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Recent Articles in Proceedings of the National Academy of Sciences of the United States of America

Lyons DE, Young AG, Keil FC
The hidden structure of overimitation.
Proc Natl Acad Sci U S A. 2007 Dec 4;
Young children are surprisingly judicious imitators, but there are also times when their reproduction of others' actions appears strikingly illogical. For example, children who observe an adult inefficiently operating a novel object frequently engage in what we term overimitation, persistently reproducing the adult's unnecessary actions. Although children readily overimitate irrelevant actions that even chimpanzees ignore, this curious effect has previously attracted little interest; it has been assumed that children overimitate not for theoretically significant reasons, but rather as a purely social exercise. In this paper, however, we challenge this view, presenting evidence that overimitation reflects a more fundamental cognitive process. We show that children who observe an adult intentionally manipulating a novel object have a strong tendency to encode all of the adult's actions as causally meaningful, implicitly revising their causal understanding of the object accordingly. This automatic causal encoding process allows children to rapidly calibrate their causal beliefs about even the most opaque physical systems, but it also carries a cost. When some of the adult's purposeful actions are unnecessary-even transparently so-children are highly prone to mis-encoding them as causally significant. The resulting distortions in children's causal beliefs are the true cause of overimitation, a fact that makes the effect remarkably resistant to extinction. Despite countervailing task demands, time pressure, and even direct warnings, children are frequently unable to avoid reproducing the adult's irrelevant actions because they have already incorporated them into their representation of the target object's causal structure. [Abstract/Link to Full Text]

Trapp RJ, Diffenbaugh NS, Brooks HE, Baldwin ME, Robinson ED, Pal JS
Changes in severe thunderstorm environment frequency during the 21st century caused by anthropogenically enhanced global radiative forcing.
Proc Natl Acad Sci U S A. 2007 Dec 4;
Severe thunderstorms comprise an extreme class of deep convective clouds and produce high-impact weather such as destructive surface winds, hail, and tornadoes. This study addresses the question of how severe thunderstorm frequency in the United States might change because of enhanced global radiative forcing associated with elevated greenhouse gas concentrations. We use global climate models and a high-resolution regional climate model to examine the larger-scale (or "environmental") meteorological conditions that foster severe thunderstorm formation. Across this model suite, we find a net increase during the late 21st century in the number of days in which these severe thunderstorm environmental conditions (NDSEV) occur. Attributed primarily to increases in atmospheric water vapor within the planetary boundary layer, the largest increases in NDSEV are shown during the summer season, in proximity to the Gulf of Mexico and Atlantic coastal regions. For example, this analysis suggests a future increase in NDSEV of 100% or more in locations such as Atlanta, GA, and New York, NY. Any direct application of these results to the frequency of actual storms also must consider the storm initiation. [Abstract/Link to Full Text]

Jarosinski K, Kattenhorn L, Kaufer B, Ploegh H, Osterrieder N
A herpesvirus ubiquitin-specific protease is critical for efficient T cell lymphoma formation.
Proc Natl Acad Sci U S A. 2007 Dec 4;
The herpesvirus ubiquitin-specific protease (USP) family, whose founding member was discovered as a protease domain embedded in the large tegument protein of herpes simplex virus 1 (HSV-1), is conserved across all members of the Herpesviridae. Whether this conservation is indicative of an essential function of the enzyme in vivo has not yet been established. As reported here, USP activity is conserved in Marek's disease virus (MDV), a tumorigenic alphaherpesvirus. A single amino acid substitution that abolishes the USP activity of the MDV large tegument protein diminishes MDV replication in vivo, and severely limits the oncogenic potential of the virus. Expression of the USP transcripts in MDV-transformed cell lines further substantiates this hypothesis. The herpesvirus USP thus appears to be required not only to maintain a foothold in the immunocompetent host, but also to contribute to malignant outgrowths. [Abstract/Link to Full Text]

Shi M, Larrondo LF, Loros JJ, Dunlap JC
A developmental cycle masks output from the circadian oscillator under conditions of choline deficiency in Neurospora.
Proc Natl Acad Sci U S A. 2007 Dec 4;
In Neurospora, metabolic oscillators coexist with the circadian transcriptional/translational feedback loop governed by the FRQ (Frequency) and WC (White Collar) proteins. One of these, a choline deficiency oscillator (CDO) observed in chol-1 mutants grown under choline starvation, drives an uncompensated long-period developmental cycle ( approximately 60-120 h). To assess possible contributions of this metabolic oscillator to the circadian system, molecular and physiological rhythms were followed in liquid culture under choline starvation, but these only confirmed that an oscillator with a normal circadian period length can run under choline starvation. This finding suggested that long-period developmental cycles elicited by nutritional stress could be masking output from the circadian system, although a caveat was that the CDO sometimes requires several days to become consolidated. To circumvent this and observe both oscillators simultaneously, we used an assay using a codon-optimized luciferase to follow the circadian oscillator. Under conditions where the long-period, uncompensated, CDO-driven developmental rhythm was expressed for weeks in growth tubes, the luciferase rhythm in the same cultures continued in a typical compensated manner with a circadian period length dependent on the allelic state of frq. Periodograms revealed no influence of the CDO on the circadian oscillator. Instead, the CDO appears as a cryptic metabolic oscillator that can, under appropriate conditions, assume control of growth and development, thereby masking output from the circadian system. frq-driven luciferase as a reporter of the circadian oscillator may in this way provide a means for assessing prospective role(s) of metabolic and/or ancillary oscillators within cellular circadian systems. [Abstract/Link to Full Text]

Selhub J, Morris MS, Jacques PF
In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations.
Proc Natl Acad Sci U S A. 2007 Dec 4;
In a recent study of older participants (age >/=60 years) in the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we showed that a combination of high serum folate and low vitamin B(12) status was associated with higher prevalence of cognitive impairment and anemia than other combinations of vitamin B(12) and folate status. In the present study, we sought to determine the joint influence of serum folate and vitamin B(12) concentrations on two functional indicators of vitamin B(12) status, total homocysteine (tHcy) and methylmalonic acid (MMA), among adult participants in phase 2 of the NHANES III (1991-1994) and the NHANES 1999-2002. Exclusion of subjects who were <20 years old, were pregnant, had evidence of kidney or liver dysfunction, or reported a history of alcohol abuse or recent anemia therapy left 4,940 NHANES III participants and 5,473 NHANES 1999-2002 participants for the study. Multivariate analyses controlled for demographic factors, smoking, alcohol use, body mass index, self-reported diabetes diagnosis, and serum concentrations of creatinine and alanine aminotransferase revealed significant interactions between serum folate and serum vitamin B(12) in relation to circulating concentrations of both metabolites. In subjects with serum vitamin B(12) >148 pmol/liter (L), concentrations of both metabolites decreased significantly as serum folate increased. In subjects with lower serum vitamin B(12), however, metabolite concentrations increased as serum folate increased starting at approximately 20 nmol/L. These results suggest a worsening of vitamin B(12)'s enzymatic functions as folate status increases in people who are vitamin B(12)-deficient. [Abstract/Link to Full Text]

