104 which should not go unchallenged. He claims that the results of treatment of early stomach cancer are not very encouraging and that it is unknown whether earlier detection can produce a worth-while increase in long-term survival. Figures are available from nine cooperating institutions in Japan1 which show that the five-year survival-rate from early gastric cancer (i.e., cancer limited to the mucosa or submucosa) is 95-5% in a group of 330 patients. Figures of 94% five-year survival in this group of patients are reported from the Aichi Cancer Research Institute, Nagoya, Japan. In several Japanese hospitals, early gastric cancer accounts for 30% of all gastric cancer cases seen, whereas in the United Kingdom it is less than 1 %. In Britain more than 95% of all patients with stomach cancer will die of this disease. We believe that this figure is Such unsupported statements as unacceptably high. Professor Hobbs has made (which are indeed contrary to the published reports from Japan) can do nothing but contribute further to the possibly unwarranted pessimism about stomach cancer. Llandough Hospital, Penarth, Glamorgan CF6 1XX.

D. M. D. EVANS J. L. CRAVEN.

BOWIE AND DICK TEST FOR AUTOCLAVES

SIR,-Dr Morris and Mr Everall (Dec. 7, p. 1382) draw attention to conflicting results, obtained from different rolls of 3M Autoclave tape no. 1222 in the routine performance of the Bowie and Dick autoclave tape test. Without first examining the test sheets in question, it is impossible to make specific comment; we have, however, never disputed that in marginal cases it may well be difficult to distinguish between a pass or a fail with this test. Neither have we contended that individual rolls of tape are without variation. These exist, as with all manufactured items, but we are satisfied that they are no greater now than when the Bowie and Dick tape test was first introduced. What is unquestionably true is that poor or inadequate storage conditions can have an adverse effect upon the performance of the tape. We have always called for effective stock control and stock rotation of our product, and for storage in a clean, dry environment. Indeed our outer packaging states precisely: 1. store in a cool dry place; 2. avoid prolonged exposure to strong sunlight. We are in complete agreement with the recommendations calling for the clear identification of individual rolls by means of a core stamp, and we are happy to confirm that such a system is in the course of implementation with the approval of the Department of Health and Social Secu-

rity. 3M United Kingdom 3M House,

Limited,

Wigmore Street, London W1A 1ET.

J. GASTON, Sales Manager, Medical Services, Health Care Products Division.

MODIFIED BOWIE-DICK TEST

SIR,-The National Health Institute of the New Zealand Department of Health has, for a number of years, recognised the limitations associated with the use of the BowieDick test. Our programme of the physical testing of sterilisers in hospitals using thermocouples has detected mechanical faults that have influenced the temperature in the load item during the so-called sterilisation cycle. In our experience, the routine use of the Bowie-Dick test has failed to indicate the true conditions of time at a temperature and can only give an indication of uniform treatment at an unspecified temperature. 1.

Kidokoro, T. Ganu Monograph Baltimore, 1971.

on

Cancer Research No. 11, p. 45.

Because temperature and the presence of moisture are the primary requirements, the Department of Health advised New Zealand hospitals in November, 1970, to use the Diack Steriliser Control (121 C) and the VAC Steriliser Control (132 C) in conjunction with other indicators such as the 3M Tape. When a fault develops in a steriliser, the most serious effect will be when the anticipated temperature within the load item is not realised. For this reason, we agree with Robert F. Smith (June 29, p. 1349). National Health Institute, Department of Health, Wellington, New Zealand.

