102

regression (2 had progression of disease by 6 months). No complete remissions were seen. The median survival for the whole group is 5 - 2 months (range 1-27). Toxicity was an important problem. Leukopenia was seen in 11 patients and thrombocytopenia in 19. 5 patients had haematemesis of whom 3 died. 1 patient died of pancytopenia and no evidence of tumour was found at post mortem. 3 patients refused to continue treatment because of nausea and vomiting. The discrepancies between our findings (and the results of Frei et al.) and those of previous studies might be explained on the basis of patient selection and different drug doses and scheduling. Toxicity in all the series is similar, suggesting that an adequate dose of nitrosoureas was given. Our survival data reflect the inefficacy of the regimen we chose, and we agree with Frei et al. that further search for more effective agents in gastrointestinal tumours is imperative. To this end we are exploiting human colorectal carcinoma zenografts growing in immunodeprived mice as a model for the experimental chemotherapy of this common and intractable clinical problem.4 A. BARRETT Institute of Cancer Research and C. GAZET J. Royal Marsden Hospital, J. W. BRADBEER Sutton, Surrey; and Mayday Hospital, Croydon M. J. PECKHAM

DELIVERY PACK FOR TRADITIONAL BIRTH ATTENDANTS

SIR,-Most births in rural India are attended by traditional birth attendants (dais) who help with childbirth on a part-time basis. In some parts of India more than 90% of deliveries are conducted by these untrained dais, despite the fact that auxiliary nurse midwives are being posted at a rate of 1 for every 10 000 population. The practice area of the rural health training centre at Naila (attached to the department of preventive and social medicine, S.M.S. Medical College, Jaipur) covers a population of about 35 000 in fifty-four villages. Dais play a pivotal role

Delivery pack. The thread is inside the gauze piece.

in rendering midwifery services, and the community accepts them on sociocultural grounds. It was felt that, as an interim measure, better use might be made of the dais by improving their standard of practice and thus augmenting the motherand-child health services. To do this we introduced a delivery pack, a very simple means of ensuring aseptic delivery that can be prepared in a primary health centre. The packet (see figure) contains a piece of string, half a razorblade, a piece of cotton and gauze, and aqueous 1% iodine solution. The razorblade, 4.

Nowak, K., Peckham, M. J., Steel, G. G. Br. J. Cancer (in the press).

wrapped in the gauze, and the string and cotton are sterilised by autoclaving. Aqueous 1% iodine is put in an empty autoclaved vial and sealed with wax. These items are put in a small polyethylene bag sealed over candle flame. The dais are instructed to wash their hands with soap, deliver the baby onto a clean sheet or towel, wash their hands again and open the pack. When the placenta has come out they tie the cord at two places with the string provided, clean the cord and, cut it, painting the cut ends with iodine and covering them with the gauze. 38 dais were identified as working in the area served by the rural health training centre. These dais were contacted and the use of the pack was demonstrated. The dais were urged to use the pack, and expectant mothers were also contacted and told about the pack. Once 1 of the dais started using the delivery pack and found it very useful, it was easy to convince the others. 22 of the 38dais are now using the pack. Department of Preventive and Social Medicine, S.M.S. Medical College, Jaipur, Rajasthan, India

S. K. CHATURVEDI

CHOLERA RESEARCH IN BANGLADESH

SiR,—The core of Dr McCord’s criticisms (June 3, p. 1208) of Cholera Research Hospital (C.R.L.) ethics is that C.R.L. "experimenters" did not realise that the task (of obtaining informed consent for research procedures from Bangalee patients) was "impossible" because patients were illiterate and couldn’t appreciate what might be done. This opinion rests on the assumption that Bangalees who can’t read can’t understand what is said to them. During seven years at C.R.L., however, I found that, when spoken to in Bengali, they (or their parents) readily understood simple explanations of procedures (like swallowing tubes or using new treatment methods), including risks and benefits (if any). Some refused, others consented, as indicated, at least for C.R.L.’s clinical study patients in 1971-75, by the physicians’ signed statement included in the chart. The only logical conclusion from McCord’s view that communication with Bangalees was "impossible" is that research (both at Dacca and Calcutta) should have been halted. If so, the benefits of that research, including oral therapy for cholera and for other diarrhoeas, would not exist. To let cholera take its toll from decade to decade for want of cheap, available therapy, because of a language barrier, seems itself unethical. . Dr Islam and others (June 3, p. 1209) imply that C.R.L. studies were not essential to the development of oral therapy. The Calcutta study’ did not demonstrate a practical oral therapy, since patients received intravenous therapy during most of their illness, and glucose-electrolytes solutions were given only for brief periods (12 h) by orogastric tube with perfusion pumps. This study, and a similar C.R.L. one, were confirmations of Phillips’ 1964 balance studies, which first showed absorption of glucose-electrolytes solutions for brief periods during cholera.2,3 All these studies lacked a practical method and a solution formula suitable for field treatment of cholera patients, and none compared total intravenous fluid requirements in patients treated with or without intravenous fluids. It seems a simple logical step from Phillips’ work (or from the confirmatory studies) to a practical regimen, and the development of the first practical oral therapy.,4 has been sometimes regarded as the culmination of a series of logical research studies moving smoothly forward, but nothing could be further 1.

