- Email: [email protected]
PRENATAL DETECTION OF TANGIER DISEASE
754 DIETARY VITAMIN D
SIR,-In the latest official dietary recommendations’ no clear-cut recommendation is made concerning vitamin D for adults, on the reasonable grounds that the chief source of the vitamin follows from the action of ultraviolet light on the skin. One consequence of this change is that vitamin D no longer appears in Ministry of Agriculture, Fisheries, and Food tables on the nutritional value of household food.2 A stated purpose of the recommendations is to "direct attention, in surveys of food intakes of different groups, to subgroups who may be at the risk of undernutrition." It is unfortunate that recipients of the M.A.F.F. release Food Facts2 will no longer have their attention drawn to the fact that there are subgroups in the U.K. who are vitamin D deficient. Department of Biochemistry, Royal Dental Hospital of London School of Dental Surgery London SW17 0RE
FRANCIS B. REED
MOLECULAR MIMICRY AND H-Ir GENES
S!R,—Ebringer has
drawn attention to the uncertainty of there exist histocompatibility-linked immune genes which code positively for specific immune responses. The gene products of H-Ir genes have not been demonstrated and the existence of these genes is only inferential. However, Ebringer’s molecular mimicry concept, which postulates antigenic cross-reactivity between the antigens used for the immunisations and the histocompatibility antigens of the low-responder mice, cannot be the explanation because high response is genetically transmitted to hybrids which exhibit the histocompatibility antigens of the low
theory that response (H-Ir)
the
Fig. 2-Part of L. pneumophila, Cambridge strain, showing fimbriae (arrows). (1% phosphotungstic acid pH 6.5; x 120 000.)
By direct staining
and fluorescence
optical microscopy reported flagellated legionellae. With improved growth media which stimulate early profuse growth of the organisms we also have found, by negative-stain electron microscopy, flagella in cultures of both the short rod and filamentous forms of Legionella pneumophila. The flagella were usually dissociated from and surrounding the organisms. When attached to bacteria, the flagella occurred singly, usually in the polar or subpolar region (fig. 1), but were sometimes observed in small numbers emerging from the side of organisms. Two strains also possessed fimbriae (fig. 2). Flagella Thomason
et
a1.4 have
now
found in all strains of the three serogroups examined, and the frequency was greatest when cultured on enriched blood agar, CYE agar + beef extract, and enriched broth medium. At first thought due to contaminant microorganisms, their repeated presence in apparently pure cultures made us consider them a characteristic property oflegionellae.
responder strains.4 Research Unit, Medical Research Council of New Zealand, University of Otago Medical School, Dunedin, New Zealand
Immunopathology
D. D. ADAMS
were
These findings will be published in detail elsewhere. Public Health
Laboratory University Hospital, Queen’s Medical Centre, Nottingham NG7 2UH
F. G. RODGERS P. W. GREAVES A. D. MACRAE
PERTUSSIS VACCINE
SiR,-Professor Stewart (Sept. 1, p. 473) cheerfully cites Ditchburn’ in support of his crusade against pertussis vaccine, while at the same time casting doubt on the validity of my data2 on the grounds that I may have been describing "croupy coughs" rather than true pertussis. However, of the 50 cases of whooping-cough referred to in my paper, 21 were notified to me by Dr Ditchburn himself. I have no reason to suppose that the remainder, notified from other areas of Shetland during the same epidemic, were less likely to have been whoopingcough due to B ordetella pertussis. Shetland Health Board, Lerwick ZE 1 0QP 1. Ditchburn RK.
Whooping-cough
J. after stopping
Med J 1979; i: 1601-03. 2. Macgregor JD. Whooping-cough vaccination: Br Med J 1979; i: 1154.
D. MACGREGOR
pertussis
a recent
immunisation. Br
Shetland
experience.
