Showing papers in "BMJ in 1959"

The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population.

Abstract: The cyclic GMP-AMP synthase (cGAS)–cGAMP–STING pathway plays a key role in innate immunity, with cGAS sensing both pathogenic and mislocalized DNA in the cytoplasm. Human cGAS (h-cGAS) constitutes an important drug target for control of antiinflammatory responses that can contribute to the onset of autoimmune diseases. Recent studies have established that the positively charged N-terminal segment of cGAS contributes to enhancement of cGAS enzymatic activity as a result of DNA-induced liquid-phase condensation. We have identified an additional cGASCD–DNA interface (labeled site-C; CD, catalytic domain) in the crystal structure of a human SRY.cGASCD–DNA complex, with mutations along this basic site-C cGAS interface disrupting liquid-phase condensation, as monitored by cGAMP formation, gel shift, spin-down, and turbidity assays, as well as time-lapse imaging of liquid droplet formation. We expand on an earlier ladder model of cGAS dimers bound to a pair of parallel-aligned DNAs to propose a multivalent interaction-mediated cluster model to account for DNA-mediated condensation involving both the N-terminal domain of cGAS and the site-C cGAS–DNA interface. We also report the crystal structure of the h-cGASCD–DNA complex containing a triple mutant that disrupts the site-C interface, with this complex serving as a future platform for guiding cGAS inhibitor development at the DNA-bound h-cGAS level. Finally, we solved the structure of RU.521 bound in two alternate alignments to apo h-cGASCD, thereby occupying more of the catalytic pocket and providing insights into further optimization of active-site–binding inhibitors.

Maximum Forced Expiratory Flow Rate as a Measure of Ventilatory Capacity with a Description of a New Portable Instrument for measuring it.

Abstract: FiG. 9.-An example of predominantly extravascular destruction. 0.4 ml. of Rh-positive red cells was labelled with 51Cr, then sensitized in vitro with Rh antibody and reinjected into the donor. The red cells were iemoved from the circulation with a half-time of approximately 20 minutes; the amount of radioactivity in the plasma never exceeded 3% of the total amount injected in the form of labelled red cells.

Effects of iproniazid in depressive syndromes.

Abstract: dystonia. It is perhaps too early to draw any conclusions from this, but the facts just quoted may suggest that extrapyramidal rigidity and disturbances of posture are due to abnormal impulses descending from above the brain-stem level. The pathological states I have been considering may be regarded as local disturbances in that they can exist in fragmentary form. There are, however, some more general disturbances of posture which are of interest. There is considerable evidence that the posture adopted by a patient in a major epileptic attack is the result of a discharge of impulses from nuclei in the brain stem probably closely related to those concerned in the maintenance of decerebrate rigidity. There is a type of epilepsy, known as akinetic epilepsy, which leads to what are called " drop-attacks." In these the patient suddenly falls to the ground without warning, there is no convulsion, loss of consciousness if it occurs is only momentary, and he is immediately able to get up again. Such attacks must presumably be due to a sudden inhibition of the antigravity postural mechanisms. In cataplexy, which is associated with narcolepsy, strong emotion causes a rather more gradual loss of power in all the muscles, so that the patient sinks to the ground and is completely immobilized for a short time. This again has been explained in terms of an inhibition of motor mechanisms generally. Finally, in patients with lesions of the frontal lobes and in some psychotic states, we find a condition of postural plasticity in which an attitude imposed by passive movement is maintained indefinitely, or the patient may remain spontaneously immobilized in the same attitude for a long time.

Effect of Mothers' Smoking Habits on Birth Weight of their Children

Abstract: It has been reported that when pregnant rats and rabbits are exposed to tobacco smoke their offspring weigh less than those of control animals (Essenberg, Schwind, and Patras, 1940; Schoeneck, 1941). A similar observation has been made in respect of pregnant women. Simpson (1957) collected data over a three-year period from American maternity hospitals and found that the incidence of premature births (those weighing 5½ 1b.— 2.5 kg.—or less) among women who smoked was double that among non-smokers and increased fairly regularly with the amount smoked. No explanation was offered for this observation, but it is clear from the data that age, parity, and social circumstances had little to do with it.

Maple syrup urine disease.

