- Email: [email protected]
The lessons of MMR
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Abuse of health-care workers’ neutral status
The lessons of MMR
Sir—Protection of health-care workers is enshrined in international law. Under the Protocol Additional to the Geneva Conventions of Aug 12, 1949, humanitarian sites and vehicles, including ambulances, are immune from attack. However, the use of humanitarian resources for military purposes strips them of this immunity. Hiding a bomb belt or a suicide bomber in an ambulance in order to transport them to the points at which they will be used is a clear breach of international law. International law does not demand that an army or country attacked through the abuse of humanitarian symbols decline to respond to such breaches. A proportionate response— searching such vehicles, for example, to ensure that they are not being so misused—is permitted. Indeed, once humanitarian immunity is lost, the misused resources, and the people within them, may be attacked and destroyed. In clear violation of this expected neutrality, Palestinian militants have used at least one hospital as an operations base, engaging in a shootout with Israeli forces from within the hospital grounds.1 Ambulances have been used by Palestinian terrorists to smuggle weapons, combatants, and even suicide bombers’ explosive belts past Israel’s defensive checkpoints.2 Elsewhere, on Jan 28, 2004, a suicide bomber drove an ambulance into a hotel in downtown Baghdad, Iraq, killing three people and wounding 15.3 Late in 2003, Red Cross workers in Iraq were the direct victims of terrorist attack when a “man drove an ambulance packed with explosives to the headquarters of the Red Cross and set them off.”4 Turkey has also been victimised by abuse of the required neutrality. The International Policy Institute for Counter-Terrorism (ICT) has catalogued examples of suicide bombers using ambulances to deliver explosives. ICT also describes three instances of female suicide bombers concealing explosives by dressing as if they were pregnant.5 Such actions have resulted in delays denying ambulances and the genuinely sick the unfettered access they require. Such delay is lamentable but usually
Sir—As Richard Horton states (Mar 6, p 747),1 “One unexpected consequence of the debate surrounding MMR has been a redirection of public attention to a condition that has often been neglected by medicine.” In particular it is a condition neglected by neurologists, because slow motor development sometimes associated with autism is not regarded as serious. What is serious is the failure to develop context-relevant language. I applaud the UK Medical Research Council (MRC) for including “lay participation” as one of its strategic themes for autism research. The language disorder is the primary handicap in the eyes of most parents of children with autism. The child who develops language is suddenly seen as so much more hopeful. The child with autism may begin speaking using phrase fragments and applying them badly out of context. My son used to scream, “What’s the matter, did your wagon get stuck?” in any frustrating situation, like not being able to squeeze toothpaste out of the tube. Normal children learn language by ear, putting together words and syllables in context-relevant baby talk. Grammatical transformations soon follow.2 What this suggests, and most parents know, is that auditory function is disturbed in autistic children. My son was 5 years old when I read the article Asphyxia at birth by William Windle.3 When I saw the huge lesions in the midbrain auditory pathway, I immediately recognised that they could be the cause of my son’s auditory and language problems. I knew he was born pale, limp, and not crying, by contrast with his older brother who had cried lustily before they could tell me his sex. Many children with autism had difficult births.4 Auditory system damage caused by asphyxia at birth is part of a pattern of brainstem damage. Brainstem centres control autonomic functions including the gastrointestinal system. Many children with autism have gastrointestinal problems, and impairment of neurological control should be what is investigated. Perhaps the biggest problem with the whole MMR fury is that no one considered possible brain systems that might be involved.
