [lipopolysaccharide (LPS)] plus L-arginine significantly reduced the tumour growth. To investigate the mechanisms of NO anti-tumour growth action, the effects of either the SNP or L-arginine/NOS pathway were analysed on the HA-hpc2 cell line. Nitrite/nitrate production, NOS activity and iNOS expression [assessed by reverse transcription-polymerase chain reaction (RT-PCR)] were tested and related to growth (assessed by [3H]thymidine incorporation assay) and apoptosis (assessed by internucleosomal DNA cleavage). SNP exerted a dual effect on tumour cells: stimulation of the proliferation up to 1 mM and inhibition at higher concentrations. These effects were related to NO production. Both proliferative and cytostatic responses were inhibited by NO scavenger 2-phenyl-4,4,5,5-tetramethyl-hemidazoline-1-oxyl3-oxide (carboxy-PTIO). The marked apoptotic DNA fragmentation induced by SNP was also abolished by PTIO association. Unlike macrophages, the human pancreatic tumour cells did not seem to express intrinsically the L-arginine/NOS pathway. Macrophages were activated by HA-hpc2 cells as well as by LPS plus cytokines [interleukin (IL)-1beta plus tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma]. In HA-hpc2/macrophage co-cultures, NOS activity and inducible NOS (iNOS) transcription were stimulated, whereas an antiproliferative response was observed. These effects were related to both macrophage amount and NO production. Addition of LPS plus cytokines to co-cultures doubled iNOS activity, nitrite/nitrate production and tumoricidal effect. These data suggest the involvement of NO in pancreatic tumour growth and support the fact that generation of high levels of NO with potential production of endogenous reactive nitrogen intermediates may contribute to induction of apoptosis and tumour growth inhibition.

In vivo laser-induced fluorescence imaging of a rat pancreatic cancer with pheophorbide-a.

Laser-induced fluorescence (LIF) of pheophorbide-a (Ph-a) was used for imaging of a rat pancreatic tumor. Using a dimensionless function (the ratio of Ph-a fluorescence by bluish autofluorescence), the fluorescence contrasts between excised tumors and their paired pancreas were investigated up to 48 h after a 9 mg kg-1 Ph-a intravenous administration. Among five tested excitation wavelengths, 355 and 610 nm excitations gave the best distinctive contrasts, both 48 h after dye injection. The LIF imaging of six intrapancreatic tumors and six healthy pancreas was carried out in vivo using two laser excitations: 355 nm (Nd:YAG + tripling) for bluish autofluorescence and 610 nm (rhodamine 6G dye) for reddish autofluorescence and dye emission. Images were recorded through bandpass filters at 470 and 640 nm (autofluorescence) and at 680 nm (dye + autofluorescence) with an intensified charged-coupled device camera. Autofluorescence as Ph-a fluorescence images did not allow accurate LIF diagnosis of pancreatic carcinoma. An image processing, including for each pixel a computed division of Ph-a fluorescence (after subtraction of reddish autofluorescence) by bluish autofluorescence intensity generated poorly contrasted tumor images in five of six and false tumor localization in one of three of the tumor-bearing pancreas. A fitting of the digital 640 nm autofluorescence up to the mean 680 nm fluorescence intensity in pancreas prior to subtraction allowed a safe diagnosis to be made with well-contrasted tumor images. To assess automation ability of the processing, a same fitting coefficient (mean of individual values) was applied. In this way, false-negative (one of six) and false-positive (two of six) images were present in tumor-bearing animals as false-positive in one-half of the controls. A successful standardized procedure was then applied with a normalization of 640 and 680 nm pancreas intensities to a same set threshold prior processing. In opposition to thin-layered hollow organs, such as bronchial tube or digestive tract, LIF imaging of carcinoma inserted in a compact organ is exhausting. The use of a dye excitable in the red wavelength range (610 nm for Ph-a) may partly solve this problem, rendering LIF imaging more accurate and potentially automated.

Evaluation of human collagen biomaterials in the healing of colonic anastomoses in dogs.

OBJECTIVE: To investigate the ability of human collagen biomaterials to secure colonic anastomoses in dogs and to evaluate the biocompatibility of anastomotic protection patches (APP). DESIGN: Experimental open study. SETTING: Experimental research centre, France. MATERIAL: 21 mongrel dogs randomised into three groups of 7 each. INTERVENTION: Standard transverse colonic end-to-end anastomoses were secured with two-layer oxidised collagen I + III sponge covered with thin crosslinked collagen IV film (APP 1) glued around the suture (n = 7); two-layer oxidised collagen I + III sponge covered with thin non-crosslinked collagen I + III film patch (APP 2) (n = 7); or sealed by fibrin sealant (n = 7), which acted as a controls. MAIN OUTCOME MEASURES: Gross examination, radiological control (barium enemas), and microscopic examination on day 35 postoperatively. RESULTS: Gross clinical and radiological examinations on day 35 showed normal wound healing in all but one dog in which the anastomoses had occluded by day 16. There was significantly less stricturing with the APP 2 patch (p < 0.05 compared with the controls). Microscopic examination showed complete absorption of the APP 2 patches as well as quicker mucosal and extracellular matrix repair than controls. The APP 1 patch gave the best healing of the muscular layer but did not reduce anastomosis stricturing, and was not totally absorbed. CONCLUSIONS: Collagen supporting devices do not alter healing of the large bowel. Encircling patches do not increase the number of adhesions or the rate of anastomotic stricturing and a thin fibrillar collagen I + III dense layer may even improve it. The speed of absorption of the patch depends on the type of dense collagen film. These results argue for a prospective clinical evaluation in humans.

