934 One patient, aged 41, with corneal pigmentation, who had had normal fundi two years earlier, had speckled pigmentation in the macular area. Another patient, aged 50, without corneal changes, had a clump of fine pigmentations in the macula. The retinal changes remained unchanged after four to six months.
treatment.
Department of Ophthalmology, University Hospital, 750 14 Uppsala, Sweden.
LENA OHMAN IVAR WAHLBERG
GENTAMICIN-RESISTANT PSEUDOMONAS ÆRUGINOSA
SIR,—The emergence of bacterial resistance
to
gentamicin
during therapy has been reported.I-4 MayI describe my own sad experience of a recent episode? Four patients attending the surgical outpatient department with varicose ulcer which on swabbing grew Pseudomonas ceruginosa were treated with topical gentamicin (’Cidomycin’) by a registrar without the knowledge of his consultant. Although all the strains were sensitive initially to gentamicin, they developed resistance after 2-3 weeks of treatment. On inquiry the registrar said that he did not know that gentamicin and cidomycin were the same antibiotic. Details of the isolates are given below:
+ Growth. No growth. *Minimum mhibnory concentration -
by the agar dilution technique.
ample evidence that repeated topical application of antibiotic will promote bacterial resistance ’1 6 whether it is used for prophylaxis or treatment. This disturbing incident emphasises even more strongly that valuable or potentially lifesaving antibiotics should be used only when absolutely necessary-and never topically. Since local antibiotics seldom contribute to the prevention of postoperative wound infections or to the healing of the lesion itself, perhaps it would be wiser to choose an antiseptic instead(though bacteria can resist disinfectants as well.8) Although strains A, B, and C are identical in serological and phage typings, we have failed to incriminate any common source for these infections. After this episode all stock of gentamicin for local use was withdrawn from the outpatient department, and the microbiology laboratory no longer reports sensitivity testing ofgentamicin on swabs taken from ulcers, pressure sores, eyes, ears, or wound infections (unless parenteral therapy is indicated). A committee (consisting of general surgeon, orthopaedic surgeon, physician, pharmacist, senior nursing officer, and microbiologist) has been formed to formulate an antibiotic policy9 in order to minimise misuse of antibiotics in future. There is
an
I am greatly indebted to the cross infection reference laboratory, Central Public Health Laboratory, Colindale, for typing these strains. Public Health Laboratory, Whipps Cross Hospital, Leytonstone, London E11 1NR. 1. 2.
SIR,-In assessing contradictory results reported with unsaturated fatty acids as suppressors of the immune response, great care must be taken to distinguish between in-vitro and in-vivo experiments. Whilst there is general agreement about the former,’-’ this is not so for the latter. Nothing can usefully be said at this stage of the "blind" human kidney transplantation study still in progress, and we must also await independent confirmation of the positive reportg in multiple sclerosis. In animal transplant experiments, 13 some have had positive results9 10 and others have not." Uldall et al.’s experiments13 were significant at p=0.05 to 025-"a level of significance we are reluctant to accept". On the other hand, Mertin8 cites unpublished work by Hughes et al. in which linoleic acid has been shown to suppress allergic encephalomyelitis in guineapigs. However, administration of gamma-linolenate (more powerful invitro than linoleic acid itself’4) to M.S. patients over some weeks did not diminish the ability of their lymphocytes to respond to thyroid (F,) antigen, in sharp contrast to the in-vitro findings.1 2 6 On the other hand, the sensitivity of the lymphocytes to linoleic acid was reduced-i.e., returned more towards normal. IS Clearly we are dealing here with a complex situation in which in-vitro and invivo responses differ. It must be borne in mind that "polyunsaturated tatty aods are only one of a number of factors which may influence the interaction of sensitised lymphocytes with specific antigen invivo, and ... the final intensity may represent the algebraic sum of enhancing and inhibitory influences".’6 If linoleic acid is effective in vitro as well as in vivo, there ought to be obvious suppression of immunologically induced disease, and gammalinolenate should be more efficient than linoleic acid itself.’4 Only continuing animal experiment of the type reported by Professor Delbarrell and direct clinical trial will establtsh whether the prospects opened by in-vitro experimentation are going to be fulfilled in vivo. Multiple Sclerosis Research Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP.
