COCAINE ABUSE AND EATING DISORDERS

390 vaccines containing compounds binding self components must be I evaluated in chimpanzees or in man. 11 There have been some disturbing reports of low efficacy for currently HB vaccines. Being a result of tolerance induction due to the HSA-binding capacity of the vaccine, such non-responses can be expected to be much more frequent if synthetic peptides with even higher HSA-binding ability were to be used. Moreover, people with low-titre non-protective anti-HBs could be even worse off when exposed to such a vaccine, and subsequent HBV infection in such individuals could result in acute or fatal fulminant hepatitis. We think that the use of native HBsAg or pre-S coded peptides in future HB vaccines would be very unwise. HBsAg deprived of pre-S coded structures in combination with anti-idiotypic antibodies (the internal image of the alone or in combination with HBcAg,13 which we have found to be highly immunogenic in man, would be a wiser choice in the search for more effective vaccines.

antigenl2)

Elias

Bengtsson Research Unit, Department of Infectious Diseases, Karolinska Institute,

Roslagstull Hospital, S-11489 Stockholm, Sweden

ULLA HELLSTRÖM STAFFAN SYLVAN

1. Machida A, Kishimoto S, Ohnuma H, et al. A polypeptide containing 55 ammo acid residues coded by the pre-S region of hepatitis B virus deoxyribonucleic acid bears the receptor for polymerized human as well as chimpanzee albumins. Gastroenterology 1984; 86: 910-18. 2. Stibbe W, Gerlich WH. Structural relationships between minor and major proteins of hepatitis B surface antigen. J Virol 1983; 46: 626-28. 3. Hellström U, Sylvan S. Human serum albumin and the enigma of chronic hepatitis

type B:

Hypothesis. Scand J Immunol (in press). DE, Detomaso P, Papanice MA, et al. Receptor activity for polymerised human albumin in hepatitis B vaccine. Lancet 1985; i: 1515-16. 5. Hellström U, Sylvan S. Regulation of the immune response to hepatitis B virus (HBV) and human serum albumin. Scand J Immunol (in press). 6. Brotman B, Prince AM. Occurence of AUSAB test positivity unrelated to prior exposure to hepatitis B virus J Infect Dis 1984; 150: 714-20. 7 Jilg W, Schmidt M, Deinhardt F, Zachoval R. Hepatitis B vaccination: how long does protection last? Lancet 1984; ii: 458. 8. Neurath AR, Kent SBH, Strick NS, et al. Hepatitis B virus contains pre-S geneencoded domains. Nature 1985, 315: 154-56 9. Milich DR, Thornton GB, Neurath AR, et al. Enhanced immunogenicity of the pre-S region of hepatitis B surface antigen. Science 1985; 228: 1195-99. 10. Coursaget P, Barres JL, Chiron JP, Adamovicz P. Hepatitis B vaccine with and without polymerized albumin receptors. Lancet 1985; i: 1152-53. 11. Sylvan SPE, Hellström UB, Lundbergh P Detection of cellular and humoral immunity to hepatitis B surface antigen (HBsAg) in asymptomatic HBsAg carriers. Clin Expl Immunol 1985, 62: 288-95. 12. Liew FY. New aspects of vaccine development. Clin Expl Immunol 1985; 62: 225-41. 13. Iwarson S, Tabor E, Thomas HC, et al. Protection against hepatitis B virus infection by immunization with hepatitis B core antigen. Gastroenterology 1985; 88: 763-67. 4. Sansonno

FETAL DIAGNOSIS OF &bgr;-THALASSAEMIA BY DNA ANALYSIS IN ITALY best strategy for fetal diagnosis of &bgr;-thalassaemia by analysis in the Mediterranean area, where molecular defects are heterogeneous, has yet to be defined. Two approaches have been proposed-direct detection of the most frequent mutations by

