Showing papers in "Journal of the Royal Society of Medicine in 1965"

The environment and disease: association or causation?

Abstract: In 1965, Austin Bradford Hill published the article "The Environment and Disease: Association or Causation?" in the Proceedings of the Royal Society of Medicine. In the article, Hill describes nine criteria to determine if an environmental factor, especially a condition or hazard in a work environment, causes an illness. The article arose from an inaugural presidential address Hill gave at the 1965 meeting of the Section of Occupational Medicine of the Royal Society of Medicine in London, England. The criteria he established in the article became known as the Bradford Hill criteria and the medical community refers to them when determining whether an environmental condition causes an illness. The criteria outlined in "The Environment and Disease: Association or Causation?" help identify the causes of many diseases, including cancers of the reproductive system.

The nature of herpes zoster: a long-term study and a new hypothesis.

Abstract: Dr Hope-Simpson presents a study of all cases of herpes zoster occurring in his general practice during a sixteen-year period. The rate was 3.4 per thousand per annum, rising with age, and the distribution of lesions reflected that of the varicella rash.It was found that severity increased with age, but that the condition did not occur in epidemics, and that there was no characteristic seasonal variation. A low prevalence of varicella was usually associated with a high incidence of zoster.Dr Hope-Simpson suggests that herpes zoster is a spontaneous manifestation of varicella infection. Following the primary infection (chickenpox), virus becomes latent in the sensory ganglia, where it can be reactivated from time to time (herpes zoster). Herpes zoster then represents an adaptation enabling varicella virus to survive for long periods, even without a continuous supply of persons susceptible to chickenpox.

Crohn's disease with cutaneous involvement.

Abstract: M Y, female, aged 70 In 1959 this patient began to have diarrheea, with discharge of mucus and blood. She was admitted to the London Hospital under the care of Professor J M Ledingham. In the first instance she was treated conservatively and this included steroid therapy. In 1961 a subtotal colectomy and ileostomy was performed. The rectum was not removed. Pathological examination ofthe specimen revealed the typical changes of Crohn's disease, maximal in the distal colon. In January 1963 she had an attack of intestinal obstruction. This subsided spontaneously, but active disease in the rectal stump began to cause symptoms. At this time there was considerable excoriation of the anal skin with two fistuli and large tags. The excision of the rectum was carried out on January 18, 1963. Her course was uneventful except that the perineal wound remained indolent and did not heal. For about six months she remained well apart from discharge from the unhealed perineal wound. Then the inflammation in the old wound began to extend forwards to both groins. She was admitted to St Mark's Hospital in October 1963. Her general condition was good. There was indolent ulceration in the natal cleft, extending in the fourchette and up i)to the inguinal regions on both sides. There were also non-ulcerative lesions on both lower legs. Biopsies from various areas were reported on as follows: 'There were collections of giant cells and epithelioid cells which strongly suggest sarcoid reaction. The appearances support tile clinical diagnosis of Crohn's disease.'

Book Review: The Structure and Metabolism of the Pancreatic Islets

Abstract: The Story of the Progress of Medicine by C F V Smout MD pp viii + 156 illustrated 30s Bristol: John Wright 1964 All profits on the sale of this book are to be given to the University of Birmingham for research in medicine. It is intended mainly for the layman, and is based on a series of 'popular' lectures. To tell the story of the progress of medicine within the compass of 150 pages is no easy task, and it is obvious that the author has encountered difficulties in the selection of his material. It is not surprising that his work tends to be a little unbalanced. Edward Jenner well deserves his four pages and four figures, but the same cannot be said of Harbledown Hospital or of Tom Hood's ballad on body-snatching. The valuable space might have been given to Sir Charles Bell, who is dismissed in two brief sentences, or to Sir J Y Simpson, who has only half a sentence. Although himself eminent as an anatomist, Professor Smout makes no mention of the Alexander Monros, three in number, nor of the notorious Dr Robert Knox. Nevertheless the story will serve its purpose as an introduction to the fascinating paths of medical history, not only for the layman but also for the medical student. The 48 figures are clearly reproduced, and the bibliography of 97 references provides a good guide to deeper study.

Displacement of one drug by another from carrier or receptor sites.

