796

Correlation between bone aluminium content (in ug bone wetweight) and osteoid volume (percentage of spongiosa volumerepresented by osteoid).0 patients with predominant hyperparathyroidism.. patients with predominant osteomalacia. patients with normal X-ray examination.

There was no relationship between bone aluminium content,osteoclast number, and marrow fibrosis, in accord with Alfreyand al. who found no correlation between bone aluminiumand plasma parathyroid hormone levels. Bone aluminium con-tent was also unrelated to osteoblast number or mineralisationfront but, in contrast, it correlated with osteoid volume (seefigure).Our observation supports the hypothesis suggested by

Parkinson et al .2 and Ward et aU of a relation between osteo-malacic bone-disease of dialysis patients and aluminium intoxi-cation. The mechanism(s) by which aluminium accumulationin bone interferes with normal mineralisation are unknown.

Nephrology Serviceand Calcified Tissue Laboratory,

Hopital Necker-Enfants Malades,Paris

and Höpital Fernand Widal

G. COURNOT-WITMERJ. ZINGRAFFR. BOURDONT. DRÜEKES. BALSAN

CLONIDINE AND GROWTH-HORMONE SECRETION

SIR,-I. Gil-Ad and colleagues (Aug. 11, p. 278) describea clonidine-stimulation test for growth hormone (GH)release. The conclusion that oral clonidine is a more potentand reliable stimulus for GH secretion than are hypoglycaemia,arginine, and levodopa is surprising. In our experience with theclonidine test in adults, both by the intravenous and oralroute,lO we found that donidine-stimulated serum-GH levelsare not different from the levels induced by levodopa in

healthy individuals," but are significantly lower than those in-duced by hypoglycsemia (unpublished). Moreover, in ’3 of 15subjects GH levels did not rise above 5 ng/ml after intravenousclonidine infusion (0-15 mg over 10 min). On the other handno patient among 15 hypertensives released GH after the sameschedule of clonidine administration." The conflicting resultsmay depend on the different ages of the subjects studied andon the dose (0-15 mg clonidine orally in boys aged 3-17 yearsor the same dose intravenously in adults with body-weight of60-80 kg). Although the clonidine test may be considered in

10. Ferrari C, Testori G, Caldara R, Barbieri C. Effects of antihypertensivedrugs on growth hormone secretion. Br Med J 1977; iii: 123-24.

11. Barbieri C, Ferrari C, Caldara R, Curtarelli G. Growth hormone secretionin hypertensive patients: evidence for a derangement in central adrenergicfunction. Clin Sci (in press).

the evaluation of GH secretion in children, it does not seemsuitable for adults because higher drug doses are frequently as-sociated with severe side-effects.

2nd Department of Medicine,Fatebenefratelli Hospital,Milan, Italy

C. FERRARIR. CALDARAG. P. TESTORIR. CROSSIGNANIC. BARBIERI

ACTUAL OR STANDARD BICARBONATESiR,—Dr Horsey (Aug. 11, p.311) is right to advise labora-

tories to report actual, rather than standard, bicarbonate con-centrations. However, by saying that "PaC02 and pH are rou-tine measurements" he implies, I think, that a bicarbonatevalue calculated from these indices should be reported. Whilea calculated value is usually adequate, some caution is

required for in acutely ill patients the true bicarbonate valueand the calculated value may differ by as much as 10 mmol/1.This happens because the term pK/ in the Henderson-Hassel-balch equation is not always the constant value of 6-1 whichit is commonly assumed to be, but can vary over the range5.9-6.2 in severely ill patients-especially those receiving in-travenous fluids and artificial respiration.

This has certainly been true in our experience, and in thatof U.S. and U.K. workers.’ These discrepancies are not due toanalytical error and are not seen in normal individuals. Unfor-tunately, this fact is still not widely recognised and the prob-lem is compounded by the new generation of blood-gas ma-chines programmed to solve the equation automatically. I feelthat a measured bicarbonate value should be reported at leastdaily for patients in intensive-care units.

Department of Pathology,Hôtel-Dieu of St Joseph Hospital,Windsor, Ontario N9A 1E1, Canada T. A. HYDE

