323
Control of antibiotic-resistant
Streptococcus pneumoniae
in Romania
SIR,-Multiresistant strains of Streptococcus pneumoniae (resistant to three or more classes of antibiotic) have been reported from many parts of the world.1 In November, 1990, we isolated a multiresistant strain of S pneumoniae, serotype 19, from a 1-year-old Romanian child adopted by a family in the UK. The isolate showed resistance to penicillin (minimum inhibitory concentration 2-0 mg/1) and was also resistant to erythromycin,
high-level
tetracycline, trimethoprim, sulphamethoxazole, and cefuroxime, remaining susceptible to chloramphenicol, cefotaxime, and rifampicin. These results were confirmed by the Antibiotic Reference Laboratory (Public Health Laboratory Service, Colindale). Subsequently a multiresistant strain of S pneumoniae (also serotype 19) has been isolated from another (unrelated) adopted Romanian child in the UK. The first child came from Sinaia. Three children’s hospitals in Sinaia (chronic sick, tuberculosis, and acute paediatric) were visited in May, 1991, and nose swabs were collected from 78 inpatients aged 1-16 years. The swabs were examined in the UK within 96 h of sample collection for the presence of S pneumoniae. Sixteen strains but
isolated from 15 of the 78 children. These strains were tested for susceptibility to penicillin, oxacillin, tetracycline, erythromycin, were
sulphamethoxazole, trimethoprim, chloramphenicol, rifampicin, and cefotaxime by disc susceptibility testing. Only two of the strains were susceptible to all the antibiotics tested. The percentages of resistant strains were penicillin and oxacillin 25%, tetracycline
56%, erythromycin 6%, sulphamethoxazole 44%, trimethoprim 31%, chloramphenicol 6%, and rifampicin 6%. None were resistant to cefotaxime. 31 % were multiresistant. Seven of the nine tetracycline-resistant strains were isolated from children in one hospital, in which tetracycline was frequently given (as young as 2 years) and the overcrowded conditions provided opportunity for patient-to-patient spread of microorganisms. Mastro et al2 pointed out the importance of knowing the antibiotic resistance and serotype patterns of S pneumoniae for effective acute respiratory tract infection control programmes in developing countries.3 Charitable organisations provide resources including antibiotics to Romania, but without information about the prevalence of antibiotic resistance and with no effective systems to monitor or control the spread of antibiotic-resistant bacteria. We suggest that establishment of effective systems of monitoring and controlling antibiotic-resistant bacteria is as essential to relief operations for Romania as is the provision of antibiotics.
Departments of
Microbiology and Paediatrics,
Royal Hampshire County Hospital, Winchester SO22 5DG, UK
895) multiple (6 or more) duodenal biopsy specimens were by histopathological and parasitological methods, specifically to look for the presence of parasites to giardia. We are 13,
of reports showing that repeated stool examination is better than multiple duodenal biopsy, and therefore do not share Blanshard and Gazzard’s concern (unless their unpublished data contain evidence to support this). Furthermore the clinical response to metronidazole in microsporidiosis is different from that in giardiasis; unless reinfection takes place, a 2-week course of metronidazole is curative in most patients.’ In 18 patients with proven microsporidiosis and diarrhoea and who tolerated metronidazole, 10 had lasting improvement, 8 of whom needed maintenance therapy to prevent recurrence or worsening of diarrhoea within a few days. We do not believe that the effect of metronidazole results from direct action on microsporidial infection because of the persistent presence of parasites in repeat duodenal biopsy specimens, as reported, and continuous excretion of spores in the stool during treatment in all 5 patients examined by van Gool et al.2 Measurements of amounts of parasites in random biopsy specimens and spore counts in stool are difficult to interpret because variability per biopsy and stool sample, even in the same patient, appears large. We did not look for ultrastructural changes in the parasites. It is very unlikely that functionally important changes occur since intracellular infection, including excretion of spores, persists in the rapidly renewing duodenal enterocytes. The fact that none of our patients responding clinically had an important weight gain is consistent with persistence of malabsorption. We postulate that metronidazole by its action on the intestinal flora may reduce the intraluminal digestion of malabsorbed nutrients and in this way produce a reduction of stool output leading to symptomatic relief. not aware
Department of Internal Medicine (AIDS-Unit), Department of Medical Microbiology, and Department of Gastroenterology, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands
KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990; 3: 171-96. 2. Mastro TD, Ghafour A, Nomani NK, et al. Antimicrobial resistance of pneumococci in children with acute respiratory tract infection in Pakistan. Lancet 1991; 337: 156-59. 3. World Health Organisation. Respiratory infections in children: management in small hospitals. Background notes and a manual for doctors. WHO/RSD/86 26. Geneva:
WHO, 1986.