Abstract: The medium of drug transfer is the water of plasma and extracellular fluid. Without complicating factors, the level of drug at a receptor site would be equal to that in the tissues and in plasma, and in dynamic equilibrium. Actually, almost all drugs are reversibly bound to proteins in plasma or tissue. The bound drug, often a high proportion of the total, acts as a reservoir, preventing wild fluctuations between ineffective and toxic levels of the biologically active unbound fraction. Displacement from a receptor site diminishes drug activity, but displacement from plasma or tissue proteins augments the effect by making more unbound drug available at the receptor site. Atropine has no intrinsic activity, but displaces acetylcholine or pilocarpine from receptors at para-sympathetic nerve endings. Similarly guanethidine competes with noradrenaline at sympathetic nerve endings, but in turn is displaced by amphetamine-like drugs. Many acidic drugs (phenylbutazone, sulfonamides, coumarin anticoagulants, salicylates, &c.) are highly bound to one or two sites on albumin molecules. When the limited carrying capacity of the plasma proteins is filled, any unbound surplus is usually soon metabolized or excreted, so the plasma level becomes restabilized. Meanwhile, however, there may be dramatic effects such as hypoglycemia, when sulfonamides are given to patients on tolbutamide, or bleeding when phenylbutazone is given to patients on warfarin. Although hormones, like thyroxine, insulin and cortisol, are carried by specific proteins, they too can be displaced. All the antirheumatic drugs so far examined have displaced cortisol and presumably driven it into tissues. This may be one mechanism of action. Possibly the sulfonylurea drugs act by displacing insulin from proteins in the pancreas, plasma or elsewhere.

Psychotropic drugs (2). Interaction between monoamine oxidase (MAO) inhibitors and other substances.

Abstract: Monoamine oxidase inhibitors (MAOI) in clinical use have an irreversible action on MAO, and this persists until the enzyme has been resynthesized. The effects of small daily doses of MAOI are therefore cumulative. The biochemical effects of these drugs will involve several substrates of MAO, e.g. dopamine, tyramine, serotonin and, to a lesser extent, noradrenaline and adrenaline.MAO probably regulates the metabolism of catecholamines and serotonin in tissues, while catechol-O-methyltransferase is responsible for the metabolism of circulating noradrenaline and adrenaline.Certain pharmacological effects of MAOI are related to the accumulation of monoamines in various tissues that follows the decrease of intraneuronal deamination. Among these effects are reversal of the reserpine syndrome in animals and augmentation of the pharmacological action of monoamines. Other effects are unrelated to the inhibition of MAO, e.g. immediate desynchronization of EEG and initial pressor effects.MAOI may potentiate or change the action of several other drugs and even certain foods. The mechanisms involved are usually reasonably predictable from animal experiments. Substrates of MAO, e.g. dopamine and tyramine, evoke augmented and prolonged effects in patients treated with MAOI. This is partly due to an impaired metabolism of the circulating amines. In addition, inhibition of intestinal and hepatic MAO largely increases the absorption of tryamine from cheeses and other foods. Usually innocuous amounts of tyramine may therefore cause hypertensive reactions in patients treated with MAOI. Indirectly acting sympathomimetic amines, such as amphetamines, ephedrine and MAOI with amphetamine-like properties, can be potentiated, because they may release increased amounts of nor-adrenaline from sympathetic nerve endings after MAO inhibition. The effects of any amine, whether a substrate of MAO or not, may be enhanced by MAO inhibitors producing postganglionic block. This is due to ;denervation' supersensitivity of adrenergic receptors.Harmful pharmacological interaction is also possible between MAO inhibitors and agents which release (reserpine) or replete (amine precursors, e.g. L-DOPA in broad beans) monoamines centrally and peripherally. Drugs that sensitize adrenergic and tryptaminergic receptors to the action of monoamines, e.g. imipramine-like compounds, may be greatly potentiated by MAO inhibitors. The anti-hypertensive effects of thiazides and ganglion-blocking agents may be enhanced by MAOI. A few drugs are known to exert prolonged effects in occasional patients treated with MAOI, e.g. pethidine, phenothiazines and pentobarbital. MAOI may possibly decelerate the metabolism of these compounds by a nonspecific inhibition of liver microsomal enzymes. Finally, a great number of agents have been found empirically to evoke augmented effects after inhibition of MAO, e.g. insulin and anti-Parkinson drugs.

