JAMA  4 Mar 2009  Vol 301

937   These are dog days for clopidogrel. It is a wonderfully effective platelet inhibitor provided it can be metabolised into its active form by cytochrome P (CYP) isoenzymes. Last month we learned that a third of the population don’t have the right isoenzymes, and this week we learn from this retrospective study in US veterans that proton pump inhibitors probably switch them off. So if (a) you have the wrong genes or (b) you are taking a PPI, you lose the benefit of clopidogrel and fare markedly worse than those who can metabolise the clopidogrel given to them following acute coronary events and procedures (Fig on p.941). Waiting in the wings is prasugrel, an active drug needing no help from CYP mechanisms, and the subject of a study in last week’s Lancet which I am eminently informed was just a subgroup of an earlier NEJM study. Also in the intervening week I have learnt to spell prasugrel with both its rs. The way things are going, clopidogrel will be a forgotten drug in five years’ time and every doctor will know how to spell prasugrel.  http://jama.ama-assn.org/cgi/content/abstract/301/9/937

945   One thing I’ve learnt over the past two years is that it is remarkably easy to give yourself an injection of trivalent inactivated influenza vaccine; it takes very little courage and you do not have to go begging the practice nurse. It would be even easier to sneak into her fridge and give yourself a snort of intranasal live attenuated influenza vaccine, but this hasn’t caught on yet in the UK, and its chances will not be helped by this study of outcomes following the two kinds of flu vaccine in US military personnel. Over three influenza seasons, American soldiery given the jab showed a significantly lower rate of health encounters for influenza and pneumonia compared to non-vaccinated individuals; those given the snort showed a weak effect in one season only. The standard jab is not to be sneezed at.  http://jama.ama-assn.org/cgi/content/abstract/301/9/945

NEJM  5 Mar 2009  Vol 360

961   Few questions better deserve the adjective “vexed” than the question of percutaneous coronary intervention versus coronary artery bypass grafting for severe coronary artery disease. Even twenty five miles away from the nearest cardiac surgery unit, I can often hear the distant sound of shell fire when the wind is from the south. In the SYNTAX study, former uneasy neighbours Germany (invading), the Netherlands (invaded) and Sweden (neutral) randomised enough patients (1800) between them to reach the conclusion that for patients with three vessel or left main coronary artery disease, CABG produces better results at one year. Don’t expect this to end the debate as warring rivals with big egos all over the world bicker over subgroups and combined end-points. Meanwhile SYNTAX goes near the top of my duff acronym list: “Synergy between PCI with Taxus and Cardiac Surgery” (a) doesn’t yield the right initials, (b) doesn’t describe what the trial is about and (c) is disgracefully bad syntax. See me after assembly.  http://content.nejm.org/cgi/content/abstract/360/10/961

973   This is the season of Lent, when British GPs bewail their manifold sins and wickedness and find that there is no health in them or their practices. In other words, it is the time when we scramble desperately to achieve our last few QOF points before the end of March. My own practice is struggling a bit to fulfil its quota of asthma reviews. Patients who have ordered occasional single salbutamol inhalers are called in for peak flow measurements, together with others who have struggled through the year on four inhaled agents, montelukast and frequent courses of prednisolone. The latter group are the ones who end up in tertiary asthma centres and may even have measurements of sputum eosinophilia. If you were such an asthmatic in Leicester UK you might have been one of 29 patients randomised to receive and interleukin-5 monoclonal antibody which rejoices in the name of mepolizumab. If so, you were in luck: this agent reduced exacerbations along with a reduction in sputum and blood eosinophil counts.  http://content.nejm.org/cgi/content/abstract/360/10/973

985   So is mepoliz really the bizz? I saw a press headline claiming that it might help 160,000 asthmatics in the UK, but where that figure comes from, God knows. I have treated hundreds of asthmatics but I haven’t seen an eosinophil since I was a medical student. We are only just beginning to discover the significance of eosinophilia and its reduction in the management of refractory asthma and the trials are much too small to permit any extrapolation: this Canadian study recruited all of twenty patients with prednisone-dependent eosinophilic asthma, and gave mepolizumab to nine of them. Their eosinophils fell and they needed less steroid, but it’s hardly the evidence base you need to treat millions of severe asthmatics across the world. But perhaps in ten years, the asthma QOF will specify that every surgery must have a microscope, a collection of sputum pots, and a bottle of eosin/haematoxylin stain. Wouldn’t that be nostalgic?  http://content.nejm.org/cgi/content/abstract/360/10/985

1002    So just what is asthma and how do we treat it rationally? I had hoped that these questions might have been answered by the time I stood on the threshold of winding down as a clinician, but I can’t say that this review really gives the answers. When I started as a GP, we had short-acting bronchodilators, corticosteroids and theophylline; thirty years on, we can add long-acting beta-adrenergic inhalers and leukotreine inhibitors. It remains to be seen whether monoclonal antibodies to IgE and /or interleukins will finally provide a real breakthrough for the majority of patients.  http://content.nejm.org/cgi/content/extract/360/10/1002

