Science 4 July 2008:
Vol. 321. no. 5885, pp. 31 - 33
EPILEPSY: When Death Strikes Without Warning
After years of neglect, a devastating effect of epilepsy, sudden death, is drawing new scrutiny.

Science 4 July 2008:
Vol. 321. no. 5885, pp. 46 - 47
NEUROSCIENCE: The Scale of Experience
Specific cells in the hippocampus allow the rat brain to track spatial location at different scales.

Science 4 July 2008:
Vol. 321. no. 5885, pp. 47 - 48
SOCIOLOGY: Indirect Social Influence
To what extent are our decision-making and learning processes influenced indirectly by others?

Science 4 July 2008:
Vol. 321. no. 5885, pp. 48 - 50
NEUROSCIENCE: Transient Dynamics for Neural Processing
A computational view of how perception and cognition can be modeled as dynamic patterns of transient activity within neural networks.

Science 4 July 2008:
Vol. 321. no. 5885, pp. 53 - 57
Neuronal Diversity and Temporal Dynamics: The Unity of Hippocampal Circuit Operations
In the cerebral cortex, diverse types of neurons form intricate circuits and cooperate in time for the processing and storage of information. Recent advances reveal a spatiotemporal division of labor in cortical circuits, as exemplified in the CA1 hippocampal area. In particular, distinct GABAergic (-aminobutyric acid–releasing) cell types subdivide the surface of pyramidal cells and act in discrete time windows, either on the same or on different subcellular compartments. They also interact with glutamatergic pyramidal cell inputs in a domain-specific manner and support synaptic temporal dynamics, network oscillations, selection of cell assemblies, and the implementation of brain states. The spatiotemporal specializations in cortical circuits reveal that cellular diversity and temporal dynamics coemerged during evolution, providing a basis for cognitive behavior.

Science 4 July 2008:
Vol. 321. no. 5885, pp. 130 - 133
Sporadic Autonomic Dysregulation and Death Associated with Excessive Serotonin Autoinhibition
Sudden infant death syndrome is the leading cause of death in the postneonatal period in developed countries. Postmortem studies show alterations in serotonin neurons in the brainstem of such infants. However, the mechanism by which altered serotonin homeostasis might cause sudden death is unknown. We investigated the consequences of altering the autoinhibitory capacity of serotonin neurons with the reversible overexpression of serotonin 1A autoreceptors in transgenic mice. Overexpressing mice exhibited sporadic bradycardia and hypothermia that occurred during a limited developmental period and frequently progressed to death. Moreover, overexpressing mice failed to activate autonomic target organs in response to environmental challenges. These findings show that excessive serotonin autoinhibition is a risk factor for catastrophic autonomic dysregulation and provide a mechanism for a role of altered serotonin homeostasis in sudden infant death syndrome.

Science 4 July 2008:
Vol. 321. no. 5885, pp. 133 - 136
Myosin I Can Act As a Molecular Force Sensor
The ability to sense molecular tension is crucial for a wide array of cellular processes, including the detection of auditory stimuli, control of cell shape, and internalization and transport of membranes. We show that myosin I, a motor protein that has been implicated in powering key steps in these processes, dramatically alters its motile properties in response to tension. We measured the displacement generated by single myosin I molecules, and we determined the actin-attachment kinetics with varying tensions using an optical trap. The rate of myosin I detachment from actin decreases >75-fold under tension of 2 piconewtons or less, resulting in myosin I transitioning from a low (<0.2) to a high (>0.9) duty-ratio motor. This impressive tension sensitivity supports a role for myosin I as a molecular force sensor.

Science 4 July 2008:
Vol. 321. no. 5885, pp. 136 - 140
The Spread of Ras Activity Triggered by Activation of a Single Dendritic Spine
In neurons, individual dendritic spines isolate N-methyl-D-aspartate (NMDA) receptor–mediated calcium ion (Ca2+) accumulations from the dendrite and other spines. However, the extent to which spines compartmentalize signaling events downstream of Ca2+ influx is not known. We combined two-photon fluorescence lifetime imaging with two-photon glutamate uncaging to image the activity of the small guanosine triphosphatase Ras after NMDA receptor activation at individual spines. Induction of long-term potentiation (LTP) triggered robust Ca2+-dependent Ras activation in single spines that decayed in 5 minutes. Ras activity spread over 10 micrometers of dendrite and invaded neighboring spines by diffusion. The spread of Ras-dependent signaling was necessary for the local regulation of the threshold for LTP induction. Thus, Ca2+-dependent synaptic signals can spread to couple multiple synapses on short stretches of dendrite.

