638

Systolic (S) and diastolic (D) blood pressures in 3 patients duringhigh-dose ketoconazole treatment for stage D prostate cancer.

DC = discontinuation of treatment.

profile was done in 2 of these patients (4 and 7), and in 2 otherpatients who also received high-dose ketoconazole but who didnot have hypertension. All 4 patients had increases in

deoxycorticosterone, corticosterone, and 11-deoxycortisol levels.The median increase in deoxycorticosterone levels was 9-2 and 90nmol/1 for the 2 hypertensive patients, and 4-5 and 75 nmol/1 for theother 2 patients (upper normal limit =0-6 nmol/1). Cortisol andaldosterone levels stayed normal. The increase in deoxycortico-sterone and 11-deoxycortisol plasma levels without a concomitantincrease in aldosterone and cortisol indicates that the cytochromeP450 dependent adrenal 11 p-hydroxylase may be partly inhibitedby ketoconazole. 7,8

It is likely that patients who have hypertension during high-doseketoconazole treatment may be especially sensitive to the

mineralocorticosteroid effect of deoxycorticosterone. Therefore,blood pressure should be monitored during high-dose ketoconazoletreatment.

Department of Oncology B,Finsen Institute,2100 Copenhagen, Denmark KRISTIAN AABO

Janssen Pharmaceutica,Beerse, Belgium ROLAND DE COSTER

1. Santen RJ, Van den Bossche H, Symoens J, Brugmans J, De Coster R. Site of action oflow dose ketoconazole on androgen biosynthesis m men. J Clin Endocrinol Metab1983; 57: 732-36.

2. Shurmeyer Th, Neischlag E. Ketoconazole-induced drop m serum and saliva

testosterone. Lancet 1982; ii: 1098.3. Pont A, Williams PL, Ashar S, et al. Ketoconazole blocks testosterone synthesis. Arch

Intern Med 1982; 142: 2137-47.4. Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet

1984; ii: 433-35.5. Pont A, Williams PL, Loose DS, et al. Ketoconazole blocks adrenal steroid synthesis.

Ann Intern Med 1982; 97: 370-72.6. White MC, Kendall-Taylor P. Adrenal hypofunction in patients taking ketoconazole.

Lancet 1985; i: 44-45.7. Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D. Ketoconazole blocks adrenal

steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest1983; 71: 1495-99.

8. De Coster R, Caers I, Coene M-C, Amery W, Beerens D, Haelterman C. Effects ofhigh dose ketoconazole therapy on the main plasma testicular and adrenal steroidsin previously untreated prostatic cancer patients. Clin Endocrinol 1986; 24: 657-64.

MYDRIATIC RESPONSE TO TOPICAL NALOXONE INANOREXIA NERVOSA

SiR,—Topical application of naloxone causes a relative mydriasisin opioid abusers,’ in normal subjects after topically appliedmorphine and in exercising athletes3 (endogenous opioid), but notin normal resting controls. I have found that topical naloxone has asimilar effect on the eyes of some patients with anorexia nervosa.

Six young females with anorexia being treated as inpatients at theGordon Hospital, London SW1, or Queen Elizabeth MilitaryHospital, Woolwich, agreed to take part in this study. None of themwere opioid abusers. They gave their informed consent. Upper facephotographs were taken with a flash. A sterile solution of naloxone0- 16 % in saline was then applied to one eye. Saline from an identicalbottle was administered to the other eye. 20-30 min later a further

photograph was taken. Care was taken that the volunteers weregazing into the distance, and that uniform, dim, neutral illuminationwas used.3 Pupil sizes were measured from the photographsenlarged to life size. No anisocoria was detected in photographstaken before administration of naloxone drops.

