Science 16 May 2008:
Vol. 320. no. 5878, pp. 903 - 909
Design Logic of a Cannabinoid Receptor Signaling Network That Triggers Neurite Outgrowth
Cannabinoid receptor 1 (CB1R) regulates neuronal differentiation. To understand the logic underlying decision-making in the signaling network controlling CB1R-induced neurite outgrowth, we profiled the activation of several hundred transcription factors after cell stimulation. We assembled an in silico signaling network by connecting CB1R to 23 activated transcription factors. Statistical analyses of this network predicted a role for the breast cancer 1 protein BRCA1 in neuronal differentiation and a new pathway from CB1R through phosphoinositol 3-kinase to the transcription factor paired box 6 (PAX6). Both predictions were experimentally confirmed. Results of transcription factor activation experiments that used pharmacological inhibitors of kinases revealed a network organization of partial OR gates regulating kinases stacked above AND gates that control transcription factors, which together allow for distributed decision-making in CB1R-induced neurite outgrowth.

Science 16 May 2008:
Vol. 320. no. 5878, pp. 946 - 949
Early Forebrain Wiring: Genetic Dissection Using Conditional Celsr3 Mutant Mice
Development of axonal tracts requires interactions between growth cones and the environment. Tracts such as the anterior commissure and internal capsule are defective in mice with null mutation of Celsr3. We generated a conditional Celsr3 allele, allowing regional inactivation. Inactivation in telencephalon, ventral forebrain, or cortex demonstrated essential roles for Celsr3 in neurons that project axons to the anterior commissure and subcerebral targets, as well as in cells that guide axons through the internal capsule. When Celsr3 was inactivated in cortex, subcerebral projections failed to grow, yet corticothalamic axons developed normally, indicating that besides guidepost cells, additional Celsr3-independent cues can assist their progression. These observations provide in vivo evidence that Celsr3-mediated interactions between axons and guidepost cells govern axonal tract formation in mammals.

Nature 453, 292-293 (15 May 2008) | doi:10.1038/453292a; Published online 14 May 2008
Signal transduction: The rhodopsin story continued
Determination of the architecture of an invertebrate photoreceptor protein, squid rhodopsin, is a notable event. It illuminates the mechanism of invertebrate vision and a ubiquitous intracellular signalling system.
Many invertebrates have excellent visual systems1. Squid, for example, are formidable hunters that rely on their acute visual abilities to catch their prey.

Nature 453, 406-409 (15 May 2008)
Free choice activates a decision circuit between frontal and parietal cortex
We often face alternatives that we are free to choose between. Planning movements to select an alternative involves several areas in frontal and parietal cortex that are anatomically connected into long-range circuits. These areas must coordinate their activity to select a common movement goal, but how neural circuits make decisions remains poorly understood. Here we simultaneously record from the dorsal premotor area (PMd) in frontal cortex and the parietal reach region (PRR) in parietal cortex to investigate neural circuit mechanisms for decision making. We find that correlations in spike and local field potential (LFP) activity between these areas are greater when monkeys are freely making choices than when they are following instructions. We propose that a decision circuit featuring a sub-population of cells in frontal and parietal cortex may exchange information to coordinate activity between these areas. Cells participating in this decision circuit may influence movement choices by providing a common bias to the selection of movement goals.

The Lancet Volume 371, Issue 9624 Pages 1572-1573
Brain imaging and the inner life
“The intense intellectual and emotional life, and the heightening of sensations which came with the advance of civilization, made it clear to men that only a part of pain, pleasure, and profi t of life lay in physical things. Thoughts, emotions, and sensations demanded legal
recognition”, wrote Samuel Warren and Louis Brandeis in the landmark 1890 paper that fi rst introduced the right to privacy to legal discourse. Warren and Brandeis saw themselves as articulating a moral idea that was already implicitly recognised but fi nally forced into the open by “recent inventions and business methods”—that is, by “instantaneous” photography and tabloid gossip columns.

The Lancet Volume 371, Issue 9624 Pages 1612-1623
Stroke
Stroke is the second most common cause of death and major cause of disability worldwide. Because of the ageing population, the burden will increase greatly during the next 20 years, especially in developing countries. Advances have occurred in the prevention and treatment of stroke during the past decade. For patients with acute stroke, management in a stroke care unit, intravenous tissue plasminogen activator within 3 h or aspirin within 48 h of stroke onset, and decompressive surgery for supratentorial malignant hemispheric cerebral infarction are interventions of proven benefit; several other interventions are being assessed. Proven secondary prevention strategies are warfarin for patients with atrial fibrillation, endarterectomy for symptomatic carotid stenosis, antiplatelet agents, and cholesterol reduction. The most important intervention is the management of patients in stroke care units because these provide a framework within which further study might be undertaken. These advances have exposed a worldwide shortage of stroke health-care workers, especially in developing countries.

