Nature. 2008 Feb 7;451(7179):720-4.
Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease.

Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.

Nature 451, 627 (7 February 2008) | doi:10.1038/451627b; Published online 6 February 2008
Italian neuroscientists are ready to start the debate
Neurotechnologies such as cognitive enhancement (see Nature 450, 1157–1159; 2007 and Nature 451, 520–521; doi:10.1038/451520a 2008) and brain reading are likely to have huge social impact.

Nature 451, 638-639 (7 February 2008) | doi:10.1038/451638a; Published online 6 February 2008
Neuropathology: Alzheimer's in real time
A hallmark of Alzheimer's disease is the presence in the brain of protein deposits, or plaques, which are thought to form over a long period. But studies in mice suggest that the plaques can grow overnight.
Alzheimer's disease is the commonest neurodegenerative disorder in ageing human populations. It is characterized by memory loss and behavioural alterations in its early stages, and by severe cognitive impairment and dementia later on.

Nature 451, 720-724 (7 February 2008) | doi:10.1038/nature06616; Received 1 November 2007; Accepted 13 December 2007
Rapid appearance and local toxicity of amyloid- plaques in a mouse model of Alzheimer's disease
Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid- precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1–2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.

JAMA. 2008;299(5):547-554.
Atherosclerotic Plaque Composition and Occurrence of Restenosis After Carotid Endarterectomy
Context  Previous studies have assessed the predictive value of clinical and angiographic parameters for development of restenosis after vascular interventions. The composition of the atherosclerotic plaque at the intervention site has not been evaluated as a marker for restenosis.
Objective  To investigate the relationship between atherosclerotic plaque histology and the occurrence of restenosis after carotid endarterectomy.
Design, Setting, and Patients  The Athero-Express study is a longitudinal vascular biobank study that includes the collection of atherosclerotic plaques of patients undergoing primary carotid endarterectomy. Five hundred patients were prospectively followed up between April 1, 2002, and March 14, 2006, to assess carotid artery restenosis measured by duplex ultrasound 1 year after the intervention.
Main Outcome Measures  Risk of carotid restenosis in relation to predefined histological characteristics (macrophage and smooth muscle cell infiltration, collagen, calcifications, intraplaque bleeding, luminal thrombus, and lipid core size), adjusted for clinical characteristics (multivariate logistic regression analysis).
Results  At 1 year, 85 patients (17%) developed 50% or greater restenosis, including 40 patients (8%) who developed 70% or greater restenosis of the target vessel. Patients whose histological examination of the plaque revealed marked macrophage infiltration (n = 286) had a lower risk than those with none or minor macrophage infiltration (n = 214) of developing 50% or greater restenosis (risk difference, 11.5% vs 24.3%; adjusted odds ratio [OR], 0.43; 95% confidence interval [CI], 0.26-0.72) and a lower risk of developing 70% or greater restenosis (risk difference, 4.5% vs 12.6%; adjusted OR, 0.36; 95% CI, 0.17-0.74). Patients (n = 177) with a plaque having a large lipid core size (>40%) had a lower risk than those (n = 94) with a plaque having a lipid core size of less than 10% of developing 50% or greater restenosis (risk difference, 11.3% vs 25.5%; adjusted OR, 0.40; 95% CI, 0.19-0.81) and a lower risk of developing 70% or greater restenosis (risk difference, 5.6% vs 14.9%; adjusted OR, 0.42; 95% CI, 0.17-1.04), independent of clinical characteristics.
Conclusions  Plaque composition is an independent predictor of restenosis after carotid endarterectomy. The dissection of a lipid-rich, inflammatory plaque is associated with reduced risk of restenosis.

JAMA Vol. 299 No. 5, February 6, 2008    
Trends in the Use of Percutaneous Closure of Patent Foramen Ovale and Atrial Septal Defect in Adults, 1998-2004
Percutaneous closure of patent foramen ovale/atrial septal defect (PFO/ASD) is perceived as having minimal risk and has been proposed for a broad array of indications.1 The widespread application of this procedure, especially PFO closure, is controversial because of limited data on its efficacy and safety in many settings, including prevention of recurrent cryptogenic stroke.2 We studied trends in the prevalence of PFO/ASD closure in the United States.
Methods We analyzed data from 1998 through 2004 of the Nationwide Inpatient Sample, the largest publicly available all-payer US inpatient database; this stratified sample approximates a 20% sample of US community hospitals. The Hospital of the University of Pennsylvania institutional review board granted an exemption for this study.
The cohort included participants aged 20 years or older with a procedure code from the International Classification of Diseases, Ninth Revision (ICD-9) designating "Repair of ASD with prosthesis, closed technique".

