Science 14 March 2008: Vol. 319. no. 5869, p. 1471
NEUROSCIENCE: Hiding From Biting Insects in Plain Scent
Researchers report online in Science this week that instead of driving away biting bugs, the insect repellent DEET actually conceals us from them, dulling the insects' sensitivity to certain body odors.
Science 14 March 2008: Vol. 319. no. 5869, pp. 1495 - 1496
NEUROSCIENCE: A Quiescent Working Memory
Many of our actions or decisions are guided by what we experienced in the recent past.
Science 14 March 2008: Vol. 319. no. 5869, pp. 1523 - 1526
Amyloid Fibrils of the HET-s(218–289) Prion Form a β Solenoid with a Triangular Hydrophobic Core
Prion and nonprion forms of proteins are believed to differ solely in their three-dimensional structure, which is therefore of paramount importance for the prion function. However, no atomic-resolution structure of the fibrillar state that is likely infectious has been reported to date. We present a structural model based on solid-state nuclear magnetic resonance restraints for amyloid fibrils from the prion-forming domain (residues 218 to 289) of the HET-s protein from the filamentous fungus Podospora anserina. On the basis of 134 intra- and intermolecular experimental distance restraints, we find that HET-s(218–289) forms a left-handed β solenoid, with each molecule forming two helical windings, a compact hydrophobic core, at least 23 hydrogen bonds, three salt bridges, and two asparagine ladders. The structure is likely to have broad implications for understanding the infectious amyloid state.
Science 14 March 2008: Vol. 319. no. 5869, pp. 1536 - 1539
Neurokinin 1 Receptor Antagonism as a Possible Therapy for Alcoholism
Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.
Science 14 March 2008:Vol. 319. no. 5869, pp. 1543 - 1546
Synaptic Theory of Working Memory
It is usually assumed that enhanced spiking activity in the form of persistent reverberation for several seconds is the neural correlate of working memory. Here, we propose that working memory is sustained by calcium-mediated synaptic facilitation in the recurrent connections of neocortical networks. In this account, the presynaptic residual calcium is used as a buffer that is loaded, refreshed, and read out by spiking activity. Because of the long time constants of calcium kinetics, the refresh rate can be low, resulting in a mechanism that is metabolically efficient and robust. The duration and stability of working memory can be regulated by modulating the spontaneous activity in the network.
Nature 452, 220-224 (13 March 2008) | doi:10.1038/nature06563; Received 7 May 2007; Accepted 9 January 2008
Adaptive coding of visual information in neural populations
Our perception of the environment relies on the capacity of neural networks to adapt rapidly to changes in incoming stimuli. It is increasingly being realized that the neural code is adaptive, that is, sensory neurons change their responses and selectivity in a dynamic manner to match the changes in input stimuli. Understanding how rapid exposure, or adaptation, to a stimulus of fixed structure changes information processing by cortical networks is essential for understanding the relationship between sensory coding and behaviour. Physiological investigations of adaptation have contributed greatly to our understanding of how individual sensory neurons change their responses to influence stimulus coding, yet whether and how adaptation affects information coding in neural populations is unknown. Here we examine how brief adaptation (on the timescale of visual fixation) influences the structure of interneuronal correlations and the accuracy of population coding in the macaque (Macaca mulatta) primary visual cortex (V1). We find that brief adaptation to a stimulus of fixed structure reorganizes the distribution of correlations across the entire network by selectively reducing their mean and variability. The post-adaptation changes in neuronal correlations are associated with specific, stimulus-dependent changes in the efficiency of the population code, and are consistent with changes in perceptual performance after adaptation. Our results have implications beyond the predictions of current theories of sensory coding, suggesting that brief adaptation improves the accuracy of population coding to optimize neuronal performance during natural viewing.
JAMA Vol. 299 No. 10, March 12, 2008
Primary Care Screening for Dementia and Mild Cognitive Impairment
To the Editor: In their Commentary, Dr Brayne and colleagues raise many critical issues regarding the need to identify effective methods to screen for dementia. We suggest that this include detection of the mild cognitive impairment (MCI) syndrome, where there is objective decline in cognitive functioning. Longitudinal clinical studies indicate that participants with amnestic MCI have a substantially increased rate of progression to clinically probable Alzheimer disease.