PRENATAL DETECTION OF TANGIER DISEASE
SiR,—I suggest that determination of the
content
of the
electrophoretically slower-moving high-density lipoprotein (HDL) component of amniotic fluid may be useful in prenatal diagnosis of Tangier disease. My colleagues and I have shown; that the HDL of amniotic fluid, when subjected to crossed immunoelectrophoresis, has a typical profile consisting of a fast-moving serum-HDL fraction and a slower-moving component consisting mainly of apolipoprotein A-I. We have since been able to locate the slow-moving HDL moiety in the fetal and neonatal lung (unpublished). It seems therefore plausible that in amniotic fluid this slow-moving apoA-I fraction is derived from the fetal lung. Since in Tangier disease the concentration of apoA-I in serum is less than 1% of normal6 one may expect a significant reduction in the content of the slow apoA-l component of amniotic fluid in affected pregnancies. We hope
1. Committee of Medical Aspects of Food Policy. Recommended daily amounts of food, energy and nutrients for groups of people in the United Kingdom (Rep Health Soc Subj no 15). Department of Health and Social Security, 1979. 2. Ministry of Agriculture, Fisheries and Food. Nutritional value of household food as a percentage of recommended intakes of the nutritional food survey (Food Facts 1979; no 5). 3. Ebringer A. Lancet 1979; i: 1186. 4. McDevitt HO, Benacerraf B. Adv Immunol 1969; 11: 31. 5. Gebhardt DOE, Beintema A, Reman F, van Gent CM. Clin Chim Acta 1979; 94: 93. 6. Assmann G, Capurso A, Smootz E, Wellner U. Atherosclerosis 1978, 30: 321.
755
investigate this question as soon as we have amniotic-fluid samples from women who may be carriers of the gene responsible for Tangier disease. to
Department of Obstetrics and Gynaecology, University Hospital, Leiden, Netherlands
DAVID O. E. GEBHARDT
HETEROPHILIC ANTIBODIES CAUSING FALSELY RAISED THYROID-STIMULATING-HORMONE RESULT
SIR,—Analysis of thyroid-stimulating hormone (TSH) is regarded as the most reliable and sensitive way of diagnosing primary hypothyroidism and insufficient thyroid replacement therapy, and the results of TSH assays are very often crucial to clinical decision taking. We have come across an instance of analytical interference which led to falsely raised TSH levels. In our experience prealbumin is a more important thyroxine T4) carrier than was previously thought, and in this laboratory we measure thyroxine-binding globulin and prealbumin to get an estimate of the free, non-protein bound fraction (FT4). In some cases the TSH is raised though FT4 values are normal. In such cases TSH levels are usually between 20 and 30 mU/1, but levels up to 50 mU/1 have been observed (refermU/1). The TSH assayswere done with a range <7-S commercial radioimmunoassay (Pharmacia) based on rabbit anti-TSH antibodies. When these problem sera were analysed with a TSH assay based on human anti-TSH antibodies (Dr L. Wide, Akademiska Sjukhuset, Uppsala) normal TSH results were obtained in most cases. TSH levels thus obtained accorded with the levels of FT 4’ As far as we know these patients with discrepant TSH and FT values were not clinically hypothyroid. Furthermore some of these patients revealed, on TRH testing, no further increase of TSH. These latter patients were treated with T because of previously high TSH levels. The serum factor responsible for falsely high TSH values has been isolated. On gel filtration it behaves differently from true TSH, exhibiting a molecular weight of around 150 000. Immunochemical investigations and chromatography on ’Protein A-Sepharose’ reveal properties indistinguishable from those of IgG. Incubation of this isolated fraction with rabbit Ig abolished the immunological TSH-activity. Likewise, addition of small amounts of rabbit Ig to the patient’s serum before analysis yields normal TSH results matching those obtained when human anti-TSH antibodies were used. Retrospectively we have found that at least 5% of all sera with high TSH seen in this laboratory during the past twelve months reveal normal TSH levels if rabbit Ig is added to the samples before analysis. In a neonatal TSH screening programme at least one serum with a raised TSH could be classified as normal when this pretreatment was done. The child showed no signs of hypothyroidism. This experience shows that heterophilic antibodies against rabbit Ig can result in falsely high TSH values if rabbit antibodies are used in the assay. This difficulty may apply to any immunoassay where rabbit antibodies are used, though we would expect the problem to be exposed only when the RIA is used to quantitate at antigen levels close to the detection limit. In obviating this kind of interference other factors, such as the design of the assay, need to be considered but the occurrence of heterophilic antibodies in general should be borne in mind. The manufacturers of the TSH assay have been told about this interference and claim to have eliminated the problem since June of this year; and our experience confirms this.
ence
Department of Clinical Chemistry, Danderyds Sjukhus, S-182 03 Danderyd, Sweden
GUNILLA HEDENBORG TOM PETTERSSON ANDERS CARLSTRÖM
T, Carlström A. The significance of thyroxine binding globulin prealbumin in the equilibrium between bound and free thyroxine. 3rd European Congress of Clinical Chemistry, 1979; abst p. 16.
