JAMA 10 Jun 2009 Vol 301
Lipoprotein (a) is present in atherosclerotic arteries but not healthy ones, and it is a perfect candidate for causing plaque, since it contains both cholesterol and a prothrombotic glycoprotein (apolipoprotein [a]).

However, it is very difficult to study its association with myocardial infarction; and since we have no tolerable drugs which reduce LPA, such an association has no obvious practical consequences anyway.

So I was strongly inclined to pass over this Danish study, but I’m glad that I didn’t. It is quite an intellectual tour de force as well as a logistic feat, combining three types of study within the population of Copenhagen, and it shows how the deft use of genomics can obviate the need for a randomised controlled trial.

The key element here is mendelian randomisation, the reshuffling of genetic material which happens each time we make a baby. I won’t go into further detail here, but if you are interested in such cutting edge stuff, I would strongly recommend a look at this paper and its accompanying editorial (p.2386).

Cardiac computerised tomography exposes patients to large amounts of radiation for large sums of money and often negligible clinical benefit. In the USA, you can apparently get it done in “small community hospitals”, which were lumped together with larger centres in this exceedingly unsophisticated before-and-after study.

Before these centres participated in the Advanced Cardiovascular Imaging Consortium in Michigan, they used twice the dose of X-rays that they did afterwards. But if you really need to know how furred-up your coronary arteries are, and want much smaller doses of radiation, it’s best to wait for the arrival of prospectively triggered sequential scanning in your area, or even better, single heartbeat acquisitions.

Most of my readers, I know, do not rush about putting in central venous lines and intubating people and doing all sorts of exciting televisual things that result in pools of blood on the hospital floor. But one or two do, and for your sakes I mention this useful systematic review of corticosteroids in the treatment of severe sepsis and septic shock in adults. Heroic doses are not required: I will merely quote the conclusion – “Corticosteroid therapy has been used in varied doses for sepsis and related syndromes for more than 50 years, with no clear benefit on mortality. Since 1998, studies have consistently used prolonged low-dose corticosteroid therapy, and analysis of this subgroup suggests a beneficial drug effect on short-term mortality.”

NEJM 11 Jun 2009 Vol 360

Like so many diabetic trials, this one tries to do a bit too much with its painstakingly assembled cohort of patients (2368 in all), but I do think it sends out an important message about the management of type 2 diabetes with stable coronary heart disease. Do as you like. Treat them with insulin provision – either by injecting it directly or by flogging the beta-cells with a sulfonylurea – or else try insulin sensitization, by metformin or a glitazone: it will make no difference to outcomes. Similarly, choose revascularization or medical management: again, it will make no difference. The only subgroup which fared appreciably better consisted of those for whom coronary artery bypass grafting was “deemed the preferred method of revascularization”. Note that patients with left main coronary artery disease were excluded from this trial, called BARI-2D.

Wow: could this be a trial which gives a clear message about the treatment of locally advanced prostate cancer? The headline message is that if the chosen initial treatment is external-beam radiotherapy, then survival will be improved if androgen suppression is continued for three years rather than six months. This was an important fact to establish, since androgen suppression has a lot of unwelcome side-effects. However, the effect size is modest and the statistics only just reach significance.

Here is what you wanted to hear: a large database study from Israel confirms earlier observational evidence that metoclopramide in early pregnancy is not associated with adverse fetal outcomes. There were more than 78 000 controls to compare with 3458 cases where mothers had been prescribed metoclopramide in the first trimester, and there were no significant differences in fetal anomalies, preterm delivery, birth weight, or perinatal death.

Zika virus outbreak on Yap Island! Avoid Micronesians! Actually, the first statement is true, but the second is false, because although the inhabitants of Yap are Micronesians, it’s their mosquitoes and not themselves that are thought to transmit this virus. Micronesia is the name given to a cluster of 607 Pacific islands, and the mystery here is how this rare virus ever got there. The previous 14 reported cases were from Africa and Asia, whereas Yap Island in the middle of nowhere can now claim 49 confirmed and 59 probable cases. The traditional money of the Yapese consists of carved stones up to 4m in diameter: no change given; stop yapping. Fortunately for them, Zika is no deadly killer plague virus, but something that causes conjunctivitis, rash, fever and arthralgia for a few days.

The Island of Yap
Is a speck on the map:
But it’s slightly easier
To detect Micronesia.
A virus called Zika
Made some Islanders sicker,
But they all got better,
And there’s an end to the metter:
Let’s twist no knicker
For a virus called Zika.

Lancet 13 Jun 2009 Vol 373

EURODIAB has capital letters like an acronym, but surely it’s just an abbreviation. Anyway, it does what it says on the tin: here it reports that alarming numbers of Eurochildren are getting diab. It’s called a multicentre prospective registration study and the good thing is that ascertainment rates are higher than 90%, so it’s pretty reliable. Less reliable, perhaps, is its estimate that new cases of type 1 diabetes in children under 5 will double in Europe by 2020. Let’s hope that between now and then, a vaccine to prevent the disease will be developed.

If you are going to do a proper randomised trial of something, you need to do a proper literature review first; best of all, do a meta-analysis. By the time you have done that, and filled out the funding bid forms, you will probably have lost the will to live; or at any rate the will to do the study. But never mind. If you persevere, you can publish the meta-analysis and your own RCT as a single paper, like these British investigators of progesterone for the prevention of preterm birth in twin pregnancy. Progesterone does not prevent preterm birth in twin pregnancies; it does not prevent adverse outcomes either, which is a subtly different question. The acronym of the trial is STOPPIT. Do not prescribe progesterone for twin pregnancies; do not come up with silly acronyms. Stoppit at once.

For an account of the life of James Parkinson, man of God, ardent child-beater and author of An Essay on the Shaking Palsy, you will have to go to a Lancet of some years back for an excellent piece by Druin Burch. For an account of the shaking palsy itself, this seminar on Parkinson’s disease is worth reading for a wealth of useful information, though the three professors who write it seem a little unconnected with the shop floor.

The most characteristic feature, without which the diagnosis cannot be made, is bradykinesia: slowness of initiation of voluntary movement with progressive reduction in speed or amplitude of repetitive actions. Since the diagnosis is entirely clinical, you might as well try and elicit the right signs.

If you love airports and can drop everything at a moment’s notice to get free flights to all sorts of exotic destinations, then flight medicine is the thing for you, and pays handsomely, according to a colleague I was talking to a while back. This nice practical review goes into the medical issues associated with commercial flights and is of interest to all of us who get put on the spot by patients who wish to travel by air and ask us for advice. It’s probably a bit basic for hardened flight medics who are sent out to accompany those taken ill abroad.

BMJ 13 Jun 2009 Vol 338

Only ten years ago, the words “stroke” and “TIA” (not a real word, but never mind) induced a sort of sad shrug in most British doctors. Now stroke medicine is a specialty in its own right and alone among medical conditions, stroke demands “hyperacute” care (see p.1419): 999 ambulance, immediate scan, thrombolysis, wham, bang. TIA demands a clinic appointment the same week, carotid ultrasound, and carotid endarterectomy within two weeks if there is a suitable lesion, according to the NICE guideline. How does real life in our dear NHS compare? According to this study, achievement is about 20% and there are no figures for how many strokes occur in the 80% of patients who have to wait longer.

http://www.bmj.com/cgi/content/extract/338/jun04_1/b2083

Do you dare to do a TYM? I am old, I am old, and I shall wear the bottoms of my trousers rolled, but I am not sure I can bear to find out. People are so kind when I forget their names. It is great fun to go to places for the first time and then be told I have been there before. I think I have just the right amount of Alzheimer’s. No need for a baseline score, thanks. If you feel differently, visit the website and do the self-administered cognitive screening test. It is almost certain to be the instrument of choice from now on, however much people quibble about its predictive characteristics, because it performs better than the MMSE and is available without copyright restrictions (see the Lancet comment piece, Taxing Your Memory, p.2009).

Another quick pointer for readers who spill blood on hospital floors: a nice little (longer on the website) piece by some Army doctors about damage control resuscitation for patients with major trauma. Carry on, Major; and good luck.

Archives of Internal Medicine 8 Jun 2009 Vol 169

I like the Archives for its wide range of topics, but this week’s is full of weak studies from which I have plucked this one merely for personal interest. If you sleep badly, your blood pressure is more likely to rise. This is one of many studies under the umbrella of CARDIA (Coronary Artery Risk Development in Young Adults) which has followed a cohort of 5115 from 1985. In 2002 it invited some of them to participate in this study: they had to be normotensive and non-pregnant. The upshot is that if you sleep badly – as assessed by various questions and three nights of actigraphy – your BP is more likely to go up. The authors even claim that this explains the difference in BP between blacks and whites in their cohort, and that measures to improve sleep may help hypertension. Cognitive behavioural therapy for everything, say I.