SIR,-The

DNA

few complementary oligonucleotides and indirect analysis of restriction fragment length polymorphism (RFLP) linkage to the &bgr;-thalassaemia chromosomes within single families.22 Unfortunately, neither method is useful in every case. Oligonucleotides are of practical use only in restricted areas, where the gene defect is homogeneous;3and the usefulness of RFLP linkage analysis varies in different populations, and4 in our experience in Italy it can be used in only 65% of couples.4 The finding of new polymorphic sites in the (3-globin gene cluster may sometimes significantly increase the feasibility of fetal diagnosis by the RFLP approach. The AvaII polymorphism at the /3 gene levels raised the feasibility of fetal diagnosis of &bgr;-thálassaemia among Cypriots from 35% to 70%. Preliminary data in a small series suggested that the same polymorphism might be S promising in Italian populations also.5 To assess the usefulness of the AvaIl-tp&bgr; polymorphism in the fetal diagnosis of (3-thalassaemia in Italy we have re-evaluated for this polymorphic site a large series of normal and (3-thalassaemic chromosomes from Italian regions, previously characterised for other RFLP in the (3-globin gene cluster ( j3 haplotype).6 The results are summarised in the table. a

ABSENCE OF

AVaII-tp&bgr; POLYMORPHISM IN ITALIAN POPULATION

Absence of the 411- site, the origin for a 3’9 9 kb fragment, is in normal chromosomes (3-9%) but more frequent in (3-thalassaemic chromosomes (22 -3%). In both cases it was only observed in chromosomes with the common 5’ -globin haplotype, +----. Within the pattern of polymorphisms defined as haplotype 1,6 which is common both in non-thalassaemic and in thalassaemic Italian people, the 3’9kb fragment was in only 7 -4% of the normal but in up to 60% of thalassaemic chromosomes. Thus in normal Italians, as in Cypriots, the frequency of the 3’99 kb fragment in normal chromosomes is low, whereas in thalassaemic chromosomes it is more frequent in Cypriots (71%) than in Italians (22 -3%). Moreover, within haplotype I the 3 -9kb fragment is found in only 60% of Italian thalassaemic chromosomes, whereas it was found in at least 80% of Cypriots.Perhaps the molecular defects linked to haplotype I in Italy are more heterogeneous than the (3-thalassaemic mutation seen in Cypriots.’1 Since theAvaII-iN(3 polymorphism permits discrimination of only some of the normal and p-thalassaemic Italian chromosomes belonging to haplotype I, it only moderately increases the feasibility of fetal diagnosis via RFLP. Data for 43 Italian couples at risk show that 100% feasibility is increased only by about one-sixth (from 65% to 76%). Definition of a unique programme for the fetal diagnosis of P-thalassaemia in Italy thus remains difficult. Perhaps the best strategy when molecular defects are heterogeneous will be to rely on combined direct and indirect assays. This may be relevant to other genetic diseases that prove to be heterogeneous at the molecular level. rare

Medical Clinic A,

University of Turin Haematology Laboratory, Istituti Clinici di Perfezionamento,

20122 Milan, Italy

CLARA CAMASCHELLA GIUSEPPE SAGLIO ANNA SERRA LAURA CREMONESI MAURIZIO TRAVI MAURIZIO FERRARI

SL, Wainscoat JS, Old JM, et al. Feasibility of prenatal diagnosis of &bgr;-thalassaemia with synthetic DNA probes in two Mediterranean populations.

1. Them

Lancet 1985; ii: 345-47. 2. Old JM, Petrou M, Modell

B, Weatherall DJ. Feasibility of antenatal diagnosis of &bgr;-thalassaemia by DNA polymorphisms in Asian Indian and Cypriot population. Br J Haematol 1984; 57: 255-63. 3. Rosatelli C, Falchi AR, Tuveri T, et al. Prenatal diagnosis of &bgr;-thalassemia with the synthetic oligomer technique. Lancet 1985; ii: 241-43. 4. Camaschella C, Saglio G, Serra A, et al. DNA polymorphism analysis in the Italian population and prenatal diagnosis of thalassemia. In: Fraccaro M, Simoni G, Brambati B, eds. First trimester fetal diagnosis. Berlin: Springer, 1985: 276-82. 5. Wainscoat JS, Old JM, Thein SL, Weatherall DJ. A new DNA polymorphism for prenatal diagnosis of &bgr;-thalassaemia in Mediterranean populations. Lancet 1984; ii: 1299-301. 6. Orkin SH, Kazazian HH Jr, Antonarakis SE, et al. Linkage of thalassaemia mutation and globin gene polymorphisms with DNA polymorphisms in human &bgr; globin gene cluster. Nature 1982; 296: 627-31. 7. Old JM, Fitches A, Heath C, Petrou M, Modell B, Ward RHT, Weatherall DJ. Feasibility of first trimester diagnosis of &bgr;-thalassemia using DNA polymorphisms in the Cypriot population. In: Fraccaro M, Simoni G, Brambati B, eds. Berlin. Springer, 1985: 263-70.

