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secretion, may play a direct role in the development of myelo-fibrosis. In this syndrome there is a selective deficiency ofa-granules in platelets and megakaryocytes, associated with areticulinic myelofibrosis. 1-3 Ultrastructural and cytochemicalevidence of a lack of a-granules was correlated with the absence ofplatelet concentration of several polypeptides normally stored in thea-granules, notably platelet-derived growth factor (PDGF) andPF4, while their levels were normal or high in plasma.4,5The electron microscope reveals that isolated megakaryocytes

from patients with the GPS6 have several abnormalities: many smallimmature granules were present but they did not mature intoa-granules and the demarcation membranes were distended andcontained a dense material, which may be the proteins secreted bythe immaturea -granules. In culture, megakaryocytes studied by theindirect immunofluorescence test were labelled with an anti-PF4antibody only at the earlier stage and this labelling disappearedduring the late stages of maturation.7 These findings suggested thatthe proteins were synthesised in the precursors of the a-granules butthey could not mature and their content was discharged and passedinto the distended demarcation membranes. This release of

polypeptides from the immature a-granules to the outside mightexplain the fibrosis present in the bone marrow since PF4 maypresent an anticollagenase-like activity and PDGF stimulates thereplication of fibroblasts.8 Since in GPS the red and white bloodcells are normal and only the platelets ate decreased, we cannotsupport the hypothesis that PDGF enhances erythroid colonygrowth9 via stimulation of mesenchymal cells throughprostaglandin synthesis.Department of Angiohaematology,Hôpital Lariboisiere,75475 Paris, France

J. F. DESCHAMPSJ. P. CAEN

ANTIBODY RESPONSES AND SKIN REACTIVITYAFTER INTRADERMAL HEPATITIS B VIRUS

VACCINE

SIR,-Although Dr Miller and colleagues (Dec 24/31, p 1454)showed that intradermal inoculation with a reduced dose ofhepatitis B virus (HBV) vaccine (’H-B-Vax’; Merck Sharp &

Dohme) produces a seroconversion rate similar to that by intramus-cular inoculation, we find that antibody levels (anti-HBs) after thethird intradermal dose of vaccine are considerably lower.Our studylOwas designed to establish whether less vaccine was

needed with the intradermal route and to find out whether a singlemultisite injection produced such a high seroconversion rate thatfollow-up vaccinations could be reduced or omitted, as with rabiesvaccination. 11 We were also interested to see if skin reactions were

1. Drouet L, Praloran V, Cywiner-Golenzer C, Trehen C, Flandrin G, Caen J. Deficitcongénital en alpha granules plaquettaires et fibrose reticulinique medullaire.Hypothèse physiopathogénique. Nouv Rev Fr Hématol 1981; 23: 95-100

2. Coller BS, Hultin MB, Nurden AT, Rosa J-P, Lane BP. Isolated &agr;-granule deficiency(gray platelet syndrome) with slight increase in bone marrow reticulin and possibleglycoprotein and/or protease defect. Thromb Haemostas 1983; 50: 211 (abstr).

3. Berndt MC, Castaldi PA, Gordon S, Halley H, McPherson VJ. Morphological andbiochemical confirmation of gray platelet syndrome in two siblings. NZ J Med 1983,13: 387-90.

4 Nurden AT, Kunicki TJ, Dupuis D, Soria C, Caen JP. Specific protein andglycoprotein deficiencies in platelets isolated from two patients with the grayplatelet syndrome Blood 1982; 59: 709-18.

5 Levy-Toledano S, Caen JP, Breton-Gorius J, et al. Gray platelet syndrome: granuledeficiency. J Lab Clin Med 1981; 98: 831-48

6 Breton-Gorius J, Vamchenker W, Nurden A, Levy-Toledano S, Caen J. Defectivea -granule production in megakaryocytes from gray platelet syndrome. Am J Pathol1981; 102: 10-19

7 Deschamps J-F, Bodevin E, Caen J Usefulness of antibodies for the recognition ofabnormal PDGF and PF4 release in the cultured megakaryocytes of gray plateletsyndrome: relation with myelofibrosis. Blood 1983; 62 (suppl 1): 168a.

