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Journal Watch Archive - April 2009

JAMA  1 April 2009  Vol 301

1349    This pragmatic trial from Seattle looked at whether it was more cost-effective to provide housing and support for homeless people with severe alcohol problems or keep them on a waiting list and let them turn up to hospitals, prisons, shelters and emergency services in the usual way. Remarkably, by providing housing for these despised individuals, they halved the costs they incurred: this study proves that it is actually cheaper to provide homes for “hopeless drunks” than to leave them to fend for themselves.  http://jama.ama-assn.org/cgi/content/abstract/301/13/1349

1358    Here is a Clinical Review of Cimex lectularius, the humble blood-sucking bed bug which is seldom a vector for disease and doesn’t even cause itchy bite marks on 70% of its victims. It is nevertheless a curse to hoteliers and hard to get rid of. There is apparently a Mexican proverb which advises that “the best way to put an end to bed bugs is to set fire to the bed”. In fact there are stories and proverbs and curses associated with bed bugs from the dawn of literature, and from all parts of the world. The little beasts feature in the earliest bedroom jokes, together with copulation and farting, just as in the latest ones, as you’ll find if you compare The Clouds by Aristophanes with the many American bedbug websites. The earliest recorded name for them is sar-an which is Old Sumerian for “numerous in straw” – a rueful reference to the likelihood that five thousand years ago, your Sumerian bed would be riddled with bugs. The same applied to Arabic beds, as shown by the proverb, “a bed bug has a hundred children, and says ‘how few.’”  A Spanish proverb comforts the afflicted by saying that “you can’t have more bed bugs than a blanketful.” There is a charming story about a rich man, his beautiful wife, a bed bug and a visiting flea in the fables of Kalila and Dimna, widely circulating in India and Iran about 2,000 years ago. The innocent, hospitable bed bug gets killed for a bite inflicted by the flea. There are legendary Hopi sex stories about bed bugs. But the most remarkable bed bug story is to be found in the apocryphal Acts of John, proving that among the sober, chaste and pious early Christians there must have been some entertaining fibbers with a lively sense of humour. The apostle is trying to get a bit of kip on a straw mattress but the bed bugs are stopping him, so he orders them to leave the room in the name of God. Next morning the bed bugs are found huddling together outside the door. John allows them back inside and to bed because they have been obedient to the divine will, and says to his followers, “Be ye like the bed-bugs.” http://jama.ama-assn.org/cgi/content/abstract/301/13/1358

NEJM  2 Apr 2009  Vol 360

1385    Most of the half-million annual deaths from cervical cancer occur in countries which will never be able to afford whole-population screening using regular cervical cytology, which is partially effective but enormously expensive. This landmark study from rural India used a single test for human papillomavirus and showed a near-halving of cervical cancer deaths compared with cytological testing or visual inspection of the cervix with acetic acid. Most HPV infection is acquired soon after women become sexually active and disappears harmlessly in a few years, so the positives that are significant are those in older women: between 30 and 59 years old in this cluster randomised trial. Read the editorial on p.1453 to appreciate what a real breakthrough this study represents for screening policy throughout the world. http://content.nejm.org/cgi/content/abstract/360/14/1385

1395   Statins are great drugs provided you take them in time, but taking them when you have organ failure may be too late. People with established heart failure get no discernible benefit and this trial (named after the Roman goddess of dawn, AURORA) shows the same for people with advanced renal failure requiring haemodialysis. Those randomised to rosuvastatinshowed the expected drop in LDL-cholesterol but no improvement in outcome. The goddess did not smile on this trial, and we cannot sing

AURORA lucis rutilat
caelum laudibus intonat
mundus exultans iubilat
gemens infernus ululat,
cum ille rex fortissimus
mortis confractis viribus
pede conculcans tartara
solvit catena miseros!

Not until Easter, anyway.

http://content.nejm.org/cgi/content/abstract/360/14/1395

1429  The reasons why some boys and fewer girls wet their beds are somewhat obscure, but it’s probably worth following the advice of this clinical review of (nocturnal) enuresis and doing a clinical examination, urine dipstick and ultrasound to rule out constipation, infection or a structural or neurogenic cause. The treatments are the same as they’ve been for decades: an alarm device, a tricyclic antidepressant, or (with due care) desmopressin. http://content.nejm.org/cgi/content/extract/360/14/1429

Lancet  4 Apr 2009  Vol 373

1175    Just because something is associated with something else in fairly linear fashion, likeLDL cholesterol and cardiovascular events, doesn’t mean that you can necessarily drive the process the other way. But with statins this does seem to happen, and the benefit seems proportionate to the LDL-C lowering, as in this analysis of the JUPITER trial in initially healthy subjects given a fixed dose (20mg) of rosuvastatin. The degree to which these people responded in terms of LDL-C lowering roughly matched the degree to which they had fewer CV events. But an even better fit was the degree to which C-reactive protein was reduced. So JUPITER provides more evidence that the anti-inflammatory effects of statins may be even more important than their lipid-lowering effects. Juppiter Optimus Maximus. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60447-5/abstract