Plant of the Week: Paeonia “Garden Treasure”

The genetic modification of plants is the basis of civilisation. Sumer was founded on the breeding of wheat, and China on the breeding of rice. We don’t know how exactly which garden flowers the Sumerians bred five thousand years ago – the names are mostly obscure – but we do know that the Chinese have been breeding peonies for at least 1,600 years.

When they were first brought to Europe, they caused a sensation, especially in France, where new kinds were bred soon after their arrival. These were from the two basic categories of peony, the herbaceous kind and the so-called tree peonies, which are really just moderate sized sprawling shrubs. Both sorts abound in the colours pink and white and purple and red, but yellow has always been rare, confined to a few tree peonies and a couple of herbaceous species which are unsuitable for hybridizing.

The French breeders took this as a challenge. They tried to interbreed yellow tree peonies with various herbaceous varieties, but ended up declaring that this was impossible. They concentrated instead on producing a number of hybrids between the tree species lutea and the various tree peonies arriving in shipments from China and Japan. Some of these yellow-flowered Lemoine tree hybrids are becoming available again, and they are exquisite, especially “L’Espérance” and “Argosy.”

In the USA and Japan, one or two peony breeders challenged the French orthodoxy that you couldn’t get a tree to mate with a herbaceous peony. With enormous patience and a huge failure rate, they produced a tiny number of viable offspring. Here were slightly woody low plants with flowers of beautiful clear yellows, often with central flashes of crimson. When one of them, called Bartzella, first came on sale in 1998, it was offered at $1,000.

“Garden Treasure”” came soon after, and was judged by the very picky American Peony Society to be even better than Bartzella. Now it has begun to arrive in England. We saw it in flower at Wisley less than a fortnight ago, blazing with beauty from 100 metres away, and bought one last week in Shropshire for £80. A lot for a plant? Not really. Once in the ground, it will flower for 50 years or more. Admittedly for only one week of the year. But what a thing to look forward to! Worth the price of a nice meal for two, any day.

Newborn babies feature in Richard’s blog this week, as he finds out how extremely premature babies fare with modern neonatal care, and how a baby’s weight in its first three months can affect its weight in the future. Tuberculosis and chronic obstructive pulmonary disease are among the other things that Richard tells us about, as well, of course, as recommending a plant of the week.

JAMA  3 Jun 2009  Vol 301

Depression is both an inherited trait and a learnt behaviour, and for centuries it was quite prized in the young, as a disincentive to frivolous behaviour and a sign of a religious or philosophical disposition. As Oliver Edwards said to the notoriously depressive Samuel Johnson around 1760, “You are a philosopher, Dr Johnson. I have tried too in my time to be a philosopher; but, I don’t know how, cheerfulness was always breaking in.”  The adolescent children of depressive parents are at high risk of developing depression, and this interesting study sought to discover if that can be prevented by teaching cheerfulness – i.e. cognitive therapy. The comparator was our false friend “usual care”, but at least the investigators here apologize for that in their commentary section. What they find is that CB works well in preventing depression in these vulnerable youths unless a parent has active depressive illness, in which case it avails little.

Extremely premature birth is defined as birth before 27 weeks’ gestation. This Swedish study shows how these tiny babies fare with modern intensive neonatal care. Survival at 22 weeks is almost 10%, rising to 85% at 26 weeks.

Babies who get fat in the first three months of life are more likely to become fat, insulin resistant young adults with bad lipid profiles. So it would seem (with wide confidence intervals) from this Dutch cohort of 217 healthy participants now aged 18 to 24 years. It may be that this is a risk factor which is modifiable by giving babies less food than they demand, but it would be a tough study to carry out and we would need to wait about 60 years for some hard outcomes. So my advice to mothers and health visitors would be: don’t weigh babies without good reason, and feed them when they are hungry.

NEJM  4 Jun 2009  Vol 360

The arrival of a new antimicrobial drug is always an occasion for celebration, especially when it is one that was found by good old-fashioned chance and experiment rather than the sort of high tech molecular targeting which none of us could do in our garden shed. The diarylquinolone TMC207 was found to be active – very active indeed, in fact – against Mycobacterium tuberculosis after experiments performed on M smegmatis. So all you need are some agar plates, an incubator, and a supply of whatever it is that gives this mycobacterium its name. If this agent lives up to its early promise, it could be a valuable addition to the weaponry against multidrug-resistant tuberculosis.

In the later nineteenth century, lean writers like Chekhov and Robert Louis Stevenson coughed up blood politely into their handkerchiefs as they travelled across Europe in railway carriages seeking a cure for their tuberculosis. As the same time, the United States of America received millions of the poor and dispossessed of Europe, many of whom had active TB. Quarantine stations began to be set up, the most famous of which was Ellis Island, where immigrants could be kept isolated for months. The word quarantine, by the way, derives from the Italian word for forty, the number of days that the seventeenth century Venetian authorities decreed a ship that might be carrying plague should wait anchored in the Lagoon. Nowadays America is a lot harder to get into, but immigrants and refugees – especially the latter – still account for more than half of the active TB in the US. The solution vigorously advocated in this paper is overseas screening (and treatment) by designated local doctors before entry to the States. It certainly works, but there are no data about what happened to the refugees while they were forced to postpone their flight to freedom.

Chronic obstructive pulmonary disease is, well, chronic, obstructive (partly, anyway), and pulmonary. You tell people to stop smoking, immunize them against influenza and pneumococcus, and give them mucolytics, bronchodilators and antibiotics as required. It’s the fourth commonest cause of death in industrialized nations and might get to number 3 if current tobacco promotion policies prevail. It’s hard to say anything else useful about COPD, but this article on its immunology at least says things that are interesting. It goes in detail through all the damaging things that build up in smokers’ phlegm and also speculates on why many smokers nonetheless manage to avoid getting COPD – it may all depend on T-cell regulation.

Lancet  6 Jun 2009  Vol 373

Gradually, if all goes well, we are going to reach a situation in which most cervical cancer is prevented by polyvalent human papillomavirus vaccination and women only need be screened twice in a lifetime. We are by no means there yet, and this trial of a quadrivalent HPV vaccine shows some of the difficulties. The per-protocol success rate in women aged 24-45 was 90%, but taking a more real-life intention-to-treat analysis, this falls to 31% for preventing persistent new infection within 26 months. And this study tells us nothing about the duration of immunity. For a good analysis of where we stand at the moment, read the accompanying editorial on p.1921.

Every month, somebody sends me a magazine called “Guidelines”, and once or twice a year (I can’t remember, because I always give it away) I get a fat little Compendium of Guidelines as well. And then there are the NICE guidelines, which form a weighty dust-covered green heap on a consulting room shelf. My computer is loaded with lots more guidelines. The practice generates its own guidelines too. When I am dying, people will treat me according to end-of-life guidelines, and at my funeral they will sing “Guide me, O thou great Jehovah”. Until that day, I will continue to rail against guidelines, which are always a mixture of evidence and “expert opinion” and are out of date before the ink is dry on their innumerable pages and appendices. This preambulatory rant leads us to the study in question (CLOTS trial 1), which examines the RCP and SIGN guideline recommendation that all patients suffering from immobility due to acute stroke should be made to wear thigh length graduated compression stockings. Well, they shouldn’t. These stockings increase the incidence of skin breaks, ulcers, blisters and necrosis and do nothing to reduce deep vein thrombosis after stroke.

An excellent seminar on neurofibromatosis type 2 gives you a chance to know everything about it if you happen to have a patient or family with the condition – it occurs in one in 25 000 live births and is inherited as an autosomal dominant with almost 100% penetrance by the age of 60. It has a genetic locus called NF2. That’s the kind of genetics I can remember. It usually presents with hearing loss in young adulthood due to vestibular schwannoma. The other common manifestations are meningiomas and ependymomas. Enough about NF2: what are the other neurofibromatoses? There’s NF1, formerly called von Recklinghausen’s disease or peripheral neurofibromatosis – that’s the commonest kind, formally separated from NF2 only as recently as 1987. The third kind is still called schwannomatosis.

BMJ  6 Jun 2009  Vol 338

Writing about cancer screening in these columns, I’ve tended to adopt the wearily sceptical tone of a GP who deals the daily burden of anxiety brought on by “abnormal” mammograms, CIN3 of the cervix, high PSAs and so forth, but I was put on my mettle last year when the greatest figure in the field, Martin Vessey FRS, wrote to chide me gently for my blindness to the population benefits of screening. Knowing that MV may be reading this, I shall try to look at this study of flexible sigmoidoscopy for the prevention of colorectal carcinoma from his position as chairman of a national screening committee. What we want, of course, is to reduce the increasing mortality burden of this common cancer in the general population. There may be preventive measures – reducing red meat consumption, perhaps, or banning barbecues, or encouraging the use of NSAIDs, but these are not serious propositions for the moment. The main screening options are testing for occult blood in stool samples (the currently preferred strategy), universal one-time sigmoidoscopy, or universal one-time colonoscopy. At first sight, this Norwegian trial is a flop: “a reduction in incidence of colorectal cancer screening with flexible sigmoidoscopy could not be shown after 7 years’ follow-up.” The accompanying editorial (p.1339) on the other hand hails the trial as “suggesting that the intervention may be effective in reducing mortality from colorectal cancer”. Both ineffective and effective: it all depends on which data you choose to look at. The trial does show a definite large decrease in cancers for those who turned up for the investigation, diluted out if you look at intention-to-treat (I.e. all those invited): so if people could be persuaded to turn up in large numbers to have a tube up their bottoms, this might work. I see a difficult advertising campaign ahead.

