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Marine pollution and limb reduction defects
extent of excess mortality associated with HIV has seldom been measured. This lack of data has emboldened some individuals (lately with encouragement from segments of the UK press) to claim that HIV is not responsible for either deaths or even AIDS in Africa. In a clear-cut epidemiological study in rural Uganda, Mulder and colleagues now destroy that quaint notion: these researchers have quantified the substantial excess mortality associated with HIV infection. This prospective study shows that, for example, young adults testing positive for HIV antibody were 60 times as likely to die during the subsequent 2-year observation period as were otherwise similar persons who tested negative. Mortality was well in excess of background rates in all age groups but was highest in precisely those persons (men and women aged 25-34 years) in whom HIV infection was most common. The extraordinary death rate in HIV-positive persons compared with that in the uninfected confirms observations throughout the world that HIV is an important cause of premature
protocols for recognition and management of HIV-related clinical conditions and the resources to implement them are urgently needed in sub-Saharan Africa. As in many other areas of the developing world, health service demands resulting from HIV severely strain already inadequate health infrastructures. The study by Mulder and associates does a major service by quantifying the greatly increased mortality due HIV infection in one part of Africa. At the same time it squelches the mischievous claim of some that HIV on that continent and the AIDS that results from it are unimportant. The overwhelming data on the impact of HIV in Africa should now reinforce the conscience for a worldwide prevention effort. to
Timothy J Dondero,
1
mortality. An ironic feature of this work is that it does not require a belief that HIV is the cause of AIDS. Rather, the study shows that the simple finding of antibodies against HIV in an individual’s serum predicts a likelihood of death within the next several years far above that for a seronegative individual. Although most reasonable observers do accept that HIV causes AIDS, even sceptics cannot fail to acknowledge the high prevalence of antibody to HIV in Africa. If there are any left who will not even accept that antibody to HIV indicates infection with the virus, their explanation of how HIV seropositivity leads to early death must be curious indeed. Other studies in Africa have documented the serious proportional contribution of HIV and AIDS to mortalityl,2 and to the burgeoning of tuberculosis3 there. Anyone who has paid a visit to a medical ward or pulmonary service in an African hospital, however fleeting, also understands this impact. What distinguishes the latest study is that, because of the prospective cohort design, it quantifies in absolute as well as relative terms the mortality associated with HIV above and beyond the mortality from other causes. The calculations of "excess mortality" assume that some HIV-infected persons will die of unrelated causes, at a rate equivalent to that in the uninfected. Hardest hit by excess deaths were the 25-34-year-olds, usually a group with low mortality. Nearly 90% of their deaths were in excess of background rates and were attributable to HIV. Perhaps most startling was that this massively increased mortality in young adults as a group occurred while only about 15% of the group were actually infected. Sadly, in many urban populations in east and southern Africa the HIV prevalence in young adults is much higher than in the rural population studied. The associated increased mortality in the urban areas must therefore be even greater. The strong association of HIV with excess mortality, combined with a knowledge of the natural history of HIV infection, underscores the critical importance of the AIDS epidemic in Africa. However, more information is needed to clarify how many of the excess deaths could have been delayed through optimum medical prevention and therapy of such HIV-associated illnesses as tuberculosis, other pneumonias, and diarrhoeal disease. Practical
990
James W Curran
Division of HIV/AIDS, Center for Infectious Diseases, and Office of the Director; Centers for Disease Control and Prevention, Atlanta, Georgia, USA
2
3
DeCock KM, Porter A, Odehouri K, et al. Rapid emergence of AIDS in Abidjan, Ivory Coast. Lancet 1989; ii: 408-11. DeCock KM, Barrere B, Lafontaine M-F, et al. Mortality trends in Abidjan, Cote d’Ivoire, 1983-1988. AIDS 1991; 5: 393-98. Richards SB, St Louis ME, Nieburg P, et al. Impact of the HIV epidemic on trends in tuberculosis in Abidjan, Cote d’Ivoire. Tubercule Lung Dis (in press).
