Science 15 February 2008: Vol. 319. no. 5865, pp. 958 - 962
A Mouse Model of Mitochondrial Disease Reveals Germline Selection Against Severe mtDNA Mutations
The majority of mitochondrial DNA (mtDNA) mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA mutations would be expected to be severe. To determine the fate of the more severe mtDNA mutations, we introduced mtDNAs containing two mutations that affect oxidative phosphorylation into the female mouse germ line. The severe ND6 mutation was selectively eliminated during oogenesis within four generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, severe mtDNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness.

Science 15 February 2008: Vol. 319. no. 5865, pp. 966 - 968
The Critical Importance of Retrieval for Learning
Learning is often considered complete when a student can produce the correct answer to a question. In our research, students in one condition learned foreign language vocabulary words in the standard paradigm of repeated study-test trials. In three other conditions, once a student had correctly produced the vocabulary item, it was repeatedly studied but dropped from further testing, repeatedly tested but dropped from further study, or dropped from both study and test. Repeated studying after learning had no effect on delayed recall, but repeated testing produced a large positive effect. In addition, students' predictions of their performance were uncorrelated with actual performance. The results demonstrate the critical role of retrieval practice in consolidating learning and show that even university students seem unaware of this fact.

Nature 451, 826-829 (14 February 2008) | doi:10.1038/nature06618; Received 15 October 2007; Accepted 17 December 2007
Removal of phospho-head groups of membrane lipids immobilizes voltage sensors of K+ channels
A fundamental question about the gating mechanism of voltage-activated K+ (Kv) channels is how five positively charged voltage-sensing residues in the fourth transmembrane segment are energetically stabilized, because they operate in a low-dielectric cell membrane. The simplest solution would be to pair them with negative charges. However, too few negatively charged channel residues are positioned for such a role. Recent studies suggest that some of the channel's positively charged residues are exposed to cell membrane phospholipids and interact with their head groups. A key question nevertheless remains: is the phospho-head of membrane lipids necessary for the proper function of the voltage sensor itself? Here we show that a given type of Kv channel may interact with several species of phospholipid and that enzymatic removal of their phospho-head creates an insuperable energy barrier for the positively charged voltage sensor to move through the initial gating step(s), thus immobilizing it, and also raises the energy barrier for the downstream step(s).

Nature 451, 830-834 (14 February 2008) | doi:10.1038/nature06529; Received 30 July 2007; Accepted 6 December 2007; Published online 30 January 2008; Corrected 14 February 2008
A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels
Ca2+/calmodulin-dependent regulation of voltage-gated CaV1–2 Ca2+ channels shows extraordinary modes of spatial Ca2+ decoding and channel modulation, vital for many biological functions. A single calmodulin (CaM) molecule associates constitutively with the channel's carboxy-terminal tail, and Ca2+ binding to the C-terminal and N-terminal lobes of CaM can each induce distinct channel regulations. As expected from close channel proximity, the C-lobe responds to the roughly 100-M Ca2+ pulses driven by the associated channel, a behaviour defined as 'local Ca2+ selectivity'. Conversely, all previous observations have indicated that the N-lobe somehow senses the far weaker signals from distant Ca2+ sources.

JAMA. 2008;299(6):619-620.
Scientists Probe Immune System’s Role in Brain Function and Neurological Disease
Emerging evidence suggests that proteins associated with the immune system may play additional roles in normal brain development and in the healthy adult brain. Studies also suggest that perturbations of these roles may underlie some neurological diseases.
Contrary to dogma that the blood-brain barrier protects the brain from the immune system by acting as a barricade to its components, scientists have found that certain key immune system proteins are, in fact, expressed and active in healthy brains. For instance, a growing body of evidence highlighted at the annual meeting of the Society for Neuroscience in November suggests that proteins of the major histocompatibility complex class 1 (MHC 1), a large family of immune system proteins that mediate the identification and rejection of transplanted organs, help maintain appropriate connections in the developing and adult brain. And a study published in December suggests that the classic complement cascade, the immune system component charged with tagging foreign entities for destruction by phagocytes, plays a crucial role in pruning synapses in the developing brains of mice.
These findings not only offer new avenues for understanding the development and molecular machinery of the central nervous system, they also may ultimately help scientists unravel the hitherto elusive etiologies of some developmental and neurodegenerative diseases.

