- Email: [email protected]
THE BRAN WAGON
42 Dr Henter and colleagues (May 9, p 1091) discuss a difficulty that we acknowledge in distinguishing haemophagocytic lymphohistiocytosis from infection-associated haemophagocytic syndrome. We also suggest that these two conditions may share common pathogenetic pathways. However, to accept them as one disorder is to deny the strong evidence of familial incidence of disease in some situations and spontaneous permanent remission in sporadic cases in which a virus seems to be operating. We prefer a separate classification for the present and would aggregate the two only when these important differences in cases can be understood and
explained. TONY CHU G. J. D’ANGIO
Department of Pathology, Izaak Walton Killam Hospital for Children, Halifax, Nova Scotia B3J 3G9, Canada
BLAISE E. FAVARA S. LADISCH M. NESBIT J. PRITCHARD Writing Group of the Histiocyte Society
HUMAN PAPILLOMAVIRUS TYPE 16 DNA IN ANAL SQUAMOUS CELL CARCINOMA
SIR,-Squamous cell carcinoma (SCC) of the cervix, vulva, and penis are associated with the sexual transmission of human papillomaviruses (HPV) and these viruses do seem to have oncogenic potential. Anal SCC could also be related to the sexual transmission of HPV. This uncommon malignancy has been reported in anoreceptive homosexual men’"’ but receptive anal sexual activity is not confined to males. Peters and Mack’s study3 of anal cancer in both sexes in Los Angeles County supported the views that sexual activity involving the anus is related to anal cancer. Furthermore, anal warts have been linked with anal cancer.4,5These lesions usually contain HPV 6 and 11, but 8 % also contain HPV 16, the predominant type associated with invasive cervical, vulval, and penile cancer. A study of homosexual men has demonstrated cytological evidence of HPV infection associated with epithelial dysplasia in the absence of clinically apparent anal warts.’ The
-
evidence suggests that anal SCC may be associated with the sexual transmission of HPV 16, and this view is supported by uncontrolled reports of HPV 16 DNA in 8 anal or perianal cancers.8-11 We report here the preliminary results of a study of HPV 16 DNA in anal SCC and control tissues. Fresh surgical or biopsy tissue was obtained from 13 patients with anal malignancies and from 10 patients undergoing haemorrhoidectomy. Tissue from a SCC of the cervix known to contain HPV 16 DNA was used as a positive control. Specimens were homogenised, disrupted, and digested with proteinase K, and DNA was extracted. 10 Ilg DNA samples were digested with BamHI, EcoRI, and Pst! and the resulting fragments were separated by electrophoresis. As controls the gels were also loaded with digested DNA from CaSki cells (a positive control for HPV 16 DNA) and from hela cells (which contain HPV 18 sequences but no HPV 16 DNA). A lane of each gel was also loaded with 50 pg linear HPV 16 DNA, the amount in 10 g DNA equivalent to one copy of the genome per cell. DNA-DNA hybridisation was done under stringent conditions. The anal malignancies were SCC (10), malignant melanoma (2), and adenocarcinoma (1). There were 7 men and 6 women, aged 40-91. The controls were 6 men and 4 women aged 34-56. No control had any clinical evidence of past or current HPV infection. 1 cancer patient had perianal warts. There were no histological features of HPV infection in the control specimens. HPV 16 DNA sequences were detected in 6/10 anal SCCs but not in the 10 controls (p=0-011)orin tissue from the anal malignant melanomas and adenocarcinoma. In no experiment was hybridisation detected between the HPV 16 DNA probe and the negative control (hela) or anal wart DNA but there was consistent hybridisation with the positive control (CaSki) and a signal was obtained from hybridisation with the linear HPV 16 DNA. The
number of viral genomes per cell was less than 5 copies in 1 case of anal SCC, about 100 in another, and intermediate in the other 4. If HPV is a factor in the genesis of both cervical and anal cancer the lower incidence of anal cancer may be due to a less frequent exposure of or reduced susceptibility of anal epithelium to HPV 16 or the absence of co-factors. The patients with anal SCC were recruited from several centres and a sexual history had been taken in only 1; a case-control study is now required to assess the prevalence of anal sex in anal cancer patients. In the UK the prevalence of genital warts and cervical intraepithelial neoplasia has lately been increasing, as have deaths from cervical cancer in women under 35. It remains to be seen whether there will be a corresponding increase in anal cancer. Immunosuppression may influence the development of HPVrelated neoplasia. 12 Homosexual men with HIV infection have been reported to have intraepithelial squamous anal carcinoma (4 cases13) or invasive anal cancer (2 cases14). With the spread of AIDS the incidence of anal cancer may increase. We thank Prof H. zur Hausen for the HPV- 16-containing plasmid, and the cases of anal cancer under their care.