8. Castro Malaspina M, Rabellino EM, Yen A, Nachman RL, Moore MAS. Humanmegakaryocyte stimulation of proliferation of bone marrow fibroblasts. Blood 1981;57: 781-87

9. Delwiche F, Raines E, Powell JS, Ross R, Adamson J W Platelet-derived growth factor(PGDF) enhances in vitro erythroid colony growth via stimulation of mesenchymalcells. Blood 1983; 62 (suppl 1): 121a

10. Zoulek G, Lorbeer B, Jilg W, Dienhardt F. Evaluation of a reduced dose of hepatitis Bvaccine administered intradermally. J Med Virol (in press).

11. Nicholson KG, Prestage H, Cole PJ, et al. Multisite intradermal antirabies vaccination.Lancet 1981; ii: 915.

ANTIBODY TITRES AFTER INTRADERMAL (I) AND INTRAMUSCULAR (II)VACCINATION OF HBV VACCINE

Group I (intradermal vaccination): 9 adults, mean age 27±9. Group II (intramuscularvaccination and intramuscular plus* 5 lag intradermal challenge at 6 months): 10 adults,mean age 27±6.

t Geometric means of responders.

provoked in immune persons by intradermal injection of a smalldose of vaccine ; such reactions would be an easy method of detectingimmune persons and for monitoring the success of vaccinationwithout the need for laboratory support.The seroconversion rates achieved with a lower dose of vaccine

given intradermally and a higher dose given intramuscularly werecomparable at seven months (table): at six months, the levels ofanti-HBs titres after two vaccinations were almost comparable but’thethird (booster) injection at six months resulted in much higher levelsin the intramuscular group.In the intradermal group, no skin reaction was detected after the

first two vaccinations but after the third a skin reaction (indurationand/or erythema) was detected in 2 out of 9 vaccinees. In the othergroup 4 out of 10 had positive skin reactions after the third injection.Alum adjuvant alone given intradermally did not cause a skinreaction in any vaccinee, nor were any side-effects observed afterintradermal vaccination. 4 adults, immune through naturalinfection and positive for anti-HBc and anti-HBs, were inoculatedintradermally with 5 pg of vaccine. Only 1 had a skin reaction but 3weeks later anti-HBs level had risen in all 4 from 4758 to 47 923mIU/ml (geometric mean).Our study indicates that a single multisite injection of a reduced

dose of HBV vaccine is not sufficient to induce an immune

response; however, even a substantial reduction in dose achievesseroconversion if the usual course of three injections is maintained.However, the persistence of the much lower antibody titres must beevaluated in a larger study before intradermal vaccination with a lowdose can be recommended for general use. Skin testing detects onlysome immune persons or vaccine responders and is not suitable,therefore, as a screening procedure.

Max von Pettenkofer Institute,University of Munich,D-8000 Munich 2, West Germany

G. ZOULEKB. LORBEERW. JILGF. DEINHARDT

PREVENTING MILD MENTAL IMPAIRMENT

SIR,-I do not quarrel with the conclusions of your Jan 28 editorialon the importance of early childhood education to help remedysocial inequities. Your summary of American experience, however,is considerably more conservative than the evidence warrants.Persons unfamiliar with the Head Start, ESEA Title I, and SpecialEducation programmes in the United States may not appreciate theimportance of such programmes in facilitating the achievement ofchildren at risk. Almost every study of Head Start and earlyintervention programmes has demonstrated short-term gains in testscores, both in IQ and achievement tests, and many have recordedsubstantial long-term social and educational effects. Analysis of

1. The effects of the Head Start Program on children’s cognitive development.Washington, DC: US Department of Health and Human Services, ACYF, 1983.

2. Lazar DR. Lasting effects of early education: a report from the Consortium forLongitudinal Studies. Monogr Soc Res Child Devel 1982; serial 195.

