Emotion-related Gastritis

The relationship of emotional stress to abnormalities of the gastric mucosa was considered in a review of 788 consecutive upper gastrointestinal endoscopies. Fifty-three precent of patients with gastritis not related to any generally accepted predisposing or precipitating cause had significant emotional problems documented on their clinical records, while only 10% of the comparable group of duodenal ulcer patients and 25% of a similar group of medical in-patients had significant emotional problems documented. Since this difference was statistically significant (P less than 0.01 and P less than 0.05, respectively), the data suggest that emotional stress may play a contributing role in the production of gastric mucosal abnormaltieis.     

ON THE METABOLISM OF TWO ADRENOCORTICOTROPHIN ANALOGUES

The metabolism of Synacthen® (corticotrophin-(1–24)-tetracosapeptide) and C-41795-Ba ([ d -Ser¹, Lys¹⁷, Lys¹⁸]-corticotrophin-(1–18)-octadecapeptide amide) have been compared in the rat following intravenous injection. Using Synacthen and C-41795-Ba labelled with tritium it was possible to follow the tissue distribution of the two peptides. The kidney was shown to concentrate intact peptide and fragments of both peptides. Autoradiography of perfused kidney sections demonstrated the uptake of radioactivity into the lysosomes of the kidney proximal tubule cells. Comparison of the distribution of radioactive products formed from the tetracosapeptide labelled in different positions indicates that, prior to renal uptake, metabolism is taking place at other sites in the body. It is suggested that rapid cleavage occurs extracellularly at or near the N- and C-termini. Then large fragments remaining in the circulation, together with any intact material, are filtered through the glomerulus and are taken up by endocytosis into the proximal tubule cells of the kidney. The synthetic N- and C-terminal protection of the octadecapeptide appears to inhibit the extracellular attack and so the concentration of intact peptide in the kidneys is initially higher than the tetracosapeptide. Although concentrations of radioactivity in other tissues are low in comparison with the kidneys, the quantities are quite high when the weight of the tissues are considered. Chromatographic analysis of this radioactivity reveals that the octadecapeptide gives rise to much higher tissue levels of intact peptide and we believe that this acts as a depot and gives rise to the sustained blood concentrations and prolonged biological effects observed with this peptide.     

VARIATIONS IN MANAGEMENT OF ADNEXAL TUMOURS

Three interesting cases in which unconventional treatment has been very successful are presented. The first was a fibrous histiocytoma of the conjunctiva which recurred twice after apparently complete surgical excision, but which responded to immunotherapy using dinitrochlorobenzene. The second was a squamous cell carcinoma of the lower eyelid treated by total surgical excision of the lid; the wound was allowed to heal by granulation with an excellent cosmetic result. The third was a squamous cell carcinoma of the limbus treated by lamellar excision with the Crock Contact-lens Corneal Cutter; the wound was allowed to granulate, and in so doing, caused negligible astigmatism.     

IMMUNOCYTOCHEMICAL EVIDENCE FOR A MODULATION OF GALECTIN 3 (Mac-2), A CARBOHYDRATE BINDING PROTEIN,IN PULMONARY FIBROSIS

Galectin 3 is an endogenous mammalian carbohydrate-binding protein with affinity for terminal β-galactose residues, polylactosamine glycans, and ABH-blood group carbohydrate epitopes. To determine the distribution and regulation of galectin 3 during pulmonary injury, which is known to be accompanied by profound changes in the carbohydrate moieties of cell surface glycoproteins of alveolar cells, a rat model of irradiation-induced lung inflammation and repair was used. Immunocytochemistry showed that in normal rat lungs, galectin 3 was localized to alveolar macrophages, with weaker staining of bronchial epithelial cells. Shortly after irradiation-induced lung injury, when there is active proliferation of type II alveolar epithelial cells and re-epithelialization of alveolar basement membranes by type I cells, the total galectin concentration in the lung increased dramatically. This increase was due in part to an increased population of galectin 3-positive interstitial and alveolar macrophages. In addition, galectin 3 was expressed prominently at the surface of the newly formed type I alveolar epithelium and to lesser extent at the apical surface of type II cells. These findings suggest that the increased synthesis and secretion of galectin 3 during irradiation-induced lung injury, together with ligation of secreted lectin at the surface of alveolar epithelial cells, may play roles in pulmonary alveolar epithelial expansion and differentiation during injury and repair.     

THE ROLE OF META-ANALYSIS IN MONITORING CLINICAL TRIALS

The randomized clinical trial is the gold standard methodology for evaluating treatment interventions. The randomized trial is a prospective experimental study, the embodiment of the scientific method applied to the clinic. Both organizational and ethical considerations encourage the use of formal criteria for termination. Such criteria, typically based on an overall 5 per cent significance test, are frequently portrayed as guidelines, but none the less usually succeed in focusing the debate on termination decisions and thus facilitate decision making. The use of the 5 per cent criterion is entirely arbitrary and is not based in any way on optimality considerations. No credible model for optimizing the decision to terminate trials has been developed. Meta-analysis is an evolving technique for evaluating the totality of the evidence on general treatment strategies. It has enjoyed considerable success in influencing medical opinion and treatment practice in selected areas. Its role is in establishing proof of concept of general treatment strategies, and is thus a consensus builder, making use of data from trials which may be heterogeneous in the details of treatment administration and patient selection, but similar in conceptual intent. The level of evidence required for consensus is not well understood and cannot be defined precisely. The retrospective nature of meta-analysis and the risks of biased data acquisition mandate a conservative approach to data analysis and interpretation. Randomized trials and meta-analyses have distinct but complementary goals. Meta-analysis can be used productively in planning new clinical trials, and in supplying updated information to study monitors in the course of a trial. However, it is not advisable to employ meta-analysis in formal statistical procedures for terminating clinical trials.     