E. J. FIELD
BILIARY FACTOR AND FALSE-POSITIVE ALPHA-FETOPROTEIN ASSAYS
SIR,-We have compared the diagnostic value of y-fetopro(A.F.P.) assay results obtained by immunodiffusion in agar
tein and
in the serum of children with Of 223sera tested by both techniques, 121 were positive by immunodiffusion and gave an immunological identity with the A.F.P. isolated from fetal sera. With this technique, we detect quantities of A.F.P. above 250 ng/ml. All these positive results were in patients with hepatoma, teratoma, or acute
by radioimmunoassay
tumours.
1. Mertin, J., Shenton, B. K., Field. E. J. Br. med. J. 1973, ii, 777. 2 Field, E. J., Shenton, B. K., Joyce, G. ibid. 1974, i, 412. 3. Mertin, J., Hughes, D., Shenton, B. K., Dickenson, J P Klin Wschr 1974.
52, 248. 4. Mertin, J., Hughes, D., Stewart-Wynne, E. Lancet, 1974, i, 1005 5 Paty, D. W., Cousin, H. K., McDonald, L. E. ibid. 1975, i, 1197. 6. Jenssen, H. L., Kohler, H., Günther, J., Meyer-Rienecker, H ibid 1974,
ii,
1327.
B. CHATTOPADHYAY
Darrell, J. H., Waterworth, P. M. Br. med. J. 1967, ii, 535. Hamilton-Miller, J. M. T., Reynolds, A. V., Brumfitt, W. Lancet, 1974, ii,
527. 3. Seal, D. V., Strangeways, J. E. M. ibid. 1975, i, 48. 4. Barnham, M., Maddocks, A. C., Gaya, H. ibid. 1975, i, 576. 5. Alder, V. G., Gillespie, W. A. ibid. 1967, ii, 1067. 6. Lowbury, E. J. L., Ayliffe, G. A. J. Drug Resistance in Antimicrobial
Therapy. Springfield, Illinois, 1974.
7 Gilmore, O. J. A., Martin, T. D. M. Br. 8. Lancet, 1974, ii, 1054. 9. British Medical Journal, 1975, ii, 582.
UNSATURATED FATTY ACIDS AND CELLULAR IMMUNITY
J. Surg. 1974, 61,
281.
7. Mertin, J., Hughes, D. Int. Archs Allergy. 1975, 48, 203. 8. Millar, J. H. D., Zilkha, K. J., Langman, M. J. S., Payling-Wright, H, Smith, A. D., Belin, J., Thompson, R. H. S. Br. med. J. 1973, i, 765 9. Mertin, J. Lancet, 1974, ii, 717. 10. Ring, J., Seifert, J., Mertin, J., Brendel, W ibid. 1974, ii, 1331 11. Brok, J., Field, E. J. ibid. 1975, i, 1382. 12. Salaman, J. R., Millar, D. ibid. p 857. 13. Uldall, P. R., Wilkinson, R., McHugh, M. I., Field, E J, Shenton, B R. Baxby, K., Taylor, R. M. R. ibid. 1975, ii, 128. 14. Field, E. J., Shenton, B. K. Acta neurol. scand. 1975, 52, 121, 15. Shenton, B. K., Jenssen, H. L., Kòhler, H, Meyer-Rienecker, H, Field, E J IRCS, Med. Sci. 1975, 3, 503. 16. Field, E. J., Shenton, B. K. Br med. J. 1973, iv, 738 17 Delbarre, F. Lancet, 1975, ii, 720.
935 hepatitis. No other tumours or benign diseases were positive in children more than 2 months old. Among the 102 cases negative by immunodiffusion we found 17 A.F.P. levels above 100 000 ng/ml by radioimmunoassay; the higher dilution of the tested serum, the greater was the quantity of A.F.P. measured with this technique. All these falsepositive sera were icteric and were from patients with liver diseases or carcinoma with liver metastasis. In 14 icteric samples out of 121 positive sera (2 hepatoma, 3 teratoma, and 9 hepatitis) the amount of A.F.P. estimated by R.I.A. differed also according to the dilution of the serum used for the test. In all the other cases the levels were nearly the same whatever the dilution. To see whether the presence of bile could interfere with the R.I.A. method and be responsible for false-positive results, we added to normal and pathological sera a quantity of bile -corresponding to 3 ng/ml of A.F.P., and we found large variations in A.F.P. levels. We do not know which component of the bile inhibits the antigen/antibody complex in R.I.A. Not all bile samples have the same effect. Institut de Recherches sur