Pierce, N. F., Banwell, J. G., Mitra, R. C., Caranasos, G. J., Keimowitz, R. I., Mondal, A., Manji, P. M. Gastroenterology, 1968, 55, 333.

2. 3.

Phillips, R. A. Fedn Proc. 1964, 23, 705. Phillips, R. A., Wallace, C. K., Blackwell, Q. in Cholera Research Symposium, Honolulu, Jan. 24-29, 1964. Public Health Service Publication no. 1328. Washington D.C., 1965. 4. Nalin, D. R., Cash, R. A., Islam, R., Molls, M., Phillips, R. A. Lancet, 1968, ii, 370.

103 from the truth. The first attempts

(in the Phillipines) to develop a practical regimen rapidly followed Phillips’ balance studies, but failed because of inappropriate methods and solution concentrations. The problems to be solved included development of a formula and a simplified practical balance method avoiding too much or too little water and electrolyte absorption, and determining what to do about shocked patients, defining the role of oral rehydration v. oral maintenance, adapting the method to children as well as adults, deciding how much to give &c. For several years after the Philippine failures

no

practical regimen appeared,

and there the

matter

rested, until Dr David Sachar, Dr James Taylor, and Dr Ruth Hare and their co-workers initiated C.R.L.’s physiological studies of gut electric potentials and unidirectional intestinal sodium fluxes during cholera (using intestinal tubes and isotopes).5,6 When glucose was present in the intestinal perfusates they used, net salt and water absorption occurred, as Phillips (then director of C.R.L.) had reported earlier. This, together with an enormous cholera epidemic which strained the C.R.L.’s intravenous fluid production capacity, rekindled the issue and inspired Hirschhorn and co-workers7 to reconfirm and further develop Phillips’ work. Visits to C.R.L. by the Calcutta workers soon led to the similar confirmatory study in Calcutta’ noted by Islam et al. At Dacca, the reconfirmation of Phillips’ work led initially (1967) to another abortive attempt (50% failures) in Chittagong to develop a practical oral therapy maintenance method. Not until a redesigned study was completed (February-April, 1968) was the first effective and practical oral therapy method developed, as formally presented at the 1968 Tropical Medicine and Malariology Congress in Teheran and published that

August.4 As noted in my report to the then director, C.R.L., the late Phillips, in early May of 1968, having sent the report of C.R.L.’s practical oral therapy method to The Lancet,4 I visited Calcutta to discuss the method and results with the Calcutta investigators, and they expressed the opinion that the method involved impractical "heroic" quantities of oral fluids. Up to my visit, instead of progressing from their confirmatory study to develop a practical method using glucose, they had decided to test instead a maltose-electrolytes solution, believing that this would be practical. Like the Phillipine and Chittagong trials, the maltose trial turned out not to be useful. Between my visit and that of my colleague Dr Cash several months later, the Calcutta group shifted its efforts towards a valuable study (published in 1969)8 confirming our earlier work on the use of oral maintenance therapy, which included appropriate references to our work. Since confirmation is an essential part of scientific medical progress, their study was an important contribution. C.R.L. continued its leading role in this field,9 with the first papers on field use of oral therapy in rural areas,10 oral therapy in children," in patients with non-cholera diarrhoeas,’2 in patients treated with oral therapy alone (no intravenous fluids for rehydration),13 with glycine added, 14 and with adequate Dr

potassium. 15

The Calcutta studies, like the Dacca studies, were done with the assistance of foreign investigators, and the practical advances they generated are for many an ample benefit in return for the risks involved. It behooves us to turn our attention from the already extensive discussion of C.R.L.’s ethics to the vastly more important subject of the ethics of continued non-application of these methods in many endemic cholera and diarrhoea zones of developing countries, and to get on with the job of correcting current deficiencies in delivery of these advances to the populations at risk. Center for Vaccine Development, University of Maryland School

of Medicine, 29 South Greene Street,

Baltimore, Maryland 21201, U.S.A.

