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from the truth. The first attempts (in the Phillipines) to de-velop a practical regimen rapidly followed Phillips’ balancestudies, but failed because of inappropriate methods and solu-tion concentrations. The problems to be solved included devel-opment of a formula and a simplified practical balance methodavoiding too much or too little water and electrolyte absorp-tion, 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, decidinghow much to give &c. For several years after the Philippinefailures no practical regimen appeared, and there the matterrested, until Dr David Sachar, Dr James Taylor, and Dr RuthHare and their co-workers initiated C.R.L.’s physiological stu-dies of gut electric potentials and unidirectional intestinalsodium fluxes during cholera (using intestinal tubes and iso-topes).5,6 When glucose was present in the intestinal perfusatesthey used, net salt and water absorption occurred, as Phillips(then director of C.R.L.) had reported earlier. This, togetherwith an enormous cholera epidemic which strained theC.R.L.’s intravenous fluid production capacity, rekindled theissue and inspired Hirschhorn and co-workers7 to reconfirmand further develop Phillips’ work. Visits to C.R.L. by the Cal-cutta workers soon led to the similar confirmatory study inCalcutta’ noted by Islam et al.At Dacca, the reconfirmation of Phillips’ work led initially

(1967) to another abortive attempt (50% failures) in Chitta-gong 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 methoddeveloped, as formally presented at the 1968 Tropical Medi-cine and Malariology Congress in Teheran and published thatAugust. 4

As noted in my report to the then director, C.R.L., the lateDr Phillips, in early May of 1968, having sent the report ofC.R.L.’s practical oral therapy method to The Lancet,4 Ivisited Calcutta to discuss the method and results with the Cal-cutta investigators, and they expressed the opinion that themethod involved impractical "heroic" quantities of oral fluids.Up to my visit, instead of progressing from their confirmatorystudy to develop a practical method using glucose, they haddecided to test instead a maltose-electrolytes solution, believingthat this would be practical. Like the Phillipine and Chitta-gong trials, the maltose trial turned out not to be useful.Between my visit and that of my colleague Dr Cash severalmonths later, the Calcutta group shifted its efforts towards avaluable study (published in 1969)8 confirming our earlierwork on the use of oral maintenance therapy, which includedappropriate references to our work. Since confirmation is anessential part of scientific medical progress, their study was animportant contribution.

C.R.L. continued its leading role in this field,9 with the firstpapers on field use of oral therapy in rural areas,10 oral ther-apy in children," in patients with non-cholera diarrhoeas,’2 inpatients treated with oral therapy alone (no intravenous fluidsfor rehydration),13 with glycine added, 14 and with adequatepotassium. 15

5. Sachar, D. B., 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.

The Calcutta studies, like the Dacca studies, were done withthe assistance of foreign investigators, and the practicaladvances they generated are for many an ample benefit inreturn for the risks involved. It behooves us to turn our atten-tion from the already extensive discussion of C.R.L.’s ethics tothe vastly more important subject of the ethics of continuednon-application of these methods in many endemic cholera anddiarrhoea zones of developing countries, and to get on with thejob of correcting current deficiencies in delivery of theseadvances 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 TESTWORK?

SiR,—The oral glycerol test devised by Klockhoff andLindblom’ is often used to help in identifying patients withMeniere’s disease who might benefit from surgical decompres-sion of the endolymphatic system. Glycerol 1.25-1.5 g/kgbody-weight diluted with an equal volume of water is given bymouth. Audiograms are recorded before and 2-3 h after gly-cerol intake; and in patients whose hearing does improve, atemporary improvement of 15-20 dB at several frequenciesoccurs, often with a corresponding improvemment in speechdiscrimination. The mechanism is assumed to be by the osmo-tic action of the glycerol which causes a rise of some 18 mos-mol/kg water in the plasma. We have observed this responseclinically but we are not convinced that the mechanism ofaction is osmotic, or only osmotic.We have occasionally observed this improvement in thresh-

