Science 18 April 2008: Vol. 320. no. 5874, pp. 369 - 373
A Model for Neuronal Competition During Development
We report that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived nerve growth factor (NGF) promoted expression of its own receptor TrkA in mouse and rat neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain-derived neurotrophic factor and neurotrophin-4, which, through the receptor p75, can kill neighboring neurons with low retrograde NGF-TrkA signaling whereas neurons with high NGF-TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. We suggest that three target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects.

Science 18 April 2008:
Vol. 320. no. 5874, pp. 385 - 388
The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex
We investigated whether fluoxetine, a widely prescribed medication for treatment of depression, restores neuronal plasticity in the adult visual system of the rat. We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders.

Nature 452, 816-818 (17 April 2008) | doi:10.1038/452816a; Published online 16 April 2008
Triumph of the medieval mind
Modern science began several hundred years earlier than we have come to imagine. It got going in the twelfth century — and with it, the long-standing rift between reason and faith.
The popular caricature locates the origins of modern science in the natural philosophies of ancient Greece and the rediscovery of their spirit during the Renaissance and the Enlightenment. It passes decorously over the intervening period, deemed to be a hotbed of superstition. In fact, the notion of a Universe governed by laws accessible to human reason — the precondition for science — emerged in Western Europe largely during the twelfth century, several hundred years earlier than we have come to imagine.

Nature 452, 887-891 (17 April 2008) | doi:10.1038/nature06721; Received 14 November 2007; NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration
Neurodegeneration can be triggered by genetic or environmental factors. Although the precise cause is often unknown, many neurodegenerative diseases share common features such as protein aggregation and age dependence. Recent studies in Drosophila have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) against activity-induced neurodegeneration and injury-induced axonal degeneration. Here we show that NMNAT overexpression can also protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein 70 (Hsp70). NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of poly-glutamine expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Our results implicate NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions.

Nature 452, 892-895 (17 April 2008) | doi:10.1038/nature06816
Retinotopic order in the absence of axon competition
The retinotectal projection has long been studied experimentally and theoretically, as a model for the formation of topographic brain maps. Neighbouring retinal ganglion cells (RGCs) project their axons to neighbouring positions in the optic tectum, thus re-establishing a continuous neural representation of visual space. Mapping along this axis requires chemorepellent signalling from tectal cells, expressing ephrin-A ligands, to retinal growth cones, expressing EphA receptors4. High concentrations of ephrin A, increasing from anterior to posterior, prevent temporal axons from invading the posterior tectum. However, the force that drives nasal axons to extend past the anterior tectum and terminate in posterior regions remains to be identified. We tested whether axon–axon interactions, such as competition, are required for posterior tectum innervation. By transplanting blastomeres from a wild-type (WT) zebrafish into a lakritz (lak) mutant, which lacks all RGCs5, we created chimaeras with eyes that contained single RGCs. These solitary RGCs often extended axons into the tectum, where they branched to form a terminal arbor. Here we show that the distal tips of these arbors were positioned at retinotopically appropriate positions, ruling out an essential role for competition in innervation of the ephrin-A-rich posterior tectum. However, solitary arbors were larger and more complex than under normal, crowded conditions, owing to a lack of pruning of proximal branches during refinement of the retinotectal projection. We conclude that dense innervation is not required for targeting of retinal axons within the zebrafish tectum but serves to restrict arbor size and shape.

JAMA. 2008;299(15):1813-1817.
Reporting Mortality Findings in Trials of Rofecoxib for Alzheimer Disease or Cognitive Impairment
A Case Study Based on Documents From Rofecoxib Litigation
Sponsors have a marketing interest to represent their products in the best light. This approach conflicts with scientific standards that require the symmetric and comparable reporting of safety and efficacy data. Selective reporting of the results of clinical trials can misrepresent the risk-benefit profile of drugs. We summarize how the sponsor represented mortality findings associated with rofecoxib in clinical trials of patients with Alzheimer disease or cognitive impairment. We reviewed documents that became available during litigation related to rofecoxib involving Merck & Co, including internal company analyses and information provided by the sponsor to the FDA. We also evaluated information in 2 published articles that reported results of these trials. In one article (reporting results of protocol 091) published in 2004, 11 "non-drug related deaths" were reported (9 deaths among 346 rofecoxib patients and 2 deaths among 346 placebo patients). In another article (reporting results of protocol 078) published in 2005, 39 deaths were reported among patients taking study treatment or within 14 days of the last dose (24 among 725 rofecoxib patients and 15 among 732 placebo patients) and an additional 22 deaths in the off-drug period (17 in rofecoxib patients and 5 in placebo patients). However, these articles did not include analyses or statistical tests of the mortality data, and the 2 articles concluded that regarding safety, rofecoxib is "well tolerated."

