274 close linkage to disorders fully expressed in affected individuals, the bulk of the information can be extracted by counting. This information is easily expressed as a simple fraction, whose components have the advantage of additivity and efficiency (they are maximum likelihood estimators). Comparisons can be made by simple methods. While it is undesirable to waste the information from less informative families, serious problems arise in highly mutable conditions, such as Duchenne dystrophy, and estimates available from these families are influenced by assumptions about carrier status. Mosaicism of the founder carrier is a further possible source of erroneous inference. In the data of Donald et al the 63 informative meioses, all non-recombinant, could be expressed as 0/63 or as a lod score of 63 log(2) (or 18-96). Their total lod was 17-17, giving a lod of 1 69 at a recombination fraction of zero for the contribution of the soft data. This represents a mere one-tenth of the information, and is suggestive of some recombination. If attention is restricted to their hard data, and if the recombination fraction were 5%, then they would have expected 3.15 recombinant events: they found none. The chance of one non-recombinant is 0-95 and of 63 is 0-95 to the power of 63, which is about 4%. The exact 2 x2 analysis of the comparison of the hard data of Fishbeck et alz can be derived from the table and gives the similar result of 3-5%: -
0 8
63 116
63 124
8
179
187
Some foods in the normal Western diet contain large quantities of in particular may contain large amounts which pasteuration would not be expected to affect. In rural communities where transport time both to and from pasteurisation plant is lengthy, the coliform count in pre-sale milk may be as high as lObjml3 (personal communication, Department of Environmental Health, Western Isles Council, Scotland). Theoretically, milk fat may aid absorption of bacterial LPS, though this has yet to be shown in man. In addition, the dairy industry has an increasing incidence of coliform mastitis,4 which can be difficult to diagnose in the early stages and could thus contaminate bulk supplies of milk with mastitis-causing strains. These observations may explain some of the discrepancy between the incidence of rheumatoid arthritis in Europe and Third World rural communities,s and also the anecdotal reports of clinical improvement on an exclusion diet. LPS has been demonstrated in synovial fluid with the Limulus amoebocyte lysate assay in a small control group of patients with rheumatoid arthritis. The unexpected positive results were explained, perhaps erroneously, as an effect of raised synovial leucocyte count.6 Investigation of contamination by LPS and its relation to rheumatoid arthritis may lead to selection of those patients most likely to benefit from an exclusion diet, and to establish the nature of the arthritogenic antigen and its place in the pathogenesis of the polyarthropathies.
LPS, and milk
Bradford Royal Infirmary, Bradford, West Yorkshire BD9 6RJ
While there are doubtless other syndromes which will closely simulate Duchenne’s muscular dystrophy, and I am only too well aware from recent diagnostic errors that misinterpretation of partials, especially of the Taq polymorphism, can also lead to apparent recombination, there is as yet no reason to doubt a recombination fraction of at least 2 %. If it were 2 % the chance of 63 successive non-recombinants would be 28%. Until the position is clearer it would seem wise to base estimates of recombination frequency on hard data, and to publish full details of recombinant families. With extensive probing, misdiagnosis will often present as an apparent double-crossover.
TIMOTHY
J. INGLIS
1. Editorial. Bowel flora and ankylosing spondylitis. Lancet 1986; ii: 1259. 2. Goldenberg DL, Reed JI, Rice PA. Arthritis in rabbits induced by killed neisseria gonorrhoeae and gonococcal lipopolysaccharide. J Rheumatol 1984; 11: 3-8. 3. Yamaguchi Y, Yamaguchi K, Babb JL, Gans H. In vitro quantitation of the rat liver’s ability to eliminate endotoxin from portal vein blood. J Reticulo-Endothehal Soc
1982; 32: 409-22. 4. Anon. Mastitis surveillance scheme—January to June 1980. Vet Rec 1980; 107: 297-98. 5. Solomon L, Robin G, Valkenberg HA. Rheumatoid arthritis in an urban South African negro population. Ann Rheum Dis 1975; 34: 128-35. 6. Elm RJ, Knowles R, Barth WF, Wolff SM. Lack of specificity of the Limulus lysate test m the diagnosis of pyogenic arthritis. J Infect Dis 1978, 137: 507-13.
CONTROL OF EPIDEMIC METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS
Genetics
Laboratory, Department of Biochemistry, University of Oxford, Oxford OX1 3QU
J. H. EDWARDS
LM, Heitmancik JF, Caskey CT, et al. Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy. Nature 1986; 322: 73-77. Fishbeck KH, Ritter AW, Tirschwell DL, et al. Recombination with pERT87 (DXS164) in families with X-linked muscular dystrophy. Lancet 1986; ii: 104.
