- Email: [email protected]
Myocardial evidence of dystrophin mosaic in a Duchenne muscular dystrophy carrier
1235
pain. There were no physical signs to suggest intra-abdominal catastrophe and after stopping the infusion the pain completely resolved. Thus the administration of streptokinase may be associated with abdominal pain rather than back pain. Back pain during streptokinase infusion may mimic thoracic aortic dissection, which is of particular importance in view of the differential diagnosis in patients presenting to cardiac care units with severe chest pain. Finally, the first patient did not have a myocardial infarction, thus bringing into question the suggestion of Lear et al that the mechanism of the association is secondary to clot lysis. West Suffolk
Hospital, Bury St Edmunds,
Suffolk IP33 2QZ, UK
R. MAHADEVA P. W. L. SIKLOS
1. Shah M, Taylor RT.
Drug points; low back pain associated with streptokinase. BMJ 1990; 301: 1219. 2. Dickinson RJ, Rosser A. Low back pain associated with streptokinase. BMJ 1991; 302: 111. 3. Porter NJ, Nikoletos K. Low back pain associated with streptokinase. BMJ 1991; 302: 111.
MR,—Ur Lear and colleagues sensibly suggest simple analgesia and conservative management of low back pain associated with streptokinase, allowing the completion of the thrombolytic infusion for acute myocardial infarction. However, I report one further case of this obscure adverse effect, the pathogenesis of which is not known, which may suggest a more cautious approach. A patient with a clinically certain acute myocardial infarction and no history of renal disease developed severe low back pain after 10-15 minutes of infusion and frank haematuria when he voided his bladder 15 minutes later. Thereafter he had only microscopic haematuria, which completely resolved within 12 hours. There was no hypertension, rash, oedema, or bronchospasm to suggest an allergic reaction as noted in a previous case.1 The back pain resolved with simple analgesia and did not recur. Myocardial infarction was subsequently proven with enzyme and electrocardiographic changes, but no urinary tract abnormality was evident. This patient consequently did not complete the streptokinase infusion. Could it be that this pain may sometimes be of urinary tract origin? Urinalysis is not mentioned in previous reports. Department of Elderly Medicine, Bolton General Hospital, Bolton, Lancashire BL4 0JR, UK
R. D
1. Dickinson RJ, Rosser A. Low back pain associated with streptokinase. 111.
JENKINS
BMJ 1991; 302:
Myocardial evidence of dystrophin mosaic in a Duchenne muscular dystrophy carrier SIR,-Because of defective X-chromosomal genes and musclefibre membranes lacking the gene product dystrophin, 1 in 3000 newborn boys will have fatal Duchenne muscular dystrophy (DMD). Chromosomal and DNA analysis or skeletal-muscle dystrophin immunohistochemistry may substantiate the clinical evidence but do not exclude the heterozygote symptom-free carrier status often (30% spontaneous mutations are estimated) in question. Even in the proven carrier our overall yield of the genetic defect remains low (much lower with the "index patient") and all multinucleated skeletal muscle fibres can express dystrophin. Random X-chromosome inactivation does not lead to the expected mosaic expression of dystrophin from individual nuclei, since in multinucleated muscle fibres dystrophin-competent nuclei make up for incompetent ones. Mononucleated muscle cell dystrophin, however, should reflect the genetic mosaic. With deep rectal biopsy specimens we failed to delineate individual myocyte dystrophin. 20 routine myocardial biopsy samples, however, showed every single cell to be dystrophin-positive, irrespective of cardiomyopathy or reaction after heart transplantation (Dys-2 antibody, Novocastra, Newcastle; fluorescence and indirect peroxidase technique). We describe a 40-year-old childless DMD carrier. In 1981 mesenteric vessel occlusion necessitated small bowel resection and parenteral nutrition. Metabolic indices have been kept normal, except for a continuously raised (unexplained) serum creatine kinase (around 250 U/1). In 1984 an unspecific myopathic muscle biopsy finding was attributed to some "metabolic imbalance". We then learned that her only brother died at age 30 confined to a wheel-chair, and