The European journal of surgery. Supplement. : = Acta chirurgica. Supplement最新文献

Genomic techniques offer new approaches to the investigation of the aetiology and pathophysiology of intestinal disorders. An important field that is relevant to treatment is the pharmacogenetic investigation of gene variations that may predict response to certain drugs in order to target these drugs more precisely. For the surgeon the perioperative situation will be here of great interest. To date only about 8000 of the estimated 30,000-50,000 human genes have been characterised, so the use of techniques for global analysis of gene expression may allow the identification of new pathways or molecules. In can be anticipated that genomic methods will profoundly influence the treatment of gastrointestinal disorders and will lead to new insights into both aetiology and pathophysiology of chronic intestinal inflammation.

Functional gastrointestinal disorders are characterised by central and peripheral physiological changes, associated with psychological factors. Successful drug development has been hindered by lack of adequate characterisation of the nature of symptoms and their physiological and psychological correlates. Animal models of chronic stress are lacking. High levels of drug safety are now demanded for treating non-life threatening conditions. Once close to market, patient pressure groups, health care providers and insurers, government, and the internet can all influence a drug's success. Serotonin-modifying drugs have been the main recent focus of development, with mixed results. Cisapride has been withdrawn because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists have been developed on the questionable assumption that they modify visceral sensation in patients. Problems have arisen with alosetron being associated with ischaemic colitis and a high incidence of constipation. The 5-HT4 agonists have their major effect on inducing peristalsis, and may modify gut secretion and sensory function. Tegaserod and prucalopride show promise in patients with constipation and related symptoms. 5-HT1 agonists may play a role in treating functional dyspepsia, partly by improving impaired gastric accommodation to a meal. Antidepressants, often found to be clinically beneficial in these disorders, also affect serotonin metabolism. Past successes, such as loperamide or the somatostatin analogue octreotide, involved targeting end organ receptors influencing motor function or secretion. Modifying sensory function is much more challenging. Future research with novel compounds need to keep these recent lessons in mind.

The use of biomarkers in medicine, and in epidemiology in particular, is not new but recent developments in molecular biology and genetics have increased the opportunities for their use. Epidemiological studies based on biomarkers, which belong to the discipline defined as 'molecular epidemiology', offer new avenues to investigate associations between genetic and environmental factors, diseases, and medical interventions. Important recent contributions of molecular epidemiology to cancer research include the definitive evidence of the carcinogenicity of aflatoxin in humans, and the elucidation of the mechanisms of tobacco-related carcinogenesis. However, molecular epidemiology studies are subject to problems of design and analysis similar to those of 'traditional' epidemiological studies. If biomarkers offer new opportunities to overcome some of the limitations of epidemiology, their added value over traditional approaches should be systematically assessed. Biomarkers should be validated though transitional studies; consideration to sources of bias and confounding in molecular epidemiology studies should be no less stringent than in traditional studies.

Gastrointestinal peptides including mammalian bombesin-like peptides, cholecystokinin (CCK), gastrin, and neurotensin stimulate DNA synthesis and cell proliferation in cultured cells and are implicated as growth factors in a number of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation. These agonists bind to G protein-coupled receptors (GPCRs) that promote Galpha q-mediated activation of beta isoforms of phospholipase C to produce two second messengers: Inositol (1,4,5) trisphosphate {Ins (1, 4, 5) P3} that mobilises Ca2+ from internal stores, and diacylglycerol that activates the classic and new isoforms of the protein kinase C (PKC) family. PKCs play a critical part in transducing bombesin/gastrin releasing peptide (GRP) receptor signals into activation of protein kinase cascades. Protein kinase D (PKD), a serine/threonine protein kinase with distinct structural and enzymological properties, is activated by phosphorylation in living cells through a new PKC-dependent signal transduction pathway. GPCR agonists including bombesin/GRP induce a rapid and striking activation of PKD by PKC. These results indicate that PKD functions downstream from PKCs and identify a new phosphorylation cascade that is activated by gastrointestinal peptide agonists. The bombesin/GRP GPCR also promotes rapid Rho-dependent assembly of focal adhesions, formation of actin stress fibres and tyrosine phosphorylation of multiple cellular proteins. We identified p125 focal adhesion kinase (FAK), p130 Crk-associated substrate (CAS) and paxillin as prominent targets of gastrointestinal peptide-stimulated tyrosine phosphorylation and developed a model that envisages a G12/Rho-dependent pathway connecting GPCR activation to the tyrosine phosphorylation of these focal adhesion proteins. Separate pathways mediate gastrointestinal peptide stimulation of additional tyrosine kinase pathways including transactivation of Src and epidermal growth factor receptor (EGFR). Tyrosine phosphorylation has a critical role in gastrointestinal peptide-induced cellular migration and cooperates with Gq-stimulated events to promote mitogenesis. The growth-promoting effects of neuropeptides and the elucidation of the signalling pathways that mediate their effects assume an added importance because these agonists and their receptors are increasingly implicated in sustaining the proliferation of clinically aggressive solid tumours including those from lung, pancreas, and colon.