Hallatschek O, Hersen P, Ramanathan S, Nelson DR
Genetic drift at expanding frontiers promotes gene segregation.
Proc Natl Acad Sci U S A. 2007 Dec 4;
Competition between random genetic drift and natural selection play a central role in evolution: Whereas nonbeneficial mutations often prevail in small populations by chance, mutations that sweep through large populations typically confer a selective advantage. Here, however, we observe chance effects during range expansions that dramatically alter the gene pool even in large microbial populations. Initially well mixed populations of two fluorescently labeled strains of Escherichia coli develop well defined, sector-like regions with fractal boundaries in expanding colonies. The formation of these regions is driven by random fluctuations that originate in a thin band of pioneers at the expanding frontier. A comparison of bacterial and yeast colonies (Saccharomyces cerevisiae) suggests that this large-scale genetic sectoring is a generic phenomenon that may provide a detectable footprint of past range expansions. [Abstract/Link to Full Text]

Guo M, Jin S, Sun D, Hew CL, Pan SQ
Recruitment of conjugative DNA transfer substrate to Agrobacterium type IV secretion apparatus.
Proc Natl Acad Sci U S A. 2007 Dec 3;
Bacterial type IV secretion system (T4SS) belongs to a growing class of evolutionarily conserved transporters that translocate DNA and proteins into a wide variety of organisms including bacterial and eukaryotic cells. Archetypal is the Agrobacterium tumefaciens VirB/D4 T4SS that transfers oncogenic T-DNA to various eukaryotic cells, which is transferred as a nucleoprotein T-complex with VirD2 as the pilot protein. As a derivative of plasmid conjugation systems, the VirB/D4 T4SS can also transfer certain mobilizable plasmids and bacterial proteins like VirE2 and VirF, although it is unknown how the membrane-bound T4SS recruits different transfer substrates. Here, we show that a cytoplasmic VirD2-binding protein (VBP) is involved in the recruitment of the T-complex to the energizing components of the T4SS, including VirD4, VirB4, and VirB11. VBP is also important for the recruitment of a conjugative plasmid to a different transfer system independent of VirB/D4. These data indicate that VBP functions as a previously unrecognized recruiting protein that helps couple nucleoprotein substrates to the appropriate transport sites for conjugative DNA transfers. VBP has three functionally redundant homologs, and similar homologs can be found in different bacterial genomes, suggesting a previously uncharacterized class of proteins involved in conjugative DNA transfers. [Abstract/Link to Full Text]

Wang S, Tulina N, Carlin DL, Rulifson EJ
The origin of islet-like cells in Drosophila identifies parallels to the vertebrate endocrine axis.
Proc Natl Acad Sci U S A. 2007 Dec 3;
Single-cell resolution lineage information is a critical key to understanding how the states of gene regulatory networks respond to cell interactions and thereby establish distinct cell fates. Here, we identify a single pair of neural stem cells (neuroblasts) as progenitors of the brain insulin-producing neurosecretory cells of Drosophila, which are homologous to islet beta cells. Likewise, we identify a second pair of neuroblasts as progenitors of the neurosecretory Corpora cardiaca cells, which are homologous to the glucagon-secreting islet alpha cells. We find that both progenitors originate as neighboring cells from anterior neuroectoderm, which expresses genes orthologous to those expressed in the vertebrate adenohypophyseal placode, the source of endocrine anterior pituitary and neurosecretory hypothalamic cells [Whitlock KE (2005) Trends Endocrinol Metab 16:145-151]. This ontogenic-molecular concordance suggests that a rudimentary brain endocrine axis was present in the common ancestor of humans and flies, where it orchestrated the islet-like endocrine functions of insulin and glucagon biology. [Abstract/Link to Full Text]

Wargo AR, Huijben S, de Roode JC, Shepherd J, Read AF
Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model.
Proc Natl Acad Sci U S A. 2007 Dec 3;
Malaria infections frequently consist of mixtures of drug-resistant and drug-sensitive parasites. If crowding occurs, where clonal population densities are suppressed by the presence of coinfecting clones, removal of susceptible clones by drug treatment could allow resistant clones to expand into the newly vacated niche space within a host. Theoretical models show that, if such competitive release occurs, it can be a potent contributor to the strength of selection, greatly accelerating the rate at which resistance spreads in a population. A variety of correlational field data suggest that competitive release could occur in human malaria populations, but direct evidence cannot be ethically obtained from human infections. Here we show competitive release after pyrimethamine curative chemotherapy of acute infections of the rodent malaria Plasmodium chabaudi in laboratory mice. The expansion of resistant parasite numbers after treatment resulted in enhanced transmission-stage densities. After the elimination or near-elimination of sensitive parasites, the number of resistant parasites increased beyond that achieved when a competitor had never been present. Thus, a substantial competitive release occurred, markedly elevating the fitness advantages of drug resistance above those arising from survival alone. This finding may explain the rapid spread of drug resistance and the subsequently brief useful lifespans of some antimalarial drugs. In a second experiment, where subcurative chemotherapy was administered, the resistant clone was only partly released from competitive suppression and experienced a restriction in the size of its expansion after treatment. This finding raises the prospect of harnessing in-host ecology to slow the spread of drug resistance. [Abstract/Link to Full Text]

Lahlou H, Sanguin-Gendreau V, Zuo D, Cardiff RD, McLean GW, Frame MC, Muller WJ
Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression.
Proc Natl Acad Sci U S A. 2007 Dec 3;
Elevated expression and activation of the focal adhesion kinase (FAK) occurs in a large proportion of human breast cancers. Although several studies have implicated FAK as an important signaling molecule in cell culture systems, evidence supporting a role for FAK in mammary tumor progression is lacking. To directly assess the role of FAK in this process, we have used the Cre/loxP recombination system to disrupt FAK function in the mammary epithelium of a transgenic model of breast cancer. Using this approach, we demonstrate that FAK expression is required for the transition of premalignant hyperplasias to carcinomas and their subsequent metastases. This dramatic block in tumor progression was further correlated with impaired mammary epithelial proliferation. These observations provide direct evidence that FAK plays a critical role in mammary tumor progression. [Abstract/Link to Full Text]

Zhang DD, Brecke P, Lee HF, He YQ, Zhang J
Global climate change, war, and population decline in recent human history.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19214-9.
Although scientists have warned of possible social perils resulting from climate change, the impacts of long-term climate change on social unrest and population collapse have not been quantitatively investigated. In this study, high-resolution paleo-climatic data have been used to explore at a macroscale the effects of climate change on the outbreak of war and population decline in the preindustrial era. We show that long-term fluctuations of war frequency and population changes followed the cycles of temperature change. Further analyses show that cooling impeded agricultural production, which brought about a series of serious social problems, including price inflation, then successively war outbreak, famine, and population decline successively. The findings suggest that worldwide and synchronistic war-peace, population, and price cycles in recent centuries have been driven mainly by long-term climate change. The findings also imply that social mechanisms that might mitigate the impact of climate change were not significantly effective during the study period. Climate change may thus have played a more important role and imposed a wider ranging effect on human civilization than has so far been suggested. Findings of this research may lend an additional dimension to the classic concepts of Malthusianism and Darwinism. [Abstract/Link to Full Text]