surgeons who allowed us to examine ICRF Colorectal Cancer Unit, St Mark’s Hospital, London ECIV 2PS; and Molecular Virology Laboratory, Imperial Cancer Research Fund, London WC2 1.
J. G. PALMER N. A. SHEPHERD I. R. JASS L. V. CRAWFORD J. M. A. NORTHOVER
HS, Patchevsky AS, Marks G. Cloacogenic carcinoma of the Cooper Dis Colon Rectum 1979; 22: 557-58. homosexual
anorectum
in
men.
2. Li F, Osborn D, Cronin CM. Anorectal squamous carcinoma in two homosexual men. Lancet 1982; ii: 391. 3. Peters RK, Mack TM. Patterns of anal carcinoma by gender in Los Angeles County. Br J Cancer 1983; 48: 629-36. 4. Gillat DA, Teasdale C. Squamous cell carcinoma of the anus arising within condylomata accuminata. Eur J Surg Oncol 1985, 11: 369-71. 5. Prasad LM, Abcarian H. Malignant potential of perianal condyloma accuminata. Dis Colon Rectum 1980; 23: 191-97. 6. McCance DJ, Lowe D, Simmons P, Thomson JPS. Human papilloma virus in condyloma acuminata of the anus. J Clin Pathol 1986; 39: 927. 7. Medley G. Anal smear test to diagnose occult anorectal infection with human papilloma virus. Br J Vener Dis 1984: 60: 205. 8. Beckman AM, Daling JR, McDougal JK. Human papillomavirus in anogenital carcinomas. J Cell Biochem 1985; suppl 9c: 68. 9. Wells M, Griffiths S, Lewis F, Dixon MF, Bird CC. Identification of human papillomavirus in paraffin sections of anal condylomas and squamous carcinomas by in situ DNA hybridisation. J Pathol 1987; 151: A64. 10. Hill SA, Coghill SB. Human papillomavirus in squamous carcinoma of the anus.
Lancet 1986; ii: 1333. 11. Scheurlen W, Strmlau A, Gissman L, et al. Rearranged HPV 16 molecules in an anal carcinoma and in a laryngeal carcinoma. Int J Cancer 1986; 38: 671-76. 12. Schneider V, Kay S, Lee HM. Immunosuppression as a high risk factor in the development of condyloma accuminatum and squamous neoplasia of the cervix. Acta Cytol 1983; 27: 220-24. 13. Croxson T, Chabon AB, Rorat E, Borash IM. Intraepithelial carcinoma of the anus in homosexual men. Dis Colon Rectum 1984; 27: 325-30. 14. Howard LC, Paterson Brown S, Weber JN, et al. Squamous carcinoma of the anus in young homosexual men with T-helper cell depletion. Gemtour Med 1986; 62: 393-95.