COCAINE ABUSE AND EATING DISORDERS

SIR,-An accumulating body of evidence suggests a link between eating disorders, anorexia nervosa and bulimia. 1- However, there have been no systematic studies of the prevalence of eating disorders among individuals with severe drug abuse. We have done this with cocaine abusers, chosen because alterations in eating behaviour are commonly described in such substance abuse and the

individuals4,5 We administered a structured diagnostic interview to 259 consecutive callers to the national cocaine "hot line" who met

391 EATING DISORDER CHARACTERISTICS OF I

I

259 COCAINE ABUSERS I

I

METHYLENE-BLUE FOR

RIBOFLAVIN-UNRESPONSIVE GLUTARICACIDURIA TYPE II

DSM-III criteria for cocaine abuse. The interview assessed all DSM-III criteria for eating disorders, generated lifetime diagnoses of anorexia nervosa (ANN) and bulimia, provided data on frequency and duration of binging and purging behaviour, and supplied information about drug habits and the influence of drug use on eating patterns. To test the usefulness of our interview it was administered in questionnaire form to 157 consecutive admissions to Fair Oaks Hospital. The eating disorder diagnoses generated were then compared with clinical diagnoses. Of 33 patients with a clinical eating disorder diagnosis, 32 were correctly identified by the questionnaire. Among the remaining 124 patients without an eating

disorder,

2

were

diagnosed by questionnaire

as

having

an

eating

disorder (bulimia); both of these patients were obese. Of 21 cocaine abusers contained within the sample, 6 had a clinical diagnosis of either anorexia or bulimia and all were correctly identified by questionnaire. These findings suggested that the interview could be applied to assessment over the telephone of the prevalence of eating disorders. 57 (22%) of the 259 cocaine abusers met DSM-III criteria for bulimia, 18 (7%) met DSM-III criteria for both ANN and bulimia, and 6 (2%) met DSM-III criteria for ANN alone. While some have hypothesised that cocaine abuse may be perpetuated by an attempt to "self-medicate" an underlying disorder, we found little evidence to suggest that cocaine was being used for self-treatment of an underlying eating disorder. No more than 26% of any diagnostic group felt that cocaine helped their eating symptoms. Among cocaine abusers with no eating disorder diagnosis, 82% (146/178) binged twice a month or less, while 60% (45/75) of those with a lifetime diagnosis of bulimia had a history of binging at least once a week. Since few among the "no diagnosis" group even approached meeting the criteria for bulimia (only 6 had "possible bulimia"), it appeared that cocaine use was not simply simulating a bulimic syndrome. Earlier surveys of eating disordered patients have uncovered a high rate of drug abuse. Our data suggest that cocaine abusers will often have a concomitant eating disorder, supporting the -link between substance abuse and eating disorders. The nature of this link is unknown. Perhaps individuals with eating disorders and substance abuse have a third disorder in common, such as affective disorder. Alternatively, the propensity to addictive and compulsive behaviours may be expressed as the abuse of food or drugs. Patients with eating disorders should be questioned and possibly tested for drug abuse. Our data highlight the importance of screening patients with cocaine abuse for eating disorders. When anorexia nervosa or bulimia are suspected in such patients, the clinician should be wary of attributing abnormalities of eating. behaviour to drug abuse alone. Eating Disorders Program and Research Facilities, Fair Oaks Hospital, Summit, New Jersey 07901, USA

