- Email: [email protected]
GROWTH HORMONE TREATMENT AND CIRCULATING THYROXINE
1030 CILIATED ORGANISMS IN DIALYSIS FLUID
TABLE I-PERCENTAGE OF TOTAL FALL IN MORTALITY IN FINLAND FROM ALL CAUSES
OTHER
1969-71 DUE TO AMENABLE, NON-AMENABLE, AND
(PARTLY AMENABLE+ VIOLENT CAUSES) CAUSES
OF DEATH
in dialysis fluid by Dr Roxby 916) are well known to cytothem occasionally in Papanicolaou
SIR,—The ciliated organisms colleagues (April 19,
and his
CAUSES OF DEATH
(FINLAND)
p
who encounter stained cervical smears and in fixed and stained smears of sputum from patients suspected of having carcinoma of the bronchus. They were first described 30 years ago by Papanicolaou himself, who used the term ciliocytophthoria (CCP) to describe this effect. ’The ciliated bodies are ciliated fragments of cytoplasm pinched off from the glandular epithelial cells lining the respiratory and genital tracts. The reason for this is not clear, although Pierce and Hirsch in 1958 noted that CCP was most likely to be found in sputum samples from patients with a recent history of respiratory virus infection.2 I suspect that the ciliated bodies seen in dialysis fluid are derived from the ciliated cells lining the fallopian tubes. Roxby et al are not the first to think that the ciliated bodies are some sort of parasitic organism because in wet preparations the cilia seem to move. I have calmed down at least two very excited microbiologists in my time who made similar observations. Still, CCP merits further investigation.
pathologists,
TABLE II-TRENDS IN CERTAIN DISEASES TERMED AS AMENABLE
seen
Department of Pathology, St Mary’s Hospital Medical School,
D. V. COLEMAN
London W21PG
Papanicolaou GN. Degenerative changes in ciliated cells exfoliating from bronchial epithelium as a cytologic criterion in the diagnosis of diseases of the lung. NY State J
1.
1969-81 actually contributes far more to the overall decrease in death rates (table I). The contribution is greater ifone adds to the percentage of the fall due to "non-amenable" causes the half of the contribution from "amenable causes" which Poikolainen and Eskola estimate not to be due to "medical intervention". Then the contribution to the decline in deaths from all causes due to environmental, social, nutritional, and genetic influences rises to 49-6% in males and 62 - 4% in females compared with the 10 - 8% and 13 - 4% attributable to medical intervention. The other main reason for the overall decline in total deaths is the fall in those diseases defined as "others" ("partly amenable" plus violent causes of death) in table I. The main cause of death in this group is ischaemic heart disease about which the Finnish workers state, "our results do not suggest that such health care interventions have had any great impact on the decline of mortality". This reinforces the conclusions that non-health service factors are the major influences on mortality.’ Variations in certified death rates for specific causes can be artifactual (eg, changing diagnostic fashions) or due to changes in the case-fatality or incidence of the disease which is the cause of death. Poikolainen and Eskola presume that the fall in mortality rates in "amenable causes of death" was due principally to a decrease in case fatality during the 1970s secondary to the introduction and greater uptake of certain treatments. They do not fully discuss the fact that for certain of the diseases presented their incidence rates (ie, the number of people at risk of death) also fell considerably during the 1970s. For others mortality had been decreasing before the widespread introduction of new treatments. Examples of this are presented in table 11. A last question, however, is how useful is it to try and separate the effects of advances in health care from those in other fields? The interrelations among them are complex and probably not arithmetical as suggested by the Finnish workers’ model. For most treatments, the fitter the patient, the greater is the chance of success. Surely this extends to communities-ie, the healthier the population, the more effective will be its health services. Common Services Agency, Scottish Health Service,
MARTIN DONAGHY
Edinburgh
1. National Board of Health Finland. Health Services: year book ofthe National Board of
Health 1981-1982. Helsinki, 1982. 2 World Health Organisation. World Health WHO.
Organisation
statistics annuals. Geneva:
Med 1956; 56: 2647-50. 2. Pierce OH, Hirsch JG. Ciliocytophthoria: Relationship to viral respiratory infections of humans. Proc Soc Exp Biol Med 1958; 98: 489-92.
WHY CONFINE CHORIONIC VILLUS (PLACENTAL) BIOPSY TO THE FIRST TRIMESTER?