Kuiken TA, Marasco PD, Lock BA, Harden RN, Dewald JP
Redirection of cutaneous sensation from the hand to the chest skin of human amputees with targeted reinnervation.
Proc Natl Acad Sci U S A. 2007 Nov 28;
Amputees cannot feel what they touch with their artificial hands, which severely limits usefulness of those hands. We have developed a technique that transfers remaining arm nerves to residual chest muscles after an amputation. This technique allows some sensory nerves from the amputated limb to reinnervate overlying chest skin. When this reinnervated skin is touched, the amputees perceive that they are being touched on their missing limb. We found that touch thresholds of the reinnervated chest skin fall within near-normal ranges, indicating the regeneration of large-fiber afferents. The perceptual identity of the limb and chest was maintained separately even though they shared a common skin surface. A cutaneous expression of proprioception also occurred in one reinnervated individual. Experiments with peltier temperature probes and surface electrical stimulation of the reinnervated skin indicate the regeneration of small diameter temperature and pain afferents. The perception of an amputated limb arising from stimulation of reinnervated chest skin may allow useful sensory feedback from prosthetic devices and provides insight into the mechanisms of neural plasticity and peripheral regeneration in humans. [Abstract/Link to Full Text]

Moore MJ, Bell CD, Soltis PS, Soltis DE
Using plastid genome-scale data to resolve enigmatic relationships among basal angiosperms.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19363-8.
Although great progress has been made in clarifying deep-level angiosperm relationships, several early nodes in the angiosperm branch of the Tree of Life have proved difficult to resolve. Perhaps the last great question remaining in basal angiosperm phylogeny involves the branching order among the five major clades of mesangiosperms (Ceratophyllum, Chloranthaceae, eudicots, magnoliids, and monocots). Previous analyses have found no consistent support for relationships among these clades. In an effort to resolve these relationships, we performed phylogenetic analyses of 61 plastid genes ( approximately 42,000 bp) for 45 taxa, including members of all major basal angiosperm lineages. We also report the complete plastid genome sequence of Ceratophyllum demersum. Parsimony analyses of combined and partitioned data sets varied in the placement of several taxa, particularly Ceratophyllum, whereas maximum-likelihood (ML) trees were more topologically stable. Total evidence ML analyses recovered a clade of Chloranthaceae + magnoliids as sister to a well supported clade of monocots + (Ceratophyllum + eudicots). ML bootstrap and Bayesian support values for these relationships were generally high, although approximately unbiased topology tests could not reject several alternative topologies. The extremely short branches separating these five lineages imply a rapid diversification estimated to have occurred between 143.8 +/- 4.8 and 140.3 +/- 4.8 Mya. [Abstract/Link to Full Text]

Wang XJ, Hayes JD, Henderson CJ, Wolf CR
Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19589-94.
Isothiocyanates and phenolic antioxidants can prevent cancer through activation of Nrf2 (NF-E2 p45-related factor 2), a transcription factor that controls expression of cytoprotective genes through the antioxidant response element (ARE) enhancer. Using a human mammary MCF7-derived AREc32 reporter cell line, we now report that all-trans retinoic acid (ATRA), and other retinoic acid receptor alpha (RARalpha) agonists, markedly reduces the ability of Nrf2 to mediate induction of ARE-driven genes by cancer chemopreventive agents including the metabolite of butylated hydroxyanisole, tert-butylhydroquinone (tBHQ). The basal and tBHQ-inducible expression of aldo-keto reductase (AKR) AKR1C1 and AKR1C2 genes, which are regulated by Nrf2, was also repressed by ATRA in AREc32 cells. Antagonists of RARalpha augmented induction of ARE-driven gene expression by tBHQ, as did knockdown of RARalpha by using RNAi. The expression of the ARE-gene battery was increased in the small intestine of mice fed on a vitamin A-deficient diet, and this increase was repressed by administration of ATRA. By contrast, in the small intestine of Nrf2 null mice, the expression of ARE-driven genes was not affected by vitamin A status. In MCF7 cells, ATRA did not block the nuclear accumulation of Nrf2 but reduced the binding of Nrf2 to the ARE enhancer as a consequence of forming a complex with RARalpha. These data suggest that cross-talk between Nrf2 and RARalpha could markedly influence the sensitivity of cells to electrophiles and oxidative stressors and, as a consequence, to carcinogenesis. [Abstract/Link to Full Text]

Chen X, Liu CT, Zhang M, Zhang H
A forest-based approach to identifying gene and gene gene interactions.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19199-203.
Multiple genes, gene-by-gene interactions, and gene-by-environment interactions are believed to underlie most complex diseases. However, such interactions are difficult to identify. Although there have been recent successes in identifying genetic variants for complex diseases, it still remains difficult to identify gene-gene and gene-environment interactions. To overcome this difficulty, we propose a forest-based approach and a concept of variable importance. The proposed approach is demonstrated by simulation study for its validity and illustrated by a real data analysis for its use. Analyses of both real data and simulated data based on published genetic models show the effectiveness of our approach. For example, our analysis of a published data set on age-related macular degeneration (AMD) not only confirmed a known genetic variant (P value = 2E-6) for AMD, but also revealed an unreported haplotype surrounding single-nucleotide polymorphism (SNP) rs10272438 on chromosome 7 that was significantly associated with AMD (P value = 0.0024). These significance levels are obtained after the consideration for a large number of SNPs. Thus, the importance of this work is twofold: it proposes a powerful and flexible method to identify high-risk haplotypes and their interactions and reveals a potentially protective variant for AMD. [Abstract/Link to Full Text]

Singh S, Plassmeyer M, Gaur D, Miller LH
Mononeme: A new secretory organelle in Plasmodium falciparum merozoites identified by localization of rhomboid-1 protease.
Proc Natl Acad Sci U S A. 2007 Nov 28;
Compartmentalization of proteins into subcellular organelles in eukaryotic cells is a fundamental mechanism of regulating complex cellular functions. Many proteins of Plasmodium falciparum merozoites involved in invasion are compartmentalized into apical organelles. We have identified a new merozoite organelle that contains P. falciparum rhomboid-1 (PfROM1), a protease that cleaves the transmembrane regions of proteins involved in invasion. By immunoconfocal microscopy, PfROM1 was localized to a single, thread-like structure on one side of the merozoites that appears to be in close proximity to the subpellicular microtubules. PfROM1 was not found associated with micronemes, rhoptries, or dense granules, the three identified secretory organelles of invasion. Release of merozoites from schizonts resulted in the movement of PfROM1 from the lateral asymmetric localization to the merozoite apical pole and the posterior pole. We have named this single thread-like organelle in merozoites, the mononeme. [Abstract/Link to Full Text]

