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

Tomkowicz B, Rybinski K, Foley B, Ebel W, Kline B, Routhier E, Sass P, Nicolaides NC, Grasso L, Zhou Y
Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):17965-70.
Endosialin/TEM1 was originally discovered as a human embryonic fibroblast-specific antigen and was later found to be differentially expressed in tumor stroma and endothelium. Endosialin/TEM1 overexpression has been observed in many cancers of various tissue origin, including colon, breast, pancreatic, and lung. The knockout (KO) mouse model showed the absence of endosialin/TEM1 expression reduced growth, invasion, and metastasis of human tumor xenografts. In addition, lack of endosialin/TEM1 led to an increase in small immature blood vessels and decreased numbers of medium and large tumor vessels. This abnormal angiogenic response could be responsible for the reduced tumor growth and invasion observed in endosialin/TEM1 KO mice, suggesting a role for endosialin/TEM1 in controlling the interaction among tumor cells, endothelia, and stromal matrix. Here we report the identification of fibronectin (FN) and collagen types I and IV as specific ligands for endosialin/TEM1. More importantly, cells expressing endosialin/TEM1 exhibit enhanced adhesion to FN as well as enhanced migration through matrigel, although these properties could be blocked by a humanized antibody directed against human endosialin/TEM1. Our results pinpoint to a molecular mechanism by which expression of endosialin/TEM1 in the tumor stroma and endothelium may support tumor progression and invasion. [Abstract/Link to Full Text]

Purcell EB, Siegal-Gaskins D, Rawling DC, Fiebig A, Crosson S
A photosensory two-component system regulates bacterial cell attachment.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18241-6.
Flavin-binding LOV domains are blue-light photosensory modules that are conserved in a number of developmental and circadian regulatory proteins in plants, algae, and fungi. LOV domains are also present in bacterial genomes, and are commonly located at the amino termini of sensor histidine kinases. Genes predicted to encode LOV-histidine kinases are conserved across a broad range of bacterial taxa, from aquatic oligotrophs to plant and mammalian pathogens. However, the function of these putative prokaryotic photoreceptors remains largely undefined. The differentiating bacterium, Caulobacter crescentus, contains an operon encoding a two-component signaling system consisting of a LOV-histidine kinase, LovK, and a single-domain response regulator, LovR. LovK binds a flavin cofactor, undergoes a reversible photocycle, and displays increased ATPase and autophosphorylation activity in response to visible light. Deletion of the response regulator gene, lovR, results in severe attenuation of cell attachment to a glass surface under laminar flow, whereas coordinate, low-level overexpression of lovK and lovR results in a light-independent increase in cell-cell attachment, a response that requires both the conserved histidine phosphorylation site in LovK and aspartate phosphorylation site in LovR. Growing C. crescentus in the presence of blue light dramatically enhances cell-cell attachment in the lovK-lovR overexpression background. A conserved cysteine residue in the LOV domain of LovK, which forms a covalent adduct with the flavin cofactor upon absorption of visible light, is necessary for the light-dependent regulation of LovK enzyme activity and is required for the light-dependent enhancement of intercellular attachment. [Abstract/Link to Full Text]

Tanaka F, Cicourel A, Movellan JR
Socialization between toddlers and robots at an early childhood education center.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):17954-8.
A state-of-the-art social robot was immersed in a classroom of toddlers for >5 months. The quality of the interaction between children and robots improved steadily for 27 sessions, quickly deteriorated for 15 sessions when the robot was reprogrammed to behave in a predictable manner, and improved in the last three sessions when the robot displayed again its full behavioral repertoire. Initially, the children treated the robot very differently than the way they treated each other. By the last sessions, 5 months later, they treated the robot as a peer rather than as a toy. Results indicate that current robot technology is surprisingly close to achieving autonomous bonding and socialization with human toddlers for sustained periods of time and that it could have great potential in educational settings assisting teachers and enriching the classroom environment. [Abstract/Link to Full Text]

Bushel PR, Heinloth AN, Li J, Huang L, Chou JW, Boorman GA, Malarkey DE, Houle CD, Ward SM, Wilson RE, Fannin RD, Russo MW, Watkins PB, Tennant RW, Paules RS
Blood gene expression signatures predict exposure levels.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18211-6.
To respond to potential adverse exposures properly, health care providers need accurate indicators of exposure levels. The indicators are particularly important in the case of acetaminophen (APAP) intoxication, the leading cause of liver failure in the U.S. We hypothesized that gene expression patterns derived from blood cells would provide useful indicators of acute exposure levels. To test this hypothesis, we used a blood gene expression data set from rats exposed to APAP to train classifiers in two prediction algorithms and to extract patterns for prediction using a profiling algorithm. Prediction accuracy was tested on a blinded, independent rat blood test data set and ranged from 88.9% to 95.8%. Genomic markers outperformed predictions based on traditional clinical parameters. The expression profiles of the predictor genes from the patterns extracted from the blood exhibited remarkable (97% accuracy) transtissue APAP exposure prediction when liver gene expression data were used as a test set. Analysis of human samples revealed separation of APAP-intoxicated patients from control individuals based on blood expression levels of human orthologs of the rat discriminatory genes. The major biological signal in the discriminating genes was activation of an inflammatory response after exposure to toxic doses of APAP. These results support the hypothesis that gene expression data from peripheral blood cells can provide valuable information about exposure levels, well before liver damage is detected by classical parameters. It also supports the potential use of genomic markers in the blood as surrogates for clinical markers of potential acute liver damage. [Abstract/Link to Full Text]

Moses AM, Liku ME, Li JJ, Durbin R
Regulatory evolution in proteins by turnover and lineage-specific changes of cyclin-dependent kinase consensus sites.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17713-8.
Evolutionary change in gene regulation is a key mechanism underlying the genetic component of organismal diversity. Here, we study evolution of regulation at the posttranslational level by examining the evolution of cyclin-dependent kinase (CDK) consensus phosphorylation sites in the protein subunits of the pre-replicative complex (RC). The pre-RC, an assembly of proteins formed during an early stage of DNA replication, is believed to be regulated by CDKs throughout the animals and fungi. Interestingly, although orthologous pre-RC components often contain clusters of CDK consensus sites, the positions and numbers of sites do not seem conserved. By analyzing protein sequences from both distantly and closely related species, we confirm that consensus sites can turn over rapidly even when the local cluster of sites is preserved, consistent with the notion that precise positioning of phosphorylation events is not required for regulation. We also identify evolutionary changes in the clusters of sites and further examine one replication protein, Mcm3, where a cluster of consensus sites near a nucleocytoplasmic transport signal is confined to a specific lineage. We show that the presence or absence of the cluster of sites in different species is associated with differential regulation of the transport signal. These findings suggest that the CDK regulation of MCM nuclear localization was acquired in the lineage leading to Saccharomyces cerevisiae after the divergence with Candida albicans. Our results begin to explore the dynamics of regulatory evolution at the posttranslational level and show interesting similarities to recent observations of regulatory evolution at the level of transcription. [Abstract/Link to Full Text]

Gilbert MT, Rambaut A, Wlasiuk G, Spira TJ, Pitchenik AE, Worobey M
The emergence of HIV/AIDS in the Americas and beyond.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18566-70.
HIV-1 group M subtype B was the first HIV discovered and is the predominant variant of AIDS virus in most countries outside of sub-Saharan Africa. However, the circumstances of its origin and emergence remain unresolved. Here we propose a geographic sequence and time line for the origin of subtype B and the emergence of pandemic HIV/AIDS out of Africa. Using HIV-1 gene sequences recovered from archival samples from some of the earliest known Haitian AIDS patients, we find that subtype B likely moved from Africa to Haiti in or around 1966 (1962-1970) and then spread there for some years before successfully dispersing elsewhere. A "pandemic" clade, encompassing the vast majority of non-Haitian subtype B infections in the United States and elsewhere around the world, subsequently emerged after a single migration of the virus out of Haiti in or around 1969 (1966-1972). Haiti appears to have the oldest HIV/AIDS epidemic outside sub-Saharan Africa and the most genetically diverse subtype B epidemic, which might present challenges for HIV-1 vaccine design and testing. The emergence of the pandemic variant of subtype B was an important turning point in the history of AIDS, but its spread was likely driven by ecological rather than evolutionary factors. Our results suggest that HIV-1 circulated cryptically in the United States for approximately 12 years before the recognition of AIDS in 1981. [Abstract/Link to Full Text]

Abrahams BS, Tentler D, Perederiy JV, Oldham MC, Coppola G, Geschwind DH
Genome-wide analyses of human perisylvian cerebral cortical patterning.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17849-54.
Despite the well established role of the frontal and posterior perisylvian cortices in many facets of human-cognitive specializations, including language, little is known about the developmental patterning of these regions in the human brain. We performed a genome-wide analysis of human cerebral patterning during midgestation, a critical epoch in cortical regionalization. A total of 345 genes were identified as differentially expressed between superior temporal gyrus (STG) and the remaining cerebral cortex. Gene ontology categories representing transcription factors were enriched in STG, whereas cell-adhesion and extracellular matrix molecules were enriched in the other cortical regions. Quantitative RT-PCR or in situ hybridization was performed to validate differential expression in a subset of 32 genes, most of which were confirmed. LIM domain-binding 1 (LDB1), which we show to be enriched in the STG, is a recently identified interactor of LIM domain only 4 (LMO4), a gene known to be involved in the asymmetric pattering of the perisylvian region in the developing human brain. Protocadherin 17 (PCDH17), a neuronal cell adhesion molecule, was highly enriched in focal regions of the human prefrontal cortex. Contactin associated protein-like 2 (CNTNAP2), in which mutations are known to cause autism, epilepsy, and language delay, showed a remarkable pattern of anterior-enriched cortical expression in human that was not observed in mouse or rat. These data highlight the importance of expression analysis of human brain and the utility of cross-species comparisons of gene expression. Genes identified here provide a foundation for understanding molecular aspects of human-cognitive specializations and the disorders that disrupt them. [Abstract/Link to Full Text]

Porter KK, Metzger RR, Groh JM
Visual- and saccade-related signals in the primate inferior colliculus.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17855-60.
The inferior colliculus (IC) is normally thought of as a predominantly auditory structure because of its early position in the ascending auditory pathway just before the auditory thalamus. Here, we show that a majority of IC neurons (64% of 180 neurons) in awake monkeys carry visual- and/or saccade-related signals in addition to their auditory responses (P < 0.05). The response patterns involve primarily excitatory visual responses, but also increased activity time-locked to the saccade, slow rises in activity time-locked to the onset of the visual stimulus, and inhibitory responses. The presence of these visual-related signals suggests that the IC plays a role in integrating visual and auditory information. More broadly, our results show that interactions between sensory pathways can occur at very early points in sensory processing streams, which implies that multisensory integration may be a low-level rather than an exclusively high-level process. [Abstract/Link to Full Text]

Zehr JP, Bench SR, Mondragon EA, McCarren J, DeLong EF
Low genomic diversity in tropical oceanic N2-fixing cyanobacteria.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17807-12.
High levels of genomic and allelic microvariation have been found in major marine planktonic microbial species, including the ubiquitous open ocean cyanobacterium, Prochlorococcus marinus. Crocosphaera watsonii is a unicellular cyanobacterium that has recently been shown to be important in oceanic N2 fixation and has been reported from the Atlantic and Pacific oceans in both hemispheres, and the Arabian Sea. In direct contrast to the current observations of genomic variability in marine non-N2-fixing planktonic cyanobacteria, which can range up to >15% nucleotide sequence divergence, we discovered that the marine planktonic nitrogen-fixing cyanobacterial genus Crocosphaera has remarkably low genomic diversity, with <1% nucleotide sequence divergence in several genes among widely distributed populations and strains. The cultivated C. watsonii WH8501 genome sequence was virtually identical to DNA sequences of large metagenomic fragments cloned from the subtropical North Pacific Ocean with <1% sequence divergence even in intergenic regions. Thus, there appears to be multiple strategies for evolution, adaptation, and diversification in oceanic microbial populations. The C. watsonii genome contains multiple copies of several families of transposases that may be involved in maintaining genetic diversity through genome rearrangements. Although genomic diversity seems to be the rule in many, if not most, marine microbial lineages, different forces may control the evolution and diversification in low abundance microorganisms, such as the nitrogen-fixing cyanobacteria. [Abstract/Link to Full Text]

Gaur D, Singh S, Singh S, Jiang L, Diouf A, Miller LH
Recombinant Plasmodium falciparum reticulocyte homology protein 4 binds to erythrocytes and blocks invasion.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17789-94.
Plasmodium falciparum invasion of human erythrocytes involves several parasite and erythrocyte receptors that enable parasite invasion by multiple redundant pathways. A key challenge to the development of effective vaccines that block parasite infection of erythrocytes is identifying the players in these pathways and determining their function. Invasion by the parasite clone, Dd2, requires sialic acid on the erythrocyte surface; Dd2/NM is a variant selected for its ability to invade neuraminidase-treated erythrocytes that lack sialic acid. The P. falciparum protein, reticulocyte homology 4 (PfRH4), is uniquely up-regulated in Dd2/NM compared with Dd2, suggesting that it may be a parasite receptor involved in invasion. The aim of the present study was to determine the role of PfRH4 in invasion of erythrocytes and to determine whether it is a target of antibody-mediated blockade and thus a vaccine candidate. We show that both native PfRH4 and a recombinant 30-kDa protein to a conserved region of PfRH4 (rRH4(30)) bind strongly to neuraminidase-treated erythrocytes. rRH4(30) blocks both the erythrocyte binding of the native PfRH4 and invasion of neuraminidase-treated erythrocytes by Dd2/NM. Taken together, these results indicate that PfRH4 is a parasite receptor involved in sialic acid-independent invasion of erythrocytes. Although antibodies to rRH4(30) block binding of the native protein to erythrocytes, these antibodies failed to block invasion. These findings suggest that, although PfRH4 is required for invasion of neuraminidase-treated erythrocytes by Dd2/NM, it is inaccessible for antibody-mediated inhibition of the invasion process. [Abstract/Link to Full Text]

Epping MT, Wang L, Plumb JA, Lieb M, Gronemeyer H, Brown R, Bernards R
A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17777-82.
Understanding the pathways that are targeted by cancer drugs is instrumental for their rational use in a clinical setting. Inhibitors of histone deacetylases (HDACI) selectively inhibit proliferation of malignant cells and are used for the treatment of cancer, but their cancer selectivity is understood poorly. We conducted a functional genetic screen to address the mechanism(s) of action of HDACI. We report here that ectopic expression of two genes that act on retinoic acid (RA) signaling can cause resistance to growth arrest and apoptosis induced by HDACI of different chemical classes: the retinoic acid receptor alpha (RARalpha) and preferentially expressed antigen of melanoma (PRAME), a repressor of RA signaling. Treatment of cells with HDACI induced RA signaling, which was inhibited by RARalpha or PRAME expression. Conversely, RAR-deficient cells and PRAME-knockdown cells show enhanced sensitivity to HDACI in vitro and in mouse xenograft models. Finally, a combination of RA and HDACI acted synergistically to activate RA signaling and inhibit tumor growth. These experiments identify the RA pathway as a rate-limiting target of HDACI and suggest strategies to enhance the therapeutic efficacy of HDACI. [Abstract/Link to Full Text]

Zhang Q, Cao YQ, Tsien RW
Quantum dots provide an optical signal specific to full collapse fusion of synaptic vesicles.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17843-8.
Synaptic vesicles are responsible for releasing neurotransmitters and are thus essential to brain function. The classical mode of vesicle recycling includes full collapse of the vesicle into the plasma membrane and clathrin-mediated regeneration of a new vesicle. In contrast, a nonclassical mode known as "kiss-and-run" features fusion by a transient fusion pore without complete loss of vesicle identity and offers possible advantages for increasing the throughput of neurotransmission. Studies of vesicular traffic have benefited greatly from fluorescent probes like FM dyes and synaptopHluorin. However, intrinsic properties of these probes limit their ability to provide a simple and precise distinction between classical and nonclassical modes. Here we report a novel optical probe specific to full collapse fusion, capitalizing on the size and superior photo-properties of photoluminescent quantum dots (Qdots). Qdots with exposed carboxyl groups were readily taken up by synaptic vesicles in an activity-, Ca(2+)-, and clathrin-dependent manner. Electron microscopy showed that Qdots were harbored within individual vesicles in a 1:1 ratio. The release of Qdots was activity- and Ca(2+)-dependent, similar to FM dyes. As artificial cargo, approximately 15 nm in diameter, Qdots will not escape vesicles during kiss-and-run but only with full collapse fusion. Strikingly, Qdots unloaded with kinetics substantially slower than destaining of FM dye, indicating that full-collapse fusion contributed only a fraction of all fusion events. As a full-collapse-fusion-responsive reporter, Qdots will likely promote better understanding of vesicle recycling at small CNS nerve terminals. [Abstract/Link to Full Text]

Llin�s RR, Choi S, Urbano FJ, Shin HS
Gamma-band deficiency and abnormal thalamocortical activity in P/Q-type channel mutant mice.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17819-24.
Thalamocortical in vivo and in vitro function was studied in mice lacking P/Q-type calcium channels (Cav2.1), in which N-type calcium channels (Cav2.2) supported central synaptic transmission. Unexpectedly, in vitro patch recordings from thalamic neurons demonstrated no gamma-band subthreshold oscillation, and voltage-sensitive dye imaging demonstrated an absence of cortical gamma-band-dependent columnar activation involving cortical inhibitory interneuron activity. In vivo electroencephalogram recordings showed persistent absence status and a dramatic reduction of gamma-band activity. Pharmacological block of T-type calcium channels (Cav3), although not noticeably affecting normal control animals, left the knockout mice in a coma-like state. Hence, although N-type calcium channels can rescue P/Q-dependent synaptic transmission, P/Q calcium channels are essential in the generation of gamma-band activity and resultant cognitive function. [Abstract/Link to Full Text]

Saini HK, Griffiths-Jones S, Enright AJ
Genomic analysis of human microRNA transcripts.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17719-24.
MicroRNAs (miRNAs) are important genetic regulators of development, differentiation, growth, and metabolism. The mammalian genome encodes approximately 500 known miRNA genes. Approximately 50% are expressed from non-protein-coding transcripts, whereas the rest are located mostly in the introns of coding genes. Intronic miRNAs are generally transcribed coincidentally with their host genes. However, the nature of the primary transcript of intergenic miRNAs is largely unknown. We have performed a large-scale analysis of transcription start sites, polyadenylation signals, CpG islands, EST data, transcription factor-binding sites, and expression ditag data surrounding intergenic miRNAs in the human genome to improve our understanding of the structure of their primary transcripts. We show that a significant fraction of primary transcripts of intergenic miRNAs are 3-4 kb in length, with clearly defined 5' and 3' boundaries. We provide strong evidence for the complete transcript structure of a small number of human miRNAs. [Abstract/Link to Full Text]

Park SJ, Goodman MB, Pruitt BL
Analysis of nematode mechanics by piezoresistive displacement clamp.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17376-81.
Studying animal mechanics is critical for understanding how signals in the neuromuscular system give rise to behavior and how force-sensing organs and sensory neurons work. Few techniques exist to provide forces and displacements appropriate for such studies. To address this technological gap, we developed a metrology using piezoresistive cantilevers as force-displacement sensors coupled to a feedback system to apply and maintain defined load profiles to micrometer-scale animals. We show that this system can deliver forces between 10(-8) and 10(-3) N across distances of up to 100 mum with a resolution of 12 nN between 0.1 Hz and 100 kHz. We use this new metrology to show that force-displacement curves of wild-type nematodes (Caenorhabditis elegans) are linear. Because nematodes have approximately cylindrical bodies, this finding demonstrates that nematode body mechanics can be modeled as a cylindrical shell under pressure. Little is known about the relative importance of hydrostatic pressure and shell mechanics, however. We show that dissipating pressure by cuticle puncture or decreasing it by hyperosmotic shock has only a modest effect on stiffness, whereas defects in the dpy-5 and lon-2 genes, which alter body shape and cuticle proteins, decrease and increase stiffness by 25% and 50%, respectively. This initial analysis of C. elegans body mechanics suggests that shell mechanics dominates stiffness and is a first step in understanding how body mechanics affect locomotion and force sensing. [Abstract/Link to Full Text]

Canadell JG, Le Qu�r� C, Raupach MR, Field CB, Buitenhuis ET, Ciais P, Conway TJ, Gillett NP, Houghton RA, Marland G
Contributions to accelerating atmospheric CO2 growth from economic activity, carbon intensity, and efficiency of natural sinks.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18866-70.
The growth rate of atmospheric carbon dioxide (CO(2)), the largest human contributor to human-induced climate change, is increasing rapidly. Three processes contribute to this rapid increase. Two of these processes concern emissions. Recent growth of the world economy combined with an increase in its carbon intensity have led to rapid growth in fossil fuel CO(2) emissions since 2000: comparing the 1990s with 2000-2006, the emissions growth rate increased from 1.3% to 3.3% y(-1). The third process is indicated by increasing evidence (P = 0.89) for a long-term (50-year) increase in the airborne fraction (AF) of CO(2) emissions, implying a decline in the efficiency of CO(2) sinks on land and oceans in absorbing anthropogenic emissions. Since 2000, the contributions of these three factors to the increase in the atmospheric CO(2) growth rate have been approximately 65 +/- 16% from increasing global economic activity, 17 +/- 6% from the increasing carbon intensity of the global economy, and 18 +/- 15% from the increase in AF. An increasing AF is consistent with results of climate-carbon cycle models, but the magnitude of the observed signal appears larger than that estimated by models. All of these changes characterize a carbon cycle that is generating stronger-than-expected and sooner-than-expected climate forcing. [Abstract/Link to Full Text]

Jiang L, Taylor JM, Khaneja N, Lukin MD
Optimal approach to quantum communication using dynamic programming.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17291-6.
Reliable preparation of entanglement between distant systems is an outstanding problem in quantum information science and quantum communication. In practice, this has to be accomplished by noisy channels (such as optical fibers) that generally result in exponential attenuation of quantum signals at large distances. A special class of quantum error correction protocols, quantum repeater protocols, can be used to overcome such losses. In this work, we introduce a method for systematically optimizing existing protocols and developing more efficient protocols. Our approach makes use of a dynamic programming-based searching algorithm, the complexity of which scales only polynomially with the communication distance, letting us efficiently determine near-optimal solutions. We find significant improvements in both the speed and the final-state fidelity for preparing long-distance entangled states. [Abstract/Link to Full Text]

Rowe JA, Handel IG, Thera MA, Deans AM, Lyke KE, Kon� A, Diallo DA, Raza A, Kai O, Marsh K, Plowe CV, Doumbo OK, Moulds JM
Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17471-6.
Malaria has been a major selective force on the human population, and several erythrocyte polymorphisms have evolved that confer resistance to severe malaria. Plasmodium falciparum rosetting, a parasite virulence phenotype associated with severe malaria, is reduced in blood group O erythrocytes compared with groups A, B, and AB, but the contribution of the ABO blood group system to protection against severe malaria has received little attention. We hypothesized that blood group O may confer resistance to severe falciparum malaria through the mechanism of reduced rosetting. In a matched case-control study of 567 Malian children, we found that group O was present in only 21% of severe malaria cases compared with 44-45% of uncomplicated malaria controls and healthy controls. Group O was associated with a 66% reduction in the odds of developing severe malaria compared with the non-O blood groups (odds ratio 0.34, 95% confidence interval 0.19-0.61, P < 0.0005, severe cases versus uncomplicated malaria controls). In the same sample set, P. falciparum rosetting was reduced in parasite isolates from group O children compared with isolates from the non-O blood groups (P = 0.003, Kruskal-Wallis test). Statistical analysis indicated a significant interaction between host ABO blood group and parasite rosette frequency that supports the hypothesis that the protective effect of group O operates through the mechanism of reduced P. falciparum rosetting. This work provides insights into malaria pathogenesis and suggests that the selective pressure imposed by malaria may contribute to the variable global distribution of ABO blood groups in the human population. [Abstract/Link to Full Text]