JAMA. 2008;299(5):513.
Alzheimer Disease Trigger
A new study indicates that primates exposed to lead as infants show Alzheimer disease–like pathology later (Wu J et al. J Mol Neurosci. 2008;28[1]:3-9). A research team led by investigators at the University of Rhode Island in Kingston exposed Macaca fascicularis monkeys from birth to age 400 days to lead levels that produced no obvious sign of toxicity. After approximately 23 years, examination of the brains of the lead-exposed monkeys revealed many hallmarks of Alzheimer disease despite undetectable levels of lead in the blood. Brains of these monkeys harbored neuronal plaques and neurofibrillary tangles and exhibited increased expression of Alzheimer disease–related genes.
The team also found a decrease in DNA methyltransferase activity and higher oxidative damage to DNA in the brains of lead-exposed monkeys.
The study indicates that lead exposure early in life may predispose animals to later neurodegenerative disease, possibly through alterations in DNA methylation.

JAMA  2008;299(5):513Vol. 299 No. 5, February 6, 2008    
Sleep Deprivation
Cognitive effects of sleep deprivation can be reversed with the brain peptide orexin-A, according to animal studies conducted by investigators at the Wake Forest University School of Medicine in Winston-Salem, NC, and the University of California at Los Angeles (Deadwyler SA et al. J Neurosci. 2007;27[52]:14239-14247).
Orexin-A, also called hypocretin-1, is a naturally occurring peptide that is produced in the brain and regulates sleep. The researchers studied the effects of orexin-A on Macaca mulatta monkeys that were kept awake for 30 to 36 hours and were subsequently given cognitive problems of varying difficulty. Cognitive skills were significantly impaired in control monkeys, but not in monkeys given intranasal or intravenous orexin-A prior to testing.
Imaging of the monkeys' brain activity during testing showed that the brain returned to its non–sleep-deprived pattern with orexin-A administration. Also, orexin-A had no effect on performance in animals that were not sleep-deprived.

JAMA. 2008;299(5):514-515.
Notice to Readers: Recommendation From the Advisory Committee on Immunization Practices (ACIP) for Use of Quadrivalent Meningococcal Conjugate Vaccine (MCV4) in Children Aged 2-10 Years at Increased Risk for Invasive Meningococcal Disease
On October 17, 2007, the Food and Drug Administration approved quadrivalent meningococcal conjugate vaccine (MCV4) (Menactra®, Sanofi Pasteur, Swiftwater, Pennsylvania) for use in children aged 2-10 years, in addition to its prior approval for use in persons aged 11-55 years.1 Previous Advisory Committee on Immunization Practices (ACIP) recommendations called for routine vaccination with meningococcal polysaccharide vaccine (MPSV4) (Menomune®, Sanofi Pasteur) of children aged 2-10 years who are at increased risk for meningococcal disease. These children include travelers to or residents of countries in which meningococcal disease is hyperendemic or epidemic, children who have terminal complement component deficiencies, and children who have anatomic or functional asplenia. This notice provides updated recommendations for meningococcal vaccination among children aged 2-10 years at increased risk for meningococcal disease.

BMJ  2008;336:225-226 (2 February), doi:10.1136/bmj.39429.434907.80 (published 10 January 2008)
Caring for people with dementia
The focus should be on what can be done rather than on the lack of a cure
In the accompanying prospective cohort study, Xie and colleagues show that people can live for several years after being diagnosed as having dementia and many are already frail at the time of diagnosis.1 The authors estimated survival times after the onset of dementia in 438 people according to age, self reported health, disability, and severity of cognitive impairment. The estimated median survival time from the onset of dementia was 4.1 years (interquartile range 2.5-7.6) for men and 4.6 years (2.9-7.0) for women. Survival between the youngest (56-69 years) and oldest people (90 years) differed by nearly seven years. Sex, age of onset, and disability significantly predicted mortality in the presence of dementia. The study shows that dementia is a terminal condition, the course of which unfolds with coexisting age related impairment and ill health.

BMJ  2008;336:246-248 (2 February), doi:10.1136/bmj.39462.534630.AD
Cognitive Function Mind games: do they work?
Last week a government report highlighted that the number of people in England with dementia is set to rise by 30% over the next 15 years. James Butcher investigates whether programs such as Nintendo’s Brain Age, which claims to improve cognitive function, could help elderly users.

BMJ  2008;336:258-262 (2 February), doi:10.1136/bmj.39433.616678.25 (published 10 January 2008)
Survival times in people with dementia: analysis from population based cohort study with 14 year
follow-up
Objectives To provide estimates of survival after onset of dementia by age, sex, self reported health, disability, and severity of cognitive impairment.
Design Analysis of participants from prospective population based cohort study in 1991-2003, with follow-up of dementia status in all individuals after two and six years (in one centre) and 10 years and in subsamples additionally at six and eight years and mortality until 2005.
Setting Multicentre population based study in England and Wales: two rural and three urban centres.
Participants 438 participants who developed dementia from a population based study of 13 004 individuals aged 65 years and over drawn from primary care population registers.
Main outcome measures Sociodemographic factors, cognitive function, specific health conditions, and self reported health collected at each interview. Cox’s proportional hazards regression models were used to identify predictors of mortality from the selected variables in people who received diagnosis of dementia according the study’s criteria.
Results By December 2005, 356 of the 438 (81%) participants who developed dementia during the study had died. Estimated median survival time from onset of dementia to death was 4.1 years (interquartile range 2.5-7.6) for men and 4.6 years (2.9-7.0) for women. There was a difference of nearly seven years in survival between the younger old and the oldest people with dementia: 10.7 (25th centile 5.6) for ages 65-69; 5.4 (interquartile range 3.4-8.3) for ages 70-79; 4.3 (2.8-7.0) for ages 80-89, and 3.8 (2.3-5.2) years for ages 90. Significant factors that predicted mortality in the presence of dementia during the follow-up included sex, age of onset, and disability.
Conclusion These analyses give a population based estimated median survival for incident dementia of 4.5 years. Such estimates can be used for prognosis and planning for patients, carers, service providers, and policy makers.

