candidate for implantation and the complexities of surgery in young children. There is additional uncertainty about the effects of growth on the long-term fate of the implant. Luxford et al8reported the outcome of implantation in a 2-year-old prelingually deaf child. Her behaviour improved after implantation and she was able to produce a few more intelligible words. With respect to implantation in elderly people, Horn et al9 reported a successful outcome in patients over 65 years. The results of their survey suggest that this group did just as well as younger adults. Thus, cochlear implants are now established as a recognised treatment for profound deafness and many more deaf people could benefit from them. In the UK the Government has agreed to fund implantation within the National Health Service; previously such operations had been financed by charitable donations. The existing implantation centres are to be funded and several additional centres are being established around the country. In other European countries and in North America, cochlear implantation has been well established for several years. a

1. Editorial. Cochlear implantation for the profoundly deaf. Lancet 1988; i: 686-87. 2. Gantz BJ, Tyler RS, Knutson JF, et al. Evaluation of 5 different cochlear implant designs: audiologic assessment and predictors of performance. Laryngoscope 1988; 98: 1100-06. 3. Wilson BS, Finley CC, Lawson DT, Wolford RD, Eddington D, Rabinowitz WM. Better speech recognition with cochlear implants. Nature 1991; 352: 236-38. 4. Cohen ML, Hoffman RA, Stronschen M. Medical or surgical complications related to the Nucleus multichannel cochlear implant. Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 8-13. 5. Webb RL, Lenhardt E, Clark GM, et al. Surgical complications with the cochlear multiple-channel intracochlear implant. Ann Otol Rhinol Laryngol 1991; 100: 131-36. 6. Balkany T, Gantz B, Nadol JB. Multichannel cochlear implants in partially ossified cochleas. Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 3-7. 7. McCormick B. Paediatric cochlear implantation in the UK-a delayed journey on a well marked route. Br J Audiol 1991; 25: 145-49. 8. Luxford WM, House WF, Hough JVD, et al. Experiences with the Nucleus multichannel cochlear implant in three young children. Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 14-16. 9. Horn K, McMahon NB, Lewis JS, et al. Functional use of the Nucleus 22-channel cochlear implant in the elderly. Laryngoscope 1991; 101: 284-88.

Informed consent: how informed? Most activities carried out by doctors have a simple benevolent aim, even if the means of achieving it may be tortuous and the outcome sometimes questionable. Medical research shares this aim with one vital difference-the patient who participates in research may not benefit personally and may be inconvenienced or even harmed. If there are rewards to be reaped others may therefore reap them later. What motivates patients to participate in research? For some, participation is a purely philanthropic gesture; other reasons include direct financial inducements, a desire to oblige the doctor, or the hope of obtaining the latest treatment. For researchers the first motive is the ideal, but in the enterprise society






importance. To avoid harming the participants, there have to be constraints-eg, ethical committee review. Another powerful constraint is telling the patient what he is volunteering to undergo. The Nuremberg War Crimes judges laid down ten basic principles, of which the first was that voluntary consent of the subject was essential. This consent requires that the subject should have sufficient knowledge and comprehension of what is proposed for him to make an "understanding and enlightened decision". Knowledge includes understanding the nature, purpose, and methods of the study, and the possible effects on the subject. The Declaration of Helsinki2

re-emphasised these fundamental obligations on medical researchers. Like other self-evident truths, the need for informed consent has not always been universally recognised, even after the Nuremberg judges stated it so plainly. The columns of the Lancet bear witness to "research by fraud"3 and research verging on "common assault",4in which patients participated in pure research disguised as clinical investigation or treatment. Pappworth,s5 in his celebrated polemic, described dental extractions in which cardiac catheterisation was carried out unknown to the patient. It is difficult not to sympathise with his conclusion that there was a fraudulent element in this research. Even more questionable was the attitude of the cardiologist with whom this work was discussed-he felt that it would be sufficient, to secure their consent, to tell patients that a small sample of blood was to be removed. Such happenings are far removed from the guidelines produced for the modem generation of clinical researchers.6,7 There are two reasons for a more

enlightened approach. First, cynical deception

seldom survives exposure even before formal mechanisms to correct abuses have been established. For this reason autocrats, whether medical or political, are well advised to avoid too much media exposure. Secondly and more creditably, medical practice has been increasingly concerned with respect for patients as autonomous beings whose needs include freedom to plan their own lives and happiness.8 Discussion may not be enough for patients to acquire sufficient knowledge to make informed decisions. The Royal College of Physicians recommends an information sheet, time to reflect, and (in most cases) a written consent form.6 The Association of the British Pharmaceutical Industry (ABPI) is less specific but also favours written consent and provision of all "pertinent information".But what is relevant/pertinent? Patients may have difficulty grasping concepts of probability and risk, especially of "minimal risk". Even the simple analogy of travelling as a scheduled passenger on an airline9 is likely to deter many potential recruits. A list of adverse effects may be factually correct but nevertheless present a bleak picture to the uninitiated.