The Lancet Volume 371, Issue 9624 Pages 1587-1594
Carotid bruits as a prognostic indicator of cardiovascular death and myocardial infarction: a meta-analysis
Background
Although carotid bruits are deemed to be markers of generalised atherosclerosis, they are poor predictors of cerebrovascular events. We investigated whether a carotid bruit predicts myocardial infarction and cardiovascular death.
Methods
In this meta-analysis, we searched Medline (1966 to August, 2007) and Embase (1974 to August, 2007) with the terms “carotid” and “bruit”. Bibliographies of all the retrieved articles were also searched. Articles were included if they reported the incidence of myocardial infarction or cardiovascular death in adults. Outcome variables were extracted in duplicate and included the rate of myocardial infarction and cardiovascular mortality. Quality of the articles was independently assessed with the Hayden rating scheme. Data were pooled with a random effects model.
Findings
Of the 22 articles included, 20 (91%) used prospective cohorts. Our analysis included 17 295 patients with 62 413·5 patient-years of follow-up, with a median sample size of 273 patients (range 38–4736) followed up for 4 years (2–7). The rate of myocardial infarction in patients with carotid bruits was 3·69 (95% CI 2·97–5·40) per 100 patient-years (eight studies) compared with 1·86 (0·24–3·48) per 100 patient-years in those without bruits (two studies). Yearly rates of cardiovascular death were also higher in patients with bruits (16 studies) than in those without (four studies) (2·85 [2·16–3·54] per 100 patient-years vs 1·11 [0·45–1·76] per 100 patient-years). In the four trials in which direct comparisons of patients with and without bruits were possible, the odds ratio for myocardial infarction was 2·15 (1·67–2·78) and for cardiovascular death 2·27 (1·49–3·49).
Interpretation
Auscultation for carotid bruits in patients at risk for heart disease could help select those who might benefit the most from an aggressive modification strategy for cardiovascular risk.

NEJM Volume 358:2127-2137  May 15, 2008  Number 20
Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage
Background Intracerebral hemorrhage is the least treatable form of stroke. We performed this phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes.
Methods We randomly assigned 841 patients with intracerebral hemorrhage to receive placebo (268 patients), 20 µg of rFVIIa per kilogram of body weight (276 patients), or 80 µg of rFVIIa per kilogram (297 patients) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke.
Results Treatment with 80 µg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the intracerebral hemorrhage at 24 hours was 26% in the placebo group, as compared with 18% in the group receiving 20 µg of rFVIIa per kilogram (P=0.09) and 11% in the group receiving 80 µg (P<0.001). The growth in volume of intracerebral hemorrhage was reduced by 2.6 ml (95% confidence interval [CI], –0.3 to 5.5; P=0.08) in the group receiving 20 µg of rFVIIa per kilogram and by 3.8 ml (95% CI, 0.9 to 6.7; P=0.009) in the group receiving 80 µg, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 µg of rFVIIa per kilogram, and 29% in the group receiving 80 µg). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 µg of rFVIIa than in the placebo group (9% vs. 4%, P=0.04).
Conclusions Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. (ClinicalTrials.gov number, NCT00127283 [ClinicalTrials.gov] .)

NEJM Volume 358:2174-2176  May 15, 2008  Number 20
Intracerebral Hemorrhage — Improving Outcome by Reducing Volume?
Intracerebral hemorrhage accounts for 10 to 15% of all strokes. It is the type of stroke with the highest mortality, with a 1-year survival rate of less than 50%.1 Most intracerebral hemorrhages occur in patients who have hypertension, which is the major modifiable risk factor for the occurrence of intracerebral hemorrhage.2

Although improvements in the early recognition and general intensive care of patients with intracerebral hemorrhage have been associated with decreased mortality, no specific intervention has proved efficacious.

NEJM Volume 358:e23  May 15, 2008  Number 20
Management of Carotid Stenosis — Polling Results
In early April, we presented the case of a 67-year-old man with asymptomatic carotid disease in Clinical Decisions,1 an interactive feature designed to assess how readers would manage a clinical problem for which there may be more than one appropriate treatment. The patient was a nonsmoker with a history of hypertension and hyperlipidemia who was noted to have a carotid bruit on routine examination. He was also found to have a stenosis of 70 to 80% of the right internal carotid artery with an irregular plaque and an elevated peak velocità.

NEJM Volume 358:2177-2179  May 15, 2008  Number 20
Mild Traumatic Brain Injury in U.S. Soldiers Returning from Iraq
To the Editor: We wish to express a number of concerns about the methods used in the study of mild traumatic brain injury by Hoge et al. (Jan. 31 issue).1 We learned through firsthand experience in the combat zone that immediately after a concussion, the soldier's reported account is most accurate during the initial 24 hours after the blast incident.2 We therefore would be concerned about recall bias introduced 3 to 4 months after a return from deployme