OUTPATIENT BREAST BIOPSY

SIR,-Mr Joffe and his colleagues (Aug. 11, p. 294) reporttheir favourable experience with outpatient excision of 30

benign breast lumps. Over the past 10 years at this center wehave done breast biopsies under local anaesthesia on over 800outpatients, and we have compared our outpatient and in-patient breast-biopsy experience.2 Breast biopsy as an out-patient procedure is safe, well accepted by patients,2 cheaper,takes less time, and avoids the risks of general anxsthesia. Wehave increasingly used outpatient biopsy to confirm the

diagnosis of breast malignancy. Most of our breast-cancerpatients now have their diagnosis histologically confirmedbefore hospital admission. While we routinely aspirate breastcysts, our experience with fine-needle aspiration for cytologicaldiagnosis of solid breast lumps is limited. Core cutting needlebiopsy is frequently used to establish the diagnosis rather thanopen biopsy when malignancy is suspected. Evaluation ofpatients for metastatic disease is more efficient since it is onlydone when the diagnosis is confirmed. Also, extensive discus-sion of definitive treatment with the patient is carried out onlyafter the diagnosis has been confirmed. Many reports indicatethere is no change in survival when there is a delay of two tothree weeks between biopsy and mastectomy compared withpatients investigated by frozen section followed up by im-mediate mastectomy.3-7 The two-step procedure of diagnostic1. Hyde TA. The inconstant constant pK. Can Med Assoc J 1979; 120:

1486-87.2. Walker GM, Foster RS Jr, McKegney CP, McKegney FP. Arch Surg 1978;

113: 942-46.3. Scheel A. Acta Radiol 1953; 39: 249-54.4. Pierce EH, Clogett OT, McDonald JR, et al. Surg Gynecol Obstet 1956;

103: 559-64.5. Jackson PP, Pitts HH. Am J Surg 1959; 98: 184-89.6. Abramson DJ. Ann Surg 1966; 163: 478-83.7. Hasgensen CD. Diseases of the breast. Philadelphia: WB Saunders, 1971,

99.

797

biopsy before definitive therapy was recently endorsed at a con-ference on the treatment of primary breast cancer sponsored bythe national Cancer Institute. 8

We interviewed 102 of our biopsy patients and found thatmost were satisfied with the outpatient biopsy experience. Hos-pital costs were seven times higher for inpatient biopsies ofbenign breast lumps than for outpatient biopsy.

For some patients breast biopsy under local anxsthesia is in-appropriate : occasional small lumps that might be obscured bylocal infiltration, very large benign lesions that would be tech-nically difficult to excise while maintaining patient comfort, orlesions only demonstrable by roentgenograpy are a few exam-ples. However, in my experience, general anxsthesia for exci-sion of a benign lesion or for establishment of the diagnosis ofmalignancy is needed in less than 5% of cases.

Vermont Regional Cancer Centerand Department of Surgery,

University of Vermont,Burlington, Vermont 05405, U.S.A. ROGER S, FOSTER, JR

AUTOANTIBODIES IN RHEUMATIC DISEASES

SIR,-Dr Blake and colleagues (Aug. 4, p. 224) describe thedetection of antithyroid antibody activity in patients with var-ious arthritides. Since 1975 we have found antithyroid anti-bodies in a high proportion of sera from patients with rheuma-toid arthritis (RA) and ankylosing spondylitis (AS).The percentages of antithyroid antibodies found in 90 cases

of adult RA, 15 of juvenile RA, and 27 of AS were, respec-tively, 18%, 27%, and 17%. These percentages are much

higher than the ones Blake et al. recorded, probably becausewe sought antimicrosomal antibodies, by immunofluorescencelwhich is a much more sensitive method than the tanned-red-cell test.One of us (A. G.-T.) is now screening all patients with posi-

tive thyroid microsomal antibodies for endocrine disease. Thetable shows the results of the first 5 patients with adult RA in

ENOCRINE STUDIES ON FIVE ADULTS WITH RA

RF=rheumatoid factor; ATA=antithyroid antibodies; ANA=antinuc-lear antibodies.*Juvenile diabetes mellitus; tdiffuse goitre; thypothyroidism;hyperthyroidism, nodular goitre.

whom we found endocrine disease (thyroid disease in 4 andjuvenile diabetes mellitus in 1).Whether Blake’s hypothesis that antithyroid activity is pro-

duced by the synovial fluid is correct or not, our findings dostress that these antibodies correlate with subclinical endocrinedisease; microsomal antibodies could play a role as a markerfor the detection of endocrine disease in patients who seem tohave rheumatic disease only (mainly RA or AS).Our findings were presented at the XIVth International Congress of

Rheumatology, held in San Francisco, in 1977 (abstr 534) and at theIII Congressus Latinus et Portucalensis Rheumatology (Acta ReumPort 1978; 6: 76-77, 79).Department of Medicine,Sta. Maria University Hospital,Lisbon, Portugal

ESTELA MONTEIROCELESTE CEBOLEIROA. GALVÃO-TELES

8. Anonymous. New Engl J Med 1979; 301: 340.1. Roitt IM, Doniach D. Immunofluorescent tests for the detection of auto-anti-

bodies. Geneva: World Health Organisation, 1969: 1-2.