her only sister has two boys with similar muscle wasting and weakness. We diagnosed DMD. The patient’s and affected nephew’s multiplex-polymerase chain reaction and cDNA analyses (done by Prof. J. Murken) have not disclosed the genetic defect. Her second skeletal muscle biopsy specimen revealed minimal non-specific myopathic changes and occasional (less than 3%) dystrophin-negative fibres (figure), which are seen with any necrotising myopathy and often missed in biopsy samples from DMD carriers. In our experience these might be suspicious of, but could not prove, a carrier status. Ambulatory right-heart catheterisation with endomyocardial biopsy (after ethical committee approval) took 14 min and showed myocardial dystrophin that was different from controls and about 50% of "normal" heart muscle cells in small clusters to be dystrophin negative (figure). This finding accords with the cardiac mosaic expression of dystrophin (well-preserved throughout the animals’
SIR,-We report a further case of low back pain associated with the administration of streptokinase. A 72-year-old woman was admitted with a 4 h history of chest pain due to an anteroseptal myocardial infarction. There were no contraindications to thrombolytic therapy and streptokinase was given without immediate ill-effects. However, 36 h later she developed low back pain with radiation into both anterior thighs. Over the next 24 h the pain became very severe and was controlled only by large, frequent doses of diamorphine. At the same time weakness of leg movement became evident and progressed to almost complete paralysis. Knee and ankle reflexes were lost. Computed tomography showed haemorrhages into both iliopsoas muscles. Over the next three weeks the pain gradually settled and full mobility returned. Back pain may occur during the administration of streptokinase and although severe, ceases within a few minutes of stopping the drug. Rarely, as in our case and a previous report, back pain may present after an interval of 36-48 h as a result of bleeding into the iliopsoas muscles. Departments of Medicine and Radiology, Derbyshire Royal Infirmary,
Derby DE1 2QY, UK
Z. A. MAKHDOOM F. MACLEOD G. K. T. HOLMES S. ELLIOTT
1 Gillanders IA, Nakielny R, Channer KS. Spontaneous iliopsoas haemorrhage: an unusual complication for streptokinase therapy. Postgrad MedJ 1990; 66: 862-63.
Dystrophin mosaic in DMD carrier. Left: one occasional dystrophin-negative fibre (*) in biceps muscle; right more than 50% dystrophin-negative cells in heart muscle (Dys-2immunoreactivity, indirect peroxidase, x about 160).
1236
life) in heterozygote canine and mdx mouse carriers, whose skeletal muscle fibres become dystrophin-positive with maturation.’"’ Whenever the gene defect cannot be spotted in probable DMD carriers, endomyocardial biopsy should be a sensitive diagnostic method. We did not detect false-positive mosaicism in any of 20 controls. In the DMD carrier described here, serial sections of three right-heart biopsy specimens all showed the lyonised dystrophinpositive and dystrophin-negative cells mixed to a similar extent. Clusters of dystrophin-positive myocytes did not exceed 20 cells, so that the diagnostic dystrophin-negative cells could not have been missed in our sections of more than 100 cardiomyocytes. Since all the 20 control biopsy samples were of equal size, we expect the risk of false-negative results to be negligible. This method might prove effective with all DMD carriers, but patchy myocardial dystrophin staining in affected Becker’s muscular dystrophy (BMD) boys,3where some dystrophin is produced by the defective genes, is likely to perturb mosaicism in BMD carriers. A 1% overall incidence of mostly minor and self-limiting complications with endomyocardial biopsy is estimated in cardiology patientswho are at higher risk. We are sure that many women who want to prevent the unnecessary birth of a dystrophic boy will give their informed consent to this procedure. If it yields fast and clear results, endomyocardial biopsy will be the first diagnostic tool available that can even safely rule out a somatic heterozygote DMD carrier status. Friedrich-Baur- Institute, Klinikum Innenstadt,
Ludwig-Maximilians University, D-8000 Munich 2, Germany
MARTIN SCHMIDT-ACHERT PETRA FISCHER DIETER PONGRATZ
1.