PUPIL ENLARGEMENT IN RESPONSE TO TOPICAL NALOXONE IN

PATIENTS WITH ANOREXIA

Endogenous opioids (endorphins) have been implicated inanorexia nervosa and bulimia and systemic naloxone has been usedin the treatment of anorexia,4 although the exact nature of itstherapeutic action is not clear. The results of this study (table) alsosuggest that abnormally high levels of endorphins are present inanorexia nervosa. The simple, non-invasive pupil test describedmay be of clinical value both as a confirmatory diagnostic test and indetermining whether endorphin levels fluctuate in the disease. Infour of the five responders the pupil response was obvious on directinspection, so photographs may not be necessary routinely. The onenon-responder was tested immediately after a main meal, whereasthe other five volunteers were tested between or before meals.Further work is in progress to determine whether pupil responsevaries diurnally or in response to food.

I thank Dr J. Gomez for her help and advice, Dr P. Dally for allowing meaccess to his patients, and Dupont (UK) for donating naloxone powder.

Department of Ophthalmology,Queen Elizabeth Military Hospital,London SE18 4QH M. F. P. GRIFFITHS

1. Ghodse AH, Bewley TH, Kearney MK, Smith SE. Mydriatic response to topicalnaloxone in opiate abusers. Br J Psychiatry 1986; 148: 44-46.

2. Bellini C, Bacaini M, D’Egidio P, et al. Naloxone anisocoria: a non-invasive

inexpensive test for opiate addiction. Int J Clin Pharm Res 1982; 11: 55-60.3. Allen M, Thierman J, Hamilton D. Naloxone eye drops reverse the miosis of

runners—implications for an endogenous opiate test. Can J Appl Sport Sci 1983; 8:98-103.

4. Moore R, Mills IH, Forster A. Naloxone in the treatment of anorexia nervosa: Effecton weight gain and lipolysis. J Roy Soc Med 1981; 74: 129-31.

DIABETES IN RURAL WEST AFRICA

SiR,—Professor Teuscher and colleagues (April 4, p 765) reportthe absence of diabetes in two West African (Togolese) villages,and subsequently (June 27, p 1496) they criticise the WHOclassification of diabetes mellitus, in which malnutrition-relateddiabetes mellitus (MRDM) ranks third. Dr de Caestecker and DrBates (July 25, p 22) reported 33 diabetic patients from the urbanarea of Kumasi, Ghana, and found that 3 patients fulfilled all thecriteria for MRDM while 4 other patients qualified on all criteriaexcept age of onset. We have looked at diabetes in rural Ghana, inthree different hospital populations-namely, Agogo and Dormaa,in the forest area, populated by Akan people; Dzodze, in the Volta

639

region, populated by Ewe people; and Bawku, Upper-East region,with a variety of tribes.

In Agogo and Dormaa diabetes is fairly common. Cassava (inunfermented form) and plantain (boiled and pounded, eaten as fufu)are the main staple foods. In Agogo Hospital, catering for 170 000people, the records of 90 diabetic outpatients were studied; the maleto female ratio was 49:41; 16 were below 30 years of age at onset, andthe mean age at onset of diabetes was 44 years. Only 2 patients hadever had ketosis. Body mass index was recorded in only 12 patients;8 met all the criteria of Ahujal for MRDM (BMI below 19 kg/m2,age at onset below 30 years, poor control on insulin, absence ofketosis, and poor socioeconomic status). In Dormaa Hospital,catering for 100 000 people, 60 newly discovered cases and 20already registered cases were studied; the sex ratio was 55 males to25 females. Mean BMI was 21.5 kg/m, mean age at onset was 47years. Only 1 patient met all criteria for MRDM.

In contrast, diabetes was rarely seen in Bawku Hospital, serving300 000 people; the only diabetes cases seen were Akan traders,from Kumasi. The staple food in the Bawku area is not cassava, butmillet and maize. In the Dzodze district hospital for 150 000 people,diabetes was also uncommon; only 1 patient, an Akan, was beingtreated with insulin (Dr P. Doe Dagbui, personal communication).Cassava is an important staple food among the Ewe, the ethnicgroup studied by Teuscher et al, but is consumed in fermentedform.The prevalence of MRDM was low in the Akan; more striking is

the prevalence of non-insulin-dependent diabetes mellitus in theseareas, especially when compared with Bawku and Dzodze areas,where boiled cassava is not consumed. Our findings in the ruralAkan areas seem to accord with the findings in the urban Akan ofKumasi and Accra;"’ insulin-dependent diabetes mellitus seemsrare.