Abstract: The resemblance to phenylketonuria is so marked that a similar genetic mechanism suggests itself, especially as the four cases of Menkes et al. were in one family. This aspect is being pursued. After this paper was written we heard that Cusworth, Dancis, Menkes, Miller, and Westall had independently found keto-acids in the urine of their cases and identified them as the a-keto-acids corresponding to valine, leucine, and isoleucine (Westall, private communication). A possible explanation of the presence of ketoand hydroxy-acids in the urine in their cases, while the urinary concentrations of the parent amino-acids were not always raised, would be that the blood and tissue keto-acid concentration has to build up to a critical level before enough amino-acid is formed by transamination to exceed the renal threshold. The reverse situation holds in phenylketonuria, where the blood phenylalanine concentration has to build up to a critical level before phenylpyruvic acid appears in the urine. The alternative explanation, that the metabolic error is becoming more severe and more extensive with time, seems unlikely; it would suggest an acquired rather than an inborn error of metabolism. This condition could easily be mistaken for phenylketonuria. Clinically they are very similar, they give exactly similar reactions with 2: 4-dinitrophenylhydrazine reagent and identical urinary indole patterns. However, the ferric chloride reaction, while somewhat similar, is not identical in the two conditions. The smell of the urine is easily missed, and can be masked by preservatives; in this case the smell was not noticed until we deliberately examined the urine for it, having been led by the chemical reactions to consider \" maple syrup urine disease \" as a possible diagnosis. Acidification with dilute sulphuric acid in the cold enhances the smell considerably; it may be worth investigating, in this way, every case diagnosed as having phenylketonuria. Of course, amino-acid chromatography can differentiate the conditions conclusively. \"Maple syrup urine disease\" is not a satisfactory name for the condition. Although one could use for example \" leucic aciduria,\" there is no logical reason for picking one rather than another substance in the urine to provide a name for the disease. If it is confirmed that the metabolic defect stuggested above is the cause of the condition, \"carboxylase deficiency disease\" might best meet the need. Further work on the identification of the abnormal substances present in the body fluids and on determining the site and extent of the metabolic defect is continuing.

Nasal Staphylococci and Sepsis in Hospital Patients

Abstract: continuance of injections caused a decrease in haemoglobin values as well as in red-cell counts. Injection of serum from normal bled mice into normal mice caused reticulocytosis, and continued injections produced polycythaemia. Erythropoietin produces reticulocytosis when injected into normal mice, but not in nephritic mice. The erythropoietic principle produced in the kidney, however, brings about reticulocytosis when injected into nephritic mice, but not in normal mice. From these findings it has been possible to test serum from mice as well as from human beings with regard to two different erythropoietic principles. The titre of erythropoietin as well as that of the erythropoietic principle produced in the kidney generally increases in the anaemic patient, if the anaemia is not to be ascribed to lack of one of these principles. No rise in the titre of the erythropoietic principle produced in the kidney has been found in anaemic patients suffering from chronic nephritis. This indicates that the lack of the erythropoietic principles produced in the kidney may be the cause of the anaemia accompanying nephritis in man. No rise in the titre of the erythropoietic principle produced in the kidney has been found in anaemic patients suffering from chronic infection (ulcerative colitis, rheumatic arthritis). This finding has led to the conclusion that some, if not all, of the anaemias seen in chronic infections may be caused by the absence of the erythropoietic principle of the kidney. Totally nephrectomized bled mice are able to increase their erythropoietin titre. This observation shows that erythropoietin is produced outside the kidney. No rise in the erythropoietin titre was found in a patient suffering from chronic hepatitis. This indicates that the erythropoietin is produced in the liver.

Menstruation and acute psychiatric illnesses.

Abstract: This survey was done at the suggestion of Dr. Max Hamilton, of the Department of Psychiatry, University of Leeds. We thank him for guidance and encouragement throughout the inquiry. We warmly appreciate the interest in the study shown by the late Professor D. R. MacCalman and Professor G. R. Hargreaves. Our thanks are also due to Miss Mary Stewart and Mrs. M. Johnson for much secretarial assistance.

Present position of immunization against poliomyelitis with live virus vaccines.