Intestinal absorption of PLAGA microspheres in the rat.

Rhodamine B-labelled poly (DL-lactide-co-glycolide) (PLAGA) microspheres of 2 different sizes, 1-5 microns and 5-10 microns, were administered as a single dose (1.44 x 10(9) and 1.83 x 10(8) particles, respectively) into the ileal lumen of adult rats. The content of rhodamine in the mesenteric vein and ileal lumen was analysed periodically from 10 min to 48 h as well as the distribution of microspheres in the intestinal mucosa and various other tissues. The concentration of rhodamine decreased progressively in the intestinal lumen and was negligible after 24 h. The number of microspheres in the mesenteric vein increased rapidly and reached a maximum after 4 h whatever the size of the particles. It then decreased progressively, but more rapidly with microspheres > 5 microns than with microspheres < 5 microns. The absorption efficiency was low for the former batch (about 0.11% of the administered dose) and higher for the latter (about 12.7%). The intraileal administration of free rhodamine B was followed by intense labelling of the epithelial cells and basement membranes in mesenteric lymph nodes, spleen, kidney and liver. PLAGA microspheres mainly crossed the intestinal mucosa at the site of Peyer's patches where microspheres of < 5 microns appeared after 3 h. Microspheres > 5 microns were retained in the ileal lumen. A few small microspheres were occasionally observed in the epithelial cells. Only the smallest particles were recovered in the liver, lymph nodes and spleen while basement membranes were always labelled. It is concluded that PLAGA microspheres could be useful for the oral delivery of antigens if their size is between 1 and 5 microns.

Biomaterial supports for colonic wall defect healing. An experimental study in the rat.

New artificial biomaterials were tested for support of gastro-intestinal tract wound healing in the rat. Double layered collagenic matrices were prepared with purified collagens extracted from human placental tissues. Two types of patches were tested, the first constituted from a collagen type I + III layer covered by collagen IV in a liquid phase (patch I + III/IV) and the second from a collagen IV layer covered by liquid collagen IV (patch IV/IV). The matrices were applied with fibrin sealant to the edges of a 1 cm diameter colonic wall defect in the rat. Healing evolution was determined by macroscopic, microscopic and immunostaining studies. The reconstitution of the three colonic wall layers was achieved within 45 days without retraction or inflammatory reaction, while the biomaterial was resorbed. Human collagen I and III antibodies failed to stain extracellular matrix. This failure may be a consequence of outdated antibodies or more likely epitope alteration during extraction and preparation of the collagens. A human collagen type IV antibody staining of the scar zone showed the basement membranes of newly developed vessels within 10 days, and newly formed colonic mucosa within 20 days. The collagen reconstituted matrix was able to assist healing of normal digestive tract defects as shown by the labelling of the new synthesized extracellular matrix by collagen type IV antibody. These findings support the use of collagen biomaterial in gastro-intestinal anastomosis. This new surgical approach allowing healing of colonic wall defects could reduce occurrence of anastomotic leakage in human.

Photodynamic imaging of a rat pancreatic cancer with pheophorbide a.

Laser-induced fluorescence of pheophorbide a (Ph-a) was used for in vitro photodynamic imaging (PDI) of a rat pancreatic acinar tumor. A 400 nm excitation induced a 470 nm autofluorescence and a 678 nm dye fluorescence in tumors and their surrounding pancreas 24 h after a 9 mg kg-1 body weight Ph-a intravenous administration. With lower intensities in these blood-rich tumors than in pancreas, Ph-a fluorescence signals are unable to provide tumor images. A dimensionless function (the ratio of Ph-a fluorescence by autofluorescence, called Rt for the tumor and Rp for the pancreas) was used for fluorescence contrast calculation (C = Rt/Rp) between six tumors and their paired pancreas. Among five available laser excitation wave-lengths, only the 355 nm excitation gave a distinctive contrast (C = 1.5). The PDI of six intrapancreatic tumors and their intraperitoneal metastasis and of two control normal pancreas was thus performed ex vivo using a 355 nm excitation source delivered by a tripled Nd:YAG laser and a charged-coupled device camera. Fluorescence images were recorded at 680 nm (dye), 640 nm (background) and 470 nm (autofluorescence) through three corresponding 10 nm width bandpass filters. Computed division for each pixel of Ph-a fluorescence values by autofluorescence generated false color image. In this way, contrasted tumor images were obtained. But in five out of six animals false-positive images were present due to an autofluorescence decrease in some normal pancreatic areas. A 470 nm autofluorescence imaging on the same tumors gave in all cases false-positive image and false-negative in half of the cases. These observations suggest that autofluorescence alone is unable to achieve accurate PDI of pancreatic carcinoma and that using Ph-a as a PDI dye needs strong improvements.