Marine pollution and limb reduction defects See page 1033
"Pollution
suspected in birth deformities" (Sunday Times, London, Jan 9, 1994). So the story began. Five children in the Isle of Wight, UK, were born over a period of 23 months with missing or deformed hands; four who were born between February, 1989, and May, 1990, lived in the same seaside town. All the mothers reported that they regularly swam in the sea during pregnancy. Was marine pollution to blame? Over the next 3 weeks five other clusters of babies born with limb reduction defects were reported (Sunday Times, Jan 16, 23, 30). All were in coastal areas of the UK. Widespread national and international media coverage followed and studies began in several countries to compare the prevalence of limb reduction defects in babies born in coastal areas with those born inland. The results of three studies, from the UK, Italy, and Latin America, are reported in this week’s Lancet. All three found no difference in rates of limb reduction defects for babies born in coastal and inland areas. The researchers did not examine the causes of the limb defects that did occur, and the report of the Office of Population Censuses & Surveys (OPCS) in the UK did not set out to identify clusters or to throw any light on whether environmental factors could be linked with the six clusters described in the Sunday Times. Nevertheless, the results of the studies suggest that marine pollution is unlikely to be the answer. The UK coastal clusters have, it seems, arisen by chance. And the parents of the affected babies are no nearer to an explanation of the cause. Identifying whether clusters of cases represent real increases in the prevalence of a condition or are simply chance findings is often difficult and may, as illustrated here, need detailed investigation. Such research is costly
and time consuming. It is therefore surprising that the press reports of the six UK clusters were sufficient to generate studies such as those reported from Italy and Latin America before analysis of the UK cases had been published. Moreover, the publicity given to the UK cases sparked hopes of identifying a cause of the limb defects and aroused fears of sea bathing or living near the sea, all of which have turned out to be unfounded. So what does cause limb reduction defects? An interruption of blood supply to the developing limb is thought to be responsible in some cases: uterine artery occlusion and handling of the uterus or uterine vessels have been associated with bilateral brainstem ischaemic lesions and peripheral limb deficiency in an animal model;’ and transverse limb reduction defects due to fetal vascular occlusion have been described in human beings.2 Limb defects have been linked with chorionic villus sampling;3 the mechanisms remain unclear but may involve amniotic puncture with band formation, fetal compression due to acute oligohydramnios, or entrapment of hands or feet in the exocoelomic gel. At a molecular level, mutations in one gene, Gdf 5, have lately been shown to be responsible for limb abnormalities in mice.’ Whether similar genetic mutations play a part in human beings remains to be seen, but at least some clues about the basis of skeletal formation are now forthcoming. Once we begin to understand the roles of regulatory genes and gene products, the place of environmental factors in interference with limb development may become clearer. Pollutants may yet be implicated-but that is another story. Astrid James The Lancet, London, UK 1 Webster WS, Lipman AH, Brown-Woodman PDC, Osborn RA. Moebius unmasked: pathogenesis of the Moebius syndrome in an animal model. Teratology 1988; 38: 199A. 2 Hoyme HF, Jones KL, van Allen MI, Saunders BS, Benirschke K. Vascular pathogenesis of transverse limb reduction defects. J Pediatr 1982; 101: 839-43. 3 Firth HV, Boyd PA, Chamberlain P, MacKenzie IZ, Lindenbaum RH, Huson SM. Severe limb abnormalities after chorion villus sampling at 56-66 days’ gestation. Lancet 1991; 337: 762-63. 4 Shepard TH, Kapur RP, Fantel AG. Limb-reduction defects and chorion villus sampling. Lancet 1991; 337: 1092. 5 Storm EE, Huynh TV, Copeland NG, Jenkins NA, Kingsley DM, Lee S-J. Limb alterations in brachypodism mice due to mutations in a new member of the TGF&bgr;-superfamily. Nature 1994; 368: 639-43.