Lancet  7 Mar 2009  Vol 373

811   All over the world, oncologists are carrying out the detailed, unglamorous trials which might give you a better chance of survival if and when you get cancer. This UK/Canadian trial is a typical and in its way a quite noble example. Getting together 1350 patients in 80 centres with operable adenocarcinoma of the rectum is no mean achievement: they were then randomised to receive preoperative radiotherapy or selective postoperative chemoradiotherapy. After a median follow-up of four years, the investigators are able to tell surgeons two things: first that patients should receive preoperative radiotherapy because this trial confirms that it is beneficial, in line with previous studies; and second, that the plane of surgery achieved (next paper, p.821) is an important predictor of local recurrence, and should be routinely assessed.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60484-0/abstract 
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60485-2/abstract

829   You may have greater patience than I have with the concepts of the “metabolic syndrome” and “salt-sensitive hypertension”, in which case you will be interested in this Chinese study which establishes a link between the two. If on the other hand you are interested in hard end-points and how to treat patients, you may want to move on.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60144-6/abstract

850   I get quite a lot of heartburn these days, and for all I know I may have Barrett’s oesophagus. I don’t intend to find out any time soon, and in fact my having heartburn isn’t particularly predictive anyway: in population studies, 1.7% of the population have the abnormalities that Barrett identified (a raised level of the squamocolumnar junction, with the presence of goblet cells) and 40% of these have no symptoms. The only way we will ever find out if follow-up of Barrett’s can reduce oesophageal carcinoma is by endoscoping everybody, and at the end of this review I was wishing Barrett had never invented his oesophagus.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60487-6/abstract

BMJ Journals  March 2009

BMJ  577  “Resting heart rate … independently predicts myocardial infarction or coronary death, but not stroke, in women.” That’s the conclusion of the Women’s Health Initiative prospective study of nearly 130,000 American women. “Predicts” is a funny word. A tight bunch of isobars moving north-eastwards across the Atlantic predicts bad weather in the west of Scotland, and it happens, every time. On the other hand, a resting pulse rate of 72 is just one more little factor to stick into a risk equation for women who are quite unlikely to get myocardial infarcts.  http://www.bmj.com/cgi/content/abstract/338/feb03_2/b219

ADC  210   The epidemiology of critically ill children is explored in this survey of paediatric intensive care units in England and Wales. Most of us are spared the sight of critically ill children most of the time, but some of us still do out-of-hours shifts where most of the workload consists of triaging children in various stages of illness. In my very limited experience, children from areas of deprivation and from the south Asian population are high users of such services, and the same goes for ICU occupancy. This is a worrying indicator that there must be something dysfunctional about the pattern of help-seeking behaviour in these groups, or else in the primary care they often receive.  http://adc.bmj.com/cgi/content/abstract/94/3/210

ADC  220  Steve Mithen’s book After the Ice is a fascinating account of how human societies developed over the last 15,000 years, in which the hero of the narrative (Lubbock) travels across time and place to observe the first rearing of cattle in the West and Africa, and the first cultivation of rice in the flood plains of China and India. Here in twenty-first century England, we see lots of babies with cow’s milk intolerance causing various degrees of food protein-induced enterocolitis syndrome (FPIES). We often advise parents to give their tots more rice, which we regard as intrinsically hypoallergenic. Not so, says this Australian paper, based on a series of 14 children who presented with severe FPIES caused by rice in the same time period as 17 presented with cow’s milk induced FPIES. Both these foods are relative newcomers to the human diet, and rice tends to cause more severe illness than cow’s milk in affected babies. Be on the lookout: it’s easily missed, according to this paper.  http://adc.bmj.com/cgi/content/abstract/94/3/220

Heart  448   It’s not looking too good for those of us who prefer writing about exercise to actually making the time and effort to do some. This study looks at 20,177 Britons without cardiovascular disease who took part in two major health surveys and were followed up for mortality over a mean of 6.6 years. Those who took regular vigorous exercise for 150 minutes or more each week were half as likely to die over that period. The ones who took cardiovascular drugs were the least likely to take exercise. This paper inspires an editorial on p. 441 with the apt title “Exercise: the neglected risk factor and the neglected treatment.”  http://heart.bmj.com/cgi/content/abstract/95/6/448

Ann Intern Med  3 Mar 2009  Vol 293

441    A couple of evenings ago, I had a call from an anticoagulation nurse about an elderly patient she was trying to contact about her out-of-control INR. She wanted her to have oral vitamin K and was going to send a taxi 20 miles to deliver it. But this Canadian study of vitamin K versus placebo shows that such well-intentioned effort is futile. Non-bleeding patients taking warfarin with INRs between 4.5 and 10 do equally well with or without oral vitamin K. No need for the taxis or the Mounties or the helicopters: the little ol’ lady in the log cabin can just wait and recover.  http://www.annals.org/cgi/content/abstract/150/5/293

JAMA  11 Mar 2009  Vol 301

1025   Smallpox virus only lives on in two heavily guarded laboratories, one in the USA and the other in Russia, but fear of smallpox lives on while ever there are individuals or organisations who hate the human race sufficiently to contemplate destroying it. The Japanese, having been exposed to the first use of nuclear weapons, are taking no chances. They dug out some old smallpox vaccine and retested its immunogenicity. It works: we could all be protected, should the need ever arise. Which is more than you can say of nuclear weapons.  http://jama.ama-assn.org/cgi/content/abstract/301/10/1025

