Imperial Cancer Research Fund,. PO Box 123,. London WC2A 3PX. 1 Lowry WS, Atkinson RJ. Tumour suppressor genes and risk of metastasis in ovarian ...
Ability to detect malodour might be genetic EDITOR,-In their study of subjects suffering from trimethylaminuria R Ayesh and colleagues observed that six of the 11 patients were unaware of their malodour.1 I report a small controlled study of the ability of normal, healthy subjects to detect the odour of trimethylamine. A mother complained that her 6 year old daughter had an unpleasant smell, which was present most of the time but was worse during hot weather and in the mornings. The problem was so severe that she showered the girl and changed her clothing several times a day. There was no history of incontinence of urine or faeces, and she was otherwise asymptomatic. The girl had three siblings, and neither they nor the parents suffered from malodour. Physical examination yielded unremarkable findings, and no unpleasant smell was detected by any of the three doctors who examined her at various intervals, although on at least one of these occasions the mother said that the smell was present. Results of analysis of urine and of screening for urinary organic and amino acids were normal, but raised urinary trimethylamine excretion was detected by mass spectrometry (G Thompson, Royal Children's Hospital, Melbourne, Australia). She was started on a diet low in choline and free of fish, with modest effect. Samples of early morning urine from the patient and her asymptomatic sister were presented in unmarked containers for olfactory testing at a departmental meeting. None of the nine participants complained of rhinitis, coryza, or anosmia. Three of the subjects were unable to detect any odour in either specimen; of the remaining six, all could detect an unpleasant smell in the urine from the affected patient and none in the control urine. Lison et al observed that the ability to detect the unpleasant smell resulting from the excretion of metabolites of asparagus in urine is genetically determined and has a bimodal distribution.2 I speculate that the same may be true of the ability to detect trimethylamine in urine. I therefore advise caution in dismissing a complaint that a person suffers from malodour simply because you cannot detect the smell yourself. P HEATON
Paediatric Department, Taranaki Healthcare, Private Bag 2016, New Plymouth 4620, New Zealand 1 Ayesh R, Mitchell SC, Zhang A, Smith RL. The fish odour syndrome: biochemical, familial, and clinical aspects. BMJ 1993;307:655-7. (11 September.) 2 Lison M, Blondheim SH, Melmed RN. A polymorphism of the ability to smell urinary metabolites of asparagus. BMY 1980; 281:1676-8.
Resuscitation in severe head injury EDr1OR,-Douglas Gentleman and colleagues emphasise the importance of resuscitation in the management of severe head injury.' A paper from the traumatic coma data bank published earlier this year studied 699 cases of severe head injury and showed that initial systemic hypotension was associated with a 150% increase in mortality.2 This suggests that initial systemic hypotension is profoundly detrimental to the outcome of head injury. The study is the largest recent study to examine the influence of initial systemic hypotension and hypoxia on severe head injury. Fluid replacement is an important problem in severe head injury. Gentleman and colleagues suggest rapid replacement with normal saline or Hartmann's solution. Hypertonic 7-5% sodium chloride is more effective than Hartmann's solution in raising systolic blood pressure for
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traumatic hypotension, particularly in the early phase after injury.3 Furthermore, hypertonic solutions may be particularly beneficial with regard to the survival of patients suffering from severe head injury.4 JOHN N WILDEN
Department of Neurosurgery, Royal London Hospital, London El 1BB 1 Gentleman D, Dearden M, Midgley S, Maclean D. Guidelines for resuscitation and transfer of patients with serious head injury. BMJ 1993;307:547-52. (28 August.) 2 Chesnut RM, Marshall LF, Klauber MR, Blunt BA, Baldwin N, Eisenberg HM, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993;34:216-22. 3 Mattox KI_ Maningas PA, Moore EE, Mateer JR, Marx JA, Aprahamian C, et al. Prehospital hypertonic saline/dextran infusion for post-traumatic hypotension. The USA multicenter trial. Ann Surg 1991;213:482-91. 4 Vassar MJ, Perry CA, Gannaway WI, Holcroft JW. 7-5% sodium chloride/dextran for resuscitation of trauma patients undergoing helicopter transport. Arch Surg 1991;126:1065-72.