Hess ST, Gould TJ, Gudheti MV, Maas SA, Mills KD, Zimmerberg J
Dynamic clustered distribution of hemagglutinin resolved at 40 nm in living cell membranes discriminates between raft theories.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17370-5.
Organization in biological membranes spans many orders of magnitude in length scale, but limited resolution in far-field light microscopy has impeded distinction between numerous biomembrane models. One canonical example of a heterogeneously distributed membrane protein is hemagglutinin (HA) from influenza virus, which is associated with controversial cholesterol-rich lipid rafts. Using fluorescence photoactivation localization microscopy, we are able to image distributions of tens of thousands of HA molecules with subdiffraction resolution ( approximately 40 nm) in live and fixed fibroblasts. HA molecules form irregular clusters on length scales from approximately 40 nm up to many micrometers, consistent with results from electron microscopy. In live cells, the dynamics of HA molecules within clusters is observed and quantified to determine an effective diffusion coefficient. The results are interpreted in terms of several established models of biological membranes. [Abstract/Link to Full Text]

Rubin CT, Capilla E, Luu YK, Busa B, Crawford H, Nolan DJ, Mittal V, Rosen CJ, Pessin JE, Judex S
Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17879-84.
Obesity, a global pandemic that debilitates millions of people and burdens society with tens of billions of dollars in health care costs, is deterred by exercise. Although it is presumed that the more strenuous a physical challenge the more effective it will be in the suppression of adiposity, here it is shown that 15 weeks of brief, daily exposure to high-frequency mechanical signals, induced at a magnitude well below that which would arise during walking, inhibited adipogenesis by 27% in C57BL/6J mice. The mechanical signal also reduced key risk factors in the onset of type II diabetes, nonesterified free fatty acid and triglyceride content in the liver, by 43% and 39%, respectively. Over 9 weeks, these same signals suppressed fat production by 22% in the C3H.B6-6T congenic mouse strain that exhibits accelerated age-related changes in body composition. In an effort to understand the means by which fat production was inhibited, irradiated mice receiving bone marrow transplants from heterozygous GFP+ mice revealed that 6 weeks of these low-magnitude mechanical signals reduced the commitment of mesenchymal stem cell differentiation into adipocytes by 19%, indicating that formation of adipose tissue in these models was deterred by a marked reduction in stem cell adipogenesis. Translated to the human, this may represent the basis for the nonpharmacologic prevention of obesity and its sequelae, achieved through developmental, rather than metabolic, pathways. [Abstract/Link to Full Text]

Doose S, Neuweiler H, Barsch H, Sauer M
Probing polyproline structure and dynamics by photoinduced electron transfer provides evidence for deviations from a regular polyproline type II helix.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17400-5.
Polyprolines are well known for adopting a regular polyproline type II helix in aqueous solution, rendering them a popular standard as molecular ruler in structural molecular biology. However, single-molecule spectroscopy studies based on F�rster resonance energy transfer (FRET) have revealed deviations of experimentally observed end-to-end distances of polyprolines from theoretical predictions, and it was proposed that the discrepancy resulted from dynamic flexibility of the polyproline helix. Here, we probe end-to-end distances and conformational dynamics of poly-l-prolines with 1-10 residues using fluorescence quenching by photoinduced-electron transfer (PET). A single fluorophore and a tryptophan residue, introduced at the termini of polyproline peptides, serve as sensitive probes for distance changes on the subnanometer length scale. Using a combination of ensemble fluorescence and fluorescence correlation spectroscopy, we demonstrate that polyproline samples exhibit static structural heterogeneity with subpopulations of distinct end-to-end distances that do not interconvert on time scales from nano- to milliseconds. By observing prolyl isomerization through changes in PET quenching interactions, we provide experimental evidence that the observed heterogeneity can be explained by interspersed cis isomers. Computer simulations elucidate the influence of trans/cis isomerization on polyproline structures in terms of end-to-end distance and provide a structural justification for the experimentally observed effects. Our results demonstrate that structural heterogeneity inherent in polyprolines, which to date are commonly applied as a molecular ruler, disqualifies them as appropriate tool for an accurate determination of absolute distances at a molecular scale. [Abstract/Link to Full Text]

Lahm A, Paolini C, Pallaoro M, Nardi MC, Jones P, Neddermann P, Sambucini S, Bottomley MJ, Lo Surdo P, Carf� A, Koch U, De Francesco R, Steink�hler C, Gallinari P
Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17335-40.
Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on standard substrates. We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymatic assay, suggesting that the observed activity rather reflects the involvement of endogenous copurified class I HDACs. Moreover, an HDAC4 catalytic domain purified from bacteria was 1,000-fold less active than class I HDACs on standard substrates. A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. Given the high structural conservation of HDAC active sites, we predicted the class IIa His-Nepsilon2 to be too far away to functionally substitute the class I Tyr-OH in catalysis. Consistently, a Tyr-to-His mutation in class I HDACs severely reduced their activity. More importantly, a His-976-Tyr mutation in HDAC4 produced an enzyme with a catalytic efficiency 1,000-fold higher than WT, and this "gain of function phenotype" could be extended to HDAC5 and -7. We also identified trifluoroacetyl-lysine as a class IIa-specific substrate in vitro. Hence, vertebrate class IIa HDACs may have evolved to maintain low basal activities on acetyl-lysines and to efficiently process restricted sets of specific, still undiscovered natural substrates. [Abstract/Link to Full Text]

Gao S, Kinzig KP, Aja S, Scott KA, Keung W, Kelly S, Strynadka K, Chohnan S, Smith WW, Tamashiro KL, Ladenheim EE, Ronnett GV, Tu Y, Birnbaum MJ, Lopaschuk GD, Moran TH
Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17358-63.
Hypothalamic fatty acid metabolism has recently been implicated in the controls of food intake and energy homeostasis. We report that intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMP-activated kinase (AMPK), activates acetyl-CoA carboxylase (ACC), the key regulatory enzyme in fatty acid biosynthesis, in the arcuate nucleus (Arc) and paraventricular nucleus (PVN) in the hypothalamus. Arc overexpression of constitutively active AMPK prevents the Arc ACC activation in response to ICV leptin, supporting the hypothesis that AMPK lies upstream of ACC in leptin's Arc intracellular signaling pathway. Inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid, a specific ACC inhibitor, blocks leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY. These results show that hypothalamic ACC activation makes an important contribution to leptin's anorectic effects. Furthermore, we find that ICV leptin up-regulates the level of malonyl-CoA (the intermediate of fatty acid biosynthesis) specifically in the Arc and increases the level of palmitoyl-CoA (a major product of fatty acid biosynthesis) specifically in the PVN. The rises of both levels are blocked by 5-tetradecyloxy-2-furoic acid along with the blockade of leptin-mediated hypophagia. These data suggest malonyl-CoA as a downstream mediator of ACC in leptin's signaling pathway in the Arc and imply that palmitoyl-CoA, instead of malonyl-CoA, could be an effector in relaying ACC signaling in the PVN. Together, these findings highlight site-specific impacts of hypothalamic ACC activation in leptin's anorectic signaling cascade. [Abstract/Link to Full Text]

Itzkan I, Qiu L, Fang H, Zaman MM, Vitkin E, Ghiran IC, Salahuddin S, Modell M, Andersson C, Kimerer LM, Cipolloni PB, Lim KH, Freedman SD, Bigio I, Sachs BP, Hanlon EB, Perelman LT
Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17255-60.
This article reports the development of an optical imaging technique, confocal light absorption and scattering spectroscopic (CLASS) microscopy, capable of noninvasively determining the dimensions and other physical properties of single subcellular organelles. CLASS microscopy combines the principles of light-scattering spectroscopy (LSS) with confocal microscopy. LSS is an optical technique that relates the spectroscopic properties of light elastically scattered by small particles to their size, refractive index, and shape. The multispectral nature of LSS enables it to measure internal cell structures much smaller than the diffraction limit without damaging the cell or requiring exogenous markers, which could affect cell function. Scanning the confocal volume across the sample creates an image. CLASS microscopy approaches the accuracy of electron microscopy but is nondestructive and does not require the contrast agents common to optical microscopy. It provides unique capabilities to study functions of viable cells, which are beyond the capabilities of other techniques. [Abstract/Link to Full Text]

Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS
Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17518-23.
The signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P(2)), likely functions in multiple signaling pathways. Here, we report the characterization of a mouse mutant lacking Vac14, a regulator of PI(3,5)P(2) synthesis. The mutant mice exhibit massive neurodegeneration, particularly in the midbrain and in peripheral sensory neurons. Cell bodies of affected neurons are vacuolated, and apparently empty spaces are present in areas where neurons should be present. Similar vacuoles are found in cultured neurons and fibroblasts. Selective membrane trafficking pathways, especially endosome-to-TGN retrograde trafficking, are defective. This report, along with a recent report on a mouse with a null mutation in Fig4, presents the unexpected finding that the housekeeping lipid, PI(3,5)P(2), is critical for the survival of neural cells. [Abstract/Link to Full Text]

De Cian A, Cristofari G, Reichenbach P, De Lemos E, Monchaud D, Teulade-Fichou MP, Shin-Ya K, Lacroix L, Lingner J, Mergny JL
Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17347-52.
Quadruplex ligands are often considered as telomerase inhibitors. Given the fact that some of these molecules are present in the clinical setting, it is important to establish the validity of this assertion. To analyze the effects of these compounds, we used a direct assay with telomerase-enriched extracts. The comparison of potent ligands from various chemical families revealed important differences in terms of effects on telomerase initiation and processivity. Although most quadruplex ligands may lock a quadruplex-prone sequence into a quadruplex structure that inhibits the initiation of elongation by telomerase, the analysis of telomerase-elongation steps revealed that only a few molecules interfered with the processivity of telomerase (i.e., inhibit elongation once one or more repeats have been incorporated). The demonstration that these molecules are actually more effective inhibitors of telomeric DNA amplification than extension by telomerase contributes to the already growing suspicion that quadruplex ligands are not simple telomerase inhibitors but, rather, constitute a different class of biologically active molecules. We also demonstrate that the popular telomeric repeat amplification protocol is completely inappropriate for the determination of telomerase inhibition by quadruplex ligands, even when PCR controls are included. As a consequence, the inhibitory effect of many quadruplex ligands has been overestimated. [Abstract/Link to Full Text]

Fraser C, Hollingsworth TD, Chapman R, de Wolf F, Hanage WP
Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis.
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17441-6.
The natural course of HIV-1 infection is characterized by a high degree of heterogeneity in viral load, not just within patients over time, but also between patients, especially during the asymptomatic stage of infection. Asymptomatic, or set-point, viral load has been shown to correlate with both decreased time to AIDS and increased infectiousness. The aim of this study is to characterize the epidemiological impact of heterogeneity in set-point viral load. By analyzing two cohorts of untreated patients, we quantify the relationships between both viral load and infectiousness and the duration of the asymptomatic infectious period. We find that, because both the duration of infection and infectiousness determine the opportunities for the virus to be transmitted, this suggests a trade-off between these contributions to the overall transmission potential. Some public health implications of variation in set-point viral load are discussed. We observe that set-point viral loads are clustered around those that maximize the transmission potential, and this leads us to hypothesize that HIV-1 could have evolved to optimize its transmissibility, a form of adaptation to the human host population. We discuss how this evolutionary hypothesis can be tested, review the evidence available to date, and highlight directions for future research. [Abstract/Link to Full Text]

Bodyak N, Ayus JC, Achinger S, Shivalingappa V, Ke Q, Chen YS, Rigor DL, Stillman I, Tamez H, Kroeger PE, Wu-Wong RR, Karumanchi SA, Thadhani R, Kang PM
Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16810-5.
Observations in hemodialysis patients suggest a survival advantage associated with activated vitamin D therapy. Left ventricular (LV) structural and functional abnormalities are strongly linked with hemodialysis mortality. Here, we investigated whether paricalcitol (PC, 19-nor-1,25(OH)(2)D(2)), an activated vitamin D compound, attenuates the development of LV abnormalities in the Dahl salt-sensitive (DSS) rat and whether humans demonstrate comparable findings. Compared with DSS rats fed a high-salt (HS) diet (6% NaCl for 6 weeks), HS+PC was associated with lower heart and lung weights, reduced LV mass, posterior wall thickness and end diastolic pressures, and increased fractional shortening. Blood pressures did not significantly differ between the HS groups. Plasma brain natriuretic peptide levels, and cardiac mRNA expression of brain natriuretic peptide, atrial natriuretic factor, and renin were significantly reduced in the HS+PC animals. Microarray analyses revealed 45 specific HS genes modified by PC. In a retrospective pilot study of hemodialysis patients, PC-treated subjects demonstrated improved diastolic function and a reduction in LV septal and posterior wall thickness by echocardiography compared with untreated patients. In summary, PC attenuates the development of LV alterations in DSS rats, and these effects should be examined in human clinical trials. [Abstract/Link to Full Text]

Ridnour LA, Windhausen AN, Isenberg JS, Yeung N, Thomas DD, Vitek MP, Roberts DD, Wink DA
Nitric oxide regulates matrix metalloproteinase-9 activity by guanylyl-cyclase-dependent and -independent pathways.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16898-903.
Matrix metalloproteinases (MMPs) are of central importance in the proteolytic remodeling of matrix and the generation of biologically active molecules. MMPs are distinguished by a conserved catalytic domain containing a zinc ion, as well as a prodomain that regulates enzyme activation by modulation of a cysteine residue within that domain. Because nitric oxide (NO) and derived reactive nitrogen species target zinc ions and cysteine thiols, we assessed the ability of NO to regulate MMPs. A dose-dependent, biphasic regulatory effect of NO on the activity of MMPs (MMP-9, -1, and -13) secreted from murine macrophages was observed. Low exogenous NO perturbed MMP/tissue inhibitor of metalloproteinase (TIMP)-1 levels by enhancing MMP activity and suppressing the endogenous inhibitor TIMP-1. This was cGMP-dependent, as confirmed by the cGMP analog 8-bromo-cGMP, as well as by the NO-soluble guanylyl cyclase-cGMP signaling inhibitor thrombospondin-1. Exposure of purified latent MMP-9 to exogenous NO demonstrated a concentration-dependent activation and inactivation of the enzyme, which occurred at higher NO flux. These chemical reactions occurred at concentrations similar to that of activated macrophages. Importantly, these results suggest that NO regulation of MMP-9 secreted from macrophages may occur chemically by reactive nitrogen species-mediated protein modification, biologically through soluble guanylyl-cyclase-dependent modulation of the MMP-9/TIMP-1 balance, or proteolytically through regulation of MMP-1 and -13, which can cleave the prodomain of MMP-9. Furthermore, when applied in a wound model, conditioned media exhibiting peak MMP activity increased vascular cell migration that was MMP-9-dependent, suggesting that MMP-9 is a key physiologic mediator of the effects of NO in this model. [Abstract/Link to Full Text]

P�rez-Escudero A, de Polavieja GG
Optimally wired subnetwork determines neuroanatomy of Caenorhabditis elegans.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17180-5.
Wiring cost minimization has successfully explained many structures of nervous systems. However, in the nematode Caenorhabditis elegans, for which anatomical data are most detailed, wiring economy is thought to play only a partial role and alone has failed to account for the grouping of neurons into ganglia [Chen BL, Hall DH, Chklovskii DB (2006) Proc Natl Acad Sci USA 103:4723-4728; Kaiser M, Hilgetag CC (2006) PLoS Comput Biol 2:e95; Ahn Y-Y, Jeong H, Kim BJ (2006) Physica A 367:531-537]. Here, we test the hypothesis that optimally wired subnetworks can exist within nonoptimal networks, thus allowing wiring economy to give an improved prediction of spatial structure. We show in C. elegans that the small subnetwork of wires connecting sensory and motor neurons with sensors and muscles, comprising only 15% of connections, is close to optimal and alone predicts the main features of the spatial segregation of neurons into ganglia and encephalization. Moreover, a method to dissect networks into optimal and nonoptimal components is shown to find a large near-optimal subnetwork of 84% of neurons with a very low position error of 5.4%, and that explains clustering of neurons into ganglia and encephalization to fine detail. In general, we expect realistic networks not to be globally optimal in wire cost. We thus propose the strategy of using near-optimal subnetworks to understand neuroanatomical structure. [Abstract/Link to Full Text]

Recent Articles in BMJ: British Medical Journal

Chong EW, Wong TY, Kreis AJ, Simpson JA, Guymer RH
Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis.
BMJ. 2007 Oct 13;335(7623):755.
OBJECTIVE: To evaluate the effectiveness of dietary antioxidants in the primary prevention of age related macular degeneration (AMD). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Search of seven databases without limits on year or language of publication, and retrieval of references in pertinent reviews and articles. METHODS: Two reviewers independently searched the databases and selected the studies, using standardised criteria. Randomised clinical trials and prospective cohort studies were included. Of the 4192 abstracts initially identified, 12 studies (nine prospective cohort studies and three randomised clinical trials) met the selection criteria and were included. Data extraction and study quality evaluation were independently reviewed, using standardised criteria. Results were pooled quantitatively using meta-analytic methods. RESULTS: The nine prospective cohort studies included 149 203 people, with 1878 incident cases of early AMD. The antioxidants investigated differed across studies, and not all studies contributed to the meta-analysis of each antioxidant. Pooled results from prospective cohort studies indicated that vitamin A, vitamin C, vitamin E, zinc, lutein, zeaxanthin, alpha carotene, beta carotene, beta cryptoxanthin, and lycopene have little or no effect in the primary prevention of early AMD. The three randomised clinical trials did not show that antioxidant supplements prevented early AMD. CONCLUSIONS: There is insufficient evidence to support the role of dietary antioxidants, including the use of dietary antioxidant supplements, for the primary prevention of early AMD. [Abstract/Link to Full Text]

Evans J
Primary prevention of age related macular degeneration.
BMJ. 2007 Oct 13;335(7623):729. [Abstract/Link to Full Text]

Mason S, Knowles E, Colwell B, Dixon S, Wardrope J, Gorringe R, Snooks H, Perrin J, Nicholl J
Effectiveness of paramedic practitioners in attending 999 calls from elderly people in the community: cluster randomised controlled trial.
BMJ. 2007 Nov 3;335(7626):919.
OBJECTIVE: To evaluate the benefits of paramedic practitioners assessing and, when possible, treating older people in the community after minor injury or illness. Paramedic practitioners have been trained with extended skills to assess, treat, and discharge older patients with minor acute conditions in the community. DESIGN: Cluster randomised controlled trial involving 56 clusters. Weeks were randomised to the paramedic practitioner service being active (intervention) or inactive (control) when the standard 999 service was available. SETTING: A large urban area in England. PARTICIPANTS: 3018 patients aged over 60 who called the emergency services (n=1549 intervention, n=1469 control). MAIN OUTCOME MEASURES: Emergency department attendance or hospital admission between 0 and 28 days; interval from time of call to time of discharge; patients' satisfaction with the service received. RESULTS: Overall, patients in the intervention group were less likely to attend an emergency department (relative risk 0.72, 95% confidence interval 0.68 to 0.75) or require hospital admission within 28 days (0.87, 0.81 to 0.94) and experienced a shorter total episode time (235 v 278 minutes, 95% confidence interval for difference -60 minutes to -25 minutes). Patients in the intervention group were more likely to report being highly satisfied with their healthcare episode (relative risk 1.16, 1.09 to 1.23). There was no significant difference in 28 day mortality (0.87, 0.63 to 1.21). CONCLUSIONS: Paramedics with extended skills can provide a clinically effective alternative to standard ambulance transfer and treatment in an emergency department for elderly patients with acute minor conditions. TRIAL REGISTRATION: ISRCTN27796329 [controlled-trials.com]. [Abstract/Link to Full Text]

Woollard M
Paramedic practitioners and emergency admissions.
BMJ. 2007 Nov 3;335(7626):893-4. [Abstract/Link to Full Text]

Loosemore M, Knowles CH, Whyte GP
Amateur boxing and risk of chronic traumatic brain injury: systematic review of observational studies.
BMJ. 2007 Oct 20;335(7624):809.
OBJECTIVE: To evaluate the risk of chronic traumatic brain injury from amateur boxing. SETTING: Secondary research performed by combination of sport physicians and clinical academics. DESIGN, DATA SOURCES, AND METHODS: Systematic review of observational studies in which chronic traumatic brain injury was defined as any abnormality on clinical neurological examination, psychometric testing, neuroimaging studies, and electroencephalography. Studies were identified through database (1950 to date) and bibliographic searches without language restrictions. Two reviewers extracted study characteristics, quality, and data, with adherence to a protocol developed from a widely recommended method for systematic review of observational studies (MOOSE). RESULTS: 36 papers had relevant extractable data (from a detailed evaluation of 93 studies of 943 identified from the initial search). Quality of evidence was generally poor. The best quality studies were those with a cohort design and those that used psychometric tests. These yielded the most negative results: only four of 17 (24%) better quality studies found any indication of chronic traumatic brain injury in a minority of boxers studied. CONCLUSION: There is no strong evidence to associate chronic traumatic brain injury with amateur boxing. [Abstract/Link to Full Text]

McCrory P
Boxing and the risk of chronic brain injury.
BMJ. 2007 Oct 20;335(7624):781-2. [Abstract/Link to Full Text]

Legg L, Drummond A, Leonardi-Bee J, Gladman JR, Corr S, Donkervoort M, Edmans J, Gilbertson L, Jongbloed L, Logan P, Sackley C, Walker M, Langhorne P
Occupational therapy for patients with problems in personal activities of daily living after stroke: systematic review of randomised trials.
BMJ. 2007 Nov 3;335(7626):922.
OBJECTIVE: To determine whether occupational therapy focused specifically on personal activities of daily living improves recovery for patients after stroke. DESIGN: Systematic review and meta-analysis. DATA SOURCES: The Cochrane stroke group trials register, the Cochrane central register of controlled trials, Medline, Embase, CINAHL, PsycLIT, AMED, Wilson Social Sciences Abstracts, Science Citation Index, Social Science Citation, Arts and Humanities Citation Index, Dissertations Abstracts register, Occupational Therapy Research Index, scanning reference lists, personal communication with authors, and hand searching. REVIEW METHODS: Trials were included if they evaluated the effect of occupational therapy focused on practice of personal activities of daily living or where performance in such activities was the target of the occupational therapy intervention in a stroke population. Original data were sought from trialists. Two reviewers independently reviewed each trial for methodological quality. Disagreements were resolved by consensus. RESULTS: Nine randomised controlled trials including 1258 participants met the inclusion criteria. Occupational therapy delivered to patients after stroke and targeted towards personal activities of daily living increased performance scores (standardised mean difference 0.18, 95% confidence interval 0.04 to 0.32, P=0.01) and reduced the risk of poor outcome (death, deterioration or dependency in personal activities of daily living) (odds ratio 0.67, 95% confidence interval 0.51 to 0.87, P=0.003). For every 100 people who received occupational therapy focused on personal activities of daily living, 11 (95% confidence interval 7 to 30) would be spared a poor outcome. CONCLUSIONS: Occupational therapy focused on improving personal activities of daily living after stroke can improve performance and reduce the risk of deterioration in these abilities. Focused occupational therapy should be available to everyone who has had a stroke. [Abstract/Link to Full Text]

McPherson KM, Ellis-Hill C
Occupational therapy after stroke.
BMJ. 2007 Nov 3;335(7626):894-5. [Abstract/Link to Full Text]

van Sluijs EM, McMinn AM, Griffin SJ
Effectiveness of interventions to promote physical activity in children and adolescents: systematic review of controlled trials.
BMJ. 2007 Oct 6;335(7622):703.
OBJECTIVE: To review the published literature on the effectiveness of interventions to promote physical activity in children and adolescents. DESIGN: Systematic review. DATA SOURCES: Literature search using PubMed, SCOPUS, Psychlit, Ovid Medline, Sportdiscus, and Embase up to December 2006. Review methods Two independent reviewers assessed studies against the following inclusion criteria: controlled trial, comparison of intervention to promote physical activity with no intervention control condition, participants younger than 18 years, and reported statistical analyses of a physical activity outcome measure. Levels of evidence, accounting for methodological quality, were assessed for three types of intervention, five settings, and three target populations. RESULTS: The literature search identified 57 studies: 33 aimed at children and 24 at adolescents. Twenty four studies were of high methodological quality, including 13 studies in children. Interventions that were found to be effective achieved increases ranging from an additional 2.6 minutes of physical education related physical activity to 283 minutes per week of overall physical activity. Among children, limited evidence for an effect was found for interventions targeting children from low socioeconomic populations, and environmental interventions. Strong evidence was found that school based interventions with involvement of the family or community and multicomponent interventions can increase physical activity in adolescents. CONCLUSION: Some evidence was found for potentially effective strategies to increase children's levels of physical activity. For adolescents, multicomponent interventions and interventions that included both school and family or community involvement have the potential to make important differences to levels of physical activity and should be promoted. A lack of high quality evaluations hampers conclusions concerning effectiveness, especially among children. [Abstract/Link to Full Text]