1190   For nearly eleven years I’ve kept my eye on trials of different interventions forcoronary artery disease, but if and when my turn comes to have one, I’m by no means sure which way I’d jump. If I just had angina which was well controlled with medical treatment, I shouldn’t be in any hurry for an invasive intervention at all, because COURAGE tells me that I’m unlikely to benefit. This collaborative analysis of individual patient data tells me that even if I had three-vessel coronary disease, and decided to let someone interfere, I’d do just as well with percutaneous intervention as with coronary artery bypass grafting. But these are all quite old trials, and techniques have moved on – CABG no longer uses mainly venous grafts, and PCI with balloons and bare metal stents has given way to drug-eluting stenting, though for no good reason I can discover. In a thoughtful editorial, David Taggart (p.1150) discusses these technical advances and the difficulty of giving patients an informed choice in such matters.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60552-3/abstract

1198    Novel opioid antagonists for opioid-induced bowel dysfunction have been around for some time already, but they haven’t yet surfaced in British palliative and primary care. In the case of methylnaltrexone this may soon change, because there have been convincing trials of oral administration to people with advanced illnesses, albeit involving small numbers. However, cost may be a barrier with this drug and with alvimopan, which is still being trialled mainly for post-operative ileus.   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60139-2/abstract

BMJ  4 Apr 2009  Vol 338

808     Here is a Scandinavian study which claims to show that appendicitis or mesenteric adenitis protect against subsequent ulcerative colitis, but that appendicectomy itself does not. The problem for me is that I don’t know which category I fall in. I had my appendix removed, very incompetently, when I was 9, and was later told that it was normal. But I certainly had agonising right iliac fossa pain the day before. Perhaps I had “mesenteric adenitis” but I’ll never know. If I did, then I’m protected against UC, but otherwise I’m not. Unless Scandinavian record keeping is uncommonly good, I think there may be room for a bit of doubt in the figures, though perhaps not enough to alter the conclusion of this study. I tried to work it out but was deterred by opaque Scandinavian technical prose, which becomes slightly interesting in the “possible mechanisms” section. http://www.bmj.com/cgi/content/abstract/338/mar09_2/b716

812    It is worth case finding for type 2 diabetes if you believe that early treatment makes a difference. I am not sure about the evidence base for this, and certainly I don’t consider that UKPDS alone suffices. Here is the validation of a risk score – the QDScore – which is based on ethnic origin, social class, immediate family history, treatment for blood pressure, known cardiovascular disease and steroid use. It predicts about half of incident type 2 DM over a ten year period. But if we were serious about this, we’d be doing 5-yearly fasting blood sugars for everyone over 50, or 40 if SE Asian or obese, and offering big exercise and diet interventions while there were still enough beta-cells to rescue. http://www.bmj.com/cgi/content/full/338/mar17_2/b880

823    Around the time I got appendicitis, I went to a visiting fair and paid sixpence to look at a bearded lady in a freak show. That was a lot of money to see a fat woman with too much androgen, and her plight still fills me with horror, fifty years later. Hirsutism is a blight to the body image of many women, but there is now a range of options to treat it: this short review provides good clear advice on how to use oral contraceptives, metformin, spironolactone and finasteride in various clinical scenarios. In all but severe or rapidly progressive cases investigation is unnecessary.  http://www.bmj.com/cgi/content/extract/338/mar27_1/b847

Plant of the Week: Cimicifuga simplex “Brunette”

Having mentioned bed bugs at such length, I feel compelled to offer Siberian bug bane as the plant for this week, though it is grown for autumn rather than for spring effect. Just now it may be pushing its first tufts of ferny leaf through the soil, unnoticed amidst the beauty of primroses, fritillaries, hepaticas and daffodils. When these fresh delights have faded, it continues to grow until its divided leaves reach up to about a metre. It doesn’t usually flower until October, when it is very welcome, especially in this bronze-leaved version with pink flushed bottle-brushes of flower. Take its dried leaves with you whenever you visit the cheaper hotels of Siberia, or indeed New York.

JAMA  8 Apr 2009  Vol 301

1439    Whenever you look at a trial with heart failure in the title, bear in mind that the average age of patients with breathlessness attributable to impaired circulation in the UK is 76, most of them have co-morbidity, and about half of them have a systolic ejection fraction over 45%. I have read most of the HF trials carried out up to 2006, and many beyond, and I can’t think of a single one which has recruited a population like this. However, if you have some younger male patients with an ejection fraction under 35, then you might like to look at this randomised control of exercise, because 72% of the recruited patients were male and their mean age was 59. Thirty-six sessions of exercise failed to make any significant difference to survival or hospitalisation. The crumbs of comfort which the investigators gather are (a) you can do some retrospective subgroup tweaking and create a 13% benefit to fitter patients (but this is what is known as cheating), (b) patients with this type of HF did not die during exercise, and (c) using the Kansas City Cardiomyopathy Questionnaire you can extract a small but statistically significant improvement in score, for all this effort. See p.1451 if you want to decide if this is clinically relevant.  http://jama.ama-assn.org/cgi/content/abstract/301/14/1439
http://jama.ama-assn.org/cgi/content/abstract/301/14/1451

1460    “As we get older we do not get any younger” begins a wonderful parody which sums up the message of TS Eliot’s Four Quartets. Like everyone between the ages of fifty and sixty, Eliot was struck by the feeling that increasing age does not bring any increase in wisdom or tranquillity. This is the message of the brown-baked compound familiar ghost in section II of Little Gidding, ending

From wrong to wrong the exasperated spirit
Proceeds, unless restored by that refining fire
Where you must move in measure, like a dancer.

