Are metal stents effective for palliation of malignant dysphagia and fistulas?

BACKGROUND: One of the available treatments for unresectable oesophagogastric malignancies is the insertion of metal stents. AIMS: We evaluated prospectively 147 patients suffering from malignant dysphagia and/or fistula, after inserting a self-expandable metal stent. PATIENTS AND METHODS: The study included 147 patients (87 males, mean age 73 years). Dysphagia before and after stent placement was scored. Patients were divided in two groups according to dysphagia grade: group A (grade 0, 1) and group B (grades 2, 3, 4). Three types of stents were used: the Ultraflex stent (covered and uncovered) and the Flamingo one (covered). The total number of self-expandable metal stents placed was 183. A total of 92 of them were inserted following the combined endoscopic and fluoroscopic approach (42 by injecting lipiodol), while 91 were placed under endoscopic control only. Early and late complications were evaluated. RESULTS: Mean dysphagia score in group A, 1 day and 1 month after the procedure, was slightly reduced from 0.8 to 0.5/0.6 (p=NS), respectively. However, there was a statistically significant improvement (p<0.001) of mean dysphagia score in group B, from 2.4 initially to 1.1/1.4. Early complications occurred in 37 cases, late ones in 51. According to severity, minor complications occurred in 24 patients, major in 42, while life-threatening ones in 22. Survival ranged from 1 to 611 days and 1-week mortality was 9%. Stent-related death occurred in six patients. CONCLUSIONS: All kinds of endoscopic methods used for stenting in the present study were easy to perform even on an out-patient basis. Insertion of self-expandable metal stents is effective in patients with dysphagia scores > or = 2. It might not clinically improve patients with dysphagia score <2, so selection of patients for stenting is essential to avoid unnecessary procedures. Moreover, their high cost, high complication rates and low overall survival may improve following better selection criteria.

Analysis of the conversion of delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-alpha-aminobutyrate by active-site mutants of Aspergillus nidulans isopenicillin N synthase.

BACKGROUND: Penicillins and cephalosporins constitute a major class of clinically useful antibiotics. A key step in their biosynthesis involves the oxidative cyclisation of delta-(Lalpha-aminoadipoyl)-L-cysteinyl-D-valine to isopenicillin N by isopenicillin N synthase (IPNS). This chemically remarkable transformation has been extensively studied using substrate analogues. The conversion of an analogue in which the valine is replaced by alpha-aminobutyrate results in three products, two epimeric penams and a cepham. The ratio of these products in reactions catalysed by four different IPNS isozymes has been used previously to probe the thermicity of the chemical mechanism. But how IPNS restricts the products from the natural substrate to a single penam (isopenicillin N) has remained unknown. RESULTS: A key active-site residue, Leu223, identified according to a model of enzyme-substrate binding, has been altered to sterically less demanding residues. As the steric constraints on the upper part of the active site are reduced, the ratio of the beta-methyl penam to the cepham increases when the alpha-aminobutyrate-containing substrate analogue is used. These results suggest a mechanism for processing of the natural substrate in which IPNS uses steric control to restrict the conformational freedom of an intermediate such that the only product is the penam. CONCLUSIONS: Using steric pressure to control conformation, and hence to disfavour reactions leading to alternate products, is probably the result of evolutionary selection for a biologically active product at the expense of biologically inactive byproducts. It is likely that this sort of enzymatic catalysis is used in situations where substrate conversion is highly exothermic and a variety of products are possible.

RT-PCR based diagnosis and molecular characterisation of mumps viruses derived from clinical specimens collected during the 1996 mumps outbreak in Portugal.

Clinical specimens collected during an outbreak of mumps were characterised by RT-PCR, nested PCR, and nucleotide sequencing. Mumps virus was positively identified in 12/21(57%) saliva, 9/21(43%), throat and 1/33(3%) urine specimens and further sequence comparison revealed that at least six strains of viruses, which differed from 0-9.43% at the nucleotide levels, were cocirculating during the epidemic. However, phylogenetic analysis showed that these viruses grouped with two previously identified lineages which were mostly composed of other European mumps virus isolates.

Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin--analysis of gastrointestinal bleeding during the UK-TIA trial.