Santomasso BD, Roberts WK, Thomas A, Williams T, Blach�re NE, Dudley ME, Houghton AN, Posner JB, Darnell RB
A T cell receptor associated with naturally occurring human tumor immunity.
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19073-8.
The onconeural antigens appear to serve as tumor rejection antigens in the paraneoplastic neurologic disorders. Here, we used an unbiased peptide binding screen, followed by studies in HLA-A2.1 transgenic mice to identify naturally processed HLA-A2.1 restricted epitopes of the paraneoplastic cerebellar degeneration breast/ovarian cancer antigen cdr2. These mice were used to clone high-avidity cdr2-specific CD8(+) T cells that recognize human tumor cells presenting endogenously loaded MHC class I-cdr2 peptide. T cells with this specificity were detected in the peripheral blood of two HLA-A2.1(+) paraneoplastic cerebellar degeneration patients. We cloned T cell receptor (TCR) alpha and beta genes from cdr2-specific T cells; electroporation of RNA encoding this TCR turned nonreactive donor T cells into efficient killers of human cdr2-expressing tumor cells. Cloned cdr2-specific TCR genes provide a clinically relevant means for immunologic targeting of human gynecologic cancers. [Abstract/Link to Full Text]

Peters W, Jacobson AR, Sweeney C, Andrews AE, Conway TJ, Masarie K, Miller JB, Bruhwiler LM, P�tron G, Hirsch AI, Worthy DE, van der Werf GR, Randerson JT, Wennberg PO, Krol MC, Tans PP
An atmospheric perspective on North American carbon dioxide exchange: CarbonTracker.
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):18925-30.
We present an estimate of net CO(2) exchange between the terrestrial biosphere and the atmosphere across North America for every week in the period 2000 through 2005. This estimate is derived from a set of 28,000 CO(2) mole fraction observations in the global atmosphere that are fed into a state-of-the-art data assimilation system for CO(2) called CarbonTracker. By design, the surface fluxes produced in CarbonTracker are consistent with the recent history of CO(2) in the atmosphere and provide constraints on the net carbon flux independent from national inventories derived from accounting efforts. We find the North American terrestrial biosphere to have absorbed -0.65 PgC/yr (1 petagram = 10(15) g; negative signs are used for carbon sinks) averaged over the period studied, partly offsetting the estimated 1.85 PgC/yr release by fossil fuel burning and cement manufacturing. Uncertainty on this estimate is derived from a set of sensitivity experiments and places the sink within a range of -0.4 to -1.0 PgC/yr. The estimated sink is located mainly in the deciduous forests along the East Coast (32%) and the boreal coniferous forests (22%). Terrestrial uptake fell to -0.32 PgC/yr during the large-scale drought of 2002, suggesting sensitivity of the contemporary carbon sinks to climate extremes. CarbonTracker results are in excellent agreement with a wide collection of carbon inventories that form the basis of the first North American State of the Carbon Cycle Report (SOCCR), to be released in 2007. All CarbonTracker results are freely available at http://carbontracker.noaa.gov. [Abstract/Link to Full Text]

Nakane D, Miyata M
Cytoskeletal "jellyfish" structure of Mycoplasma mobile.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19518-23.
Mycoplasma mobile, a parasitic bacterium lacking a peptidoglycan layer, glides on solid surfaces in the direction of a membrane protrusion at a cell pole by a unique mechanism. Recently, we proposed a working model in which cells are propelled by leg proteins clustering at the protrusion's base. The legs repeatedly catch and release sialic acids on the solid surface, a motion that is driven by the force generated by ATP hydrolysis. Here, to clarify the subcellular structure supporting the gliding force and the cell shape, we stripped the membrane by Triton X-100 and identified a unique structure, designated the "jellyfish" structure. In this structure, an oval solid "bell" approximately 235 wide and 155 nm long is filled with a 12-nm hexagonal lattice and connected to this structure are dozens of flexible "tentacles" that are covered with particles of 20-nm diameter at intervals of approximately 30 nm. The particles appear to have 180 degrees rotational symmetry and a dimple at the center. The relation of this structure to the gliding mechanism was suggested by its cellular localization and by analyses of mutants lacking proteins essential for gliding. We identified 10 proteins as the components by mass spectrometry and found that these do not show sequence similarities with other proteins of bacterial cytoskeletons or the gliding proteins previously identified. Immunofluorescence and immunoelectron microscopy revealed that two components are localized at the bell and another that has the structure similar to the F(1)-ATPase beta subunit is localized at the tentacles. [Abstract/Link to Full Text]

Couturier C, Sarkis C, S�ron K, Belouzard S, Chen P, Lenain A, Corset L, Dam J, Vauthier V, Dubart A, Mallet J, Froguel P, Rouill� Y, Jockers R
Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19476-81.
Obesity is a major public health problem and is often associated with type 2 diabetes mellitus, cardiovascular disease, and metabolic syndrome. Leptin is the crucial adipostatic hormone that controls food intake and body weight through the activation of specific leptin receptors (OB-R) in the hypothalamic arcuate nucleus (ARC). However, in most obese patients, high circulating levels of leptin fail to bring about weight loss. The prevention of this "leptin resistance" is a major goal for obesity research. We report here a successful prevention of diet-induced obesity (DIO) by silencing a negative regulator of OB-R function, the OB-R gene-related protein (OB-RGRP), whose transcript is genetically linked to the OB-R transcript. We provide in vitro evidence that OB-RGRP controls OB-R function by negatively regulating its cell surface expression. In the DIO mouse model, obesity was prevented by silencing OB-RGRP through stereotactic injection of a lentiviral vector encoding a shRNA directed against OB-RGRP in the ARC. This work demonstrates that OB-RGRP is a potential target for obesity treatment. Indeed, regulators of the receptor could be more appropriate targets than the receptor itself. This finding could serve as the basis for an approach to identifying potential new therapeutic targets for a variety of diseases, including obesity. [Abstract/Link to Full Text]

Zhou F, Pu Y, Wei T, Liu H, Deng W, Wei C, Ding B, Omura T, Li Y
The P2 capsid protein of the nonenveloped rice dwarf phytoreovirus induces membrane fusion in insect host cells.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19547-52.
Insect transmission is an essential process of infection for numerous plant and animal viruses. How an insect-transmissible plant virus enters an insect cell to initiate the infection cycle is poorly understood, especially for nonenveloped plant and animal viruses. The capsid protein P2 of rice dwarf virus (RDV), which is nonenveloped, is necessary for insect transmission. Here, we present evidence that P2 shares structural features with membrane-fusogenic proteins encoded by enveloped animal viruses. When RDV P2 was ectopically expressed and displayed on the surface of insect Spodoptera frugiperda cells, it induced membrane fusion characterized by syncytium formation at low pH. Mutational analyses identified the N-terminal and a heptad repeat as being critical for the membrane fusion-inducing activity. These results are corroborated with results from RDV-infected cells of the insect vector leafhopper. We propose that the RDV P2-induced membrane fusion plays a critical role in viral entry into insect cells. Our report that a plant viral protein can induce membrane fusion has broad significance in studying the mechanisms of virus entry into insect cells and insect transmission of nonenveloped plant and animal viruses. [Abstract/Link to Full Text]