Giles-Corti B, Salmon J
Encouraging children and adolescents to be more active.
BMJ. 2007 Oct 6;335(7622):677-8. [Abstract/Link to Full Text]

Westaby S, Archer N, Manning N, Adwani S, Grebenik C, Ormerod O, Pillai R, Wilson N
Comparison of hospital episode statistics and central cardiac audit database in public reporting of congenital heart surgery mortality.
BMJ. 2007 Oct 13;335(7623):759.
OBJECTIVE: To verify or refute the value of hospital episode statistics (HES) in determining 30 day mortality after open congenital cardiac surgery in infants nationally in comparison with central cardiac audit database (CCAD) information. DESIGN: External review of paediatric cardiac surgical outcomes in England (HES) and all UK units (CCAD), as derived from each database. SETTING: Congenital heart surgery centres in the United Kingdom. DATA SOURCES: HES for congenital heart surgery and corresponding information from CCAD for the period 1 April 2000 to 31 March 2002. HES was restricted to the 11 English centres; CCAD covered all 13 UK centres. MAIN OUTCOME MEASURE: Mortality within 30 days of open heart surgery in infants aged under 12 months. RESULTS: In a direct comparison for the years when data from the 11 English centres were available from both databases, HES omitted between 5% and 38% of infants operated on in each centre. A median 40% (range 0-73%) shortfall occurred in identification of deaths by HES. As a result, mean 30 day mortality was underestimated at 4% by HES as compared with 8% for CCAD. In CCAD, between 1% and 23% of outcomes were missing in nine of 11 English centres used in the comparison (predominantly those for overseas patients). Accordingly, CCAD mortality could also be underestimated. Oxford provided the most complete dataset to HES, including all deaths recorded by CCAD. From three years of CCAD, Oxford's infant mortality from open cardiac surgery (10%) was not statistically different from the mean for all 13 UK centres (8%), in marked contrast to the conclusions drawn from HES for two of those years. CONCLUSIONS: Hospital episode statistics are unsatisfactory for the assessment of activity and outcomes in congenital heart surgery. The central cardiac audit database is more accurate and complete, but further work is needed to achieve fully comprehensive risk stratified mortality data. Given unresolved limitations in data quality, commercial organisations should reconsider placing centre specific or surgeon specific mortality data in the public domain. [Abstract/Link to Full Text]

Singleton S
Data sources and performance measurement.
BMJ. 2007 Oct 13;335(7623):730. [Abstract/Link to Full Text]

Westaby S, Archer N, Wilson N
Surgical mortality: Media attack.
BMJ. 2007 Oct 27;335(7625):839; author reply 839-40. [Abstract/Link to Full Text]

Aylin P, Bottle A, Elliott P, Jarman B
Surgical mortality: Hospital episode statistics v central cardiac audit database.
BMJ. 2007 Oct 27;335(7625):839; author reply 839-40. [Abstract/Link to Full Text]

Minns Lowe CJ, Barker KL, Dewey M, Sackley CM
Effectiveness of physiotherapy exercise after knee arthroplasty for osteoarthritis: systematic review and meta-analysis of randomised controlled trials.
BMJ. 2007 Oct 20;335(7624):812.
OBJECTIVE: To evaluate the effectiveness of physiotherapy exercise after elective primary total knee arthroplasty in patients with osteoarthritis. DESIGN: Systematic review. DATA SOURCES: Database searches: AMED, CINAHL, Embase, King's Fund, Medline, Cochrane library (Cochrane reviews, Cochrane central register of controlled trials, DARE), PEDro, Department of Health national research register. Hand searches: Physiotherapy, Physical Therapy, Journal of Bone and Joint Surgery (Britain) Conference Proceedings. Review methods Randomised controlled trials were reviewed if they included a physiotherapy exercise intervention compared with usual or standard physiotherapy care, or compared two types of exercise physiotherapy interventions meeting the review criteria, after discharge from hospital after elective primary total knee arthroplasty for osteoarthritis. OUTCOME MEASURES: Functional activities of daily living, walking, quality of life, muscle strength, and range of motion in the knee joint. Trial quality was extensively evaluated. Narrative synthesis plus meta-analyses with fixed effect models, weighted mean differences, standardised effect sizes, and tests for heterogeneity. RESULTS: Six trials were identified, five of which were suitable for inclusion in meta-analyses. There was a small to moderate standardised effect size (0.33, 95% confidence interval 0.07 to 0.58) in favour of functional exercise for function three to four months postoperatively. There were also small to moderate weighted mean differences of 2.9 (0.61 to 5.2) for range of joint motion and 1.66 (-1 to 4.3) for quality of life in favour of functional exercise three to four months postoperatively. Benefits of treatment were no longer evident at one year. CONCLUSIONS: Interventions including physiotherapy functional exercises after discharge result in short term benefit after elective primary total knee arthroplasty. Effect sizes are small to moderate, with no long term benefit. [Abstract/Link to Full Text]

Herbert R, Fransen M
Management of chronic knee pain.
BMJ. 2007 Oct 20;335(7624):786. [Abstract/Link to Full Text]

Goodacre S, Cross E, Lewis C, Nicholl J, Capewell S
Effectiveness and safety of chest pain assessment to prevent emergency admissions: ESCAPE cluster randomised trial.
BMJ. 2007 Sep 29;335(7621):659.
OBJECTIVE: To determine whether introducing chest pain unit care reduces emergency admissions without increasing reattendances and admissions over the next 30 days. DESIGN: Cluster randomised before and after intervention trial. SETTING: 14 diverse acute hospitals in the United Kingdom. PARTICIPANTS: Patients attending the emergency department with acute chest pain during the year before and the year after the intervention started. INTERVENTION: Establishment of chest pain unit care compared with continuation of routine care. MAIN OUTCOME MEASURES: Proportion of chest pain attendances resulting in admission; reattendances and admissions over the next 30 days; daily emergency medical admissions (all causes); and proportion of emergency department attendances with chest pain. RESULTS: The introduction of chest pain unit care was associated with weak evidence of an increase in emergency department attendances with chest pain (16% v 3.5%; P=0.08); no change in the proportion of chest pain attendances resulting in admission (odds ratio 0.998, 95% confidence interval 0.940 to 1.059; P=0.945); small increases in the proportion reattending (odds ratio 1.10, 1.00 to 1.21; P=0.036) or being admitted (1.30, 0.97 to 1.74; P=0.083) over the next 30 days; and evidence of increased daily medical admissions (1.7 per day, 95% confidence interval 0.8 to 2.5; P<0.001). However, this last finding was highly sensitive to changes in the method used to handle missing data. CONCLUSION: The introduction of chest pain unit care did not reduce the proportion of patients with chest pain admitted and may have been associated with increased emergency department attendances with chest pain. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55318418. [Abstract/Link to Full Text]

Clancy M
Effectiveness of chest pain units.
BMJ. 2007 Sep 29;335(7621):623-4. [Abstract/Link to Full Text]

Leitch A, McGinness P, Wallbridge D
Calculate the QT interval in patients taking drugs for dementia.
BMJ. 2007 Sep 15;335(7619):557. [Abstract/Link to Full Text]

Wald DS, Bestwick JP, Wald NJ
Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis.
BMJ. 2007 Sep 22;335(7620):599.
OBJECTIVE: To develop a population screening strategy for familial hypercholesterolaemia. DESIGN: Meta-analysis of published data on total and low density lipoprotein (LDL) cholesterol in people with and without familial hypercholesterolaemia according to age. Thirteen studies reporting on 1907 cases and 16 221 controls were used in the analysis. Included studies had at least 10 cases and controls with data on the distribution of cholesterol in affected and unaffected individuals. MAIN OUTCOME MEASURES: Detection rates (sensitivity) for specified false positive rates (0.1%, 0.5%, and 1%) in newborns and in age groups 1-9, 10-19, 20-39, 40-59, and > or =60 years. RESULTS: Serum cholesterol concentration discriminated best between people with and without familial hypercholesterolaemia at ages 1-9, when the detection rates with total cholesterol were 88%, 94%, and 96% for false positive rates of 0.1%, 0.5%, and 1%. The results were similar with LDL cholesterol. Screening newborns was much less effective. Once an affected child is identified, measurement of cholesterol would detect about 96% of parents with the disorder, using the simple rule that the parent with the higher serum cholesterol concentration is the affected parent. CONCLUSIONS: The proposed strategy of screening children and parents for familial hypercholesterolaemia could have considerable impact in preventing the medical consequences of this disorder in two generations simultaneously. [Abstract/Link to Full Text]

Hadfield GS, Humphries SE
Familial hypercholesterolaemia: Cascade testing is tried and tested and cost effective.
BMJ. 2007 Oct 6;335(7622):683. [Abstract/Link to Full Text]

Hopcroft KA
Familial hypercholesterolaemia: Child-parent screening may have adverse psychological effects.
BMJ. 2007 Oct 6;335(7622):683. [Abstract/Link to Full Text]

Calonge N, Guirguis-Blake J
Screening for familial hypercholesterolaemia.
BMJ. 2007 Sep 22;335(7620):573-4. [Abstract/Link to Full Text]

Stewart CE, Stephens DA, Fielder AR, Moseley MJ
Objectively monitored patching regimens for treatment of amblyopia: randomised trial.
BMJ. 2007 Oct 6;335(7622):707.
OBJECTIVES: To compare visual outcome in response to two prescribed rates of occlusion (six hours a day and 12 hours a day). DESIGN: Unmasked randomised trial. SETTING: Research clinics in two London hospitals. PARTICIPANTS: 97 children with a confirmed diagnosis of amblyopia associated with strabismus, anisometropia, or both. INTERVENTIONS: 18 week period of wearing glasses (refractive adaptation) followed by occlusion prescribed ("patching") for six or 12 hours a day. MAIN OUTCOME MEASURES: Visual acuity measured by logMAR letter recognition; objectively monitored rate of occlusion (hours a day). RESULTS: The mean age of children at study entry was 5.6 (SD 1.5) years. Ninety were eligible for occlusion but 10 dropped out in this phase, leaving 80 children who were randomised to a prescribed dose rate of six (n=40) or 12 (n=40) hours a day. The mean change in visual acuity of the amblyopic eye was not significantly different (P=0.64) between the two groups (0.26 (95% confidence interval 0.21 to 0.31) log units in six hour group; 0.24 (0.19 to 0.29) log units in 12 hour group). The mean dose rates (hours a day) actually received, however, were also not significantly different (4.2 (3.7 to 4.7) in six hour group v 6.2 (5.1 to 7.3) in 12 hour group; P=0.06). The visual outcome was similar for those children who received three to six hours a day or more than six to 12 hours a day, but significantly better than that in children who received less than three hours a day. Children aged under 4 required significantly less occlusion than older children. Visual outcome was not influenced by type of amblyopia. CONCLUSIONS: Substantial (six hours a day) and maximal (12 hours a day) prescribed occlusion results in similar visual outcome. On average, the occlusion dose received in the maximal group was only 50% more than in the substantial group and in both groups was much less than that prescribed. Younger children required the least occlusion. TRIALS REGISTRATION: Clinical Trials NCT00274664. [Abstract/Link to Full Text]

Lempert P
Occlusion studies are ambiguous.
BMJ. 2007 Oct 27;335(7625):842. [Abstract/Link to Full Text]

Loudon SE, Simonsz HJ
Occlusion therapy for amblyopia.
BMJ. 2007 Oct 6;335(7622):678-9. [Abstract/Link to Full Text]

Kramer MS, Matush L, Vanilovich I, Platt R, Bogdanovich N, Sevkovskaya Z, Dzikovich I, Shishko G, Mazer B
Effect of prolonged and exclusive breast feeding on risk of allergy and asthma: cluster randomised trial.
BMJ. 2007 Oct 20;335(7624):815.
OBJECTIVE: To assess whether exclusive and prolonged breast feeding reduces the risk of childhood asthma and allergy by age 6.5 years. DESIGN: Cluster randomised trial. SETTING: 31 Belarussian maternity hospitals and their affiliated polyclinics. PARTICIPANTS: A total of 17,046 mother-infant pairs were enrolled, of whom 13,889 (81.5%) were followed up at age 6.5 years. INTERVENTION: Breastfeeding promotion intervention modelled on the WHO/UNICEF baby friendly hospital initiative. MAIN OUTCOME MEASURES: International study of asthma and allergies in childhood (ISAAC) questionnaire and skin prick tests of five inhalant antigens. RESULTS: The experimental intervention led to a large increase in exclusive breast feeding at 3 months (44.3% v 6.4%; P<0.001) and a significantly higher prevalence of any breast feeding at all ages up to and including 12 months. The experimental group had no reduction in risks of allergic symptoms and diagnoses or positive skin prick tests. In fact, after exclusion of six sites (three experimental and three control) with suspiciously high rates of positive skin prick tests, risks were significantly increased in the experimental group for four of the five antigens. CONCLUSIONS: These results do not support a protective effect of prolonged and exclusive breast feeding on asthma or allergy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37687716 [controlled-trials.com]. [Abstract/Link to Full Text]

Silvers KM, Epton MJ, Frampton CM
Allergy after breast feeding: Study was not designed to test the hypothesis.
BMJ. 2007 Nov 3;335(7626):899. [Abstract/Link to Full Text]

Gahagan S
Breast feeding and the risk of allergy and asthma.
BMJ. 2007 Oct 20;335(7624):782-3. [Abstract/Link to Full Text]

Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ
Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study.
BMJ. 2007 Sep 29;335(7621):651.
OBJECTIVE: To examine the absolute risks or benefits on cancer associated with oral contraception, using incident data. DESIGN: Inception cohort study. SETTING: Royal College of General Practitioners' oral contraception study. PARTICIPANTS: Directly standardised data from the Royal College of General Practitioners' oral contraception study. MAIN OUTCOME MEASURES: Adjusted relative risks between never and ever users of oral contraceptives for different types of cancer, main gynaecological cancers combined, and any cancer. Standardisation variables were age, smoking, parity, social class, and (for the general practitioner observation dataset) hormone replacement therapy. Subgroup analyses examined whether the relative risks changed with user characteristics, duration of oral contraception usage, and time since last use of oral contraception. RESULTS: The main dataset contained about 339,000 woman years of observation for never users and 744,000 woman years for ever users. Compared with never users ever users had statistically significant lower rates of cancers of the large bowel or rectum, uterine body, and ovaries, tumours of unknown site, and other malignancies; main gynaecological cancers combined; and any cancer. The relative risk for any cancer in the smaller general practitioner observation dataset was not significantly reduced. Statistically significant trends of increasing risk of cervical and central nervous system or pituitary cancer, and decreasing risk of uterine body and ovarian malignancies, were seen with increasing duration of oral contraceptive use. Reduced relative risk estimates were observed for ovarian and uterine body cancer many years after stopping oral contraception, although some were not statistically significant. The estimated absolute rate reduction of any cancer among ever users was 45 or 10 per 100,000 woman years, depending on whether the main or general practitioner observation dataset was used. CONCLUSION: In this UK cohort, oral contraception was not associated with an overall increased risk of cancer; indeed it may even produce a net public health gain. The balance of cancer risks and benefits, however, may vary internationally, depending on patterns of oral contraception usage and the incidence of different cancers. [Abstract/Link to Full Text]

Meirik O, Farley TM
Risk of cancer and the oral contraceptive pill.
BMJ. 2007 Sep 29;335(7621):621-2. [Abstract/Link to Full Text]

Colbourn TE, Asseburg C, Bojke L, Philips Z, Welton NJ, Claxton K, Ades AE, Gilbert RE
Preventive strategies for group B streptococcal and other bacterial infections in early infancy: cost effectiveness and value of information analyses.
BMJ. 2007 Sep 29;335(7621):655.
OBJECTIVE: To determine the cost effectiveness of strategies for preventing neonatal infection with group B streptococci and other bacteria in the UK and the value of further information from research. DESIGN: Use of a decision model to compare the cost effectiveness of prenatal testing for group B streptococcal infection (by polymerase chain reaction or culture), prepartum antibiotic treatment (intravenous penicillin or oral erythromycin), and vaccination during pregnancy (not yet available) for serious bacterial infection in early infancy across 12 maternal risk groups. Model parameters were estimated using multi-parameter evidence synthesis to incorporate all relevant data inputs. DATA SOURCES: 32 systematic reviews were conducted: 14 integrated results from published studies, 24 involved analyses of primary datasets, and five included expert opinion. Main outcomes measures Healthcare costs per quality adjusted life year (QALY) gained. RESULTS: Current best practice (to treat only high risk women without prior testing for infection) and universal testing by culture or polymerase chain reaction were not cost effective options. Immediate extension of current best practice to treat all women with preterm and high risk term deliveries without testing (11% treated) would result in substantial net benefits. Currently, addition of culture testing for low risk term women, while treating all preterm and high risk term women, would be the most cost effective option (21% treated). If available in the future, vaccination combined with treating all preterm and high risk term women and no testing for low risk women would probably be marginally more cost effective and would limit antibiotic exposure to 11% of women. The value of information is highest (67m pounds sterling) if vaccination is included as an option. CONCLUSIONS: Extension of current best practice to treat all women with preterm and high risk term deliveries is readily achievable and would be beneficial. The choice between adding culture testing for low risk women or vaccination for all should be informed by further research. Trials to evaluate vaccine efficacy should be prioritised. [Abstract/Link to Full Text]

Briggs AH
New methods of analysing cost effectiveness.
BMJ. 2007 Sep 29;335(7621):622-3. [Abstract/Link to Full Text]

Phillips R, Amos A, Ritchie D, Cunningham-Burley S, Martin C
Smoking in the home after the smoke-free legislation in Scotland: qualitative study.
BMJ. 2007 Sep 15;335(7619):553.
OBJECTIVE: To explore the accounts of smokers and non-smokers (who live with smokers) of smoking in their homes and cars after the Scottish smoke-free legislation; to examine the reported impact of the legislation on smoking in the home; and to consider the implications for future initiatives aimed at reducing children's exposure to secondhand smoke in the home. DESIGN AND SETTING: A qualitative cross sectional study involving semistructured interviews conducted across Scotland shortly after the implementation of the legislation on 26 March 2006. PARTICIPANTS: A purposively selected sample of 50 adults (aged 18-75) drawn from all socioeconomic groups, included smokers living with smokers, smokers living with non-smokers, and non-smokers living with smokers. RESULTS: Passive smoking was a well recognised term. Respondents had varied understandings of the risks of secondhand smoke, with a few rejecting evidence of such risks. Children, however, were perceived as vulnerable. Most reported that they restricted smoking in their homes, with a range of restrictions across social classes and home smoking profiles. Spatial, relational, health, and aesthetic factors influenced the development of restrictions. Children and grandchildren were important considerations in the development and modification of restrictions. Other strategies were also used to militate against secondhand smoke, such as opening windows. The meaning of the home as somewhere private and social identity were important underlying factors. Respondents reported greater restrictions on smoking in their cars. There were diverse views on the smoke-free legislation. Few thought it had influenced their smoking in the home, and none thought it had affected how they restricted smoking in their homes. CONCLUSIONS: These data suggest two normative discourses around smoking in the home. The first relates to acceptable social identity as a hospitable person who is not anti-smoker. The second relates to moral identity as a caring parent or grandparent. Awareness of the risks of secondhand smoke, despite ambivalence about health messages and the fluidity of smoking restrictions, provides clear opportunities for public health initiatives to support people attain smoke-free homes. [Abstract/Link to Full Text]

Chapman S
The future of smoke-free legislation.
BMJ. 2007 Sep 15;335(7619):521-2. [Abstract/Link to Full Text]

Akhtar PC, Currie DB, Currie CE, Haw SJ
Changes in child exposure to environmental tobacco smoke (CHETS) study after implementation of smoke-free legislation in Scotland: national cross sectional survey.
BMJ. 2007 Sep 15;335(7619):545.
OBJECTIVE: To detect any change in exposure to secondhand smoke among primary schoolchildren after implementation of smoke-free legislation in Scotland in March 2006. DESIGN: Comparison of nationally representative, cross sectional, class based surveys carried out in the same schools before and after legislation. SETTING: Scotland. PARTICIPANTS: 2559 primary schoolchildren (primary 7; mean age 11.4 years) surveyed in January 2006 (before smoke-free legislation) and 2424 in January 2007 (after legislation). OUTCOME MEASURES: Salivary cotinine concentrations, reports of parental smoking, and exposure to tobacco smoke in public and private places before and after legislation. RESULTS: The geometric mean salivary cotinine concentration in non-smoking children fell from 0.36 (95% confidence interval 0.32 to 0.40) ng/ml to 0.22 (0.19 to 0.25) ng/ml after the introduction of smoke-free legislation in Scotland-a 39% reduction. The extent of the fall in cotinine concentration varied according to the number of parent figures in the home who smoked but was statistically significant only among pupils living in households in which neither parent figure smoked (51% fall, from 0.14 (0.13 to 0.16) ng/ml to 0.07 (0.06 to 0.08) ng/ml) and among pupils living in households in which only the father figure smoked (44% fall, from 0.57 (0.47 to 0.70) ng/ml to 0.32 (0.25 to 0.42) ng/ml). Little change occurred in reported exposure to secondhand smoke in pupils' own homes or in cars, but a small decrease in exposure in other people's homes was reported. Pupils reported lower exposure in cafes and restaurants and in public transport after legislation. CONCLUSIONS: The Scottish smoke-free legislation has reduced exposure to secondhand smoke among young people in Scotland, particularly among groups with lower exposure in the home. We found no evidence of increased secondhand smoke exposure in young people associated with displacement of parental smoking into the home. The Scottish smoke-free legislation has thus had a positive short term impact on young people's health, but further efforts are needed to promote both smoke-free homes and smoking cessation. [Abstract/Link to Full Text]

Haw SJ, Gruer L
Changes in exposure of adult non-smokers to secondhand smoke after implementation of smoke-free legislation in Scotland: national cross sectional survey.
BMJ. 2007 Sep 15;335(7619):549.
OBJECTIVE: To measure change in adult non-smokers' exposure to secondhand smoke in public and private places after smoke-free legislation was implemented in Scotland. DESIGN: Repeat cross sectional survey. SETTING: Scotland. PARTICIPANTS: Scottish adults, aged 18 to 74 years, recruited and interviewed in their homes. INTERVENTION: Comprehensive smoke-free legislation that prohibits smoking in virtually all enclosed public places and workplaces, including bars, restaurants, and cafes. OUTCOME MEASURES: Salivary cotinine, self reported exposure to smoke in public and private places, and self reported smoking restriction in homes and in cars. RESULTS: Overall, geometric mean cotinine concentrations in adult non-smokers fell by 39% (95% confidence interval 29% to 47%), from 0.43 ng/ml at baseline to 0.26 ng/ml after legislation (P<0.001). In non-smokers from non-smoking households, geometric mean cotinine concentrations fell by 49% (40% to 56%), from 0.35 ng/ml to 0.18 ng/ml (P<0.001). The 16% fall in cotinine concentrations in non-smokers from smoking households was not statistically significant. Reduction in exposure to secondhand smoke was associated with a reduction after legislation in reported exposure to secondhand smoke in public places (pubs, other workplaces, and public transport) but not in homes and cars. We found no evidence of displacement of smoking from public places into the home. CONCLUSIONS: Implementation of Scotland's smoke-free legislation has been accompanied within one year by a large reduction in exposure to secondhand smoke, which has been greatest in non-smokers living in non-smoking households. Non-smokers living in smoking households continue to have high levels of exposure to secondhand smoke. [Abstract/Link to Full Text]

Garvey JF, McElwaine P, Monaghan TS, McNicholas WT
Banning smoking: Confessions of an accordion cleaner.
BMJ. 2007 Sep 29;335(7621):630. [Abstract/Link to Full Text]