CIMETIDINE AND GASTRIC CANCER: NEGATIVESTUDIES IN DOGS

SiR,-Cimetidine and gastric cancer was the subject ofmuch Lancet correspondence following a preliminary com-munication by Elder et al. and the response to that paper byone of us. Elder et al. drew attention to the structural resem-blance between a possible nitrosoderivative of cimetidine andthe carcinogen, N-methyl-N’-nitro-N-nitrosoguanidine(MNNG) which, in some species, behaves as a direct locallyactive carcinogen for the stomach. Adenocarcinomas of thestomach or duodenum in response to MNNG administered in

drinking water have been reported in rats4 and hamsters,5while in rabbits exposed in the same way, squamous cancersof the tracheobronchial tree were the main finding.6 Only thenon-glandular part of the mouse stomach seems to be sensitiveto the induction of cancer by orally administered MNNG, butskin tumours arise in response to topical application.’ All offour dogs given MNNG in the drinking water (167 mg/1 reduc-ing to 87 mg/1) for 15 months acquired multiple papillaryadenocarcinomas of the stomach, arising mainly in the antrumand cardiac regions. The cancers were detected 17-35 monthsfrom the start of treatment.8 Mucosal atrophy, especially ofthe antrum, was a feature in all four animals.The fact that no excess of gastric or any other kind of neo-

plasm was observed in rats exposed throughout their lives todaily doses of cimetidine equivalent to 60 times the dose givento man9 provides persuasive evidence that the clinical use ofcimetidine carries no carcinogenic risk. We can now add to thisnegative evidence by reporting the lack of endoscopic or histo-pathological evidence of neoplasia, preneoplasia, or hyper-plasia of the gastric mucosa in dogs exposed continuously tocimetidine for over 3 years.The study, which began in March, 1976, involves eighteen dogs.

Twelve (eight male and four female) receive 144 mg/kg cimetidineorally in tablet form every day and six (four male and two female)receive placebo tablets. The ’Purina Meal’ fed to all dogs containedabout 3.6 mg/kg nitrite expressed as sodium nitrite and 117 mg/kgnitrate expressed as potassium nitrate. The mean daily consumptionwas 1-14 mg/day of nitrite and 37.3 mg/day of nitrate. All the dogshave become obese but the treated animals a little less so than the con-trols. No treatment-related effects on haematological, clinical chemis-try, urinalysis, ophthalmoscopic, or electrocardiographic indices havebeen observed in examinations done 6-monthly for up to 3-L years. Onecontrol male had convulsions and was killed 30 months after the startof the study. The remaining seventeen animals are alive and well. 40months after the start of the study biopsies of gastric mucosa weredone via a Fujinon FG-QBF gastroscope from all surviving dogs after-sedation with acetylpromazine and thiopentone anaesthesia. Pylorus,prepyloric canal, antrum, and body and fundus of the stomach wereinspected then biopsy specimens were taken from about six sites in aring around the stomach at the level of the middle of the antrum andfrom six points in a ring around the middle of the body. From elevendogs a further 4-7 specimens were taken from along the lesser curvefrom the prepyloric region up to the cardiac sphincter. 255 specimens

1. Elder JB, Ganguli PC, Gillespie IE. Cimetidine and gastric cancer. Lancet1979; i: 1005-06.

2. Roe FJC. Cimetidine and gastric cancer. Lancet 1979; i: 1039-40.3. Elder JB, Ganguli PC, Gillespie IE. Gastnc cancer in patients who have

taken cimetidine. Lancet 1979; ii: 245.4. Sugimura T, Fujimura S. Tumour production in glandular stomach of rat

by N-methyl-N’nitro-N-nitrosoguanidine. Nature 1967; 216: 943-44.5. Fujimura S, Kogure K, Oboshi S, et al. Production of tumours in glandular

stomach of hamster by N-methyl-N’nitro-N-nitrosoguanidine: Cancer Res1970; 30: 1444-48.

6. Sugimura T, Fujimura S, Kogure K, et al. Production of adenocarcinomain glandular stomach of experimental animals by N-methyl-N’-nitro-N-nitrosoguanidme. Gann Monogr 1969; 8: 157-96.

7. Takayama S, Kuwabara N, Azama, Y, Sugimura T. Skin tumours in micepainted with N-methyl-N’-nitro-N-nitrosoguanidine.and N-ethyl-N’-nitro-N-nitrosoguanidine. J Natl Cancer Inst 1971; 46: 973-80.

8. Shimosato Y, Tanaka N, Kogure K, Fujimura S, Kawachi T, Sugimura T.Histopathology of tumours of canine alimentary tract produced by N-meth-yl-N’-nitro-N-nitrosoguanidine, with particular reference to gastric car-cinomas. J Natl Cancer Inst 1971; 47: 1053-70.

9. Brimblecombe RW, Duncan WAM, Durant GJ, Emmett JC, GanellinCR, Leslie GB, Parsons ME. Characterization and development of cimeti-dine as a histamine H2-receptor antagonist. Gastroenterology 1978; 74:339-47.