SIR,—Mr Nicolaides and co-workers’ report (March 8, p 543) shows that transabdominal chorionic villus sampling should be extended beyond the first trimester of pregnancy. For several years we have been using chorionic plate biopsy in second trimester pregnancies with a high probability of chromosomal abnormality.l,2 The speed and simplicity of the diagnosis, as Nicolaides et al found, prompted us to do chorionic plate biopsy in five cases of oligohydramnios and malformed fetuses, in which three cytogenetic abnormalities were detected. We find the transcervical route very effective. Our study on second-trimester transabdominal and transcervical chorionic plate biopsy suggests that, in certain circumstances, the transcervical route is simpler and yields more suitable amounts of chronic material for laboratory diagnosis. The patient’s obstetric condition, the presence or absence of amniotic fluid, the location of the placenta, and the distance from the internal os should define whether the transcervical or transabdominal approach should be preferred. Department of Obstetrics and Gynaecology, University Medical School of Szeged, H-6701 Szeged, Hungary
J. SZABÓ J. GELLÉN
Institute of Medical Biology, University Medical School of
G. SZEMERE
Szeged
Szabó J, Herczeg J, Thurzó L, Szemere G. Karyotyping from uncultured human trophoblast in the first trimester of pregnancy. Obstet Gynecol 1984; 64: 807-10. 2. Szabó J, Gellén J, Szemere G. Chorionic biopsy in the mid-trimester. Br J Obstet 1.
Gynaecol (in press)
GROWTH HORMONE TREATMENT AND CIRCULATING THYROXINE
SIR,-Dr Kaplan and colleagues’ paper (March 29, p 697) on recombinant-DNA-derived methionyl growth hormone (GH) in GH deficient children is encouraging, especially at a time when supplies of GH for clinical use are limited. However, in the second paragraph of their discussion, Kaplan et al state that the reduction in circulating thyroxine levels in GH-treated patients has not been
explained.
1031 GH autoregulates its secretion via a short-loop, postitive feedback mechanism operating on somatostatin release. Hypothalamic somatostatin content is increased in rats treated with GH, 1,2 and intraventricular GH stimulates GH release into the hypophysial hypophysectomy reduces hypothalamic portal somatostatin,4 and this situation is reversed by GH administration. 1,2 Somatostatin is also a potent inhibitor of thyrotropin secretion,5,6 so there is a reciprocal relation between GH and thyrotropin, via somatostatin. We have shown that children with GH deficiency who are on intravenous GH infusions exhibit a reduced response to thyrotropin-releasing hormone. Lippe et al reported on six children with idiopathic GH deficiency in whom secondary hypothyroidism developed while they were on GH therapy, this being reversed on discontinuation of treatment. This was suggested to be the result of GH-induced stimulation of endogenous somatostatin release which, in turn, inhibited thyrotropin secretion. Nevertheless, compensatory mechanisms in the hypothalamicpituitary-thyroid axis probably come into play since only a minority of GH-treated children become overtly hypothyroid during
blood.3 Conversely,
thyrotropin
therapy.7
when
C jejuni CH5 (a strain unable to produce haemolysin) was injected into a rabbit ileal loop, bacteria isolated from blood 3 h later did produce the haemolysin. This experiment suggests that haemolysin production may be an inducible virulence factor in
strains. the role of these factors in pathogenicity is as yet unclear, it is tempting to speculate that cytotoxin 1 may be involved in attachment of the bacteria to mammalian cells, similar to the role played by other haemagglutinating factors.4 Cytotoxin 2 could give an organism an advantage for survival in blood by providing a mechanism for obtaining iron. some
Although
Division of Microbiology, Food and Drug Administration, Washington, DC 20204, USA
1. McCardell
BA, Madden JM, Lee EC. Campylobacter Jejuni and Campylobacter coli production of a cytotonic toxin immunologically similar to cholera toxin. J Food
Prot 1984; 47: 943-49. 2. O’Brien
3.
Department of Endocrinology, Hospital de Especialidades Quirúrgicas, 28040 Madrid, Spain
ANTONIO GÓMEZ-PAN
Endocrinology Service, Hospital Provincial, Madrid
MARIA D. RODRÍGUEZ-ARNAO
B. A. MCCARDELL
J. M. MADDEN J. T. STANFIELD
4.
