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The rising problem of obesity is causing major health problems, reduced quality of life and reduced life expectancy. It now generates approximately 10% of all health costs. The progression of the problem indicates preventive measures have been unsuccessful so far. Only bariatric surgical treatments have been able to achieve substantial and durable weight loss. Gastric banding and gastric bypass are used in more than 90% of bariatric operations. The proportion of each varies from greater than 95% bands in Australia, about 50/50 in Europe and USA and nearly 100% bypass in South America. The availability of follow up is a prime determinant of choice. Understanding the mechanisms of effect for the bariatric procedures is central to optimizing their effect. The traditional narrow concepts of restrictive (blocking the transit of food) and malabsorptive (preventing the absorption of food) should be discarded and the importance of induction of satiety, change of taste, diversion of chyme, neural and hormonal mediation and the effects of aversion need to be included. The primary mechanism of effect for gastric banding is the generation of a background of satiety and early post-prandial satiation via specifically structured vagal afferents at the level of the band. At five years after banding or bypass, there is typically a loss of 30-35 kg representing 50-60% of excess weight. This weight loss has been shown to be associated with major improvement or complete resolution of multiple common and serious health problems plus improvement in quality of life and in survival. Level 1 evidence supports the use of the gastric band over optimal lifestyle therapy. Randomized controlled trials has shown gastric banding to achieve better weight loss, health and quality of life than optimal lifestyle therapies for adults above a BMI of 30 and adolescents above a BMI of 35. In adults with mild to severe obesity and type 2 diabetes gastric banding leads to remission in three out of four individuals. Perioperative risk is significant with gastric bypass and late revisional procedures can be required after both procedures. Gastric banding is indicated in any adult who has a BMI over 30, has problems with their obesity and has made substantial effort to reduce their weight by lifestyle methods. Gastric bypass or biliopancreatic diversion should be considered in those with BMI greater than 35 if banding is contraindicated or has been unsuccessful.

Background: Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer; however, their use as preventive agents is limited by their inherent toxicity. Drugs that selectively inhibit cyclooxygenase-2 (COX-2) may be useful in this setting as they are supposedly less toxic. No study has directly compared the ability of standard NSAIDs and selective COX-2 inhibitors to inhibit colorectal cancer at clinically relevant doses., Methods: Aberrant crypt foci (ACF) were induced in Sprague-Dawley rats by using 1,2-dimethylhydrazine (DMH). Test agents or vehicle were then administered for 3 weeks, twice daily through orogastric gavage. At the end of this period, the number and multiplicity of ACF were determined. The agents tested at equivalent anti-inflammatory doses were: sulindac and indomethacin (standard NSAIDs), meloxicam (selective COX-2 inhibitor), celecoxib (specific COX-2 inhibitor) and sulindac sulfone (no known COX activity). Acute gastrotoxicity of NSAID in rats was compared by using quantitative histology., Results: All test agents reduced the number of ACF. There was a 42% reduction with indomethacin, 46% with sulindac, 46% with meloxicam, 22% with celecoxib and 36% with sulindac sulfone. Only the COX-2 inhibitors caused no significant gastrotoxicity in rats., Conclusions: Cyclooxygenase-2 inhibitors are potentially ideal chemopreventive agents as they inhibit ACF and are not gastrotoxic.

We have determined the dose-response relationship between sulindac administration and inhibition of tumour growth in the rat. The effect of tumour-inhibiting doses of sulindac on the production of prostaglandin E in tumours and macroscopically normal colon was then examined. Growth of pre-existing tumours was significantly reduced following administration of sulindac at 0.1 (P=0.004), 1 (P=0.01), 3 (P<0.001) and 10 mg/kg b.d. (P=0.002) for 4 weeks. There was no significant difference in prostaglandin E synthesis between tumours from control rats and those treated with sulindac at either 3 or 10 mg/kg b.d. (P=0.09 and 0.4, respectively). Prostaglandin E synthesis was reduced by 33 and 32% in macroscopically normal tissue from these treatment groups. These data show that sulindac inhibits tumour growth at low doses and do not support a role for the inhibition of prostaglandin synthesis, by sulindac, in the inhibition of tumour growth.