I suppose ghosts are allowed to jumble their metaphors a bit. It is true that old age brings no relief from exasperation, or generalised anxiety: but cognitive behavioural therapy can be used with good effect, as this randomised trial in 67-year olds shows. But in this instance the comparator was usual care, rather than dancing in that refining fire.  http://jama.ama-assn.org/cgi/content/abstract/301/14/1460

NEJM  9 Apr 2009  Vol 360

1487    There is a two-way relationship between asthma and acid reflux: if acid trickles up your oesophagus at night, you are more likely to cough and wheeze, and if you cough and wheeze you push your gastro-oesophageal sphincter up through your diaphragm and get more reflux. So how about trying a proton pump inhibitor for your poorly controlled asthmatics? Don’t bother, is the message of this double-blind randomised trial which used an expensive new PPI, esomeprazole, even though it wasn’t sponsored by the drug’s manufacturers. Not only does this study bin the idea of treating asthma with PPIs, but it also goes a long way to disproving the notion that asymptomatic reflux has an important role in refractory asthma.  http://content.nejm.org/cgi/content/abstract/360/15/1487

1500    Large sections of this week’s New England Journal are covered in brown fat, as if it had been left near the oven and someone had rested the Easter roast on it. The fat in question, however, has not bubbled from some delicious piece of meat but from the hidden recesses of healthy adults. You probably have some yourself, although in your pre-clinical course you were taught that it only occurs in newborn babies and small rodents. But if you look hard enough, especially in the supraclavicular area, you will probably find some scattered deposits of cold-activated brown adipose tissue, just as if you were an infant or a vole. And their function is probably the same – to convert energy into heat and so preserve core temperature through thermogenesis. The thinner you are, the more likely you are to have brown fat, and the colder you are, the more likely it is to show metabolic activity. This is illustrated in three papers which display some stunning feats of scientific technique, based on PET-CT scanning after the injection of 18F-flourodeoxyglucose. In this first study, we are shown the distribution of brown fat in 24 healthy young men of varying adiposity.  http://content.nejm.org/cgi/content/abstract/360/15/1500

1509    The next study looks at the presence of brown fat in nearly two thousand patients who had had PET-CT isotope scans performed for diagnostic purposes in a single US centre. It seems that three times as many women as men have substantial reserves of brown fat, but that the amount falls with age in both sexes. Oddly enough, if you take a beta-blocker you are ten times less likely to show brown fat activity.  http://content.nejm.org/cgi/content/abstract/360/15/1509

1518   The third study goes studies the metabolic function of human brown fat in greater detail thanks to the altruism of five healthy volunteers from Finland and Sweden. They submitted themselves to the afore-mentioned PET-CT scans and radioactive isotopes, exposed one foot to immersion in icy water, and also allowed a plastic surgeon to delve into their supraclavicular regions in search of the elusive brown adipocytes. As a result we know a lot more about the cellular function of human brown fat cells and the fact that their metabolism increases fifteen-fold during exposure to cold. But now that we have found this “hidden organ” which turns fat into heat, can we switch it on to treat obesity by a process of autocombustion? Alas, the prospects seem poor, for reasons discussed in the useful editorial on p.1553.  http://content.nejm.org/cgi/content/abstract/360/15/1518

1526    Myocarditis may perhaps be commoner than we think, since much of it occurs following viral illnesses and remits spontaneously after an initial phase of dilated cardiomyopathy. Without doing echocardiograms on everyone who feels tired and easily exhausted after flu, we’ll never know and it probably doesn’t matter. But in other circumstances, inflammation of the cells we depend on to keep us alive can be a very serious business indeed, and this review is an excellent single-author guide to the clinical scenarios by which it presents and their consequences – table 1 is required reading for anyone mugging up for medical membership.  http://content.nejm.org/cgi/content/extract/360/15/1526

Lancet  11 Apr 2009  Vol 338

1253    Taking an oral bisphosphonate is a ritual lasting at least half an hour, during which you must drink lots of water and stay upright. Intravenous zoledronic acid on the other hand can achieve the same effect in 15 minutes once a year. This multicentre trial (HORIZON) in patients taking long-term oral glucocorticoids doesn’t really tell us much that we didn’t already know: it shows that in these patients IV zoledronic acid is superior to daily risedronate on all counts except immediate side-effects, both for treatment and prevention of osteoporosis. The end-points were bone density by dual energy X-ray absorptiometry at 6 and 12 months, and four measurements of two biomarkers for bone turnover: β-C-terminal telopeptides of type 1collagen (βCTx) and procollagen type1aminoterminal propeptide (P1NP). It’s time we gave up oral bisphosphonates and got our practice nurses trained up to give IV zoledronic acid to all our patients needing osteoporosis prevention and treatment.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60250-6/abstract

1264    The noble tradition of the healthy volunteer is alive and well in medicine, and we should salute such individuals whenever we hear of them. In my overlong piece on bed bugs last week, I failed to mention RL Usinger who fed himself to a colony of them every week for seven years to study his reactions to their bites. I make amends here. I also hail the heroes of this study on the effect of avotermin on the healing of scars. These volunteers were literally scarred for life by this experiment, but those who had avotermin injected before full-thickness skin wounds were inflicted on them showed better healing, as judged blindly by a panel of doctors and lay people. It seems that we need more trials of this transforming growth factor in real surgical situations such as cosmetically prominent procedures, or in individuals with a tendency to form keloid.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60322-6/abstract