AD, Lively TA, Chang TW, et al. Purification of Shigella dysenteriae I (Shigalike) toxin from Escherichia coli 0157 H7 strain associated with haemorrhagic colitis. Lancet 1983; ii: 573. McCardell BA, Madden JM, Shah DB. Isolation and characterisation of a cytolysin by Vibrio cholerae serogroup non-O1. Can J Microbiol 1985; 31: 711-20. Finkelstein RA, Arita M, Clements JD, et al. Isolation and purification of an adhesive factor (’cholera lectin’) from Vibrio cholerae. In: Proceedings of 13th US-Japan Joint Conference on Cholera, 1977: 137-51
HTLV-I ASSOCIATED MYELOPATHY, A NEW CLINICAL ENTITY 1.
Kanatusuka A, Makino H, Matsushima Y, et al. Effect of hypophysectomy and growth hormone administration
on
Neuroendocrinology 1979; 29:
somatostatin content 186-90.
2. Patel Y. Growth hormone stimulates
hypothalamic
in
the rat
somatostatin.
hypothalamus.
Life Sci 1979;
24:
1589-94. 3. Chihara
K, Minamitami N, Kaji K, et al. Intraventricularly injected growth hormone stimulates somatostatin release into rat hypophyseal portal blood. Endocrinology
1981, 109: 2279-81. 4. Baker BL, Yen YY. The influence of hypophysectomy on the stores of somatostatin in the hypothalamus and pituitary stem. Proc Soc Exp Biol Med 1976; 151: 599-602. 5. Hall R, Besser GM, Schally AV, et al. Actions of growth hormone-release inhibiting hormone in healthy men and acromegaly. Lancet 1973; ii: 581-84. 6 Carr D, Gómez-Pan A, Weightman DR, et al. Growth hormone-release inhibiting hormone: actions on thyrotrophin and prolactin secretion after thyrotrophinreleasing hormone. Br Med J 1975; iii: 67-69. 7. Gómez-Pan A, Arroyo T, Hervás F, et al. The physiological role of somatostatin in the control of growth hormone and thyrotrophin secretion. In. La Cauza F, Root AW, eds Problems in pediatric endocrinology. New York: Academic Press, 1980: 21-27. 8. Lippe BM, Van Herle AJ, La Franchi SH, et al. Reversible hypothyroidism in growth hormone deficient children treated with human growth hormone. J Clin Endocrinol Metab 1975; 40: 612-18.
PRODUCTION OF CYTOTOXINS BY CAMPYLOBACTER
SIR,—Besides the ganglioside GM1 binding cytotonic toxin, we have found that Campylobacter spp produce two distinct factors cytotoxic for Chinese hamster ovary (CHO) cells when the concentration of fetal calf serum in the tissue culture medium is reduced to 0 -7%. We have purified one factor by fast protein liquid chromatography and found that it has a molecular weight of 70 000 and an isoelectric point of about 9-0. This factor, cytotoxin 1, is insensitive to heat (100°C for 5 min) and trypsin (1 mg/ml, 1 h at 37° C). Although it is inactivated by normal rabbit serum and binds to several membrane and serum factors (serine, fetuin,
phosphatidyl-N, N-dimethylethanolamine, phosphatidyl-N, N-monomethylethanolamine, pepstatin, and focuse), it is not inactivated by them either singly or in combination. Both crude concentrated and purified cytotoxin 1 cause haemagglutination but not haemolysis of rabbit red blood cells. The second factor, cytotoxin 2, is also cytotoxic for CHO cells. In contrast to cytotoxin 1, it is haemolytic for rabbit red blood cells. Cytotoxin 2 is trypsin sensitive, heat labile, and not neutralised by normal rabbit serum or by antibody to the cytotoxin produced by by Shigella dysenteriae type 1.2 However, cytotoxin 2 is neutralised 3 antibody to the cytolysin produced by Vibrio cholerae non-O 1. In
a
survey of 60 strains, all Cjejunilcoli tested were positive for 1 and about 45% were positive for cytotoxin 2. However,
cytotoxin