Simel and Feussner10 now confirms what many have suspected-a patient’s decision about participating in a study depends on what he is told about it. These researchers sought to recruit patients attending hospital with various disorders to a sham clinical trial. Half were randomised to a comparison of usual treatments versus drugs that may act twice as fast and half to a trial of drugs that may act half as fast as normal treatment. More patients agreed to participate in the first protocol than in the second (67 vs 42%) and interview indicated that the simple statement about speed of action played a powerful part in preferences. More than one conclusion emerges from this study. The first, drawn by the investigators, is that the provision of quantitative information is likely to facilitate a patient’s decision. The more sceptical reader may be left wondering about the curious incompleteness in information provided for participants in this "study". If the trial drug in the second protocol worked only half as fast why was the trial being carried out at all? The rational patient presumably concluded that there were compensatory advantages not documented in the protocol: alternatively, were there hidden benefits to the investigator rather than to the patient? What feelings were elicited about an institution which is apparently anxious to test an inferior mode of treatment? 58% of patients seem to have drawn their own conclusions about a study as presented to them in clearly deficient outline. Existing guidelines for trials inevitably tend to dwell on potential risks. Perhaps investigators should be more open about sharing with patients the potential benefits and purpose of their studies. The final message from Simel and Feussner’s work is possibly the most depressing-the philanthropic motive seems to have been conspicuous by its absence, most patients being motivated by the desire to obtain something better for themselves. In the face of limited information on which to base a decision the greater good was not a major consideration. The age of altruism may be passing in this as in other areas of medicine. A

study by

1. The

Nuremberg Code, 1947. In: Duncan AS, Dunstan GR, Welbourn RB, eds. Dictionary of medical ethics. London: Darton, Longman and Todd, 1981: 130-32. 2. The Declaration of Helsinki. In: Duncan AS, Dunstan GR, Welbourn RB, eds. Dictionary of medical ethics. London: Darton, Longman and Todd, 1981: 132-35. 3. Ogilvie H. Whither medicine? Lancet 1952; ii: 820-24. 4. Cullinan ER. The physician’s obligation to society. Lancet 1958; i: 944. 5. Pappworth MH. Human guinea pigs: experimentation on man. London: Routledge & Kegan Paul, 1967: 192-93. 6. Royal College of Physicians working party on research involving patients. London:


1990: 15-19.

7. Association of the British Pharmaceutical

Industry. Guidelines of good clinical research practice. London: ABPI, 1988: 8-9. 8. Byrne P. Issues in the ethics of medical research. In: Byrne P, ed. Medicine in contemporary society: Kings College Studies 1986-1987. London: King Edward’s Hospital Fund for London, 1987: 9-39. 9. Royal College of Physicians working party on research on healthy volunteers. London: RCP, 1986: 5. 10. Simel DL, Feussner JR. A randomized controlled trial comparing quantitative informed consent formats. J Clin Epidermiol 1991; 44: 771-77.


ester transfer


Cholesterol is an essential component of the membranes of every human cell. Cholesterol is required for tissue repair, growth, and cell turnover; in specialised cells of the gonads, adrenals, and skin it is the precursor of steroid hormones and vitamin D.’ However, about 4-6 g of cholesterol enters the circulation each day, which greatly exceeds these essential requirements.2Since there is no system for cholesterol catabolism in the peripheral tissues the excess cholesterol arriving at the periphery must be returned to the liver if it is to be eliminated. The process by which this comes about is termed reverse cholesterol transport. Much is now known about the outward flow of cholesterol from the liver, but the sequence of events in reverse cholesterol transport has been a harder nut to crack. A remarkable apolipoprotein, apo B1003 present in very-low-density lipoprotein (VLDL) in which cholesterol is secreted from the liver, persists throughout the conversion of VLDL to low-density lipoprotein (LDL) and finally allows the receptormediated cellular uptake of LDL. Radiolabelling of apo B can therefore be used to follow this sequence. Serum high-density lipoprotein (HDL), the concentration of which is inversely related to coronary heart disease risk, has long been implicated in reverse cholesterol transport,3but the rate of removal of its protein moiety (mainly apolipoprotein AI and All) from the circulation is too slow to explain this form of transport if catabolism of the whole HDL particle by the liver is required.4A clue to the enigma of reverse cholesterol transport has now been found in an old observation: cholesterol is insoluble in water but will dissolve slowly in serum,s where it becomes incorporated into HDL and VLDL.6HDL accepts free cholesterol initially onto its surface. The enzyme lecithin:cholesterol acyl transferase (LCAT) esterifies this cholesterol. The resulting cholesteryl ester (which is even more hydrophobic than free cholesterol) enters the lipid droplet at the core of HDL. There is some evidence that cells have a receptor for HDL that facilitates the egress of cholesterol;7 a small rapidly metabolised subfraction of HDL may be the initial acceptor.8 This subfraction contains apo AI and phospholipid and has prebeta rather than the usual alpha electrophoretic mobility-hence the name prebeta HDL.9 Prebeta HDL may be released peripherally when triglyceride-rich lipoproteins undergo lipolysis.9 HDL can probably deliver some of its cholesterol directly to the liver without the whole lipoprotein particle being catabolised.10 In many species, including man, there is an alternative route for the disposal of cholesteryl ester in HDL10 via transfer to VLDL, a process dependent upon a hydrophobic 74 kDa glycoprotein called cholesteryl ester transfer protein. 1,11,12 This protein shuttles triglycerides in the opposite direction out of

Informed consent: how informed?

665 candidate for implantation and the complexities of surgery in young children. There is additional uncertainty about the effects of growth on the...
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