888
full complement of ova in the female is already established at birth.1,4 Moreover, there are vastly more sperm than ova to be produced so that, on average, a human sperm is the end result of several hundred more divisions than is an egg. That the actual number of divisions partly depends on the age of the man accords with the finding that for disorders with an excess of paternally derived new mutations there is often a positive association between mutation frequency and paternal age. Well-known examples of such conditions are achondroplasia and haemophilia A. 1,2 A different explanation is required for the link between maternal age and certain chromosome disorders, notably Down syndrome. Some ingenious hypotheses, including late fertilisation due to infrequent intercourse, have been proposed but none is completely satisfactory. It remains uncertain whether the ova that reach maturity towards the end of a woman’s reproductive life are inherently more prone to non-disjunction during meiosis or whether the putative mechanisms for detecting and eliminating such faulty ova are impaired with advancing age.3 Important questions also remain unanswered about disorders with an excess of paternally derived new mutations in the absence of a clear paternal age effect. The issue has lately been raised in connection with retinoblastoma and with neurofibromatosis type I (NF-1, Von Recklinghausen’s disease).5 In Von Recklinghausen’s disease there is a very high mutation rate, arising mainly during spermatogenesis. Meiotic interchange between the chromosome 17 pair in the vicinity of the NF-gene can be detected by genetic recombination of flanking markers but has been found to occur more frequently in the female, so this event is almost certainly not the source of most NF-II mutations.6 It seems that at some late stage in the development of the sperm certain regions of the DNA are in a much more vulnerable state with respect to induction of mutations than are the correspnding regions in the ovum. There is nothing heretical in such a concept. Passage of certain genes through male rather than female gametogenesis can determine whether they are to be expressed after fertilisation and indeed throughout the subsequent lifetime of the offspring.7 This process of "imprinting" implies some differences in the condition of the DNA in sperm and egg without violating the principle that the actual base sequences (the genetic code) remain the same. Differential methylation of the DNA is a probable mechanism but, bearing in mind that sperm differ from other tissues in the composition of their chromosomal structural proteins,8 the macromolecular organisation of chromatin (ie, the degree of supercoiling of the DNA and its interaction with nuclear proteins) could also be important. This is largely uncharted territory for human genetics although considerable progress is being made in understanding the details of DNA fine structure (and how that affects function) in lower organisms.9 As part of the greater equation relating environmental mutagens to genetic damage, determinants of DNA vulnerability in the developing sperm and egg deserve close attention. 1. 2. 3. 4. 5.
Vogel F, Rathenberg R. Spontaneous mutations in man. Adv Hum Genet 1975; 5: 223-318. Vogel F, Motulsky AG. Human genetics: problems and approaches. 2nd ed. Berlin: Springer, 1986. Hassold TJ, Jacobs PA. Trisomy in man. Ann Rev Genet 1984; 18: 69-97. Chandley AC. Meiosis in man. Trends Genet 1988; 4: 79-84. Jadayel D, Fain P, Upadhyaya MA, et al. Paternal origin of new mutations in Von Recklinghausen neurofibromatosis. Nature 1990; 343: 558-59.
6. Fain PM, Goldgar DE, Wallace MR, et al. Refined physical mapping of the NFI region on chromosome 17. Am J Hum Genet 1989; 45: 721-28. 7. Sapienza C, Peterson AC, Rossant J, Balling R. Degree of methylation of transgenes is dependent on gamete of origin. Nature 1987; 328: 251-54. 8. Hecht NB. Molecular biology of structural chromosomal proteins of the mammalian testis. In: Adolph KW, ed. Molecular biology of chromosome function. New York: Springer, 1989: 396-420. 9. Maclean N, Hall BK. Cell commitment and differentiation. Cambridge: Cambridge Univ Press, 1987.