Abstract: Immunization against poliomyelitis with orally administered live attenuated poliovirus vaccine presents special problems not previously encountered with other live virus vaccines employed in human beings, and it is entirely proper to approach it in the most cautious and critical manner. The recent communications (Dick and Dane, 1958; Dane et al., 1958; Clarke et al., 1958) and editorial comments (leading article, 1958) in the British Medical Journal did not take into account all the available published and unpublished data that were available to the writers, and, in my opinion, did not give a complete picture of the present status of our knowledge on this subject. Accordingly I am prompted to bring up to date the information available to me on four topics that came under special consideration in the recent discussions: (1) neurotropism of viruses excreted by the vaccinated individuals and after further multiplication in contacts; (2) persistence of antibody and its relation to resistance of the intestinal tract to reinfection ; (3) effect of multiple doses of Salk vaccine and of high levels of neutralizing antibody produced by killed virus vaccine on multiplication of poliovirus in the pharynx and intestines of children; and (4) the present status of field trials with the large lots of the three types of vaccine that I prepared two years ago.

Induction of sarcoma in the rat by iron-dextran complex.

Abstract: In the present patient extreme debility and prolonged antibiotic therapy were probably the most important factors in the development of systemic candidiasis. Latterly the progress of the disease may have been accelerated by cortisone therapy and by intravenous administration of 20% glucose saline. Indeed, Duhig and Mead (1951) and Schaberg and his colleagues regarded the prolonged use of intravenous glucose saline as an important factor in establishing the infection in theircases. Some form of injection appears to be common to all cases of systemic candidiasis irrespective of the use of antibiotics. Here, however, infection from the alimentary tract may have occurred at operation, since local peritoneal exudate infected with C. tropicalis was present between the stomach and liver at necropsy. Systemic candidiasis has been reported after duodenal perforation or abdominal operations on a number of occasions (Brown et al.; Schaberg et al.; Caplan, 1955; Matthias and Rees; Barrett et al.). This case illustrates the various clinical factors predisposing to the development of systemic candidiasis. The history suggests that Candida may proliferate in the blood of a patient without any clinical signs of systemic moniliasis appearing other than pyrexia. Unexplained pyrexia occurring in prolonged debilitating diseases, especially where antibiotics and intravenous alimentation have been used, is an indication for culturing the blood in media suitable for the growth of fungi. Summary

Results of Treatment in Malignant Hypertension

Abstract: Eight years have elapsed since the introduction of ganglion-blocking agents in the treatment of severe hypertension. Various reports have been published dealing with immediate and short-term results, and the time seems opportune for a detailed survey of the achievements over a longer period of years. The present report deals exclusively with malignant hypertension under this treatment, and the course of the treated cases is compared with a control series taken from Hammersmith Hospital over the period 1935-56 (Kincaid-Smith, McMichael, and Murphy, 1958). Although a \" doubleblind \" trial on alternate cases might have been more convincing, early amelioration of cardiac failure and blindness in treated patients ruled out this method on ethical grounds. The expectation of life in our control series did not differ significantly from that observed previously by Keith et al. (1939) and Schottstaedt and Sokolow (1953). Material

Treatment of diabetes mellitus. I. Insulin: physiological and therapeutic actions.

Abstract: It is about 35 years since Banting and Best discovered insulin, and, in spite of a vast amount of research, the exact mode of action of this hormone is still unknown. The structure of the insulin molecule has been brilliantly demonstrated by Sanger and his colleagues (Ryle et al., 1955), who showed that insulin is a protein with a molecular weight of 6,000 or multiples thereof. Each molecule consists of two polypeptide chains held together by -S-Slinkages derived from the amino-acid cystine. The A chain is made up of 21 amino-acid residues and the B chain of 30. It is convenient to consider first the actions of insulin and then the effects of such actions, as the former are

Follow-up Study of Arterial Pressure in the Population of a Welsh Mining Valley.