From 1979 to 1985 2435 patients having had transient ischaemic attacks (TIAs) or minor ischaemic strokes, were enrolled in the UK TIA trial and were randomised to receive either aspirin 300 mg, daily or aspirin 1200 mg or placebo. Analysis of reported upper gastrointestinal bleeding events (defined as haematemesis or melaena, or both) showed a risk of bleeding in a dose dependent manner, odds ratios (95% CI) for 300 mg of aspirin = 3.3 (1.2 to 9.0) and for 1200 mg = 6.4 (2.5 to 16.5) and, as would be expected, an increased risk of hospitalisation because of bleeding also in a dose dependent manner, odds ratio = 3.6 (0.7 to 17.2) for 300 mg and 8.7 (2.0 to 37.6) for 1200 mg. Further analysis suggested greater risks of bleeding from duodenal ulcers than gastric ulcers and that bleeding is more likely early in the course of treatment with aspirin used as secondary prevention. There was also an increased risk of lower gastrointestinal bleeding, defined as fresh blood per rectum for both doses of aspirin, odds ratio 1.8 (0.5 to 6.1) for 300 mg of aspirin, and 1.5 (0.4 to 5.3) for 1200 mg of aspirin.

Nonsteroidal anti-inflammatory drug-induced gastric damage: epidemiology.

Although figures vary considerably, the ingestion of aspirin or other non-aspirin non-steroidal anti-inflammatory drugs is associated with an increased risk of gastric ulceration, ulcer bleeding, ulcer complications and of death by a factor of around 3. Evidence for duodenal ulcer (DU) disease is less convincing, but the risk of complications of DU disease, bleeding and perforation, are increased to much the same extent as for gastric ulcer. Whether this increase in complications for DU represents exacerbation of an existing DU diathesis remains unresolved.

Outbreaks of gastroenteritis due to Norwalk-like virus in two long-term care facilities for the elderly.

In February 1993, outbreaks of gastroenteritis due to Norwalk-like viruses occurred simultaneously among the elderly residents of two long-term care facilities. Facility A instituted infection control measures that included increased surveillance, reinforcement of handwashing, keeping symptomatic residents in their rooms and relieving symptomatic staff of their work duties until 48 h after resolution of their symptoms. Facility B instituted a more stringent set of control measures that included all those implemented by facility A plus the following: staff from affected units were not permitted to work on other units, affected units were closed to new admissions, enteric precautions were instituted for ill residents, residents were restricted to their own units and education was provided to staff and residents about gastroenteritis. Facility A had an attack rate of 9%; the attack rate for facility B was 11% (P = 0.38). The duration of the outbreak was 29 days in facility A and 24 days in facility B. The impact these infection control measures had on the course of the outbreaks is difficult to determine. However, it is doubtful that the more stringent measures implemented at facility B had any greater effect on the course of the outbreak. A better understanding of the precise mechanisms of viral transmission is required in order to determine the most appropriate control measures for gastroenteritis due to Norwalk-like viruses in long term care facilities.

The use of proprietary medicines by patients presenting with peptic ulcer haemorrhage.

1. Medication, social and symptom histories were compared in patients with severe haemorrhage from a peptic ulcer (n = 71) and matched control subjects. Self-medication with proprietary agents was catalogued in addition to therapy prescribed by general medical practitioners. 2. Prior to the bleed, only 4% of ulcer patients had been free of symptoms normally associated with peptic ulceration, whereas 76% of the control group had been asymptomatic. 3. Gastro-irritant proprietary medicines were used regularly by 23% of ulcer patients compared with only 4% of controls. However, proprietary antacids were used chronically by 46% of ulcer patients compared with only 7% of controls. Bicarbonate was the antacid of choice used by 13% of ulcer patients. The odds ratio for the association between development of bleeding peptic ulcer and the use of indigestion remedies was 11.5% (95% CI 1.1, 121). 4. Fifty-one percent of ulcer patients were prescribed agents known to cause gastro-intestinal damage, whereas only 25% of the control group were prescribed similar agents. Only 7% of the control group were prescribed anti-ulcer therapy compared with 37% of those with bleeding ulcer. 5. A large proportion of patients with haemorrhage from a peptic ulcer had had symptoms sufficient to warrant recourse to self-medication with antacids without medical knowledge. Exacerbation of peptic ulcer by self-medication with proprietary products is likely to be of lesser significance.