JAMA Vol. 299 No. 10, March 12, 2008
Primary Care Screening for Dementia and Mild Cognitive Impairment
To the Editor: In their Commentary, Dr Brayne and colleagues contend that there is insufficient evidence to recommend screening for dementia in primary care. However, they acknowledge that the presence of dementia is widely missed by physicians. Professional organizations concerned with the health of older adults have called for diagnostic assessment of dementia when it is suspected. Screening is a valid approach for determining when there is a reasonable chance that dementia is present and increasing the proportion of cases detected.
JAMA Vol. 299 No. 10, March 12, 2008
Primary Care Screening for Dementia and Mild Cognitive Impairment—Reply
In Reply: In our Commentary, we concluded that at present there is insufficient evidence for the systematic introduction of dementia screening in primary care and recommended that the scientific community design and conduct a randomized controlled trial that would compare dementia screening to case-finding enhancement in regard to reducing the overall societal burden of dementia.
JAMA Vol. 299 No. 10, March 12, 2008
FDA Warns of Adverse Events Linked to Smoking Cessation Drug and Antiepileptics
Patients taking the smoking cessation drug varenicline or antiepileptic drugs may be at risk of developing severe neuropsychiatric symptoms, according to recent alerts from the US Food and Drug Administration (FDA).
BMJ 2008;336:515-516 (8 March), doi:10.1136/bmj.39482.666366.80 (published 14 February 2008)
Antidepressants and suicide Treatment is probably too sporadic to affect overall suicide rates
Two accompanying observational studies by Biddle and colleagues and Wheeler and colleagues add to the recent literature regarding changes in antidepressant use and changes in suicide rates. The current controversy began in 2003,whenreanalyses of data from clinical trials raised concerns that antidepressants might precipitate suicidal thoughts or attempts at suicide. Children and adolescents starting treatment with several newer antidepressants had a 4% risk of developing suicidal ideation or behaviour, compared with 2% in those receiving placebo. However, clinical trials cannot determine whether antidepressants increase or decrease the risk of genuine suicide attempts or death from suicide because these outcomes are, fortunately, too rare. No deaths from suicide and few attempts at suicide have occurred to date in trials of antidepressants in adolescents, so any clinical trial that could reliably assess effects on death from suicide would require several times more participants than have been included in all such trials to date.
BMJ 2008;336:516-517 (8 March), doi:10.1136/bmj.39510.531597.80 (published 4 March 2008)
Efficacy of antidepressants Is not an absolute measure, and it depends on how clinical significance is defined
In February 2008, Kirsch and colleagues reported a meta-analysis of the efficacy of antidepressants using data from clinical trials submitted to the Food and Drug Administration. They provocatively concluded, "there seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients." In January this year, we published an article about the selective publication of antidepressant trials and its influence on apparent efficacy, in which we also used FDA data. Our main finding was that antidepressant drugs are much less effective than is apparent from journal articles. From the FDA data we derived an overall effect size of 0.31. Kirsch and colleagues used FDA data from four of the 12 drugs we examined and calculated an overall effect size of 0.32.
BMJ 2008;336:539-542 (8 March), doi:10.1136/bmj.39475.603935.25 (published 14 February 2008)
Suicide rates in young men in England and Wales in the 21st century: time trend study
Objectives To explore trends in suicide in young people to investigate the recent observation that after year on year rises in the 1970s, 1980s, and early 1990s, rates in young men are now declining.
Design Time trend analysis.
Setting England and Wales, 1968-2005.
Population Men and women aged 15-34 years.
Results Since the 1990s, rates of suicide in young men have declined steadily and by 2005 they were at their lowest level for almost 30 years. This decline is partly because of a reduction in poisoning with car exhaust gas as an increased number of cars have catalytic converters; but there have been declines in suicides from all common methods, including hanging, suggesting a more pervasive effect. Other risk factors for suicide, such as unemployment and divorce, have also decreased. Possible recent reductions in alcohol use among young men and increases in prescribing of antidepressants do not seem to be temporally related to the decline in suicide.