J. R. REID A. P. DIXON.

NITROBLUE-TETRAZOLIUM TESTS

SIR,-We were interested in the article (Nov. 23, p. 1248) by Dr Segal on the nitroblue-tetrazolium (N.B.T.) test. We do not intend to comment on the sections concerned with the N.B.T. test as a physiological test of neutrophil function, but, having completed over 7000 N.B.T. tests in the investigation of bacterial infection, we feel qualified to challenge his dismissal of the use of the N.B.T. test as an aid to clinical diagnosis. We should like to comment on three aspects. Firstly, it should be apparent from Dr Segal’s article that there is no such thing as the N.B.T. test. The number of variations of technique which have been used is bewildering and unhelpful. Park’s original contention was that useful discrimination between (bacterially) infected patients and patients free of infection could be achieved by using the technique which he devised.1 Numerous papers have followed, many using a variation of the technique,2-4 and have either confirmed or denied this original assertion, often on small numbers of patients, and taking the normal range as the range described in the early papers.2 If any investigator modifies a technique, he surely owes it to the technique, his patients, and to the scientific method to compare formally the two techniques and to establish a normal range for the modified technique on a large series of controls. Several investigators have incorporated into their modified techniques factors which make comparisons with the original test extremely difficult. 2-4 To give a

simple example, which we can confirm, the concentration of heparin has recently been shown to have a profound effect on the result of the test.5 How many of those who condemned the N.B.T. test, controlled this factor carefully ? We have always adhered to Park’s technique exactly, 6 apart from a staining modification which has no effect on the test value. We propose to refer to our technique as Park’s (N.B.T.) test, since, although we dislike eponyms, we wish it to be quite clear that this is our technique. Secondly, we have found from training other people to perform the test that reading of the result is a very variable factor, even to the extent of a positive result being converted to a negative result and vice versa, when compared with the reading of an experienced observer. Reading became more and more accurate and comparable over a period of several weeks. Most of the errors were due to those factors which 7 we detailed in an earlier report. Thirdly, we have always been disappointed at the failure of some authors to appreciate that assessing the N.B.T. test requires a very high standard of bacteriological work, to ensure that the results against which the N.B.T. test results are being viewed are beyond criticism. To give two simple 1. 2. 3. 4. 5. 6. 7.

Park, B. H., Fikrig, S. M., Smithwick, E. M. Lancet, 1968, ii, 532. Steigbigel, R. T., Johnson, P. K., Remington, J. S. New Engl. J. Med. 1974, 290, 235. Segal, A. W., Trustey, Sheila F., Levi, A. J. Lancet, 1973, ii, 879. Drysdale, H. C. ibid. 1972, ii, 1198. Hohn, D. C., Lehrer, R. I. Infect. Immun. 1974, 10, 772. Freeman, R., King, B. Lancet, 1971, ii, 1154. Freeman, R., King, B. J. clin. Path. 1972, 25, 912.

105

examples from our own experience: it is completely wrong to imply infection by the mere presence of an organism in a particular site; and our own work on the organisms to be isolated from sputum and bronchial secretion have clearly shown that chest infection cannot be accurately diagnosed by this means in some patients.8 Thus, it would be wrong to compare the results of N.B.T. tests with sputum culture, or indeed, from our further experience, with sputum purulence. Our second example is derived from our early work with this test. We recorded 20% false-positive results in a series of tests done on open-heart surgical patients, and were about to conclude that the test was of no value, when it became apparent that all the patients concerned could be shown to have serological evidence of infection with Mycoplasma pneumonice.9 This novel infection, the nature of which is still under investigation, was thus first described as a common complication of open-heart surgery by virtue of the N.B.T. test.1o We are pleased to note that Gordon and his colleagues have also found positive results in patients infected with this organism, albeit under different