SIR,—Gessain and colleagues’ have reported that about 60% of patients with tropical spastic paraparesis (TSP) had antibodies to human T- lymphotropic virus type I (HTLV-I) in their serum. We have seen patients with similar myelopathies with high titres of HTLV-I antibody in serum and even in the CSF, and think this myelopathy is the same as that described in HTLV-I antibody positive TSP by Gessain et al. However, our patients live, not in the tropics, but in a temperate zone, Kagoshima prefecture, where adult T-cell leukaemia/lymphoma (ATLL) is endemic and where about 16% of the population have HTLV-I antibody.2 For our patients, therefore, we propose the diagnostic term HTLV-I associated myelopathy (HAM). We report here on six patients (four women and two men, age 25-58), all of whom had myelopathy of gradual onset and slowly progressive course (3 months to 11 years before hospital admission); spastic paraparesis with pyramidal signs associated with mild sensory and sphincter disturbances; and normal findings on myelography, computerised tomography of the spine, and magnetic resonance imaging. Thinking that this group might represent a new clinical entity we did further studies in an attempt to find the cause. Since one patient had atypical lymphocytes in serum and CSF similar to ATLL cells, we looked for HTLV-I antibody using ’Serodia-A TLA’ (Fujirebio Inc).3 Seventy-eight patients with other neurological disorders formed the control group. The six patients showed very high HTLV-I antibody titres (512-8192X) in the serum and CSF (64-512X). Twelve controls (15%) also had positive titres (16-2048x) in the serum although only one had a positive titre (16x) in the CSF. Confirmation by western blot with MT-2 cell lysate antigens4,5 was done in all six patients and in several controls, including two with ATLL and three HTLV-I carriers. The IgG of the study group, but not the IgM, reacted in both serum and CSF (figure). The most remarkable finding is that the p32 band was detected clearly besides the p24 band in all CSF samples from the study group. IgG synthesis rates within the blood/brain barrierwere increased in all six patients. These data suggest that the myelopathy was associated with HTLV-1. Antibody in the CSF may have special significance for the diagnosis and may also offer insight into the pathogenesis of HAM. Although most of our HAM patients had some atypical lymphocytes similar to those found in ATLL, white blood cell counts were normal, and they could not be said to have leukaemia. A pre-ATLL state is a possibility, however. HTLV-I may be neurovirulent directly, by infecting cells in the central nervous system, or indirectly, through an immunopathological process.
TABLE I-PERCENTAGE OF TOTAL FALL IN MORTALITY IN FINLAND FROM ALL CAUSES
OTHER
1969-71 DUE TO AMENABLE, NON-AMENABLE, AND
(PARTLY AMENABLE+ VIOLENT CAUSES) CAUSES
OF DEATH
in dialysis fluid by Dr Roxby 916) are well known to cytothem occasionally in Papanicolaou
SIR,—The ciliated organisms colleagues (April 19,
and his
CAUSES OF DEATH
(FINLAND)
p
who encounter stained cervical smears and in fixed and stained smears of sputum from patients suspected of having carcinoma of the bronchus. They were first described 30 years ago by Papanicolaou himself, who used the term ciliocytophthoria (CCP) to describe this effect. ’The ciliated bodies are ciliated fragments of cytoplasm pinched off from the glandular epithelial cells lining the respiratory and genital tracts. The reason for this is not clear, although Pierce and Hirsch in 1958 noted that CCP was most likely to be found in sputum samples from patients with a recent history of respiratory virus infection.2 I suspect that the ciliated bodies seen in dialysis fluid are derived from the ciliated cells lining the fallopian tubes. Roxby et al are not the first to think that the ciliated bodies are some sort of parasitic organism because in wet preparations the cilia seem to move. I have calmed down at least two very excited microbiologists in my time who made similar observations. Still, CCP merits further investigation.
pathologists,
TABLE II-TRENDS IN CERTAIN DISEASES TERMED AS AMENABLE
seen
Department of Pathology, St Mary’s Hospital Medical School,
D. V. COLEMAN
London W21PG
Papanicolaou GN. Degenerative changes in ciliated cells exfoliating from bronchial epithelium as a cytologic criterion in the diagnosis of diseases of the lung. NY State J
1.