Drug interaction in the field of analgesic drugs.

Abstract: The evidence for believing that mixtures of aspirin, phenacetin, and caffeine provide advantages over the individual components of these mixtures is reviewed, and doubt expressed as to the rationale for the use of these mixtures in ordinary medical practice. The syndrome of ;analgesic nephropathy' is also reviewed, and on the basis of experiments in healthy volunteers it is suggested that individual ingredients of analgesic mixtures be scrutinized more carefully in an attempt to track down the agents responsible for toxic effects.The use of phenothiazine compounds, alone or in mixture with narcotics, is reviewed, and the opinion expressed that methotrimeprazine has special analgesic attributes.The narcotic antagonists represent an extremely interesting group of drugs which possess analgesic activity as well as the ability to antagonize certain effects of morphine and other narcotic agents. The patterns of respiratory effect, psychotomimesis, and abstinence phenomena seen with these antagonists illustrate the possibility of dissociating certain effects usually assumed to be linked inseparably in drugs possessing the analgesic power of morphine.

The post-mortem incidence of abdominal aortic aneurysm.

Abstract: The incidence of death due to rupture of an abdominal aneurysm, as determined by postmortem examination rather than by death certification, is not known accurately; still less is known of the incidence of unruptured aneurysm or of the natural history of the disease. The Chelmsford Hospital Group serves a fairly compact population of about 200,000; a large sample of all deaths in the area is investigated by post-mortem examination which is carried out in 85% of hospital deaths, in most sudden unexpected deaths and, in recent years, in many deaths of patients attended by general practitioners: Table 1 shows the number of deaths and post-mortem examinations during the last two years. It was thought that a review of abdominal aneurysms occurring in this material might answer some questions about the disease and indicate profitable lines for future investigation.

Opportunistic infections. human cytomegalovirus infection.

Abstract: the body's defences against invasion by potential pathogens or as a side-effect of drugs and other therapeutic measures. Their particular frequency as iatrogenous diseases has made them a danger common enough and grave enough to necessitate constant watch for their development when any patient is under treatment with corticosteroids, cytotoxic agents and broad-spectrum antibiotics, or with radiotherapy. 'Opportunistic infections' are often the immediate cause of death in cases of chronic debilitating disease, particularly cancer. In assessing their importance in cases of this sort it has to be remembered that they have to some extent taken the place of terminal bronchopneumonia as the closing stage in the course of the illness. Many patients with cancer nowadays live much longer than would have been the case before the introduction of modern advances in the treatment of neoplastic diseases; moreover, simple pneumonia in these patients is often not the danger that it was once, for it may be cut short and cured by giving antibiotics. Many of the micro-organisms that cause 'opportunistic infections' are resistant to drugs, or respond only to treatment with drugs, such as the antifungal antibiotic, amphotericin B, of which the side-effects are liable to be particularly dangerous in these chronically debilitated patients. It is sometimes the case, then, that there is nothing to be done to overcome an 'opportunistic infection'. As has been mentioned, this cannot be an excuse for failure to establish early diagnosis of the presence of such infections their prevention, or their successful treatment, may provide the chance of bringing the patient's underlying disease under control and, at least in some cases, of restoring his health. The four cases summarized in this paper include instances of infection by bacterial, fungal, viral and protozoal 'opportunists'. In one of the cases all four of these groups of organisms were represented, and no fewer than seven different types of organism were recognized at necropsy.

Bowel content shift during normal defaecation.

Abstract: Prognosis: The overall mortality rate, estimated as recently as 1961 (Lillington & Bernatz 1961), when the condition is untreated, is about 25% at twelve hours and 70% at twenty-four hours. Up to 1946 (Eliason & Welty 1946) the mortality rate was almost 100%. Thoracotomy with direct suture of the tear has a mortality rate of 10-33% according to different observers, with a low morbidity rate of 13-22 days, whereas in surgical drainage without suture of the tear the mortality rate varies from 46% to 66% with a morbidity lasting from six weeks to one and a half years.

Enzyme stimulation and inhibition in the metabolism of drugs.