THE BRAN WAGON
SiR,—Iagree to some extent with your editorial on bran (April 4, p 782). The pendulum has swung too far in one direction since Burkittl and others drew attention to the relation between the lack of fibre in the diet and the high incidence of some of the diseases prevalent in the western world (eg, chronic constipation, diverticular disease, and irritable bowel syndrome2-3), but practically unknown in native Africans. You only refer to the minor problems resulting from a diet rich in fibre such as abdominal discomfort, fermentation, bloated feeling, and lack of acceptability, but completely overlook some more serious problems. Such a diet can significantly impair the absorption of certain minerals, particularly calcium, by forming insoluble phytates, and this may accelerate osteoporosis in elderly people. The absorption of certain trace elements (eg, zinc, which is essential for tissue repair and healing of bone fractures4). On the other hand, prescriptions for laxatives account for 1 5-2-5 % of the total annual drug expenditure of a district general hospital, a large percentage of this being from departments of geriatric medicine where there is a large long-stay population.
43
Modification of the inpatient’s diet would definitely reduce expenditure on bulking agents, apart from other considerations.
CLINICAL AND BACTERIOLOGICAL DATA I
-
-
-
-
Balance has, therefore, be achieved, and it is the responsibility of the nutritionist and dietician to exercise moderation with fibre intake when advising about healthy eating, and to pay particular attention to those whose mineral and trace element status may already be critical. Such at-risk groups should have this status to
monitored regularly. Department of General Medicine for the Elderly, Memorial Hospital,
i
Y. P. SURI
Darlington DL3 6HX
1. Burkitt DP, Walker ARP, Painter NS. Effect of dietary fibre on stools and transit-times, and its role in the causation of disease. Lancet 1972; ii: 1408-12. 2. Manning AP, Heaton KW. Bran and the irritable bowel. Lancet 1976; i: 588. 3. Cann PA, Reid WW, Holdsworth CD. What is the benefit of coarse wheatbran in patients with irritable bowel syndrome? Gut 1984; 24: 168-73. 4. Reinhold JG. High phytate content of rural Iranian bread a possible cause of human zinc deficiency. Am J Clin Nutr 1971; 24: 1204-06. 5. Reinhold JG. Phytate concentration of leavened and unleavened Iranian bread. Ecol Food Nutr 1972; 1: 187-92. 6. Husain SL. Oral zinc sulphate in leg ulcers. Lancet 1969; i: 1069-71. 7. Greaves MW, Skillen AW. Effects of long-continued ingestion of zinc sulphate in patients with venous leg ulceration. Lancet 1970; ii: 889-91.
POLIOVACCINATTON IN THE GAMBIA
SIR,-Dr Hanlon and colleagues (April 4, p 800) suggest that a booster dose of killed poliovaccine might be more effective than oral poliovaccine in stopping an epidemic of poliomyelitis. A high rate of immunisation with the killed vaccine might be effective in preventing an epidemic, but injections during an epidemic may provoke poliomyelitis in children already infected with poliovirus. Intramuscular injection of any inflammatory substance can increase the risk of paralytic poliomyelitis by as much as 25-fold among, in exceptional circumstances, a maximum of 25 % of clùldren.1 Provocation poliomyelitis occurs with injections of diphtheria/pertussis/tetanus vaccine2 which, I am told, gives rise to unease among vaccinators. The risk of provocation poliomyelitis with the killed poliovaccine is small but occurred in the Cutter incident and, I believe, in accidents with previous vaccines.3 Provocation would only occur in children already infected with poliovirus and with viraemia, and might be mistaken for coincident
paralysis. The risk of provocation increases when unsterile and dirty needles and syringes are used,4 because the injections are more inflammatory. During an epidemic of poliomyelitis, injections should be given to small children for urgent medical reasons only. At other times, injections should be given sparingly and always
aseptically. Department of Community Medicine, University of Leeds, Leeds LS2 9LN
H. V. WYATT
1. Wyatt HV. Provocation of poliomyelitis by multiple injections. Trans R Soc Trop Med Hyg 1985; 79: 355-58. 2. Wyatt HV. Injections and poliomyelitis: What are the risks of vaccine-associated paralysis? Dev Biol Stand 1986; 65: 123-26. 3. Wyatt HV. Provocation poliomyelitis. Neglected clinical observations from 1914 to 1950. Bull Hist Med 1981; 55: 543-57. The popularity of injections in the Third World: consequences for poliomyelitis. Soc Sci Med 1984; 19: 911-15.