1. Kunkel 2.
DIETARY LIPOPOLYSACCHARIDES AS ARTHRITOGENIC ANTIGEN?
SiR,—Your editorial review’ of the relation between microbe and disease in ankylosing spondylitis introduces current thinking on the antigenhost interaction in polyarthropathies. The range of microorganisms that are implicated raises the possibility of a common arthritogenic antigen. The lipid A moiety of lipopolysaccharide (LPS) would fit this role. Indeed, LPS from Neisseria gonorrhoeae can cause arthritis when injected into rabbit knees.2 Given access to periarticular tissues, LPS could initiate a polyclonal B cell response and a T cell response. If synovial cell surface antigens resemble antigenic determinants in LPS, then an immunological misinterpretation could take place, with perturbation of the normal B/T cell interaction, positive feedback, and the eventual formation of anti-antibodies, including rheumatoid factor. The natural invasiveness of gastrointestinal and genitourinary pathogens provides their LPS with access to the systemic circulation. However, except in inflammatory-bowel-related arthropathies, such access does not explain the development of arthritis in ankylosing spondylitis or rheumatoid arthritis. Alternatively, there might be an environmental source of LPS. Natural absorption of small amounts of LPS from the intestine has been demonstrated in rats, with eventual detoxification in the liver.3
SiR,—MethiciMin-resistant Staphylococcus aureus (MRSA) is prevalent in many UK hospitals. A well-characterised strain encountered in episodes of hospital cross-infection is referred to as the epidemic MRSA (EMRSA)2 and guidelines for its control have been published.3 Recent experience in South Yorkshire prompts us to suggest that control measures which rely on detection of colonised patients by swabbing are inadequate. The EMRSA was introduced into a general surgical ward at a district general hospital in June this year, by a patient from London with a wound infection. Our experience is of three patients from that ward who were not known to carry the EMRSA. Case 1.-A 66-year-old man transferred to a teaching hospital for haemodialysis and respiratory support. On arrival at the intensive care unit on Sept 1, 1986, nose, throat, perineum, wound, and sputum were screened for MRSA, as recommended in the guidelines,3(using selective media but not enrichment broth) and found to be negative. The patient was given intravenous cefuroxime and metronidazole from Aug 28 to Sept 5 plus a single dose of gentamicin on Aug 29. Cefuroxime was replaced by ceftazidime from Sept 5. Negative cultures were obtained from bronchial aspirates on Sept 3, 5, and 6 but on Sept 8 a light growth of multiresistant S aureus indistinguishable from EMRSA was obtained. Case 2.-A 47-year-old man with 30 % bums transferred to the burns unit at the same teaching hospital on Sept 22. Swabs taken from burns, nose, throat, and perineum were negative 011 admission. Two doses of oral flucloxacillin were given on Sept 23 and subsequent swabs from burns yielded a heavy growth of the EMRSA. Case 3.-A 69-year-old man transferred to the intensive care unit in the district general for respiratory support. Cultures from nose and wounds were negative on transfer. The patient received
275
metronidazole from Sept 30, 1986, onwards and ampicillin and
gentamicin from Oct 5; on Oct 27 swabs yielded a heavy growth of EMRSA. These three cases show that it is not sufficient to screen patients from endemic areas by swabbing. They may be colonised with very small numbers of organisms which go undetected by conventional laboratory methods. Once selective antibiotic pressures are applied, heavy colonisation may become apparent, bringing a risk of cross-infection to other susceptible patients. Control measures in the district general hospital have so far limited the spread of the organism to three infections, ten colonised patients, and no detectable colonisation of staff. Secondary spread in the teaching hospital was limited to two members of the staff. We now recommend that any patient transferred from the affected ward to high dependency units be nursed in isolation, regardless of the results of screening swabs. We thank the division of hospital infection, Central Public Health Laboratory, Colindale, for typing our strains. Public Health Laboratory, Northern General Hospital, Sheffield S5 7AU
KARL G. KRISTINSSON
Department of Microbiology, Doncaster Royal Infirmary
PATRICIA FENTON
Public Health Laboratory, Northern General Hospital
PAUL NORMAN
1
aureus.
Division of Haematology, Karolinska Hospital, S-104 01 Stockholm, Sweden
PETER REIZENSTEIN
1 Chi
CH, Lagerlof B, Lantz B, Reizenstein P. Autopsy findings in leukaemia. Scand J Haematol 1976, 17: 251-57 2. Reizenstein P, Penchansky M, Lantz B, Holmberg K, Lagerlof B. Prevention of septicemia and early death in acute leukaemia Curr Chemother 1978, 248-50. 3. Reizenstein P Systemic candidiasis in patients with hematologic diseases Scand J Infect Dis 1978; 16 (suppl) 44-45. 4. Lantz B, Reizenstem P. Management of septicemia and early death in acute leukemia. Acta Med Scand 1977; 202: 523-28.
