1084

syringe manufacturers, pharmaceutical industry, and diabetic patients. The coordinator and the committee will enlist the support and patience of professional groups and diabetics, and will also draw on the considerable experience of colleagues in other countries who have already introduced U-100 insulin. C. HARDWICK, Chairman

British Diabetic Association, 10 Queen Anne Street, London W1M 0BD

A. BLOOM, Chairman, Medical and Scientific Section H. KEEN, Chairman, Medical Advisory Committee P. J. WATKINS, Secretary, Medical Advisory Committee

POSTMENOPAUSAL OSTEOPOROSIS

SiR,-The observation by Dr Manelogas and colleagues p. 597)-that the only significant differences to be oophorectomised women who had lost bone rapidly higher urinary free cortisol excretion and a paradoxi-

(Sept. 22, found in was a

cally diminished cortisol response to corticotropin-is a major step toward an explanation of postmenopausal osteoporosis. I do wonder, however, if these findings in oophorectomised be extended to women who have had a normal menopause. The ovary, certainly in the early years after menopause, may continue to produce steroid-precursors. Normal menopause is therefore likely to be associated with hormone profiles significantly different from those described by Manelogas et al. It would be interesting to see the results of similar studies in postmenopausal women with intact ovaries, subdivided into those with very fast and those with very slow bone loss.

before any significant soft tissue change could have occurred. The sleep attacks persisted in two other individuals despite considerable regression of their clinical acromegaly. Guilleminault and van den Hoed now hold that "valid diagnosis of patients with daytime sleepiness requires systematic polygraphic monitoring including monitoring of cardiac and respiratory variables". Sleep laboratories are notoriously expensive, and in conditions of financial stringency we feel that skilled clinical assessment (including, of course, questioning of the spouse, wherever possible) still has a role to play in the attribution of diurnal somnolence to sleep apnoea. The same probably applies to the many cases of hypertension, cor pulmonale, cardiac arrhythmia, morning headache, and abnormal daytime behaviour now being investigated "polygraphically" (as possible cases of sleep apnoea) in laboratories throughout the U.S.A. It seems likely that excessive daytime sleep in acromegalic patients has a variety of causes, including sleep apnoea. It would seem to us unwise, however, to attribute all paroxysmal diurnal sleep in acromegalics to this mechanism. In our opinion other causes both exist-and have to be excluded-before all sleepy acromegalics are automatically submitted to tra-

cheostomy.

women can

postmenopausal

Department of Reproductive Biology, Case Western Reserve University, Cleveland, Ohio 44106, U.S.A.

WULF H. UTIAN

SIR,-We welcome the interest shown by Dr Rees and Dr

Ayres (Sept. 8, p. 524) and by Dr Guilleminault and Dr van den Hoed (Oct. 6, p. 750) in our preliminary communication of Aug. 18 on the association of narcolepsy and acromegaly. Guilleminault and van den Hoed assert that the "daytime somnolence of acromegalics is clearly associated with the obstructive sleep apnoea syndrome". They imply that our patients were drowsy by day because they slept poorly at night, and that they slept poorly by night because their acromegaly obstructed their upper respiratory passages. We are familiar with intermittent or permanent airwayss obstruction as a possible complication of acromegaly. Our department has indeed recently reported on one aspect of this.’ We are also familiar with sleep apnoea as a cause of diurnal somnolence. But as Guilleminault himself once pointed out,’ this is a condition which it should be possible to recognise clinically. In his own words, "the spouse or other bed partner is the best source of current information and appropriate questioning always results in a vivid description of the loud snoring and unusual nocturnal respiratory pattern". Other clinical components of the sleep apnoea syndrome may include abnormal sleep behaviour (violent movements, somnambulism, and others) and repeated morning headache or "grogginess". Our patients slept normally and felt well in the mornings. Following their daytime "naps" they awoke feeling refreshed, whereas patients with sleep apncea often feel drowsy after diurnal sleep. Moreover, in three of our patients the diurnal somnolence resolved within a few days of implantation with yttrium-90, J, McKelvie P, Joplin GF. Reversal of laryngeal obstruction following of acromegaly. J Laryngol Otol 1979; 93: 403-04. Guilleminault C, Tilkian A, Dement WC. The sleep apnoea syndromes. Ann treatment

2.

RevMed 1976: 465-84.