DECLINING MORTALITY FROM DOWN SYNDROME—NO CAUSE FOR COMPLACENCY The life expectancy of babies born with Down syndrome has improved dramatically over the past half-century. Record and Smith,l who analysed data on Down syndrome births in Birmingham between 1942 and 1952, reported that less than half survived the first year and only about 40% were alive at five years. Fryers2 contrasted these figures with the results of several subsequent studies from around the world, including his own Salford series of 1961-80 Down syndrome births of whom 81 % survived the first year and 71 % were alive at five years. He concluded that the decline in mortality over that period had been "very impressive". Other studies3.4 have confirmed the improvement in life expectancy, which may now have reached a plateau, with about 90% surviving to five years. The commonest causes of death in Down syndrome are respiratory infection and complications of congenital heart disease ;5 the improving survival is presumably attributable to more effective treatment of these conditions. The precise contribution of a more interventionist therapeutic approach, which has arisen as a result of changing ethical perceptions of Down syndrome, is difficult to quantify. Even within the past decade, there may have been a substantial shift in attitudes to the neonatal care of such infants.4,6 The most direct consequence of the lengthening lifespan of Down syndrome individuals is the anticipated increase in the number of affected people, children and adults, in the population. This outcome is likely despite the decline in birth frequency of Down syndrome that has been observed in many communities largely because of the lower fertility of older (higher risk) women.2 Down syndrome therefore illustrates the sometimes paradoxical relation between incidence, prevalence, and survival, in which a declining incidence may be more than offset by improved survival resulting in an increased prevalence. There are several important implications for service providers. First, because intellectually impaired children and their families experience substantial physical, emotional, and social difficulties/-9 the burden on health, educational, and social services is liable to increase. Second, couples receiving genetic counselling after Down syndrome pregnancy can now be told that there is a nine in ten chance of a similarly affected subsequent child surviving early childhood.’ Third, planners need to take account of the changing cost-benefit ratios associated with prenatal screening, in view of the proportionately greater potential savings generated by the avoidance of a Down syndrome birth. Finally, we require more detailed information about the quality of life of Down syndrome survivors and their families in the 1990s. Extending life expectancy can scarcely be regarded as a medical triumph if the effect is merely to prolong the time-scale of suffering, handicap, and dependency. Until we are more sure that the birth of a child with Down syndrome heralds a lifetime of joy and sorrow in
889
approximate proportions experienced by the rest of the population, we can ill afford to rest on our professional the
laurels. RG, Smith A. Incidence, mortality, and sex distribution of mongoloid defectives. Br J Prev Social Med 1955; 9: 10-15. Fryers T. The epidemiology of severe intellectual impairment. London:
1. Record 2.
Academic Press, 1984. 3. Baird, PA, Sadovnick AD. Life expectancy in Down’s syndrome. J Pediatr 1987; 110: 849-54.
JA, Pearn JH, Firman D. Childhood deaths in Down’s Syndrome. Survival curves and causes of death from a total population study in Queensland, Australia, 1976 to 1985. J Med Genet 1989; 26: 764-68. Thase ME. Longevity and mortality in Down’s syndrome. J Ment Defic Res 1982; 26: 177-92. Smith GF, Diamond E, Lejeune J, et al. The rights of infants with Down’s Syndrome. JAMA 1984; 251: 229. Kushlick A, Blunden R. The epidemiology of mental subnormality. In: Clarke AM, Clarke ABD, eds. Mental deficiency: the changing outlook. London: Methuen, 1974: 31-81. Gath A. Down’s syndrome and the family. London: Academic Press, 1978. Carr J. The effect on the family of a severely mentally handicapped child. In: Clarke AM, Clarke ADB, Berg JM, eds. Mental deficiency: the changing outlook. London: Methuen, 1985: 512-48.
4. Bell
5. 6. 7.
8.
9.