circumstances." Another common mistake which springs to mind is that of ignoring the possibility of bacterial infection being present elsewhere in the body when investigating the aetiology of a specific lesion. The ubiquitous nature of asymptomatic urinary-tract infection is such that it should always be checked when the test is done. We also insist that the test is assessed by bacteriological studies done on the day of testing, since some simple infections are self-limiting and disappear without treatment. How many of those who have criticised the N.B.T. test conform to these principles, and, in particular, how many include routine paired serology in their assessment ? How many also include the results of culture of catheter tips from infusions, despite the fact that these are commonly infected, and that the N.B.T. test readily shows this? 12 We would also disagree with some of Dr Segal’s stated causes of false positives and negatives. We accept that the N.B.T, test, properly performed, distinguishes patients with bacterial infection from those patients with no infection. In our view, therefore, this test, when positive, suggests a discrete list of possible infective agents as the cause of an illness and is not unhelpful but of unique value. As bacteriologists we accept leprosy as a bacterial disease, as is infection with mycoplasma. The positive results in malaria, toxoplasmosis, fungal infection, and parasitic diseases are not necessarily falsely so, if it can be shown that neutrophils play some part in the pathogenesis of these infections. In any event, they are useful results in clinical diagnosis. In inflammatory bowel disease we would agree that unexplained positive results occur, but an infective aetiology remains a strong possibility in some of these diseases.13 Cocchi 14 suggested another possible reason for this, but are we to call the detection of circulating endotoxin a cause of a false-positive result in a test designed to detect the presence of bacteria, or their products ? We, with others, have reported the false-positive results to be found in psoriasis,I5 and also suggested that a common process might link this with the results in polycythaemia and myelofibrosis. Of the other conditions listed by Dr Segal we have little experience, although we certainly do not obtain false-positive results after operation or myocardial 8. 9. 10.

Freeman, R., King, B. Anaesthesia, 1973, 28, 527. Freeman, R., King, B., Hambling, M. H. Thorax, 1973, 28, 617. Freeman, R., King, B., Hambling, M. H. J. thorac. cardiovasc. Surg. 1973, 66, 642. 11. Gordon, A. M., Rowan, R. M., Brown, T., Carson, H. G. J. clin. Path. 1973, 26, 52. 12. Freeman, R., King, B. Lancet, 1972, ii, 992. 13. Thayer, W., Brown, M., Sangtree, M. H., Katz, J., Hersh, T. Gastroenterology, 1969, 57, 311. 14. Cocchi, P. Lancet, 1974, ii, 1322. 15. Roberts, M. M., Freeman, R., King, B., Mostoufi, K., Cotterill, J. A. ibid. 1974, i, 940.

infarction. Finally, we must point out that typhoid vacinto the body of a bacterial antigen. cination is the to the false-negative results listed, we must Turning reiterate a point made forcibly by one of the annotations which were criticised.16 For the N.B.T. test to work it must be apparent that the phagocytic system be intact. Thus, in all the instances of immune-deficiency states given it may well be that this proviso does not apply. We do not regard this as the fault of the test. In some cases which we have dealt with, this unexpected negative result has led to the correct diagnosis. The same point applies to those patients receiving steroid 17 and similar drugs. The infective lesion to be detected should also be active and uncontrolled. If adequate antibiotic therapy is in progress it is to be expected that the test will revert to negative. In overwhelming systemic bacterial infection we have found negative tests occasionally. In all such cases, there was ample ancillary evidence of bone-marrow failure or immunosuppression, and a grave prognosis resulted. We have found no problem in performing the test, and obtaining excellent results, in nephrosis or sickle-cell disease, findings which others have confirmed.I8,19 In the only series of bacterial and viral meningitides studied by the Park (N.B.T.) test, of which we are aware, excellent correlation was demonstrated. 20 We should like to emphasise that we do not use the N.B.T. test to detect pyogenic infection, but infection in general, and with the above conditions, under which we operate, we have found it to be uniquely helpful. Finally, we offer a brief series of examples from our own series. We have paid particular attention to Dr Segal’s remarks and extracted some results from the past year’s work. The patients concerned are all candidates for openheart surgery. Before operation they are screened for occult infection, and thus represent a group of patients in whom bacterial infection, even if asymptomatic, has been excluded as far as possible. These preoperative patients form the control group. We have then followed the patients after operation, performing frequent N.B.T. tests by Park’s method. For the first three days each patient has daily blood-cultures, urine cultures, sputum cultures, and a chest X-ray. Hsematological variables are also assessed daily. Thereafter, all these investigations were performed whenever the N.B.T. test was done. Finally, antibodies to Mycoplasma pneumonice, and a panel of viral antigens, were measured comparing a preoperative serum sample with a convalescent sample. All catheter tips were cultured on removal of the catheters. The groups gave the following results:

