524
experience with 424 cancer patients receiving morphine alone,morphine plus haloperidol in daily doses up to 5 mg (used as anantiemetic), and morphine plus larger doses of haloperidol (up to20-30 mg/day). The figure shows that there is clearly no left shiftin the dose histograms (and plots of cumulative distributionsconfirm this). Patients receiving haloperidol were in fact generally
. being treated with higher doses of morphine, and the distributionsfor the morphine only patients and morphine plus low dosehaloperidol are significantly different at the 5% level (KolmogorovSmirnov test).There are limitations to this sort of retrospective review. The data
may reflect the bias of the prescribing physicians whose thresholdfor using haloperidol as an antiemetic is generally lower if patientsare receiving high doses of morphine. However, the data do showthat there is not even a suggestion of any opioid-sparing effect in ourpatients. Haloperidol remains our antiemetic of choice for narcoticor radiation induced nausea and emesis 10 but the evidence that it isanalgesic or that it has a specific opioid-potentiating effect is
unconvincing.We thank Dr R. G. Twycross for allowing us to study his patients.
Royal Marsden Hospital,London SW 36JJ G. W. HANKS
Department of Mathematics, Statistics,and Computing, Oxford Polytechnic P. J. THOMAS
Sir Michael Sobell House,Churchill Hospital, Oxford
T. TRUEMANE. WEEKS
THREE CASES OF ALLERGIC REACTION TO HUMANINSULIN
SIR,-Parr et all consider that the only indication for transferringa patient to human insulin (HI) is the rarely encountered generalisedallergic response to insulins of animal origin. However, Carveth-Johnson et -al2 have reported an allergic reaction to HI in a patientknown to be sensitive to highly purified beef insulins. Frankland3 3
questioned this observation, which was ascribed by Blandford et al4to the "hapten carrier" characteristics of immunogenic porcine orbovine insulin in relation to the "haptenic" role of HI in theinduction of the generalised allergic response observed. Threerecent observations shed some light on this issue.A 47-year-old man with a history of asthma had a swelling at the
injection site followed by acute dyspnoea 8 months after startingtreatment with a highly purified beef insulin (PBI). Highly purifiedporcine insulin (PPI, Novo and Nordisk) caused the same reaction,as did HI (Novo). A standard 3-week desensitisation protocol withPPI and hydrocortisone injections led to a progressivedisappearance of the local reaction, and treatment was continuedwith PPI.A 35-year-old pregnant woman with a history of asthma and
penicillin allergy, and two previous uncomplicated pregnancies,required insulin for gestational diabetes from 19 weeks to delivery.After 2 months of treatment with PPI, she had a strong andimmediate reaction at the injection site. Intracutaneous tests usingone unit of PPI (Organon, Novo, Nordisk) resulted in wheal-and-flare of more than 5 mm and up to 15 mm in less than 5 min. Testsshowed a milder reaction to HI, which could be administered up tothe time of delivery with only a slight local reaction for 60 min aftereach injection.A 29-year-old woman with a history of penicillin allergy received
PBI without allergic reaction in the last 10 weeks of her first
pregnancy. She was treated with PPI 23 months later, at the 32nd
10. Hanks GW. Antiemetics for terminal cancer patients. Lancet 1982; i: 1410.
1. Parr JH, Abraham RR, Davie MWJ, Dornhorst A, Wynn V. Whither the latest insulin?Lancet 1982; ii: 831.
2. Carveth-Johnson AO, Mylvagama K, Child DF. Generalised allergic reaction withsynthetic human insulin. Lancet 1982; ii: 1287.
3. Frankland AW. Generalised allergic reaction with synthetic human insulin. Lancet1982; ii: 1468.
4. Blandford RL, Sewell H, Sharp P, Hearnshaw JR. Generalised allergic reaction withsynthetic human insulin. Lancet 1982; ii: 1468.
week of a second pregnancy. Swelling of hands, teet, and earsdeveloped immediately accompanied by nausea and dizziness, and apersistent rash. Shift to HI led to the same reaction. Insulin wasstopped and the patient remained mildly diabetic (fasting bloodglucose 7 mmol/1) until 37 weeks, when she delivered a normal babvThe generalised skin reaction lasted for several days after insulinwithdrawal. Intracutaneous tests were positive with all forms ofinsulin, including HI at high dilutions (1/400).We conclude that primary allergy to HI has not yet been
demonstrated. The hapten-carrier theory, advanced in a case wherethe generalised allergic response disappeared 18 months afterwithdrawal of insulin, may or may not account for a demonstratedreaction 23 months after a short period of treatment with PBIDesensitisation protocols with PPI have generally proved effective.In patients with insulin allergy, a record of intermittent insulintreatment, or allergic manifestations, transfer to HI is unlikely to bethe answer, although it may be of use if used from the outset in
patients with a history of allergic disease.