le Cancer,
rue
Guy-Mocquet,
Scientifiques
94800 Villejuif, B.P. no. 8, France.
C. RIMBAUT C. RUDANT D. BUFFE
CHRONIC GRANULOCYTOPENIA AND MONOCYTOPENIA WITH APPARENT GOOD HEALTH
SIR,—Although fever, mouth ulcerations, skin infections, and other symptoms occur in many cases, a patient with severe neutropenia may not be ill at all. 12 Spaet and Dameshek3 and others’assume that in chronic neutropenia, monocytes compensate fairly well for the shortage of neutrophils. On the other hand Baehner and Johnston" emphasise the failure of compensatory monocytosis to protect the host from bacterial infection when neutrophil reserves are diminished. We wish to report the case of a 56-year-old woman who, for at least 14 months, had hardly any granulocytes or monocytes in her peripheral blood. The leucocyte-count was normal throughout (range 5 .85—6 . 65 x 109/l) and on several occasions the differential count showed an absolute lymphocytosis of 100% (small lymphocytes, two-thirds of which were identified as T lymphocytes by sheep-red-cell rosettes). Hb was normal (13 g/dl). The platelet-count ranged from 290 to 600x 109/l. The E.S.R. was normal throughout. No cyclic change in neutrophil-count occurred. A blood-sample taken after exhausting exercise did not reveal a significant change in the neutrophilcount, suggesting no major shift of these cells from the marginat pool. Repeated bone-marrow studies showed a striking paucity of granulocytic elements with erythroid and lymphocytic cells predominating. Megakaryocytes were normal. No family history, associated disorders, or exposure to possible toxic drugs or poisons had been recorded. She has been well during the period of observation, except for an upper-respiratory-tract infection which responded to antibiotics. Clinically there was no splenomegaly, and the only abnormality was the blood picture. During the past 2 months oxymetholone was given, 250 mg daily. The neutrophils, which were initially absent, rose to 0 175 x 109/1 with no appearance of monocytes. At that time a bone-marrow granulocytic discharge was provoked by intravenous endotoxin (’Pyrifer’ 25 mg) showing a small but delayed peak in neutrophil-count in the peripheral blood (0.495 x 109/l at 7 h). Leucocyte mobilisation was studied by Rebuck’s skin-window technique.7 The initial response 1 Kyle, R. A., Linman, J. W. New Engl. J. Med. 1968, 279, 1015. 2 Lancet, 1968, ii, 1282. 3 Spaet, T. H., Dameshek, W. Am. J. Med. 1952, 13, 35. 4. Wriedt, K., Kauder, E., Mauer, A. M. New Engl. J. Med. 1970, 283, 107. 5 Dale, D. C., Wolff, S. M. Blood, 1971, 38, 138. 6 Baehner, R. L., Johnston, R. B., Jr. ibid. 1972, 40, 31. 7 Rebuck, J. W., Crowley, J. H. Ann. N. Y. Acad. Sci. 1955, 59, 757
delayed, after 5 h there was a nearly normal number of neutrophils and by 12 h the most striking feature was the near absence of the mononuclear component. In this patient a preleukxmic condition cannot be excluded. Although in preleukasmic monocytosis is quite common 89 monocytopenia may also
was
occur.10 Fundacion Hematológica, Corrientes 3550, Mar del Plata,
E. REWALD F. MOSCARDI
Argentina.
CHOLESTEROL CONTENT OF TUBE FEEDS
SIR,-I have had under my
care a young man with type-iv unconscious following a cerebral thrombosis. He was normally on clofibrate and a low-cholesterol diet. Inquiry revealed that the standard tube feed used at the hospital contained three eggs and two pints of milk, giving an undesirably high cholesterol and saturated-fatty-acid intake for this patient. A rapid survey of tube-feed recipes in seven other hospitals showed cholesterol contents ranging from 40 to 1340 mg per day. Diets containing one or two eggs and one to two pints of milk were not uncommon, and some hospitals used double cream. Free fatty acids increase fibrinogen synthesis by human liver in vitro," and saturated long-chain fatty acids activate Hageman factor and the intrinsic coagulation pathway in vitro’2 There is an inverse correlation between fasting triglyceride levels and blood fibrinolytic activity measured by euglobulinlysis time." Thus diets rich in cholesterol and fatty acids may favour thrombosis and impede fibrinolysis, and thereby lessen the chances of recovery from cerebral thrombosis, or increase the risk of deep-vein thrombosis in unconscious patients. I hope that the composition of tube feeds will be reviewed in the light of this possibility.