1275    The avotermin study was a nice simple proof-of-concept job, but this next proof-of-concept study is anything but straightforward. It seems to prove the concept that catheter ablation of the renal sympathetic nerves can cure resistant hypertension. The results are certainly impressive: reductions of a mean 27/17 mm Hg at one year of follow-up in patients who had previously stayed above 177/101 despite treatment with three or more drugs. But there are some very pertinent questions raised about the entry criteria in the accompanying editorial (p.1228), and it is likely to be some time before we send off our uncontrolled hypertensives to the renal catheter lab.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60566-3/abstract

1301    Everybody should take regular salicylates: that’s not as controversial a statement as it sounds, because salicylates are abundant in most fresh vegetables and fruits. The real question addressed by this systematic review is whether everybody should take artificial salicylate (aspirin) to prevent cancer. Pretty well all the evidence – observational and interventional – suggests that aspirin confers some protection against colonic cancer, but probably only after ten years of continuous dosing. Similar regular intake may also protect against cancers of the oesophagus, stomach and breast: an effect shared by other NSAIDs and rapidly lost on discontinuation.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60243-9/abstract

BMJ  11 Apr 2009  Vol 338

867    Those of you who follow guidelines probably prescribe nicotine replacement therapy as first line treatment when people ask for help to stop smoking. Very well: you will double cessation rates compared with nothing, but for long term abstinence the number-needed-to-treat is 29. This systematic review does not discuss other treatments or whether patients benefit from long-term maintenance therapy, since these questions are not addressed by the trials they examine. But the fact is that there are more effective alternatives, especially combined treatment, and since nicotine addiction is harder to break and much more harmful than opioid addiction, long-term substitution therapy is quite logical. For more useful studies, see Ann Intern Med.  http://www.bmj.com/cgi/content/abstract/338/apr02_3/b1024

876    I spent my student elective in 1974 staying with a family in Iran, which ever since then I have regarded as the most hospitable and civilised country in the world. I refer to individuals rather than governments, of course; and I write, admittedly, as a male who has visited only a few countries in the world. If you go anywhere near a native person in Iran, you will be approached courteously and offered a glass of scalding hot tea, with a lump of sugar to hold between your teeth as you drink it. The harmful effect on the incisor teeth of some Iranians is easy to observe, but the effect on the Iranian oesophagus has only just come to be realised. This case-control study examines tea-drinking habits in relation to the extraordinary incidence of oesophageal cancer in northern Iran. The hotter the tea and the faster you gulp it, the more likely you are to get cancer of the oesophagus.  http://www.bmj.com/cgi/content/abstract/338/mar26_2/b929

881    Here is a good practical account of the cauda equina syndrome, beautifully illustrated with a horse’s tail of nerves on the front cover of this week’s BMJ. Fortunately, it is rare, and any given GP may never see a case in her/his life; by the same token, it is unfortunately easy to miss. The moral here is that anyone with increasing urinary difficulty or retention should be tested for loss of perianal sensation, whether or not there are any back or leg symptoms. This article is unusual (and commendable) for its inclusion of medicolegal data, which show that although orthopaedic surgeons may be more likely to get sued, GPs also need to watch out.  http://www.bmj.com/cgi/content/extract/338/mar31_1/b936

885    Investigating hypertension in a young person is certainly a challenge to Rational Testing, but I continue to find this series disappointing. Hypertension presents to GPs, and we have to do the testing: we are accustomed to being told how to be rational by clinical biochemists and academics, but also accustomed to ignoring them. The fact is that primary aldosteronism is a difficult diagnosis to establish, which is why we miss most of it, and this piece skates over the difficulties in order to reach the unusually neat outcome in their chosen patient, who became normotensive following removal of a solitary right adrenal tumour. In real life, this is a minefield of inadequate sampling conditions, incidentalomas, and variable responses to targeted treatment. To pretend it is simple is a bit of a Conn.  http://www.bmj.com/cgi/content/extract/338/apr06_1/b1043

Ann Intern Med  7 Apr 2009  Vol 150

437   One of the questions raised in this week’s BMJ systematic review of nicotine replacement is whether psychological support really does have an effect beyond the effect of the nicotine. This Kansas study attempted to address a slightly wider question, using a range of options, including nicotine replacement or bupropion, with or without psychological support, or the latter alone, at one of two levels of intensity. All smokers were targeted, whether or not they were “ready to quit”, and the study ran for two years, so that people could have more than one go at quitting. The outcome was self-reported cessation, which was about the same in all groups, and pretty impressive at 23-27%. Nonetheless the investigators conclude that more psychological support can produce better results.  http://www.annals.org/cgi/content/abstract/150/7/437

447    For the great majority of smokers, the greatest health benefit we can offer them is help to give up smoking. This is especially true of medically ill smokers, and this trial randomised 127 of them to receive either a nicotine patch alone for 10 weeks or as many patches, inhalators or prescriptions for bupropion as they liked for as long as they liked. This was a small, rather crude unblinded trial with 25% of participants lost to follow-up, but the combination group did almost twice as well.  http://www.annals.org/cgi/content/abstract/150/7/447

474   Confused about the association of low-density lipoprotein subfractions with cardiovascular outcomes? Don’t worry: this systematic review shows that everybody is. And will probably stay that way, harmlessly.  http://www.annals.org/cgi/content/abstract/150/7/474

Parody of the Week: Chard Whitlow by Henry Reed (1941)

If you know the Four Quartets by TS Eliot, you will never be able to read them in quite the same way again once you’ve heard or read this parody, written at the time of the London Blitz when Eliot was a fire warden - hence the references to hiding under the stairs or in the Tube, and to stirrup-pumps.