4. Wyatt HV.
Origins and
YOGHURT WITH BIFIDOBACTERIUM LONGUM REDUCES ERYTHROMYCIN-INDUCED GASTROINTESTINAL EFFECTS
SIR,--0ral
antibiotic therapy often alters the intestinal flora (including an increase in clostridial spores count), and this can have serious consequences such as pseudomembranous colitis. Administration of non-indigenous microorganisms such as Saccharomyces boulardii have been suggested as a way of reducing such sideeffects.2 Bifidobacterium longum is part of the normal human intestinal microflora; yoghurts containing viable bacteria of this species (BA yoghurts) are commercially available and might re-equilibrate intestinal flora. To see if BA yoghurts could prevent
I
I
J
*Abdommal pain, nausea, vomiting, loose stools. tLimit of detection 3 7/g logic faeces. Significant mcrease in stool weight and stool number when compard both with placebo period D-1 (p < 0 005) and with BA period D3 (p < 0-025) (t test for paired values).
antibiotic-associated
gastrointestinal effects we did a double-blind placebo-controlled study in adults given erythromycin. This antibiotic was chosen because it is widely used in outpatient care, is associated with a high rate of diarrhoea, and might not be destroyed by p-lactamase-producing intestinal bacteria. Ten healthy volunteers (five men, five women) of average age 29 years (range 22-50) gave their informed consent to the study. They took erythromycin 1 g by mouth twice daily for two 3-day study periods with a 3-week interval between them. Over each 3-day study period the volunteers took, together with erythromycin, three BA or three placebo yoghurts daily in a random order. Stool weight and frequency were noted on the day before (D- 1) and on the third day (D3) of each period. Abdominal disturbances were recorded throughout the study. The composition of the rectal microflora was analysed on D-1 and D3. Fecal weight, stool frequency, and abdominal complaints were significantly increased when erythromycin was given with placebo yoghurt but not when BA yoghurt was being taken (table). Clostridial spores were detected on D-1 of both periods in eight volunteers (mean 5.31 (SD 1-55) and 5.15 [1’05] 10glO!g faeces during placebo and BA periods, respectively). On D3 clostridial spores were still present in seven volunteers taking placebo yoghurts (mean count 5-50 [1’07]) but in only one taking BA yoghurts. The simultaneous intake of BA yoghurt with erythromycin reduced the frequency of gastrointestinal disorders seen in volunteers taking erythromycin and placebo yoghurt. The sharp fall in clostridial spore count suggests that BA yoghurts could reduce antibiotic-induced alterations of the intestinal microflora. BA yoghurts provided by St-Hubert, Janjoc, and Sapta dairy products, BP
29, 54710 Ludres, France. We thank Isabelle Houcke and Jean Marc Marchand for technical assistance.
Department of Gastroenterology, Microbiology Laboratory, and Faculty of Pharmacy, University of Lille II, 59087 Lille, France
J. F. COLOMBEL A. CORTOT C. NEUT C. ROMOND
1. Nord CE, Heimdahl A, Kager L. Antimicrobial induced alterations of the human oropharyngeal and intestinal microflora. Scand J Infect Dis 1986; suppl 49: 64-72. 2. Toothaker RD, Elmer GW. Prevention of clindamycin-induced mortality in hamsters by Saccharomyces boulardii Antimicrob Agents Chemother 1984; 26: 552-56. 3. Bergan T. Pharmamkinetic differentiation and consequences for normal microflora. Scand J Infect Dis 1986; suppl 49: 91-99.