1. Pettersson
and
General Medical Council THE reconstituted General Medical Council met for the first time on Sept. 27. It has 93 members and the names of the 50 elected members were reported in The Lancet on Aug. 25 (p. 428). The remaining 43 members (34 appointed, 9 nominated on the recommendation of the Privy Council) are:
Appointed-Prof. W. H. Trethowan (Birmingham University); Prof. J. H. Peacock (Bristol University); Mr Walpole Lewin (Cambridge University) ; Prof. D. R. Wood (Leeds University); Prof. Robert Kilpatrick (Leicester University); Prof. Kevin McCarthy (Liverpool University); Prof. A. H. Crisp (London University); Prof. T. W. Glenister (London University); Dr M. P. W. Godfrey (London University); Prof. Wó I. N. Kessel (Manchester University); Prof. Sir John Walton (Newcastle upon Tyne University); Prof. A. D. M. Greenfield (Nottingham University) ; Mr J. M. Potter (Oxford University); Prof. W. A. J. Crane (Sheffield University); Prof. J. B. L. Howell (Southampton University) ; Prof. H. L. Duthie (University of Wales); Prof. Ian MacGillivray (Aberdeen University); Prof. J. P. Duguid (Dundee University); Prof. James Williamson (Edinburgh University); Prof. E. K. Cruickshank (Glasgow University); Prof. I. C. Roddie (Queen’s University, Belfast); Sir Gordon Wolstenholme (Society of Apothecaries of London); Lord Richardson (Royal College of Physicians of London); Mr M. C. T. Reilly (Royal College of Surgeons of England); Mr D. B. Fraser (Royal College of Obstetricians and Gynaecologists); Dr R. F. Robertson (Royal College of Physicians of Edinburgh); Mr Donald McIntosh (Royal College of Surgeons of Edinburgh); Sir Robert Wright (Royal College of Physicians and Surgeons of Glasgow); Dr D. H. Irvine (Royal College of General Practitioners); Prof. J. R. Anderson (Royal College of Pathologists); Dr P. H. Connell (Royal College of Psychiatrists) ; Prof. L. A. Gillanders (Royal College of Radiologists); Dr J. E. Riding (Faculty of Anaesthetists); Dr W. G. Harding (Faculty of Community Medicine). Nominated-Miss Catherine Mary Hall (general secretary, Royal College of Nursing), Sir Norman Lindop (director, Hatfield Polytechnic), Mrs Jean Robinson (former chairman, Patients’ Association), Prof. Margaret Stacey (professor of sociology, University of Warwick), Sir Henry Yellowlees (chief medical officer, D.H.S.S.) (England); Mr Trevor Gray (Wales); Prof. J. J. A. Reid (chief medical officer, Scottish Home and Health Department), Rev. Francis Taylor Smith (Scotland) ; Mr W. R. Pinkerton (Northern Ireland). President At the meeting on Sept. 27 Lord Richardson, whose office is to end on June 15, 1980, was elected President.
term
of
Medical Education
Under the Medical Act 1978 the Education Committee of the General Medical Council is for the first time provided for by statute and will exercise most of the educational functions which have previously been assigned by the Medical Acts to the Council, as well as certain new functions. Section 15(1), (4), and (5) of the Medical Act 1978 states: There shall be established a committee of the General Council be known as the Education Committee having the general function of promoting high standards of medical education and co-ordinating all stages of medical education. "(4) For the purpose of discharging their general function under subsection (1) above the Education Committee shall (a) determine the extent of the knowledge and skill which is to be required for the granting of primary United Kingdom qualifications and secure that the instruction given in universities in the United Kingdom to persons studying for such qualifications is sufficient to equip them with knowledge and skill of that extent; (b) determine the standard of proficiency which is to be required from candidates at qualifying examinations and secure the maintenance of that standard; and (c) determine patterns of experience which may be recognised as suitable for giving to those engaging in such employment as is mentioned in section 15(2) of the Medical Act 1956 general clinical training for the purposes of the practice of their profession.