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cost benefits of the Ypsilanti Preschool Project3 shows a

considerable financial gain for the community that puts its moneyinto preventive programme for young children rather than intoremedial education, welfare, and penal systems. If good resultsare to be achieved the quality of the intervention programme is ofcritical importance.Advanced Study in Child Development,Erikson Institute, Chicago, 60601 Illinois, USA BARBARA T. BOWMAN

SIR,-We were most interested in your Jan 28 editorial (p 200).We have studied a series of 500 children presenting with symptomsof mild mental retardation (MMR), a condition usually linked, asyou point out, with poverty and sociocultural deprivation. How-ever, in some cases a biomedical cause has been suggested.5-7By statistical analysis we distinguished three subcategories in whatat first glance seemed to be a homogeneous group. Thesesubcategories were significantly different (by chi square) for variousfactors such as IQ, sibship size, frequency of MMR among sibs, andpaternal occupation. Moreover, in one subgroup organic factorswere predominant. Some highly significant differences betweenthis subgroup (n = 70) and the other two (n=430) are as follows:

Factor Characteristics of subgroupPaternal occupation More fathers with regular employmentSize of sibship Less children per familySociocultural level Close to general populationPremature births More than in two other subgroupsApgar score Low

This suggests, in this subgroup (14% of the total), a closer linkwith an organic aetiology than in the other two subgroups. In 66%of the whole series sociocultural deprivation seemed predominant.We are currently exploring the remaining 20%. So far we havefound some familial cases of monogenic disease, chromosomeanomalies (apparently balanced translocations and Xq23 fragilesite), and a few environmentally related diseases such as fetal alcoholsyndrome. Not all cases of MMR are due to socioeconomic

deprivation. At least 14% and perhaps up to one-third of all MMRshows an organic aetiology and might be preventable.Department of Genetics,Institut de Morphologic Pathologique,B6270 Loverval, Belgium

Y. GILLEROTL. KOULISCHER

DOWN’S SYNDROME AND HYPOTHYROIDISM:COINCIDENCE OR CONSEQUENCE?

SIR,-Thyroid dysfunction in patients with Down’s syndrome is achallenging medical problem because of the increased incidence ofautoimmune thyroiditis in this patient group. However, bothpatients with Down’s syndrome and patients with hypothyroidismclinically do have several signs and symptoms in common, making ita difficult clinical diagnosis. The syndrome is named for Dr J. L. H.Down, medical superintendent of the Earlswood Asylum for Idiotsin London, who in 1866 published a paper differentiating these twopatient groups.8 8 ,

Thyroid dysfunction in adults with Down’s syndrome is wellrecognised. But at what age in childhood did it develop in patientswho are detected in the adult age groups?In 1979, our research group started a preventive medicine

programme for Down’s syndrome individuals.9 As part of their

3. Schweinhart LJ, Welkart DP. Young children grow up: the effects of the PerryPreschool Program on youth through age 15. Ypsilanti, Michigan: High/ScopePress, 1980.

4 Gillerot Y, Koulischer L. Le retard mental léger: Etude de 500 cas. Louvain Méd 1983;102: 461-71.

5. Costeff H, Cohen BE, Weller LE. Biological factors in mild mental retardation. DevelopMed Child Neurol 1983; 25: 580-87.

6. Birch HG, Richardson SA, Baird D, Horobin G, Illsley R. A clinical and

epidemiological study: Mental subnormality in the community. Baltimore:Williams and Wilkins, 1970.

7. Hagberg B, Hagberg G, Lewerth A, Lindberg U. Mild mental retardation in Swedishschool children. Acta Paediatr Scand 1981; 70: 441-52.

8. Langdon Down J. Observations on an ethnic classification of idiots. Clin Lect Rep LandHasp 1866; 3: 259.

9. Coleman M. Medical care of Down’s syndrome children and adults. In: Edgar EB,Haring NG, Jenkins JR, Pious CG, eds. Mentally handicapped children. Baltimore:University Park Press, 1982: 33-45.

annual routine evaluation, patients had laboratory tests for

thyroxine (T4), triiodothyronine, and thyroid-stimulating hormone(TSH). Criteria for diagnosis of hypothyroidism were a T4 below5 fg/dl and a TSH value above 10 flU. In borderline cases,thyrotropin-releasing hormone (TRH) and free T4 concentrationswere measured. In borderline cases, an exaggerated TSH responseto TRH and a low free T4 are considered diagnostic.