Science 4 July 2008:
Vol. 321. no. 5885, pp. 140 - 143
Finite Scale of Spatial Representation in the Hippocampus
To determine how spatial scale is represented in the pyramidal cell population of the hippocampus, we recorded neural activity at multiple longitudinal levels of this brain area while rats ran back and forth on an 18-meter-long linear track. CA3 cells had well-defined place fields at all levels. The scale of representation increased almost linearly from <1 meter at the dorsal pole to 10 meters at the ventral pole. The results suggest that the place-cell map includes the entire hippocampus and that environments are represented in the hippocampus at a topographically graded but finite continuum of scales.

Nature 454, 6-7 (2008)
Neuroscientist: my data published without authorization are 'misleading'
Max Planck researchers charged with misusing data.
The director of a top laboratory in Germany has charged that two of his former research students took data from his laboratory without his permission and published scientifically incorrect interpretations of them against his advice.
Neuroscientist Nikos Logothetis, of the Max Planck Institute for Biological Cybernetics in Tübingen, further claims that the journal involved, Human Brain Mapping, acted incorrectly by publishing the paper after he told them the data were inappropriate.

Nature 454, 114-117 (3 July 2008)
Functional asymmetry in Caenorhabditis elegans taste neurons and its computational role in chemotaxis
Chemotaxis in Caenorhabditis elegans, like chemotaxis in bacteria1, involves a random walk biased by the time derivative of attractant concentration, but how the derivative is computed is unknown. Laser ablations have shown that the strongest deficits in chemotaxis to salts are obtained when the ASE chemosensory neurons (ASEL and ASER) are ablated, indicating that this pair has a dominant role. Although these neurons are left–right homologues anatomically, they exhibit marked asymmetries in gene expression and ion preference. Here, using optical recordings of calcium concentration in ASE neurons in intact animals, we demonstrate an additional asymmetry: ASEL is an ON-cell, stimulated by increases in NaCl concentration, whereas ASER is an OFF-cell, stimulated by decreases in NaCl concentration. Both responses are reliable yet transient, indicating that ASE neurons report changes in concentration rather than absolute levels. Recordings from synaptic and sensory transduction mutants show that the ON–OFF asymmetry is the result of intrinsic differences between ASE neurons. Unilateral activation experiments indicate that the asymmetry extends to the level of behavioural output: ASEL lengthens bouts of forward locomotion (runs) whereas ASER promotes direction changes (turns). Notably, the input and output asymmetries of ASE neurons are precisely those of a simple yet novel neuronal motif for computing the time derivative of chemosensory information, which is the fundamental computation of C. elegans chemotaxis. Evidence for ON and OFF cells in other chemosensory networks suggests that this motif may be common in animals that navigate by taste and smell.

Nature 454, 118-121 (3 July 2008)
Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving
Relapse to cocaine use after prolonged abstinence is an important clinical problem. This relapse is often induced by exposure to cues associated with cocaine use. To account for the persistent propensity for relapse, it has been suggested1 that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high for extended periods. We and others identified an analogous phenomenon in rats that was termed 'incubation of cocaine craving': time-dependent increases in cue-induced cocaine-seeking over the first months after withdrawal from self-administered cocaine. Cocaine-seeking requires the activation of glutamate projections that excite receptors for -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens. Here we show that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2). Furthermore, we show that these new receptors mediate the incubation of cocaine craving. Our results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. We propose that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.

JAMA. 2008;300(1):81-90.
A 70-Year-Old Man With a Transient Ischemic Attack Review of Internal Carotid Artery Stenosis
Mr V, a man with severe coronary, aortic, and peripheral artery disease, had an episode of brain ischemia caused by severe preocclusive carotid artery disease in the neck. The major treatment options for his symptomatic carotid artery disease are optimizing medical treatment, carotid endarterectomy, and carotid artery stenting. Selection of treatment must take into consideration his severe symptomatic coronary artery disease as well as Mr V's concerns about surgery. Carotid endarterectomy presents a risk of myocardial infarction unless his coronary disease is treated effectively before surgery. Carotid stenting is problematic because the severity of the preocclusive arterial narrowing makes passing a protective device beyond the stenosis difficult without first performing potentially hazardous angioplasty. Optimizing medical treatment may be the best option for his severe systemic atherosclerosis. Treatment decisions in complex patients like Mr V require weighing the particular risks and benefits of available options, and the patient's own wishes and fears. These decisions, in this and other complex patients, often cannot be directly informed by results from randomized trials.