1969-81 actually contributes far more to the overall decrease in death rates (table I). The contribution is greater ifone adds to the percentage of the fall due to "non-amenable" causes the half of the contribution from "amenable causes" which Poikolainen and Eskola estimate not to be due to "medical intervention". Then the contribution to the decline in deaths from all causes due to environmental, social, nutritional, and genetic influences rises to 49-6% in males and 62 - 4% in females compared with the 10 - 8% and 13 - 4% attributable to medical intervention. The other main reason for the overall decline in total deaths is the fall in those diseases defined as "others" ("partly amenable" plus violent causes of death) in table I. The main cause of death in this group is ischaemic heart disease about which the Finnish workers state, "our results do not suggest that such health care interventions have had any great impact on the decline of mortality". This reinforces the conclusions that non-health service factors are the major influences on mortality.’ Variations in certified death rates for specific causes can be artifactual (eg, changing diagnostic fashions) or due to changes in the case-fatality or incidence of the disease which is the cause of death. Poikolainen and Eskola presume that the fall in mortality rates in "amenable causes of death" was due principally to a decrease in case fatality during the 1970s secondary to the introduction and greater uptake of certain treatments. They do not fully discuss the fact that for certain of the diseases presented their incidence rates (ie, the number of people at risk of death) also fell considerably during the 1970s. For others mortality had been decreasing before the widespread introduction of new treatments. Examples of this are presented in table 11. A last question, however, is how useful is it to try and separate the effects of advances in health care from those in other fields? The interrelations among them are complex and probably not arithmetical as suggested by the Finnish workers’ model. For most treatments, the fitter the patient, the greater is the chance of success. Surely this extends to communities-ie, the healthier the population, the more effective will be its health services. Common Services Agency, Scottish Health Service,
MARTIN DONAGHY
Edinburgh
1. National Board of Health Finland. Health Services: year book ofthe National Board of
Health 1981-1982. Helsinki, 1982. 2 World Health Organisation. World Health WHO.
Organisation
statistics annuals. Geneva:
Med 1956; 56: 2647-50. 2. Pierce OH, Hirsch JG. Ciliocytophthoria: Relationship to viral respiratory infections of humans. Proc Soc Exp Biol Med 1958; 98: 489-92.
WHY CONFINE CHORIONIC VILLUS (PLACENTAL) BIOPSY TO THE FIRST TRIMESTER?
SIR,—Mr Nicolaides and co-workers’ report (March 8, p 543) shows that transabdominal chorionic villus sampling should be extended beyond the first trimester of pregnancy. For several years we have been using chorionic plate biopsy in second trimester pregnancies with a high probability of chromosomal abnormality.l,2 The speed and simplicity of the diagnosis, as Nicolaides et al found, prompted us to do chorionic plate biopsy in five cases of oligohydramnios and malformed fetuses, in which three cytogenetic abnormalities were detected. We find the transcervical route very effective. Our study on second-trimester transabdominal and transcervical chorionic plate biopsy suggests that, in certain circumstances, the transcervical route is simpler and yields more suitable amounts of chronic material for laboratory diagnosis. The patient’s obstetric condition, the presence or absence of amniotic fluid, the location of the placenta, and the distance from the internal os should define whether the transcervical or transabdominal approach should be preferred. Department of Obstetrics and Gynaecology, University Medical School of Szeged, H-6701 Szeged, Hungary
J. SZABÓ J. GELLÉN
Institute of Medical Biology, University Medical School of
G. SZEMERE
Szeged
Szabó J, Herczeg J, Thurzó L, Szemere G. Karyotyping from uncultured human trophoblast in the first trimester of pregnancy. Obstet Gynecol 1984; 64: 807-10. 2. Szabó J, Gellén J, Szemere G. Chorionic biopsy in the mid-trimester. Br J Obstet 1.
Gynaecol (in press)
GROWTH HORMONE TREATMENT AND CIRCULATING THYROXINE
SIR,-Dr Kaplan and colleagues’ paper (March 29, p 697) on recombinant-DNA-derived methionyl growth hormone (GH) in GH deficient children is encouraging, especially at a time when supplies of GH for clinical use are limited. However, in the second paragraph of their discussion, Kaplan et al state that the reduction in circulating thyroxine levels in GH-treated patients has not been
explained.