Karginov FV, Conaco C, Xuan Z, Schmidt BH, Parker JS, Mandel G, Hannon GJ
A biochemical approach to identifying microRNA targets.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19291-6.
Identifying the downstream targets of microRNAs (miRNAs) is essential to understanding cellular regulatory networks. We devised a direct biochemical method for miRNA target discovery that combined RNA-induced silencing complex (RISC) purification with microarray analysis of bound mRNAs. Because targets of miR-124a have been analyzed, we chose it as our model. We honed our approach both by examining the determinants of stable binding between RISC and synthetic target RNAs in vitro and by determining the dependency of both repression and RISC coimmunoprecipitation on miR-124a seed sites in two of its well characterized targets in vivo. Examining the complete spectrum of miR-124 targets in 293 cells yielded both a set that were down-regulated at the mRNA level, as previously observed, and a set whose mRNA levels were unaffected by miR-124a. Reporter assays validated both classes, extending the spectrum of mRNA targets that can be experimentally linked to the miRNA pathway. [Abstract/Link to Full Text]

Shibasaki T, Takahashi H, Miki T, Sunaga Y, Matsumura K, Yamanaka M, Zhang C, Tamamoto A, Satoh T, Miyazaki JI, Seino S
Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19333-19338.
cAMP is well known to regulate exocytosis in various secretory cells, but the precise mechanism of its action remains unknown. Here, we examine the role of cAMP signaling in the exocytotic process of insulin granules in pancreatic beta cells. Although activation of cAMP signaling alone does not cause fusion of the granules to the plasma membrane, it clearly potentiates both the first phase (a prompt, marked, and transient increase) and the second phase (a moderate and sustained increase) of glucose-induced fusion events. Interestingly, all granules responsible for this potentiation are newly recruited and immediately fused to the plasma membrane without docking (restless newcomer). Importantly, cAMP-potentiated fusion events in the first phase of glucose-induced exocytosis are markedly reduced in mice lacking the cAMP-binding protein Epac2 (Epac2(ko/ko)). In addition, the small GTPase Rap1, which is activated by cAMP specifically through Epac2 in pancreatic beta cells, mediates cAMP-induced insulin secretion in a protein kinase A-independent manner. We also have developed a simulation model of insulin granule movement in which potentiation of the first phase is associated with an increase in the insulin granule density near the plasma membrane. Taken together, these data indicate that Epac2/Rap1 signaling is essential in regulation of insulin granule dynamics by cAMP, most likely by controlling granule density near the plasma membrane. [Abstract/Link to Full Text]

Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, B�lec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC
Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7.
Elevated expression of members of the BCL-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells. Small molecule obatoclax (GX15-070), which is predicted to occupy a hydrophobic pocket within the BH3 binding groove of BCL-2, antagonizes these members and induces apoptosis, dependent on BAX and BAK. Reconstitution in yeast confirmed that obatoclax acts on the pathway and overcomes BCL-2-, BCL-XL-, BCL-w-, and MCL-1-mediated resistance to BAX or BAK. The compound potently interfered with the direct interaction between MCL-1 and BAK in intact mitochondrial outer membrane and inhibited the association between MCL-1 and BAK in intact cells. MCL-1 has been shown to confer resistance to the BCL-2/BCL-XL/BCL-w-selective antagonist ABT-737 and to the proteasome inhibitor bortezomib. In both cases, this resistance was overcome by obatoclax. These findings support a rational clinical development opportunity for the compound in cancer indications or treatments where MCL-1 contributes to resistance to cell killing. [Abstract/Link to Full Text]

Staniland S, Ward B, Harrison A, van der Laan G, Telling N
Rapid magnetosome formation shown by real-time x-ray magnetic circular dichroism.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19524-8.
Magnetosomes are magnetite nanoparticles formed by biomineralization within magnetotactic bacteria. Although there have been numerous genetic and proteomic studies of the magnetosome-formation process, there have been only limited and inconclusive studies of mineral-phase evolution during the formation process, and no real-time studies of such processes have yet been performed. Thus, suggested formation mechanisms still need substantiating with data. Here we report the examination of the magnetosome material throughout the formation process in a real-time in vivo study of Magnetospirillum gryphiswaldense, strain MSR-1. Transmission EM and x-ray absorption spectroscopy studies reveal that full-sized magnetosomes are seen 15 min after formation is initiated. These immature magnetosomes contain a surface layer of the nonmagnetic iron oxide-phase hematite. Mature magnetite is found after another 15 min, concurrent with a dramatic increase in magnetization. This rapid formation result is contrary to previously reported studies and discounts the previously proposed slow, multistep formation mechanisms. Thus, we conclude that the biomineralization of magnetite occurs rapidly in magnetotactic bacteria on a similar time scale to high-temperature chemical precipitation reactions, and we suggest that this finding is caused by a biological catalysis of the process. [Abstract/Link to Full Text]

Davis RE, Swiderski RE, Rahmouni K, Nishimura DY, Mullins RF, Agassandian K, Philp AR, Searby CC, Andrews MP, Thompson S, Berry CJ, Thedens DR, Yang B, Weiss RM, Cassell MD, Stone EM, Sheffield VC
A knockin mouse model of the Bardet Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19422-7.
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder that results in retinal degeneration, obesity, cognitive impairment, polydactyly, renal abnormalities, and hypogenitalism. Of the 12 known BBS genes, BBS1 is the most commonly mutated, and a single missense mutation (M390R) accounts for approximately 80% of BBS1 cases. To gain insight into the function of BBS1, we generated a Bbs1(M390R/M390R) knockin mouse model. Mice homozygous for the M390R mutation recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. The obese mutant mice were hyperphagic and hyperleptinemic and exhibited reduced locomotor activity but no elevation in mean arterial blood pressure. Morphological evaluation of Bbs1 mutant brain neuroanatomy revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Similar abnormalities were also observed in the brains of Bbs2(-/-), Bbs4(-/-), and Bbs6(-/-) mice, establishing these neuroanatomical defects as a previously undescribed BBS mouse model phenotype. Ultrastructural examination of the ependymal cell cilia that line the enlarged third ventricle of the Bbs1 mutant brains showed that, whereas the 9 + 2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Together with data from transmission electron microscopy analysis of photoreceptor cell connecting cilia, the Bbs1 M390R mutation does not affect axonemal structure, but it may play a role in the regulation of cilia assembly and/or function. [Abstract/Link to Full Text]

Barbano PE, Spivak M, Flajolet M, Nairn AC, Greengard P, Greengard L
A mathematical tool for exploring the dynamics of biological networks.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19169-74.
We have developed a mathematical approach to the study of dynamical biological networks, based on combining large-scale numerical simulation with nonlinear "dimensionality reduction" methods. Our work was motivated by an interest in the complex organization of the signaling cascade centered on the neuronal phosphoprotein DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of molecular weight 32,000). Our approach has allowed us to detect robust features of the system in the presence of noise. In particular, the global network topology serves to stabilize the net state of DARPP-32 phosphorylation in response to variation of the input levels of the neurotransmitters dopamine and glutamate, despite significant perturbation to the concentrations and levels of activity of a number of intermediate chemical species. Further, our results suggest that the entire topology of the network is needed to impart this stability to one portion of the network at the expense of the rest. This could have significant implications for systems biology, in that large, complex pathways may have properties that are not easily replicated with simple modules. [Abstract/Link to Full Text]

