Although localization of tumours by radiolabelled antibodies is in principle a specific method, in practice the technique is dependent upon qualitative and quantitative differences in antigen expression between malignant and benign tissue. Pancreatic disease is similar to other gastrointestinal malignancies in which RIL has been evaluated. The expression of a small number of antigens has been demonstrated to enable some differentiation between pancreatic cancer and principally chronic pancreatitis. To date the cross-reactivity of antibodies has resulted in limited specificity but it does appear that CEA, CA19-9, TAG-72 and BW494 are appropriate target antigens. Studies in RIL have indicated that BW494 has the optimal characteristics, although studies with chronic pancreatitis are limited. Further information on the fate of the administered antibody and the interactions with tumour-associated antigen is required before clinical application can be considered. At present this technique does not have a role in primary diagnosis. In the near future, however, RIL may prove useful as a complementary investigation to conventional methods particularly in the assessment of recurrent malignancy.

Serological tests for pancreatic cancer have been criticized too harshly as a result of being tested in inappropriate roles. They are never likely to become sufficiently specific for screening an asymptomatic population unless some way can be found of defining a population with a particularly high risk for the disease. Nor are they appropriate in the investigation of the jaundiced patient. The markers that are carried by secreted mucins seem the most promising and in view of the marked heterogeneity of carbohydrate expression on mucins a combination of tests for two or three carefully selected markers is likely to be better than one. The high cost per test that results from using commercially available radioimmunoassay kits with a short shelf-life can be reduced by using enzyme-linked assays which have a much longer shelf-life. These tests are likely to be of most help in the investigation of non-jaundiced patients with unexplained abdominal pain or weight loss. In this group of patients it seems probable that serological tests will compliment scanning techniques but further studies are needed to assess this.

There are abnormalities in the structure and/or function of several oncogenes and growth factors in human pancreatic cancer, notably the EGF receptor and its ligand TGF alpha, c-erb B-2 proto-oncogene, Ki-ras oncogene and the tumour suppressor gene p53. The temporal sequence of their activation and the nature of the aetiological agents responsible for their activation are not yet clear. In vitro pancreatic culture systems and transgenic animal experiments are needed to reconstruct and define those molecular events that are necessary and sufficient for the neoplastic phenotype.

In the last two decades, we have witnessed revolutionary advances in pancreatic imaging as well as increased availability of megavoltage radiotherapy equipment and sophisticated radiotherapy planning devices. Several advances in the radiotherapy of pancreatic cancer have been made for the patient with resectable disease. Postoperative radiotherapy combined with chemotherapy confers a survival advantage after 'curative' resection. Preoperative and intraoperative intraoperative radiotherapy may do the same, but this requires further evaluation. Preoperative irradiation may improve the resectability rate, but the clinical data are still very limited. For locally unresectable disease, PHD radiotherapy with adjuvant 5-FU should now be the standard treatment in suitable cases with a median survival time of about one year. High LET radiation beams have failed to produce improved survival in two prospective randomized studies. Intraoperative radiotherapy is an effective means of pain control and enhances control of local disease, but has not been shown to improve survival rate significantly. Interstitial radiotherapy also improves local control, but it is associated with a high mortality rate and an even higher major complication rate. Wide-area radiation therapy and preoperative radiotherapy both seem to show promise in this group of patients. Patients with metastatic disease should be treated palliatively on an individual basis.

Acinar cells are one of the best studied models of exocytotic secretion. A number of different hormones and neurotransmitters interact with specific membrane receptors, and it is commonly held that pancreatic secretagogues stimulate enzyme release via the elevation of either cytosolic free Ca2+ or cellular cyclic adenosine monophosphate. The discovery of the pivotal role played by phospholipid metabolism in the chain of events leading to secretion, together with the introduction of sensitive techniques to monitor cytosolic free Ca2+, has generated a series of studies that have challenged this classical model. Thus, several observations in pancreatic acini as well as other cell types have argued against the notion that a generalized increase in cytosolic free Ca2+ represents a sufficient and necessary stimulus for exocytosis in nonexcitable cells. Furthermore, the demonstration that a single agonist activates multiple transduction pathways has served to refute the schematic view that receptor agonists activate only one second messenger system. The aim of this article is to review the recent advances in understanding the molecular and cellular mechanisms of signal transduction, with particular emphasis on the inositol lipid pathway, and to integrate this information into a new working model of enzyme secretion from acinar cells.