Lancet Volume 371, Issue 9610 Pages 380-381
Brain-based ethics
For most of human history, claims about the ethical principles by which we should live have been the province of priests, prophets, and philosophers, to be encoded by law-makers. The Hammurabi code, dating from some 1750 BCE, and the biblical Ten Commandments, inscribed on tablets of stone, are key moments in western (Judaeo-Christian and Islamic) cultural history; the Analects of Confucius play a similar part in Chinese culture, as do the Hindu Vedas in India. European medical ethics may date from Hippocrates, and more recently from the Nuremberg Code on human experimentation arising from the postwar trials of the Nazi doctors in 1947. But where do these ethical principles come from.

Lancet Volume 371, Issue 9610, 2 February 2008-8 February 2008, Pages 387-394
Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study
Background
Information about the variation in the risk for venous thromboembolism (VTE) and in prophylaxis practices around the world is scarce. The ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study is a multinational cross-sectional survey designed to assess the prevalence of VTE risk in the acute hospital care setting, and to determine the proportion of at-risk patients who receive effective prophylaxis.
Methods
All hospital inpatients aged 40 years or over admitted to a medical ward, or those aged 18 years or over admitted to a surgical ward, in 358 hospitals across 32 countries were assessed for risk of VTE on the basis of hospital chart review. The 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines were used to assess VTE risk and to determine whether patients were receiving recommended prophylaxis.
Findings
68 183 patients were enrolled; 30 827 (45%) were categorised as surgical, and 37 356 (55%) as medical. On the basis of ACCP criteria, 35 329 (51·8%; 95% CI 51·4–52·2; between-country range 35·6–72·6) patients were judged to be at risk for VTE, including 19 842 (64·4%; 63·8–64·9; 44·1–80·2) surgical patients and 15 487 (41·5%; 41·0–42·0; 21·1–71·2) medical patients. Of the surgical patients at risk, 11 613 (58·5%; 57·8–59·2; 0·2–92·1) received ACCP-recommended VTE prophylaxis, compared with 6119 (39·5%; 38·7–40·3; 3·1–70·4) at-risk medical patients.
Interpretation
A large proportion of hospitalised patients are at risk for VTE, but there is a low rate of appropriate prophylaxis. Our data reinforce the rationale for the use of hospital-wide strategies to assess patients' VTE risk and to implement measures that ensure that at-risk patients receive appropriate prophylaxis.

NEJM Volume 358:667-675  February 14, 2008  Number 7
Association between Microdeletion and Microduplication at 16p11.2 and Autism
Background Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role.
Methods As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland.
Results Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor.
Conclusions We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations.

NEJM Volume 358:676-688  February 14, 2008  Number 7
B-Cell Depletion with Rituximab in Relapsing–Remitting Multiple Sclerosis
Background There is increasing evidence that B lymphocytes are involved in the pathogenesis of multiple sclerosis, and they may be a therapeutic target. Rituximab, a monoclonal antibody, selectively targets and depletes CD20+ B lymphocytes.
Methods In a phase 2, double-blind, 48-week trial involving 104 patients with relapsing–remitting multiple sclerosis, we assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse.
Results As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P<0.001) and of total new gadolinium-enhancing lesions over the same period (P<0.001); these results were sustained for 48 weeks (P<0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5% vs. 34.3%, P=0.02) and week 48 (20.3% vs. 40.0%, P=0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups.
Conclusions A single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. This trial was not designed to assess long-term safety or to detect uncommon adverse events. The data provide evidence of B-cell involvement in the pathophysiology of relapsing–remitting multiple sclerosis. (ClinicalTrials.gov number, NCT00097188 [ClinicalTrials.gov] .)

NEJM Volume 358:753-754  February 14, 2008  Number 7
IL7RA Polymorphisms and Susceptibility to Multiple Sclerosis
To the Editor: Two independent, well-powered studies have recently identified the interleukin-7 receptor  (IL7RA) gene as a susceptibility gene for multiple sclerosis,1,2 thus extending and confirming earlier observations.3,4 A functional, nonsynonymous single-nucleotide polymorphism (SNP), rs6897932, located
in the alternatively spliced sixth exon of the gene, was highlighted as the susceptibility-modifying polymorphism, with the C allele increasing the risk of disease (odds ratio, approximately 1.2)