Microsporidiosis in HIV-1 infected individuals SIR,-Dr Blanshard and Dr Gazzard (June 15, p 1488) add to
knowledge about microsporidia as pathogens in man and to the importance of accurate diagnostic procedures in chronic diarrhoea in HIV-infected individuals. The lack of response to metronidazole in their 4 patients may result from the short course (3 days) taken by some of their patients. Furthermore, the exceptionally severe diarrhoea in their patients is, in our experience suggestive of another concomitant opportunistic infection, such as cytomegalovirus enteritis. The lack of sensitivity of stool examination for the diagnosis of symptomatic giardiasis is generally accepted, and when there is doubt duodenal biopsy is advised.’ In all patients in our study (April
T. VAN GOOL R. J. VAN KETEL J. F. W. M. BARTELSMAN
Enhanced local immunity in vaginal secretions of HIV-infected women
MICHAEL MILLAR MICHAEL GROVER FRAN OSBOURNE ANTONIOS ANTONIOU
Klugman
J. K. M. EEFTINCK SCHATTENKERK
1. Hill DR. Giardia lamblia. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. New York: Churchill Livingstone, 1990: 2110-15. 2. Van Gool T, Hollister WS, Eeftinck Schattenkerk JKM, et al. Diagnosis of Enterocytozoon bieneusi microsporidiosis in AIDS patients by recovery of spores from faeces. Lancet 1990; 336: 697-98.
p 1.
p
examined
SIR,-Dr Forest (April 6, p 835) and Dr O’Hagan (May 25, 1289) emphasise the need to focus research on mucosal immunity
in HIV genital infection. The finding of antibiotics to HIV in mucosal fluids of infected subjects, such as saliva, tears, breast milk, semen, or vaginal secretions, establishes that the virus elicits a local immune response in HIV infection.1 The presence of antibodies to HIV in vaginal mucosa has been proposed to hamper HIV infection via heterosexual intercourse,l which could explain the seemingly low efficacy observed in female-to-male HIV transmission. We have investigated antibodies to HIV-1 in vaginal secretions, not collected during menstruation, of 28 heterosexual HIV-1infected women (20 African women living in central Africa and 8 caucasian women living in France, all at stage II/CDC of HIV infection). 7 (5 African and 2 caucasian) healthy HIV-1seronegative women were selected as controls. IgG, IgM, and IgA concentrations in vaginal secretions were measured by ELISA against standard references. Vaginal secretions were also evaluated for IgG, IgM, and IgA antibodies directed to the env-encoded glycoprotein gpl60, by an indirect ELISA test with a recombinant native gpl60 as antigen, revealed by peroxidase-conjugated sheep anti-human IgG, IgM, or IgA. Total IgG in vaginal secretions was significantly higher in HIV-1-infected women than in controls
(means of 1350 µg/ml vs 219 µg/ml; p < 0001), as were IgM (173 µg/ml vs 1 ug/ml, p < 0’001) and IgA concentrations (450 Ilg/ml vs 125 µg/ml, p < 0 001).In HIV-1-infected women, IgG values were
324
three times higher than those for IgA. In 22 (79%) of 28 HIV-1-infected women vaginal secretions had antibodies of the IgG or IgA isotypes to gpl60, but no antibody of the IgM isotype was detectable. 