"15(1)
to
_
SIR,-In the latest official dietary recommendations’ no clear-cut recommendation is made concerning vitamin D for adults, on the reasonable grounds that the chief source of the vitamin follows from the action of ultraviolet light on the skin. One consequence of this change is that vitamin D no longer appears in Ministry of Agriculture, Fisheries, and Food tables on the nutritional value of household food.2 A stated purpose of the recommendations is to "direct attention, in surveys of food intakes of different groups, to subgroups who may be at the risk of undernutrition." It is unfortunate that recipients of the M.A.F.F. release Food Facts2 will no longer have their attention drawn to the fact that there are subgroups in the U.K. who are vitamin D deficient. Department of Biochemistry, Royal Dental Hospital of London School of Dental Surgery London SW17 0RE
FRANCIS B. REED
MOLECULAR MIMICRY AND H-Ir GENES
S!R,—Ebringer has
drawn attention to the uncertainty of there exist histocompatibility-linked immune genes which code positively for specific immune responses. The gene products of H-Ir genes have not been demonstrated and the existence of these genes is only inferential. However, Ebringer’s molecular mimicry concept, which postulates antigenic cross-reactivity between the antigens used for the immunisations and the histocompatibility antigens of the low-responder mice, cannot be the explanation because high response is genetically transmitted to hybrids which exhibit the histocompatibility antigens of the low
theory that response (H-Ir)
the
Fig. 2-Part of L. pneumophila, Cambridge strain, showing fimbriae (arrows). (1% phosphotungstic acid pH 6.5; x 120 000.)
By direct staining
and fluorescence
optical microscopy reported flagellated legionellae. With improved growth media which stimulate early profuse growth of the organisms we also have found, by negative-stain electron microscopy, flagella in cultures of both the short rod and filamentous forms of Legionella pneumophila. The flagella were usually dissociated from and surrounding the organisms. When attached to bacteria, the flagella occurred singly, usually in the polar or subpolar region (fig. 1), but were sometimes observed in small numbers emerging from the side of organisms. Two strains also possessed fimbriae (fig. 2). Flagella Thomason
et
a1.4 have
now
found in all strains of the three serogroups examined, and the frequency was greatest when cultured on enriched blood agar, CYE agar + beef extract, and enriched broth medium. At first thought due to contaminant microorganisms, their repeated presence in apparently pure cultures made us consider them a characteristic property oflegionellae.
responder strains.4 Research Unit, Medical Research Council of New Zealand, University of Otago Medical School, Dunedin, New Zealand
Immunopathology
D. D. ADAMS
were
These findings will be published in detail elsewhere. Public Health
Laboratory University Hospital, Queen’s Medical Centre, Nottingham NG7 2UH
F. G. RODGERS P. W. GREAVES A. D. MACRAE
PERTUSSIS VACCINE
SiR,-Professor Stewart (Sept. 1, p. 473) cheerfully cites Ditchburn’ in support of his crusade against pertussis vaccine, while at the same time casting doubt on the validity of my data2 on the grounds that I may have been describing "croupy coughs" rather than true pertussis. However, of the 50 cases of whooping-cough referred to in my paper, 21 were notified to me by Dr Ditchburn himself. I have no reason to suppose that the remainder, notified from other areas of Shetland during the same epidemic, were less likely to have been whoopingcough due to B ordetella pertussis. Shetland Health Board, Lerwick ZE 1 0QP 1. Ditchburn RK.
Whooping-cough
J. after stopping
Med J 1979; i: 1601-03. 2. Macgregor JD. Whooping-cough vaccination: Br Med J 1979; i: 1154.
D. MACGREGOR
pertussis
a recent
immunisation. Br
Shetland
experience.