The
nose
and the lower
airways
Medical students usually first study the nose as part of the respiratory system. Its function as a humidifier is acknowledged, but attention is quickly diverted to the structure, physiology, and pathology of the lungs. Doctors who are not destined to become otorhinolaryngologists seldom think much more about the nose and its relation to the lower airways. How many know that the smallest cross-sectional area of the conducting airways is at the internal nasal ostium (0-3 cm2 on each side), or that the nose accounts for nearly half the total airway resistance? Because it has a rich blood supply with plentiful arteriovenous anastomoses, it can increase the temperature of inspired air by as much as 25°C between external nares and nasopharynx. Not only does the nose provide warm moist air to the lower airways but also it
guards them from large particles and from soluble noxious gases such as ozone, sulphur dioxide, and formaldehyde.’,2 In physiological terms the nose is a dynamic organ. We are all aware of its sudden changes in resistance to air flow and its ability to switch on watery secretion like a tap. These properties stem from the venous sinusoids (pseudoerectile tissue) of the turbinates and nasal septum, and from the profusion of mainly serous glands in the nasal mucosa. Here there are about 8 glands per mm2 compared with 1 or less in the trachea and lower airways. Both the venous sinusoids and the glands are under autonomic control, and it is interesting that this produces in most people a regular reciprocating alteration in nasal resistance between the two nasal cavities, with a periodicity of 2-7 hours. By comparison, the lower airways seem physiologically much more stable. Despite these many differences, there has been a tendency to link the nose and the lung in various disease states, especially asthma. Does the nasobronchial reflex exist? Does nasal inflammation lead sooner or later to bronchial abnormalities? The evidence is against these possibilities, whether for allergic, non-allergic, or exerciseinduced asthma. Despite the frequent association of allergic rhinitis and allergic asthma, only about 8-11% of patients with allergic rhinitis actually have asthma.3 Even at the height of an attack of hay fever, whether induced naturally or by laboratory challenge, there is seldom any change in pulmonary mechanics.4 In the case of exercise-induced asthma, an interesting report from Picado and his colleagues5 in Barcelona has shown that the nose responds with the normal physiological fall in resistance during exercise whether the subjects are asthmatic, rhinitic, or normal. By use of FEVI to detect exercise-induced asthma and at the same time posterior rhinomanometry to calculate nasal resistance, it was possible to show precisely the same relative decrease in nasal resistance among all subjects as they exercised, even though the starting point for patients with rhinitis was different from that in subjects with clear noses. Working on similar lines and using an acoustic reflection technique, Rubinstein and colleagues6 showed that not only the nose but also the trachea can dilate during exercise. This increase in cross-sectional area of the trachea occurred even in patients who simultaneously developed exercise-induced asthma. This curious dichotomous response presumably reflects the fact that the trachea, like the nose, may have the potential to change its cross-sectional area due to alterations in the vascular beds of its wall.7 The divorce between the responses of upper and lower airways to exercise in asthma is potentially beneficial. McFadden and colleagues* have shown that exerciseinduced bronchoconstriction is related to the degree to which relatively cool and dry air enters the lower airways. Compared with the nose, the lower airways are poor at warming and humidifying air, and bronchoconstriction may result from the temporary development of hyperosmolarity in their walls. The longer that nasal breathing can be maintained during exercise, the less likely are the lower airways to have to take over the function of heating and humidification. Normally we are forced to switch to mouth breathing when ventilation reaches 30-60 litres per minute. Clearly the more dilated
991
protocols for recognition and management of HIV-related clinical conditions and the resources to implement them are urgently needed in sub-Saharan Africa. As in many other areas of the developing world, health service demands resulting from HIV severely strain already inadequate health infrastructures. The study by Mulder and associates does a major service by quantifying the greatly increased mortality due HIV infection in one part of Africa. At the same time it squelches the mischievous claim of some that HIV on that continent and the AIDS that results from it are unimportant. The overwhelming data on the impact of HIV in Africa should now reinforce the conscience for a worldwide prevention effort. to
Timothy J Dondero,
1
mortality. An ironic feature of this work is that it does not require a belief that HIV is the cause of AIDS. Rather, the study shows that the simple finding of antibodies against HIV in an individual’s serum predicts a likelihood of death within the next several years far above that for a seronegative individual. Although most reasonable observers do accept that HIV causes AIDS, even sceptics cannot fail to acknowledge the high prevalence of antibody to HIV in Africa. If there are any left who will not even accept that antibody to HIV indicates infection with the virus, their explanation of how HIV seropositivity leads to early death must be curious indeed. Other studies in Africa have documented the serious proportional contribution of HIV and AIDS to mortalityl,2 and to the burgeoning of tuberculosis3 there. Anyone who has paid a visit to a medical ward or pulmonary service in an African hospital, however fleeting, also understands this impact. What distinguishes the latest study is that, because of the prospective cohort design, it quantifies in absolute as well as relative terms the mortality