Cooper BJ, Gallagher EA, Smith CA, Valentine BA, Winand NJ. Mosaic expression of dystrophin m carriers of canine X-linked muscular dystrophy. Lab Invest 1990;
2
Karpati G, Zubrzycka-Gaam EE, Carpenter S, Bulman DE, Ray PN, Worton RG. Age-related conversion of dystrophin-negative to -positive fiber segments of skeletal but not cardiac muscle fibers m heterozygote mdx mice J Neuropathol Exp
62: 171-78.
Neurol 1990; 49: 96-105. 3. Anan R, Higuchi I, Ichinari K, et al. Myocardial patchy staining of dystrophin in Becker’s muscular dystrophy associated with cardiomyopathy Am Heart J 1992; 123: 1088-89. 4. Hosenpud JD. Complications of endomyocardial biopsy. In: Kron J, Morton MJ, eds. Complications of cardiac catheterization and angiography, prevention and management. Mount Kisco, NY: Futura Publishing Company, 1989 135-54.
Artifactual p53 point mutations: possible effect of gene secondary structure on PCR and direct sequence analysis a defined region of the p53 the most frequently observed genetic tumour-suppressor gene lesions in human cancers.l-4 Germline p53 mutations also underlie the Li-Fraumeni syndrome and contribute to cancer predisposition. In a search for germline p53 mutations in families affected by multiple cancers, the polymerase chain reaction (PCR) was used to amplify specific regions of the gene, followed by direct sequencing. In one case, direct sequence analysis of a PCR product, including p53 exons 7 and 8, revealed two heterozygous point mutations in codons 273 and 283 of the gene. Both mutations involved the substitution of C to T. However, direct sequence analysis of a second PCR product from the same individual done to verify the finding, failed to show both exon 8 mutations. Furthermore, no such mutations were detected by sequencing the other strand PCR product. We therefore concluded that exon 8 carries a wild-type sequence in both alleles. Although direct sequence determination of a PCR product is considered to be an accurate analytical method, our results suggest that each direct sequence analysis should be repeated with independent PCR products because of possible errors accumulating in the initial PCR steps. The positions of the mutations we detected, at codons 273 and 283 of the p53 gene, are important. These are the most frequently mutated codons in this gene.s The DNA in the region of residues 273 and 283 has a stable secondary structure. Perhaps, because of this structure, the polymerase is locally confronted by difficulties and cannot synthesise correctly the complementary DNA strand.
SIR,-Somatic mutations within are
We emphasise that since most of the data on p53 structure arise from PCR and sequence analysis depending on polymerase activity, one must be very cautious in interpreting each result. In addition, stable secondary structure that introduces mistakes in the polymerisation reaction of the p53 gene in vitro may similarly contribute to the creation of mutational "hot spots" in vivo on defined regions of this gene.
Institute of Haematology, Chaim Sheba Medical Centre, Tel Hashomer 52621, Israel
ORNA MOR ZEHAVA GROSSMAN ORIT JAKOBOVITZ FRIDA BROK-SIMONI GIDEON RECHAVI
1. Malkin D, Li FP, Strong C, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 1990; 250: 1233-38. 2. Santibanez-Koref MF, Birch JM, Haley AL, et al. p53 germline mutations in Li-Fraumeni syndrome. Lancet 1991; 338: 1490-91. 3. Toguchida J, Toshikazu Y, Yamaguchi T, et al. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 1992; 326: 1301-08. 4. Malkin D, Jolly KW, Barbier N, et al. Germline mutations of the p53 tumorsuppressor gene in children and young adults with second malignant neoplasms. N Engl J Med 1992; 326: 1309-15. 5. Levine AJ, Mormand J, Finlay CA The p53 tumor suppressor gene. Nature 1991; 351: 453-56.
