253
We feel that our experience may be of value to others who
have to cope with immunosuppressed patients outside special-
ist centres.
We thank Dr B. Jameson for her advice.
Departments of Microbiology and R. M. PERINPANAYAGAM
Hæmatology,
Queen Mary’s Hospital, P. E. CROME
London SW15 5PN P. A. HÁPUGODA
LUNCHTIME GIN AND TONIC A CAUSE OF
REACTIVE HYPOGLYCÆMIA
S!R,—Iwonder how silly research-workers can become? The
summary of the paper by Dr O’Keefe and Professor Marks’ de-
scribes ten healthy young individuals drinking the equivalent
of three large gin and tonics at lunchtime, one with ordinary
tonic and one with ’Slimline’. The paper then goes into great
detail about how they all felt later on. In plain fact they were
all "sloshed"-as well they might be-and the rest of the
paper is quite valueless. It is rare for ten healthy young people
to drink three large gin and tonics before lunch. Why are Dr
O’Keefe and Professor Marks wasting their time and other
people’s money?
International Sugar Research Foundation,
London W1Y 3AA J. A. C. HUGILL
"’*"’This letter has been shown to Professor Marks, whose reply
follows.-ED.L.
SIR,-May I suggest that clue to the reason for Mr
a
Hugill’s vitriolic comments on our work is to be found in his
address? The International Sugar Research Foundation must
feel threatened by the accumulating evidence2 that John Yud-
kin’s description of their major product as pure, white, and
deadly is not too far wide of the mark.
We distinguished clearly between the pharmacological
effects of alcohol upon the brain (what Mr Hugill presumably
means by "sloshed") and the symptoms of neuroglycopenia
due to hypoglycaemia. The signs and symptoms of the two con-
ditions are often similar, and may confuse even medical men.
The point is that gin and saccharin (’Slimline’) did not cause
hypoglycaemia and neuroglycopenia in the same subjects as gin
and sugar (tonic) did. This should not surprise anyone engaged
in hypoglycaemia research since sugary solutions such as tonic
and lemonade can cause hypoglyceernia occasionally; this con-
dition is known as essential reactive hypoglycaemia and may be
an important and potentially dangerous clinical condition, es-
pecially in drivers and airline pilots.3.4
There is no reason to believe that our findings apply exclus-
ively to healthy young people. Middle-aged people, probably,
even the elderly react in the same way. We investigated
healthy volunteers first, as is usual in medical research. Had
we chosen to begin with alcoholics, our results would probably
have been an even greater waste of time from Mr Hugill’s
point of view, especially since alcoholics have an increased
tendency to develop reactive hypoglycaemia anyway.5
We never said that large numbers of healthy young people
regularly drink three large gin and tonics before lunch. Never-
theless, if only one in a thousand did so occasionally this would
still mean that a considerable number of individuals would be
exposed to a potentially dangerous situation, especially since
there is evidence from animal work6 that a "raised blood sugar
tempered intoxication whilst lowered blood sugar enhanced
it".
1. O’Keefe, S. J. D., Marks, V. Lancet, 1977, ii, 1286.
2. Ahrens, R. A. Am. J. clin. Nutr. 1974, 27, 403.
3. Raichle, M. E., King, W. H. Aerospace Med. 1972, 43, 76.
4. Harper, C. R., Kidera, G. J. ibid. 1973, 44, 769.
5. Marks, V., Wright, J. H. Proc. R. Soc. Med. 1977, 70, 337.
6. Sammalisto, L. Acta physiol scand. 1962, 55, 313.
Lest Mr should think that if our volunteers had had
Hugill
something with
to eat their drink all would have been well, let
me disabuse him. In a further series of experiments we are
finding that certain types of food exaggerate the reactive
hypoglycaemia produced by gin and tonic.
University of Surrey,
Guildford, Surrey GU2 5XH VINCENT MARKS
ERYTHROPOIETIN
SIR,-You make the point’ that much is still to be learned
about erythropoietin despite the fact that over seventy years
have elapsed since hormonal control of erythropoiesis was first
suspected.2 You make no mention, however, of work suggest-
ing a possible role of intrarenal prostaglandin metabolism in
the control of production of erythropoietin or its precursor in
the kidney.
Prostaglandins of the E series increase the erythropoietic
activity in the perfusate of the isolated, perfused dog kidney,
and also increase cyclic A.M.P.’ Prostaglandins E stimulate
erythropoiesis in the post-hypoxic polycythaemic mouse.4 Indo-
methacin, a potent inhibitor of prostaglandin synthetase,
blocks the rise in serum erythropoietin titre after renal-artery
constriction in the dog.’ Abnormal renal prostaglandin meta-
bolism is important in the pathogenesis of Bartter’s syndrome6
and secondary erythrocytosis, with increased circulating levels
of erythropoietin, has been described in this syndrome.’