JAMA. 2008;299(15):1771.
Prognosis of Transient Neurological Attacks
To the Editor: In their cohort study, Dr Bos and colleagues show Kaplan-Meier curves for the risk of ischemic heart disease and vascular death, as well as stroke, after transient neurological attacks (TNAs). These appear to indicate that the absolute event rates of these outcomes in this population equal or surpass the 20% 10-year risk of coronary events associated with coronary risk equivalents used in US guidelines to determine aggressiveness of use of statins and other therapies. There is evidence that patients with a history of ischemic stroke have a risk of coronary events equal to that of coronary risk equivalents, although patients with stroke are included as risk equivalents only in European (not US) guidelines.

JAMA. 2008;299(15):1771-1772.
Prognosis of Transient Neurological Attacks
To the Editor: Dr Bos and colleagues reported that elderly patients with nonfocal TNAs had a higher risk of major vascular disease and dementia than those without TNAs. This result suggests that lumping various signs and symptoms into TNAs was valid. The opposite approach would be to split the components of TNA and investigate each complaint on its own, but this was not done because an empirical base for subdivision did not exist. While such data may not exist for TNAs, they do for several causes of unconsciousness, a constituent of TNA.
If short-lived, such attacks are classified under transient loss of consciousness, mainly consisting of epilepsy and syncope (transient loss of consciousness due to cerebral hypoperfusion). In elderly persons, cardiac, orthostatic, and postprandial syncope occur more often and reflex syncope less often than in young persons.

JAMA. 2008;299(15):1772-1773.
Prognosis of Transient Neurological Attacks—Reply
In Reply: Dr Elkind raises the interesting question of whether the excess risk of vascular disease among TNA patients raises their absolute 10-year risk over 20%, which according to current guidelines would warrant aggressive lipid control and other vascular risk reduction therapies. These guidelines are based on persons aged 20 to 75 years and are hard to extrapolate to an older population such as the one we studied because in elderly persons the 10-year risk of stroke and ischemic heart disease is exceedingly high. Moreover, it is common practice to base treatment recommendations on risk factor profiles, taking into account age, sex, and other cardiovascular risk factors. Our data lack power for such a detailed analysis of the prognosis of TNA patients. We therefore can only report the mean absolute risk, which is hard if not impossible to extrapolate from one community to another.

JAMA. 2008;299(15):1774.
Determining Hospice Benefit for Patients With Dementia
 To the Editor: In her Clinical Crossroads article, Dr Mitchell discussed the problems associated with advanced dementia. The article stated that patients with advanced Alzheimer disease and other related dementias are eligible for the Medicare Hospice Benefit when they reach Functional Assessment Staging (FAST) stage 7c (unable to ambulate independently). However, at least in some geographical areas they are actually eligible for hospice care when they reach FAST stage 7a (speech limited to fewer than 6 intelligible words during an average day).

JAMA. 2008;299(15):1774-1775.
Determining Hospice Benefit for Patients With Dementia-Reply
In Reply: In response to Dr Cherney, an estimated life expectancy of less than 6 months is the main eligibility criterion for hospice. In 1996, the National Hospice Organization (now known as the National Hospice and Palliative Care Organization) developed guidelines to estimate the prognosis for noncancer diagnoses for the purposes of determining hospice eligibility. In these guidelines, the FAST scale2 was included as a component of the eligibility criteria for patients with a primary diagnosis of dementia. Individual hospice providers may interpret these guidelines differently. However, the original National Hospice Organization guidelines, most recent Centers for Medicare & Medicaid Services coverage guidelines, current interpretation by major hospice providers, and a recent review article indicate that for patients with dementia to qualify for hospice they must be at or beyond FAST stage 7 and be unable to ambulate independently. This effectively makes the cut-off stage 7c on the FAST scale.