HIV is a retrovirus infecting CD4-positive cells causing profound immunosuppression, eventually clinically manifest as AIDS. The cells principally infected by HIV are T4 lymphocytes (helper) and macrophages. The eventual loss of helper cell function is the prime reason for immunodeficiency which renders the individual susceptible to opportunistic infections. HIV infection was first described in male homosexuals. However, the trend now is for seroprevalence to rise rapidly in intravenous drug abusers in the West. In addition, African AIDS is thought to be almost exclusively heterosexual in nature, a paradox which is not yet fully explained in comparison with the relatively low but increasing incidence in heterosexuals in the Western world. Virtually every organ system in the body can be affected clinically during the course of HIV infection. The gastrointestinal tract is a major target, and the physiological sequelae are an important cause of morbidity and mortality. The pathophysiology of intestinal infection is not yet fully understood, however two main mechanisms have been postulated. The first is reduced intestinal immunity resulting in chronic opportunistic infections, which themselves caused altered intestinal function. The second is that HIV itself affects the intestinal mucosa, causing malfunction. The mechanisms by which the latter occurs are controversial but may result from either direct infection of mucosal epithelial cells or macrophages within the mucosa. Reports have documented the presence of HIV genome in both epithelial argentachromaffin cells and macrophages. In addition, profound degeneration of intrinsic jejunal autonomic neurones has been demonstrated, but the functional significance of such denervation is as yet unknown. The clinical stage of HIV infection at which intestinal mucosal immunity fails is by definition when opportunistic infection occurs (that is, clinical progression to stage IV disease), namely AIDS, however a detailed knowledge of the mechanisms of intestinal immune failure are lacking.

Reports in the literature on 21 cohorts of workers exposed to asbestos were reviewed and analyzed to determine whether there is a causal association between asbestos and colorectal cancer. The latest report up to 1988 was used for each cohort. The end point was the standardized morbidity or mortality ratio as the measure of relative risk. Two additional cohorts using mortality as the end point were excluded because the authors failed to use comparable diagnostic methods for the asbestos-exposed populations and controls. The summary standardized morbidity or mortality ratio for all 21 cohorts was 0.97 (P greater than 0.05), and there was no dose-response relationship in the two studies with such data. The evidence does not meet the established criteria for making a judgment that there is a causal relationship between asbestos and colorectal cancer.

Bismuth therapy has shown efficacy against two major gastrointestinal disorders: peptic ulcer disease and diarrhea. In peptic ulcer disease it is as effective as the H2-receptor antagonists, costs considerably less, and offers a lower rate of relapse. When Helicobacter pylori is implicated, bismuth acts as an antimicrobial agent, suppressing the organism but not eliminating it. In recent studies, bismuth compounds have been used with conventional antibiotics, producing elimination of the organism, histological improvement, and amelioration of symptoms for periods longer than one year. Bismuth subsalicylate has shown modest efficacy in treating traveler's diarrhea and acute and chronic diarrhea in children, and it is effective prophylactically for traveler's diarrhea. An epidemic of neurological toxicity was reported in France in the 1970's with prolonged bismuth treatment, usually bismuth subgallate and subnitrate. Such toxicity has been rare with bismuth subsalicylate and colloidal bismuth subcitrate. However, recent studies have demonstrated intestinal absorption of bismuth (about 0.2% of the ingested dose) and sequestration of this heavy metal in multiple tissue sites, even occurring with conventional dosing over a 6-week period. These findings have inspired recommendations that treatment periods with any bismuth-containing compound should last no longer than 6-8 weeks, followed by 8-week bismuth-free intervals.