Biomaterials for primary closure of a choledochotomy in dogs.

Since primary closure of the common bile duct is often not undertaken because of the risks of biliary leakage and peritonitis, we have evaluated feasibility and reliability of closure using biomaterials. In three groups of dogs, an unsutured choledochotomy was closed with circular glued patches: a scleroprotein patch in 4 dogs and an oxidized, compressed human collagen patch reinforced (n = 6) or not (n = 6) with three stitches. The scleroprotein patch (n = 4) was resorbed too soon, and in 2 dogs the unstitched collagen patches became unglued; biliary leakage was the result in both instances. The bile duct healed successfully within 1 month in the other 10 animals fitted with collagen patches, despite one common bile duct stricture. Safe primary closure of a choledochotomy may be envisioned in humans if the duct suture is protected by this new collagen biomaterial.

Effect of pantothenic acid and ascorbic acid supplementation on human skin wound healing process. A double-blind, prospective and randomized trial.

This study aimed at testing human skin wound healing improvement by a 21-day supplementation of 1.0 g ascorbic acid (AA) and 0.2 g pantothenic acid (PA). 49 patients undergoing surgery for tattoos, by the successive resections procedure, entered a double-blind, prospective and randomized study. Tests performed on both skin and scars determined: hydroxyproline concentrations, number of fibroblasts, trace element contents and mechanical properties. In the 18 supplemented patients, it was shown that in skin (day 8) Fe increased (p < 0.05) and Mn decreased (p < 0.05); in scars (day 21), Cu (p = 0.07) and Mn (p < 0.01) decreased, and Mg (p < 0.05) increased; the mechanical properties of scars in group A were significantly correlated to their contents in Fe, Cu and Zn, whereas no correlation was shown in group B. In blood, AA increased after surgery with supplementation, whereas it decreased in controls. Although no major improvement of the would healing process could be documented in this study, our results suggest that the benefit of AA and PA supplementation could be due to the variations of the trace elements, as they are correlated to mechanical properties of the scars.

Experimental pancreatic cancer in the rat treated by photodynamic therapy.

Selective histological necrosis of experimental pancreatic carcinoma by photodynamic therapy (PDT) has been successful with haematoporphyrin derivatives and phthalocyanine as photosensitizers. This report describes the feasibility of PDT with pheophorbide A as the photosensitizer to treat azaserine-induced pancreatic rat carcinoma and analyses survival of the animals. An organ distribution study 24 h after pheophorbide A administration (9 mg/kg intravenously) gave a selectivity ratio of 13.5:1 between tumour and surrounding tissue. Light of 660 nm and 100 J/cm2 induced selective necrosis of the tumour. Six of nine rats were cured in 120 days whereas all 36 control animals died within 35 days (P < 0.01). The pancrease and hepatic pedicle were relatively unaffected by PDT, but the duodenum was injured.

Implication of cholecystokinin in pancreatic adaptation after biliopancreatic bypass in the rat.

Biliopancreatic bypass (BPB), a bariatric surgical procedure, leads to a malnutrition-induced general visceral atrophy except for the pancreas. This work investigates the implication of cholecystokinin (CCK) in the exocrine pancreatic adaptive process using a plasma CCK assay and the CCK receptor antagonist CR 1409. No significant reduction in weight and DNA content of the pancreas was noted 36 days after BPB, while a strong decrease in protein, enzymes and RNA contents indicating cellular hypotrophy became apparent. CR 1409 treatment strongly depressed pancreatic weight and its DNA content in BPB animals, suggesting an additional hypoplasia; however, the reduction in pancreatic enzyme content was not aggravated. BPB increased plasma CCK concentrations by 160%, unrelated to CR 1409 treatment. These results indicate that: (1) CCK is involved in the pancreatic adaptive response after BPB in rats, and (2) in the context of a protein malnutrition state, CCK dissociates its pancreatic growth and enzymatic effects, favouring the former.

Trophic and enzymatic adaptation of the intestine to biliopancreatic bypass in the rat.

Biliopancreatic bypass (BPB), the exclusion of a duodenojejunal loop from the digestive continuity, has been proposed as a bariatric procedure for treatment of morbid obesity. The present study in rats investigated the effect of this surgical procedure on the mucosae of the ileum directly anastomosed to the stomach, and of the jejunum irrigated only by biliopancreatic secretions. The proximal part of the ileum adapted by two-fold increases in its mucosal mass, total protein and RNA content; DNA content was four-fold higher than in sham-operated animals. There was a correlated increase of mucosal enzyme content, except for lactase. In the distal ileal mucosae, a slight, transient augmentation of mucosal mass, protein, DNA and RNA content was observed which tended to compensate for the shortening of the functional gut. No morphological changes were found in the excluded loop, probably because of an endoluminal stimulation by biliopancreatic secretions. Thus, in BPB, biliopancreatic secretions seem to exert trophic effects on the intestinal mucosa, but they are less potent than the endoluminal nutrition that restores the oral-aboral mucosal gradient.