hyperlipidaemia
who
10a Leigham Court Road, London SW16 2PJ.
was
GILLIAN CRAIG
LINKAGE AND ASSOCIATION
SIR,-Dr Mathews (Oct. 11, p. 681) reports a positive correlation between death-rates from ischsemic heart-disease and particular histocompatibility antigens (HLA-8 and haplotype 1-8) in Europe, America, and Japan. While I agree with his conclusion that his "findings provide some support for immunogenetic hypotheses for vascular disease in man", his suggestion that "HLA-8 (and possibly W15) are linked to genes which predispose to hypercholesterolaemia and ischaemic heart-disease" is difficult to justify and perhaps misleading. The word linkage is used to mean the close proximity on the same chromosome of two or more genetic loci (for example, ABH-secretion, Lutheran blood-group, and myotonic dystrophy),’4 but, because genetic exchange will inevitably occur at a proportion of meiotic divisions, relationships between-individual alleles will continually change. Only within pedigrees might particular alleles at linked loci be expected to be correlated, and not between populations such as those reported by Dr Mathews. The occasional existence of linkage disequilibrium within a population’5 is because the population is behaving, genetically, as an extended pedigree. The association between a disease and an allele when presBlair, T. R., Bayrd, E. D., Pease, G. L. J. Am. med. Ass. 1966, 198, 21 Saarni, M. I., Linman, J. W. Am. J. Med. 1973, 55, 38. 10. Kaur, J., Catovsky, D., Valdimarsson, H., Jensson, O., Spiers, A.D.S. Br. med. J. 1972, iv, 327. 11. Pilgeram, L. O., Pickart, L. R. J. Atheroscler. Res. 1968, 8, 155 12. Ganong, W. F. Review of Medical Physiology, p. 390. Los Altos, California, 8. 9.
1973. 13. Sweet, B., Rifkind, B. M., McNicol, G. P. J. Atheroscler. Res. 1966, 6, 359. 14. Harper, P. S., Rivas, M. L., Bias, W. B., Hutchinson, J. R., Dyken, P. R., McKusick, V. A. Am. J. hum. Genet. 1972, 24, 310. 15. Falk, C. T. Transplantation, 1975, 19, 266.
treatment.
Department of Ophthalmology, University Hospital, 750 14 Uppsala, Sweden.
LENA OHMAN IVAR WAHLBERG
GENTAMICIN-RESISTANT PSEUDOMONAS ÆRUGINOSA
SIR,—The emergence of bacterial resistance
to
gentamicin
during therapy has been reported.I-4 MayI describe my own sad experience of a recent episode? Four patients attending the surgical outpatient department with varicose ulcer which on swabbing grew Pseudomonas ceruginosa were treated with topical gentamicin (’Cidomycin’) by a registrar without the knowledge of his consultant. Although all the strains were sensitive initially to gentamicin, they developed resistance after 2-3 weeks of treatment. On inquiry the registrar said that he did not know that gentamicin and cidomycin were the same antibiotic. Details of the isolates are given below:
+ Growth. No growth. *Minimum mhibnory concentration -
by the agar dilution technique.
ample evidence that repeated topical application of antibiotic will promote bacterial resistance ’1 6 whether it is used for prophylaxis or treatment. This disturbing incident emphasises even more strongly that valuable or potentially lifesaving antibiotics should be used only when absolutely necessary-and never topically. Since local antibiotics seldom contribute to the prevention of postoperative wound infections or to the healing of the lesion itself, perhaps it would be wiser to choose an antiseptic instead(though bacteria can resist disinfectants as well.8) Although strains A, B, and C are identical in serological and phage typings, we have failed to incriminate any common source for these infections. After this episode all stock of gentamicin for local use was withdrawn from the outpatient department, and the microbiology laboratory no longer reports sensitivity testing ofgentamicin on swabs taken from ulcers, pressure sores, eyes, ears, or wound infections (unless parenteral therapy is indicated). A committee (consisting of general surgeon, orthopaedic surgeon, physician, pharmacist, senior nursing officer, and microbiologist) has been formed to formulate an antibiotic policy9 in order to minimise misuse of antibiotics in future. There is
an
I am greatly indebted to the cross infection reference laboratory, Central Public Health Laboratory, Colindale, for typing these strains. Public Health Laboratory, Whipps Cross Hospital, Leytonstone, London E11 1NR. 1. 2.