MRDM exists in rural West Africa.3 The great heterogeneity ofcultures and environments that make up the continent Africa (youreditorial, July 25, p 192) calls for care to be taken in drawingconclusions from surveys like Teuscher’s.

PSO Accra,PO Box 20061,2500 EB The Hague, Netherlands;

and Agogo, Dormaa, and Bawku Hospitals,Presbyterian Church of Ghana

TJIP VAN DER WERFSJOERD ZWARTREIN STEENSTRA

1. Ahuja MM. Diabetes: Special problems in developing countries. Bull Deliv HealthCare Diabetics Devel Countries 1980; 1: 5-6.

2. Owusu SK. Diabetes in Ghana: a 10 year study. Ghana Med J 1976 (June): 93-96.3. Abu-Bakare A, Taylor R, Gill GV, Alberti KGMM. Tropical or malnutrition-related

diabetes: a real syndrome? Lancet 1986; i: 1135-38.

1,25-DIHYDROXYVITAMIN D3, THE c-mycONCOGENE, AND CELL REGULATION

SIR,-A May 16 Lancet editorial discusses the role of 1,25-dihydroxyvitamin D3 (1,25[OH]DJ in growth, differentiation,and immunoregulation and concludes that although a unifyinghypothesis for the mechanism of action of 1,25(OH)2D3 in a varietyof cell types has yet to be proposed the notion that the hormone has afundamental role in regulating intracellular calcium has appeal. Iwould like to draw attention to evidence for an alternative basis forthe wide biological role of 1,25(OH)2D3-namely, that its anti-proliferative/pro-differentiation actions might be related to effectson oncogene expression.The pro-differentiation effects of 1,25(OH)D in promyelocytic

leukaemia cells (HL-60) are preceded by a striking decrease in theexpression of c-myc.1,2 Moreover, removal of 1,25(OH),D,, fromcultures of HL-60 cells results in a reversion-of the cells to a more

myeloblastic phenotype, renewed cell replication, and a rapidincrease in c-myc mRNA.3 The antiproliferative, immunosuppres-sive effects on lymphocytes4 might also be related to c-myc since1,25(OH)D inhibits c-myc mRNA expression in normal humanlymphocytes activated in vitro with mitogenic lectins.5Both in HL-60 cells and in lectin-activated lymphocytes

1,25(OH)2D3 exerts its effects at the Gl stage of the cell cycle.6,’ Itdoes not influence the transition of lymphocytes from GO to G17This cell-cycle specificity, together with the finding thatextracellular calcium cannot influence the antiproliferative effect on

lectin-stimulated lymphocytes,’ favours a genomic mechanism ofaction consistent with the inhibitory effect on c-myc expression.Support for this view is provided by the report of Simpson et al8 thatl,25(OH):;D;j inhibits c-myc directly at the transcriptional level.Another dimension to the link between 1,25(OH)2D, and c-myc

has emerged lately. My co-workers and I9 have obtained evidence tosuggest that the expression of the receptor protein for 1,25(OH)2D3in eukaryotic cells, in general, might be associated with theexpression of c-myc. We have suggested that this could account forthe ubiquity of the 1,25(OH)2D3 receptor protein in a plethora ofcell types. It is tempting to speculate that 1,25(OH)2D3 might be anegative feedback signal in a regulatory loop of oncogene-drivenproliferation and differentiation, whereby expression of oncogenessensitises the cells to 1,25(OH)2D3 (by enhancing expression of itsreceptor protein) and then the hormone, acting via its receptor,closes the loop by suppressing oncogene expression. Evidence that1,25(OH)2D3 is synthesised in situ by a variety of cells10-12 is in linewith this hypothesis and raises the possibility of an autocrineregulatory role of 1,25(OH)2D3 in fundamental cell processes thatare perturbed by oncogenes.