3 HIV-1 seropositive women showed only IgA antibodies to gp 160 in vaginal secretions; 1 HIV-1-infected woman showed only IgG antibodies. By contrast, the controls lacked antibodies to gpl60. Our findings of raised IgG, IgM, and IgA concentrations in vaginal secretions of HIV-1-positive, healthy women demonstrate that the local immune system in vaginal mucosa is considerably activated from the symptomless stage of the disease. The enhancement of the mucosal immune response probably affects the production of intravaginal secretory IgA to gp 160 found in most cases. The unexpected high intravaginal IgG concentration is probably the result of increased transudation of serum-borne IgG antibody, associated with local secretory IgA/which suggests both systemic and mucosal origins of the specific IgG antibodies to HIV, as demonstrated in cervicovaginal fluid of women with genital HSV-2 infection.2 The presence of local antibodies to HIV may be important in antiviral immunity. Humoral antibodies to HIV have proved neutralising, but only weakly. However, because the vaginal mucosa is a relatively isolated cellular layer that is exposed to the outside environment, local antibodies in vaginal secretions could be more efficient in the neutralisation process, just as antibodies can be neutralising in vitro, but not in vivo. Moreover, mucosal secretory antibodies of IgA and, to a lesser extent, IgG isotypes are known to be protective against some other viral diseases, presumably by blocking viral attachment and/or entry into cells.3 In vaginal secretions, secretory IgA antibodies and secretory or transudative IgG antibodies directed to the env-encoded surface glycoproteins would be very good candidates for neutralisation.1 Nevertheless, the vaginal secretions of 6 (21 %) of 28 HIV-1-infected women in this series did not show any detectable antibody response to HIV; partial antibody response to HIV with only one isotype was observed in 4 (14%) of 28 women, suggesting important individual heterogeneity of vaginal immunity to HIV in about one-third of patients. In the absence of local specific immunity, the free viral particles of cervico-vaginal secretions might be more infectious. Such individual variations in the level of the local specific immune response to HIV antigens should be considered in the design of vaccines against HIV, if the development of mucosal immunity to HIV represents a major factor in the prevention of viral transmission at the sites of sexual exposure. Unit of Microbial Immunology, Institut Pasteur, 75724 Paris, France; and Institut Pasteur de Bangui, BP 923, Bangui, Republic of Central Africa
N. S. Lu L. BELEC P. M. V. MARTIN J. PILLOT
1. Bélec L,
Georges AJ, Steenman G, Martin PMV Antibodies to human immunodeficiency virus in vaginal secretions of heterosexual women. J Infect Dis 1989; 160: 385-91.
2. McDermott MR, Brais LJ, Evelegh MJ. Mucosal and systemic antiviral antibodies m mice inoculated intravaginally with herpex simplex virus type 2. J Gen Virol 1990;
71: 1497-504. 3.
Mestecky J, Kutteh WH, Ladjeva I, Peterman JH. The common mucosal immune system in the human genital tract and mammary gland. In Mettler L, Billington WD, eds. Reproductive immunology. Amsterdam: Elsevier Science Publishers (Biomedical division), 1989: 251-58.
Low-dose aspirin and nulliparae SIR,-Dr Uzan and colleagues (June 15, p 1427) have confirmed that low-dose aspirin has a role in the prevention of fetal growth retardation in multiparous women at risk of a poor outcome. However, we cannot agree with their conclusion that low-dose aspirin now seems "justifiable" in "any patient considered at high risk, even if in her first pregnancy". We have completed a pilot randomised, double-blind, placebo-controlled trial to assess the role of low-dose aspirin in nulliparous women with singleton pregnancies. These pregnancies were identified as at risk of a poor outcome by a haemoglobin concentration of greater than 132 g/dl at 12-18 weeks’ gestation.1 All women had a diastolic blood pressure of less than 90 mm Hg and no proteinuria at this time.