Eborall H, Davies R, Kinmonth AL, Griffin S, Lawton J
Patients' experiences of screening for type 2 diabetes: prospective qualitative study embedded in the ADDITION (Cambridge) randomised controlled trial.
BMJ. 2007 Sep 8;335(7618):490.
OBJECTIVES: To provide insight into factors that contribute to the anxiety reported in a quantitative study of the psychological effect of screening for type 2 diabetes. To explore expectations of and reactions to the screening experience of patients with positive, negative, and intermediate results. DESIGN: Prospective qualitative interview study of patients attending a screening programme for type 2 diabetes. SETTING: Seven general practices in the ADDITION (Cambridge) trial in the east of England. PARTICIPANTS: 23 participants (aged 50-69) attending different stages in the screening process. RESULTS: Participants' perceptions changed as they progressed through the screening programme; the stepwise process seemed to help them adjust psychologically. The first screening test was typically considered unimportant and was attended with no thought about its implications. By the final diagnostic test, type 2 diabetes was considered a strong possibility, albeit a "mild" form. After diagnosis, people with screen detected type 2 diabetes tended to downplay its importance and talked confidently about their plans to control it. Participants with intermediate results seemed uncertain about their diagnosis, and those who screened negative were largely unaware of their remaining high risk. CONCLUSIONS: This study helps in understanding the limited psychological impact of screening for type 2 diabetes quantified previously, in particular by the quantitative substudy of ADDITION (Cambridge). The findings have implications for implementing such a screening programme in terms of timing and content. [Abstract/Link to Full Text]

Stolk RP
Screening for diabetes.
BMJ. 2007 Sep 8;335(7618):457-8. [Abstract/Link to Full Text]

Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, Johnson JA
Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review.
BMJ. 2007 Sep 8;335(7618):497.
OBJECTIVE: To review the literature on the association between antidiabetic agents and morbidity and mortality in people with heart failure and diabetes. DESIGN: Systematic review and meta-analysis of controlled studies (randomised trials or cohort studies) evaluating antidiabetic agents and outcomes (death and admission to hospital) in patients with heart failure and diabetes. DATA SOURCES: Electronic databases, manual reference search, and contact with investigators. REVIEW METHODS: Two reviewers independently extracted data. Risk estimates for specific treatments were abstracted and pooled estimates derived by meta-analysis where appropriate. RESULTS: Eight studies were included. Three of four studies found that insulin use was associated with increased risk for all cause mortality (odds ratio 1.25, 95% confidence interval 1.03 to 1.51; 3.42, 1.40 to 8.37 in studies that did not adjust for diet and antidiabetic drugs; hazard ratio 1.66, 1.20 to 2.31; 0.96, 0.88 to 1.05 in the studies that did). Metformin was associated with significantly reduced all cause mortality in two studies (hazard ratio 0.86, 0.78 to 0.97) compared with other antidiabetic drugs and insulin; 0.70, 0.54 to 0.91 compared with sulfonylureas); a similar trend was seen in a third. Metformin was not associated with increased hospital admission for any cause or for heart failure specifically. In four studies, use of thiazolidinediones was associated with reduced all cause mortality (pooled odds ratio 0.83, 0.71 to 0.97, I2=52%, P=0.02). Thiazolidinediones were associated with increased risk of hospital admission for heart failure (pooled odds ratio 1.13 (1.04 to 1.22), I2=0%, P=0.004). The two studies of sulfonylureas had conflicting results, probably because of differences in comparator treatments. Important limitations were noted in all studies. CONCLUSION: Metformin was the only antidiabetic agent not associated with harm in patients with heart failure and diabetes. It was associated with reduced all cause mortality in two of the three studies. [Abstract/Link to Full Text]

Snoek FJ
Self management of type 2 diabetes.
BMJ. 2007 Sep 8;335(7618):458-9. [Abstract/Link to Full Text]

Peel E, Douglas M, Lawton J
Self monitoring of blood glucose in type 2 diabetes: longitudinal qualitative study of patients' perspectives.
BMJ. 2007 Sep 8;335(7618):493.
OBJECTIVE: To explore views of patients with type 2 diabetes about self monitoring of blood glucose over time. DESIGN: Longitudinal, qualitative study. SETTING: Primary and secondary care settings across Lothian, Scotland. PARTICIPANTS: 18 patients with type 2 diabetes. MAIN OUTCOME MEASURES: Results from repeat in-depth interviews with patients over four years after clinical diagnosis. RESULTS: Analysis revealed three main themes-the role of health professionals, interpreting readings and managing high values, and the ongoing role of blood glucose self monitoring. Self monitoring decreased over time, and health professionals' behaviour seemed crucial in this: participants interpreted doctors' focus on levels of haemoglobin A(1c), and lack of perceived interest in meter readings, as indicating that self monitoring was not worth continuing. Some participants saw readings as a proxy measure of good and bad behaviour-with women especially, chastising themselves when readings were high. Some participants continued to find readings difficult to interpret, with uncertainty about how to respond to high readings. Reassurance and habit were key reasons for continuing. There was little indication that participants were using self monitoring to effect and maintain behaviour change. CONCLUSIONS: Clinical uncertainty about the efficacy and role of blood glucose self monitoring in patients with type 2 diabetes is mirrored in patients' own accounts. Patients tended not to act on their self monitoring results, in part because of a lack of education about the appropriate response to readings. Health professionals should be explicit about whether and when such patients should self monitor and how they should interpret and act upon the results, especially high readings. [Abstract/Link to Full Text]

Eborall HC, Griffin SJ, Prevost AT, Kinmonth AL, French DP, Sutton S
Psychological impact of screening for type 2 diabetes: controlled trial and comparative study embedded in the ADDITION (Cambridge) randomised controlled trial.
BMJ. 2007 Sep 8;335(7618):486.
OBJECTIVE: To quantify the psychological impact of primary care based stepwise screening for type 2 diabetes. DESIGN: Controlled trial and comparative study embedded in a randomised controlled trial. SETTING: 15 practices (10 screening, five control) in the ADDITION (Cambridge) trial in the east of England. PARTICIPANTS: 7380 adults (aged 40-69) in the top fourth for risk of having undiagnosed type 2 diabetes (6416 invited for screening, 964 controls). INTERVENTIONS: Invited for screening for type 2 diabetes or not invited (controls), incorporating a comparative study of subgroups of screening attenders. Attenders completed questionnaires after a random blood glucose test and at 3-6 months and 12-15 months later. Controls were sent questionnaires at corresponding time points. Non-attenders were sent questionnaires at 3-6 months and 12-15 months. MAIN OUTCOME MEASURES: State anxiety (Spielberger state anxiety inventory), anxiety and depression (hospital anxiety and depression scale), worry about diabetes, and self rated health. RESULTS: No significant differences were found between the screening and control participants at any time-for example, difference in means (95% confidence intervals) for state anxiety after the initial blood glucose test was -0.53, -2.60 to 1.54, at 3-6 months was 1.51 (-0.17 to 3.20), and at 12-15 months was 0.57, -1.11 to 2.24. After the initial test, compared with participants who screened negative, those who screened positive reported significantly poorer general health (difference in means -0.19, -0.25 to -0.13), higher state anxiety (0.93, -0.02 to 1.88), higher depression (0.32, 0.08 to 0.56), and higher worry about diabetes (0.25, 0.09 to 0.41), although effect sizes were small. Small but significant trends were found for self rated health across the screening subgroups at 3-6 months (P=0.047) and for worry about diabetes across the screen negative groups at 3-6 months and 12-15 months (P=0.001). CONCLUSIONS: Screening for type 2 diabetes has limited psychological impact on patients. Implementing a national screening programme based on the stepwise screening procedure used in the ADDITION (Cambridge) trial is unlikely to have significant consequences for patients' psychological health. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99175498 [controlled-trials.com]. [Abstract/Link to Full Text]

Twisselmann B
Joy of rapid responses. Summary of responses.
BMJ. 2004 Mar 13;328(7440):645. [Abstract/Link to Full Text]

Fazel M
Why I'm a reluctant rapid responder.
BMJ. 2004 Feb 14;328(7436):413. [Abstract/Link to Full Text]

Wharfield L
Joy of rapid responses. Rapid responses are useful...but perhaps not entirely effective.
BMJ. 2004 Mar 13;328(7440):645. [Abstract/Link to Full Text]

Colquitt PJ
Joy of rapid responses. Rapid responses are useful...
BMJ. 2004 Mar 13;328(7440):645. [Abstract/Link to Full Text]

Parmar MS
Joy of rapid responses. Don't take points raised in open and free discussion personally.
BMJ. 2004 Mar 13;328(7440):644-5. [Abstract/Link to Full Text]

Vasenwala M
Joy of rapid responses. Readers read articles more closely when they can respond.
BMJ. 2004 Mar 13;328(7440):645. [Abstract/Link to Full Text]

Pewsner D, J�ni P, Egger M, Battaglia M, Sundstr�m J, Bachmann LM
Accuracy of electrocardiography in diagnosis of left ventricular hypertrophy in arterial hypertension: systematic review.
BMJ. 2007 Oct 6;335(7622):711.
OBJECTIVE: To review the accuracy of electrocardiography in screening for left ventricular hypertrophy in patients with hypertension. DESIGN: Systematic review of studies of test accuracy of six electrocardiographic indexes: the Sokolow-Lyon index, Cornell voltage index, Cornell product index, Gubner index, and Romhilt-Estes scores with thresholds for a positive test of > or =4 points or > or =5 points. DATA SOURCES: Electronic databases ((Pre-)Medline, Embase), reference lists of relevant studies and previous reviews, and experts. STUDY SELECTION: Two reviewers scrutinised abstracts and examined potentially eligible studies. Studies comparing the electrocardiographic index with echocardiography in hypertensive patients and reporting sufficient data were included. DATA EXTRACTION: Data on study populations, echocardiographic criteria, and methodological quality of studies were extracted. DATA SYNTHESIS: Negative likelihood ratios, which indicate to what extent the posterior odds of left ventricular hypertrophy is reduced by a negative test, were calculated. RESULTS: 21 studies and data on 5608 patients were analysed. The median prevalence of left ventricular hypertrophy was 33% (interquartile range 23-41%) in primary care settings (10 studies) and 65% (37-81%) in secondary care settings (11 studies). The median negative likelihood ratio was similar across electrocardiographic indexes, ranging from 0.85 (range 0.34-1.03) for the Romhilt-Estes score (with threshold > or =4 points) to 0.91 (0.70-1.01) for the Gubner index. Using the Romhilt-Estes score in primary care, a negative electrocardiogram result would reduce the typical pre-test probability from 33% to 31%. In secondary care the typical pre-test probability of 65% would be reduced to 63%. CONCLUSION: Electrocardiographic criteria should not be used to rule out left ventricular hypertrophy in patients with hypertension. [Abstract/Link to Full Text]

Bourdillon PJ
QRS voltage criteria can be useful.
BMJ. 2007 Oct 20;335(7624):787. [Abstract/Link to Full Text]

Vanezis AP, Bhopal R
Ethnicity is relevant.
BMJ. 2007 Oct 20;335(7624):787. [Abstract/Link to Full Text]

Nielsen OW, Sajadieh A
Diagnosing left ventricular hypertrophy in arterial hypertension.
BMJ. 2007 Oct 6;335(7622):681-2. [Abstract/Link to Full Text]

Conen D, Ridker PM, Buring JE, Glynn RJ
Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study.
BMJ. 2007 Sep 1;335(7617):432.
OBJECTIVE: To compare cardiovascular risk among women with high normal blood pressure (130-9/85-9 mm Hg) against those with normal blood pressure (120-9/75-84 mm Hg) and those with baseline hypertension. DESIGN: Prospective cohort study. SETTING: Women's health study, United States. PARTICIPANTS: 39 322 initially healthy women classified into four categories according to self reported baseline blood pressure and followed for a median of 10.2 years. MAIN OUTCOME MEASURES: Time to cardiovascular death, myocardial infarction, or stroke (major cardiovascular event-primary end point); progression to hypertension. RESULTS: 982 (2.5%) women developed a major cardiovascular event, and 8686 (30.1%) women without baseline hypertension progressed to hypertension. The age adjusted event rate for the primary end point was 1.6/1000 person years among women with normal blood pressure, 2.9/1000 person years among those with high normal blood pressure, and 4.3/1000 person years among those with baseline hypertension. Compared with women with high normal blood pressure (reference group), those with normal blood pressure had a lower risk of a major cardiovascular event (adjusted hazard ratio 0.61, 95% confidence interval 0.48 to 0.76) and of incident hypertension (0.42, 0.40 to 0.44). The hazard ratio for a major cardiovascular event in women with baseline hypertension was 1.30 (1.08 to 1.57). Women who progressed to hypertension (reference group) during the first 48 months of the study had a higher cardiovascular risk than those who remained normotensive (adjusted hazard ratio 0.64, 0.50 to 0.81). Women with high normal blood pressure at baseline who progressed to hypertension (reference group) had similar outcome rates to women with baseline hypertension (adjusted hazard ratio 1.17, 0.88 to 1.55). CONCLUSION: The cardiovascular risk of women with high normal blood pressure is higher than that of women with normal blood pressure. The cardiovascular risk of women who progress to hypertension is increased shortly after a diagnosis of hypertension has been made. TRIAL REGISTRATION: Clinical trials NCT00000479 [ClinicalTrials.gov]. [Abstract/Link to Full Text]

Nash IS
Reassessing normal blood pressure.
BMJ. 2007 Sep 1;335(7617):408-9. [Abstract/Link to Full Text]

Foster NE, Thomas E, Barlas P, Hill JC, Young J, Mason E, Hay EM
Acupuncture as an adjunct to exercise based physiotherapy for osteoarthritis of the knee: randomised controlled trial.
BMJ. 2007 Sep 1;335(7617):436.
OBJECTIVE: To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee. DESIGN: Multicentre, randomised controlled trial. SETTING: 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midlands, United Kingdom. PARTICIPANTS: 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis. INTERVENTIONS: Advice and exercise (n=116), advice and exercise plus true acupuncture (n=117), and advice and exercise plus non-penetrating acupuncture (n=119). MAIN OUTCOME MEASURES: The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months. Secondary outcomes included function, pain intensity, and unpleasantness of pain at two weeks, six weeks, six months, and 12 months. RESULTS: Follow-up rate at six months was 94%. The mean (SD) baseline pain score was 9.2 (3.8). At six months mean reductions in pain were 2.28 (3.8) for advice and exercise, 2.32 (3.6) for advice and exercise plus true acupuncture, and 2.53 (4.2) for advice and exercise plus non-penetrating acupuncture. Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 (95% confidence interval -1.0 to 0.9) for advice and exercise plus true acupuncture and 0.25 (-0.8 to 1.3) for advice and exercise plus non-penetrating acupuncture. Similar non-significant differences were seen at other follow-up points. Compared with advice and exercise alone there were small, statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture. CONCLUSION: The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores. Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups, making it unlikely that this was due to acupuncture needling effects. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88597683 [controlled-trials.com] . [Abstract/Link to Full Text]

Recent Articles in CMAJ : Canadian Medical Association Journal

Fowler RA, Sabur N, Li P, Juurlink DN, Pinto R, Hladunewich MA, Adhikari NK, Sibbald WJ, Martin CM
Sex-and age-based differences in the delivery and outcomes of critical care.
CMAJ. 2007 Dec 4;177(12):1513-9.
BACKGROUND: Previous studies have suggested that a patient's sex may influence the provision and outcomes of critical care. Our objective was to determine whether sex and age are associated with differences in admission practices, processes of care and clinical outcomes for critically ill patients. METHODS: We used a retrospective cohort of 466,792 patients, including 24,778 critically ill patients, admitted consecutively to adult hospitals in Ontario between Jan. 1, 2001, and Dec. 31, 2002. We measured associations between sex and age and admission to the intensive care unit (ICU); use of mechanical ventilation, dialysis or pulmonary artery catheterization; length of stay in the ICU and hospital; and death in the ICU, hospital and 1 year after admission. RESULTS: Of the 466,792 patients admitted to hospital, more were women than men (57.0% v. 43.0% for all admissions, p < 0.001; 50.1% v. 49.9% for nonobstetric admissions, p < 0.001). However, fewer women than men were admitted to ICUs (39.9% v. 60.1%, p < 0.001); this difference was most pronounced among older patients (age > or = 50 years). After adjustment for admission diagnoses and comorbidities, older women were less likely than older men to receive care in an ICU setting (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.66-0.71). After adjustment for illness severity, older women were also less likely than older men to receive mechanical ventilation (OR 0.91, 95% CI 0.81-0.97) or pulmonary artery catheterization (OR 0.80, 95% CI 0.73-0.88). Despite older men and women having similar severity of illness on ICU admission, women received ICU care for a slightly shorter duration yet had a longer length of stay in hospital (mean 18.3 v. 16.9 days; p = 0.006). After adjustment for differences in comorbidities, source of admission, ICU admission diagnosis and illness severity, older women had a slightly greater risk of death in the ICU (hazard ratio 1.20, 95% CI 1.10-1.31) and in hospital (hazard ratio 1.08, 95% CI 1.00-1.16) than did older men. INTERPRETATION: Among patients 50 years or older, women appear less likely than men to be admitted to an ICU and to receive selected life-supporting treatments and more likely than men to die after critical illness. Differences in presentation of critical illness, decision-making or unmeasured confounding factors may contribute to these findings. [Abstract/Link to Full Text]

Bierman AS
Sex matters: gender disparities in quality and outcomes of care.
CMAJ. 2007 Dec 4;177(12):1520-1. [Abstract/Link to Full Text]

Baxter NN
Equal for whom? Addressing disparities in the Canadian medical system must become a national priority.
CMAJ. 2007 Dec 4;177(12):1522-3. [Abstract/Link to Full Text]

Ramin B
Climate of change.
CMAJ. 2007 Nov 6;177(10):1320. [Abstract/Link to Full Text]

Flemons WW, Davies JM, MacLeod B
Disclosing medical errors.
CMAJ. 2007 Nov 6;177(10):1236. [Abstract/Link to Full Text]

Levinson W, Gallagher TH
Disclosing medical errors to patients: a status report in 2007.
CMAJ. 2007 Jul 31;177(3):265-7. [Abstract/Link to Full Text]

Davies G
Reflections on the birth of conjoined twins.
CMAJ. 2007 Nov 6;177(10):1235. [Abstract/Link to Full Text]

Walker K
The tragedy that should never have happened.
CMAJ. 2007 Jul 31;177(3):312. [Abstract/Link to Full Text]

Poole RF
Reflections on the birth of conjoined twins.
CMAJ. 2007 Nov 6;177(10):1235. [Abstract/Link to Full Text]

Akerman BR
Reflections on the birth of conjoined twins.
CMAJ. 2007 Nov 6;177(10):1235. [Abstract/Link to Full Text]

Gogol M
Reflections on the birth of conjoined twins.
CMAJ. 2007 Nov 6;177(10):1235-6. [Abstract/Link to Full Text]

Copes R, Scott J
Radon exposure: can we make a difference?
CMAJ. 2007 Nov 6;177(10):1229-31. [Abstract/Link to Full Text]

Palda VA, Davis D, Goldman J
A guide to the Canadian Medical Association handbook on clinical practice guidelines.
CMAJ. 2007 Nov 6;177(10):1221-6. [Abstract/Link to Full Text]

Pe�uelas O, Frutos-Vivar F, Esteban A
Noninvasive positive-pressure ventilation in acute respiratory failure.
CMAJ. 2007 Nov 6;177(10):1211-8.
Noninvasive positive-pressure ventilation is a type of mechanical ventilation that does not require an artificial airway. Studies published in the 1990s that evaluated the efficacy of this technique for the treatment of diseases as chronic obstructive pulmonary disease, congestive heart failure and acute respiratory failure have generalized its use in recent years. Important issues include the selection of the ventilation interface and the type of ventilator. Currently available interfaces include nasal, oronasal and facial masks, mouthpieces and helmets. Comparisons of the available interfaces have not shown one to be clearly superior. Both critical care ventilators and portable ventilators can be used for noninvasive positive-pressure ventilation; however, the choice of ventilator type depends on the patient's condition and therapeutic requirements and on the expertise of the attending staff and the location of care. The best results (decreased need for intubation and decreased mortality) have been reported among patients with exacerbations of chronic obstructive pulmonary disease and cardiogenic pulmonary edema. [Abstract/Link to Full Text]

Kaul P, Chang WC, Westerhout CM, Graham MM, Armstrong PW
Differences in admission rates and outcomes between men and women presenting to emergency departments with coronary syndromes.
CMAJ. 2007 Nov 6;177(10):1193-9.
BACKGROUND: Previous studies examining sex-related differences in the treatment of coronary artery disease have focused on patients in hospital. We sought to examine sex-related differences at an earlier point in care--presentation to the emergency department. METHODS: We collected data on ambulatory care and hospital admissions for 54,134 patients (44% women) who presented to an emergency department in Alberta between July 1998 and March 2001 because of acute myocardial infarction, unstable angina, stable angina or chest pain. We used logistic regression and Cox regression analyses to determine sex-specific associations between the likelihood of discharge from the emergency department or coronary revascularization within 1 year and 1-year mortality after adjusting for age, comorbidities and socioeconomic factors. RESULTS: Following the emergency department visit, 91.3% of patients with acute myocardial infarction, 87.4% of those with unstable angina, 40.7% of those with stable angina and 19.8% of those with chest pain were admitted to hospital. Women were more likely than men to be discharged from the emergency department: adjusted odds ratio (and 95% confidence interval [CI]) 2.25 (1.75-2.90) for acute myocardial infarction, 1.71 (1.45-2.01) for unstable angina, 1.33 (1.15-1.53) for stable angina and 1.46 (1.36-1.57) for chest pain. Women were less likely than men to undergo coronary revascularization within 1 year: adjusted odds ratio (and 95% CI) 0.65 (0.57-0.73) for myocardial infarction, 0.39 (0.35-0.44) for unstable angina, 0.35 (0.29-0.42) for stable angina and 0.32 (0.27-0.37) for chest pain. Female sex had no impact on 1-year mortality among patients with acute myocardial infarction; it was associated with a decreased 1-year mortality among patients with unstable angina, stable angina and chest pain: adjusted hazard ratio (and 95% CI) 0.60 (0.46-0.78), 0.60 (0.46-0.78) and 0.74 (0.63-0.87) respectively. INTERPRETATION: Women presenting to the emergency department with coronary syndromes are less likely than men to be admitted to an acute care hospital and to receive coronary revascularization procedures. These differences do not translate into worse outcomes for women in terms of 1-year mortality. [Abstract/Link to Full Text]

Buffo-Sequeira I, Fraser DD
Widened mediastinum in a child with severe trauma.
CMAJ. 2007 Nov 6;177(10):1181-2. [Abstract/Link to Full Text]

Bruno TF, Donoff M
Superior vena cava syndrome and telangiectasia in a man with lymphoma.
CMAJ. 2007 Nov 6;177(10):1177-9. [Abstract/Link to Full Text]

Baerlocher MO
Differences in healthy life expectancy among men and women.
CMAJ. 2007 Nov 6;177(10):1174. [Abstract/Link to Full Text]

Eddy C
Statistics don't count.
CMAJ. 2007 Nov 6;177(10):1173. [Abstract/Link to Full Text]

Silversides A
Homeless in Toronto.
CMAJ. 2007 Nov 6;177(10):1172. [Abstract/Link to Full Text]

Kondro W
Generational attitudes and attributes to affect physician workforce.
CMAJ. 2007 Nov 6;177(10):1172. [Abstract/Link to Full Text]

Duval S
Pharmacists to red flag risky drug interactions.
CMAJ. 2007 Nov 6;177(10):1171. [Abstract/Link to Full Text]

Brooks J
America poised on the precipice of health reform.
CMAJ. 2007 Nov 6;177(10):1170-1. [Abstract/Link to Full Text]

Eggertson L
Adverse events reported for HPV vaccine.
CMAJ. 2007 Nov 6;177(10):1169-70. [Abstract/Link to Full Text]

Lopes C
Health care in France: facing hard choices.
CMAJ. 2007 Nov 6;177(10):1167-9. [Abstract/Link to Full Text]

Stanbrook MB, Attaran A, Flegel K, MacDonald N, Sibbald B, Straus S, H�bert PC
It's time to take back the health care debate.
CMAJ. 2007 Nov 6;177(10):1157, 1159. [Abstract/Link to Full Text]

