Science 11 April 2008:
Vol. 320. no. 5873, p. 167 PARKINSON'S DISEASE:
Signs of Disease in Fetal Transplants
New studies reveal that fetal tissue implants can survive a decade or more in Parkinson's patients but in some cases appear to acquire signs of the disease--a surprising finding that could shed light on the disease’s mechanisms.

Science 11 April 2008:
Vol. 320. no. 5873, pp. 168 - 170 PSYCHOPHARMACOLOGY:
Tackling Alcoholism With Drugs
New treatments, some now in clinical trials, reflect a growing awareness that people with different genetic profiles and drinking histories may need different therapies.

Science 11 April 2008:
Vol. 320. no. 5873, pp. 183 - 184 NEUROSCIENCE:
Refreshing Connections
The exchange of desensitized glutamate receptors with unoccupied ones can counteract the effects of desensitization at the synapse.

Science 11 April 2008:
Vol. 320. no. 5873, pp. 185 - 186 NEUROSCIENCE:
Axons Seek Neighborly Advice
Cell contact-dependent communication between adjacent motor and sensory neurons prevents miswiring of developing neural circuits.

Science 11 April 2008:
Vol. 320. no. 5873, pp. 201 - 205
Surface Mobility of Postsynaptic AMPARs Tunes Synaptic Transmission
AMPA glutamate receptors (AMPARs) mediate fast excitatory synaptic transmission. Upon fast consecutive synaptic stimulation, transmission can be depressed. Recuperation from fast synaptic depression has been attributed solely to recovery of transmitter release and/or AMPAR desensitization. We show that AMPAR lateral diffusion, observed in both intact hippocampi and cultured neurons, allows fast exchange of desensitized receptors with naïve functional ones within or near the postsynaptic density. Recovery from depression in the tens of millisecond time range can be explained in part by this fast receptor exchange. Preventing AMPAR surface movements through cross-linking, endogenous clustering, or calcium rise all slow recovery from depression. Physiological regulation of postsynaptic receptor mobility affects the fidelity of synaptic transmission by shaping the frequency dependence of synaptic responses.

Science 11 April 2008:
Vol. 320. no. 5873, pp. 233 - 236
Segregation of Axial Motor and Sensory Pathways via Heterotypic Trans-Axonal Signaling
Execution of motor behaviors relies on circuitries effectively integrating immediate sensory feedback to efferent pathways controlling muscle activity. It remains unclear how, during neuromuscular circuit assembly, sensory and motor projections become incorporated into tightly coordinated, yet functionally separate pathways. We report that, within axial nerves, establishment of discrete afferent and efferent pathways depends on coordinate signaling between coextending sensory and motor projections. These heterotypic axon-axon interactions require motor axonal EphA3/EphA4 receptor tyrosine kinases activated by cognate sensory axonal ephrin-A ligands. Genetic elimination of trans-axonal ephrin-A  EphA signaling in mice triggers drastic motor-sensory miswiring, culminating in functional efferents within proximal afferent pathways. Effective assembly of a key circuit underlying motor behaviors thus critically depends on trans-axonal signaling interactions resolving motor and sensory projections into discrete pathways.

Science 11 April 2008:
Vol. 320. no. 5873, pp. 239 - 243
Leiomodin Is an Actin Filament Nucleator in Muscle Cells
Initiation of actin polymerization in cells requires nucleation factors. Here we describe an actin-binding protein, leiomodin, that acted as a strong filament nucleator in muscle cells. Leiomodin shared two actin-binding sites with the filament pointed end–capping protein tropomodulin: a flexible N-terminal region and a leucine-rich repeat domain. Leiomodin also contained a C-terminal extension of 150 residues. The smallest fragment with strong nucleation activity included the leucine-rich repeat and C-terminal extension. The N-terminal region enhanced the nucleation activity threefold and recruited tropomyosin, which weakly stimulated nucleation and mediated localization of leiomodin to the middle of muscle sarcomeres. Knocking down leiomodin severely compromised sarcomere assembly in cultured muscle cells, which suggests a role for leiomodin in the nucleation of tropomyosin-decorated filaments in muscles.