Prudic KL, Oliver JC, Sperling FA
The signal environment is more important than diet or chemical specialization in the evolution of warning coloration.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19381-6.
Aposematic coloration, or warning coloration, is a visual signal that acts to minimize contact between predator and unprofitable prey. The conditions favoring the evolution of aposematic coloration remain largely unidentified. Recent work suggests that diet specialization and resultant toxicity may play a role in facilitating the evolution and persistence of warning coloration. Using a phylogenetic approach, we investigated the evolution of larval warning coloration in the genus Papilio (Lepidoptera: Papilionidae). Our results indicate that there are at least four independent origins of aposematic larval coloration within Papilio. Controlling for phylogenetic relatedness among Papilio taxa, we found no evidence supporting the hypothesis that either diet specialization or chemical specialization facilitated the origin of aposematic larvae. However, there was a significant relationship between the signal environment and the evolution of aposematic larvae. Specifically, Papilio lineages feeding on herbaceous or narrow-leaved plants, regardless of the plants' taxonomic affiliation, were more likely to evolve aposematic larvae than were lineages feeding only on trees/shrubs or broad-leaved plants. These results demonstrate that factors other than diet specialization, such as the signal environment of predator-prey interactions, may play a large role in the initial evolution and persistence of aposematic coloration. [Abstract/Link to Full Text]

Santomasso BD, Roberts WK, Thomas A, Williams T, Blach�re NE, Dudley ME, Houghton AN, Posner JB, Darnell RB
A T cell receptor associated with naturally occurring human tumor immunity.
Proc Natl Acad Sci U S A. 2007 Nov 19;
The onconeural antigens appear to serve as tumor rejection antigens in the paraneoplastic neurologic disorders. Here, we used an unbiased peptide binding screen, followed by studies in HLA-A2.1 transgenic mice to identify naturally processed HLA-A2.1 restricted epitopes of the paraneoplastic cerebellar degeneration breast/ovarian cancer antigen cdr2. These mice were used to clone high-avidity cdr2-specific CD8(+) T cells that recognize human tumor cells presenting endogenously loaded MHC class I-cdr2 peptide. T cells with this specificity were detected in the peripheral blood of two HLA-A2.1(+) paraneoplastic cerebellar degeneration patients. We cloned T cell receptor (TCR) alpha and beta genes from cdr2-specific T cells; electroporation of RNA encoding this TCR turned nonreactive donor T cells into efficient killers of human cdr2-expressing tumor cells. Cloned cdr2-specific TCR genes provide a clinically relevant means for immunologic targeting of human gynecologic cancers. [Abstract/Link to Full Text]

Cobb NJ, S�nnichsen FD, McHaourab H, Surewicz WK
Molecular architecture of human prion protein amyloid: a parallel, in-register beta-structure.
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):18946-51.
Transmissible spongiform encephalopathies (TSEs) represent a group of fatal neurodegenerative diseases that are associated with conformational conversion of the normally monomeric and alpha-helical prion protein, PrP(C), to the beta-sheet-rich PrP(Sc). This latter conformer is believed to constitute the main component of the infectious TSE agent. In contrast to high-resolution data for the PrP(C) monomer, structures of the pathogenic PrP(Sc) or synthetic PrP(Sc)-like aggregates remain elusive. Here we have used site-directed spin labeling and EPR spectroscopy to probe the molecular architecture of the recombinant PrP amyloid, a misfolded form recently reported to induce transmissible disease in mice overexpressing an N-terminally truncated form of PrP(C). Our data show that, in contrast to earlier, largely theoretical models, the con formational conversion of PrP(C) involves major refolding of the C-terminal alpha-helical region. The core of the amyloid maps to C-terminal residues from approximately 160-220, and these residues form single-molecule layers that stack on top of one another with parallel, in-register alignment of beta-strands. This structural insight has important implications for understanding the molecular basis of prion propagation, as well as hereditary prion diseases, most of which are associated with point mutations in the region found to undergo a refolding to beta-structure. [Abstract/Link to Full Text]

Recent Articles in BMJ: British Medical Journal

Korponay-Szab� IR, Szabados K, Pusztai J, Uhrin K, Ludm�ny E, Nemes E, Kaukinen K, Kapit�ny A, Koskinen L, Sipka S, Imre A, M�ki M
Population screening for coeliac disease in primary care by district nurses using a rapid antibody test: diagnostic accuracy and feasibility study.
BMJ. 2007 Dec 6;
OBJECTIVE: To evaluate the feasibility and diagnostic accuracy of screening for coeliac disease by rapid detection of IgA antibodies to tissue transglutaminase performed in primary care. Design District nurses screened 6 year old children using rapid antibody testing of finger prick blood. They also collected capillary blood samples for laboratory determination of IgA and IgG antibodies to endomysium and IgA antibodies to tissue transglutaminase. Children with positive rapid test results were directly sent for biopsy of the small intestine. Setting Primary care in J�sz-Nagykun-Szolnok county, Hungary. PARTICIPANTS: 2690 children (77% of 6 year olds living in the county) and 120 nurses. MAIN OUTCOME MEASURES: Positivity for antibodies to endomysium or transglutaminase in the laboratory and coeliac disease confirmed at biopsy. RESULTS: 37 children (1.4%, 95% confidence interval 0.9% to 1.8%) had biopsy confirmed coeliac disease. Only five of these children had been diagnosed clinically before screening. Rapid testing had a 78.1% sensitivity (70.0% to 89.3%) and 100% specificity (88.4% to 100%) for a final diagnosis of coeliac disease by biopsy. Sensitivity was 65.1% (50.2% to 77.6%) and specificity was 100% (99.8% to 100%) compared with combined results of IgA and IgG laboratory tests. Trained laboratory workers detected 30 of the 31 newly diagnosed IgA competent patients with the rapid test kit used blindly. Median time to biopsy after a positive rapid test result was significantly shorter (20 days, range 4-148) than after a positive laboratory result (142 days, 70-256; P<0.001). Children with coeliac disease detected at screening were smaller and had worse health status than their peers but they improved on a gluten-free diet. CONCLUSIONS: A simple rapid antibody test enabled primary care nurses to detect patients with coeliac disease in the community who were not picked up in clinical care. Extra training is needed to improve sensitivity. [Abstract/Link to Full Text]

Berendt L, H�kansson C, Bach KF, Dalhoff K, Andreasen PB, Petersen LG, Andersen E, Poulsen HE
Effect of European Clinical Trials Directive on academic drug trials in Denmark: retrospective study of applications to the Danish Medicines Agency 1993-2006.
BMJ. 2007 Dec 6;
OBJECTIVE: To determine the impact of the European Union's Clinical Trials Directive on the number of academic drug trials carried out in Denmark. DESIGN: Retrospective review of applications for drug trials to the Danish Medicines Agency, 1993-2006. Review methods Applications for drug trials for alternate years were classified as academic or commercial trials. A random subset of academic trials was reviewed for number of participants in and intended monitoring of the trials. RESULTS: Academic and commercial drug trials showed an identical steady decline from 1993 to 2006 and no noticeable change after 2004 when good clinical practice became mandatory for academic trials. CONCLUSION: The Clinical Trials Directive introduced in May 2004 to ensure good clinical practice for academic drug trials was not associated with a decline in research activity in Denmark; presumably because good clinical practice units had already been in place in Danish universities since 1999. With such an infrastructure academic researchers can do drug trials under the same regulations as drug companies. [Abstract/Link to Full Text]