Sibbald R, Downar J, Hawryluck L
Perceptions of "futile care" among caregivers in intensive care units.
CMAJ. 2007 Nov 6;177(10):1201-8.
BACKGROUND: Many caregivers in intensive care units (ICUs) feel that they sometimes provide inappropriate or excessive care, but little is known about their definition of "futile care" or how they attempt to limit its impact. We sought to explore how ICU staff define medically futile care, why they provide it and what strategies might promote a more effective use of ICU resources. METHODS: Using semi-structured interviews, we surveyed 14 physician directors, 16 nurse managers and 14 respiratory therapists from 16 ICUs across Ontario. We analyzed the transcripts using a modified grounded-theory approach. RESULTS: From the interviews, we generated a working definition of medically futile care to mean the use of considerable resources without a reasonable hope that the patient would recover to a state of relative independence or be interactive with his or her environment. Respondents felt that futile care was provided because of family demands, a lack of timely or skilled communication, or a lack of consensus among the treating team. Respondents said they were able to resolve cases of futile care most effectively by improving communication and by allowing time for families to accept the reality of the situation. Respondents felt that further efforts to limit futile care should focus on educating the public and health care professionals about the role of the ICU and about alternatives such as palliative care; mandating early and skilled discussion of resuscitation status; establishing guidelines for admission to the ICU; and providing legal and ethical support for physicians who encounter difficulties. There was a broad consistency in responses among all disciplines. INTERPRETATION: ICU physicians, nurses and respiratory therapists have similar and well-formed opinions about how to define and resolve medically futile care and where to focus future efforts to limit the impact of futile care in the ICU. [Abstract/Link to Full Text]

Dubois J, Rypens F, Garel L, David M, Lacroix J, Gauvin F
Incidence of deep vein thrombosis related to peripherally inserted central catheters in children and adolescents.
CMAJ. 2007 Nov 6;177(10):1185-90.
BACKGROUND: Peripherally inserted central catheters (PICC) in children and adolescents are being used with increasing frequency. We sought to determine the incidence and characterize risk factors of deep vein thrombosis associated with peripherally inserted central catheters in a pediatric population. METHODS: We conducted a prospective study involving consecutive patients referred to the radiology department of a tertiary care university-affiliated hospital for insertion of a peripherally inserted central catheter. We included patients aged 18 years or less who weighed more than 2.5 kg and had a peripherally inserted central catheter successfully inserted in his or her arm between June 2004 and November 2005. The primary outcome was the occurrence of partial or complete deep vein thrombosis evaluated by clinical examination, ultrasonography and venous angiography. RESULTS: A total of 214 patients (101 girls, 113 boys) were included in the study. Partial or complete deep vein thrombosis occurred in 20 patients, for an incidence of 93.5 per 1000 patients and 3.85 per 1000 catheter-days. Only 1 of the cases was symptomatic. In the univariable analyses, the only variable significantly associated with deep vein thrombosis was the presence of factor II mutation G20210A (odds ratio 7.08, 95% confidence interval 1.11-45.15, p = 0.04), a genetic mutation that increases the risk of a blood clot and that was present in 5 (2.3%) of the 214 patients. INTERPRETATION: The incidence of deep vein thrombosis related to peripherally inserted central catheters in our study was lower than the incidence related to centrally inserted venous catheters described in the pediatric literature (11%-50%). [Abstract/Link to Full Text]

Leith M
Reconsidering survival.
CMAJ. 2007 Oct 23;177(9):1148. [Abstract/Link to Full Text]

Jorens PG
Accuracy of point-of-care measurements.
CMAJ. 2007 Oct 23;177(9):1070. [Abstract/Link to Full Text]

Brindley PG, Butler MS, Cembrowski G, Brindley DN
Falsely elevated point-of-care lactate measurement after ingestion of ethylene glycol.
CMAJ. 2007 Apr 10;176(8):1097-9.
BACKGROUND: A patient presented with severe acidosis and a point-of-care lactate measurement of 42 mmol/L. Mesenteric ischemia was suspected, with a potential need for laparotomy; however, plasma lactate measurements were below 4 mmol/L. Ethylene glycol ingestion was subsequently diagnosed. We therefore wished to determine why discrepancies in lactate measurements occur and whether this "lactate gap" could be clinically useful. METHODS: We phlebotomized blood, added various concentrations of metabolites of ethylene glycol, and tested the resulting samples with the 5 most common lactate analyzers. RESULTS: With the Radiometer 700 point-of-care analyzer, glycolate addition resulted in an artifactual, massive lactate elevation, even at low glycolate concentrations. Another major ethylene glycol metabolite, glyoxylate (but not oxalate or formate), caused similar elevations. The i-STAT and Bayer point-of-care analyzers and the Beckman and Vitros laboratory analyzers reported minimal lactate elevations. Lactate gap was determined by comparing the Radiometer result with the corresponding result from any of the other analyzers. INTERPRETATION: We demonstrated how inappropriate laparotomy or delayed therapy might occur if clinicians are unaware of this phenomenon or have access to only a single analyzer. We also showed that lactate gap can be exploited to expedite treatment, diagnose late ethylene-glycol ingestion and terminate dialysis. By comparing lactate results from the iSTAT or Bayer devices with that from the Radiometer, ethylene-glycol ingestion can be diagnosed at the point of care. This can expedite diagnosis and treatment by hours, compared with waiting for laboratory results for plasma ethylene glycol. [Abstract/Link to Full Text]

Behroozi D
Screening men for osteoporosis.
CMAJ. 2007 Oct 23;177(9):1069; author reply 1069-70. [Abstract/Link to Full Text]

Brown JP, Josse RG
2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada.
CMAJ. 2002 Nov 12;167(10 Suppl):S1-34.
OBJECTIVE: To revise and expand the 1996 Osteoporosis Society of Canada clinical practice guidelines for the management of osteoporosis, incorporating recent advances in diagnosis, prevention and management of osteoporosis, and to identify and assess the evidence supporting the recommendations. OPTIONS: All aspects of osteoporosis care and its fracture complications - including classification, diagnosis, management and methods for screening, as well as prevention and reducing fracture risk - were reviewed, revised as required and expressed as a set of recommendations. OUTCOMES: Strategies for identifying and evaluating those at high risk; the use of bone mineral density and biochemical markers in diagnosis and assessing response to management; recommendations regarding nutrition and physical activity; and the selection of pharmacologic therapy for the prevention and management of osteoporosis in men and women and for osteoporosis resulting from glucocorticoid treatment. EVIDENCE: All recommendations were developed using a justifiable and reproducible process involving an explicit method for the evaluation and citation of supporting evidence. VALUES: All recommendations were reviewed by members of the Scientific Advisory Council of the Osteoporosis Society of Canada, an expert steering committee and others, including family physicians, dietitians, therapists and representatives of various medical specialties involved in osteoporosis care (geriatric medicine, rheumatology, endocrinology, obstetrics and gynecology, nephrology, radiology) as well as methodologists from across Canada. Benefits, harm and costs: Earlier diagnosis and prevention of fractures should decrease the medical, social and economic burdens of this disease. RECOMMENDATIONS: This document outlines detailed recommendations pertaining to all aspects of osteoporosis. Strategies for identifying those at increased risk (i.e., those with at least one major or 2 minor risk factors) and screening with central dual-energy x-ray absorptiometry at age 65 years are recommended. Bisphosphonates and raloxifene are first-line therapies in the prevention and treatment of postmenopausal osteoporosis. Estrogen and progestin/progesterone is a first-line therapy in the prevention and a second-line therapy in the treatment of postmenopausal osteoporosis. Nasal calcitonin is a second-line therapy in the treatment of postmenopausal osteoporosis. Although not yet approved for use in Canada, hPTH(1-34) is expected to be a first-line treatment for postmenopausal women with severe osteoporosis. Ipriflavone, vitamin K and fluoride are not recommended. Bisphosphonates are the first-line therapy for the prevention and treatment of osteoporosis in patients requiring prolonged glucocorticoid therapy and for men with osteoporosis. Nasal or parenteral calcitonin is a first-line treatment for pain associated with acute vertebral fractures. Impact-type exercise and age-appropriate calcium and vitamin D intake are recommended for the prevention of osteoporosis. VALIDATION: All recommendations were graded according to the strength of the evidence; where the evidence was insufficient and recommendations were based on consensus opinion alone, this is indicated. These guidelines are viewed as a work in progress and will be updated periodically in response to advances in this field. [Abstract/Link to Full Text]

Khan AA, Hodsman AB, Papaioannou A, Kendler D, Brown JP, Olszynski WP
Management of osteoporosis in men: an update and case example.
CMAJ. 2007 Jan 30;176(3):345-8.
In 2002, Osteoporosis Canada published clinical practice guidelines for the diagnosis and management of osteoporosis. The current paper supplements that guideline and provides a review and synthesis of the current literature on the diagnosis and management of osteoporosis in men. [Abstract/Link to Full Text]

Turnbull J, Muckle W, Masters C
Homelessness and health.
CMAJ. 2007 Oct 23;177(9):1065-6. [Abstract/Link to Full Text]

Recent Articles in The Journal of Clinical Investigation

Selva DM, Hogeveen KN, Innis SM, Hammond GL
Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene.
J Clin Invest. 2007 Dec 3;117(12):3979-3987.
The liver produces plasma sex hormone-binding globulin (SHBG), which transports sex steroids and regulates their access to tissues. In overweight children and adults, low plasma SHBG levels are a biomarker of the metabolic syndrome and its associated pathologies. Here, we showed in transgenic mice and HepG2 hepatoblastoma cells that monosaccharides (glucose and fructose) reduce human SHBG production by hepatocytes. This occurred via a downregulation of hepatocyte nuclear factor-4alpha (HNF-4alpha) and replacement of HNF-4alpha by the chicken OVA upstream promoter-transcription factor 1 at a cis-element within the human SHBG promoter, coincident with repression of its transcriptional activity. The dose-dependent reduction of HNF-4alpha levels in HepG2 cells after treatment with glucose or fructose occurred in concert with parallel increases in cellular palmitate levels and could be mimicked by treatment with palmitoyl-CoA. Moreover, inhibition of lipogenesis prevented monosaccharide-induced downregulation of HNF-4alpha and reduced SHBG expression in HepG2 cells. Thus, monosaccharide-induced lipogenesis reduced hepatic HNF-4alpha levels, which in turn attenuated SHBG expression. This provides a biological explanation for why SHBG is a sensitive biomarker of the metabolic syndrome and the metabolic disturbances associated with increased fructose consumption. [Abstract/Link to Full Text]

Weindl G, Naglik JR, Kaesler S, Biedermann T, Hube B, Korting HC, Schaller M
Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling.
J Clin Invest. 2007 Dec 3;117(12):3664-3672.
Mammalian TLRs are central mediators of the innate immune system that instruct cells of the innate and adaptive response to clear microbial infections. Here, we demonstrate that human epithelial TLR4 directly protected the oral mucosa from fungal infection via a process mediated by polymorphonuclear leukocytes (PMNs). In an in vitro epithelial model of oral candidiasis, the fungal pathogen Candida albicans induced a chemoattractive and proinflammatory cytokine response but failed to directly modulate the expression of genes encoding TLRs. However, the addition of PMNs to the C. albicans-infected model strongly upregulated cytoplasmic and cell-surface epithelial TLR4 expression, which correlated directly with protection against fungal invasion and cell injury. C. albicans invasion and cell injury was restored by the addition of TLR4-specific neutralizing antibodies and knockdown of TLR4 using RNA interference, even in the presence of PMNs, demonstrating the direct role of epithelial TLR4 in the protective process. Furthermore, treatment with neutralizing antibodies specific for TNF-alpha resulted in strongly reduced TLR4 expression accompanied by augmented epithelial cell damage and fungal invasion. To our knowledge, this is the first description of such a PMN-dependent, TLR4-mediated protective mechanism at epithelial surfaces, which may provide significant insights into how microbial infections are managed and controlled in the oral mucosa. [Abstract/Link to Full Text]

Hanai JI, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme VP, Lecker SH
The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity.
J Clin Invest. 2007 Dec 3;117(12):3940-3951.
Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1alpha, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins. [Abstract/Link to Full Text]

Calzascia T, Pellegrini M, Hall H, Sabbagh L, Ono N, Elford AR, Mak TW, Ohashi PS
TNF-alpha is critical for antitumor but not antiviral T cell immunity in mice.
J Clin Invest. 2007 Dec;117(12):3833-45.
TNF-alpha antagonists are widely used in the treatment of inflammatory and autoimmune diseases, but their use is associated with reactivation of latent infections. This highlights the importance of TNF-alpha in immunity to certain pathogens and raises concerns that critical aspects of immune function are impaired in its absence. Unfortunately, the role of TNF-alpha in the regulation of T cell responses is clouded by a myriad of contradictory reports. Here, we show a role for TNF-alpha and its receptors, TNFR1 and TNFR2, specifically in antitumor immunity. TNF-alpha-deficient mice exhibited normal antiviral responses associated with strong inflammation. However, TNF-alpha/TNFR1-mediated signals on APCs and TNF-alpha/TNFR2 signals on T cells were critically required for effective priming, proliferation, and recruitment of tumor-specific T cells. Furthermore, in the absence of TNF-alpha signaling, tumor immune surveillance was severely abrogated. Finally, treatment with a CD40 agonist alone or in combination with TLR2 stimuli was able to rescue proliferation of TNF-alpha-deficient T cells. Therefore, TNF-alpha signaling may be required only for immune responses in conditions of limited immunostimulatory capacity, such as tumor surveillance. Importantly, these results suggest that prolonged continuous TNF-alpha blockade in patients may have long-term complications, including potential tumor development or progression. [Abstract/Link to Full Text]

Hickey MM, Lam JC, Bezman NA, Rathmell WK, Simon MC
von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis.
J Clin Invest. 2007 Dec 3;117(12):3879-3889.
The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated hematocrit and increased serum levels of erythropoietin and VEGF. Previous studies have implicated hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in this disorder, although the effects of this mutation on pVHL function are not fully understood. In order to explore the mechanisms underlying the development of this polycythemia, we generated mice homozygous for the R200W mutation (Vhl(R/R)). Vhl(R/R) mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2alpha isoform, was upregulated in ES cells and tissues from Vhl(R/R) mice. Furthermore, we observed a striking phenotype in Vhl(R/R) spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of Vhl(R/R) splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2alpha genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vhl(R/R) mice. This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics. [Abstract/Link to Full Text]

Regard JB, Kataoka H, Cano DA, Camerer E, Yin L, Zheng YW, Scanlan TS, Hebrok M, Coughlin SR
Probing cell type-specific functions of G(i) in vivo identifies GPCR regulators of insulin secretion.
J Clin Invest. 2007 Dec;117(12):4034-43.
The in vivo roles of the hundreds of mammalian G protein-coupled receptors (GPCRs) are incompletely understood. To explore these roles, we generated mice expressing the S1 subunit of pertussis toxin, a known inhibitor of G(i/o) signaling, under the control of the ROSA26 locus in a Cre recombinase-dependent manner (ROSA26(PTX)). Crossing ROSA26(PTX) mice to mice expressing Cre in pancreatic beta cells produced offspring with constitutive hyperinsulinemia, increased insulin secretion in response to glucose, and resistance to diet-induced hyperglycemia. This phenotype underscored the known importance of G(i/o) and hence of GPCRs for regulating insulin secretion. Accordingly, we quantified mRNA for each of the approximately 373 nonodorant GPCRs in mouse to identify receptors highly expressed in islets and examined the role of several. We report that 3-iodothyronamine, a thyroid hormone metabolite, could negatively and positively regulate insulin secretion via the G(i)-coupled alpha(2A)-adrenergic receptor and the G(s)-coupled receptor Taar1, respectively, and protease-activated receptor-2 could negatively regulate insulin secretion and may contribute to physiological regulation of glucose metabolism. The ROSA26(PTX) system used in this study represents a new genetic tool to achieve tissue-specific signaling pathway modulation in vivo that can be applied to investigate the role of G(i/o)-coupled GPCRs in multiple cell types and processes. [Abstract/Link to Full Text]

Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-O M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J
The parathyroid is a target organ for FGF23 in rats.
J Clin Invest. 2007 Dec 3;117(12):4003-4008.
Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis. [Abstract/Link to Full Text]

van Herwaarden AE, Wagenaar E, van der Kruijssen CM, van Waterschoot RA, Smit JW, Song JY, van der Valk MA, van Tellingen O, van der Hoorn JW, Rosing H, Beijnen JH, Schinkel AH
Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism.
J Clin Invest. 2007 Nov;117(11):3583-92.
Cytochrome P450 3A (CYP3A) enzymes constitute an important detoxification system that contributes to primary metabolism of more than half of all prescribed medications. To investigate the physiological and pharmacological roles of CYP3A, we generated Cyp3a-knockout (Cyp3a-/-) mice lacking all functional Cyp3a genes. Cyp3a-/- mice were viable, fertile, and without marked physiological abnormalities. However, these mice exhibited severely impaired detoxification capacity when exposed to the chemotherapeutic agent docetaxel, displaying higher exposure levels in response to both oral and intravenous administration. These mice also demonstrated increased sensitivity to docetaxel toxicity, suggesting a primary role for Cyp3a in xenobiotic detoxification. To determine the relative importance of intestinal versus hepatic Cyp3a in first-pass metabolism, we generated transgenic Cyp3a-/- mice expressing human CYP3A4 in either the intestine or the liver. Expression of CYP3A4 in the intestine dramatically decreased absorption of docetaxel into the bloodstream, while hepatic expression aided systemic docetaxel clearance. These results suggest that CYP3A expression determines impairment of drug absorption and efficient systemic clearance in a tissue-specific manner. The genetic models used in this study provide powerful tools to further study CYP3A-mediated xenobiotic metabolism, as well as interactions between CYP3A and other detoxification systems. [Abstract/Link to Full Text]

Wahlstr�m J, Dengjel J, Persson B, Duyar H, Rammensee HG, Stevanovi? S, Eklund A, Weissert R, Grunewald J
Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis.
J Clin Invest. 2007 Nov;117(11):3576-82.
Sarcoidosis is an inflammatory disease of unknown etiology, most commonly affecting the lungs. Activated CD4+ T cells accumulate in the lungs of individuals with sarcoidosis and are considered to be of central importance for inflammation. We have previously shown that Scandinavian sarcoidosis patients expressing the HLA-DR allele DRB1*0301 are characterized by large accumulations in the lungs of CD4+ T cells expressing the TCR AV2S3 gene segment. This association afforded us a unique opportunity to identify a sarcoidosis-specific antigen recognized by AV2S3+ T cells. To identify candidates for the postulated sarcoidosis-specific antigen, lung cells from 16 HLA-DRB1*0301pos patients were obtained by bronchoalveolar lavage. HLA-DR molecules were affinity purified and bound peptides acid eluted. Subsequently, peptides were separated by reversed-phase HPLC and analyzed by liquid chromatography-mass spectrometry. We identified 78 amino acid sequences from self proteins presented in the lungs of sarcoidosis patients, some of which were well-known autoantigens such as vimentin and ATP synthase. For the first time, to our knowledge, we have identified HLA-bound peptides presented in vivo during an inflammatory condition. This approach can be extended to characterize HLA-bound peptides in various autoimmune settings. [Abstract/Link to Full Text]

Le Gall S, Stamegna P, Walker BD
Portable flanking sequences modulate CTL epitope processing.
J Clin Invest. 2007 Nov;117(11):3563-75.
Peptide presentation is critical for immune recognition of pathogen-infected cells by CD8+ T lymphocytes. Although a limited number of immunodominant peptide epitopes are consistently observed in diseases such as HIV-1 infection, the relationship between immunodominance and antigen processing in humans is largely unknown. Here, we have demonstrated that endogenous processing and presentation of a human immunodominant HIV-1 epitope is more efficient than that of a subdominant epitope. Furthermore, we have shown that the regions flanking the immunodominant epitope constitute a portable motif that increases the production and antigenicity of otherwise subdominant epitopes. We used a novel in vitro degradation assay involving cytosolic extracts as well as endogenous intracellular processing assays to examine 2 well-characterized HIV-1 Gag overlapping epitopes presented by the same HLA class I allele, one of which is consistently immunodominant and the other subdominant in infected persons. The kinetics and products of degradation of HIV-1 Gag favored the production of peptides encompassing the immunodominant epitope and destruction of the subdominant one. Notably, cytosolic digestion experiments revealed flanking residues proximal to the immunodominant epitope that increased the production and antigenicity of otherwise subdominant epitopes. Furthermore, specific point mutations in these portable flanking sequences modulated the production and antigenicity of epitopes. Such portable epitope processing determinants provide what we believe is a novel approach to optimizing CTL responses elicited by vaccine vectors. [Abstract/Link to Full Text]

Muscoli C, Cuzzocrea S, Ndengele MM, Mollace V, Porreca F, Fabrizi F, Esposito E, Masini E, Matuschak GM, Salvemini D
Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice.
J Clin Invest. 2007 Nov;117(11):3530-9.
Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, often because chronic opiate therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing side effects. The mechanisms leading to tolerance are poorly understood. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice was consistently associated with the appearance of several tyrosine-nitrated proteins in the dorsal horn of the spinal cord, including the mitochondrial isoform of superoxide (O2-) dismutase, the glutamate transporter GLT-1, and the enzyme glutamine synthase. Furthermore, antinociceptive tolerance was associated with increased formation of several proinflammatory cytokines, oxidative DNA damage, and activation of the nuclear factor poly(ADP-ribose) polymerase. Inhibition of NO synthesis or removal of O2- blocked these biochemical changes and inhibited the development of tolerance, pointing to peroxynitrite (ONOO-), the product of the interaction between O2- and NO, as a signaling mediator in this setting. Indeed, coadministration of morphine with the ONOO- decomposition catalyst, Fe(III) 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin, blocked protein nitration, attenuated the observed biochemical changes, and prevented the development of tolerance in a dose-dependent manner. Collectively, these data suggest a causal role for ONOO- in pathways culminating in antinociceptive tolerance to opiates. Peroxynitrite (ONOO-) decomposition catalysts may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain. [Abstract/Link to Full Text]

Kelly J, Ali Khan A, Yin J, Ferguson TA, Apte RS
Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice.
J Clin Invest. 2007 Nov;117(11):3421-6.
Abnormal angiogenesis plays a key role in diseases of aging such as heart disease, certain cancers, and eye diseases including age-related macular degeneration. Macrophages have been shown previously to be both anti- and proangiogenic, and their role in regulating angiogenesis at sites of tissue injury is critical and complex. In this study, we analyzed cytokine gene expression patterns of mouse macrophages by real-time quantitative PCR and tested the functional effects of senescence on gene expression and macrophage polarization. Following laser injury to the retina, IL-10 was upregulated and Fas ligand (FasL), IL-12, and TNF-alpha were downregulated in ocular macrophages of old mice (>18 months of age). Downregulation of FasL on macrophages led to a loss of the antiangiogenic phenotype, as evidenced by the inability of these macrophages to inhibit vascular endothelial cells. Our results demonstrate that senescence, FasL, and IL-10 are key determinants of macrophage function that alter the growth of abnormal postdevelopmental blood vessels in disease processes including blinding eye disease. [Abstract/Link to Full Text]

Weinman EJ, Biswas RS, Peng Q, Shen L, Turner CL, E X, Steplock D, Shenolikar S, Cunningham R
Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium-hydrogen exchanger regulatory factor-1.
J Clin Invest. 2007 Nov;117(11):3412-20.
Parathyroid hormone (PTH), via activation of PKC and/or protein kinase A, inhibits renal proximal tubular phosphate reabsorption by facilitating the internalization of the major sodium-dependent phosphate transporter, Npt2a. Herein, we explore the hypothesis that the effect of PTH is mediated by phosphorylation of serine 77 (S77) of the first PDZ domain of the Npt2a-binding protein sodium-hydrogen exchanger regulatory factor-1 (NHERF-1). Using recombinant polypeptides representing PDZ I, S77 of NHERF-1 is phosphorylated by PKC but not PKA. When expressed in primate kidney epithelial cells (BSC-1 cells), however, activation of either protein kinase phosphorylates S77, suggesting that the phosphorylation of PDZ I by PKC and PKA proceeds by different biochemical pathways. PTH and other activators of PKC and PKA dissociate NHERF-1/Npt2a complexes, as assayed using quantitative coimmunoprecipitation, confocal microscopy, and sucrose density gradient ultracentrifugation in mice. Murine NHERF-1-/- renal proximal tubule cells infected with adenovirus-GFP-NHERF-1 containing an S77A mutation showed significantly increased phosphate transport compared with a phosphomimetic S77D mutation and were resistant to the inhibitory effect of PTH compared with cells infected with wild-type NHERF-1. These results indicate that PTH-mediated inhibition of renal phosphate transport involves phosphorylation of S77 of the NHERF-1 PDZ I domain and the dissociation of NHERF-1/Npt2a complexes. [Abstract/Link to Full Text]