1034   The trouble with viruses is that they are so spooky: some of them (not smallpox, which is big and ungainly) can mutate with amazing rapidity, as illustrated by two studies of oseltamivir-resistant influenza A (H1N1), one from the United States and one from the Netherlands. We all think we understand how the introduction of anti-microbial drugs can exert selective pressures on a microbial population, but something really startling has happened here: all H1N1 flu viruses in the USA became resistant to osteltamivir simultaneously within a couple of years (see chart on p.1067). On a world scale, change often happened fastest in countries with the lowest rates of osteltamivir prescribing. What this drug has done is select a strain of the virus which is simply fitter than the existing strains, whether or not they encounter osteltamivir. Wham, bang, Killer Mutant Virus Plague takes over the world, in little more than the duration of a B movie. These viruses are just as virulent as normal influenza A viruses, and there were deaths in both these studies. The editorial (p.1066) is upbeat about our capacity to outwit the influenza virus with drugs designed to attack other bits of its codon, but if I were a pharma research director I might decide to invest in attacking a less adaptable enemy.  http://jama.ama-assn.org/cgi/content/abstract/301/10/1034
http://jama.ama-assn.org/cgi/content/abstract/301/10/1042

1047   Now what’s the connection between virulent viruses and an article on palliative care for Latino patients? Oddly enough, it is a close one, although you have to go back 500 years to trace it. Spanish sailors arriving in South America brought with them measles and smallpox and new strains of influenza: it was these, rather than horses or armour of Toledo steel that enabled a few dozen conquistadores to overcome millions of native South Americans, with consequences that shape the life of a whole continent to this day. Impoverished Spanish-speaking Central Americans flood into the USA and exist on the margins of society, officially non-existent and non-entitled to even the basics of medical care, while ardently clinging to their traditional religious and spiritual beliefs. The consequences for their experience of terminal illness are described here.  http://jama.ama-assn.org/cgi/content/abstract/301/10/1047

NEJM  12 Mar 2009  Vol 360

1085   We live in a state of controlled burning, fuelled by diatomic oxygen: but if you want to burn fast, go for triatomic oxygen, or ozone. This is the unstable gas that gives the air a characteristic smell after lightning (so they say) and is also formed in conditions of urban air pollution. We know that thunderstorms cause a surge in asthma admissions (though we don’t know for sure that this is caused by ozone), but what about the effect of low level ozone exposure from traffic fume filled environments? Can we really distinguish the ozone effect from the effect of fine carbon particles? This study is confident it can, and concludes that while O₃ levels are not associated with an increase cardiovascular death, they are associated with death from respiratory causes. http://content.nejm.org/cgi/content/abstract/360/11/1085

1102   For the last fifteen years, I and most of the local community have been fighting to save our little local hospital, and this has finally resulted in a Bid for Innovation which invites ideas from everybody everywhere to create a new local health economy. Management-speakers are going to descend on us with their rafts and put markers in the sand, there will be blue skies thinking outside the box, brains will storm, and everything will have legs: it will be like a scene from Hieronymus Bosch. But one thing that’s clear is that traditional boundaries between primary and secondary care are going to have to change. In the USA, this is already happening with the proliferation of hospitalists looking after in-patients in American hospitals. But oddly enough, this is a change in the opposite direction to the one we envisage in the UK. Hospitalists there are not seen as a rebirth of medical generalism but as an unwelcome departure from the tradition of primary care doctors looking after their own patients in hospital. In other words, the radical split between primary and secondary care, familiar to us for decades in the NHS, is only just happening in the USA. Here in the UK, it is time we made it unhappen.  http://content.nejm.org/cgi/content/abstract/360/11/1102

1113   For most doctors, the eye isn’t really part of the body: it’s a sort of globular intruder, doing its own thing and looked after by people less like us than watch repairers, armed with funny microscopes and lasers and tiny instruments. Primary open angle glaucoma is not a diagnosis I ever make, because I don’t measure visual fields or IOPs: I get a letter from someone who has measured them and I hand it over to an ophthalmologist. Then I prescribe the drops. When the drops change, I change them on the computer. Why all this can’t be done by someone else, I never question.  http://content.nejm.org/cgi/content/extract/360/11/1113

Lancet  14 Mar 2009  Vol 373

897    Stent time again! Pop out for a coffee, remember an urgent call. These latest stents are biodegradable and elute everolimus. Careful follow-up of 29 patients over 2 years shows that they really work, with coronary arteries not only patent but actually throbbing healthily once the stent has dissolved away. Lots of pretty pictures.   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60325-1/abstract

911    Our small bore central heating system was ineffective for years because we live in an area with lots of lime scale. The options were to flush out the pipes with chemicals, clean them out physically, or replace them. The options for non-acute coronary disease are just the same; but which one works best? This study is described as a “quantitative 20-year synopsis and network meta-analysis” – an enormous Medline search plotted out as an accumulation of randomised evidence about various kinds of percutaneous intervention versus medical management (pipe replacement doesn’t feature here). And hey presto, there is nothing to choose between them, as COURAGE taught us two years ago. And I don’t know what the plumber did to our pipes, but that worked too. Perhaps he keeps biodegradable stents in his van.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60319-6/abstract

919   For the last two weeks we’ve discussed the merits of clopidogrel and prasugrel, but is there room in the market for yet another orally available antiplatelet agent? Schering-Plough would like us to believe so, and The Lancet, championing a new relationship between pharma and the medical community, is happy to advertise it by giving prime-time billing to this safety and tolerability study in the context of non-acute stent insertion. I really can’t see why: the drug (SCH 530348) doesn’t even have a name, and won’t be ready for clinical use for many years, once it has proved its place alongside or instead of clopidogrel and aspirin. It is a selective antagonist of platelet protease-activated receptor-1, and so works by a different mechanism from existing agents.   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60230-0/abstract