FEVER WITH PURPURA and purpura, whether traumatic or spontaneous, conditions for which medical advice is often sought, especially in children. Traumatic bruises occur on the shins and forehead of toddlers from falls and rough and tumble games; if sites such as the lower face, back, or buttocks are bruised or if the lesions are linear or wind round the body contours non-accidental injury must be suspected. Previous episodes of bleeding or bruising in the patient or his family should alert the medical attendant to the possibility of clotting disorders or thrombocytopenia. Bruising may be mimicked by the Mongolian blue spot on the buttocks or lower limbs especially in babies whose parents come from the Indian sub-continent, China, or an Arab country. When fever accompanies purpura, the doctor should not be dissuaded from considering child abuse in the differential diagnosis although other causes of the subcutaneous bleeding are more likely. Meningococcaemia or, less frequently, bacteraemia due to Haemophilus influenzae type b, pneumococci, staphylococci, gonococci, or Pseudomonas aeruginosa is the most urgent consideration.1 Pre-admission antibiotic administration has sometimes2 but not alwaysbeen shown to interfere with the laboratory diagnosis of meningococcal infections but not other forms of meningitis. Nevertheless, a life saved by the early injection of antibiotic is surely preferable to the occasional failure to demonstrate the pathogens in the blood or cerebrospinal fluid. Primary care physicians should give benzylpenicillin before arranging urgent hospital admission to any patient with suspected meningococcaemia. Since fever and purpura may also be presenting features of Haemophilus inj7uenzae type b bacteraemia, Jacobs et al4 recommend that chloramphenicol be given in addition to penicillin. For patients who are allergic to penicillin, chloramphenicol alone or a third-generation cephalosporin alone should be considered. Purpura is not always found in patients with meningococcaemia and must never be relied upon as an essential diagnostic sign. In a ten-year study of bacteraemia at the Boston City Hospital,** 12 of 25 patients with subsequently proven meningococcaemia had no signs of serious invasive disease on presentation and 10 of them were
Bruising are
initially admitted to hospital. Although leucocytosis is said to be a useful indicator of bacteraemia 6’ the 2 patients who died of unsuspected meningococcaemia in the Boston City Hospital series5 had leucopenia. In a study of 1279 patients with meningococcal meningitis between 1940 and 1979,a purpuric rash was noted in 29 % of cases in the first decade but in only 15% in the next thirty years. During epidemics of meningococcal meningitis the frequency of rashes and especially purpura rises to 50% or more compared with only 10-20% in non-epidemic times.9 In a retrospective study of 129 children admitted with fever and petechiae, Nguyen et all found that 26 had invasive bacterial infections-13 culture-proven meningococci, 8 Hinfluenzae, 2 Staphylococcus aureus, and 1 each Streptococcus pneumoniae and Escherichia coli. Most of the remainder had proven or suspected viral infections. No single laboratory test was sufficiently sensitive to detect all those with life-threatening bacterial sepsis, but those without serious disease tended to have mostly normal laboratory findings. In a prospective study7 of 190 children presenting with fever ( 38°C) and petechiae, but excluding children with purpura fulminans or known bleeding diatheses and all newborn babies, 13 had meningococcal disease, 19 streptococcal infection, and 28 viral disease. The laboratory test predictors for serious bacterial sepsis in this series were abnormal cerebrospinal fluid and a raised white blood cell count or increased absolute band form count; once again no single test or physical finding was sensitive enough to detect all such patients. The finding of petechiae in streptococcal pharyngitis had previously been recorded in 8 children.1O 2 had total peripheral white blood counts of 9-0 and 9-65 x 109/1, respectively, and the remainder had frank leucocytosis. There were no abnormalities in the cerebrospinal fluid and all the patients had negetive blood cultures except 1 from whom beta-haemolytic streptococci were grown. Thus many children presenting with fever and purpura have mild self-limiting diseases, mainly viral infections. The vasculitic and thrombocytopenic potential of rubella, measles, varicella, respiratory syncytial virus, and enteroviruses is well known. The occasional finding of purpura in streptococcal pharyngitis and the fine petechiae on the head and neck of a child with whooping cough spasms must be recognised. Some children with fever and purpura have leukaemia, idiopathic or other forms of thrombocytopenia, or a bleeding diathesis. In HenochSchonlein vasculitis purpura is concentrated on the buttocks and lower limbs and is often accompanied by abdominal pain, rectal bleeding, haematuria, or arthropathy. However, the most important consideration is the recognition and prompt treatment of the patient, with or without meningitis, who has meningococcal or H influenzae bacteraemia, for whom a delay of even an hour or two in starting antibacterial therapy can be fatal owing to the rapid development of endotoxic shock and disseminated intravenous coagulation.1 not
1. Bohr
V, Hansen B, Jessen O, et al. Eight hundred and seventy-five cases of bacterial meningitis. Part I of a three part series: Clinical data, prognosis, and the role of specialized hospital departments. J Infect 1983; 7: 21-30. 2. Bohr V, Rasmussen N, Hansen B, et al. 875 cases of bacterial meningitis: Diagnostic procedures and the impact of preadmission antibiotic therapy. Part III of a three part series. J Infect 1983; 7: 193-202. 3. Pickens S, Sangster G, Gray JA, Murdoch JMcC. Effects of preadmission antibiotics on the bacterial diagnosis of pyogenic meningitis. Scand J Infect Dis 1978; 10: 183-85.