Yang CL, Zhu X, Ellison DH
The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.
J Clin Invest. 2007 Nov;117(11):3403-11.
The pathogenesis of essential hypertension remains unknown, but thiazide diuretics are frequently recommended as first-line treatment. Recently, familial hyperkalemic hypertension (FHHt) was shown to result from activation of the thiazide-sensitive Na-Cl cotransporter (NCC) by mutations in WNK4, although the mechanism for this effect remains unknown. WNK kinases are unique members of the human kinome, intimately involved in maintaining electrolyte balance across cell membranes and epithelia. Previous work showed that WNK1, WNK4, and a kidney-specific isoform of WNK1 interact to regulate NCC activity, suggesting that WNK kinases form a signaling complex. Here, we report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes, further supporting the WNK signaling complex hypothesis. We demonstrate that physiological regulation of NCC in oocytes results from antagonism between WNK3 and WNK4 and that FHHt-causing WNK4 mutations exert a dominant-negative effect on wild-type (WT) WNK4 to mimic a state of WNK3 excess. The results provide a mechanistic explanation for the divergent effects of WT and FHHt-mutant WNK4 on NCC activity, and for the dominant nature of FHHt in humans and genetically modified mice. [Abstract/Link to Full Text]

Aberg KM, Radek KA, Choi EH, Kim DK, Demerjian M, Hupe M, Kerbleski J, Gallo RL, Ganz T, Mauro T, Feingold KR, Elias PM
Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice.
J Clin Invest. 2007 Nov;117(11):3339-49.
The skin is the first line of defense against microbial infection, and psychological stress (PS) has been shown to have adverse effects on cutaneous barrier function. Here we show that PS increased the severity of group A Streptococcus pyogenes (GAS) cutaneous skin infection in mice; this was accompanied by increased production of endogenous glucocorticoids (GCs), which inhibited epidermal lipid synthesis and decreased lamellar body (LB) secretion. LBs encapsulate antimicrobial peptides (AMPs), and PS or systemic or topical GC administration downregulated epidermal expression of murine AMPs cathelin-related AMP and beta-defensin 3. Pharmacological blockade of the stress hormone corticotrophin-releasing factor or of peripheral GC action, as well as topical administration of physiologic lipids, normalized epidermal AMP levels and delivery to LBs and decreased the severity of GAS infection during PS. Our results show that PS decreases the levels of 2 key AMPs in the epidermis and their delivery into LBs and that this is attributable to increased endogenous GC production. These data suggest that GC blockade and/or topical lipid administration could normalize cutaneous antimicrobial defense during PS or GC increase. We believe this to be the first mechanistic link between PS and increased susceptibility to infection by microbial pathogens. [Abstract/Link to Full Text]

Zaini J, Andarini S, Tahara M, Saijo Y, Ishii N, Kawakami K, Taniguchi M, Sugamura K, Nukiwa T, Kikuchi T
OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice.
J Clin Invest. 2007 Nov;117(11):3330-8.
The exceptional immunostimulatory capacity of DCs makes them potential targets for investigation of cancer immunotherapeutics. We show here in mice that TNF-alpha-stimulated DC maturation was accompanied by increased expression of OX40 ligand (OX40L), the lack of which resulted in an inability of mature DCs to generate cellular antitumor immunity. Furthermore, intratumoral administration of DCs modified to express OX40L suppressed tumor growth through the generation of tumor-specific cytolytic T cell responses, which were mediated by CD4+ T cells and NKT cells. In the tumors treated with OX40L-expressing DCs, the NKT cell population significantly increased and exhibited a substantial level of IFN-gamma production essential for antitumor immunity. Additional studies evaluating NKT cell activation status, in terms of IFN-gamma production and CD69 expression, indicated that NKT cell activation by DCs presenting alpha-galactosylceramide in the context of CD1d was potentiated by OX40 expression on NKT cells. These results show a critical role for OX40L on DCs, via binding to OX40 on NKT cells and CD4+ T cells, in the induction of antitumor immunity in tumor-bearing mice. [Abstract/Link to Full Text]

Heineke J, Auger-Messier M, Xu J, Oka T, Sargent MA, York A, Klevitsky R, Vaikunth S, Duncan SA, Aronow BJ, Robbins J, Cromblehol TM, Molkentin JD
Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart.
J Clin Invest. 2007 Nov;117(11):3198-210.
The transcription factor GATA4 is a critical regulator of cardiac gene expression, modulating cardiomyocyte differentiation and adaptive responses of the adult heart. We report what we believe to be a novel function for GATA4 in murine cardiomyocytes as a nodal regulator of cardiac angiogenesis. Conditional overexpression of GATA4 within adult cardiomyocytes increased myocardial capillary and small conducting vessel densities and increased coronary flow reserve and perfusion-dependent cardiac contractility. Coculture of HUVECs with either GATA4-expressing cardiomyocytes or with myocytes expressing a dominant-negative form of GATA4 enhanced or reduced HUVEC tube formation, respectively. Expression of GATA4 in skeletal muscle by adenoviral gene transfer enhanced capillary densities and hindlimb perfusion following femoral artery ablation. Deletion of Gata4 specifically from cardiomyocytes reduced myocardial capillary density and prevented pressure overload-augmented angiogenesis in vivo. GATA4 induced the angiogenic factor VEGF-A, directly binding the Vegf-A promoter and enhancing transcription. GATA4-overexpressing mice showed increased levels of cardiac VEGF-A, while Gata4-deleted mice demonstrated decreased VEGF-A levels. The induction of HUVEC tube formation in GATA4-overexpressing cocultured myocytes was blocked with a VEGF receptor antagonist. Pressure overload-induced dysfunction in Gata4-deleted hearts was partially rescued by adenoviral gene delivery of VEGF and angiopoietin-1. To our knowledge, these results demonstrate what is to our knowledge a previously unrecognized function for GATA4 as a regulator of cardiac angiogenesis through a nonhypoxic, load, and/or disease-responsive mechanism. [Abstract/Link to Full Text]

Tirziu D, Chorianopoulos E, Moodie KL, Palac RT, Zhuang ZW, Tjwa M, Roncal C, Eriksson U, Fu Q, Elfenbein A, Hall AE, Carmeliet P, Moons L, Simons M
Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice.
J Clin Invest. 2007 Nov;117(11):3188-97.
Although studies have suggested a role for angiogenesis in determining heart size during conditions demanding enhanced cardiac performance, the role of EC mass in determining the normal organ size is poorly understood. To explore the relationship between cardiac vasculature and normal heart size, we generated a transgenic mouse with a regulatable expression of the secreted angiogenic growth factor PR39 in cardiomyocytes. A significant change in adult mouse EC mass was apparent by 3 weeks following PR39 induction. Heart weight; cardiomyocyte size; vascular density normalization; upregulation of hypertrophy markers including atrial natriuretic factor, beta-MHC, and GATA4; and activation of the Akt and MAP kinase pathways were observed at 6 weeks post-induction. Treatment of PR39-induced mice with the eNOS inhibitor L-NAME in the last 3 weeks of a 6-week stimulation period resulted in a significant suppression of heart growth and a reduction in hypertrophic marker expression. Injection of PR39 or another angiogenic growth factor, VEGF-B, into murine hearts during myocardial infarction led to induction of myocardial hypertrophy and restoration of myocardial function. Thus stimulation of vascular growth in normal adult mouse hearts leads to an increase in cardiac mass. [Abstract/Link to Full Text]

Pasternak GW
When it comes to opiates, just say NO.
J Clin Invest. 2007 Nov;117(11):3185-7.
Repeated use of opiate analgesic drugs such as morphine for the relief of chronic pain may result in the development of opiate tolerance and dependence, leading to a narrowing of the drug's therapeutic index and increased side effects. Previous preclinical work has shown that interruption of a signaling cascade involving the N-methyl-D-aspartate receptor and NO prevents morphine tolerance. In this issue of the JCI, Muscoli and colleagues extend our understanding of the role of NO in tolerance by demonstrating that, in mice, tolerance to chronic morphine administration is associated with NO conversion to peroxynitrite, which accumulates and nitrates tyrosine moieties within various proteins in the spinal cord (see the related article beginning on page 3530). This and other data suggest that peroxynitrite plays a role in opiate tolerance and that regulation of peroxynitrite may be utilized for the management of opiate-induced tolerance. [Abstract/Link to Full Text]

Jager MJ, Klaver CC
Macrophages feel their age in macular degeneration.
J Clin Invest. 2007 Nov;117(11):3182-4.
Macular degeneration, during which the posterior part of the eye known as the macula suffers from thinning, atrophy, and bleeding caused by abnormal angiogenesis (blood vessel formation), predominantly affects elderly adults and results in the loss of central vision. In this issue of the JCI, Kelly et al. investigate the regulation of innate immune cells, specifically macrophages, in ocular neovascularization following eye injury in mice (see the related article beginning on page 3421). They found that, as the mice aged, increased expression of IL-10 by senescent macrophages and changes in their expression of other cytokines altered the ability of these cells to restrain trauma-induced angiogenesis in the eye. These data provide insight into the effect of senescence on macrophage function and angiogenesis and have important implications for age-related diseases such as macular degeneration. [Abstract/Link to Full Text]

Hernando N, Wagner C, Biber J, Murer H
Kidney kinase network regulates renal ion cotransport.
J Clin Invest. 2007 Nov;117(11):3179-82.
Protein kinases catalyze the phosphorylation of serine/threonine or tyrosine residues, which may directly alter a protein's functional properties. Kinases can also regulate protein functions indirectly, for example, by controlling the composition and/or subcellular localization of members of multiprotein complexes that associate with the regulated protein. In this issue of the JCI, two separate studies by Weinman et al. and Yang et al. examine the second of these two modes of kinase-mediated regulation and demonstrate the effects of kinases on two Na(+)-driven renal cotransporters (see the related articles beginning on pages 3403 and 3412). Their results reveal important implications for phosphate and salt homeostasis, respectively. [Abstract/Link to Full Text]

Walsh K, Shiojima I
Cardiac growth and angiogenesis coordinated by intertissue interactions.
J Clin Invest. 2007 Nov;117(11):3176-9.
Cardiac hypertrophy and angiogenesis are coordinately regulated during physiological or adaptive cardiac growth, and disruption of the balanced growth and angiogenesis leads to contractile dysfunction and heart failure. Coordination of growth and angiogenesis is in part mediated by the secretion of angiogenic growth factors from myocytes in response to hypertrophic stimuli, which enables the vasculature to "catch up" to the growth of the myocardium. In this issue of the JCI, two studies provide novel insights into the regulatory mechanisms of cardiac growth and coronary angiogenesis. Heineke et al. demonstrate that GATA4 acts as a stress-responsive transcription factor in murine cardiac myocytes that induces the expression of angiogenic growth factors (see the related article beginning on page 3198). Tirziu et al. show that enhanced coronary angiogenesis per se leads to hypertrophic growth of myocytes through a nitric oxide-dependent mechanism (see the related article beginning on page 3188). These studies, together with previous reports, suggest the existence of reciprocal signals between the myocardium and the vasculature that promote the growth of each other in a paracrine fashion. [Abstract/Link to Full Text]

Thummel KE
Gut instincts: CYP3A4 and intestinal drug metabolism.
J Clin Invest. 2007 Nov;117(11):3173-6.
First-pass metabolism is a common cause of incomplete and variable absolute bioavailability for an orally dosed drug. The drug-metabolizing enzyme CYP3A4 is often implicated in this process, resulting, in some cases, in systemic exposures of less than 15% of the administered dose. By creating an elegant CYP3A4-transgenic mouse model, van Herwaarden et al. show in this issue of the JCI that first-pass metabolism of the anticancer agent docetaxel by the gut wall, and not the liver, is likely to be the major cause of its low oral bioavailability in humans (see the related article beginning on page 3583). This study helps explain interpatient differences in efficacy and safety following oral therapy with approved CYP3A4 substrates and provides a powerful new tool for preclinical predictions of first-pass metabolism for new drugs in development. [Abstract/Link to Full Text]

Zhou D
OX40 signaling directly triggers the antitumor effects of NKT cells.
J Clin Invest. 2007 Nov;117(11):3169-72.
Pathways involving the costimulatory molecule OX40 and OX40 ligand (OX40L) enhance tumor rejection. It was presumed that this effect was mediated by changes in DCs and/or T cells. In this issue of the JCI, Zaini et al. report that, in mice, intratumoral injection of DCs genetically modified to express OX40L suppressed the growth of a preexisting melanoma by directly triggering an antitumor NKT cell response (see the related article beginning on page 3330). This work suggests that the intratumoral NKT cell population may be harnessed for cancer immunotherapy and that OX40 costimulation may be used as a unique trigger of the antitumor activity of these cells. [Abstract/Link to Full Text]

Slominski A
A nervous breakdown in the skin: stress and the epidermal barrier.
J Clin Invest. 2007 Nov;117(11):3166-9.
In this issue of the JCI, Aberg and colleagues report that psychological stress disrupts the skin's antimicrobial barrier and increases the severity of cutaneous infections (see the related article beginning on page 3339). This effect is mediated by endogenous glucocorticoids produced secondarily to stress-related activation of the hypothalamic-pituitary-adrenal axis. Thus, this study provides what I believe to be the first mechanistic link between psychological stress and increased susceptibility to microbial infection. [Abstract/Link to Full Text]

Teyton L
The saga of MHC-bound peptides: a renaissance for antigen presentation?
J Clin Invest. 2007 Nov;117(11):3164-6.
In this issue of the JCI, two separate studies on MHC-bound peptides reopen the debate on the utility of peptides for the purposes of vaccination and treatment of autoimmune diseases. In the first study, by Wahlstr�m et al., peptides bound to HLA-DR17 from bronchoalveolar lavage cells of sarcoidosis patients were analyzed in order to identify target antigens of the autoimmune response (see the related article beginning on page 3576). In the second study, by Le Gall et al., the modulation of epitope immunodominance and the processing and presentation of HIV peptides for MHC class I recognition were shown to be dependent on flanking residues that were N terminal to the natural epitopes (see the related article beginning on page 3563). Both studies highlight the tremendous therapeutic potential of MHC-bound peptides. They also emphasize that technical issues are still plaguing this field and hindering our understanding of MHC presentation in vivo. [Abstract/Link to Full Text]

Polyak K
Breast cancer: origins and evolution.
J Clin Invest. 2007 Nov;117(11):3155-63.
Breast cancer is not a single disease, but rather is composed of distinct subtypes associated with different clinical outcomes. Understanding this heterogeneity is key for the development of targeted cancer-preventative and -therapeutic interventions. Current models explaining inter- and intratumoral diversity are the cancer stem cell and the clonal evolution hypotheses. Although tumor initiation and progression are predominantly driven by acquired genetic alterations, recent data implicate a role for microenvironmental and epigenetic changes as well. Comprehensive unbiased studies of tumors and patient populations have significantly advanced our molecular understanding of breast cancer, but translating these findings into clinical practice remains a challenge. [Abstract/Link to Full Text]

Silvestri G, Paiardini M, Pandrea I, Lederman MM, Sodora DL
Understanding the benign nature of SIV infection in natural hosts.
J Clin Invest. 2007 Nov;117(11):3148-54.
In striking contrast to HIV infection, natural SIV infection of African nonhuman primates is asymptomatic and usually does not induce significant CD4+ T cell depletion despite high levels of virus replication. Recently, significant progress has been made in understanding the mechanisms underlying the remarkable difference in infection outcome between natural and nonnatural HIV/SIV hosts. These advances include the identification of limited immune activation as a key factor protecting natural SIV hosts from AIDS and the discovery of low CC chemokine receptor 5 expression on CD4+ T cells as a specific and consistent immunologic feature in these animals. Further elucidation of the pathways by which the differences in immune activation between natural and nonnatural hosts are manifest holds promise for the design of novel therapeutic approaches to HIV infection. [Abstract/Link to Full Text]

Honey K
Making the move from academia to industry: how has Luciano Rossetti fared?
J Clin Invest. 2007 Nov;117(11):3145. [Abstract/Link to Full Text]

Turka LA
A method to our madness.
J Clin Invest. 2007 Nov;117(11):3144.
Until recently, journal editorial operations and decisions seemed impenetrable to me. Now I have a view from the inside out. [Abstract/Link to Full Text]

Recent Articles in Medical Science Monitor : International Medical Journal of Experimental and Clinical Research

Tsalis K
Septic shock; current pathogenetic concepts from a clinical perspective. Adelais G. Tsiotou, George H. Sakorafas, George Anagnostopoulos, John Bramis Med Sci Monit, 2005; 11(3): RA76-85.
Med Sci Monit. 2006 Aug;12(8):LE15-6. [Abstract/Link to Full Text]

Tsiotou AG, Sakorafas GH, Anagnostopoulos G, Bramis J
Septic shock; current pathogenetic concepts from a clinical perspective.
Med Sci Monit. 2005 Mar;11(3):RA76-85.
Sepsis is an infection-induced syndrome characterized by a generalized inflammatory state and represents a frequent complication in the surgical patient. The normal reaction to infection involves a series of complex immunologic processes. A potent, complex immunologic cascade ensures a prompt protective response to microbial invasion in humans. Although activation of the immune system during microbial invasion is generally protective, septic shock develops in a number of patients as a consequence of excessive or poorly regulated immune response to the offending organism (Gram-negative or Gram-positive bacteria, fungi, viruses, or microbial toxins). This unbalanced reaction may harm the host through a maladaptive release of endogenously generated inflammatory compounds. Many mechanisms are involved in the pathogenesis of septic shock, including the release of cytokines, the activation of neutrophils, monocytes, and microvascular endothelial cells, as well as the activation of neuroendocrine reflexes and plasma protein cascade systems, such as the complement system, the intrinsic (contact system) and extrinsic pathways of coagulation, and the fibrinolytic system. In critically ill patients, the gastrointestinal tract plays a central role in the pathogenesis of septic shock. The potential for complementary and synergistic interaction of the different components in this cascade highlights the difficulty encountered in trying to identify a single means of altering the progression of sepsis and septic shock to multiple organ dysfunction syndrome (MODS) and multiple organ failure (MOF). [Abstract/Link to Full Text]

Lovisi GM
Post-traumatic stress disorder in Polish stroke patients who survived Nazi concentration camps.
Med Sci Monit. 2006 Aug;12(8):LE15. [Abstract/Link to Full Text]

Pachalska M, Grochmal-Bach B, MacQueen BD, Fra?czuk B
Post-traumatic stress disorder in Polish stroke patients who survived Nazi concentration camps.
Med Sci Monit. 2006 Apr;12(4):CR137-49.
BACKGROUND: Many persons who survived Nazi concentration camps are now in advanced age, so that rehabilitation centers in Poland are seeing increasing numbers of such patients, especially after strokes. In many cases, the process of rehabilitation is severely hampered by Post-Traumatic Stress Disorder (PTSD), while the neuropsychological consequences of the stroke itself often evoke traumatic memories and simultaneously disorganize or destroy the patient's previous coping mechanisms. The present study describes the program developed by the authors for concentration camp survivors in post-stroke rehabilitation, including the use of art therapy and specially prepared films to help the patients cope with PTSD. MATERIAL/METHODS: The experimental group (KL) consisted of 8 such patients (4 men, 4 women, average age 79.1+/-4.28) with mild post-stroke aphasia who went through the PTSD program, while the comparison group (C) included 8 post-stroke patients, matched for age and gender, who were not concentration camp survivors and showed no premorbid symptoms of PTSD. All subjects were tested at baseline and again 3 months later, using structured interview and observation, self-rating scales for three basic negative emotions (anger, anxiety and sadness) and the Frustration and Aggression Test for the Disabled. RESULTS: The results showed significant differences between the groups at baseline, while at follow-up the differences between groups had changed in both extent and distribution. CONCLUSIONS: Qualitative analysis of the results allows for some important observations about the etiology and course of PTSD in these persons. [Abstract/Link to Full Text]

Ford GP, Reardon DC
Prolonged unintended brain cooling may inhibit recovery from brain injuries: case study and literature review.
Med Sci Monit. 2006 Aug;12(8):CS74-9.
BACKGROUND: Tracheal intubation of comatose patients is common, but contrary to most standards for respiratory care, heated nebulizers are not always used. This deviation from recommendations appears to be widespread. CASE REPORT: In the case examined, a tracheotomized patient suffering from severe anoxic brain injury was unintentionally exposed to chilled air, 17 degrees C (63 degrees F) at the cannula, for a period of 31 months. A month after upper respiratory tract warming was restored the vegetative state lifted, as marked by the patient's ability to verbalize responses to questions. CONCLUSIONS: This clinical experience led us to a review of the literature. Among other findings, we learned that brain temperature is strongly affected by the temperature of arterial blood flow. Arterial blood, in turn, is strongly affected by the air temperature in the lungs. Experiments have shown that the introduction of colder air in the lungs will produce rapid cooling of at least some surface brain tissues. Chilled aortic blood is also more viscous and less efficient in transfer of oxygen. Hypothermia of brain tissue may significantly affect the endocrine system and neurochemistry. Through inferences from the literature, we also identify other possible effects. We hypothesize that intubated delivery of air into the lungs at a temperature significantly below body temperature, especially over a prolonged period, is likely to inhibit recovery and may even produce iatrogenic effects. We recommend the use of heated nebulizers. Research strategies are recommended. [Abstract/Link to Full Text]

Woszczyk D, Ko?odziej-Jasku?a A, Myka?a-Cie?la J, Bal A, ?abuzek K, Gasi?ska T
Focal lesions in the ultrasonographic examination of the spleen as a symptom of various disease statuses: literature survey and case descriptions.
Med Sci Monit. 2006 Aug;12(8):CS67-73.
BACKGROUND: Ultrasonography (US) is an easy and non-invasive technique of visualizing spleen. Thanks to its repeatability, it plays an important role in the diagnostics of, among others, developmental anomalies, such as supernumerary or lobated spleens, as well as focal lesions. It is also used in monitoring the size of the spleen and it considerably facilitates diagnosis after certain injuries. Thanks to the application of the Doppler method, it also facilitates the diagnostics of pathologies within the spleen's vessels. CASE REPORT: This paper presents six different cases of focal lesions in the spleen, including lesions in the course of histiocytosis, in the course of sarcoidosis, as well as isolated abscesses of the spleen. The authors also present the case of a spleen with numerous metastatic lesions, the case of a near-splenic cyst, and the case of asymptomatic focal lesions of unknown origin. In all the presented cases, the lesions were accidentally revealed during ultrasonographic examination, which was the starting point for further diagnostics. CONCLUSIONS: Though rare, morphologic lesions in the spleen should always be taken into consideration when performing a routine ultrasonographic examination of the abdominal cavity, and the organ itself should not be ignored. US is a widely available, noninvasive, and useful method for diagnosing splenic abnormalities, including focal changes. [Abstract/Link to Full Text]

Krecicki T, Liebhart J, Morawska-Kochman M, Liebhart E, Zato?ski M, Zalesska-Krecicka M
Corticosteroid-induced laryngeal disorders in asthma.
Med Sci Monit. 2006 Aug;12(8):CR351-4.
BACKGROUND: Inhaled corticosteroids have proven to be the most effective agent available in treating bronchial asthma, and such treatment is believed to be very safe. Concerns regarding side effects of inhaled corticosteroids usually focus on potential systemic effects, where local side effects are often overlooked. The purpose of this study was to analyze and assess the influence of inhaled corticosteroids on the vocal cords of patients treated for bronchial asthma. MATERIAL/METHODS: Fifty patients (mean age: 50 years, range: 22 to 83 years) suffering from asthma and receiving corticosteroidal inhaled agents entered in this study. All of the patients underwent detailed videoscopic examination of the larynx. None complained of any laryngeal disorders or dysfunction before the diagnosis of asthma. All of the patients were non-smokers. RESULTS: Significant changes in the laryngeal status were observed. Changes included atrophy of laryngeal mucosa, vocal fold atrophy, and vocal fold bowing. CONCLUSIONS: Damage to the larynx is an important factor in patients with asthma treated with inhaled corticosteroids, which elicit apoptosis of the epithelium. [Abstract/Link to Full Text]