Abstract: planning and formulating the possibilities of research, and observing the material from which their hypothesis can be constructed, before any of the ambitious programmes of which they may be capable can even be begun. In this respect time and money are almost interchangeable terms. Even the preparation of this lecture, and the selection and review of the points by which I might hope to bring home the challenge and the possibilities throughout the whole field, has necessarily employed time for which many other activities have been competing. Unless one has research teams suitably recruited from able physicians and laboratory technicians, and amply supported by the necessary funds, the ideas which are needed to follow up possibilities will not be thrown up, the hypotheses will not be formulated, and the work will never be done. In this respect it is interesting to compare the way in which the design of our bodies makes allowance fo(r the service of our brains with the way in which research into the activities of the brain is provided for in modern society. The human brain is an organ weighing between forty and fifty ounces, roughly one-fortieth of the total body weight. Yet it receives no less than 25% of the total blood supply circulating through the body, and it receives it first: immediately after its oxygenation and refreshment in the lungs, and before its distribution elsewhere. If we compare this distribution with the distribution of money by the community for the care and study of mental illness as a fraction of the total sum spent upon the care of all illness, the comparison is striking. The average expenditure on medical care of patients in the mental hospitals of this country is in the region of five shillings per week per patient (Robinson, 1958). Comparable figures for the overall cost of medical care for patients in general hospitals (and the teaching hospitals are specifically excluded from this comparison owing to their disproportionately but necessarily high cost of operation), are twenty-five to sixty shillings a week. Therefore, while the organization of the human body allocates to the maintenance of the brain roughly twelve times the proportion by weight of all its most vital resources in comparison to those given to the rest of the body, the distribution of money in the community in which we live almost exactly reverses these proportions. Expenditure upon the care of bodily ailments, other than those affecting the brain, exceeds by twelve to twenty times that provided for medical care, treatment, and research into mental illness. And this is all the more incongruous, even from the purely economical aspect, when one realizes that at the present time 40%/. of all the beds in the National Health Service are occupied by patients suffering from mental illness. One of the objects of this address has been to outline some of the tools and methods of modern research in psychiatry, which in the last twenty-five years have increased immeasurably the possibilities for progress. If we add to these tools and methods the natural skills and interest of those already active in the field, and recognize that almost the only significant limiting factors upon our progress are those of time and money, then we reach the point at which the implications become inescapable. Money must be made available to those with the initiative, interest, resource, and responsibility to use it; and made available even in advance of specifically endorsed projects with a predictably favourable outcome. If enough able and imaginative people are to be,;sustained in their willingness to commit themselves to the uncertainties of research, somebody must be prepared to gamble something on them: otherwise the projects of which they are potentially capable may never be conceived, or may remain crippled in their execution by lack of funds-at least in this country. This, then, is the challenge which faces us. But if we retain the wit to see that the exploration of man's mind and its psychophysiological foundation in his brain is at least as significant an activity as the exploration of that extension of its environment which we call outer space, and so devote to clinical research in psychiatry even a fraction of the expenditure already laid down for cosmic rocketry, we need not fail.

Sjögren's syndrome and systemic lupus erythematosus.

Abstract: For some time there has been evidence that Sjogren's syndrome is a \" collagen disease\" (Cardell and Gurling, 1954; Ramage and Kinnear, 1956). As the capacity of connective tissue to react to injury is limited to a few basic patterns, probably few \" collagen diseases\" are worth considering as separate entities. Any evidence demonstrating that what are now thought to be two separate \" collagen diseases\" are really different forms of the same disease is therefore desirable. In this paper clinical and pathological evidence is produced showing that SjoSgren's syndrome may be a chronic and relatively benign form of systemic lupus erythematosus.

Periarthritis of the Shoulder

Abstract: Periarthritis, or capsulitis, of the shoulder is characterized by severe pain and progressive limitation of movement of unknown cause. In most cases the symptoms increasingly dominate the patient's activities and interfere with his sleep for many months. The pain and spasm gradually abate and the shoulder becomes stiff (frozen shoulder). Movement usually recovers slowly until full function is regained with either a normal range of movement or limitation so trivial as to cause no functional disability. This paper presents the results obtained by injecting hydrocortisone into the shoulder-joint while manipulation was being carried out under anaesthesia during the irritable and painful stage. These results are compared with those obtained by oral cortisone in one group, and in some respects with those following palliative physiotherapy, rest, and occasional late manipulation in another group. Consideration of the results of any form of treatment in periarthritis demands accurate diagnosis and a knowledge of the natural history of the disease. Precise diagnosis is necessary because shoulder pain may be due to a number of causes within and without the joint of varying severity and prognosis. A knowledge of the average time between onset and recovery is of outstanding importance if the effects of treatment are to be assessed in a disease which usually resolves spontaneously.

A controlled trial of imipramine in treatment of depressive states.