not as permanently harmful as the murders that provoke it. And it is allowed by international law. The true reason for the misuse of the guaranteed neutrality of health-care workers, patients, organisations, and their symbols has not been entirely established. The obvious explanation is that terrorists use ambulances, apparently pregnant women, and others as a convenient way to deliver explosives in a war in which they feel that any action is justified. Alternatively, women disguised to appear pregnant and ambulances might be used for the express purpose of provoking a response, even one that is proportionate and appropriate, in a calculated effort to incite people to join the perpetrators’ cause. The problems that relief workers and non-combatant civilians face in wartorn areas are troubling to all people of good conscience. However, like the allegorical child who kills his parents and then pleads for mercy because he is an orphan, terrorists have created an environment in which the sick and injured, along with every pregnant woman and every ambulance, is a potential terrorist weapon. The healthcare community must not satisfy itself with deploring the unfortunate consequences of this abuse of neutrality in violation of international law. We must insist that parties to conflicts, no matter how justified they perceive their cause, not use civilians and ambulances as weapons of war. *John R Cohn, Asaf Romirowsky, Jerome M Marcus *Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA (JRC); Middle East Forum, Philadelphia, PA, USA (AR); and Berger and Montague PC, Philadelphia, PA, USA (JMM) (e-mail: [email protected]) 1 2
3 4
5
Dudkeritch M. Pessah suicide attacks foiled. Jerusalem Post Apr 1, 2004. Siegel J. ICRC ‘shocked’ by explosives in Palestinian ambulance. Jerusalem Post Mar 31, 2002. Gettleman J. Bomb carried by ambulance kills 3 in Iraq. New York Times Jan 28, 2004. Filkins D. 34 die in Iraq as terrorists bomb Red Cross, Iraq Police. New York Times Oct 28, 2003. Beyler C. Chronology of suicide bombings carried out by women. Herzliya: International Policy Institute for CounterTerrorism, 2003. http://www.ict.org.il/ articles/articledet.cfm?articleid=471 (accessed Apr 7, 2004).
THE LANCET • Vol 363 • May 1, 2004 • www.thelancet.com
1473
For personal use. Only reproduce with permission from The Lancet publishing Group.
CORRESPONDENCE
Autism is caused by impairment in the brain, not the gastrointestinal tract, and probably not that much by genes either; several reports of identical twins discordant for autism have been published.5 The impairment in the brain that prevents normal language development should be the focus of research, and how such impairment can come about. Brainstem damage caused by oxygen deprivation at birth deserves attention as a reasonable starting point, especially if funds are short, before more esoteric causes are considered. Eileen Nicole Simon Conrad Simon Memorial Research Initiative, 11 Hayes Avenue, Lexington, MA 02420, USA (e-mail: [email protected]) 1 2
3 4
5
Horton R. The lessons of MMR. Lancet 2004; 363: 747–49. Brown R. A first language: the early stages. Cambridge, MA: Harvard University Press, 1973. Windle WF. Brain damage by asphyxia at birth. Sci Am 1969; 221: 76–84. Wilkerson DS, Volpe AG, Dean RS, Titus JB. Perinatal complications as predictors of infantile autism. Int J Neurosci 2002; 112: 1085–98. Steffenburg S, Gillberg C, Hellgren L, et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 1989; 30: 405–16
A prisoner with acute renal failure Sir—Doris Chan and colleagues’ Case report (Jan 10, p 126)1 is a cautionary tale of the folly of treating alcohol withdrawal seizures with standard anticonvulsant medication. The treatment of multiple alcohol withdrawal seizures with an oral or a parenteral short-acting benzodiazepine is an established evidence-based protocol.2 The only long-term management consideration is a rule-out workup for other causes of seizures—ie, central nervous system tumours or other space-taking lesions. Once satisfied that the patient has had a withdrawal seizure, the interdiction of alcohol consumption is the treatment. In fact, there might be evidence that standard antiseizure medication (phenytoin, carbamazepine, etc) could actually kindle alcohol withdrawal seizures.2 Robert Maslansky Division of Alcoholism and Drug Abuse, Department of Psychiatry, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA (e-mail: [email protected]) 1 2
Chan D, Sinniah R, Irish A. A prisoner with acute renal failure. Lancet 2004; 363: 126. Soyka M, Lutz W, Kauert G, et al. Epileptic seizures and alcohol withdrawal: significance of additional use (and misuse) of drugs and electroencephalographic findings. Epilepsia 1989; 2: 109–13.
