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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Recent Articles in BMJ: British Medical Journal

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

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

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

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

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

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

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

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

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

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

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

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

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

Afshari A, Wetterslev J, Brok J, M�ller A
Antithrombin III in critically ill patients: systematic review with meta-analysis and trial sequential analysis.
BMJ. 2007 Nov 23;
OBJECTIVE: To evaluate the benefits and harms of antithrombin III in critically ill patients. DESIGN: Systematic review and meta-analysis of randomised trials. DATA SOURCES: CENTRAL, Medline, Embase, International Web of Science, LILACS, the Chinese Biomedical Literature Database, and CINHAL (to November 2006); hand search of reference lists, contact with authors and experts, and search of registers of ongoing trials. Review methods Two reviewers independently selected parallel group randomised clinical trials comparing antithrombin with placebo or no intervention and extracted data related to study methods, interventions, outcomes, bias risk, and adverse events. Disagreements were resolved by discussion. Trials in any type of critically ill patients in intensive care were eligible. All trials, irrespective of blinding or language status, that compared any antithrombin III regimen with no intervention or placebo were included. Trials were considered to be at low risk of bias if they had adequate randomisation procedure, blinding, and used intention to treat analysis. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models according to heterogeneity. MAIN OUTCOME MEASURES: Mortality, length of stay in intensive care or hospital, quality of life, severity of sepsis, respiratory failure, duration of mechanical ventilation, incidence of surgical intervention, intervention effect among various populations, and adverse events (such as bleeding). RESULTS: 20 trials randomly assigning 3458 patients met inclusion criteria. Eight trials had low risk of bias. Compared with placebo or no intervention, antithrombin III did not reduce overall mortality (relative risk 0.96, 95% confidence interval 0.89 to 1.03). No subgroup analyses on risk of bias, populations of patients, or with and without adjuvant heparin yielded significant results. Antithrombin III increased the risk of bleeding events (1.52, 1.30 to 1.78). Heterogeneity was observed in only a few analyses. CONCLUSION: Antithrombin III cannot be recommended for critically ill patients based on the available evidence. [Abstract/Link to Full Text]

Torossian A, Graf J, Bauhofer A
Antithrombin III in critically ill patients.
BMJ. 2007 Nov 23; [Abstract/Link to Full Text]

Pickett KE, Wilkinson RG
Child wellbeing and income inequality in rich societies: ecological cross sectional study.
BMJ. 2007 Nov 24;335(7629):1080.
OBJECTIVES: To examine associations between child wellbeing and material living standards (average income), the scale of differentiation in social status (income inequality), and social exclusion (children in relative poverty) in rich developed societies. DESIGN: Ecological, cross sectional studies. SETTING: Cross national comparisons of 23 rich countries; cross state comparisons within the United States. POPULATION: Children and young people. MAIN OUTCOME MEASURES: The Unicef index of child wellbeing and its components for rich countries; eight comparable measures for the US states and District of Columbia (teenage births, juvenile homicides, infant mortality, low birth weight, educational performance, dropping out of high school, overweight, mental health problems). RESULTS: The overall index of child wellbeing was negatively correlated with income inequality (r=-0.64, P=0.001) and percentage of children in relative poverty (r=-0.67, P=0.001) but not with average income (r=0.15, P=0.50). Many more indicators of child wellbeing were associated with income inequality or children in relative poverty, or both, than with average incomes. Among the US states and District of Columbia all indicators were significantly worse in more unequal states. Only teenage birth rates and the proportion of children dropping out of high school were lower in richer states. CONCLUSIONS: Improvements in child wellbeing in rich societies may depend more on reductions in inequality than on further economic growth. [Abstract/Link to Full Text]

Black ME, Jeffery HE
Child wellbeing and inequalities in rich countries.
BMJ. 2007 Nov 24;335(7629):1054-5. [Abstract/Link to Full Text]

Yank V, Rennie D, Bero LA
Financial ties and concordance between results and conclusions in meta-analyses: retrospective cohort study.
BMJ. 2007 Dec 8;335(7631):1202-5.
OBJECTIVE: To determine whether financial ties to one drug company are associated with favourable results or conclusions in meta-analyses on antihypertensive drugs. DESIGN: Retrospective cohort study. SETTING: Meta-analyses published up to December 2004 that were not duplicates and evaluated the effects of antihypertensive drugs compared with any comparator on clinical end points in adults. Financial ties were categorised as one drug company compared with all others. MAIN OUTCOME MEASURES: The main outcomes were the results and conclusions of meta-analyses, with both outcomes separately categorised as being favourable or not favourable towards the study drug. We also collected data on characteristics of meta-analyses that the literature suggested might be associated with favourable results or conclusions. RESULTS: 124 meta-analyses were included in the study, 49 (40%) of which had financial ties to one drug company. On univariate logistic regression analyses, meta-analyses of better methodological quality were more likely to have favourable results (odds ratio 1.16, 95% confidence interval 1.07 to 1.27). Although financial ties to one drug company were not associated with favourable results, such ties constituted the only characteristic significantly associated with favourable conclusions (4.09, 1.30 to 12.83). When controlling for other characteristics of meta-analyses in multiple logistic regression analyses, meta-analyses that had financial ties to one drug company remained more likely to report favourable conclusions (5.11, 1.54 to 16.92). CONCLUSION: Meta-analyses on antihypertensive drugs and with financial ties to one drug company are not associated with favourable results but are associated with favourable conclusions. [Abstract/Link to Full Text]

Lane JA, Howson J, Donovan JL, Goepel JR, Dedman DJ, Down L, Turner EL, Neal DE, Hamdy FC
Detection of prostate cancer in unselected young men: prospective cohort nested within a randomised controlled trial.
BMJ. 2007 Dec 1;335(7630):1139.
OBJECTIVE: To investigate the feasibility of testing for prostate cancer and the prevalence and characteristics of the disease in unselected young men. DESIGN: Prospective cohort nested within a randomised controlled trial, with two years of follow-up. SETTING: Eight general practices in a UK city. PARTICIPANTS: 1299 unselected men aged 45-49. INTERVENTION: Prostate biopsies for participants with a prostate specific antigen level of 1.5 ng/ml or more and the possibility of randomisation to three treatments for those with localised prostate cancer. MAIN OUTCOME MEASURES: Uptake of testing for prostate specific antigen; positive predictive value of prostate specific antigen; and prevalence of prostate cancer, TNM disease stage, and histological grade (Gleason score). RESULTS: 442 of 1299 men agreed to be tested for prostate specific antigen (34%) and 54 (12%) had a raised level. The positive predictive value for prostate specific antigen was 21.3%. Ten cases of prostate cancer were detected (2.3%) with eight having at least two positive results in biopsy cores and three showing perineural invasion. One tumour was of high volume (cT2c), Gleason score 7, with a positive result on digital rectal examination; nine tumours were cT1c, Gleason score 6, and eight had a negative result on digital rectal examination. Five of the nine eligible participants (55%) agreed to be randomised. No biochemical disease progression in the form of a rising prostate specific antigen level occurred in two years of follow-up. CONCLUSIONS: Men younger than 50 will accept testing for prostate cancer but at a much lower rate than older men. Using an age based threshold of 1.5 ng/ml, the prevalence of prostate cancer was similar to that in older men (3.0 ng/ml threshold) and some cancers of potential clinical significance were found. TRIAL REGISTRATION: Current Controlled Trials ISRCTN20141297. [Abstract/Link to Full Text]

Rucker D, Padwal R, Li SK, Curioni C, Lau DC
Long term pharmacotherapy for obesity and overweight: updated meta-analysis.
BMJ. 2007 Dec 8;335(7631):1194-9.
OBJECTIVE: To summarise the long term efficacy of anti-obesity drugs in reducing weight and improving health status. DESIGN: Updated meta-analysis of randomised trials. DATA SOURCES: Medline, Embase, the Cochrane controlled trials register, the Current Science meta-register of controlled trials, and reference lists of identified articles. All data sources were searched from December 2002 (end date of last search) to December 2006. STUDIES REVIEWED: Double blind randomised placebo controlled trials of approved anti-obesity drugs used in adults (age over 18) for one year or longer. RESULTS: 30 trials of one to four years' duration met the inclusion criteria: 16 orlistat (n=10 631 participants), 10 sibutramine (n=2623), and four rimonabant (n=6365). Of these, 14 trials were new and 16 had previously been identified. Attrition rates averaged 30-40%. Compared with placebo, orlistat reduced weight by 2.9 kg (95% confidence interval 2.5 kg to 3.2 kg), sibutramine by 4.2 kg (3.6 kg to 4.7 kg), and rimonabant by 4.7 kg (4.1 kg to 5.3 kg). Patients receiving active drug treatment were significantly more likely to achieve 5% and 10% weight loss thresholds. Orlistat reduced the incidence of diabetes and improved concentrations of total cholesterol and low density lipoprotein cholesterol, blood pressure, and glycaemic control in patients with diabetes but increased rates of gastrointestinal side effects and slightly lowered concentrations of high density lipoprotein. Sibutramine lowered concentrations of high density lipoprotein cholesterol and triglycerides but raised blood pressure and pulse rate. Rimonabant improved concentrations of high density lipoprotein cholesterol and triglycerides, blood pressure, and glycaemic control in patients with diabetes but increased the risk of mood disorders. CONCLUSIONS: Orlistat, sibutramine, and rimonabant modestly reduce weight, have differing effects on cardiovascular risk profiles, and have specific adverse effects. [Abstract/Link to Full Text]

Armitage JN, Sibanda N, Cathcart PJ, Emberton M, van der Meulen JH
Mortality in men admitted to hospital with acute urinary retention: database analysis.
BMJ. 2007 Dec 8;335(7631):1199-202.
OBJECTIVES: To investigate mortality in men admitted to hospital with acute urinary retention and to report on the effects of comorbidity on mortality. DESIGN: Analysis of the hospital episode statistics database linked to the mortality database of the Office for National Statistics. SETTING: NHS hospital trusts in England, 1998-2005. PARTICIPANTS: All men aged over 45 who were admitted to NHS hospitals in England with a first episode of acute urinary retention. MAIN OUTCOME MEASURES: Mortality in the first year after acute urinary retention and standardised mortality ratio against the general population. RESULTS: During the study period, 176 046 men aged over 45 were admitted to hospital with a first episode of acute urinary retention. In 100 067 men with spontaneous acute urinary retention, the one year mortality was 4.1% in men aged 45-54 and 32.8% in those aged 85 and over. In 75 979 men with precipitated acute urinary retention, mortality was 9.5% and 45.4%, respectively. In men with spontaneous acute urinary retention aged 75-84, the most prevalent age group, the one year mortality was 12.5% in men without comorbidity and 28.8% in men with comorbidity. The corresponding figures for men with precipitated acute urinary retention were 18.1% and 40.5%. Compared with the general population, the highest relative increase in mortality was in men aged 45-54 (standardised mortality ratio 10.0 for spontaneous and 23.6 for precipitated acute urinary retention) and the lowest for men 85 and over (1.7 and 2.4, respectively). CONCLUSIONS: Mortality in men admitted to hospital with acute urinary retention is high and increases strongly with age and comorbidity. Patients might benefit from multi-disciplinary care to identify and treat comorbid conditions. [Abstract/Link to Full Text]

Qureshi NN, Hatcher J, Chaturvedi N, Jafar TH
Effect of general practitioner education on adherence to antihypertensive drugs: cluster randomised controlled trial.
BMJ. 2007 Nov 17;335(7628):1030.
OBJECTIVE: To determine the impact of a simple educational package for general practitioners on adherence to antihypertensive drugs. DESIGN: Cluster randomised controlled trial. SETTING: Six randomly selected communities in Karachi, Pakistan. PARTICIPANTS: 200 patients with hypertension taking antihypertensive drugs; 78 general practitioners. INTERVENTION: Care by general practitioners specially trained in management of hypertension compared with usual care. MAIN OUTCOME MEASURE: Correct dosing, defined as percentage of prescribed doses taken, measured with electronic medication event monitoring system (MEMS) bottle. RESULTS: 200 patients were enrolled, and 178 (89%) successfully completed six weeks of follow-up. Adherence was significantly greater in the special care group than in the usual care group (unadjusted mean percentage days with correct dose 48.1%, 95% confidence interval 35.8% to 60.4%, versus 32.4%, 22.6% to 42.3%; P=0.048). Adherence was also higher among patients who had higher levels of education (P<0.001), were encouraged by family members (P<0.001), believed in the effect of drugs (P<0.001), and had the purpose of the drugs explained to them (P<0.001). CONCLUSIONS: Special training of general practitioners in management of hypertension, emphasising good communication between doctors and patients, is more effective than usual care provided in the communities in Karachi. Such simple interventions should be adopted by other developing countries that are now facing an increasing burden of hypertension. TRIAL REGISTRATION: Clinical trials NCT00330408 [ClinicalTrials.gov]. [Abstract/Link to Full Text]

Schroeder K, Fahey T
Improving adherence to drugs for hypertension.
BMJ. 2007 Nov 17;335(7628):1002-3. [Abstract/Link to Full Text]

Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D
Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study.
BMJ. 2007 Dec 1;335(7630):1134.
OBJECTIVE: To examine the relation between body mass index (kg/m2) and cancer incidence and mortality. DESIGN: Prospective cohort study. PARTICIPANTS: 1.2 million UK women recruited into the Million Women Study, aged 50-64 during 1996-2001, and followed up, on average, for 5.4 years for cancer incidence and 7.0 years for cancer mortality. MAIN OUTCOME MEASURES: Relative risks of incidence and mortality for all cancers, and for 17 specific types of cancer, according to body mass index, adjusted for age, geographical region, socioeconomic status, age at first birth, parity, smoking status, alcohol intake, physical activity, years since menopause, and use of hormone replacement therapy. RESULTS: 45,037 incident cancers and 17 203 deaths from cancer occurred over the follow-up period. Increasing body mass index was associated with an increased incidence of endometrial cancer (trend in relative risk per 10 units=2.89, 95% confidence interval 2.62 to 3.18), adenocarcinoma of the oesophagus (2.38, 1.59 to 3.56), kidney cancer (1.53, 1.27 to 1.84), leukaemia (1.50, 1.23 to 1.83), multiple myeloma (1.31, 1.04 to 1.65), pancreatic cancer (1.24, 1.03 to 1.48), non-Hodgkin's lymphoma (1.17, 1.03 to 1.34), ovarian cancer (1.14, 1.03 to 1.27), all cancers combined (1.12, 1.09 to 1.14), breast cancer in postmenopausal women (1.40, 1.31 to 1.49) and colorectal cancer in premenopausal women (1.61, 1.05 to 2.48). In general, the relation between body mass index and mortality was similar to that for incidence. For colorectal cancer, malignant melanoma, breast cancer, and endometrial cancer, the effect of body mass index on risk differed significantly according to menopausal status. CONCLUSIONS: Increasing body mass index is associated with a significant increase in the risk of cancer for 10 out of 17 specific types examined. Among postmenopausal women in the UK, 5% of all cancers (about 6000 annually) are attributable to being overweight or obese. For endometrial cancer and adenocarcinoma of the oesophagus, body mass index represents a major modifiable risk factor; about half of all cases in postmenopausal women are attributable to overweight or obesity. [Abstract/Link to Full Text]

Villar J, Carroli G, Zavaleta N, Donner A, Wojdyla D, Faundes A, Velazco A, Bataglia V, Langer A, Narv�ez A, Valladares E, Shah A, Campod�nico L, Romero M, Reynoso S, de P�dua KS, Giordano D, Kublickas M, Acosta A
Maternal and neonatal individual risks and benefits associated with caesarean delivery: multicentre prospective study.
BMJ. 2007 Nov 17;335(7628):1025.
OBJECTIVE: To assess the risks and benefits associated with caesarean delivery compared with vaginal delivery. DESIGN: Prospective cohort study within the 2005 WHO global survey on maternal and perinatal health. SETTING: 410 health facilities in 24 areas in eight randomly selected Latin American countries; 123 were randomly selected and 120 participated and provided data PARTICIPANTS: 106,546 deliveries reported during the three month study period, with data available for 97,095 (91% coverage). MAIN OUTCOME MEASURES: Maternal, fetal, and neonatal morbidity and mortality associated with intrapartum or elective caesarean delivery, adjusted for clinical, demographic, pregnancy, and institutional characteristics. RESULTS: Women undergoing caesarean delivery had an increased risk of severe maternal morbidity compared with women undergoing vaginal delivery (odds ratio 2.0 (95% confidence interval 1.6 to 2.5) for intrapartum caesarean and 2.3 (1.7 to 3.1) for elective caesarean). The risk of antibiotic treatment after delivery for women having either type of caesarean was five times that of women having vaginal deliveries. With cephalic presentation, there was a trend towards a reduced odds ratio for fetal death with elective caesarean, after adjustment for possible confounding variables and gestational age (0.7, 0.4 to 1.0). With breech presentation, caesarean delivery had a large protective effect for fetal death. With cephalic presentation, however, independent of possible confounding variables and gestational age, intrapartum and elective caesarean increased the risk for a stay of seven or more days in neonatal intensive care (2.1 (1.8 to 2.6) and 1.9 (1.6 to 2.3), respectively) and the risk of neonatal mortality up to hospital discharge (1.7 (1.3 to 2.2) and 1.9 (1.5 to 2.6), respectively), which remained higher even after exclusion of all caesarean deliveries for fetal distress. Such increased risk was not seen for breech presentation. Lack of labour was a risk factor for a stay of seven or more days in neonatal intensive care and neonatal mortality up to hospital discharge for babies delivered by elective caesarean delivery, but rupturing of membranes may be protective. CONCLUSIONS: Caesarean delivery independently reduces overall risk in breech presentations and risk of intrapartum fetal death in cephalic presentations but increases the risk of severe maternal and neonatal morbidity and mortality in cephalic presentations. [Abstract/Link to Full Text]

Shorten A
Maternal and neonatal effects of caesarean section.
BMJ. 2007 Nov 17;335(7628):1003-4. [Abstract/Link to Full Text]

Roberts SE, Williams JG, Yeates D, Goldacre MJ
Mortality in patients with and without colectomy admitted to hospital for ulcerative colitis and Crohn's disease: record linkage studies.
BMJ. 2007 Nov 17;335(7628):1033.
OBJECTIVE: To compare mortality outcomes in the three years after elective colectomy, no colectomy, and emergency colectomy among people admitted to hospital for inflammatory bowel disease, to inform whether the threshold for elective colectomy in clinical practice is appropriate. DESIGN: Record linkage studies. SETTING: Oxford region (1968-99) and England (1998-2003). PARTICIPANTS: 23,464 people with hospital stay for more than three days for inflammatory bowel disease, including 5480 who had colectomy. MAIN OUTCOME MEASURES: Case fatality, relative survival, and standardised mortality ratios. RESULTS: In the Oxford region, three year mortality was lower after elective colectomy than after either no colectomy or emergency colectomy, although this was not significant. For England, mortality three years after elective colectomy for ulcerative colitis (3.7%) and Crohn's disease (3.3%) was significantly lower than that after either admission without colectomy (13.6% and 10.1%; both P<0.001) or emergency colectomy (13.2% and 9.9%; P<0.001 for colitis and P<0.01 for Crohn's disease). Three or more months after elective colectomy, mortality was similar to that in the general population. Adjustment for comorbidity did not affect the findings. CONCLUSIONS: In England, the clinical threshold for elective colectomy in people with inflammatory bowel disease may be too high. Further research is now required to establish the threshold criteria and optimal timing of elective surgery for people with poorly controlled inflammatory bowel disease. [Abstract/Link to Full Text]

Dawwas MF
Colectomy and IBD. Does surgery improve survival?
BMJ. 2007 Dec 1;335(7630):1109-10. [Abstract/Link to Full Text]

Sanderson JD, Parkes GC
Timing of surgery for inflammatory bowel disease.
BMJ. 2007 Nov 17;335(7628):1006. [Abstract/Link to Full Text]

Bellamy L, Casas JP, Hingorani AD, Williams DJ
Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
BMJ. 2007 Nov 10;335(7627):974.
OBJECTIVE: To quantify the risk of future cardiovascular diseases, cancer, and mortality after pre-eclampsia. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Embase and Medline without language restrictions, including papers published between 1960 and December 2006, and hand searching of reference lists of relevant articles and reviews for additional reports. REVIEW METHODS: Prospective and retrospective cohort studies were included, providing a dataset of 3,488,160 women, with 198,252 affected by pre-eclampsia (exposure group) and 29,495 episodes of cardiovascular disease and cancer (study outcomes). RESULTS: After pre-eclampsia women have an increased risk of vascular disease. The relative risks (95% confidence intervals) for hypertension were 3.70 (2.70 to 5.05) after 14.1 years weighted mean follow-up, for ischaemic heart disease 2.16 (1.86 to 2.52) after 11.7 years, for stroke 1.81 (1.45 to 2.27) after 10.4 years, and for venous thromboembolism 1.79 (1.37 to 2.33) after 4.7 years. No increase in risk of any cancer was found (0.96, 0.73 to 1.27), including breast cancer (1.04, 0.78 to 1.39) 17 years after pre-eclampsia. Overall mortality after pre-eclampsia was increased: 1.49 (1.05 to 2.14) after 14.5 years. CONCLUSIONS: A history of pre-eclampsia should be considered when evaluating risk of cardiovascular disease in women. This association might reflect a common cause for pre-eclampsia and cardiovascular disease, or an effect of pre-eclampsia on disease development, or both. No association was found between pre-eclampsia and future cancer. [Abstract/Link to Full Text]

Recent Articles in CMAJ : Canadian Medical Association Journal

Weir E
Pondering public health and purity.
CMAJ. 2007 Dec 4;177(12):1620. [Abstract/Link to Full Text]

Hogg W
A do-it-yourself stereophonic stethoscope.
CMAJ. 2007 Dec 4;177(12):1549. [Abstract/Link to Full Text]

Gosset B
Sound medicine: an introduction to cacophonology.
CMAJ. 2007 Dec 4;177(12):1547-8. [Abstract/Link to Full Text]

Curwin J
The Goo Tolerance Index: a foolproof method for choosing a medical specialty.
CMAJ. 2007 Dec 4;177(12):1545-6. [Abstract/Link to Full Text]

Hillmer M, Redelmeier DA
Exercising privacy rights in medical science.
CMAJ. 2007 Dec 4;177(12):1542-4.
Privacy laws are intended to preserve human well-being and improve medical outcomes. We used the Sportstats website, a repository of competitive athletic data, to test how easily these laws can be circumvented. We designed a haphazard, unrepresentative case-series analysis and applied unscientific methods based on an Internet connection and idle time. We found it both feasible and titillating to breach anonymity, stockpile personal information and generate misquotations. We extended our methods to snoop on celebrities, link to outside databases and uncover refusal to participate. Throughout our study, we evaded capture and public humiliation despite violating these 6 privacy fundamentals. We suggest that the legitimate principle of safeguarding personal privacy is undermined by the natural human tendency toward showing off. [Abstract/Link to Full Text]

Chan K
A clinical trial gone awry: the Chocolate Happiness Undergoing More Pleasantness (CHUMP) study.
CMAJ. 2007 Dec 4;177(12):1539-41.
The randomized controlled trial is the "gold standard" for evaluating the benefits and harms of interventions. The Chocolate Happiness Undergoing More Pleasantness (CHUMP) study was designed to compare the effects of dark chocolate, milk chocolate and normal chocolate consumption on happiness. Although the intention-to-treat analysis showed that participants who received either dark or milk chocolate were happier than those who received no additional chocolate, the actual-consumption analysis showed that there were no differences between any of the groups. The reason for this result is that many participants switched groups mid-study because of their personal chocolate preferences. Although the CHUMP study was pleasurable, it demonstrated the difficulties associated with performing a truly blinded clinical trial. [Abstract/Link to Full Text]

Cyr C, Lanthier L
One giant leap for mankind? A cost-utility analysis of abolishing the law of gravity.
CMAJ. 2007 Dec 4;177(12):1536-8.
BACKGROUND: Canada's Neo Rhino Party, a joke political party created in 2006 as a successor to the Parti Rhinoc�ros, is planning a new regulation to repeal the law of gravity, which could have an important impact on diseases attributable to gravity on earth. METHODS: We sought to estimate the number of quality-adjusted life-years that would be saved if the proposed regulation is passed and determine the cost-effectiveness of adapting Boris Volfson's antigravity machine for use on earth. We performed an economic analysis using a hidden Markov model. RESULTS: Our results suggest that a microgravity environment would save over 2 million quality-adjusted life-years. The cost for every quality-adjusted life-year saved is estimated to be $328. INTERPRETATION: Microgravity is the solution to the health care crisis in Canada. In addition, using technological, statistical and medical jargon gives us the opportunity to defy the laws of physics, mathematics and medicine. [Abstract/Link to Full Text]

Rockwood K, Chertkow H
A cellular-telephone model of assessing frontal lobe function in physicians.
CMAJ. 2007 Dec 4;177(12):1533-5.
As people age, they recognize that social conduct has become worse. This is not just a failing of the young but also a reflection of modern technology, notably the cellular telephone. We observed that the behaviour induced by the use of such devices is so egregious as to be medically informative. We offer a descriptive phenomenology and neuroanatomical classification of aberrant behaviour in relation to cellular telephone use by physicians at medical conferences. Although the cellular telephone is a scourge, its ability to add to the diagnostic armamentarium in cognitive neurology should not be overlooked, especially if a fee code can be attached. [Abstract/Link to Full Text]

Ward LM, Gaboury I, Ladhani M, Zlotkin S
Vitamin D deficiency among Italian children.
CMAJ. 2007 Dec 4;177(12):1530. [Abstract/Link to Full Text]

Chepesiuk R
Advertisement.
CMAJ. 2007 Dec 4;177(12):1529. [Abstract/Link to Full Text]

H�bert PC
Advertisement.
CMAJ. 2007 Dec 4;177(12):1529. [Abstract/Link to Full Text]

Proctor G
Advertisement.
CMAJ. 2007 Dec 4;177(12):1529. [Abstract/Link to Full Text]

Lippi G, Montagnana M, Targher G
Vitamin D deficiency among Italian children.
CMAJ. 2007 Dec 4;177(12):1529-30; author reply 1530. [Abstract/Link to Full Text]

Holtby S
Advertisement.
CMAJ. 2007 Dec 4;177(12):1528. [Abstract/Link to Full Text]

Kang M
Advertisement.
CMAJ. 2007 Dec 4;177(12):1528. [Abstract/Link to Full Text]

Hopkins J
Advertisement.
CMAJ. 2007 Dec 4;177(12):1528. [Abstract/Link to Full Text]

Beaudet M
Advertisement.
CMAJ. 2007 Dec 4;177(12):1528. [Abstract/Link to Full Text]

Lippman A, Boscoe M, Shimmin C
Vaccination against human papillomavirus.
CMAJ. 2007 Dec 4;177(12):1527-1528. [Abstract/Link to Full Text]

Cassels AK
Vaccination against human papillomavirus.
CMAJ. 2007 Dec 4;177(12):1526; author reply 1527-8. [Abstract/Link to Full Text]