Science 11 April 2008:
Vol. 320. no. 5873, pp. 246 - 249
Video-Rate Far-Field Optical Nanoscopy Dissects Synaptic Vesicle Movement
We present video-rate (28 frames per second) far-field optical imaging with a focal spot size of 62 nanometers in living cells. Fluorescently labeled synaptic vesicles inside the axons of cultured neurons were recorded with stimulated emission depletion (STED) microscopy in a 2.5-micrometer by 1.8-micrometer field of view. By reducing the cross-sectional area of the focal spot by about a factor of 18 below the diffraction limit (260 nanometers), STED allowed us to map and describe the vesicle mobility within the highly confined space of synaptic boutons. Although restricted within boutons, the vesicle movement was substantially faster in nonbouton areas, consistent with the observation that a sizable vesicle pool continuously transits through the axons. Our study demonstrates the emerging ability of optical microscopy to investigate intracellular physiological processes on the nanoscale in real time.

Nature 452, 674-675 (2008) | doi:10.1038/452674a
Poll results: look who's doping
In January, Nature launched an informal survey into readers' use of cognition-enhancing drugs. Brendan Maher has waded through the results and found large-scale use and a mix of attitudes towards the drugs.
The US National Institutes of Health is to crack down on scientists 'brain doping' with performance-enhancing drugs such as Provigil and Ritalin, a press release declared last week. The release, brainchild of evolutionary biologist Jonathan Eisen of the University of California, Davis, turned out to be an April Fools' prank.

Nature 452, 707-708 (10 April 2008)
Neurodegeneration: A question of balance
When a disease-associated gene is mutated, is the cellular activity of its protein product enhanced or reduced? For at least one neurodegenerative disease, spinocerebellar ataxia 1, the answer seems to be both. Ten devastating neurodegenerative disorders, including Huntington's disease, that are caused by mutations in unrelated genes have one feature in common: in the disease gene, the CAG nucleotide triplet, which encodes the glutamine amino acid, is repeated many times. Consequently, the resulting protein contains a tract of glutamine residues, and disorders with this feature are known collectively as polyglutamine-repeat diseases.

Nature 452, 713-718 (10 April 2008)
Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.

Nature 452, 759-763 (10 April 2008)
Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons
During development, sympathetic neurons extend axons along a myriad of distinct trajectories, often consisting of arteries, to innervate one of a large variety of distinct final target tissues. Whether or not subsets of neurons within complex sympathetic ganglia are predetermined to innervate select end-organs is unknown. Here we demonstrate in mouse embryos that the endothelin family member Edn3, acting through the endothelin receptor EdnrA, directs extension of axons of a subset of sympathetic neurons from the superior cervical ganglion to a preferred intermediate target, the external carotid artery, which serves as the gateway to select targets, including the salivary glands. These findings establish a previously unknown mechanism of axonal pathfinding involving vascular-derived endothelins, and have broad implications for endothelins as general mediators of axonal growth and guidance in the developing nervous system. Moreover, they suggest a model in which newborn sympathetic neurons distinguish and choose between distinct vascular trajectories to innervate their appropriate end organs.

JAMA. 2008;299(14):1653-1654.
Rapid Stroke Treatment an Elusive Goal
New Orleans—Although the availability of thrombolytic therapy in the form of tissue plasminogen activator (tPA) was seen as a potential milestone in treating ischemic stroke when it was approved by the US Food and Drug Administration in 1996, the reality is that few patients receive it. The failure of most individuals experiencing ischemic stroke to recognize their symptoms and promptly seek care, coupled with the delays by emergency departments to deliver timely care when such patients come through their doors, means that only a small proportion (estimated at less than 5%) of eligible patients with stroke receive tPA within the therapeutic window of 3 hours from symptom onset.

BMJ  2008;336:765-769 (5 April), doi:10.1136/bmj.39514.653588.80
Polymyalgia rheumatica
Polymyalgia rheumatica is the most common inflammatory rheumatic disease in elderly white people, and it is a common indication for long term treatment with glucocorticosteroids in patients based in the community.1 2 Although the symptoms are very characteristic, several other autoimmune, infectious, endocrine, and malignant disorders can present with similar symptoms. The course of disease is heterogeneous and unpredictable, and giant cell arteritis is seen in about 30% of patients.3 Glucocorticosteroids rapidly improve disease symptoms in most patients but may have serious side effects. This review looks at the current understanding of diagnosis and the management of polymyalgia rheumatica.