DAVID R. NALIN

HOW DOES THE KLOCKHOFF-LINDBLOM TEST WORK?

SiR,—The oral glycerol test devised by Klockhoff and Lindblom’ is often used to help in identifying patients with Meniere’s disease who might benefit from surgical decompression of the endolymphatic system. Glycerol 1.25-1.5 g/kg body-weight diluted with an equal volume of water is given by mouth. Audiograms are recorded before and 2-3 h after glycerol intake; and in patients whose hearing does improve, a temporary improvement of 15-20 dB at several frequencies occurs, often with a corresponding improvemment in speech discrimination. The mechanism is assumed to be by the osmotic action of the glycerol which causes a rise of some 18 mosmol/kg water in the plasma. We have observed this response clinically but we are not convinced that the mechanism of action is osmotic, or only osmotic. We have occasionally observed this improvement in threshold in patients with, not Meniere’s disease, but presenile deafness in whom there was no clinical indication of any hydrops of the endolymphatic space. Furthermore in patients with Meniere’s disease we have recorded a similar temporary improvement in hearing threshold in response to a fructose intake, instead of glycerol. The maximum concentration in the plasma of fructose after an oral intake of 1 g/kg body-weight seldom exceeds 1 mmol/1, and this increase is transient compared with the sustained concentration of glycerol in the

plasma. Blood-glucose in diabetes mellitus can rise above 25 mmol/1 (450 mg/dl)-i.e., an additional 15-20 mosmol/kg plasma water over

the renal-threshold value-but diabetes mellitus is said

to

predispose to fluctuant hearing loss (not to its alleviation) through its connection with hyperlipidamiia. In a non-diabetic patient who responded to glycerol and fructose with a temporarily improved hearing threshold, an equivalent dose of gluhad no effect. We concluded that this patient had a metabolic block in an actively respiring tissue in the cochlea, preventing glucose from entering the cell or due to failure of cose

hexosephosphate-isomerase activity. In searching for a metabolic explanation we have found, in agreement with previous investigators, that plasma lactate and Taylor, J. O., Saha, J. R., Phillips, R. A. Gastroenterology, 1969, 56, 512. 6. Taylor, J. O., Kinzie, J., Hare, R., Hare, K. Fed. Proc. 1968, 27, 386. 7. Hirschhorn, N., Kinzie, J., Sachar, D., Northrup, R., Taylor, J. O., Ahmad, S., Phillips, R. A. New Engl. J. Med. 1968, 279, 176. 8. Pierce, N. F., Sack, R. B., Mitra, R., Banwell, J., Brigham, K., Fedson, D., Mondal, A. Ann. intern. Med. 1969, 70, 1173. 9. Nalin, D. R , Cash, R. A. in Cholera, (edited by D. Barua and W. Burrows); p. 253. Philadelphia 1974. 10 Cash, R. A., Nalin, D. R., Rochat, R., Reller, B., Haque, Z., Rahman, M. Am J. trop Med. 1970, 19, 653. 11. Nalin, D. R., Cash, R. A. J. Pediat. 1971, 78, 355. 12. Nalin, D R., Cash, R. A., Trans. R. Soc. trop. Med. Hyg. 1970, 64, 769. 13 Cash, R.A , Nalin, D. R., Forrest, J., Abrutyn, E. Lancet, 1970, ii, 549. 14. Nalin, D R , Cash, R. A., Rahman, M., Yunus, M. Gut, 1970, 11, 768. 15. Nalin, D. R., Cash, R. A. Bull. Wld. Hlth Org. 1970, 43, 361. 5. Sachar, D. B.,

pyruvate rise sharply fructose ingestion. However, we observed no such rise in the plasma concentrations of these 3-carbon compounds after the administration of glycerol, despite, or because of, the considerable overloading of the hepatic machinery with this 3-carbon compound. In so far as glycerol is being metabolised, since it is a fully hydrogenated compound we considered that the N.A.D.N.A.D.P. system would be kept in the fully reduced state in the liver and that this might lead to fat synthesis. We have some evidence that the concentrations of plasma-triglycerides do rise after oral glycerol. 1. Klockhoff, I.,

Lindblom, U. Acta otolar. 1967, suppl. 224, p. 449.

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Cholera research in Bangladesh.

102 regression (2 had progression of disease by 6 months). No complete remissions were seen. The median survival for the whole group is 5 - 2 months...
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