Tumour suppressor genes m ovarian cancer EDITOR,-W S Lowry and R J Atkinson examined the relation between the histopathological grade of disease and loss of heterozygosity on chromosome 17 in ovarian carcinoma.' As they state, there is a greater frequency of loss of heterozygosity in advanced ovarian carcinomas than in those at an early stage.2-5 Eccles et al suggested that loss of heterozygosity may occur at pTHH59 (D17S4), mapping to chromosome 17q25, at an earlier stage in the carcinogenic process than loss of heterozygosity on 17p.2 Other studies, however, do not support this interpretation. Pooled data show that in 57 of 77 cases with loss anywhere on chromosome 17 the loss can be explained by hemizygosity or homozygosity for all loci on chromosome 17.3-5 By far the most likely chromosomal mechanism by which this occurs in non-disjunction. Lowry and Atkinson agree that anaplastic tumours commonly have loss over the entire chromosome 17, including D17S4. If loss on 17q (rather than 17p) occurs as an early step then loss in anaplastic tumours would have to occur in more than one stage to create loss over the whole chromosome. The simplest explanation would be loss on 1 7q first, followed later by loss of the whole chromosome. Given the linkage of the gene for familial breast-ovarian cancer, BRCA1, to chromosome 17q12-21, the inference is that early loss occurs on 17q and an aberrant or absent gene product of BRCAI results. This is followed later by loss of the whole chromosome that initially showed loss of 17q only. I suspect, however, that this may not be what happens in ovarian carcinoma. Linkage analysis suggests that BRCA1 is situated between two closely spaced markers at 1 7q 1221. Therefore one might expect to see a higher frequency of loss of heterozygosity within this region. Altogether 343 sporadic ovarian carcinomas have been analysed in an attempt to find such events.-" No consistent peak of loss was seen adjacent to the BRCAl locus. Only two of the 343 carcinomas showed definite interstitial deletions that could include BRCAI. Six others may have been interstitial deletions.' In addition, only three of the 343 showed either a mitotic recombination event (resulting in homozygosity) or a deletion that started above BRCA1. This raises the alternative possibility that BRCAI is not a recessive tumour suppressor gene but is dominant and that the loss seen in hereditary and sporadic tumours is accounted for by nearby tumour suppressor genes, distinct from BRCAI. Although it is the wild type gene that shows loss in studies of breast-ovarian cancers in BRCA1 linked families, this does not rule out the possibility that the mutant gene acts in a dominant fashion at the
cellular level. There are precedents for inherited genes that predispose to cancer not acting as tumour suppressor genes, and the loss on 17q in breast and ovarian cancer might be accounted for by other tumour suppressor (or cancer related) genes on chromosome 17. If this is so then finding interstitial deletions may not help to localise the position of BRCAI . Genotype to phenotype correlations will be feasible only when the genes responsible for the disease have been identified. I thank Drs J Trowsdale and D M Black for comments. WILLIAM FOULKES Imperial Cancer Research Fund, PO Box 123, London WC2A 3PX 1 Lowry WS, Atkinson RJ. Tumour suppressor genes and risk of metastasis in ovarian cancer. BMJ 1993;307:542. (28 August.) 2 Eccles D, Russell SEH, Haites NE, Atkinson R, Bell DW, Gruber L, et al. Early loss of heterozygosity on 17q in ovarian cancer. Oncogene 1992;7:2069-72. 3 Phillips N, Ziegler M, Saha B, Xynos F. Allelic loss on chromosome 17 in human ovarian carcinoma. Int J Cancer 1993;54:85-91. 4 Clihby W, Ridand S, Hartmann L, Dodson M, Halling KC, Keeney G, et al. Human epithelial ovarian cancer allelotype. CancerRes 1993;53:2393-8. 5 Foulkes WD, Black DM, Stamp GWH, Solomon E, Trowsdale J. Very frequent loss of heterozygosity throughout chromosome 17 in sporadic ovarian cancer. IntJ Cancer 1993;54: 2205. 6 Jacobs IJ, Smith SA, Wiseman RW, Futreal PA, Harrington T, Osbome RJ, et al. A deletion unit on chromosome 17q in epithelial ovarian tumors distal to the familial breast/ovarian cancer locus. Cancer Res 1993;53:1218-21. 7 Yang-Feng TL, Han H, Chen K-C, U S-B, Claus EB, Carcangui ML, et al. Allelic loss in ovarian cancer. Int J Cancer 1993;54:546-5 1. 8 Saito H, Inazawa J, Saito S, Kasumi F, Koi F, Sagae S, et al. Detailed deletion mapping of chromosome 17q in ovarian and breast cancers: 2-cM region on 17q21-3 often and commonly deleted in tumors. CancerRes 1993;53:3382-5.