entry

Controls.-Mean N.B.T. score 6-78%, range 3-11% (50 patients). Chest infection.-Mean N.B.T. score 25’9%, range 18-37% (11 patients). Chest disease.-(Infecticn excluded) this group includes 4 cases of pulmonary embolism; values 5%, 12%, 8%, and 4% (17 patients). Mean N.B.T. score 7-06%, range, 4-12%. Urinary-tract infection.-(a) Cystitis, subsequent intravenous pyelogram (i.v.r.) normal. Mean N.B.T. score 130°,.0, range 9-17°° (15 patients). (b) Pyelonephritis, subsequent i.v.p. abnormal. Mean N.B.T. score 272°,0, range 15-59% (10 patients). In this last group two patients had positive blood-cultures and had scores of 56% and 59%, respectively. Mycoplasma pneumonice infections.-Mean N.B.T. score 24’1 % range 13-41°° (10 patients).

Statistical

analysis

shows

a

clearly significant difference

0.001 in all cases), when the control group is compared with any of the infected groups. Comparing chest disease

(P


0’06). There is a significant difference between the results in non-infective chest disease and chest infection (P < 0-001), confirming other results in this context.21 A notable feature is that, although both the cystitis and the pyelonephritis patients differ significantly from the controls, they also differ significantly from each other (p < 0-01). Since the control group and the subsequent groups are undergoing the same process, and may be on occasion the same patients, we feel the results are valid. We have shown that the N.B.T. scores in patients from whom an infected intravenous or intra-arterial catheter is removed differ statistically significantly from controls and patients with sterile catheters, in other published work.22 We feel justified, therefore, Sir, in asking Dr Segal not to dismiss what we consider is an extremely useful test. That it is no longer a simple test to distinguish pyogenic infection we would support, but we hope we have indicated that technical standardisation, intelligent interpretation, and good clinical bacteriology will place the Park (N.B.T.) test in the forefront of diagnostic tests. We should add that none of the bacteriological examinations on any of the patients which we have just described was performed by us; nor were the results known to us at the time of N.B.T. no

testing. We hope to analyse a much greater number of our results in the

near

future.

Department of Microbiology, School of Medicine, University of Leeds, Leeds 2.

R. FREEMAN B. KING.

GEOGRAPHICAL DISTRIBUTION OF MULTIPLE SCLEROSIS recent letters support the view that multiple SIR,-Two sclerosis (M.S.) has specific patterns of geographical distribution. The evidence of Professor Agranoff and Professor Goldberg (Nov. 2, p. 1061) suggests a distributive correlation with areas of high consumption of dairy produce; that of Dr Dean (Dec. 14, p. 1445) a correlation with areas of high levels of hygiene. We can suggest a similar distributive correlation with lead-ore deposits. Previous reports of clusters of M.S. cases in areas with high lead content of the soil in Berkshire and Gloucestershire,23 and in the Mendips,24 led us to consider whether lead might have an xtiological significance. Superficial comparison of the areas of lead-ore deposit in the world 25,26 and areas with a high incidence of M.S. 27 again suggest the possibility of a correlation. This correlation, the reported mimicking of M.S. by cases of chronic plumbism,23 and the significant lowering of antibody synthesis in mice exposed to lead 28 might appear to strengthen the case for lead as a causal factor and suggest the activation of a latent or chronic virus infection by lead poisoning. However, in experiments with mice which had survived infection of the central nervous system with measles virus, we failed to produce reactivation of the virus after exposure of the animals to toxic levels of lead. 21. 22. 23.

24. 25.

Rowan, R. M., Gordon, A. M., Chaudhuri, A. K. R., Moran, F. Br. med. J. 1974, iii, 317. Freeman, R., King, B. J. clin. Path. (in the press). Campbell, A. M. G., Herdan, G., Tatlow, W. F. T., Whittle, E. G. Brain, 1950, 73, 52. Campbell, A. M. G. Unpublished. Bateman, A. M. Economical Mineral Deposits; p. 531. London, 1950.