PRENATAL DETECTION OF TANGIER DISEASE
SiR,—I suggest that determination of the
content
of the
electrophoretically slower-moving high-density lipoprotein (HDL) component of amniotic fluid may be useful in prenatal diagnosis of Tangier disease. My colleagues and I have shown; that the HDL of amniotic fluid, when subjected to crossed immunoelectrophoresis, has a typical profile consisting of a fast-moving serum-HDL fraction and a slower-moving component consisting mainly of apolipoprotein A-I. We have since been able to locate the slow-moving HDL moiety in the fetal and neonatal lung (unpublished). It seems therefore plausible that in amniotic fluid this slow-moving apoA-I fraction is derived from the fetal lung. Since in Tangier disease the concentration of apoA-I in serum is less than 1% of normal6 one may expect a significant reduction in the content of the slow apoA-l component of amniotic fluid in affected pregnancies. We hope
1. Committee of Medical Aspects of Food Policy. Recommended daily amounts of food, energy and nutrients for groups of people in the United Kingdom (Rep Health Soc Subj no 15). Department of Health and Social Security, 1979. 2. Ministry of Agriculture, Fisheries and Food. Nutritional value of household food as a percentage of recommended intakes of the nutritional food survey (Food Facts 1979; no 5). 3. Ebringer A. Lancet 1979; i: 1186. 4. McDevitt HO, Benacerraf B. Adv Immunol 1969; 11: 31. 5. Gebhardt DOE, Beintema A, Reman F, van Gent CM. Clin Chim Acta 1979; 94: 93. 6. Assmann G, Capurso A, Smootz E, Wellner U. Atherosclerosis 1978, 30: 321.
755
investigate this question as soon as we have amniotic-fluid samples from women who may be carriers of the gene responsible for Tangier disease. to
Department of Obstetrics and Gynaecology, University Hospital, Leiden, Netherlands
DAVID O. E. GEBHARDT
HETEROPHILIC ANTIBODIES CAUSING FALSELY RAISED THYROID-STIMULATING-HORMONE RESULT
SIR,—Analysis of thyroid-stimulating hormone (TSH) is regarded as the most reliable and sensitive way of diagnosing primary hypothyroidism and insufficient thyroid replacement therapy, and the results of TSH assays are very often crucial to clinical decision taking. We have come across an instance of analytical interference which led to falsely raised TSH levels. In our experience prealbumin is a more important thyroxine T4) carrier than was previously thought, and in this laboratory we measure thyroxine-binding globulin and prealbumin to get an estimate of the free, non-protein bound fraction (FT4). In some cases the TSH is raised though FT4 values are normal. In such cases TSH levels are usually between 20 and 30 mU/1, but levels up to 50 mU/1 have been observed (refermU/1). The TSH assayswere done with a range <7-S commercial radioimmunoassay (Pharmacia) based on rabbit anti-TSH antibodies. When these problem sera were analysed with a TSH assay based on human anti-TSH antibodies (Dr L. Wide, Akademiska Sjukhuset, Uppsala) normal TSH results were obtained in most cases. TSH levels thus obtained accorded with the levels of FT 4’ As far as we know these patients with discrepant TSH and FT values were not clinically hypothyroid. Furthermore some of these patients revealed, on TRH testing, no further increase of TSH. These latter patients were treated with T because of previously high TSH levels. The serum factor responsible for falsely high TSH values has been isolated. On gel filtration it behaves differently from true TSH, exhibiting a molecular weight of around 150 000. Immunochemical investigations and chromatography on ’Protein A-Sepharose’ reveal properties indistinguishable from those of IgG. Incubation of this isolated fraction with rabbit Ig abolished the immunological TSH-activity. Likewise, addition of small amounts of rabbit Ig to the patient’s serum before analysis yields normal TSH results matching those obtained when human anti-TSH antibodies were used. Retrospectively we have found that at least 5% of all sera with high TSH seen in this laboratory during the past twelve months reveal normal TSH levels if rabbit Ig is added to the samples before analysis. In a neonatal TSH screening programme at least one serum with a raised TSH could be classified as normal when this pretreatment was done. The child showed no signs of hypothyroidism. This experience shows that heterophilic antibodies against rabbit Ig can result in falsely high TSH values if rabbit antibodies are used in the assay. This difficulty may apply to any immunoassay where rabbit antibodies are used, though we would expect the problem to be exposed only when the RIA is used to quantitate at antigen levels close to the detection limit. In obviating this kind of interference other factors, such as the design of the assay, need to be considered but the occurrence of heterophilic antibodies in general should be borne in mind. The manufacturers of the TSH assay have been told about this interference and claim to have eliminated the problem since June of this year; and our experience confirms this.
ence
Department of Clinical Chemistry, Danderyds Sjukhus, S-182 03 Danderyd, Sweden
GUNILLA HEDENBORG TOM PETTERSSON ANDERS CARLSTRÖM
T, Carlström A. The significance of thyroxine binding globulin prealbumin in the equilibrium between bound and free thyroxine. 3rd European Congress of Clinical Chemistry, 1979; abst p. 16.