Abstract: REFERENCES Bartter, F. C. (1956). Metabolism, 5, 369. Black, D. A. K., and Milne, M. D. (1952). Clin. Sci., 11, 397. Brooks, R. V., McSwiney, R. R., Prunty, F. T. G., and Wood, F. J. Y. (1957). Amer. J. Med., 23, 391. Buchem, F. S. P. van, Doorenbos, M., and Elings, H. S. (1956). Lancet, 2, 335. Campbell, C. M., Nicolaides, N., and Steinbeck, A. W. (1956). Ibid., 2, 553. Chalmers, T. M., FitzGerald, M. G., James, A. H., and Scarborough, H. (1956). Ibid., 1, 127. Crane, M. G., Short, G., Peterson, J. E., and Weiss, S. (1958). Amer. J. Med., 24, 313. Vogel, P. J., and Richland, K. J. (1956). J. Lab. clin. Med., 48. 1. Conn, J. W. (1955a). Ibid., 45, 6. (1955b). Ibid., 45, 661. -and Louis, L. H. (1956). Ann. intern. Med., 44, 1. Dustan, H. P., Corcoran, A. C., and Page, I. H. (1956). J. cliii. Invest., 35, 1357. Eales, L., and Linder, G. C. (1956). Quart. J. Med., 25, 539. Evans, B. M., Hughes Jones, N. C., Milne, M. D., and Steiner S. (1954). Clin. Sci., 13, 305. Fine, D., Meiselas, L. E., Colsky, J., and Oxenhorn, S. (1957). New Engl. J. Med., 256, 147. FitzGerald, M. G., Fourman, P., James, A. H., and Scarborough, H. (1957). Scot. med. J., 2, 473. Fourman, P. (1954). Clin. Sci., 13, 93. Foye, L. V., jun., and Feichtmeir, T. V. (1955). Anier. J. Med., 19, 966. Hatch, F. T. (1954). Metabolism, 3, 160. Hellem, A. J. (1956). Acta med. scand., 155, 271. Hewlett, J. S., McCullagh, E. P., Farrell, G. L., Dustan. H. P.. Poutasse, E. F., and Proudfit, W. L. (1957). J. Amer. med. Ass., 164, 719. Kretchmer, N., Dickinson, A., and Karl, R. (1957). A.M.A. J. Dis. Child., 94, 452. Luetscher, J. A., jun. (1956). Advanc. inztern. Med., 8 155. Mader, I. J., and Iseri, L. T. (1955). Amer. J. Med 19 976 Mahler, R. F., and Stanbury, S. W. (1956). Quart. J. Med., 25, 21. Milne, M. D., Muehrcke, R. C., and Aird, I. (1957). Ibid., 26, 317. Pawan, G. L. S. (1955). Biochem. J., 60, xii. Renwick, R., Robson, J. S., and Stewart, C. P. (1955). J. clin. Invest., 34, 1037. Russell, G. F. M., Marshall, J., and Stanton, J. B. (1956). Scot. med. J., 1, 122. -Tucker, J. B., and Fraser, J. D. (1957). Ibid., 2, 403. Schwartz, W. B., and Relman, A. S. (1953). J. cliti. Invest., 32, 258. Skanse, B., Moller, F., Gydell, K., Johansson, S., and Wulff, M. B. (1957). Acta med. scand., 158, 181. Wyngaarden, J. B., Keitel, H. G., and Isselbacher, J. (1954). New Engl. J. Med., 250, 597.

Auto-immune disease. II. Pathology of the immune response.

Abstract: In the first lecture I gave an outline of a theoretical approach to immunology which I claimed had special virtues for the understanding of some immunopathological states. Its basic contentions were that mutation of specific immunological pattern was always taking place and that, unless there was an appropriate homoeostatic mechanism, clones of cells immunologically directed against body components would inevitably appear. Such cells undoubtedly do appear in pathological conditions, and on our current view represent the result of some breakdown of the homoeostatic mechanism. It is convenient to use the terms \"forbidden clone \" or \" forbidden pattern \" to refer to such clones and the immunological patterns they

Secretion of blood group antigens and peptic ulcer.

Abstract: Although there is no evidence at Cambridge that undergraduate suicides have increased in number in recent years, certain post-war developments may have had an adverse effect. One of these has been the increase in the number of students, which adds to the difficulties of supervision even though the tutorial body may have been strengthened to some extent; in the period 1948 to 1957 the numbers at Cambridge have increased by over 1,200. In a big university the detection of the earliest stages of mental ill-health must almost inevitably fall on those with whom undergraduates are in daily contact. When it is suspected that trouble is brewing the patient can be guided to where specialized help can be obtained. The increase in the number of undergraduates must mean that tutors find it more difficult to get to know each man personally so that they are in a position to detect small, but possibly significant, changes in personality or performance. Nor do present economic trends make this part of a tutor's work any easier. That cases of mental ill-health are sometimes not detected in the earliest stages is unfortunate, but under present conditions is not surprising. The crux of the problem has recently been admirably summed up by one of Her Majesty's coroners: \"The truth is that suicide is a most complex phenomenion and highly unpredictable; our knowledge of its roots is scanty indeed\" (Thurston, 1958). Student suicides are an end stage of the problem of mental health in universities about which undoubtedly far too little is known even by those most directly concerned. Figures of incidence of mental ill-health have been given for certain universities (Still, 1954 ; Malleson, 1954), but none are available for those universities with the highest incidence of suicide. Information and statistics are the bricks and mortar of prevention, and until mental di ease in university students is regarded in the same way as any other illness, as a misfortune and not something of a stigma, it is unlikely that much progress will be made in preventing its occurrence.