The Lancet Volume 371, Issue 9619 (5 April 2008-11 April 2008)
Effectiveness of screening for neuroblastoma at 6 months of age: a retrospective population-based cohort study
Pages 1173-1180
Background
In Japan, a nationwide programme between 1984 and 2003 screened all infants for urinary catecholamine metabolites as a marker for neuroblastoma. Before 1989, this was done by qualitative spot tests for vanillylmandelic acid in urine, and subsequently by quantitative assay with high-performance liquid chromatography (HPLC). However, the Japanese government stopped the mass-screening programme in 2003, after reports that it did not reduce mortality due to neuroblastoma. We aimed to assess the effectiveness of the programme, by comparing the rates of incidence and mortality from neuroblastomas diagnosed before 6 years of age in three cohorts.
Methods
We did a retrospective population-based cohort study on all children born between 1980 and 1998, except for a 2-year period from 1984. We divided these 22 289 695 children into three cohorts: children born before screening in 1980–83 (n=6 130 423); those born during qualitative screening in 1986–89 (n=5 290 412); and those born during quantitative screening 1990–98 (n=10 868 860). We used databases from hospitals, screening centres, and national cancer registries. Cases of neuroblastoma were followed up for a mean of 78·7 months.
Findings
21·56 cases of neuroblastoma per 100 000 births over 72 months were identified in the qualitatively screened group (relative risk [RR] 1·87, 95% CI 1·66–2·10), and 29·80 cases per 100 000 births over 72 months in the quantitatively screened group (RR 2·58, 2·33–2·86). The cumulative incidence of neuroblastoma in the prescreening cohort (11·56 cases per 100 000 births over 72 months) was lower than that in other cohorts (p<0·0001 for all comparisons), but more neuroblastomas were diagnosed after 24 months of age in this cohort (p=0·0002 for qualitative screening vs prescreening, p<0·0001 for quantitative screening vs prescreening). Cumulative mortality was lower in the qualititative screening (3·90 cases per 100 000 livebirths over 72 months) and quantitative screening cohorts (2·83 cases) than in the prescreening cohort (5·38 cases). Compared with the prescreening cohort, the relative risk of mortality was 0·73 (95% CI 0·58–0·90) for qualitative screening, and 0·53 (0·42–0·63) for quantitative screening. Mortality rates for both the qualitative and quantitative screening groups were lower than were those for the prescreening cohort (p=0·0041 for prescreening vs qualitative screening, p<0·0001 for prescreening vs quantitative screening).
Interpretation
More infantile neuroblastomas were recorded in children who were screened for neuroblastoma at 6 months of age than in those who were not. The mortality rate from neuroblastoma in children who were screened at 6 months was lower than that in the prescreening cohort, especially in children screened by quantitative HPLC. Any new screening programme should aim to decrease mortality, but also to minimise overdiagnosis of tumours with favourable prognoses (eg, by screening children at 18 months).

NEJM Volume 358:1572-1579  April 10, 2008  Number 15
Long-Term Results of Carotid Stenting versus Endarterectomy in High-Risk Patients
Background We previously reported that, in a randomized trial, carotid stenting with the use of an emboli-protection device is not inferior to carotid endarterectomy for the treatment of carotid artery disease at 30 days and at 1 year. We now report the 3-year results.
Methods The trial evaluated carotid artery stenting with the use of an emboli-protection device as compared with endarterectomy in 334 patients at increased risk for complications from endarterectomy who had either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%. The prespecified major secondary end point at 3 years was a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and 1080 days (3 years).
Results At 3 years, data were available for 260 patients (77.8%), including 85.6% of patients in the stenting group and 70.1% of those in the endarterectomy group. The prespecified major secondary end point occurred in 41 patients in the stenting group (cumulative incidence, 24.6%; Kaplan–Meier estimate, 26.2%) and 45 patients in the endarterectomy group (cumulative incidence, 26.9%; Kaplan–Meier estimate, 30.3%) (absolute difference in cumulative incidence for the stenting group, –2.3%; 95% confidence interval, –11.8 to 7.0). There were 15 strokes in each of the two groups, of which 11 in the stenting group and 9 in the endarterectomy group were ipsilateral.
Conclusions In our trial of patients with severe carotid artery stenosis and increased surgical risk, no significant difference could be shown in long-term outcomes between patients who underwent carotid artery stenting with an emboli-protection device and those who underwent endarterectomy. (ClinicalTrials.gov number, NCT00231270 [ClinicalTrials.gov] .)