full complement of ova in the female is already established at birth.1,4 Moreover, there are vastly more sperm than ova to be produced so that, on average, a human sperm is the end result of several hundred more divisions than is an egg. That the actual number of divisions partly depends on the age of the man accords with the finding that for disorders with an excess of paternally derived new mutations there is often a positive association between mutation frequency and paternal age. Well-known examples of such conditions are achondroplasia and haemophilia A. 1,2 A different explanation is required for the link between maternal age and certain chromosome disorders, notably Down syndrome. Some ingenious hypotheses, including late fertilisation due to infrequent intercourse, have been proposed but none is completely satisfactory. It remains uncertain whether the ova that reach maturity towards the end of a woman’s reproductive life are inherently more prone to non-disjunction during meiosis or whether the putative mechanisms for detecting and eliminating such faulty ova are impaired with advancing age.3 Important questions also remain unanswered about disorders with an excess of paternally derived new mutations in the absence of a clear paternal age effect. The issue has lately been raised in connection with retinoblastoma and with neurofibromatosis type I (NF-1, Von Recklinghausen’s disease).5 In Von Recklinghausen’s disease there is a very high mutation rate, arising mainly during spermatogenesis. Meiotic interchange between the chromosome 17 pair in the vicinity of the NF-gene can be detected by genetic recombination of flanking markers but has been found to occur more frequently in the female, so this event is almost certainly not the source of most NF-II mutations.6 It seems that at some late stage in the development of the sperm certain regions of the DNA are in a much more vulnerable state with respect to induction of mutations than are the correspnding regions in the ovum. There is nothing heretical in such a concept. Passage of certain genes through male rather than female gametogenesis can determine whether they are to be expressed after fertilisation and indeed throughout the subsequent lifetime of the offspring.7 This process of "imprinting" implies some differences in the condition of the DNA in sperm and egg without violating the principle that the actual base sequences (the genetic code) remain the same. Differential methylation of the DNA is a probable mechanism but, bearing in mind that sperm differ from other tissues in the composition of their chromosomal structural proteins,8 the macromolecular organisation of chromatin (ie, the degree of supercoiling of the DNA and its interaction with nuclear proteins) could also be important. This is largely uncharted territory for human genetics although considerable progress is being made in understanding the details of DNA fine structure (and how that affects function) in lower organisms.9 As part of the greater equation relating environmental mutagens to genetic damage, determinants of DNA vulnerability in the developing sperm and egg deserve close attention. 1. 2. 3. 4. 5.
Vogel F, Rathenberg R. Spontaneous mutations in man. Adv Hum Genet 1975; 5: 223-318. Vogel F, Motulsky AG. Human genetics: problems and approaches. 2nd ed. Berlin: Springer, 1986. Hassold TJ, Jacobs PA. Trisomy in man. Ann Rev Genet 1984; 18: 69-97. Chandley AC. Meiosis in man. Trends Genet 1988; 4: 79-84. Jadayel D, Fain P, Upadhyaya MA, et al. Paternal origin of new mutations in Von Recklinghausen neurofibromatosis. Nature 1990; 343: 558-59.
6. Fain PM, Goldgar DE, Wallace MR, et al. Refined physical mapping of the NFI region on chromosome 17. Am J Hum Genet 1989; 45: 721-28. 7. Sapienza C, Peterson AC, Rossant J, Balling R. Degree of methylation of transgenes is dependent on gamete of origin. Nature 1987; 328: 251-54. 8. Hecht NB. Molecular biology of structural chromosomal proteins of the mammalian testis. In: Adolph KW, ed. Molecular biology of chromosome function. New York: Springer, 1989: 396-420. 9. Maclean N, Hall BK. Cell commitment and differentiation. Cambridge: Cambridge Univ Press, 1987.