London W12

A. J. BARNES

G. F. JOPLIN C. PALLIS

FATAL ASTHMA

SIR,-Professor Stolley and Rita Schinnar, in their letter of

(p. 897), try to use your Aug. 18 editorial to reopen a six-year gap, on the surprising increase in asthma deaths in the U.K. during 1966-67. They still believe the cause to have been the "toxic" overuse of the beta-agonist isoprenaline aerosol, the overuse of which results, however, in tolerance not toxicity. Their other arguments have been answered in my letter of Sept. 7, 1972, in the American Review of Respiratory Diseases and also in a discussion of the so-called toxic properties of aerosol propellants and of the widely varying relations between isoprenaline use and asthma mortality in Australia, the U.S.A., West Germany, France, Italy, Sweden, and Japan, set out in my book Guide to Bronchial Asthma (1975). The conclusion from all these data can only be that the rise and fall of asthma mortality has a multifactorial Etiology which is only partly known. Isoprenaline cannot be an important cause because it has been replaced worldwide by other aerosols with different properties, but asthma mortality does

Oct. 27

discussion, after

ACROMEGALY AND NARCOLEPSY

1. Cassar

Department of Medicine, Royal Postgraduate Medical School,

not

seem to

have declined.

9 Park Crescent, London N3 2NL

H. HERXHEIMER

MAGNESIUM AND SUDDEN DEATH FROM HEART DISEASE

SiR,-From their data on the ion content of heart muscle from patients in Burnley and Hull Dr B. and Dr J. Chipperfield (Oct. 6, p. 709) suggest that deviation of the potassium/ sodium ratio from 2-8—3-0 may be associated with increased risk of sudden death in ischaemic heart disease (IHD). They cite Dr M. S. Seelig’s observation that the Western diet is deficient in magnesium, and her suggestion that the lower magnesium content of soft water could be important in increasing IHD sudden deaths and that it might possibly underlie the high incidence of cardiovascular disease in soft-water areas. The implications are not clear-is hypomagnesxmia, low cellular magnesium levels, or actual myocardial deficiency of magnesium the important factor? Why should such a deficiency affect men more seriously than women, when the men and women studied had consumed the same diet? Could the

1085

explanation lie in the higher intake of alcohol in men?’ In an earlier study Chipperfield et al.2 found significantly increased concentrations of both myocardial magnesium and myocardial potassium in soft-water areas. Their suggestion, then, was that a myocardial cellular deficit of magnesium might be the important factor in increasing IHD sudden deaths. Subsequently they emphasised that the magnesium/ potassium 3 ratio is not significantly lower in subjects dying

from IHD. In view of the great magnesium conserving power of the kidney we feel that it is unlikely that low magnesium in soft water makes a major contribution to sudden IHD deaths. We agree that cell membrane changes aM important in maintaining the levels of intra/extra cellular potassium, magnesium, calcium, and sodium in the myocardium, and that any significant change in the intra/extra cellular ratio in myocardial metal levels might interfere with contraction, possibly leading to arrhythmias and sudden death. It is not clear how many of the Chipperfields’ patients had abnormal serum or low or high myocardial metal concentrations at necropsy. The deaths were due to accidents, suicide, bronchopneumonia, or cancer. Could coexisting disease have caused hyper (or hypo) magnesasmia and increased (or lowered) myocardial metal levels? In the fluid/electrolyte depleted burned patient hypomagnessemia, hypokalaemia, and hyper-

natrsemia can occur.4 Cell magnesium levels

can be low in the presence of normal and myocardial magnesium concentrations, and this may contribute to sudden death in IHD patients. Low cell levels, even when myocardial magnesium levels are raised, are difficult to exclude in patients with IHD who die suddenly. Blood loss and dehydration are common in accidents, and could cause increased myocardial concentrations of magnesium and potassium by compensatory mechanisms. Similarly, the method of suicide might have produced dehydration and altered serum or myocardial metal concentrations. Finally, in malignant disease blood levels of certain constituents may be affected, and it is conceivable that magnesium, potassium, and sodium levels in serum, cell, and/or myocardium may be altered in these states. We are reluctant to accept the "tentative suggestion" that a high potassium/sodium ratio may be the important factor in causing sudden death in IHD cases in soft water areas. Low myocardial-cell magnesium levels could be more important. As the work of R. B. S. and others has shown, hypomagnesxmia can lead directly to cardiac arrhythmias and may predispose to sudden death.

or

even

high

serum

Department of Medicine, Ashington General Hospital, Ashington NE63 0SA

EWEN A. CAMERON RAM B. SINGH

OSTEOMYELITIS AND LYMPHOMA

SiR,-Squamous-cell carcinoma,

sarcoma,

adenocarcinoma,

basal-cell carcinoma, and a plasmacytoma, all arising at the sites of chronic osteomyelitis, have been described;6 however, lymphoma has not been reported in this setting. A 30-year-old man was shot in the left thigh in 1948 while hunting and sustained an open fracture of the left femur. Chronic staphylococcal osteomyelitis draining through two a

1. Hall R. Magnesium metabolism. In: Progress in clinical medicine, 6 ed. London: Churchill Livingstone, 1971: 301-05. 2. Chipperfield B, Chipperfield JR, Behr G, Buxton P. Magnesium and potassium content of normal heart muscle in areas of hard and soft water. Lancet 1976; i: 121-22. 3. Chipperfield B, Chipperfield JR. Differences in metal content of the heart muscle in death from ischemic heart disease. Am Heart J 1978; 95:

732-37. 4. Pruitt BA Jr. Fluid and electrolyte replacement in burned patient. Surg Clin North Am 1978; 58: 1304-10. 5. Singh RB, Singh VP, Jha VK. Magnesium and the heart. Acta Cardiol 1976;

5: 401-09.