RISK OF UNEXPLAINED STILLBIRTH AT DIFFERENT GESTATIONAL AGES
SIR,-Once delivered a baby is no longer at risk of stillbirth. P. L. Yudkin and colleagues’ (May 23, p 1192) use of fetuses undelivered at the start of a gestational period as the denominator for stillbirth risk is therefore not as appropriate as use of the number of fetuses undelivered during the period (expressed as fetus-weeks of exposure to risk). These indices diverge (see table) when a large proportion of those women pregnant at the beginning of a gestational period are delivered during the period (and are therefore at risk for only a part of the period): at 39-40 weeks, the indices differ by 50 % because, as Yudkin et al show, as few as a third of women
explained. TONY CHU G. J. D’ANGIO
Department of Pathology, Izaak Walton Killam Hospital for Children, Halifax, Nova Scotia B3J 3G9, Canada
BLAISE E. FAVARA S. LADISCH M. NESBIT J. PRITCHARD Writing Group of the Histiocyte Society
HUMAN PAPILLOMAVIRUS TYPE 16 DNA IN ANAL SQUAMOUS CELL CARCINOMA
SIR,-Squamous cell carcinoma (SCC) of the cervix, vulva, and penis are associated with the sexual transmission of human papillomaviruses (HPV) and these viruses do seem to have oncogenic potential. Anal SCC could also be related to the sexual transmission of HPV. This uncommon malignancy has been reported in anoreceptive homosexual men’"’ but receptive anal sexual activity is not confined to males. Peters and Mack’s study3 of anal cancer in both sexes in Los Angeles County supported the views that sexual activity involving the anus is related to anal cancer. Furthermore, anal warts have been linked with anal cancer.4,5These lesions usually contain HPV 6 and 11, but 8 % also contain HPV 16, the predominant type associated with invasive cervical, vulval, and penile cancer. A study of homosexual men has demonstrated cytological evidence of HPV infection associated with epithelial dysplasia in the absence of clinically apparent anal warts.’ The
-
evidence suggests that anal SCC may be associated with the sexual transmission of HPV 16, and this view is supported by uncontrolled reports of HPV 16 DNA in 8 anal or perianal cancers.8-11 We report here the preliminary results of a study of HPV 16 DNA in anal SCC and control tissues. Fresh surgical or biopsy tissue was obtained from 13 patients with anal malignancies and from 10 patients undergoing haemorrhoidectomy. Tissue from a SCC of the cervix known to contain HPV 16 DNA was used as a positive control. Specimens were homogenised, disrupted, and digested with proteinase K, and DNA was extracted. 10 Ilg DNA samples were digested with BamHI, EcoRI, and Pst! and the resulting fragments were separated by electrophoresis. As controls the gels were also loaded with digested DNA from CaSki cells (a positive control for HPV 16 DNA) and from hela cells (which contain HPV 18 sequences but no HPV 16 DNA). A lane of each gel was also loaded with 50 pg linear HPV 16 DNA, the amount in 10 g DNA equivalent to one copy of the genome per cell. DNA-DNA hybridisation was done under stringent conditions. The anal malignancies were SCC (10), malignant melanoma (2), and adenocarcinoma (1). There were 7 men and 6 women, aged 40-91. The controls were 6 men and 4 women aged 34-56. No control had any clinical evidence of past or current HPV infection. 1 cancer patient had perianal warts. There were no histological features of HPV infection in the control specimens. HPV 16 DNA sequences were detected in 6/10 anal SCCs but not in the 10 controls (p=0-011)orin tissue from the anal malignant melanomas and adenocarcinoma. In no experiment was hybridisation detected between the HPV 16 DNA probe and the negative control (hela) or anal wart DNA but there was consistent hybridisation with the positive control (CaSki) and a signal was obtained from hybridisation with the linear HPV 16 DNA. The
number of viral genomes per cell was less than 5 copies in 1 case of anal SCC, about 100 in another, and intermediate in the other 4. If HPV is a factor in the genesis of both cervical and anal cancer the lower incidence of anal cancer may be due to a less frequent exposure of or reduced susceptibility of anal epithelium to HPV 16 or the absence of co-factors. The patients with anal SCC were recruited from several centres and a sexual history had been taken in only 1; a case-control study is now required to assess the prevalence of anal sex in anal cancer patients. In the UK the prevalence of genital warts and cervical intraepithelial neoplasia has lately been increasing, as have deaths from cervical cancer in women under 35. It remains to be seen whether there will be a corresponding increase in anal cancer. Immunosuppression may influence the development of HPVrelated neoplasia. 12 Homosexual men with HIV infection have been reported to have intraepithelial squamous anal carcinoma (4 cases13) or invasive anal cancer (2 cases14). With the spread of AIDS the incidence of anal cancer may increase. We thank Prof H. zur Hausen for the HPV- 16-containing plasmid, and the cases of anal cancer under their care.
