Richard Lehman’s journal review – 9 August 2010

Richard LehmanJAMA  4 Aug 2010  Vol 304

This week’s JAMA is about the health consequences of violence. These are bad, and these articles just act as gloomy reminders of how bad they are, and how little medicine can do about them. I suppose it’s worth trying a brief intervention to reduce violence and alcohol abuse in adolescents who present to emergency departments (p.527), but the solution to the problem must lie elsewhere, though where I cannot tell you. Advocacy does not help the mental health of Chinese women survivors of intimate partner violence (p.536) according to a small trial conducted in Hong Kong, which I suppose is one of the few parts of China where the problem is even acknowledged. As for the Central African Republic (p.544) or the Democratic Republic of Congo (p.553), how ever are we going to address the human cost of so many decades of suffering and violence? I guess we all just feel a helpless horror, and move on to the next thing, glad that we are luckier. But it is not so long ago that it was perfectly respectable in our own culture to glorify violence, as I was reminded by reading a biography of Siegfried Sassoon over the last week. He and the other poets of the Great War 1914-1918 led us some years ago to visit Ypres where we saw the New Menin Gate. We were moved to tears and we then rushed off to visit the grave of a half-uncle of my wife’s, who died from gassing at the age of 18, a few weeks before the war ended. Sassoon’s reaction to the gate was rather different:

Who will remember, passing through this Gate,
The unheroic Dead who fed the guns?
Who shall absolve the foulness of their fate,—
Those doomed, conscripted, unvictorious ones?

Crudely renewed, the Salient holds its own.
Paid are its dim defenders by this pomp;
Paid, with a pile of peace-complacent stone,
The armies who endured that sullen swamp.

Here was the world’s worst wound. And here with pride
‘Their name liveth for ever,’ the Gateway claims.
Was ever an immolation so belied
As these intolerably nameless names?
Well might the Dead who struggled in the slime
Rise and deride this sepulchre of crime.

On Passing the New Menin Gate  1927/8

NEJM  5 Aug 2010  Vol 363

513   This is a good week for people with the uncommon autosomal dominant condition of C1 inhibitor deficiency, or hereditary angioedema. Or rather it is a good week for Americans with this condition. In Europe, blood-derived CI inhibitor concentrate has been available for 30 years but until last year no such rescue treatment was licensed by the American FDA due to fear of viral contamination. In fact no case of viral contamination has been reported from Europe and there have been no deaths here from hereditary angioedema; whereas there have been several deaths in the USA. This trial is designed to show the FDA that nanofiltered C1 inhibitor concentrate is safe and effective: which it is, as is un-nanofiltered CI inhibitor concentrate.

523   The next trial shows the FDA that there may be an alternative to C1 inhibitor concentrate which is not a blood product: a newly developed recombinant plasma kallikrein inhibitor called ecallantide. I first came across kallikrein as a medical student in 1968 and I think this is the first time I have ever heard again of this egregiously named inflammatory substance. Well, knock out the kallikrein and you suppress the angioedema, according to this pharma-sponsored trial: but there are so few people with this condition that one wonders whether Dyax will find it worthwhile to market ecallantide.

532    The standard preventive treatment for HA is tranexamic acid, though the one patient I have ever treated for this condition doesn’t find it very helpful. Now there is icatibant, which ignores kallikrein but blocks another part of the inflammatory pathway, the bradykinin B2 receptor. In two studies here, it performs moderately well but again the manufacturer (Jerini) who paid for the trials may not have scored a big enough bull-eye to make it worth marketing.

552    Hypertrophic cardiomyopathy is also a heritable condition, considerably commoner than hereditary angioedema. Those who are going to get it carry sarcomere-gene mutations which can lead to myocardial fibrosis and eventually to the clinical syndrome of heart failure with a hypertrophic ventricle. Tracing the pre-clinical course of this process is a delicate high-tech business involving genomic analysis, repeated cardiac MRI, and levels of serum biomarkers. This is not the sort of stuff that you and I get up to much, even in our spare time, but it’s nice to know that somebody is doing it. With the right screening biomarker – which may be serum-C-terminal propeptide of type 1 procollagen (PICP) – we may be able to pick out the people at risk at the early stages of myocardial fibrosis and do something about it.

564   Transverse myelitis is rare, and long may it remain so. I’ve seen one possible case in my working lifetime: the incidence is 1.3-8 per million. This is in about the same ball park as lightning strikes on human beings; and just as it takes millions of lightning bolts to strike one person, it takes millions of infections and immunisations to cause one case of TM. For this reason, we know very little about how to treat it, and this clinical review is strong on description but weak on interventions.

Lancet  7 Aug 2010  Vol 376

419    The ACCORD trial, you will remember, was stopped early because of a 22% increase in mortality among the group randomised to tighter glycaemic control of longstanding type 2 diabetes. By a variety of means, the glycated haemoglobin of the intervention group had been brought down to a median of 6.3% compared with 7.6% in the usual care group. The trial has been criticised for the zeal with which the investigators pushed the sugar levels down, causing a threefold increase in severe hypoglycaemia, but they have already demonstrated that this was not the cause of the mortality difference. Here they demonstrate that the effect on microvascular outcomes in their study was non-significant – something we already knew. By a good deal of special pleading you can just about argue for a benefit to the eye, and this is what the accompanying editorial tries to do (p.391). With tighter control of glucose, says this ophthalmologist on scant evidence, we might be able to avoid a lot of cataracts. However, I would rather be alive with a lens implant than dead with a normal eye.