Diabetology Service,Hôtel Dieu,75181 Pans, France
J. J. ALTMANM. PEHUETG. SLAMAC. TCHOBROUTSKY
SKELETAL LEAD BURDEN IN ABORIGINE PETROLSNIFFERS
SIR,-An X-ray fluorescence (XRF) system similar to that ofAhlgren and Mattsson has been developed in Australia. Previouslyused on isolated occupationally lead-exposed subjects, the low-costapparatus (8000) was flown to an Aboriginal settlement 300 kmeast of Darwin, where one of us detected moderately raised bloodlead levels 2-4-3-1 µmol/1 (1 µmol/1=20.7 µg/d1) in fourteenhabitual petrol-inhaling teenagers.2 Four years later "sniffing"continued unabated and measurements of lead were made in bone,blood, and hair. Petrol inhaling is endemic in other remote nativepopulations, such as the Canadian Arctic. The inhaled organic leadis converted to inorganic lead which competes with calcium fordeposition in bone.The fore or middle finger is lightly clamped and bilaterally exposed for
1000 s from two IGBq Co sources collimated to irradiate 1 ml of the secondphalanx. Characteristic K X-rays emitted by lead are measured with a solidstate detector-spectrometer. The count rate is related to lead concentration bycomparison with measurements on "phantoms" containing a knownconcentration of lead. The absorbed dose is about 500 mrad (5 mGy) to the I r-n-I
of irradiated finger, representing a mean active bone marrow dose of less than0.2 2 mrad averaged over the total body bone marrow. The lower level of
detection is 20 ppm bone mineral mass (ppm). The standard deviation 01repeated measurements on eight subjects was ±14 ppm.
Blood lead levels of 70 sniffers and 40 non-sniffers were measured by atomicabsorption spectometry. For hair analysis large samples were taken, inctudmshair 3-4 cm from the hair-ends, prepared, and analysed, the hair being soakedin 2% EDTA to remove external contamination. For hair readings 67 sniffersare compared with 51 non-sniffers. Blood and hair leads correlated (p<0.005)but there was no significant correlation between hair lead and bone lead
In all cases with detectable bone lead (20 ppm), blood lead was alsoraised-ie, thus there were no false positives using XRF-and all XRF pos!t!vecases had blood lead above 1. 7 µmol/1 (table). Sniffing is a childhood andteenage group activity and the members of a group can be ascertained Ther:were two groups of regular sniffers, each with about 30 members of who.T.about 6 were females. "Retired" sniffers are included in the sniffer cohon
Among the 60 sniffers tested by XRF, values for bone lead of 20 ppm or overwere found in 23 (table). XRF was used in 18 non-sniffer controls and bone lead a,:
was not detected in any.
1. Ahlgren L, Mattsson S. An X-ray fluorescence technique for the in-vivo determinationof lead concentration in bone matrix. Phys Med Biol 1979; 25: 136-45.
2. Eastwell HD. Petrol inhalation in aboriginal towns: its remedy. the homelandsmovement. Med J Aust 1979; ii: 221-24.
3 Boeckx RL, Postl B, Coodin PJ. Gasoline sniffing and tetraethyl lead poisoning inchildren. Pediatrics 1977; 60: 140-45.
4. Ahlgren L, Haegar-Aronson B, Mattsson S, Schutz A. In-vivo determination of lead inthe skeleton after occupational exposure to lead. Br J Indust Med 1980; 37: 109-13.
5. Reilly C. A comparison of zincs in scalp hair of residents of Oxford UK and BrisbaneQld. Proc Nutr Soc Aust 1981; 6: 141-43.
525
LEAD PROFILE:
BOXE (ppm), BLOOD (µmol/1), AND HAIR (ppm) CONCENTRATIONS
The mean blood lead level was significantly greater (r.=110; t=16-8;p<0.001) in sniffers (2.55 µmol/1) than in non-smfFers (0 6 µmol/1). 25 sniffershad bone lead not detectable on XRF but raised blood lead values (mean 2 - 6µmol/1). Their sniffing may have been recent so that bone lead had not reacheddetectable levels. Mean hair lead also differed significantly between sniffersand non-sl11ffers (n=118, t=8-35; p<0.001) with means of 23 - and 12.4
ppm, respectively.The present results indicate a need for chelation therapy in many
of these young subjects because of high blood leads. Chelation is notlikely to lower bone lead significantly. So far, Aboriginal authoritieshave refused to add mercaptanes to petrol used locally, to make itunfit for inhalation.
We thank Dr C. Reilly, Queensland Institute of Technology, for the hairlead measurements, and to Mr E. Low, Royal Brisbane Hospital, for blood leadlevels. The XRF equipment and the technician’s salary were provided by agrant from the Australian National Health and Medical Research Council.
’
University Department of Psychiatry,Clinical Sciences Building,Royal Brisbane Hospital,Queensland 4029, Australia H. D. EASTWELL
Department of Physics,Queensland Institute of Technology
B. J. THOMASB. W. THOMAS
ENLARGEMENT OF CEREBRAL VENTRICLES INSCHIZOPHRENICS IS CONFINED TO THOSE
WITHOUT KNOWN GENETIC PREDISPOSITION
SIR,-A proportion of schizophrenics show moderate cerebralventricular enlargement, though efforts to delineate this groupother than by computerised tomography (CT) have met with littlesuccess.