associated with HIV above and beyond the mortality from other causes. The calculations of "excess mortality" assume that some HIV-infected persons will die of unrelated causes, at a rate equivalent to that in the uninfected. Hardest hit by excess deaths were the 25-34-year-olds, usually a group with low mortality. Nearly 90% of their deaths were in excess of background rates and were attributable to HIV. Perhaps most startling was that this massively increased mortality in young adults as a group occurred while only about 15% of the group were actually infected. Sadly, in many urban populations in east and southern Africa the HIV prevalence in young adults is much higher than in the rural population studied. The associated increased mortality in the urban areas must therefore be even greater. The strong association of HIV with excess mortality, combined with a knowledge of the natural history of HIV infection, underscores the critical importance of the AIDS epidemic in Africa. However, more information is needed to clarify how many of the excess deaths could have been delayed through optimum medical prevention and therapy of such HIV-associated illnesses as tuberculosis, other pneumonias, and diarrhoeal disease. Practical
990
James W Curran
Division of HIV/AIDS, Center for Infectious Diseases, and Office of the Director; Centers for Disease Control and Prevention, Atlanta, Georgia, USA
2
3
DeCock KM, Porter A, Odehouri K, et al. Rapid emergence of AIDS in Abidjan, Ivory Coast. Lancet 1989; ii: 408-11. DeCock KM, Barrere B, Lafontaine M-F, et al. Mortality trends in Abidjan, Cote d’Ivoire, 1983-1988. AIDS 1991; 5: 393-98. Richards SB, St Louis ME, Nieburg P, et al. Impact of the HIV epidemic on trends in tuberculosis in Abidjan, Cote d’Ivoire. Tubercule Lung Dis (in press).
Marine pollution and limb reduction defects See page 1033
"Pollution
suspected in birth deformities" (Sunday Times, London, Jan 9, 1994). So the story began. Five children in the Isle of Wight, UK, were born over a period of 23 months with missing or deformed hands; four who were born between February, 1989, and May, 1990, lived in the same seaside town. All the mothers reported that they regularly swam in the sea during pregnancy. Was marine pollution to blame? Over the next 3 weeks five other clusters of babies born with limb reduction defects were reported (Sunday Times, Jan 16, 23, 30). All were in coastal areas of the UK. Widespread national and international media coverage followed and studies began in several countries to compare the prevalence of limb reduction defects in babies born in coastal areas with those born inland. The results of three studies, from the UK, Italy, and Latin America, are reported in this week’s Lancet. All three found no difference in rates of limb reduction defects for babies born in coastal and inland areas. The researchers did not examine the causes of the limb defects that did occur, and the report of the Office of Population Censuses & Surveys (OPCS) in the UK did not set out to identify clusters or to throw any light on whether environmental factors could be linked with the six clusters described in the Sunday Times. Nevertheless, the results of the studies suggest that marine pollution is unlikely to be the answer. The UK coastal clusters have, it seems, arisen by chance. And the parents of the affected babies are no nearer to an explanation of the cause. Identifying whether clusters of cases represent real increases in the prevalence of a condition or are simply chance findings is often difficult and may, as illustrated here, need detailed investigation. Such research is costly
and time consuming. It is therefore surprising that the press reports of the six UK clusters were sufficient to generate studies such as those reported from Italy and Latin America before analysis of the UK cases had been published. Moreover, the publicity given to the UK cases sparked hopes of identifying a cause of the limb defects and aroused fears of sea bathing or living near the sea, all of which have turned out to be unfounded. So what does cause limb reduction defects? An interruption of blood supply to the developing limb is thought to be responsible in some cases: uterine artery occlusion and handling of the uterus or uterine vessels have been associated with bilateral brainstem ischaemic lesions and peripheral limb deficiency in an animal model;’ and transverse limb reduction defects due to fetal vascular occlusion have been described in human beings.2 Limb defects have been linked with chorionic villus sampling;3 the mechanisms remain unclear but may involve amniotic puncture with band formation, fetal compression due to acute oligohydramnios, or entrapment of hands or feet in the exocoelomic gel. At a molecular level, mutations in one gene, Gdf 5, have lately been shown to be responsible for limb abnormalities in mice.’ Whether similar genetic mutations play a part in human beings remains to be seen, but at least some clues about the basis of skeletal formation are now forthcoming. Once we begin to understand the roles of regulatory genes and gene products, the place of environmental factors in interference with limb development may become clearer. Pollutants may yet be implicated-but that is another story. Astrid James The Lancet, London, UK 1 Webster WS, Lipman AH, Brown-Woodman PDC, Osborn RA. Moebius unmasked: pathogenesis of the Moebius syndrome in an animal model. Teratology 1988; 38: 199A. 2 Hoyme HF, Jones KL, van Allen MI, Saunders BS, Benirschke K. Vascular pathogenesis of transverse limb reduction defects. J Pediatr 1982; 101: 839-43. 3 Firth HV, Boyd PA, Chamberlain P, MacKenzie IZ, Lindenbaum RH, Huson SM. Severe limb abnormalities after chorion villus sampling at 56-66 days’ gestation. Lancet 1991; 337: 762-63. 4 Shepard TH, Kapur RP, Fantel AG. Limb-reduction defects and chorion villus sampling. Lancet 1991; 337: 1092. 5 Storm EE, Huynh TV, Copeland NG, Jenkins NA, Kingsley DM, Lee S-J. Limb alterations in brachypodism mice due to mutations in a new member of the TGF&bgr;-superfamily. Nature 1994; 368: 639-43.
