1000
When he was informed of this he did not recognise any personal risk factor for HIV infection (homosexuality, intravenous drug use, multiple partners) and said that he had had no sexual activity in the 2 months since the accident. The doctor who had thrown out the incriminated syringe confirmed that on that day several syringes used to collect blood from anti-HIV-1positive individuals had been accidentally thrown out with the garbage. In this case the "window" was more than 67 days and less than 106 days, the western blot showing gag, pol, and env reactivities. This shows that, after an accidental needlestick, HIV tests must continue beyond the second month. The routine use of the p24 assay for donations would have allowed detection of HIV infection at the donation preceding the first antibody-positive one but not at the first donation, made 38 days after the accident. Exclusion by pre-donation interview and testing for anti-HBc remain the only means to identify antibody-negative HIV-infected donors. Our observation underlines the limits of this filter; this donor, recently pricked by a potentially contaminated needle, was at risk of HIV infection. This case and another published last year9 suggest that a prospective study of p24 in blood from a large number of donors is needed to establish whether the routine use of this assay would improve the safety of blood transmission. JEAN-JACQUES LEFRÈRE Institut National ANNE-MARIE COUROUCE de Transfusion Sanguine, 75012 Paris, France PHILIPPE ROUGER Centre National de Transfusion Paris
NAJIB DUEDARI
Sanguine,
MARIE-HÉLÈNE ELGHOUZZI
1. Ward JW, Holmberg SD, Allen JR, et al. Transmission of human immunodeficiency virus (HIV) by blood transfusion screened as negative for HIV antibody N Engl J Med 1988; 318: 473-78. 2. Nelson K, Donahue J, Munoz A, et al Risk of transfusion-transmitted HIV-1 and HTLV-I/II. Transfusion 1991; 31 (suppl): S170. 3. Busch MP, Eble BE, Khayam-Bashi H, et al. Evaluation of screened blood donations for human immunodeficiency virus type 1 infection by culture and DNA amplification of pooled cells. N Engl JMed 1990; 323: 1308-12. 4. Couroucé AM. Prévalence et caractéristiques épidémiologiques des sujects découverts infectes par le VIH à l’occasion d’un don de sang. Rev Fr Transf Hématol 1990; 33: 431-38. 5. Soto B, Rey C, Pineda J, Aguado I, Leal M, Lissen E. HIV-1 ag as the one marker in the early stage of HIV-1 infection. Vox Sang 1991; 60: 241. 6. Alter HJ, Epstein JS, Swenson SG, et al. Prevalence of human immunodeficiency type 1 p24 antigen in US blood donors: an assessment of the efficacy of testing in donor screening. N EnglJ Med 1990; 323: 1312-17. 7. Busch MP, Taylor PE, Lenes BA, et al. Screening of selected male blood donors for p24 antigen of human immunodeficiency virus type 1 N Engl J Med 1990; 323: 1308-12. 8. Busch MP, Mosley JW, Alter HJ, Epstein JS. (Reply to Irani et al.) N Engl J Med
1991; 325: 1175 MS, Dudley AW, Lucco LJ. Case of HIV-1 transmission by antigen-positive, antibody-negative blood. N Engl J Med 1991; 325: 1174-75.