929   “To salvage the acutely ischaemic myocardium without addressing the underlying causes of the disease is futile”, declares The Lancet’s cover page, quoting from this analysis of three EURASPIRE surveys. Not so much futile as life-saving, I’d have thought. These surveys are of people whose disease has already required treatment, and show a lot of middle-aged to elderly people with CHD giving up smoking, taking statins, gaining weight and becoming diabetic, as European people tend to do as they approach 70, the cut-off age for these surveys. Doom, gloom, failure! Well, not ideal, perhaps, but I can remember a time when most Europeans did not live to 70.   hhtp://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60330-5/abstract

941   David Sackett once said that when you get know one area of medicine thoroughly, it’s time to move on to another before you become an “authority” and start obstructing ideas that don’t coincide with your own. Heart failure is a specialist area full of authority figures with tunnel vision, as you can see from this week’s BMJ letters and Rapid Responses – from a cardiologist who rarely sees heart failure without systolic dysfunction, a geriatrician who sees little else, and so forth. Here’s a seminar summing up the present state of knowledge about a few of the subtypes of circulatory impairment which cardiologists are currently willing to engage with. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60236-1/abstract

956   One subtype that’s really easy to understand is aortic stenosis. Even here, though, the valvular problem is almost invariably linked to stiffening of the arterial tree and secondary effects on the heart muscle – the “double-loaded left ventricle”. Although we work to fixed definitions of disease severity based on the valvular flow measurements, the tipping point to symptomatic impairment and sometimes rapid progression to death is variable, as this review points out. It’s the same with all kinds of circulatory impairment: you can measure one thing, but lots of other things interfere, and they refuse to keep still, which is why it’s called the circulation.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60211-7/abstract

BMJ  14 Mar 2009  Vol 338

639    Don’t smoke, drink up to 14units of alcohol a week, eat fresh fruit and vegetables and take lots of exercise: not only will you find the Meaning of Life according to Monty Python, but you’ll also avoid strokes according to the EPIC of Norfolk. This study followed up 20,000 men and women of Norfolk for 11 years, and although their scoring system and methodology here leave a little to be desired, the general message is clear: after controlling for BP, cholesterol, BMI, age, sex, diabetes and aspirin use, you can still reduce your risk of stroke by a factor of two if you smoke, and a bit less if you don’t.   http://www.bmj.com/cgi/content/abstract/338/feb19_2/b349

645   Thyroid eye disease is linked with thyroid autoimmunity, and can present either with the classic Graves’ disease combination of thyrotoxicosis, diffuse goitre and exophthalmos, or almost as often can be associated with hypothyroidism. We don’t see it often and it’s easily missed, especially if there isn’t obvious exophthalmos, and such cases are the ones where optic atrophy can be a presenting feature, because by failing to pop out, the eyeball gets the full impact of the swollen surrounding tissues. An odd condition and usually the prelude to a string of oculoplastic procedures which have worked pretty well for the two patients I know with the condition.  http://www.bmj.com/cgi/content/extract/338/mar06_1/b560

Arch Intern Med  9 Mar 2009  Vol 169

430   Palliative care in England often seems like a continuation of Anglicanism by other means. 95% of hospice doctors disapprove of assisted dying, but nearly all of them sign up to the notion of “double effect”: this means that you’re allowed to give patients treatments which may hasten death, provided you have a plausible excuse to present to God, a kindly English headmaster who rarely resorts to corporal punishment. But Dutch Calvinism doesn’t hold with excuses, since God has decided what to do with you beforehand anyway, and in most cases it’s corporal punishment for eternity. For terminal sedation, Dutch doctors have produced grown-up guidelines and talk openly about such things with their patients, who may even go further and opt deliberately for an easeful death. And because these guidelines are humane and rational, they actually keep to them, according to this monitoring study.   http://archinte.ama-assn.org/cgi/content/abstract/169/5/430

447   It seems to me that the alleviation of insomnia, like the alleviation of pain, or nausea, or depression, or whatever else people suffer from, is not a matter of moral judgement but something we should be glad to be able to do for them. This French study shows that people who have insomnia lasting a year mostly keep getting it. I don’t pretend that benzodiazepines are the ideal answer for sleeplessness, but intermittent prescribing of them, or indeed intermittent usage, are not signs of moral weakness.  http://archinte.ama-assn.org/cgi/content/abstract/169/5/447

463    We all learn the signs of infective endocarditis in our first year as clinical students, and then proceed to miss it at first presentation many years later, having seen no cases in between. This big prospective international cohort study provides a very useful survey of the presentation, aetiology and outcome of “SBE” in the twenty-first century. The commonest pathogen in developed countries is Staphylococcus aureus, so forget the “subacute” – these patients get ill quickly. The classic signs are rarely seen in their full textbook glory. Half of all patients end up with valve replacement surgery.  http://archinte.ama-assn.org/cgi/content/abstract/169/5/463