1474
Unprotected sex and alloimmune activation Sir—Barry Peters and co-workers (Feb 14, p 518)1 report that unprotected sex results in alloimmune activation and in reduced susceptibility to HIV-1. This conclusion was drawn from the results of mixed leucocyte reactions (MLRs) and from in-vitro HIV-1 infectivity studies of CD4+ T cells in heterosexual couples having unprotected sex and in women and men having protected sex. First of all, we believe that some of the data are not correctly presented. Table 2 is meant to show MLR stimulation indices from couples having unprotected sex in comparison with such indices from women and men having protected sex after stimulation with control cells from third-party men and women. However, the data for women and men having unprotected sex are not those after stimulation with control cells, but after stimulation with their partner’s cells. This fact can be deduced from table 1 in which the same data are presented. When comparing the correct control-cell-stimulated MLR data from women and men having unprotected sex (table 1) with women and men having protected sex (table 2), no differences are apparent. We think that the important question of whether unprotected sex results in a significantly higher alloimmune response than protected sex for a time remains unanswered. To test this theory, the authors should have compared MLR data after stimulation with the partner’s cells rather than using control cells for both the study groups. Unfortunately, this could not be done because previous sex partners of women and men who were practising protected sex at the time of the study were not available. Subdividing this study group into participants who had been practising protected sex for 6–12 months and more than 12 months to control for the duration of the putative alloimmune response elicited by previous unprotected sex does not solve this problem. The observation that women and men having unprotected sex generate a significantly higher alloimmune reaction against their partner’s cells than against control cells (table 1 and figure 1) does not provide evidence on its own. A similar difference among women and men who are having protected sex for 6–12 months or more than 12 months might have persisted over time; however, this analysis was not done. The significantly lower in-vitro susceptibility of CD4+ T cells to HIV-1 in women and men having unprotected
sex than those having protected sex is intriguing. For the reasons described above, we believe that whether an increased alloimmune reaction is responsible for the observed in-vitro HIV-1 resistance remains unproven. Furthermore, in-vitro HIV-1 infection was done with phytohaemagglutininactivated CD4+ T cells, which might not represent the susceptibility of allostimulated target cells. Thus, the possibility of tolerance towards alloantigens as a consequence of unprotected sex might not be excluded by the present data, in line with maternal tolerance towards the fetus as the result of previous exposure to paternal alloantigens via unprotected sex,2 previous pregnancies,3 or blood transfusions.4 *Wim Jennes, Luc Kestens Laboratory of Immunology, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium (e-mail: [email protected]) 1
2
3
4
Peters B, Whittall T, Babaahmady K, Gray K, Vaughan R, Lehner T. Effect of heterosexual intercourse on mucosal alloimmunisation and resistance to HIV-1 infection. Lancet 2004; 363: 518–24. Wang JX, Knottnerus AM, Schuit G, Norman RJ, Chan A, Dekker GA. Surgically obtained sperm, and risk of gestational hypertension and pre-eclampsia. Lancet 2002; 359: 673–74. Dekker G. The partner’s role in the etiology of preeclampsia. J Reprod Immunol 2002; 57: 203–15. Katano K, Aoki K, Ogasawara MS, Suzumori K. Adverse influence of numbers of previous miscarriages on results of paternal lymphocyte immunization in patients with recurrent spontaneous abortions. Am J Reprod Immunol 2000; 44: 289–92.