“QOF for diabetes: can Practices and Patients both be Winners?” is the title of a short lecture I shall be giving in Birmingham and London next week. Tickets are changing hands for astronomical sums. This analysis of the effect of the introduction QOF on diabetic outcomes could not have come at a better time for me. The presentation is a bit obscure and the printed version omits the key table, but the message is clear: the coming of QOF slowed down the improvement in targets such as HbA1c , blood pressure and cholesterol. “The surprising and important message is that left to themselves, doctors tend to pursue good clinical practice for the benefit of their patients, while if made to jump through hoops for money, they will jump the hoops and leave it at that,” as I shall be telling my audience.

Ann Intern Med  2 Jun 2009  Vol 150

How likely are you, a non-diabetic adult aged between 45 and 64, to cross the magic threshold of fasting blood sugar and become a fully paid-up type 2 diabetic? This study validates a new risk score based on glucose, waist circumference, triglycerides, maternal diabetes, black race, paternal diabetes, LDL-cholesterol, short stature, uric acid, age over 55, hypertension, rapid pulse and non-use of alcohol. It’s pretty good. Get searching your computer, download this paper (it’s free), find those high-risk patients and call them in for exercise and weight reduction before they reach 7 mmol/L fasting glucose.

Or should we be looking to reduce their levels of aldosterone? I’ve been interested in this hormone for many years since it became clear that it plays a key role in heart failure and resistant hypertension. This intriguing review looks at its role in the so-called metabolic syndrome as well, which is a conglomeration of risk factors often associated with the later development of diabetes. Blocking aldosterone can improve pancreatic insulin secretion, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation. It looks as if we might be giving our pre-diabetic and diabetic patients a lot more spironolactone and eplerenone in the future.

Plant of the Week: Parahebe catarractae

Not a shrub, not a perennial, not an alpine: this invaluable little space-filler is often described as a sub-shrub, a mass of wiry stems covered in attractive small evergreen leaves and small fragrant white flowers veined with violet throughout the summer. There are mauve-purple sorts which are best avoided. If you want something entirely trouble-free to cover an edge or tumble over a stone all year round, this is the thing. But it does need sun, and you need to lift it off the ground from time to time to destroy any infant gastropods that it might be providing asylum to.

Proton pump inhibitors are the nation’s favourite drugs, a cure for every discomfort around the epigastrium or oesophagus. Coleridge - or Hazlitt or Lamb or de Quincey or Leigh Hunt - one of those guys anyway - once speculated that most wars might simply be the result of a bad digestion. PPIs for World Peace! is my slogan. Flood North Korea with omeprazole. Don’t let the Dear Leader struggle on with Gaviscon and Rennies. But wait - here is a paper confirming the dastardly suspicion that PPIs might be associated with an increased risk of hospital-acquired pneumonia. Never mind: nuclear war is more important.

NEJM   28 May 2009  Vol 360
Although we don’t understand the natural history of oesophageal cancer exactly, at least some of it arises in areas of intestinal metaplasia at the lower end of the gullet, called Barrett’s oesophagus. In fact the accompanying editorial claims that all oesophageal adenocarcinoma (5-year survival, 15%) arises from Barrett’s, as metaplasia becomes dysplasia and dysplasia becomes cancer. We also know that these cancers are increasing at an alarming rate - fivefold in the last three decades. So a trial showing that radiofrequency ablation cures Barrett’s in 80% of patients at one year must be good news. It’s also good news that this trial used sham ablation as the control. Bad news, however, that it was relatively underpowered to prove a reduction in cancer, and that radio ablation can cause strictures in 6% of patients. And screening for Barrett’s is definitely not on the agenda - it’s too common and too little of it progresses to cancer.

In my school days, I would often walk down Beech Hill Road in Sheffield thinking of chemical explosives, or girls, or Beethoven, but never of age, neuropathology and dementia. Alas, how things change. Here the pathologists of Beech Hill Rd report on what they found when they sliced through 456 brains from donors aged from 69 to 103 who had taken part in an MRC study of cognitive function. The classic tangles and plaques of Alzheimer’s more frequently accompany dementia in the younger elderly than in the very aged, as you’d expect.

As we gaze in wonder at the fossil of our 47-million-year-old ancestor Ida the early primate, this is a good time to weigh up the pros and cons of human evolution. Big brain: probably good. Upright posture: not so sure. So many of the intractable ills we deal with every day are down to that: postnasal sinuses that drain upwards, a back that’s always giving trouble, hips and knees that degenerate, and varicose leg veins. Our big brains aren’t much help when it comes to dealing with veins with useless valves. But it seems from this very good review that we have been missing something important - iliac vein obstruction. About 60% of non-symptomatic adults have non-thrombotic iliac vein obstruction at the point where it is crossed by the iliac or hypogastric artery. In symptomatic people, the percentage exceeds 90, and the answer may be - you guessed it - the placement of venous stents. Apparently these stay patent for many years and provide symptom relief in the great majority of patients with advanced venous disease.

Over the years I’ve been compiling a list of topics for the Easily Missed series, Addison’s disease has stayed near the top, not surprisingly. We simply don’t know how many people go into septic shock and die of it without the diagnosis ever being made: what is clear from this review is that adrenal insufficiency is difficult to study, particularly in critically ill people. It’s good to see such a first-class single author review appear from Dresden, a city which suffered a brain drain in the days of the GDR because you couldn’t get West German TV reception there, and has fared even worse since due to economic migration and prejudice against “Ossies”. Anyway, read this review; and visit Dresden for its lovely situation on a bend of the Elbe, its marvellously reconstructed buildings, the Zwinger gallery full of great paintings, and the Semper opera full of musical singers who don’t wobble hideously in the modern fashion.

Lancet  30 May 2009  Vol 373
Twenty years ago in Oxford, aspirin was considered a divine substance and I recollect being rebuked sharply by Colin Baigent for suggesting that it might not matter if GPs did not give it immediately to patients with suspected myocardial infarction provided they got it on arrival in hospital. Absence of evidence was no excuse for sloppy practice. In this vast meta-analysis, Colin (now Prof Baigent) finds much absence of evidence, not about this particular issue, but about the net benefit of aspirin for the primary prevention of vascular disease. We all so much want it to be a cheap safe panacea, but it isn’t a panacea and it’s not particularly safe; it may even increase total stroke mortality when used for primary prevention. Cheap it certainly is, but then so are statins nowadays, and they do more good and less harm.

Cystic fibrosis gets a Lancet seminar this week. We all know it’s autosomally recessive, but it is genetically complex, and malfunction of the transmembrane conductance regulator has complex consequences. The basic end result is to produce sticky airways secretions that hold on to germs (especially Pseudomonas aeruginosa) rather than get rid of them, and that block airways rather than clear them. The pancreas gets gummed up too, but that is easier to treat. Until gene therapy becomes a reality, most treatment is aimed at postponing death from pulmonary infection and damage, using antibiotics and nebulised hypertonic saline: this has improved life expectancy from 30 to 37 in the past decade, and today children with CF are expected to live to 50.

BMJ   30 May 2009  Vol 338
Unannounced on its front cover, the BMJ has scooped up a really important study of door-to-balloon time in relation to mortality in ST elevation myocardial infarction. Looking at what happened to 43 801 American patients in hospital, the Yale team comes up with a mortality curve with the tightest of confidence intervals, clearly showing that every minute counts. The authors worked under the supervision of Harlan Krumholz, so everything in this paper is in the right order, clearly stated, closely discussed, and ending with a simple clinical message: there is a benefit from reducing door-to-needle time for all patients undergoing PCI, including those currently treated within 90 minutes of hospital admission.

On a good night, without wine and with an essay by Richard Feynman and a piece of paper to hand, I can persuade myself that I understand the rudiments of quantum physics. On the other hand, the more I read about string theory or prion-related diseases, the more confused I become. I know people have won Nobel prizes for these things, but you can’t help wondering, just a little bit, why they are taking so long to become intelligible to the majority of fairly intelligent people. Here is a study of “disease-related prion protein” in 63,000 British tonsils, using two tests. If one was positive, the other wasn’t, so the end result was: no confirmed CJD prions. Whatever they are. Or do. I am reminded of Hilaire Belloc’s words:
But Scientists, who ought to know,
Assure us that it must be so …
Oh! let us never, never doubt
What nobody is sure about.
From The Microbe, in More Beasts for Bad Children, 1912

Another unannounced scoop for the BMJ is the result of at least ten years’ hard thought by Doug Altman on the subject of prognosis and prognostic research. This may not be your particular cup of tea, but with Doug around, you can be very sure that it is well brewed and contains only the best ingredients. No milk or sugar, thank you. Three more cups to come.