489   Another place where physician assisted death is an option for terminally ill patients is Oregon, and here, as in the Netherlands, numbers are few and the process is carefully monitored. This survey sent invitations to 178 individuals who had expressed an interest in PAD and had a 28% response rate: not brilliant, but then these people had other things on their minds, and the study still provides valuable insights into why people explore this option. Most are simply afraid of loss of control, and physical symptoms were rated of little importance in themselves. A third of the 47 respondents were already having hospice care. In the end, 18 were given prescriptions and nine died by using them.  http://archinte.ama-assn.org/cgi/content/abstract/169/5/489

Plant of the Week: Clematis cirrhosa var. balearica

This South European evergreen clematis has been around in England for 210 years, and it’s a good round-the-year cover plant, with very dark cut leaves in the best varieties, including some that repeat flower in the summer after the main crop in March. Its freckled bells are a real delight, even though they have no scent. But it does need a lot of space and it can take a long time to come into flower. The variety “Wisley Cream” has larger flowers, but no freckles, so I would suggest you have no truck with it.

JAMA  18 Mar 2009  Vol 301

1131   Here at last is a write-up of the CAPTIVATE trial, which should be compulsory reading for all who are easily captivated by soft surrogate end-points. Pactimibe was a drug that might have made a fortune for Sankyo by reducing vascular cholesterol accumulation through inhibition of acyl coenzyme A:cholesterol acyltransferase (ACAT). The chosen primary end-point was maximum carotid intima-media thickness (CIMT) which is measurable by ultrasound. During the fifteen months of this international trial on individuals with familial hypercholesterolaemia, the maximum CIMT did not increase, but ten times as many people in the active treatment group had major cardiovascular events (including death) as in the placebo group, and the trial was stopped in October 2005. O beware, beware of the instant gratification promised by soft surrogates, especially by that fat madam, cholesterol.  http://jama.ama-assn.org/cgi/content/abstract/301/11/1131

1155   For most GPs, looking after dying patients is an intermittent form of occupational stress. Think back over the previous year: you will be able to recount to yourself instantly all the people you knew and cared for over the years and whose deaths you attended. You may have rung them from home and called in at weekends: the reward for which, in the terminology of this article, is compassion satisfaction. But the price you can pay for doing too much of this is burn-out or compassion fatigue. These difficult issues are discussed in this paper on “self-care of physicians caring for patients at the end of life”, a title revealing a distinct lack of team spirit. Because the people who bear the greatest burden in my experience are the community palliative care nurses, who at their best are simply heroic. (N.B. If palliative care is a particular interest, you may also like to look at p.1140 – “Religious coping and use of intensive life-prolonging care near death in patients with advanced cancer”, which seems to show that people who have religious belief want more life-prolonging treatment.)http://jama.ama-assn.org/cgi/content/abstract/301/11/1140
http://jama.ama-assn.org/cgi/content/abstract/301/11/1155

NEJM  19 Mar 2009  Vol 360

1250    Cytomegalovirus used to come to every human child through its mother’s milk, so that we were once all in a state of equilibrium with this persistent DNA virus from infancy. But thanks to artificial feeding this symbiosis is no longer universal, and 27,000 pregnant American women get new CMV infection every year. In a third of these, the fetus will get infected, causing death in 0.5% and permanent disability in about 20%. If I’ve done my sums right, that might equate to 450 seriously affected British babies annually. So a fully protective CMV vaccine would be a very good thing, but this trial of a new contender was only 50% successful. The editorial on p.1250 is a fascinating read, but don’t expect a breakthrough any time soon.  http://content.nejm.org/cgi/content/abstract/360/12/1191

1217   In 1799, twenty-year-old Humphry Davy from Cornwall was working as an assistant to the Bristol physician Thomas Beddoes at his new Pneumatic Institute, where he planned to cure all diseases by the use of newly discovered gases. Davy decided to try out three quarts of “pure hydrocarbonate”, or carbon monoxide. At the third quart he collapsed. “I seemed sinking into annihilation, and had just power enough to drop the mouthpiece from my unclosed lips.” As he sank back he (typically) still remembered to take his pulse, which was “threadlike and beating with excessive quickness”. He was given oxygen by his terrified assistant, and lay for the rest of the day suffering from “nausea, loss of memory, and deficient sensation”, with initial chest pain and later an agonising pain between the eyes. He concluded that had he continued the experiment he would have “destroyed life immediately without producing any painful sensations.”  If you read this review of CO poisoning written 210 years later, you will not learn a great deal more. Some people suffer lasting cognitive damage following CO, but Davy kept enough little grey cells to become the greatest chemist of his age and president of the Royal Society. As for chronic CO poisoning from defective heating appliances, nobody knows how much about it: it’s probably a lot commoner than we think. 
(The Humphry Davy story is taken from The Age of Wonder by Richard Holmes, 2008. For an account of how 900,000 people were murdered using carbon monoxide, see Vassily Grossman’s incomparable 1944 account of Treblinka in A Writer at War).  http://content.nejm.org/cgi/content/extract/360/12/1217

Lancet  21 Mar 2009  Vol 373 

1016   Two or three times a year we get called out to see some poor old lady with agonising back pain, which is usually easily diagnosed as vertebral compression fracture well before the patient is able to get to the X ray department. We foretell at least a month of misery and strong opioids, which are often the prelude to constipation, falls, reduced mobility and depression. Vertebral collapse is actually a preventable emergency in most cases, but once it has occurred, a rapid pain-relieving procedure is highly desirable. Balloon vertebroplasty is an effective intervention, according to this study, funded by Medtronic Spine LLC, and given the acronym FREE. If only that adjective were true, it would be adopted instantly by the NHS: instead, expect long debates about funding priorities and service organisation while old ladies struggle on, bent over in pain.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60010-6/abstract