I have investigated a patient with renal cortical carcinoma
and secondary erythrocytosis who had raised circulating eryth-
ropoietin levels, together with a very high concentration of
erythropoietin in tumour extract but no detectable erythro-
poietic activity in extract of adjacent normal kidney. Erythro-
poietin was measured by an in-vitro assay utilising fetal mouse
liver cells in culture. Extracts of tumour contained very high
concentrations of prostaglandin E (by radioimmunoassay),
normal values being found in extract of adjacent normal kid-
ney.
These observations suggest a relationship between erythro-
and prostaglandin E within the kidney, possibly via the
poietin
effects of prostaglandin E on the renal vasculature but more
probably by stimulation of cyclic A.M.P. production.
Academic Division of Medicine,
Royal Hospital,
Sheffield S1 3SR M. GREAVES
DOXORUBICIN-INDUCED HAIR LOSS AND
POSSIBLE MODIFICATION BY SCALP COOLING
SIR,-Doxorubicin (’Adriamycin’), an effective agent in
breast cancer, is increasingly used in combination chemo-
therapy regimens with encouraging results; unfortunately
severe hair loss is common. We have performed an uncontrolled
pilot study of lowering scalp temperature by ’Cryogel’ bags
(each 26 x 10 cm) containing a gel which crystallises at —1S°C.
These are cooled in a deep-freeze and then the bags (usually
four) are applied to the scalp 10 min before drug administra-
tion, being secured by a stockingette bandage until half an
hour after treatment ends. Chemotherapy consists of adriamy-
cin 50 mg, vincristine 2.0 mg, and 5-fluorouracil 500 mg intra-
1. Lancet, 1977, i, 1137.
2. Carnot, P. Deflandre, C. C.r. Acad. Sci. 1906, 143, 432.
3. Paulo, L. Z., Wilkerson, L. D., Byung, L. R., George, W. J., Fisher, J. W.
Proc. Soc. exp. Biol. Med. 1973, 142, 771.
4. Schooley, J. C., Mahlmann, L. J.
5. Mujovic, V. M., Fisher, J. W. J. Pharmac. exp. Ther. 1974, 191, 575.
6. Gill, J. R. Jnr., Frolich, J. C., Bowden, R. E., Taylor, A. A., Keister, H. R.,
Oates, J. A., Seyberth, H. W., Bartter, F. C. Am. J. Med. 1976, 61, 43.
7. Jepson, J., McGarry, E. E., Blood, 1968, 32, 370.
254
HAIR LOSS IN PATIENTS ON ADRIAMYCIN, WITH OR WITHOUT
SCALP COOLING
venously, followed, over the next 24 h, by chlorambucil 10 mg
and methotrexate orally 5 mg, 6-hourly for four doses.
Of the first 77 patients receiving this chemotherapy regimen
40 were allocated at random to receive scalp cooling (see
table). 13 experienced total hair loss, 7 severe loss, whilst the
remaining 20 had slight or no epilation. Of 37 non-cooled pa-
tients, 23 lost all their hair and 7 had severe losses.
The system described is far from satisfactory; the bags are
difficult to keep in position and a sufficiently reduced tempera-
ture is hard to maintain. Most patients therefore, if not all
were inadequately treated but may have benefited. This sug-
gests that the principle should be pursued and to this end a
prototype cooler has been designed which is similar to a hair
dryer except the air is driven through carbon-dioxide snow.
A number of mechanisms might explain these observations.
Vasoconstriction induced by temperature fall should reduce
the drug quantities reaching the hair follicles. This effect
may be transitory, and timing is probably critical. Adriamycin
is concentrated in mammalian cells by an energy-dependent
transport process which is temperature sensitive and this
should be beneficial. Finally the temperature fall should lower
hair-follicle metabolism, so, perhaps, reducing the efficacy of
cytotoxic agents at their point of action. The mechanical
cooler should simplify and standardise treatment, and will
form the basis of a randomised prospective clinical study.
Belvoir Park Hospital,
Belfast BT8 8JR, and
Hume Street Hospital,
Dublin G. A. EDELSTYN
MURIEL MACDONALD
Department of Medical Statistics,
Charing Cross Hospital,
London W6 K. D. MACRAE
GIARDIASIS
SiR,—Jokipii and Jokipiil have presented useful informa-
tion about giardiasis. The high frequency of positive findings
on the first stool examination may relate to the early presenta-
tion of these patients, who had usually returned home by the
time of onset of symptoms, to physicians who were aware of
the possibility of giardiasis in this group of travellers. We have
studied 40 overland travellers with giardiasis.2 They had
usually been travelling in India and South East Asia and pre-
sented weeks or even months after the onset of symptoms. The
parasitological diagnosis was made by stool examination after
formol-ether concentration in 34 patients and by examination
of jejunal aspirate and/or jejunal mucosal impression smears in
6 patients. 3 of these 6 had diarrhoea and marked malabsorp-
tion. The frequency of positive stool examinations was similar
in those patients with normal absorption (47%) and those with
impaired absorption of two or three test substances (44% posi-
tive). The different times of presentation probably account for
the difference between these figures and the higher frequency
of positive stool examinations (66%) derived from the data of
Jokipii and Jokipii for patients with proven giardiasis.