Nisker J
Vaccination against human papillomavirus.
CMAJ. 2007 Dec 4;177(12):1526-7; author reply 1527-8. [Abstract/Link to Full Text]

Ferenczy A
Vaccination against human papillomavirus.
CMAJ. 2007 Dec 4;177(12):1525; author reply 1527-8. [Abstract/Link to Full Text]

Brophy JM
Vaccination against human papillomavirus.
CMAJ. 2007 Dec 4;177(12):1525-6; author reply 1527-8. [Abstract/Link to Full Text]

Mansi JA
Vaccination against human papillomavirus.
CMAJ. 2007 Dec 4;177(12):1524; author reply 1527-8. [Abstract/Link to Full Text]

Franco EL, de Pokomandy A, Spence AR, Burchell AN, Trottier H, Mayrand MH, Lau S
Vaccination against human papillomavirus.
CMAJ. 2007 Dec 4;177(12):1524-5; author reply 1527-8. [Abstract/Link to Full Text]

Ogilvie GS, Remple VP, Marra F, McNeil SA, Naus M, Pielak KL, Ehlen TG, Dobson SR, Money DM, Patrick DM
Parental intention to have daughters receive the human papillomavirus vaccine.
CMAJ. 2007 Dec 4;177(12):1506-12.
BACKGROUND: Concerns have been raised that parents may be reluctant to have their daughters receive the human papillomavirus (HPV) vaccine, because of a belief that doing so might be interpreted as condoning earlier and more frequent sexual activity. We determined intentions regarding vaccination among Canadian parents and factors that predicted parental intention to have their daughters vaccinated against HPV. METHODS: Parents of children 8-18 years of age, recruited from across Canada, were asked to respond to questions in the context of a grade 6, publicly funded, school-based HPV vaccine program. We performed backward logistic regression analysis to identify factors predictive of parents' intention to have their daughters vaccinated against HPV. RESULTS: Of the 1350 respondents with female children, more than 70% (73.8%; 95% confidence interval [CI] 71.5%-76.1%) intended to have their daughters undergo vaccination against HPV. In multivariable modelling, parents who had positive attitudes toward vaccines (odds ratio [OR] 9.9, 95% CI 4.7-21.1), those who were influenced by subjective norms (OR 9.2, 95% CI 6.6-12.9), those who felt that the vaccine had limited influence on sexual behaviour (OR 3.2, 95% CI 2.2-4.6) and those who thought someone they knew was likely to get cervical cancer (OR 1.5, 95% CI 1.1-2.1) were more likely to intend that their daughters receive the HPV vaccine. Parents who were older (v. younger) (OR 0.6, 95% CI 0.4-0.8) and those who resided in British Columbia or Yukon Territory (v. Atlantic Canada) (OR 0.5, 95% CI 0.3-0.9) were less likely to intend that their daughters receive the HPV vaccine. INTERPRETATION: Most of the parents surveyed intended that their daughters would receive vaccination against HPV. Overall attitudes toward vaccines in general and toward the HPV vaccine in particular constituted the most significant predictor of parental intention with regard to vaccination. [Abstract/Link to Full Text]

Lear SA, Humphries KH, Frohlich JJ, Birmingham CL
Appropriateness of current thresholds for obesity-related measures among Aboriginal people.
CMAJ. 2007 Dec 4;177(12):1499-505.
BACKGROUND: Despite the high prevalence of obesity and diabetes in the Canadian Aboriginal population, it is unknown whether the current thresholds for body mass index and waist circumference derived from white populations are appropriate for Aboriginal people. We compared the risk of cardiovascular disease among Canadian Aboriginal and European populations using the current thresholds for body mass index and waist circumference. METHODS: Healthy Aboriginal (n = 195) and European (n = 201) participants (matched for sex and body mass index range) were assessed for demographic characteristics, lifestyle factors, total and central adiposity and risk factors for cardiovascular disease. Among Aboriginal and European participants, we compared the relation between body mass index and each of the following 3 factors: percent body fat, central adiposity and cardiovascular disease risk factors. We also compared the relation between waist circumference and the same 3 factors. RESULTS: The use of body mass index underestimated percent body fat by 1.3% among Aboriginal participants compared with European participants (p = 0.025). The use of waist circumference overestimated abdominal adipose tissue by 26.7 cm2 among Aboriginal participants compared with European participants (p = 0.007). However, there was no difference in how waist circumference estimated subcutaneous abdominal and visceral adipose tissue among the 2 groups. At the same body mass index and waist circumference, we observed no differences in the majority of cardiovascular disease risk factors among Aboriginal and European participants. The prevalence of dyslipidemia, hypertension, impaired fasting glucose and metabolic syndrome was similar among participants in the 2 groups after adjustment for body mass index, waist circumference, age and sex. INTERPRETATION: We found no difference in the relation between body mass index and risk of cardiovascular disease between men and women of Aboriginal and European descent. We also found no difference between waist circumference and cardiovascular disease risk among these groups. These data support the use of current anthropometric thresholds in the Canadian Aboriginal population. [Abstract/Link to Full Text]

K�rber A, Dissemond J
Necrobiosis lipoidica diabeticorum.
CMAJ. 2007 Dec 4;177(12):1498. [Abstract/Link to Full Text]

Dawrant J, Pacaud D
Pediatric hypocalcemia: making the diagnosis.
CMAJ. 2007 Dec 4;177(12):1494-7. [Abstract/Link to Full Text]

Jacob GP
Goats and sewing machines.
CMAJ. 2007 Dec 4;177(12):1491. [Abstract/Link to Full Text]

Lessard S
West Nile rates soar in 2007.
CMAJ. 2007 Dec 4;177(12):1489. [Abstract/Link to Full Text]

Recent Articles in The Journal of Clinical Investigation

Bode L, Salvestrini C, Park PW, Li JP, Esko JD, Murch S, Freeze HH
Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function.
J Clin Invest. 2007 Dec 6;
Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-gamma, TNF-alpha, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate- or syndecan-1-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-gamma, TNF-alpha, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients. [Abstract/Link to Full Text]

Aikawa T, Whipple CA, Lopez ME, Gunn J, Young A, Lander AD, Korc M
Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells.
J Clin Invest. 2007 Dec 6;
Cells isolated from many types of human cancers express heparin-binding growth factors (HBGFs) that drive tumor growth, metastasis, and angiogenesis. The heparan sulfate proteoglycan glypican-1 (GPC1) is a coreceptor for HBGFs. Here we show that both cancer cell-derived and host-derived GPC1 are crucial for efficient growth, metastasis, and angiogenesis of human and mouse cancer cells. Thus downregulation of GPC1 in the human pancreatic cancer cell line PANC-1, using antisense approaches, resulted in prolonged doubling times and decreased anchorage-independent growth in vitro as well as attenuated tumor growth, angiogenesis, and metastasis when these cells were transplanted into athymic mice. Moreover, athymic mice that lacked GPC1 exhibited decreased tumor angiogenesis and metastasis following intrapancreatic implantation with either PANC-1 or T3M4 human pancreatic cancer cells and fewer pulmonary metastases following intravenous injection of murine B16-F10 melanoma cells. In addition, hepatic endothelial cells isolated from these mice exhibited an attenuated mitogenic response to VEGF-A. These data indicate that cancer cell- and host-derived GPC1 are crucial for full mitogenic, angiogenic, and metastatic potential of cancer cells. Thus targeting GPC1 might provide new avenues for cancer therapy and for the prevention of cancer metastasis. [Abstract/Link to Full Text]

Persson KE, McCallum FJ, Reiling L, Lister NA, Stubbs J, Cowman AF, Marsh K, Beeson JG
Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies.
J Clin Invest. 2007 Dec 6;
Antibodies that inhibit Plasmodium falciparum invasion of erythrocytes are believed to be an important component of immunity against malaria. During blood-stage infection, P. falciparum can use different pathways for erythrocyte invasion by varying the expression and/or utilization of members of 2 invasion ligand families: the erythrocyte-binding antigens (EBAs) and reticulocyte-binding homologs (PfRhs). Invasion pathways can be broadly classified into 2 groups based on the use of sialic acid (SA) on the erythrocyte surface by parasite ligands. We found that inhibitory antibodies are acquired by malaria-exposed Kenyan children and adults against ligands of SA-dependent and SA-independent invasion pathways, and the ability of antibodies to inhibit erythrocyte invasion depended on the pathway used by P. falciparum isolates. Differential inhibition of P. falciparum lines that varied in their use of specific EBA and PfRh proteins pointed to these ligand families as major targets of inhibitory antibodies. Antibodies against recombinant EBA and PfRh proteins were acquired in an age-associated manner, and inhibitory antibodies against EBA175 appeared prominent among some individuals. These findings suggest that variation in invasion phenotype might have evolved as a mechanism that facilitates immune evasion by P. falciparum and that a broad inhibitory response against multiple ligands may be required for effective immunity. [Abstract/Link to Full Text]

Scamuffa N, Siegfried G, Bontemps Y, Ma L, Basak A, Cherel G, Calvo F, Seidah NG, Khatib AM
Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells.
J Clin Invest. 2007 Dec 6;
The proprotein convertases (PCs) are implicated in the activation of various precursor proteins that play an important role in tumor cell metastasis. Here, we report their involvement in the regulation of the metastatic potential of colorectal tumor cells. PC function in the human and murine colon carcinoma cell lines HT-29 and CT-26, respectively, was inhibited using siRNA targeting the PCs furin, PACE4, PC5, and PC7 or by overexpression of the general PC inhibitor alpha1-antitrypsin Portland (alpha1-PDX). We found that overexpression of alpha1-PDX and knockdown of furin expression inhibited processing of IGF-1 receptor and its subsequent activation by IGF-1 to induce IRS-1 and Akt phosphorylation, all important in colon carcinoma metastasis. These data suggest that the PC furin is a major IGF-1 receptor convertase. Expression of alpha1-PDX reduced the production of TNF-alpha and IL-1alpha by human colon carcinoma cells, and incubation of murine liver endothelial cells with conditioned media derived from these cells failed to induce tumor cell adhesion to activated murine endothelial cells, a critical step in metastatic invasion. Furthermore, colon carcinoma cells in which PC activity was inhibited by overexpression of alpha1-PDX when injected into the portal vein of mice showed a significantly reduced ability to form liver metastases. This suggests that inhibition of PCs is a potentially promising strategy for the prevention of colorectal liver metastasis. [Abstract/Link to Full Text]

Bhagat G, Naiyer AJ, Shah JG, Harper J, Jabri B, Wang TC, Green PH, Manavalan JS
Small intestinal CD8TCRgammadeltaNKG2A intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease.
J Clin Invest. 2007 Dec 6;
Intraepithelial lymphocytes (IELs) bearing the gammadelta TCR are more abundant in the small intestinal mucosa of patients with celiac disease (CD) compared with healthy individuals. However, their role in disease pathogenesis is not well understood. Here, we investigated the functional attributes of TCRgammadelta(+) IELs isolated from intestinal biopsies of patients with either active celiac disease (ACD) or those on a gluten-free diet (GFD). We found that compared with individuals with ACD, individuals on GFD have a higher frequency of CD8(+)TCRgammadelta(+) IELs that express the inhibitory NK receptor NKG2A and intracellular TGF-beta1. TCR triggering as well as cross-linking of NKG2A increased both TGF-beta1 intracellular expression and secretion in vitro. Coculture of sorted TCRgammadelta(+)NKG2A(+) IELs, IL-15-stimulated TCRalphabeta(+) IELs, and HLA-E(+) enterocytes resulted in a decreased percentage of cytotoxic CD8(+)TCRalphabeta(+) IELs expressing intracellular IFN-gamma and granzyme-B and surface NKG2D. This inhibition was partially abrogated by blocking either TGF-beta alone or both NKG2A and HLA-E. Thus, our data indicate that suppression was at least partially mediated by TGF-beta secretion as a result of engagement of NKG2A with its ligand, HLA-E, on enterocytes and/or TCRalphabeta(+) IELs. These findings demonstrate that human small intestinal CD8(+)TCRgammadelta(+) IELs may have regulatory potential in celiac disease. [Abstract/Link to Full Text]

Cai L, Ji A, de Beer FC, Tannock LR, van der Westhuyzen DR
SR-BI protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance.
J Clin Invest. 2007 Dec 6;
Septic shock results from an uncontrolled inflammatory response, mediated primarily by LPS. Cholesterol transport plays an important role in the host response to LPS, as LPS is neutralized by lipoproteins and adrenal cholesterol uptake is required for antiinflammatory glucocorticoid synthesis. In this study, we show that scavenger receptor B-I (SR-BI), an HDL receptor that mediates HDL cholesterol ester uptake into cells, is required for the normal antiinflammatory response to LPS-induced endotoxic shock. Despite elevated plasma HDL levels, SR-BI-null mice displayed an uncontrollable inflammatory cytokine response and a markedly higher lethality rate than control mice in response to LPS. In addition, SR-BI-null mice showed a lack of inducible glucocorticoid synthesis in response to LPS, bacterial infection, stress, or ACTH. Glucocorticoid insufficiency in SR-BI-null mice was due to primary adrenal malfunction resulting from deficient cholesterol delivery from HDL. Furthermore, corticosterone supplementation decreased the sensitivity of SR-BI-null mice to LPS. Plasma from control and SR-BI-null mice exhibited a similar ability to neutralize LPS, whereas SR-BI-null mice showed decreased plasma clearance of LPS into the liver and hepatocytes compared with normal mice. We conclude that SR-BI in mice is required for the antiinflammatory response to LPS-induced endotoxic shock, likely through its essential role in facilitating glucocorticoid production and LPS hepatic clearance. [Abstract/Link to Full Text]