JAMA. 2008;299(15):1763.
Guideline: Dementia Drugs’ Benefits Uncertain
The latest review of medications approved by the US Food and Drug Administration for the treatment of patients with dementia shows that even though the drugs pass muster statistically on scales that measure patients' cognitive function, they produce little if any clinically meaningful benefit (Raina P et al. Ann Intern Med. 2008;148[5]:379-397). Results of the review, experts say, point to an urgent need for more thorough, independent research on the pharmacologic treatment of dementia.
A guideline based on the review advises physicians that because evidence of effectiveness is scant, the drugs should not be used routinely for patients with dementia (Qaseem A et al. Ann Intern Med. 2008;148[5]:370-378).

BMJ  2008;336:781-782 (12 April), doi:10.1136/bmj.39511.514051.80 (published 14 March 2008)
Continuous deep sedation in patients nearing death Imprecise taxonomy makes interpreting trends difficult
Deep sedation is occasionally the only effective treatment for refractory symptoms and suffering in terminally ill patients. In their accompanying study, Rietjens and colleagues report a significant rise in continuous deep sedation in the Netherlands from 5.6% in 2001 to 7.1% in 2005, while cases of euthanasia declined over the same period.
Continuous deep sedation is an accepted treatment in the Netherlands for patients whose life expectancy is two weeks or less. The Dutch study reports that 1200 fewer people died as a result of euthanasia but 1800 more died as a result of terminal sedation in 2005 than in 2001. Although the increase follows the publication in 2002 of guidelines for general practitioners on the use of continuous deep sedation, and attention in the Dutch media, the cause of this trend is unclear.

BMJ  2008;336:810-813 (12 April), doi:10.1136/bmj.39504.531505.25 (published 14 March 2008)
Research Continuous deep sedation for patients nearing death in the Netherlands: descriptive study
Objectives To study the practice of continuous deep sedation in 2005 in the Netherlands and compare it with findings from 2001.
Design Questionnaire study about random samples of deaths reported to a central death registry in 2005 and 2001.
Setting Nationwide physician study in the Netherlands.
Participants Reporting physicians received a questionnaire about the medical decisions that preceded the patient’s death; 78% (n=6860) responded in 2005 and 74% (n=5617) in 2001.
Main outcome measures Characteristics of continuous deep sedation (attending physician, types of patients, drugs used, duration, estimated effect on shortening life, palliative consultation). Requests for euthanasia.
Results The use of continuous deep sedation increased from 5.6% (95% confidence interval 5.0% to 6.2%) of deaths in 2001 to 7.1% (6.5% to 7.6%) in 2005, mostly in patients treated by general practitioners and in those with cancer (in 2005, 47% of sedated patients had cancer v 33% in 2001). In 83% of cases sedation was induced by benzodiazepines, and in 94% patients were sedated for periods of less than one week until death. Nine per cent of those who received continuous deep sedation had previously requested euthanasia but their requests were not granted. Nine per cent of the physicians had consulted a palliative expert.
Conclusions The increased use of continuous deep sedation for patients nearing death in the Netherlands and the limited use of palliative consultation suggests that this practice is increasingly considered as part of regular medical practice.

NEJM Volume 358:1750-1751  April 17, 2008  Number 16
Outcome after Language Mapping for Glioma Resection
To the Editor: To preserve language function during glioma resection in or near language areas, Sanai and colleagues, including Berger (Jan. 3 issue), advocate negative mapping through intraoperative cortical stimulation (negative cortical stimulation) instead of traditional positive cortical stimulation. Positive cortical stimulation identifies cortical sites associated with and sites not associated with motor, somatosensory, or language function, whereas negative cortical stimulation typically identifies only sites not associated with such function.
However, language requires not only cortical language sites but also subcortical (white-matter) language tracts to connect them. So preserving language function depends on preserving not only cortical language sites but also subcortical language tracts in the resected region.