BMJ  2008;336:322-325 (9 February), doi:10.1136/bmj.39457.485347.80
Assessing mental capacity: the Mental Capacity Act
Assessing mental capacity is an important part of a clinician’s role, and the recent Mental Capacity Act can help doctors when making such decisions Summary points The Mental Capacity Act has resulted in increased formalisation of capacity law and assessment The act has increased the expectation that healthcare workers should be competent at assessing capacity The act has also increased the need for training and education, especially awareness and understanding of the code of practice, independent mental capacity advocates, and advance decisions
 
Lancet Volume 371, Issue 9611, 9 February 2008-15 February 2008, Pages 500-509
Pathogenic flaviviruses
Haemorrhagic disease, encephalitis, biphasic fever, flaccid paralysis, and jaundice are typical manifestations of diseases in human beings after infections by mosquito-borne or tick-borne flaviviruses such as yellow fever, dengue, West Nile, St Louis encephalitis, Japanese encephalitis, tick-borne encephalitis, Kyasanur Forest disease, and Omsk haemorrhagic fever. Although the characteristics of these viruses are well defined, they are still unpredictable with increases in disease severity, unusual clinical manifestations, unexpected methods of transmission, long-term persistence, and the discovery of new species. This Seminar will compare the epidemiological and clinical features of the medically important flaviviruses, consider the effect of human activity on their evolution and dispersal, and draw attention to new findings and some of the unanswered questions, unresolved issues, and controversies that remain.

Lancet Volume 371, Issue 9611, 9 February 2008, Page 530
Case Report Restless arms
In the late 1980s, a 39-year-old man started to feel burning and itching in his arms, 5–15 min after going to bed. These sensations would rapidly become unbearable, and lead to an irrepressible urge to move his arms. He would then get out of bed, repeatedly stretch his arms, and scratch them energetically or put them under cold running water—all of which offered only temporary relief. He experienced these symptoms several times per night, and lost much sleep. His wife noticed that even while asleep, he would repeatedly stretch his arms. During the daytime, he was unaffected, except for sleepiness caused by his nocturnal symptoms. His medical history was otherwise unremarkable, except for hay fever and asthma.

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).1,2 We genotyped nine haplotype-tagging SNPs in IL7RA in two independent case–control collections from Olmsted County, Minnesota, and Belfast, Northern Ireland, neither of which, to our knowledge, has previously been tested for IL7RA (Table 1). Clinical and demographic data for both collections have been described elsewhere.5 Analysis of the Olmsted County genotype data revealed an association between multiple sclerosis and the rs6897932*C allele (P=0.00504; 10,000-permutation–corrected P=0.035; odds ratio, 1.5; 95% confidence interval [CI], 1.1 to 2.0). However, this association was not found in the Belfast collection. CC genotype counts (vs. T carriage) were increased in patients with multiple sclerosis, as compared with controls, in Olmsted County (P=0.0049; odds ratio, 1.6; 95% CI, 1.1 to 2.3).

NEJM Volume 358:737-739  February 14, 2008  Number 7
A Hot Spot of Genetic Instability in Autism
Sixty-five years after Leo Kanner first described autism,1 we are beginning to move beyond description of this clinically heterogeneous neurobehavioral syndrome toward a deeper understanding of its biologic complexity. In areas such as genetics and neuroscience, researchers have joined the search for objective measures to elucidate autism's pathogenesis.
It has become clear that the solutions to autism will be neither simple nor uniform among patients with various autistic syndromes. At least 60 different genetic, metabolic, and neurologic disorders have been associated with autism and involve approximately 10% of patients, whose clinical presentations frequently vary, even among those with known disorders.2 For example, some (but not all) children with Rett's syndrome, the fragile X syndrome, Down's syndrome, fetal valproate embryopathy, or congenital rubella may also present with autism.