Of all the hepatotropic viruses, HBV is associated with the greatest worldwide morbidity and mortality. This is because of the ease of transmission and the potential for progression to a chronic infective carrier state, with the complications of cirrhosis and hepatocellular carcinoma. The use of PCR has shown that some of the earlier concepts concerning the interpretation of serological data were inaccurate. Many patients with anti-HBe and anti-HBs have viral DNA detectable by PCR, and some hepatocellular carcinoma patients have detectable HBV DNA in their livers in the absence of all serological markers of HBV disease. The clearance of HBV infected cells from the liver is dependent on the interplay between the interferon system and the cellular limb of the host immune response. The importance of the nucleocapsid proteins as targets for sensitized cytotoxic T cells has been established for chronic HBV infection. The importance of pre-S sequences as inducers and targets of the virus-neutralizing humoral immune response is becoming established, but their precise role must await the development of in vitro models of hepadnavirus infection and a greater understanding of the mechanisms of viral uptake. The epidemiology and clinical course of the disease can be modified by immunization, immune stimulation and antiviral chemotherapy. For the developing world, a programme of immunization at birth would be the most effective way of eliminating this disease, but at present the cost is prohibitive. For the developed world, immunization is realistic for the at-risk population, and anti-viral and immunostimulatory therapy available for those already infected. In adult acquired chronic HBV infection alpha-interferon produces HBe antigen clearance in 40-60% of cases and is followed by resolution of the hepatic inflammation. Results in neonatally acquired infection are less impressive and prednisolone priming followed by interferon may be needed. The presence of a mutation in the pre-core region of some virus isolates has recently been described. Hepatocytes infected with this virus cannot produce HBe antigen and the course of the liver disease is fairly rapid. Whether this mutant causes liver damage in the same way as the wild virus or is directly cytopathic remains unclear, and its relationship to fulminant hepatitis is under investigation.

Known properties of hepatitis A virus are described in this article. HAV is a small non-enveloped picornavirus, grouped in the Enterovirus family, with unique biological features. The genome structure resembles that of other picornaviruses. Replication in cell cultures takes much longer than that of other picornaviruses and the yield is much lower. HAV is extremely heat- and pH-stable. Variants may induce cytopathogenic effects in vitro. Normally, however, the virus is non-cytopathogenic. The elimination of virus in vivo is assumed to be caused by action of HAV antigen specific CD8+ lymphocytes. In industrialized countries there is a declining incidence of reported hepatitis A cases, and the prevalence of antibodies in younger populations is low. Vaccines have been developed and in studies using human volunteers, good immunogenicity has been demonstrated. In the very near future a cell cultured derived, highly purified, inactivated vaccine will be available.

Epidemiological studies on SRSVs, human calicivirus and astroviruses have been limited by the problems of establishing them in cell culture and the inability to transmit them to animals or to use strains from animals as a source of antigen for diagnostic tests. The use of EM and the subsequent development of RIAs and EIAs in a few research centres has shown that they are a cause of outbreaks and sporadic cases of diarrhoea and vomiting. SRSVs have increasingly been recognized as a major cause of outbreaks of gastroenteritis in the community and in hospital wards. The symptoms of illness are generally mild and of short duration and patients seldom require medical attention. However, because of the high attack rates and large numbers of persons of all age groups involved, there is often considerable economic loss and disruption of services. Evidence is accumulating that polluted water, molluscan shellfish, and contaminated cold foods are major sources of infection. Recently a SRSV has been shown to be the cause of epidemics and sporadic cases of waterborne enterically transmitted non-A, non-B hepatitis (hepatitis E virus) which have occurred in the USSR, India, Mexico and Africa. Astroviruses and human caliciviruses are occasional causes of outbreaks of vomiting and diarrhoea in infants and the elderly which can necessitate the closure of hospital wards and cause considerable disruption. Symptoms are generally mild and of short duration and therefore the majority of cases are unlikely to be investigated by laboratories. Diagnosis of infections is at present limited to the few laboratories that have developed their own assays or have access to electronmicroscopy facilities.