1031 GH autoregulates its secretion via a short-loop, postitive feedback mechanism operating on somatostatin release. Hypothalamic somatostatin content is increased in rats treated with GH, 1,2 and intraventricular GH stimulates GH release into the hypophysial hypophysectomy reduces hypothalamic portal somatostatin,4 and this situation is reversed by GH administration. 1,2 Somatostatin is also a potent inhibitor of thyrotropin secretion,5,6 so there is a reciprocal relation between GH and thyrotropin, via somatostatin. We have shown that children with GH deficiency who are on intravenous GH infusions exhibit a reduced response to thyrotropin-releasing hormone. Lippe et al reported on six children with idiopathic GH deficiency in whom secondary hypothyroidism developed while they were on GH therapy, this being reversed on discontinuation of treatment. This was suggested to be the result of GH-induced stimulation of endogenous somatostatin release which, in turn, inhibited thyrotropin secretion. Nevertheless, compensatory mechanisms in the hypothalamicpituitary-thyroid axis probably come into play since only a minority of GH-treated children become overtly hypothyroid during
blood.3 Conversely,
thyrotropin
therapy.7
when
C jejuni CH5 (a strain unable to produce haemolysin) was injected into a rabbit ileal loop, bacteria isolated from blood 3 h later did produce the haemolysin. This experiment suggests that haemolysin production may be an inducible virulence factor in
strains. the role of these factors in pathogenicity is as yet unclear, it is tempting to speculate that cytotoxin 1 may be involved in attachment of the bacteria to mammalian cells, similar to the role played by other haemagglutinating factors.4 Cytotoxin 2 could give an organism an advantage for survival in blood by providing a mechanism for obtaining iron. some
Although
Division of Microbiology, Food and Drug Administration, Washington, DC 20204, USA
1. McCardell
BA, Madden JM, Lee EC. Campylobacter Jejuni and Campylobacter coli production of a cytotonic toxin immunologically similar to cholera toxin. J Food
Prot 1984; 47: 943-49. 2. O’Brien
3.
Department of Endocrinology, Hospital de Especialidades Quirúrgicas, 28040 Madrid, Spain
ANTONIO GÓMEZ-PAN
Endocrinology Service, Hospital Provincial, Madrid
MARIA D. RODRÍGUEZ-ARNAO
B. A. MCCARDELL
J. M. MADDEN J. T. STANFIELD
4.
AD, Lively TA, Chang TW, et al. Purification of Shigella dysenteriae I (Shigalike) toxin from Escherichia coli 0157 H7 strain associated with haemorrhagic colitis. Lancet 1983; ii: 573. McCardell BA, Madden JM, Shah DB. Isolation and characterisation of a cytolysin by Vibrio cholerae serogroup non-O1. Can J Microbiol 1985; 31: 711-20. Finkelstein RA, Arita M, Clements JD, et al. Isolation and purification of an adhesive factor (’cholera lectin’) from Vibrio cholerae. In: Proceedings of 13th US-Japan Joint Conference on Cholera, 1977: 137-51
HTLV-I ASSOCIATED MYELOPATHY, A NEW CLINICAL ENTITY 1.
Kanatusuka A, Makino H, Matsushima Y, et al. Effect of hypophysectomy and growth hormone administration
on
Neuroendocrinology 1979; 29:
somatostatin content 186-90.
2. Patel Y. Growth hormone stimulates
hypothalamic
in
the rat
somatostatin.
hypothalamus.
Life Sci 1979;
24:
1589-94. 3. Chihara
K, Minamitami N, Kaji K, et al. Intraventricularly injected growth hormone stimulates somatostatin release into rat hypophyseal portal blood. Endocrinology
1981, 109: 2279-81. 4. Baker BL, Yen YY. The influence of hypophysectomy on the stores of somatostatin in the hypothalamus and pituitary stem. Proc Soc Exp Biol Med 1976; 151: 599-602. 5. Hall R, Besser GM, Schally AV, et al. Actions of growth hormone-release inhibiting hormone in healthy men and acromegaly. Lancet 1973; ii: 581-84. 6 Carr D, Gómez-Pan A, Weightman DR, et al. Growth hormone-release inhibiting hormone: actions on thyrotrophin and prolactin secretion after thyrotrophinreleasing hormone. Br Med J 1975; iii: 67-69. 7. Gómez-Pan A, Arroyo T, Hervás F, et al. The physiological role of somatostatin in the control of growth hormone and thyrotrophin secretion. In. La Cauza F, Root AW, eds Problems in pediatric endocrinology. New York: Academic Press, 1980: 21-27. 8. Lippe BM, Van Herle AJ, La Franchi SH, et al. Reversible hypothyroidism in growth hormone deficient children treated with human growth hormone. J Clin Endocrinol Metab 1975; 40: 612-18.