Vecchioli-Scaldazza C, Morosetti C
Urodynamic findings in female patients with urinary incontinence with intrinsic sphincteric deficiency.
Med Sci Monit. 2006 Aug;12(8):CR345-50.
BACKGROUND: The aim of the study was to evaluate differences in urodynamic findings in women with urinary incontinence between subjects with or without intrinsic sphincter deficiency (ISD). MATERIAL/METHODS: Sixty consecutive female patients with a history and urodynamically confirmed diagnosis of pure urinary incontinence were evaluated. Patients were divided into two groups according to their abdominal Valsalva leak-point pressure (AVLPP) values using a cutoff of 60 cm H(2)O: group A patients with AVLPP </=60 cm H(2)O and group B patients with AVLPP >60 cm H(2)O. RESULTS: Qmax and Qave in group A were higher than in group B; flow time was significantly shorter in group A than in group B. PVR in group A was lower than in group B. In pressure flow study, all detrusor findings in group A had a pressure value lower than in group B. MUCP in patients with AVLPP </=60 cm H(2)O was significantly lower than in group B, but the degrees of specificity and sensitivity in group A and B were 90% and 43.3%, respectively. CONCLUSIONS: The results of this study confirm a more efficient bladder emptying in patients with AVLPP </=60 cm H(2)O. [Abstract/Link to Full Text]

Falagas ME, Bliziotis IA, Soteriades ES
A prospective study of services utilization of a hospital-based employee health clinic.
Med Sci Monit. 2006 Aug;12(8):CR341-4.
BACKGROUND: Little is known regarding the utilization of services of a hospital-based employee health clinic (EHC). MATERIAL/METHODS: We evaluated the utilization of services of the EHC of a tertiary hospital in Greece. Demographic and clinical data were prospectively collected and analyzed for all employees who visited the EHC during a 24-month period (01/06/2003-31/05/2005). RESULTS: A total of 939 primary and 55 follow-up visits were recorded. Of all 994 visits, 419 were made by nurses (42%), 270 by administrative staff (27%), and only 15 visits by physicians (1%). Only 5.6% of physicians used the EHC during the study period (14 out of 252 doctors) whereas 35.4% of the nurses (218 out of 615) visited the EHC at least once (p<0.001). Three hundred and one of the rest 544 employees (55.3%) visited the EHC, significantly more than physicians (p < 0.001) and nurses (p<0.001). The majority of employees who visited the clinic were females (78%), while the most common reason for consultation was periodic evaluation accounting for 108 visits (11%), followed by abdominal pain (99 visits, 10%), dizziness (48 visits, 5%), and respiratory tract infections (44 visits, 5%). A significant reduction in the number of visits was observed after the 9(th) month of the study, coinciding with a change in the worker's health insurance policy (p<0.001). CONCLUSIONS: Periodic evaluations, abdominal pain, dizziness, respiratory tract infections, and weakness/malaise cover the bulk of consultation visits of a hospital-based EHC. Physicians were the group of employees that visited the EHC less often. [Abstract/Link to Full Text]

Alexopoulos EC
Occupational health services in Greek hospitals.
Med Sci Monit. 2006 Oct;12(10):LE20-1. [Abstract/Link to Full Text]

Olszewska E, Chodynicki S, Chyczewski L, Rogowski M
Some markers of proliferative activity in cholesteatoma epithelium in adults.
Med Sci Monit. 2006 Aug;12(8):CR337-40.
BACKGROUND: The aim of this study was to determine the proliferative capacity in certain layers of the cholesteatoma epithelium and normal skin. MATERIAL/METHODS: Cholesteatoma and skin were obtained during ear surgical procedures. The number of PCNA- and Ki-67-positive cells were counted within each of three microscopic fields at a magnification of x400. Fourteen normal skin specimens collected from the retroauricular area were used as controls. RESULTS: The skin specimens were found to have a lower proliferative capacity than the cholesteatoma epithelium. This activity was mainly observed in the cell nuclei of the basal layer of the epidermis. The percentage of PCNA-positive cells was 23% in the epidermis and 45.7% in the cholesteatoma epithelium. Immunohistochemical investigation of the epidermis revealed 7% Ki-67-positive cells, mainly located in the basal layer of the epidermis. The presence of Ki-67 antigen in the cell nuclei was determined in the parabasal layer of the cholesteatoma epithelium and stroma. Ki-67-positive cells made up 22% of the cholesteatoma epithelium, compared with 7% in the skin. CONCLUSIONS: Proliferative activity is mainly observed in the basal and suprabasal layers of the cholesteatoma epithelium. The proliferative capacity of the cholesteatoma epithelium is different in the various areas of the epithelium and does not depend on its thickness. [Abstract/Link to Full Text]

Vilar-Compte D, Cornejo P, Valle-Salinas A, Rold�n-Marin R, Iguala M, Cervantes Y, L�pez I
Influenza vaccination in patients with breast cancer: a case-series analysis.
Med Sci Monit. 2006 Aug;12(8):CR332-6.
BACKGROUND: Our aim was to evaluate the serological response and safety of influenza vaccine in patients with breast cancer in Mexico. MATERIAL/METHODS: Between October and December 2001, patients with breast cancer were vaccinated with a split virus vaccine. Hemagglutination inhibition assay titers were measured before vaccination and 4-6 weeks later. Titer ratios were used as the primary measure of response. When comparing rate of response according to treatment, stage, or other patient-related variables, individuals with post vaccination titers >/=1:40 for all 3 antigen strains were called respondents. RESULTS: We analyzed 146 patients who were vaccinated and had influenza antibodies measured before and after vaccination. Seventy-two (49.3%) had locally advanced breast cancer, 117 (80.1%) were receiving cancer treatment, 91 (62.3%) were on chemotherapy. Response to vaccine was 47.2%; we found an additional 25.3% of patients who responded to two of the serotypes. In patients receiving chemotherapy the response rate was lower (p=NS). CONCLUSIONS: The results of the present study show that influenza vaccine is safe and well tolerated in patients with breast cancer, but we observed a lessening of the immune response among patients receiving chemotherapy. Influenza vaccination should be recommended in all patients with breast cancer, regardless of the anti-neoplastic treatment. [Abstract/Link to Full Text]

Khalsa SB, Cope S
Effects of a yoga lifestyle intervention on performance-related characteristics of musicians: a preliminary study.
Med Sci Monit. 2006 Aug;12(8):CR325-31.
BACKGROUND: Previous research has suggested that yoga and meditation practices are effective in stress management, alleviating anxiety and musculoskeletal problems and improving mood and cognitive and physical performance. Musicians experience a number of challenges in their profession including high levels of stress, performance anxiety and performance-related musculoskeletal conditions. Yoga and meditation techniques are therefore potentially useful practices for professional musicians. MATERIAL/METHODS: Musicians enrolled in a prestigious 2-month summer fellowship program were invited to participate in a regular yoga and meditation program at a yoga center during the course of the program. The 10 participants in the yoga program completed baseline and end-program questionnaires evaluating performance-related musculoskeletal conditions, performance anxiety, mood and flow experience. Fellows not participating in the yoga program were recruited to serve as controls and completed the same assessments (N=8). RESULTS: The yoga participants showed some improvements relative to control subjects on most measures, with the relative improvement in performance anxiety being the greatest. CONCLUSIONS: The results from this preliminary study suggest that yoga and meditation may be beneficial as a routine practice to reduce performance anxiety in musicians. [Abstract/Link to Full Text]

Windisch G, Tesch NP, Grechenig W, Peicha G
The triceps brachii muscle and its insertion on the olecranon.
Med Sci Monit. 2006 Aug;12(8):BR290-4.
BACKGROUND: The purpose of this anatomical study was to define the insertion of the tendon of the triceps brachii muscle and the course of the lateral cubital retinaculum (LCR) as an enhancement of the triceps tendon. MATERIAL/METHODS: One hundred cadaver specimens were assessed and the widths of the triceps tendon and the olecranon and the expansion of the LCR were determined. RESULTS: The width of the tendon ranged between 1.9 and 4.2 cm (mean: 2.81) and the width of the olecranon between 1.8-3.8 cm (mean: 2.5). In 65 of the 100 specimens, the width of the tendon was greater than that of the olecranon. The fibers on the medial side inserted exactly on the medial aspect of the olecranon, whereas on the lateral aspect the fibers left the olecranon to reach the posterior border of the ulna. In 28 specimens the olecranon was wider than the tendon of the triceps, and in seven extremities the tendon occupied exactly the whole area of the olecranon. The LCR measured 2.3-7.2 cm (mean: 4.04 cm). CONCLUSIONS: By preserving parts of the triceps tendon on the olecranon and preserving the lateral cubital retinaculum, the extension strength will be maximized, allowing early active elbow motion. Using the triceps brachii muscle for any approach, only the medial aspect might be used as a guideline to reach the olecranon. On the lateral side the fibers of the triceps tendon fan out as the LCR to join into the ulna and the antebrachial fascia. [Abstract/Link to Full Text]

Hasan N, Ali I, Naseem I
Photodynamic inactivation of trypsin by the aminophylline-riboflavin system: involvement of hydroxyl radical.
Med Sci Monit. 2006 Aug;12(8):BR283-9.
BACKGROUND: Riboflavin finds ubiquitous occurrence in plants and animals and functions as a coenzyme participating in various oxidation-reduction reactions during the course of metabolism. Photosensitized riboflavin generates reactive oxygen species (ROS). Aminophylline is an antiasthmatic drug and a known phosphodiesterase inhibitor. In this study we examined the effect of photoilluminated riboflavin on aminophylline using trypsin as the target molecule. MATERIAL/METHODS: The possible loss of trypsin activity due to autolysis was assayed after incubation in fluorescent light. Changes in trypsin activity caused by photoilluminated riboflavin alone and with aminophylline were monitored as functions of concentration and time. These effects were also analyzed by SDS-PAGE to visualize protein degradation. Spectra of riboflavin, alone and with aminophylline, under different conditions were taken to monitor the structural changes for elucidating the possible reaction mechanism involved. Free radical scavengers were also included in some experiments. RESULTS: Aminophylline alone is not known to posses any photosensitizing characteristics. However, in the presence of riboflavin and fluorescent light, aminophylline caused inactivation and fragmentation of trypsin. This fragmentation was found to be concentration dependent and was mediated by ROS. In all cases, thiourea, a scavenger of hydroxyl radicals, was most effective in scavenging the damaging effect of the riboflavin-aminophylline combination. CONCLUSIONS: Based on our results we suggest that photoilluminated riboflavin generates the singlet and triplet excited states that, upon energy transfer, generate (1)O(2). and (3)O(2). oxygen. These activated oxygen species probably attack aminophylline leading to its oxidation, generating hydroxyl radicals which presumably cause inactivation and fragmentation of trypsin. [Abstract/Link to Full Text]

Tyagi MG, Goyal S, Sathyakumar K, Subbana PK
Influence of erythrocyte function-enhancing drugs on the bronchoprotective actions of chemokine receptor blockers in mice.
Med Sci Monit. 2006 Aug;12(8):BR279-82.
BACKGROUND: CC chemokine receptors are likely to have important roles in the regulation of leukocytes and mast cells. Chemokine receptors are crucial in orchestrating innate and acquired immune responses as well as in allergic inflammation. A disturbance in erythrocyte function can lead to bronchial hyperreactivity and asthma. MATERIAL/METHODS: This study was conducted on Swiss albino mice weighing between 25 to 35 g. The animals were divided into eight groups (n=8). Groups of mice (n=8) were pretreated with the chemokine receptor blockers A122058 (600 microg/kg i.p.) or cyclophosphamide (20 mg/kg i.p.). Other groups received A122058 or cyclophosphamide in combination with either erythropoietin and quercetin. The effects of these drugs on bronchoconstriction and salivation induced by carbachol were evaluated. RESULTS: The results of this study suggest that blockade of chemokine receptors significantly potentiated erythropoietin- and quercetin-induced inhibition of carbachol-induced bronchoconstriction (P<0.05) compared with the control group. However, pentoxifylline did not produce significant bronchoprotection against carbachol-induced bronchoconstriction (P>0.05). CONCLUSIONS: The results of this study suggest that blockade of chemokine receptors and enhancement of the erythrocyte function together potentiate the bronchoprotective effects of these drugs. This combination could be a novel strategy in combating bronchial hyper-responsiveness. [Abstract/Link to Full Text]

Cetinkaya A, Bulbuloglu E, Kurutas EB, Kantarceken B
N-acetylcysteine ameliorates methotrexate-induced oxidative liver damage in rats.
Med Sci Monit. 2006 Aug;12(8):BR274-8.
BACKGROUND: Methotrexate (MTX), a folic acid antagonist, is widely used as a cytotoxic chemotherapeutic agent for malignancies as well as in the treatment of various inflammatory diseases. The efficacy of this agent is often limited by severe side effects and toxic conditions. The present study was undertaken to determine whether N-acetylcysteine (NAC), as a potent antioxidant compound, could ameliorate MTX-induced oxidative liver damage. MATERIAL/METHODS: A single dose of MTX (20 mg/kg, intraperitoneal) to rats was followed by intraperitoneal saline or NAC administration (150 mg/kg, MTX + NAC group) for the next 5 days. On the fifth day the rats were sacrificed and liver tissue samples were obtained and stored to measure reduced glutathione (GSH) and malondialdehyde (MDA) levels and myeloperoxidase (MPO), superoxide dismutase (SOD), and catalase (CAT) activity. RESULTS: MTX caused decreased GSH level and SOD and CAT activity and increased MDA level and MPO activity in the liver homogenates. These changes were significantly reversed by NAC treatment. CONCLUSIONS: These results confirm that administration of NAC decreases MTX-induced oxidative damage to the liver. These data indicate that NAC may be of therapeutic use in preventing hepatotoxicity in patients receiving MTX treatment. [Abstract/Link to Full Text]

Jezierska A, Matysiak W, Motyl T
ALCAM/CD166 protects breast cancer cells against apoptosis and autophagy.
Med Sci Monit. 2006 Aug;12(8):BR263-73.
BACKGROUND: Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a 105-kDa transmembrane glycoprotein linked with cell migration and development and with cancer progression (malignant melanoma, prostate cancer and, very recently, breast cancer). This report is the first evaluation of ALCAM/CD166 in an estrogen-dependent (MCF-7) and a metastatic (MDA-MB-231) breast cancer cell line and a reference breast cell line (HBL-100). The effects of estrogen and anti-estrogen treatment, bcl-2 overexpression, and ALCAM gene silencing on ALCAM/CD166 protein concentration and cell survival were investigated. MATERIAL/METHODS: Laser scanning cytometry, confocal microscopy, and Western blotting were used for the determination of ALCAM/CD166 protein and biochemical markers of apoptosis and autophagy. RESULTS: 17-beta-estradiol increased and tamoxifen inhibited ALCAM/CD166 expression and survival of MCF-7 cells. Overexpression of the bcl2 gene in MCF-7 bcl2/neo, MDA-MB-231 bcl2/neo, and HBL-100 bcl2/neo cells significantly increased ALCAM/CD166 expression and was accompanied by decreasing MMP-2 concentrations. Appearance of the ALCAM/CD166 protein was noted in HBL-100 bcl2/neo in contrast to an almost undetectable level in HBL-100 cells. ALCAM gene silencing in MCF-7 cells decreased the concentration of BCL-2 and increased levels of apoptosis (89-kDa PARP, active caspase7) and autophagy (MAP1LC3, Beclin1) markers. CONCLUSIONS: The above results indicate that ALCAM-ALCAM interactions are crucial to the survival and primary site maintenance of breast cancer cells. Impaired expression of ALCAM/CD166 is associated with the induction of two types of programmed cell death, apoptosis and autophagy, in breast cancer cells. This adhesion molecule can therefore be regarded as a potential novel breast cancer indicator and therapeutic target. [Abstract/Link to Full Text]

Xu CS, Leung AW
Photodynamic effects of pyropheophorbide-a methyl ester in nasopharyngeal carcinoma cells.
Med Sci Monit. 2006 Aug;12(8):BR257-62.
BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common cancers, and exploring novel therapeutic modalities will improve the clinical outcomes. It has been confirmed that photodynamic therapy can efficiently deactivate malignant cells. The aim of the present study was to explore the photodynamic effects of pyropheophorbide-a methyl ester (MPPa) in CNE2 nasopharyngeal carcinoma cells. MATERIAL/METHODS: CNE2 cells were subjected to photodynamic therapy with MPPa, in which the drug concentration was 0.25 to 4 microM and light energy 1 to 8 J/cm(2). Photodynamic toxicity was investigated 24 h after treatment. Apoptosis was determined using flow cytometry with annexin V-FITC and propidum iodine staining and with nuclear staining with Hoechst 33258. The mitochondrial membrane potential (DeltaPsim) was evaluated by Rhodamine 123 assay. RESULTS: There was no dark cytotoxicity of MPPa in the CNE2 cells at doses of 0.25-4 microM, and MPPa resulted in dose- and light-dependent phototoxicity. The apoptotic rate 8 h after PDT with MPPa (2 microM) increased to 16.43% under a light energy of 2 J/cm(2). Mitochondrial membrane potential (DeltaPsim) collapsed when the CNE2 cells were exposed to 2 microM MPPa for 20 h and then 2 J/cm(2) irradiation. CONCLUSIONS: Photodynamic therapy with MPPa significantly enhanced apoptosis and the collapse of DeltaPsim. This can be developed for treating nasopharyngeal carcinoma. [Abstract/Link to Full Text]

Ustinaviciene R, Januskevicius V
Association between occupational asthenopia and psycho-physiological indicators of visual strain in workers using video display terminals.
Med Sci Monit. 2006 Jul;12(7):CR296-301.
BACKGROUND: There is a body of scientific literature examining functional changes in vision due to video display terminals (VDTs). The aim of our study was to determine the relationship of functional visual strain and symptoms of asthenopia and to evaluate the association between subjective and objective indicators of visual strain. MATERIAL/METHODS: Four hundred four office workers with and without involvement in VDT work were included in the study. To evaluate visual strain we used a questionnaire for subjective complaints, evaluated the main ophthalmologic indicators, and measured psycho-physiological indicators. RESULTS: The questionnaire data showed that 88.5% of the VDT workers complained of various vision disorders. VDT workers who complained of worsened vision, redness of the eyes, eye pain, and diplopia during work were found to show more significant changes in the psycho-physiological indicators objectively reflecting strain of the vision analyzer. In the group of people with symptoms of asthenopia, the differences in the indicators of visual sensomotoric reaction, constancy of clear vision, and changes in the periods of clear and unclear vision were statistically reliably greater than in people without symptoms of visual strain. CONCLUSIONS: The subjective perception of visual strain related to VDT work was confirmed by ophthalmologic and psycho-physiological measurements. Changes in ocular and psycho-physiological function before and at the end of the workday are a good objective index of visual and central nervous system strain. [Abstract/Link to Full Text]

Telles S, Naveen KV
Effect of yoga on somatic indicators of distress in professional computer users.
Med Sci Monit. 2006 Oct;12(10):LE21-2. [Abstract/Link to Full Text]

Tripathi BK, Srivastava AK
Diabetes mellitus: complications and therapeutics.
Med Sci Monit. 2006 Jul;12(7):RA130-47.
Diabetes mellitus has now assumed epidemic proportions in many countries of the world. With the present population of 19.4 million diabetics, and approximately 60 million by the year 2025, India would rank first in its share of the global burden of diabetes. Diabetes mellitus is characterized by derangement in carbohydrate, protein, and fat metabolism caused by complete or relative insufficiency of insulin secretion and/or insulin action. There are two main forms of diabetes, type 1 (insulin-dependent diabetes mellitus) and type 2 (non-insulin-dependent diabetes mellitus). Insulin sensitizers (thiazolidinediones), new-generation insulin secretagogue (glimepiride), acarbose, and designer insulin (lispro and aspart) have enormously helped in achieving better metabolic control. Despite the great strides that have been made in the understanding and management of type 2 diabetes, insulin resistance and diabetes-related complications are increasing unabated. The present review not only updates our knowledge in delineating the molecular mechanism(s) causal to insulin sensitivity or resistance, but also provides clues for the prognosis of diabetes and its better management. [Abstract/Link to Full Text]

Yang Z, Wu J
Small RNAs and development.
Med Sci Monit. 2006 Jul;12(7):RA125-9.
Small RNAs, including microRNAs (miRNAs), short interfering RNAs (siRNAs), and siRNA-like scan RNAs (scnRNAs), are known to be crucial for regulatory functions in diverse species, with special focus on their interference in the development of plants as well as of C. elegans, Drosophila, and other animals. The functions of small RNAs on the complex regulatory network of metazoan embryonic development are presented in this article. In addition, indirect evidence is summarized here for those miRNAs which are important regulators controlling the biological processes of germ-cell development. [Abstract/Link to Full Text]

Naoum JJ, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C
Lymphotoxin-alpha and cardiovascular disease: clinical association and pathogenic mechanisms.
Med Sci Monit. 2006 Jul;12(7):RA121-4.
Inflammation plays an important role in atherosclerotic plaque formation, rupture and thrombogenicity. Many cytokines are the most important biomediates of inflammation and its associated vascular lesions. Lymphotoxin-alpha (LTalpha) is part of the tumor necrosis factor (TNF) family of cytokines that mediates an inflammatory or immunologic response that can affect cell death or differentiation, and provide an important link of communication between lymphocytes and stromal cells. Several genetic and clinical studies implicate LTalpha, and its binding and regulatory partner galectin-2, as a risk factor in the pathogenesis of cardiovascular diseases including miocardial infarction, aortic aneurysm, and cerebral infarction. The LTalpha gene variability is also associated with an increased level of C-reactive protein, an inflammatory marker. In knockout mice, loss of LTalpha leads to a reduction of atherosclerotic lesion size. Together, these findings support the cytokine LTalpha as a mediator of inflammation and its association with the pathogenesis of cardiovascular disease. However, the molecular mechanisms of LTalpha -induced cellular responses are largely unknown. Preliminary studies indicate that the combination of LTalpha subunits, specific interaction with its potential receptors and other cytokines, and signal transduction pathways may significantly contribute to the overall effects of LTalpha on the inflammation, gene expression, and functions of cardiovascular cells. More clinical and basic science studies are warranted to further understand the role of LTalpha in cardiovascular disease. [Abstract/Link to Full Text]

Abdel Aziz MT, Abdel Aziz MZ, Atta HM, Shaker OG, Abdel Fattah MM, Mohsen GA, Ahmed HH, El Derwi DA
Screening for human papillomavirus (HPV) in Egyptian women by the second-generation hybrid capture (HC II) test.
Med Sci Monit. 2006 Jul;12(7):MT43-9.
BACKGROUND: HPV infection is the main cause of cervical cancer and cervical intraepithelial neoplasia worldwide. The second-generation HC II test is a liquid hybridization assay designed to detect 18 HPV types. The aim of the present study was to detect the rate of HPV infection and its various genotypes among Egyptian women. MATERIAL/METHODS: We evaluated 166 Egyptian women. They were classified according to cytology into those with normal cytology, chronic nonspecific cervicitis, and squamous intraepithelial lesions (SILs). RESULTS: The overall prevalence of HPV DNA in the studied groups was 15.06% (25/166). Among the 25 HPV-positive women, 16 (64%) were infected with high-risk HPV types, 4 (16%) with low risk HPV types, while 5 (20%) had both types. Twenty-one (84%) of the infected women harbored at least one high-risk HPV type, while 9 (36%) harbored at least one low-risk HPV type. Values of HPV viral load for low-risk HPV infection showed no significant difference in the normal and chronic nonspecific cervicitis groups. But when HPV viral load of high-risk HPV infection was compared in the normal, chronic nonspecific cervicitis, and SIL groups, a significant difference was found. The same was detected between chronic nonspecific cervicitis and SIL and between normal cytology and SIL, suggesting an association between viral load and risk of SIL and, accordingly, cancer. CONCLUSIONS: It may be concluded that HPV testing using the HC II assay is a useful tool when combined with cytology in the diagnosis of high-risk HPV viral types in apparently normal tissues. [Abstract/Link to Full Text]

Kiessling AH, Isgro F, Lehmann A, Piper S, Blome M, Saggau W
Evaluating a new method for maintaining body temperature during OPCAB and robotic procedures.
Med Sci Monit. 2006 Jul;12(7):MT39-42.
BACKGROUND: We evaluated the performance of a new temperature management system (Allon Thermowrap, MTRE, Israel) in maintaining normothermia during OPCAB (Off-Pump Coronary Artery Bypass) procedures and Zeus-robotic IMA (internal mammary artery) takedowns. MATERIAL/METHODS: One hundred patients were prospectively randomized to either a conventional temperature management method (thick blanket, warm intravenous fluids, operating room temperature 25 degrees C), or the new Allon Thermowrap system (pads with temperature-controlled water circulation placed on the patient's back, legs, and arms). The mean age, body surface area, total operating time, and OR air temperature were similar in both groups. RESULTS: The Allon Thermowrap system maintained a higher bladder and nasopharyngeal temperature (p<0.05). The SVR decreased (p<0.05) and the cardiac index increased (p<0.05) in patients with a body temperature>35.80 degrees C. Without reaching a significant level, the postoperative blood loss was lower in the Allon Thermowrap group. CONCLUSIONS: The Allon Thermowrap system significantly out-performed conventional techniques in achieving and maintaining normothermia during off-pump and robotic procedures. [Abstract/Link to Full Text]