Prescribing new drugs: a survey of hospital consultants in the West Midlands

Objective — To investigate the factors that influence how consultants introduce new drugs into their clinical practice. Method — A postal questionnaire survey of hospital consultants. Setting — 169 consultants in medical specialties in six hospitals (general or teaching hospitals) in the West Midlands region, United Kingdom. Key findings — Ninety‐two completed questionnaires (54 per cent) were returned. Eighty consultants (87 per cent) reported using a new drug in the previous two years; 60 (65 per cent) had used either one or two new drugs and these were generally in their specialist field. There was no significant difference between hospitals in how easy it was to introduce a new drug. Sixty‐one consultants (67 per cent) said that the procedure required an application to the hospital drug and therapeutics committee. Consultants frequently asked patients' general practitioners to prescribe a new drug. Consultants rated independent sources of information more highly than non‐independent sources. The most important factors reported to influence prescribing decisions about new drugs were drug characteristics, such as efficacy and safety, and evidence from scientific literature. Sixty‐four respondents (70 per cent) saw drug company representatives up to once a week and 57 (62 per cent) had been involved in clinical trials of new drugs in the previous five years. Conclusion — In general, the consultants reported that they used only a small number of new drugs. There is considerable pressure on hospital doctors to control prescribing and costs of new drugs through policies that require approval by the drug and therapeutics committee. Although contact with the pharmaceutical industry was high, consultants reported that independent sources of information were more important. Factors such as clinical trial evidence and improved drug characteristics were said to be the most influential in reaching decisions to prescribe new drugs.     

ALLERGIC VASCULITIS CLINICAL AND HISTOLOGICAL FEATURES AND INCIDENCE OF RENAL INVOLVEMENT

SUMMARY.— Twenty one patients with allergic vasculitis are reported. The skin lesions appear to be distinctive; their natural history and response to systemic corticosteroids are discussed.
The histology of the skin lesions, which was studied in 15 patients, shows characteristic features.
Seven patients were found to have renal involvement. After 1 years follow-up 4 had completely recovered; in the remaining 3 there was only minimal impairment of renal function, and one of these had had pre-existing hypertension.
Allergic vasculitis is a distinct clinical entity which can be distinguished from polyarteritis nodosa. This distinction is important when there is renal involvement as the prognosis of the two conditions is so different.     

Use of Transgenic Animals in Understanding Molecular Mechanisms of Toxicity*

Understanding molecular mechanisms of chemical toxicity and the potential risks of drugs to man is a pivotal part of the drug development process. With the dramatic increase in the number of new chemical entities arising from high throughput screening, there is an urgent need to develop systems for the rapid evaluation of potential drugs so that those agents which are most likely to be free of adverse effects can be identified at the earliest possible stage in drug development. The complex mechanisms of action of chemical toxins has made it extremely difficult to evaluate the precise toxic mechanism and also the relative role of specific genes in either potentiating or ameliorating the toxic effect. This problem can be addressed by the application of genetic strategies. Such strategies can exploit strain differences in susceptibility to specific toxic agents or, with the rapidly developing technologies, can exploit the use of transgenic animals where specific genes can be manipulated and subsequent effects on chemical toxicity evaluated. Transgenic animals can be exploited in a variety of ways to understand mechanisms of chemical toxicity. For example, a human gene encoding a drug metabolizing enzyme can be directly introduced and the effects on toxic response evaluated. Alternatively, specific genes can be deleted from the mouse genome and the consequences on toxicological response determined. Many toxic chemical agents modulate patterns of gene expression within target cells. This can be used to screen for responses to different types of toxic insult. In such experiments the promotor of a stress-regulated gene can be ligated to a suitable reporter gene, such as lacZ, or green fluorescent protein, and inserted into the genome of an appropriate test species. On administration of a chemical agent, cells which are sensitive to the toxic effects of that chemical will express the reporter, which can then be identified using an appropriate assay system. This latter strategy provides the potential for screening a large number of compounds rapidly for their potential toxic effects and also provides information on tissue and cellular specificity. Experiments using transgenic animals can be complex, and care must be taken to ensure that the results are not affected by background activities within the species being used. For example, the introduction of a specific human cytochrome P450 gene may have no effect on the metabolic disposition of a drug or toxin because of the background activity within the mouse. As the toxicity of a chemical agent is determined by a wide range of different factors including drug uptake, metabolism, detoxification and repair, differences between man and the species being used could potentially generate a toxic response in the animal model whereas no toxicity may be observed in man. In spite of these confounding factors, the application of transgenic animals to toxicological issues has enormous potential for speeding up the drug discovery process and will undoubtedly become part of this process in the future.