Medical treatment at Glastonbury Festival EDITOR,-MOst commentators on our remarks on the funding of the health care of profit making events such as the Glastonbury Festival' have either failed to read our letter fully or have misunderstood the points raised. Although we used the example of the Glastonbury Festival, the purpose of the letter was to draw attention to the expense of the health care required for large events. Many of these events make considerable profits for the organisers. At present there is a limited "pot" of money available to fund health care under the NHS and the current mechanisms which exist to recoup costs from distant purchasers leave a substantial shortfall.' Therefore the costs of additional health care for revellers must be met from funds that would otherwise be used to treat local residents. There has been no debate as to whether local residents are happy to sacrifice their health resources. The health care costs of an event are related to the number and nature of injuries. In this vein it is interesting to note that at the Glastonbury Festival 2-8% of the revellers sought medical aid. This compares badly with other large outdoor crowd events, where a figure of 1% is the norm.2' The pattern of injuries seen in Bath confirmed that most were as a result of attendance at this event, but space prohibited us from furnishing the details in our letter. Such a breakdown is under consideration for publication elsewhere. Events such as going to the cinema and others suggested by Christopher Howes4 are clearly of low risk, and those suggested by Giles Pattison, such as playing in the park,5 do not readily fall under the umbrella of large profit making events. We have proposed a novel idea to raise additional health care funding from large, profit making events that are likely to be associated with substantial morbidity. Although medical insurance is one 1009
solution, there is a need to debate other ways of reaching the same goal. Those who have misunderstood our proposal are detracting from this important issue. SIMON BRITrEN MARK S WHITELEY PETER F FOX MARK I GOODWIN MICHAELHORROCKS
HIV infection and AIDS as thin as possible when specialist services can at one visit provide an experienced doctor, health adviser, nurse, psychologist, specialist pharmacist, etc? We believe that HIV positive patients have shown their preference by continuing to attend large genitourinary medicine clinics in central London for their care. MICHAELADLER ERICAALLASON-JONES PATRICKFRENCH ROB GEORGE DANIELLE MERCEY
University Department of Surgery, Royal United Hospital Trust, Bath BAl 3NG 1 Britten S, Whiteley MS, Fox PF, Goodwin MI, Horrocks M. Annual influx of temporary residents to the Glastonbury Festival. BMJ 1993;307:561. (28 August.) 2 Chambers J, Guly H. The impact of a music festival on local health services. Health Trends 1991;23:122-3. 3 Sanders AB, Criss E, Steckl P, Meislin HW, Raife J, Allen D. An analysis of medical care at mass gatherings. Ann Emerg Med 1986;15:515-9. 4 Howes C. Medical treatment at the Glastonbury Festival. BMJ 1993;307:865. (2 October.) 5 Pattison G. Medical treatment at the Glastonbury Festival. BMJ 1993;307:865. (2 October.)
Funding policies for HIV and AIDS ED1TOR,-As service providers working in an area with a high prevalence of HIV infection we were concerned by Mark McCarthy and Sarah Layzell's comments in their article on funding policies for HIV and AIDS.1 The sexually transmitted disease service in Britain is based on the fundamental principle of open access. This well proved public health approach is the envy of the world and should not be dismantled because of the purchaserprovider split; block funding to provide a service to all comers regardless of residence must continue. Genitourinary physicians do not, and do not wish to, provide primary health care. Liaison and shared care with general practitioners are recognised as important parts of the management of HIV positive patients. As a direct result of our commitment to support local services, 94% of our patients with far advanced disease are managed by general practices with back up from our palliative care team. Over 60% of patients have died at home and 90% died where they had said that they wanted to die. No general practitioner was prepared to manage these complex cases without support. Furthermore, 200 interventions prevented admission to hospital. McCarthy and Layzell confuse the debate about the balance of funding between prevention and treatment by implying that the national situation can be compared with that in Camden and Islington Health Authority. We treat roughly a tenth of the cases of AIDS in England and are therefore funded to provide services to a high proportion of people who are not residents, whereas money for prevention is meant to fund only work with the resident population. Money allocated under "HIV prevention" accounts for only a small part of the money spent on prevention. "HIV funding" for drug services is primarily used to fund needle exchanges. Genitourinary medicine clinics have a key role in preventing HIV infection as attendance at a clinic is highly correlated with high risk sexual behaviour; thus a percentage of their funding could legitimately be billed as expenditure on prevention. McCarthy and Layzell lament that Camden and Islington Health Authority has only just developed an HIV prevention strategy. This is one of the first strategies to be developed nationally and has been cited as a model of good practice by the Department of Health and has achieved national recognition. As McCarthy is a purchaser of health care we would have expected the authors to advocate choice for patients, but they seem to deplore our attempts to provide services that are popular with patients. Why make the distribution of cases of
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James Pringle House, Middlesex Hospital, London WiN 8AA 1 McCarthy M, Layzell S. Funding policies for HIV and AIDS: time for change. BMJ 1993;307:367-9. (7 August.)