Authors’ reply Sir—Our major aim was to determine whether HLA antigens in seminal fluid elicit alloimmunity or indeed tolerance in women practising unprotected sex with regular partners. We found that 23 of the 29 women and men showed significantly higher MLRs to the partner’s than to unrelated control cells, consistent with alloimmunity, and six showed the converse results, raising the possibility of tolerance. These were surprising findings that might be important in our understanding of genital immunity. Wim Jennes and Luc Kestens’ point about the confusing labelling of part of table 2 is correct, since comparison was clearly made between MLRs of cells from women having unprotected sex stimulated with their partners’ cells, and cells from those having protected sex stimulated with unrelated control cells. We stated this in both the Results and Discussion, and a comparison of MLRs between women practising unprotected
THE LANCET • Vol 363 • May 1, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Abuse of health-care workers’ neutral status
The lessons of MMR
Sir—Protection of health-care workers is enshrined in international law. Under the Protocol Additional to the Geneva Conventions of Aug 12, 1949, humanitarian sites and vehicles, including ambulances, are immune from attack. However, the use of humanitarian resources for military purposes strips them of this immunity. Hiding a bomb belt or a suicide bomber in an ambulance in order to transport them to the points at which they will be used is a clear breach of international law. International law does not demand that an army or country attacked through the abuse of humanitarian symbols decline to respond to such breaches. A proportionate response— searching such vehicles, for example, to ensure that they are not being so misused—is permitted. Indeed, once humanitarian immunity is lost, the misused resources, and the people within them, may be attacked and destroyed. In clear violation of this expected neutrality, Palestinian militants have used at least one hospital as an operations base, engaging in a shootout with Israeli forces from within the hospital grounds.1 Ambulances have been used by Palestinian terrorists to smuggle weapons, combatants, and even suicide bombers’ explosive belts past Israel’s defensive checkpoints.2 Elsewhere, on Jan 28, 2004, a suicide bomber drove an ambulance into a hotel in downtown Baghdad, Iraq, killing three people and wounding 15.3 Late in 2003, Red Cross workers in Iraq were the direct victims of terrorist attack when a “man drove an ambulance packed with explosives to the headquarters of the Red Cross and set them off.”4 Turkey has also been victimised by abuse of the required neutrality. The International Policy Institute for Counter-Terrorism (ICT) has catalogued examples of suicide bombers using ambulances to deliver explosives. ICT also describes three instances of female suicide bombers concealing explosives by dressing as if they were pregnant.5 Such actions have resulted in delays denying ambulances and the genuinely sick the unfettered access they require. Such delay is lamentable but usually
Sir—As Richard Horton states (Mar 6, p 747),1 “One unexpected consequence of the debate surrounding MMR has been a redirection of public attention to a condition that has often been neglected by medicine.” In particular it is a condition neglected by neurologists, because slow motor development sometimes associated with autism is not regarded as serious. What is serious is the failure to develop context-relevant language. I applaud the UK Medical Research Council (MRC) for including “lay participation” as one of its strategic themes for autism research. The language disorder is the primary handicap in the eyes of most parents of children with autism. The child who develops language is suddenly seen as so much more hopeful. The child with autism may begin speaking using phrase fragments and applying them badly out of context. My son used to scream, “What’s the matter, did your wagon get stuck?” in any frustrating situation, like not being able to squeeze toothpaste out of the tube. Normal children learn language by ear, putting together words and syllables in context-relevant baby talk. Grammatical transformations soon follow.2 What this suggests, and most parents know, is that auditory function is disturbed in autistic children. My son was 5 years old when I read the article Asphyxia at birth by William Windle.3 When I saw the huge lesions in the midbrain auditory pathway, I immediately recognised that they could be the cause of my son’s auditory and language problems. I knew he was born pale, limp, and not crying, by contrast with his older brother who had cried lustily before they could tell me his sex. Many children with autism had difficult births.4 Auditory system damage caused by asphyxia at birth is part of a pattern of brainstem damage. Brainstem centres control autonomic functions including the gastrointestinal system. Many children with autism have gastrointestinal problems, and impairment of neurological control should be what is investigated. Perhaps the biggest problem with the whole MMR fury is that no one considered possible brain systems that might be involved.