BMJ  2008;336:1447-1448 (28 June)
Seroprotection against serogroup C meningococcal disease
Is higher if vaccination is given in the second decade of life rather than in the first
Neisseria meningitidis is a leading cause of bacterial meningitis worldwide. Most cases in developed countries are caused by endemic disease. The incidence is around 1-2 per 100 000, with rates among infants as high as 20 per 100 000. Children younger than 2 years have the highest incidence of meningococcal disease, with a second peak between 15 and 24 years. Most cases are caused by serogroups A, B, C, W-135, and Y. Serogroups C and B predominate in temperate countries. In the accompanying study, Snape and colleagues evaluate the persistence of serum bactericidal antibody against meningococcal serogroup C in a large cohort of adolescents originally immunised with serogroup C meningococcal conjugate vaccines at 6-15 years of age. These vaccines, now used in many countries, were licensed on the basis of immunogenicity rather than clinical efficacy.

BMJ  2008;336:1453 (28 June
Invasive meningococcal disease Cerebral perfusion in invasive meningococcal disease
I am surprised that the SIGN guidelines (and therefore this summary of them1) make no mention of the importance of adequate cerebral perfusion in those with invasive meningococcal disease. Cerebral perfusion pressure is the difference between the mean arterial pressure (which is usually low from the associated hypotensive shock) and the intracranial pressure (which is often high as a result of meningeal inflammation and cerebral oedema).
Consequently, cerebral perfusion pressure takes a "double whammy," and the end result may be clinically significant cerebral ischaemia from profoundly inadequate cerebral perfusion, which is likely to worsen neurological outcomes.

BMJ  2008;336:1487-1491 (28 June)
Seroprotection against serogroup C meningococcal disease in adolescents in the United Kingdom: observational study
Objective To determine the persistence of bactericidal antibody titres following immunisation with serogroup C meningococcal glycoconjugate vaccine at age 6-15 years in order to examine changes in persistence of antibodies with age.
Design Observational study.
Setting Secondary and tertiary educational institutions in the United Kingdom.
Participants Healthy adolescents aged 11-20 years previously immunised between 6 and 15 years of age with one of the three serogroup C meningococcal vaccines.
Intervention Serum obtained by venepuncture.
Main outcome measures Percentage of participants with (rabbit complement) serum bactericidal antibody titres of at least 1:8; geometric mean titres of serogroup C meningococcal serum bactericidal antibody.
Results Five years after immunisation, 84.1% (95% confidence interval 81.6% to 86.3%) of 987 participants had a bactericidal antibody titre of at least 1:8. Geometric mean titres of bactericidal antibody were significantly lower in 11-13 year olds (147, 95% confidence interval 115 to 188) than in 14-16 year olds (300, 237 to 380) and 17-20 year olds (360, 252 to 515) (P<0.0001 for both comparisons). Within these age bands, no significant difference in geometric mean titres of bactericidal antibody between recipients of the different serogroup C meningococcal vaccines was seen. More than 70% of participants had received a vaccine from one manufacturer; in this cohort, geometric mean titres were higher in those immunised at aged 10 years or above than in those immunised before the age of 10.
Conclusions Higher concentrations of bactericidal antibody are seen five years after immunisation with serogroup C meningococcal vaccine at age 10 years or above than in younger age groups, possibly owing to immunological maturation. This provides support for adolescent immunisation programmes to generate sustained protection against serogroup C meningococcal disease not only for the vaccine recipients but also, through the maintenance of herd immunity, for younger children.