431   The major trials which overturned orthodoxy about glycaemic control in type 2 diabetes were published over two years ago, but change has been slow in coming: NICE/QOF has only just announced the U-turn which I and Harlan Krumholz urged on it 16 months ago. Drugs for diabetes continue to be advertised on the basis that they get glycated Hb down below 7.5. The trouble is, one wishes them well: we badly need new drugs which will improve outcomes in type 2 diabetes. But what  outcomes? Glycated Hb, microalbuminuria, changes in lipid fractions, and even measures of beta-cell function have all proved useless predictors in the past. Weight loss and freedom from hypoglycaemia may not predict long-term benefit either, but at least they are patient-important short-term benefits. So good luck (pending further data on hard outcomes) to once-weekly exenatide, which when added to metformin clearly outperforms sitagliptin or pioglitazone on these criteria in the DURATION-2 study.

440   Ten rabbits were sacrificed for this study; enough for a rather large pie, and enough perhaps to change the future of joint replacement. Some of these animals had their hip joints excised and replaced with a bioscaffold: within weeks they had grown new hip joints and were running around as if nothing had happened. So how do you do this in humans? You can try and learn from the editorial on p.394, but I wouldn’t recommend it: your eye will keep falling on the Figure of a man with an excised knee joint stuck to his back. Salvador Dali meets the Hammer House of Horror.

BMJ  7 Aug 2010  Vol 341

288   Lots of brain MRI reports mention “white matter hyperintensities of uncertain clinical significance”. What these really mean is generally anyone’s guess, as a bunch of widely heterogeneous studies show in this systematic review. But the two Nordic professors who write the editorial about them (p.259) guess that they must be very serious indeed and should lead to screening for risk factors for stroke and dementia, whatever these risk factors may. Blood pressure? Educational status? Smoking? Sure, if you lump all the studies done in the general population you can come up with a threefold risk of stroke and a double risk of dementia, but this strangely melts away when you look at high risk populations. Until we can tell patients something sensible about these lesions, I suggest saying as little as possible.

289    Here’s the meta-analysis of calcium supplements in relation to risk of myocardial infarction that caused all the fuss. These were calcium supplements without vitamin D given in placebo-controlled trials, none of them with MI as a primary end-point. Almost all the calcium supplements most doctors prescribe have added vitamin D so I wouldn’t have thought this paper worth commenting on except that it has produced so much anxiety, and an editorial from the cardiology professor John Cleland (p.260) in which he airs his strong views on the treatment of osteoporosis and the duration of drug patents. I have often heard John express strong opinions, but never before on these particular subjects. I suppose that like me he has grown weary of heart failure and aspirin.

Ann Intern Med  3 Aug 2010  Vol 153

    It starts early, as they found when they looked at fatty deposits in the coronary arteries of American servicemen killed in Vietnam. But what, exactly, is “it”? Here in the CARDIA study it is a coronary calcium score, measured in middle age and then compared with lipid fraction levels 15 or 20 years previously. The higher your LDL-cholesterol when you’re 30ish, the more calcium there is likely to be in your coronaries when you’re 45ish. But the “it” that matters is symptomatic, life-shortening coronary artery disease and I don’t think this study tells us anything definite about that.

153    Fortunately my BMI is static at about 28, ideal for a man of my age. I therefore eat as much as I like of whatever I like. But what if I needed to lose weight, as I keep thinking I might have to? I would definitely go for unlimited fat and protein and miss out on bread and stuff. A low fat diet would be tedious, although it can result in equal weight loss. After all, the main aim of a good meal is to eat as much fish and butter as possible: and a high fat and protein diet results in a better lipid profile at 2 years. This is just the latest study to illustrate this of a low glycaemic index diet, a possible advantage which pales into insignificance beside the culinary benefit.

Plant of the Week: Tamarix ramosissima

I am at heart a trees-and-shrubs gardener, but the problem is that there are so few trees and shrubs that flower after the end of June. One solution is to fling a late-flowering clematis into every large plant that gets boring in the summer, and this I strongly recommend. Brother Stefan Franczak of Warsaw (1917-2009) dedicated his life to prayer and providing the world with hybrids to fit this purpose, with names chosen to annoy the Communist government under which he spent much of his life. “Polish Spirit” is the most famous, but there are about a hundred others, and the tradition is being maintained worthily by Szczepan Marcziński.

Still, that does leave the enterprising gardener with a bit of a challenge in August. Surely there is something big that has half-decent flowers in the summer holidays? The late-flowering tamarisk that once bore the name of pentandra is worth a try. Only just, though, because it is no match for the spring-flowering tamarisk that is all flower and no leaf. Here the pink sprays have to compete with similar sprays of green. And the flowers gradually go brown and dusty, with a seaside look all too familiar in British August.