Mucosal adaptation to indomethacin induced gastric damage in man--studies on morphology, blood flow, and prostaglandin E2 metabolism.

The effect of 28 days' continuous administration of oral indomethacin on gastroduodenal morphology, gastric mucosal blood flow, and gastric mucosal prostaglandin E2 (PGE2) metabolism in man was studied to define further the mechanisms of mucosal injury induced by indomethacin. Indomethacin caused acute gastroduodenal damage in all cases, which was maximal at 24 hours of administration. With continued intake, mucosal adaptation occurs resulting in resolution of endoscopic mucosal damage. At the time of maximal mucosal damage, gastric mucosal blood flow was significantly reduced compared with values before treatment (p less than 0.001 in fundus and p less than 0.002 in antrum), with good correlation between the severity of damage and the magnitude of the reduction in blood flow (r = 0.76). Mucosal recovery was associated with a return of the blood flow to normal. PGE2 in mucosal homogenate was significantly reduced by indomethacin in both the fundus (p less than 0.01) and antrum (p less than 0.01) after 24 hours but there was no correlation between the magnitude of this reduction and the severity of mucosal damage (r = -0.34). Despite mucosal recovery by 28 days, PGE2 values remained significantly below those before treatment in both the fundus (p less than 0.01) and antrum (p less than 0.01). The PGE2 degradation capacity was not influenced by indomethacin. In conclusion, mucosal adaptation to acute damage by indomethacin occurs in man and seems independent of local PGE2 metabolism.

The effects of indomethacin on gastroduodenal morphology and mucosal pH gradient in the healthy human stomach.

To define further the injury and the mechanisms of mucosal injury induced by indomethacin, the effect of 28-day continuous administration of oral indomethacin on gastroduodenal morphology, gastric histology, and the protective mucus-bicarbonate barrier overlying gastroduodenal mucosa in humans was studied. In the studies, indomethacin caused acute gastroduodenal damage in 100% of cases, with maximal damage at 24 hours of administration. With continued intake this damage resolves, although a minority (two study subjects) progressed to discrete ulceration. Why these two subjects failed to adapt is unknown. Biopsy specimens taken during the studies showed no significant changes in inflammatory or regenerative features, and thus failed to shed any light on this process of adaptation to damage. Mucosal pH gradient studies showed a significant increase in juxtamucosal pH at the time of maximal damage (24 hours); this is thought to represent passive diffusion of alkali from damaged mucosa. In conclusion, mucosal adaptation to acute damage by indomethacin occurs in humans. The mechanisms through which the mucosa adapts in this intriguing way remain unknown.

Effect of bismuth subcitrate and sucralfate on rat duodenal and human gastric bicarbonate secretion in vivo.

Acid and alkali secretion have been examined together with prostaglandin E2 production in response to two mucosal protective drugs, colloidal bismuth subcitrate and sucralfate. Doses of colloidal bismuth subcitrate in the therapeutic range (120 and 1200 mg) had no effect on alkali secretion or luminal PGE2 output when perfused into the stomach of human volunteers. Similarly, in the anaesthetised rat, neither gastric acid nor duodenal alkali secretions were influenced by iv (12 mg/kg) or topical (120 mg/ml) administration of colloidal bismuth subcitrate. In contrast, perfusion of the human stomach with 1 g sucralfate stimulated bicarbonate output by 50%, a response which was unaffected by indomethacin (25 mg/h). A rise of 64% in gastric PGE2 output after sucralfate was, however, prevented by indomethacin pretreatment. Alkali secretion by rat duodenum was also increased by sucralfate but the response depended on the basal secretory rate. Low basal secretors (less than 3 mumol) showed a 75% stimulation whereas rats with high basal secretory rates (greater than 3 mumol) showed no significant response. All duodenal preparations regardless of basal secretory rate showed a stimulation of bicarbonate output with topical PGE2. The results suggest that enhancement of gastroduodenal bicarbonate secretion may play a role in the protective action of sucralfate but is unlikely to explain mucosal protection by colloidal bismuth subcitrate.

Effect of enprostil on amphibian gastroduodenal and human gastric bicarbonate secretion.