PRODUCTION OF CYTOTOXINS BY CAMPYLOBACTER
SIR,—Besides the ganglioside GM1 binding cytotonic toxin, we have found that Campylobacter spp produce two distinct factors cytotoxic for Chinese hamster ovary (CHO) cells when the concentration of fetal calf serum in the tissue culture medium is reduced to 0 -7%. We have purified one factor by fast protein liquid chromatography and found that it has a molecular weight of 70 000 and an isoelectric point of about 9-0. This factor, cytotoxin 1, is insensitive to heat (100°C for 5 min) and trypsin (1 mg/ml, 1 h at 37° C). Although it is inactivated by normal rabbit serum and binds to several membrane and serum factors (serine, fetuin,
phosphatidyl-N, N-dimethylethanolamine, phosphatidyl-N, N-monomethylethanolamine, pepstatin, and focuse), it is not inactivated by them either singly or in combination. Both crude concentrated and purified cytotoxin 1 cause haemagglutination but not haemolysis of rabbit red blood cells. The second factor, cytotoxin 2, is also cytotoxic for CHO cells. In contrast to cytotoxin 1, it is haemolytic for rabbit red blood cells. Cytotoxin 2 is trypsin sensitive, heat labile, and not neutralised by normal rabbit serum or by antibody to the cytotoxin produced by by Shigella dysenteriae type 1.2 However, cytotoxin 2 is neutralised 3 antibody to the cytolysin produced by Vibrio cholerae non-O 1. In
a
survey of 60 strains, all Cjejunilcoli tested were positive for 1 and about 45% were positive for cytotoxin 2. However,
cytotoxin
SIR,—Gessain and colleagues’ have reported that about 60% of patients with tropical spastic paraparesis (TSP) had antibodies to human T- lymphotropic virus type I (HTLV-I) in their serum. We have seen patients with similar myelopathies with high titres of HTLV-I antibody in serum and even in the CSF, and think this myelopathy is the same as that described in HTLV-I antibody positive TSP by Gessain et al. However, our patients live, not in the tropics, but in a temperate zone, Kagoshima prefecture, where adult T-cell leukaemia/lymphoma (ATLL) is endemic and where about 16% of the population have HTLV-I antibody.2 For our patients, therefore, we propose the diagnostic term HTLV-I associated myelopathy (HAM). We report here on six patients (four women and two men, age 25-58), all of whom had myelopathy of gradual onset and slowly progressive course (3 months to 11 years before hospital admission); spastic paraparesis with pyramidal signs associated with mild sensory and sphincter disturbances; and normal findings on myelography, computerised tomography of the spine, and magnetic resonance imaging. Thinking that this group might represent a new clinical entity we did further studies in an attempt to find the cause. Since one patient had atypical lymphocytes in serum and CSF similar to ATLL cells, we looked for HTLV-I antibody using ’Serodia-A TLA’ (Fujirebio Inc).3 Seventy-eight patients with other neurological disorders formed the control group. The six patients showed very high HTLV-I antibody titres (512-8192X) in the serum and CSF (64-512X). Twelve controls (15%) also had positive titres (16-2048x) in the serum although only one had a positive titre (16x) in the CSF. Confirmation by western blot with MT-2 cell lysate antigens4,5 was done in all six patients and in several controls, including two with ATLL and three HTLV-I carriers. The IgG of the study group, but not the IgM, reacted in both serum and CSF (figure). The most remarkable finding is that the p32 band was detected clearly besides the p24 band in all CSF samples from the study group. IgG synthesis rates within the blood/brain barrierwere increased in all six patients. These data suggest that the myelopathy was associated with HTLV-1. Antibody in the CSF may have special significance for the diagnosis and may also offer insight into the pathogenesis of HAM. Although most of our HAM patients had some atypical lymphocytes similar to those found in ATLL, white blood cell counts were normal, and they could not be said to have leukaemia. A pre-ATLL state is a possibility, however. HTLV-I may be neurovirulent directly, by infecting cells in the central nervous system, or indirectly, through an immunopathological process.