old in patients with, not Meniere’s disease, but presenile deaf-ness in whom there was no clinical indication of any hydropsof the endolymphatic space. Furthermore in patients withMeniere’s disease we have recorded a similar temporary im-

provement in hearing threshold in response to a fructose in-take, instead of glycerol. The maximum concentration in theplasma of fructose after an oral intake of 1 g/kg body-weightseldom exceeds 1 mmol/1, and this increase is transient com-pared 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 waterover 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-diabeticpatient who responded to glycerol and fructose with a tempor-arily improved hearing threshold, an equivalent dose of glu-cose had no effect. We concluded that this patient had a meta-bolic block in an actively respiring tissue in the cochlea,preventing glucose from entering the cell or due to failure ofhexosephosphate-isomerase activity.

In searching for a metabolic explanation we have found, inagreement with previous investigators, that plasma lactate andpyruvate rise sharply fructose ingestion. However, we observedno such rise in the plasma concentrations of these 3-carboncompounds after the administration of glycerol, despite, orbecause of, the considerable overloading of the hepaticmachinery with this 3-carbon compound.

In so far as glycerol is being metabolised, since it is a fullyhydrogenated compound we considered that the N.A.D.N.A.D.P.system would be kept in the fully reduced state in the liver andthat this might lead to fat synthesis. We have some evidencethat the concentrations of plasma-triglycerides do rise afteroral glycerol.

1. Klockhoff, I., Lindblom, U. Acta otolar. 1967, suppl. 224, p. 449.

104

A further consideration in the interpretation of the glyceroltest is the fact that the osmoreceptors respond to an increaseof 6 mosmol/kg plasma water by initiating increased secretionof antidiuretic hormone.2 If the osmoreceptors respond to gly-cerol as an osmotic agent in the same way as they react tosodium chloride and sucrose, the effect of the glycerol intakemay be through antidiuretic hormone acting on a water reab-sorbing surface (e.g., the stria vascularis3). An added complica-tion is the finding by Buckman and Peake that plasma hyper-osmosis leads to an increased prolactin secretion in the sametime-span as the effect of glycerol intake. Prolactin has beenshown to be a liporegulatory hormone.5The glycerol test is of immediate clinical usefulness in oto-

logy, but the usual explanation of how it works-namely, bythe osmotic action of glycerol-may be too simple.Department of Biochemistry,St George’s Hospital,Lincoln LN1 1EF L. NAFTALIN

E.N.T. Department,County Hospital,Lincoln K. J. H. MALLETT

MYELOFIBROSIS ASSOCIATED WITHRUBIDAZONE

SIR,-Rubidazone, an anthracycline antibiotic, is beingused extensively in the treatment of haematological and solidmalignancies.6.7 We wish to report an unusual complication ofthis drug.A 57-year-old male was admitted to the University of Utah

Medical Center in May, 1977, because of easy bruising. Therewas no history of exposure to irradiation or toxic chemicals.Physical examination revealed multiple ecchymoses and ster-nal tenderness, but no adenopathy or hepatosplenomegaly.The leucocyte-count was ll-2x010’’/l, with a differentialof 83% myeloblasts, 1% neutrophils, and 16% lymphocytes.Auer rods were not seen. A bone-marrow aspirate and biopsywere diagnostic for acute myeloblastic leukaemia. On June 1 hewas treated with a combination of rubidazone, cytarabine, vin-cristine, and prednisone on the South Western OncologyGroup protocol 7626. Subsequently, prolonged pancytopeniadeveloped. No consolidation chemotherapy was given.Repeated bone-marrow biopsies showed a hypoplastic marrowwith no evidence of leukxmia. On Aug. 29, early fibrosis wasnoted for the first time in the bone-marrow. Repeated blood-counts revealed persistent pancytopenia (table).The patient was readmitted on Feb. 13, 1978, because of

fever and pain in the left knee. Physical examination revealedleukaemic cutaneous nodules, sternal tenderness, a spleen palp-

2. Verney, E. B., Proc. R. Soc. B. 1947, 135, 25.3. Naftalin, L. Otolar. Clin. N. Am. 1975, 8, 475.4. Buckman, M. T., Peake, G. T. Science, 1973, 181, 755.5. Meier, A. H. in Comparative Endocrinology of Prolactin (edited by H.-D.