104 women fulfilled the entry criteria, 5 had contraindications to
aspirin, and 32 (31 %) declined to enter the study because they were unhappy about taking drugs during pregnancy. This is similar to the rate of refusal of 28% (42/148) in primigravid women identified as being at risk with uteroplacental doppler studies as a screening test.2 67 women were randomised at 18 weeks’ gestation-33 to low-dose aspirin and 34 to an identical placebo. There were no other changes to routine antenatal care. Demographic characteristics did differ between the groups. The frequency of hypertensive disorders of pregnancy3 did not differ between the low-dose aspirin group (9%, 3/33) and the placebo group (24%, 8/34). The frequency of hypertension in the placebo group shows that haemoglobin concentration at about 18 weeks’ gestation can be used to identify an at-risk group. Mean gestational age and frequency of induction of labour did not differ between the groups. No infants were born with an Apgar score of less than 7 at 5 min and there were no stillbirths or neonatal deaths. Unexpectedly, the emergency caesarean section rate was higher in the low-dose aspirin group than in the placebo group (24% vs 15%). Previous low-dose aspirin studies led us to expect a reduction in the caesarean section rate in association with low-dose aspirin therapy. Seven of the eight caesarean sections in the aspirin group and one in the placebo group were done for dystocia (p < 005). The median birthweight in the low-dose aspirin group was higher than in the placebo group (3500 g vs 3230 g). It is well recognised that increased birthweight is associated with a higher incidence of caesarean section for dystocia in nulliparae.4 This small study draws attention to important potential difficulties that may derive from more widespread use of low-dose aspirin. Firstly, will normal healthy nulliparae without other risk factors or with imprecise predictors be prepared to take drugs in pregnancy? Secondly, if the use of low-dose aspirin shifts the birthweight distribution upwards, will this have implications at a time when most obstetricians are seeking to reduce operative delivery rates? not
N. J. DAVIES Liverpool Maternity Hospital, Liverpool L7 7BN, UK 1.
R. G. FARQUHARSON S. A. WALKINSHAW
Murphy JF, O’Riordan J, Newcombe RG, et al. Relation of haemoglobin levels in first
and second trimesters to outcome of pregnancy. Lancet 1986; i: 992-94. 2. McParland P, Pearce JM, Chamberlain GVP. Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension. Lancet 1990; 335: 1552-55. 3. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 151: 892-98. 4. Turner MJ, Rasmussen MJ, Boylan PC, et al. The influence of birthweight on labor in nulliparas. Obstet Gynecol 1990; 76: 159-62.
Desferrioxamine for Alzheimer’s disease SIR,-Professor McLachlan and co-workers (June 1, p 1304) provide new evidence supporting a role for aluminium (Al) in Alzheimer’s disease (AD). By demonstrating, in a blinded, controlled trial that desferrioxamine, presumably by chelating and detoxifying Al, slowed the progression of AD, this study satisfies one of the most important of the set of nine criteria (experimental support/intervention) proposed by the late Sir Austin Bradford HiIP for evaluating cause-and-effect relations between diseases and potential aetiological factors. Several of these criteria have been fulfilled by epidemiological studies of the association between AI in drinking water and dementia/AD:2-5 the association is specific since other diseases tested were not related to drinking water Al; it has been found consistently; and there is a dose-response curve (albeit less clear in the British study4). Nor is Bradford Hill’s biological plausibility criterion violated since Al affects several enzymes and other biomolecules relevant to AD, it is neurotoxic to many species by several routes of exposure, and it is present in senile plaques and neurofibrillary tangles (NFT), which are the neuropathological hallmarks of AD. Al is also present in NFT in brain and spinal cord of related neurological disorders (the analogy criterion) 6 This evidence does not prove that Al causes AD but we do not understand why so many biomedical scientists are reluctant to take Al seriously as an important human toxin. The results of McLachlan et al, which need to be confirmed, should help to
Control of antibiotic-resistant
Streptococcus pneumoniae
in Romania
SIR,-Multiresistant strains of Streptococcus pneumoniae (resistant to three or more classes of antibiotic) have been reported from many parts of the world.1 In November, 1990, we isolated a multiresistant strain of S pneumoniae, serotype 19, from a 1-year-old Romanian child adopted by a family in the UK. The isolate showed resistance to penicillin (minimum inhibitory concentration 2-0 mg/1) and was also resistant to erythromycin,