Interferon alfa and development of type 1 diabetes mellitus SIR,-Dr Fabris et al (Aug 29, p 548) describe the development of type 1 diabetes in a patient treated with interferon alfa for chronic HCV hepatitis. The patient had a number of markers of autoimmune destruction of beta-cells. Whether the autoimmune reaction was triggered by interferon was not clear, since the patient already had insulin autoantibodies before interferon therapy. However, Fabris et al ignore the fact that interferon can also induce insulin resistance.’ Impairment of body sensitivity to insulin may have caused an extra burden to beta-cells and thus made those more vulnerable to the autoimmune attack during interferon therapy. There is much information suggesting that stimulated beta-cells are more vulnerable to destructive processes than beta-cells "atrest".2,J Thus, by stimulating insulin secretion indirectly via insulin resistance, interferon may have accelerated the autoimmune destruction of beta-cells, leading to diabetes. Second
Department of Medicine, University of Helsinki, SF-00290 Helsinki, Finland
VEIKKO A. KOIVISTO
1. Koivisio VA, Pelkonen R, Cantell K. Effect of interferon on glucose tolerance and insulin sensitivity. Diabetes 1989; 38: 641-47. 2. Shah SC, Malone JI, Simpson NE. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989; 320: 550-54. 3. Kampe O, Anderson A, Bjork E, et al. High-glucose stimulation of 64,000-M (r) islet cell autoantigen expression. Diabetes 1989; 38: 1326-28.
CORRECTIONS Importance of complete follow-up of spontaneous fetal loss after amniocentesis and chorion villus sampling.-In this article by Ms J. L. Halliday and colleagues (Oct 10, p 886), in the discussion the last sentence of the penultimate paragraph (p 889) should have appeared at the end of the fifth paragraph of that section, and reference 15 in paragraph five was wrongly numbered; it should have read 16. Vibrio cholerae 01
septicaemia.-In this letter by Dr B. Jamil and 910), the fifth sentence of the final paragraph should have read: "Survival from vibrio septicaemia tends to be low with colleagues (Oct 10,
p
non-eventful recoveries documented for non-01 ..."
septicaemia
with V cholerae
Pneumococcal immunisation and the healthy elderly.-In this letter by Dr N. Steven and Dr P. Wright (Oct 24, p 1036), the final sentence of the penultimate paragraph should have read: "... 29% and 31 %, respectively, if those patients with high dependency or advanced malignancy were "
included."
pain. There were no physical signs to suggest intra-abdominal catastrophe and after stopping the infusion the pain completely resolved. Thus the administration of streptokinase may be associated with abdominal pain rather than back pain. Back pain during streptokinase infusion may mimic thoracic aortic dissection, which is of particular importance in view of the differential diagnosis in patients presenting to cardiac care units with severe chest pain. Finally, the first patient did not have a myocardial infarction, thus bringing into question the suggestion of Lear et al that the mechanism of the association is secondary to clot lysis. West Suffolk
Hospital, Bury St Edmunds,
Suffolk IP33 2QZ, UK
R. MAHADEVA P. W. L. SIKLOS
1. Shah M, Taylor RT.
Drug points; low back pain associated with streptokinase. BMJ 1990; 301: 1219. 2. Dickinson RJ, Rosser A. Low back pain associated with streptokinase. BMJ 1991; 302: 111. 3. Porter NJ, Nikoletos K. Low back pain associated with streptokinase. BMJ 1991; 302: 111.
MR,—Ur Lear and colleagues sensibly suggest simple analgesia and conservative management of low back pain associated with streptokinase, allowing the completion of the thrombolytic infusion for acute myocardial infarction. However, I report one further case of this obscure adverse effect, the pathogenesis of which is not known, which may suggest a more cautious approach. A patient with a clinically certain acute myocardial infarction and no history of renal disease developed severe low back pain after 10-15 minutes of infusion and frank haematuria when he voided his bladder 15 minutes later. Thereafter he had only microscopic haematuria, which completely resolved within 12 hours. There was no hypertension, rash, oedema, or bronchospasm to suggest an allergic reaction as noted in a previous case.1 The back pain resolved with simple analgesia and did not recur. Myocardial infarction was subsequently proven with enzyme and electrocardiographic changes, but no urinary tract abnormality was evident. This patient consequently did not complete the streptokinase infusion. Could it be that this pain may sometimes be of urinary tract origin? Urinalysis is not mentioned in previous reports. Department of Elderly Medicine, Bolton General Hospital, Bolton, Lancashire BL4 0JR, UK