1. Jokipii, A. M. M., Jokipii, L. Lancet, 1977, i, 1095.
2. Wright, S. G., Tomkins, A. M., Ridley, D. S. Gut, 1977, 18, 343.
3. Eastham, E. J., Douglas, A. P., Watson, A. J. Lancet, 1976, ii, 95.
We support the contention that accurate parasitological diag-
nosis is as important in giardiasis as in any other infectious dis-
ease, but we disagree with the statement that "stool examina-
tions are the only means of diagnosis suitable for all suspected
cases". Intubation of the upper small bowel for aspiration and
biopsy may be done easily in patients attending hospital as
day-cases.3 These procedures should be undertaken where stool
examinations are negative yet giardiasis is a possibility.
Hospitalfor Tropical Diseases, S. G. WRIGHT
London NW1 OPE A. TOMKINS
CANCER AND VITAMIN K
to put forward the hypothesis that
SiR,—Ishould like
malignancy is caused by disturbed vitamin-K physiology of the
cell. This hypothesis is supported by the following evidence:
(a) Mitochondria have been shown’ to be much more sensi-
tive than the rest of the cell to the toxic effects of many car-
cinogenic substances (as measured in the yeast celI,2 the only
model available for measuring the sensitivity of mitochondria
or mitochondrial biogenesis). This suggests mitochondrial in-
volvement in carcinogenesis. Among these carcinogenic sub-
stances are 4-nitroquinoline-l-oxide (N.Q.o.), thioacetamide,
benzidine, and ethionine; and p-naphthylamine (N.A.) can now
be added to this list.
(b) I have been able to induce morphological differentiation
in malignant mouse neuroblastoma cells (C-1300) in vitro by
exposing them to one of the following agents: dicoumarol
(D.C.), quinidine sulfate (Q.s.), or dinitrophenol (D.N.P.).3 The
cells were grown in Falcon tissue culture bottles in Eagle’s
medium with 10% fetal calf serum, under which conditions less
than 1% of the control cells formed neurites longer than dou-
ble the cell diameter. In the presence of quinidine, 40% of the
cells show this criterion for differentiation after four days; 30%
of cells in the presence of dicoumarol showed similar differen-
tiation after two days; dinitrophenol was less effective, 13% of
the cells were differentiated on the fourth day. Alongside their
differentiation, strong inhibition of the proliferation-rate of
the cells was seen. All these substances, D.c., Q.s., and D.N.P., I
are known to release calcium ions from isolated mammalian
mitochondria.4-7
(c) There are close chemical similarities between: (1) two of
the above-mentioned carcinogens (N.Q.o. and N.A.); (2) two of
the above-mentioned differentiation-inducing agents (Q.s. and
D.C.); and (3) vitamin K (menadione).
(d) Although little is known about the site of action of vita-
min K, strong evidence has been produced for some role in
mitochondria.8-9 Vitamin K is known to have a function in the
chloroplast, and in bacteria it is known to be involved in oxidative
phosphorylation, strongly suggesting a mitochondrial role for
the vitamin in mammalian cells. Vitamin K is known to be able
to release rotenone-inhibition of the N.A.D.H.-linked branch of
the respiratory chain in mammalian cells. Although the two
dedifferentiating agents (the carcinogens N.Q.o. and N.A.) and
the two differentiation-inducing agents (n.c. and Q.s.) may
have some effects outside the mitochondria, I do not know of
any other target common for all of them, probably including
vitamin K.
(e) Presumably release, of calcium from mitochondria leads
to higher concentrations of the ion in the cytoplasm, thereby
1. Egilsson, V., Evans, I. H., Wilkie, D. in Genetics and Biogenesis of Chloro-
plasts and Mitochondria (edited by T. Bucher and others); p. 885. Amster-
dam, 1976.
2. Wilkie, D. Med. Biol. Illust. 1972, 22, 119.
3. Egilsson, V. Cell Biol. Int. Rep. (in the press).
4. Batra, S. Biochem. Pharmacol. 1976, 25, 2631.
5. Conrad, L. L., Baxter, D. J. Proc. Soc. exp. biol. Med. 1975, 150, 371.
6. Harrow, J. A. C. Biochem. Pharmacol. 1976, 25, 897.
7. Carafoli, E., Rossi, C. S., Gazzetti, P. Archs Biochem. Biophys. 1969, 131,
527.
8. Anderson, W. W., Dallam, R. D. J. biol. Chem. 1959, 234, 409.
9. Meyer, R. E. ibid. p. 688.