SIR,-Glutaricaciduria type II (multiple acyl-CoA dehydrogenase deficiency, MADD, McKusick 23168) in the first days of life is usually fatal and does not respond to riboflavin.This disease is very probably due to a severe deficiency of electron-transferring flavoprotein or of its dehydrogenase: acyl-CoA dehydrogenases cannot transfer their electrons to the respiratory chain and so become ineffective, leading to the accumulation of toxic metabolites. Goodman et al2 have suggested using methylene-blue, an electron acceptor, to treat riboflavin-unresponsive cases of MADD. A girl, born to non-consanguineous parents, was noted at the 15th hour of life to have an odour of sweaty feet. Gas chromatography revealed increased amounts of isovaleric, isobutyric, n-butyric, and hexanoic acids in her blood; and she excreted in urine abnormal amounts ofC6-CIO-dicarboxylic, ethylmalonic, methylsuccinic, and glutaric acids. Riboflavin, 100 mg/day (40 mg/kg) intramuscularly and then intravenously was started at hour 22. The acrid smell disappeared in a few hours and did not return, but the abnormal organicaciduria persisted. On day 5, lethargy and hepatomegaly appeared (with biological signs of hepatic insufficiency), accompanied with dyspnoea (compensated metabolic acidosis). The same organicaciduria persisted (in two previous cases of riboflavinresponsive-MADD with onset on day 1 the urinary organic acid profile had returned to normal by day 4 when riboflavin was used). The low-protein, low-fat diet was changed to intravenous glucose infusion. Intravenous L-carnitine 300 mg/kg daily resulted in massive short and medium chain acylcarnitine excretion (eg, isovalerylcarnitine was normal before, and 22 times higher after

carnitine). On day 6 the dyspnoea and organicaciduria were still present. Methylene-blue, 2 mg/kg per dose, was given intravenously at 1400 and 1500 hours. This resulted, 2-3 h later, in a clear improvement in the infant’s respiration and wakefulness. The same dose of methylene-blue was given at 2100 hours and at 0500 hours on day 7. Organic acids in urine collected between midnight and 0800 hours during this night were nearly normal (ethylmalonic acid 95 jumol/mmol creatinine). Riboflavin and L-carnitine were maintained. Methylene-blue injection was not given again on the morning of day 7. Urine obtained at noon contained ethylmalonic acid 398, adipic acid 138, suberic acid 69, sebacic acid 38, and glutaric acid 176 mol/mmol creatinine. The infant’s condition worsened. The therapeutic trial was stopped at the parents’ request and the infant died on day 7. Permission for necropsy was refused.

The sharp improvement in the organicaciduria after methyleneblue therapy is not likely to have been fortuitous, because of the recurrence of organicaciduria after the methylene-blue was stopped. This result suggests that acyl-CoA dehydrogenases can be reactivated by transferring their electrons to this electron acceptor. Methylene-blue should be started without delay, as soon as riboflavin unresponsiveness has become evident (the critical day may be day 4), or perhaps could be associated at first with riboflavin in every case of neonatal MADD.

JEFFREY M. JONAS MARK S. GOLD

DK, Eckert ED, Mitchell JE, et al. Affective disorder and substance abuse in women with bulimia. Psychol Med 1984; 14: 701-04. 2. Hudson JI, Pope HG, Jonas JM, et al. Phenomenologic relationship of eating disorders to major affective disorder Psychiatr Res 1983; 9: 345-54. 3 Hudson JI, Pope HG, Jonas JM, et al. Family history study of anorexia nervosa and bulimia. Br J Psychiatry 1983; 142: 133-38. 4 Estroff TW, Gold MS. Medical and psychiatric complications of cocaine abuse with possible points of pharmacologic treatment. Adv Alcoholism Substance Abuse 1985; 5 (in press) 5 Gold MS. 800-Cocaine. New York: Bantam Books, 1984. 6 Khantzian EJ. The self-medication hypothesis of addictive disorders: Focus on heroin and cocaine dependence. Am J Psychiatry 1985; 142: 1259-64.

Medical Genetics, Paediatric Clinic, Hôpital de la Salpêtrière, 75651 Pans, France

JEAN-PAUL HARPEY

1. Hatsukami

Biochemistry Laboratory, CHU Necker-Enfants Malades, Paris

CHRISTIANE CHARPENTIER MARIE COUDÉ

1. Goodman SI, Frerman FE. Glutaric acidaemia type II (multiple acyl-CoA dehydrogenation deficiency). J Inher Metab Dis 1984; 7 (suppl 1): 33-37. 2. Goodman SI, Stene DO, McCabe ERB, et al. Glutaric acidemia type II: clinical, biochemical, and morphologic considerations.J Pediatr 1982; 100: 946-50.