In the first three years, hypothyroidism was found to be

developing in 16 out of 206 (8%) of the patients under 18 years ofage: 7 were under 5 years of age and 3 were 15 or more. All had the

trisomy 21 form of Down’s syndrome; 15 out of 16 had chroniclymphocytic thyroiditis and 1 had a goitre. The patients had hadnormal thyroid function tests in previous testing, if such testing hadbeen done. For example, the infant who was picked up at six monthsof age had had a normal neonatal thyroid screening test.Even in retrospect, thyroid disease was not clinically apparent in

most cases. Most of the patients were in the age groups birth to threeyears and between five and fifteen years.We do not recommend that thyroid be routinely administered to

every Down’s syndrome child. 10 The lack of value of that approachhas been well documented by Koch et all Indeed, if thyroid isgiven inappropriately to infants, it can cause intellectual

impairment related to craniostenosis;12 If, on the other hand,treatment is given on an individual basis in cases of real thyroiddysfunction it can be of value in keeping some Down’s syndromechildren performing at their maximum levels of achievement. Thesigns and symptoms of hypothyroidism may not be apparent inDown’s syndrome children; regular laboratory tests of thyroidfunction can be as a preventive health measure in this patient group.

Department of Pediatrics,Georgetown University,School of Medicine,Washington, DC, USA

MARY COLEMANVAL ABBASSI

HANDLING MUTAGENIC DRUGS

SIR,-Concern about occupational exposure to anti-cancer drugs,first raised in 1970,1 was resurrected in 1979 by Falck andcolleagues’ report of mutagenicity in the urine of nurses handlingsuch drugs.2 Review of subsequent studies demonstrates the need foradditional research with better techniques. The usefulness of theAmes test and similar methods in screening occupationally exposedpersonnel is questionable: diet and smoking may produce falsepositives, while other factors, including concurrent exposure toantibiotics, may produce false negatives.In a comprehensive, longitudinal study with 24 h urinary

collections for 8 days Anderson et al3 demonstrated mutagenicity inthe urine of six pharmacy workers handling cancer chemotherapydrugs in a horizontal laminar-flow hood. The mutagenic responsediffered from subject to subject and with the strain of bacteria used.No subject exhibited mutagenicity before 2 days of exposure, whilemutagens were detected in the urine of one subject only at day 7. Inanother subject, no substantial amounts of mutagens were detectedthroughout the 8 day period. As in other studies there was no clearcorrelation between the amounts and type of drug handled and thetest system response. Individual technique, drug absorption and/ormetabolism, and pharmacodynamics all affect the results, and mustbe considered when making judgments based on studies that, forexample, involve only a few subjects, are based on "spot" urinesamples rather than 24 h collection, or combine different

populations. Urine mutagenicity research neither strongly supports

10. Harrell RF, Capp RH, Davis DR, Peerless J, Ravitz LR. Can nutritional supplementshelp mentally retarded children? An exploratory study. Proc Natl Acad Sci USA1981; 78: 574-78

11. Koch R, Share J, Graliker B. The effects of cytomel on young children with Down’ssyndrome (mongolism): a double-blind longitudinal study J Pediatr 1965; 66:776-78.

12. Daneman D, Howard NJ Neonatal thyrotoxicosis intellectual impairment and cranio-synostosis in later years J Pediatr 1980, 97: 257-59.

1. Ng LM Possible hazards of handling antineoplastic drugs. Pediatrics 1970; 46:648-49.

2. Falck K, Grohn P, Sorsa M, Vaino H, Heinonen E, Holsti LR. Mutagenicity in urine ofnurses handling cytostatic drugs Lancer 1979; i: 1250-51

3. Anderson RW, Puckett WH, Dana WJ, Nguyen TV, Theiss JC, Matney TS. Risk ofhandling injectable antineoplastic agents. Am J Hosp Pharm 1982; 39: 1881-87.