surgeons who allowed us to examine ICRF Colorectal Cancer Unit, St Mark’s Hospital, London ECIV 2PS; and Molecular Virology Laboratory, Imperial Cancer Research Fund, London WC2 1.
J. G. PALMER N. A. SHEPHERD I. R. JASS L. V. CRAWFORD J. M. A. NORTHOVER
HS, Patchevsky AS, Marks G. Cloacogenic carcinoma of the Cooper Dis Colon Rectum 1979; 22: 557-58. homosexual
anorectum
in
men.
2. Li F, Osborn D, Cronin CM. Anorectal squamous carcinoma in two homosexual men. Lancet 1982; ii: 391. 3. Peters RK, Mack TM. Patterns of anal carcinoma by gender in Los Angeles County. Br J Cancer 1983; 48: 629-36. 4. Gillat DA, Teasdale C. Squamous cell carcinoma of the anus arising within condylomata accuminata. Eur J Surg Oncol 1985, 11: 369-71. 5. Prasad LM, Abcarian H. Malignant potential of perianal condyloma accuminata. Dis Colon Rectum 1980; 23: 191-97. 6. McCance DJ, Lowe D, Simmons P, Thomson JPS. Human papilloma virus in condyloma acuminata of the anus. J Clin Pathol 1986; 39: 927. 7. Medley G. Anal smear test to diagnose occult anorectal infection with human papilloma virus. Br J Vener Dis 1984: 60: 205. 8. Beckman AM, Daling JR, McDougal JK. Human papillomavirus in anogenital carcinomas. J Cell Biochem 1985; suppl 9c: 68. 9. Wells M, Griffiths S, Lewis F, Dixon MF, Bird CC. Identification of human papillomavirus in paraffin sections of anal condylomas and squamous carcinomas by in situ DNA hybridisation. J Pathol 1987; 151: A64. 10. Hill SA, Coghill SB. Human papillomavirus in squamous carcinoma of the anus.
Lancet 1986; ii: 1333. 11. Scheurlen W, Strmlau A, Gissman L, et al. Rearranged HPV 16 molecules in an anal carcinoma and in a laryngeal carcinoma. Int J Cancer 1986; 38: 671-76. 12. Schneider V, Kay S, Lee HM. Immunosuppression as a high risk factor in the development of condyloma accuminatum and squamous neoplasia of the cervix. Acta Cytol 1983; 27: 220-24. 13. Croxson T, Chabon AB, Rorat E, Borash IM. Intraepithelial carcinoma of the anus in homosexual men. Dis Colon Rectum 1984; 27: 325-30. 14. Howard LC, Paterson Brown S, Weber JN, et al. Squamous carcinoma of the anus in young homosexual men with T-helper cell depletion. Gemtour Med 1986; 62: 393-95.
THE BRAN WAGON
SiR,—Iagree to some extent with your editorial on bran (April 4, p 782). The pendulum has swung too far in one direction since Burkittl and others drew attention to the relation between the lack of fibre in the diet and the high incidence of some of the diseases prevalent in the western world (eg, chronic constipation, diverticular disease, and irritable bowel syndrome2-3), but practically unknown in native Africans. You only refer to the minor problems resulting from a diet rich in fibre such as abdominal discomfort, fermentation, bloated feeling, and lack of acceptability, but completely overlook some more serious problems. Such a diet can significantly impair the absorption of certain minerals, particularly calcium, by forming insoluble phytates, and this may accelerate osteoporosis in elderly people. The absorption of certain trace elements (eg, zinc, which is essential for tissue repair and healing of bone fractures4). On the other hand, prescriptions for laxatives account for 1 5-2-5 % of the total annual drug expenditure of a district general hospital, a large percentage of this being from departments of geriatric medicine where there is a large long-stay population.