Conclusions Suicide rates in young men have declined markedly in the past 10 years in England and Wales. Reductions in key risk factors for suicide, such as unemployment, might be contributing to lower rates.
BMJ 2008;336:542-545 (8 March), doi:10.1136/bmj.39462.375613.BE (published 14 February 2008)
The population impact on incidence of suicide and non-fatal self harm of regulatory action against the use of selective serotonin reuptake inhibitors in under 18s in the United Kingdom: ecological study
Objective To investigate the population impact on the incidence of suicide and non-fatal self harm of regulatory action in 2003 to restrict the use of selective serotonin reuptake inhibitors (SSRIs) in under 18s.
Design Ecological time series study.
Setting United Kingdom.
Populations Young people in the UK aged 12-19 years (prescribing trends), in England and Wales aged 12-17 years (mortality), and in England aged 12-17 years (hospital admissions).
Main outcome measures Deaths from suicide and hospital admissions for self harm.
Results Antidepressant prescribing doubled between 1999 and 2003 but fell to the 1999 level between 2004 and 2005. These large changes in prescribing did not seem to be associated with temporal trends in suicide or self harm. In the years 1993 to 2005 the annual percentage reduction for suicide among 12-17 year olds was –3.9% (95% confidence interval –6.2% to –1.5%) in males and –3.0% (–6.6% to 0.6%) in females, with no indication of a substantial change in this rate of decrease during that period. Similarly, hospital admission rates for self harm in the years 1999 to 2005 indicated an annual percentage increase for males of 1.1% (–0.5% to 2.7%) and for females of 5.7% (3.6% to 7.8%), again with no statistical evidence of a change in rate after the regulatory action.
Conclusions The noticeable reduction in prescribing of antidepressants since regulatory action in 2003 to restrict the use of SSRIs in under 18s does not seem to have been associated with changes in suicidal behaviour in young people. Specifically, these data for England do not indicate that reductions in antidepressant use have led to an increase in suicidal behaviour.
BMJ 2008;336:522 (8 March), doi:10.1136/bmj.39507.481840.80
Traumatic brain injury Time of hospital presentation may be important
The MRC CRASH trial collaborators’ simple prognostic model can be used to predict outcomes in patients with traumatic brain injury. Although the model considered time from injury to randomisation, the time at which the patient presented to hospital was not considered as a potential independent prognostic variable. This is important because provision of key aspects of hospital trauma services such as staffing, access to operating theatres, and interventional radiology is reduced after normal working hours.
The Lancet Volume 371, Issue 9615, 8 March 2008-14 March 2008, Page 809
Association between venous and arterial thrombosis
The possibility that venous and arterial thrombosis share similar pathophysiological mechanisms is a provocative and fascinating hypothesis. With their retrospective study, Henrik Toft Sørensen and colleagues (Nov 24, p 1773) lend support to such a hypothesis by showing an increased risk of myocardial infarction and stroke in patients with previous venous thrombosis or pulmonary embolism. In the accompanying Comment, Gordon Lowe suggests that, in patients who have venous and arterial thrombosis, the coexistence of classic risk factors of atherosclerosis such as smoking, obesity, and diabetes could favour thrombosis in the two circulatory districts.
The Lancet Volume 371, Issue 9615, 8 March 2008-14 March 2008, Page 809
Association between venous and arterial thrombosis
Henrik Toft Sørensen and colleagues' Article on the clinical coincidence of venous thromboembolism and ischaemic events in the systemic circulation (stroke or myocardial infarction) is insightful and stimulating. The hypotheses put forward of common triggers of venous and arterial thrombosis make sense, but seem farfetched compared with paradoxical embolism as a more plausible explanation.
Patent foramen ovale is discarded as a potential mediator too cavalierly by both Article and Comment. Neither was it looked for nor is there any mention of searching for completely normal cerebral or coronary arteries as indirect signs of paradoxical embolism as the reason for their occlusions. Patent foramen ovale has been shown to triple the stroke rate and more than double mortality in patients with clinically apparent venous thromboembolism. Moreover, embolic myocardial infarctions mediated by patent foramen ovale have been described iteratively.