As we get older we do not get any younger.
Seasons return, and today I am fifty-five,
And this time last year I was fifty-four,
And this time next year I shall be sixty-two.
And I cannot say I should like (to speak for myself)
To see my time over again— if you can call it time:
Fidgeting uneasily under a draughty stair,
Or counting sleepless nights in the crowded Tube.

There are certain precautions— though none of them very reliable—
Against the blast from bombs and the flying splinter,
But not against the blast from heaven, vento dei venti,
The wind within a wind unable to speak for wind;
And the frigid burnings of purgatory will not be touched
By any emollient.
                                     I think you will find this put,
Better than I could ever hope to express it,
In the words of Kharma: "It is, we believe,
Idle to hope that the simple stirrup-pump
Will extinguish hell."
                                            Oh, listeners,
And you especially who have turned off the wireless,
And sit in Stoke or Basingstoke listening appreciatively to the silence,
(Which is also the silence of hell) pray not for your selves but your souls.
And pray for me also under the draughty stair.
As we get older we do not get any younger.

And pray for Kharma under the holy mountain.

You can hear Dylan Thomas reading it by following this link:
http://www.poets.org/poet.php/prmPID/150

JAMA  22/29 Apr 2009  Vol 301

1671    “Continuity of care is a defining attribute of primary care… (it) is generally recognised to have 3 dimensions – continuity in information, continuity in management, and continuity in the patient-physician relationship.” This is the opening of an interesting study of primary care as it exists in the USA, a very different beast from primary care in the UK. British primary care doctors now seem almost ashamed to mention the idea of continuity, ever since we leapt gratefully at the chance of restricting our working hours to 52.5 out of the 168 we had formerly covered. But just because we work more bearable hours we shouldn’t forget the centrality of the principle, and look to extend it to include the kind of continuity this study is about – primary care doctors looking after their patients in hospital. This was once the norm in America, as it was in pre-NHS Britain, but it has been declining steadily there over the last 10 years. Of course it is going to need a change of attitude from both secondary and primary care to reintroduce it to Britain and to preserve it in the USA – but how else is generalism to survive? We need to work much more closely with our hospital physician colleagues rather than lose sight of our patients when they are at their illest. I look forward to a time – preferably before I am on the geriatric unit – when medical ward rounds routinely include a general practitioner. We can’t work all hours, or be everywhere at once, but continuous responsibility for patients requires that we encourage shared working and better communication.  http://jama.ama-assn.org/cgi/content/abstract/301/16/1671

NEJM  23 Apr 2009  Vol 360

1705   I had two diabetic patients aged between 45 and 55 who were going into severe heart failure and seemed likely to die in the next year or two – in fact one was told she would, in accordance with survival data for diabetics in the major heart failure trials. It took several months of nagging to get these people tested for reversible ischaemia and then treated with coronary bypass surgery. “Hibernating myocardium” is not cardiological bullshit but can be the key to survival in patients like these, both of whom are living normal lives several years post-CABG. Never accept a diagnosis of “diabetic cardiomyopathy” but insist on perfusion scanning or angiography. But don’t let the cardiac surgeon tinker with the ventricular architecture itself, unless there is an aneurismal wall or something like that. This trial showed that ventricular reconstruction in patients with HF who undergo CABG does not improve outcomes over CABG alone.  http://content.nejm.org/cgi/content/abstract/360/17/1705

1718    Life begins when two gametes share their genetic material and create the code that makes you. It can end at a stroke when a cerebral artery occludes. Are some people born to die this way? Yes, according to this genomewide study which finds a stroke risk locus on chromosome 12p13. If you want to know more about genomewide studies – and you should, because they are here to stay – then read the excellently clear review on p.1759.  http://content.nejm.org/cgi/content/abstract/360/17/1718http://content.nejm.org/cgi/content/extract/360/17/1759

1749    Another nicely written review describes minimally invasive knee arthroplasty for osteoarthritis. So-called “minimal” invasion of the knee is shown on figure 3: you have to look hard to see any difference from the traditional incision. It’s reassuring to learn that “in both techniques, cutting jigs and anatomic landmarks are used to determine the depth and orientation of tibial and femoral bone resections”. As I near the time of life when I might need such surgery, the nearer to robotic it becomes, the safer I feel. The words I do not want to read are “much depends on careful case selection and the skill of the individual operator”.  http://content.nejm.org/cgi/content/extract/360/17/1749

Lancet  25 May 2009  Vol 373

1429    Relax, you’ve got acute heart failure. This is a terrifying condition and I’m not sure I’d be in a fit state to sign a consent form for an experimental intervention if I was frothing with pulmonary oedema: I’d just want morphine and furosemide and I would probably not feel at all like relaxin. However, this multinational trial (Pre-RELAX-AHF) managed to recruit 243 patients with acute HF and systolic BP above 125 and get them to try out this peptide hormone released in pregnancy which promotes peripheral vasodilatation and renal perfusion. They were not allowed any other vasodilators or any inotropes and I’m not at all clear what immediate treatment they received within the first 16 hours, before they were randomised to relaxin or placebo. The stuff certainly worked and seems safe, but this phase IIb dose-finding study certainly doesn’t clarify the use of this hormone sufficiently to predict its place in the future management of acute HF.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60622-X/abstract