The existence of a major genetic component to schizophrenia iswell established, the contributions of genes and environment beingroughly 70% and 30%, respectively. 2 Identical (MZ) twinsdiscordant for schizophrenia can be used to disentangle the geneticand environmental contributions, since any differences betweenMZ twins must be environmental. On the basis of CT scans of suchtwins we suspected that cerebral ventricular enlargementrepresents a mainly environmental process; the schizophrenicmembers of the discordant pairs had larger cerebral ventricles thantheir healthy co-twins. This suggested that where a geneticpredisposition is manifest (ie, by family history of major psychiatricdisorder or by concordance in an MZ co-twin) there should be noevidence of cerebral ventricular enlargement on CT scan.We tested this hypothesis in 21 schizophrenic MZ twins (12 with
co-twins discordant and 9 with co-twins concordant forschizophrenia) and 18 age-matched controls from 18 healthy MZpairs. All subjects were interviewed for psychiatric diagnosis, 4
Editorial The CT scan in schizophrenia. Lancet 1982; ii: 968.Gottesman II, Shields J. Schizophrenia. the epigenetic puzzle Cambridge: Cambridge
University Press, 19823. Reveley AM, Reveley MA, Clifford CA, Murray RM Cerebral ventricular size in
twins discordant for schizophrenia. Lancet 1982; i: 540-41.4. Spitzer RL, Endicott J, Robins E Research diagnostic criteria instrument no 58 New
York. New York State Psychiatric Institute, 1975.
TOTAL VENTRICULAR VOLUME IN SCHIZOPHRENICS
family history, birth complications, and medical history. 1
schizophrenic and 1 control with excessive alcohol abuse had beenpreviously excluded. Total ventricular volume (TVV) was assessedblindly by a semiautomated method.
6
The results (table) confirmed our hypothesis: the 7
schizophrenics with a family history of major psychiatric disorderhad TVVs significantly smaller than the 14 who did not (t=2’98,p<0. 01). Analysis of variance, controlling for present age, showedfamily history to be the only significant predictor of ventricular size(.F=7-48, p=0016) among the schizophrenics. Concordance ordiscordance in the MZ co-twins did not have a significant effect(F=1 22; p = 0 - 288), perhaps because concordance could ariseequally on the basis of shared environment as on the basis of sharedgenes.We also examined the effect of reported birth complications to
which twins are especially liable. 44% of our 18 controls, and 29% ofthe 21 schizophrenics gave a history of birth weight less than 1 - 5 kg,breech or difficult forceps delivery, or neonatal asphyxia. Amongthe controls, but not the schizophrenics, there was a highlysignificant association of larger cerebral ventricles with reportedbirth complications (F=16-0; p=0-001). Examination of the
schizophrenic series individually showed that while those with birthcomplications had, as expected, a negative family history and largeTVV, another group with equally large ventricles did not reportbirth complications.Our findings suggest that where genetic predisposition is high,
individuals may become schizophrenic without any additionalprecipitating factors. Where genetic predisposition is lower, orperhaps even absent, an environment precipitant is required beforethe individual becomes ill. Cerebral ventricular enlargement wasonly seen where genetic predisposition appeared low and mayreflect the presence of an environmental factor. Complicated birthis associated with ventricular enlargement and may be one suchfactor, though it is obviously non-specific since our birth-
complicated controls were not schizophrenic, and does not providea full explanation, since many of our schizophrenics had quite largecerebral ventriclule without hrain injury
Genetics Section,Institute of Psychiatry,London SE5 8AF
A. M. REVELEYM. A. REVELEYR. M. MURRAY
ACTIVITIES OF NEWER QUINOLONES AGAINSTLEGIONELLA GROUP ORGANISMS
SIR,—Using a technique similar to that described by Dr Green-wood and Mr Laverick (July 30, p 279), except that bufferedcharcoal yeast extract agar was used, as opposed to legionella bloodagar, I confirm that members of the Legionellaceae are verysensitive to ciprofloxacin and, like these workers, I found that therewas no significant inoculum effect.In addition to the strains of Legionellaceae which they examined,
I also examined both serogroups of L longbeachae, L jordanis, andthe U7W strain which is an, as yet, undesignated legionella. Theseorganisms also were sensitive to ciprofloxacin at the same level asother Legionellaceae.
Department of Laboratory Medicine,Ruchill Hospital,Bilsland Drive,
Glasgow G20 9NB R. J. FALLON
5. Thompson W D, Orvaschel H, Prusott BA, Kidd KK. An evaluation of the familyhistory method for ascertaining psychiatric disorders Arch Gen Psychiatry 1982; 39:53-58.
6. Reveley AM, Reveley MA. Aqueduct stenosis and schizophrenia J Neurol NeurosurgPsychiatry 1983; 46: 18-22.