not as permanently harmful as the murders that provoke it. And it is allowed by international law. The true reason for the misuse of the guaranteed neutrality of health-care workers, patients, organisations, and their symbols has not been entirely established. The obvious explanation is that terrorists use ambulances, apparently pregnant women, and others as a convenient way to deliver explosives in a war in which they feel that any action is justified. Alternatively, women disguised to appear pregnant and ambulances might be used for the express purpose of provoking a response, even one that is proportionate and appropriate, in a calculated effort to incite people to join the perpetrators’ cause. The problems that relief workers and non-combatant civilians face in wartorn areas are troubling to all people of good conscience. However, like the allegorical child who kills his parents and then pleads for mercy because he is an orphan, terrorists have created an environment in which the sick and injured, along with every pregnant woman and every ambulance, is a potential terrorist weapon. The healthcare community must not satisfy itself with deploring the unfortunate consequences of this abuse of neutrality in violation of international law. We must insist that parties to conflicts, no matter how justified they perceive their cause, not use civilians and ambulances as weapons of war. *John R Cohn, Asaf Romirowsky, Jerome M Marcus *Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA (JRC); Middle East Forum, Philadelphia, PA, USA (AR); and Berger and Montague PC, Philadelphia, PA, USA (JMM) (e-mail: [email protected]) 1 2
3 4
5
Dudkeritch M. Pessah suicide attacks foiled. Jerusalem Post Apr 1, 2004. Siegel J. ICRC ‘shocked’ by explosives in Palestinian ambulance. Jerusalem Post Mar 31, 2002. Gettleman J. Bomb carried by ambulance kills 3 in Iraq. New York Times Jan 28, 2004. Filkins D. 34 die in Iraq as terrorists bomb Red Cross, Iraq Police. New York Times Oct 28, 2003. Beyler C. Chronology of suicide bombings carried out by women. Herzliya: International Policy Institute for CounterTerrorism, 2003. http://www.ict.org.il/ articles/articledet.cfm?articleid=471 (accessed Apr 7, 2004).
THE LANCET • Vol 363 • May 1, 2004 • www.thelancet.com
1473
For personal use. Only reproduce with permission from The Lancet publishing Group.
CORRESPONDENCE
Autism is caused by impairment in the brain, not the gastrointestinal tract, and probably not that much by genes either; several reports of identical twins discordant for autism have been published.5 The impairment in the brain that prevents normal language development should be the focus of research, and how such impairment can come about. Brainstem damage caused by oxygen deprivation at birth deserves attention as a reasonable starting point, especially if funds are short, before more esoteric causes are considered. Eileen Nicole Simon Conrad Simon Memorial Research Initiative, 11 Hayes Avenue, Lexington, MA 02420, USA (e-mail: [email protected]) 1 2
3 4
5
Horton R. The lessons of MMR. Lancet 2004; 363: 747–49. Brown R. A first language: the early stages. Cambridge, MA: Harvard University Press, 1973. Windle WF. Brain damage by asphyxia at birth. Sci Am 1969; 221: 76–84. Wilkerson DS, Volpe AG, Dean RS, Titus JB. Perinatal complications as predictors of infantile autism. Int J Neurosci 2002; 112: 1085–98. Steffenburg S, Gillberg C, Hellgren L, et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 1989; 30: 405–16
A prisoner with acute renal failure Sir—Doris Chan and colleagues’ Case report (Jan 10, p 126)1 is a cautionary tale of the folly of treating alcohol withdrawal seizures with standard anticonvulsant medication. The treatment of multiple alcohol withdrawal seizures with an oral or a parenteral short-acting benzodiazepine is an established evidence-based protocol.2 The only long-term management consideration is a rule-out workup for other causes of seizures—ie, central nervous system tumours or other space-taking lesions. Once satisfied that the patient has had a withdrawal seizure, the interdiction of alcohol consumption is the treatment. In fact, there might be evidence that standard antiseizure medication (phenytoin, carbamazepine, etc) could actually kindle alcohol withdrawal seizures.2 Robert Maslansky Division of Alcoholism and Drug Abuse, Department of Psychiatry, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA (e-mail: [email protected]) 1 2
Chan D, Sinniah R, Irish A. A prisoner with acute renal failure. Lancet 2004; 363: 126. Soyka M, Lutz W, Kauert G, et al. Epileptic seizures and alcohol withdrawal: significance of additional use (and misuse) of drugs and electroencephalographic findings. Epilepsia 1989; 2: 109–13.