The incidence, frequency of complications and mortality of gastric ulcer disease are increased four-fold in the elderly taking non-steroidal anti-inflammatory drugs (NSAID). There is controversy as to whether this reflects increased usage of NSAID or specific vulnerability associated with age. We have investigated two possible mechanisms for this increase in gastrointestinal effects in the elderly: (i) increased susceptibility to acute gastrotoxicity; and (ii) reduced adaptation to NSAID, in a model of young (2 month), mature (12 month) and aged (24 month) rats. Aspirin damaged 7.7% of the volume of gastric mucosa in the young rat. In mature and aged rats, this increased to 11.3% (P < 0.002 compared to control) and 21.9% (P < 0.005 compared to control), respectively. Thus, aspirin caused a three-fold increase in the severity of acute gastric mucosal injury in aged animals. However, indomethacin, ibuprofen and L745 337 did not produce any significant acute gastric mucosal damage in 2-, 12- or 24-month-old rats. Significant gastric adaptation to diclofenac treatment occurred in both aged and young rats as measured by gastric mucosal damage. The aged gastric mucosa adapted equally as well as the young gastric mucosa to diclofenac. The findings of this study provide only modest support to the hypothesis of increased vulnerability of the stomach in the aged. Aspirin was associated with greater damage in the aged. Adaptation to diclofenac-induced damage was not reduced in the aged and there was not an increased susceptibility to damage by the non-aspirin NSAID tested. The selective cyclo-oxygenase-2 inhibitor, L745 337, was the least toxic agent and may represent a group of NSAID which cause fewer gastrointestinal complications in the elderly., (© 1998 The Official Publication of the Asian Pacific Association for the Study of the Liver and the Asian Pacific Association of Gastroenterology.)

Increasing evidence suggests that non-steroidal anti-inflammatory drugs (NSAID) differ in gastrotoxicity. This study aimed to compare the effects of a short-acting NSAID, tiaprofenic acid, with indomethacin on experimental gastric ulcer healing in a rat model. Similar anti-inflammatory and prostaglandin-inhibitory doses of indomethacin (1 mg/kg) and tiaprofenic acid (2 mg/kg) were administered to rats with acetic acid-induced ulcers. After 2 weeks treatment, rats were killed and ulcer size determined. In addition, histological sections of ulcers were assessed for ulcer contraction and mucosal regeneration. The degree of inhibition of prostaglandin E2 (PGE2) synthesis was 72% at 2 h after tiaprofenic acid and 64% at 2 h after indomethacin administration, respectively. Rats treated with indomethacin for 2 weeks had significantly larger ulcers, both macroscopically and microscopically, than controls. Rats treated with tiaprofenic acid for 2 weeks had ulcers of a similar size to those of controls. Indomethacin-treated ulcers showed a failure in mucosal regeneration. Tiaprofenic acid-treated ulcers had significantly more regeneration than indomethacin-treated ulcers. We conclude that tiaprofenic acid inhibits mucosal prostaglandin levels but does not inhibit experimental gastric ulcer healing. These findings suggest that inhibition of PGE2 synthesis is not the only factor in generating gastrotoxicity and that a shift to low gastrotoxic NSAID may be clinically worthwhile.

Liver metastases account for over 70% of deaths resulting from colorectal carcinoma, with survival rates varying between 6-18 months. At present, surgical resection offers the only hope for a cure, while chemotherapy, focal destructive techniques and selective internal radiation offer palliative care. Tamoxifen, a non-steroidal anti-oestrogen is primarily known for treating oestrogen receptor (ER)-positive breast cancer. Some studies suggest that tamoxifen may have beneficial effects in malignancies other than breast cancer. These inhibitory effects, which have been shown to be independent of the ER, highlight new mechanisms of therapeutic action. Using an intrasplenic animal model we report the efficacy of tamoxifen on experimental liver metastases. In this model, a dimethyl hydrazine-induced colon carcinoma cell suspension is introduced into the portal circulation via the spleen, which results in secondary tumour deposits in the liver in virtually all animals. Tamoxifen was administered at a dose of 1 mg/kg suspended in 1.0% methyl cellulose. The control group received an equal volume of the vehicle. The reagents were administered s.c. on the day of metastases induction and were continued daily over a 4 week period. The effect of tamoxifen on tumour growth was assessed by stereology and bromodeoxyuridine immunohistochemistry at selected time points. Data were assessed by a multiple analysis of variance where P < 0.05 was considered significant. In the control group the volume of metastases increased from 44 +/- 41 mm3 at day 10 to 517 +/- 380 mm3, 1394 +/- 598 mm3 and 2082 +/- 675 mm3 by days 16, 22 and 28, respectively. Daily administration of tamoxifen exerted an inhibitory effect on tumour growth during the first 3 weeks, recording a volume of 421 +/- 299 mm3 by day 22 compared with the control group at that time point (P = 0.00004). The inhibitory effect diminished by the fourth week recording a tumour volume of 1344 +/- 674 mm3 by day 28. Inhibition of tumour growth at day 22 coincides with a reduction of cells in the S phase of the cell cycle. The percentage of brdU-positive nuclear profiles in metastases of tamoxifen-treated mice at 3 weeks was 35.87 +/- 5.60% compared with 48.01 +/- 3.96% in the control group (P = 0.001). These data suggest that tamoxifen has a potent inhibitory action on colorectal liver metastases by exerting an effect on cell proliferation.