6. Waldvogel FA, Medoff G, Swartz MN: Osteomyelitis: A review of clinical features, therapeutic considerations and unusual aspects. N Engl J Med 1970; 282: 198-206, 260-66, 316-22.

sinus tracts developed. He took sulfasoxasole (’Gantrisin’) for 25 years. In 1974 a 10 cm large mass arose adjacent to a still draining sinus tract. The overlying skin was ulcerated and the whole anterior thigh surrounding the mass felt indurated. Squamouscell carcinoma was suspected, but biopsy revealed dense monomorphic infiltrates of small-to-medium lymphocytes below the epidermis. Histology of a left inguinal and right axillary lymph-node showed obliteration of nodal architecture due to an ill-defined nodular process, in which the large cleaved follicular centre cell was predominant. Although the origin of the lymphoma could not be proved, extranodal lymphoma of the left thigh metastatic to lymph-nodes was suspected. Radiotherapy to the left thigh and, later, chemotherapy were given. However, the disease recurred, and in 1978 biopsy of a left axillary lymph-node showed a diffuse growth with the large cleaved follicular centre cell still predominant. Immunological studies of the malignant lymphocytes from this lymph-node revealed 34% lymphocytes with surface immunoglobulins; the percentages of cells marking with specific antisera were: IgG 40%, IgA 0% IgM 2%, IgD 1%, kappa light chains 42%, lambda light chains 1%. 64% of the lymphocytes formed rosettes with sheep erythrocytes, but these cells were small and thought not to be part of the neoplastic component. These studies suggesteda B-cell neoplasm with IgG kappa as the predominant surface immunoglobulin. The patient died with malignant pleural effusions and progressive disease in May, 1979. Permission for necropsy was

refused.

-

Damashek and Schwartz postulated 20 years ago that chronic antigenic stimulation may result in lymphoid hyperplasia and, eventually, in neoplastic lymphoid transformation.7 In our patient the physical proximity of the extranodal lymphoma and the chronic osteomyelitis suggests that chronic stimulation of the lymphoid system may have had led to the lymphoma. Extranodal lymphomas have been noted at sites of chronic inflammation, as in autoimmune thyroiditis,’8 coeliac sprue and dermatitis herpetiformis,9 Sjogren’s syndrome and chronic sialoadenitis. 10 Chronic osteomyelitis may also represent a precursor condition for development of an extranodal lymphoma. The rarity of lymphoma in osteomyelitis indicates that additional pathogenetic mechanisms must be necessary for the lymphoma to develop in such circumstances. Departments of Medicine and Pathology, Vanderbilt University Hospital and Nashville V. A. Hospital, Nashville, Tennessee, U.S.A.

D. N. POSNETT* R. D. COLLINS S. B. KRANTZ

*Present address: Rockefeller University, New York, N.Y. 10021, U.S.A.

CLOMIPRAMINE AND CLONAZEPAM IN CATAPLEXY and paralysis of volunin association with narcolepsy. Amphetamine treatment of narcolepsy does not usually affect cataplexy greatly, but in 1970 Passouant and his colleagues showed that the tricyclic drug clomipramine had a specific effect on this disabling symptom.’ We have now treated 75 patients with cataplexy with clomipramine 10-150 mg daily for four to seven years. The frequency of attacks of cataplexy fell within 24-48 h of the start of treatment. Initial

SiR,--Cataplexy,

loss of muscle

tary movement, generally

tone

occurs

7. Damashek W, Schwartz RS: Leukemia and auto-immunization—some possible relationships. Blood 1959; 14: 1151-58. 8. Burke JS, Butler JJ, Fuller LM: Malignant lymphomas of the thyroid. A clinical pathologic study of 35 patients including ultrastructural observations. Cancer 1977; 39: 1587-1602. 9. Freeman HG, Weinstein WM, Shnitka TK, Piercey JRA, Wensel RH. Primary abdominal lymphoma: Presenting manifestation of celiac sprue or complicating dermatitis herpetiformis. Am J Med 1977; 63: 585-94. 10. Nime FA, Cooper HS, Eggleston JC: Primary malignant lymphomas of the salivary glands. Cancer 1976; 37: 906-12. 1. Passouant P, Baldy-Moulinier M, Aussiloux C. Etat de mal cataplectique au cours d’une maladie de Gelineau: influence de la clomipramine. Revue

Neurol 1970; 123: 56-60.

Magnesium and sudden death from heart disease.

1084 syringe manufacturers, pharmaceutical industry, and diabetic patients. The coordinator and the committee will enlist the support and patience of...
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