1474
Unprotected sex and alloimmune activation Sir—Barry Peters and co-workers (Feb 14, p 518)1 report that unprotected sex results in alloimmune activation and in reduced susceptibility to HIV-1. This conclusion was drawn from the results of mixed leucocyte reactions (MLRs) and from in-vitro HIV-1 infectivity studies of CD4+ T cells in heterosexual couples having unprotected sex and in women and men having protected sex. First of all, we believe that some of the data are not correctly presented. Table 2 is meant to show MLR stimulation indices from couples having unprotected sex in comparison with such indices from women and men having protected sex after stimulation with control cells from third-party men and women. However, the data for women and men having unprotected sex are not those after stimulation with control cells, but after stimulation with their partner’s cells. This fact can be deduced from table 1 in which the same data are presented. When comparing the correct control-cell-stimulated MLR data from women and men having unprotected sex (table 1) with women and men having protected sex (table 2), no differences are apparent. We think that the important question of whether unprotected sex results in a significantly higher alloimmune response than protected sex for a time remains unanswered. To test this theory, the authors should have compared MLR data after stimulation with the partner’s cells rather than using control cells for both the study groups. Unfortunately, this could not be done because previous sex partners of women and men who were practising protected sex at the time of the study were not available. Subdividing this study group into participants who had been practising protected sex for 6–12 months and more than 12 months to control for the duration of the putative alloimmune response elicited by previous unprotected sex does not solve this problem. The observation that women and men having unprotected sex generate a significantly higher alloimmune reaction against their partner’s cells than against control cells (table 1 and figure 1) does not provide evidence on its own. A similar difference among women and men who are having protected sex for 6–12 months or more than 12 months might have persisted over time; however, this analysis was not done. The significantly lower in-vitro susceptibility of CD4+ T cells to HIV-1 in women and men having unprotected
sex than those having protected sex is intriguing. For the reasons described above, we believe that whether an increased alloimmune reaction is responsible for the observed in-vitro HIV-1 resistance remains unproven. Furthermore, in-vitro HIV-1 infection was done with phytohaemagglutininactivated CD4+ T cells, which might not represent the susceptibility of allostimulated target cells. Thus, the possibility of tolerance towards alloantigens as a consequence of unprotected sex might not be excluded by the present data, in line with maternal tolerance towards the fetus as the result of previous exposure to paternal alloantigens via unprotected sex,2 previous pregnancies,3 or blood transfusions.4 *Wim Jennes, Luc Kestens Laboratory of Immunology, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium (e-mail: [email protected]) 1
2
3
4
Peters B, Whittall T, Babaahmady K, Gray K, Vaughan R, Lehner T. Effect of heterosexual intercourse on mucosal alloimmunisation and resistance to HIV-1 infection. Lancet 2004; 363: 518–24. Wang JX, Knottnerus AM, Schuit G, Norman RJ, Chan A, Dekker GA. Surgically obtained sperm, and risk of gestational hypertension and pre-eclampsia. Lancet 2002; 359: 673–74. Dekker G. The partner’s role in the etiology of preeclampsia. J Reprod Immunol 2002; 57: 203–15. Katano K, Aoki K, Ogasawara MS, Suzumori K. Adverse influence of numbers of previous miscarriages on results of paternal lymphocyte immunization in patients with recurrent spontaneous abortions. Am J Reprod Immunol 2000; 44: 289–92.
Authors’ reply Sir—Our major aim was to determine whether HLA antigens in seminal fluid elicit alloimmunity or indeed tolerance in women practising unprotected sex with regular partners. We found that 23 of the 29 women and men showed significantly higher MLRs to the partner’s than to unrelated control cells, consistent with alloimmunity, and six showed the converse results, raising the possibility of tolerance. These were surprising findings that might be important in our understanding of genital immunity. Wim Jennes and Luc Kestens’ point about the confusing labelling of part of table 2 is correct, since comparison was clearly made between MLRs of cells from women having unprotected sex stimulated with their partners’ cells, and cells from those having protected sex stimulated with unrelated control cells. We stated this in both the Results and Discussion, and a comparison of MLRs between women practising unprotected
THE LANCET • Vol 363 • May 1, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.