Bruzzi P
Non-drug industry funded research.
BMJ. 2007 Dec 6; [Abstract/Link to Full Text]

Parker M
Treatment of displaced intracapsular hip fractures in elderly patients.
BMJ. 2007 Dec 4; [Abstract/Link to Full Text]

Underwood M, Ashby D, Cross P, Hennessy E, Letley L, Martin J, Mt-Isa S, Parsons S, Vickers M, Whyte K
Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study.
BMJ. 2007 Dec 4;
OBJECTIVE: To determine whether older patients with chronic knee pain should be advised to use topical or oral non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN: Randomised controlled trial and patient preference study. SETTING: 26 general practices. PARTICIPANTS: People aged >/=50 with knee pain: 282 in randomised trial and 303 in preference study. INTERVENTIONS: Advice to use topical or oral ibuprofen. Primary outcome measures WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, major and minor adverse effects. RESULTS: Changes in global WOMAC scores at 12 months were equivalent. In the randomised trial the difference (topical minus oral) was two points (95% confidence interval -2 to 6); in the preference study, it was one point (-4 to 6). There were no differences in major adverse effects in the trial or study. The only significant differences in secondary outcomes were in the randomised trial. The oral group had more respiratory adverse effects (17% v 7%,95% confidence interval for difference -17% to -2%), the change in serum creatinine was 3.7 mmol/l less favourable (0.9 micromol/l to 6.5 micromol/l); and more participants changed treatments because of adverse effects (16% v 1%, -16% to -5%). In the topical group more participants had chronic pain grade III or IV at three months, and more participants changed treatment because of ineffectiveness. CONCLUSIONS: Advice to use oral or topical preparations has an equivalent effect on knee pain over one year, and there are more minor side effects with oral NSAIDs. Topical NSAIDs may be a useful alternative to oral NSAIDs. Trial registration ISRCTN 79353052. [Abstract/Link to Full Text]

Carnes D, Anwer Y, Underwood M, Harding G, Parsons S
Influences on older people's decision making regarding choice of topical or oral NSAIDs for knee pain: qualitative study.
BMJ. 2007 Dec 4;
OBJECTIVE: To explore the factors that influence older people's decision making regarding use of topical or oral ibuprofen for their knee pain. DESIGN: Qualitative interview study nested within a randomised controlled trial and a patient preference study that compared advice to use oral or topical non-steroidal anti-inflammatory drugs (NSAIDs) for knee pain in older people. SETTING: 11 general practices. PARTICIPANTS: 30 people aged >/=50 with knee pain. RESULTS: Participants' decision making was influenced by their perceptions of the associated risk of adverse effects, presence of other illness, nature of their pain, advice received, and practicality. Although participants' understanding of how the medications worked was sometimes poor their decision making about the use of NSAIDs seemed logical and appropriate. Participants' model for treatment was to use topical NSAIDs for mild, local, and transient pain and oral NSAIDs for moderate to severe, generalised, and constant pain (in the absence of other more serious illness or risk of adverse effects). Participants showed marked tolerance and normalisation of adverse effects. CONCLUSION: Participants had clear ideas about the appropriate use of oral and topical NSAIDs. Taking such views into account when prescribing may improve adherence, judgment of efficacy, and the doctor-patient relationship. Tolerance and normalisation of adverse effects in these patients indicate that closer monitoring of older people who use NSAIDs might be needed. [Abstract/Link to Full Text]

Dieppe P
Osteoarthritis of the knee in primary care.
BMJ. 2007 Dec 4; [Abstract/Link to Full Text]

Frihagen F, Nordsletten L, Madsen JE
Hemiarthroplasty or internal fixation for intracapsular displaced femoral neck fractures: randomised controlled trial.
BMJ. 2007 Dec 4;
OBJECTIVE: To compare the functional results after displaced fractures of the femoral neck treated with internal fixation or hemiarthroplasty. DESIGN: Randomised trial with blinding of assessments of functional results. SETTING: University hospital. PARTICIPANTS: 222 patients; 165 (74%) women, mean age 83 years. Inclusion criteria were age above 60, ability to walk before the fracture, and no major hip pathology, regardless of cognitive function. INTERVENTIONS: Closed reduction and two parallel screws (112 patients) and bipolar cemented hemiarthroplasty (110 patients). Follow-up at 4, 12, and 24 months. MAIN OUTCOME MEASURES: Hip function (Harris hip score), health related quality of life (Eq-5d), activities of daily living (Barthel index). In all cases high scores indicate better function. RESULTS: Mean Harris hip score in the hemiarthroplasty group was 8.2 points higher (95% confidence interval 2.8 to 13.5 points, P=0.003) at four months and 6.7 points (1.5 to 11.9 points, P=0.01) higher at 12 months. Mean Eq-5d index score at 24 months was 0.13 higher in the hemiarthroplasty group (0.01 to 0.25, P=0.03). The Eq-5d visual analogue scale was 8.7 points higher in the hemiarthroplasty group after 4 months (1.9 to 15.6, P=0.01). After 12 and 24 months the percentage scoring 95 or 100 on the Barthel index was higher in the hemiarthroplasty group (relative risk 0.67, 0.47 to 0.95, P=0.02. and 0.63, 0.42 to 0.94, P=0.02, respectively). Complications occurred in 56 (50%) patients in the internal fixation group and 16 (15%) in the hemiarthroplasty group (3.44, 2.11 to 5.60, P<0.001). In each group 39 patients (35%) died within 24 months (0.98, 0.69 to 1.40, P=0.92) CONCLUSIONS: Hemiarthroplasty is associated with better functional outcome than internal fixation in treatment of displaced fractures of the femoral neck in elderly patients. Trial registration NCT00464230. [Abstract/Link to Full Text]