9. Irani
Neural tube rupture as a cause of neural tube defects SIR,-In your Jan comment, from the
25 editorial
on
neural tube closure you
perspective of experimental embryology, incidentally on a matter that has divided clinicians for over a century. The observation that spina bifida in laboratory animals may result occasionally from reopening of a previously closed neural tube is consistent with what Morgagni, in the 18th century,’ suggested takes place in man. The association of hydrocephalus and spina bifida led him to propose that a pressure gradient resulted in rupture of closed neural tube for cases of spina bifida with or without hydrocephalus. Numerous observers in the 19th century endorsed this or a similar view as an explanation not only for spina bifida but also anencephaly.2 Von Recklinghausen3was among the first to challenge this, suggesting instead that arrested development was the cause of human neural tube defects, a view that has eventually predominated, despite the extensive defence by Gardner4 this century of the theory that neural tube rupture or a related event is the cause of all or almost all neural tube defects in man. Certainly the pathological evidence indicates that many neural tube defects in man are caused by primary failure of neural tube closure and that Gardner was almost certainly wrong to imply that most neural tube defects are due to post-closure rupture. But there has been little concession among modem clinicians to allow that the latter mechanism may cause even a small fraction of neural tube
defects. Warkany,6 for example, states unequivocally that he believes neither anencephaly nor myelomeningocele is due to neural tube rupture or an analogous intracranial "cataclysm". Thus, the cited reports in rodents6 (as well as earlier suggestive observations in chicks7) that environmental factors (eg, cytoxan) or specific genotypes produce spina bifida after neural tube closure indicate that more serious attention should be given to such a possible origin of at least a proportion of human neural tube defects. The possibility of post-closure rupture has some clinical importance, as Warkany himself notes. The human neural tube closes around day 28 from conception, about two weeks after the first missed menstrual period, before many pregnancies are even suspected. If factors after this time might be pertinent to the origin of human neural tube defects, then later maternal factors should be considered in studies of possible causes. And one should not assume that preventive strategies such as maternal folic acid administration necessarily will only be effective in the periconceptual period. Some studies of prenatal multivitamin and/or folic acid
supplementation reported
a
negative-ie, protective-association
with neural tube defect, despite the inclusion of women who began supplementation after neural tube closure.8 And one study interpreted such association in terms of evidence for post-closure rupture of the neural tube in man. This is, admittedly, only indirect weak epidemiological evidence for this embryological mechanism (and at odds with the implications of another report9). Nevertheless, the "rupture" mechanism may be plausible for at least some cases of neural tube defects in man, as it is in laboratory animals. School of Public Health, University of California, Berkeley, CA 94720, USA
ERNEST B. HOOK
Morgagni JB. The seats and causes of diseases investigated by anatomy, 3 vols. Translated by Alexander B, Miller A, Caldwell T. London, 1769. 2. Ballantyne, JW Manual of antenatal pathology and hygiene, the embryo. Edinburgh: William Green, 1904, reprinted: Clinton, South Carolina: Jacobs Press, 1991: 1.
302-05. 3.
von
Recklinghausen E. Untersuchungen uber die spina bifida Arch Pathol Anat 1886;
105: 243, cited by Gardner (ref 4). 4. Gardner 5 6.
NJ. The dysraphic states from syringomyelia to anencephaly. Amsterdam: Excerpta Medica, 1973: 201. Warkany J Congenital malformations: notes and comments. Chicago: Year Book Medical, 1971: 275-82. Copp AJ, Brook FA, Estibeiro P, Shum ASW, Cockroft DL. The embryonic development of mammalian neural tube defects. Progr Neurobiol 1990; 35: 363-403.
7. 8.
9.
Campbell LR, Dayton DH, Sohal GS. Neural tube defects: a review of human and animal studies in the etiology of neural tube defects. Teratology 1986; 34: 171-87 Mulinare G, Cordero JF, Erickson JD, Berry RJ. Periconceptual use of multivitamins and the occurrence of neural tube defects. JAMA 1988; 260: 3141-45. Milunsky A, Jick H, Jick S, et al. Multivitamin/folic add supplementation m early pregnancy reduces the prevalence of neural tube defects. JAMA 1989, 262: 2847-57.