The
nose
and the lower
airways
Medical students usually first study the nose as part of the respiratory system. Its function as a humidifier is acknowledged, but attention is quickly diverted to the structure, physiology, and pathology of the lungs. Doctors who are not destined to become otorhinolaryngologists seldom think much more about the nose and its relation to the lower airways. How many know that the smallest cross-sectional area of the conducting airways is at the internal nasal ostium (0-3 cm2 on each side), or that the nose accounts for nearly half the total airway resistance? Because it has a rich blood supply with plentiful arteriovenous anastomoses, it can increase the temperature of inspired air by as much as 25°C between external nares and nasopharynx. Not only does the nose provide warm moist air to the lower airways but also it
guards them from large particles and from soluble noxious gases such as ozone, sulphur dioxide, and formaldehyde.’,2 In physiological terms the nose is a dynamic organ. We are all aware of its sudden changes in resistance to air flow and its ability to switch on watery secretion like a tap. These properties stem from the venous sinusoids (pseudoerectile tissue) of the turbinates and nasal septum, and from the profusion of mainly serous glands in the nasal mucosa. Here there are about 8 glands per mm2 compared with 1 or less in the trachea and lower airways. Both the venous sinusoids and the glands are under autonomic control, and it is interesting that this produces in most people a regular reciprocating alteration in nasal resistance between the two nasal cavities, with a periodicity of 2-7 hours. By comparison, the lower airways seem physiologically much more stable. Despite these many differences, there has been a tendency to link the nose and the lung in various disease states, especially asthma. Does the nasobronchial reflex exist? Does nasal inflammation lead sooner or later to bronchial abnormalities? The evidence is against these possibilities, whether for allergic, non-allergic, or exerciseinduced asthma. Despite the frequent association of allergic rhinitis and allergic asthma, only about 8-11% of patients with allergic rhinitis actually have asthma.3 Even at the height of an attack of hay fever, whether induced naturally or by laboratory challenge, there is seldom any change in pulmonary mechanics.4 In the case of exercise-induced asthma, an interesting report from Picado and his colleagues5 in Barcelona has shown that the nose responds with the normal physiological fall in resistance during exercise whether the subjects are asthmatic, rhinitic, or normal. By use of FEVI to detect exercise-induced asthma and at the same time posterior rhinomanometry to calculate nasal resistance, it was possible to show precisely the same relative decrease in nasal resistance among all subjects as they exercised, even though the starting point for patients with rhinitis was different from that in subjects with clear noses. Working on similar lines and using an acoustic reflection technique, Rubinstein and colleagues6 showed that not only the nose but also the trachea can dilate during exercise. This increase in cross-sectional area of the trachea occurred even in patients who simultaneously developed exercise-induced asthma. This curious dichotomous response presumably reflects the fact that the trachea, like the nose, may have the potential to change its cross-sectional area due to alterations in the vascular beds of its wall.7 The divorce between the responses of upper and lower airways to exercise in asthma is potentially beneficial. McFadden and colleagues* have shown that exerciseinduced bronchoconstriction is related to the degree to which relatively cool and dry air enters the lower airways. Compared with the nose, the lower airways are poor at warming and humidifying air, and bronchoconstriction may result from the temporary development of hyperosmolarity in their walls. The longer that nasal breathing can be maintained during exercise, the less likely are the lower airways to have to take over the function of heating and humidification. Normally we are forced to switch to mouth breathing when ventilation reaches 30-60 litres per minute. Clearly the more dilated
991