1440     There are various situations in which it would be handy to manufacture a new blood vessel, one of them being in renal haemodialysis patients whose arterio-venous fistulas are blocking up at all available sites. The new vessels were grown from the patients’ own fibroblasts in sheets around a stainless steel mandrel. Nice word, mandrel; it began by meaning “a miner’s pick (1516)” according to the OED; not to be confused with a mandrill, “the largest, most hideous, and most ferocious of the baboons, Cyanocephalus maimon or mormon, of W. Africa” (SOED,1933). Slip the fibroblastic vessel off its mandrel (not mandrill or mormon) and onto the hand of your renal patient, and you have a working fistula in 7 out of 10 cases.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60248-8/abstract

1455    If you have serious multiple trauma then you seriously want your doctors to know what is wrong with you the moment you arrive. So whoomph – through the whole body CT scanner - and there are all your damaged pieces plain to see! This was once a science fiction dream, but now it’s reality, and immediate whole-body improved survival in this survey of data from the German Trauma Society. A more serious-sounding organisation would be hard to conceive.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60232-4/abstract

1463    A long and worthy seminar on early breast cancer covers almost all its bases: it is really just a long review of every kind of breast cancer except the kind I most want to know more about – which is early intraductal carcinoma, the kind that gets picked up on mammograms. There was a distressing letter in the BMJ a few weeks ago from a woman who had undergone all sorts of unpleasant and mutilating treatment for a condition which might perhaps have regressed spontaneously. Or does it? I await another review.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60316-0/abstract

1480    For some reason the Italians have a long history of research into coeliac disease, and I believe – though don’t take my word for it – that gluten-free pasta was invented before gluten-free bread. Two Italian gastroenterologists here present another comprehensive review of a condition which is ten times commoner than we thought up to 15 years ago. It’s a great illustration of the way that diagnostic tests – first antibodies and now genotyping – can revolutionise our understanding, but can also put in doubt much conventional wisdom about a condition. It’s far from clear, for example, that forcing asymptomatic people with positive tests to avoid gluten does them any favours – and most of them give up the diet anyway. But the thing I always look for in a paper of this kind is a reference to Hin et al, BMJ 1999, because I urged this primary care case-finding study on Harold with the words “do this and everyone who writes about coeliac disease in the future will cite Hin et al.”  Well, ten years on and they still are: it’s reference 90 in this article and it was also cited in the Arch Intern Med systematic review I mentioned last week. If Harold Hin had decided to become an academic, instead of using his wisdom and energy to manage my practice with kindly efficiency, the research literature of primary care would be so much the richer.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60254-3/abstract

BMJ   25 Apr 2009  Vol 338

986    People with a tender spot over the greater trochanter are traditionally said to have trochanteric bursitis, but there is scant evidence that this condition really exists – see the editorial on p.961. I have given hundreds of steroid injections at such points and find that they give relief in about half of the patients – the same as in this trial. Exposing people to radiation in the form of fluoroscopic guidance will result in more steroid reaching the synovial fold over the greater trochanter, but will make no difference to the rate of success. Steroid injections make people feel better, and the lateral thigh is a convenient spot for injecting triamcinolone. This will prevent hay fever, amongst other things. Often it relieves lateral thigh pain as well. Or shoulder pain, as we learnt the other week.  http://www.bmj.com/cgi/content/abstract/338/apr14_1/b1088

996    I’m not sure by what criteria the BMJ decides which papers to print in compressed form as a pico research article, as opposed to the full Monty, but this one on high dose inhaled steroid for wheeze following respiratory syncytial virus is certainly worth looking up in full on the website if you deal with such children – as we GPs do all winter long – and are tempted to use this treatment in the hope of reducing airways inflammation. Because it doesn’t work: in fact nothing works. This is a damned elusive pimpernel.  http://www.bmj.com/cgi/content/full/338/mar31_2/b897

998    This article reviews all the evidence we have about clopidogrel in acute coronary syndromes. It does not, however, discuss in detail the recent evidence that clopidogrel doesn’t get converted into its active metabolite in about a third of the population. So much work for nothing, if prasugrel replaces this drug completely in the near future, as I think is likely.  http://www.bmj.com/cgi/content/extract/338/apr14_1/b1180

1003    I don’t write many papers myself, but comfort myself with the thought that I am sometimes the cause of papers from others. The study which gave rise to this article on diagnostic strategies used in primary care was carried out by Carl Heneghan et al without any prompting from me, but it did coincide with my urging the BMJ to run a whole series on primary care diagnosis, mapped out by Kevin Barraclough. I found myself without time to remain part of the series team, but here are the first results, which I urge you, with all due partiality, to read, mark, learn and inwardly digest. The diagnostic methods discussed here are those actually observed to be used in real primary care. The point is not so much that they are original to this paper – though some are – but that this is the first time they have been studied and discussed in this way, and illustrated with a large series of examples, of which the first is excluding serious illness in feverish children (p.1006).  http://www.bmj.com/cgi/content/extract/338/apr20_1/b946http://www.bmj.com/cgi/content/extract/338/apr20_1/b1187

Ann Intern Med  April 2009

I couldn’t find much of interest in the printed journal this week, but I will break my usual rule and point you to the Annals website for an early release article.