Jones, W. R., Williams, D. Minerals and Mineral Deposits; p. 138. London, 1948. 27. McAlpine, D., Lumsden, C. E., Acheson, E. D. Multiple Sclerosis: a Reappraisal; p. 35. Edinburgh, 1965. 28. Koller, L. D., Kovavic, S. Nature, 1974, 249, 148. 26.

Immunofluorescence and protection studies had indicated that virus persisted in the tissues beyond the acute stage of the infection. These negative results do not discredit the idea of lead in the aetiology of M.S. On the other hand, the geographical correlation of lead and M.S., together with the other correlations, may indicate no more than a multifactorial aaiology. Considered separately, each geographical correlation may simply be a restatement that M.S. is predominantly a disease of those areas with high living standards and high population densities. Department of Bacteriology, The Medical School, University Walk, Bristol BS8 1TD.

L. W. GREENHAM D. B. PEACOCK.

ACID-BASE DIAGRAMS

SIR,-We agree with van Ypersele de Strihou and Frans1 that acid-base diagrams have two potential uses-one pragmatic, the other theoretical. Our paper2 dealt mainly with the latter, and how information of physiological interest might be obscured if we focused on the nearly straight-line relations between Paco, and calculated plasma-bicarbonate concentration. The pragmatic function of acid-base diagrams is served adequately by straight-line confidence bands relating Paco2 and calculated plasma-bicarbonate concentration. If pragmatic considerations are paramount, however, there may be easier ways to evaluate clinical acid-base data than by referring to diagrams. For example, in uncomplicated metabolic acidosis, the numerical value of the Paco, is usually within several mm. Hg of the number denoted by the two digits to the right of the decimal point in the pH value. That relation holds well down to an arterial blood pH of 7-10-7-15, below which Paco2 tends to level off between 10-15 mm. Hg.3,4 In uncomplicated chronic respiratory acidosis, blood-pH is usually near normal, except with extreme hypercapnia,5 so plasma-total-C02 content and Paco, are usually increased nearly proportionately. A raised Paco2 associated with a blood-pH < 7-32 means either that the respiratory acidosis is at least partly acute or that metabolic acidosis is also present. The distinction depends mainly on the clinical findings unless the plasma-total-CO2 content is subnormal, in which case a metabolic acidosis coexists. Of course, acid-base data should always be interpreted in the light of the clinical findings. And, as Schwartz and his colleaguess emphasised, that a set of data lie within a particular " single-factor confidence band need not mean the patient has that disturbance, because coexisting complex disturbances may yield similar "

findings. In mild-to-moderate chronic single-factor disturbances, compensatory mechanisms tend to restore blood-pH nearly to normal. Accordingly, subjects with such disorders will have nearly proportionate changes of arterial CO2 tension and plasma-bicarbonate concentration, so the relation between those two variables approximates to a straight line. This is reflected, for example, by the correlation coefficient of 0-80 found by van Ypersele de Strihou and Frans in their acidotic patients.1 Although that coefficient is higher than those we found using random values,2 our point was that the coefficient must be judged in relation to the background " r values of 0-63-0-68 derived from the "

Ypersele de Strihou, C., Frans, A. Lancet, 1974, ii, 1089. Fulop, M., Fulop, M. ibid. p. 637. Bone, J. M., Cowie, J., Lambie, A. T., Robson, J. S. Clin. Sci. molec. Med. 1974, 46, 113. 4. Fulop, M., Dreyer, N., Tannenbaum, H. ibid. p. 539. 5. Brackett, N. C., Jr., Wingo, C. F., Muren, O., Solano, J. T. New Engl. J. Med. 1969, 280, 124. 6. Arbus, G. S., Hebert, L. A., Levesque, P. R., Etsten, B. E., Schwartz, W. B. ibid. p. 117. 1. 2. 3.

van

Letter: Nitroblue-tetrazolium test.

104 which should not go unchallenged. He claims that the results of treatment of early stomach cancer are not very encouraging and that it is unknown...
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