DECLINING MORTALITY FROM DOWN SYNDROME—NO CAUSE FOR COMPLACENCY The life expectancy of babies born with Down syndrome has improved dramatically over the past half-century. Record and Smith,l who analysed data on Down syndrome births in Birmingham between 1942 and 1952, reported that less than half survived the first year and only about 40% were alive at five years. Fryers2 contrasted these figures with the results of several subsequent studies from around the world, including his own Salford series of 1961-80 Down syndrome births of whom 81 % survived the first year and 71 % were alive at five years. He concluded that the decline in mortality over that period had been "very impressive". Other studies3.4 have confirmed the improvement in life expectancy, which may now have reached a plateau, with about 90% surviving to five years. The commonest causes of death in Down syndrome are respiratory infection and complications of congenital heart disease ;5 the improving survival is presumably attributable to more effective treatment of these conditions. The precise contribution of a more interventionist therapeutic approach, which has arisen as a result of changing ethical perceptions of Down syndrome, is difficult to quantify. Even within the past decade, there may have been a substantial shift in attitudes to the neonatal care of such infants.4,6 The most direct consequence of the lengthening lifespan of Down syndrome individuals is the anticipated increase in the number of affected people, children and adults, in the population. This outcome is likely despite the decline in birth frequency of Down syndrome that has been observed in many communities largely because of the lower fertility of older (higher risk) women.2 Down syndrome therefore illustrates the sometimes paradoxical relation between incidence, prevalence, and survival, in which a declining incidence may be more than offset by improved survival resulting in an increased prevalence. There are several important implications for service providers. First, because intellectually impaired children and their families experience substantial physical, emotional, and social difficulties/-9 the burden on health, educational, and social services is liable to increase. Second, couples receiving genetic counselling after Down syndrome pregnancy can now be told that there is a nine in ten chance of a similarly affected subsequent child surviving early childhood.’ Third, planners need to take account of the changing cost-benefit ratios associated with prenatal screening, in view of the proportionately greater potential savings generated by the avoidance of a Down syndrome birth. Finally, we require more detailed information about the quality of life of Down syndrome survivors and their families in the 1990s. Extending life expectancy can scarcely be regarded as a medical triumph if the effect is merely to prolong the time-scale of suffering, handicap, and dependency. Until we are more sure that the birth of a child with Down syndrome heralds a lifetime of joy and sorrow in
889
approximate proportions experienced by the rest of the population, we can ill afford to rest on our professional the
laurels. RG, Smith A. Incidence, mortality, and sex distribution of mongoloid defectives. Br J Prev Social Med 1955; 9: 10-15. Fryers T. The epidemiology of severe intellectual impairment. London:
1. Record 2.
Academic Press, 1984. 3. Baird, PA, Sadovnick AD. Life expectancy in Down’s syndrome. J Pediatr 1987; 110: 849-54.
JA, Pearn JH, Firman D. Childhood deaths in Down’s Syndrome. Survival curves and causes of death from a total population study in Queensland, Australia, 1976 to 1985. J Med Genet 1989; 26: 764-68. Thase ME. Longevity and mortality in Down’s syndrome. J Ment Defic Res 1982; 26: 177-92. Smith GF, Diamond E, Lejeune J, et al. The rights of infants with Down’s Syndrome. JAMA 1984; 251: 229. Kushlick A, Blunden R. The epidemiology of mental subnormality. In: Clarke AM, Clarke ABD, eds. Mental deficiency: the changing outlook. London: Methuen, 1974: 31-81. Gath A. Down’s syndrome and the family. London: Academic Press, 1978. Carr J. The effect on the family of a severely mentally handicapped child. In: Clarke AM, Clarke ADB, Berg JM, eds. Mental deficiency: the changing outlook. London: Methuen, 1985: 512-48.
4. Bell
5. 6. 7.
8.
9.