Arch Intern Med  25 May 2009  Vol 169
“From 2001 through 2004, 35.4% of US adults aged 40 years and older (69 million Americans) had vestibular dysfunction.” A truly dizzying statistic. “These data suggest the importance of diagnosing, treating, and potentially screening for vestibular deficits to reduce the burden of injuries and deaths in the United States.” Hmm. They suggest to me that a lot of people get a bit of the wobbles now and then. And just what is this treatment of which they speak? If the US wants to reduce its burden of injuries and deaths, I’d suggest gun control and universal medical coverage.

I rather like some American usages, like “2001 through 2004″ which is more precise than our “from 2001 to 2004″. But what about this? “Rapidity and modality of imaging for LBP is associated with patient and physician characteristics but the directionality of associations with desirable care processes is opposite of associations for measures targeting underuse.” No wonder so many Americans get vertigo. This study of imaging for low back pain in a health system which encourages overinvestigation gives rise to a nicely written editorial with the title “Imaging Idolatry”. The word idolatry reminds one of America’s deep roots in the English Bible, which is mostly the work of William Tyndale. Here, just for a treat, is how to write English prose:

“But the serpent was subtler than all the beasts of the field which the Lord God had made, and said unto the woman. Ah sir, that God hath said, ye shall not eat of all manner trees in the garden. And the woman said unto the serpent, of the fruit of the trees in the garden we may eat, but of the fruit of the tree that is in the middes of the garden (said God) see that ye eat not, and see that ye touch it not: lest ye die.
Then said the serpent unto the woman: tush ye shall not die: but God doth know, that whensoever ye shall eat of it, your eyes should be opened and ye should be as God and know both good and evil. And the woman saw that it was a good tree to eat of and lusty unto the eyes and a pleasant tree for to make wise. And took of the fruit of it and ate, and gave unto her husband and also with her, and he ate. And the eyes of both of them were opened, that they understood how they were naked. Then they sewed fig leaves together and made them aprons.”
Genesis the.iii.Chapter. 1530  William Tyndale or Huchyns

Plant of the Week: Geranium renardii

Amongst its other joys, June is the high season for hardy geraniums, those steady fillers of every garden gap. Some of them flower for a long season, but this one bears its flowers for a couple of weeks only, when they are a lovely opal white veined with violet. But this is definitely a plant that every garden needs. It is, as Graham Stuart Thomas wrote,”a first-class foliage plant forming a solid dome of sage-green, prettily lobed, deeply veined, circular leaves.” What more can you ask?

Our traditional view of cardiac myocytes is that they sit there from birth, beating away about 40 million times a year until after about 80 years they get tired and start packing up. In fact, a recent Swedish study shows that new myocytes are produced throughout life, albeit in rather modest numbers - 1% at age 25 and 0.45% at age 75. Bone marrow stem cells are known to turn into cardiomyocytes if they are injected into the myocardium, but nobody has yet shown that this can result in clinically meaningful benefit. This Dutch study is no exception, but at least it showed a small, short-term increase in myocardial perfusion in a group of patients with chronic myocardial ischaemia refractory to medical treatment. The scanner noticed the difference even if the patients didn’t.

“Come Sleepe, O Sleepe, the certaine knot of peace,
The baiting place of wit, the balme of woe”
writes Sir Philip Sidney in his 39th sonnet, perhaps inspiring the more famous passage in Shakespeare’s Macbeth. Those who can take a good night’s sleep for granted have little sympathy for those who can’t: Lady Macbeth interrupts her husband’s very promising speech on the subject with a brisk “What do you mean?” In Shakespeare’s day, poppy, alcohol and mandragora were popular sedatives, but taking sleeping drugs has always been considered a moral weakness by non-insomniacs. The modern equivalent of moral self-improvement is cognitive behavioural therapy, where instead of being ordered to snap out of it, you are taught how. We know this works for sleep disturbance, but this Canadian study is one of the few to examine how it interacts with drug treatment. In the short term, CBT and zolpidem together produce the best results, and for long term success, discontinue the zolpidem while continuing the CBT. I can feel it working … wake up! When is there ever going to be enough CBT available in the UK to treat every patient with insomnia?

All right, all right, I know I should be fitter. Twelve Japanese authors rub it in with this meta-analysis of cardiorespiratory fitness as a predictor of all-cause mortality and cardiovascular events in healthy men and women. The association is clear, thought the heterogeneity amongst the studies is pretty striking.

NEJM   21 May 2009  Vol 360
The most radical change in medical services in the last ten years has centred on the provision of rapid reperfusion for myocardial infarction. The evidence that it works for ST-elevation MI is well established, but for NSTEMI acute coronary syndromes the benefit of immediate versus delayed reperfusion therapy is less clear. The TIMACS trial helps to clarify the situation by showing that the difference between coronary angiography at a mean 14 hours and a mean 50 hours in this group is not great. You have to tinker about with the results a bit - those wretched composite end-points get in the way once again - to tease out the main message, which is that the patients worth whizzing off asap to the nearest catheter lab are the ones with high risk scores. As you thought. Better still, this paper is accompanied by an editorial which contains a very useful table of treatment strategies for acute coronary syndromes (meaning those without ST elevation). The bottom line again: “The magnitude of benefit correlates with the patient’s level of risk.”

Lancet  23 May 2009  Vol 373
“Diabetes is a mess,” I sighed a few weeks ago. It has just become a worse mess with this meta-analysis of the effect of intensive control of glucose on cardiovascular outcomes and death in type 2 diabetes. The headline message is that “intensive control of glucose” reduces non-fatal myocardial infarction by 17%. This conclusion is reached by analysing five trials, three of which have a roughly similar design - ADVANCE, ACCORD and VADT - all examining outcomes after reducing GHb below 7 for several years in typical cohorts of type 2 patients aged around 65+. The other two are wildly different - UKPDS, which randomised patients on diagnosis in their early fifties to regimes which produced long-term GHb levels over 7, and the PROactive study which randomised patients with established macrovascular disease to have pioglitazone or placebo added to their existing regimes. The authors of this paper, to be fair, spend almost a third of it discussing its limitations, and even manage to squeeze in a favourable reference to the recent editorial on the subject I wrote with Harlan Krumholz. But this “meta-analysis” seems designed to obscure the clear message of three trials that can actually inform real-life practice in long-standing diabetes, which is that lowering GHb below 7 in this large group has no clear benefit and increases hypoglycaemia. The other two studies lumped in with them address different questions entirely. People with diabetes need evidence which helps them to choose the treatment which will benefit them most as individuals, whereas conflating disparate data leads in the opposite direction.

Here is another meta-analysis, this time quite uncontroversial as it simply tries to establish the size and timing of the well-known relationship between gestational diabetes and later type 2 diabetes. The risk size varies from 3.28 to 22.27 in various clusters of studies: the mean risk ratio combining them all is 7.43. Very high, in other words, and deserving of preventive action if we can find out what works.

There are three kinds of outcome in diabetes trials: (a) surrogate end-points only (this applies to 82% of current trials);(b) patient outcomes which are undesirable but treatable (most retinopathy, symptomatic vascular disease); and (c) patient outcomes that have a permanent detrimental effect, varying from toe amputation to death. For some reason, it has become traditional in diabetes research to confuse these three classes of outcome as much as possible. The FIELD trial randomised 9795 patients with type 2 diabetes to receive fenofibrate or placebo, and three main outcomes have been reported. For major cardiovascular events, fenofibrate made no difference; for retinopathy requiring laser treatment (a type b outcome, which does not equate to visual loss), fenofibrate provided a reduction of 31%; and the study here shows a similar reduction in amputation events, significant only for toe amputation. The front cover of The Lancet bids us to “marvel at the unexpectedly large effect of treatment with a fibrate on both diabetic retinopathy and amputations.”  What we should really marvel at is that fewer than 10% of the patients in this study were taking a statin, so the results are impossible to extrapolate to a real-life population of diabetics on appropriate treatment.

There are two types of surgical cure for diabetes. One is bariatric surgery, which can cure more than 50% of obese diabetics using relatively safe and simple procedures. The other is pancreas transplantation, a complex and hazardous procedure often performed in tandem with renal transplantation. If you are poorly enough to warrant combined transplantation, you are twice as likely to live to two years if you get it done. Thereafter there are clear benefits in the regression of diabetic changes in all affected organs, but long-term survival benefit is not clearly assured.