Mean
platelet volume and myocardial infarction
SIR,-Platelet volume is an important physiological variable that determines primary haemostatic function.l Several studies have produced evidence that changes in platelet size may be causally related to occlusion of the coronary artery. We showed that a raised mean platelet volume (MPV), measured 6 months after myocardial infarction (MI), was associated with an increased risk of further infarct or of dying within 2 years of the index infarct (Dec 7, p 1409). Mr Thomas (Jan 25, p 250) suggests that the changes in MPV were non-specific markers of tissue ischaemia, citing results from his Master of Surgery thesis. Thomas took blood into edetic acid (EDTA) from the long saphenous vein of 22 patients with chronic venous insufficiency both before and after 60 minutes of leg dependency. He found that platelet count decreased and MPV increased and concluded that his results were attributable to ischaemia. Platelet size may vary for several reasons. Firstly, large or small platelets can be produced at thrombopoiesis.l Secondly, artifactual changes in MPV can arise, dependent on the anticoagulant used. Although platelet volume does not change with time if sodium citrate/prostaglandin E1(PGEJ is used, time-dependent increases in MPV are seen with EDTA.’ This difficulty can be overcome by mathematically correcting MPV for the time elapsed between venesection and measurement or by waiting until swelling has
When he was informed of this he did not recognise any personal risk factor for HIV infection (homosexuality, intravenous drug use, multiple partners) and said that he had had no sexual activity in the 2 months since the accident. The doctor who had thrown out the incriminated syringe confirmed that on that day several syringes used to collect blood from anti-HIV-1positive individuals had been accidentally thrown out with the garbage. In this case the "window" was more than 67 days and less than 106 days, the western blot showing gag, pol, and env reactivities. This shows that, after an accidental needlestick, HIV tests must continue beyond the second month. The routine use of the p24 assay for donations would have allowed detection of HIV infection at the donation preceding the first antibody-positive one but not at the first donation, made 38 days after the accident. Exclusion by pre-donation interview and testing for anti-HBc remain the only means to identify antibody-negative HIV-infected donors. Our observation underlines the limits of this filter; this donor, recently pricked by a potentially contaminated needle, was at risk of HIV infection. This case and another published last year9 suggest that a prospective study of p24 in blood from a large number of donors is needed to establish whether the routine use of this assay would improve the safety of blood transmission. JEAN-JACQUES LEFRÈRE Institut National ANNE-MARIE COUROUCE de Transfusion Sanguine, 75012 Paris, France PHILIPPE ROUGER Centre National de Transfusion Paris
NAJIB DUEDARI
Sanguine,
MARIE-HÉLÈNE ELGHOUZZI
1. Ward JW, Holmberg SD, Allen JR, et al. Transmission of human immunodeficiency virus (HIV) by blood transfusion screened as negative for HIV antibody N Engl J Med 1988; 318: 473-78. 2. Nelson K, Donahue J, Munoz A, et al Risk of transfusion-transmitted HIV-1 and HTLV-I/II. Transfusion 1991; 31 (suppl): S170. 3. Busch MP, Eble BE, Khayam-Bashi H, et al. Evaluation of screened blood donations for human immunodeficiency virus type 1 infection by culture and DNA amplification of pooled cells. N Engl JMed 1990; 323: 1308-12. 4. Couroucé AM. Prévalence et caractéristiques épidémiologiques des sujects découverts infectes par le VIH à l’occasion d’un don de sang. Rev Fr Transf Hématol 1990; 33: 431-38. 5. Soto B, Rey C, Pineda J, Aguado I, Leal M, Lissen E. HIV-1 ag as the one marker in the early stage of HIV-1 infection. Vox Sang 1991; 60: 241. 6. Alter HJ, Epstein JS, Swenson SG, et al. Prevalence of human immunodeficiency type 1 p24 antigen in US blood donors: an assessment of the efficacy of testing in donor screening. N EnglJ Med 1990; 323: 1312-17. 7. Busch MP, Taylor PE, Lenes BA, et al. Screening of selected male blood donors for p24 antigen of human immunodeficiency virus type 1 N Engl J Med 1990; 323: 1308-12. 8. Busch MP, Mosley JW, Alter HJ, Epstein JS. (Reply to Irani et al.) N Engl J Med
1991; 325: 1175 MS, Dudley AW, Lucco LJ. Case of HIV-1 transmission by antigen-positive, antibody-negative blood. N Engl J Med 1991; 325: 1174-75.