1033   Monoclonal antibodies for cancer immunotherapy: a nice short review of an important subject. For once, the illustrations are there to help comprehension rather than display the authors’ unrivalled knowledge and understanding of a hundred different known and proposed cellular mechanisms, and the same can be said of the text. You don’t have to spend all that much time with FcγRIII knockout mice before you are actually getting near to human cancer treatment, and even more interestingly, cancer prevention. It all sounds rather promising.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60251-8/abstract

BMJ  21 Mar 2009  Vol 338

696    In England, patients who come to me with osteoarthritis of the knee get told to lose weight (where necessary) and keep active and to avoid orthopaedic surgeons and their useless arthroscopic procedures but to come back when they need a knee replacement. According to this study, “In France, patients with OA of the knee usually visit their rheumatologists every 6 to 12 months.” This trial randomised one group to “usual care” (tisanes? suppositoires?) and the other to three structured consultations extolling weight loss and exercise. In the short term, these patients did more exercise and lost more weight. Cue Gallic shrug.  http://www.bmj.com/cgi/content/abstract/338/feb23_1/b421

705   I recently went to a lecture about thyroid nodules which convinced me that (a) ultrasound is a useless investigation and (b) most patients are better off if you don’t detect these wretched things, because even if they show malignant features on fine needle biopsy, it’s usually impossible to tell if they will ever do anything significant. This week’s BMJ  contains not only this Clinical Review but also another piece (p.713) on Rational Imaging of the Incidental Thyroid Nodule. The case study there consists of possibly the only man in medical history to have both a thyroid “follicular cancer” and a resectable bronchial carcinoma detected at the same time. I am not sure what we are supposed to learn from him. These articles have not changed my view that the only rational imaging for thyroid nodules is no imaging. Don’t go out of your way to find them, and if you do, refer them to a rational thyroid surgeon.  http://www.bmj.com/cgi/content/extract/338/mar13_1/b733 
http://www.bmj.com/cgi/content/extract/338/mar04_3/b611

Ann Intern Med  17 Mar 2009  Vol 150

365   Learn from the bitter experience of an old man, and do not dabble lightly with B-type natriuretic peptide. Oh, how many of the best years of my life I’ve spent, etc – and I still can’t tell you how to use this seemingly God-sent biomarker for cardiac ventricular strain. When the Americans belatedly discovered this peptide, they launched into several studies (like the appallingly titled “Breathing Not Properly” – BNP – geddit?) which seemed to show that it was a good discriminator between respiratory and cardiac breathlessness in the emergency department. Here a team from Australia decided to investigate whether point of care testing for BNP in their emergency department actually made any difference to patient outcomes and the cost of care. It didn’t. BNP remains a tantalisingly good prognostic marker in search of a validated clinical application.  http://www.annals.org/cgi/content/abstract/150/6/365

379   How much aspirin is enough? The answer used to be 600mg for a headache, but few people take aspirin for headaches any more; and 75mg for cardiovascular protection, which has been British Standard Practice for decades. Foreigners have used all sorts of silly doses, such as 162 mg (for heaven’s sake), but Britons always take 75mg, and they are right, according to the CHARISMA Investigators. Any more than that, and you get no benefit and may do harm, especially in combination with clopidogrel.  http://www.annals.org/cgi/content/abstract/150/6/379

Plant of the Week: Camellia “Betty Sheffield”
My wife’s mother was called Betty and she was born in Sheffield, so we have a special fondness for this plant, as we were more than specially fond of her. There is also a form called “Betty Sheffield Supreme”, a name which does better justice to her memory, but it is hard to find and not really worth the effort. It has a mixture of two shades of pink in its flowers, whereas Betty plain has just a satisfying rich pink in lovely double blooms of great profusion.

In this case the plant is worthy of the person, though her personal loveliness was not confined to any season or soil. Camellias are of course of brief beauty and can only be grown on acid soils: their flowers brown off all too quickly and then they are just structural features with beautiful shiny evergreen leaves.

1242   The problem of pain was the subject of CS Lewis’s first attempt at popular theological argument, prompting a fellow don at Magdalen College, Oxford in 1940 to remark that “the problem of pain is quite bad enough without Lewis writing about it.” It is indeed easier to write about pain than to endure it all the time, as I’m told that Lewis acknowledges - I would look it up myself, but I fear for the safety of nearby ornaments. Every pain is different, but there are some generic aspects to chronic pain management which we tend to skimp on in primary care, and that is the issue which this US trial attempted to address. The intervention was administered by a psychologist and an “internist”, and usually involved a face-to-face assessment with specific treatment recommendations plus a 4-session workshop encouraging self-management and activity. The gains, though significant, were sadly modest at the end of 12 months for these patients with chronic musculoskeletal pain.  http://jama.ama-assn.org/cgi/content/abstract/301/12/1242

