BMJ  2006;333:387-388 (19 August), doi:10.1136/bmj.333.7564.387

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Length variability in -synuclein gene predisposes to Parkinson's disease

The aetiology of Parkinson's disease is largely unknown, but genetic factors may be implicated. The most promising association of a gene with susceptibility for Parkinson's disease seems to be that of the -synuclein gene, but previous studies gave conflicting results.

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A collaboration of 18 teams of researchers worldwide analysed published and unpublished individual data for more than 5000 people. They found that variability in the length of a dinucleotide repeat sequence (REP1) in the promoter of the -synuclein gene was associated with susceptibility to Parkinson's disease: the 263 base pair allele conveyed an increased risk of developing the disease, whereas the 259 base pair allele seemed to be protective. However, the gene variants did not seem to modify the age of disease onset.

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The gene codes for the -synuclein protein, which is abnormally aggregated in the neurones of people with Parkinson's disease, although only about 1% of people with the disease have a mutated -synuclein gene. The -synuclein protein is also the major compound of Lewy bodies, the pathohistological marker of Parkinson's disease. If overexpression of the -synuclein gene was a common underlying pathophysiological mechanism in people with the disease, this would offer opportunities for new drugs targeted at reducing expression of the gene. As yet, however, there is no robust evidence for this. Large longitudinal studies are needed to assess whether the gene has a modifying effect on the course of the disease.

JAMA 2006;296: 661-70[Abstract/Full Text]

Adherence to antiretroviral treatment is high in Africa

Concerns raised over the ability of people infected with HIV in sub-Saharan Africa to adhere to antiretroviral treatment seem to contribute to delayed access to treatment. A recent meta-analysis showed that these concerns are unjustified.

A comprehensive search for available data on adherence rates found 31 studies (17 573 patients) from North America and 27 studies (12 116 patients) from 12 countries in sub-Saharan Africa. In North America it was estimated that 55% (95% CI 49% to 62%) of patients achieved adequate adherence, whereas the corresponding figure for Africa was 77% (68% to 85%). The quality of studies was comparable between the two continents, with most studies relying on patients' self reports and pill counts.

It seems that assertions about low rates of adherence among poor people might have been based on misinterpretations of the evidence from North America. Poor adherence reported among individuals living in poverty in North America seems to be due to poor patient-doctor relationships, untreated depression, substance misuse, and other factors that are common among poor people in North America, rather than poverty itself.

Formulating policies based on assumptions may leave millions of people without effective treatment, say the authors. The World Health Organization has estimated that, of those people who urgently require antiretroviral therapy, the proportion who are actually receiving it is 10% in Burkina Faso, 16% in Cameroon, 5% in Côte d'Ivoire, 3% in the Democratic Republic of Congo, 14% in Malawi, 8% in Nigeria, 13% in South Africa, and 3% in Tanzania.

JAMA 2006;296: 679-90[Abstract/Full Text]

Gene model improves accuracy of prognosis in lung cancer

A prognostic model that incorporates gene expression profiles seems to be a significantly better predictor of the risk of recurrence of non-small cell lung carcinoma after surgery than a model that incorporates only clinical staging. This could ultimately translate into better choice of candidates for adjuvant chemotherapy and better long term outcomes for these patients. Currently, patients with clinical stage IA cancer undergo surgery followed by observation. About a quarter of these people have a recurrence of disease and seem to be candidates for more aggressive treatment.

The study authors used genetic data from 89 patients with early stage disease to create the lung metagene model, which was validated in two independent cohorts of patients comprising a total of 109 patients. The model's overall predictive accuracy was 72% in one cohort and 78% in the other.

Although various gene expression models have been developed, this is the first time that such a model seems to offer opportunities for improving clinical decision making. The authors call for a randomised controlled trial to test whether the current standard of care would be improved by using the new genomic tool to guide use of adjuvant chemotherapy.

N Engl J Med 2006;355: 570-80[Abstract/Full Text]

Vaccine reduces incidence of H influenzae type B disease in Kenya

Most African countries lack surveillance systems for registering infection with Haemophilus influenzae type B. The incidence of invasive disease is unknown, and few countries have introduced routine vaccination with conjugate vaccine since it became available in 1991.

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In 2000 a surveillance system was set up in the Kifili district of Kenya, which has a population of children under 5 years old of about 38000. In 2002 routine three dose vaccination with Hib conjugated vaccine was introduced for infants at 6, 10, and 14 weeks old. The incidences of invasive H influenzae type B disease in children aged under 5 (one year before and one and three years after vaccination was introduced) were 66, 47, and 7.6 per 100 000, respectively. The corresponding figures for children younger than 2 years were 119, 82, and 16 per 100 000. In the third year after the vaccine was introduced the incidence of invasive disease fell to 12% of that at baseline. The vaccine effectiveness was 88%, similar to that in other settings.