R. D
1. Dickinson RJ, Rosser A. Low back pain associated with streptokinase. 111.
JENKINS
BMJ 1991; 302:
Myocardial evidence of dystrophin mosaic in a Duchenne muscular dystrophy carrier SIR,-Because of defective X-chromosomal genes and musclefibre membranes lacking the gene product dystrophin, 1 in 3000 newborn boys will have fatal Duchenne muscular dystrophy (DMD). Chromosomal and DNA analysis or skeletal-muscle dystrophin immunohistochemistry may substantiate the clinical evidence but do not exclude the heterozygote symptom-free carrier status often (30% spontaneous mutations are estimated) in question. Even in the proven carrier our overall yield of the genetic defect remains low (much lower with the "index patient") and all multinucleated skeletal muscle fibres can express dystrophin. Random X-chromosome inactivation does not lead to the expected mosaic expression of dystrophin from individual nuclei, since in multinucleated muscle fibres dystrophin-competent nuclei make up for incompetent ones. Mononucleated muscle cell dystrophin, however, should reflect the genetic mosaic. With deep rectal biopsy specimens we failed to delineate individual myocyte dystrophin. 20 routine myocardial biopsy samples, however, showed every single cell to be dystrophin-positive, irrespective of cardiomyopathy or reaction after heart transplantation (Dys-2 antibody, Novocastra, Newcastle; fluorescence and indirect peroxidase technique). We describe a 40-year-old childless DMD carrier. In 1981 mesenteric vessel occlusion necessitated small bowel resection and parenteral nutrition. Metabolic indices have been kept normal, except for a continuously raised (unexplained) serum creatine kinase (around 250 U/1). In 1984 an unspecific myopathic muscle biopsy finding was attributed to some "metabolic imbalance". We then learned that her only brother died at age 30 confined to a wheel-chair, and her only sister has two boys with similar muscle wasting and weakness. We diagnosed DMD. The patient’s and affected nephew’s multiplex-polymerase chain reaction and cDNA analyses (done by Prof. J. Murken) have not disclosed the genetic defect. Her second skeletal muscle biopsy specimen revealed minimal non-specific myopathic changes and occasional (less than 3%) dystrophin-negative fibres (figure), which are seen with any necrotising myopathy and often missed in biopsy samples from DMD carriers. In our experience these might be suspicious of, but could not prove, a carrier status. Ambulatory right-heart catheterisation with endomyocardial biopsy (after ethical committee approval) took 14 min and showed myocardial dystrophin that was different from controls and about 50% of "normal" heart muscle cells in small clusters to be dystrophin negative (figure). This finding accords with the cardiac mosaic expression of dystrophin (well-preserved throughout the animals’
SIR,-We report a further case of low back pain associated with the administration of streptokinase. A 72-year-old woman was admitted with a 4 h history of chest pain due to an anteroseptal myocardial infarction. There were no contraindications to thrombolytic therapy and streptokinase was given without immediate ill-effects. However, 36 h later she developed low back pain with radiation into both anterior thighs. Over the next 24 h the pain became very severe and was controlled only by large, frequent doses of diamorphine. At the same time weakness of leg movement became evident and progressed to almost complete paralysis. Knee and ankle reflexes were lost. Computed tomography showed haemorrhages into both iliopsoas muscles. Over the next three weeks the pain gradually settled and full mobility returned. Back pain may occur during the administration of streptokinase and although severe, ceases within a few minutes of stopping the drug. Rarely, as in our case and a previous report, back pain may present after an interval of 36-48 h as a result of bleeding into the iliopsoas muscles. Departments of Medicine and Radiology, Derbyshire Royal Infirmary,
Derby DE1 2QY, UK
Z. A. MAKHDOOM F. MACLEOD G. K. T. HOLMES S. ELLIOTT
1 Gillanders IA, Nakielny R, Channer KS. Spontaneous iliopsoas haemorrhage: an unusual complication for streptokinase therapy. Postgrad MedJ 1990; 66: 862-63.