The non-steroidal anti-inflammatory drug, sulindac, inhibits the growth of colorectal tumours in animal models of colon cancer and causes regression of polyps in patients with familial adenomatous polyposis. The mechanism by which sulindac exerts this inhibitory effect is not known, but it has been postulated to be via the inhibition of prostaglandin synthesis. However, two recent studies have indicated that sulindac sulphone, the non-prostaglandin inhibiting metabolite of sulindac, may be important in tumour inhibition. In the present study, we examined the effect of sulindac sulphone on the formation of aberrant crypt foci, the earliest identifiable lesions in the development of colorectal cancer, in the rat colon. We have previously shown that sulindac causes a dose dependent inhibition of aberrant crypt formation in this model. Aberrant crypt foci were induced with two oral doses of 1,2-dimethyl hydrazine at 25 mg/kg per dose. Treatment with sulindac sulphone at either 10 mg/kg b.d., or 20 mg/kg, b.d., was started on the day following administration of the first carcinogen dose and was continued for 3 weeks. Colons were then removed and examined for aberrant crypt foci. Colonic crypts were visualized by staining the unsectioned colon in 0.2% methylene blue solution. There was a significant reduction in the number of aberrant foci in rats treated with sulindac sulphone at 20 mg/kg, b.d. (ANOVA, P = 0.0054). The mechanism by which non-steroidal anti-inflammatory drugs inhibit formation of aberrant crypt foci is not clear; however, these data suggest that it is not due to the inhibition of prostaglandin synthesis.

The experimental study of possible therapies for control of the growth of liver metastases requires the availability of a model which is technically feasible and appears to exhibit growth characteristics similar to human tumours. We report on the development of an intrasplenic injection model of liver metastases, and describe the histology, growth pattern and blood flow demonstrated by light microscopy, stereology and laser Doppler flowmetry. The hepatic metastases were induced in mice by intrasplenic injection of dimethylhydrazine (DMH) induced primary colonic carcinoma cells (10(6) cells in 1 mL). The growth and development of metastases was studied over a period of 3 weeks at predetermined time points. Tumour cells were visible in the hepatic sinusoids by day 7 by light microscopy. Macroscopically visible tumours with a diameter of 0.18 +/- 0.02 cm (mean +/- s.d.) were seen by day 10. By this time the tumours had derived a blood supply from the hepatic sinusoids adjacent to the tumour periphery. With further vascularization the tumours reached a diameter of 0.96 +/- 0.50 cm by day 22. Metastatic growth was quantitated by stereological analysis of tumour volume in relation to non-diseased hepatic tissue. Normal mouse liver had a mean volume of 1.13 +/- 0.14 cm3. Tumour growth occurred in three phases. During the initial slow phase the volume of metastases increased from 0.03 +/- 0.02 cm3 at day 10 to 0.22 +/- 0.24 cm3 by day 16. Rapid tumour growth, occurring over the next 3 days, constituted the intermediate phase with metastatic volume reaching 1.21 +/- 0.74 cm3 by day 19 (P = 0.0003 compared with day 16). This growth was followed by a plateau phase when the metastatic volume was 1.40 +/- 0.55 cm3 at day 22. The volume of total liver and of tumour necrosis followed a similar growth pattern. A necrotic tumour volume of 0.004 +/- 0.006 cm3 first seen on day 10 increased to 0.05 +/- 0.06 cm3 by day 16, and to 0.25 +/- 0.20 cm3 by day 22 (P = 0.0022 compared with day 16). The blood flow in metastases measured by laser Doppler flowmetry was lower compared to the non-diseased liver. Tumour blood flow, expressed as a percentage of normal liver blood flow, was 63.31 +/- 26.28% at day 10 and diminished to 27.91 +/- 8.99% by day 22, with an increase in tumour size and age. The decrease in flow was significant between days 13 and 16 (P = 0.0015). This intrasplenic mouse model of metastases is reproducible and should prove useful in the study of treatment of hepatic metastases.