NEJM  26 Mar 2009  Vol 360

1310    Oddly enough, the human foreskin carries a theological pedigree almost a long as the problem of pain, though I am not sure whether CS Lewis ever wrote on the subject. God is found commanding its removal to Abram and his household as early as Genesis Ch 17, whereupon Abram becomes Abraham; Paul, apostle of Jesus to the Gentiles, later prudently decided that God no longer demanded it, whereas Muhammad, who was made of sterner stuff, got out the knife once more for all his followers. The rather curious result is that the foreskin is regarded a sacrosanct in certain European countries, including Britain, but is routinely done away with as soon as possible in large parts of the Middle East and also – for less obvious reasons – the United States of America. Africa falls between, and of course circumcision has been in the news a lot as a possible means of containing the spread of HIV. This study examines its effect on two other sexually transmitted infections – herpes simplex virus 2 and syphilis. Such is the popularity of the procedure in Uganda that randomisation was between immediate and delayed circumcision, rather than no circumcision at all. The immediately circumcised duly showed fewer of both infections. Expect changes in African health policy that will produce bagsful of foreskins to rival those brought back from Philistia by David, who later became the legendary King of Israel (see 1 Sam 18.25).  http://content.nejm.org/cgi/content/abstract/360/13/1298

1310    More uncomfortable reading for male readers of the New England Journal: 38,343 annual digital rectal examinations and PSA tests in the intervention group, thousands of transrectal prostate biopsies, hundreds of radical prostatectomies and lots of radiation above the genitals. And after 7 years, the result of all this prostate screening? 50 deaths from prostate cancer in the screened group and 44 in the control group. This was – and still is, since it is only half-complete – the US trial called PLCO, where the PSA cut-off for biopsy was 4.0. Treatment data are not given, and the study goes on: it has not been stopped for futility. But it’s not looking good.  http://content.nejm.org/cgi/content/abstract/360/13/1310

1320    The study called ERSPC by contrast is really a series of linked trials in European countries with differing recruitment and randomisation procedures and a PSA cut-off of 3.0 in every country except Finland. At 14 years from randomisation, there was no difference in prostate cancer mortality, but at fifteen years the control group suddenly fares a lot worse (see Fig 2); and if you take the mean of about 9 years, you get a 20% difference in favour of screening. This benefit was limited to those under 70, and to prevent one death from prostate cancer you would have offer screening to 1410 men and submit 48 to surgery and/or radiotherapy. Digital rectal examination and PSA are just not good enough for the detection of the prostate cancers that matter. The trials go on, but I think the strategy is dead.  http://content.nejm.org/cgi/content/abstract/360/13/1320

1329   There aren’t many effective interventions for chronic obstructive pulmonary disease, but one that seems to produce real improvements in quality of life in trial settings is pulmonary rehabilitation. This article is a straightforward description of how it’s done in the USA. “The successful coordinator has excellent interpersonal skills, since (at least initially) a primary task is to motivate people to do what they find unpleasant.”  Most people with COPD show an initial benefit, but this declines after a few months. Keeping people doing things they find unpleasant is never easy.  http://content.nejm.org/cgi/content/extract/360/13/1329

Lancet  28 Mar 2009  Vol 373

1083    Body mass index is one of many measurements in medicine that enjoys a popularity beyond its modest deserts, but at least we have data from lots of prospective studies which are pooled here to give an estimate of cause-specific mortality in 900,000 adults. At a BMI below 22.5, smokers die much faster and thus give all thin people a spuriously bad prognosis. If you read the Summary you will get the opposite impression due to misuse of the word “inversely”. Cardiovascular mortality tends to rise steadily with all levels of BMI, but a little middle age spread does no harm to overall prognosis provided you stay below 30. Once BMI goes over 40, you are looking at a drop of life expectancy of 8-10 years, similar to life-long smoking.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60318-4/abstract

1105   This nationwide study looked at the rate of epilepsy in every little Dane who bashed his or her head in childhood and was taken to hospital. The risk varies with severity of injury, as you’d expect: kids with skull fractures, or with impaired consciousness for less than 30 minutes, have a twofold risk of later epilepsy, while severe brain injury with unconsciousness of over 30 minutes results in a sevenfold risk.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60214-2/abstract

1119    If you have renal cell carcinoma, your only real chance of long-term survival is that somebody will chance to spot it before you have any symptoms. Even this is no guarantee: more small renal masses are being removed each year because of incidental detection on scanning, but still mortality has increased. So this seminar on the subject concentrates on two ends of the scale: the optimal management of small renal masses and the management of metastatic renal cell cancer. Here there is modest progress, much hyped in the press; bevacizumab does prolong life usefully in a significant proportion of patients.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60229-4/abstract

BMJ  28 Mar 2009  Vol 338

758    When I became a GP, obstetrics was still a routine part of our job, though I quickly abandoned the role of accoucheur without the slightest regret. The last time I tried to stop premature labour was before that at the Middlesex hospital, where on the instruction of my senior registrar I exhausted that hospital’s entire stock of injectable ethyl alcohol. The lady in question enjoyed her intravenous treat and duly stopped contracting. This most ancient of tocolytics does not get a mention in this review of adverse reactions to drugs given to stop labour, but the beta-adrenergic drugs we used more commonly do get a bad mention here, whereas something called atosiban gets the all clear, and nifedipine lies somewhere between.  http://www.bmj.com/cgi/content/full/338/mar05_2/b744