Zacharakis E, Papadopoulos V, Ganidou M, Zacharakis E
Incarcerated Spigelian hernia: a case report.
Med Sci Monit. 2006 Jul;12(7):CS64-6.
BACKGROUND: Spigelian hernia is a rare partial abdominal wall defect in the transversus abdominus aponeurosis or Spigelian fascia. We here report the case of a patient with incarcerated greater omentum in a Spigelian hernia. CASE REPORT: The patient presented with a six-hour history of nausea, constant abdominal pain, and a palpable mass in the left lower quadrant. Abdominal computed tomography revealed that omentum was strangulated in a Spigelian hernia that was successfully treated by plug and mesh repair. No recurrence has been observed during three-year follow-up. CONCLUSIONS: In our case, plug and mesh repair was a safe and effective method of repairing an incarcerated Spigelian hernia with durability through three years of follow-up. [Abstract/Link to Full Text]

Bose AC, Kate V, Ananthakrishnan N, Srinivasan S
Primary cutaneous malignant fibrous histiocytoma: a case report.
Med Sci Monit. 2006 Jul;12(7):CS61-3.
BACKGROUND: Malignant fibrous histiocytoma (MFH) is one of the commonest soft tissue sarcomas to occur in the extremities, but presentation as a primary cutaneous lesion is rare. MFH can present as a cutaneous lesion in the form of a primary tumor or as metastasis from MFH at other sites, such as primary MFH of the breast; however, both presentations are very rare. CASE REPORT: We report here a 55-year-old male patient with cutaneous MFH on the right thigh region. The patient presented with two swellings on the outer aspect of the thigh of three months' duration, which ulcerated following the first month. The swellings were non-tender, soft, compressible, and not fixed to underlying structures. Histopathologic examination of the excised tumor revealed highly pleomorphic spindle-shaped cells arranged in sheets and irregular fascicles with a focal storiform pattern. Many thin-walled blood vessels and focal inflammatory cell infiltration with occasional focus of myxoid change was seen. Storiform-pleomorphic type of MFH grade II was diagnosed. Wide local excision was done. The patient made an uneventful recovery. CONCLUSIONS: Although MFH is one of the commonest soft tissue sarcomas, cutaneous presentation is very rare. A high index of suspicion is necessary to keep this possibility in mind, as it can present in different forms, including the pedunculated types, which can be compressible. MFH variants such as atypical fibrous histiocytoma or atypical fibroxanthoma can occur sometimes as cutaneous MFH. Wide local excision is commonly possible in most of the cases for therapy. [Abstract/Link to Full Text]

Kurtz ME, Kurtz JC, Given CW, Given B
Effects of a symptom control intervention on utilization of health care services among cancer patients.
Med Sci Monit. 2006 Jul;12(7):CR319-24.
BACKGROUND: In this study we investigated the effects of a clinical nursing symptom control intervention on utilization of physician, hospital and emergency room services. MATERIAL/METHODS: Two hundred twenty-two patients currently undergoing chemotherapy were recruited for the study, and were randomized into either the 10-contact, 20-week experimental intervention group (110), where the intervention focused on assisting the patient in managing their symptoms, or to a conventional care control group (112). RESULTS: A random effects regression model revealed that patients in the intervention group reported fewer emergency room visits than patients in the control group (p=0.050). Greater symptom severity and more comorbid conditions were also predictive of more emergency room visits. The intervention was effective in reducing the number of hospital visits for the subgroup of patients who at baseline reported above average symptom severity (p=0.023). CONCLUSIONS: These findings suggest that a nursing intervention focusing on educating patients regarding specific strategies to be applied for controlling symptoms may be worthwhile, as the patients may regain some control in managing their symptoms and thus ultimately require fewer emergency room services and hospital visits. Such a straightforward approach may empower patients, enhance their quality of life and reduce overall costs of cancer care. [Abstract/Link to Full Text]

Gungor S, Damadoglu E, Aybatli A, Yilmaz A, Kir A, Akkaya E
Typical pulmonary carcinoid tumors: presentation and outcome of 24 cases.
Med Sci Monit. 2006 Jul;12(7):CR315-8.
BACKGROUND: The aim of the study was to determine the presenting clinical-radiological features and outcomes of typical pulmonary carcinoid tumors in our center. MATERIAL/METHODS: The medical records of 24 patients with typical pulmonary carcinoid tumor diagnosed between January 1995 and December 2003 were retrospectively reviewed. Follow-up information on patients was obtained from direct patient contact in February 2004. RESULTS: There were 17 female and 7 male patients with a mean age of 40.3 years (range: 17-69 years). Sixteen patients (66.7%) were nonsmokers. The most frequent presenting symptom was cough, followed by hemoptysis. Twenty-three patients had an abnormal chest X-ray, showing atelectasis in seven. Bronchoscopy revealed mass lesion in all cases. In 13 cases, tumor was located in the lobar bronchi. Diagnosis of carcinoid tumor was established with bronchoscopy in 19 patients and with thoracotomy in five cases. While surgery was the treatment modality in 23 patients, one patient refused treatment. Lobectomy was performed in 15 cases and six of them were sleeve lobectomy. One patient died two days after operation due to ischemic heart disease, two were lost to follow-up, and 21 patients were still alive. Survival for the 21 patients was between 5 and 96 months. Eight patients had survival of more than five years. CONCLUSIONS: Our data suggest that typical pulmonary carcinoids are different from major lung cancer types with respect to sex, age predilection, and smoking history. Surgery is the treatment of choice for pulmonary carcinoid tumors. These patients had excellent prognosis after surgical treatment. [Abstract/Link to Full Text]

Shahin GM, van der Heijden GJ, Kelder JC, Boulaksil M, Knaepen PJ, Six AJ
Long-term follow-up of mitral valve repair: a single-center experience.
Med Sci Monit. 2006 Jul;12(7):CR308-14.
BACKGROUND: Our aim was to conduct a long-term follow-up of patients after mitral valve repair for incompetence. We identified determinants for mortality and compared mortality with standardized mortality rates of the Dutch population. MATERIAL/METHODS: We included in this single-center retrospective study 119 patients operated from March 1976 to February 1981. Patients with previous mitral valve surgery, isolated mitral stenosis, and congenital heart disease were excluded. Routine echocardiography was performed every 6 to 12 months. The cumulative probability of survival was calculated (Kaplan-Meier). The variables that statistically significantly associated with mortality were selected for multivariate analysis. Maximum follow-up was 27 years and complete in 98%. Mean age was 49.4 years, and 55% were preoperatively in New York Heart Association (NYHA) class III. Concomitant cardiac procedures were performed in 49%. RESULTS: The 30-day postoperative mortality was 6.7% and the 20-year overall mortality was 63%. The standardized mortality rate was 30%, which was based on survival rates of the general Dutch population. In 27 cases (22.7%), re-operation was performed. Independent predictors for mortality were, after univariate and multivariate analysis, concomitant coronary artery bypass grafting (p=0.002), renal impairment (p=0.027), age above 60 years (p=0.05), and ejection fraction<or=40% (p=0.05). CONCLUSIONS: The observed mortality exceeded the expected mortality. Concomitant coronary artery bypass grafting, renal impairment, age above 60 years, and reduced left ventricular function were independent predictors of mortality in patients with surgical repair for mitral valve regurgitation. [Abstract/Link to Full Text]

Federici L, Klouche K, Amigues L, Kanouni T, Lopez-Martinez E, Latry P, Beraud JJ, Rossi JF
Outcome and prognosis of severe thrombotic microangiopathies treated by plasma exchange.
Med Sci Monit. 2006 Jul;12(7):CR302-7.
BACKGROUND: Plasma exchange (PE) therapy has dramatically improved the outcome of thrombotic microangiopathies (TMA) in adults. However, resistance to PE, which indicates a poor prognosis, is observed in 1/3 of patients and remains not fully understood. We evaluated in this study the survival and the long-term outcome of severe TMA treated by PE and identified the predictive factors of resistance to PE and of mortality. MATERIAL/METHODS: Records of adults with severe TMA treated by PE were reviewed. Clinical and biological data, therapeutic delay to PE, plasma volume exchange per procedure, and number of PE sessions were collected. Mortality was assessed at one month and at one-year follow-up. All data were analyzed and compared between survived/deceased and between responder/non-responder patients. RESULTS: Nineteen females and six males were included. Mean age (+/-SD) was 46.8+/-16.3 years, Glasgow coma score 11+/-3, and Sequential Organ Failure Assessment (SOFA) score 5.8+/-2.8. Nineteen patients partially or fully responded to PE. Twenty patients were alive at one month and 19 at one year. The response to PE was the single discriminating parameter between survivors and non-survivors. A longer delay of PE and a neoplastic cause of TMA were significantly higher in the non-responders. CONCLUSIONS: Severe TMA treated by PE had a fair prognosis, with a survival rate at 76% after one year of follow-up. Unresponsiveness to PE was the only predictive factor of mortality; a neoplastic etiology of TMA and a longer therapeutic delay of PE were predictive of resistance to PE. [Abstract/Link to Full Text]

Petrofsky JS, Lohman E, Lee S, de la Cuesta Z, Labial L, Iouciulescu R, Moseley B, Korson R, Al Malty A
The influence of alterations in room temperature on skin blood flow during contrast baths in patients with diabetes.
Med Sci Monit. 2006 Jul;12(7):CR290-5.
BACKGROUND: Contrast baths (CB) have been used for over two thousand years. But it only was recently that CB were shown to improve limb circulation to a greater extent than that which can be seen after continuous exposure to a warm, constant temperature, bath. However, other studies show that this type of response to temperature can be impaired if the sympathetic nervous system applies vasoconstriction to the blood vessels. Therefore the purpose of the present investigation was to examine the relationship between sympathetic outflow on the magnitude of the change of blood flow (BF) during contrast baths in controls and with people diabetes. Sympathetic vasoconstriction activity was altered by global heating. MATERIAL/METHODS: Fourteen patients with type 2 diabetes were compared to 14 age-matched controls. BF was measured during 16 minutes of serial contrast baths of the foot following 3 minutes of warm water and 1 min of cold immersion at 2 different room temperatures, 19 and 32 deg C. RESULTS: When subjects were exposed to global heating (warm room) there is a greater response to CB than when subjects were initially in a cooler room. However, for both temperatures, subjects with diabetes had a response that was over 50% less than that seen in control subjects. CONCLUSIONS: Removing sympathetic vasoconstrictor tone by global heating benefits subjects with diabetes and control subjects in their response to CB. For subjects with diabetes, global heating may be necessary to increase blood flow to acceptable levels for effective therapy. [Abstract/Link to Full Text]

Lowe JC, Yellin J, Honeyman-Lowe G
Female fibromyalgia patients: lower resting metabolic rates than matched healthy controls.
Med Sci Monit. 2006 Jul;12(7):CR282-9.
BACKGROUND: Many features of fibromyalgia and hypothyroidism are virtually the same, and thyroid hormone treatment trials have reduced or eliminated fibromyalgia symptoms. These findings led the authors to test the hypothesis that fibromyalgia patients are hypometabolic compared to matched controls. MATERIAL/METHODS: Resting metabolic rate (RMR) was measured by indirect calorimetry and body composition by bioelectrical impedance for 15 fibromyalgia patients and 15 healthy matched controls. Measured resting metabolic rate (mRMR) was compared to percentages of predicted RMR (pRMR) by fat-free weight (FFW) (Sterling-Passmore: SP) and by sex, age, height, and weight (Harris-Benedict: HB). RESULTS: Patients had a lower mRMR (4,306.31+/-1077.66 kJ vs 5,411.59+/-695.95 kJ, p=0.0028) and lower percentages of pRMRs (SP: -28.42+/-15.82% vs -6.83+/-12.55%, p<0.0001. HB: -29.20+/-17.43% vs -9.13+/-9.51%, p=0.0008). Whereas FFW, age, weight, and body mass index (BMI) best accounted for variability in controls' RMRs, age and fat weight (FW) did for patients. In the patient group, TSH level accounted for 28% of the variance in pain distribution, and free T3 (FT3) accounted for 30% of the variance in pressure-pain threshold. CONCLUSIONS: Patients had lower mRMR and percentages of pRMRs. The lower RMRs were not due to calorie restriction or low FFW. Patients' normal FFW argues against low physical activity as the mechanism. TSH, FT4, and FT3 levels did not correlate with RMRs in either group. This does not rule out inadequate thyroid hormone regulation because studies show these laboratory values do not reliably predict RMR. [Abstract/Link to Full Text]

Petrofsky JS, Cuneo M, Lee S, Johnson E, Lohman E
Correlation between gait and balance in people with and without Type 2 diabetes in normal and subdued light.
Med Sci Monit. 2006 Jul;12(7):CR273-81.
BACKGROUND: Balance and gait are both impaired in people with diabetes but no study has examined both in the same subjects in people either with or even without diabetes or related these to room lighting. MATERIAL/METHODS: Twelve subjects with type 2 diabetes (D) and 15 age-matched controls (C) were examined under conditions of full light, eyes closed (no light) and low light (5 candle power). Balance was assessed during standing by a computerized posturography device. Gait was analyzed during the initiation of movement, while walking at uniform speed and during turns of 0.66 meters diameter through accelerometers, foot contact sensors and the electomyogram recorded from the gastrocnemius and tibialus anterior muscles. RESULTS: Subjects with diabetes had poorer balance during standing in diminished light compared to full light and no light conditions. When the room light was dimmed, sway during standing increased by an average of 25% in D. Control subjects did not have different sway with diminished light compared to the other lighting conditions. Gait was slower, circumduction greater and muscle use greater in D than C. There was a significant negative correlation between balance and gait; the worse the balance, the slower and poorer the gait for both groups of subjects (p<0.05), impaired balance accounting for 70% of the deviation in gait in D whereas it only accounted for 52% in C. CONCLUSIONS: Balance and gait are related in people with and without diabetes. Diabetes causes balance and gait to both be impaired compared to C. [Abstract/Link to Full Text]

Jezierska A, Olszewski WP, Pietruszkiewicz J, Olszewski W, Matysiak W, Motyl T
Activated Leukocyte Cell Adhesion Molecule (ALCAM) is associated with suppression of breast cancer cells invasion.
Med Sci Monit. 2006 Jul;12(7):BR245-56.
BACKGROUND: Activated Leukocyte Cell Adhesion Molecule (ALCAM) is expressed in different kinds of normal and neoplastic tissues. Data on the tissue distribution of ALCAM suggest that this protein is involved in tumor progression and metastasis. The lack of available data on ALCAM protein expression in breast cancer prompted us to undertake a study on the involvement of this adhesion molecule in tumor development. MATERIAL/METHODS: The expressions of ALCAM and reference biomarkers were examined in 56 breast cancer specimens by laser scanning cytometry and confocal microscopy. The results were related to clinical and pathological parameters, i.e. histological grade, tumor diameter, lymph node involvement, NPI, steroid receptor (estrogen, ER, and progesterone, PgR) expression, and HER2/neu over-expression. RESULTS: High levels of ALCAM significantly correlated with small tumor diameter (p=0.009), low tumor grade (p=0.001), and the presence of progesterone (p=0.009) and estrogen (p=0.006) receptors. Declining ALCAM concentrations correlated with HER2/neu gene amplification, inasmuch as the obtained p value, 0.065, was very close to the established statistical significance level of p=0.05. The ALCAM/MMP-2 ratio was significantly higher in cancer cases characterized by small tumor size (p=0.04) and low tumor grade (p=0.022). CONCLUSIONS: Analysis of ALCAM expression in relation to other molecular biomarkers revealed that ALCAM expression and the ALCAM/MMP-2 ratio are more promising indicators of breast cancer progression than MMP-2, E-cadherin, and alpha-catenin. Low ALCAM concentration correlated with an aggressive tumor phenotype, which supports the view that this adhesion molecule is a tumor suppressor marker with prognostic significance. [Abstract/Link to Full Text]

Ahmadi K, McCruden AB
Androgen binding site in J111 cell line.
Med Sci Monit. 2006 Jul;12(7):BR239-44.
BACKGROUND: The finding of sex steroid receptor protein in non classical reproductive tissues suggested the possibility that sex steroids may have a relevance to the immune system. MATERIAL/METHODS: The J111 cells were maintained in RPMI 1640 complete medium at 37 degrees C in 5% CO2 in air. Cells were resuspended at 1x10(6) cells in 0.2 ml complete medium in 1.5 ml eppendorf tubes. A single saturating concentration 1x10(-9) M of [3H]5alpha-DHT was added to the cells suspension. Unlabelled steroids (5alpha-DHT, 17-beta estradiol, or the synthetic glucocorticoid triamcinolone acetonid) were added over the range 1x10(-8) to 1x10(-9) M. Duplicate tubes were incubated at 37 degrees C for 1h. For autoradiography, the supernatant was discarded and the pellet resuspended in 0.2 ml medium. For binding assay, Labeled cells were separated from unbound steroid by immunomagnetic bead using anti-CD68 antibody. RESULTS: In autoradiography, a population of approximately 96% of J111 cells that contain receptors for androgen has been demonstrated. The results of immunomagnetic showed that binding identified in the J111 cells was modest selective towards androgenic compounds. Schatchard analysis of data showed the KD value of 2.5x10(-9) M and the number of receptor in each cell was found to be 257+/-1. Little competition was seen from 17 beta estradiol or the synthetic glucocorticoid triamcinolone acetonid. CONCLUSIONS: These data indicate that androgen binding in J111 cells is of modest affinity and specific, due to the inability of 100-fold molar excess of estradiol to displace bound [3H]-5alphaDHT. [Abstract/Link to Full Text]

Baysallar M, Aydogan H, Kilic A, Kucukkaraaslan A, Senses Z, Doganci L
Evaluation of the BacT/ALERT and BACTEC 9240 automated blood culture systems for growth time of Brucella species in a Turkish tertiary hospital.
Med Sci Monit. 2006 Jul;12(7):BR235-8.
BACKGROUND: The isolation of Brucella species from blood may be achieved by using classic culture techniques, but detection of the organism is difficult due to its slow growth. The time-to-detection of Brucella can take up to 30 days using the Castaneda blood culture method. Automated blood culture systems have reduced the growth time of Brucella. MATERIAL/METHODS: In this report we would like to contribute our experience on detection time in the isolation of Brucella species from 33,039 blood culture sets using BacT/ALERT between 1995 and 2000 (13 isolates) and thereafter using both the BACTEC and BacT/ALERT systems (17 isolates). RESULTS: Thirty Brucella spp. (17 by both systems and 13 by BacT/ALERT only) were isolated from 33,039 blood culture sets between 1995 and 2002. Brucellae were recovered between 1.8 and 3.7 days (mean: 2.5 days) in the BacT/ALERT blood culture system and between 2.1 and 3.8 days (mean: 2.8 days) in BACTEC 9240 system. CONCLUSIONS: We concluded that the mean time-to-detection could be <or=3 days, which is considered rapid enough for starting appropriate evidence-based treatment in an endemic setting. [Abstract/Link to Full Text]

Tvrd�k D, Dundr P, Pov�sil C, Pytl�k R, Plankov� M
Up-regulation of p21WAF1 expression is mediated by Sp1/Sp3 transcription factors in TGFbeta1-arrested malignant B cells.
Med Sci Monit. 2006 Jul;12(7):BR227-34.
BACKGROUND: TGFbeta1 has a profound effect on the growth of various mammalian cell types, including B lymphocytes. The inhibitory action of TGFbeta1 is mediated by deactivation of the cell cycle machinery. Several feedback-sensitive pathways determine whether the cells are stopped in G1 phase or allowed to leave G1 phase and enter S phase. Cell cycle-associated molecules, e.g. cyclin-dependent kinase inhibitors (CKIs), may become targets for the inhibitory signaling pathways induced by TGFbeta1. MATERIAL/METHODS: Our experimental DoHH2 cell line model was derived from a patient with malignant non-Hodgkin's lymphoma of follicular origin. The effect of TGFbeta1 on cell cycle progression was studied by flow cytometry. We examined the effect of TGFbeta1 on the expression of p21WAF1 by immunoblotting and RT-PCR. The binding activity of transcription factors to the p21 gene promoter was determined by gel mobility shift assay (GMSA). RESULTS: Our results showed that TGFbeta1 treatment increased the number of cells arrested in G0/G1 phase compared with untreated control cells. Moreover, we found that p21WAF1 expression was significantly up-regulated on the protein level after TGFbeta1 treatment. Similarly to the protein level, the expression of p21 mRNA was increased in TGFbeta1-treated cells. We further examined the binding activity of the Sp family of transcription factors to examine their role in p21WAF1 up-regulation. CONCLUSIONS: The results indicated that p21WAF1 over-expression in TGFbeta1-arrested malignant B cells is mediated by binding of Sp1/Sp3 transcription factors to the (-92/-71), (-77/-58), and (-65/-45) elements of the promoter region of the p21 gene. [Abstract/Link to Full Text]

Shimanuki S, Nagasawa T, Nishizawa N
Plasma HDL subfraction levels increase in rats fed proso-millet protein concentrate.
Med Sci Monit. 2006 Jul;12(7):BR221-6.
BACKGROUND: Millet has been consumed as human food in the countries of Asia and Africa. We reported previously the effects of dietary protein concentrates from proso millet (Panicum miliaceum L.) on plasma levels of high-density lipoprotein HDL cholesterol. Of note is that of these HDL subfractions, HDL2 particles may have the more strongly protective effect against the risk of coronary heart disease than HDL3. However, it is unclear how dietary millet protein affects plasma levels of HDL subfractions. MATERIAL/METHODS: We examined the effect of feeding of proso-millet protein concentrate (PMPC) for 21 days on plasma levels of HDL cholesterol, HDL subfractions and lecithin: cholesterol acyltransferase (LCAT) activities in rats. RESULTS: Results showed a clear elevation of plasma levels of HDL cholesterol (p<0.05) without an increase in low density lipoprotein cholesterol levels and enhancement of LCAT activities (p<0.06) by the intake of a PMPC diet compared with a casein diet. This increase in HDL cholesterol levels was substantially due to the elevation of HDL2 subfractions (p<0.05). CONCLUSIONS: PMPC could have a beneficial effect on cardiovascular disease because HDL2 subfractions may have the more strongly protective effect against the risk of coronary heart disease. [Abstract/Link to Full Text]

Jenicek M
How to read, understand, and write 'Discussion' sections in medical articles. An exercise in critical thinking.
Med Sci Monit. 2006 Jun;12(6):SR28-36.
Writing and reading 'Discussion' sections in medical articles require a procedure as exact and structured as that involved in raising questions, choosing materials and methods and producing results for a health research study. The medical article as a whole can be considered an exercise in modern argumentation and its 'Discussion' section, a systematic critical appraisal of a path from theses to conclusions. The methodology of modern critical thinking applies perfectly to article writing, reading, and understanding. Structuring the 'Discussion' section as a review of argumentation benefits more than the study and its authors. It allows the reader to grasp the real relevance and validity of the study and its usability for his or her decision-making in clinical and community care, research and health policies and program proposal, implementation, and evaluation. [Abstract/Link to Full Text]

Glattard E, Muller A, Aunis D, Metz-Boutigue MH, Stefano GB, Goumon Y
Rethinking the opiate system? Morphine and morphine-6-glucuronide as new endocrine and neuroendocrine mediators.
Med Sci Monit. 2006 Jun;12(6):SR25-7.
Since the 80s, intrigued by presence of morphine precursors in some mammalian cells, different laboratories were able to characterize morphine and morphine precursors in animal tissues. Endogenous morphine studies continued during 90s and this alkaloid was successfully characterized from more organs and fluids of vertebrates, including brain, adrenal gland, heart, cerebrospinal fluid and urine. Then, in the last three years a high rate of publications dealing with this topic emerged, leading to a better understanding of the endogenous morphine system. In this regard, this article comment all the new data recently collected on this rising subject and replace the morphine and its derivative, morphine-6-glucuronide, in the mammalian physiology. [Abstract/Link to Full Text]