“Glycemic control in type 2 diabetes: time for an evidence-based about-face?”, by two US authors, presents exactly the same argument that Harlan Krumholz and I made in our BMJ editorial last week. We have decided not to add to the responses, which reach top numbers for a second week. This article does the job for us, in more detail than we had space for, with excellent summaries of all the available evidence proving that reduction of glycated haemoglobin below 7.5 in established type 2 diabetes is a misdirected effort.  http://www.annals.org/cgi/content/full/0000605-200906020-00118v1

Plant of the Week: Dicentra formosa “Langtrees White”

The dicentras are great friends for the neglectful gardener, growing well in most situations without any attention, and forming good clumps of pretty cut greyish foliage with flowers of pink or white over a long period. This one holds its flowers relatively high whereas the two other whites, Dicentra cucullaria and D. eximea “Alba” have purer white flowers closer to the leaves. The plants are easily split, so a friend with one will probably oblige you with a bit if you indulge in persuasive admiration.

The showy sister of these plants is the Bleeding Heart, of which enough said. If you must have a showy dicentra, try and find D. macrantha, a Chinese plant with hanging pale yellow flowers of a very odd and intriguing shape. Not for my garden, as it “needs shelter from any wind, and from late frost, and a moist  leafy and sandy soil, with protection from slugs.

NEJM  30 Apr 2009  Vol 360

1815    I usually avoid discussing HIV in these columns, because the role of a GP in my part of the world is just to make a timely diagnosis and hand the patient over to an expert for treatment. That can be more difficult than it sounds: a number of people have written to suggest that HIV is an essential topic for our “Easily Missed” series, because people still die of it in the UK without the diagnosis ever being made ante mortem. I shall always remember a patient of my own who refused HIV testing until he had florid AIDS and was nearly dead. Thanks to modern antiretroviral treatment, he is perfectly well many years later. So does the timing of antiretroviral therapy really matter? Well, that patient was certainly lucky, and nobody would choose to wait for a person with HIV to become symptomatic before starting treatment, but this quite complex long-term study from Canada tries to establish a CD4+ threshold level for treatment, using that most convincing of end-points, death. I won’t try to describe the results in detail but essentially this large stratified trial shows that earlier is better.  http://content.nejm.org/cgi/content/abstract/360/18/1815

1827   Hepatitis C infection is another bit of complex virology I tend to leave to virologists, though again it brings to mind a memorable patient, this time a former waiter from Barcelona who may have inspired the role of Manuel in Fawlty Towers. His death from hepatocellular carcinoma as a result of hepatitis C infection was awful. That is why successful combined therapy for this indolent and elusive virus would be a great step forward; but it is too early to celebrate, as shown by this paper and the one after it (p.1827). The promising new drug is telaprevir, which is more active against HCV genotype 1 infection than existing agents, and these two trials (PROVE1 and PROVE2) use various regimens with peginterferon, with or without ribavirin. It seems you need all three to get a good response in chronic HCV genotype 1 infection: but you are still lucky if more than two-thirds of patients respond.  http://content.nejm.org/cgi/content/abstract/360/18/1827http://content.nejm.org/cgi/content/abstract/360/18/1839

1851    The main aim of the JUPITER trial was to show that rosuvastatin can lower arterial events in people with low overall cardiovascular risk but slightly raised C-reactive protein. But a large trial like this was also useful for testing the hypothesis that statins can reduce venous thromboembolism as well. Most data to support this had so far been observational, but this randomised controlled trial proves that rosuvastatin definitely does protect against VTE. In fact taking deep vein thrombosis on its own, the rate was halved (HR 0.45, 95% CI 0.25 to 0.79). Tell me a reason why everyone shouldn’t be on a statin, sooner or later.  http://content.nejm.org/cgi/content/abstract/360/18/1851

Lancet  2 May 2009  Vol 372

1525    This is certainly a week of small increments rather than breakthroughs in the medical journals, but just how small can an increment be and still be worthwhile? Here we are talking about a survival advantage of 4-5 weeks in people who know they are dying of non-small-cell lung cancer. Given that the drug concerned, cetuximab, seems very well tolerated when added to standard platinum-based chemotherapy, it would seem unkind to grudge this small advantage in patients with advanced disease; but in the long term, the real benefit of this study may be in demonstrating that the epidermal growth factor receptor is a useful target for treatment earlier in the disease.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60569-9/abstract

1533    In several situations, such as renal disease, heart failure and cancer, anaemia is associated with an adverse prognosis as well as poorer quality of life. So correcting anaemia using human erythropoiesis-stimulating agents seems a very attractive idea, likely to increase survival as well as make patients feel better. But just like lowering glycated haemoglobin in type 2 diabetes, you can only find out by doing the trials; and then the result may be the opposite of what you expect. This meta-analysis of 53 trials of erythropoietin analogues in cancer patients shows a definite increase in mortality. Remember Galileo: until he came along, everybody knew that heavier objects fell faster than light ones, because they made a bigger bump in the ground. But he actually climbed the leaning tower, did the experiment and proved that common sense can deceive. Every specialty of medicine has its Pope and a conclave of cardinals, telling you what to think on pain of banishment: but medicine progresses by taking no notice of them and looking at the facts instead.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60502-X/abstract

1550    Chances are that whatever kind of medicine you practise, you will come across the occasional patient whose life has been saved from haematological malignancy by haemopoietic cell transplantation. For these triumphs we can thank Peter Medawar and others who worked out the fundamentals of modern immunology in a series of painstaking animal and human experiments in the 1940s and 1950s. But the risk of allotransplantation in this situation is that the graft may attack the host, a process first described by Billingham fifty years ago. We now know that graft versus host disease arises when donor T cells respond to genetically defined proteins on host cells. If you have a patient with this condition, or if you want to spend half an hour with a beautifully clear run through this aspect of modern immunology, then here is the article you need.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60237-3/abstract

1562    Bring out your silly names! There are new drugs in the wings to stimulate platelet production in chronic immune thrombocytopenic purpura. I am afraid I shall have to keep to my custom of breaking into verse at this point:

O Thrombocytopenic Purpura!
No subject ever once was murkier,
Till doctors skilled in blood and bone
Started to use Prednisolone;

Or in their fight ‘gainst this Hobgoblin
Resorted to Immunoglobulin;
Else, growing desperate, were seen
Calling the surgeons to remove the spleen.