NEJM Volume 358:e17  April 10, 2008  Number 15
Cerebral Embolism of Probable Aortic Origin
A 70-year-old woman was hospitalized for intermittent, reversible cerebral ischemia causing weakness of the right side for several days, before resolving. A computed tomographic (CT) scan showed no intracranial abnormalities. She was found to have 99% stenosis of the left carotid artery, and a left carotid endarterectomy was performed. Aspirin therapy (325 mg daily) was initiated, and the patient was discharged. Carotid ultrasonography performed as part of routine follow-up 2 years later was normal, without clinically significant stenosis on either side. One month later, the patient was admitted with acute left hemiparesis. A CT scan revealed a new calcified object in the proximal right middle cerebral artery. Thrombolytic agents were not given, because the time of onset of the stroke could not be ascertained. A repeat CT scan obtained 3 days later showed a large infarction in the distribution of the right middle cerebral artery. Three days after admission, respiratory distress developed. A CT scan of the chest revealed dense calcific plaques lining the thoracic aorta, the likely source of the embolus in the right middle cerebral artery. The patient was discharged to a long-term care facility, without neurologic improvement, after a prolonged hospital stay. The aortic arch should be considered a potential source of cerebral embolism and infarction.

NEJM Volume 358:1617-1621  April 10, 2008  Number 15
Management of Carotid Stenosis
A 67-year-old man with a history of hypertension and hyperlipidemia is seen for a routine examination. His medications include hydrochlorothiazide (25 mg daily), simvastatin (20 mg daily), and aspirin (81 mg daily). He drinks alcohol rarely and does not smoke. His body-mass index (the weight in kilograms divided by the square of the height in meters) is 27, consistent with overweight. His blood pressure is 140/85 mm Hg, and his heart rate is 72 beats per minute and regular. His cardiac examination is normal. Auscultation of the neck shows normal carotid upstrokes but reveals a middle-pitched bruit only in systole at the angle of the right jaw. A detailed neurologic examination is normal. On questioning, the patient does not report any history of transient neurologic deficits — specifically, no unilateral weakness or sensory symptoms, visual disturbances, or speech or language difficulty.

NEJM Volume 358:1604-1613  April 10, 2008  Number 15
Case 11-2008 — A 45-Year-Old Man with Changes in Mental Status after Liver Transplantation
Presentation of Case
A 45-year-old man was admitted to this hospital for orthotopic liver transplantation. The patient had been well until the age of 18 years, when a diagnosis of non-A, non-B hepatitis was made after a 1-month episode of jaundice; the source of exposure was thought to be tattoos. Jaundice recurred intermittently thereafter. Six years before admission, the episodes became more frequent and severe, and chronic pruritus developed. Serologic testing disclosed antibodies to hepatitis C virus (HCV) and hepatitis B virus (HBV) core and surface antigens; tests for hepatitis B surface antigen and antibodies to hepatitis A were negative. The patient began drinking heavily during this time. A diagnosis of hepatic cirrhosis was made 2 years before admission, which was complicated during the next 2 years by esophageal varices, fluid retention, ascites, and hepatic encephalopathy. Although the hepatitis C viral load was 900,000 RNA copies per milliliter of plasma, he was not believed to be a candidate for antiviral therapy because of continued alcohol use.

NEJM olume 358:1641-1642  April 10, 2008  Number 15
Lead Poisoning Due to Adulterated Marijuana
To the Editor: As a consequence of strict regulations, lead intoxication has not occurred in Germany in recent decades. Recently, during a period of 3 to 4 months, 29 patients (16 to 33 years of age) were admitted to four different hospitals in the greater Leipzig area (population, approximately 650,000) with classic signs and symptoms of lead intoxication. Twenty of these patients were admitted to our hospital (University Hospital Leipzig), 16 on an emergency basis (Table 1). The patients presented with abdominal cramps, nausea, anemia of varying severity, and fatigue. Most patients had basophilic stippling and a "Burton's line," and some had neurologic symptoms. In other hospitals, one patient had severe encephalopathy with hallucinations
and peripheral neuropathy with permanent extensor palsy in the forearm, and another patient underwent exploratory laparoscopy.