high-level
tetracycline, trimethoprim, sulphamethoxazole, and cefuroxime, remaining susceptible to chloramphenicol, cefotaxime, and rifampicin. These results were confirmed by the Antibiotic Reference Laboratory (Public Health Laboratory Service, Colindale). Subsequently a multiresistant strain of S pneumoniae (also serotype 19) has been isolated from another (unrelated) adopted Romanian child in the UK. The first child came from Sinaia. Three children’s hospitals in Sinaia (chronic sick, tuberculosis, and acute paediatric) were visited in May, 1991, and nose swabs were collected from 78 inpatients aged 1-16 years. The swabs were examined in the UK within 96 h of sample collection for the presence of S pneumoniae. Sixteen strains but
isolated from 15 of the 78 children. These strains were tested for susceptibility to penicillin, oxacillin, tetracycline, erythromycin, were
sulphamethoxazole, trimethoprim, chloramphenicol, rifampicin, and cefotaxime by disc susceptibility testing. Only two of the strains were susceptible to all the antibiotics tested. The percentages of resistant strains were penicillin and oxacillin 25%, tetracycline
56%, erythromycin 6%, sulphamethoxazole 44%, trimethoprim 31%, chloramphenicol 6%, and rifampicin 6%. None were resistant to cefotaxime. 31 % were multiresistant. Seven of the nine tetracycline-resistant strains were isolated from children in one hospital, in which tetracycline was frequently given (as young as 2 years) and the overcrowded conditions provided opportunity for patient-to-patient spread of microorganisms. Mastro et al2 pointed out the importance of knowing the antibiotic resistance and serotype patterns of S pneumoniae for effective acute respiratory tract infection control programmes in developing countries.3 Charitable organisations provide resources including antibiotics to Romania, but without information about the prevalence of antibiotic resistance and with no effective systems to monitor or control the spread of antibiotic-resistant bacteria. We suggest that establishment of effective systems of monitoring and controlling antibiotic-resistant bacteria is as essential to relief operations for Romania as is the provision of antibiotics.
Departments of
Microbiology and Paediatrics,
Royal Hampshire County Hospital, Winchester SO22 5DG, UK
895) multiple (6 or more) duodenal biopsy specimens were by histopathological and parasitological methods, specifically to look for the presence of parasites to giardia. We are 13,
of reports showing that repeated stool examination is better than multiple duodenal biopsy, and therefore do not share Blanshard and Gazzard’s concern (unless their unpublished data contain evidence to support this). Furthermore the clinical response to metronidazole in microsporidiosis is different from that in giardiasis; unless reinfection takes place, a 2-week course of metronidazole is curative in most patients.’ In 18 patients with proven microsporidiosis and diarrhoea and who tolerated metronidazole, 10 had lasting improvement, 8 of whom needed maintenance therapy to prevent recurrence or worsening of diarrhoea within a few days. We do not believe that the effect of metronidazole results from direct action on microsporidial infection because of the persistent presence of parasites in repeat duodenal biopsy specimens, as reported, and continuous excretion of spores in the stool during treatment in all 5 patients examined by van Gool et al.2 Measurements of amounts of parasites in random biopsy specimens and spore counts in stool are difficult to interpret because variability per biopsy and stool sample, even in the same patient, appears large. We did not look for ultrastructural changes in the parasites. It is very unlikely that functionally important changes occur since intracellular infection, including excretion of spores, persists in the rapidly renewing duodenal enterocytes. The fact that none of our patients responding clinically had an important weight gain is consistent with persistence of malabsorption. We postulate that metronidazole by its action on the intestinal flora may reduce the intraluminal digestion of malabsorbed nutrients and in this way produce a reduction of stool output leading to symptomatic relief. not aware
Department of Internal Medicine (AIDS-Unit), Department of Medical Microbiology, and Department of Gastroenterology, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands
KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990; 3: 171-96. 2. Mastro TD, Ghafour A, Nomani NK, et al. Antimicrobial resistance of pneumococci in children with acute respiratory tract infection in Pakistan. Lancet 1991; 337: 156-59. 3. World Health Organisation. Respiratory infections in children: management in small hospitals. Background notes and a manual for doctors. WHO/RSD/86 26. Geneva:
WHO, 1986.