The Lancet Volume 371, Issue 9615, 8 March 2008-14 March 2008, Pages 809-810
Association between venous and arterial thrombosis – Authors' reply
Francesco Violi, Lorenzo Loffredo, and Bernhard Meier raise two interesting questions about our paper on the association between venous thromboembolism and subsequent hospital admission for arterial cardiovascular events.
Violi and Loffredo refer to a low rate of venous thrombosis in patients with peripheral arterial disease reported in two published studies and suggest that the association between venous thromboembolism and arterial events could be independent of the pathophysiology of atherosclerotic disease. However, the studies did not include controls without cardiovascular disease, so those studies actually do not provide direct data on the association between peripheral vascular disease and venous thromboembolism.
The Lancet Volume 371, Issue 9615, 8 March 2008-14, Pages 813-820
Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study
Background
The increasing survival rates of children who are born very preterm raise issues about the risks of neurological disabilities and cognitive dysfunction. We aimed to investigate neurodevelopmental outcome and use of special health care at 5 years of age in a population-based cohort of very preterm children.
Methods
We included all 2901 livebirths between 22 and 32 completed weeks of gestation from nine regions in France in Jan 1–Dec 31, 1997, and a reference group of 667 children from the same regions born at 39–40 weeks of gestation. At 5 years of age, children had a medical examination and a cognitive assessment with the Kaufman assessment battery for children (K-ABC), with scores on the mental processing composite (MPC) scale recorded. Data for health-care use were collected from parents. Severe disability was defined as non-ambulatory cerebral palsy, MPC score less than 55, or severe visual or hearing deficiency; moderate deficiency as cerebral palsy walking with aid or MPC score of 55–69; and minor disability as cerebral palsy walking without aid, MPC score of 70–84, or visual deficit (<3/10 for one eye).
Findings
In total, 1817 (77%) of the 2357 surviving children born very preterm had a medical assessment at 5 years and 396 (60%) of 664 in the reference group. Cerebral palsy was diagnosed in 159 (9%) of children born very preterm. Scores for MPC were available for 1534 children born very preterm: 503 (32%) had an MPC score less than 85 and 182 (12%) had an MPC score less than 70. Of the 320 children in the reference group, the corresponding values were 37 (12%) and 11 (3%), respectively. In the very preterm group, 83 (5%) had severe disability, 155 (9%) moderate disability, and 398 (25%) minor disability. Disability was highest in children born at 24–28 completed weeks of gestation (195 children [49%]), but the absolute number of children with disabilities was higher for children born at 29–32 weeks (441 children [36%]). Special health-care resources were used by 188 (42%) of children born at 24–28 weeks and 424 (31%) born at 29–32 weeks, compared with only 63 (16%) of those born at 39–40 weeks.
Interpretation
In children who are born very preterm, cognitive and neuromotor impairments at 5 years of age increase with decreasing gestational age. Many of these children need a high level of specialised care. Prevention of the learning disabilities associated with cognitive deficiencies in this group is an important goal for modern perinatal care for children who are born very preterm and for their families.
The Lancet Volume 371, Issue 9615, 8 March 2008-14 March 2008, Page 870
Woke up paralysed—without injury or stroke
At 0930 h on April 1, 2004, a 35-year-old man was brought to our emergency department by autorickshaw. He usually worked in the city, but had spent a pleasant day's holiday working in the paddy fields—until waking up, at 0230 h, unable to move his limbs. He had felt perfectly well, retiring to bed at 2200 h. He had no medical history of note. His bladder and bowels were working normally.
His heart rate was 125 per min; his pulse was regular, and good in volume; his blood pressure was 160/110 mm Hg. The patient was taking 24 breaths per min, but maintaining arterial oxygen saturations of 97%. He had flaccid paralysis of all four limbs (power 0/5 throughout—hence, reflexes could not be elicited); however, sensory examination gave normal findings. So did examination of the cranial nerves—except that the facial muscles were weak throughout, giving the patient a myasthenic look. We observed alopecia areata.