43
Modification of the inpatient’s diet would definitely reduce expenditure on bulking agents, apart from other considerations.
CLINICAL AND BACTERIOLOGICAL DATA I
-
-
-
-
Balance has, therefore, be achieved, and it is the responsibility of the nutritionist and dietician to exercise moderation with fibre intake when advising about healthy eating, and to pay particular attention to those whose mineral and trace element status may already be critical. Such at-risk groups should have this status to
monitored regularly. Department of General Medicine for the Elderly, Memorial Hospital,
i
Y. P. SURI
Darlington DL3 6HX
1. Burkitt DP, Walker ARP, Painter NS. Effect of dietary fibre on stools and transit-times, and its role in the causation of disease. Lancet 1972; ii: 1408-12. 2. Manning AP, Heaton KW. Bran and the irritable bowel. Lancet 1976; i: 588. 3. Cann PA, Reid WW, Holdsworth CD. What is the benefit of coarse wheatbran in patients with irritable bowel syndrome? Gut 1984; 24: 168-73. 4. Reinhold JG. High phytate content of rural Iranian bread a possible cause of human zinc deficiency. Am J Clin Nutr 1971; 24: 1204-06. 5. Reinhold JG. Phytate concentration of leavened and unleavened Iranian bread. Ecol Food Nutr 1972; 1: 187-92. 6. Husain SL. Oral zinc sulphate in leg ulcers. Lancet 1969; i: 1069-71. 7. Greaves MW, Skillen AW. Effects of long-continued ingestion of zinc sulphate in patients with venous leg ulceration. Lancet 1970; ii: 889-91.
POLIOVACCINATTON IN THE GAMBIA
SIR,-Dr Hanlon and colleagues (April 4, p 800) suggest that a booster dose of killed poliovaccine might be more effective than oral poliovaccine in stopping an epidemic of poliomyelitis. A high rate of immunisation with the killed vaccine might be effective in preventing an epidemic, but injections during an epidemic may provoke poliomyelitis in children already infected with poliovirus. Intramuscular injection of any inflammatory substance can increase the risk of paralytic poliomyelitis by as much as 25-fold among, in exceptional circumstances, a maximum of 25 % of clùldren.1 Provocation poliomyelitis occurs with injections of diphtheria/pertussis/tetanus vaccine2 which, I am told, gives rise to unease among vaccinators. The risk of provocation poliomyelitis with the killed poliovaccine is small but occurred in the Cutter incident and, I believe, in accidents with previous vaccines.3 Provocation would only occur in children already infected with poliovirus and with viraemia, and might be mistaken for coincident
paralysis. The risk of provocation increases when unsterile and dirty needles and syringes are used,4 because the injections are more inflammatory. During an epidemic of poliomyelitis, injections should be given to small children for urgent medical reasons only. At other times, injections should be given sparingly and always
aseptically. Department of Community Medicine, University of Leeds, Leeds LS2 9LN
H. V. WYATT
1. Wyatt HV. Provocation of poliomyelitis by multiple injections. Trans R Soc Trop Med Hyg 1985; 79: 355-58. 2. Wyatt HV. Injections and poliomyelitis: What are the risks of vaccine-associated paralysis? Dev Biol Stand 1986; 65: 123-26. 3. Wyatt HV. Provocation poliomyelitis. Neglected clinical observations from 1914 to 1950. Bull Hist Med 1981; 55: 543-57. The popularity of injections in the Third World: consequences for poliomyelitis. Soc Sci Med 1984; 19: 911-15.