Microsporidiosis in HIV-1 infected individuals SIR,-Dr Blanshard and Dr Gazzard (June 15, p 1488) add to
knowledge about microsporidia as pathogens in man and to the importance of accurate diagnostic procedures in chronic diarrhoea in HIV-infected individuals. The lack of response to metronidazole in their 4 patients may result from the short course (3 days) taken by some of their patients. Furthermore, the exceptionally severe diarrhoea in their patients is, in our experience suggestive of another concomitant opportunistic infection, such as cytomegalovirus enteritis. The lack of sensitivity of stool examination for the diagnosis of symptomatic giardiasis is generally accepted, and when there is doubt duodenal biopsy is advised.’ In all patients in our study (April
T. VAN GOOL R. J. VAN KETEL J. F. W. M. BARTELSMAN
Enhanced local immunity in vaginal secretions of HIV-infected women
MICHAEL MILLAR MICHAEL GROVER FRAN OSBOURNE ANTONIOS ANTONIOU
Klugman
J. K. M. EEFTINCK SCHATTENKERK
1. Hill DR. Giardia lamblia. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. New York: Churchill Livingstone, 1990: 2110-15. 2. Van Gool T, Hollister WS, Eeftinck Schattenkerk JKM, et al. Diagnosis of Enterocytozoon bieneusi microsporidiosis in AIDS patients by recovery of spores from faeces. Lancet 1990; 336: 697-98.
p 1.
p
examined
SIR,-Dr Forest (April 6, p 835) and Dr O’Hagan (May 25, 1289) emphasise the need to focus research on mucosal immunity
in HIV genital infection. The finding of antibiotics to HIV in mucosal fluids of infected subjects, such as saliva, tears, breast milk, semen, or vaginal secretions, establishes that the virus elicits a local immune response in HIV infection.1 The presence of antibodies to HIV in vaginal mucosa has been proposed to hamper HIV infection via heterosexual intercourse,l which could explain the seemingly low efficacy observed in female-to-male HIV transmission. We have investigated antibodies to HIV-1 in vaginal secretions, not collected during menstruation, of 28 heterosexual HIV-1infected women (20 African women living in central Africa and 8 caucasian women living in France, all at stage II/CDC of HIV infection). 7 (5 African and 2 caucasian) healthy HIV-1seronegative women were selected as controls. IgG, IgM, and IgA concentrations in vaginal secretions were measured by ELISA against standard references. Vaginal secretions were also evaluated for IgG, IgM, and IgA antibodies directed to the env-encoded glycoprotein gpl60, by an indirect ELISA test with a recombinant native gpl60 as antigen, revealed by peroxidase-conjugated sheep anti-human IgG, IgM, or IgA. Total IgG in vaginal secretions was significantly higher in HIV-1-infected women than in controls
(means of 1350 µg/ml vs 219 µg/ml; p < 0001), as were IgM (173 µg/ml vs 1 ug/ml, p < 0’001) and IgA concentrations (450 Ilg/ml vs 125 µg/ml, p < 0 001).In HIV-1-infected women, IgG values were
324
three times higher than those for IgA. In 22 (79%) of 28 HIV-1-infected women vaginal secretions had antibodies of the IgG or IgA isotypes to gpl60, but no antibody of the IgM isotype was detectable. 