BMJ   23 May 2009  Vol 338
If you lower blood pressure, you will lower the risk of coronary heart disease and stroke, irrespective of baseline BP. You will achieve this reduction much more effectively by using low doses of three agents than by using higher doses of one or two. These well-known but commonly ignored facts emerge once again from this immense labour of Polypill love by Law, Morris and Wald. The moral of this meta-analysis of 147 trials is that if everyone took BP lowering medication we would reduce myocardial infarction by 45% and stroke by 60%. They claim that it is therefore irrelevant to measure BP, but this is a non sequitur: they assume we agree that risk assessment as a whole is a waste of time. That is only the case if we ignore the right of individuals to decide which treatments they would like to take.

As a medical student, I was puzzled that gynaecologists used the laparoscope to examine the abdominal cavity while general surgeons did all their operations through large wounds which I held open with a retractor. Then about twenty years ago, they all started doing everything through laparoscopes and severed many an artery and bile duct while climbing their learning curves. Had virtual reality training been more widespread then, this might not have happened, and even now it doesn’t seem to be mandatory, or this RCT would not have got ethical approval. It shows that it is as stupid to let a surgeon do laparoscopy without training on a virtual reality set as it would be to let a fighter pilot fly without simulator training.

More about the (relative) futility of blood pressure monitoring. The PROGRESS study reported here in pico form shows that the random variation of BP is huge and undermines the reliability of office checks following changes to treatment. The accompanying editorial and Fiona Godlee’s Editor’s Choice both call for a complete rethink on how we treat and monitor blood pressure. Tempting though it is to imagine a world in which constant checking of BP and other risk factors became a thing of the past, I am not quite convinced that giving everybody a cocktail of drugs they mostly don’t need is the best answer.

The Diagnosis in General Practice series continues with an excellent article on chronic cough by Kevin Barraclough, accompanied by a piece on the “test of treatment” by Paul Glasziou and colleagues. We first discussed this pairing of “practice” topics and “theory” topics three years ago, and it’s nice to see it working so well. This is about what actually happens to patients: if you think you can do it better, tell us how. Kevin disputes the relevance of diagnosing pertussis serologically in chronic cough, but having had access to salivary testing I can assure him that it turns up all the time and it’s a very useful tool for calling an end to the diagnostic chase. Patients go from being frustrated and anxious to being impressed and intrigued, and immediately start diagnosing it in their friends and relatives. Sometimes correctly.

Ann Intern Med  19 May 2009  Vol 150
If the dowager has a hump, she will die more quickly. This is not just an association with osteoporosis but is independently linked with the degree of hyperkyphosis in older women.

Here’s a nice little study - well, quite big, actually, involving 164 US hospitals - showing that quality of outcome is not related to volume of coronary artery bypass procedures but to quality of adherence to non-surgical measures. A little hospital can do just as well as a big one, not by hiring a star surgeon but simply by ensuring good peri- and post-operative practice - appropriate prophylactic antibiotics, leg compression, statins, ß-blockers and aspirin.

Sitting on the desk by my right elbow are 147 pages of the clinical Quality and Outcomes Framework by which our practice will earn enough to keep me in the manner to which I am accustomed. If some kind reader would give me a locum for 3 months, I would go through this whole wretched thing and examine its evidence base critically, as I tried to with a single diabetic indicator. Nowhere is the whole exercise more tenuous and unscientific than with so-called chronic kidney disease. Patients with this non-disease are usually elderly with co-morbidities that actually affect their well-being, and the only trial which includes substantial numbers of such people is ALLHAT. We will get points for treating them with angiotensin-converting enzyme inhibitors and angiotensin II-receptor antagonists. This review of the current American guidelines recommending these treatments shows that there is little hard evidence to support their use in people over 70. Perhaps I should become used to a little less income.

Plant of the Week: Decumaria sinensis
At this time of year, every street in England should be filled with a sweet odour of orange blossom honey, wafted from this evergreen climber as it produces its creamy tufts of intensely fragrant flower. Why it isn’t planted everywhere is a complete mystery to me. I think we have the only plant in North Oxfordshire, where it grows up the house wall as easily as ivy, but much more readily controlled. It could cover walls, fences, sheds, tree stumps and anything you care all the year round and never need attention. And then every late May you would be blown away by its wonderful scent.

Another figure who enlivened my days in the heart failure arena was John Cleland, a fervent campaigner against aspirin. I don’t know if a willow bough fell on young John’s jam-jar when he was fishing for sticklebacks by some boyhood Scottish brook, but his ardour against salicylates is remarkable. And gradually the medical world is having second thoughts on the subject. Two or three years ago, we were suggesting daily 75mg aspirin to everyone with diabetes, hypertension and/or peripheral vascular disease, and indeed to most patients with heart failure, but the evidence is remarkably thin. In this meta-analysis the effect of aspirin and or dipyridamole on cardiovascular events in PAD does not reach statistical significance. For nonfatal stroke alone, there is a protective effect.

NEJM  14 May 2009  Vol 2006
It seems that the more you inhibit platelet aggregation, the more you prevent strokes, while leaving total cardiovascular mortality relatively unaffected. This is true of the ACTIVE A study reported here; combining aspirin with clopidogrel in atrial fibrillation achieved a 28% reduction in strokes but the rates of vascular death in the aspirin-only and the combined group was identical. Also, while the difference in fatal strokes between the groups was 23 in favour of combined treatment, the difference in fatal bleeds was 15 against. So this study doesn’t quite show the clear advantage that might inspire you to audit all your AF patients unsuitable for warfarin and urge them to take clopidogrel with their aspirin.

This interesting Canadian study randomised 800 babies presenting to an emergency department with bronchiolitis to receive nebulised epinephrine (adrenaline), high dose oral dexamethasone (1mg/kg), neither or both. The oral steroids and the nebulised adrenaline did nothing on their own. But combined with each other, the effect was to reduce hospital admissions. This is nicely illustrated in the cumulative admissions plot in Figure 3, but alas, when the statisticians got to work adjusting for multiple comparisons, significance was no longer achieved. Even bigger studies are needed.

As far as I know, nobody ever died of crumbly toenails, but apparently people have been known to die from liver failure due to oral terbinafine. This article on fungal nail disease mentions this but doesn’t quantify it, and doesn’t even come off the fence completely about liver function testing. Cost is no longer a barrier to terbinafine prescribing, but I don’t know that I could face harming a patient to treat a harmless condition, so I think I will insist on LFTs before treatment and at 6 weeks. All other treatments are a waste of time.

Lancet  16 May 2009  Vol 373
I never grudge orthopaedic surgeons their expensive cars, because on the whole they do more obvious good to my patients than any other group of specialists. Whatever they may lack in communication skills and thinking outside the operating theatre, they make up for by fixing stuff. It took them a while to notice that immobile legs can get deep vein thrombosis, but now that realisation has dawned, thromboprophylaxis following total knee replacement has become routine. The nurses go round giving enoxaparin every 12 hours; but that may soon be a thing of the past. Each morning, as the orthopaedic surgeon throws his suit jacket into the back of the Porsche, the drug trolley will rumble round the ward laden with rivaroxaban, a fixed-dose oral factor Xa inhibitor, which proved superior to enoxaparin in this randomised trial (RECORD4).

Much of this week’s Lancet is taken up with high-level hand-wringing about climate change. Anthropogenic climate change needs an anthropogenic answer, and since anthropes rarely change behaviour in favour of greater discomfort and lesser wealth, this needs to go beyond mere exhortation. Non-anthropogenic climate change is even scarier; a mere 15,000 years ago the place where I am typing this was the terminal moraine of a vast glacier covering northern Europe. What worries me most is the fact that all the scientific solutions seem to be proposed by grey-heads of my age or older, while the youths who ought to be coming up with the goods are too busy flying off around the world career-building.

BMJ   16 May 2009  Vol 338
When the great Peter Medawar collected together his essays attacking bad science, he called the book Pluto’s Republic, after a malapropism attributed to an American lady of his acquaintance. PLUTO, the king of the underworld, also gives his name to this study – a “pragmatic multicentre randomised controlled non-inferiority trial” of the kind that Medawar might well have consigned to his infernal republic. I am inclined to be kinder, because it is difficult to study an intervention like ultraviolet B phototherapy for mild to severe psoriasis taken out into the community except in a fairly pragmatic, non-inferiority-seeking sort of way. The main point you need to establish is that patients can give themselves this therapy safely and effectively at home rather than having to come up to hospital all the time – and in this Dutch study, they could.

Fifteen years ago, a paper appeared from Dundee showing that levels of the then newly-discovered cardiac hormone B-natriuretic peptide were more predictive of heart failure and death following myocardial infarction than measurement of the systolic ejection fraction. This led me on a long wild-goose chase which ended when an MRC-funded pilot study showed that it was impossible to titrate individual treatment on the basis of BNP. Here a French study of elderly patients following MI confirms that BNP is a good prognostic marker: that’s the easy bit. What to do with that knowledge is still the problem – as discussed in the accompanying editorial.