BMJ  2008;336:1502-1504 (28 June)
Pregnancy Plus Migraine in pregnancy
The authors explore whether migraine affects pregnancy, how pregnancy alters migraine, and how to treat and prevent migraine in pregnancy
Migraine is common, with a one year prevalence of 12-15% in the Western world.1 The case described here (see the Scenario box) illustrates many of the problems that arise when a patient who has migraines becomes pregnant.
Scenario
A 32 year old woman with a history of episodic headache has recently become aware she is pregnant. She has had troublesome headaches from childhood. She has no other medical problems. Her sister and mother have migraines. She is a non-smoker. In the previous five years, her headaches have become more frequent, with five to seven attacks a month of disabling left or right sided, throbbing pain around the parietal and temporal region. The pain is aggravated by physical activity and any movement and associated with nausea and marked vomiting, prominent photophobia, and phonophobia. The attacks last two to three days. She had no aura symptoms.

The Lancet
Vol: 371 Issue: 9631, June, 28 - July, 4 2008 pp: 2150-2151
Oral substitution treatments for opioid dependence
Illicit opioid dependence, once largely a problem in developed countries, has become an increasingly important public-health concern over the past few decades in countries such as China, India, Indonesia, Iran, Malaysia, Pakistan, and Russia. In 2003, its health effects were estimated to account for 0·7% of global disease burden.
Many developing countries have prohibited the use of pharmacological treatments for opioid dependence that are used in developed countries (and in WHO's Model List of Essential Medicines)—ie, oral agonist maintenance treatment with methadone and buprenorphine. The preferred forms of so-called treatment in these countries have often been imprisonment, enforced opioid withdrawal, and a coerced form of drug-free rehabilitation in prison-like settings. The ineffectiveness of detoxification as a treatment in itself and the probable ineffectiveness of coerced drug-free treatment have prompted some countries to use the opioid antagonist naltrexone in oral form for relapse prevention after enforced detoxification. This method has been used despite no evidence from randomised trials that oral naltrexone is better than placebo and an increased risk of overdose when patients on oral naltrexone relapse to opioid use, as most do.
The use of oral naltrexone is often an indicator of moral disapproval of substitution treatments with opioid agonists because they stabilise addicts rather than attempt to produce abstinence. This disapproval might be justified by concerns about the risks of diversion of methadone and buprenorphine to the black market, with consequent increases in opioid dependence and deaths from overdoses in people who are untreated. Less attention is given to prevention of the major public-health effects of untreated opioid dependence—ie, HIV transmission in injectors and overdose deaths in untreated people who are opioid dependent and in opioid users after release from imprisonment or enforced abstinence.

The Lancet
Vol: 371 Issue: 9631, June, 28 - July, 4 2008   pp: 2169-2170
Management of acute organophosphorus pesticide poisoning
In their Review (Feb 16, p 597), Michael Eddleston and colleagues summarise the treatment of acute organophosphorus pesticide poisoning. They recommend pralidoxime chloride or obidoxime as a loading dose followed by an infusion until atropine has not been needed for 12–24 h and the patient has been extubated, as well as retreatment with the oxime in case of recurring cholinergic features. This recommendation is not evidence-based and should not be regarded as the gold standard. Eddleston and colleagues present many theoretical and practical reasons why oximes might not be useful to patients with overwhelming self-poisoning, but they do not translate these considerations into clinical practice.
A placebo-controlled trial of oxime treatment for organophosphorus pesticide poisoning showed that pralidoxime plus atropine does not have any benefit over atropine alone. The need for mechanical ventilation, median days on mechanical ventilation, median days in the intensive-care unit, frequency of the intermediate syndrome, and mortality rate were similar in each group. Additionally, a meta-analysis concluded that oxime was associated with either a null effect or possible harm. Therefore, it is time to revise the role of oximes in acute organophosphorus pesticide poisoning, and to do a large, high-quality, randomised controlled trial with appropriate stratification of patients according to baseline severity, time to presentation, and class of organophosphorus pesticide (diethyl or dimethyl), with predefined subgroup hypotheses. The erythrocyte acetylcholinesterase activity and the potential for ex-vivo reactivation have to be measured for reliable interpretation.