Moutouh-de Parseval LA, Verhelle D, Glezer E, Jensen-Pergakes K, Ferguson GD, Corral LG, Morris CL, Muller G, Brady H, Chan K
Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34 cells.
J Clin Invest. 2007 Dec 6;
Sickle-cell disease (SCD) and beta thalassemia constitute worldwide public health problems. New therapies, including hydroxyurea, have attempted to augment the synthesis of fetal hemoglobin (HbF) and improve current treatment. Lenalidomide and pomalidomide are members of a class of immunomodulators used as anticancer agents. Because clinical trials have demonstrated that lenalidomide reduces or eliminates the need for transfusions in some patients with disrupted blood cell production, we investigated the effects of lenalidomide and pomalidomide on erythropoiesis and hemoglobin synthesis. We used an in vitro erythropoiesis model derived from human CD34(+) progenitor cells from normal and SCD donors. We found that both compounds slowed erythroid maturation, increased proliferation of immature erythroid cells, and regulated hemoglobin transcription, resulting in potent induction of HbF without the cytotoxicity associated with other HbF inducers. When combined with hydroxyurea, pomalidomide and, to a lesser extent, lenalidomide were found to have synergistic effects on HbF upregulation. Our results elucidate what we believe to be a new mechanism of action of pomalidomide and lenalidomide and support the hypothesis that pomalidomide, used alone or in combination with hydroxyurea, may improve erythropoiesis and increase the ratio of fetal to adult hemoglobin. These findings support the evaluation of pomalidomide as an innovative new therapy for beta-hemoglobinopathies. [Abstract/Link to Full Text]

Tschumper RC, Geyer SM, Campbell ME, Kay NE, Shanafelt TD, Zent CS, Nowakowski GS, Call TG, Dewald GW, Jelinek DF
Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of chronic lymphocytic leukemia patients.
J Clin Invest. 2007 Dec 6;
Survival of patients with B cell chronic lymphocytic leukemia (B-CLL) can be predicted by analysis of mutations in the immunoglobulin heavy chain variable gene (IGHV). Patients without mutations (unmutated [UM]) are at greater risk for disease progression and death than patients with mutations (M). Despite this broad prognostic difference, there remains wide intragroup variation in the clinical outcome of UM patients, especially those with low/intermediate Rai risk disease. We evaluated UM B-CLL patients with low/intermediate Rai risk to determine the relationship between IGHV, IGH diversity (IGHD), and IGH joining (IGHJ) gene usage and time to treatment (TTT). Irrespective of IGHV usage, UM patients whose B-CLL cells expressed the IGHD3-3 gene had a significantly shorter TTT than other UM B-CLL patients, and specifically, use of the IGHD3-3 gene in reading frame 2 (RF2) predicted shorter TTT. As expected, Rai risk was the best single prognostic factor for TTT; however, IGHD usage was also a significant variable for TTT. Therefore, both IGHD gene and IGHD RF usage have prognostic relevance in UM B-CLL patients with low/intermediate Rai risk disease. In addition, these data support the concept that antigen-driven selection of specific Ig receptors plays a role in the clinical course of B-CLL. [Abstract/Link to Full Text]

Chung SW, Liu X, Macias AA, Baron RM, Perrella MA
Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice.
J Clin Invest. 2007 Dec 3;
Sepsis is characterized by a systemic response to severe infection. Although the inflammatory phase of sepsis helps eradicate the infection, it can have detrimental consequences if left unchecked. Therapy directed against inflammatory mediators of sepsis has shown little success and has the potential to impair innate antimicrobial defenses. Heme oxygenase-1 (HO-1) and the product of its enzymatic reaction, CO, have beneficial antiinflammatory properties, but little is known about their effects on microbial sepsis. Here, we have demonstrated that during microbial sepsis, HO-1-derived CO plays an important role in the antimicrobial process without inhibiting the inflammatory response. HO-1-deficient mice suffered exaggerated lethality from polymicrobial sepsis. Targeting HO-1 to SMCs and myofibroblasts of blood vessels and bowel ameliorated sepsis-induced death associated with Enterococcus faecalis, but not Escherichia coli, infection. The increase in HO-1 expression did not suppress circulating inflammatory cells or their accumulation at the site of injury but did enhance bacterial clearance by increasing phagocytosis and the endogenous antimicrobial response. Furthermore, injection of a CO-releasing molecule into WT mice increased phagocytosis and rescued HO-1-deficient mice from sepsis-induced lethality. These data advocate HO-1-derived CO as an important mediator of the host defense response to sepsis and suggest CO administration as a possible treatment for the disease. [Abstract/Link to Full Text]

Parish CL, Castelo-Branco G, Rawal N, Tonnesen J, Sorensen AT, Salto C, Kokaia M, Lindvall O, Arenas E
Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice.
J Clin Invest. 2007 Dec 3;
Dopamine (DA) cell replacement therapy in Parkinson disease (PD) can be achieved using human fetal mesencephalic tissue; however, limited tissue availability has hindered further developments. Embryonic stem cells provide a promising alternative, but poor survival and risk of teratoma formation have prevented their clinical application. We present here a method for generating large numbers of DA neurons based on expanding and differentiating ventral midbrain (VM) neural stem cells/progenitors in the presence of key signals necessary for VM DA neuron development. Mouse VM neurospheres (VMNs) expanded with FGF2, differentiated with sonic hedgehog and FGF8, and transfected with Wnt5a (VMN-Wnt5a) generated 10-fold more DA neurons than did conventional FGF2-treated VMNs. VMN-Wnt5a cells exhibited the transcriptional and biochemical profiles and intrinsic electrophysiological properties of midbrain DA cells. Transplantation of these cells into parkinsonian mice resulted in significant cellular and functional recovery. Importantly, no tumors were detected and only a few transplanted grafts contained sporadic nestin-expressing progenitors. Our findings show that Wnt5a improves the differentiation and functional integration of stem cell-derived DA neurons in vivo and define Wnt5a-treated neural stem cells as an efficient and safe source of DA neurons for cell replacement therapy in PD. [Abstract/Link to Full Text]

Debies MT, Gestl SA, Mathers JL, Mikse OR, Leonard TL, Moody SE, Chodosh LA, Cardiff RD, Gunther EJ
Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19/p53 pathway lesions but not p16 loss.
J Clin Invest. 2007 Dec 3;
Breast cancers frequently progress or relapse during targeted therapy, but the molecular mechanisms that enable escape remain poorly understood. We elucidated genetic determinants underlying tumor escape in a transgenic mouse model of Wnt pathway-driven breast cancer, wherein targeted therapy is simulated by abrogating doxycycline-dependent Wnt1 transgene expression within established tumors. In mice with intact tumor suppressor pathways, tumors typically circumvented doxycycline withdrawal by reactivating Wnt signaling, either via aberrant (doxycycline-independent) Wnt1 transgene expression or via acquired somatic mutations in the gene encoding beta-catenin. Germline introduction of mutant tumor suppressor alleles into the model altered the timing and mode of tumor escape. Relapses occurring in the context of null Ink4a/Arf alleles (disrupting both the p16(Ink4a) and p19(Arf) tumor suppressors) arose quickly and rarely reactivated the Wnt pathway. In addition, Ink4a/Arf-deficient relapses resembled p53-deficient relapses in that both displayed morphologic and molecular hallmarks of an epithelial-to-mesenchymal transition (EMT). Notably, Ink4a/Arf deficiency promoted relapse in the absence of gross genomic instability. Moreover, Ink4a/Arf-encoded proteins differed in their capacity to suppress oncogene independence. Isolated p19(Arf) deficiency mirrored p53 deficiency in that both promoted rapid, EMT-associated mammary tumor escape, whereas isolated p16(Ink4a) deficiency failed to accelerate relapse. Thus, p19(Arf)/p53 pathway lesions may promote mammary cancer relapse even when inhibition of a targeted oncogenic signaling pathway remains in force. [Abstract/Link to Full Text]

McNamara JO, Kolonias D, Pastor F, Mittler RS, Chen L, Giangrande PH, Sullenger B, Gilboa E
Multivalent 4-1BB binding aptamers costimulate CD8 T cells and inhibit tumor growth in mice.
J Clin Invest. 2007 Dec 3;
4-1BB is a major costimulatory receptor that promotes the survival and expansion of activated T cells. Administration of agonistic anti-4-1BB Abs has been previously shown to enhance tumor immunity in mice. Abs are cell-based products posing significant cost, manufacturing, and regulatory challenges. Aptamers are oligonucleotide-based ligands that exhibit specificity and avidity comparable to, or exceeding, that of Abs. To date, various aptamers have been shown to inhibit the function of their cognate target. Here, we have described the development of an aptamer that binds 4-1BB expressed on the surface of activated mouse T cells and shown that multivalent configurations of the aptamer costimulated T cell activation in vitro and mediated tumor rejection in mice. Because aptamers can be chemically synthesized, manufacturing and the regulatory approval process should be substantially simpler and less costly than for Abs. Agonistic aptamers could therefore represent a superior alternative to Abs for the therapeutic manipulation of the immune system. [Abstract/Link to Full Text]

Park HJ, Georgescu SP, Du C, Madias C, Aronovitz MJ, Welzig CM, Wang B, Begley U, Zhang Y, Blaustein RO, Patten RD, Karas RH, Van Tol HH, Osborne TF, Shimano H, Liao R, Link MS, Galper JB
Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP.
J Clin Invest. 2007 Dec 3;
Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein-coupled inward rectifying K(+) channel GIRK1/4 and results in an acetylcholine-sensitive K(+) current, I(KACh). We describe a unique relationship between lipid homeostasis, the lipid-sensitive transcription factor SREBP-1, regulation of the cardiac parasympathetic response, and the development of ventricular arrhythmia. In embryonic chick atrial myocytes, lipid lowering by culture in lipoprotein-depleted serum increased SREBP-1 levels, GIRK1 expression, and I(KACh) activation. Regulation of the GIRK1 promoter by SREBP-1 and lipid lowering was dependent on interaction with 2 tandem sterol response elements and an upstream E-box motif. Expression of dominant negative SREBP-1 (DN-SREBP-1) reversed the effect of lipid lowering on I(KACh) and GIRK1. In SREBP-1 knockout mice, both the response of the heart to parasympathetic stimulation and the expression of GIRK1 were reduced compared with WT. I(KACh), attenuated in atrial myocytes from SREBP-1 knockout mice, was stimulated by SREBP-1 expression. Following myocardial infarction, SREBP-1 knockout mice were twice as likely as WT mice to develop ventricular tachycardia in response to programmed ventricular stimulation. These results demonstrate a relationship between lipid metabolism and parasympathetic response that may play a role in arrhythmogenesis. [Abstract/Link to Full Text]

Gaultier A, Arandjelovic S, Li X, Janes J, Dragojlovic N, Zhou GP, Dolkas J, Myers RR, Gonias SL, Campana WM
A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents.
J Clin Invest. 2007 Dec 3;
Injury to the peripheral nervous system (PNS) initiates a response controlled by multiple extracellular mediators, many of which contribute to the development of neuropathic pain. Schwann cells in an injured nerve demonstrate increased expression of LDL receptor-related protein-1 (LRP1), an endocytic receptor for diverse ligands and a cell survival factor. Here we report that a fragment of LRP1, in which a soluble or shed form of LRP1 with an intact alpha-chain (sLRP-alpha), was shed by Schwann cells in vitro and in the PNS after injury. Injection of purified sLRP-alpha into mouse sciatic nerves prior to chronic constriction injury (CCI) inhibited p38 MAPK activation (P-p38) and decreased expression of TNF-alpha and IL-1beta locally. sLRP-alpha also inhibited CCI-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. In cultures of Schwann cells, astrocytes, and microglia, sLRP-alpha inhibited TNF-alpha-induced activation of p38 MAPK and ERK/MAPK. The activity of sLRP-alpha did not involve TNF-alpha binding, but rather glial cell preconditioning, so that the subsequent response to TNF-alpha was inhibited. Our results show that sLRP-alpha is biologically active and may attenuate neuropathic pain. In the PNS, the function of LRP1 may reflect the integrated activities of the membrane-anchored and shed forms of LRP1. [Abstract/Link to Full Text]

Abdollahi-Roodsaz S, Joosten LA, Koenders MI, Devesa I, Roelofs MF, Radstake TR, Heuvelmans-Jacobs M, Akira S, Nicklin MJ, Ribeiro-Dias F, van den Berg WB
Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis.
J Clin Invest. 2007 Dec 3;
TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial or host-derived ligands found in arthritic joints. Here, we show that TLR2 and TLR4, but not TLR9, are involved in the pathogenesis of autoimmune arthritis and play distinct roles in the regulation of T cells and cytokines. We investigated the involvement of TLR2, TLR4, and TLR9 in the progression of arthritis using IL-1 receptor antagonist-knockout (IL1rn(-/-)) mice, which spontaneously develop an autoimmune T cell-mediated arthritis. Spontaneous onset of arthritis was dependent on TLR activation by microbial flora, as germ-free mice did not develop arthritis. Clinical and histopathological evaluation of IL1rn(-/-)Tlr2(-/-) mice revealed more severe arthritis, characterized by reduced suppressive function of Tregs and substantially increased IFN-gamma production by T cells. IL1rn(-/-)Tlr4(-/-) mice were, in contrast, protected against severe arthritis and had markedly lower numbers of Th17 cells and a reduced capacity to produce IL-17. A lack of Tlr9 did not affect the progression of arthritis. While any therapeutic intervention targeting TLR2 still seems complicated, the strict position of TLR4 upstream of a number of pathogenic cytokines including IL-17 provides an interesting potential therapeutic target for rheumatoid arthritis. [Abstract/Link to Full Text]

Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR
Adoptive transfer of effector CD8 T cells derived from central memory cells establishes persistent T cell memory in primates.
J Clin Invest. 2007 Dec 3;
The adoptive transfer of antigen-specific T cells that have been expanded ex vivo is being actively pursued to treat infections and malignancy in humans. The T cell populations that are available for adoptive immunotherapy include both effector memory and central memory cells, and these differ in phenotype, function, and homing. The efficacy of adoptive immunotherapy requires that transferred T cells persist in vivo, but identifying T cells that can reproducibly survive in vivo after they have been numerically expanded by in vitro culture has proven difficult. Here we show that in macaques, antigen-specific CD8(+) T cell clones derived from central memory T cells, but not effector memory T cells, persisted long-term in vivo, reacquired phenotypic and functional properties of memory T cells, and occupied memory T cell niches. These results demonstrate that clonally derived CD8(+) T cells isolated from central memory T cells are distinct from those derived from effector memory T cells and retain an intrinsic capacity that enables them to survive after adoptive transfer and revert to the memory cell pool. These results could have significant implications for the selection of T cells to expand or to engineer for adoptive immunotherapy of human infections or malignancy. [Abstract/Link to Full Text]

Ota T, Gayet C, Ginsberg HN
Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents.
J Clin Invest. 2007 Dec 3;
ER stress can cause hepatic insulin resistance and steatosis. Increased VLDL secretion could protect the liver from ER stress-induced steatosis, but the effect of lipid-induced ER stress on the secretion of VLDL is unknown. To determine the effect of lipids on hepatic ER stress and VLDL secretion, we treated McA-RH7777 liver cells with free fatty acids. Prolonged exposure increased cell triglycerides, induced steatosis, and increased ER stress. Effects on apoB100 secretion, which is required for VLDL assembly, were parabolic, with moderate free fatty acid exposure increasing apoB100 secretion, while greater lipid loading inhibited apoB100 secretion. This decreased secretion at higher lipid levels was due to increased protein degradation through both proteasomal and nonproteasomal pathways and was dependent on the induction of ER stress. These findings were supported in vivo, where intravenous infusion of oleic acid (OA) in mice increased ER stress in a duration-dependent manner. apoB secretion was again parabolic, stimulated by moderate, but not prolonged, OA infusion. Inhibition of ER stress was able to restore OA-stimulated apoB secretion after prolonged OA infusion. These results suggest that excessive ER stress in response to increased hepatic lipids may decrease the ability of the liver to secrete triglycerides by limiting apoB secretion, potentially worsening steatosis. [Abstract/Link to Full Text]

Fern�ndez A, Sanguino A, Peng Z, Ozturk E, Chen J, Crespo A, Wulf S, Shavrin A, Qin C, Ma J, Trent J, Lin Y, Han HD, Mangala LS, Bankson JA, Gelovani J, Samarel A, Bornmann W, Sood AK, Lopez-Berestein G
An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic.
J Clin Invest. 2007 Dec 3;117(12):4044-4054.
Targeting kinases is central to drug-based cancer therapy but remains challenging because the drugs often lack specificity, which may cause toxic side effects. Modulating side effects is difficult because kinases are evolutionarily and hence structurally related. The lack of specificity of the anticancer drug imatinib enables it to be used to treat chronic myeloid leukemia, where its target is the Bcr-Abl kinase, as well as a proportion of gastrointestinal stromal tumors (GISTs), where its target is the C-Kit kinase. However, imatinib also has cardiotoxic effects traceable to its impact on the C-Abl kinase. Motivated by this finding, we made a modification to imatinib that hampers Bcr-Abl inhibition; refocuses the impact on the C-Kit kinase; and promotes inhibition of an additional target, JNK, a change that is required to reinforce prevention of cardiotoxicity. We established the molecular blueprint for target discrimination in vitro using spectrophotometric and colorimetric assays and through a phage-displayed kinase screening library. We demonstrated controlled inhibitory impact on C-Kit kinase in human cell lines and established the therapeutic impact of the engineered compound in a novel GIST mouse model, revealing a marked reduction of cardiotoxicity. These findings identify the reengineered imatinib as an agent to treat GISTs with curbed side effects and reveal a bottom-up approach to control drug specificity. [Abstract/Link to Full Text]

Rao Y, Liu ZW, Borok E, Rabenstein RL, Shanabrough M, Lu M, Picciotto MR, Horvath TL, Gao XB
Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons.
J Clin Invest. 2007 Dec 3;117(12):4022-4033.
Sleep is a natural process that preserves energy, facilitates development, and restores the nervous system in higher animals. Sleep loss resulting from physiological and pathological conditions exerts tremendous pressure on neuronal circuitry responsible for sleep-wake regulation. It is not yet clear how acute and chronic sleep loss modify neuronal activities and lead to adaptive changes in animals. Here, we show that acute and chronic prolonged wakefulness in mice induced by modafinil treatment produced long-term potentiation (LTP) of glutamatergic synapses on hypocretin/orexin neurons in the lateral hypothalamus, a well-established arousal/wake-promoting center. A similar potentiation of synaptic strength at glutamatergic synapses on hypocretin/orexin neurons was also seen when mice were sleep deprived for 4 hours by gentle handling. Blockade of dopamine D1 receptors attenuated prolonged wakefulness and synaptic plasticity in these neurons, suggesting that modafinil functions through activation of the dopamine system. Also, activation of the cAMP pathway was not able to further induce LTP at glutamatergic synapses in brain slices from mice treated with modafinil. These results indicate that synaptic plasticity due to prolonged wakefulness occurs in circuits responsible for arousal and may contribute to changes in the brain and body of animals experiencing sleep loss. [Abstract/Link to Full Text]

Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, Ceccarelli C, Santini D, Paterini P, Marcu KB, Chieco P, Bonaf� M
IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland.
J Clin Invest. 2007 Dec 3;117(12):3988-4002.
High serum levels of IL-6 correlate with poor outcome in breast cancer patients. However, no data are available on the relationship between IL-6 and mammary stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Herein, we address this issue in the MCF-7 breast cancer cell line and in primary human mammospheres (MS), multicellular structures enriched in stem/progenitor cells of the mammary gland. MS from node invasive breast carcinoma tissues expressed IL-6 mRNA at higher levels than did MS from matched non-neoplastic mammary glands. In addition, IL-6 mRNA was detected only in basal-like breast carcinoma tissues, an aggressive breast carcinoma variant showing stem cell features. IL-6 treatment triggered Notch-3-dependent upregulation of the Notch ligand Jagged-1 and promotion of MS and MCF-7-derived spheroid growth. Moreover, IL-6 induced Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promoted a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. Finally, autocrine IL-6 signaling relied upon Notch-3 activity to sustain the aggressive features of MCF-7-derived hypoxia-selected cells. In conclusion, these data support the hypothesis that IL-6 induces malignant features in Notch-3-expressing stem/progenitor cells from human ductal breast carcinoma and normal mammary gland. [Abstract/Link to Full Text]

Huang Z, Richmond TD, Muntean AG, Barber DL, Weiss MJ, Crispino JD
STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice.
J Clin Invest. 2007 Dec 3;117(12):3890-3899.
Thrombocytosis is associated with inflammation, and certain inflammatory cytokines, including IFN-gamma, stimulate megakaryocyte and platelet production. However, the roles of IFN-gamma and its downstream effector STAT1 in megakaryocyte development are poorly understood. We previously reported that STAT1 expression was significantly downregulated in Gata1-knockdown murine megakaryocytes, which also have impaired terminal maturation. Here, we show that ectopic expression of STAT1, or its target effector IRF-1, rescued multiple defects in Gata1-deficient megakaryopoiesis in mice, inducing polyploidization and expression of a subset of platelet-expressing genes. Enforced expression of STAT1, IRF-1, or GATA-1 enhanced phosphorylation of STAT1, STAT3, and STAT5 in cultured Gata1-deficient murine megakaryocytes, with concomitant megakaryocyte maturation. In contrast, enhanced thrombopoietin signaling, conferred by enforced expression of constitutively active JAK2 or c-MPL, induced phosphorylation of STAT3 and STAT5, but not STAT1, and failed to rescue megakaryocyte maturation. Finally, megakaryocytes from Stat1(-/-) mice were defective in polyploidization. Together, these findings reveal a unique role for STAT1 in megakaryopoiesis and provide new insights into how GATA-1 regulates this process. Our studies elucidate potential mechanisms by which various inflammatory disorders can cause elevated platelet counts. [Abstract/Link to Full Text]

Seshasayee D, Lee WP, Zhou M, Shu J, Suto E, Zhang J, Diehl L, Austin CD, Meng YG, Tan M, Bullens SL, Seeber S, Fuentes ME, Labrijn AF, Graus YM, Miller LA, Schelegle ES, Hyde DM, Wu LC, Hymowitz SG, Martin F
In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation.
J Clin Invest. 2007 Dec 3;117(12):3868-3878.
Thymic stromal lymphopoietin (TSLP) potently induces deregulation of Th2 responses, a hallmark feature of allergic inflammatory diseases such as asthma, atopic dermatitis, and allergic rhinitis. However, direct downstream in vivo mediators in the TSLP-induced atopic immune cascade have not been identified. In our current study, we have shown that OX40 ligand (OX40L) is a critical in vivo mediator of TSLP-mediated Th2 responses. Treating mice with OX40L-blocking antibodies substantially inhibited immune responses induced by TSLP in the lung and skin, including Th2 inflammatory cell infiltration, cytokine secretion, and IgE production. OX40L-blocking antibodies also inhibited antigen-driven Th2 inflammation in mouse and nonhuman primate models of asthma. This treatment resulted in both blockade of the OX40-OX40L receptor-ligand interaction and depletion of OX40L-positive cells. The use of a blocking, OX40L-specific mAb thus presents a promising strategy for the treatment of allergic diseases associated with pathologic Th2 immune responses. [Abstract/Link to Full Text]

Hu CY, Rodriguez-Pinto D, Du W, Ahuja A, Henegariu O, Wong FS, Shlomchik MJ, Wen L
Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice.
J Clin Invest. 2007 Dec 3;117(12):3857-3867.
The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell-depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients. [Abstract/Link to Full Text]

Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, Travis WD, Bornmann W, Veach D, Clarkson B, Bromberg JF
Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas.
J Clin Invest. 2007 Dec;117(12):3846-56.
Persistently activated or tyrosine-phosphorylated STAT3 (pSTAT3) is found in 50% of lung adenocarcinomas. pSTAT3 is found in primary adenocarcinomas and cell lines harboring somatic-activating mutations in the tyrosine kinase domain of EGFR. Treatment of cell lines with either an EGFR inhibitor or an src kinase inhibitor had no effect on pSTAT3 levels, whereas a pan-JAK inhibitor (P6) blocked activation of STAT3 and inhibited tumorigenesis. Cell lines expressing these persistently activated mutant EGFRs also produced high IL-6 levels, and blockade of the IL-6/gp130/JAK pathway led to a decrease in pSTAT3 levels. In addition, reduction of IL-6 levels by RNA interference led to a decrease in tumorigenesis. Introduction of persistently activated EGFR into immortalized breast epithelial cells led to tumorigenesis, IL-6 expression, and STAT3 activation, all of which could be inhibited with P6 or gp130 blockade. Furthermore, inhibition of EGFR activity in multiple cell lines partially blocked transcription of IL-6 and concurrently decreased production and release of IL-6. Finally, immunohistochemical analysis revealed a positive correlation between pSTAT3 and IL-6 positivity in primary lung adenocarcinomas. Therefore, mutant EGFR could activate the gp130/JAK/STAT3 pathway by means of IL-6 upregulation in primary human lung adenocarcinomas, making this pathway a potential target for cancer treatment. [Abstract/Link to Full Text]

Babu AN, Murakawa T, Thurman JM, Miller EJ, Henson PM, Zamora MR, Voelkel NF, Nicolls MR
Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis.
J Clin Invest. 2007 Dec 3;117(12):3774-3785.
Small airway fibrosis (bronchiolitis obliterans syndrome) is the primary obstacle to long-term survival following lung transplantation. Here, we show the importance of functional microvasculature in the prevention of epithelial loss and fibrosis due to rejection and for the first time, relate allograft microvascular injury and loss of tissue perfusion to immunotherapy-resistant rejection. To explore the role of alloimmune rejection and airway ischemia in the development of fibroproliferation, we used a murine orthotopic tracheal transplant model. We determined that transplants were reperfused by connection of recipient vessels to donor vessels at the surgical anastomosis site. Microcirculation through the newly formed vascular anastomoses appeared partially dependent on VEGFR2 and CXCR2 pathways. In the absence of immunosuppression, the microvasculature in rejecting allografts exhibited vascular complement deposition, diminished endothelial CD31 expression, and absent perfusion prior to the onset of fibroproliferation. Rejecting grafts with extensive endothelial cell injury were refractory to immunotherapy. After early microvascular loss, neovascularization was eventually observed in the membranous trachea, indicating a reestablishment of graft perfusion in established fibrosis. One implication of this study is that bronchial artery revascularization at the time of lung transplantation may decrease the risk of subsequent airway fibrosis. [Abstract/Link to Full Text]