SIR,-In assessing contradictory results reported with unsaturated fatty acids as suppressors of the immune response, great care must be taken to distinguish between in-vitro and in-vivo experiments. Whilst there is general agreement about the former,’-’ this is not so for the latter. Nothing can usefully be said at this stage of the "blind" human kidney transplantation study still in progress, and we must also await independent confirmation of the positive reportg in multiple sclerosis. In animal transplant experiments, 13 some have had positive results9 10 and others have not." Uldall et al.’s experiments13 were significant at p=0.05 to 025-"a level of significance we are reluctant to accept". On the other hand, Mertin8 cites unpublished work by Hughes et al. in which linoleic acid has been shown to suppress allergic encephalomyelitis in guineapigs. However, administration of gamma-linolenate (more powerful invitro than linoleic acid itself’4) to M.S. patients over some weeks did not diminish the ability of their lymphocytes to respond to thyroid (F,) antigen, in sharp contrast to the in-vitro findings.1 2 6 On the other hand, the sensitivity of the lymphocytes to linoleic acid was reduced-i.e., returned more towards normal. IS Clearly we are dealing here with a complex situation in which in-vitro and invivo responses differ. It must be borne in mind that "polyunsaturated tatty aods are only one of a number of factors which may influence the interaction of sensitised lymphocytes with specific antigen invivo, and ... the final intensity may represent the algebraic sum of enhancing and inhibitory influences".’6 If linoleic acid is effective in vitro as well as in vivo, there ought to be obvious suppression of immunologically induced disease, and gammalinolenate should be more efficient than linoleic acid itself.’4 Only continuing animal experiment of the type reported by Professor Delbarrell and direct clinical trial will establtsh whether the prospects opened by in-vitro experimentation are going to be fulfilled in vivo. Multiple Sclerosis Research Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP.
E. J. FIELD
BILIARY FACTOR AND FALSE-POSITIVE ALPHA-FETOPROTEIN ASSAYS
SIR,-We have compared the diagnostic value of y-fetopro(A.F.P.) assay results obtained by immunodiffusion in agar
tein and
in the serum of children with Of 223sera tested by both techniques, 121 were positive by immunodiffusion and gave an immunological identity with the A.F.P. isolated from fetal sera. With this technique, we detect quantities of A.F.P. above 250 ng/ml. All these positive results were in patients with hepatoma, teratoma, or acute
by radioimmunoassay
tumours.
1. Mertin, J., Shenton, B. K., Field. E. J. Br. med. J. 1973, ii, 777. 2 Field, E. J., Shenton, B. K., Joyce, G. ibid. 1974, i, 412. 3. Mertin, J., Hughes, D., Shenton, B. K., Dickenson, J P Klin Wschr 1974.
52, 248. 4. Mertin, J., Hughes, D., Stewart-Wynne, E. Lancet, 1974, i, 1005 5 Paty, D. W., Cousin, H. K., McDonald, L. E. ibid. 1975, i, 1197. 6. Jenssen, H. L., Kohler, H., Günther, J., Meyer-Rienecker, H ibid 1974,
ii,
1327.
B. CHATTOPADHYAY
Darrell, J. H., Waterworth, P. M. Br. med. J. 1967, ii, 535. Hamilton-Miller, J. M. T., Reynolds, A. V., Brumfitt, W. Lancet, 1974, ii,
527. 3. Seal, D. V., Strangeways, J. E. M. ibid. 1975, i, 48. 4. Barnham, M., Maddocks, A. C., Gaya, H. ibid. 1975, i, 576. 5. Alder, V. G., Gillespie, W. A. ibid. 1967, ii, 1067. 6. Lowbury, E. J. L., Ayliffe, G. A. J. Drug Resistance in Antimicrobial
Therapy. Springfield, Illinois, 1974.
7 Gilmore, O. J. A., Martin, T. D. M. Br. 8. Lancet, 1974, ii, 1054. 9. British Medical Journal, 1975, ii, 582.
UNSATURATED FATTY ACIDS AND CELLULAR IMMUNITY
J. Surg. 1974, 61,
281.