3 HIV-1 seropositive women showed only IgA antibodies to gp 160 in vaginal secretions; 1 HIV-1-infected woman showed only IgG antibodies. By contrast, the controls lacked antibodies to gpl60. Our findings of raised IgG, IgM, and IgA concentrations in vaginal secretions of HIV-1-positive, healthy women demonstrate that the local immune system in vaginal mucosa is considerably activated from the symptomless stage of the disease. The enhancement of the mucosal immune response probably affects the production of intravaginal secretory IgA to gp 160 found in most cases. The unexpected high intravaginal IgG concentration is probably the result of increased transudation of serum-borne IgG antibody, associated with local secretory IgA/which suggests both systemic and mucosal origins of the specific IgG antibodies to HIV, as demonstrated in cervicovaginal fluid of women with genital HSV-2 infection.2 The presence of local antibodies to HIV may be important in antiviral immunity. Humoral antibodies to HIV have proved neutralising, but only weakly. However, because the vaginal mucosa is a relatively isolated cellular layer that is exposed to the outside environment, local antibodies in vaginal secretions could be more efficient in the neutralisation process, just as antibodies can be neutralising in vitro, but not in vivo. Moreover, mucosal secretory antibodies of IgA and, to a lesser extent, IgG isotypes are known to be protective against some other viral diseases, presumably by blocking viral attachment and/or entry into cells.3 In vaginal secretions, secretory IgA antibodies and secretory or transudative IgG antibodies directed to the env-encoded surface glycoproteins would be very good candidates for neutralisation.1 Nevertheless, the vaginal secretions of 6 (21 %) of 28 HIV-1-infected women in this series did not show any detectable antibody response to HIV; partial antibody response to HIV with only one isotype was observed in 4 (14%) of 28 women, suggesting important individual heterogeneity of vaginal immunity to HIV in about one-third of patients. In the absence of local specific immunity, the free viral particles of cervico-vaginal secretions might be more infectious. Such individual variations in the level of the local specific immune response to HIV antigens should be considered in the design of vaccines against HIV, if the development of mucosal immunity to HIV represents a major factor in the prevention of viral transmission at the sites of sexual exposure. Unit of Microbial Immunology, Institut Pasteur, 75724 Paris, France; and Institut Pasteur de Bangui, BP 923, Bangui, Republic of Central Africa
N. S. Lu L. BELEC P. M. V. MARTIN J. PILLOT
1. Bélec L,
Georges AJ, Steenman G, Martin PMV Antibodies to human immunodeficiency virus in vaginal secretions of heterosexual women. J Infect Dis 1989; 160: 385-91.
2. McDermott MR, Brais LJ, Evelegh MJ. Mucosal and systemic antiviral antibodies m mice inoculated intravaginally with herpex simplex virus type 2. J Gen Virol 1990;
71: 1497-504. 3.
Mestecky J, Kutteh WH, Ladjeva I, Peterman JH. The common mucosal immune system in the human genital tract and mammary gland. In Mettler L, Billington WD, eds. Reproductive immunology. Amsterdam: Elsevier Science Publishers (Biomedical division), 1989: 251-58.
Low-dose aspirin and nulliparae SIR,-Dr Uzan and colleagues (June 15, p 1427) have confirmed that low-dose aspirin has a role in the prevention of fetal growth retardation in multiparous women at risk of a poor outcome. However, we cannot agree with their conclusion that low-dose aspirin now seems "justifiable" in "any patient considered at high risk, even if in her first pregnancy". We have completed a pilot randomised, double-blind, placebo-controlled trial to assess the role of low-dose aspirin in nulliparous women with singleton pregnancies. These pregnancies were identified as at risk of a poor outcome by a haemoglobin concentration of greater than 132 g/dl at 12-18 weeks’ gestation.1 All women had a diastolic blood pressure of less than 90 mm Hg and no proteinuria at this time.