Dellman, J. A. Johnson, and D. M. Klachko); p. 153. New York, 1977.6. Benjamin, R. S., Keating, M. J., McCredie, K. B., Luna, M A., Loo, T. L.,

Freireich, E. J. Proc. Am. Ass. Cancer Res. 1976, 727. Jacquillat, C., Weil, M., Gemon-Auclerc, M. F., Izrael, V., Bussel, A.,

Boiron, M., Jean Bernard. Cancer, 1976, 37, 653.

able 3 cm below the left costal margin, and a warm, swollen,tender left knee. His packed cell volume was 0-33, and a plate-let-count was 23-Ox 109/1. The leucocyte-count was 61 5 109Awith 90% myeloblasts, 1% neutrophils, and 9% lymphocytes.The blood smear revealed abnormal erythrocyte morphologymorphology with anisocytosis, poikilocytosis, target cells, andmany teardrop cells. An iliac-crest bone-marrow biopsyrevealed a markedly fibrotic marrow infiltrated with leukaemiccells. The patient was treated with several regimens of com-bination chemotherapy with no improvement in his hxmatolo-gical indices. The patient died after a prolonged hospitalcourse. Necropsy confirmed myelofibrosis.Our patient’s initial presentation did not fit into the group

of patients described with the accelerated variant of myelofi-brosis.8 He had an initial cellular marrow without increasedfibrosis. He had had no prior chemotherapy, and no exposureto toxic chemicals. We believe that his prolonged pancytopeniaand his bone-marrow fibrosis was most probably secondary totherapy with rubidazone. Rubidazone should probably beadded to the list of chemical agents causing fibrosis of thebone-marrow.

Department of Medicine,University of Utah Medical Center,Salt Lake City, Utah 84132, U. S.A.

DAVID S. CHENGHARMON J. EYRE

CRYPTOCOCCUS IN BAGPIPES

SIR,-Dr Cobcroft and others9 may be overdogmatic intheir warning of the dangers of playing the bagpipe. That fun-gal spores in the bag reach the player’s mouth by back-flowthrough the mouthpiece valve is a supposition for which theyoffer no evidence. In any case, valves vary greatly in efficiency.Some pipers use the tip of their tongue instead of a valve,which may virtually eliminate back-flow. Pipers may be classi-fied into "wet" and "dry" blowers. The wet blower mayrequire to replace his pipe-bag, because of rotting, more fre-quently than the dry blower. But a large proportion of salivamay be caught before it reaches the bag by putting a water-trap into the mouthpiece stock: such a trap can be improvisedfrom a cork, the barrel of a 5 ml disposable plastic syringe, andsome waterproof glue.Whether or not a patient is immunosuppressed, a prohibi-

tion on playing a favourite musical instrument may suppressmorale-which can also be dangerous. Patients should be con-sidered individually. An efficient valve, a water trap, perhapsa fungicide in the bag, are possible precautions.

Undoubtedly some patients, because of reduced respiratorycapacity or for other reasons, may become unable to play theHighland bagpipe. In such a case a patient might be advisedto consider seeking a Lowland bagpipe as an alternative. Thisis similar to the Highland, but rather smaller and is blown bya bellows operated by the right elbow while the bag is underthe left. These can be difficult to obtain, but a manufacturer

8. Douglas, R., Rasch, P. C. Am. J. clin. Path. 1977, 67, 334.9. Cobcroft, R., Kronenberg, H., Wilkinson, T. Lancet, 1978, i, 1309.

HAMATOLOGICAL AND MARROW FINDINGS