The Lancet
Vol: 371 Issue: 9631, June, 28 - July, 4 2008 pp: 2170
Management of acute organophosphorus pesticide poisoning
Michael Eddleston and colleagues' Review on organophosphate poisoning is interesting. The burden of poisoning in Asian countries can be likened to an epidemic, with mass suicides reported from rural India by farmers who incur severe financial loss. Although the key to halting this epidemic lies in improving the welfare of farmers and reducing their debt trap, certain measures could reduce case-fatality. In several Asian countries, the sale of highly toxic insecticides is not restricted. With the advent of less toxic but equally potent insecticides, replacement of toxic insecticides with compounds such as pyrethroids and neonicotinoids that have versatile application and favourable environmental and toxicological profiles seems a good strategy. The banning of class I compounds in Sri Lanka was effective in reducing case-fatality. High-concentration formulations that cover several acres of land also account for severe intoxication and death. Dispensing dilute preparations of insecticide, sale regulation, and safe-storage measures need to be implemented to reduce the severity of poisoning and offer a chance for poisoned patients to reach hospital for medical assistance. 

The Lancet
Vol: 371 Issue: 9631, June, 28 - July, 4 2008 pp: 2170-2171
Management of acute organophosphorus pesticide poisoning – Authors' reply
We acknowledge Houssem Hmouda and colleagues' concern that the exact role of oximes in any particular patient who has taken organophosphorus pesticides is unclear. However, the study they cite was not a randomised controlled trial and used low bolus doses of pralidoxime that would not be expected to benefit patients poisoned with the dimethyl organophosphorus insecticides seen in the study. The cited meta-analysis combined mostly non-randomised studies and as such is likely to be confounded by selection and performance bias.
Neither the meta-analysis nor Hmouda and colleagues consider the most recently published study, which used a higher dose and recruited patients who presented early—a median of 2 h after ingestion. This study showed a benefit of pralidoxime chloride. At present, the balance of published evidence favours the early use of pralidoxime; hence our recommendation of current WHO guidelines in the panel of management guidelines, while discussing the limitations of this advice in the text.

The Lancet
Vol: 371 Issue: 9631, June, 28 - July, 4 2008    pp: 2201-2212
Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood
Summary
Juvenile dermatomyositis, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterised by weakness in proximal muscles and pathognomonic skin rashes. The length of time before the initiation of treatment affects presenting symptoms, laboratory measures, and pathophysiology. It also affects disease outcomes, including the development of pathological calcifications, which are associated with increased morbidity. Both genetic and environmental risk factors seem to have a role in the cause of juvenile dermatomyositis; HLA B8–DRB1*0301 ancestral haplotype is a strong immunogenetic risk factor, and antecedent infections and birth seasonality suggest that environmental stimuli might increase risk. Activation of dendritic cells with upregulation of genes induced by type-1 interferon (α) in muscle and peripheral blood seems to be central to disease pathogenesis. Treatment often includes combinations of corticosteroids, methotrexate, and other immunosuppressive agents. Disease outcome, if treatment is initiated early, is generally good. Randomised controlled trials are needed to define the most effective treatments.

The Lancet
Vol: 371 Issue: 9631, June, 28 - July, 4 2008 pp: 2222
Mysterious episodic coma
In June, 2006, an 84-year-old man was admitted to hospital with confusion, slowed speech and movement, frequent urination, and urinary incontinence. Within 48 h, he was in a coma. Intermittently, white blood cells were found in his urine, so antibiotics were prescribed. The patient recovered gradually, over several days, and was discharged. In the next 5 months, he had six similar presentations, on each occasion becoming comatose. The working diagnosis of urinary-tract infection, as a cause of coma, was not entirely convincing: white blood cells were not always present in the patient's urine; blood cultures were consistently negative; on blood testing, the white-cell count and concentration of C-reactive protein were normal; the patient had no fever. However, no other cause of coma had been identified. The patient had no notable medical history, other than stomach cancer, which had been treated 12 years before, by roux-en-Y gastrectomy; and ongoing paroxysmal atrial fibrillation. ESR, and concentrations of bilirubin and γ-glutamyltransferase were slightly high, but results of other blood tests—including virological, immunological, and toxicological screens, and concentration of D-lactate—were normal. Ultrasonography of the abdomen showed three gallstones, but normal bile ducts, gallbladder, and liver. Abdominal radiography, with a barium swallow, showed the gastrojejunostomy, but nothing unexpected. MRI of the head, magnetic-resonance angiography, and analysis of cerebrospinal fluid showed nothing of note. Therefore, as the patient recovered from coma in December, 2006, we kept him in hospital for observation and further investigation.