Department of Medicine,University of California, San Diego;

and VA Medical Center,San Diego, California 92161,USA STAVROS C. MANOLAGAS

1. Reitsma PH, Rothberg PG, Astrin SM, et al. Regulation of myc gene expression inHL60 leukaemia cells by a vitamin D metabolite. Nature 1983; 306: 492-95.

2. Brelvi ZS, Studzinski GP. Changes in the expression of oncogenes encoding nuclearphosphoproteins but not C-Ha-ras have a relationship to monocytic differentiationof HL60 cells. J Cell Biol 1986; 102: 2234-43.

3. Bar-Shavit Z, Kahn AJ, Stone KR, et al. Reversibility of vitamin D-induced humanleukaemia cell-line maturation. Endocrinology 1986; 118: 679-86.

4. Manolagas SC, Provvedini DM, Tsoukas CD. Interactions of 1,25-dihydroxyvita-min D3 and the immune system. Mol Cell Endocrinol 1985; 43: 113-22.

5. Matsui T, Takahashi R, Nakao Y, et al. 1,25-dihydroxyvitamin D3-regulatedexpression of genes involved in human T-lymphocyte proliferation anddifferentiation. Cancer Res 1986; 46: 5827-31.

6. Studzinski GP, Bhandal AK, Brelvi ZS. Cell cycle sensitivity of HL-60 cells to thedifferentiation-inducing effects of 1,25-dihydroxyvitamin D3 Cancer Res 1985; 45:3898-905.

7. Manolagas SC, Provvedini DM, Murray EJ, et al. The antiproliferative effect ofcalcitriol on human lymphocytes. J Clin Endocrinol Metab 1986; 63: 394-400.

8. Simpson RU, Todd H, Begley DA. Transcriptional regulation of the c-mycprotooncogene by 1,25-dihydroxyvitamin D3 in HL-60 promyclocytic leukemiacells. J Biol Chem 1987; 262: 4104-08.

9. Manolagas SC, Provvedini DM, Murray EJ, et al. Association between the expressionof the c-myc oncogene mRNA and the expression of the receptor protein for1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 1987; 84: 856-60.

10. Koeffler HP, Reichel H, Bishop JE, Norman AW. Gamma-interferon stimulatesproduction of 1,25-dihydroxyvitamin D3 by normal human macrophages. BiochemBiophys Res Commun 1985; 127: 596-603.

11. Adams JS, Sharma OP, Gacod MA, Singer FR. Metabolism of 25 hydroxyvitamin D3by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1987; 72:1856-60.

12. Mudde AH, van den Berg H, Boshuis PG, et al. Ectopic production of 1,25-dihydroxyvitamin D by B-cell lymphoma as a cause of hypercalcemia. Cancer 1987;59: 1543-46.

AVOIDABLE DRUG INTERACTION, NOTMENINGITIS

SiR,-Not that it matters to the point of your Round the Worldcorrespondent’s report on An Abundance of Physicians? (Aug 1, p267) but he has got the facts wrong: the young woman in questionwas given pethidine (meperidine) although she.was known to haveingested monoamine-oxidase inhibitors/tricyclic antidepressants.She became agitated with a high fever and died. Failure to diagnosemeningitis was never in question, and meningitis was not found atnecropsy. The accusations of culpability your correspondentdiscusses were based on the precipitation of a well-recognised andavoidable drug interaction and on failure promptly to attend thepatient when nurses reported her distress.

Department of Pathologyand Laboratory Medicine,

Women & Infants Hospitalof Rhode Island,

Providence, Rhode Island 02905, USA A. S. KNISELY

* Our RTW correspondent recalls meningitis bein,g mentioned inearly reports of this distressing case, but Dr Knisely is correct: thefinal issue was one of avoidable drug reaction.-ED. L.