Diagnosis and Prognosis of Cauda Equina Syndrome Produced by Protrusion of Lumbar Disk

Abstract: This paper draws attention to the poor prognosis for complete recovery of function in some patients with cauda equina syndrome due to compression by prolapse or extrusion of lumbar disk. The study of a comprehensive group of these patients in a neurological centre brings out two important points (1) the relative ease of arriving at an early diagnosis ; and (2) that early operation is an essential prerequisite for improvement in prognosis.

Maple syrup urine disease; an inborn error of the metabolism of valine, leucine, and isoleucine associated with gross mental deficiency.

Abstract: The following case of maple syrup urine disease is the first one to be recorded in this country in this century. Only two definite cases have been reported in the United States. Case Report A girl aged 4 months with severe mental deficiency was admitted to the Hospital for Sick Children. She is the first child of healthy non-consanguineous parents, with no family history of mental deficiency. Her condition at birth appeared normal, and breast-feeding was started without difficulty. When 1 week old she stopped sucking and had to be tube-fed. She made slow progress from this time, remaining in hospital for the first three months of life because of feeding difficulty and failure to thrive. At 4 months she was noticed to be jerking her limbs and occasionally to become breathless and cyanosed. On examination she was a fair-haired, blue-eyed infant weighing 9 lb. 10 oz. (4,365 g.). She was anaemic (haemoglobin 9.47 g. per 100 ml.) and had a mild bilateral seborrhoeic blepharitis. The head configuration was within normal limits and the head circumference 16 in. (40 cm.). There was no control of head movements, although she occasionally attempted to follow a bright light with her eyes. The limbs were thin, with a slight increase of tone, and brisk tendon reflexes equal on both sides. The optic disks were pale. A firm liver edge was palpable one to two fingerbreadths below the costal margin. Lumbar puncture produced a normal cerebrospinal fluid under normal pressure. The E.E.G. showed an abnormal record with a severe generalized abnormality with multifocal discharges of a kind often seen in those metabolic disorders which are accompanied by seizures. The I.Q. on the Griffiths scale was 55. The urine was examined to exclude phenvlketonuria. The urine was free from protein, and gave a heavy precipitate with 2:4-dinitrophenylhydrazine. but an equivocal reaction with ferric chloride. On smelling a fresh specimen the similarity to maple syrup was detected. On twodimensional paper chromatography of the urine, valine, leucine, and isoleucine were found in very large amounts. These amino-acids were also present in the blood, C.S.F., and saliva in great excess. Keto-acids were present in the urine in very large amounts,

Reactions of cancer patients on being told their diagnosis.

Abstract: very short-acting anticholinesterase drug; when it is given intravenously, myasthenic weakness improves in 30-40 seconds and the increase in strength lasts about five minutes. However, when it is injected into a patient in a cholinergic crisis there is temporary aggravation of the muscle weakness. This test probably has some value in differentiating the two types of crisis, but it may be difficult to evaluate the result owing to the very short action of the drug.