Dystrophin mosaic in DMD carrier. Left: one occasional dystrophin-negative fibre (*) in biceps muscle; right more than 50% dystrophin-negative cells in heart muscle (Dys-2immunoreactivity, indirect peroxidase, x about 160).
1236
life) in heterozygote canine and mdx mouse carriers, whose skeletal muscle fibres become dystrophin-positive with maturation.’"’ Whenever the gene defect cannot be spotted in probable DMD carriers, endomyocardial biopsy should be a sensitive diagnostic method. We did not detect false-positive mosaicism in any of 20 controls. In the DMD carrier described here, serial sections of three right-heart biopsy specimens all showed the lyonised dystrophinpositive and dystrophin-negative cells mixed to a similar extent. Clusters of dystrophin-positive myocytes did not exceed 20 cells, so that the diagnostic dystrophin-negative cells could not have been missed in our sections of more than 100 cardiomyocytes. Since all the 20 control biopsy samples were of equal size, we expect the risk of false-negative results to be negligible. This method might prove effective with all DMD carriers, but patchy myocardial dystrophin staining in affected Becker’s muscular dystrophy (BMD) boys,3where some dystrophin is produced by the defective genes, is likely to perturb mosaicism in BMD carriers. A 1% overall incidence of mostly minor and self-limiting complications with endomyocardial biopsy is estimated in cardiology patientswho are at higher risk. We are sure that many women who want to prevent the unnecessary birth of a dystrophic boy will give their informed consent to this procedure. If it yields fast and clear results, endomyocardial biopsy will be the first diagnostic tool available that can even safely rule out a somatic heterozygote DMD carrier status. Friedrich-Baur- Institute, Klinikum Innenstadt,
Ludwig-Maximilians University, D-8000 Munich 2, Germany
MARTIN SCHMIDT-ACHERT PETRA FISCHER DIETER PONGRATZ
1.
Cooper BJ, Gallagher EA, Smith CA, Valentine BA, Winand NJ. Mosaic expression of dystrophin m carriers of canine X-linked muscular dystrophy. Lab Invest 1990;
2
Karpati G, Zubrzycka-Gaam EE, Carpenter S, Bulman DE, Ray PN, Worton RG. Age-related conversion of dystrophin-negative to -positive fiber segments of skeletal but not cardiac muscle fibers m heterozygote mdx mice J Neuropathol Exp
62: 171-78.
Neurol 1990; 49: 96-105. 3. Anan R, Higuchi I, Ichinari K, et al. Myocardial patchy staining of dystrophin in Becker’s muscular dystrophy associated with cardiomyopathy Am Heart J 1992; 123: 1088-89. 4. Hosenpud JD. Complications of endomyocardial biopsy. In: Kron J, Morton MJ, eds. Complications of cardiac catheterization and angiography, prevention and management. Mount Kisco, NY: Futura Publishing Company, 1989 135-54.
Artifactual p53 point mutations: possible effect of gene secondary structure on PCR and direct sequence analysis a defined region of the p53 the most frequently observed genetic tumour-suppressor gene lesions in human cancers.l-4 Germline p53 mutations also underlie the Li-Fraumeni syndrome and contribute to cancer predisposition. In a search for germline p53 mutations in families affected by multiple cancers, the polymerase chain reaction (PCR) was used to amplify specific regions of the gene, followed by direct sequencing. In one case, direct sequence analysis of a PCR product, including p53 exons 7 and 8, revealed two heterozygous point mutations in codons 273 and 283 of the gene. Both mutations involved the substitution of C to T. However, direct sequence analysis of a second PCR product from the same individual done to verify the finding, failed to show both exon 8 mutations. Furthermore, no such mutations were detected by sequencing the other strand PCR product. We therefore concluded that exon 8 carries a wild-type sequence in both alleles. Although direct sequence determination of a PCR product is considered to be an accurate analytical method, our results suggest that each direct sequence analysis should be repeated with independent PCR products because of possible errors accumulating in the initial PCR steps. The positions of the mutations we detected, at codons 273 and 283 of the p53 gene, are important. These are the most frequently mutated codons in this gene.s The DNA in the region of residues 273 and 283 has a stable secondary structure. Perhaps, because of this structure, the polymerase is locally confronted by difficulties and cannot synthesise correctly the complementary DNA strand.