Tang X, Zhu Y, Han L, Kim AL, Kopelovich L, Bickers DR, Athar M
CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice.
J Clin Invest. 2007 Dec;117(12):3753-64.
Mutations in the tumor suppressor p53 are detectable in over 50% of all human malignancies. Mutant p53 protein is incapable of transactivating its downstream target genes that are required for DNA repair and apoptosis. Chronic exposure to UVB induces p53 mutations and is carcinogenic in both murine and human skin. CP-31398, a styrylquinazoline compound, restores the tumor suppressor functions of mutant forms of p53 in tumor cells. However, its effectiveness in vivo remains unclear. Here, we demonstrate that CP-31398 blocked UVB-induced skin carcinogenesis and was associated with increases in p53, p21, and BclXs. CP-31398 downregulated Bcl2, proliferating nuclear cell antigen, and cyclin D1. Activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase also occurred in both tumor and perilesional skin following treatment. CP-31398 induced the expression of p53-dependent target proteins, and this was followed by apoptosis in UVB-irradiated wild-type mice but not in their p53-deficient littermates. Similar effects were observed in human skin carcinoma A431 cells expressing mutant p53. In addition, CP-31398 induced mitochondrial translocation of p53, leading to changes in mitochondrial membrane permeability pore transition (MPT) and consequent cytochrome c release in these cells. Blocking MPT diminished p53 translocation and apoptosis. These studies indicate that reconstituting p53 tumor suppressor functions in vivo by small molecular weight compounds may block the pathogenesis and progression of skin cancer. [Abstract/Link to Full Text]

Koh YJ, Kang S, Lee HJ, Choi TS, Lee HS, Cho CH, Koh GY
Bone marrow-derived circulating progenitor cells fail to transdifferentiate into adipocytes in adult adipose tissues in mice.
J Clin Invest. 2007 Dec 3;117(12):3684-3695.
Little is known about whether bone marrow-derived circulating progenitor cells (BMDCPCs) can transdifferentiate into adipocytes in adipose tissues or play a role in expanding adipocyte number during adipose tissue growth. Using a mouse bone marrow transplantation model, we addressed whether BMDCPCs can transdifferentiate into adipocytes under standard conditions as well as in the settings of diet-induced obesity, rosiglitazone treatment, and exposure to G-CSF. We also addressed the possibility of transdifferentiation to adipocytes in a murine parabiosis model. In each of these settings, our findings indicated that BMDCPCs did not transdifferentiate into either unilocular or multilocular adipocytes in adipose tissues. Most BMDCPCs became resident and phagocytic macrophages in adipose tissues - which resembled transdifferentiated multilocular adipocytes by appearance, but displayed cell surface markers characteristic for macrophages - in the absence of adipocyte marker expression. When exposed to adipogenic medium in vitro, bone marrow cells differentiated into multilocular, but not unilocular, adipocytes, but transdifferentiation was not observed in vivo, even in the contexts of adipose tissue regrowth or dermal wound healing. Our results suggest that BMDCPCs do not transdifferentiate into adipocytes in vivo and play little, if any, role in expanding the number of adipocytes during the growth of adipose tissues. [Abstract/Link to Full Text]

Schafer ZT, Brugge JS
IL-6 involvement in epithelial cancers.
J Clin Invest. 2007 Dec;117(12):3660-3.
In this issue of the JCI, two reports provide intriguing new information on the role of the inflammatory cytokine IL-6 in breast and lung cancer. The study by Sansone et al. implicates IL-6 in the instigation of malignant properties in breast cancer stem cells (see the related article beginning on page 3988). The study by Gao et al. identifies mutant variants of EGFR as inducers of IL-6 in lung adenocarcinomas (see the related article beginning on page 3846). These studies add to our understanding of potential roles for IL-6 in cancer and further motivate investigations of IL-6-targeted chemotherapeutics. [Abstract/Link to Full Text]

El-Deiry WS
Targeting mutant p53 shows promise for sunscreens and skin cancer.
J Clin Invest. 2007 Dec 3;117(12):3658-3660.
Chronic exposure to UV light is a risk factor for skin cancer in which signature mutations in the p53 tumor suppressor gene occur due to DNA damage and contribute to cancer development. In this issue of the JCI, Tang et al. report on their study of a nonimmunodeficient mouse model of UVB-induced skin cancer and human skin carcinoma cells and show that the mutant p53 conformation-modifying drug CP-31398 not only treats these tumors but also prevents them (see the related article beginning on page 3753). These studies have important implications for chemoprevention as well as therapy of common, mutant p53-driven tumors. [Abstract/Link to Full Text]

Scadden DT
The weight of cell identity.
J Clin Invest. 2007 Dec;117(12):3653-5.
Recent studies involving molecular modification of adult somatic cells have pointed to a remarkable plasticity in cell identity. In this issue of the JCI, Koh and colleagues assessed whether bone marrow-derived cells could alter their fate under circumstances conducive to adipocyte generation in vivo (see the related article beginning on page 3684). These cells remained true to their roots, indicating how difficult it will be to exploit cell plasticity for therapeutic purposes. [Abstract/Link to Full Text]

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

Casares FM, Mantione K
Pesticides may be altering constitutive nitric oxide release, thereby compromising health.
Med Sci Monit. 2006 Oct;12(10):RA235-40.
Numerous studies, focusing on the effects of environmental pollutants such as pyrethroids, organochlorines, organophosphate pesticides, etc, appear to affect intracellular ion balance, particularly calcium. We speculate that these chemicals may specifically target constitutive nitric oxide synthase (cNOS)-mediated processes, e.g., immune. The alteration of intracellular Ca2+ transients by these pollutants may represent an important common mechanism responsible for the abrogation of cNOS activation. Moreover, one can hypothesize that exposure to sublethal levels of pesticides that alter calcium transients, could potentially lead to immune, neural and vascular dysfunction in animals. This may be especially true for marine organisms that can be found close to shore and in estuaries, which are more likely to be exposed to these compounds resulting from riverine and other inputs. [Abstract/Link to Full Text]

Aller MA, Arias JL, S�nchez-Pat�n F, Arias J
The inflammatory response: an efficient way of life.
Med Sci Monit. 2006 Oct;12(10):RA225-34.
The successive pathophysiological mechanisms that develop in the interstitium of tissues when these undergo acute post-traumatic inflammation are considered increasingly complex trophic functional systems for using oxygen. The nervous or immediate functional system presents ischemia-revascularization and edema, which favor nutrition by diffusion through injured tissue. In this phase of the inflammatory response, while the progression of the interstitial edema produces progressive distancing of the epithelial cells from the capillaries, it simultaneously enhances lymphatic circulation, which assumes an unusually important role. During immune system function, tissue nutrition is carried out by leukocytes through symbiosis with bacteria. Improper use of oxygen persists in this immune phase. Activated phagocytes would require anaerobic glycolysis as the main source of ATP for their functions. During this immune phase, lymphatic circulation still plays a major role. The dilatation of lymphatics may be mediated by cytokines, leuokotrienes, and prostaglandins produced at the trauma site by activated resident and infiltrating cells. Finally, the endocrine functional system facilitates the arrival of oxygen, transported by red blood cells and capillaries. Their trophic potential permits the tissue specialization required for tissue repair to take place. However, if complications occur during the evolution of acute inflammation, the tissues could go back to using more primitive trophic mechanisms. In summary, the ability of the interstitial tissue to express increasingly complex nutritional systems in relation to oxygen use could reflect the importance of this space as a battleground for inflammation and, as a result, for evolution. [Abstract/Link to Full Text]

Nakajima T
Signaling cascades in radiation-induced apoptosis: roles of protein kinase C in the apoptosis regulation.
Med Sci Monit. 2006 Oct;12(10):RA220-4.
Apoptosis is a biologic mechanism for eliminating damaged cells from the cell population. Apoptosis is known to be induced by irradiation and can prevent the development of disease states such as carcinogenesis or abnormal tissue formation. On the other hand, if the mechanism is properly controlled, radiotherapy can be used to kill cancer cells more efficiently. Radiation-induced apoptosis is regulated by the balance between cellular anti-apoptotic and (pro-)apoptotic signals. Many regulators of radiation-induced apoptosis have been identified and analyzed. Protein kinase C (PKC) is a family of serine/threonine kinases and one of the regulators in radiation-induced apoptosis. PKC has some subtypes, each of whose functions has been analyzed in radiation-induced signaling cascades. It has been demonstrated that each of PKC subtypes has distinct functions in radiation-induced apoptosis. Moreover, some participants in PKC-related signaling cascades have been identified in radiation-induced apoptosis. Interestingly, PKC-related signaling cascades have been found to be regulated in part by ATM (the gene that is mutated in the human genetic disorder ataxia telangiectasia). ATM is a protein related to cell-cycle checkpoints and cell radiosensitivity, and it also regulates radiation-induced apoptosis. This article reviews recent developments in the understanding of radiation-induced apoptosis, focusing on PKC functions, and the relationship with ATM. [Abstract/Link to Full Text]

Kream RM, Stefano GB
De novo biosynthesis of morphine in animal cells: an evidence-based model.
Med Sci Monit. 2006 Oct;12(10):RA207-19.
Recent empirical findings have contributed valuable mechanistic information in support of a regulated de novo biosynthetic pathway for chemically authentic morphine in animal cells, with many similarities to the extensively characterized multi-enzyme plant pathway in opium poppy (Papaver somniferum). The present review elaborates an evidence-based model of cellular morphine expression that reflects a coalescence of these recent biochemical data with historical data gleaned from over thirty years of neurochemical/neuropharmacological investigation into the etiology and biological significance of dopamine (DA)-related heterocyclic conjugate molecules, termed tetrahydroisoquinoline (TIQ) or benzylisoquinoline (BIQ) alkaloids, and with outstanding work completed over the last decade that has elucidated biochemical and molecular bases of morphine and related isoquinoline alkaloid expression in plant systems. In essence, we are now afforded a rare window of opportunity to firmly establish essential biochemical linkages between plant and animal biosynthetic pathways that have been conserved throughout evolution. [Abstract/Link to Full Text]

Kream RM, Stefano GB
Morphine synthesis in animals.
Med Sci Monit. 2006 Oct;12(10):ED1-2. [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]

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]

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

Guan Y
Comments to: Budd-Chiari syndrome: current options in the interventional radiology treatment exemplified by three selected cases.
Med Sci Monit. 2006 Oct;12(10):LE19-20. [Abstract/Link to Full Text]

Kwa?niewska-Rutczy?ska A, Bako? L, Januszewicz M, Wr�blewski T, Krawczyk M, Rowi?ski O
Budd-Chiari syndrome: current options in interventional radiology treatment exemplified by three selected cases.
Med Sci Monit. 2006 Jan;12(1):CS4-12.
BACKGROUND: Budd-Chiari syndrome (BCS) is rare clinical state characterized by stenosis or complete obstruction of hepatic veins. Currently, interventional radiology techniques are more frequently used as a single method of treatment or as a bridge to liver transplantation. CASE REPORT: This study presents current interventional radiology techniques used in BCS treatment. Depending on the etiology of BCS, two main techniques are used: the transjugular intrahepatic portocaval shunt (TIPS) or percutaneous angioplasty (PTA) of the stenosed hepatic veins. Our first case was treated by PTA of the stenosed ostium of the hepatic vein. In the second, BCS was complicated by portal vein thrombosis and a TIPS was placed along with portal vein fibrynolysis. In the third case the TIPS was used as a single interventional radiological treatment. CONCLUSIONS: TIPS placement or angioplasty of hepatic vein ostium stenosis allow the successful treatment of BCS or an extension of the period of waiting for a liver transplantation. [Abstract/Link to Full Text]

Hosnuter M, Buyukates M, Babuccu B
An unusual case of lymphedema tarda.
Med Sci Monit. 2006 Oct;12(10):CS99-102.
BACKGROUND: Lymphedema is the result of the equilibrium between the load to be cleared and the transport capacity of the clearing system. Lymphedema may be classified as primary or secondary, based on the underlying etiology. Primary lymphedema is an unusual disorder characterized by inadequate lymphatic drainage. Lymphedema tarda is a rare form of primary lymphedema. CASE REPORT: The case of lymphedema tarda documented here was chronic, progressive, and resistant to medical therapy and recurred several times after previous operations. CONCLUSIONS: We performed two-staged operations and we recommend that the staged excisional procedures offers reliable long-term improvement and minimizes postoperative complications in chronic advanced lymphedema. [Abstract/Link to Full Text]

Tanaka M, Sawai H, Okada Y, Yamamoto M, Funahashi H, Hayakawa T, Takeyama H, Manabe T
Malignant solitary fibrous tumor originating from the peritoneum and review of the literature.
Med Sci Monit. 2006 Oct;12(10):CS95-8.
BACKGROUND: Solitary fibrous tumor (SFT) is a rare neoplasm frequently involving the pleura. Benign and malignant forms of the tumor occur, the benign variant being three to four times more common than the malignant. CASE REPORT: We present herein a rare case of large malignant solitary fibrous tumor (SFT) originating from the peritoneum. An abdominal computed tomography scan revealed a well-defined solid tumor with mixed density. An abdominal ultrasonography (US) revealed a well-circumscribed solid tumor containing a partially cystic lesion. T1-weighted abdominal magnetic resonance imaging demonstrated a hypo- to isointensity, which was a hypo- to hyperintensity on T2-weighted images. Liposarcoma originating from the retroperitoneum was suggested, and the patient underwent a complete resection of the tumor as well as the left kidney because tumor invasion of the upper left kidney was suspected. Immunohistochemically, the spindle-shaped cells were positive for CD34, and the diagnosis was SFT originating from the peritoneum. At the 14-month follow-up evaluation, no recurrence or metastasis was detected. CONCLUSIONS: This case gave us some difficulty, and the correct diagnosis of the peritoneal mass was valuable. To diagnose the malignant potential of this type of tumor accurately may have value to direct the appropriate therapeutic operations after surgery and postoperative progress observation. [Abstract/Link to Full Text]