I draw your attention to this short paper on streptococcal perianal infection in children not (heaven forbid) because it’s by me, but as a tale of perseverance akin to Robert the Bruce and his spider, designed to inspire you to write for the BMJ. In 1996, our then registrar Sarah Pinder did a nice little awareness and case-finding study of this topic, which showed that most local GPs had never heard of it, despite the likelihood that they were probably seeing it twice a year. We urged Sarah to write it up for the BMJ at the time, but instead she got married, had babies and moved to Australia. Not long after, a new serological test appeared that for the first time made it easy to diagnose coeliac disease, and I urged Harold Hin to do a case-finding study for that, as I’ve told you oft and anon. Meanwhile I was working with less effect on BNP. All this gave me the idea for a BMJ series called “Commoner than you think”, which I proposed to them in 2002. Sorry, too ill-defined, was the reply. Then in 2006, Fiona Godlee asked if I’d like to write something for her new-look journal, and I proposed the same idea again, but now as part of a bigger series on Diagnosis at Presentation. Eventually, with the invaluable help of Anthony Harnden and Mabel Chew, this bit became “Easily Missed”. Then I finally had to track down Sarah in Australia and produce draft after draft of this little piece, known in our household as “bums”. And now, 13 years on, it appears in print, complete with a picture of a bum. If you hadn’t recognised this condition before, you will now: and if that’s the case, it was all worth it.

Arch Intern Med  11 May 2009  Vol 169
The Beginning of a New Era for the Archives and the Nation, declares the new editor, Rita Redberg, modestly placing herself by the side of Barack Obama. Those interested in American health care reform ideas will have a lot of important reading in her journal and in the other two I report on, but I shall try to keep to my general rule of not commenting directly on matters of politics. I shall simply slave on here in Egypt, making bricks without straw under the rule of Lord High Darzi until he is replaced by another Pharaoh who knew not Joseph.

ALLHAT is one of those trials which will not go away, like UKPDS. Both of them could be said to have too many interventions and too many end-points, and have been the subject of much special pleading and unwarranted extrapolation. But both have unexpected and important lessons for clinical practice, confirmed by subsequent trials. In the case of UKPDS, it’s that blood pressure control is more important than tight glycaemic control, and that metformin is the most beneficial drug. In the case of ALLHAT, the message is that all drug classes for hypertension are equally good at reducing most cardiovascular end-points, and that thiazide diuretics may be the best because they prevent heart failure, and the hyperglycaemia they induce does not produce any adverse cardiovascular consequences.

Various medical conditions have from time to time been known as Syndrome X, indicating general mystification, and none is more mystifying than cardiac chest pain on exertion in women with normal coronary arteries. The Women’s Ischaemia Syndrome Evaluation Study (WISE) followed up women with ischaemic symptoms but normal coronary arteries for a mean of 5.2 years and compared them with a cohort of asymptomatic women from the St James Women Take Heart Study. The 540  “WISE women” (as the study describes them) did markedly worse than the Take Hearters. In women with 4 or more cardiac risk actors, their annual event rate exceeded 25% while it was 6.5% in the asymptomatic.

Pre-scientific medicine developed some pretty effective rituals for pain relief, the most impressive and persistent being acupuncture. This study, like many others, shows that it works well for a lot of people, whether you follow the traditional points or do it at random. To perform acupuncture, you just need a set of sterile long thin needles and an impressive manner. Exhibit charts of ancient Chinese pricks on the walls of your room. Enquire about the exact nature and location of the chronic low back pain and perform a slow and meticulous examination. It may help to insist that the patient comes in a loin cloth. After a period of serious contemplation, proceed to introduce the needles wherever you like. Make sure you charge a high fee. This increases your reputation and allows you to wear finer robes.

Plant of the Week: Iris “Black Swan”
All bearded irises are lovely, and with most the scent seems to complement the colour: a rich fruit salad smell from the pink and brown ones, something more exotic from the blues, and chocolate and liquorice from this almost black one. Definitely a flower to turn heads, especially when planted where the sun can shine through it, producing an effect like very dark stained glass.

I imagine that all the many iris varieties with “black” in their name are very similar. Split them regularly and give bits to admirers.

JAMA   6 May 2009  Vol 301
Homeless and ill in Chicago, which would you want most - a doctor or a roof over your head? This randomised trial offered chronically ill homeless people 18 months of guaranteed housing after hospital discharge, or usual care. Return visits to hospital were about a quarter fewer in the housed group. Civilisation is the building of cities, the encouragement of arts and learning from the interchange and wealth that they create, and the care of the poor. Not necessarily in that order.

Nobody seems very sure what the human nasal sinuses are there for. From the doctor’s point of view, they exist to cause facial pain, postnasal discharge and the unnecessary prescribing of antibiotics. All this is nicely discussed (with contributions from the patient) in a case-based discussion here, with pictures of what you might find in acute rhinosinusitis if you had a nasendoscope handy. Most acute sinusitis is viral, resolves within 10 days; by this time over 50% of bacterial sinusitis will also have resolved, as far as we can tell. The commonest bacterial pathogens are Streptococcus pneumoniae and Haemophilus influenzae, followed by Moraxella catarrhalis and Staphylococcus aureus. You can only tell which from cultures obtained from endoscopic sampling, and amoxicillin remains a sensible first-line choice of antibiotic. Wait for ten days, if you can persuade the patient to do so.

NEJM   7 May 2009  Vol 360
Coronary stents were quite a new thing when I started writing a few comments on medical journal articles ten years ago. They were all bare metal then, but trials soon appeared comparing radioactive stents (a very bad idea, causing arterial fibrosis) with stents which leach out (elute) immunosuppressant drugs such as sirolimus and paclitaxel. Coinciding with the widespread adoption of immediate percutaneous intervention for myocardial infarction, use of these drug-eluting stents shot up, and bare metal stents soon became yesterday’s technology. But was this just another triumph of marketing over evidence? It seems largely so, judging by this analysis of the Swedish Angiography and Angioplasty Registry which looks at 48,000 Swedes stented from 2003 to 2006. Overall, there was no difference in rates of death or myocardial infarction between those receiving bare metal or drug-eluting stents. Only if you take patients in the highest decile of risk can you find clear justification for using the expensive kind of stent.

OK, I know stents are boring, but bear with me for another sentence or two. The reason everyone started using drug-eluting stents was, once again, that all-pervading enemy of patient-relevant medicine, the important-sounding surrogate end-point (ISSEP). In this latest trial comparing paclitaxel-eluting with bare metal stents following myocardial infarction, the ISSEP is called binary restenosis. Within the first 12 months, patients receiving the two kinds of stent would have noticed no difference at all. Their rates of death and stent thrombosis were identical. But those receiving the drug-eluting stents showed a lower rate of binary restenosis. Aha, that has to be good. Except that the Swedish data suggest it makes no difference to longer term outcomes in most patient groups.

People who have tried to eat the common earth-ball fungus report that it is rather nasty. It is called Scleroderma, meaning hard-skinned. Human scleroderma, or systemic sclerosis, is definitely nasty. This review is big on mechanisms - that is its brief - and light on management. The traditional NEJM colour scheme, based on haematoxylin-eosin staining, is subtly varied with blues and greens in the illustrations. Lots of different cellular mechanisms might lead to the overproduction of collagen and other glycoproteins which characterises this distressing disease, but nobody has yet found a reliable way of switching them off.

Lancet   9 May 2009  Vol 373
Last week I voiced the opinion that few health issues had greater global importance than the prevention of type 2 diabetes. This study of voglibose makes me wish I hadn’t put it that way. It charts the progression of 1780 Japanese “patients” from impaired glucose tolerance to type 2 diabetes. These people were not ill at all: they simply had some evidence of compromise to their beta-cell function, causing some of them to go from one arbitrary threshold up to the next. “Impaired glucose tolerance” and “type 2 diabetes” are not diseases in themselves, they are labels. They are also ISSEPs, important-sounding surrogate end-points for a process we half understand, and which unchecked can lead to patient-important end-points (PIEPs) such as myocardial infarction, visual loss, neuropathy or sepsis. This trial gets several black marks in my book: it compared one ISSEP with another; it compared an expensive new drug with placebo, instead of the best available comparator, which is metformin; it was industry-sponsored, and all the authors had taken fees from Takeda; there was a huge discontinuation rate; it was terminated too early to assess any PIEPs; the reporting of outcomes in the summary is arbitrary and sometimes inaccurate; and so on. Do a-glucosidase inhibitors have an important role to play in the prevention of the risks associated with increasing blood sugar levels? This study doesn’t give me a clue.

While I’m in drum-banging mode, I would say that few interventions are more important than resuscitation at birth, and if babies are to get the best chance of avoiding brain damage, this needs to be done by somebody good at it as quickly as possible, i.e. by a paediatrician, in a hospital. My “conflict of interest” here is that I have fought a long battle to prevent our local obstetric unit from being downgraded to a large midwife-led unit, more than 45 minutes from any paediatric or obstetric help. This study from Bristol shows that babies who require resuscitation have an increased risk of a low IQ score at 8 years of age, regardless of their apparent health in the neonatal period.