9. Irani
Neural tube rupture as a cause of neural tube defects SIR,-In your Jan comment, from the
25 editorial
on
neural tube closure you
perspective of experimental embryology, incidentally on a matter that has divided clinicians for over a century. The observation that spina bifida in laboratory animals may result occasionally from reopening of a previously closed neural tube is consistent with what Morgagni, in the 18th century,’ suggested takes place in man. The association of hydrocephalus and spina bifida led him to propose that a pressure gradient resulted in rupture of closed neural tube for cases of spina bifida with or without hydrocephalus. Numerous observers in the 19th century endorsed this or a similar view as an explanation not only for spina bifida but also anencephaly.2 Von Recklinghausen3was among the first to challenge this, suggesting instead that arrested development was the cause of human neural tube defects, a view that has eventually predominated, despite the extensive defence by Gardner4 this century of the theory that neural tube rupture or a related event is the cause of all or almost all neural tube defects in man. Certainly the pathological evidence indicates that many neural tube defects in man are caused by primary failure of neural tube closure and that Gardner was almost certainly wrong to imply that most neural tube defects are due to post-closure rupture. But there has been little concession among modem clinicians to allow that the latter mechanism may cause even a small fraction of neural tube
defects. Warkany,6 for example, states unequivocally that he believes neither anencephaly nor myelomeningocele is due to neural tube rupture or an analogous intracranial "cataclysm". Thus, the cited reports in rodents6 (as well as earlier suggestive observations in chicks7) that environmental factors (eg, cytoxan) or specific genotypes produce spina bifida after neural tube closure indicate that more serious attention should be given to such a possible origin of at least a proportion of human neural tube defects. The possibility of post-closure rupture has some clinical importance, as Warkany himself notes. The human neural tube closes around day 28 from conception, about two weeks after the first missed menstrual period, before many pregnancies are even suspected. If factors after this time might be pertinent to the origin of human neural tube defects, then later maternal factors should be considered in studies of possible causes. And one should not assume that preventive strategies such as maternal folic acid administration necessarily will only be effective in the periconceptual period. Some studies of prenatal multivitamin and/or folic acid
supplementation reported
a
negative-ie, protective-association
with neural tube defect, despite the inclusion of women who began supplementation after neural tube closure.8 And one study interpreted such association in terms of evidence for post-closure rupture of the neural tube in man. This is, admittedly, only indirect weak epidemiological evidence for this embryological mechanism (and at odds with the implications of another report9). Nevertheless, the "rupture" mechanism may be plausible for at least some cases of neural tube defects in man, as it is in laboratory animals. School of Public Health, University of California, Berkeley, CA 94720, USA
ERNEST B. HOOK
Morgagni JB. The seats and causes of diseases investigated by anatomy, 3 vols. Translated by Alexander B, Miller A, Caldwell T. London, 1769. 2. Ballantyne, JW Manual of antenatal pathology and hygiene, the embryo. Edinburgh: William Green, 1904, reprinted: Clinton, South Carolina: Jacobs Press, 1991: 1.
302-05. 3.
von
Recklinghausen E. Untersuchungen uber die spina bifida Arch Pathol Anat 1886;
105: 243, cited by Gardner (ref 4). 4. Gardner 5 6.
NJ. The dysraphic states from syringomyelia to anencephaly. Amsterdam: Excerpta Medica, 1973: 201. Warkany J Congenital malformations: notes and comments. Chicago: Year Book Medical, 1971: 275-82. Copp AJ, Brook FA, Estibeiro P, Shum ASW, Cockroft DL. The embryonic development of mammalian neural tube defects. Progr Neurobiol 1990; 35: 363-403.
7. 8.
9.
Campbell LR, Dayton DH, Sohal GS. Neural tube defects: a review of human and animal studies in the etiology of neural tube defects. Teratology 1986; 34: 171-87 Mulinare G, Cordero JF, Erickson JD, Berry RJ. Periconceptual use of multivitamins and the occurrence of neural tube defects. JAMA 1988; 260: 3141-45. Milunsky A, Jick H, Jick S, et al. Multivitamin/folic add supplementation m early pregnancy reduces the prevalence of neural tube defects. JAMA 1989, 262: 2847-57.
Mean
platelet volume and myocardial infarction
SIR,-Platelet volume is an important physiological variable that determines primary haemostatic function.l Several studies have produced evidence that changes in platelet size may be causally related to occlusion of the coronary artery. We showed that a raised mean platelet volume (MPV), measured 6 months after myocardial infarction (MI), was associated with an increased risk of further infarct or of dying within 2 years of the index infarct (Dec 7, p 1409). Mr Thomas (Jan 25, p 250) suggests that the changes in MPV were non-specific markers of tissue ischaemia, citing results from his Master of Surgery thesis. Thomas took blood into edetic acid (EDTA) from the long saphenous vein of 22 patients with chronic venous insufficiency both before and after 60 minutes of leg dependency. He found that platelet count decreased and MPV increased and concluded that his results were attributable to ischaemia. Platelet size may vary for several reasons. Firstly, large or small platelets can be produced at thrombopoiesis.l Secondly, artifactual changes in MPV can arise, dependent on the anticoagulant used. Although platelet volume does not change with time if sodium citrate/prostaglandin E1(PGEJ is used, time-dependent increases in MPV are seen with EDTA.’ This difficulty can be overcome by mathematically correcting MPV for the time elapsed between venesection and measurement or by waiting until swelling has