Auto-immune Disease: I. Modern Immunological Concepts

Abstract: Medicine has been the mother of all the biological sciences. There are many reasons for this, but one of them is specially relevant to my present topic. It is simply that while the body functions smoothly things are taken for granted. It is only when things go wrong that it becomes possible to perceive that there is something in normal function which requires understanding. The central theme of these lectures is that the phenomena seen clinically in diseases of the so-called auto-immune group can be interpreted to throw light on the nature of immunological processes, and equally that recent developments in theoretical immunology are becoming highly relevant to clinical medicine. We were all taught to regard antibody production and other immune responses as manifestations of a process of defence against invading micro-organisms or any other type of foreign material entering the tissues. In some way the body was enabled to recognize what was foreign and to swing into action the immunological responses needed to speed its removal. The meaning of foreignness was something that seemed to worry nobody. Only with the recognition that there are disease conditions in which antibody is actually directed against body components-acquired haemolytic anaemia, for instance-did a real sense of the importance of the body's ability to differentiate between self and not self come into being. In Melbourne I am closely associated with our Clinical Research Unit, but only as an immunological consultant without clinical responsibility. My approach to the medical problems must necessarily be at the theoretical level, but at the present time I believe that it is better to try to present a working approach to generalization about the auto-immune diseases than to add to the volume of clinical descriptions and therapeutic trials. The approach will be based very largely on a concept of immunity which is still a heterodox one-although it has some distinguished proponentswhich has been called the clonal selection theory (Burnet, 1959). The stimulus to adopt such a theory came largely from a consideration of the pathology of immunity, and perhaps its chief virtue over earlier theories is its direct relevance to the problems of autoimmune disease. The Facts of Immunity Every human being has an immunological individuality that differentiates him from every other person-with only the minor qualification that identical

The insulin equivalence of salicylate.

Abstract: Interest in the action of salicylate in diabetes mellitus has been revived by the observation that aspirin is capable of controlling the hyperglycaemia and glycosuria and of abolishing moderately severe ketosis in diabetes mellitus (Reid, Macdougall, and Andrews, 1957). Disadvantages of the therapy are early development of nausea and vomiting in a few patients, and the more frequent but none the less annoying sideeffects of tinnitus and deafness. Nausea and vomiting

Chromosomes in a Case of Pure Gonadal Dysgenesis

Abstract: Brumfitt, W., Willoughby, M. L. N., and Bromley, L. I. (1957). Lancet, 2, 1306. Buchanan, J., Buchanan, W. W., Melrose, A. G., McGuinness, J. B., and Price. A. U. (1958). Ibid., 2, 719. Edwards, G., and Fear, E. C. (1958). Brit. med. J., 2, 1010. Elmes, P. C., Fletcher, C. M., and Dutton, A. A. C. (1957). Ibid., 2, 1272 English, A. R., McBride, T. J., van Halsema, G., and Carlozzi, M. (1956). Antihiot. and Chemother.. 6, 511. Fairbrother, R. W., and Southall, J. E. (1957). Lancet, 2, 974. Garrod, L. P. (1957). Brit. med. J., 2, 57. Gould, J C., and Bowie, J. H. (1952). Edinib. med. J., 59, 178. Helm, W. H., May, J. R., and Livingstone, J. L. (1956). Lancet, 1, 775. Hers, J. F. P., and Mulder, J. (1953). J. Path. Bact., 66, 103. Hewitt, D. (1956). Brit. J. prev. soc. Med., 10, 45. Hill, A. Bradford (1955). Principles of Medical Statistics, 6th.ed. Lancet Ltd., Lonidon. Jones, W. F., jun., and Finland, M. (1957a). New Engl. J. Med., 257. 481. (1957b). Ibid., 257, 536. Lancet, 1954, 1, 450.

Chronic Q Fever: 2. Morbid Anatomical and Bacteriological Findings in a Patient with Endocarditis