FEVER WITH PURPURA and purpura, whether traumatic or spontaneous, conditions for which medical advice is often sought, especially in children. Traumatic bruises occur on the shins and forehead of toddlers from falls and rough and tumble games; if sites such as the lower face, back, or buttocks are bruised or if the lesions are linear or wind round the body contours non-accidental injury must be suspected. Previous episodes of bleeding or bruising in the patient or his family should alert the medical attendant to the possibility of clotting disorders or thrombocytopenia. Bruising may be mimicked by the Mongolian blue spot on the buttocks or lower limbs especially in babies whose parents come from the Indian sub-continent, China, or an Arab country. When fever accompanies purpura, the doctor should not be dissuaded from considering child abuse in the differential diagnosis although other causes of the subcutaneous bleeding are more likely. Meningococcaemia or, less frequently, bacteraemia due to Haemophilus influenzae type b, pneumococci, staphylococci, gonococci, or Pseudomonas aeruginosa is the most urgent consideration.1 Pre-admission antibiotic administration has sometimes2 but not alwaysbeen shown to interfere with the laboratory diagnosis of meningococcal infections but not other forms of meningitis. Nevertheless, a life saved by the early injection of antibiotic is surely preferable to the occasional failure to demonstrate the pathogens in the blood or cerebrospinal fluid. Primary care physicians should give benzylpenicillin before arranging urgent hospital admission to any patient with suspected meningococcaemia. Since fever and purpura may also be presenting features of Haemophilus inj7uenzae type b bacteraemia, Jacobs et al4 recommend that chloramphenicol be given in addition to penicillin. For patients who are allergic to penicillin, chloramphenicol alone or a third-generation cephalosporin alone should be considered. Purpura is not always found in patients with meningococcaemia and must never be relied upon as an essential diagnostic sign. In a ten-year study of bacteraemia at the Boston City Hospital,** 12 of 25 patients with subsequently proven meningococcaemia had no signs of serious invasive disease on presentation and 10 of them were
Bruising are
initially admitted to hospital. Although leucocytosis is said to be a useful indicator of bacteraemia 6’ the 2 patients who died of unsuspected meningococcaemia in the Boston City Hospital series5 had leucopenia. In a study of 1279 patients with meningococcal meningitis between 1940 and 1979,a purpuric rash was noted in 29 % of cases in the first decade but in only 15% in the next thirty years. During epidemics of meningococcal meningitis the frequency of rashes and especially purpura rises to 50% or more compared with only 10-20% in non-epidemic times.9 In a retrospective study of 129 children admitted with fever and petechiae, Nguyen et all found that 26 had invasive bacterial infections-13 culture-proven meningococci, 8 Hinfluenzae, 2 Staphylococcus aureus, and 1 each Streptococcus pneumoniae and Escherichia coli. Most of the remainder had proven or suspected viral infections. No single laboratory test was sufficiently sensitive to detect all those with life-threatening bacterial sepsis, but those without serious disease tended to have mostly normal laboratory findings. In a prospective study7 of 190 children presenting with fever ( 38°C) and petechiae, but excluding children with purpura fulminans or known bleeding diatheses and all newborn babies, 13 had meningococcal disease, 19 streptococcal infection, and 28 viral disease. The laboratory test predictors for serious bacterial sepsis in this series were abnormal cerebrospinal fluid and a raised white blood cell count or increased absolute band form count; once again no single test or physical finding was sensitive enough to detect all such patients. The finding of petechiae in streptococcal pharyngitis had previously been recorded in 8 children.1O 2 had total peripheral white blood counts of 9-0 and 9-65 x 109/1, respectively, and the remainder had frank leucocytosis. There were no abnormalities in the cerebrospinal fluid and all the patients had negetive blood cultures except 1 from whom beta-haemolytic streptococci were grown. Thus many children presenting with fever and purpura have mild self-limiting diseases, mainly viral infections. The vasculitic and thrombocytopenic potential of rubella, measles, varicella, respiratory syncytial virus, and enteroviruses is well known. The occasional finding of purpura in streptococcal pharyngitis and the fine petechiae on the head and neck of a child with whooping cough spasms must be recognised. Some children with fever and purpura have leukaemia, idiopathic or other forms of thrombocytopenia, or a bleeding diathesis. In HenochSchonlein vasculitis purpura is concentrated on the buttocks and lower limbs and is often accompanied by abdominal pain, rectal bleeding, haematuria, or arthropathy. However, the most important consideration is the recognition and prompt treatment of the patient, with or without meningitis, who has meningococcal or H influenzae bacteraemia, for whom a delay of even an hour or two in starting antibacterial therapy can be fatal owing to the rapid development of endotoxic shock and disseminated intravenous coagulation.1 not
1. Bohr
V, Hansen B, Jessen O, et al. Eight hundred and seventy-five cases of bacterial meningitis. Part I of a three part series: Clinical data, prognosis, and the role of specialized hospital departments. J Infect 1983; 7: 21-30. 2. Bohr V, Rasmussen N, Hansen B, et al. 875 cases of bacterial meningitis: Diagnostic procedures and the impact of preadmission antibiotic therapy. Part III of a three part series. J Infect 1983; 7: 193-202. 3. Pickens S, Sangster G, Gray JA, Murdoch JMcC. Effects of preadmission antibiotics on the bacterial diagnosis of pyogenic meningitis. Scand J Infect Dis 1978; 10: 183-85.