104 women fulfilled the entry criteria, 5 had contraindications to
aspirin, and 32 (31 %) declined to enter the study because they were unhappy about taking drugs during pregnancy. This is similar to the rate of refusal of 28% (42/148) in primigravid women identified as being at risk with uteroplacental doppler studies as a screening test.2 67 women were randomised at 18 weeks’ gestation-33 to low-dose aspirin and 34 to an identical placebo. There were no other changes to routine antenatal care. Demographic characteristics did differ between the groups. The frequency of hypertensive disorders of pregnancy3 did not differ between the low-dose aspirin group (9%, 3/33) and the placebo group (24%, 8/34). The frequency of hypertension in the placebo group shows that haemoglobin concentration at about 18 weeks’ gestation can be used to identify an at-risk group. Mean gestational age and frequency of induction of labour did not differ between the groups. No infants were born with an Apgar score of less than 7 at 5 min and there were no stillbirths or neonatal deaths. Unexpectedly, the emergency caesarean section rate was higher in the low-dose aspirin group than in the placebo group (24% vs 15%). Previous low-dose aspirin studies led us to expect a reduction in the caesarean section rate in association with low-dose aspirin therapy. Seven of the eight caesarean sections in the aspirin group and one in the placebo group were done for dystocia (p < 005). The median birthweight in the low-dose aspirin group was higher than in the placebo group (3500 g vs 3230 g). It is well recognised that increased birthweight is associated with a higher incidence of caesarean section for dystocia in nulliparae.4 This small study draws attention to important potential difficulties that may derive from more widespread use of low-dose aspirin. Firstly, will normal healthy nulliparae without other risk factors or with imprecise predictors be prepared to take drugs in pregnancy? Secondly, if the use of low-dose aspirin shifts the birthweight distribution upwards, will this have implications at a time when most obstetricians are seeking to reduce operative delivery rates? not
N. J. DAVIES Liverpool Maternity Hospital, Liverpool L7 7BN, UK 1.
R. G. FARQUHARSON S. A. WALKINSHAW
Murphy JF, O’Riordan J, Newcombe RG, et al. Relation of haemoglobin levels in first
and second trimesters to outcome of pregnancy. Lancet 1986; i: 992-94. 2. McParland P, Pearce JM, Chamberlain GVP. Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension. Lancet 1990; 335: 1552-55. 3. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 151: 892-98. 4. Turner MJ, Rasmussen MJ, Boylan PC, et al. The influence of birthweight on labor in nulliparas. Obstet Gynecol 1990; 76: 159-62.
Desferrioxamine for Alzheimer’s disease SIR,-Professor McLachlan and co-workers (June 1, p 1304) provide new evidence supporting a role for aluminium (Al) in Alzheimer’s disease (AD). By demonstrating, in a blinded, controlled trial that desferrioxamine, presumably by chelating and detoxifying Al, slowed the progression of AD, this study satisfies one of the most important of the set of nine criteria (experimental support/intervention) proposed by the late Sir Austin Bradford HiIP for evaluating cause-and-effect relations between diseases and potential aetiological factors. Several of these criteria have been fulfilled by epidemiological studies of the association between AI in drinking water and dementia/AD:2-5 the association is specific since other diseases tested were not related to drinking water Al; it has been found consistently; and there is a dose-response curve (albeit less clear in the British study4). Nor is Bradford Hill’s biological plausibility criterion violated since Al affects several enzymes and other biomolecules relevant to AD, it is neurotoxic to many species by several routes of exposure, and it is present in senile plaques and neurofibrillary tangles (NFT), which are the neuropathological hallmarks of AD. Al is also present in NFT in brain and spinal cord of related neurological disorders (the analogy criterion) 6 This evidence does not prove that Al causes AD but we do not understand why so many biomedical scientists are reluctant to take Al seriously as an important human toxin. The results of McLachlan et al, which need to be confirmed, should help to