Mahilum-Tapay L, Laitila V, Wawrzyniak JJ, Lee HH, Alexander S, Ison C, Swain A, Barber P, Ushiro-Lumb I, Goh BT
New point of care Chlamydia Rapid Test--bridging the gap between diagnosis and treatment: performance evaluation study.
BMJ. 2007 Dec 8;335(7631):1190-4.
OBJECTIVE: To evaluate the performance of a new Chlamydia Rapid Test with vaginal swab specimens as a potential tool for chlamydia diagnosis and screening. DESIGN: Performance evaluation study. Settings A young people's sexual health centre (site 1) and two genitourinary medicine clinics (sites 2 and 3) in the United Kingdom. PARTICIPANTS: 1349 women aged between 16 and 54 attending one of the three clinics. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value, and negative predictive value of the Chlamydia Rapid Test versus polymerase chain reaction and strand displacement amplification assays; correlation between the Chlamydia Rapid Test visual signal and organism load; acceptability to participants of self collected vaginal swabs as the specimen type for Chlamydia testing. RESULTS: Polymerase chain reaction positivity rates for Chlamydia trachomatis infection were 8.4% (56/663) at site 1, 9.4% (36/385) at site 2, and 6.0% (18/301) at site 3. Compared with polymerase chain reaction assay, the resolved sensitivity, specificity, positive predictive value, and negative predictive value of the Chlamydia Rapid Test were 83.5% (91/109), 98.9% (1224/1238), 86.7% (91/105), and 98.6% (1224/1242). Compared with strand displacement amplification assay, sensitivity and specificity of the Chlamydia Rapid Test were 81.6% (40/49) and 98.3% (578/588). Organism load of self collected vaginal swabs ranged from 5.97x10(2) to 1.09x10(9) Chlamydia plasmids per swab, which correlated well with the Chlamydia Rapid Test's visual signal (r=0.6435, P<0.0001). Most (95.9%) surveyed participants felt comfortable about collecting their own swabs. CONCLUSIONS: The performance of the Chlamydia Rapid Test with self collected vaginal swabs indicates that it would be an effective same day diagnostic and screening tool for Chlamydia infection in women. The availability of Chlamydia Rapid Test results within 30 minutes allows for immediate treatment and contact tracing, potentially reducing the risks of persistent infection and onward transmission. It could also provide a simple and reliable alternative to nucleic acid amplification tests in chlamydia screening programmes. [Abstract/Link to Full Text]

Buist M, Harrison J, Abaloz E, Van Dyke S
Six year audit of cardiac arrests and medical emergency team calls in an Australian outer metropolitan teaching hospital.
BMJ. 2007 Dec 8;335(7631):1210-2.
PROBLEM: In-hospital cardiac arrest often represents failure of optimal clinical care. The use of medical emergency teams to prevent such events is controversial. In-hospital cardiac arrests have been reduced in several single centre historical control studies, but the only randomised prospective study showed no such benefit. In our hospital an important problem was failure to call the medical emergency team or cardiac arrest team when, before in-hospital cardiac arrest, patients had fulfilled the criteria for calling the team. DESIGN: Single centre, prospective audit of cardiac arrests and data on use of the medical emergency team during 2000 to 2005. SETTING: 400 bed general outer suburban metropolitan teaching hospital. STRATEGIES FOR CHANGE: Three initiatives in the hospital to improve use of the medical emergency team: orientation programme for first year doctors, professional development course for medical registrars, and the evolving role of liaison intensive care unit nurses. KEY MEASURES FOR IMPROVEMENT: Incidence of cardiac arrests. EFFECTS OF THE CHANGE: Incidence of cardiac arrests decreased 24% per year, from 2.4/1000 admissions in 2000 to 0.66/1000 admissions in 2005. LESSONS LEARNT: Medical emergency teams can be efficacious when supported with a multidisciplinary, multifaceted education system for clinical staff. [Abstract/Link to Full Text]

Jefferson T, Foxlee R, Mar CD, Dooley L, Ferroni E, Hewak B, Prabhala A, Nair S, Rivetti A
Physical interventions to interrupt or reduce the spread of respiratory viruses: systematic review.
BMJ. 2007 Nov 27;
OBJECTIVE: To systematically review evidence for the effectiveness of physical interventions to interrupt or reduce the spread of respiratory viruses. DATA EXTRACTION: Search strategy of the Cochrane Library, Medline, OldMedline, Embase, and CINAHL, without language restriction, for any intervention to prevent transmission of respiratory viruses (isolation, quarantine, social distancing, barriers, personal protection, and hygiene). Study designs were randomised trials, cohort studies, case-control studies, and controlled before and after studies. DATA SYNTHESIS: Of 2300 titles scanned 138 full papers were retrieved, including 49 papers of 51 studies. Study quality was poor for the three randomised controlled trials and most of the cluster randomised controlled trials; the observational studies were of mixed quality. Heterogeneity precluded meta-analysis of most data except that from six case-control studies. The highest quality cluster randomised trials suggest that the spread of respiratory viruses into the community can be prevented by intervening with hygienic measures aimed at younger children. Meta-analysis of six case-control studies suggests that physical measures are highly effective in preventing the spread of SARS: handwashing more than 10 times daily (odds ratio 0.45, 95% confidence interval 0.36 to 0.57; number needed to treat=4, 95% confidence interval 3.65 to 5.52); wearing masks (0.32, 0.25 to 0.40; NNT=6, 4.54 to 8.03); wearing N95 masks (0.09, 0.03 to 0.30; NNT=3, 2.37 to 4.06); wearing gloves (0.43, 0.29 to 0.65; NNT=5, 4.15 to 15.41); wearing gowns (0.23, 0.14 to 0.37; NNT=5, 3.37 to 7.12); and handwashing, masks, gloves, and gowns combined (0.09, 0.02 to 0.35; NNT=3, 2.66 to 4.97). The incremental effect of adding virucidals or antiseptics to normal handwashing to decrease the spread of respiratory disease remains uncertain. The lack of proper evaluation of global measures such as screening at entry ports and social distancing prevent firm conclusions being drawn. CONCLUSION: Routine long term implementation of some physical measures to interrupt or reduce the spread of respiratory viruses might be difficult but many simple and low cost interventions could be useful in reducing the spread. [Abstract/Link to Full Text]

Dawes M
Using physical barriers to reduce the spread of respiratory viruses.
BMJ. 2007 Nov 27; [Abstract/Link to Full Text]

Mattocks C, Ness A, Deere K, Tilling K, Leary S, Blair SN, Riddoch C
Early life determinants of physical activity in 11 to 12 year olds: cohort study.
BMJ. 2007 Nov 23;
OBJECTIVE: To examine factors in early life (up to age 5 years) that are associated with objectively measured physical activity in 11-12 year olds. DESIGN: Prospective cohort study. SETTING: Avon longitudinal study of parents and children, United Kingdom. PARTICIPANTS: Children aged 11-12 years from the Avon longitudinal study of parents and children. MAIN OUTCOME MEASURE: Physical activity levels in counts per minute (cpm) and minutes of moderate to vigorous physical activity for seven days measured with a uniaxial actigraph accelerometer. RESULTS: Valid actigraph data, defined as at least three days of physical activity for at least 10 hours a day, were collected from 5451 children. Several factors were associated with physical activity at ages 11-12 years. Regression coefficients are compared with the baseline of "none" for categorical variables: maternal brisk walking during pregnancy (regression coefficient 5.0, 95% confidence interval -8.5 to 18.5; cpm for <1 h/wk and >/=2 h/wk of physical activity 17.7, 5.3 to 30.1), maternal swimming during pregnancy (21.5, 10.9 to 32.1 and cpm for <1 h/wk and >/=2 h/wk of physical activity 24.2, 7.8 to 40.7), parents' physical activity when the child was aged 21 months (28.5, 15.2 to 41.8 and cpm of physical activity for either parent active and both parents active 33.5, 17.8 to 49.3), and parity assessed during pregnancy (2.9, -7.6 to 13.4 and cpm of physical activity for 1 and >/=2 parity 21.2, 7.1 to 35.3). CONCLUSIONS: Few factors in early life predicted later physical activity in 11-12 year olds. Parents' physical activity during pregnancy and early in the child's life showed a modest association with physical activity