761    Depression scoring systems were devised and validated in research settings and then imposed on British GPs via the QOF system for every patient newly presenting with depression. Two studies of their use are presented side-by-side here; the first one finds – surprise, surprise – that doctors try to administer these things but do not base their treatment decisions on them; and the second finds that on the whole, patients don’t mind filling them in. Such is the mighty evidence base for giving doctors financial incentives to use depression questionnaires.  http://www.bmj.com/cgi/content/abstract/338/mar19_1/b750
http://www.bmj.com/cgi/content/abstract/338/mar19_1/b663

763    This article on chronic constipation in adults shows what it calls the correct position for defecation, illustrated by a pensive naked man sitting on a white lavatory with his feet supported by a footstool. A courteous American correspondent of mine, Jonathan Isbit, would half approve. Jonathan says he was inspired by my first piece in the BMJ, a Personal View called “In Praise of Hunch Backing” to back his hunch that many bowel diseases and almost all constipation are the result of modern man adopting the sitting position to defecate. Jonathan would have our knees much higher while defecating than a mere footstool can ensure. Squatting over a hole in the ground, we would prevent appendicitis by pushing our right knees into our iliac fossae and prevent colon cancer, diverticulitis and constipation by getting our rectus muscles into bowel-squeezing action. However, careful placement of the feet is necessary, so as not to give the word “footstool” a whole new meaning.  http://www.bmj.com/cgi/content/extract/338/mar20_1/b831

Arch Intern Med   23 Mar 2009  Vol 169

551    There have been dozens of trials of vitamin D supplementation for the prevention of non-vertebral fractures and if you pool them all you get equivocal results. However, if you carry out a meta-analysis by oral dosage, there’s a clear difference between trials using a low dose of vitamin D and trials using more than 400u daily. People over 65 reduce their fracture risk by at least 20% if they take a decent amount of vitamin D.  http://archinte.ama-assn.org/cgi/content/abstract/169/6/551

562    Eating large quantities of red meat is a bad thing for global resources and also a bad thing for people, according to this simple but enormous study of self-reported food intake in 500,000 Americans aged between 50 and 71. There was a 30% difference in mortality between the groups reporting the highest and the lowest red meat intake, when adjusted for a wide but possibly insufficient range of confounders. The extra deaths are from cardiovascular disease and cancer. But you can eat white meat – meaning chicken, I think – not just with impunity but with benefit.  http://archinte.ama-assn.org/cgi/content/abstract/169/6/562

572   If you are interested in hypertriglyceridaemia, then here’s some detailed epidemiology for you to revel in from 5610 people aged over 20 studied in NHaNES 1999-2004. As usual, it’s a confusing picture, especially as there was no standardisation of sampling conditions, and only rather vague associations emerge, chief of which is physical inactivity.  http://archinte.ama-assn.org/cgi/content/abstract/169/6/572

610    If you have a close relative who has had venous thromboembolism, your own chances of getting one are at least doubled, according to yet another important study of the subject from Leiden. In fact it’s usually more useful clinically to factor in a family history than to take blood for a so-called thrombophilia screen.   http://archinte.ama-assn.org/cgi/content/abstract/169/6/610

616    Having been unwisely drawn into a public argument about diabetes, I have only one hope of getting everybody to agree with me, and that is to keep saying nice things about metformin. It’s the only treatment which can actually be shown to improve outcomes in type 2 diabetes without any shadow of doubt, and every patient with this condition should be persuaded to take it unless the gastrointestinal side-effects are completely intolerable. The key to its action is probably to reduce insulin resistance, and the trial here attempts to gauge its value in type 2 diabetics who require insulin. This important fact fails to get a mention in the title of this paper, which also claims to report “long-term” effects, though the mean follow-up was 4.3 years. Over this relatively short period, patients randomised to metformin lost weight, had better glycaemic control, needed less insulin, and had fewer macrovascular adverse events. But unfortunately, as in so many diabetic trials, the investigators chose to lump all sorts of dubious” microvascular” outcomes into their primary end-point and thereby failed to reach statistical significance by dilution.  http://archinte.ama-assn.org/cgi/content/abstract/169/6/616

Plant of the Week: Daphne odora

Daphne, you will remember, was the nymph who eluded the amorous attentions of Apollo by turning into a tree. This was a popular subject for artists and sculptors like Bernini (see The Mirror of the Gods  Malcolm Bull, 2005) and even for the first composer of a German opera, though sadly we have lost the music which Heinrich Schϋtz wrote in 1627 to be sung by his tree.

Many plants were once given the name of Daphne, but for some reason Linnaeus settled the title on a genus of low shrubs, little resembling the nymphs of Thessaly except perhaps in their gorgeous perfume. Of all the daphnes, this small evergreen plant is perhaps the most ravishingly scented, though there are many competitors among her sisters and cousins. In fact it is possible, with reasonable care, to enjoy the scent of different daphnes throughout the year. Let us begin like the Iranians at Now Ruz, the spring equinox:

March-April: Daphne odora, D blagayana
April-May: D tangutica, D collina
May-June: D x burkwoodii, D cneorum
June-July: D x hybrida, D sericea
July-Oct: D x transatlantica, D x napolitana
Oct-Nov: D susannae
Nov-March: D bholua, D jezoensis, D mezereum

The trouble is that one or other of these will invariably die on you just when you most look forward to it. D odora is relatively robust, though tradition has it that the clone with yellow-edged leaves, Aureomarginata, is the only one reliably hardy in English gardens. I have just bought a handsome Japanese clone called Sakiwaka with good plain leaves and I’ll let you know how it gets on next winter.