SIR,-Somatic mutations within are
We emphasise that since most of the data on p53 structure arise from PCR and sequence analysis depending on polymerase activity, one must be very cautious in interpreting each result. In addition, stable secondary structure that introduces mistakes in the polymerisation reaction of the p53 gene in vitro may similarly contribute to the creation of mutational "hot spots" in vivo on defined regions of this gene.
Institute of Haematology, Chaim Sheba Medical Centre, Tel Hashomer 52621, Israel
ORNA MOR ZEHAVA GROSSMAN ORIT JAKOBOVITZ FRIDA BROK-SIMONI GIDEON RECHAVI
1. Malkin D, Li FP, Strong C, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 1990; 250: 1233-38. 2. Santibanez-Koref MF, Birch JM, Haley AL, et al. p53 germline mutations in Li-Fraumeni syndrome. Lancet 1991; 338: 1490-91. 3. Toguchida J, Toshikazu Y, Yamaguchi T, et al. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 1992; 326: 1301-08. 4. Malkin D, Jolly KW, Barbier N, et al. Germline mutations of the p53 tumorsuppressor gene in children and young adults with second malignant neoplasms. N Engl J Med 1992; 326: 1309-15. 5. Levine AJ, Mormand J, Finlay CA The p53 tumor suppressor gene. Nature 1991; 351: 453-56.
Interferon alfa and development of type 1 diabetes mellitus SIR,-Dr Fabris et al (Aug 29, p 548) describe the development of type 1 diabetes in a patient treated with interferon alfa for chronic HCV hepatitis. The patient had a number of markers of autoimmune destruction of beta-cells. Whether the autoimmune reaction was triggered by interferon was not clear, since the patient already had insulin autoantibodies before interferon therapy. However, Fabris et al ignore the fact that interferon can also induce insulin resistance.’ Impairment of body sensitivity to insulin may have caused an extra burden to beta-cells and thus made those more vulnerable to the autoimmune attack during interferon therapy. There is much information suggesting that stimulated beta-cells are more vulnerable to destructive processes than beta-cells "atrest".2,J Thus, by stimulating insulin secretion indirectly via insulin resistance, interferon may have accelerated the autoimmune destruction of beta-cells, leading to diabetes. Second
Department of Medicine, University of Helsinki, SF-00290 Helsinki, Finland
VEIKKO A. KOIVISTO
1. Koivisio VA, Pelkonen R, Cantell K. Effect of interferon on glucose tolerance and insulin sensitivity. Diabetes 1989; 38: 641-47. 2. Shah SC, Malone JI, Simpson NE. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989; 320: 550-54. 3. Kampe O, Anderson A, Bjork E, et al. High-glucose stimulation of 64,000-M (r) islet cell autoantigen expression. Diabetes 1989; 38: 1326-28.
CORRECTIONS Importance of complete follow-up of spontaneous fetal loss after amniocentesis and chorion villus sampling.-In this article by Ms J. L. Halliday and colleagues (Oct 10, p 886), in the discussion the last sentence of the penultimate paragraph (p 889) should have appeared at the end of the fifth paragraph of that section, and reference 15 in paragraph five was wrongly numbered; it should have read 16. Vibrio cholerae 01
septicaemia.-In this letter by Dr B. Jamil and 910), the fifth sentence of the final paragraph should have read: "Survival from vibrio septicaemia tends to be low with colleagues (Oct 10,
p
non-eventful recoveries documented for non-01 ..."
septicaemia
with V cholerae
Pneumococcal immunisation and the healthy elderly.-In this letter by Dr N. Steven and Dr P. Wright (Oct 24, p 1036), the final sentence of the penultimate paragraph should have read: "... 29% and 31 %, respectively, if those patients with high dependency or advanced malignancy were "
included."