Intracerebral haemorrhage is a gloomy topic, and I really admire those who have attempted to do randomised trials in a situation as urgent and hazardous as this. People have tried dissolving the clot with urokinase and aspirating it stereotactically; limiting its spread with activated recombinanat factor VII; or limiting its damage with neuroprotectant drugs: all to no avail in terms of patient outcomes. The aspects of management that still matter most are secondary ones such as stopping gastric bleeding (which is present in 30% of cases) and lowering blood pressure.

BMJ   9 May 2009  Vol 338
I’m all for the BMJ publishing papers that will improve clinical practice in primary care, which is why I’ve put a lot of time and effort into promoting two series in the Practice section and helping to edit one. But I find this research paper from the Netherlands (helped by the Welsh) a bit puzzling. The aim seems to be to reduce antibiotic prescribing for lower respiratory tract infection. Even the full text of the article (on the website) doesn’t contain enough evidence to satisfy me that this is a safe and laudable aim, or that there was a robust case definition for LRTI in this study. The choice of interventions in this cluster randomised trial was normal care, care guided by measurement of C-reactive protein, or care following a focussed communications skill course. The primary outcome was antibiotic prescribing. This was just over 50% in the non-testing, non-trained group and 25-30% in the other groups, including a group that used both CRP and communications skills. A good study to stimulate discussion; less good to change clinical practice, at least for an old lag like me.

The original title for the series that Anthony Harnden and I proposed to the BMJ was Commoner Than You Think? but on the whole the final title Easily Missed? is better. This is well illustrated by Kawasaki disease, and here is a full clinical review written by Anthony as main author, outside our series. Kawasaki disease is not, as far as we know, commoner than most doctors think: in the UK it is so uncommon that most GPs will never see a case. But if they do, then they must try not to miss it. Treatment with immunoglobulin in the first 10 days can reduce life-threatening complications. I know I’m biased, but I can’t think you’re going to find a better guide to it than this: pore over the pictures, look out for the baby or child who is iller than her/his fever warrants; and don’t wait for desquamation of the fingers, because by then the coronary arteritis will already have happened.
P.S. Note that this condition, first described by Kawasaki, is never referred to as Kawasaki’s disease, on either side of the Atlantic. It therefore breaks the usual rules that govern the medical eponymous genitive. Like you care.

Ann Intern Med  5 May 2009  Vol 150
The optimal duration of anticoagulation following deep vein thrombosis depends on the balance between the likelihood of recurrent DVT versus the bleeding risk from continued warfarin. This Italian trial (AESOPUS) went on for 7 years but still doesn’t provide a very clear steer on whether it is useful to perform repeat ultrasonography at 3 months as a guide to continuing anticoagulation at this point. I won’t try and go into detail but there is a suggestion that outcomes may be better if you adopt the strategy of stopping warfarin at 3 months if the USS shows clear veins, but continuing it for 9-21 months if the veins still look blocked; but you will double the rate of major bleeds.

A lot of us wish that prostate specific antigen testing had never been invented, because its value as a prognostic marker in advanced disease is outweighed by its Perfectly Stupid Attributes as a screening test. This study of molecular markers for risk of death from prostate cancer confirms what we were taught as medical students: prostate Ca for most men over 70 is a disease they die with rather than die from - that was true of 78.5% of the men in this study which followed up mainly moderately-differentiated tumours. The Gleason score remains a good basic indicator, but the authors here have come up with three added tissue sample tests which provide some incremental refinement.

Plant of the Week: Paeonia mlokosewitschii
Pardon me, but I can’t help praising this exquisite flower every year at the time of its appearance. Here is Reginald Farrer trying to remember how to spell its name and what it looks like, holed up in remote Western China in 1913 with a case of whisky and his trusty companion Bill Purdom:

“P. Mlokosievitschii. - This pleasant little assortment of syllables should be practised daily, but only before dinner (unless teetotal principles of the strictest are adopted), by all who wish to talk familiarly of a sovereign among Paeonies - a rare plant, and rendered almost impregnable by its unpronounceable name. It has an ample habit and lovely dark foliage, amid and above which are borne huge flowers like strayed water-lilies of delicate saffron or citron yellow. It is in the wilds of the Caucasus that this temptation has its lair.”

The English Rock Garden 1918

In fact its wide-lobed leaves are of a light rather than a dark green, and the flowers can be of light buff mixed with pink, in what some claim to be the species - though never having been tempted as far as its lair in the wilds of the Caucasus, I wouldn’t really know. All I know is that in its commonest and best form, Mollie-the-Witch of gardens, the big papery globe-flowers are of an indescribably soft yet intense pure yellow. For a few days each year they are the most beautiful thing in the garden.

Ludwik Franciszek Mlokosiewicz was a Polish explorer, zoologist and botanist (1831-1909). His name has been mangled by botanists, but he can hold no such grouse against zoologists, who get it right in Tetrao mlokosiewiczi, the Caucasian Black Grouse. Strange how people have such difficulty spelling and pronouncing Polish names: Polish is a euphonious language with simple and consistent rules of spelling in the Roman alphabet. Yet even I couldn’t spell or pronounce my father’s Christian name till I was about 13. Mieczyslaw.

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.

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.

Lancet 2 May 2009 Vol 372
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.

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.

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.

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.

BMJ 2 May 2009 Vol 338
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 …

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.

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 ß-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.

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.

Arch Intern Med 27 Apr 2009 Vol 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.

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.

This week Richard ponders continuity of care, hibernating myocardium, and whether gluten free bread came before gluten free pasta - or the other way round.

JAMA  22/29 Apr 2009  Vol 301
“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.

NEJM  23 Apr 2009  Vol 360
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.

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.

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”.

Lancet  25 May 2009  Vol 373
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.

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.

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.

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.

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.

BMJ   25 Apr 2009  Vol 338
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 accompanying a randomised controlled trial. 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.

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.

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.

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).

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.

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.”

This week, Richard immerses himself in diabetes (”What a mess”), before covering an extensive range of subjects from the polypill to suicide, IQ, hyperhidrosis, and “irritable” bowels - all the while planning to compile “The Good Death Cookbook” - maybe…

JAMA  15 Apr 2009  Vol 301
Diabetes: what a mess. You can get some idea of it from this week’s JAMA, which is devoted to the diseases which cause sugary urine. The DIAD study lumped together 1123 patients with “type 2″ diabetes - mostly a cyclical process of insulin resistance and progressive beta-cell failure. This confers a risk of coronary artery disease which varies from enormously increased in younger women to modestly increased in older men. The aim here was to discover and treat asymptomatic coronary artery disease and compare outcomes at a median of about 5 years. There was no significant difference. But the event rates were lower than predicted, which is something that always happens in cardiovascular trials these days, because so many patients are already on protective treatments. And the screening test was frankly rubbish: adenosine-stress radionuclide myocardial perfusion imaging, which had a positive predictive value of 12%.

Most dementia is vascular; most of it occurs in old people; and more of it occurs in old people with diabetes (hazard ratio 1.6). That’s all very straightforward, but how does treatment affect this outcome? Well, it probably cuts both ways, but the evidence isn’t all that good. This study of integrated health care records in California traces 16 667 patients with type 2 diabetes between 1980 and 2002 and finds that severe hypoglycaemia carries a risk of dementia proportionate to the number of episodes. Something to bear in mind if you believe in tight glycaemic control. On the other hand, a study which has just appeared on-line in Diabetologia (Xu WL et al) found that poor fasting blood sugar control (>7.8mmol/L) was associated with an increase in Alzheimer’s disease in their Swedish cohort of  1 475 elderly people with type 2 diabetes followed up for 9 years.

Let’s switch to youngsters who suddenly get type 1 diabetes. There is a whiff of optimism around them: a cure may even be within our grasp. This would have to arrest and reverse the auto-immune process which ends in total beta-cell destruction, and promising results were reported in 2007 using autologous nonmyeloablative haemopoietic stem cell transplantation. I’m not going to try and explain this to you: you can look it up in JAMA 2007;297:1599. Sceptics raised their eyebrows at reports of insulin independence in these 23 patients with newly diagnosed type 1 diabetes, aged between 13 and 31; but this report confirms that this has lasted for a mean of 31 months in 12 of the patients. Moreover, they show increasing levels of C-peptide, a marker for beta-cell function; so a cure may be on the cards for some of them. But against this, the procedure carries a risk of severe infection, late endocrine dysfunction and infertility.

So can diabetes be cured? Here’s a two-page whistle-stop guide to all the ways we might do it. Currently we can cure a few patients with type 1 using whole pancreas transplants, and a lot of patients with type 2 using bariatric surgery. So many, in fact, that some kind of rationing will need to be imposed, and another article argues that we should start with a BMI over 50.