Juniors and consultants should follow guidelines EDrToR,-Alastair McColl's suggestion that guidelines may be more useful to junior than senior staff raises the question of who should be the target of clinical guidelines.' Hospital consultants vary widely in their adherence to agreed standards.2 3 At a recent seminar on the development of guidelines, held at a local district general hospital, a consultant said that he would be happy to have guidelines for his NHS practice but not for his private work. The "incredibly powerful lever of contracting" has yet to influence private practice in Britain, unlike in the United States, where the demands of insurance companies have been one of the main forces driving the development of guidelines.45 Clinical guidelines are increasingly being developed from systematic reviews of published data and must be seen as defining acceptable and appropriate standards of care. They are surely appropriate not only for junior hospital staff but also for consultants in their NHS and private work. This aspect of the debate on guidelines has been neglected in Britain. CHRIS GRIFFITHS Hackney Collaborative Clinical Guidelines Project, Department of General Practice, St Bartholomew's Medical College, London ECIM 6BQ 1 McColl A. Implementing clinical guidelines. BMJ 1993;307:6789. (11 September.) 2 Bell D, Layton A, Gabbay J. Use of a guideline based questionnaire to audit hospital care of acute asthma. BMJ
1991;302:1440-3. 3 Dunn RB, Lewis PA. Compliance with standardised assessment scales for elderly people among consultant geriatricians in Wessex. BMY 1993;307:606. 4 Haines A, Feder G. Guidance on guidelines. BMJ 1992;305: 785-6. 5 Farmer A. Medical practice guidelines: lessons from the United States. BMJ 1993;307:313-7.
Drug regimens that break a country's drug laws EDrroR,-Doctors in Britain have unrivalled autonomy in their right to exercise clinical judgment in their treatment of drug addicts. This privilege must, however, be treated with care, otherwise the eventual result will be local and international calls for new controls on all members of the medical profession. A citizen who was a resident of the United States contacted us earlier this year, asking us to take over his care from another doctor in Britain. On making inquiries with this doctor and the patient we learnt that the patient had been travelling between the United States and Britain and had received prescribed supplies of diamorphine (heroin) and cocaine-both drugs prohibited in the United
States regardless of any claimed medical indication. A daily dose of 900 mg heroin had been prescribed. Other doctors (in Britain and the United States) had judged his opiate requirement in the preceding months and years to be about one tenth of this dose, or up to 80 mg methadone daily. Pharmaceutical cocaine had also been prescribed, making this American visitor one of perhaps only about a dozen people in Britain (and hence in the world) to receive prescribed cocaine in the name of treatment of addiction. The individual decisions of different doctors in Britain will inevitably vary. But if this privileged autonomy is not treated with sensitivity by doctors and patients we should not be surprised if there are calls for increased regulation, control, and conformity. Indeed, the existing controls on prescribing heroin and cocaine were introduced largely in response to just such prescribing by a few doctors in the mid-1960s' and to a population of addicts that included several hundred North American narcotic addicts who had been drawn to Britain by the more liberal prescribing policies.2' To institute drug regimens that clash so fundamentally with the drug laws and treatment programmes of the country to which the patient will soon return is to invite calls for international harmonisation from the rest of Europe and, particularly, the United States. Paradoxically, it would result in more calls for prohibition and curbs on the clinical freedom for everyone, to the detriment of the "British system" as a whole. JOHN STRANG MICHAELFARRELL
National Addiction Centre, Maudsley Hospital and Institute of Psychiatry, London SE5 8AF 1 Interdepartnental Committee on Drug Addiction. Second report. London, HMSO, 1965. 2 Spear HB. The growth of heroin addiction in the United Kingdom. JAddicnon 1969;64:245-55. 3 Zacune J. A comparison of Canadian narcotic addicts in Great Britain and Canada. Bulletin on Narcotics 1971;23:41-9. 4 Blackwell, J. The saboteurs of Britain's opiate policy: overprescribing physicians or American-style junties? Int J Addict
1988;23:517-26.
Seeing is believing EDITOR,-In their comments on Minerva's picture of an ingested coin visible in an anteroposterior radiograph of the neck' John Baillie and Malcolm S Branch state that "as small children are unreliable historians, any child under the age of 5 being assessed for foreign body ingestion should have plain radiography from the base of the skull to the anus."2 Most ingested foreign bodies that pass beyond the gastro-oesophageal junction traverse the rest of the gastrointestinal tract uneventfully. Given that this is the case, I believe that a radiograph of only the chest (including the neck) is required to ensure that the foreign body is not impacted above the gastro-oesophageal junction. Radiographs of the abdomen are indicated only if the child develops symptoms suggesting complications, such as intestinal obstruction, or if the foreign body is such that the likelihood of complications is high and its removal is desirable. On average the dose of radiation required for a posteroanterior radiograph of the chest is 0-3 mGy while that of an anteroposterior radiograph of the abdomen is 10mGy. Use of this strategy would therefore limit exposure to x rays in this not insignificant proportion of children. CAROLINE PARK Accident and Emergency Department, Selly Oak Hospital, Birmingham B29 6JD 1 Minerva pictures. BMY 1993;307:273. (24 July.) 2 Baillie J, Branch MS. Seeing is believing. BMY 1993;307:684-5.
(11 September.)
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