1. Pettersson
and
General Medical Council THE reconstituted General Medical Council met for the first time on Sept. 27. It has 93 members and the names of the 50 elected members were reported in The Lancet on Aug. 25 (p. 428). The remaining 43 members (34 appointed, 9 nominated on the recommendation of the Privy Council) are:
Appointed-Prof. W. H. Trethowan (Birmingham University); Prof. J. H. Peacock (Bristol University); Mr Walpole Lewin (Cambridge University) ; Prof. D. R. Wood (Leeds University); Prof. Robert Kilpatrick (Leicester University); Prof. Kevin McCarthy (Liverpool University); Prof. A. H. Crisp (London University); Prof. T. W. Glenister (London University); Dr M. P. W. Godfrey (London University); Prof. Wó I. N. Kessel (Manchester University); Prof. Sir John Walton (Newcastle upon Tyne University); Prof. A. D. M. Greenfield (Nottingham University) ; Mr J. M. Potter (Oxford University); Prof. W. A. J. Crane (Sheffield University); Prof. J. B. L. Howell (Southampton University) ; Prof. H. L. Duthie (University of Wales); Prof. Ian MacGillivray (Aberdeen University); Prof. J. P. Duguid (Dundee University); Prof. James Williamson (Edinburgh University); Prof. E. K. Cruickshank (Glasgow University); Prof. I. C. Roddie (Queen’s University, Belfast); Sir Gordon Wolstenholme (Society of Apothecaries of London); Lord Richardson (Royal College of Physicians of London); Mr M. C. T. Reilly (Royal College of Surgeons of England); Mr D. B. Fraser (Royal College of Obstetricians and Gynaecologists); Dr R. F. Robertson (Royal College of Physicians of Edinburgh); Mr Donald McIntosh (Royal College of Surgeons of Edinburgh); Sir Robert Wright (Royal College of Physicians and Surgeons of Glasgow); Dr D. H. Irvine (Royal College of General Practitioners); Prof. J. R. Anderson (Royal College of Pathologists); Dr P. H. Connell (Royal College of Psychiatrists) ; Prof. L. A. Gillanders (Royal College of Radiologists); Dr J. E. Riding (Faculty of Anaesthetists); Dr W. G. Harding (Faculty of Community Medicine). Nominated-Miss Catherine Mary Hall (general secretary, Royal College of Nursing), Sir Norman Lindop (director, Hatfield Polytechnic), Mrs Jean Robinson (former chairman, Patients’ Association), Prof. Margaret Stacey (professor of sociology, University of Warwick), Sir Henry Yellowlees (chief medical officer, D.H.S.S.) (England); Mr Trevor Gray (Wales); Prof. J. J. A. Reid (chief medical officer, Scottish Home and Health Department), Rev. Francis Taylor Smith (Scotland) ; Mr W. R. Pinkerton (Northern Ireland). President At the meeting on Sept. 27 Lord Richardson, whose office is to end on June 15, 1980, was elected President.
term
of
Medical Education
Under the Medical Act 1978 the Education Committee of the General Medical Council is for the first time provided for by statute and will exercise most of the educational functions which have previously been assigned by the Medical Acts to the Council, as well as certain new functions. Section 15(1), (4), and (5) of the Medical Act 1978 states: There shall be established a committee of the General Council be known as the Education Committee having the general function of promoting high standards of medical education and co-ordinating all stages of medical education. "(4) For the purpose of discharging their general function under subsection (1) above the Education Committee shall (a) determine the extent of the knowledge and skill which is to be required for the granting of primary United Kingdom qualifications and secure that the instruction given in universities in the United Kingdom to persons studying for such qualifications is sufficient to equip them with knowledge and skill of that extent; (b) determine the standard of proficiency which is to be required from candidates at qualifying examinations and secure the maintenance of that standard; and (c) determine patterns of experience which may be recognised as suitable for giving to those engaging in such employment as is mentioned in section 15(2) of the Medical Act 1956 general clinical training for the purposes of the practice of their profession.
"15(1)
to
_