Abstract: Studies in recent years have disclosed two types of drug interaction which may be important in drug therapy:(1) Administration of one drug can speed up the metabolism of another drug Animal experiments show that this results from the ability of drugs to induce the synthesis of drug-metabolizing enzymes in liver microsomes This effect has considerable importance in pharmacologic and toxicologic studies carried out in animals, and recent work indicates that it may explain altered therapeutic responses observed in some patients when they receive several drugs at the same time Substances present in the environment, such as the insecticides chlordane and DDT, have been shown in animals to stimulate drug-metabolizing enzymes in liver, but the significance of this observation for man is not known Drugs which stimulate drug metabolism also enhance the hydroxylation of testosterone, estradiol, progesterone and cortisol by enzymes in liver microsomes Further research is required to establish the physiological importance of this interaction of drugs in steroid metabolism(2) One drug may inhibit the metabolism of another drug and thus intensify and prolong its pharmacologic action Although this effect is well documented in animals, recent reports suggest that this may also be important in man For instance, the action of coumarin anticoagulants can be potentiated by administration of certain drugs which inhibit their metabolism Monoamine oxidase inhibitors block the metabolism of certain sympathomimetic amines and this can lead to serious side-effects Thus, hypertensive crises have been observed in patients receiving monoamine oxidase inhibitors who have eaten cheese with a high tyramine content

Transport and Diffusion in Red Blood Cells

Abstract: Directions for treatment and management are for the most part clear and sound; but remarks on page 325 may lead the student to believe that there is still a place for the use, in syphilis, of" Neosalvarsan", "Mapharside" and even bismuth, iodides and inunctions of mercury. And though pressure cones are discussed at some length, and it is said that, in the presence of such a cone, a lumbar puncture may cause sudden failure of the vital functions, it should have been made clear that lumbar puncture in any patient with a cerebral tumour is fraught with danger. Instead, on page 443, we find the procedure casually listed among laboratory aids to the diagnosis of tumour, and the statement made that spinal tap may disclose a rise of intracranial pressure. But, within the limits that had to be imposed, Dr. Elliott has written a good book, the worth of which is greatly enhanced by an excellent list of references at the end of each chapter. The printing and binding are of the highest quality.

Cysts of the jaw: a long-term survey of types and treatment.

Abstract: Cysts of the jaws occur frequently, but familiarity should not breed contempt, for there are many pitfalls in diagnosis and treatment. The complicated development of the facial region leads to special problems and the classification of a cyst can be very difficult. There is lack of appreciation of the frequency of multiple cysts, while the problem of recurrence is not discussed in textbooks. To clarify these points an analysis was made of 320 patients, covering a period of fifteen years, consisting of all patients treated by me in private and at St George's Hospital together with all cases treated by me and by my colleagues at Mount Vernon Hospital. I am indebted to Mr A ThextonandMr I Lawswho assisted in the analysis. Table 1 shows the incidence of each type of cyst in the series.

Influence of acid-base balance on efficacy and toxicity of drugs.

Abstract: Changes in acid-base balance have a profound influence on many aspects of the action of drugs. This is illustrated by data on the absorption of drugs from the stomach and intestine, in changes in distribution of drugs between plasma and cells, and the effect of change in urinary pH.As a general principle, these changes in the pharmacology of weak acids and bases are governed by physicochemical principles, which influence the proportion of the ionized and unionized components according to the pH of the medium and also to the peculiar property of biological membranes which allow the free passage of the lipoid-soluble unionized component and impede transfer of the water-soluble ionized fraction.Lipoid-soluble weak acids are excreted at higher clearances in alkaline urine, and conversely weak bases in acid urine. This is shown to be of practical importance in the treatment of poisoning, in the diagnosis of addiction to drugs and in studies of drug metabolism. In general, the excretion of natural metabolites is less likely to be influenced by urinary pH, as these substances are usually less lipoid-soluble than many widely used drugs. pH-dependent excretion is, however, of practical importance in relation to the urinary content of many indolic metabolites and also in the excretion of pigments derived from the degradation of haemoglobin. Urobilinogen excretion is certainly pH-dependent, a higher clearance rate occurring in alkaline urine. However, work is necessary to decide whether some of the porphyrins also show this important physiological property.