Human adenoviruses are classified into 47 serotypes and six subgenera (A-F) with different tropisms. In recent years adenovirus type 40 (Ad40) and 41 (Ad41) of subgenus F have been shown to be causative agents in enteric infections, which is second in importance only to rotaviruses as a cause of infantile gastroenteritis. Infection with EAds occurs worldwide and has been associated with 4-17% of cases of diarrhoea in children. AD40 and Ad41 primarily affect young children less than 2 years of age and occur throughout the year. The clinical characteristics include watery diarrhoea accompanied by vomiting, low grade fever and mild dehydration. A distinct feature of EAds infection is the protracted diarrhoea (mean 8.6 and 12.2 days for Ad40 and Ad41, respectively). Respiratory symptoms are infrequent. Serotypes Ad40 and Ad41 differ from all other (established) adenoviruses by being unable to replicate in conventional cell cultures. These fastidious viruses only grow in selected cell lines, 293 cells being the most commonly used. In spite of the difficulty of isolating Ad40 and Ad41, they can be directly identified and typed by ELISA and solid-phase immune electron microscopy. The amount of viral DNA in stool specimens is sufficient for identification by DNA restriction and dot-blot assays. The recent development of highly sensitive and specific monoclonal antibody-based ELISAs enable accurate diagnosis of adenovirus gastroenteritis in routine work and make possible the evaluation of the role of the enteric adenoviruses in diarrhoeal disease in the developing countries.

Since their discovery in the 1970s, the human rotaviruses have been recognized as the most important cause of acute infectious gastroenteritis among infants and children worldwide. Rotavirus has been found to infect almost all mammalian and avian species tested, and is primarily a disease of the young. In humans, rotavirus is the most frequent gastrointestinal pathogen in infants and children less than 2 years of age. In developing countries, the attack rate peaks at 6 months of age, whereas in developed areas of the world the virus is most commonly found among children 6-12 months of age. Rotavirus displays a marked seasonality in temperate climates, with the number of cases peaking in the colder winter months. In tropical climates, this seasonality is not as apparent, and infection may occur year round. Symptoms of rotavirus infection are non-specific and include vomiting and diarrhoea, occasionally accompanied by a low grade fever. Dehydration is more common with rotavirus infection than with most bacterial pathogens, and is the most common cause of death related to rotavirus infection. Treatment is non-specific and includes the use of oral rehydration therapy, especially in developing countries where malnutrition is common. Strategies for the prevention of rotavirus infection are dependent on advances in the understanding of the molecular biology of the rotavirus. The genetic structure of the virus has been extensively studied, and a number of the structural proteins have been identified. The neutralization antigens, located on VP4 and VP7, may be important in conferring immunity to rotavirus in vivo. Two animal-derived and several reassortant rotavirus vaccines are currently being evaluated in field studies, and a number of other candidate vaccines are being tested in vitro and in animal studies.

In summary, the pathogenesis of many gut virus infections remains uncertain. However, human and animal studies indicate that the majority of gut viruses infect villous enterocytes. Viruses appear to have different affinities for enterocytes at different sites on the villus. Infection of enterocytes leads to cell death, extrusion into the lumen, and villous atrophy when the rate of cell production in the crypts cannot keep pace with the rate of enterocyte loss. This results in a reduced surface area as well as impairment of digestive and absorptive functions. This may also result in a net secretory state. All these changes, along with others such as reduced enzymatic activity and reduced epithelial integrity, may contribute to the induction of an acute but transient malabsorptive diarrhoea which may persist until the digestive/absorptive functions of the enterocyte are restored. However, if colonic compensation is sufficient to handle the increased fluid load, diarrhoea may not be evident. The roles of villous ischaemia, altered countercurrent exchanger of altered immune responses still remain uncertain and require further investigation.