But Hark! What Silly Names are heard
Approaching to the Haemic Ward?
Let us begin, Rituximab:
Thou first the Silly Prize dost grab.

But now appears Eltrombopag;
The Prize is surely in his bag!
But no, there is yet Romiplostim
Which now the Silly Prize hath lost ‘im.

And now our Poet must confess defeat,
For he his Silly Rhyming Match doth meet:
The latest drug is tamatinib fosdium
‘Gainst which all Poetry is lost, dee dum.

So let us praise the Pharmacologists,
Who spend their time devising bolloxes
Like these, in grand cacophony,
To celebrate the cure of ITP.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60255-5/abstract

BMJ  2 May 2009  Vol 338

1047   The name of Venus has inspired much poetry, some (I confess) even finer than my own. But I am not sure that her name has ever previously been connected with the maggot. I have spent a happy hour trawling through the works of Erasmus Darwin on the Gutenberg site, just to make sure, as this wide-dabbling Midlands GP and versifier is the most likely suspect for such a crime. Charles Darwin’s grandfather knew perfectly well that maggots were the larvae of insects but he retained a fondness for the old theory of spontaneous generation:

(For) without parents, by spontaneous birth,
Rise the first specks of animated earth.
From Nature’s womb, the plant or insect swims,
And buds or breathes, with microscopic limbs!
The Temple of Nature 1802

And Venus herself, of course, rose by spontaneous generation from the sea, as you will remember from the Botticelli painting you discovered with awe in your teens, and queued for hours to gawp at in the Uffizi Gallery. However, in this paper the connection is nothing grander than a maggoty pun: VeNUS II investigated larval therapy for venous ulcers. The munching maggots work well for ulcer debridement but do not improve the overall healing rate. The editorial on p.1050 argues that this is a useful contribution, but only if you don’t have enough trained humans to do the job with a knife. So perhaps maggot therapy will never fly. So the buzz goes…
http://www.bmj.com/cgi/content/abstract/338/mar19_2/b773

1058    Once a woman has had three negative cervical smears, her chance of developing cervical cancer is about 4 in 10,000. This does not vary significantly with age, according to this prospective observational study from the Netherlands. That seems a fairly straightforward message, easily communicated to most women, but in a national screening programme we seem very averse to giving anyone any choice. A better targeted screening policy is well overdue.
http://www.bmj.com/cgi/content/abstract/338/apr24_1/b1354

1064   We spend a great deal of time and trouble making sure that patients with chronic systolic heart failure get increasing doses of ACE inhibitors and β-adrenergic blockers, though the evidence for up-titration of these drugs is extremely weak; but in the UK it is still uncommon to find heart failure patients treated with cardiac resynchronisation therapy or biventricular pacing. I hope this good little clinical review does something to change practice, because this treatment is widely applicable and improves quality of life, reduces hospital admission and reduces mortality. “Identifying suitable patients is straightforward; there is no upper age limit of benefit; the implant technique is of low risk; and the treatment is highly cost effective.” So go on, shock your paymasters: don’t rest content with getting your basic QOF points for heart failure, but while you are about it, go through your HF patients and refer the appropriate ones for pacing. http://www.bmj.com/cgi/content/extract/338/apr28_2/b1265

1070    The Rational Testing series here advises on the appropriate blood tests for investigating hirsutism. The commonest cause in younger women is polycystic ovarian syndrome, for want of a better label: and here is a useful list of the right biochemistry to send off, if your lab will oblige. Ultrasonography of the ovaries is rarely necessary. http://www.bmj.com/cgi/content/extract/338/apr28_1/b912

 Arch Intern Med  27 Apr 2009  Vol 169

169   Preventing type 2 diabetes is one of the most urgent public health  tasks in the developed countries of the world: add the Indian subcontinent to that; then China: and you might as well say the whole world. Unfortunately, this study of lifestyle risk factors and new-onset diabetes looks at an age range where it is no longer so important: an average age of 73 at enrolment, which exceeds the average age at death in many countries. Still, if you are retired in the West and want to know how to avoid diabetes, here are some tips. The dietary score is a mish-mash of fatty factors and glycaemic index, and I make nothing of that; BMI is set at 25, which seems a bit mean; alcohol is beneficial, but only up to 2 units a day; exercise is definitely good; smoking is definitely bad.  http://archinte.ama-assn.org/cgi/content/short/169/8/798

Plant of the Week: Magnolia sinensis 

This is normally a tree which flowers later in May, but in this year’s peculiar English spring it is out at the same time as a neighbouring Japanese quince and a lilac bush, giving a strange, unplanned-for palette of colours which would normally appear a month apart. Nothing, however, can spoil the absolute beauty of this small tree’s pendent flowers of purest white, surrounding a boss of deep red. If you can, plant it on a bank where passers-by can look up and enjoy it, and catch its pungently sensual scent. There is little to choose between this and the almost identical species wilsoniae, but do not bother with their near relative sieboldii, whose flowers disappoint by never opening to their full beauty.