WHICH SPATULA FOR CERVICAL CYTOLOGY?
SIR,-In Dr Husain’s letter (Nov 22,
p 1226) the illustration the "BSCC [British Society for Clinical Cytology] spatula" was in fact the prototype of the Aylesbury spatula that we devised and submitted to Husain and others for their opinion. The Women’s National Cancer Control Campaign and Department of Health and Social Security were not involved in its development. We were shown a drawing of the BSCC spatula which differed considerably-for instance, in the angle of the head of the spatula to the shaft, the inside curve of the head, and the width of the extended tip. We considered our own design more appropriate. An article on our successful trial of the Aylesbury spatula has just been
labelled
as
published.l
Cooke EM, Casewell MW, Emmerson AM, Gaston M, de Saxe M, Mayon-White RT, Galbraith NS. Methicillin-resistant Staphylococcus aureus in the UK and
Ireland a questionnaire survey. J Hosp Infect 1986; 8: 143-48. 2. Sanderson PJ Staying one jump ahead of resistant Staphylococcus
leukaemia and an average age of 57 years the frequency of complete remission seems to be 86%.
Br Med J
1986; 293: 473-74 3. Combined Working Party of the Hospital Infection Society and British Society for Antimicrobial Chemotherapy Guidelines for the control of epidemic methicillin resistant Staphylococcus aureus. J Hosp Infect 1986; 7: 193-201.
SYSTEMIC CANDIDIASIS
SlR—1 agree with your Dec 13 editorial, that many serological procedures to demonstrate Candida albicans antigens or antibodies in granulocytopenic patients may be both time-consuming and expensive. I also agree that negative serology should not usually prevent treatment. Nevertheless, you have underlined the difficulties without emphasising the possibilities of diagnosing systemic candidiasis. Before systematic diagnosis and treatment was available, 15 out of 48 patients with acute myeloid leukaemia who died from septicaemia had widespread candida infiltrations at necropsy, not only in the lungs but also in extrapulmonary organs. Entire microscopic fields were filled with mycelia. Of patients who had this finding in the lungs but not in other organs almost 50% died of candidiasis.!,2 49% of patients with acute myeloid leukaemia died within 3 months of diagnosis. The percentage of premature deaths could be reduced to 9 % and that of candidiasis to 10 % by starting 5-fluorocytosine and amphotericin-B combination treatment when two of the following diagnostic criteria were fulfilled:3,4 Increase in candida antibody ELISA titre, even if within normal limits, over the baseline value at admission. With this technique, that is more sensitive than haemagglutination, there were only 10 %
Cytology Department, Stoke Mandeville Hospital, Aylesbury, Bucks HP21 8AL
MARGARET WOLFENDALE M. USHERWOOD
1. Wolfendale MR, Howe-Guest R, Usherwood MMcD, Draper GJ Controlled trial of a new cervical spatula. Br Med J 1987; 294: 33-35.
*j*This letter has been shown follows.-ED. L.
to
Dr
Husain, whose reply
SiR,—There was an error in the spatulae illustrated in my letter (Nov 22, p 1226). The one shown as the British Society for Clinical Cytology (BSCC) spatula was incorrectly labelled and was in fact the first version that was produced after a collaborative exercise by several parties concerned in the early Aylesbury trials. This design was later modified by Dr Wolfendale to the final Aylesbury spatula. We in the BSCC went through two versions between 1973 and 1978 and I illustrate the final version here as number 5 (figure). Our intent was to have two different ends to accommodate the variety of cervices. I apologise for the error.
false negatives.
Overgrowth of candida in faecal cultures.-False-negative rate about 25%. Retrosternal pain and/or oral thrush.-50% false negatives and 30% false positives when in-vivo findings were compared with post-mortem findings.
Low, continuous fever not responding after more than 4 days of antibiotic combination treatment 11out of 16 patients in whom systematic candidiasis had been diagnosed on these criteria became afebrile after anti-candida treatment. It is important to use these simple, inexpensive, and rapid clinical criteria so that treatment can be started early. The outcome in acute leukaemia lately has been related more to the quality of supportive treatment than to the selection of cytostatic combination, and in a recent group of patients at this hospital with acute myeloid
Spatula shapes. 1 traditional Ayre spatula; 2 final design of Aylesbury spatula; 3 design of Aylesbury spatula; 4 Lemer spatula; and 5 final design of =
=
=
=
first BSCC
=
spatula. Regional Cytology Unit, Division of Pathology, St Stephen’s Hospital, London SW10 9TH
O. A. N. HUSAIN