Aberrant crypt foci are microscopic lesions found in the colons of rodents treated with carcinogens, and in patients with premalignant colorectal conditions. They consist of single or multiple abnormal crypts and show cellular changes ranging from dysplasia to microscopic adenomacarcinoma. It is thought that these lesions represent the initial stages of the adenomacarcinoma path that results in the development of colorectal neoplasia. We have examined the effect of sulindac and indomethacin on the formation of aberrant crypt foci in rats treated with dimethylhydrazine (DMH). Aberrant crypt foci were induced in male Sprague-Dawley rats with two oral doses of dimethyl hydrazine at 25 mg/kg per dose. Rats were randomized to receive sulindac at 3 mg/kg (n = 20) or 10 mg/kg (n = 18) b.d., indomethacin at 1 mg/kg per day (n = 18) or 2 mg/kg per day (n = 19) or control (n = 37). Drug treatment was started on the day following the first dose of carcinogen and continued for 3 weeks. Colons were fixed flat overnight in 10% formalin and stained with 0.2%. Methylene Blue solution before being studied. There was a significant reduction in the number of aberrant crypt foci in rats treated with 10 mg/kg b.d., sulindac (P = 0.001) and indomethacin at 2 mg/kg per day (P = 0.0002). Sulindac, at 3 mg/kg b.d., and indomethacin, at 1 mg/kg per day, did not have a statistically significant effect (P = 0.089 and P = 0.052, respectively). None of the drug treatments affected the relative frequency of single crypt vs multiple crypt foci. Previous studies have shown that sulindac and indomethacin will significantly inhibit the growth and development of tumours in DMH treated rats. The current data suggest that one of the pathways of action of NSAID is to inhibit the formation of early preneoplastic lesions.

The aim of this study was to investigate the nature and distribution of sulphated macromolecules of the extracellular matrix in rat gastric mucosa. This was achieved by developing an in vivo labelling system. An intraperitoneal injection of 1 mCi [35S]-sulphate was given for either 4 h (0.01% incorporation into macromolecular fraction) or 8 h (0.13% incorporation). At the end of the labelling period the stomach was removed and the mucosa and submucosa was either taken as a single combined sample or separated into four layers by blunt dissection. Each sample was papain digested and analysed by ion-exchange chromatography. This analysis revealed sulphated species of differing charge existing in differing proportions throughout the mucosa. These sulphated species eluted at NaCl concentrations of approximately 0 (A), 0.19 (B), 0.34 (C) and 0.78 mol/L (D) from a Q-Sepharose ion exchange column. Further analysis by size exclusion chromatography and chemical and enzymatic digestion showed that peaks B and C had molecular weights of 2.4 x 10(5) and 2.8 x 10(5), respectively and were resistant to chondroitinase ABC, heparitinase and nitrous acid digestion. Peak D was found to contain a polydisperse population of molecules with a molecular weight range of approximately 1 x 10(4) to 6 x 10(4). This sample was susceptible to nitrous acid and chondroitinase ABC digestion and was found predominantly in the sample isolated from deeper in the tissue. We have thus developed an in vivo labelling technique for sulphated macromolecules that can be used in the further study of injury to the gastric mucosa.

Prostaglandins (PG) protect the gastric mucosa against damage by several irritants, but the mechanisms remain unclear. A standard rat model of gastric injury induced by 50% ethanol was used to test the hypothesis that PG protection occurs either by increasing luminal fluid volume and hence diluting the irritant, or by production of protective factors within this fluid. Quantitative histology was used to assess microscopic mucosal damage. The increase in luminal fluid volume in prostaglandin E2 (PGE2)-treated animals was measured, and the ability of this increased fluid to protect saline-treated animals via dilution of the irritant was assessed. The transfer of protection by exchange of luminal fluid from PG to non-PG treated animals was also tested. Results showed that PGE2 induced a specific increase in luminal fluid volume of 45.6%. When given together with ethanol treatment the extra fluid volume was not protective. Removal of luminal fluid after PG and before ethanol treatment did not abolish protection and no protective factor was transferred with the luminal fluid. In conclusion, this study has shown that neither dilution of ethanol by accumulation of luminal fluid nor the presence of luminal factors is responsible for PG protection.

A technique of quantitative histology was used to assess the influence of time after injury on the histological expression of gastric mucosal damage. Rats, pretreated with either natural prostaglandin E2 or saline, were subjected to intragastric administration of either 50% or 100% ethanol. Fifteen minutes later the ethanol was removed from the stomach. Rats were sacrificed at either 30 min or 24 h after ethanol instillation. In rats pretreated with saline and subjected to 100% ethanol with or without prostaglandin pretreatment, the extent of deep mucosal damage was markedly underestimated by early evaluation. Only 5.4% of the volume of the gastric mucosa showed evidence of damage at 30 min after ethanol, compared with 57.3% of the volume of the mucosa, at 24 h after 100% ethanol exposure. Assessment of gastric mucosa 24 h after ethanol injury showed that PGE2 reduces the extent of surface area damaged and the volume of the mucosal damage. When 50% ethanol was used as the injurious agent, no difference was noted in the volume of the mucosa damaged when the stomach was assessed at either 30 min or 24 h after injury. These results indicate that full histological expression of injury is not present 30 min after 100% ethanol instillation, at least in part because of fixation of the gastric mucosa by 100% ethanol. Fifty per cent ethanol, which does not cause mucosal fixation, may be better as a test agent.