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Although secular trends in other relevant epidemiological variables might have contributed to the change in the incidence of disease, the authors argue that the marked reduction in the incidence was primarily due to the vaccination programme. A control surveillance of invasive pneumococcal disease showed no significant change during the observed period.

JAMA 2006;296: 671-8[Abstract/Full Text]

Statins reduce the risk of ischaemic stroke after recent transient ischaemic attack or stroke

High doses of statins seem to reduce the risk of ischaemic stroke in people without known coronary heart disease and low density lipoprotein cholesterol concentrations of 2.6-4.9 mmol/l who recently had transient ischaemic attack or a stroke. The trial randomised more than 4700 eligible patients to 80 mg of atorvastatin a day or placebo.

After a median follow-up of five years, people taking statins were less likely to have had another stroke than those taking placebo (adjusted hazard ratio 0.84 (95% CI 0.71 to 0.99), P = 0.05). They were also less likely to have a major cardiovascular event during follow-up (hazard ratio 0.80 (0.69 to 0.92), P = 0.002).

However, overall mortality was similar in the two groups (P = 0.98). People taking atorvastatin had an increased risk of haemorrhagic stroke (adjusted hazard ratio 1.66 (1.08 to 2.55)) and higher values of liver enzymes.

The authors discuss why a previous large trial did not find this effect. The most likely explanation seems to be the timeliness of starting statins. In this latest trial, people started statins between one and six months after the first event, compared with several years in the other trial.

N Engl J Med 2006;355: 549-59[Abstract/Full Text]

Inhibition of interleukin 1 works for neonatal-onset multisystem inflammatory disease

Neonatal-onset multisystem inflammatory disease, or chronic infantile neurological cutaneous articular syndrome, is a rare hereditary systemic autoinflammatory disease characterised by fever, urticaria, aseptic meningitis, deforming arthropathy, hearing loss, seizures, and mental retardation. The most common associated mutation is that of a cold-induced autoinflammatory syndrome 1 (CIAS1) gene, which encodes cryopyrin—a regulator of inflammation. Current standard treatment is based on high doses of corticosteroids, anti-rheumatic drugs, and biological agents that target tumour necrosis factor, but this has only limited results, and in most affected people the disease is chronically active.

A series of 18 patients, aged between 4 and 32 years, reacted remarkably well to anakinra, an antagonist of interleukin 1 receptor, given subcutaneously in a dose of 1-2 mg/kg body weight/day. Within days of starting treatment, all patients' daily symptom scores markedly improved when compared with baseline. After three months, levels of serum amyloid fell from a median of 174 mg/l at baseline to 8 mg/l, C reactive protein fell from 5.29 mg/dl to 0.34 mg/dl, and the erythrocyte sedimentation rate fell from a median of 57.7 mm in first hour to 18.0 mm. Magnetic resonance imaging showed structural improvements in the inner ear and the brain.

Withdrawal of treatment in 11 people led without exception to a relapse within days, with rapid improvement of symptoms after anakinra was reintroduced. No difference in response to treatment was observed between people with a mutated CIAS1 gene and those without the mutation.

N Engl J Med 2006;355: 581-92[Abstract/Full Text]

Endarterectomy or stenting for carotid disease?

Although guidelines uniformly recommend that endarterectomy be performed soon after an ischaemic event in patients with moderate to severe carotid stenosis, angioplasty and stenting have increasingly been used as alternatives. A Cochrane systematic review of randomised trials from 2005 compared the two approaches but concluded that there was no evidence on which to base a change of recommendations.

This new trial would double the number of patients in an updated review, but it doesn't seem to have the potential to change its conclusions. The trial recruited 1200 people with severe carotid stenosis within 180 days of transient ischaemic attack or moderate stroke. The one sided P value for non-inferiority of stenting was 0.09, indicating a 9% chance of erroneously concluding that stenting is not inferior to endarterectomy.

The predefined non-inferiority margin of 2.5% or more was not met: the absolute difference in the primary outcomes was 0.51% (90% CI - 1.89% to 2.91%). All 30 day outcomes were the same in both groups, but haemorrhagic ipsilateral stroke and death showed a tendency towards better results with endarterectomy. The trial also failed to show that angioplasty and stenting might be safer than endarterectomy.

The accompanying commentary (doi: 10.1016/S0140-6736(06)69123-X) warns that no evidence favours one treatment over the other, and says that this latest trial "has provided surgeons and interventionists with evidence to support their personal prejudices." We await results from other large ongoing trials.

Lancet 2006 doi: 10.1016/S0140-6736(06)69122-8

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