The last year has seen the publication of three good long-term randomised trials - ACCORD, ADVANCE and VADT - proving that glycaemic control below HbA1c of 7 does not improve outcomes in type 2 diabetes. The only room for argument is about so-called “microvascular” outcomes - a curious rag-bag category which ranges from microalbuminuria to renal death and from background retinopathy to blindness. There was a 21% reduction in “nephropathy” from five years’ tight control in ACCORD, but I personally would not bargain a higher risk of hypoglycaemia for slightly less detectable protein in my pee when I’m 70-something, which is what this actually means. Read all about it in the editorial I wrote with Harlan Krumholz in this week’s BMJ. Then compare it with this piece about the three studies entitled “Glucose control in type 2 diabetes: still worthwhile and worth pursuing”. As Harlan headed his e-mail to me, “you gotta be kidding.”

NEJM  16 Apr 2009  Vol 360
The Intelligence Quotient (IQ) is about the most criticised measurement in the whole of science, but faute de mieux it’s the chosen one in this important study of fetal exposure to antiepileptic drugs. I’ve never tried to join MENSA or to test my own IQ, but I imagine that’s easy-peasy compared with doing it in three-year-olds. Anyway, that’s what the NEAD study did on an interim basis to 309 children born to mothers taking sodium valproate, phenytoin, carbamazepine or lamotrigine. The take-home message (if you believe it) is that valproate is the drug most likely to impair IQ and lamotrigine the least likely. More data from more IQ tests in three years’ time.

Among medics the best known Italian group after the Mafia is called GISSI - Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. Give yourself a treat, say it out aloud. For some reason, they decided it was worth studying the effect of valsartan on the recurrence of atrial fibrillation after cardioversion. Ecco, valsartan has no effect on recurrent AF.

The journals all have a bit about diabetes this week, and in this case it’s the genetics of type 1A diabetes. That’s plain type 1 to you and me, if you believe in these distinctions - for a sceptical view, download and keep Declassifying Diabetes, an entertaining editorial by EAM Gale, Diabetologia 2006;49:1989. Genome-wide studies have uncovered lots of risk loci, none of them worth committing to memory unless you are a seriously demented gene gnome. Essentially things have only got worse since 1976 when James Neel, a leading geneticist of the time, titled a book chapter “Diabetes Mellitus: A Geneticist’s Nightmare.”

Lancet  18 Apr 2009  Vol 373
Gah! Having waded through the diabetic mire for weeks, I’m not sure I can face another study with too many interventions and a mass of surrogate end-points. The original Polypill, you may remember, was a single tablet containing several ingredients, to be taken by everybody over a certain age, to save bothering with coronary risk scores. Here, by contrast, are several different Polycaps to be taken by a variety of different single-risk groups with ages between 45 and 80. The drugs in combination behave more or less exactly as you would expect them to. Simvastatin lowers cholesterol, aspirin reduces urinary thromboxane B2, atenolol lowers the pulse rate and blood pressure, ramipril and bendroflumethiazide just lower BP. The point being? I can’t tell you, because I can’t work it out. Even when it gets some real end-points, I can’t see what this study is going to prove.

The Lancet’s contribution to diabetic enlightenment this week is the CALDIRET study in which German ophthalmologists discover that calcium dobesilate does not prevent diabetic macular oedema. So that’s that for calcium dobesilate. But the editorial about the trial on p.1316 ends with an Icelandic riddle which I want you to think about:
“We should distinguish between the prevention of retinopathy and the prevention of diabetic blindness. Diabetic blindness can be reduced or prevented without preventing retinopathy. Systematic screening for diabetic retinopathy and preventive laser treatment for those who develop macular oedema or proliferative retinopathy reduces the rate of blindness to about 0.5% in the diabetic population, irrespective of the prevalence of retinopathy.”
If I read this right, the 25% reduction in “microvascular endpoints” reported in tight control group of UKPDS, which consisted largely of diabetic retinopathy, has no meaning for the patient important outcome, which is visual loss. Blimey, I am losing the will to live.

So on to suicide. Here’s a longish seminar on the subject, full of interesting detail. International differences in suicide rates are very striking. Social factors, the availability of methods, and even the media coverage of prominent examples all seem to have a stronger influence than medical interventions. Nonetheless, it’s possible that primary care detection and treatment of depression may have a small role in preventing suicide.

I was hoping that mitral regurgitation might provide an oasis of mechanical simplicity in a somewhat gruelling week of medical reading: but not so. The valve itself looks deceptively simple but it gets distorted by whatever is happening to the left atrium and especially the left ventricle. You can look at lovely coloured whooshes of blood on Doppler echo but knowing when to intervene and how is anything but simple. It is particularly tricky to work out the chicken-and-egg situation of “functional” MR in heart failure, where the ventricular remodelling distorts the valve, the leakage of blood back into the atrium distorts the atrium, and atrial dilatation further opens the valve. This is not good news for the failing heart. But intervene at your peril.

BMJ  18 Apr 2009  Vol 338
Here’s the abbreviated version of a Swedish study of the effect of exercise in middle-aged men on their eventual longevity. Doing exercise between the ages of 50 and 60 has no immediate effect on mortality, but look again ten years later and the effect is as large as giving up smoking. Alas, for me, it may be too late because (a) I have only one year left before 60, (b) if I increase my exercise now I may actually increase my immediate mortality risk and (c) I’m too busy writing these things.

If you’re the kind of doctor who looks after burns and scalds, here’s a nice clear clinical review. It seems that there haven’t been any major advances in recent years, and it’s high time we got some new ways to deal with large area burns.

The educational pages of the BMJ win out over the research studies almost every week, and I certainly learnt something from this “Patient’s Journey” piece about hyperhidrosis. I was vaguely aware that there was a treatment called iontophoresis but no patient of mine has ever accessed it and I was quite unaware of how life-changing it can be. On the other hand, it does have to be given once a week and nobody quite knows how it works. There is a useful list of support groups.

Obstructive sleep apnoea in adults: do you miss it? Read this short piece to find out. OK, this is just a short plug for our new series Easily Missed. Suggestions for new topics are always welcome.

Arch Intern Med  13 Apr 2009  Vol 169
“Irritable Bowel Syndrome” is a dustbin diagnosis and I long for some rational means of explaining it to patients and some rational way to treat it. When serological testing for coeliac disease became available in the mid-1990s, I was sure that a trawl through our IBS patients would yield rich pickings, and that was the basis for my work partner Harold Hin’s landmark case finding study published in 1999. But we actually failed to find an increased prevalence in IBS. Others have done larger studies since then, and here is a systematic review. On the whole, coeliac disease is four times as prevalent in people with “irritable” bowels.

It sometimes seems to me that I am the only person who doesn’t know what unhealthy food is. I even thought of compiling a book called The Good Death Cookbook, junking the idea that you can stay healthy by avoiding certain types of food. Eat what you like, provided it includes lots of fresh fruit and vegetables, and just the amount of energy you need. Here is an attempt to review all the evidence supporting a causal link between dietary factors and coronary heart disease. I am delighted to see that there is insufficient evidence to exclude any kind of food, including saturated fat, meat or eggs; salt isn’t even mentioned. On the other hand, there is good evidence to yum up monounsaturated fat and eat like a Mediterranean.

Having eaten your Mediterranean food, you need to burn it off. This cluster randomised trial was conducted in Bilbao and Toledo - more Atlantic than Mediterranean bits of Spain - and assessed exercise prescribed in primary care. It provides some evidence that Spaniards who take too little exercise take a bit more when it is offered to them by their GPs.

Plant of the Week: Koelreuteria paniculata

I love trees with shrimp-pink new foliage in the spring. The one most often grown is Acer pseudoplatanus “Brilliantissimum”, which lives up to its name for a short season, though it is better to grow the related clone “Prinz Handjery” for leaves that don’t brown off so readily, and also for its frequent yellow flower spikes. Another slow-growing aristocrat is the little horse chestnut which sounds like a haematological malignancy, Aesculus erythroblastos. This produces wonderful tiers of pink fingers followed by typical horse chestnut flowers a week or two later. But perhaps the best all-year value is provided by this small tree or large shrub, the Golden Rain Tree.

I say small tree, because that is what it is likely to be in central England; in a favoured European spot, it might reach 20m, and the one in Sydney Botanical Garden grows well above that. At this point in the English spring, the tree is bursting with flame-like projections of flesh pink, which in time will become dark green pinnate leaves of uniquely complex form. Then in August, it will cover itself in panicles of golden yellow flower. As autumn sets in, these will produce bladder-like fruits and the leaves will turn bright yellow. What more can you ask? Scent, I suppose, and blue flowers, but our climate will never, alas, support the jacaranda tree.

Make do with this, if you have space. And try throwing a viticella clematis up it, to flower darkly amidst its golden rain.