Cirrhosis, a pathological condition defined by deranged hepatic architecture resulting from progressive fibrosis, is the final common pathway through which nearly all chronic diseases of the liver produce morbidity and mortality. Historically, treatments for hepatic fibrosis have been directed against specific causes of chronic liver injury, and include corticosteroids for autoimmune hepatitis, interferon for hepatitis B and C, and iron depletion for haemochromatosis. However, there is no effective treatment for most causes of chronic liver disease. Fortunately, the past decade has witnessed great advances in our understanding of the fundamental pathophysiological mechanisms underlying fibrosis of the liver. It is now recognised that hepatic stellate cells (myofibroblast-like cells that encircle the sinusoids) are primarily responsible for hepatic fibrosis and subsequent progression to cirrhosis. In response to liver injury stellate cells undergo a phenotypic transformation that is termed activation, and characterised by chemotaxis, proliferation, contraction, fibrogenesis, and extracellular matrix degradation. Under conditions of persistent injury the behavioural responses of these stellate cells act in concert to bring about fibrosis of the liver. Recent investigations elucidating the signal transduction pathways that link hepatic injury to stellate cell function suggest novel targets at which treatment for fibrosis may be directed. For example, antagonism of TGF-beta receptor signaling has been shown to modulate fibrosis in animal models. This work, as well as other studies in both humans and animals, indicates that hepatic fibrosis may be slowed or reversed. These results suggest that a rational approach to treatment can be developed based on our detailed understanding of the molecular and cellular mechanisms underlying cirrhosis, which will have a major impact on the clinical management of patients with chronic liver disease.

This short review is based on only a small selected sample of research to illustrate the wide variety of cellular mechanisms that underlie the neural basis of digestive diseases. The enteric nervous system and its effector cells are involved in the control of most gastrointestinal activities. The review summarises the neural mechanisms involved in normal and abnormal gastrointestinal functions. The gastrointestinal tract is exposed to a tremendous variety of foreign substances including those ingested with food and those produced by the extensive commensal and pathological bacterial flora. Normal functions controlled by the enteric neural circuits are well adapted to distinguish nutrients from harmful stimuli. The main enteric neural circuits have been identified in experimental animals and are being investigated in humans. The enormous variety of motor patterns observed in normal gastrointestinal tract is the result of interplay of a few fundamental mechanisms, including myogenic mechanisms; neurogenic accommodation, neurogenic propulsive mechanisms and migrating neurogenic motor activity. Motor dysfunctions of the gut are likely to be caused by abnormalities of one or more of these mechanisms. Disturbances of enteric neural functions can arise from physiological defence reactions to harmful insults, from abnormal activation of physiological circuits, or from pathological alterations of the enteric circuits. Vomit and expulsive propulsion and inflammation or bacteria neurally induced changes in motility are physiological defence mechanisms. Pathological alterations include toxic, autoimmune, genetic lesions also secondary to systemic diseases and can be partial and graded.

There are various techniques available for laparoscopic exploration of the common bile duct, but the most widely used are pharmacological relaxation of the sphincter of Oddi and saline flushing, laparoscopic transcystic exploration, and laparoscopic choledochotomy. Altogether 1319 patients have been reported in retrospective and prospective uncontrolled studies with more than 50 patients in each. The conclusion is that it is possible to make a laparoscopic exploration of the common bile duct in selected cases with low morbidity and mortality. As surgeons gain more experience they also learn who is and who is not a suitable candidate for this surgical option.

A complete evaluation of reflux operations depends on measurements of preoperative and postoperative clinical symptoms such as dysphagia and heartburn, assessment of quality of life and objective measurements of 24-hour oesophageal pH monitoring and manometry. Quality of life can be measured with questionnaires such as the Gastrointestinal Symptom Rating Scale (GSRS), the Psychological General Wellbeing Index (PGWB) and the Reflux-related Visual Analogue Scale (RVAS). Failure of treatment is indicated by persistent symptoms such as heartburn, need for antisecretory medication, and new symptoms such as severe dysphagia. The advantages of laparoscopic operations are mainly a quick recovery and a good cosmetic results. Good short-term cure of symptoms is reported in 90%-97% of patients who have laparoscopic fundoplication. The long-term clinical outcome is equal to or better than that of open operations. Several clinical studies have shown that laparoscopic fundoplication is effective in improving symptom ratings and the quality of life.