The protective and ulcer healing properties of prostaglandins are well established. We have explored the possible mode of action of enprostil, a synthetic dehydroprostaglandin E2, on amphibian gastroduodenal mucosal bicarbonate secretion in vitro and on human gastric bicarbonate secretion in vivo. Addition of enprostil (10(-6) M) to the luminal solution of isolated amphibian gastric mucosa produced a 28% increase in bicarbonate secretion without a change in transmucosal potential difference. The same concentration of enprostil added to the luminal solution of isolated amphibian duodenal mucosa produced a 37% increase in bicarbonate secretion and was associated with a rise in transmucosal potential difference. The gastric output of bicarbonate from the human stomach has been calculated using a perfusion technique before, during, and after perfusion with enprostil (35 micrograms) in six healthy volunteers. A significant 78% increase in bicarbonate secretion occurred during the period of enprostil perfusion, falling to normal during the postenprostil period. These changes were caused mainly by an increase in gastric secretory volume with insignificant increases in bicarbonate concentration. These results suggest that stimulation of gastroduodenal bicarbonate secretion by enprostil may play a role in its protective actions.

Effect of bismuth subcitrate on amphibian gastroduodenal bicarbonate secretion.

The ulcer healing and cytoprotective properties of colloidal bismuth (De-Nol) are well established although its mode of action is unclear. We have examined the action of bismuth subcitrate, the active ingredient of De-Nol, on gastroduodenal bicarbonate secretion by isolated amphibian mucosa. Addition of bismuth subcitrate (10(-6) to 10(-4) M) to the luminal solution produced a dose dependent increase in bicarbonate secretion from both gastric and duodenal mucosae without a change in transmucosal potential difference. The magnitude of this stimulation was greater for gastric than duodenal mucosae at all dose ranges. A second bismuth salt, bismuth oxynitrate, produced similar increases in bicarbonate secretion from gastric mucosae. Pretreatment of gastric mucosa with the cyclooxygenase inhibitor, indomethacin (10(-5) and 10(-4) M), did not abolish the secretory response to bismuth subcitrate. Similar treatment with the chloride transport inhibitor, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) (10(-3) M) prevented the secretory response to bismuth subcitrate.

Effect of sucralfate on human gastric bicarbonate secretion and local prostaglandin E2 metabolism.

The protective and ulcer-healing properties of sucralfate on gastroduodenal mucosa are well established. In this study, the possible mode of action of sucralfate in humans has been explored by examining its effect on gastric bicarbonate secretion and luminal prostaglandin E2 (PGE2) output from the intact stomach. The gastric output of bicarbonate and PGE2 has been calculated using a perfusion technique before, during, and after perfusion with sucralfate (8 mg/ml) in eight healthy volunteers. A significant increase in bicarbonate output occurred during the period of sucralfate perfusion returning to basal values during the post-sucralfate period. Pretreatment with indomethacin (25 mg/hour) failed to influence this secretory response. Luminal PGE2 output was significantly increased in the post-sucralfate perfusion period only. These changes were caused mainly by an increase in gastric secretory volume with insignificant increases in concentrations of bicarbonate and PGE2. These results suggest that stimulation of gastric bicarbonate secretion and PGE2 output by sucralfate may play a role in its protective actions.

Mechanisms of gastric damage by non-steroidal anti-inflammatory drugs.

All non-steroidal anti-inflammatory drugs (NSAIDs) used in the treatment of rheumatic diseases may cause gastrointestinal mucosal injury. The mechanisms by which these agents damage mucosa are not fully understood, although, reduction of mucosal defence by the depletion of endogenous, protective prostaglandins has been deemed important. NSAIDs have been shown to decrease the magnitude of the mucus-bicarbonate barrier, disrupt the epithelial cell layer, reduce the surface hydrophobicity of epithelial cells and to diminish mucosal blood flow. Such effects render the mucosa more susceptible to damage by acid, pepsin, bile salts and alcohol. In addition, direct mucosal injury may be caused by the physiochemical properties of NSAIDs, being weak acids. There is now increasing evidence that gastroduodenal mucosa adapts to acute damage by these drugs with mucosal injury recovering during continued administration. The mechanisms governing such adaptation remain unknown and require further investigation.