4. Wyatt HV.
Origins and
YOGHURT WITH BIFIDOBACTERIUM LONGUM REDUCES ERYTHROMYCIN-INDUCED GASTROINTESTINAL EFFECTS
SIR,--0ral
antibiotic therapy often alters the intestinal flora (including an increase in clostridial spores count), and this can have serious consequences such as pseudomembranous colitis. Administration of non-indigenous microorganisms such as Saccharomyces boulardii have been suggested as a way of reducing such sideeffects.2 Bifidobacterium longum is part of the normal human intestinal microflora; yoghurts containing viable bacteria of this species (BA yoghurts) are commercially available and might re-equilibrate intestinal flora. To see if BA yoghurts could prevent
I
I
J
*Abdommal pain, nausea, vomiting, loose stools. tLimit of detection 3 7/g logic faeces. Significant mcrease in stool weight and stool number when compard both with placebo period D-1 (p < 0 005) and with BA period D3 (p < 0-025) (t test for paired values).
antibiotic-associated
gastrointestinal effects we did a double-blind placebo-controlled study in adults given erythromycin. This antibiotic was chosen because it is widely used in outpatient care, is associated with a high rate of diarrhoea, and might not be destroyed by p-lactamase-producing intestinal bacteria. Ten healthy volunteers (five men, five women) of average age 29 years (range 22-50) gave their informed consent to the study. They took erythromycin 1 g by mouth twice daily for two 3-day study periods with a 3-week interval between them. Over each 3-day study period the volunteers took, together with erythromycin, three BA or three placebo yoghurts daily in a random order. Stool weight and frequency were noted on the day before (D- 1) and on the third day (D3) of each period. Abdominal disturbances were recorded throughout the study. The composition of the rectal microflora was analysed on D-1 and D3. Fecal weight, stool frequency, and abdominal complaints were significantly increased when erythromycin was given with placebo yoghurt but not when BA yoghurt was being taken (table). Clostridial spores were detected on D-1 of both periods in eight volunteers (mean 5.31 (SD 1-55) and 5.15 [1’05] 10glO!g faeces during placebo and BA periods, respectively). On D3 clostridial spores were still present in seven volunteers taking placebo yoghurts (mean count 5-50 [1’07]) but in only one taking BA yoghurts. The simultaneous intake of BA yoghurt with erythromycin reduced the frequency of gastrointestinal disorders seen in volunteers taking erythromycin and placebo yoghurt. The sharp fall in clostridial spore count suggests that BA yoghurts could reduce antibiotic-induced alterations of the intestinal microflora. BA yoghurts provided by St-Hubert, Janjoc, and Sapta dairy products, BP
29, 54710 Ludres, France. We thank Isabelle Houcke and Jean Marc Marchand for technical assistance.
Department of Gastroenterology, Microbiology Laboratory, and Faculty of Pharmacy, University of Lille II, 59087 Lille, France
J. F. COLOMBEL A. CORTOT C. NEUT C. ROMOND
1. Nord CE, Heimdahl A, Kager L. Antimicrobial induced alterations of the human oropharyngeal and intestinal microflora. Scand J Infect Dis 1986; suppl 49: 64-72. 2. Toothaker RD, Elmer GW. Prevention of clindamycin-induced mortality in hamsters by Saccharomyces boulardii Antimicrob Agents Chemother 1984; 26: 552-56. 3. Bergan T. Pharmamkinetic differentiation and consequences for normal microflora. Scand J Infect Dis 1986; suppl 49: 91-99.
RISK OF UNEXPLAINED STILLBIRTH AT DIFFERENT GESTATIONAL AGES
SIR,-Once delivered a baby is no longer at risk of stillbirth. P. L. Yudkin and colleagues’ (May 23, p 1192) use of fetuses undelivered at the start of a gestational period as the denominator for stillbirth risk is therefore not as appropriate as use of the number of fetuses undelivered during the period (expressed as fetus-weeks of exposure to risk). These indices diverge (see table) when a large proportion of those women pregnant at the beginning of a gestational period are delivered during the period (and are therefore at risk for only a part of the period): at 39-40 weeks, the indices differ by 50 % because, as Yudkin et al show, as few as a third of women