Abstract: Q fever is generally regarded as being different from other rickettsial infections in that the primary lesion is not in the endothelial cells of small vessels and in other parts of the cardiovascular system (Wolbach, 1948), but it is possible that vasculitis is a feature of the chronic rather than of the acute disease. It is of interest in this general context that a number of French workers (see Donzelot et al. (1950) and Giroud and Pfister (1957) for description of cases and references) have described cases with the symptoms and signs of subacute endocarditis following typhus or other rickettsial infections, but the exact part played by the rickettsiae in producing the cardiac damage is hard to assess. With our present patient we have no means of knowing for certain whether the aortic valvulitis was due entirely to R. burneti or whether there had been previous damage due to rheumatic fever which had allowed the valve to be colonized by R. burneti in the manner suggested by Marmion et al. (1953). In spite of the detection of a cardiac murmur in 1929, the patient led an extremely active life; nor do we know the timing of this murmur. No cardiac abnormality was noted at the time of his illness in Panama. When he first attended the Middlesex Hospital the diastolic murmur was only just audible, and it might well be argued that the lesion had originated at the beginning of the chronic illness. The importance of the case reported here lies in the proof that R. burneti can cause a chronic illness with endocarditis. Such cases are probably rare, although the clinical picture differs so much from the classical case of Q fever that the diagnosis might easily be missed. The.possibility of Q fever should be considered in patients with subacute endocarditis from whom no bacteria have been isolated. So far the prognosis for such established cases of chronic Q fever appears to be grave. Summary A case is described of a prolonged and fatal illness which at first resembled subacute bacterial endocarditis with some atypical features. On further investigation the illness was found to be due to a chronic infection with Rickettsia burneti, the causative agent of Q fever. The patient, a middle-aged man, had an acute pneumonia resembling Q fever; he recovered and was apparently well for six months. He then became ill with a swinging fever and signs of aortic valve incompetence which lasted until his death from cerebral haemorrhage and acute pulmonary oedema some 18 months later. Serological evidence of infection with R. burneti was found at the beginning of the chronic illness, and the rickettsia was isolated from the blood stream during life and from various organs, including the aortic valves, after death. The literature, concerning similar cases is briefly reviewed, and we have concluded that Q fever may pursue a chronic course and that on occasion the site of infection may be in the heart valves. [Note.-Since these two papers were submitted for publication Evans, Powell, and Burrell (Lancet, 1959, 1, 864) report the isolation of R. burneti from the aortic valve of a patient with endocarditis who died five months after an illness resembling Q fever.] We thank Dr. F. H. Scadding, under whose care the patient was admitted, for allowing us to publish this case, and for his advice and criticism. We are grateful to Dr. B. P. Marmion for his advice about the problem and for his help in the preparation of this paper. REFERENCES

P.T.C. Taste Response and Thyroid Disease

Abstract: The deaths from leukaemia in England and Wales for the period 1945 to 1957 have been classified under three headings-acute leukaemias of all types, chronic myeloid leukaeniia, and chronic lymphatic leukaemia. The age-specific mortality rates have been calculated for each type of leukaemia, for each sex, and for three periods of time-1945 to 1949, 1950 to 1954, and 1955 to 1 957. A study of these data suggests that the principal feature in the real increase in leukaemia is a change in the incidence of acute leukaemia. This is compatible with the concept that an increased exposure to ionizing radiations plays some part in the changed incidence of the disease.

Reliability of Some Adrenal Function Tests

Abstract: Ever since the hormone-producing role of the adrenal cortex became clearly recognized attempts have been made to obtain, by chemical means, measures of its varying activity under different conditions and in different diseases. The chemical tests developed have in the main attempted to estimate the quantity of adrenocortical metabolites appearing in the urine, though more recently it has become possible to measure directly the concentration of adrenal hormone in the plasma. It has not been possible to measure the total mass of adrenal metabolites in urine because the nature of more than half of these has been, and indeed still is, quite unknown. The only course, therefore, has been to estimate certain types of compounds which represent one group of the metabolites and to deduce the behaviour of the adrenal cortex from the results of such estimates. Two difficulties were encountered in this approach. First, the complex composition of urine rendered difficult the separation of the chosen group of adrenal metabolites from a wide variety of contaminating substances. Secondly, the extent to which the chemical estimates varied with the true activity of the adrenal cortex was completely unknown, though indirect deductions could sometimes be drawn. Because of these fundamental difficulties the only satisfactory or possible way in which the validity of a test could be assessed was by comparing the chemical results obtained with the results of careful clinical impression. To use such an arbiter of the validity of a test is fraught with danger, for the clinical diagnosis is often limited in accuracy and the essential purpose of the test is to improve this accuracy. The chemical assay gives a quantitative measure, and this the clinical assessment is rarely able to do. Because of lack of other criteria of validity it became usual to regard any test as justified if it gave low figures in Addison's disease and figures well above the normal range in conditions of hyperadrenalism such as Cushing's syndrome or after corticotrophin stimulation. By such relatively crude criteria were most of the earlier tests of adrenal actively justified. With the great progress which has taken place during the past 10 years in the chemistry and nature of these adrenal hormones and their metabolites, and in their methods of estimation, such crude criteria of validity are no longer sufficient, and a more critical appraisal may justifiably be expected. Much additional information about these tests can be obtained by deliberately altering the intensity of the adrenal cortical activity and noting the extent to which the various measures follow the changes induced. Thus stimulation of the gland is readily and rapidly achieved with corticotrophin, and inhibition of the gland is effected with equal facility by the administration of suitable synthetic steroids of the types introduced for modern adrenal steroid therapy.