7. Mertin, J., Hughes, D. Int. Archs Allergy. 1975, 48, 203. 8. Millar, J. H. D., Zilkha, K. J., Langman, M. J. S., Payling-Wright, H, Smith, A. D., Belin, J., Thompson, R. H. S. Br. med. J. 1973, i, 765 9. Mertin, J. Lancet, 1974, ii, 717. 10. Ring, J., Seifert, J., Mertin, J., Brendel, W ibid. 1974, ii, 1331 11. Brok, J., Field, E. J. ibid. 1975, i, 1382. 12. Salaman, J. R., Millar, D. ibid. p 857. 13. Uldall, P. R., Wilkinson, R., McHugh, M. I., Field, E J, Shenton, B R. Baxby, K., Taylor, R. M. R. ibid. 1975, ii, 128. 14. Field, E. J., Shenton, B. K. Acta neurol. scand. 1975, 52, 121, 15. Shenton, B. K., Jenssen, H. L., Kòhler, H, Meyer-Rienecker, H, Field, E J IRCS, Med. Sci. 1975, 3, 503. 16. Field, E. J., Shenton, B. K. Br med. J. 1973, iv, 738 17 Delbarre, F. Lancet, 1975, ii, 720.
935 hepatitis. No other tumours or benign diseases were positive in children more than 2 months old. Among the 102 cases negative by immunodiffusion we found 17 A.F.P. levels above 100 000 ng/ml by radioimmunoassay; the higher dilution of the tested serum, the greater was the quantity of A.F.P. measured with this technique. All these falsepositive sera were icteric and were from patients with liver diseases or carcinoma with liver metastasis. In 14 icteric samples out of 121 positive sera (2 hepatoma, 3 teratoma, and 9 hepatitis) the amount of A.F.P. estimated by R.I.A. differed also according to the dilution of the serum used for the test. In all the other cases the levels were nearly the same whatever the dilution. To see whether the presence of bile could interfere with the R.I.A. method and be responsible for false-positive results, we added to normal and pathological sera a quantity of bile -corresponding to 3 ng/ml of A.F.P., and we found large variations in A.F.P. levels. We do not know which component of the bile inhibits the antigen/antibody complex in R.I.A. Not all bile samples have the same effect. Institut de Recherches sur
le Cancer,
rue
Guy-Mocquet,
Scientifiques
94800 Villejuif, B.P. no. 8, France.
C. RIMBAUT C. RUDANT D. BUFFE
CHRONIC GRANULOCYTOPENIA AND MONOCYTOPENIA WITH APPARENT GOOD HEALTH
SIR,—Although fever, mouth ulcerations, skin infections, and other symptoms occur in many cases, a patient with severe neutropenia may not be ill at all. 12 Spaet and Dameshek3 and others’assume that in chronic neutropenia, monocytes compensate fairly well for the shortage of neutrophils. On the other hand Baehner and Johnston" emphasise the failure of compensatory monocytosis to protect the host from bacterial infection when neutrophil reserves are diminished. We wish to report the case of a 56-year-old woman who, for at least 14 months, had hardly any granulocytes or monocytes in her peripheral blood. The leucocyte-count was normal throughout (range 5 .85—6 . 65 x 109/l) and on several occasions the differential count showed an absolute lymphocytosis of 100% (small lymphocytes, two-thirds of which were identified as T lymphocytes by sheep-red-cell rosettes). Hb was normal (13 g/dl). The platelet-count ranged from 290 to 600x 109/l. The E.S.R. was normal throughout. No cyclic change in neutrophil-count occurred. A blood-sample taken after exhausting exercise did not reveal a significant change in the neutrophilcount, suggesting no major shift of these cells from the marginat pool. Repeated bone-marrow studies showed a striking paucity of granulocytic elements with erythroid and lymphocytic cells predominating. Megakaryocytes were normal. No family history, associated disorders, or exposure to possible toxic drugs or poisons had been recorded. She has been well during the period of observation, except for an upper-respiratory-tract infection which responded to antibiotics. Clinically there was no splenomegaly, and the only abnormality was the blood picture. During the past 2 months oxymetholone was given, 250 mg daily. The neutrophils, which were initially absent, rose to 0 175 x 109/1 with no appearance of monocytes. At that time a bone-marrow granulocytic discharge was provoked by intravenous endotoxin (’Pyrifer’ 25 mg) showing a small but delayed peak in neutrophil-count in the peripheral blood (0.495 x 109/l at 7 h). Leucocyte mobilisation was studied by Rebuck’s skin-window technique.7 The initial response 1 Kyle, R. A., Linman, J. W. New Engl. J. Med. 1968, 279, 1015. 2 Lancet, 1968, ii, 1282. 3 Spaet, T. H., Dameshek, W. Am. J. Med. 1952, 13, 35. 4. Wriedt, K., Kauder, E., Mauer, A. M. New Engl. J. Med. 1970, 283, 107. 5 Dale, D. C., Wolff, S. M. Blood, 1971, 38, 138. 6 Baehner, R. L., Johnston, R. B., Jr. ibid. 1972, 40, 31. 7 Rebuck, J. W., Crowley, J. H. Ann. N. Y. Acad. Sci. 1955, 59, 757
delayed, after 5 h there was a nearly normal number of neutrophils and by 12 h the most striking feature was the near absence of the mononuclear component. In this patient a preleukxmic condition cannot be excluded. Although in preleukasmic monocytosis is quite common 89 monocytopenia may also
was
occur.10 Fundacion Hematológica, Corrientes 3550, Mar del Plata,
E. REWALD F. MOSCARDI
Argentina.