Pishdad GR, Pishdad P, Sabzi A
A case of transient central hyperthyroidism.
Med Sci Monit. 2006 Oct;12(10):CS103-5.
BACKGROUND: Thionamides are the main therapeutic arsenal for treating hyperthyroidism. Perhaps the first case of a patient who developed a transient pituitary hyperthyroidism after discontinuation of a lengthy intake of a thionamide is reported. CASE REPORT: A 48-year-old woman presented with menstrual irregularities when hypothyroidism with pituitary enlargement was detected. She had been undergoing treatment with methimazole for Graves's hyperthyroidism since the age of 34. Three months after discontinuation of methimazole she presented with clinical and laboratory evidence of thyrotoxicosis, with elevated thyroid-stimulating hormone (TSH) levels and blunted response to thyrotropin releasing hormone (TRH). This secondary hyperthyroidism was self-limited and resolved a few months later. CONCLUSIONS: Chronic primary hypothyroidism caused by lengthy use of thionamides can result in pituitary hyperplasia and transient thyrotrope dysfunction. [Abstract/Link to Full Text]

Bober K, Swietli?ski J
Diagnostic utility of ultrasonography for respiratory distress syndrome in neonates.
Med Sci Monit. 2006 Oct;12(10):CR440-6.
BACKGROUND: Respiratory distress syndrome (RDS) is the most frequent cause of respiratory failure treated in the neonatal intensive care unit (NICU). The diagnosis is usually based on clinical manifestation and chest X-ray. The aim of the study was to investigate the possible role of chest ultrasound in the diagnosis of the RDS. MATERIAL/METHODS: Ultrasound examination was performed in 131 consecutive newborns admitted to the NICU in their first day of life with symptoms of respiratory failure. The method of ultrasound examination of the chest is based on the "mirror reflection" phenomenon arising on the pulmonary-diaphragmatic border. RESULTS: Retrohepatic or retrosplenic hyperechogenicity was shown in 109 of the 131 examined newborns and the diagnosis was confirmed by X-ray in 101 cases. RDS was diagnosed in no patient without retrohepatic or retrosplenic hyperechogenicity. In eight patients with positive ultrasound images unconfirmed by chest X-ray, congenital pneumonia (four cases) and pneumothorax (one case) were diagnosed and in three cases no pathology was found. CONCLUSIONS: The ultrasound examination is characterized by 100% sensitivity and 92% specificity in RDS. There was a strong positive correlation between ultrasound and X-ray imaging in the description of RDS severity (tau = 0.835; p < 0.001). Ultrasound examination cannot replace chest X-ray in the respiratory failure work-up as it overestimates the diagnosis, but it can be useful in excluding RDS as a cause of respiratory insufficiency in newborns. [Abstract/Link to Full Text]

Ceran F, Ozcan A
The relationship of the Functional Rating Index with disability, pain, and quality of life in patients with low back pain.
Med Sci Monit. 2006 Oct;12(10):CR435-9.
BACKGROUND: The study was planned to determine the relationship of the Functional Rating Index (FRI) with disability, pain, and quality of life in patients with low back pain. MATERIAL/METHODS: A total of 84 patients with low back pain, of whom 58 were women and 26 were men, with average age of 47.8 +/- 12.0 years participated in this study. The Functional Rating Index was used to determine the functional status of the patients. Disability was evaluated using the Roland-Morris Disability Questionnaire (RMQ), pain intensity was evaluated with the Visual Analog Scale (VAS), and the Short Form-36 (SF-36) was used to assess quality of life. The Pearson correlation coefficient was used for correlation of the FRI with the RMQ, VAS, and SF-36. The internal consistency for test-retest reproducibility of FRI was assessed with Cronbach's alpha. RESULTS: There was a strong positive correlation between the FRI and the RMQ (p < 0.05). It was found that an increase in severity of pain was associated with the FRI survey score (p < 0.05). There was a negative statistically significant correlation between the FRI and all parameters of SF-36 (p < 0.05). FRI demonstrated high internal consistency, with alpha = 0.960. The test-retest correlation was r = 0.926 (p = 0.000). CONCLUSIONS: Our study reveals that the FRI, as a reliable instrument in assessing functional status, is associated with the RMQ, the VAS, and all items of the SF-36 in patients with LBP. It was concluded that changes in functional status were related to changes in disability, pain, and quality of life. [Abstract/Link to Full Text]

Ekim H, Kutay V, Hazar A, Akbayrak H, Ba?el H, Tuncer M
Effects of posterior pericardiotomy on the incidence of pericardial effusion and atrial fibrillation after coronary revascularization.
Med Sci Monit. 2006 Oct;12(10):CR431-4.
BACKGROUND: The aim of this prospective, randomized study was to assess the efficacy of posterior pericardiotomy in decreasing the prevalence of pericardial effusion and postoperative atrial fibrillation (AF). MATERIAL/METHODS: The study was performed in 100 patients who underwent elective coronary artery bypass grafting surgery (CABG) between October 2003 and July 2005. They were randomized to receive posterior pericardiotomy (Group A) or no posterior pericardiotomy (Group B). A 4-cm longitudinal incision was made parallel and posterior to the left phrenic nerve, extending from the left inferior pulmonary vein to the diaphragm in group A patients. Posterior pericardiotomy was not performed in group B patients. RESULTS: Early pericardial effusion developed in 6 patients (12%) of group A and 21 patients (42%) of group B; no late pericardial effusion developed in group A, but did in 3 patients (6%) of group B. The number of patients who developed postoperative AF was significantly lower in the fenestration group compared with the control group (10% vs. 30%, p < 0.010). The overall incidence of supraventricular tachycardia in patients with early pericardial effusion was significantly higher than in patients without early pericardial effusion (18 patients vs. 9 patients). CONCLUSIONS: These findings suggest that posterior pericardiotomy reduces the prevalence of early pericardial effusion and related AF by improving pericardial drainage in patients undergoing coronary artery bypass surgery. [Abstract/Link to Full Text]

Samarbaf-Zadeh AR, Tajbakhsh S, Moosavian SM, Sadeghi-Zadeh M, Azmi M, Hashemi J, Masjedi-Zadeh A
Application of fluorescent in situ hybridization (FISH) for the detection of Helicobacter pylori.
Med Sci Monit. 2006 Oct;12(10):CR426-30.
BACKGROUND: Peptic ulceration following infection of the stomach with H. Pylori is a common disease. Accurate and rapid detection of the bacteria can lead to the implementation of appropriate treatment and recovery. Chronic infection of the gastric milieu with H. Pylori may lead to gastric carcinoma. Routine detection of this bacterium in peptic ulcer is based on the urease test and culture of peptic biopsies. Unfortunately, the sensitivity and specificity of both tests are not satisfying. Molecular techniques have been successfully applied for the rapid and accurate detection of bacterial agents in clinical samples. This study was undertaken to evaluate the sensitivity and specificity of fluorescent in situ hybridization (FISH) in the detection of H. Pylori in patients suffering from dyspepsia. MATERIAL/METHODS: One hundred gastric biopsy samples taken by endoscopy from the antrum and corpus of the stomach were tested by FISH and compared with the conventional culture method complemented by biochemical tests. RESULTS: FISH detected H. Pylori in 48 clinical samples, while the conventional method detected 42 samples. The sensitivity and specificity of FISH for the detection of H. Pylori were calculated as 98% and 100%, respectively. CONCLUSIONS: The findings of this study suggest that FISH is a highly suitable and rapid method for diagnosing H. Pylori. Especially when the samples are taken from the antrum and the corpus of the stomach, this technique potentially can be applied routinely for the detection of this bacterium in clinical samples. [Abstract/Link to Full Text]

Sadeghi-Bazargani H, Ehdaeivand F, Arshi S, Eftekhar H, Sezavar H, Amanati L
Low-dose oral contraceptive to re-induce menstrual bleeding in amenorrheic women on DMPA treatment: a randomized clinical trial.
Med Sci Monit. 2006 Oct;12(10):CR420-5.
BACKGROUND: Depot medroxy progesterone acetate (DMPA) is one of the most reliable contraceptive methods with a failure rate less than 0.3 percent. It is injected every three months and Although it has many advantages over many other hormonal contraceptives, But a major disadvantage of it is bleeding disorders which comprise most of the discontinuance reasons. Our Aim was to study bleeding complications of DMPA when used as a contraceptive in Ardabil district and clinical trial of LD and Ethynil oestradiol in controlling these complications. MATERIAL/METHODS: All the 917 women who referred to ardabil's health centers for having a DMPA injection for the first time, were entered into a longitudinal study. Those complaining of menstrual cessation were entered into a double blinded randomized clinical trial. Data were collected by means of 9 questionnaires 7 of them used for descriptive and 2 for clinical trial study. Data was analyzed by SPSS statistical package. RESULTS: Those DMPA users with a cesarean section history had a higher chance of bleeding complications. Four hundred forty-four of the 917 women receiving the injection discontinued using it before the end of the study period. The main reason for discontinuation (in 70%) was irregular menstrual bleedings and menstrual cessation. In the clinical trial of women with bleeding cessation, 70% of those receiving the LD-OC pill experienced menstrual bleedings again, compared with only 22.7% in the placebo group. The discontinuation rate in the drug group was lower than in the placebo group as well (p < 0.05). CONCLUSIONS: Treating menstrual cessation caused by DMPA with LDs, improves the complication and decreases the discontinuance rate. [Abstract/Link to Full Text]

Ordonez FJ, Rosety M, Rosety-Rodriguez M
Influence of 12-week exercise training on fat mass percentage in adolescents with Down syndrome.
Med Sci Monit. 2006 Oct;12(10):CR416-9.
BACKGROUND: Current findings suggest that more attention needs to be given to the increase in body mass achieved by disabled populations, especially by individuals with mental retardation, to minimize long-term negative health consequences. Accordingly, it would be of interest to design adequate strategies based on physical activities that may be easily performed to ensure adherence as a healthy lifestyle choice for these populations. MATERIAL/METHODS: To attain this goal, 22 male adolescents with Down's syndrome (mean age: 16.2 +/- 1.0 years) underwent a 12-week physical exercise intervention consisting of three sessions of one hour per week in both water and on land for 12 weeks. Fat mass percentage was calculated from anthropometric measurements according to the Durnin-Womersley equation. A paired t test was performed to evaluate possible differences in antropometrical characteristics between before and after the physical exercise intervention. RESULTS: According to the body mass index, it was observed that 31.8% of the studied individuals presented overweight and 27.3% of them were obese before starting our experiment. The mean value of the percentage of fat mass was reduced significantly, from 31.8 +/- 3.7% to 26 +/- 2.3%, at the end of the study (p = 0.021). CONCLUSIONS: We may conclude that the adolescents with Down's syndrome were able to reduce their fat mass percentage significantly when performing a 12-week training program, which could have important impact on the comorbidity associated with obesity and on the quality of life of this population. [Abstract/Link to Full Text]

Dabrowski A, Skoczylas T, Ciecha?ski A, Wallner G, Zinkiewicz K, Cwik G, G�rczy?ski R, Borowski A
Dukes' classification as a prognostic factor in patients with squamous cell carcinoma of the thoracic esophagus undergoing combined-modality treatment.
Med Sci Monit. 2006 Oct;12(10):CR409-15.
BACKGROUND: Several disadvantages of the TNM classification have resulted in a search for a simpler, clearer, and more reliable staging system for esophageal cancer. We evaluated Dukes' classification as a prognostic indicator in 81 patients with squamous cell carcinoma of the thoracic esophagus treated with combined-modality therapy. MATERIAL/METHODS: The pathological staging was determined according to the TNM and Dukes' classification. The cumulative survival rates were calculated using the Kaplan-Meier method. The differences in survival between the patients in particular stages of both classifications were estimated with the log-rank test. RESULTS: The differences in cumulative survival rates between TNM I and TNM IIa, between TNM IIa and TNM IIb and between TNM IIb and TNM III patients were 20.2% (37.2 vs. 46.6), 27.5% (46.6 vs. 33.8) and 60.7% (33.8 vs. 13.3), respectively, and were not statistically significant (P = 0.58, P = 0.53 and P = 0.18). The cumulative survival rates for TNM III and TNM IV patients were similar (13.3 and 14.3). The difference in cumulative survival rates between Dukes' A and B patients amounted to 52.5% (54.3 vs. 25.8), which was statistically significant (P = 0.02). The difference in cumulative survival rates between Dukes' B and C patients was 41.5% (25.8 vs. 15.1), but fell short of statistical significance (P = 0.12). The cumulative survival rates for Dukes' C and D patients were similar (15.1 and 16.6). CONCLUSIONS: Dukes' staging system for esophageal cancer is simpler, clearer and more accurate, and could thus be a better prognostic tool than the TNM classification. [Abstract/Link to Full Text]

Petrofsky JS, Lohman E, Suh HJ, Garcia J, Anders A, Sutterfield C, Khandge C
The effect of aging on conductive heat exchange in the skin at two environmental temperatures.
Med Sci Monit. 2006 Oct;12(10):CR400-8.
BACKGROUND: Ageing diminishes the blood flow (BF) response of the skin to autonomic stressors. While the diminished response of skin BF to global heating has been well documented, the effect of this reduction in skin BF on the ability of the skin to dissipate heat has not. When heat is added to the skin by the application of hot packs, if heat is not adequately removed, the skin can become dangerously hot and become damaged. The present investigation examined the heat dissipating properties of the skin in older individuals. This study has importance for the therapeutic application of hot packs which might cause burns easier in older people. MATERIAL/METHODS: In the present investigation, 10 younger and 10 older subjects were examined. The average age of the younger group was 25.9+/-3.4 years and the older group was 60 +/- 5.8 years. Heat was applied through a 49 gram brass probe that was heated to 41 degrees C and by a Peltier junction in a cool and warm environment. RESULTS: Skin required about 20 calories of heat to raise skin temperature 1 degrees C the cool room and double this Figure in the warm room. Ageing reduced the caloric requirement to increase skin temperature under both conditions (p < 0.01). CONCLUSIONS: The results of the experiments showed that older individuals had impaired ability of the skin to dissipate heat in both environments. Special precautions should be taken in physical therapy when applying hot packs in older populations. [Abstract/Link to Full Text]