CHOLESTEROL CONTENT OF TUBE FEEDS
SIR,-I have had under my
care a young man with type-iv unconscious following a cerebral thrombosis. He was normally on clofibrate and a low-cholesterol diet. Inquiry revealed that the standard tube feed used at the hospital contained three eggs and two pints of milk, giving an undesirably high cholesterol and saturated-fatty-acid intake for this patient. A rapid survey of tube-feed recipes in seven other hospitals showed cholesterol contents ranging from 40 to 1340 mg per day. Diets containing one or two eggs and one to two pints of milk were not uncommon, and some hospitals used double cream. Free fatty acids increase fibrinogen synthesis by human liver in vitro," and saturated long-chain fatty acids activate Hageman factor and the intrinsic coagulation pathway in vitro’2 There is an inverse correlation between fasting triglyceride levels and blood fibrinolytic activity measured by euglobulinlysis time." Thus diets rich in cholesterol and fatty acids may favour thrombosis and impede fibrinolysis, and thereby lessen the chances of recovery from cerebral thrombosis, or increase the risk of deep-vein thrombosis in unconscious patients. I hope that the composition of tube feeds will be reviewed in the light of this possibility.
hyperlipidaemia
who
10a Leigham Court Road, London SW16 2PJ.
was
GILLIAN CRAIG
LINKAGE AND ASSOCIATION
SIR,-Dr Mathews (Oct. 11, p. 681) reports a positive correlation between death-rates from ischsemic heart-disease and particular histocompatibility antigens (HLA-8 and haplotype 1-8) in Europe, America, and Japan. While I agree with his conclusion that his "findings provide some support for immunogenetic hypotheses for vascular disease in man", his suggestion that "HLA-8 (and possibly W15) are linked to genes which predispose to hypercholesterolaemia and ischaemic heart-disease" is difficult to justify and perhaps misleading. The word linkage is used to mean the close proximity on the same chromosome of two or more genetic loci (for example, ABH-secretion, Lutheran blood-group, and myotonic dystrophy),’4 but, because genetic exchange will inevitably occur at a proportion of meiotic divisions, relationships between-individual alleles will continually change. Only within pedigrees might particular alleles at linked loci be expected to be correlated, and not between populations such as those reported by Dr Mathews. The occasional existence of linkage disequilibrium within a population’5 is because the population is behaving, genetically, as an extended pedigree. The association between a disease and an allele when presBlair, T. R., Bayrd, E. D., Pease, G. L. J. Am. med. Ass. 1966, 198, 21 Saarni, M. I., Linman, J. W. Am. J. Med. 1973, 55, 38. 10. Kaur, J., Catovsky, D., Valdimarsson, H., Jensson, O., Spiers, A.D.S. Br. med. J. 1972, iv, 327. 11. Pilgeram, L. O., Pickart, L. R. J. Atheroscler. Res. 1968, 8, 155 12. Ganong, W. F. Review of Medical Physiology, p. 390. Los Altos, California, 8. 9.
1973. 13. Sweet, B., Rifkind, B. M., McNicol, G. P. J. Atheroscler. Res. 1966, 6, 359. 14. Harper, P. S., Rivas, M. L., Bias, W. B., Hutchinson, J. R., Dyken, P. R., McKusick, V. A. Am. J. hum. Genet. 1972, 24, 310. 15. Falk, C. T. Transplantation, 1975, 19, 266.