Sedgeman JA, Sarwari A
The effect of a Health Realization/Innate Health psychoeducational seminar on stress and anxiety in HIV-positive patients.
Med Sci Monit. 2006 Oct;12(10):CR397-9.
BACKGROUND: Chronic stress and depression have a negative impact on immune functioning and threaten the well-being of HIV-positive patients. Although therapy methods, such as Cognitive Behavioral Therapy, have been shown to reduce stress and depression in such patients, not all patients are willing or able to undergo therapy over time. The Health Realization/Innate Health (HR/IH) psychoeducational approach is a brief intervention alternative that can be presented in a classroom setting. It engages participants' innate capacity to realize peace of mind. MATERIAL/METHODS: Eight volunteer participants from patients in the Positive Health Clinic at West Virginia University School of Medicine attended a 1-1/2 day HR/IH seminar called "Finding Your Natural Peace of Mind". Shortly before the seminar started, the Brief Symptom Inventory (BSI) was administered by a Clinic staff member. The BSI was administered again immediately following the seminar. The BSI was mailed to the participants four weeks following the seminar with a return envelope. Participants' confidentiality was maintained through a coded ID. Pre-, post- and follow-up results were compared. RESULTS: Each case was evaluated individually. The participant who pre-tested in the "psychiatric inpatient" range of the BSI showed no change after the seminar or at follow-up. The participants who tested in the non-patient normal range before the seminar showed some improvement after and at follow-up. The participants who scored in the "psychiatric outpatient" range entering the seminar all showed improvement that was sustained upon follow-up. CONCLUSIONS: The HR/IH psychoeducational approach deserves further study as a brief intervention for stress-reduction in HIV-positive patients. [Abstract/Link to Full Text]

Goletti D, Macchia I, Leone P, Pace M, Sernicola L, Pavone-Cossut MR, Maggiorella MT, Cafaro A, Ensoli B, Titti F
Innate anti-viral immunity is associated with the protection elicited by the simian immunodeficiency virus (SIV) live attenuated virus vaccine in cynomolgus monkeys.
Med Sci Monit. 2006 Oct;12(10):BR330-40.
BACKGROUND: The Delta-nef live attenuated virus vaccine approach offered in the SIV-macaque model the opportunity to identify humoral and cell-mediated immune responses associated with protection against viral infections. In addition, soluble factors different from those related to specific immune responses appear to correlate with the establishment and maintenance of the protective status. MATERIAL/METHODS: Investigated were: 1) the ability of CD8+ T cells from cynomolgus monkeys vaccinated with SIV Delta-nef and long-term protected against sequential SIVs and SHIV challenges to inhibit in vitro SHIV replication in an acute infection cell system, 2) the ability of cell-free supernatants from CD8+ T cell cultures to inhibit replication of HIV in chronically infected cells, and 3) whether the antiviral activity of CD8+ T cells correlated with IFNgamma production. RESULTS: Soluble factor(s) secreted by CD8+ T cells from Delta-nef vaccinated monkeys significantly inhibited SHIV replication in an autologous cell system. This effect was not dependent on beta-chemokine secretion and correlated with an increased IFNgamma production. In addition, since supernatants from CD8+ T cells inhibited HIV production in chronically infected monocytic cells, the suppressive activity was not related to the viral strain. CONCLUSIONS: Vaccination with the live attenuated virus induces both a CD8+ T cell-dependent antiviral activity and IFNgamma responses potentially responsible for the protection from challenge with heterologous highly pathogenic SHIV89.6P. It is conceivable that boosting the "natural" along with the antigen-specific immunity is a desirable outcome to improve the protective efficacy of any vaccine approach. [Abstract/Link to Full Text]

Nieto-Fernandez FE, Ruiz A, Ntukogu N, Nodimelle L, Pryor SC
Short term lead exposure induces a stress-like response in adult mice.
Med Sci Monit. 2006 Oct;12(10):BR325-9.
BACKGROUND: Developmental and perinatal lead exposure in rats affects the Hypothalamus-Pituitary-Adrenal Cortex (HPA) axis function resulting in elevated corticosterone blood levels thus affecting the level of stress responsivity of the offspring. The majority of the studies on lead exposure and stress have been done by exposing the animal indirectly during gestation, or lactation periods. This study presents evidence supporting that short term lead exposure affects a stress-like response in adult lead-exposed mice. MATERIAL/METHODS: DBA/2J mice were exposed to three different lead concentrations, 250, 500 and 1000 ppm, in the drinking water for a two week period. After the exposure period the animals were subjected to behavioral tests, i.e., social contact, and the plus maze using a computer-assisted videomonitoring system, Videomex-V (Columbia Instruments). The levels of ACTH and corticosterone in plasma were also measured using a Radioimmunoassay (RIA). RESULTS: Exposed animals displayed a significant decrease in the length of time the mice pairs spent within social contact distance (5.18 +/- 0.58 seconds for controls and 3.23 +/- 0.34 seconds for 1000 ppm exposure), and a significant decrease in the percent of time the mice stayed in the open arms of the plus maze (7% for controls and 1% for 1000 ppm exposure) a measure indicator of anxiety. In addition exposed mice showed increased blood levels of ACTH (573 +/- 106 microg/dL for 1000 ppm and 127 +/- 25 microg/dL for control mice) and corticosterone (195.12 +/- 52.47 controls and 87.33 +/- 10.94 for exposed). CONCLUSIONS: These results support the hypothesis that exposure to lead of the adult mice affects a behavioral and hormonal response consistent with stress. [Abstract/Link to Full Text]

Vessey DA, Kelley M, Li L, Huang Y, Zhou HZ, Zhu BQ, Karliner JS
Role of sphingosine kinase activity in protection of heart against ischemia reperfusion injury.
Med Sci Monit. 2006 Oct;12(10):BR318-24.
BACKGROUND: Sphingosine kinase (SKase) has been implicated in the protection of hearts from ischemia/reperfusion injury. This hypothesis was further examined. MATERIAL/METHODS: Changes in SKase activity and cardiac function (left ventricular developed pressure, LVDP, and infarct size) in response to ischemia and reperfusion were studied in adult rat hearts by the ex vivo Langendorff method. Following initial equilibration or preconditioning, there was 45 min no-flow ischemia and then 45 min of reperfusion. RESULTS: SKase activity declined 61% during ischemia and did not recover upon reperfusion. LVDP also did not recover upon reperfusion and the infarct size was 47%. A short 30 min period of ischemia was associated with variable recovery of SKase activity that directly correlated with LVDP recovery. Preconditioning of hearts reduced the decrease in SKase activity during ischemia by half, and upon reperfusion activity returned to normal. The LVDP recovered 79% and infarct size was small. Preconditioned hearts had higher S-1-P levels after ischemia/reperfusion relative to non-preconditioned hearts. The decline in SKase activity during ischemia of preconditioned hearts could not be mimicked in vitro by treatment with protein phosphatases. Attempts to alter activity of SKase from control, preconditioned, ischemic, or reperfused hearts by phosphorylation with ERK1/2 were unsuccessful. Treatment of non-preconditioned hearts at reperfusion with 100 nM S-1-P improved recovery of LVDP. The SKase inhibitor dimethylsphingosine blocked hemodynamic recovery in preconditioned hearts. CONCLUSIONS: The data support a role for SKase activity in recovery of hemodynamic function after ischemic injury and also in the cardioprotective effect of preconditioning. [Abstract/Link to Full Text]

Nahum E, Skippen PW, Gagnon RE, Macnab AJ, Skarsgard ED
Correlation of near-infrared spectroscopy with perfusion parameters at the hepatic and systemic levels in an endotoxemic shock model.
Med Sci Monit. 2006 Oct;12(10):BR313-7.
BACKGROUND: To determine the correlation of near-infrared spectrophotometry (NIRS) readings from the liver surface with invasive measurements of blood flow and tissue perfusion parameters in an animal model of endotoxemic shock. MATERIAL/METHODS: Laparotomy was performed in 12 Yorkshire piglets, and ultrasound blood flow probes were placed on the hepatic artery and portal vein. Hepatic vein, portal vein, and femoral artery catheters were inserted for intermittent blood sampling, and a pulmonary artery catheter was inserted via the jugular vein for cardiac output measurements. Near-infrared spectrophotometry optodes were placed across the right hepatic lobe. Endotoxemic shock was induced by continuous infusion of Escherichia coli lipopolysaccharide 055: B5. Pearson correlations were calculated between the perfusion parameters and the near-infrared spectrophotometry (NIRS) readings. RESULTS: After endotoxemic shock induction, liver blood flow decreased from 144 +/- 36 to 62 +/- 24 ml*min(-1)*100 g(-1) and oxygen delivery to the liver decreased from 20 +/- 6 to 7 +/- 4 ml*min(-1)*100 g(-1). Near-infrared spectrophotometry readings of oxyhemoglobin concentration decreased by 11.7+/-15.1 micromol*L(-1), and readings of deoxyhemoglobin concentration increased by 12.3 +/- micromol*L(-1). There were significant correlations (p < 0.05 for r2 > 0.11) between the oxyhemoglobin readings and liver oxygen delivery (r2 = 0.58), liver blood flow (r2 = 0.73) and cardiac output (r2 = 0.80). Deoxyhemoglobin readings highly correlated (p < 0.05 for r2 > 0.11) with mixed venous lactate (r2 = 0.87) and with hepatic vein lactate (r2 = 0.82). CONCLUSIONS: Noninvasive near-infrared spectrophotometry measurements of hepatic oxyhemoglobin and deoxyhemoglobin correlate with liver hemodynamics as well as with global and specific organ perfusion parameters and may serve, in the future, as a useful tool to monitor tissue perfusion in septic patients. [Abstract/Link to Full Text]

Meletis J, Viniou N, Terpos E
Novel agents for the management of myelodysplastic syndromes.
Med Sci Monit. 2006 Sep;12(9):RA194-206.
Therapeutic decisions in patients with myelodysplastic syndromes (MDS) are very complex. The dilemma that confronts the management of MDS is illustrated by the presence of only one agent (5-azacitidine), which has been approved by the U.S.A. Food and Drug Administration, with an indication for all subtypes of this disease and another one (lenalidomide) for the management of a specific MDS subgroup, the 5q-syndrome. Current classifications and prognostic systems do not take into account the considerable clinical heterogeneity of MDS or their diverse biology. Supportive care, low-intensity treatment, acute myeloid leukemia-type therapy, and stem cell transplantation (SCT) produce unsatisfactory results because patients continue to be exposed to the inherent complications of worsening cytopenias and leukemic transformation. Recent years have witnessed an evolution in our understanding of pathophysiology pathways in MDS. At the same time, many novel and targeted therapies are being investigated in clinical trials, offering patients the prospect of sustained benefit and changing the natural course of the disease. Hypomethylating agents, immunomodulatory drugs, and farnesyl-tranferase inhibitors have produced very promising results in terms of response and survival in MDS patients. This review summarizes all recent data on the role of novel agents and SCT in the treatment of patients with MDS in an attempt to better understand their possible therapeutic status in the management of these patients. [Abstract/Link to Full Text]

Talar-Wojnarowska R, Malecka-Panas E
Molecular pathogenesis of pancreatic adenocarcinoma: potential clinical implications.
Med Sci Monit. 2006 Sep;12(9):RA186-93.
Despite scientific efforts and significant progress in understanding the basic cellular event in pancreatic adenocarcinoma (PA), survival rates have not changed much during the last 20 years. Prognosis in pancreatic cancer remains unsatisfactory due to its late clinical presentation, low surgical resectability rates, and resistance to chemotherapy. Novel therapeutic strategies are needed in order to improve the prognosis of patients with PA. Improvement of our knowledge of the molecular biology of pancreatic cancer may have important clinical implications in pancreatic cancer risk assessment, early diagnosis, and management. In human pancreatic cancer, a specific sequence of oncogene and tumor suppressor gene alterations is observed, including K-ras, HER-2/neu, p16, p53, and DPC4. The prevalence of these genetic alterations rises with increasing severity of dysplasia of the ductal mucosal lesions. Drugs that target these molecular abnormalities hold great promise for PA treatment in the near future. The focus of this review is to evaluate the gene mutations in pancreatic cancer, with emphasis on those studies that are most important to the clinical practice. Our review also summarizes current aspects of PA treatment and the differential diagnosis of pancreatic cancer and chronic pancreatitis. [Abstract/Link to Full Text]

Wang X, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C
Mouse models of neointimal hyperplasia: techniques and applications.
Med Sci Monit. 2006 Sep;12(9):RA177-85.
Neointimal hyperplasia is a major cause of the failure in vascular reconstructive procedures such as angioplasty, vascular stenting, small caliber vascular graft, and vein graft. However, the underlying molecular mechanisms are not yet fully understood. The study of neointimal hyperplasia has relied heavily on the use of experimental animal models. Recent development in gene manipulation techniques in mice offers a unique opportunity to unravel the molecular basis of the neointimal response at the genetic level, which is critical to develop new strategies to prevent human neointimal hyperplasia. Several mouse models for studying neointimal hyperplasia have recently been established including blood-flow cessation, mechanical injury, and vein bypass graft. In an attempt to elaborate these models, this review highlights the characteristics, advantages, disadvantages, and applications of these mouse models in vascular disease. In addition, the difference between mouse models and human lesions is discussed. Thus, this review provides updated information and helps vascular surgeons and other vascular biologists in selecting appropriate mouse models for their research on neointimal hyperplasia. [Abstract/Link to Full Text]